Manual of Neurologic Therapeutics 6th edition (March 1999): By Martin A Samuels

MD By Lippincott, Williams & Wilkins

By OkDoKey

Manual of Neurologic Therapeutics
CONTENTS
Contributing Authors
Preface to the Sixth Edition
Preface to the First Edition
Dedication
I. NEUROLOGIC SYMPTOMS
Chapter 1 Coma and Other Alterations in Consciousness
Telmo M. Aquino and Martin A. Samuels
Chapter 2 Headache
Daniel B. Hier
Chapter 3 Intellectual Dysfunction: Mental Retardation and Dementia
Raymond J. Fernandez and Martin A. Samuels
Chapter 4 Dizziness
Howard D. Weiss
Chapter 5 Backache
Richard C. Hinton
Chapter 6 Epilepsy
Raymond J. Fernandez and Martin A. Samuels
Chapter 7 Brain Death and Persistent Vegetative State
Thomas M. Walshe III
II. NEUROLOGIC DISEASES
Chapter 8 Infectious Diseases
Stephen M. Sagar and Dawn McGuire
Chapter 9 Neuropsychiatric Disorders
George B. Murray
Chapter 10 Stroke
Richard C. Hinton
Chapter 11 Neoplasms
Howard D. Weiss
Chapter 12 Trauma: Severe Head Injury, Spinal Cord Injury
Robert L. Martuza and Jean-Valery C. E. Coumans
Chapter 13 Demyelinating Diseases
Daniel B. Hier
Chapter 14 Toxic and Metabolic Disorders
Stephen M. Sagar
Chapter 15 Movement Disorders
Robert D. Helme
Chapter 16 Diseases of Nerve and Muscle
Thomas M. Walshe III
Chapter 17 Problems Associated with Chronic Neurologic Deficits
Thomas M. Walshe III and Howard D. Weiss
Appendix: Patient Information Guide
CONTRIBUTING AUTHORS
Telmo M. Aquino, M.D., Mariscal Estigararibia 840, Asuncin, Paraguay, South
America
Jean-Valery C. E. Coumans, M.D., Resident, Department of Neurosurgery,
Georgetown University; Resident, Department of Neurosurgery, Georgetown
University Medical Center, 3800 Reservoir Road NW, Washington, DC 20007
Raymond J. Fernandez, M.D., Associate Professor of Pediatrics and Neurology,
Departments of Pediatrics and Neurology, University of South Florida, Tampa, Florida;
Vice President, Pediatric Neurology Corporation, 880 Sixth Street South, Suite 430, St.
Petersburg, Florida, 33701
Robert D. Helme, M.B.B.S, Ph.D., F.R.A.C.P., Professor of Geriatric Medicine,
Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville,
Victoria; Director, National Ageing Research Institute, North West
Hospital, Poplar Road, Parkville, Victoria, 3052 Australia
Daniel B. Hier, M.D., Neurologist-in-Chief, Department of Neurology, University of
Illinois Hospital, Chicago, Illinois; Department Head, Department of Neurology,
University of Illinois, 912 South Wood Street, Chicago, Illinois 60612
Richard C. Hinton, M.D., Clinical Associate Professor, Department of Neurology,
University of Texas Southwestern Medical School, Dallas, Texas; Director of Stroke
Service, Department of Neurology, Presbyterian Hospital of Dallas, 8200 Walnut Hill,
Dallas, Texas 75231
Robert L. Martuza, M.D., Professor and Chairman, Department of Neurosurgery,
Georgetown University and Georgetown University Hospital, 3800 Reservoir Road NW,
Washington, DC 20007
Dawn McGuire, M.D., Assistant Professor of Neurology and Medicine,
Department of Neurology, UCSF Medical Center, San Francisco, California;
Medical Director, Western Neuro AIDS Program, California-Pacific Medical
Center, Davies Campus, Castro and Duboce, San Francisco, California 94114
George B. Murray, M.D., Associate Professor of Psychiatry, Department of
Psychiatry, Harvard Medical School; Psychiatrist, Department of Psychiatry,
Massachusetts General Hospital, Fruit Street, Warren 605, Boston,
Massachusetts 02114
Stephen M. Sagar, M.D., Professor, Departments of Neurology and Oncology, Case
Western Reserve University, Cleveland, Ohio; Director of Neuro-Oncology, University
Hospitals of Cleveland, Ireland Cancer Center, 11100 Euclid Avenue, Cleveland,
Ohio 44106
Martin A. Samuels, M.D., Professor of Neurology, Harvard Medical School, Boston,
Massachusetts; Neurologist-in-Chief and Chairman, Department of Neurology, Brigham
and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115
Thomas M. Walshe III, M.D., Assistant Professor of Neurology, Harvard Medical
School, Boston, Massachusetts; Associate Chief of Neurology, Brockton West Roxbury
VAMC, 940 Belmont Street, Brockton, Massachusetts 02401
Howard D. Weiss, M.D., Associate Professor of Neurology, Johns Hopkins
University School of Medicine, Baltimore, Maryland; Chernow Distinguished
Clinical Scholar inNeurology, Division of Neurology, Sinai Hospital, 2411 West
Belvedere Avenue, Baltimore, Maryland 21215
DEDICATION
This book is dedicated to Vincent P. Perlo, M.D. Dr. Perlo is a distinguished neurologist
who is one of the world's foremost authorities on myasthenia gravis. Early in his career
he founded a myasthenia gravis clinic at Massachusetts General Hospital, which
became one of two major centers in North America for the care of patients with this
disease. Much of what is now known about the epidemiology, phenomenology, and
course of the disease was learned based on the carefully executed epidemiologic
studies of Vincent Perlo and his collaborators at Mount Sinai Hospital in New York.
The contributors of this Manual were all residents who studied under Dr. Perlo during
the 1970s. The science of myasthenia gravis was learned from Dr. Perlo's studies, but
the art of managing the often complex and challenging manifestations was learned
directly from Vince himself. His extraordinary experience with this difficult disease was
revealed by the apparent ease of his therapeutic style. Like a skilled athlete or musician,
he seemed to act effortlessly, almost intuitive in his understanding of what was
attributable to the disease itself versus the toxicities of the therapy. Gentle in his
approach, he is universally loved and respected by his patients, colleagues, and
students.
As residents privileged to have studied at his feet, we are pleased to dedicate the sixth
edition of the Manual of Neurologic Therapeutics to a master neurologic practitioner,
Vincent P. Perlo.
The first five editions of the Manual were dedicated to Raymond D. Adams, C. Miller
Fisher, Edward P. Richardson, J r., David C. Poskanzer, and Robert R. Young. All were
members of the faculty of the Neurology Service at Massachusetts General Hospital
when the original contributors were residents.
PREFACE TO THE SIXTH EDITION
It has been twenty years since publication of the first edition of the Manual of Neurologic
Therapeutics. At that time, the term neurologic therapeutics was considered an
oxymoron, akin to airline food or military intelligence. I hatched the idea in 1974 while
chief resident of internal medicine at the Boston City Hospital. Together with my
Co-chief Resident Ralph Freidin and under the guidance of the chief of medicine, Alan
B. Cohen, we had compiled a contributor volume called Emergency Medicine:
Diagnostic and Treatment Protocols from Boston City Hospital. The book was published
by Little, Brown, which had its medical division offices on Beacon Hill. On reentering my
neurology training program at Massachusetts General Hospital (I had taken a year away
to serve as medical chief resident), I called J on Davidson, a medical editor at Little,
Brown whom I had met through the Emergency book project. We met at the Bull &
Finch Pub under the Hampshire House on Beacon Street (better known in subsequent
years as Cheers) and I proposed a manual of neurologic therapeutics written entirely by
me and my co-residents in neurology. It was to be completed during the leisurely
second year of our training program, during which we spent most of our time in
neuropathology. He agreed and gave me an opportunity that I had no right to expect,
but for which I am eternally grateful.
I simply assigned two topics to each of my fellow residents. After months of agonizing
editing and rewriting, mostly under the tutelage of our editor Diana Odell Potter, the
book appeared in 1978, one generation ago. In the score of years that have intervened,
the field of neurologic therapeutics has burgeoned. Annual popular courses in therapy
are now offered at the major neurological societies. Several large books have been
published and more are in production. The Manual of Neurologic Therapeutics has now
sold over 100,000 copies in several languages around the world.
Since the last edition of the Manual, which was published in 1994, three new triptan
drugs (naratriptan, rizatriptan, and zolmitriptan) have appeared, and an oral and nasal
form of sumatriptan have been released for the abortive treatment of migraines. A new
less toxic anticholinesterase medication (donepezil) is now available to slow the
progression of Alzheimer's disease. Several new antiepileptic drugs (topiramate,
lamotrigine, gabapentin, and tiagabine) have been added to the armamentarium for the
treatment of intermittent seizures and fosphenytoin has appeared for the management
of status epilepticus. New potent drugs are available for the treatment of HIV infection,
dramatically altering the neurologic manifestations of the disease, and the first
scientifically approved treatment for acute stroke (intravenous tissue plasminogen
activator) is available for general use.
Brain tumor treatment is far more effective using new stereotactic radiosurgical
approaches. Patients with Parkinson disease benefit from better, less toxic dopamine
agonists and several creative surgical approaches to the disease, including pallidotomy
and various deep brain stimulation techniques. Advances in neuroscience and
molecular genetics have led to better, earlier, and more reliable diagnostic tests along
with more accurate genetic counseling for an ever-enlarging array of genetically
determined neurological diseases, such as the hereditary sensory-motor neuropathies
and the spino-cerebellar degenerations.
The goal of the Manual of Neurologic Therapeutics continues to be a clear, logical
presentation of proven, evidence-based therapeutic approaches to neurological
illnesses. Enough diagnostic information is included to aid the experienced physician in
properly categorizing a clinical problem followed by a stepwise approach to treatment.
On the twentieth anniversary of the Manual of Neurologic Therapeutics, I thank my
colleagues who came together in 1978 to begin the project and have stayed together
through six editions. Their dedication to the success of this book has, in part, elevated
neurologic therapeutics to the level of prominence that it now enjoys.
Martin A. Samuels, M.D.
Boston, 1998
PREFACE TO THE FIRST EDITION
Until very recently the neurologist's primary task was to categorize and organize the
structure and pathologic alterations of the nervous system. In fact, neurology has long
been known as a discipline with elegantly precise and specific diagnostic capabilities but
little or no therapeutic potentiality. Further, many surgeons, pediatricians, and internists
have traditionally thought of the neurologist as an impractical intellectual who spends
countless hours painstakingly localizing lesions while ignoring pragmatic considerations
of treatment. Perhaps this conception is largely attributable to the peculiar complexity of
the nervous system and the consequent relative naivete of physicians in their
understanding of its functions.
Many of the classic descriptions of disease states in other medical disciplines were
completed in the last century; in neurology, these have only been described in the past
generation, and only in the last ten years has neurology begun to be characterized by
subcellular mechanistic concepts of disease. This maturity has meant that the
neurologist is now as much involved in the therapeutic aspects of his specialty of
medicine as any of his colleagues. Certain neurologic diseases, such as epilepsy, have
been treatable for relatively long periods of time, but understanding of the subcellular
mechanisms of other diseases has led to newer, more effective forms of therapy.
An example of this is the enlarged understanding we now have of the biochemical
alterations in Parkinson's disease, and the resultant therapeutic implications. Now,
much as the endocrinologist treats diabetes with insulin and the cardiologist treats
congestive heart failure with digitalis, the neurologist treats Parkinson's disease with
L-dopa. In all these situations, the underlying condition is not cured; rather, an attempt is
made to alter the pathophysiologic processes by utilizing a scientific understanding of
the function of the diseased system.
This manual embodies a practical, logical approach to the treatment of neurologic
problems, based on accurate diagnosis, that should prove useful to both clinician and
student. No attempt is made to reiterate the details of the neurologic examination; it is
assumed that the reader is competent to examine the patientalthough particularly
important or difficult differential diagnostic points are mentioned when appropriate. In
this regard, it should be emphasized that this manual is only a guide to diagnosis and
therapy, and each patient must be treated individually. The manual is organized to best
meet the needs of the clinician facing therapeutic problems. Thus, the first seven
chapters are concerned with symptoms, such as dizziness and headache, while the last
ten consider common diseases, such as stroke and neoplasms.
I thank the many colleagues and friends whose criticism and comments were useful in
the preparation of this book, in particular Drs. G. Robert DeLong, C. Miller Fisher,
George Kleinman, J ames B. Lehrich, Steven W. Parker, Henry C. Powell, E. P.
Richardson, J r., Maria Salam, Bagwan T. Shahani, Peter Weller, J ames G. Wepsic, and
Robert R. Young. In addition I am indebted to Sara Nugent and Helen Hyland for their
assistance in the preparation of the many manuscripts, and to Diana Odell Potter,
formerly of Little, Brown and Company, for her editorial skills. J ane Sandiford, formerly
of Little, Brown, and Kathleen O'Brien and Carmen Thomas of Little, Brown provided
invaluable assistance in the final preparation of this material. Deep appreciation goes to
Lin Richter, Editor in Chief of the Medical Division, Little, Brown and Company, for her
support throughout this effort. I further thank J on Paul Davidson, also formerly of Little,
Brown, for his valuable encouragement and help early in the course of this project.
Much support and encouragement was derived from my new colleagues in the Peter
Bent Brigham Hospital Neurology Section, The Longwood Avenue Neurology Program,
and the West Roxbury Veterans Administration Hospital. A great deal of inspiration
came from the birth of my daughter Marilyn, and my deepest thanks go to my wife,
Linda, who provided constant encouragement, editorial skill, and infinite patience.
M.A.S.
CHAPTER 1. COMA AND OTHER ALTERATIONS IN CONSCIOUSNESS
Manual of Neurologic Therapeutics
CHAPTER 1. COMA AND OTHER ALTERATIONS IN
CONSCIOUSNESS
Telmo M. Aquino and Martin A. Samuels
General principles
Pathophysiology
Diagnosis
Pseudocoma states
Etiology
Laboratory screening
Management
Persistent coma
Sleep disorders
I. General principles. When confronted with a patient with impaired consciousness,
the clinician proceeds in an orderly, systematic manner. He or she gathers information
while performing specific therapeutic maneuvers aimed at maintaining vital functions
and avoiding further neurologic damage.
Impairment of consciousness may derive from a variety of causes. The first priority is to
define and treat, as expeditiously as possible, those causes that are potentially
reversible (see sec. V).
II. Pathophysiology
Consciousness consists of two components: awareness and arousal (or wakefulness).
Awareness refers to the higher level integration of multiple sensory inputs that permit
meaningful understanding of self and environment. The mechanisms of awareness
reside diffusely in the cerebral cortex. Arousal refers to a more primitive set of
responses, the structures for which are located entirely within the brainstem and
diencephalon and that are synchronized by a diffuse network of nuclei and
interconnecting tracts. The ascending reticular activating system (ARAS) mediates such
responses as eye opening to painful stimuli, which is one clinical expression of intact
arousal mechanisms. Other testable aspects of ARAS functioning include corneal
reflexes, pupillary reactions, and ocular motility, either spontaneous or reflex (e.g.,
oculocephalic and vestibulo-ocular reflexes). Via thalamic relay nuclei, the ARAS
projects diffusely to the cerebral cortex, acting thus as a switch for the cortical
awareness system. In normal circumstances, it is the cycling of this system that
accounts for the sleep-wake cycles and the corresponding EEG findings.
With these simple anatomic and physiologic points in mind, one can conceive of 3
mechanisms by which consciousness may be impaired:
A. Bilateral diffuse cerebral cortex failure, leading to a state of impaired
awareness with intact arousal mechanisms (the so-called vegetative state). This
circumstance most commonly results from a diffuse anoxic or ischemic insult such
as cardiac arrest or the end stage of degenerative diseases.
B. Brainstem or thalamic failure, leading to a state of impaired arousal. In such
cases, awareness is untestable, since the ARAS switch is shut off and would
produce, in effect, a state of pathologic sleep. In clinical practice, a state of
brainstem failure could be due to either:
1. Primary brainstem pathology, such as midbrain and/or diencephalic
hemorrhage or infarction.
2. Secondary brainstem injury due to compression from masses that are
normally situated in other compartments; examples of this are transtentorial
(uncal) or cerebellar herniations due to a mass in the temporal lobe or the
cerebellum, respectively. Such compressing masses can cause permanent
brain lesions (e.g., Duret hemorrhages) by distorting the brainstem's vascular
supply through stretch or torque.
C. Combined bilateral cortical and brainstem failure is seen most commonly in
cases of metabolic encephalopathy and intoxications in which the relative
participation of brainstem, as opposed to cortical, dysfunction varies, depending
on the toxin involved and the type and severity of the metabolic derangement.
III. Diagnosis
A. History. Frequently, no information is available. Whenever possible, family,
friends, ambulance personnel, and physicians who have previously treated the
patient should be contacted. Important features of the history are trauma,
previous illnesses, medications, use of drugs or alcohol, and psychiatric disorders.
B. General physical examination
1. Vital signs: airway patency, circulatory and ventilatory status, and fever.
2. Skin: signs of trauma, stigmata of liver disease, needle marks, and infective or
embolic phenomena.
3. Head: Battle sign (i.e., hematoma over the mastoid process), localized
tenderness, and crepitus and/or hemorrhage from ears or nostrils indicate
basilar skull fracture.
4. Neck stiffness might be indicative of infection, trauma, or subarachnoid
bleeding. (Do not manipulate the neck if there is suspicion of cervical spine
fracture.)
5. Chest, abdomen, heart, and extremities must be examined routinely. Rectal
and pelvic examinations plus a stool test for blood should also be performed.
6. Breath may suggest liver failure (fetor hepaticus, liver breath), ketoacidosis,
alcohol ingestion, or uremia.
C. A neurologic examination is performed in all patients and recorded. Aiming to
define presence, location, and nature of the causal process, special emphasis is
placed on the following:
1. Observation of the patient
a. If the patient lies in a natural, comfortable position, as though in natural
sleep, coma is probably not very deep. Yawning and sneezing have the
same significance, although other automatisms such as coughing,
swallowing, or hiccuping do not necessarily reflect light coma.
b. Jaw and lid tone also indicates the severity of unconsciousness. Open lids
and hanging jaw bespeak deep coma.
2. Level of unconsciousness. Abnormalities of consciousness comprise a
continuum, ranging from mild confusion to total unresponsiveness. It is useful
in clinical practice to categorize patients with abnormal consciousness
according to stages of progressive unresponsiveness. Given the imprecision
surrounding the meanings of terms describing levels of consciousness, it is
good practice to describe in detail on the record the responses of the patient to
various stimuli. Use of terms such as lethargy, somnolence, or obtundation
should be substantiated by a brief descriptive paragraph in the record.
a. Confusion (or encephalopathy) is defined as the inability to maintain a
coherent stream of thought or action. The neurologic substrate for
confusion is inattention. Attention is difficult to define, but it refers to the
ability of the individual to sort out and stratify the many sensory inputs and
potential motor outputs so that a particular thought or action may be
completed in an organized and logical fashion. It is evident from the
concept that the mechanisms for attention must involve both arousal and
awareness. Thus, confusion may be seen in states of cortical and/or ARAS
dysfunction. The most common cause of confusion is metabolic or toxic
derangement, although it may be seen with certain focal cortical lesions,
particularly those of the right parietal lobe. Confusion is evident clinically
when the apparently awake patient fails tasks requiring sustained attention,
such as the serial 7's test, a go/no-go protocol, digit span, or spelling the
word world backwards. Such patients may also show very disturbed writing
with characteristic perseveration on letters with curved portions such as Os,
Cs, and Ds.
Delirium is a confusional state plus excess sympathetic activity. The term
delirium applies when the confused patient also has tachycardia,
diaphoresis, tremor, mydriasis, and hypertension. In general, pure
confusion is seen in most metabolic encephalopathies including mild
intoxication with sedative drugs, whereas delirium is caused by disorders
that lead to increased levels of circulating catecholamines, such as
intoxication with stimulant drugs (e.g., phencyclidine, amphetamines), high
fever, and withdrawal from alcohol or sedative drugs (e.g.,
benzodiazepines, barbiturates).
b. Drowsiness is characterized by ready arousal, ability to respond verbally,
and fending-off movements induced by verbal stimuli.
c. Stupor is characterized by incomplete arousal to noxious stimuli. There is
no or little response to verbal commands. No verbal response or moaning is
elicited. The motor responses are still of the purposeful, fending-off type.
d. Light coma is characterized by primitive and disorganized motor
responses to noxious stimuli. There is no response to attempts at arousal.
e. Deep coma is characterized by absence of response to noxious stimuli.
f. When there is a question of psychogenic unresponsiveness, try to obtain
a forced conscious response, e.g., by letting the patient's hand fall toward
the face. Do not apply noxious stimuli to eyes, testicles, breasts, or other
sensitive areas. Tickling the nostrils with cotton is usually sufficient for this
purpose.
3. Respiration. The respiratory pattern is helpful in localizing and, in certain
instances, determining the nature of the process.
a. Cheyne-Stokes respiration is characterized by periods of hyperventilation
that gradually diminish to apnea of variable duration; breathing then
resumes and gradually builds up again to hyperventilation. Cheyne-Stokes
breathing indicates bilateral deep hemispheric and basal ganglionic
dysfunction. The upper brainstem also may be involved.
Note: Cheyne-Stokes respiration is most commonly observed in
nonneurologic conditions, such as congestive heart failure.
b. Central neurogenic hyperventilation refers to continuous rapid, regular,
and deep respirations at a rate of about 25 per minute. It has no segmental
localizing significance. Regularity is an unfavorable prognostic sign since
increasing regularity correlates with increasing depth of coma.
Systemic acidosis (e.g., diabetic ketoacidosis, lactic acidosis) and
hypoxemia should be excluded (normal pH, bicarbonate, and 2 partial
pressure of oxygen [PO
2
] determinations over 70 mm Hg in 24 hours is
considered adequate for this purpose) before it is concluded that
hyperventilation is of neurogenic origin.
c. Apneustic breathing consists of a prolonged inspiratory phase followed by
apnea (the inspiratory cramp). It may be followed by cluster breathing,
which consists of closely grouped respirations followed by apnea. Either
pattern implies pontine damage.
d. Ataxic breathing and gasping breathing (Biot respirations) imply damage
to the medullary respiratory centers. In ataxic breathing, respirations are
chaotic. Gasping breathing is characterized by gasps followed by apnea of
variable duration. Both are agonal events and usually precede respiratory
arrest.
e. Depressed breathing consists of shallow, slow, and ineffective breathing
caused by medullary depression, usually produced by drugs.
f. Coma with hyperventilation is seen frequently in metabolic disorders.
1. Metabolic acidosis (e.g., diabetic ketoacidosis, uremia, ingestion of
organic acids, lactic acidosis).
2. Respiratory alkalosis (e.g., hepatic encephalopathy).
4. Position of the head and eyes. The normal cerebral hemisphere tends to
move both head and eyes conjugately toward the opposite side. In hemispheric
lesions, the healthy hemisphere becomes unopposed, deviating the head and
eyes toward the lesion and away from the hemiparesis. The reverse occurs in
pontine lesions, in which the eyes deviate toward the hemiparesis and away
from the lesion.
5. Visual fields and funduscopy
a. In patients who are not completely unresponsive, visual fields should be
tested with threatening movements, which normally evoke a blink.
Asymmetry of the blink response suggests hemianopia (in the absence of
blindness or optic nerve damage). Air movement in the eyes can produce a
false-positive response.
b. Funduscopy may reveal papilledema suggestive of increased intracranial
pressure. A subhyaloid hemorrhagea rounded, well-defined clot on the
retinal surfaceis commonly associated with subarachnoid hemorrhage.
6. Pupils. Note size, roundness, and equality to light reaction, both directly and
consensually.
a. Midposition (35 mm) nonreactive pupils are evidence of midbrain
damage.
b. Reactive pupils indicate midbrain intactness. In the presence of
unresponsiveness and absent extraocular movements and corneal reflexes,
reactive pupils suggest metabolic abnormality (e.g., hypoglycemia) or drug
ingestion (e.g., barbiturate).
c. A unilaterally dilated and unreactive pupil in a comatose patient
(Hutchinson pupil) may be a sign of third nerve compression due to
temporal lobe herniation. Other components of third nerve dysfunction (e.g.,
drooping of the eyelid and abduction of the eye as the result of unopposed
action of the lateral rectus muscle) may occur concomitantly or follow
pupillary dilatation. Less frequently, direct or compressive midbrain damage
is expressed by a dilated, nonreactive pupil.
Note: A fixed and/or dilated pupil in an alert patient is not a sign of brain
herniation. This finding may be due to essential anisocoria, old injury to the
iris, migraine, a posterior communicating artery aneurysm, Adie syndrome,
or a mydriatic agent that was inadvertently or purposefully instilled in the
eye. One or 2 drops of 1% pilocarpine (a parasympathetic agonist) instilled
into the eye will result in miosis in patients in whom the oculomotor nerve is
compressed (e.g., aneurysm) but will fail to do so if parasympathetic
receptors in the iris are occupied by a mydriatic drug (e.g., scopolamine).
d. Small but reactive pupils signify pontine damage, as in infarction or
hemorrhage. Opiates and pilocarpine also produce pinpoint reactive pupils.
A magnifying glass may be necessary to appreciate the pupillary reaction.
e. Dilatation of the pupils in response to a painful stimulus in the neck (the
normal ciliospinal reflex) indicates lower brainstem integrity.
7. Extraocular movements. If the patient is responsive enough to follow
commands, saccadic and pursuit eye movements should be tested. A large
number of ocular and gaze palsies may be present. In unresponsive patients, a
great deal of information may be obtained by testing the vestibulo-ocular reflex
(VOR), which is mediated by pathways that traverse the brainstem from the
vestibular nuclei in the medulla to the oculomotor nuclei in the midbrain. The
most useful tests of the VOR are as follows:
a. Doll's-head maneuver, passive head turning, or oculocephalic reflex
(do not perform this maneuver when there is a question of cervical
spine injury) is performed by turning the patient's head with quick lateral
and vertical displacements. In unconscious patients, the reflex is normal
or preserved if the eyes move in the orbits in the direction opposite to the
rotating head, maintaining their position in relation to the environment.
Abnormal response (no movement of the eyes in the orbits, or asymmetry
of movements) is suggestive of a destructive lesion at the pontine-midbrain
level. Barbiturate poisoning also may abolish the reflex. In conscious (or
partially conscious) patients, the VOR is suppressed (or partially
suppressed). In this circumstance, the integrity of the pathways mediating
the VOR may be tested by asking the patient to look at a fixed visual
stimulus while the head is turned passively by the examiner.
b. Ice water calorics are reflex eye movements in response to irrigation of
the tympanic membrane with cold water. The ice water calorics test the
integrity of the VOR.
1. Position the head 30 degrees with respect to the horizontal. Make
certain that the external auditory canal is not occluded with cerumen
and that the tympanic membrane is intact. Instill 30 mL of ice water into
the external auditory canal of one ear, and observe the eyes. Repeat
the procedure in the opposite ear after 3 to 5 minutes.
2. The normal response in a conscious patient is nystagmus, which
consists of tonic deviation of the eyes toward the ice water infusion
(slow phase), followed by a quick corrective movement toward the
opposite side (fast phase). The slow phase of the nystagmus is
mediated by brainstem pathways extending from the vestibular nuclei in
the medulla to the oculomotor nuclei in the midbrain. The fast phase is
a corrective movement generated from the frontal lobe contralateral to
the direction of the fast phase. It requires integrity of the frontal cortex,
the descending frontopontine fibers, and the brainstem eye movement
pathways extending from the medulla to the midbrain. The fast phase
can be present only when a slow phase occurs. Thus, the VOR is
extremely useful in evaluating comatose patients because it provides
information about both brainstem function (the slow phase of the
nystagmus) and cerebral hemisphere function (the fast phase of the
nystagmus). Several responses are possible in performing the VOR test
on a comatose patient.
a. Slow phases can be defective in one or both directions (of course,
fast phases will be absent as well), suggesting brainstem failure as a
cause of the coma.
b. Slow phases will be normal bilaterally, but no fast phases are noted
in either direction; this suggests bilateral cerebral hemisphere
dysfunction as the cause of the coma.
c. Slow and fast phases are normal bilaterally (i.e., a normal response).
This finding exonerates both the cerebral hemispheres and
brainstem and suggests that the unresponsive state is not true coma
but a conversion reaction (i.e., hysterical coma).
3. An abnormal VOR helps to localize the abnormality causing the coma.
The nature of the abnormality may be structural or functional. This
distinction requires historical data or other tests to clarify.
8. Motor responses may be spontaneous, induced, or reflexive.
a. Spontaneous
1. Seizures may be focal, in which case they have some localizing value.
Generalized seizures do not help in localizing the lesion but are a
somewhat favorable sign, since they indicate some degree of integrity of
the motor system from its origin in the frontal cortex to its termination in
the muscle. Multifocal seizures are suggestive of a metabolic process.
2. Myoclonic jerks also point to metabolic encephalopathies (e.g.,
hypoxia, hepatic failure uremia). Asterixis has the same significance.
3. Absence of movements on one side of the body, or asymmetry of
movements, suggests hemiparesis.
b. Induced movements (e.g., fending-off or other complex, purposeful
movements, such as scratching the nose in response to tickling of the
nostril) require integrity of the corresponding corticospinal tract. Poorly
organized, incomplete movements, especially when unilateral, suggests
corticospinal tract dysfunction or damage.
c. Reflex movements are always elicited by a stimulus and have a certain
time relationship between stimulus and response.
1. Decerebrate movements consist of extension, adduction, and internal
rotation of the arms and extension of the legs. The lesion is in the upper
brainstem, between the red nucleus and the vestibular nuclei.
2. Decorticate movements consist of flexion and adduction of the arms
and extension of the legs. The lesion is deep hemispheric or just above
the midbrain.
3. Abduction of a limb usually indicates relative intactness of the motor
system. Such a limb usually will regain full function if the underlying
cause of the coma can be managed successfully.
9. Sensory system. In drowsy or obtunded patients, the response to noxious
stimuli may be asymmetric, evidencing a hemisensory defect in the absence of
paralysis. Facial and corneal sensation should be tested, since they also may
be asymmetric. A sensory level on the trunk suggests spinal cord damage.
IV. Pseudocoma states
A. Psychogenic unresponsiveness. The patient appears unresponsive but is
physiologically awake. The neurologic examination is otherwise normal, and there
may be active opposition to attempts at eye opening by the examiner. With ice
water calorics, there will be slow and quick components of nystagmus. The
electroencephalogram (EEG) is normal or may show only drowsiness.
B. In the locked-in syndrome, a destructive process (usually basilar artery occlusion
with brainstem infarction) interrupts the descending corticobulbar and corticospinal
tracts, sparing only the fibers controlling blinking and vertical eye movements. The
patient is able to communicate by means of blinks or vertical eye movements but
otherwise is completely paralyzed.
C. Severe bilateral prefrontal lobe disease may produce profound apathy (abulia),
which may be severe enough to result in a state of akinetic mutism. Such patients
appear awake but are mute and either fail to respond to stimuli or respond only
after very long delays.
D. Nonconvulsive status epilepticus simulating coma is relatively rare. Usually
there are some telltale signs of seizure activity such as rhythmic blinking of the
eyelids or conjugate jerking of the eyes. Nearly all such patients are known
epileptics. If this diagnosis is considered, a small test dose of intravenous
benzodiazepine (e.g., lorazepam, 1 to 4 mg) should result in improvement. The
EEG is diagnostic of continuous seizure activity, and the definitive therapy is
usually valproate or benzodiazepines.
V. Etiology
Causes of impaired consciousness are multiple, many of which are not primarily
neurologic. Consequently, a detailed history derived from all available sources, thorough
physical and neurologic examinations, and extensive laboratory screening often are
needed. Causes of impaired consciousness can be categorized as follows:
A. Coma due to primary brain injury or disease is usually associated with a
demonstrable structural lesion.
1. Trauma
a. Concussion.
b. Contusion.
c. Laceration or traumatic intracerebral hemorrhage.
d. Subdural hematoma.
e. Epidural hematoma.
2. Vascular disease
a. Intracerebral hemorrhage
1. Hypertensive (putaminal, thalamic, pontine, cerebellar, or lobar).
2. Ruptured aneurysm with intraparenchymatous hematoma.
3. Arteriovenous malformation.
4. Miscellaneous (e.g., bleeding disorders, intratumoral hemorrhages,
congophilic angiopathy).
b. Subarachnoid hemorrhage
1. Ruptured aneurysm.
2. Arteriovenous malformation.
3. Secondary to trauma (e.g., contusion, laceration).
c. Infarct
1. Thrombosis of intracranial and extracranial vessels.
2. Embolism.
3. Vasculitis.
4. Malaria.
3. Infections
a. Meningitis.
b. Encephalitis.
c. Abscess.
4. Neoplasms
a. Primary intracranial.
b. Metastatic.
c. Nonmetastatic complications of malignancy (e.g., progressive multifocal
leukoencephalopathy).
5. Seizures (status epilepticus).
B. Coma due to systemic causes (affecting the brain secondarily)
1. Metabolic encephalopathies
a. Hypoglycemia.
b. Diabetic ketoacidosis.
c. Hyperglycemic nonketotic hyperosmolar states.
d. Uremia.
e. Hepatic encephalopathy.
f. Hyponatremia.
g. Myxedema.
h. Hypercalcemia and hypocalcemia.
2. Hypoxic encephalopathies
a. Severe congestive heart failure.
b. Chronic obstructive pulmonary disease with decompensation.
c. Hypertensive encephalopathy.
3. Toxicity
a. Heavy metals.
b. Carbon monoxide.
c. Drugs (e.g., opiates, barbiturates, cocaine).
d. Alcohol.
4. Physical causes
a. Heat stroke.
b. Hypothermia.
5. Deficiency states (e.g., Wernicke encephalopathy).
VI. Laboratory screening
A. Routine. Complete blood count (CBC), urinalysis, electrolytes, blood urea
nitrogen (BUN), creatinine, blood sugar, calcium, phosphate, liver function studies,
enzymes, osmolality, electrocardiogram (ECG), and chest x-ray.
B. Toxic screen should be obtained, when clinically indicated, in blood, urine, and
gastric aspirate, and should include screening for opiates, barbiturates, sedatives,
antidepressants, cocaine, and alcohol.
C. Special studies
1. Skull x-rays.
2. Computed tomography (CT) scan (see sec. VI.C.6).
3. Magnetic resonance imaging (MRI) (see sec. VI.C.6).
4. EEG.
5. Angiography.
6. Lumbar puncture should be done if there is suspicion of intracranial infection
(e.g., meningitis, encephalitis). Keep in mind the possibility of temporal lobe or
cerebellar herniation in patients with increased intracranial pressure. The
advent of CT and MRI has made it possible to diagnose intracranial
hemorrhage without resorting to lumbar puncture in the majority of patients.
When the hemorrhage is small enough to escape undetected by CT or MRI,
lumbar puncture is safe and will determine whether angiography is needed.
VII. Management
A. Immediate therapeutic measures are initiated promptly in all comatose patients
to forestall further neurologic damage.
1. Establish a good airway. Intubation and artificial ventilation may be
necessary. Do not manipulate the head and neck until it is known for certain
that there was no neck trauma. Nasotracheal intubation is preferred over the
orotracheal method for this reason.
2. Insert a large-bore intravenous (IV) catheter.
3. Draw blood for routine studies and toxic screen if indicated (see sec. VI).
4. In possible Wernicke encephalopathy, give thiamine (100 mg IV) to prevent
acute deficiency due to the administration of dextrose.
5. Give 25 to 50 mL of 50% dextrose in water (D/W) IV.
6. If there is some evidence that coma results from opiate overdose, give
naloxone, 0.4 mg IV q510min, until consciousness returns. In patients with
opiate dependency, this might provoke an acute withdrawal state requiring
narcotic therapy. The duration of action of naloxone is shorter than that of
methadone, so that repeat doses may be necessary.
B. Management of the specific processes (e.g., trauma, infections, tumor) is
covered in the corresponding chapters.
C. Nursing care of the comatose patient is crucial in management. Fastidious
nursing care is essential to prevent the multiple complications of the unresponsive
state.
1. Circulation. Give fluids to maintain blood pressure at sufficient levels to
ensure adequate cerebral, myocardial, and renal perfusion. In the initial stages,
at least, cardiac monitoring is useful.
2. Ventilation. Adequate oxygenation and prevention of infection, aspiration,
and hypercapnia are the goals.
a. Remove dentures.
b. Insert and tape a short oropharyngeal airway of a size adequate to prevent
the tongue from obstructing airflow.
c. Prevent aspiration by suction of secretions.
1. Suction the nasopharynx and mouth frequently.
2. Place the patient in the lateral decubitus position, with the neck slightly
extended and the face turned toward the mattress. If there are no
contraindications (e.g., raised intracranial pressure), Trendelenburg
position is helpful for drainage of tracheobronchial secretions.
d. If ventilation is unsatisfactory or secretions are uncontrollable, insert a
cuffed endotracheal tube. If intubation is necessary for more than 3 days,
consider tracheostomy.
e. Insert a nasogastric tube and evacuate gastric contents to improve
ventilation and prevent aspiration.
f. Obtain arterial blood gases as often as necessary to ensure adequate
ventilation.
3. Skin. Turn the patient q12h. Keep sheets tightly drawn. Pad bony
prominences to prevent formation of sores and nerve compression.
4. Nutrition should be provided initially by IV solutions. Later, when the situation
is stable, tube feedings are started. Vitamin supplements are used.
5. Bowel care. Diarrhea may result from the tube feedings, antacids given
concomitantly with steroids, and fecal impaction. Frequent rectal examinations
for impaction are necessary.
6. Bladder care
a. A condom catheter may be used for male patients. Penile maceration
should be avoided.
b. If an indwelling catheter becomes necessary, a three-way catheter should
be used, with continuous irrigation with 0.25% acetic acid. This acidifies the
urine and prevents stone formation.
c. Clamp the catheter intermittently to maintain bladder tone. Release q34h.
7. Eyes. Avert corneal injury by taping the eyelids closed or by using
methylcellulose eye drops, two drops in each eye bid or tid.
8. Restlessness and agitation. In the recovery phase of many metabolic
processes, head trauma, and drug intoxications, agitation and restlessness
may occur. Avoid unnecessary sedation. If heavy sedation becomes necessary
due to excessive severity or duration of agitation, a short-acting
benzodiazepine (e.g., lorazepam, 1 to 2 mg q12h) may be indicated. A potent
neuroleptic (e.g., haloperidol, 1 to 5 mg IM q12h) may also be used.
D. Management of cerebral edema and increased intracranial pressure. A number of
processes (e.g., trauma, hemorrhage, large infarcts, tumors) may result in
cerebral edema and a consequent rise in intracranial pressure. When focal
masses are present, increased intracranial pressure may lead to herniation of
brain from one compartment to another, e.g., temporal lobe (uncal) herniation from
the supratentorial to infratentorial compartment, across the rigid dural tentorium
cerebelli. When the increased pressure is generalized, systemic blood pressure
rises reflexively as if in an effort to maintain cerebral perfusion pressures at
adequate levels. If the baroreceptor reflex arc is intact, this systemic hypertension
will result in a reflex bradycardia. The combination of hypertension and
bradycardia (Cushing reflex) is a sign of critically increased intracranial pressure.
When intracranial pressure rises beyond the ability of systemic blood pressure to
compensate, cerebral perfusion pressures fall, leading to global cerebral ischemic
anoxia.
In many patients, neurologic deterioration is caused by increased intracranial
pressure, which may be reversible. Treatment of increased intracranial pressure
may be lifesaving until definitive therapy aimed at correcting the specific
pathologic process can be carried out.
1. General measures are important in managing patients with increased
intracranial pressure. Patients should be placed in bed with the head elevated
45 degrees and in the midline. Stimulation by family and staff (e.g., turning the
head, suctioning) should be kept to a minimum.
2. Avoid hypotonic IV solutions or fluids that contain large amounts of free
water (e.g., 5% D/W). Restrict fluids to 1,000 mL of normal saline/m
2
body
surface area/day, and monitor blood pressure, serum osmolality, and urine
output. In children, initially restrict fluids to one half to one third of maintenance,
using 0.20% to 0.45% saline in 5% D/W.
3. Hyperventilation produces hypocapnia and respiratory alkalosis, decreasing
cerebral blood flow and effectively reducing intracranial pressure. Its effects
are immediate. The partial pressure of carbon dioxide (PCO
2
) should be
lowered to 25 mm Hg.
4. Hyperosmolar agents. Mannitol 20% may be given in a dose of 1.0 g/kg IV
over 10 to 30 minutes, according to the severity of the situation. The usual
dose for a normal adult is 500 mL of the 20% solution or 100 g of mannitol. A
dose of 25 g may be repeated q4h. In children, 0.25 to 1.00 g/kg may be given
over 10 to 30 minutes and repeated q4h as necessary. The effect starts within
minutes and lasts for several hours. An indwelling bladder catheter is
necessary. Monitor vital signs, electrolytes, BUN, and osmolality frequently,
aiming for a serum osmolality of 300 to 320 mOsm/L.
5. Steroids. Dexamethasone (Decadron) may be administered, 10 mg, by rapid
IV infusion followed by 4 to 6 mg IV q6h. In infants and children, the initial dose
of dexamethasone is 0.15 mg/kg, followed by 0.25 mg/kg/day, divided into four
doses. The effect begins in 4 to 6 hours and peaks at 24 hours. The effect of
steroids is greater on vasogenic cerebral edema (e.g., that associated with
brain tumors) than on cytotoxic cerebral edema (e.g., that associated with
anoxia). Occasionally, much higher doses (e.g., up to 100 mg of
dexamethasone) will provide additional benefit. Steroids are rarely, if ever,
used when stroke or head trauma is the cause for the increased intracranial
pressure but are quite useful to treat brain tumor-related edema or acute
disseminated encephalomyelopathy.
6. Barbiturate coma. When other methods of controlling increased intracranial
pressure fail and when adequately experienced personnel and facilities are
available, intravenous barbiturates may be used to control increased
intracranial pressure. Although there is no definite evidence that this technique
reduces the morbidity and mortality of coma from any cause, there is some
indication that it may be useful in some situations (e.g., severe Reye
syndrome; see Chap. 14, sec. I.E.5.d). When barbiturates are used, the
following guidelines should be followed:
a. The patient should be placed in a neurologic or neurosurgical intensive care
unit or in an intensive care unit staffed with personnel experienced in the
techniques of intracranial pressure monitoring.
b. An intracranial pressure monitoring device should be placed by a
neurosurgeon or experienced critical care physician. The specific device
varies from center to center, but a subarachnoid bolt, intraventricular
catheter, or Camino catheter frequently is used.
c. An arterial monitoring line is placed.
d. The mean cerebral perfusion pressure ( ) is calculated using the
following formula:
e. The goal of therapy is to maintain a of greater than 50 mm Hg.
f. If the conventional methods as listed in sec. VII.D.1, sec. VII.D.2, sec.
VII.D.3, sec. VII.D.4 and sec. VII.D.5 have failed, pentobarbital, 3 to 5
mg/kg, is administered by rapid IV infusion.
g. Pentobarbital, 1 to 2 mg/kg/hour, is administered, aiming for:
1. Pentobarbital serum level of 2 to 4 mg/dL.
2. greater than 50 mm Hg.
3. Mean arterial blood pressure of 60 to 90 mm Hg.
7. Surgery. When all else has failed, large craniectomies have been performed to
decompress the intracranial contents under conditions of massively increased
and medically unresponsive intracranial pressures. Such procedures may be
lifesaving, but patients in this dire circumstance are nearly all left with severe
permanent neurologic disability.
E. Seizures should be vigorously treated (see Chap. 6 for details).
F. Subsequent management depends on the nature of the underlying disorder. The
strategies of diagnosis and management are parallel and are based on the basic
pathophysiologic principles outlined in sec. II. A decision tree protocol for the
management of the comatose patient is summarized in Fig. 1-1, which
emphasizes the interaction between diagnostic maneuvers aimed at determining
the site and nature of the underlying disorder and the selection of therapy.
FIG. 1-1. Diagnosis and treatment protocol in the comatose patient. ARAS,
ascending reticular activating system; LP, lumbar puncture; LFTs, liver function
tests; ABGs, arterial blood gases; BS, blood sugar; AVM, arteriovenous
malformation.
VIII. Persistent coma. Patients who are chronically unresponsive with preserved
brainstem function are said to be in a persistent vegetative state (see also Chap. 7, sec.
II). In a general hospital, many patients are chronically comatose secondary to
hypoxic-ischemic encephalopathy (e.g., after cardiac arrest), and it is important to be
able to prognosticate about the likelihood of a favorable outcome. Fig. 1-2 summarizes
the results of a large cooperative study of such patients, showing that simple bedside
tests (e.g., eye movements, motor responses) can be used to predict statistically the
ultimate outcome. It should be emphasized that this study applies to patients with
nontraumatic, non-drug-induced, and nondegenerative diseaseinduced coma. In
other words, only patients known to be comatose from a hypoxic-ischemic insult can be
analyzed using the data summarized in Fig. 1-2.
FIG. 1-2. Features predictive of neurologic recovery in hypoxic-ischemic coma patients
in accordance with their best functional state within the first year. Residual anesthetics,
anticonvulsants, or metabolic derangements may be confounding. (Modified from Levy
DE, et al. Predicting outcome from hypoxic-ischemic coma. JAMA 1985;253:1420.)
IX. Sleep disorders
A. Physiology of sleep
1. There are two types of normal sleep. Nonrapid eye movement (non-REM)
sleep is characterized by 4 levels, defined by EEG patterns, corresponding
roughly to the depth of sleep (I being the lightest; IV the deepest). During
non-REM sleep, body tone is maintained, and the person shifts postures
frequently. The other variety, REM sleep, is characterized by total loss of tone
in all muscles except the extraocular muscles and some muscles of the
nasopharynx. An electromyograph (EMG) placed on these muscles will
document this fact.
2. The EEG taken during REM sleep shows light sleep, which can be
distinguished from stage I non-REM sleep only by placing EMG and
electronystagmograph (ENG) leads over the extraocular muscles to document
the characteristic rapid conjugate movement of the eyes.
3. Normally, when a person goes to sleep, he or she passes through at least 1
cycle of non-REM sleep (I through IV) before entering REM sleep. The relation
between REM and non-REM portions of sleep changes with age. In infants, a
large proportion of time is spent in REM sleep, but this decreases with age; in
adults, only about 20% of the night is spent in REM sleep. It is during this
portion that dreaming is thought to occur.
4. It is believed that control of the relation between the waking state with REM
and non-REM sleep is mediated in part by the reticular activating system in the
brainstem.
B. Categories of sleep disorders. There are a large number of sleep disorders,
which have been traditionally divided into 4 major categories: disorders of initiating
and maintaining sleep (DOIMS), or insomnias; disorders of excessive somnolence
(DOES), or hypersomnias; disorders of the sleep-wake schedule; and dysfunction
associated with sleep, sleep stages, or partial arousal (parasomnias). This
classification was revised in 1990 as the International Classification of Sleep
Disorders (ICSD) and is based on pathophysiologic mechanisms rather than
presenting symptoms.
1. Dyssomnias
a. Intrinsic sleep disorders
1. Psychophysiologic insomnia.
2. Sleep state misperception.
3. Idiopathic insomnia.
4. Narcolepsy.
5. Recurrent hypersomnia.
6. Idiopathic hypersomnia.
7. Posttraumatic hypersomnia.
8. Obstructive sleep apnea syndrome.
9. Central sleep apnea syndrome.
10. Central alveolar hypoventilation syndrome.
11. Periodic limb movement disorder.
12. Restless legs syndrome.
13. Intrinsic sleep disorder not otherwise specified.
b. Extrinsic sleep disorders
1. Inadequate sleep hygiene.
2. Environmental sleep disorder.
3. Altitude insomnia.
4. Adjustment sleep disorder.
5. Insufficient sleep syndrome.
6. Limit-setting sleep disorder.
7. Sleep-onset association disorder.
8. Food allergy insomnia.
9. Nocturnal eating (drinking) syndrome.
10. Hypnotic-dependent sleep disorder.
11. Stimulant-dependent sleep disorder.
12. Alcohol-dependent sleep disorder.
13. Toxin-induced sleep disorder.
14. Extrinsic sleep disorder NOS.
c. Circadian rhythm sleep disorders
1. Time zone change (jet lag) syndrome.
2. Shift work sleep disorder.
3. Irregular sleep-wake pattern.
4. Delayed sleep phase syndrome.
5. Advanced sleep phase syndrome.
6. Non-24-hour sleep-wake disorder.
7. Circadian rhythm sleep disorder NOS.
2. Parasomnias
a. Arousal disorders
1. Confusional arousals.
2. Sleepwalking.
3. Sleep terrors.
b. Sleep-wake transition disorders
1. Rhythmic movement disorder.
2. Sleep starts.
3. Sleep talking.
4. Nocturnal leg cramps.
c. Parasomnias usually associated with REM sleep
1. Nightmares.
2. Sleep paralysis.
3. Impaired sleep-related penile erections.
4. Sleep-related painful erections.
5. REM sleep-related sinus arrest.
6. REM sleep behavior disorder.
d. Other parasomnias
1. Sleep bruxism.
2. Sleep enuresis.
3. Sleep-related abnormal swallowing syndrome.
4. Nocturnal paroxysmal dystonia.
5. Sudden unexplained nocturnal death syndrome.
6. Primary snoring.
7. Infant sleep apnea.
8. Congenital central hypoventilation syndrome.
9. Sudden infant death syndrome.
10. Benign neonatal sleep myoclonus.
11. Other parasomnia not otherwise specified.
3. Sleep disorders associated with medical/psychiatric disorders
a. Associated with mental disorders
1. Psychoses.
2. Mood disorders.
3. Anxiety disorders.
4. Panic disorders.
5. Alcoholism.
b. Associated with neurologic disorders
1. Cerebral degenerative disorders.
2. Dementia.
3. Parkinsonism.
4. Fatal familial insomnia.
5. Sleep-related epilepsy.
6. Electrical status epilepticus of sleep.
7. Sleep-related headaches.
c. Associated with other medical disorders
1. Sleeping sickness.
2. Nocturnal cardiac ischemia.
3. Chronic obstructive pulmonary disease.
4. Sleep-related asthma.
5. Sleep-related gastroesophageal reflux.
6. Peptic ulcer disease.
7. Fibrositis syndrome.
4. Proposed sleep disorders
a. Short sleeper.
b. Long sleeper.
c. Subwakefulness syndrome.
d. Fragmentary myoclonus.
e. Sleep hyperhidrosis.
f. Menstrual-associated sleep disorder.
g. Pregnancy-associated sleep disorder.
h. Terrifying hypnagogic hallucinations.
i. Sleep-related neurogenic tachypnea.
j. Sleep-related laryngospasm.
k. Sleep choking syndrome.
C. Treatment of the most common sleep disorders
1. Sleep apnea syndromes
a. Obstructive
1. Weight loss.
2. Continuous positive airway pressure (CPAP).
3. Tracheostomy.
4. Surgical correction of anatomically narrowed airway (e.g., adenoid
removal, tonsillectomy, ovulectomy, jaw realignment).
b. Central
1. Theophylline or caffeine.
2. Progesterone.
3. Electrical pacing of the diaphragm.
2. Narcolepsy (see Chap. 6, sec. X.A for details of treatment)
a. Sleep attacks and excessive daytime sleepiness
1. Methylphenidate.
2. Pemoline.
3. Amphetamines.
4. Caffeine.
b. Cataplexy
1. Tricyclic antidepressants (especially clomipramine and protriptyline).
2. Monoamine oxidase inhibitors.
c. Sleep paralysis usually responds to stimulants.
d. Hypnagogic hallucinations usually respond to stimulants.
3. Depression
a. Psychotherapy.
b. Antidepressant drugs.
4. Periodic movements of sleep and restless legs syndrome
a. Benzodiazepines (diazepam, lorazepam, clonazepam).
b. Anticonvulsants.
c. L-dopa-carbidopa.
d. Bromocriptine.
5. Drug and alcohol dependency
a. Psychotherapy.
b. Behavior modification.
Selected Readings
Anch A, Browman CP, Mitler MM. Sleep: a scientific perspective. Englewood Cliffs, NJ : Prentice Hall,
1988.
Bates D. The management of medical coma. J Neurol Neurosurg Psychiatry 1993;56:589.
Diagnostic Classification Steering Committee. ICSDM international classification of sleep disorders:
diagnostic and coding manual. Rochester, MN: American Sleep Disorders Association, 1990.
Easton J D. Coma and related disorders. In: Stein J H. Internal medicine, 4th ed. St. Louis: Mosby,
1993:1014.
Fisher CM. The neurological evaluation of the comatose patient. Acta Neurol Scand [Suppl 36] 1969;1:56.
Fishman RA. Brain edema. N Engl J Med 1975;293:706.
Gloor P. Consciousness as a neorological concept in epileptology: a critical review. Epilepsia
1986;27:514.
Kinney H, Korein J , Panigrahy BA, et al. Neuropathological findings in the brain of Karen Ann Quinlan. N
Engl J Med 1994;330:1469.
Kinney H, Samuels MA. Neuropathology of the persistent vegetative state: a review. J Neuropath Exp
Neurol 1994;53:548.
Kinomura S, Larsson J , Gulys B, et al. Activation by attention of the human reticular formation and
thalamic intralaminar nuclei. Science 1996;271:512.
Levy DE, Caronna J J , Singer BH. Predicting outcome from hypoxic-ischemic coma. JAMA
1985;253:1420.
Matheson J K. Sleep and its disorders. In: Stein J H. Internal medicine, 4th ed. St. Louis: CV Mosby,
1993:1003.
Plum F, Posner J B. Diagnosis of stupor and coma, 3rd ed. Philadelphia: FA Davis Co, 1980.
Ropper AH, ed. Neurological and neurosurgical intensive care, 3rd ed. New York: Raven Press, 1993.
Zeman AZJ , Grayling AC, Cowey A. Contemporary theories of consciousness. J Neurol Neurosurg
Psychiatry 1997;62:549.
CHAPTER 2. HEADACHE
Manual of Neurologic Therapeutics
CHAPTER 2. HEADACHE
Daniel B. Hier
Evaluation of the patient with headache
Migraine headache
Cluster headache
Psychogenic headaches
Trigeminal neuralgia
Atypical facial pain
Temporal arteritis (giant cell arteritis)
Postconcussion syndrome
Idiopathic intracranial hypertension
Other headache syndromes
Headache is one of the most commonly heard complaints in the offices of internists and
neurologists. Most people accept that an occasional headache is normal. Patients come
to physicians because of unusual headache severity or frequency. Patients seek
medical attention for headaches that have changed in character, become more severe,
or become more frequent. A few patients seek attention for headaches that are of
explosive onset or relentless progression. Most chronic or recurrent headaches are
either migraine headaches, cluster headaches, or psychogenic headaches. Acute
severe headaches carry a more ominous prognosis and may reflect serious underlying
disease.
I. Evaluation of the patient with headache
A. History. A careful history provides both the data necessary for correct diagnosis
and the therapeutic rapport necessary for successful treatment of most
headaches. Special inquiry should be made into the quality of the head pain, its
frequency, its duration, its location, and any associated symptoms (Table 2-1).
The family's history of headache and the patient's psychosocial history also are
essential to the evaluation.
TABLE 2-1. Important Features of Pain in the Evaluation of Chronic Recurrent
Headaches
B. Physical examination. Each patient with a complaint of headache should
undergo careful neurologic and general physical examination. Occasionally, the
examination will yield clues as to the etiology of the headache (Table 2-2), but
generally it will serve to reassure both patient and physician that nothing serious is
causing the pain.
TABLE 2-2. Important Physical Findings in the Evaluation of Headache
C. Ancillary tests
1. Any headache patient in whom neurologic examination discloses an
abnormality should undergo further studies.
2. When the neurologic examination is normal, no further studies are indicated
except when:
a. An element of the history suggests a specific diagnosis (e.g., epilepsy or
brain tumor).
b. The headaches have developed a new quality, are more severe, or have
become intractable to treatment.
c. The headaches are atypical (e.g., trigeminal neuralgia in a patient under
age 30).
II. Migraine headache
A. Description. Migraine is a recurrent, throbbing headache. Although the headache
is usually unilateral, opposite sides of the head may be affected during different
attacks. In children, the headache is often bifrontal rather than unilateral. People
with migraine have a greater than expected prevalence of infantile colic, motion
sickness, and episodic abdominal pains in childhood.
1. In classic migraine, a visual aura precedes the throbbing headache by 10 to
20 minutes. Commonly, this prodrome consists of scintillations, migrating
scotomata, or waviness and blurriness of vision. The prodrome is followed by a
unilateral throbbing headache that intensifies over 1 to 6 hours. The headache
usually abates in 6 to 24 hours but occasionally lasts longer. Vomiting, nausea,
photophobia (light sensitivity), phonophobia (sound sensitivity), irritability, and
malaise are common.
Most patients experience their first migraine headache between the ages of 10
and 30 years, although about 25% will recall childhood vomiting attacks or
motion sickness. About 60% to 75% of patients are women. In women,
migraine headaches commonly occur premenstrually.
2. Migraine variants
a. In common migraine, the characteristic throbbing headache occurs
without the visual prodrome of classic migraine. Common migraine usually
has a slightly longer course than classic migraine.
b. In migraine associe, the headache is accompanied by a transient
neurologic deficit. Examples of migraine associe are ophthalmoplegic
migraine, hemiplegic migraine, and migraine with aphasia. The neurologic
deficit usually precedes the headache but may follow it or even occur in the
absence of headache (migraine dissocie).
c. Rarely, these neurologic deficits persist, suggesting that cerebral infarction
has occurred (complicated migraine). In these patients, vasoconstrictors
(e.g., ergotamine, sumatriptan) should be used with caution or not at all
because of the danger of exacerbating cerebral infarction.
d. Lower-half headaches are unilateral facial pains affecting the nose,
palate, cheek, and ear. These pains are believed to be attacks of atypical
migraine. They may be associated with nausea and vomiting. Lower-half
headaches may respond to treatment with ergotamine, beta blockers,
sumatriptan, or antidepressants.
e. Occasionally, attacks of migraine may last for days without remission.
Some attacks are associated with severe continuing pain as well as
persistent nausea and vomiting complicated by dehydration. This
unremitting form of migraine has been termed status migrainosus. Status
migrainosus may require treatment with intravenous hydration and either
sumatriptan or dihydroergotamine. Sometimes a course of intravenous or
oral corticosteroids is required to halt an attack of status migrainosus.
f. Some patients with migraine develop a syndrome of nearly continuous
headaches known as chronic daily headaches. Chronic daily headaches
are duller and less well localized than acute migraine headaches; nausea
and vomiting are often absent. In some migraine headache patients,
chronic daily headaches simply reflect the natural history of the disorder; in
others, chronic daily headaches signal overuse of sedative medication,
narcotics, barbiturates, or ergotamines. In patients overusing these drugs,
chronic daily headaches are best treated by carefully supervised drug
withdrawal. Antidepressants or beta blockers are sometimes useful in
aborting a prolonged attack of chronic headaches. In refractory cases of
chronic daily headaches we have used intravenous dihydroergotamine-45
(DHE-45) 1 mg IV every 8 hours for 1 to 3 days with good results.
B. Treatment of migraine
1. General measures
a. In many patients, inciting factors can be identified and partially controlled.
Some patients report an increase in the frequency and severity of their
migraine attacks in relation to smoking, alcohol ingestion, lack of sleep,
stress, fatigue, or the ingestion of certain foods, especially chocolate and
tyramine-containing cheeses. Vasodilators (e.g., nitroglycerin,
dipyridamole) can elicit migraine headaches in some individuals.
b. Anxiety and depression should be treated with appropriate psychotherapy
and medication.
c. In about one third of women with migraine who are taking oral
contraceptives, the incidence of headaches is increased. Discontinuation
of oral contraceptives in these women for a trial period may be worthwhile.
On the other hand, some women with migraine who start on oral
contraceptives experience improvement in their headaches.
d. Cerebral arteriography is usually contraindicated during an attack of
migraine, since vasospasm and cerebral infarction have been reported to
occur as rare complications during acute attacks. The incidence of migraine
in patients with either saccular aneurysms or arteriovenous malformations
is not much higher than in the general population, so migraine alone is not
an indication for neuroradiologic procedures. However, when migraine is
accompanied by permanent neurologic deficits, seizures, or a history
suggestive of subarachnoid hemorrhage, neuroimaging and sometimes
cerebral arteriography are warranted.
2. Abortive therapy should be initiated as early as possible. The patient with
classic migraine can begin therapy at the onset of the prodrome, whereas the
patient with common migraine must await the onset of headache. Some
authorities recommend awaiting the onset of headache in either case, since
some migrainous prodromes will not be followed by headache.
Ergot preparations, sumatriptan, zolmitriptan, and isometheptene have
proved superior to placebo in aborting migraine attacks. Placebo alone
ameliorates the course of about one third of migraine attacks.
a. Ergotamine may be administered alone or in combination with antiemetics,
analgesics, or sedatives. Many preparations contain caffeine (Cafergot,
Wigraine), which also is capable of producing cerebral vasoconstriction and
is known to potentiate the action of ergotamine. When the oral route is
unsatisfactory because of nausea or vomiting, ergotamine may be
administered rectally, sublingually, or nasally (Table 2-3).
TABLE 2-3. Drugs Useful in the Abortive Therapy of Migraine Headaches
Ergotamine preparations are contraindicated in the presence of peripheral
artery or coronary artery disease, hepatic or renal disease, hypertension, or
pregnancy (Table 2-4). Side effects of ergotamine include nausea,
vomiting, and cramps. Rare cases of ergotism with mental changes and
gangrene have been reported even at therapeutic dosages.
TABLE 2-4. Adverse Reactions and Contraindications for Drugs Used in
Treatment of Headache
The usual oral dosage is 1 mg at onset, followed by 1 mg q30min, to a
maximum of 5 mg per attack or 10 mg/week (see Table 2-3).
b. Isometheptene in combination with other agents (Midrin) is somewhat less
effective than ergotamine but has fewer contraindications and adverse
reactions (see Table 2-4). The usual dosage is two capsules at onset,
followed by one capsule each hour, to a maximum of five per attack, or until
the headache is relieved (see Table 2-3).
c. Dihydroergotamine is available for parenteral administration (SC, IM, or
IV). To abort acute migraine headaches, it is recommended to administer
1.0 mg of DHE IV over 2 to 3 minutes preceded by 5 mg of
prochlorperazine to reduce nausea. If the headache does not subside
within 30 minutes, another 0.5 mg of DHE is given IV. Side effects include
diarrhea, leg cramps, and abdominal discomfort. Rare instances of
coronary artery spasm and peripheral arterial spasm have been reported.
Idiosyncratic hypersensitivity reactions may occur. Individuals familiar with
its use should administer DHE. Intravenous DHE may also be useful in
aborting prolonged periods of chronic daily headaches. Usually 3 to 9 1-mg
doses given every 8 hours are needed to end a bout of chronic daily
headaches.
DHE is now available as a nasal spray (Migranal). The usual dose is 0.5 mg
in each nostril for a total dose of 1.0 mg at headache onset. This dose may
be repeated if the headache does not subside for a total of 2.0 mg. Higher
doses have not been associated with enhanced headache relief. The
maximum dose should not exceed 3.0 mg/day or 4.0 mg/week.
d. Triptans
1. Sumatriptan (Imitrex) is an effective agent in aborting migraine
headaches. It may be given subcutaneously, orally, or by nasal inhaler.
Sumatriptan has been shown to be effective in ending migraine
headaches regardless of whether it is given at the onset of migraine or
later in the attack. Sumatriptan is also effective in relieving the nausea
associated with migraine. The usual dose is 6 mg SC, which may be
repeated in 1 hour if necessary (not to exceed 12 mg in any 24-hour
period). Sumatriptan may also be administered orally at a dose of 25 to
50 mg at onset of headache. Sumatriptan is also available in a nasal
spray (20 mg at onset of headache). Side effects are usually mild and
include local skin reactions, flushing, heat, tingling, and neck pain.
Chest discomfort of uncertain origin occurs in 3% of patients.
Sumatriptan is contraindicated in patients with angina, coronary artery
disease, history of myocardial infarction, uncontrolled hypertension, or
concomitant use of ergotamines or other vasoconstrictors. Sumatriptan
is also contraindicated in hemiplegic migraine and basilar migraine.
2. Zolmitriptan (Zomig) is another 5-HT agonist that has been approved
for use in acute migraine. It has a more rapid onset of action than oral
somatriptan. The usual dose of zolmitriptan is 2.5 to 5.0 mg at onset of
headache orally. The dose may be repeated after 2 hours if there is no
pain relief. The maximum daily dose of zolmitriptan should not exceed
10 mg. Contraindications are similar to those of sumatriptan.
3. Noratriptan (Amerge) is another 5HT
1
agonist which may have a more
slower onset of action than oral sumatriptan, but because of its longer
half-life may be associated with a lower rate of recurrence (no less than
the usual 30% to 40%). The usual dose of noratriptan is a 1- or 2.5-mg
tablet taken at the onset of headache. The dose can be repeated 4 hr
later with a maximum dose of 5 mg in 24 hr.
4. Rizatriptan (Maxalt) is another 5HT
1
agonist which may have a more
rapid onset of action than oral sumatriptan. In addition to the tablet,
rizatriptan is available in a wafer which dissolves in the mouth, a feature
which may be useful since nausea dueto delayed gastric emptying is a
common feature of acute headaches. The usual dose of rizatriptan is a
5 or 10 mg tablet or wafer at the onset of the headache. This may be
repeated in two hours to a maximum dose of 30 mg in 24 hours.
3. Preventive therapy should be considered only in patients with frequent or
disabling attacks of migraine that have failed to respond to abortive therapy
(Table 2-5).
TABLE 2-5. Drugs Useful in the Preventive Therapy of Migraine
Preventive therapy for migraine is contraindicated during pregnancy or in
women attempting to become pregnant.
Classes of drugs useful in prevention of migraine include beta blockers,
tricyclic antidepressants, methysergide, anticonvulsants, and nonsteroidal
antiinflammatory drugs (NSAIDs). Limited evidence supports the calcium
channel blockers for migraine prevention. In general, preventive therapy should
be initiated with either a beta blocker, an anticonvulsant, or an
antidepressant.
a. Beta blockers are often effective in preventing migraine headaches.
1. The most experience has been with propranolol (Inderal), but other
beta blockers such as nadolol (Corgard), 40 to 240 mg/day, and atenolol
(Tenormin), 50 to 200 mg/day, are probably equally effective in migraine
prophylaxis. Their mechanism of action in migraine is unknown. The
usual effective dosage of propranolol is between 40 and 160 mg in
divided doses. A time-released form (Inderal LA) makes once-a-day
dosing possible. Propranolol should not be used in patients with asthma
or congestive heart failure.
2. If the patient is already under treatment for hypertension, it is often
useful to substitute a beta blocker for one of the patient's
antihypertensive drugs. Excessive drowsiness and depression occur in
some patients on beta blockers. These side effects may be less with
some of the more selective beta blockers such as nadolol or atenolol.
b. Tricyclic antidepressants have been shown to be effective in migraine
prophylaxis.
1. Amitriptyline (Elavil) or imipramine (Tofranil), 50 to 75 mg in divided
doses or at bedtime, provides effective migraine prophylaxis for some
patients.
2. Other tricyclic antidepressants are probably equally effective, and
some have fewer side effects. Their action against migraine appears to
be independent of their antidepressant action. Nervousness, tremor,
and anticholinergic side effects can be troublesome in certain patients.
3. The selective serotonin reuptake inhibitors (SSRIs) have a more
favorable side effect profile than the tricyclic antidepressants and are
generally better tolerated. Uncontrolled data suggest that these SSRIs
are effective in migraine prophylaxis in some patients. Usual doses of
paroxetine (Paxil) are 10 to 60 mg daily. Usual doses of fluoxetine
(Prozac) are 10 to 40 mg daily.
c. Antiinflammatory drugs are sometimes of benefit in preventing migraine.
Some patients may benefit from the daily use of aspirin. Ibuprofen (Motrin),
400 mg tid, may be effective migraine prophylaxis in some patients. Other
NSAIDs appear to have comparable efficacy.
d. Chronic use of ergotamines often leads to undesirable side effects. Rarely,
prolonged usage of ergotamine leads to ischemic complications.
e. As other effective preventive therapies have emerged, the use of
methysergide (Sansert) as migraine prophylaxis has declined. About three
fourths of patients respond favorably to methysergide (4 to 8 mg daily in
divided doses). Although this drug has been implicated as a rare cause of
retroperitoneal, cardiac valvular, and pulmonary fibrosis, in most patients
the fibrosis is reversible if the drug is discontinued. Methysergide should be
prescribed with utmost caution. Its use is contraindicated during pregnancy
or in the presence of cardiac valvular, collagen vascular, coronary artery,
peripheral vascular, pulmonary, or fibrotic disease. No patient should be
continued on the drug for longer than 6 months at a time, and patients
should be monitored for the appearance of azotemia, dyspnea, or cardiac
murmurs. A 1-month vacation from the drug for every 6 months of use is
usually adequate to avert serious complications.
f. Anticonvulsants
1. Valproic acid (Depakote). Valproic acid (250 to 750 mg PO bid) has
been shown to reduce migraine headache frequency. Its mechanism of
action is not known. In controlled studies the frequency of migraine
headaches dropped approximately 25% to 50% on valproic acid.
2. Phenytoin (Dilantin). Some patients with migraine benefit from
phenytoin (200 to 400 mg daily). Certain of these patients probably have
headaches as seizure equivalents. The existence of migrainous
epilepsy as a distinct entity is controversial, and this drug should not be
considered as a standard treatment for migraine. However, phenytoin (5
mg/kg/day) seems to be of benefit in children with migraine.
g. Calcium channel blockers are sometimes used as second-line
prophylaxis for migraine when beta blockers or tricyclics are ineffective.
Verapamil (Isoptin, Calan), 80 mg tid or qid, may be tried. This drug is
contraindicated in sick sinus syndrome, second- or third-degree heart block,
and congestive heart failure. Side effects include edema, hypotension,
fatigue, dizziness, headache, constipation, and atrioventricular heart block.
4. Symptomatic therapy
a. Many patients obtain adequate relief of occasional migraine headaches
with aspirin or acetaminophen. Some patients get better relief when a small
amount of barbiturate is added (e.g., Fiorinal, Esgic). Propoxyphene
(Darvon) may be useful when aspirin is poorly tolerated.
b. Severe headaches should be treated with codeine, 30 to 60 mg, or
morphine, 4 to 8 mg, q34h.
c. Nausea and vomiting may be produced by the headache itself, by
ergotamine, or by narcotics. Vomiting can be controlled with promethazine
(Phenergan), 25 to 50 mg, or prochlorperazine (Compazine), 5 to 10 mg.
d. Allowing the patient to sleep by administering a hypnotic, such as
flurazepam (Dalmane), 15 to 60 mg, is generally an effective way of ending
the migraine.
e. Extensive use of drugs that contain barbiturates, caffeine, and opiates
should be avoided, since these drugs may themselves lead to withdrawal
headaches.
III. Cluster headache
A. Description. Cluster headache (histamine cephalalgia, Horton headache) is a
periodic, paroxysmal headache disorder. Excruciating unilateral head pain (often
localized to the orbit) occurs in brief episodes (15 minutes to 2 hours) without
prodrome. The headaches are distributed into clusters, occurring daily for 3 weeks
to 3 months, then remitting entirely for months or years. The pain is sharp, boring,
and piercing, and is unaccompanied by nausea or vomiting. Headaches are most
common late at night or early in the morning. This is one of the few headaches
that awaken patients from their sleep. Some patients experience facial flushing,
Horner syndrome, nasal stuffiness, or eye tearing ipsilateral to the headache. Men
are affected 5 times as frequently as women are, and most patients have their first
attack between the ages of 20 and 40. Exacerbation of the headaches due to
alcohol consumption is common. The mechanism underlying cluster headache is
not well understood but is believed to be vascular.
B. Treatment
1. Sumatriptan 6 mg SC has been shown to be superior to placebo in aborting
attacks of cluster headaches.
2. Ergotamine. The lack of aura and the short duration of cluster headaches
make abortive therapy of these headaches difficult. Occasionally, a patient can
successfully end a cluster headache by promptly taking an ergotamine
preparation (e.g., Cafergot, Wigraine, Ergomar). Other patients may improve
with ergotamine prophylaxis during an attack of cluster headaches (Cafergot,
Wigraine) one or two tablets at bedtime.
3. Methysergide. About 50% to 80% of patients improve substantially with
methysergide (4 to 8 mg daily in divided doses). Caution must be exercised in
the use of this drug (see Table 2-4), but a bout of cluster headaches is
self-limited, and it is rarely necessary to continue the drug for more than 3
months.
4. Propranolol. Uncontrolled studies indicate that propranolol (40 to 160 mg daily
in divided doses) is effective in certain patients.
5. Prednisone. Some authors recommend a short course of prednisone (20 to 40
mg daily, followed by a gradual tapering) for refractory cases of cluster
headaches.
6. Lithium carbonate, 300 mg tid or qid, has been suggested as treatment when
methysergide is ineffective or poorly tolerated. Serum levels should be kept
below 1.2 mg/dL to avert toxic effects.
7. Oxygen inhalation at a flow rate of 7 L/minute for 10 minutes is said to abort
about 80% of cluster headaches.
8. Indomethacin (Indocin) in a dosage of 25 to 50 mg tid may be effective for
some cluster headaches.
9. Histamine desensitization is of historical interest but rarely indicated.
10. Narcotics. Symptomatic relief of cluster headaches may require narcotic
agents (e.g., codeine, 30 to 60 mg q34h).
11. Calcium channel blockers such as verapamil (80 mg PO tid) may benefit
some patients with cluster headaches.
12. Intravenous DHE may abort cluster headaches in some patients.
13. Lidocaine. Intranasal instillation of 1 mL of 4% topical lidocaine may abort
cluster headaches in some patients.
IV. Psychogenic headaches
A. Description
1. The term psychogenic headache encompasses several entities, including
tension headache, muscle contraction headache, and the headaches of
anxiety and depression. The individual with sporadic headaches that are
relieved by aspirin or acetaminophen, or with occasional neck and scalp
muscle tightness that is relieved by massage, rarely consults a physician. In
contrast, most patients with psychogenic headaches who seek medical
attention have had daily or unremitting headaches for months or years that are
not relieved by simple analgesics or even narcotics (unlike the headaches of
intracranial masses).
2. In our experience, the great majority of these patients are depressed; signs of
depression, including tearfulness, hopelessness, insomnia, anorexia, and an
inability to enjoy life, are often prominent. Nonetheless, we have seen many
patients with chronic daily headaches who are not depressed.
3. These patients describe ill-defined, diffuse aching or pressure sensation. The
pain may be occipital, temporal, or frontal in distribution, but it is almost
invariably bilateral. The unilateral throbbing pain characteristic of migraine is
uncommon.
B. Treatment
1. General measures
a. Initiation of therapeutic rapport between physician and patient is very
often the first step toward improvement. Some patients respond positively
to the physician's forceful reassurance that nothing is physically wrong
inside their brain or head, thus dispelling fears of brain tumor or other
intracranial disease.
b. An assessment should be made as to whether anxiety or depression is
present. Some patients accept the suggestion that their headaches are
related to depression and welcome a therapeutic program directed against
it, whereas other patients will be uncomfortable with this diagnosis, even
though it is indicated. For the latter, emphasis is better left on treating the
headache. Depression and anxiety sometimes can be controlled by
examination and modification of the life events contributing to these
emotions. When the depression is severe, refractory to treatment, or
complicated by threats of suicide, the patient should be referred to a
psychiatrist.
2. Tricyclic antidepressants. Aspirin or acetaminophen may be of value for
some patients with psychogenic headaches, but when depression is prominent
the use of analgesics is usually futile, and sedating tranquilizers may deepen
the depression. Several controlled studies have shown tricyclic
antidepressants to be superior to analgesics or minor tranquilizers in the
treatment of these headaches. A variety of serotonin reuptake inhibitor
antidepressants are now available including fluoxetine. These drugs have
antidepressant effects without anticholinergic side effects.
3. Benzodiazepines. In the smaller group of patients in whom muscle
contraction and anxiety predominate, treatment with diazepam (Valium), 5 to
30 mg daily, chlordiazepoxide (Librium), 10 to 75 mg daily, or oxazepam
(Serax), 30 to 90 mg daily, in conjunction with aspirin or acetaminophen, is
useful. Alprazolam (Xanax) is a benzodiazepine drug that appears to have
both antianxiety and antidepressant actions. The usual dosage is 0.25 to 0.50
mg tid.
4. Relaxation techniques. The value of hypnosis, biofeedback, meditation, and
other relaxation techniques in the treatment of psychogenic headaches has not
been established.
V. Trigeminal neuralgia
A. Description. Trigeminal neuralgia (tic douloureux) is characterized by brief,
lancinating paroxysms of pain (lasting for seconds or minutes) in the distribution of
the fifth cranial nerve. The third and second divisions of the trigeminal nerve are
affected more frequently than the first, and trigger points can often be found on the
face. Attacks occur spontaneously or during toothbrushing, shaving, chewing,
yawning, or swallowing.
In over 90% of patients with trigeminal neuralgia, onset occurs after age 40, and
women are affected somewhat more frequently than men. In most patients, no
etiology for trigeminal neuralgia can be found. When it is associated with
hypesthesia in the distribution of the fifth cranial nerve, with other cranial nerve
palsies, or with onset before the age of 40, so-called symptomatic, or atypical,
trigeminal neuralgia should be suspected. Further investigation may reveal
multiple sclerosis, a trigeminal nerve tumor, or other posterior fossa tumor.
B. Treatment
1. Phenytoin. Many patients get relief from phenytoin alone (200 to 400 mg
daily).
2. Carbamazepine (Tegretol). About 80% of patients with trigeminal neuralgia
respond to initial treatment with carbamazepine (400 to 1,200 mg daily).
Response to carbamazepine is helpful in differentiating trigeminal neuralgia
from certain cases of atypical facial pain (see sec. VI.A). Both phenytoin and
carbamazepine can produce troublesome ataxia (especially when used
concurrently). Rare complications of carbamazepine are leukopenia,
thrombocytopenia, and liver function abnormalities, so its use requires periodic
monitoring of WBC count, platelet count, and liver function. After initial
improvement, many patients develop recurrent pain despite adequate blood
levels of one or both of these drugs.
3. Baclofen (Lioresal) may provide relief in some patients. Baclofen may be
given alone or in combination with either phenytoin or carbamazepine. The
usual initial dosage is 5 to 10 mg tid, with gradual increases as needed, up to
20 mg qid.
4. Anecdotal reports suggest that clonazepam (Clonopin) 0.5 to 1.0 mg PO tid
may be effective in some patients with trigeminal neuralgia. Gabapentin
(Neurontin) in divided doses of 900 to 2,700 mg/day may be useful in some
patients.
5. Surgery. Three surgical procedures are commonly used in the treatment of
trigeminal neuralgia:
a. Radiofrequency-selective thermal rhizotomy of the trigeminal ganglion
or rootlets can be performed percutaneously with local anesthesia in
conjunction with short-acting barbiturates. Selective destruction of pain
fibers with relative sparing of tactile-related fibers minimizes the possibility
of corneal anesthesia with subsequent abrasions and the possibility of
anesthesia dolorosa. However, some patients find the numbness
unpleasant, and procedures for first-division pain carry a higher incidence
of corneal problems. Other methods for destruction of pain fibers in the
trigeminal nerve include cryosurgery and balloon inflation in Meckel
cave.
b. Glycerol injection into the trigeminal cistern (Meckel cave) can be done
percutaneously. This may produce pain relief with minimal sensory loss on
the face.
c. For many patients, particularly those who are younger, suboccipital
craniectomy with microsurgical repositioning of a blood vessel
cross-compressing the trigeminal nerve at the root entry zone offers a
relatively safe alternative without sensory loss.
VI. Atypical facial pain
A. Description. Atypical facial pain must be distinguished from trigeminal neuralgia
and lower-half headaches. Commonly it is seen in young or middle-aged patients
as a unilateral, boring, or aching facial pain that lacks both the paroxysmal quality
and the well-defined anatomic distribution characteristic of trigeminal neuralgia.
The etiology of atypical facial pain is unknown.
B. Treatment. Patients are unimproved by either phenytoin or carbamazepine.
Surgical procedures on the trigeminal nerve are not indicated, since they do not
relieve the pain and may produce analgesia algera. Most patients should have a
trial at antidepressant therapy. Encouraging results have been reported with the
tricyclic antidepressants. Some patients may respond to SSRIs such as fluoxetine.
When the pain has a delusional quality, a major tranquilizer might be of benefit.
Many cases prove difficult to treat.
VII. Temporal arteritis (giant cell arteritis)
A. Description. Temporal arteritis, a systemic illness of elderly patients, is
characterized by inflammatory infiltrates of lymphocytes and giant cells in cranial
arteries. It manifests itself variously in temporal headache, visual loss, or
generalized malaise. When visual loss is present, it should be considered a
medical emergency. It is estimated that only about one half of patients complain
of headache or have tender temporal arteries, although nearly all patients have
some systemic symptoms, including low-grade fever, weight loss, anorexia, or
weakness. The erythrocyte sedimentation rate (ESR) is elevated in all patients,
usually to between 60 and 120 mm/hour. Onset before age 50 is uncommon. Jaw
claudication is a useful diagnostic clue to the presence of temporal arteritis.
Visual loss occurs in 10% to 40% of untreated patients.
The relationship of temporal arteritis to polymyalgia rheumatica is controversial.
There appears to be considerable overlap between the two illnesses, and some
patients with polymyalgia rheumatica exhibit giant cell arteritis on temporal artery
biopsy.
B. Diagnosis
1. The diagnosis should be confirmed by temporal artery biopsy, since this
procedure can be performed easily under local anesthesia, even in debilitated
patients. Rarely, the biopsy will be normal in the presence of active arteritis
because of patchy involvement of the temporal artery.
2. Angiography often will confirm the presence of arteritis in equivocal cases.
C. Treatment
1. High-dose corticosteroids should be initiated immediately to avert visual loss.
When the diagnosis is suspected, initiation of therapy should not await the
pathology report of the temporal artery biopsy. Prednisone (60 mg daily) will
abolish systemic symptoms and normalize the ESR within 4 weeks in most
patients. The dosage can then be gradually reduced to 5 to 10 mg daily over
several months.
2. A rise in ESR or a recrudescence of systemic symptoms sometimes
necessitates a temporary increase in corticosteroid dosage.
3. Temporal arteritis is self-limited, and corticosteroids can usually be
discontinued within 6 months to 2 years.
4. Patients must be observed for complications of high-dose corticosteroid
therapy, including psychosis, osteoporosis, vertebral body collapse, and
gastrointestinal hemorrhage.
VIII. Postconcussion syndrome
A. Description. Following cerebral concussion, patients may complain of decreased
concentration, vague headaches, dizziness, fatigue, and photophobia. The
forcefulness of these complaints does not correlate with either the severity of the
concussion or any objective finding, except that the complaint of dizziness is
sometimes correlated with the finding of nystagmus. The postconcussion
syndrome usually remits spontaneously, but it occasionally follows a protracted
course over a period of years (especially if litigation is pending). The etiology of
this syndrome is largely psychogenic; fear that cerebral damage has been
suffered plays a role in some cases. However, computed tomographic (CT) scan
of the brain may reveal unsuspected brain lesions in a small minority of patients
with postconcussion syndrome.
B. Treatment
1. Anxiety should be allayed with repeated assurances that nothing is amiss.
Benzodiazepine tranquilizers may be given if necessary.
2. Depressive symptoms may require short-term psychotherapy or a brief
course of antidepressants.
3. The management of dizziness is discussed in Chap. 4.
4. Some cerebral concussion patients describe headaches that are migrainous in
nature and that respond to migraine headache therapy. Propranolol, 20 to 40
mg qid, may be especially effective in controlling certain throbbing headaches
that follow head injury. Antidepressants such as imipramine or fluoxetine are
sometimes helpful. When litigation is pending, all forms of therapy may prove
futile.
IX. Idiopathic intracranial hypertension
A. Description. Idiopathic intracranial hypertension (IIH; also known as
pseudotumor cerebri or benign intracranial hypertension) is a syndrome of
increased intracranial pressure without evidence of mass lesion or hydrocephalus.
Headache and papilledema are usually present. Rarely, IIH occurs with
headache but not papilledema. About 90% of the patients are both obese and
female. Occurrence after age 45 is rare. The etiology of most cases is unknown,
although vitamin A intoxication, tetracycline use, corticosteroid use or withdrawal,
and dural sinus thrombosis occasionally have been implicated. About 5% of the
patients experience a decrease in visual acuity associated with the papilledema;
this loss may be permanent if increased intracranial pressure persists unrelieved.
Localizing neurologic signs do not occur, although unilateral or bilateral sixth
nerve palsies may occasionally produce diplopia. Transient visual loss, known as
visual obscurations, are common.
B. Diagnosis
1. Headache and papilledema should always prompt a thorough investigation for
mass lesions or hydrocephalus.
2. The magnetic resonance imaging (MRI) scan with gadolinium
enhancement delineates most supratentorial lesions as well as many
infratentorial lesions capable of producing papilledema. Special attention
should be paid to the patency of the venous sinuses in order to exclude either
sinus thrombosis or cortical venous thrombosis. The ventricles are either
diminished in size (slitlike) or normal in configuration. Enlarged ventricles cast
great doubt on the diagnosis of IIH and suggest hydrocephalus.
3. The MRI scan is especially useful in detecting venous sinus occlusions that
can be confused with the syndrome of IIH.
4. When these preliminary tests are normal and localizing signs are absent,
lumbar puncture can be safely performed in the presence of papilledema.
The diagnosis of benign IIH is confirmed by the finding of normal cerebrospinal
fluid (CSF) under increased pressure (usually 250 to 500 mm H
2
O). Any
abnormality of the CSF (cytology, protein, sugar) should prompt further
investigation.
5. When the CT or MRI scan is abnormal, extreme care should be exercised
before proceeding to lumbar puncture.
C. Treatment
1. About one third of these patients have spontaneous remission after the first
lumbar puncture. Most other patients can be successfully managed by
repeated lumbar punctures, daily at first, then every third day, weekly, or even
monthly, as needed. Sufficient CSF (up to about 30 mL) should be removed at
each lumbar puncture to reduce the CSF pressure to less than 180 mm H
2
O.
2. Patients who do not respond to repeated lumbar punctures may be tried on
prednisone (40 to 60 mg daily) or dexamethasone (6 to 12 mg daily).
Response to corticosteroids generally occurs within 1 week. Refractory cases
may require repeated lumbar punctures, acetazolamide (250 to 500 mg tid), or
furosemide (40 to 80 mg daily).
3. Visual fields and visual acuity need to be monitored carefully in all patients with
IIH. When visual loss is progressing despite medical therapy, surgical therapy
should be considered. Current practice is to perform optic nerve sheath
decompression for patients with progressive visual loss due to IIH.
4. Although most cases of benign IIH resolve in 6 to 12 months, a few cases will
require repeated intervention over the course of several years.
X. Other headache syndromes
A. Headache in association with fever and stiff neck (with or without mental
changes) can be due to encephalitis or meningitis (see Chap. 8).
B. The violent onset of headache (with or without loss of consciousness) followed
by stiff neck suggests subarachnoid hemorrhage (see Chap. 10). The headache is
often described in dramatic terms, such as the worst headache of my life or a
headache like something snapped in my head. Photophobia and malaise may be
present. Funduscopy may reveal preretinal (subhyaloid) hemorrhages. The
headache of ruptured saccular aneurysm is generally more severe than that of
leaking arteriovenous malformations. A dull unremitting headache that persists
for days following a subarachnoid hemorrhage is sometimes due to the increased
intracranial pressure of communicating hydrocephalus (see Chap. 3). The
headache may be relieved by lumbar puncture. Occasionally, a shunting
procedure is necessary to control the hydrocephalus.
C. Headache occurs with a variety of intracranial mass lesions such as subdural
hematoma (Chap. 12), brain tumor (Chap. 11), and brain abscess (Chap. 8). The
headache of brain tumors is usually paroxysmal at first (often worse early in the
morning, on arising). Later, the headaches become unremitting and may be
complicated by vomiting. The initial side of the headache may reflect the side of
the tumor, but this is not a highly reliable sign. Headache is the first symptom of
about 80% of posterior fossa tumors and 30% of supratentorial tumors.
D. The headache of increased intracranial pressure (Chap. 11) may be intensified
by coughing, sneezing, or bending over. Cough headache also exists as a benign
entity without known intracranial pathology.
E. Occipital headache associated with pain on movement of the neck may be due to
cervical arthritis. Arthritic changes can be confirmed by plain x-ray examinations
of the cervical spine. A trial of aspirin in combination with diazepam, 5 to 30 mg
daily, gives relief to some patients. Cervical collars and cervical traction are
occasionally of benefit. NSAIDs (e.g., ibuprofen, 400 mg tid) benefit some
patients. Other patients may benefit from the epidural injection of steroids.
When signs of radiculopathy (radicular pain in an extremity, weakness,
hyporeflexia) or myelopathy (hyperreflexia, Babinski signs, weakness, spasticity)
are present, neuroimaging with either CT or MRI may reveal spinal cord or nerve
root compression by a spondylitic bar or herniated disk. An electromyogram is
useful in cases of suspected radiculopathy. When radiculopathy or myelopathy is
present, surgical management is often indicated.
F. The headache that occurs after lumbar puncture is exacerbated by standing and
relieved by lying down. These headaches appear to be due to persistent leakage
of CSF from the subarachnoid space; most can be prevented by use of a
small-bore needle (20- or 22-gauge). Post-lumbar puncture headaches usually
can be managed by a combination of bed rest, analgesics, and hydration. When
conservative measures fail, an epidural patch with autologous blood usually
provides relief.
G. Tumors of the foramen magnum produce an occipital headache that worsens on
recumbency and is relieved by standing.
H. Nasal stuffiness or discharge associated with pain or percussion over the sinuses
suggests that the headache may be due to acute sinusitis.
I. Headache in association with a red painful eye can be produced by acute
closed-angle glaucoma. Open-angle glaucoma (which is more common) does
not produce headache.
J . There is no correlation between headache and moderate elevations of blood
pressure. An occasional patient with hypertension has relief from early morning
headaches with control of blood pressure, but hypertension should not be
considered a common cause of headache.
K. Head pain due to temporomandibular joint syndrome is characterized by pain
on chewing or jaw use, temporomandibular joint clicking and crepitation, and jaw
restriction.
L. Sudden severe headaches that are maximal at their onset (thunderclap
headaches) may occur in patients known to have migraine headaches. These
sudden, severe head pains may occur in certain known contexts (e.g., orgasmic
headache, exercise-induced headache) or may appear without obvious
precipitants. The ominous diagnosis of subarachnoid hemorrhage should be
rigorously excluded using CT, MRI, or lumbar puncture before the more benign
diagnosis of thunderclap headache is made. Migraine headache patients may also
experience benign brief stabs of cranial pain known as ice-pick pains.
Selected Readings
General
Dalessio DJ , Silberstein SD. Wolff's headache and other head pain, 6th ed. New York: Oxford University
Press, 1993.
Diamond S. Headache. Med Clin North Am 1991;75:521.
Klapper J A. Toward a standard drug formulary for the treatment of headache. Headache 1995;35:225.
Lance J W. The mechanism and management of headache, 5th ed. London: Butterworth, 1993.
Raskin NH. Headache, 2nd ed. New York: Churchill Livingstone, 1988.
Migraine and Cluster Headaches
Cady RK, et al. Treatment of acute migraine with subcutaneous sumatriptan. JAMA 1991;265:2831.
Feniuk W, et al. Rationale for the use of 5HT-like agonists in the treatment of migraine. Neurology
1991;238:s57.
Gallagher M. Acute treatment of migraine with dihydroergotamine nasal spray. Arch Neurol
1996;53:1285.
Greenberg DA. Calcium channel antagonists and their treatment of migraine. Clin Neuropharmacol
1986;9:311.
Lewis TA, Solomon GD. Advances in cluster headache management. Cleve Clin J Med 1996;64:237.
New triptans and other drugs for migraine. The Medical Letter 1998;40:97100.
Pryse-Phillips WEM, et al. Guidelines for the diagnosis and management of migraine in clinical practice.
Can Med Assoc J 1997;156:1273.
Raskin NH. Repetitive intravenous dihydroergotamine as therapy for intractable migraine. Neurology
1986;36:995.
Rosen J A. Observations on the efficacy of propranolol for the prophylaxis of migraine. Ann Neurol
1983;13:92.
Saper J R, et al. Double-blind trial of fluoxetine: chronic daily headache and migraine. Headache
1994;34:497.
Schwartz BS, Stewart WF, Simon D, Lipton SB. Epidemiology of tension-type headache. J AMA
1998;279:381.
Silberstein SD. Preventative treatment of migraine. Cephalgia 1997;17:67.
Silberstein SD. Migraine and women: the link between headache and hormones. Postgrad Med
1995;97:147.
Sorensen KJ . Valproate: a new drug for migraine prophylaxis. Acta Neurol Scand 1988;78:346.
Tfelt-Hansen P, et al. Timolol vs. propranolol vs. placebo in common migraine prophylaxis: a double-blind
multicenter trial. Acta Neurol Scand 1984;69:1.
Weber RB, Reinmuth OM. The treatment of migraine with propranolol. Neurology 1971;21:404.
Welch KMA. The therapeutics of migraine. Curr Opin Neurol Neurosurg 1993;6:264.
Psychogenic Headache
Lance J W, Curran DA. Treatment of chronic tension headache. Lancet 1964;1:1236.
Loh L, et al. Acupuncture versus medical treatment of migraine and muscle tension headache. J Neurol
Neurosurg Psychiatry 1984;47:333.
Okasha A, Ghaleb HA, Sadek A. A double-blind trial for the clinical management of psychogenic
headaches. Br J Psychol 1973;122:181.
Weatherhead AD. Headache associated with psychiatric disorders: classification and etiology.
Psychosomatics 1980;21:832.
Trigeminal Neuralgia and Atypical Facial Pain
Dalessio DJ . Medical treatment of the major neuralgias. Semin Neurol 1988;8:286.
Delaney J F. Atypical facial pain as a defense against psychosis. Am J Psychol 1976;133:10.
Fromm GH, Terrence GF, Chatta AS. Baclofen in the treatment of refractory trigeminal neuralgia.
Neurology 1979;29:550.
Hankanson S. Trigeminal neuralgia treated by injection of glycerol into trigeminal cistern. Neurosurgery
1981;9:638.
J annetta PJ . Treatment of trigeminal neuralgia by suboccipital and transtentorial cranial operations. Clin
Neurosurg 1977;24:538.
Killian J M, Fromm GH. Carbamazepine in the treatment of neuralgia. Arch Neurol 1968;19:129.
Solomon S, Lipton RB. Atypical facial pain: a review. Semin Neurol 1988;8:332.
Sweet WH. Percutaneous methods for the treatment of trigeminal neuralgia and other faciocephalic pain:
comparison with microvascular decompression. Semin Neurol 1988;8:272.
Zakrzewska J M, Thomas DGT. Patient assessment of outcome after 3 surgical procedures for the
management of trigeminal neuralgia. Acta Neurochir (Wien) 1993;122:225.
Temporal Arteritis
Aiello PD, et al. Visual prognosis in giant cell arteritis. Ophthalmology 1993;100:550.
Allison MC, Gallagher PJ . Temporal artery biopsy and corticosteroid treatment. Ann Rheum Dis
1984;43:416.
Bengtsson BA, Malmvall BE. Prognosis in giant cell arteritis including temporal arteritis and polymyalgia
rheumatica: a follow-up study on ninety patients treated with corticosteroids. Acta Med Scand
1981;209:337.
Buchbinder R, Detsky AS. Management of suspected giant cell arteritis: a decision analysis. J Rheumatol
1992;19:1120.
Chmelewski WL, et al. Presenting features and outcomes in patients undergoing temporal artery biopsy:
a review of 98 patients. Arch Intern Med 1992;152:1690.
Genereau T, Cabane J . Benefits of corticosteroids in the treatment of temporal arteritis and polymyalgia
rheumatica: advantages and disadvantagesa meta-analysis. Rev Med Interne 1992;13:387.
Hunder GG, et al. Daily and alternate-day corticosteroid regimens in treatment of giant cell arteritis:
comparison in a prospective study. Ann Intern Med 1975;82:613.
Benign Intracranial Hypertension
Corbett J J . Idiopathic intracranial hypertension (pseudotumor cerebri). In: J ohnson RT, Griffin J W, eds.
Current therapy in neurologic disease, 4th ed. St. Louis: MosbyYear Book, 1993.
Corbett J J , Thompson HS. The rational management of idiopathic intracranial hypertension. Arch Neurol
1989;46:1049.
Corbett J J , et al. Visual loss in pseudotumor cerebri: follow-up of 57 patients from five to 41 years and a
profile of 14 patients with permanent severe visual loss. Arch Neurol 1982;39:461.
Kilpatrick CJ , et al. Optic nerve decompression in benign intracranial hypertension. Clin Exp Neurol
1981;18:161.
J ohnston PK, Corbett J J , Maxner CE. Cerebrospinal fluid protein and opening pressure in idiopathic
intracranial hypertension (pseudotumor cerebri). Neurology 1991;41:1040.
Marcelis J , Silberstein SD. Idiopathic intracranial hypertension without papilledema. Arch Neurol
1991;48:392.
Wall M, George D. Idiopathic intracranial hypertension: a prospective study of 50 patients. Brain
1991;114:155.
Other Headache Syndromes
Carbatt PAT, van Crevel H. Lumbar puncture headache: controlled study of the preventive effect of 24
hours bed rest. Lancet 1981;2:1133.
Lidvall HF, Linderoth B, Norlin V. Causes of the postconcussional syndrome. Acta Neurol Scand [Suppl]
1974;56:3.
CHAPTER 3. INTELLECTUAL DYSFUNCTION: MENTAL RETARDATION AND DEMENTIA
Manual of Neurologic Therapeutics
CHAPTER 3. INTELLECTUAL DYSFUNCTION: MENTAL
RETARDATION AND DEMENTIA
Raymond J . Fernandez and Martin A. Samuels
Measurement of intelligence
Evaluation of the patient with intellectual dysfunction
Conditions with intellectual dysfunction as a major manifestation
Systemic diseases with cerebral pathology
Psychiatric diseases
Intelligence refers to the ability to comprehend ideas and their relationships and to
reason about them. This extremely complex function consists, in neurologic terms, of
multiple capacities, including those for general knowledge, memory, acquisition of new
knowledge, attention, comprehension, judgment, abstract thinking, language,
understanding of mathematical concepts, orientation, perception, and association.
Mental retardation is defined as subnormal intellectual capacity with associated deficits
in at least 2 of 10 areas of adaptive behavior. The 10 areas of adaptive behavior that
should be analyzed are communication, self-care, home living skills, social skills,
leisure, health and safety, self-direction, functional academics, community use, and
work. To determine this, it is necessary to understand better the mentally retarded
individual in the framework of his or her environment and how he or she will best
function in the home and community. The term implies a static process, the onset of
which occurs prenatally or early in life.
Dementia is defined as loss of previously acquired intellectual function. It may be a
static or progressive disorder with onset at any age. The term generally excludes acute
confusion, delirium, and abnormalities in level of consciousness. Psychiatric illnesses in
particular are excluded from the category of dementia (see Chap. 9). Isolated
abnormalities of one cortical function (e.g., isolated aphasias) are not generally
considered dementias, despite their ability to produce impairment of intellect.
I. Measurement of intelligence. Attempts to quantify intelligence and
developmental level have been made using many psychological testing methods, the
most common of which are the following:
A. The Wechsler Adult Intelligence ScaleRevised (WAIS-R) provides a verbal,
nonverbal, and overall intelligence quotient (IQ) and is appropriate for testing
people over the age of 16.
B. The Wechsler Intelligence Scale for ChildrenRevised (WISC-R) is designed
for testing children of 6 to 16 years of age; it also yields verbal, nonverbal
(performance), and full-scale IQ measurements. A discrepancy between verbal IQ
and performance IQ often provides a clue to perceptual handicaps.
C. The Stanford-Binet test (4th edition) is appropriate for people aged 2 years to
adulthood and yields mental age (MA) and IQ values. It is heavily weighted toward
verbal performance and thus may underestimate the intelligence of children with
specific communication disorders or from environments that have not stimulated
their verbal capacity.
D. The Denver II measures 4 areas of behaviorgross motor, fine motor, language,
and personal-socialand is a screening instrument for developmental
assessment in infancy and preschool years. It is not an IQ test.
E. The Early Language Milestone Scale (ELM) and the Central Linguistic
Auditory Milestones Scale (CLAMS) are easily administered screening
instruments that are sensitive indicators of delay in expressive and receptive
language up to the age of 3 years.
F. Individuals with mental retardation may then be classified according to their
intellectual capacity as mildly, moderately, or profoundly retarded.
1. The mildly retarded (educable) have IQ scores of 55 to 70. This group
constitutes approximately 75% of the retarded population. They may never
attain more than third- or fourth-grade educational skills but after reaching
adulthood should be able to function in the community with some degree of
supervision.
2. The moderately retarded (trainable) have IQs between 45 and 55. Most are
capable of learning self-care skills but will never display significant academic
achievement. Individuals in this group may live at home and attend sheltered
workshops. Those who do not live at home will require a considerable amount
of supervision in a group setting. They compose approximately 20% of the
retarded population.
3. The severely retarded (IQ 25 to 45) and profoundly retarded (IQ <25) are
totally dependent. Some are bedridden and never achieve any degree of
socialization. This group composes only approximately 5% of the retarded
population.
4. While the above classification according to intellectual capacity has been used
for many years and is useful in certain situations, more recently it has been
proposed that mentally retarded individuals be classified into one of two
groups:
a. Mild mental retardationIQ 50 to 70.
b. Severe mental retardationIQ <50.
G. Limitations of testing. These tests are of varying reliability; all suffer from poor
reproducibility, especially in young subjects, and all fail to correct for the known
effects of cultural and educational background, interest, motivation, and effort on
intelligence test scores. Furthermore, certain psychiatric disordersparticularly
depression and schizophreniamay lower IQ. Whether this occurs because of
actual lowering of intelligence or because of impaired motivation in these
conditions is unknown.
Despite these drawbacks, psychological testing is presently the only scientific
method of estimating intelligence, and it can be useful in evaluating and following
patients with intellectual dysfunctionas long as the limitations of the tests are
clearly understood by the physician.
II. Evaluation of the patient with intellectual dysfunction
A. History. A careful history of the onset and course of the intellectual dysfunction is
obtained.
1. In children, one must attempt to discern whether the problem is one of mental
retardation or dementia, since the further evaluation of the patient depends
heavily on this distinction.
2. Exact descriptions of the abnormal behavior may help in ascertaining the
cortical distribution of the dysfunction (i.e., frontal, parietal, temporal, or
occipital).
3. The course of the illness deserves special consideration, and one should
note particularly whether it occurred in steps or gradually; the former onset
suggests strokes, and the latter a degenerative process.
4. History of possible intracranial hemorrhage strongly suggests occult
hydrocephalus.
5. A general medical history is taken, with particular emphasis placed on the
following factors:
a. Prior gastric surgery (predisposing the patient to vitamin B
12
deficiency).
b. Thyroid disease.
c. Use of drugs or ingestion of toxins, such as bromide-containing drugs.
d. Family history of other neurologic or psychiatric illness.
6. In children, a careful history of the pregnancy and condition perinatally is
particularly important.
B. Physical examination
1. The general physical examination is aimed at excluding any medical illness
that may underlie the intellectual dysfunction, such as:
a. Uremia.
b. Liver failure.
c. Anemia.
d. Hypertension.
e. Malignancy.
2. In children, the condition underlying the intellectual dysfunction may be
obvious on physical examination (e.g., Down syndrome).
3. The mental status examination helps to define the extent and precise type of
dysfunction. Functions to be tested include:
a. Attention.
b. Orientation.
c. Alertness.
d. Speech.
e. Comprehension.
f. Memory.
g. Naming.
h. Repetition.
i. Reading.
j. Writing.
k. Calculations.
l. Right-left discrimination.
m. Praxis.
n. Developmental level in children.
4. The neurologic examination excludes signs of focal brain disease, such as:
a. Hemiparesis.
b. Primary modality sensory loss.
c. Hemianopia.
d. Cranial nerve abnormalities.
5. In children, particular attention is paid to head size and rate of head growth.
6. In infants under 18 months of age, transillumination of the skull is routinely
done to detect a fluid-filled structure such as a subdural effusion,
porencephalic cyst, or massive hydrocephalus.
III. Conditions with intellectual dysfunction as a major manifestation
A. Degenerative diseases
1. Alzheimer disease and Pick disease (presenile dementia and senile
dementia of the Alzheimer type)
a. Description. Alzheimer disease is a common cause of dementia. The older
concept of presenile (before age 65) and senile (after age 65) dementias
now has little clinical relevance, since the pathology (i.e., decreasing
number of cortical neurons with accumulation of lipofuscin in neurons and
the presence of neurofibrillary degeneration of neurons and senile plaques
containing the amyloid beta protein; deepening cortical sulci; and increasing
ventricular size with progressive decrease in brain weight and amyloid
infiltration of small pial vessels [congophilic angiopathy]) and the clinical
course of Alzheimer disease are known to be the same in all age groups.
1. Symptoms and signs of dysfunction. Since the cortical degeneration
is widespread, one might expect nearly every part of the cerebral cortex
to show dysfunction. In practice, most patients begin to have difficulty in
parietal and temporal lobe function, with memory loss and spatial
disorientation. As the disease progresses, signs of frontal lobe
dysfunction appear, with loss of social inhibitions and concomitant
incontinence and abulia (loss of spontaneity). Aphasia and apraxia are
common and may occur at any point in the course of the disease.
However, this sequence of events is not always seen, and some
patients will have extensive frontal lobe difficulty long before temporal
and parietal lobe functions are disturbed. Many patients with Alzheimer
disease show a variety of movement disorders including akinesia,
dystonias, and myoclonus; therefore, these findings do not necessarily
imply a different diagnosis.
In a less common degenerative dementia, Pick lobar atrophy, only
frontal and temporal pole degeneration is seen. Despite this difference
in pathology, there is no reliable method clinically to separate Alzheimer
from Pick disease. In both Alzheimer and Pick diseases, it is
exceedingly rare to see signs of pyramidal tract dysfunction (i.e.,
hemiparesis, hyperreflexia, or Babinski signs) or loss of primary
sensory modalities. Such findings should raise suspicion that a
space-occupying lesion or areas of encephalomalacia account for the
dementia.
2. Patient behavior and prognosis. Patients with Alzheimer disease can
be extremely difficult to manage. Such patients are commonly
incontinent of urine and feces, may wander away from home and be
unable to find their way back, may be agitated and confused
intermittently (particularly at night), and may use embarrassingly
inappropriate language and actions. Early in the course of the illness,
depression may be a major problem.
The disease is progressive, inevitably terminating in complete incapacity
and death. The course is extremely variable, but most patients die within
4 to 10 years of the time of diagnosis.
b. Etiology. The cause of Alzheimer disease is still unknown, but various
theories are being investigated and may have important implications for
diagnosis and treatment.
1. Genetic. Approximately 15% of Alzheimer disease cases are autosomal
dominantly inherited, and patients with 3 copies of chromosome 21 (i.e.,
Down syndrome) develop the pathologic changes characteristic of
Alzheimer disease possibly because amyloid precursor protein is
localized on chromosome 21. Genetic linkage analysis has detected
DNA markers on the long arm of chromosome 21 that segregate with
the familial Alzheimer disease trait in some families and the amount of
amyloid precursor protein in the spinal fluid in some patients with
Alzheimer disease has been found to be elevated. Some other families
have been found to have a disorder localized to other chromosomes
(i.e., 14, 19, and 1). Furthermore, it has been found that the risk for
Alzheimer disease segregates with the gene for isotype 4 of apoprotein
E in white people. In the nonwhite population a similar, but weaker,
association has been found with isotype 2 of apoprotein E. It is possible,
but unproved, that the absence of the normal apoprotein E, isotype 3,
may be related to the development of Alzheimer disease. At the
moment, the mechanism of this association is unknown. The genetic
forms of Alzheimer disease make up a minority of the patients, but may
provide clues to the pathogenesis of AD. However, at the moment these
genetic markers are not tests for Alzheimer disease and should not
be utilized as such.
Tau protein which forms the skeleton of neurofibrillary degeneration has
been noted to be decreased in the spinal fluid of some patients with
Alzhemer disease.
Despite these exciting and important genetic developments, it is
not recommended that patients undergo genetic testing, since
these studies are risk factors (not genetic tests) for Alzheimer
disease and there is presently no good preventive treatment for the
disease.
2. Amyloid. A great deal of evidence has accumulated suggesting that the
amyloid protein, which is deposited in the center of senile plaques and
in cerebral vessels of patients with Alzheimer disease, may be
pathogenetic in some or all cases of Alzheimer disease. The precursor
protein for the amyloid protein is also located on chromosome 21.
Strategies aimed at preventing the accumulation of amyloid protein may
form the rationale of some future treatment.
3. Toxins such as aluminum are not considered likely candidates for the
cause of Alzheimer disease.
4. Prions, which are known to cause some other rare neurodegenerative
diseases (e.g., Gerstmann-Straussler, fatal familial insomnia), have not
been demonstrated to be a cause of Alzheimer disease.
5. Viruses have never been consistently found in the brains of patients
with Alzheimer disease, and the disease has not been transmitted to
other animals.
6. Excitotoxins such as glutamate may have some role in the cell death in
many neurodegenerative diseases including Alzheimer disease.
Glutamate receptor blockers may have some role in future treatment
strategies.
7. Endogenously produced toxins, analogous to
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxic cause of
parkinsonism, have not been demonstrated in the brains of patients with
Alzheimer disease, but the use of deprenyl, a monoamine oxidase
inhibitor (which works to prevent the toxicity of MPTP), may have a
future role in the treatment of Alzheimer disease.
8. Inflammatory cells are found in the brains of patients who have died
with Alzheimer disease and are noted to be particularly numerous in
areas of intense cell death, suggesting that inflammation may play some
role in neuronal death, either primary or secondary. This observation
has lead to trials of antiinflammatory drugs to treat Alzheimer disease.
c. Treatment. There is no specific therapy aimed at reversing or arresting the
underlying pathologic changes of Alzheimer disease. However, several
maneuvers are often useful palliatively.
1. Abulia and inattention
a. Methylphenidate (Ritalin), 10 to 60 mg PO daily, divided into 2 or 3
doses.
b. Dextroamphetamine sulfate (Dexedrine), 10 to 60 mg PO daily,
divided into 2 or 3 doses.
2. Depression
a. Imipramine (Tofranil), 75 to 300 mg PO, once a day at bedtime.
b. Amitriptyline (Elavil), 75 to 300 mg PO, once a day at bedtime.
c. Desipramine (Norpramin), 75 to 300 mg PO, once a day at bedtime.
3. Agitation and confusion
a. Avoid periods of decreased sensory stimulation by keeping the lights
on in the patient's room at night if nighttime confusion and agitation
(sundowning) are a problem.
b. Short-acting benzodiazepines (e.g., lorazepam [Ativan], 1 to 2 mg
PO or IM at bedtime) are often effective in providing behavior control
without the long-term dangers of neuroleptic drugs.
c. Haloperidol (Haldol), 1-6 mg PO daily, divided into 2 or 3 doses.
4. Cholinergic therapy with choline or lecithin in doses up to several
grams per day has been tried in an attempt to treat the underlying
memory disorder. This is based on the observation that cholinergic
neuronal systems may be selectively diminished in the brains of patients
dying with Alzheimer disease. There is some evidence that cholinergic
therapy is capable of improving memory in selected patients with
Alzheimer disease, but this effect is not dramatic.
5. Anticholinesterase therapy is based on the observation that blocking
the enzyme that normally degrades acetylcholine (i.e.,
acetylcholinesterase) may lead to an increase in cortical acetylcholine,
thereby reversing the depletion of acetylcholine that occurs in Alzheimer
disease, presumably due to the degeneration of neurons in the basal
forebrain (i.e., the basal nucleus of Meinert and the diagonal band of
Broca). There are currently two approved anticholinesterase drugs.
a. 1,2,3,4-Tetrahydro-9-acridinamine monohydrochloride monohydrate
(tacrine hydrochloride; Cognex) does have a modest beneficial effect
on the course of Alzheimer disease. The drug is hepatotoxic in a
large number of patients, so liver function tests must be monitored
closely during drug administration. The current recommendation for
administration of tacrine, supplied in 10-, 20-, 30-, and 40-mg tablets,
is 10 mg PO qid for 6 weeks, with monitoring of serum alanine
aminotransferase, or ALT (formerly known as serum
glutamic-pyruvic transaminase, or SGPT), once per week. If ALT
remains equal to or less than 3 times the upper limit of normal, raise
the dosage to 80 mg/day for 6 more weeks. If ALT remains equal to
or less than 3 times the upper limit of normal, raise the dosage to
120 mg/day for 6 more weeks. If ALT remains equal to or less than 3
times the upper limit of normal, raise the dosage to 160 mg/day. If at
any point during the dosage escalation the ALT rises to greater than
3 times but equal to or less than 5 times the upper limit of normal,
then reduce the dosage by 40 mg/day and resume the dosage
titration when the ALT falls to equal or less than 3 times the upper
limit of normal. If at any point during the dosage escalation the
ALT rises to greater than 5 times the upper limit of normal, then
discontinue tacrine treatment immediately. Patients who develop
asymptomatic elevations in the ALT may be rechallenged with
tacrine once the level returns to normal, but patients who develop
clinical jaundice confirmed by a significant elevation in total
bilirubin (more than 3 mg/dL) should permanently discontinue
tacrine and not be rechallenged.
b. Donepezil (Aricept) is a piperidine-based acetylcho-linesterase
inhibitor which may produce modest improvement in some patients
with mild to moderately severe Alzheimer disease. It is available in 5-
and 10-mg tablets. The initial dose is 5 mg at bedtime, which can be
increased to 10 mg/d after 46 weeks of treatment. Nausea, diarrhea
, and vomiting may occur. Insomnia, fatigue, and muscle cramps are
less common. Liver function should be monitored and the drug
discontinued if hepatic toxicity appears.
6. Other therapies
a. Ginko may have a mild beneficial effect on progressive memory
loss, possibly because of a weak anticholinesterase effect.
b. Estrogen replacement therapy in postmenopausal women can
delay or slow the onset of memory loss. The mechanism is unknown.
c. Nonsteroidal antiinflammatory drugs (NSAIDs), particularly those
that readily cross the blood-brain barrier (e.g., indomethacin), may
have a mild beneficial effect on the rate of progression of memory
loss.
2. Progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome)
a. Description. Progressive supranuclear palsy is a degenerative disease in
which there is neurofibrillary and granular degeneration of neurons, chiefly
in the nuclear structures of the reticular formation of the midbrain, pretectal
regions, substantia nigra, globus pallidus, subthalamic nuclei, and dentate
nuclei of the cerebellum. These lesions account for the clinical picture of
progressive hypertonia, supranuclear ocular palsies (particularly conjugate
downward gaze), and disturbances of wakefulness. The dementia found in
progressive supranuclear palsy tends to be characterized by slowness and
abulia (the so-called subcortical dementia) rather than the multiple cognitive
deficits as seen in Alzheimer disease.
b. Treatment. There is no specific treatment for the dementia or the
movement disorder. Idazoxan, a selective a
2
-presynaptic inhibitor, has been
shown to have a modest beneficial effect on some aspects of motor
function in this disease, but the drug is not currently available in the United
States. Palliative measures as outlined in sec. III.A.1.c may be useful.
3. Parkinson disease
a. Description
1. The triad of tremor, rigidity, and akinesia that characterizes Parkinson
disease is discussed in detail in Chap. 15.
2. There is an increased incidence of dementia in parkinsonian patients.
This is sometimes difficult to recognize for 2 reasons:
a. These patients are often extremely difficult to test because their
movement disorder may be so severe as to interfere with their ability
to respond appropriately in the test situation.
b. Alzheimer disease is common in the age group affected by
Parkinson disease, so undoubtedly some of the dementia seen in
parkinsonian patients is due only to the coexistence of these 2
relatively common conditions.
3. It is generally agreed, however, that Parkinson disease itself is a
dementing illness. Some patients develop a dementia similar to that
seen in Alzheimer disease, whereas others show a more subcortical
picture, as described under progressive supranuclear palsy (see sec.
III.A.2).
There is a disorder seen in the Marianas Islands, known as Parkinson
dementia complex, in which dementia is regularly seen with Parkinson
disease. Many patients with this disease develop a motor neuron
disease that is clinically indistinguishable from amyotrophic lateral
sclerosis. The pathology of both conditions is characterized by
prominent neurofibrillary and granulovacuolar neuronal degeneration
and suggests that these syndromes may be linked by a common
pathophysiology.
b. Treatment. The treatment for the movement disorder of Parkinson disease
is discussed in Chap. 15. There is no specific therapy for the dementia, and
it is unlikely to respond to standard antiparkinsonian drug therapy. Palliative
measures as noted in sec. 3.A.1.C may be useful.
4. Huntington disease (Huntington chorea)
a. Description. Huntington disease is an autosomal dominantly inherited
disorder with variable expressivity. Pathologically, it is characterized by
degeneration of the basal ganglia (particularly the neostriatum) and
cerebral cortex. Clinically, it is characterized by progressive movement
disorder and dementia. The treatment of the movement disorder is
discussed in Chap. 15. The onset of the dementia often precedes the
movement disorder, but dementia may masquerade for many years as an
apparent psychiatric disorder characterized by immaturity, impulsivity, and
sometimes depression. As it progresses, it takes on a frontal lobe
character, with apathy and emotional lability; it finally becomes global,
affecting all cognitive functions.
b. Treatment
1. Presymptomatic diagnosis. The mutation responsible for Huntington
disease consists of an expanded segment of the gene due to insertion
of trinucleotide repeat sequences (CAG) at 4p16.3. This disease is 1
example of an unstable DNA segment that is responsible for a
neurologic disease; other examples include myotonic dystrophy, fragile
X syndrome, Kennedy syndrome (X-linked spinal-bulbar atrophy), and
spinocerebellar atrophy (SCA) types 1 and 2. This has led to
presymptomatic and even prenatal diagnosis of Huntington disease.
Furthermore, understanding the nature of the gene defect could lead to
rational therapies for the disease.
The diagnosis of presymptomatic (including prenatal) Huntington
disease can be made using direct DNA analysis with accuracy as high
as 99%. Despite the high degree of accuracy, testing should only
be performed after detailed counseling has been provided the
family, and long-term follow-up must also be available.
2. Medical treatment. No medical treatment has been proved effective for
the dementia of Huntington disease, but a few treatment modalities may
be of benefit.
a. Antidopamine therapy with haloperidol (see Chap. 15 for details).
b. Anticholinesterase therapy with tacrine or donepezil may be tried.
B. Multiinfarct (vasular) dementia and Binswanger disease
1. Description. The syndrome of multiple strokes is a cause of dementia. The
precise clinical picture depends on the locations of the infarctions or
hemorrhages.
a. When multiple lacunar infarctions have occurred in the basal ganglia,
internal capsule, and pons, a lacunar state (tat lacunaire) may develop
that is characterized by rigidity, hyperreflexia, pseudobulbar palsy, and
dementia. The dementia in this condition is primarily a subcortical type, with
prominent abulia and apathy.
b. Dementia due to multiple strokes often may be distinguished from a
degenerative disease on the basis of its history, which may show a
stepwise development of symptoms rather than the insidious, smoothly
progressing course of a degenerative disease. Furthermore, multi-infarct
dementia tends to be characterized more by inattention (i.e., chronic
confusion) rather than the amnestic, aphasic, and apraxic syndrome that is
more commonly seen in Alzheimer disease.
c. The presence of hypertension in a patient with a progressive dementing
illness and signs of bilateral pyramidal tract disease, including
pseudobulbar palsy, may suggest the lacunar state, although bilateral
cerebral infarctions or hemorrhages could present a similar clinical picture.
CT scanning or MRI often will reveal cerebral infarctions or hemorrhages
but are less likely to show small lacunar infarctions, either supratentorially
or infratentorially. These small infarctions must be suspected on clinical
grounds alone.
In some hypertensive patients, a similar clinical state is seen in which there
are very few or no discrete infarctions, but rather a diffuse loss of white
matter in the centrum semiovale sometimes called leukoariosis. This is
thought to be due to chronic ischemia in the distribution of cerebral
arterioles due to the hypertensive cerebrovascular disease arteriolar
sclerosis; it is known as Binswanger subcortical leukoencephalopathy.
d. The loss of tensile strength of the ventricular walls caused by multiple deep
infarctions combined with the effects of systemic hypertension transmitted
through the ventricular fluid may produce an association between
multi-infarct dementia and occult hydrocephalus. If this occurs, treatment of
the hydrocephalus may be indicated (see sec. III.C.4).
2. Treatment. There is no specific treatment for the dementia of multiple strokes
once it has developed, but it may be possible to influence the development or
progression of this illness by treating the risk factors for stroke, particularly
hypertension and sources of emboli (see Chap. 10). Palliative treatment as
outlined in sec. III.A.1.c may be useful. The treatment of occult hydrocephalus
may occasionally be valuable, as noted in sec. III.C.4.
C. Chronic hydrocephalus
1. Terminology. Chronic hydrocephalus may produce dementia or mental
retardation. The syndrome of acute hydrocephalus is a neurologic emergency
and does not manifest itself as a dementia (see Chap. 11). The terminology of
chronic hydrocephalus is summarized as follows:
a. Nonobstructive (ex vacuo)
1. Alzheimer disease.
2. Pick disease.
3. Multiple cerebral infarctions.
4. Huntington disease.
b. Obstructive
1. Communicating (normal pressure, low pressure, tension)
a. Postsubarachnoid hemorrhage.
b. Postmeningitis.
c. Idiopathic.
2. Noncommunicating (internal)
a. Aqueductal stenosis.
b. Masses compressing the fourth ventricle (e.g., cerebellar tumors).
c. Malformations at the foramen magnum (e.g., Arnold-Chiari and
Dandy-Walker malformations).
2. Description
a. Nonobstructive, or ex vacuo, hydrocephalus is due to degeneration or
destruction of cerebral tissue with secondary increase in ventricular size.
b. Obstructive hydrocephalus is divided clinically according to the site of
cerebrospinal fluid (CSF) blockage: If the blockage is within the ventricular
system, the term noncommunicating hydrocephalus applies; if the blockage
is outside the ventricular system, the term communicating hydrocephalus is
appropriate. It should be emphasized that in cases of obstructive
hydrocephalus that present as dementia the blockage is never complete,
since a total block of CSF flow would result in acute hydrocephalus,
massively increased intracranial pressure, and death within a few hours
(see Chap. 11).
1. In children, a common site of obstruction is within the ventricular
system (noncommunicating hydrocephalus), due either to aqueductal
stenosis or to incomplete development of the foramina of Magendie and
Luschka. This type of abnormality, often only one manifestation of a
generalized maldevelopment of the nervous system, is associated with
such abnormalities as microgyria, macrogyria, porencephaly, agenesis
of the corpus callosum, fusion of the cerebral hemispheres, agenesis of
the cerebellar vermis, spina bifida, meningocele, encephalocele,
syringomyelia, hydromyelia, and the Arnold-Chiari malformation.
Children may also develop communicating hydrocephalus due to
adhesions in the subarachnoid space at the base of the brain. These
adhesions can be produced by perinatal subarachnoid or intraventricular
hemorrhages.
2. In adults, chronic hydrocephalus is usually communicating, with the
block in the subarachnoid space. Rarely, noncommunicating
hydrocephalus due to aqueductal stenosis is seen in adults.
3. Diagnosis. The diagnosis of hydrocephalus is suspected in children whose
head circumference enlarges too rapidly and in adults who have a subcortical
type of dementia (prominent abulia, incontinence, and gait disturbance with the
intellectual deterioration) of unclear etiology. It should be remembered that
ventricular dilatation precedes an increase in head growth. A history of
intracranial hemorrhage or meningitis further raises the suspicion of chronic
hydrocephalus. Although a CT scan will reliably and safely reveal the presence
of hydrocephalus, MRI provides better anatomic detail and, while not
necessarily recommended as the initial or screening study, should eventually
be performed in all patients with hydrocephalus. Although the pattern of
ventricular enlargement on CT or MRI gives clues to the site of blockage, a
CSF flow study with radioactive indium may be required in determining the
exact site of the obstruction (if this information is deemed necessary). Cranial
ultrasound will reliably demonstrate ventricular enlargement, provided that the
anterior fontanel is open.
4. Treatment
a. Surgery
1. Rationale. Theoretically, chronic hydrocephalus may be relieved by the
shunting of CSF around the blockage. This will lower the pressure in
the ventricular system proximal to the block and thereby prevent further
damage to brain tissue. However, shunting should be done before
excessive irreversible loss of brain tissue has taken place. This can
be done easily in children before the sutures and fontanels have closed,
since the diagnosis of hydrocephalus can be made relatively early in the
course of the illness because of excessive head growth, which is readily
apparent and often precedes decompensation due to increased
intracranial pressure. However, many, if not all, patients will have
significant ventricular dilatation prior to excessive increase in head
circumference. Once the sutures have closed irreversibly, head
measurements are of no value in the diagnosis of hydrocephalus.
2. When to shunt. It is not known how long a period can elapse prior to
shunting before irreversible damage has occurred, but it appears that
the likelihood of obtaining a good result from shunting is inversely
proportional to the time from the onset of symptoms to the time of
diagnosis. No specific time limit can be set beyond which surgery can
be said to be of no benefit, but most studies in adults have shown much
better results in patients who have had symptoms for less than 6
months. However, it should be emphasized that many patients with
longer term illness have improved with shunting. Candidates for
shunting should undergo a lumbar puncture with lowering of CSF
pressure to below 100 mm H
2
O. If gait improves with this procedure,
shunting is more likely to confer a long-term benefit.
In children, the width of the cortical mantle does not necessarily
correlate with the ultimate intellectual outcome, so all should be
evaluated for shunting. However, in some early mild cases in children
(usually a communicating hydrocephalus with a known etiology, such as
intraventricular hemorrhage or postmeningitis), the patient may be
observed carefully, with frequent serial head measurements, ultrasound,
and CT scans or MRI, in the hope that the process will arrest
spontaneously and thereby render a shunting procedure unnecessary.
3. Cortical atrophy
a. Since Alzheimer disease is a common cause of dementia in adults,
one should always be sure to rule out cerebral atrophy
(hydrocephalus ex vacuo) as either the sole or partial cause of the
dementia because this aspect of the hydrocephalus will not respond
to shunting procedures, as there is no obstruction to CSF flow.
b. A radionuclide CSF flow study should show persistent activity in the
lateral ventricles and no activity over the cerebral convexities in pure
communicating hydrocephalus. Some activity seen over the
convexities, even as late as 72 hours after injection, suggests a
mixed (i.e., ex vacuo plus obstructive) form of hydrocephalus, which
is less likely to respond to surgery.
c. When a significant degree of cerebral atrophy is demonstrated
by CT scan or MRI, even if there is a component of obstructive
hydrocephalus, shunting procedures are unlikely to show good
results.
4. Indications for shunting. Patients who should have shunting
procedures include:
a. Children in whom the diagnosis of chronic progressive
hydrocephalus has been made and in whom the likelihood of
spontaneous arrest has been ruled out.
b. Adults who have a relatively recent onset of dementia; who show a
purely obstructive hydrocephalus by CT scan, MRI, or CSF flow
studies; and who respond to lowering CSF pressure by lumbar
puncture.
5. Procedures. Many shunting operations are available, but the one that is
most commonly employed is the ventriculoperitoneal shunt.
6. Complications of shunting. Even in the ideal case, with good initial
response to shunting, one must remain vigilant for complications of the
shunt. These include:
a. Infection. If the shunt becomes infected, it must be removed and the
infection treated as outlined in Chap. 8.
b. Mechanical malfunction.
c. Movement of the cannula and consequent inadequate draining of the
ventricles.
d. Emboli and endocarditis (with ventriculoatrial shunts).
e. Ascites, peritonitis, and ruptured viscus (with ventriculoperitoneal
shunts).
f. Subdural hematoma.
7. Any deterioration in mental functioning is an indication for reevaluation
of ventricular size, preferably by CT scanning.
b. Medical treatment of chronic obstructive hydrocephalus is relatively
ineffective and should be used only when surgery is not possible.
Occasionally, in children in whom the diagnosis of mild hydrocephalus has
been made, medical therapy may be used pending a decision about
surgery. The rationale for medical management of chronic obstructive
hydrocephalus is based on the observation that acetazolamide (Diamox)
may decrease the rate of CSF production by the choroid plexus. The
dosage of acetazolamide is 10 to 25 mg/kg/day PO divided into 3 doses in
children and 250 mg PO tid in adults. Serial lumbar punctures and
intermittent ventricular drainage may be used as a means of postponing a
shunt procedure in premature infants unable to tolerate the operation.
D. Spongiform encephalopathies
1. These rare diseases, which include kuru, fatal familial insomnia, bovine
encephalopathy (mad cow disease), and J akob-Creutzfeldt disease, are
characterized by diffuse cerebral, basal ganglion, and spinal cord neuronal
degeneration; glial proliferation; and spongy appearance of the cortex. They
are characterized by a rapidly progressive, subacute dementia similar to that of
Alzheimer disease but usually accompanied by striking myoclonus and
sometimes by cerebellar signs, rigidity, and weakness (see also Chap. 8).
There is usually an associated characteristic EEG pattern consisting of
high-voltage, periodic sharp activity superimposed on a slow background.
2. Treatment. There is no specific therapy for the disease itself. Palliative
measures as noted in sec. III.A.1.c are sometimes useful. In addition, the
myoclonus may respond to the use of benzodiazepine derivatives such as one
of the following:
a. Clonazepam (Klonopin), 1.5 to 2.0 mg PO daily, divided into 3 doses.
b. Diazepam (Valium), 15 to 30 mg PO daily, divided into 3 doses.
E. Viral encephalitides (see also Chap. 8)
1. Description. Many of the viral encephalitides may result in dementia due to
destruction of the cerebral cortex. Any of these diseases may be incriminated:
arbovirus infections (eastern, western, St. Louis, Venezuelan, and California
equine encephalitides), herpes simplex encephalitis, subacute sclerosing
panencephalitis, and human immunodeficiency virus (HIV). The critical factor in
the development of dementia is presumably the amount of brain destroyed by
the infection. However, the encephalitis itself may be inapparent, only
presenting with the late onset of dementia. This is particularly true of HIV and
herpes simplex encephalitis. In some patients, only memory loss is seen, but in
many others there is widespread higher cortical dysfunction.
2. Treatment. There is no specific treatment for the viral encephalitides, with the
exception of herpes simplex encephalitis (see Chap. 8). If dementia develops,
the palliative maneuvers noted in sec. III.A.1.c may be beneficial.
F. Neurosyphilis (see also Chap. 8)
1. Description. In the late stages of neurosyphilis in adults, one may see the
syndrome of dementia paralytica, or general paresis of the insane. The mental
changes take many forms, including frank psychosis, memory deficit,
impairment of judgment, excessive liability of mood, and others. Usually,
patients who have congenital paretic syphilis have been known to be defective
physically and mentally from birth. Between the ages of 6 and 21 years, the
affected child often begins to function less well in school and has associated
irritability and inattention. Psychometric tests show a decrease in IQ.
Neurologic examination may or may not be abnormal but often shows pupillary
abnormalities, choreiform movements, incoordination, spasticity, optic atrophy,
or deafness.
2. Treatment. The treatment of neurosyphilis is outlined in Chap. 8. The
dementia often does not respond well to treatment, although the further
progression of dementia is arrested in most treated patients. About one third of
adult patients have complete remission of symptoms, and another 25% show a
partial improvement. The degree of improvement depends on the stage of the
disease at which it is treated. Children with congenital syphilis have an even
poorer prognosis for recovery of normal function than do adults.
G. Posttraumatic encephalopathies
1. Description. Some patients who suffer head trauma fail to recover their full
premorbid mental capacities. This is more common in patients who lose
consciousness, particularly as a result of massive head trauma, than in trivial
head injuries, but it may be seen in either situation. Older patients are more
likely than younger ones to develop this posttraumatic dementia. If the patient
appears to recover completely from the head trauma and subsequently begins
to show a dementing illness, one must suspect development of either a
communicating hydrocephalus, precipitated by blood in the subarachnoid
space, or chronic subdural hematoma. Both of these conditions may require
neurosurgical treatment. If the patient never fully regains normal mentation,
various components of the so-called posttraumatic or postconcussion
syndrome also may be seen, including headache, dizziness, insomnia,
irritability, inability to concentrate, and personality changes. It is not known
whether these symptoms are directly related to brain damage or are
psychological in origin. Many of these symptoms resemble those of
depression, and their resolution is often delayed when litigation is pending.
2. Treatment
a. Insomnia, irritability, restlessness, personality change, loss of ability
to concentrate
1. Imipramine (Tofranil), 75 to 150 mg PO daily.
2. Amitriptyline (Elavil), 75 to 150 mg PO daily.
3. Desipramine (Norpramin), 75 to 150 mg PO daily.
b. Headache
1. Aspirin, 600 mg PO q4h or as needed for pain.
2. Polycyclic antidepressants as in Chap. 9 may also be useful if aspirin is
not effective.
c. Dementia. No specific therapy is available aside from those measures
listed above. Reassurance is important because most patients show steady
improvement even though recovery may take several years. In a minority of
patients (usually elderly patients who have survived massive head trauma),
severe permanent intellectual dysfunction may require institutionalization
and treatment as outlined in sec. III.A.1.c.
H. Congenital and early-acquired disorders
1. Definitions and classification. Disorders resulting in intellectual dysfunction
that originate prenatally or during infancy or childhood may result in mental
retardation or dementia. Differential diagnosis, diagnostic studies, and outcome
will depend on this basic distinction, which is of primary importance. A useful
method of classification is based on the time at which the illness is determined.
a. Prenatally determined
1. Chromosomal abnormalities.
2. Hereditary syndromes with multiple anomalies, but without identifiable
chromosomal abnormalities.
3. Multifactorial inheritance (polygenic and environmental factors).
4. Major malformations of uncertain etiology.
5. Congenital infections.
6. Maternal and environmental factors.
7. Metabolic and degenerative disorders.
a. Amino acid abnormalities.
b. Lysosomal storage diseases.
c. Mitochondrial diseases (e.g., Leigh disease due to cytochrome
oxidase deficiency).
d. Peroxisomal diseases (e.g., adrenoleukodystrophy).
b. Perinatally determined
1. Complications of prematurity.
2. Hypoxic-ischemic encephalopathy (uncommon in the full-term infant).
3. Infections.
4. Metabolic abnormalities.
c. Postnatally determined
1. Infections.
2. Trauma.
3. Hypoxic-ischemic insults.
4. Toxic-metabolic disorders.
5. Neoplasms.
2. Clinical and laboratory approach
a. An appropriately detailed history and physical examination will usually allow
the clinician to place the patient within one of the above categories; at
times, a specific diagnosis may be made.
b. If further diagnostic study is needed, as is often the case, biochemical,
radiologic, electrophysiologic, and genetic studies should be obtained as
indicated by the history and physical examination. A battery of routine
studies is rarely, if ever, warranted in the child with unexplained intellectual
dysfunction. Exceptions include thyroid and amino acid studies because
one may be dealing with a rare, but treatable, condition.
3. Causes of mental retardation
a. Chromosomal abnormalities. Identifiable chromosomal abnormalities may
often be diagnosed on clinical grounds alone and include trisomies 13, 18,
and 21; Klinefelter syndrome; and other less common disorders.
Chromosome studies are indicated if these disorders are suspected and
also in patients with unexplained mental retardation.
Fragile X syndrome is a common identifiable cause of mental retardation,
with a prevalence rate of 1 in 1,250 males and 1 in 2,500 females. The
clinical diagnosis of fragile X syndrome is often not made because the
phenotype varies in relation to puberty and includes a wide variety of
nonspecific findings. The classic features of large ears, a long face,
prominent jaw, and large testes are usually not present until after puberty.
Behavioral and developmental syndromes, including hyperactivity and
autism, are often earlier manifestations. Direct DNA testing is now available
that will demonstrate the genetic abnormality in the majority of affected
individuals and carriers. The abnormality consists of an expanded segment
of the FMR-1 gene, in band Xq27.3, due to insertion of trinucleotide repeat
sequences (CGG). The syndrome becomes clinically manifest when the
gene is expanded to contain at least 200 trinucleotide repeat sequences.
Direct DNA testing is the preferred method over the previously available
cytogenetic test that can demonstrate the fragile X site. If the direct DNA
test does not demonstrate the abnormality and the diagnosis remains
suspect, cytogenetic analysis should then be performed. Because findings
are nonspecific, fragile X testing is recommended in all boys in whom
mental retardation is unexplained, even in the absence of classic
dysmorphic features. While X-linked, the syndrome is dominantly inherited
and can be seen in females. Testing, therefore, should be considered in
girls with unexplained mental retardation.
b. Multiple anomalies. Hereditary syndromes with multiple anomalies but
without identifiable chromosomal abnormalities are varied, and individual
description is beyond the scope of this text. These disorders may be
classified according to associated defects; several atlases are available that
may aid in establishing a diagnosis (see Smith in Selected Readings).
c. Multifactorially determined conditions. Conditions caused by
multifactorial inheritances are found in a large percentage of mildly retarded
persons and are heavily represented within socially disadvantaged groups.
The inheritance of multiple genes from both parents is compounded by
substandard environmental factors that further impair learning. Usually no
specific abnormalities are found in these individuals.
d. Isolated malformations. Other isolated major malformations of diverse
etiologies include primary and secondary microcephaly and various
anomalies associated with hydrocephalus. Radiographic studies, including
MRI and CT, may be indicated for defining the exact nature and extent of
the anomaly.
e. Amino acid disorders and related conditions (organic acid and urea cycle
disorders) are a complex group of diseases that are difficult to distinguish
from each other and from other degenerative diseases of the nervous
system. After a variable period of normal development (at times extremely
short, as in maple syrup urine disease), signs of diffuse involvement of the
nervous system may become manifest; such signs include delay or
deterioration in intellectual or motor development, lethargy (at times
proceeding to coma), seizures, ataxia, and alterations of muscle tone.
Several disorders may be associated with fairly consistent physical features
and unusual odors, such as light pigmentation and eczema in
phenylketonuria and the characteristic smell of the urine in maple syrup
urine disease. Early diagnosis is essential, since several of these disorders
are treatable by exclusion or addition of dietary substances (Table 3-1).
Blood and urine amino acid and organic acid analyses are essential for the
diagnosis.
TABLE 3-1. Metabolic Diseases Associated with Mental Retardation That
Might be Treatable by Dietary Restriction or Supplementation
f. Lysosomal storage diseases. The lysosomal storage disorders are a
group of genetic diseases in which storage of certain metabolites occurs
within lysosomes, due to a specific enzyme deficiency. Table 3-2 lists
lysosomal storage diseases with known enzyme deficiencies and the major
accumulating metabolites. Disorders that primarily involve gray matter (e.g.,
ganglioside storage diseases) result in dementia and seizures early in their
course. As a rule, ataxia and spasticity appear early in the course of
primary white matter degenerative disease, with seizures and dementia
appearing later.
TABLE 3-2. Lysosomal Storage Diseases
g. Mitochondrial diseases. Involvement of brain, spinal cord, muscle,
peripheral nerve, and other organs can occur in a variety of mitochondrial
diseases with or without known enzyme deficiency.
1. Cytochrome C oxidase and pyruvate dehydrogenase deficiency, for
example, are causes of Leigh disease. Age of onset is usually within
the first 2 years of life; signs and symptoms include developmental
delay, failure to thrive, hypotonia, weakness, ataxia, ophthalmoplegia,
and irregular respirations. Characteristic signal abnormality may be
seen on MRI within basal ganglia and brainstem nuclei. Levels of lactate
and pyruvate are usually elevated in blood and CSF.
2. The MERRF syndrome (myoclonic epilepsy with ragged red fibers) is
associated with a point mutation in mitochondrial DNA at nucleotide pair
8,344. Clinical and laboratory features include myoclonus, ataxia,
weakness, dementia, short stature, hearing loss, and lactic acidosis,
and ragged red fibers seen on muscle biopsy.
3. The MELAS syndrome (mitochondrial encephalomyopathy, lactic
acidosis, and strokelike episodes) is associated with a point mutation at
position 3,243 of mitochondrial DNA. Features include short stature,
seizures, recurrent vomiting, recurrent headaches, recurrent strokelike
episodes, dementia, lactic acidosis, and ragged red fibers in muscle.
4. Dementia is a feature of Kearns-Sayre syndrome, along with
progressive external ophthalmoplegia, ataxia, weakness, retinal
degeneration, heart block, lactic acidosis, elevated CSF protein, and
ragged red fibers, due to a deletion of mitochondrial DNA.
5. Alper disease, characterized by early onset of seizures, dementia,
spasticity, blindness, and liver dysfunction, has been shown to be due to
deficiency of complex I of the respiratory chain. Complex I deficiency
has been associated with other mitochondrial disorders discussed in this
section, so that it appears to be nonspecific.
h. Peroxisomal diseases
1. Disorders of peroxisomal biogenesis with deficiency of multiple
peroxisomal enzymes. Included in this category are Zellweger
syndrome with characteristic dysmorphic features and absence of
peroxisomes in various tissues; neonatal adrenoleukodystrophy,
inherited in an autosomal recessive manner and associated with
accumulation of very long chain fatty acids; and infantile Refsum
disease, with elevated plasma phytanic acid levels and hyperpipecolic
acidemia that resembles Zellweger syndrome.
2. Disorders with deficiency of a single peroxisomal enzyme. X-linked
adrenoleukodystrophy usually becomes manifest in childhood, but
sometimes not until adolescence or adulthood. It is characterized by
changes in behavior and personality followed by progressive neurologic
deterioration and signs of adrenal insufficiency. Evidence of white
matter disease is seen on CT or MRI, and there is accumulation of very
long chain fatty acids in various tissues, usually measured in plasma.
i. Congenital infections. Patients with mental retardation due to the
recognizable congenital infections (e.g., herpesvirus, rubella,
toxoplasmosis, cytomegalovirus) usually have additional abnormalities;
these include intrauterine growth retardation, neonatal jaundice, petechiae,
hepatosplenomegaly, microcephaly or hydrocephalus, and intracranial
calcifications. Patients with the congenital rubella syndrome frequently have
cataracts and congenital heart lesions. Valuable laboratory studies during
the neonatal period include attempted viral isolation in urine and total and
specific IgM antibody determinations if available (if not, serial IgG titers
must be obtained to differentiate passive transfer from active antibody
production by the infant).
j. Prenatal insults. Prenatal maternal and environmental factors associated
with mental retardation include chronic placental insufficiency, toxemia,
diabetes, malnutrition, alcoholism, ingestion of certain drugs, and exposure
to radiation.
k. Perinatal insults to the developing brain may occur during labor, delivery,
or the first several days of life. These may include hypoxic-ischemic injuries
(often accompanied by intraventricular [periventricular] and/or subarachnoid
hemorrhages), trauma, infections, and toxic-metabolic disturbances. All
perinatal injuries, with the possible exception of mechanical trauma, are
more commonly seen in premature infants.
1. Periventricular (germinal matrix) hemorrhage with intraventricular
and subarachnoid extension is essentially a disease of the premature
infant. This is a common disorder that can be documented by CT or
ultrasonic scan in 40% to 50% of premature infants weighing less than
1,500 g, many of whom are apparently asymptomatic. Many infants with
large hemorrhages die or are left with serious sequelae. The majority of
infants with smaller hemorrhages survive, and although many develop
normally, hydrocephalus and nonprogressive intellectual and motor
deficits may result. Spastic diplegia with normal intelligence is a
common finding in these infants.
2. Subarachnoid hemorrhage is also associated with hypoxic insults, and
although it is more common in premature infants, it occurs with
significant frequency in full-term neonates as well. The immediate and
long-term outlooks are variable.
3. Acute subdural hemorrhage is uncommon in newborns but does
occur in full-term infants, often following traumatic instrument-assisted
deliveries. Subdural tap is indicated if this disorder is suspected.
4. Other important causes of permanent neurologic disability with onset
during the perinatal period include meningitis, symptomatic
hypoglycemia, and kernicterus.
l. Inherited metabolic diseases without enzyme deficiencies. A large
number of inherited nervous system diseases occur for which no specific
enzyme deficiency is yet known.
1. Neuronal ceroid lipofuscinoses (also known as Batten disease) are
characterized by accumulation in neurons of autofluorescent
lipopigment with consequent intellectual failure, seizures, extrapyramidal
syndromes, and blindness. These disorders are subtyped by age of
onset into infantile (Haltia-Santavuori), late-infantile
(Bielschowsky-J ansky), juvenile (Spielmeyer-Vogt), and adult (Kuf)
disease. The diagnosis is suspected clinically. Urinary dolichol levels
may be elevated; characteristic intracellular inclusions are seen on skin
biopsy.
2. Hereditary ataxias include diseases allied clinically to Friedreich ataxia.
m. Postnatal factors in mental retardation include head trauma, CNS
infections, hypoxic-ischemic insults, CNS neoplasms, and toxic-metabolic
disturbances.
n. Cerebral palsy. Chronic, nonprogressive motor disability, often associated
with seizures and mental retardation, is commonly referred to as cerebral
palsy. This group of disorders may be classified by their neurologic signs
into spastic, choreoathetotic, ataxic, and mixed varieties. Motor findings
may evolve and not become manifest until the second year of life, making
differentiation from a progressive neurologic disorder extremely difficult.
With regard to etiology, prematurity and its complications are important
factors. In the child born at term, cerebral palsy is usually prenatally
determined, and perinatal events are usually not of primary importance.
Before concluding that perinatal asphyxia is causally related to cerebral
palsy, there should be evidence of severe and prolonged intrapartum
asphyxia, moderate to severe hypoxic-ischemic encephalopathy during the
immediate perinatal period, evidence of injury to multiple organs, and
exclusion of other conditions that could also explain the clinical syndrome.
I. Demyelinating diseases
1. Description. Demyelinating diseases, of which the most common is multiple
sclerosis, are discussed in detail in Chap. 13. When the disease becomes
advanced, multiple lesions in the subcortical white matter may produce
personality change, inappropriate emotional reactions, and intellectual
deterioration. It is exceedingly rare, however, for multiple sclerosis to manifest
itself as a dementia with no other associated abnormalities. Schilder disease
may be considered a variant of multiple sclerosis; this disease, with prominent
involvement of cerebral white matter, occurs in children who may prove to have
adrenoleukodystrophy.
Progressive multifocal leukoencephalopathy (PML),
adrenoleukodystrophy, Krabbe disease, metachromatic leukodystrophy,
Alexander disease, Canavan disease, and Pelizaeus-Merzbacher disease
are relatively rare diseases of myelin, all of which may include dementia as a
prominent feature. PML is usually associated with an immunocompromised
state, most often lymphoma or acquired immune deficiency syndrome (AIDS).
2. Treatment is outlined in Chap. 13. A dramatic reversal of the dementia in
advanced demyelinating disease is unusual.
J . Intracranial space-occupying lesions
1. Description. Masses within the cranial cavity may produce dementia by
directly destroying or compressing the brain, by producing increased
intracranial pressure, or by producing hydrocephalus. Intracranial masses are
found in some patients with dementia. Any mass within the cranial cavity may
produce dementia, but the most common masses are primary brain tumors,
brain abscesses, and chronic subdural hematomas. The specific clinical picture
of each of these conditions is covered elsewhere in this book, but all should be
diagnosable by using the combination of history, physical examination, and
neuroimaging.
2. Treatment varies according to the underlying condition. However, in general,
improvement of the dementia depends on surgical removal of the mass.
IV. Systemic diseases with cerebral pathology
A. Nutritional diseases
1. Pellagra
a. Description. Pellagra is caused by nicotinamide (niacin) deficiency,
although, as in most B vitamin deficiency states, it is usually accompanied
by signs of other B vitamin deficiency diseases. It is seen in association
with chronic alcoholism, dietary peculiarities, hyperthyroidism, pregnancy,
and the stress of injury or surgical procedure. In the advanced state, it is
characterized by the classic three D'sdermatitis, diarrhea, and
dementia. Its earliest symptoms are often referable to the nervous system
and include irritability, insomnia, weakness, memory loss, and
paresthesias. Some patients may show a true dementia, but most show a
confusional state. Irreversible intellectual deterioration may occur in
untreated patients.
b. Treatment consists of nicotinamide (niacin), 500 mg PO daily for 7 to 10
days and then 50 to 100 mg PO daily until symptoms have ameliorated.
The minimum daily requirement to prevent disease is 5 to 10 mg,
depending on the patient's age.
2. Wernicke-Korsakoff syndrome
a. Description. Thiamine (vitamin B
1
) deficiency, usually caused by chronic
alcoholism but also occasionally by starvation states, may produce two
syndromes that are often seen together.
1. Wernicke encephalopathy is an acute, life-threatening disease,
covered in detail in Chap. 14.
2. Korsakoff psychosis may be caused by many disorders, including
encephalitis, posterior cerebral artery strokes, and head trauma, but it is
often the result of chronic or recurrent thiamine deficiency in alcoholics.
It is characterized by poor memory, disorientation, and tendency to
confabulate.
b. Treatment. The Wernicke-Korsakoff syndrome is treated with thiamine (see
Chap. 14 for details). However, once severe Korsakoff psychosis is well
established, a dramatic response to thiamine therapy is not to be expected.
3. Vitamin B
12
deficiency
a. Description. The neurologic implications of vitamin B
12
deficiency are
complex and are covered in more detail in Chap. 14. Rarely, vitamin B
12

deficiency may produce a subcortical type of dementia before it produces
any hematologic or spinal cord abnormalities. For this reason, all patients
being evaluated for dementia should have a serum vitamin B
12

determination as part of the initial laboratory work. If the vitamin B
12
is
within the normal range, but the diagnosis is strongly suspected, one
should measure serum methylmalonic acid and homocysteine, elevations of
which reflect intracellular cobalamin (vitamin B
12
) dysfunction.
b. Treatment. Vitamin B
12
, 1000 g IM daily for 5 days; then 1,000 g IM
monthly.
B. Chronic metabolic insults
1. Description. The major syndromes of chronic metabolic insults that may lead
to intellectual dysfunction include hypoglycemia, hypoxia, uremia, and hepatic
failure. The acute neurologic syndromes associated with these abnormalities
are described in Chap. 14. The degree of chronic intellectual loss is related to
the degree of cerebral damage induced by the metabolic insult. Once
metabolic derangement has been corrected, the patient may be left with a
permanent intellectual deficit.
a. Hypoglycemia and hypoxemia. A history of repeated episodes of
transient neurologic deficits, often with seizures, suggests recurrent attacks
of hypoglycemia or hypoxemia. Hypoglycemia is most often seen in
insulin-dependent diabetics or occasionally in patients on oral hypoglycemic
agents, whereas hypoxemia may be due to a number of conditions
including ischemic anoxia (e.g., cardiac arrest), anischemic anoxia (e.g.,
pulmonary insufficiency, carbon monoxide poisoning), or cytotoxic anoxia
(e.g., cyanide poisoning). In the chronic state, hypoxemic and hypoglycemic
encephalopathy are difficult to distinguish from one another, since both
consist of varying degrees of focal neurologic deficits (e.g., hemipareses,
aphasias, apraxias, hemianopsias, and dementia.)
In a significant proportion of patients who have undergone surgery requiring
extracorporeal circulation, there is a residual, nonprogressive disorder of
intellectual function characterized by poor memory, inability to concentrate,
and change in mood, with an affect reminiscent of depression. This is
probably due to widespread, multifocal hypoxic cerebral damage related in
some way to the cardiopulmonary bypass process.
b. Uremia and hepatic failure. The neurologic impairments in uremia and
liver failure are similar, consisting of various mixtures of confusion,
irritability, convulsions, tremor, asterixis, myoclonus, and peripheral
neuropathy. In rare patients on chronic hemodialysis, a progressive
dementia (dialysis dementia or dialysis encephalopathy) may develop,
characterized by progressive dysarthria, myoclonus, and dementia. The
EEG may show periodic sharp activity. The EEG abnormality and dysarthria
may initially respond to intravenous diazepam, but there is no proven
long-term treatment.
2. Treatment. There is no effective treatment for the dementia of any of these
metabolic abnormalities once it is established. The acute confusional state may
be treated by administering the appropriate agent (e.g., glucose, oxygen) or
treating the underlying condition (e.g., renal failure, hepatic failure) as outlined
in Chap. 14. The aim is to prevent recurrent or prolonged periods of metabolic
insult and thus prevent the development or progression of intellectual
dysfunction.
C. Endocrine disorders
1. Hypothyroidism
a. Description. Hypothyroidism can occur at any age and can be either
primary (thyroid failure), secondary (anterior pituitary failure), or tertiary
(hypothalmic failure). Congenital hypothyroidism ranges from mild to
severe. The fully developed syndrome is known as cretinism. Secondary
hypothyroidism can occur at any age due to thyroid-stimulating hormone
(TSH) deficiency as a result of anterior pituitary failure.
1. Cretinism may be evident at birth, but more commonly hypothyroidism
becomes obvious in the first several months of life. The infant shows the
characteristic facies (broad, flat nose with widely spaced eyes, coarse
features, thick lips, and protruding tongue), a hoarse cry, and an
umbilical hernia. Early diagnosis is vital, since the degree of intellectual
impairment is related to the age at which therapy is initiated. Although
rare, cretinism is an important treatable cause of mental retardation and
should be considered in every evaluation of a mentally retarded child,
even if the physical stigmata mentioned previously are absent.
2. Adult hypothyroidism. In the older child and adult, hypothyroidism is
manifested by puffy eyelids; alopecia of the outer third of the eyebrows;
dry, rough skin; brittle, dry hair; induration and doughiness of the
subcutaneous tissues; slurred speech and hoarse voice; constipation;
anemia; increased sensitivity to cold; cerebellar ataxia; muscle
weakness and slowed deep tendon reflexes; and intellectual
dysfunction. This intellectual impairment may represent any one of a
wide range of syndromes, including hallucinations, disorientation,
agitation, and confusion (myxedema madness), as well as true
dementia (memory loss, incontinence, and lowered IQ).
Myxedema coma is a medical emergency not appropriately covered in
this discussion. However, milder forms of hypothyroidism may manifest
themselves as a dementia, so every patient initially evaluated for
intellectual dysfunction should have a serum thyroxine measurement. A
serum TSH level is often useful when the thyroxine is in the low
borderline range, since it is usually elevated in primary hypothyroidism.
Furthermore, a very low TSH in the presence of a clearly low thyroxine
suggests secondary hypothyroidism. Such patients should be referred to
an endocrinologist for further evaluation of anterior pituitary function and
treatment.
b. Treatment of primary hypothyroidism
1. Cretinism. Sodium levothyroxine (Synthroid), 0.025 mg/day, increased
at weekly or biweekly intervals to 0.3 to 0.4 mg/day.
a. Adult hypothyroidism. Sodium levothyroxine (Synthroid), 0.025
mg/day, increasing at weekly intervals to 0.1 to 0.2 mg/day.
b. Treatment of secondary and tertiary hypothyroidism depends on
detailed endocrine evaluation of pituitary and hypothalamic function,
which is beyond the scope of this manual.
D. Toxic disorders
1. Heavy metal poisoning. Several varieties of chronic heavy metal poisoning
may be manifested with dementia, including poisoning by lead, mercury,
arsenic, manganese, and thallium. The diagnosis and treatment of these
conditions are discussed in Chap. 14.
2. Drug intoxications
a. Alcohol. Marchiafava-Bignami disease is a rare complication of alcohol
abuse characterized pathologically by degeneration of the corpus callosum.
The disease is indistinguishable clinically from the Alzheimer-Pick-type
dementia. There is no specific therapy, but discontinuation of alcohol use is
recommended to prevent further progression of the process. Alcohol itself,
even in an apparently well-nourished person, probably causes a dementia,
some component of which may be reversible. The basis of the alcohol
dementia may be simplification of the neuronal connectivity network due to
pruning of dendritic spines.
b. Medications. Many drugs are capable of producing mental deterioration
suggestive of dementia. Most, however, produce a toxic confusional state
easily distinguished from true dementia by such signs and symptoms as
hallucinations, tachycardia, changes in blood pressure, diaphoresis,
dysarthria, and nystagmus. Any patient with apparent dementia in whom
drug use is suspected should have toxic screening of the urine and blood,
depending on the agents suspected. Treatment of the common drug
intoxications is discussed in Chap. 14.
V. Psychiatric diseases. A number of psychiatric illnesses may result in intellectual
dysfunction caused by either interference with motivation or actual impairment of
intellect, or both.
A. Depression may simulate dementia in many respects, including inability to carry
out tests of intellectual function. A therapeutic trial of antidepressant medication is
of little value diagnostically, since many patients with Alzheimer disease may be
depressed early in the course of the illness. A slight response to antidepressant
therapy does not exclude the diagnosis of a degenerative dementing disease. On
the other hand, a patient with an apparent dementia who actually is suffering only
from depression may benefit greatly from the therapy and has a much better
prognosis than the patient with a degenerative disease. It is often difficult clinically
to distinguish depression from dementia, but some guidelines are valuable.
1. Unlike most demented patients, depressed patients usually have insight that
they are functioning poorly.
2. Aphasias and apraxias often are seen in dementias but rarely in primary
depression.
3. Careful testing reveals no memory impairment in primary depression, in
contrast to dementia.
4. Incontinence is more common in dementia, although it may be seen in very
severe depression as well.
B. Schizophrenia was originally called dementia praecox by Kraepelin, and it can,
in fact, result in a dementing illness similar in many respects to Alzheimer disease.
Some guidelines for distinguishing between schizophrenia and Alzheimer disease
are as follows:
1. The age of the patient is of considerable value in making this distinction, but
Alzheimer disease does occur rarely in younger patients in the age group at
risk for schizophrenia.
2. Apraxias and aphasias, common components of Alzheimer disease, are not
seen in schizophrenia, but when these are absent the distinction may be more
difficult than it initially seems.
3. The course of the illness should help to make the distinction; the
schizophrenia will wax and wane over many years, with only very slow
deterioration of intellect, whereas Alzheimer disease progresses inexorably,
with development of unmistakable features within a few years.
C. Attention deficit hyperactivity disorder (ADHD); Attention deficit disorder
(ADD). The main symptoms of ADHD and ADD include a limited attention span,
especially for low-interest activities, impulsivity, and hyperactivity (not present in
ADD). The syndrome is more common in males and genetic factors appear to be
important. Commonly associated problems include learning disabilities,
oppositional and defiant behavior, disorders of conduct, tic or Tourette syndrome,
and obsessive and compulsive patterns of thought and behavior. Diagnostic study
should be guided by the history and physical examination. A neuroimaging study
is usually not necessary. An EEG should be performed only if seizures or epilepsy
are suspected to be interfering with attention and learning. Psychoeducational
assessment is often necessary for educational planning and a behavior program
is always necessary. Significant improvement in attention and impulse control can
sometimes be achieved with methylphenidate (Ritalin), 0.3 mg/kg per dose, or
dextroamphetamine (Dexedrine), 0.15 mg/kg per dose, given in the morning and
at lunchtime. A third dose given after school is optional. The starting dose of
methylphenidate is usually 5 mg per dose and is increased by 2.5 to 5 mg per
dose at weekly intervals. The starting dose of dextroamphetamine is 2.5 to 5 mg,
also increased by 2.5 to 5 mg at weekly intervals. Side effects of methylphenidate
and dextroamphetamine include headache, abdominal pain, anorexia, insomnia,
liver dysfunction, and tic. Stimulants do not cause tic or Tourette syndrome, but
they might unmask the involuntary movements in genetically predisposed patients.
D. Autism. The broad neurobehavioral syndrome of autism ranges from mild to
severe and is characterized by deficits in verbal and nonverbal communications,
impaired social skills, and a limited range of activity that is often repetitive. Many
patients are mentally retarded and a significant number experience seizures.
There are many causes of autism, but in the majority of patients a specific cause
cannot be determined. Altered serotonin synthesis in dentatothalamocortical
pathways might play a role in certain patients.
Diagnostic study should be guided by the history and physical examination.
Metabolic studies are usually normal and should be performed only if there is
reasonable suspicion of underlying metabolic disease. Brain MRI should be
performed if the physical examination suggests an underlying anatomic
abnormality. An EEG should be performed if seizures are suspected and also in
patients with a history of regression in speech or behavior. The EEG should
include slow-wave sleep, so that an overnight recording is usually necessary. This
is recommended in order to look for the pattern of continuous spike and wave
activity during slow-wave sleep that is potentially treatable with antiepileptic drugs
or steroids. Other significant epileptiform patterns are also potentially treatable and
at times improvement in speech and language function may occur even in the
absence of clinically obvious seizures.
Selected Readings
Dementia
Caplan LR, Schoene WC. Clinical features of subcortical arteriosclerotic encephalopathy (Biswanger's
disease). Neurology 1978;28:1206.
Chedru F, Geschwind N. Disorders of higher cortical function in acute confusional states. Cortex
1972;8:395.
Chugani DC, Muzik O, Rothermel R, et al. Altered serotonin synthesis in the dentatothalamocortical
pathway in autistic boys. Ann Neurol 1997;42:666.
Cummings J L, Benson DF. Dementia: a clinical approach, 2nd ed. Boston: Butterworth, 1992.
Davis KL, et al. A double-blind placebo-controlled multicenter study of tacrine for Alzheimer disease. N
Engl J Med 1992;327:1253.
Ghikar J , et al. Idazoxan treatment in progressive supranuclear palsy. Neurology 1991;4:986.
Hachinski VC, Lassen NA, Marshall J . Multi-infarct dementia: a cause of mental deterioration in the
elderly. Lancet 1974;2:207.
J oachim CL, Morris J H, Selkoe DJ . Clinically diagnosed Alzheimer disease: autopsy results in 150 cases.
Ann Neurol 1988;24:50.
Martin J B, Gusella J F. Huntington's disease: pathogenesis and management. N Engl J Med
1986;315:1267.
Mental Retardation
Breningstall G. Approach to diagnosis of oxidative metabolism disorders. Pediatr Neurol 1993;9:81.
Capute AJ , Shapiro BK, Wachtel RC, et al. The Clinical Linguistic and Auditory Milestone Scale (CLAMS).
Am J Dis Child 1986;140:694.
Coplan J . ELM scale: the Early Language Milestone Scale, revised. Austin, TX: Pro-Ed, 1987.
DeVivo DC, et al. Defective glucose transport across the bloodbrain barrier as a cause of persistent
hypoglycorrhachia, seizures and developmental delay. N Engl J Med 1991;325:703.
Frankenburg WK, et al. The Denver II: a major revision and restandardization of the Denver Development
Screening Test. Pediatrics 1992;89:91.
Freeman J M, Nelson KB. Intrapartum asphyxia and cerebral palsy. Pediatrics 1988;84:240.
Huntington's Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that
is expanded and unstable on Huntington's disease chromosomes. Cell 1993;72:971.
Luckasson R, ed. Mental retardation: definition, classification and systems of support, 9th ed.
Washington, DC: American Association on Mental Retardation, 1992.
Naidu S, Moser HW. Peroxisomal disorders. Neurol Clin 1990;8(3):507.
Rapin I. Current concepts: autism. N Engl J Med 1997;337:97.
Schaefer GS, Bodensteiner J B. Evaluation of the child with idiopathic mental retardation. Pediatr Clin
North Am 1992;39(4):929.
Scriver C, ed. The metabolic basis of inherited disease, 6th ed. New York: McGraw-Hill, 1996.
Scriver CR, Beaudet AC, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease,
7th ed. New York: McGraw-Hill, 1995.
Smith, DW. In: Lyons J ones K, ed. Recognizable patterns of human malformations. Philadelphia: WB
Saunders, 1996.
Tarleton J C, Saul RA. Molecular genetic advances in fragile-X syndrome. J Pediatrics 1993;122:169.
Tulinias MH, et al. Mitochondrial encephalomyopathies in childhood: I. Biochemical and morphologic
investigations. J Pediatrics 1991;119:242.
CHAPTER 4. DIZZINESS
Manual of Neurologic Therapeutics
CHAPTER 4. DIZZINESS
Howard D. Weiss
Definitions
Clinical evaluation of patients with vertigo
Diagnosis and treatment of diseases causing vertigo
Diagnosis and treatment of disorders causing disequilibrium
Hyperventilation syndrome and psychogenic dizziness
Tinnitus
Disorders associated with presyncope
Dizziness is one of the most common complaints for which people seek medical
attention. Yet many physicians are uncomfortable and distraught when they learn that
their next patient is complaining of dizziness. This attitude reflects the bewildering
variety of disorders in the realms of neurology, otology, cardiology, ophthalmology,
psychiatry, and medicine that cause dizziness. The logical evaluation of the dizzy
patient and treatment of the disorders that cause dizziness will be reviewed in this
chapter (Fig. 4-1 and Fig. 4-2).
FIG. 4-1. Clinical spectrum of dizziness.
FIG. 4-2. Clinical evaluation of the dizzy patient.
I. Definitions. Dizziness is an ambiguous term that patients use to describe several
entirely different subjective states. Therefore, the first step in differential diagnosis is to
obtain an accurate description of the patient's subjective experience using words more
descriptive than dizzy. The complaint of dizziness generally can be divided into 1 of 4
categories:
A. Vertigo is defined as an illusion of movement of the patient or the patient's
surroundings. The vertiginous sensation may be described as rotating, spinning,
tilting, or swaying. Acute vertigo is often accompanied by autonomic symptoms
(e.g., nausea, vomiting, diaphoresis, apprehension), disequilibrium (imbalance),
and nystagmus (which may cause blurred vision). The presence of vertigo implies
a disturbance in the peripheral or central nervous system (CNS) pathways of the
vestibular system.
B. Syncope or presyncope implies a sense of impending loss of consciousness
or fainting. This is often accompanied by diaphoresis, nausea, apprehension, and
transient bilateral visual loss. Syncope occurs when cerebral perfusion falls below
the level required to supply adequate oxygen and glucose to the brain. Syncope or
presyncope generally implies hypotension, autonomic reflex, or cardiac
dysfunction (see Fig. 4-1) and has entirely different implications than vertigo.
C. Disequilibrium is a sense of imbalance, unsteadiness, or drunkenness without
vertigo that occurs in patients who have a mismatch of inputs from the systems
subserving spatial orientation. Patients with vestibular, proprioceptive, cerebellar,
visual, or extrapyramidal system disorders often will refer to their sense of
disequilibrium as dizziness.
D. Ill-defined dizziness occurs in patients suffering from various emotional
disorders, including hyperventilation syndrome, anxiety neurosis, hysterical
neurosis, and depression. The complaint is usually of a vague light-headedness,
giddiness, or fear of falling that is distinct from the vertigo, presyncope, or
disequilibrium described above. However, it is important to realize that all forms of
dizziness may provoke considerable patient anxiety and that anxiety itself is not
the sine qua non of psychogenic dizziness.
E. Some patients have difficulty in adequately describing their dizzy sensation. In this
group, it is useful to put the patient through a series of maneuvers that can trigger
various types of dizziness.
1. Some of the standard dizziness simulation tests include:
a. Checking for orthostatic hypotension.
b. Vigorous hyperventilation for 3 minutes.
c. Sudden turns when walking or spinning the patient while standing.
d. The Nylen-Brny test for positional vertigo, which can trigger acute attacks
of vertigo and nystagmus (see sec. III.B).
e. Valsalva maneuvers, which can exacerbate vertigo associated with
craniovertebral junction anomalies (e.g., Chiari malformation) or perilymph
fistula, as well as induce presyncopal light-headedness in patients with
cardiovascular disease.
2. After each maneuver, the patient is asked whether the sensation of dizziness
(if any) matches the spontaneous complaint. In cases of orthostatic
hypotension, hyperventilation syndrome, positional vertigo, and related
vestibular disorders, the patient's symptom may be reproduced, thereby
providing important diagnostic information.
II. Clinical evaluation of patients with vertigo. Evaluation requires an
understanding of vestibular system interactions with the oculomotor, auditory, and
spinocerebellar systems. There are two basic vestibular system reflexes. The
vestibulo-ocular reflexes stabilize the position of the eye with respect to space so that
images remain stationary on the retina for best acuity. The vestibulospinal reflexes
stabilize head and body position for motor control and for remaining upright.
A. Nystagmus is a useful indicator of vestibular malfunction in patients with vertigo.
Review of a few simple physiologic principles will help reduce the mystique that
often clouds the interpretation of nystagmus.
1. Semicircular canalocular reflexes. Each semicircular canal is connected via
neuronal circuitry in the brainstem to the eye muscles in such a way that
inhibition of a canal results in eye movement toward the plane of that canal.
Conversely, excitation of the canal results in eye movement away from the
plane of that canal. The semicircular canals and otolith organs in the right and
left inner ears normally send continuous equal and opposite messages to the
brainstem. However, a sudden inequality in the vestibulo-ocular pathway input
will result in a slow vestibular-induced eye deviation that is interrupted by a
quick cortically controlled corrective movement in the opposite direction
(nystagmus).
2. Labyrinthine disorders generally produce inhibition of one or more
semicircular canals. Consequently, acute unilateral peripheral vestibular
disorders produce unidirectional nystagmus, with the slow phase moving
toward the affected ear and the rapid phase beating away from the affected
ear. The nystagmus is rotary or horizontal; it increases in intensity as the eyes
are deviated in the direction of the rapid component (i.e., toward the normal
ear). Patients are often uncertain regarding the direction of their vertiginous
illusion. It is often helpful to evaluate the perceived direction of rotation with the
patient's eyes closed. Patients with acute vestibular disorders experience
vertigo as a sensation that the environment is spinning in the direction of the
fast component of the nystagmus or that their bodies are spinning in the
direction of the slow component. They tend to past-point and veer in the
direction of the slow phase of their nystagmus (i.e., toward the malfunctioning
ear).
3. Central nystagmus. Multidirectional nystagmus (nystagmus that changes
direction with different directions of gaze) is more common with drug
intoxications or brainstemposterior fossa disorders. Vertical nystagmus
(upbeat or downbeat) is almost pathognomonic of brainstem or midline
cerebellar disorders.
B. Caloric stimulation. Normal physiologic stimuli always affect both vestibular
organs at the same time. Caloric stimulation is a convenient clinical method of
investigating the function of each labyrinth separately. The test is performed with
the patient recumbent with the head flexed 30 degrees. Cool water induces a flow
of endolymph that inhibits the neural impulses from the horizontal canal on that
side. This normally results in nausea and vertigo accompanied by horizontal
nystagmus, with the slow component toward the side of cool-water stimulation and
the fast component in the opposite direction. These manifestations of cold-water
irrigation are identical to the effects of unilateral vestibular hypofunction (e.g.,
vestibular neuronitis and labyrinthitis).
The direction, duration, and amplitude of the nystagmus should be observed
carefully. A reduced response in one ear implies a disorder in the vestibular
labyrinths, vestibular nerve, or the vestibular nuclei on that side. The test should
not be performed unless the tympanic membranes are intact.
C. Electronystagmography. The retina is electronegative to the cornea; thus, eye
movements cause changing electric fields and currents. Electronystagmography
(ENG) involves placing, on the skin around the eyes, electrodes that can detect
these changes and provide a means for objectively recording eye movements.
The ENG provides quantitative data regarding direction, velocity, and duration of
the eye movements in nystagmus. Vestibular function tests use ENG to record
spontaneous nystagmus, positional nystagmus, rotation-induced nystagmus, and
caloric-induced nystagmus. ENG can also record nystagmus when the eyes are
closed. Since ocular fixation often tends to suppress nystagmus, ENG recording
with the eyes closed sometimes provides additional information that is not
available on routine clinical examination.
D. Hearing loss or tinnitus can occur in disorders of the peripheral vestibular
system (inner ear and eighth nerve) due to coinvolvement of the auditory
apparatus. Auditory symptoms seldom accompany CNS disorders. Audiologic
testing often provides useful diagnostic information in patients with vertigo.
1. Pure tone audiometry measures the listener's threshold of hearing as a
function of the frequency and intensity of a sound stimulus. The threshold by
air conduction is compared with that by bone conduction to distinguish
conductive versus sensorineural hearing loss.
2. Additional evaluations that contribute to complete audiologic assessment
include speech discrimination, speech reception, recruitment, and tone decay
(Table 4-1).
TABLE 4-1. Audiologic Evaluation of Cochlear and Retrocochlear Disorders
E. Moving platform posturography tests measure the automatic postural
responses that are used to prevent falls and quantify the ability of patients to use
various sensory cues to maintain balance.
F. Vestibular function tests, ENG, and posturography are expensive procedures.
These tests do not replace the careful clinical examination of patients with vertigo
and are not necessary to arrive at a diagnosis or treatment strategy in the vast
majority of patients with dizziness.
III. Diagnosis and treatment of diseases causing vertigo (Table 4-2).
Vestibular neuronitis and benign positional vertigo are the two most common causes of
acute vertigo and account for the majority of cases of vertigo seen in clinical practice.
TABLE 4-2. Common Disorders Producing Acute Attacks of Vertigo
A. Vestibular neuronitis (also known as acute peripheral vestibulopathy or
vestibular neuritis)
1. Description. Vestibular neuronitis is characterized by a sudden prolonged
attack of vertigo, often accompanied by nausea, vomiting, disequilibrium, and
apprehension. The symptoms are exacerbated by head movement or changes
in position. Patients feel severely ill and prefer to stay motionless in bed.
Spontaneous nystagmus occurs, with the slow phase toward the abnormal
ear, and there is reduced caloric excitability in the diseased ear. Positional
nystagmus is present in many patients. Tinnitus or a sensation of fullness in
the ear occurs in some patients. Hearing remains unimpaired, and audiologic
tests are normal. Except for unsteadiness, there are no neurologic signs (e.g.,
focal weakness, ataxia, diplopia, dysarthria, sensory loss) to suggest brainstem
disease. The disorder affects adults of any age. The acute vertigo usually
resolves spontaneously in minutes to hours but may recur over the ensuing
days or weeks. Some patients experience residual impairment of vestibular
function, which produces a state of chronic disequilibrium that is most
noticeable when the patient is moving. Follow-up studies reveal that about half
the patients will have recurrent episodes of vertigo months to years later. The
cause of vestibular neuronitis remains unknown. A viral etiology (similar to that
producing Bell palsy) has been postulated, but this has not been proved. This
disorder is a clinical syndrome rather than a well-defined disease. Careful
neurologic and neurootologic examination, as outlined, indicates a peripheral
disorder in patients with vestibular neuronitis and rules out the more ominous
central disorders.
2. Treatment
a. Drugs. Since vestibular neuronitis is a self-limited illness of unknown
cause, treatment is directed at suppressing the symptoms. The drugs listed
in Table 4-3 have some effectiveness in suppressing vertigo due to
vestibular neuronitis, motion sickness, or other vestibular disorders. When
nausea is a severe problem, the antivertigo drugs can be administered by
suppository or parenterally. Hospitalization may be necessary for patients
with profound disequilibrium or intractable vomiting requiring intravenous
rehydration.
TABLE 4-3. Drugs Useful in the Symptomatic Treatment of Vertigo
1. Antihistamines
a. Mechanism of action. Suppression of vertigo is not a general
property of all antihistamines and does not seem to correlate with
their peripheral potency as histamine antagonists. The activity of
those antihistamines that do counteract vertigo (dimenhydrinate,
diphenhydramine, meclizine, and cyclizine) seems specific and not
simply a matter of suppression of the brainstem vomiting center; in
fact, many commonly used antiemetics are of little value in relieving
patients with vertigo. The antivertigo antihistamines also exert
anticholinergic activity in the CNS. The central anticholinergic
property may be the underlying biochemical mechanism of
antivertigo activity.
b. Side effects. The major side effect of these agents is sedation. The
ability to induce somnolence is somewhat more pronounced during
therapy with dimenhydrinate or diphenhydramine. In severely
vertiginous patients, sedation may be a desirable side effect.
However, for patients who do not desire as much sedation, meclizine
or cyclizine is preferable.
Anticholinergic side effects, such as dry mouth or blurred vision,
occasionally occur with these drugs. The relatively long half-life of
meclizine enables the patient to take medication only once or twice
per day, compared with 3 or more times per day with other drugs.
c. Anticholinergic drugs that are centrally active suppress vestibular
system activity and can be useful in reducing vertigo. An adhesive
unit containing scopolamine for transdermal administration is
available. This drug delivery system is programmed to release 0.5
mg of scopolamine directly into the bloodstream through the skin
over a period of 72 hours. This small amount of drug is effective
against motion sickness and may help in the symptomatic treatment
of vestibular neuronitis and other vertiginous conditions. The
combination of scopolamine with promethazine or ephedrine may
have useful synergistic effects. The side effects (parasympathetic
blockade) and contraindications for scopolamine therapy are similar
to those for other belladonna alkaloids. Scopolamine should be used
with great caution in elderly patients for fear of triggering mental
confusion or bladder outlet obstruction.
2. Phenothiazines compose a large group of drugs with antiemetic
effects. Not all antiemetics are effective antimotion sickness or
antivertigo agents. For example, chlorpromazine (Thorazine) and
prochlorperazine (Compazine) are highly effective against chemically
induced nausea but are much less effective against motion sickness
and vertigo. However, one widely used phenothiazine derivative,
promethazine (Phenergan), also has significant antihistaminic
properties. Promethazine has been the most effective phenothiazine for
treating vertigo and motion sickness, ranking with the other
antihistamines listed in Table 4-3. Drowsiness is the major limiting side
effect of promethazine; it is much less likely to induce acute dystonias or
other extrapyramidal reactions than the other phenothiazines.
3. Sympathomimetic agents also suppress vertigo.
a. Amphetamine has been used in combination with promethazine or
scopolamine to prevent vertigo and motion sickness in astronauts.
However, amphetamine is a controlled substance due to its great
drug abuse potential and cannot be prescribed to patients with
vestibular neuronitis.
b. Ephedrine is another sympathomimetic agent that has synergistic
action when combined with other antivertigo drugs. The stimulant
effects of ephedrine may combat the sedative effects of other drugs
but can also cause insomnia, nervousness, and palpitations.
4. Mild tranquilizers such as diazepam or lorazepam are helpful in
alleviating the acute anxiety that often accompanies vertigo.
Hydroxyzine is a tranquilizer that also has antihistaminic and antiemetic
properties, giving it therapeutic value against vertigo. The usual adult
dosage of hydroxyzine is 25 to 100 mg tid or qid.
5. The duration of treatment is variable. In most patients, medications
can be discontinued when the nausea and vertigo have subsided.
Experimentally, the vestibular sedative medications retard central
compensatory mechanisms, so that prolonged use of these drugs may
be counterproductive. Nevertheless, there are some patients who
require small doses of medication on a chronic basis to remain
comfortable. Patients who do not experience symptomatic relief with
one antivertigo medication may respond well to a different medication.
The number of medications available is indicative of the fact that none is
completely satisfactory. Combinations of medications from different
classes (e.g., an anticholinergic with a sympathomimetic) may have
synergistic effects in suppressing vertigo.
b. Other measures. The patient can perform simple maneuvers to lessen the
sensation of vertigo.
1. Since head motion aggravates vertigo, the patient should be allowed to
lie still in a darkened room for the first day or two.
2. Visual fixation tends to inhibit nystagmus and diminish the subjective
feeling of vertigo in patients with peripheral vestibular disorders, such as
vestibular neuronitis. Patients may find that fixing their gaze on a nearby
object, such as a picture or outstretched finger, is preferable to lying
with eyes closed.
3. Since intellectual activity or mental concentration may facilitate vertigo,
the discomfort is best minimized by mental relaxation coupled with
intense visual fixation.
4. When nausea and vomiting are severe, intravenous fluids should be
administered to prevent dehydration.
5. When vertigo is not relieved. Many patients with acute peripheral
vestibular disorders will not have dramatic symptomatic improvement in
the first day or two. The patient feels acutely ill and may become
extremely fearful of future attacks. An important aspect of therapy in this
situation is a firm statement of reassurance that vestibular neuronitis
and most of the other acute vestibular disorders are benign and
self-limited conditions. The physician can tell the patient that the
nervous system eventually adapts to an imbalance between the two
vestibular end-organs, and the vertigo ultimately stops. Even in
disorders that permanently destroy one vestibular apparatus, the vertigo
will diminish after several days as the brain begins to adapt. Such
assurances greatly alleviate the patient's apprehension.
6. Vestibular exercises can be initiated several days after the acute
symptoms have subsided. These exercises enhance CNS
compensatory mechanisms for acute vestibular disturbances (see sec.
III.L.2).
B. Benign positional vertigo (benign paroxysmal positional vertigo; BPPV)
1. Description. Benign positional vertigo is probably the most common vestibular
syndrome seen in clinical practice. Patients with this disorder do not have
vertigo while sitting or standing still but find that attacks are precipitated by
movement or position change in the head or body. This is particularly true if the
movements are in the pitch (forward-backward) plane. This commonly occurs
when the patient lays back in bed and rolls over into the vulnerable position, at
which time the room begins to spin. The vertigo usually lasts only a few
seconds. Observant patients can often identify a head position that
reproducibly triggers the symptoms.
Changes in head position aggravate vertigo in vestibular neuronitis and many
other peripheral or central vestibular disorders. However, patients with BPPV
develop symptoms only after the appropriate head movement and not at other
times.
2. Distinction from positional vertigo of central disorders. Positional vertigo
can also occur in a variety of conditions, including serious brainstem
disorders (e.g., multiple sclerosis, infarct, tumors).
a. The Nylen-Brny maneuvers (also known as Dix-Hallpike maneuvers)
help distinguish benign positional nystagmus from more ominous central
conditions and are an important part of the clinical examination of the
vertiginous patient. The test is performed by moving the patient from the
sitting position to a lying position with the head extended 45 degrees
backward. This maneuver is repeated with the head extended and turned to
the right and then to the left. The patient is observed for the development of
nystagmus and vertigo.
b. The latency, duration, direction, and fatigability of the nystagmus reveal
important diagnostic information (Table 4-4). In BPPV, there is a latency
period of several seconds before the vertigo and nystagmus appear. Rotary
nystagmus is seen, with the rapid phase beating toward the undermost ear.
The nystagmus and vertigo are transitory (less than 30 seconds) and
disappear on repetition of the provocative maneuver (fatigue).
TABLE 4-4. Nylen-Brny Maneuver for Positional Nystagmus
The Nylen-Brny maneuvers can confirm the diagnosis of benign
positional vertigo. A negative test does not exclude the diagnosis because
the symptoms can be intermittent and do not necessarily recur every time
the head is placed in the vulnerable position.
3. Etiology. Some cases of BPPV follow head trauma, viral illnesses, middle
ear infection, or stapedectomy. Positional nystagmus is also common in
intoxications (alcohol, barbiturates). Most spontaneous cases of BPPV are
attributed to canalithiasis, i.e., degenerated otoconial debris that floats freely
within the posterior semicircular canal. This makes the canal unusually
sensitive to gravitational changes associated with different head positions.
4. Course. The course of benign positional vertigo is quite variable. In many
patients, the symptoms spontaneously subside in a few weeks, only to recur
months or years later. Some patients suffer only a single transient attack.
Seldom do patients retain a persistent susceptibility to positional vertigo that
does not abate.
5. Treatment. Symptomatic treatment with one of the vestibular sedative drugs
(see Table 4-3) is seldom of great benefit.
The canalith repositioning maneuver (also known as the Epley maneuver) has
become a standard treatment for BPPV.
The Epley maneuver is performed by quickly laying the patient on their side
with the head hanging over the edge of the bed with the affected ear
downward. After the nystagmus and vertigo abate, the head is kept
hyperextended and slowly rolled in the direction away from the affected ear
until he or she is facing the opposite side. The head and trunk are slowly
brought to a sitting position and the patient is instructed not to move their head
vertically or lie down for 24 hours. A soft cervical collar can be used to restrict
head movement, and the patient should sleep upright the night after the
maneuver.
The principle of the Epley maneuver is an attempt to rotate the patient's head
in the plane of the affected posterior semicircular canal so that the debris
moves around and out of the canal. The procedure is simple and highly
efficacious, providing immediate relief for many patients with BPPV.
Recurrences are common at which time the maneuver can be repeated.
C. Posttraumatic vertigo. Although protected by a bony capsule, the delicate
labyrinthine membranes are susceptible to trauma. Uncomplicated concussions
are followed by vertigo in over 20% of patients. (It should be remembered that
transient autonomic disturbances, such as palpitations, flushing, and sweating,
also occur after head trauma and can produce light-headed and dizzy sensations
other than vertigo.) The posttraumatic vertigo syndromes fall into two main
categories.
1. Acute posttraumatic vertigo. Vertigo, nausea, and vomiting may begin
acutely after head injury, due to sudden unilateral vestibular paresis
(labyrinthine concussion). Laceration of the tympanic membrane with blood in
the external auditory canal or hemotympanum suggests a longitudinal or
transverse fracture of the temporal bone, respectively. However, most cases of
acute posttraumatic vertigo are not associated with temporal bone fracture.
a. Symptoms. The vertigo is persistent. There is spontaneous nystagmus
with the rapid component beating away from the affected side, loss of
balance, and past pointing toward the affected side. The symptoms and
signs are aggravated by rapid head motion and worsened with the affected
side down.
b. Treatment. One of the vestibular sedative drugs (see Table 4-3) is often
effective in diminishing the unpleasant symptoms. For the acute episode,
scopolamine is often most efficacious. For long-term oral therapy, both
meclizine and dimenhydrinate have been widely used. The symptoms
spontaneously improve over the first few days and then more gradually
over the ensuing weeks. In most patients, the symptoms resolve within 1 to
3 months.
2. Posttraumatic positional vertigo. Several days or weeks after the injury, the
patient may experience recurrent brief attacks of vertigo triggered by changes
in head position.
a. Symptoms. The symptoms are identical to those outlined for benign
paroxysmal positional vertigo. The patient develops sudden brief attacks
of vertigo and nausea precipitated by changing head position.
b. Prognosis. The prognosis in posttraumatic positional vertigo is usually very
good, and most patients undergo spontaneous remission within 2 months,
and almost all within 2 years of the injury.
3. Perilymph fistula. The perilymph space surrounds the endolymph-filled
membranous labyrinth. Head trauma can produce a tear in the region of the
oval or round window, causing a perilymph fistula. When a fistula is present,
changes in middle ear pressure will directly affect the inner ear.
a. Symptoms. Patients with this problem will experience intermittent vertigo
or positional vertigo, fluctuating sensorineural hearing loss, or both.
Most patients with a fistula find that their symptoms are exacerbated by
changes in altitude (e.g., rapid ascent in an elevator) or with activities that
induce a Valsalva maneuver (e.g., straining, weight lifting). Some patients
will experience vertigo on exposure to loud sounds (the Tullio
phenomenon). Straining, sneezing, coughing, and diving (barometric
trauma) are other potential causes of perilymphatic fistulas.
b. The diagnosis is suggested by the history of vestibular or auditory
symptoms following trauma. The signs and symptoms of perilymph fistula
can be highly variable and can be confused with other disorders (e.g.,
Mnire syndrome, benign positional vertigo, abnormalities at the
craniovertebral junction). Tests monitoring the response to external
pressure changes, ENG, and posturography do not generally reveal
pathognomonic abnormalities. Perilymph fistula may account for many
cases of vertigo of unknown etiology.
c. Treatment. Perilymph fistulas usually heal spontaneously and, as a
consequence, the symptoms resolve. Surgical exploration through
tympanotomy to find and repair a perilymphatic fistula of the oval or round
window may be indicated in refractory cases where a fistula is strongly
suspected. If a fistula is found at surgery, it can be patched. Surgical
interventions are more likely to reduce vestibular symptoms than improve
hearing loss.
D. Mnire syndrome (Mnire disease)
1. Description. Mnire syndrome commonly has its onset in the third or fourth
decade of life. The patient experiences spontaneous bouts of intense vertigo
lasting for minutes to hours. Fullness or pressure in the ear, tinnitus, and
fluctuating hearing loss usually precede, but may follow, the episodes of
vertigo. A state of chronic disequilibrium that is particularly noticeable when
the patient is in motion can persist between acute attacks.
2. The course of the disease is characterized by remissions and relapses.
Early in the disease, there are often sporadic episodes of low-tone
sensorineural hearing loss, with hearing returning to normal between attacks.
As a result of multiple attacks, hearing loss becomes progressively worse, with
some spontaneous fluctuations.
3. Pathophysiology. The main pathologic finding in patients with Mnire
syndrome is a distention and increase in the volume of endolymphatic system
(endolymphatic hydrops). This may result from insufficient fluid resorption in
the endolymphatic sac or acquired blockage of the endolymphatic duct.
4. Treatment. Acute attacks are treated with bed rest and vestibular sedative
medications (see Table 4-3). In view of the uncertainty regarding the
pathogenesis, together with the variable course (which may include prolonged
remissions), it has been difficult to formulate or evaluate a rational
pharmacologic program for the prevention of attacks of Mnire syndrome.
One recent study found that all forms of treatment, including placebos, resulted
in approximately two thirds of patients being temporarily relieved of their
symptoms.
A low-sodium diet and the use of diuretics (e.g., thiazides or acetazolamide)
have been recommended in Mnire syndrome, on the basis of the theory that
these might correct fluid imbalance in the inner ear. The physiologic rationale
for this therapy has never been demonstrated, and the popularity of diuretic
low-salt therapy has declined. Tranquilizers, neuroleptics, lithium, stellate
ganglion blocks, and vasodilators (including nicotinic acid, isoxsuprine,
papaverine, intravenous histamine) have been tried, but none of these agents
is superior to placebo. The histamine derivative betahistine may have some
modest benefit in preventing attacks of Mnire syndrome.
5. Surgery for intractable disease. A small number of patients with Mnire
syndrome will have recurrent uncontrollable and disabling attacks of vertigo. In
these severe refractory cases, surgery may be necessary. There is no ideal
surgical treatment for Mnire syndrome. Cochlear endolymphatic sac shunt
operations alleviate vertigo in 70% of patients, but there is a 45% incidence of
increased hearing loss after this procedure. Intratympanic or systemic
treatment with ototoxic drugs (e.g., gentamicin or streptomycin) may prevent
acute vertigo but result in persistent disequilibrium and increased hearing loss.
Destructive procedures (such as selective transtemporal vestibular nerve
section, labyrinthectomy, or translabyrinthine vestibularectomy) are reserved
for patients with persistent disabling vertigo and severe unilateral hearing loss.
6. Differential diagnosis
a. All patients with clinical signs and symptoms of Mnire disease should be
evaluated to exclude the possibility of a cerebellopontine angle tumor
(e.g., acoustic schwannoma; see sec. IV.C). These tumors cause tinnitus,
hearing loss, and disequilibrium but rarely cause acute vertigo.
b. Infectious labyrinthitis, perilymph fistula, Cogan syndrome, vasculitides, and
hyperviscosity syndrome can produce attacks of vertigo, hearing loss, or
both.
c. Congenital syphilis. The onset of labyrinthine symptoms in congenital
syphilis is often delayed to middle age and can mimic Mnire syndrome.
Treponemal organisms persisting in the temporal bone produce a chronic
inflammatory process with endolymphatic hydrops and labyrinthine
degeneration. The course is progressive, and both ears ultimately are
involved. All patients suspected of having bilateral Mnire syndrome
should be evaluated for the possibility of occult syphilis. A fluorescent
treponemal antibody absorption (FTA-ABS) test should be obtained since
the routine screening tests (e.g., rapid plasma reagin or Venereal Disease
Research Laboratory test [VDRL]) may be negative in syphilitic labyrinthitis.
E. Labyrinthitis
1. Bacterial labyrinthitis. Bacterial infection of the middle ear or mastoid, such
as chronic otitis media, can produce toxins that inflame the cochlea, vestibular
system, or both (serous labyrinthitis). The symptoms may be indolent at first
but will gradually worsen if the infection is not treated. Direct bacterial infection
of the labyrinth (suppurative labyrinthitis) can occur in patients who have
bacterial meningitis or anatomic disruption of the membranes separating the
middle and inner ears. Fulminant vertigo, nausea, hearing loss, headache,
pain, and fever are present. Suppurative labyrinthitis is a potentially
devastating condition. Prompt diagnosis and administration of appropriate
antibiotics are imperative (see Chap. 8).
2. Viral labyrinthitis. Audiovestibular symptoms can occur in association with
common viral illnesses, including influenza, herpesvirus, rubella, mumps,
hepatitis, rubeola, and Epstein-Barr virus. Most patients improve
spontaneously without permanent hearing or balance problems.
F. Physiologic vertigo syndromes. A mismatch among inputs from the vestibular,
visual, and somatosensory systems that help maintain spatial orientation can
result in vertigo. Vertigo can also be induced by physiologic stimulation of the
normal stabilizing sensory systems.
1. Motion sickness is caused by unfamiliar body accelerations or a mismatch
between conflicting vestibular and visual stimuli to the brain. Persons in a
closed ship cabin or the rear seat of a moving automobile perceive vestibular
signals of acceleration that are contradicted by visual signals of a relatively
stationary environment. The intensity of the ensuing nausea and vertigo is a
function of the magnitude of the sensory mismatch. Motion sickness is reduced
when ample peripheral vision of the true surroundings is provided. The
medications listed in Table 4-3 are all effective in suppressing motion sickness
when taken prophylactically.
2. Vision-induced vertigo is caused by visual sensations of movement without
concomitant vestibular and somatosensory inputs (e.g., as when one is
watching movies of an automobile chase).
3. Vertigo at heights is a common physiologic phenomenon that occurs when the
distance between the subject and visible stationary objects in the environment
becomes critically large. Many people have an immediate conditioned phobic
reaction to heights that prevents adaptation to the physiologic visual-vestibular
mismatch.
G. Transient brainstem ischemia
1. Description
a. Symptoms
1. Vertigo and disequilibrium are the most common symptoms in
patients with vertebrobasilar disease and transient episodes of
brainstem ischemia. However, these will seldom be the only symptoms
of transient brainstem ischemia. It is usually erroneous to attribute
recurrent episodes of vertigo to vertebrobasilar insufficiency unless
some other manifestation of brainstem ischemia is present, such as
diplopia, dysarthria, facial or limb numbness, ataxia, hemiparesis,
Horner syndrome, or hemianopia. As a general rule, repeated
episodes of vertigo without other neurologic symptoms can be attributed
to a peripheral vestibulopathy.
2. Unsteadiness and vague blurring of vision can accompany vestibular
neuronitis as well as brainstem causes of vertigo and thus do not have
localizing value. Acute hearing loss is not encountered in brainstem
vascular disease, with the rare exception of occlusion of the anterior
inferior cerebellar artery (which may supply the inner ear via the internal
auditory artery).
b. Differential diagnosis
1. It is extremely important to distinguish patients with episodes of
transient brainstem ischemia from patients with benign disorders, such
as vestibular neuronitis, in order to initiate therapy to avert a serious
brainstem stroke (see Chap. 10).
2. Patients with transient brainstem ischemia will have an absence of
signs of residual damage between attacks. However, careful
neurologic examination during an attack of vertigo can reveal subtle
signs (e.g., a mild Horner syndrome, skew deviation, internuclear
ophthalmoplegia, vertical nystagmus, or central direction-changing
nystagmus) that clearly localize the abnormality to the brainstem and
not to the vestibular apparatus. Positional nystagmus is often elicited
in patients with brainstem ischemia. The Nylen-Brny maneuvers may
be helpful in distinguishing brainstem from vestibular disorders (see
Table 4-4).
3. The treatment of transient brainstem ischemia is reviewed in Chap. 10.
Other disorders affecting the brainstem, such as multiple sclerosis
(Chap. 13) and tumors (Chap. 11), also commonly produce vertigo or
disequilibrium.
H. Cerebellar infarction and hemorrhage
1. Clinical presentation. Patients with acute cerebellar infarction (or
hemorrhage) in the territory of the posterior inferior cerebellar artery can
present with severe vertigo and imbalance that can easily be mistaken for
acute vestibular neuronitis. Dysarthria, Horner syndrome, numbness, facial
paresis, and other signs of lateral medullary dysfunction may not be present if
the stroke is confined to the cerebellar hemisphere. Infarcts in the territory of
the superior cerebellar artery cause disequilibrium of gait and limb ataxia
without prominent vertigo.
2. Diagnosis. A high index of suspicion is necessary. Imbalance with a tendency
to veer to the affected side occurs in both vestibular and cerebellar hemisphere
dysfunction and is not helpful in differential diagnosis. Central nystagmus (e.g.,
direction-changing nystagmus with the rapid phase to the right on right gaze
and to the left on left gaze) and hemiataxia of the limbs are subtle clinical clues
that are indicative of an acute cerebellar hemisphere infarct (or hemorrhage). A
CT scan may not be adequate to demonstrate an infarct, particularly if done
early after the onset of symptoms, but will visualize cerebellar hematomas. An
MRI study is more likely to reveal the presence of a cerebellar infarct.
3. Course. Cerebellar infarcts and hematomas are often not massive and have a
benign outcome; the patient improves gradually and is left with minimal
sequelae. However, larger lesions are associated with cerebellar edema that
can compress the brainstem and fourth ventricle, producing devastating
consequences. These complications can be prevented (dehydration to prevent
edema) or treated (surgical decompression), so it is important that patients with
cerebellar infarctions or hemorrhages be promptly diagnosed and closely
monitored throughout the acute phase of their illness.
I. Oscillopsia is the illusion that stationary objects are moving to and fro. The
syndrome of oscillopsia, downbeat nystagmus, postural instability, and vertigo has
been associated with disorders at the craniovertebral junction (e.g., cerebellar
ectopia, Arnold-Chiari malformation) and cerebellar degenerations (e.g.,
olivopontocerebellar atrophy, multiple sclerosis). Baclofen, a putative
gamma-aminobutyric acid agonist, can suppress the oscillopsia in these disorders
and in other conditions causing periodic alternating nystagmus. The usual
baclofen dosage is 10 to 20 mg tid. The benzodiazepine clonazepam may also
palliate some patients with brainstem-cerebellar disorders causing oscillopsia.
J . Vestibular epilepsy. Vertigo can occur as a predominant symptom in simple or
complex partial seizures arising from cortical areas that receive vestibular
projections (the superior temporal gyrus or parietal association areas). Tinnitus,
nystagmus, and contralateral paresthesias may accompany the vertigo. The
attacks are brief and can easily be mistaken for other causes of vertigo. Most
patients will also experience absences or other more typical manifestations of
temporal lobe epilepsy. Abnormalities on the EEG will help confirm the diagnosis.
The seizures can be managed with anticonvulsant medication or resection of an
underlying focal brain lesion.
K. Migraine (see also Chap. 2, sec. II)
1. Symptoms. Vertigo can be a prominent symptom in attacks of basilar artery
migraine. Concomitant visual symptoms, sensory symptoms, altered
sensorium, and intense headache are also present during attacks.
2. Diagnosis. Recurrent vertigo in the absence of other symptoms may be a
migraine equivalent. This is a diagnosis of exclusion but should be
considered, especially if the patient has other manifestations of migraine.
3. Treatment. It is uncertain whether migraine-preventive medications (e.g.,
propranolol, valproic acid, amitriptyline) will eliminate attacks of vertigo in this
group of patients. Verapamil may be the medication of choice to prevent
attacks of basilar artery migraine.
L. Persistent vestibular dysfunction
1. Description. The CNS is able to recalibrate the relationship between
vestibular, visual, and proprioceptive signals. Therefore, regardless of cause,
acute vertigo usually resolves within several days due to CNS adaptation.
However, some patients are unable to compensate for vestibular disturbances
due to concomitant lesions in brain structures controlling vestibulo-ocular or
vestibulospinal reflexes. Other patients are unable to adapt due to deficits in
visual or proprioceptive sensory systems.
2. Treatment. Persistent vertigo, imbalance, and disequilibrium are potentially
incapacitating problems. Pharmacologic treatment in such cases is largely
empirical, and the results are disappointing. Patients with persistent symptoms
are candidates for vestibular rehabilitation, an exercise approach to the
remediation of disequilibrium and dizziness.
a. The goals of these exercises are:
1. To decrease dizziness.
2. To improve balance function in everyday situations.
3. To restore self-confidence.
b. A typical vestibular exercise program consists of:
1. Vestibular habituation exercises. Specific movements or positions
that provoke the patient's vertigo and disequilibrium are repeated. These
exercises are based on the rationale that the brain will habituate and
attenuate the vertigo response after repeated exposure to the specific
stimulus causing vertigo.
2. Balance retraining exercises. These exercises are designed to
improve coordination of muscle responses and organization of sensory
information for balance control.
IV. Diagnosis and treatment of disorders causing disequilibrium (see
Table 4-2 and Table 4-3)
A. Multiple sensory deficits
1. Description. Patients with diminished proprioception in the lower extremities
can experience severe unsteadiness, imbalance, or a drunken feeling when
attempting to walk. They will often use the term dizziness to describe their
disequilibrium. Loss of proprioception commonly occurs in patients with
peripheral neuropathy, vitamin B
12
deficiency, tabes dorsalis, and myelopathies
(such as cervical spondylosis). Vision also contributes significantly to spatial
orientation and balance. These patients are particularly dizzy and unsteady in
the dark, when there are fewer visual cues to compensate for the loss of
proprioception.
Patients with concomitant visual loss (e.g., cataracts, macular degeneration),
extrapyramidal dysfunction, orthostatic hypotension, or vestibular disturbances
may be particularly incapacitated by even mild proprioceptive deficits (the
syndrome of multiple sensory deficits ).
2. Treatment involves correcting the underlying neurologic disorder when
possible. Evaluation by a physical therapist and use of a cane or walker might
prevent serious falls. A night-light is helpful to reduce the disequilibrium when
the patient tries to walk to the bathroom in the middle of the night. These
patients may benefit from a vestibular rehabilitation exercise program.
B. Cerebellar disorders (e.g., alcoholic cerebellar degeneration, tumors, infarcts,
system degenerations) or extrapyramidal diseases (e.g., parkinsonism,
progressive supranuclear palsy) often cause unsteadiness and disequilibrium that
the patient describes as dizziness.
C. Schwannomas and other cerebellopontine angle tumors
1. Description
a. Schwannomas (tumors of Schwann cells) commonly arise from the
vestibular division of the cranial nerve in the internal auditory canal. As the
tumors slowly expand into the cerebellopontine angle, there is usually an
orderly progression of symptoms:
1. Hearing loss, tinnitus, and mild disequilibrium.
2. Headache.
3. Imbalance and incoordination.
4. Involvement of adjacent cranial nerves (facial numbness, paresthesia,
or facial weakness).
5. Symptoms of increased intracranial pressure. Although unilateral
hearing loss with or without tinnitus is almost always the initial symptom,
patients often ignore this condition and seek medical attention only
when other symptoms such as headache, imbalance, or vague
dizziness ensue.
b. Meningiomas, epidermoid tumors, and other neoplasms also may occur
in the cerebellopontine angle and produce similar symptoms.
2. Diagnosis. Unresectable acoustic schwannomas cause major morbidity.
The goal is to identify these schwannomas sufficiently early so that surgical
removal is safe and leaves minimum deficit. Therefore, all patients with
sensorineural hearing loss, particularly when combined with a vestibular
abnormality, should undergo evaluation to exclude a cerebellopontine angle
tumor.
a. Physical findings other than hearing loss are often not present.
Decreased corneal sensation, nystagmus, and facial hypesthesia are the
most commonly elicited signs.
b. The audiologic battery is useful in distinguishing cochlear disease from
retrocochlear lesions, such as acoustic schwannoma (see Table 4-1).
Classic findings in retrocochlear lesions include poor speech discrimination
in relation to pure tone threshold, no recruitment, tone decay, and impaired
stapedial reflex.
c. An MRI with gadolinium is now the imaging procedure of choice for
evaluating posterior fossa tumors and is capable of visualizing even small
intracanalicular tumors.
3. Treatment. Most cerebellopontine angle tumors should be resected; in most
instances, a surgical cure of acoustic schwannoma is possible (see Chap. 11),
sparing facial nerve function. For small tumors (i.e., less than 2 cm in
diameter), auditory function can also be spared in some instances. Since these
tumors are slow growing, some elderly patients may be followed with
sequential neurologic examination and scanning rather than surgery.
Stereotactic radiosurgery using the gamma knife is becoming a noninvasive
alternative to microsurgical resection and may be particularly indicated for
patients who are in poor medical condition for surgery and patients with
residual tumor after surgery.
D. Drug-induced disequilibrium. Intoxication with a variety of agents can produce
disequilibrium, vertigo, and other labyrinthine symptoms (Fig. 4-3). Drug
intoxications commonly produce a symmetric gaze paretic nystagmus. With eye
deviation to the side, the eyes slowly drift back to the midline, and this is followed
by a quick corrective jerk in the direction of gaze.
FIG. 4-3. Common causes of drug-induced disequilibrium.
1. Anticonvulsants. Most of the commonly used anticonvulsant drugs (e.g.,
phenobarbital, phenytoin, ethosuximide, primidone, and carbamazepine) will
produce vestibulo-ocular signs (e.g., nystagmus, vertigo) and ataxia as
blood levels exceed the toxic range. The symptoms will disappear if the drugs
are withheld, thereby allowing the blood levels to fall below the toxic range.
2. Alcohol intoxication is regularly associated with unsteadiness of gait and
dysarthria, suggestive of cerebellar dysfunction. Positional nystagmus and
positional vertigo also commonly occur. The positional vertigo is due to
variable rates of diffusion of alcohol into the cupula and endolymph, producing
transient specific gravity changes that cause the cupula to act as a gravity
sensor.
3. Salicylates. Tinnitus and vertigo are among the earliest signs of salicylate
intoxication. Hearing loss may also occur, and its severity seems to be closely
correlated with the blood salicylate level. When these symptoms appear in
patients receiving chronic large doses of salicylates, it is an indication for
discontinuing or reducing the dosage. The vestibular symptoms and hearing
loss reverse within 2 or 3 days after withdrawal of the drug.
4. Aminoglycoside antibiotics are ototoxic drugs (Table 4-5). Although all of
these drugs produce both auditory and vestibular damage, vestibular
symptoms are more frequently associated with streptomycin, gentamicin, or
tobramycin, and auditory symptoms are more frequently associated with
amikacin, kanamycin, or neomycin. These drugs produce hair cell damage in
the inner ear. The ototoxicity of these agents is directly related to the blood
drug levels and duration of therapy.
TABLE 4-5. Ototoxic Drugs
a. The patients rarely complain of vertigo but rather complain of a
disequilibrium or unsteadiness, particularly in the dark, where corrective
visual cues cannot be utilized. Oscillopsia is another common symptom
and tends to occur when the head moves (e.g., while walking), due to loss
of vestibulo-ocular reflexes. Serial caloric studies can document a
progressive bilateral loss of vestibular responsiveness.
b. Hearing loss begins at high frequencies and at times may be delayed in
onset.
c. There is no specific treatment for the labyrinthine damage. Symptoms
may begin to abate within a few days of cessation of antibiotic therapy;
however, full recovery may take more than 1 year, and some patients,
particularly the elderly, may suffer severe residual impairment of function.
d. Several precautions can prevent serious aminoglycoside ototoxicity. The
total daily dosage, duration of therapy, and blood drug levels should be
closely monitored. These precautions are especially important in patients in
whom there is renal insufficiency that interferes with the excretion of these
drugs. All patients receiving aminoglycoside antibiotics should have
frequent evaluation of their vestibular and auditory functions. The
medication should be stopped when impairment first appears.
V. Hyperventilation syndrome and psychogenic dizziness
A. Hyperventilation syndrome. Some patients who complain of dizziness suffer
from episodes of the hyperventilation syndrome. Anxiety, panic attacks, or
related emotional disturbances trigger the episodes.
1. Description. Hyperventilation results in hypocapnia, alkalosis, increased
cerebrovascular resistance, and decreased cerebral blood flow. The patient
complains of an ill-defined light-headedness, often in association with
circumoral or digital paresthesias, breathlessness, sweating, trembling,
palpitations, and panic (acute anxiety attack). Of great aid in diagnosis, as
well as in therapy, is the demonstration to the patient that the symptoms can
be reproduced by voluntary hyperventilation for 3 minutes.
2. Treatment. Prophylactic therapy of the hyperventilation syndrome is based
on the reassurance of the patient that these attacks do not represent a
life-threatening illness. Psychiatric consultation and behavioral therapy are
appropriate in severe cases. Acute episodes of hyperventilation syndrome can
be terminated by having the patient breathe into a bag (thereby allowing
rebreathing of exhaled carbon dioxide and preventing the hypocapnia and
alkalosis).
B. Psychogenic dizziness
1. Description. Some patients with neuroses or psychoses complain of dizziness
that does not fit any recognizable condition (e.g., vertigo, syncope, or
disequilibrium) and is not reproduced by any of the maneuvers in the dizziness
simulation battery. Dizziness is a symptom in more than 70% of patients with
anxiety neurosis and in more than 80% of patients with hysterical neurosis.
The dizziness in these patients has often been present for years and may be
continuous rather than episodic. Many of these patients equate dizziness with
loss of energy, difficulty concentrating, and mental fuzziness.
2. It is important to reemphasize that acute vestibular disturbances are often
accompanied by great anxiety and apprehension. Patients often report that
they feel as if they might die during severe bouts of vertigo. Chronic vestibular
disturbances can result in adverse changes in the patient's mood and outlook.
Anxiety and depression are not the sine qua non of psychogenic dizziness but
may accompany chronic vestibular disorders.
3. Management
a. The management of patients with psychogenic dizziness is based on
reassurance and trust. Patients often resent the implication that their
syndrome may be psychological, so it is insufficient merely to tell the patient
that there is nothing wrong physically; the patient will continue to worry
about serious medical illness and will go doctor shopping. The physician
must describe the psychiatric syndrome to the patient in lay terms and be
available to provide emotional support and follow-up.
b. The minor tranquilizers of the benzodiazepine family (e.g., diazepam,
lorazepam, oxazepam) may be useful in treating acute anxiety symptoms.
However, drugs that are subject to misuse must be monitored closely in
patients with anxiety or hysterical neuroses. When depressive symptoms
are prominent, the selective serotonin reuptake inhibitors are often helpful
in relieving symptoms.
VI. Tinnitus
A. Definition. Tinnitus is an unwanted noise perceived by the patient that has no
source in the external environment.
B. Description. Tinnitus associated with disorders of the middle ear, cochlea,
or auditory nerve is generally described as ringing, roaring, hollow sea shell, or
buzzing. The character of the tinnitus alone does not determine the site of the
disturbance. Identifiable causes of this type of tinnitus include noise-induced
hearing loss, presbycusis, Mnire syndrome, tympanosclerosis, and acoustic
neuroma. These disorders are generally accompanied by hearing loss. All patients
with tinnitus should be evaluated for the possibility of an acoustic neuroma. Over
half of patients with ringing do not have hearing loss, and in these patients a
cause of tinnitus is seldom identified.
C. Medications can produce tinnitus without hearing loss. Potential culprits include
salicylates, quinidine, aminophylline, indomethacin, and caffeine. These drugs
should be eliminated if possible in patients with tinnitus.
D. Pulsating tinnitus synchronous to the heartbeat usually is indicative of turbulent
blood flow. These patients may be hearing their own bruit from a stenotic or
tortuous carotid or vertebral artery. Vascular malformations (particularly dural
arteriovenous malformations and fistulas) and vascular tumors (e.g., glomus
tympanicum tumor), and benign intracranial hypertension can also cause pulsatile
tinnitus. Treating the underlying abnormality can eliminate the pulsatile tinnitus.
E. Treatment. Tinnitus can be extremely annoying, and many patients become
preoccupied by this symptom. It is often most noticeable at night, resulting in
insomnia. Chronic anxiety and depression are common accompaniments of
intractable tinnitus. Diagnosis and treatment of these concomitant emotional
problems can help reduce the devastating effects of tinnitus.
1. Medications have been of little value in eliminating chronic tinnitus. Some
patients are temporarily palliated by intravenous lidocaine, but this is not a
practical long-term treatment.
2. Masking devices. Most patients prefer to hear an external sound rather than
their tinnitus. Some patients will benefit from leaving the radio playing at night
or wearing a device that generates a masking sound. Unfortunately, these
devices are not a panacea.
VII. Disorders associated with presyncope. Many patients use the term
dizziness to describe a sense of impending faint. Other terms used by presyncopal
patients to describe their symptoms include light-headedness and giddiness, although
vertiginous patients commonly experience these symptoms as well. Symptoms
associated with presyncope, such as nausea, pallor, diaphoresis, apprehension, and
blurred vision, may also accompany vertigo; therefore, it is sometimes difficult to classify
the patient's complaints of dizziness properly. In these patients, the dizziness simulation
battery is especially useful (see sec. I.E). Although patients with acute vertigo will
occasionally fall due to sudden loss of balance, disorders associated with vertigo rarely,
if ever, cause transient loss of consciousness (syncope). Presyncopal dizziness is
usually caused by cardiovascular reflex or hemodynamic disorders.
A. Cardiovascular reflex syncope is mediated via autonomic nervous system reflex
mechanisms that lead to a vasodepressor response. The spells are characterized
by a fall in total peripheral resistance leading to right heart underfilling and a drop
in cardiac output. The spells occur in the standing or (less commonly) sitting
position. Premonitory symptoms such as nausea, pallor, light-headedness, and
diaphoresis are very common in patients with reflex syncope.
1. Vasovagal syncope is generally triggered by fear, emotional stress, or pain. It
is the most common cause of syncope in otherwise healthy young people.
2. Situational syncope (also known as vagovagal or visceral reflex syncope)
includes:
a. Micturition and defecation syncope.
b. Tussive (cough) syncope.
c. Deglutition syncope.
d. Postprandial hypotension, which may be an important cause of syncope in
elderly patients with impaired baroreflex function that cannot compensate
for splanchnic blood pooling after a meal.
3. Carotid sinus hypersensitivity can produce light-headedness and syncope
by several mechanisms: cardioinhibitory type, vasodepressor type, or a
mixed mechanism.
4. Orthostatic hypotension and syncope occur when the compensatory
sympathetic reflex mechanisms that maintain blood pressure on standing are
inadequate.
a. Primary autonomic insufficiency occurs in the Shy-Drager syndrome and
idiopathic orthostatic hypotension.
b. Secondary orthostatic hypotension can occur in patients with:
1. Autonomic neuropathies (e.g., diabetes, alcoholism, amyloidosis).
2. Medications commonly cause orthostatic hypotension, including
antihypertensive agents, nitrates, vasodilators, tranquilizers,
antidepressants, phenothiazines, and other vasoactive drugs.
3. Hypovolemia from blood loss, vomiting, excess diuresis, and
dehydration.
4. Prolonged bed rest can lead to cardiovascular deconditioning and
hypotension on standing.
B. Cardiac syncope results from inadequate left heart output. Unlike cardiovascular
reflex syncope, attacks of cardiac syncope are often of abrupt onset and may lack
premonitory symptoms.
1. Mechanical (obstructive) cardiac syncope is caused by left ventricular
outflow tract obstruction (e.g., due to aortic stenosis, hypertrophic
cardiomyopathy, pulmonary hypertension, cardiac tamponade, atrial myxoma,
global myocardial ischemia).
2. Arrhythmic cardiac syncope can be caused by ventricular tachycardia,
atrioventricular block, sick sinus syndrome, bradycardia-tachycardia syndrome,
long-QT syndrome, pacemaker malfunction, and so on.
3. Cardiac syncope can be life threatening, and evaluation of patients with
recurrent unexplained syncope should focus on ruling out a serious cardiac
disorder. The history, physical examination, and routine cardiac investigations
will provide important clues in most patients. New cardiovascular diagnostic
tests, such as electrophysiologic studies, tilt-table evaluation, and prolonged
ambulatory monitoring with continuous loop ECG recorders, have provided
diagnostic information in some cases of unexplained syncope.
C. Cerebrovascular occlusive disease does not commonly cause syncope or
presyncopal dizziness, and it is erroneous to refer to these symptoms as transient
ischemic attacks. The rare situation in which cerebrovascular disease causes
syncope is in patients with widespread narrowing or occlusion of the cervical
vessels that supply the brain, as might occur in:
1. Advanced bilateral atherosclerosis with occlusion of multiple extracranial
vessels. These patients may experience primary orthostatic cerebral ischemia
(orthostatic hypotension of the brain without systemic orthostatic hypotension).
2. Takayasu disease.
3. Subclavian steal syndrome.
Selected Readings
Brandt T, Daroff RB. The multisensory physiological and pathological vertigo syndromes. Ann Neurol
1980;7:195.
Drachman DA, Hart CW. An approach to the dizzy patient. Neurology 1972;2:323.
Furman J F, et al. Psychiatric dizziness. Neurology 1997;48:1161.
Hotson J R, Balsh RW. Acute vestibular syndrome. N Engl J Med 1998;339:680.
Kerber KA, et al. Disequilibrium in older people. Neurology 1998;51:574.
Kroenke K, et al. Causes of persistent dizziness: a prospective study of 100 patients in ambulatory care.
Ann Intern Med 1992;117:898.
Lanska DJ , et al. Benign paroxysmal positioning vertigo. Neurology 1997;48:1167.
Manolis AS, et al. Syncope: current diagnostic evaluation and management. Ann Intern Med
1990;112:850.
Troost BT, Patton J M. Exercise therapy for positional vertigo. Neurology 1992;42:1441.
Tusa RJ , et al. Most commonly asked questions about dizziness and balance. The Neurologist
1997;3:360.
CHAPTER 5. BACKACHE
Manual of Neurologic Therapeutics
CHAPTER 5. BACKACHE
Richard C. Hinton
General approach to the patient with backache
Disk syndromes
Degenerative disease of the spine (spondylosis)
Spondylolysis and spondylolisthesis
Neurologic complications of diseases involving the spine
Spinal epidural abscess
Psychiatric causes of back pain
I. General approach to the patient with backache. Backache is an extremely
common symptom with many possible causes. Proper therapy, therefore, depends
heavily on making the correct diagnosis. All patients complaining of backache should
have the following minimum evaluation:
A. History, with special reference to:
1. Location of the pain.
2. Radiation of the pain.
3. Body position that brings exacerbation or relief.
4. Trauma.
5. Litigation.
6. Drugs used for pain and amounts required for relief.
7. Malignancy.
B. Physical examination, with special reference to:
1. Signs of systemic infection.
2. Signs of occult malignancy.
3. Local tenderness, or tenderness in sciatic notch.
4. Muscle spasm.
5. Range of motion.
6. Straight-leg raising.
7. Rectal examination (prostate sphincter tone).
C. Neurologic examination, with special reference to:
1. Affect and mood.
2. Muscle weakness, atrophy, or fasciculations.
3. Sensory loss including the perineum.
4. Reflexes (deep tendon, abdominal, anal, cremasteric).
D. Laboratory
1. X-ray (posteroanterior, lateral, and oblique).
2. Complete blood count and erythrocyte sedimentation rate.
3. Serum, for:
a. Creatinine.
b. Calcium.
c. Phosphate.
d. Alkaline phosphatase.
e. Uric acid.
f. Acid phosphatase (men only).
g. Fasting blood sugar.
E. Further studies, e.g., bone scan, 2-hour postprandial blood sugar, magnetic
resonance imaging (MRI), computed tomography (CT), and myelography, depend
on the results of the above screening procedure. Usually this thorough basic
evaluation will reveal the cause of the pain, and the problem can be categorized
into one of the following diagnostic groups.
II. Disk syndromes
A. Pathophysiology. The intervertebral disk serves the dual purpose of
articulation, allowing flexibility of the spine, and cushioning, acting as a shock
absorber to prevent damage to the bones.
1. Herniation, or rupture, of an intervertebral disk refers to protrusion of the
nucleus pulposus along with some part of the anulus into the spinal canal or
intervertebral foramen. Because the anterior longitudinal ligament is much
stronger than the posterior longitudinal ligament, disk herniation almost always
occurs in a posterior or posterolateral direction. The material usually bulges as
a solid mass and retains continuity with the body of the disk, although
fragments at times may protrude through the posterior longitudinal ligament,
break off, and lie free in the spinal canal.
2. Some controversy exists concerning the factors that lead to rupture of the
intervertebral disk. Many cases can be related to trauma, either acute severe
injury or, more commonly, repeated minor injuries secondary to bending and
lifting. Another contributing factor seems to be the degenerative changes in the
disk that occur with aging: shrinking of the nucleus pulposus and thickening of
the anulus fibrosus. Disk herniation occurs most commonly in the lumbar
region, followed next in frequency by cervical disk rupture. Thoracic disk
herniation is distinctly uncommon.
B. Lumbar disk herniation
1. Clinical description. Lumbar disk herniation is most common in adult white
males, reaching a peak incidence in the fourth and fifth decades. It seems to
occur more frequently in those whose occupation involves bending and lifting.
Because the posterior longitudinal ligament in the lumbar region is stronger in
its central portion, protruded disks tend to occur in a posterolateral direction,
with compression of the nerve roots.
a. Areas affected
1. The last two lumbar interspaces (L4L5 and L5S1) are most
commonly affected, particularly L5S1. L3L4 is the next most common
site. Rupture of higher lumbar disks is rare and almost always the result
of massive trauma.
2. Because of the anatomic relationships in the lumbar spine, a protruding
disk usually compresses the nerve root emerging one level below it.
The most common disk syndromes of nerve root compression are
presented in Table 5-1. However, this anatomic arrangement is by no
means invariable. Thus, although the nerve roots affected by a disk can
be identified clinically, the exact level of the protruded disk cannot
always be localized with great certainty.
TABLE 5-1. Symptoms and Signs in Lateral Rupture of Lumbar Disk
3. If there is a free disk fragment, it usually affects the root emerging
above the herniated disk.
b. Development of symptoms. More than half of the patients will date their
symptoms to some type of trauma, either a hard fall or a twisting or bending
stress.
1. The initial complaint is usually a dull, aching, often intermittent, low
back pain of gradual onset, although at times the pain is of sudden
onset and severe. This pain is felt to be secondary to stretching of the
posterior longitudinal ligament, since the disk itself probably possesses
no pain fibers. Characteristically the pain is aggravated by activity or
exertion and by straining, coughing, or sneezing. It is usually relieved by
lying on the unaffected side with the painful leg flexed. Often there is
reflex spasm of the paravertebral muscles that causes pain and
prevents the patient from standing fully erect.
2. Course of symptoms. After a variable period of time, an aching pain
begins in the buttocks and posterior or posterolateral aspect of the thigh
and leg on the affected side, usually termed sciatica. This is often
accompanied by numbness and a tingling that radiates into the part of
the foot served by the sensory fibers of the affected root. These
symptoms may be elicited by the Lesegue test: straight-leg raising with
the patient lying prone. In the normal patient, the leg can be raised to
almost 90 degrees without pain, whereas in the patient with sciatica,
characteristic pain is produced by elevations of 30 to 40 degrees.
Eventually, loss of sensation, muscle weakness, and loss of reflexes
may ensue (see Table 5-1).
3. In the uncommon situation where a midline disk protrusion occurs in
the presence of a narrow spinal canal in the lumbar region, cauda
equina compression may result, with paraparesis and loss of sphincter
tone. A pseudoclaudication syndrome has been described, with pain in
the legs on exertion, secondary to intermittent compression of the
nerves of the cauda equina. The pathophysiology is possibly ischemia.
2. Diagnostic tests
a. Routine x-rays of the spine (including oblique projections) are not ordered
as frequently as they were prior to the advent of CT scanning. They are at
times useful in ruling out congenital anomalies or deformities, involvement
of the spine with rheumatic diseases, and metastatic or primary tumors. In
disk disease, the x-rays may be normal or may show degenerative changes
with narrowing of the intervertebral space and osteophyte formation.
b. Serum levels of calcium, phosphate, alkaline and acid phosphatase, and
glucose should be ascertained in every patient, since metabolic bone
disease, metastatic tumors of the spine, and diabetic mononeuritis may all
imitate intervertebral disk disease.
c. Lumbar puncture. Although the cerebrospinal fluid may show mildly
elevated protein in the presence of disk disease, lumbar puncture usually
adds little to the diagnostic evaluation. If a complete spinal block is present,
the protein might be very elevated with an abnormal Queckenstedt
maneuver.
d. Neurophysiologic studies. Electromyography (EMG) may be normal in
disk disease, or fibrillation potentials and positive sharp waves may be seen
in muscles innervated by the affected root after a delay of a few weeks. At
times EMG may be useful in differentiating root compression from
peripheral neuropathy, since with root compression, conduction in the
motor system is usually normal even in the presence of fasciculations and
fibrillations, and sensory conduction is unimpaired. The Hoffmann reflex
may be delayed or absent.
e. Myelography. When the diagnosis of a disk syndrome is certain, and one
is not concerned about the possibility of a cauda equina tumor or some
other abnormality, myelography need not be performed unless surgery is
contemplated. When surgery is being considered, myelography is carried
out to determine the level of disk protrusion.
f. A CT scan is useful in the diagnosis of disk disease and spinal stenosis.
Sometimes myelography can be avoided when a high-resolution CT scan is
available.
g. MRI is particularly useful in the diagnosis of compression of the spinal cord
or cauda equina. It seems to be a little less accurate than a CT scan in the
evaluation of nerve root compromise.
h. Diskography has not been found particularly helpful in evaluating disk
disease, since the results are often difficult to interpret. Furthermore, it has
been suggested that the procedure itself may produce damage to the
intervertebral disk.
3. Treatment
a. Conservative treatment. The majority of patients respond to
conservative therapy and do not require surgery.
1. In patients with mild symptoms, suggest:
a. Ways to avoid bending or straining; instruct the patient in this as
well as in proper posture.
b. Resting in bed when pain is present and avoidance of painful
activities.
c. Application of heat to the low back area.
d. Analgesics as necessary.
e. Exercises designed to strengthen the erector spine and abdominal
muscles.
f. A lumbar corset, to prevent excessive motion of the lumbar area.
2. In patients with severe incapacitating pain:
a. Strict bed rest on a firm bed may be necessary, in whatever position
is most comfortable.
b. Supporting boards underneath the mattress are useful to provide a
firm surface.
c. Analgesics are given during this period, as are antispasmodic
agents such as diazepam, and antiinflammatory agents such as
aspirin and the nonsteroidal antiinflammatory agents.
d. If the symptoms remit, activities are gradually increased after a few
days or so, and the patient is then treated as in the case of mild
symptoms.
e. Pelvic traction generally has not been found effective except to help
enforce strict bed rest.
3. In the past, strict bed rest was prescribed sometimes for 2 to 3 weeks.
However, recent studies have concluded that earlier mobilization after a
few days of bed rest is preferable.
b. Surgery is more likely to be successful when there are objective signs
of neurologic impairment. Surgery produces good to excellent results in
approximately two thirds of patients; half of the remaining are improved.
The usual indications for surgery are the following:
1. The most common indication for surgery is failure to respond to
conservative therapy. The decision for surgery in this case must be
made by the patient, with the guidance of the physician. Surgery is
usually elected when the pain is severe, incapacitating, and unrelieved
by conservative therapy, although at times the frequency of recurrences
of less severe pain may lead some patients to choose surgery.
2. Surgery without delay is mandatory in the uncommon situation in
which a midline disk compresses the cauda equina, with paraparesis
and sensory loss in the legs along with loss of sphincter control.
3. When nerve root compression is associated with motor loss,
especially quadriceps weakness or footdrop, surgery is usually
indicated. Occasionally, mild weakness may remit with conservative
therapy.
c. Chemonucleolysis is now available as a treatment for herniated lumbar
disks and involves injection of the disk with chymopapain. This procedure is
unlikely to benefit patients with sequestered disks, free disk fragments, or
osteophytic nerve root compression. In addition to anaphylaxis, other side
effects have been reported soon after injection with chymopapain, including
paraplegia, cerebral hemorrhage, and transverse myelitis/myelopathy. The
transverse myelopathy tends to begin acutely 2 to 3 weeks after
chymopapain injection, and most cases have occurred when diskography
was performed in conjunction with the procedure. Recent Food and Drug
Administration recommendations include avoiding diskography as part of
the chemonucleolysis procedure, verifying needle location, avoiding
multiple-level injections, and using supplemented local anesthesia rather
than general anesthesia.
C. Cervical disk herniation
1. Clinical description. Cervical disk rupture often follows a traumatic event after
a variable period of time but frequently occurs without any preceding traumatic
event.
a. Areas affected. Cervical disk protrusion most commonly occurs at the
C5C6 or C6C7 levels. In contrast to the lumbar region, the cervical
posterior longitudinal ligament is weaker in its central portion, so the
herniations may be midline posterior, compressing the cord, or
posterolateral, with root compression. Signs of cord compression include
spastic paraparesis and posterior column sensory loss in the legs,
hyperactive leg reflexes, and bilateral Babinski responses. Table 5-2
summarizes the root syndromes resulting from cervical disk rupture.
TABLE 5-2. Symptoms and Signs in Lateral Rupture of Cervical Disk
b. Development of symptoms. Symptoms usually begin with recurrent
attacks of pain in the posterior cervical area, often accompanied by
muscle spasm in the paravertebral muscles. Later, the pain begins to
radiate into the ipsilateral arm, with numbness and tingling in the
distribution of the particular root involved. As with lumbar disk disease, the
symptoms are usually aggravated by coughing, straining, or sneezing.
2. Diagnostic tests. The same guidelines for diagnostic evaluation presented for
lumbar disk herniation (see sec. II.B.2) apply in general to cervical disk
disease.
3. Treatment
a. The measures for conservative therapy of cervical disk include cervical
traction in addition to those outlined for the lumbar disk (see sec. II.B.3.a).
A soft cervical collar may be helpful.
b. With regard to surgery, the previously mentioned indications for surgery for
lumbar disk disease (see sec. II.B.3.b) apply to cervical disk disease as
well, but one should bear in mind that cervical cord compression can occur
and that it requires early surgery.
D. Thoracic disks
1. Clinical description. Thoracic disks are the rarest type of disk protrusion,
accounting for less than 1% of all herniated disks.
a. Areas affected. The lower four thoracic interspaces are most frequently
involved, with T11T12 being most commonly affected. Because the
extradural space is narrower in the thoracic region than in any other area of
the spine (and because the majority of the disk protrusions are central),
cord compression is more likely to occur than in the other disk syndromes.
b. Development of symptoms. At times, the onset of symptoms is acute or
subacute and associated with trauma, but the majority have a chronic
course unassociated with trauma.
1. Initially, back pain is the most common symptom, occurring in the
thoracic, lumbar, or sciatic region. Again, the pain is often aggravated by
coughing, sneezing, or straining.
2. Symptoms of cord compression, when they occur, arise from pressure
on the cord or from compromise of the arterial supply to the cord.
3. Paraplegia may occur suddenly.
4. When the herniation is lateral, the root compression may mimic
pleurodynia, angina, or visceral pain, depending on the level.
2. Diagnostic tests. Diagnostic evaluation proceeds according to the guidelines
in the section on lumbar disks (see sec. II.B.2). Compared with the other disk
syndromes, thoracic disk disease is more likely to be associated with
intervertebral disk calcification, although the calcified interspace may not be
the disk that has ruptured. If there are signs of spinal cord involvement,
myelography should be performed promptly, and usually films must be taken
with the patient lying supine.
3. Treatment
a. Many patients with root compression alone will respond go conservative
treatment (see sec. II.B.3).
b. When cord dysfunction is present, surgery is necessary. This is technically
the most difficult area for back surgery because of the narrow canal and the
usually central herniation. Surgical results are probably best with the
anterior transthoracic or transpleural approach.
III. Degenerative disease of the spine (spondylosis)
A. Pathophysiology. With advancing age, degenerative changes take place in the
spine, consisting of dehydration and collapse of the nucleus pulposus and bulging
in all directions of the anulus fibrosus. The anulus becomes calcified, and
hypertrophic changes occur in the bones at the margins of the vertebral bodies,
creating lips or spurs (osteophytes) (Fig. 5-1 and Fig. 5-2). With narrowing of the
intervertebral space, the intervertebral joints may become subluxated and
compromise the intervertebral foramina, which may also be encroached on by
osteophytic processes.
FIG. 5-1. The normal disk. The normal disk is composed of the central nucleus
pulposus (a fibrogelatinous fluid), the cartilaginous plates covering the vertebral
body sufaces, and the anulus fibrosis, which surrounds the nucleus pulposus and
provides the bulk of the disk. The anterior and posterior longitudinal ligaments
cover the respective surfaces of the disk.
FIG. 5-2. Degenerative changes of the spine.
B. Clinical description
1. Root compression indistinguishable from that produced by disk protrusion
may occur, although the pain is usually less prominent with spondylosis.
2. Dysesthesias without pain may be present in the distribution of the roots
affected, and corresponding muscle weakness and reflex changes may occur.
These are more likely to be symptomatic in the cervical region, but they may
occur in the lumbar area as well.
3. The osteophyte formation occurring in the more central portion of the
vertebral body may compress the spinal cord in the cervical region, or the
cauda equina may be compressed in the lumbar area in the presence of a
narrowed canal (lumbar stenosis). In the cervical region, this produces
spastic paraparesis, often with posterior column sensory loss, hyperactive
reflexes in the legs, and bilateral Babinski responses. Depending on the level,
the arms may or may not be involved. An interesting situation often arises
when the C5C6 interspace is involved: The biceps reflex is diminished
because of root compression, and the triceps reflex is hyperactive because of
cord compression. When there is lumbar involvement, symptoms of cauda
equina compression with paraparesis and sensory loss in the legs, along with
loss of sphincter control, may result. A curious pseudoclaudication (or
neurologic claudication) syndrome may also occur in which the patient notes
back and leg pain on standing or walking; the pain is relieved by lying down.
C. Diagnostic tests and treatment. The diagnostic workup and conservative
therapy should proceed in the same manner as for disk disease (see sec. II.B.2
and sec. II.B.3). The indications for surgery also are the same as for disk
disease: evidence of spinal cord compression, muscle weakness, or intractable
pain. For root compression, a procedure is performed to enlarge the intervertebral
foramina. When the spinal cord is compressed, a laminectomy is done to enlarge
the spinal canal.
IV. Spondylolysis and spondylolisthesis
A. Pathophysiology. Spondylolisthesis is forward displacement of one vertebral
body onto the vertebral body below it. This most commonly occurs in conjunction
with spondylolysis, a condition in which the posterior portion of the vertebral unit is
split, causing a loss of continuity between the superior and inferior articular
processes (Fig. 5-3). This is believed to result from fracture of the neural arch
shortly after birth, although it rarely becomes symptomatic until later in life; the
average age of patients seeking treatment is 35 years. The most common site of
involvement is the last lumbar vertebra (L5), which subluxates onto the sacrum.
Less commonly, spondylolisthesis may occur secondary to degenerative disease
of the spine; this usually involves L5 or L4.
FIG. 5-3. Mechanism of spondylolysis. The pincer effect of the adjacent facets on
the interposed isthmus is demonstrated with ultimate spondylolisthesis due to the
restraining mechanism of the posterior articulation that is being detached.
B. Clinical description. The most common symptom is low back pain, usually
beginning early in life and gradually worsening, that is accentuated by extension
movements. However, the pain may begin abruptly in association with an injury.
Leg pain from compression of the nerve roots is less common. With severe
deformity, cauda equina may be compressed.
C. Treatment
1. Conservative therapy consists of restriction of activity and institution of flexion
exercises. A corset may be beneficial to provide stability to the spine.
2. Surgery. As the patient grows older, if conservative therapy has failed to halt
progression of the condition, spinal fusion usually is indicated.
V. Neurologic complications of diseases involving the spine
A. Ankylosing spondylitis. Early in the course of ankylosing spondylitis there is low
back pain. In a small percentage of patients, this may radiate in a sciatic
distribution, but neurologic findings are rare. Uncommonly, compromise of the
cauda equina may occur, but this usually appears late in the course of the
disease, at a time when the disease has become inactive. Ankylosing spondylitis
progresses insidiously, with muscle wasting, pain, and sensory loss in the legs,
together with loss of sphincter control. Treatment is symptomatic.
B. Rheumatoid arthritis may result in serious neurologic complications from
involvement of the cervical spine.
1. Pathophysiology. The characteristic deformity is subluxation of one vertebra
onto another. The most common situation is atlantoaxial subluxation, which
may result in spinal cord compression. Another common site for subluxation is
C3C4. Pain without cord compression is more likely to occur with atlantoaxial
subluxation, whereas painless cord compression is more common at C3C4.
These complications of rheumatoid arthritis generally occur only as a
consequence of longstanding severe disease.
2. Treatment involves immobilization of the affected joint. This can be
accomplished temporarily with a hard four-post collar, but definitive therapy
requires spinal fusion at the involved interspace.
C. Paget disease (osteitis deformans) often produces back pain but only rarely
produces neurologic complications from involvement of the spine. However, many
well-documented cases of cord compression have been reported. Compression
may occur from narrowing of the spinal canal by hypertrophic bone, with
subsequent direct compression, from interference with the arterial supply to the
cord, or from extramedullary hematopoiesis. Cord compression may also result
from vertebral collapse with dislocation of the vertebral bodies. There is no specific
treatment for the back pain of Paget disease, so therapy consists of palliation with
back brace and analgesia.
D. Metastatic disease frequently causes back pain by involvement of vertebrae or
spinal roots. It may produce spinal cord compression either because of collapse
of extensively replaced vertebral bodies or by extramedullary (intradural or
extradural) metastatic deposits.
1. Diagnostic tests. Plain x-rays of the spine may show evidence of metastatic
disease. However, even when plain x-rays are normal, a bone scan is useful
for diagnosis in patients with unexplained back pain. Lung, breast, and prostate
cancer are the most common tumors producing back pain.
2. Treatment of the primary tumor or local radiation therapy to the involved
vertebrae, or a combination of both, is a useful palliative measure that often
provides excellent relief of pain. Spinal compression is an emergency that
often requires prompt myelography and surgical decompression, although
some patients may be treated successfully with steroids and radiation therapy.
E. Metabolic bone diseases (e.g., osteoporosis, hyperparathyroidism,
osteomalacia) frequently cause back pain but rarely produce neurologic
deficits by spinal cord or root compression. Treatment is of the underlying
condition if that is possible (i.e., diskontinue steroids, give vitamin D and calcium,
treat malabsorption or renal failure, remove parathyroid adenomas). Table 5-3
summarizes the differential diagnosis of various metabolic bone diseases that may
present with back pain, based on serum calcium, phosphate, and alkaline
phosphatase testing. If no specific treatment is possible (e.g., as in
postmenopausal osteoporosis), palliative measures such as a back brace and
analgesics are used.
TABLE 5-3. Differential Diagnosis of Various Bone Diseases That Might Cause
Back Pain
VI. Spinal epidural abscess is a purulent infection of the epidural fat pad. In many
cases this infection is preceded by vertebral osteomyelitis. The infection usually
reaches the vertebra by hematogenous spread from a distal infection, although direct
spread from local skin infection is known to occur. The disease is rare, but when it
occurs it is usually associated with severe back pain and almost always with local
tenderness. Spinal epidural abscess may cause spinal compression.
Myelography is required for diagnosis, and treatment consists of surgical removal of the
abscess and 4 to 6 weeks of intravenous antibiotic therapy.
VII. Psychiatric causes of back pain
A. Depression. In patients with chronic back pain in which the neurologic
examination is normal and categorization into any of the previously diskussed
syndromes is not possible, depression is a common finding. Such patients should
not be treated with analgesics or other modes of therapy meant for specific
backache syndromes. Tricyclic antidepressants may be useful (see Chap. 9 for
details).
B. Back pain also may be seen in the context of various characterologic diseases.
The prognosis in these cases is less favorable than in depression, and there is no
effective therapy, although psychotherapy sometimes meets with limited success.
Analgesics (particularly opiates) should be avoided, since drug dependency is a
very common complication in these patients. (Such patients often fail to have relief
of their back pain while litigation is pending.)
Selected Readings
Cailliet R. Low back pain syndrome, 3rd ed. Philadelphia: FA Davis Co, 1981.
Cailliet R. Neck and arm pain, 2nd ed. Philadelphia: FA Davis Co, 1981.
Chemonucleolysis. FDA Drug Bull 1984;14:14.
Frymoyer J W. Back pain and sciatica. N Engl J Med 1988;318:291.
Matthews WB. The neurological complications of ankylosing spondylitis. J Neurol Sci 1968;6:561.
Smith PH, Benn RT, Sharp J . Natural history of rheumatoid cervical luxations. Ann Rheum Dis
1972;31:431.
Youmans J R. Neurological surgery, Vol. 1. Philadelphia: WB Saunders, 1973.
CHAPTER 6. EPILEPSY
Manual of Neurologic Therapeutics
CHAPTER 6. EPILEPSY
Raymond J . Fernandez and Martin A. Samuels
Classification
Evaluation of the patient
Diagnostic approach
General principles in management
Generalized seizures
Partial (focal) seizures
Neonatal seizures
Discontinuation of medication in patients with seizures
Daily activities in patients with seizures
Paroxysmal conditions resembling epilepsy
Epilepsy may be defined as a state of recurrent seizures, which are not due to an
identifiable metabolic cause. Since seizures are due to hypersynchronized aberrant
electrical activity in virtually any part of the cerebral cortex, one may expect that nearly
every conceivable form of human experience could be caused by seizure discharges.
However, although this is literally true, generally the term epileptic seizure is used to
characterize relatively stereotyped recurrent attacks of involuntary experience or
behavior.
I. Classification. Many efforts have been made to classify the epilepsies by using
various parameters: etiology, symptomatology, duration, precipitating factors, postictal
phenomena, and aura. The most useful of these classifications with regard to therapy
utilizes the clinical symptomatology of the seizures; this mode of classification also
permits differentiation of true epilepsies from similar yet clinically distinct conditions.
A. Classification of epilepsies
1. Generalized
a. Absence
1. Typical (petit mal).
2. Atypical, including Lennox-Gastaut syndrome.
b. Tonic and/or clonic (grand mal)
1. Intermittent convulsions.
2. Status epilepticus.
c. Myoclonic epilepsy
1. Infantile spasms.
2. Benign myoclonus of infancy.
3. J uvenile myoclonic epilepsy (J ME).
4. Other, including subacute sclerosing panencephalitis and Lafora
disease.
d. Febrile seizures
2. Partial (focal)
a. Simple (without impairment of consciousness)
1. Motor.
2. Sensory.
3. Autonomic.
b. Complex (with impairment of consciousness), formerly known as temporal
lobe or psychomotor seizures.
1. Automatism.
2. Psychic phenomena.
3. Neonatal
B. Classification of paroxysmal conditions resembling epilepsy
1. Narcolepsy.
2. Migraine.
3. Paroxysmal abdominal pain.
4. Breath holding spells.
5. Hypercyanotic attacks.
6. Shuddering attacks.
7. Cardiovascular syncope.
8. Hysteria.
9. Malingering.
10. Trigeminal neuralgia (tic douloureux).
11. Paroxysmal vertigo.
C. Within a single attack, it is most useful diagnostically and therapeutically to
classify the seizure on the basis of its initial manifestations, if possible. Thus, a
partial motor seizure that becomes generalized (secondarily generalized) should
be considered a partial rather than a generalized attack.
II. Evaluation of the patient. A seizure is only a symptom caused by excessive
neuronal discharges. The precise cellular mechanism involved will not be discussed
herein; it is sufficient to state that this symptom can be produced by protean
abnormalities, both within and outside the nervous system. The major categories of
these abnormalities are as follows:
A. Genetic and birth factors
1. Genetic influence (primary, idiopathic, cryptogenic, essential).
2. Congenital abnormalities (including chromosomal abnormalities).
3. Antenatal factors (infections, drugs, anoxia).
4. Perinatal factors (birth trauma, asphyxia neonatorum, infections).
B. Infectious disorders
1. Meningitis.
2. Epidural or subdural abscess.
3. Brain abscess and granuloma.
4. Encephalitis.
C. Toxic factors
1. Inorganic substances (e.g., carbon monoxide).
2. Metallic substances (e.g., lead, mercury).
3. Organic substances (e.g., alcohol).
4. Drugs and drug withdrawal.
5. Allergic disorders (injection or ingestion of foreign protein).
D. Trauma or physical agents
1. Acute craniocerebral injuries.
2. Subdural or epidural hematoma and effusion.
3. Posttraumatic meningocerebral cicatrix.
4. Anoxia or hypoxia.
E. Circulatory disturbances
1. Subarachnoid hemorrhage.
2. Sinus thrombosis.
3. Encephalomalacia (thrombosis, embolus, hemorrhage).
4. Hypertensive encephalopathy.
5. Syncope.
6. Cardiac arrhythmia. The prolonged QT syndrome associated with recurrent
ventricular fibrillation, and sometimes associated with deafness, may on
occasion be diagnosed on the electrocardiogram (ECG) lead of the
electroencephalogram (EEG). The QT interval, corrected for heart rate, should
be measured, especially if the clinical diagnosis is syncope. The corrected QT
interval (QT
c
) is calculated by the following formula:
QT
c
5 QT (in seconds)/RR interval
The QT
c
should not exceed 0.45 in infants up to 6 months, 0.44 in children,
and 0.425 in adolescents and adults.
F. Metabolic or nutritional disturbances
1. Electrolyte and water imbalances (hyponatremia, hypocalcemia, water
intoxication, dehydration).
2. Carbohydrate metabolism (hypoglycemia, glycogen storage disease).
3. Amino acid metabolism (e.g., phenylketonuria).
4. Fat metabolism (e.g., lipid storage diseases).
5. Vitamin deficiency or dependency (e.g., pyridoxine dependency; biotinidase
deficiency).
G. Neoplasms
1. Primary intracranial (astrocytoma, other gliomas, meningiomas).
2. Metastatic (breast, lung, melanoma).
3. Lymphoma and leukemia.
4. Blood vessel tumors and vascular malformations.
H. Heredofamilial
1. Neurofibromatosis.
2. Tuberous sclerosis.
3. Sturge-Weber syndrome.
I. Febrile seizures
J . Degenerative diseases
K. Unknown causes
III. Diagnostic approach. The diagnosis of epilepsy rests mainly on the history; it
must be considered in any patient who suffers from recurrent attacks of stereotyped
involuntary behavior or experience. Particular diagnostic points relative to each type of
seizure will be mentioned in the subsections in each category; however, the following
general points apply broadly in the diagnosis of epilepsy.
A. EEG. There is no diagnostic test that can reliably either diagnose or exclude
epilepsy. The EEG is often normal, even in a patient with a known seizure
disorder; conversely, an abnormal EEG in the absence of symptoms does not
automatically indicate treatment for seizures. It is relatively unusual for seizure
activity to be recorded during an EEG. Therefore, the usefulness of the test is
largely dependent on interictal abnormalities, particularly when focal or lateralized
slow waves are observeda finding that suggests that a localized abnormality is
responsible for the seizure. Various activation procedures may be utilized (e.g.,
hyperventilation, photic stimulation, and sleep) to exacerbate an underlying
abnormality not recognizable on the ordinary tracing. Ambulatory and continuous
inpatient EEG monitoring is now available in many centers. This allows one to
record much larger samples of EEGs, thus increasing the chance of observing an
infrequent epileptic event. The EEG is especially important when one is evaluating
absence, a seizure pattern often confused with complex partial seizures. In
absence seizures, generalized spike and wave paroxysms are seen, whereas
focal abnormalities may be seen with partial seizures.
B. Etiology. Once the diagnosis of a seizure is made, a search for the etiology
should ensue. The diagnostic course to be followed will vary depending on the
type of seizure disorder identified and the age of the patient.
1. History. To categorize a patient's seizure properly, it is necessary to obtain a
careful history from both the patient and someone who has witnessed the
seizure(s).
a. Focality of seizures. Important historic points derive from whether the
seizures are generalized from their onset or have some partial quality. If
they are partial, it must be determined whether consciousness is altered.
Examples of altered consciousness may include disorders of arousal
mechanisms (e.g., drowsiness or momentary loss of consciousness),
abnormalities in perception such as psychic phenomena (e.g., dj vu,
jamais vu, fearfulness, paranoid or hostile feelings), or gustatory or
olfactory hallucinations.
b. The family history may reveal the existence of relatives with epilepsy or
with diseases associated with seizures.
c. The patient's past medical history may give a clue concerning remote
infections, such as meningitis or encephalitis; or a history of stroke or head
trauma may be elicited, either of which may be epileptogenic.
d. Pregnancy history. The history of the pregnancy, labor, and delivery
should be reviewed for evidence of complications known to be associated
with seizures in later life. Most notable among these are the following:
1. Prenatal problems due to developmental malformations, maternal drug
abuse, or infections.
2. Complications of labor and delivery.
3. Complications of prematurity.
2. A general physical examination might reveal a medical illness that might be
associated with seizures. Special care should be taken in examining the skin,
since neuroectodermal disorders (e.g., tuberous sclerosis, neurofibromatosis,
and Sturge-Weber syndrome) can be diagnosed in this way.
3. The neurologic examination may show some lateralizing or localizing
abnormality that would lead one to investigate more fully for an underlying
cause of a patient's seizures.
4. Once a seizure has been categorized with regard to the predominant type of
epilepsy from which the patient is suffering, further investigation and treatment
may be considered.
IV. General principles in management
A. Treat reversible metabolic conditions known to be associated with seizures, e.g.:
1. Hyponatremia.
2. Hypertension.
3. Drug withdrawal (e.g., alcohol, barbiturates).
B. Choose the proper drug for the seizure type, for example:
1. Phenytoin or valproate for generalized tonic-clonic seizures.
2. Carbomazepine for partial seizures.
3. Ethosuximide for typical absence seizures.
C. Minimize the number of drugs.
D. Simplify the dosage schedule.
E. Check blood levels when necessary, e.g.:
1. Approximately 2 weeks after adding a drug or changes in dosage.
2. When drugs known to interact are used.
3. Poor control of seizures.
4. Symptoms or signs of drug toxicity.
V. Generalized seizures
A. Absence seizures
1. Typical absence seizures (petit mal)
a. Description. Absence seizures are manifested by brief attacks of loss of
consciousness, sometimes associated with 3/second minor motor activity,
with 3/second generalized spikes and slow waves seen on the EEG.
Absence seizures usually begin when the patient is between 4 and 8 years
old. Most seizures are simple absence attacks in which the patient does not
lose body tone and does not fall. The attacks are usually 510 seconds in
duration and rarely exceed 30 seconds. Minor motor activity occasionally is
seen, facial twitching is usual, and, less often, automatisms such as lip
smacking and repetitive swallowing are seen. Sometimes these
automatisms are suggestive of complex partial (psychomotor, temporal
lobe) epilepsy, but there is no aura and no postictal state, and the patient
quickly returns to normal activity. The patient is rarely aware of these
attacks, so the history must be obtained from an observer.
b. Diagnosis. This form of epilepsy is unusual in that the clinical seizures
and the EEG are of equal diagnostic importance. The EEG shows a
highly characteristic, generalized, 3-second spike and slow-wave pattern.
An activation procedure, particularly hyperventilation, is often required to
bring out the abnormality. In the classic case, no further diagnostic
evaluation is necessary.
c. Prognosis. Most cases of classic absence seizures will resolve
spontaneously by the time the person enters the third decade of life.
However, some children also experience generalized tonic-clonic seizures
before, together with, or subsequent to, absence seizures. Although
absence seizures will resolve by the third decade of life or earlier,
generalized tonic-clonic seizures may persist. Four factors are associated
with a good prognosis (i.e., patients who do not satisfy these criteria will be
more likely to have generalized tonic-clonic seizures during childhood or in
later life):
1. Onset between the ages of 4 and 8 years and normal intelligence.
2. No other seizure type present.
3. Easy control with a single drug.
4. Classic, 3/second generalized spike and slow-wave pattern on EEG,
without other EEG abnormalities.
d. Treatment (Table 6-1 and Table 6-2)
TABLE 6-1. Treatment of Typical Absence (Petit Mal) Seizures
TABLE 6-2. Common Toxicities and Recommended Monitoring for the
Major Anti-epileptic Drugs (AEDs)
1. Ethosuximide (Zarontin). The treatment of choice for typical absence
seizures is ethosuximide, 20 to 40 mg/kg/day, divided into 2 or 3 doses.
The dosage usually begins with 20 mg/kg/day and is increased
gradually at weekly intervals until the seizures are controlled or until the
patient develops gastrointestinal upset, ataxia, or drowsiness. The
patient can be followed clinically for toxicity, or the serum levels of
ethosuximide can be measured (therapeutic range is 40 to 80 g/mL).
Patients with typical absence seizures may also have generalized
tonic-clonic seizures. If these occur, valproate should be used as the
sole drug (Table 6-3). Rarely, a combination of ethosuximide and
phenytoin or phenobarbital must be used.
TABLE 6-3. Treatment of Atypical Absence and the Lennox-Gastaut
Syndrome
2. Valproate (Depakene and Depakote) should be used if ethosuximide is
not effective. Valproate may also be used as the single drug in the
management of patients with both typical absence and generalized
tonic-clonic seizures. An initial dose of 15 mg/kg/day is recommended,
with increases of 5 to 10 mg/kg/day at 1-week intervals until seizures
are controlled or until there are clinical or biochemical signs of toxicity.
The maximum recommended dose is 60 mg/kg/day divided into 2 to 4
doses. Therapeutic serum levels are 50 to 150 g/mL.
a. Side effects. Although popular, valproate is not considered the drug
of first choice because of its potentially serious side effects. Death
due to liver failure has been reported in association with valproate
treatment. Fatal hemorrhagic pancreatitis also has been reported.
Elevation of the hepatic transaminase and serum ammonia levels
may occur in patients on valproate, which may be dose-related.
Bone marrow suppression resulting in clinically significant
thrombocytopenia and neutropenia may occur. This usually
responds to reduction in dosage, but discontinuation of the drug
might be necessary. Less serious side effects are drowsiness and
gastritis. Carnitine deficiency may occur secondary to long-term
valproate treatment leading to hyperammonemia, and this
complication should be prevented by supplementing carnitine
(l-carnitine, Carnitor) when necessary. The dosage is 50 to 100
mg/kg/day, maximum 3 g/day. Carnitor is supplied as 330-mg tablets
and as an oral solution containing 100 mg/mL.
b. Liver function tests, serum amylase levels, complete blood
count (CBC), and platelet counts should be performed prior to
treatment and at frequent intervals thereafter. A rise in the hepatic
transaminase levels and thrombocytopenia without associated
symptoms or other biochemical abnormalities may be successfully
managed by a reduction in dosage by at least 10 mg/kg/day. The
drug should be discontinued if the patient develops signs of liver
failure, pancreatitis, or biochemical abnormalities other than transient
hepatic transaminase elevation. When valproate is given
concurrently with phenobarbital, blood levels of the latter drug often
increase. This often will require a reduction of phenobarbital dosage.
Phenytoin blood levels may decrease with valproate usage.
3. Lamotrigine (Lamictal) should be tried if ethosuximide and valproate
are not effective. While not approved for use in pediatric patients, there
is considerable experience with the drug in intractable childhood
epilepsy. Hypersensitivity resulting in skin rash is the most worrisome
side effect and it occurs more frequently in children. Hypersensitivity
reactions are dose-related and also occur more commonly when
lamotrigine is used in combination with valproate (see Table 6-1 for
dosage).
4. Clonazepam (Clonopin). There is evidence that clonazepam may be
useful in the treatment of absence seizures. At present, however, it
should be reserved for cases not controlled with ethosuximide or
valproate or lamotrigine. The drug has the advantage of having very few
side effects, the most notable of which is sedation. The dosage of
clonazepam is 0.1 to 0.03 mg/kg/day PO initially, divided into 2 or 3
doses. This is increased slowly to 0.1 to 0.2 mg/kg/day.
5. Succinimides other than ethosuximide. The next drug choice for
control of absence seizures, as listed in Table 6-1, is the succinimide
derivative methsuximide (Celontin), which is closely related to
ethosuximide. This is given in dosages of 5 to 20 mg/kg/day PO, divided
into 2 or 3 doses, and
6. Acetazolamide (Diamox) is of limited value alone but is often of some
use in combination with another antiepileptic drug (AED). Added to any
of the above anticonvulsants, it occasionally improves seizure control.
The dosage is 10 to 25 mg/kg/day PO, divided into 3 doses.
7. A ketogenic diet helps to control absence seizures, but its use is
reserved for cases that are difficult to control, since the diet is
unpleasant and difficult for the patient to maintain. The acetazolamide
should be discontinued prior to institution of the ketogenic diet.
2. Atypical absence seizures, including the Lennox-Gastaut syndrome
a. Description. Atypical absence seizures and the Lennox-Gastaut syndrome
share many similarities and for this reason are discussed together. Patients
in this category have absence plus a variety of seizure types including
myoclonic, atonic, tonic, or tonic-clonic. There are idiopathic and
symptomatic types, the latter being due to a wide variety of static or
progressive diseases.
The Lennox-Gastaut syndrome usually begins during infancy or early
childhood. The seizure types listed above occur in varying combinations,
and there is evidence of developmental delay or regression depending on
the underlying disease. The EEG shows a variety of abnormalities including
interictal slow spike and wave complexes as well as spikes, polyspikes, and
slowing and disorganization of the background.
b. Diagnosis. These forms of epilepsy are recognized by the characteristic
history and EEG patterns listed above. They may be idiopathic but
frequently reflect underlying degenerative or static brain disease.
c. Prognosis. Seizure control is extraordinarily difficult, and developmental
outcome depends on the underlying process.
d. Treatment is extremely difficult, and control is rarely achieved (see Table
6-3).
1. Valproate as sole therapy should be tried initially (see sec. V.A.1.d.(2)).
2. The second choice is lamotrigine. (3) Topiramate 1 mg/kg/day initially,
increasing at weekly intervals to 3 to 8 mg/kg/day can reduce the
frequency of seizures. (4) Clonazepam may be tried next.
3. Phenytoin or phenobarbital should be tried for tonic-clonic seizures (see
sec. V.B.5.a and sec. V.B.5.b).
4. Ethosuximide is rarely effective but can be tried (see sec. V.A.1.d.(1)).
5. Other modalities such as acetazolamide or ketogenic diet may be added
to the above drug regimens.
6. Felbamate (2-phenyl-1,3-propanediol dicarbamate) can be effective in
the treatment of the Lennox-Gastaut syndrome, especially by reducing
the frequency of atonic episodes that often are particularly troublesome.
It is recommended as add-on treatment, to be used along with drugs
already being administered. It is necessary to reduce the dosage of
other drugs to avoid toxic side effects due to drug interaction. Because
of its serious hematologic toxicity, this drug should be reserved for only
the most intractable patients. See Table 6-3 for the dosage of
felbamate.
3. Nonconvulsive status epilepticus
a. Description. A patient in nonconvulsive status epilepticus may appear to
be confused or stuporous, and the EEG shows continuous generalized
spike and wave abnormalities.
b. Diagnosis is based on the clinical picture and the EEG.
c. Treatment consists of diazepam (0.3 mg/kg) or lorazepam (0.05 to 0.1
mg/kg) by IV infusion over 10 minutes.
B. Intermittent generalized tonic-clonic (grand mal) seizures
1. Description. Tonic-clonic (grand mal) convulsive epilepsy is defined as
recurrent episodes of sudden loss of consciousness, with associated
major motor activity. Tonic-clonic convulsions are characterized by sudden
loss of consciousness in which the entire body usually becomes rigid in
extension. The patient falls to the ground, sometimes with a cry, and may
urinate and be temporarily apneic. After a period of tonic rigidity, clonic jerking
of the face, trunk, and limbs ensues. The rate of clonic jerking gradually
decreases, and the patient finally becomes limp and comatose. Consciousness
gradually returns, often with a postictal state of confusion, headache, and
drowsiness. Patients may display various combinations of these components;
they may have purely tonic or purely clonic attacks, or any combination thereof.
Although many patients describe a prodromal period of irritability that varies
from a few minutes to several days before an attack, generalized tonic-clonic
seizures do not have a true aura, as may be seen in partial seizures. Because
of the apoplectic nature of the attacks, these patients, unlike patients with
absence seizures, are subject to serious injury during an attack, due to
accidents consequent to the sudden loss of consciousness. The incidence of
sudden death is increased in patients with generalized tonic-clonic seizures,
possibly due to the cardiac and pulmonary effects of the intense autonomic
activity associated with these seizures.
2. Diagnosis
a. Age range and incidence
1. A family history of epilepsy is common, and the familial nature of this
condition is generally recognized.
2. True tonic-clonic convulsive seizures usually begin before the age of
30 years but are rare before age 3 to 4 years. The vast majority of these
patients will have idiopathic epilepsy and will respond readily to
treatment with 1 or 2 drugs.
3. Between the ages of 30 and 60 years, the most common cause of
tonic-clonic convulsions is still idiopathic epilepsy, although the risk of
intracranial tumor is significantly higher than in the younger age groups.
4. Over the age of 60 years, the onset of tonic-clonic convulsions most
likely represents cerebrovascular disease (usually postcerebral
embolus), but tumor and idiopathic epilepsy remain important diagnoses
as well. At no time in life does the onset of tonic-clonic convulsions
primarily suggest brain tumor, although the incidence of brain tumor
peaks in middle life, and this diagnosis should certainly be excluded.
b. It is very important to attempt to rule out partial seizures that have
spread to become generalized (secondarily tonic-clonic seizures) as the
cause of what is apparently a primarily tonic-clonic seizure. In older children
and in adults, tonic-clonic seizures are very likely to be either idiopathic or
metabolic, whereas partial seizures, with or without spread to tonic-clonic
convulsions, represent focal brain disease and thus may have a graver
prognosis. In infants (especially neonates) and young children, seizures are
more likely to be partial, whether due to a diffuse or focal process.
It should be kept in mind that the history is often insufficient to definitely
rule out partial seizure with spread, so that many cases of what are
apparently generalized tonic-clonic convulsions are in fact partial seizures
with spread. Because these cases carry a more ominous prognosis with
respect to focal brain disease, whenever the history is vague, one should
assume that there is a possibility of partial seizures and act accordingly
(i.e., carry out a more vigorous evaluation, as outlined in sec. VI).
3. Prognosis. In patients with classic generalized tonic-clonic seizures, the
prognosis is good, because it is likely that the diagnosis will be idiopathic
epilepsy, which can easily be controlled with drugs. Often, seizures that begin
in the second or third decade become less frequent and even stop entirely,
allowing total discontinuation of anticonvulsant medications. Patients with
idiopathic tonic-clonic convulsions may experience exacerbation of their
seizures with metabolic stresses, such as drug withdrawal, fever,
hypoglycemia, and hyponatremia, all of which can produce tonic-clonic
convulsions in nonepileptic people.
4. Evaluation. Most patients who suffer their first seizure should be hospitalized
for the initial evaluation, since no predictions concerning etiology, future
course, or facility of control can be made on 1 isolated examination. Routine
studies on all patients who have suffered their first tonic-clonic convulsion
should include the following:
a. A careful neurologic examination should be aimed primarily at
determining whether any focal or lateralizing aspects of the seizure state
can be found either ictally or postictally.
b. CBC.
c. Serum electrolytes (sodium, potassium, chloride, bicarbonate).
d. Blood urea nitrogen (BUN).
e. Serum calcium.
f. Blood sugar.
g. Liver function tests (serum aspartate aminotransferase [AST]; alanine
aminotransferase [ALT]; alkaline phosphatase; total bilirubin).
h. Lumbar puncture for cerebrospinal fluid (CSF) if infection is suspected.
1. Cell count.
2. Glucose.
3. Protein.
4. Culture.
5. Syphilis serology.
i. Toxic screen and blood alcohol levels are obtained if drug or alcohol
ingestion is suspected.
j. During a generalized tonic-clonic convulsion, the EEG shows generalized
spikes. Postictally, it is generally slow, and interictally, the EEG may be
totally normal. If an abnormality is seen, care is taken to exclude a focal or
lateralizing abnormality, either ictally or postictally. However, if there is a
nonfocal, nonlateralizing EEG, the prognosis is good.
k. An MRI is the imaging method of choice and should eventually be
performed. CT scan remains a useful test and is easier to perform,
especially in an urgent situation such as trauma or suspected intracranial
hemorrhage.
5. Treatment (Table 6-4). There are 5 major drugs for the treatment of
generalized tonic-clonic seizures: valproate, carbamazepine, phenytoin,
phenobarbital, and primidone. These 4 drugs are virtually equally effective. The
decision as to which one to use for a particular patient depends on the relative
side effects and the patient's age.
TABLE 6-4. Treatment of Generalized Tonic-Clonic Convulsions and Partial
Seizures
a. Phenytoin
1. Administration
a. Therapeutic serum levels of 5 to 20 mg/mL correlate well with the
anticonvulsant properties of phenytoin. When given at 5 mg/kg/day
(about 300 mg/day in an average adult), it takes 5 to 15 days to
reach the therapeutic range. However, if a loading dose of 18 mg/kg
(15 to 20 mg/kg; maximum 1 g) is given PO, the therapeutic range
can be reached within a few hours. Since the biologic half-life of
phenytoin is usually about 24 hours, the drug needs to be given only
once per day. If the drug is given IV (either as phenytoin or
fosphenytoin), the therapeutic range can be reached in minutes.
b. Dilantinization can be accomplished at various rates. The rate at
which a patient is dilantinized depends on the clinical situation. The
therapeutic range can be reached in as little as 20 minutes or as
long as 15 days. Obviously, the number of dose-related side effects
will increase with the speed at which the patient is dilantinized, so
the general rule of thumb is to proceed as slowly as is clinically safe.
For example, a patient who has had only 1 seizure receives 5
mg/kg/day PO (about 300 mg/day in an average adult), and
therapeutic effects are expected in about 5 days. However, some
patients have excessive phenytoin metabolism, in which case the
therapeutic effects may not be demonstrated for as long as 2 weeks.
c. If the patient has had several seizures and cannot be hospitalized for
some reason, one might wish to administer 18 mg/kg in the first 24
hours, perhaps divided into 3 doses. The entire loading dose can be
given at once if even more rapid dilantinization is desired. The latter
method would result in therapeutic levels in 5 to 6 hours. Various
approaches to dilantinization are outlined in Table 6-5.
TABLE 6-5. Various Methods of Dilantinization
d. There is usually reasonably good correlation between serum
phenytoin levels and the following clinical signs:
i. Nystagmus develops when the phenytoin level is about 10 to 20
mg/mL. It is very common to see bilateral horizontal nystagmus
on lateral gaze when phenytoin levels are in the therapeutic
range.
ii. Ataxia develops when the phenytoin level is about 30 mg/mL.
The development of frank ataxia should warn the physician that
the dosage should be decreased.
iii. Lethargy develops when the phenytoin level reaches about 40
mg/mL.
2. Side effects. The side effects of phenytoin are protean, but fortunately
the most serious ones are uncommon and are usually reversible. The
untoward effects can be divided into 3 categories: local, idiosyncratic,
and dose-related.
a. Local side effects. The only local side effect of oral phenytoin is
gastric upset, which can usually be relieved if phenytoin is taken with
meals or milk. Painful and sometimes serious local tissue damage
can be seen with intravenous phenytoin infusions. This can be
avoided by infusing fosphenytoin that is not dissolved in propylene
glycol, however fosphenytoin is much more expensive than
phenytoin.
b. Idiosyncratic side effects. Several idiosyncratic effects are seen,
many of which require discontinuation of the drug. For example,
dermatitis may develop, with fever and eosinophilia. A lupuslike
syndrome occasionally occurs, with positive antinuclear antibodies;
and occasional blood dyscrasias occur, including leukopenia,
agranulocytosis, thrombocytopenia, aplastic anemia, and
pseudolymphoma. If any of these complications occur, phenytoin is
discontinued in favor of another anticonvulsant. Gingival hypertrophy
and hirsutism are common side effects of phenytoin, and although
they are not in themselves contraindications to the use of the drug,
they can be sufficiently bothersome cosmetically to indicate
replacement of phenytoin by another antiepileptic drug. For this
reason alone, many neurologists use another anticonvulsant as the
first choice in young patients.
c. Dose-related side effects. A number of dose-related side effects
also exist, including cerebellar ataxia and nystagmus, as mentioned
previously; a megaloblastic anemia due to interference with folic acid
and vitamin B
12
metabolism; low protein-bound thyroxine (T4) due to
competitive binding of phenytoin to the thyroid-binding globulin;
immunosuppression clinically expressed as recurrent infections; and
hypocalcemia with osteoporosis and elevated serum alkaline
phosphatase. The latter effect is probably caused by phenytoin's
effects on the liver, which accelerates vitamin D metabolism,
producing a relative deficiency of vitamin D. It has been reported that
long-term phenytoin use occasionally may be associated with
cerebellar degeneration and polyneuropathy. Subtle interference
with cognitive function may occur in children.
d. Treatment of side effects. Many of these side effects can be
treated without stopping the phenytoin:
i. By lowering the dosage if it is above the therapeutic range.
ii. By administering folate, vitamin B
12
, or vitamin D when indicated.
iii. By recognizing that an apparently low T4 only represents an
artifactual lowering of T4 binding to thyroid-binding globulin.
3. Drug interactions. Many commonly used drugs interfere with the
metabolism of phenytoin, thus elevating its blood level. If frequent
clinical examinations are done to monitor the blood level of phenytoin,
the dosage can be lowered until the proper therapeutic range is reached
for a particular patient. Serum levels of phenytoin may be helpful.
a. Drugs known to elevate the blood level of phenytoin or to increase
the risk of toxic side effects:
i. Isoniazid (INH).
ii. Coumarin anticoagulants.
iii. Disulfiram (Antabuse).
iv. Chloramphenicol (Chloromycetin).
v. Benzodiazepines (Librium, Valium, Serax, Clonopin).
vi. Methylphenidate (Ritalin).
vii. Phenothiazines.
viii. Estrogens.
ix. Ethosuximide (Zarontin).
x. Phenylbutazone (Butazolidin).
xi. Acute alcohol ingestion.
xii. Tolbutamide.
xiii. Halothane.
xiv. Felbamate.
b. Drugs known to lower the blood level of phenytoin or to decrease its
therapeutic effects:
i. Carbamazepine (Tegretol).
ii. Chronic alcohol abuse.
iii. Reserpine.
c. Drugs known to either lower or increase blood levels of phenytoin:
i. Phenobarbital.
ii. Valproate.
d. Drugs whose efficacy is impaired by phenytoin:
i. Corticosteroids.
ii. Coumarin anticoagulants.
iii. Oral contraceptives.
iv. Quinidine.
v. Vitamin D.
b. Phenobarbital is a barbiturate which has potent anticonvulsant properties.
1. Administration. The required dosage of phenobarbital is less
predictable than that of phenytoin. Children require 3 to 5 mg/kg/day
(the serum therapeutic range is 20 to 40 g/mL), whereas adults usually
require proportionally less, about 60 to 120 mg/day. The biologic half-life
of phenobarbital is even longer than that of phenytoin (about 96 hours),
and thus, theoretically, it can be given less frequently. However, the
sedative effects of the drug usually preclude giving the entire daily dose
at one time. Thus it is generally necessary to administer it in 2 or 3
divided doses.
There is no limiting factor to increasing the dosage of phenobarbital,
except sedation or behavioral and personality changes, and often much
higher dosages than have been recommended are required to control
seizures. The use of phenobarbital for continuous seizures is slightly
different and is covered in sec. V.C.
2. Side effects
a. The major contraindication of phenobarbital is that it produces
sedation when given in the anticonvulsant therapeutic range. Usually
this effect will decrease as the patient becomes tolerant to the drug,
but sometimes it does not. In patients in whom the sedative effects
are tied closely to the anticonvulsant effects, phenobarbital
sometimes cannot be used. Fortunately, this situation is rare.
Furthermore, as the patient becomes tolerant to the sedative
property of phenobarbital, the patient may also become tolerant to
the anticonvulsant properties, in which case the dosage must be
increased, producing drowsiness again. Usually, the drowsiness
decreases after a few days or weeks, and the potent anticonvulsive
effects remain. In school-aged children, the drug commonly causes
hyperactivity and irritability and interferes with learning, so it is rarely
used.
b. Rarely, phenobarbital may produce a megaloblastic anemia, similar
to that produced by phenytoin. This effect is responsive to folate or
vitamin B
12
, but sometimes this therapy results in exacerbation of
seizures, requiring that another anticonvulsant be used.
c. Relative vitamin D deficiency and osteomalacia may also be seen
with phenobarbital use, but less frequently than with phenytoin.
c. Carbamazepine (Tegretol) is a dibenzepin derivative that is related
structurally to imipramine (Tofranil). The drug has gained widespread
acceptance because many of the behavioral, cognitive, and other side
effects of phenobarbital and phenytoin could be avoided, especially in
school-aged children.
1. Administration. Dosage is 15 to 25 mg/kg/day, given PO in 2 or 3
doses. Barring abnormalities in the blood count or liver function tests,
the dosage may be gradually increased from the lower to the higher
doses until either unacceptable sedation or control of seizures occurs. A
serum carbamazepine test is available, and the therapeutic range is 6 to
10 g/mL. Carbamazepine may be used alone or in combination with
other AEDs.
2. Side effects include allergic skin rashes, sedation, dry mouth,
gastrointestinal upset, cholestatic jaundice, aplastic anemia, and
pancytopenia. As a result, patients should be followed closely, with
quarterly CBCs and liver function tests, and the drug should be
discontinued if there is evidence of significant bone marrow depression
or liver dysfunction. Most of these side effects have been reversible,
although irreversible and fatal blood dyscrasias have occurred very
rarely.
d. Valproate. See sec. V.A.1.d.(2).
e. Primidone (Mysoline) is closely related chemically to phenobarbital, but it
will occasionally help to control tonic-clonic convulsions when phenobarbital
fails.
1. Indications. Primidone may be used alone, but more often it is used in
combination when other AEDs fail as monotherapy. Phenobarbital and
primidone are not used in combination because of their close chemical
relationship.
2. Administration. The usual dosage for children under 6 years old is 10
to 25 mg/kg/day, divided into 2 or 3 doses. As with phenobarbital, adults
require proportionally lower dosages, usually in the range of 300 to 750
mg/day. Children should be started on 10 mg/kg/day and the dosage
gradually increased until either seizure control or unacceptable sedation
occurs. Adults should be started at low dosages (50 to 125 mg/day),
which can be gradually increased to the therapeutic range. Primidone
can only be given PO.
3. Side effects
a. The major side effect is sedation, which may be severe and less
likely to disappear with time, as it does with phenobarbital. This can
sometimes be avoided by beginning with a low dosage and gradually
increasing it to the therapeutic range (10 to 25 g/mL).
b. A syndrome of vertigo with cerebellar ataxia may develop in the
first few days of therapy but generally resolves spontaneously.
c. An allergic rash rarely develops, but when it does, primidone should
be replaced with another AED.
d. A megaloblastic anemia may also develop occasionally, most often
due to folate deficiency, but occasionally caused by vitamin B
12

deficiency. This can be treated with folate, vitamin B
12
, or both,
without discontinuing the medication.
e. Primidone has the same potential for tolerance and withdrawal as
phenobarbital, and its ability to produce life-threatening respiratory
depression in overdosage is the same as with other barbiturates.
6. Pregnancy. The question of how to manage epilepsy in the pregnant patient is
difficult. However, there are some general principles to guide the physician.
a. The precise effect on the fetus of most antiepileptic drugs is not known.
The use of AEDs has been associated with a slightly increased incidence of
serious congenital anomalies, but human studies are always limited by the
fact that epilepsy itself may have similar effects. Because of the lack of
evidence for safe use of most AEDs, it is recommended that as many
AEDs as possible be discontinued in pregnancy, particularly in the
first trimester.
b. Absence and partial seizures probably have no adverse effect on the
mother or fetus, and thus AEDs may be discontinued in some of these
patients for the duration of the pregnancy. However, if absence or partial
seizures are overwhelmingly disabling or dangerous to the patient, then the
risk to the patient must be weighed against the unknown risk to the fetus.
c. It is generally agreed that frequent tonic-clonic convulsions during
pregnancy are dangerous to the mother and fetus. Although the
clinician should attempt to decrease AEDs during pregnancy, this may not
always be possible. If the seizures cannot be controlled, it is reasonable to
use whatever AED is required, since the risk to the fetus is probably greater
with multiple tonic-clonic convulsions than it is with any of the AEDs.
d. Oral contraceptive levels fall with AED use possibly rendering them
ineffective. Break through bleeding should be taken as a sign of oral
contraceptive failure in patients taking AEDs. Consultation with an Ob-Gyn
specialist is recommended in this circumstance.
7. Folic acid supplementation 400 to 1,000 mg/day is recommended in
women of childbearing age who are taking AEDs. Toxemia of pregnancy
refers to the syndrome of acute or subacute hypertension during gestation.
Preeclampsia refers to the development of blood pressure above 140/90 mm
Hg with proteinuria, persistent edema, or both. Hyperreflexia and headache are
common features of preeclampsia but are not part of the definition. When
seizures or coma is added to this syndrome, the condition is called eclampsia.
It is generally agreed that the neurologic aspects of the illness are due to
hypertensive encephalopathy. Toxemia occurs almost exclusively in the
second half of gestation and is seen most commonly in poorly nourished
primigravidas. The etiology is unknown. The condition is associated with a high
maternal and fetal mortality; when it is diagnosed, pregnancy should be
terminated if possible. Prior to the termination of pregnancy, the following
treatment regimen is recommended:
a. Magnesium sulfate (MgSO
4
) 10 g of a 50% solution IM in divided doses in
the upper outer quadrant of each buttock, followed by 5 g of a 50% solution
IM every 4 hours in alternate buttocks, provided a patellar reflex is present,
respirations exceed 12 breaths per minute and urine output during the
preceding 4 hours exceeds 100 mL. For patients with a diastolic blood
pressure over 110 mmHg, a systolic blood pressure over 160 mm Hg, and
proteinuria greater than 3 plus by dipstick, an initial intravenous dose of 4 g
of magnesium sulfate as a 20% solution is administered followed by the
intramuscular regimen.
b. If MgSO
4
fails, lower the blood pressure with nitroprusside, 3 g/kg by
continuous IV infusion. Propranolol, 1 to 5 mg IV, may be required to block
the reflex tachycardia that is seen with nitroprusside use.
c. If seizures continue, check metabolic indices that may be associated with
seizures, in particular the serum sodium.
d. If seizures persist despite correction of metabolic abnormalities and
normalization of the blood pressure, treat with phenytoin or fosphenytoin IV,
15 mg/kg at 50 mg/minute.
e. If phenytoin fails, perform a lumbar puncture, obtain a CT scan, and infuse
diazepam (5 to 10 mg) by slow (over about 5 minutes) injection.
8. Drug withdrawal seizures. Seizures may occur as part of the withdrawal
syndrome from many drugs, the most common and important of which are
alcohol, benzodiazepines, and barbiturates. If they are caused only by
withdrawal from these agents, they should be generalized tonic-clonic
convulsions. However, if there appears to be a focal aspect to the seizure or a
postictal (Todd's) paralysis in a patient suspected of withdrawing from drugs,
the possibility of focal brain disease must be raised, and the diagnosis of
simple drug withdrawal seizures cannot be made.
In general, drug withdrawal seizures are treated acutely just as any other form
of generalized tonic-clonic convulsions. There are, however, many commonly
held misconceptions about this type of seizure, which the following points may
help to clarify:
a. Phenytoin is useful in treating alcohol, benzodiazepine, and barbiturate
withdrawal seizures, acutely and prophylactically. However, long-term AED
treatment is often unsatisfactory, since patients rarely continue their
medications faithfully when taking drugs or alcohol. Thus, most neurologists
use phenytoin only when necessary to control severe convulsions, but not
on a long-term basis. Repletion of magnesium may also help to prevent
alcohol withdrawal seizures.
b. Barbiturates in very large doses (sometimes more than 1 g of secobarbital
[Seconal]) may be necessary to control severe barbiturate withdrawal
seizures. In these cases, other AEDs are often of little value. One can only
suspect such a situation by obtaining a history from the patient's friends or
relatives. Short-acting barbiturates, such as secobarbital, are more likely to
produce a withdrawal syndrome than long-acting agents, such as
phenobarbital. However, all barbiturates can produce withdrawal
seizures. When administering barbiturates in doses higher than about 250
mg in acute situations, preparations should be made to perform
endotracheal intubation if necessary.
c. When one is faced with a known barbiturate dependent patient who has
discontinued use of the drugs abruptly, it is usually wise to administer
barbiturates prophylactically to prevent withdrawal seizure and then
gradually decrease dosage of the drug over several days or weeks. The
level of the patient's tolerance can be judged clinically by administering
secobarbital, 200 mg PO, and observing for nystagmus and cerebellar
ataxia 30 minutes later. If no toxicity is noted, secobarbital, 100 mg, can be
administered every 30 minutes until nystagmus or cerebellar ataxia is
noted. The total dose administered may be considered the patient's daily
maintenance dose. This dose can then be tapered by 50 to 100 mg every
other day to withdraw the drug completely and safely.
d. In most cases of uncomplicated alcohol withdrawal seizures (and many
cases of barbiturate withdrawal seizures as well), the illness is self-limited
and does not require AED therapy.
C. Continuous tonic-clonic convulsions (convulsive grand mal status
epilepticus)
1. Description. Generalized tonic-clonic status epilepticus is defined as either
continuous (30 minutes or longer) tonic-clonic convulsions or
convulsions that are so frequent that each attack begins before the
postictal period of the preceding one ends. For example, the patient's motor
movements may be continuous or stop intermittently. In the latter case, the
patient may respond to stimuli or even follow simple commands, but before the
patient regains total consciousness, another seizure may intervene.
2. The diagnosis of generalized tonic-clonic status epilepticus is usually not
difficult. The patient exhibits tonic or clonic movements (or both) of all limbs.
These movements are often associated with roving eye movements or clonic
eye movements, which may vary in direction from time to time. Without a
history from an observer of the onset of the seizures, there is no way to be
sure whether the seizures are classified as primarily generalized tonic-clonic
seizures or whether they are the result of spread from a partial seizure. Since
the latter holds a graver prognosis with respect to the underlying disease
process that could have precipitated the attack (i.e., it implies focal brain
disease), it is assumed that there is a focus until proved otherwise. In this way,
a serious focal brain lesion will not be overlooked, such as subdural
hematoma, which may appear as continuous, generalized tonic-clonic
seizures.
3. Prognosis. The outcome following an episode of status epilepticus depends
on the underlying disease and the duration of the seizures plus associated
metabolic abnormalities. In general, the outlook is more favorable in patients
with idiopathic epilepsy or easily correctable metabolic abnormalities in
contrast to patients with acute destructive brain insults such as hypoxia,
encephalitis, or trauma. Systemic metabolic abnormalities such as hypoxia,
acidosis, and hypoglycemia may result in a poor outcome. In addition, local
biochemical tissue changes may occur after 20 to 30 minutes of status
epilepticus, and within 60 minutes irreversible neuronal damage may be seen.
4. Evaluation. In every patient with continuous tonic-clonic convulsions, the
following evaluation should be performed:
a. A careful history (from friends or relatives) and physical examination
should be aimed at:
1. Signs of head trauma.
2. CNS infection.
3. Drug intoxication.
4. History of epilepsy and AED use.
5. Any evidence of focal characteristics of the seizures themselves.
6. Recent surgery (e.g., thyroid or parathyroid surgery that might
predispose a patient particularly to hypocalcemia).
b. A history or physical signs of insulin use might lead one to consider
hypoglycemia as a major possibility.
c. An ECG, if technically possible (sometimes it can be done interictally), may
show a long QT interval, which is evidence of possibly significant
hypocalcemia or an underlying cardiac arrhythmia that precipitated the
seizure episode and might recur.
d. Before therapy is initiated, blood is drawn and sent to the laboratory for the
following:
1. Serum glucose.
2. Serum calcium.
3. Serum sodium.
4. When specifically indicated, serum and urine may be sent for toxic
screen, and serum is sent for AED levels.
e. Nearly all patients in tonic-clonic status epilepticus are febrile, so this alone
is not an indication to do a lumbar puncture. Lumbar puncture is
technically difficult in a convulsing person and may be deferred until after
the seizures are controlled, unless strong indications are present (e.g.,
historic or physical evidence of possible bacterial meningitis).
5. Treatment (Fig. 6-1)
FIG. 6-1. Treatment of generalized tonic-clonic status epilepticus.
a
Thiamine is
given when alcoholism or malnutrition is suspected.
b
Never dilute in
glucose-containing fluids.
c
Drug of first choice in neonates.
d
In children, usually
diazepam or lorazepam is the initial drug, followed by phenytoin.
a. When to treat. Seizures rarely require emergency intervention, since
the majority are brief and self-limited. A great deal of harm can be done by
overdosing patients in an attempt to control non-life-threatening seizures
with aggressive AED therapy. Continuous, generalized tonic or clonic
convulsions (or both) require deliberate, relatively rapid therapy on an
emergency basis. Even in this situation, termination of the seizure within
seconds or minutes is rarely required and should be sought only
when the seizure activity has resulted in either severe hypoxia or
acidosis, which in turn threatens the patient's life or has been
prolonged (i.e., approaching 60 minutes).
b. General measures
1. The patient is placed in a semiprone position, preferably with the head
lower to prevent aspiration, until full consciousness is regained.
2. Care is taken to maintain an adequate airway. Usually this can be
accomplished with an oral airway, but occasionally endotracheal
intubation is required.
3. Oxygen may be administered by face mask.
4. The patient is placed in a safe environment with padded bed rails but is
not restrained, since many intraictal injuries are caused by restraint in
abnormal postures.
5. After blood is drawn for initial chemical studies, drug therapy is initiated
(see Fig. 6-1).
c. Drug therapy
1. Thiamine. In adults, thiamine (100 mg IV) is always given before
dextrose, to protect the patient against an exacerbation of Wernicke's
encephalopathy, a relatively common disease among patients with
status epilepticus.
2. Dextrose. All patients should receive dextrose (25 to 50 g by rapid IV
infusion in adults, and 2 to 4 mL/kg of 25% dextrose by IV infusion in
children), unless a normal blood sugar can be disconnected regularly by
a reliable laboratory test.
3. Sodium chloride
a. In patients with seizures thought to be secondary to hyponatremia
(serum sodium is usually lower than 120 mEq/L), hypertonic (3%)
sodium chloride should be given by slow IV drip. These patients are
usually resistant to conventional anticonvulsant therapy.
b. In most cases, hyponatremia is not recognized until the serum
sodium level is available; however, a history of compulsive water
drinking, head trauma (causing the syndrome of inappropriate
antidiuretic hormone), or hyponatremia in the past may raise a
suspicion of this diagnosis. Note that hypertonic saline infusions are
dangerous and should be reserved for severely ill patients with
strongly suspected or proved hyponatremia. In these patients, an
attempt should be made to correct only half the calculated sodium
deficit with 3% saline, which should be sufficient to terminate the
seizures. The rest of the deficit can be corrected by restricting free
water intake and waiting for diuresis to occur. Excessively rapid
correction of hyponatremia may result in cardiovascular overload or
osmotic demyelination (i.e. central pontine myelinolysis).
c. The formula for calculating the required sodium infusion is: mEq
sodium required 5 (desired serum sodium 2 patient's serum sodium)
3 (0.6 3 patient's weight in kilograms).
4. Calcium. In patients with hypocalcemia, 1 or 2 ampules of calcium
gluconate, depending on the patient's size (90 mg of elemental
calcium/ampule), should be given IV over a 5- to 10-minute period. In
illness with an unknown etiology in which the suspicion of hypocalcemia
is high (i.e., long QT interval on ECG or recent history of thyroid or
parathyroid surgery), calcium should be given also, even before the
serum calcium levels are available.
5. Phenytoin is a very effective AED. It has the advantage of having very
little effect on the patient's level of consciousness and EEG.
a. Therapeutic levels. Levels of phenytoin in the patient's serum
correlate with its clinical effectiveness. Given IV (15 mg/kg, or about
1,000 mg in adults, over 20 minutes), therapeutic levels of 10 to 20
g/mL can be reached within a few minutes. Thus, initial drug
therapy for generalized tonic-clonic status epilepticus should be
intravenous phenytoin or fosphenytoin, as described in sec. V.B.5.a.
b. Blood pressure, respiratory rate, and ECG are monitored during
the infusion, since occasionally fatalities have been reported due to
hypotension, heart block, and respiratory depression during
excessively rapid phenytoin infusions. Phenytoin should be given
undiluted, since the drug may precipitate in IV solutions. If phenytoin
must be placed in solution, only saline should be used, and the
solution should be administered with a controlled infusion pump.
c. If fosphenytoin is used, it may be diluted in any intravenous fluid.
d. Intravenous phenytoin is relatively contraindicated in patients with
known heart disease, particularly where conduction abnormalities
are known to be part of the disease process. The infusion itself
requires up to 20 minutes, after which the patient should be
observed for 20 or 30 minutes. Most seizures will improve
significantly or stop during this time.
6. Benzodiazepines
a. Diazepam (Valium) is a benzodiazepine derivative that possesses
some antiepileptic activity. The drug has gained a great deal of
popularity in the treatment of continuous generalized convulsions. It
may, however, produce serious respiratory depression or
hypotension, particularly in combination with barbiturates.
Furthermore, since its anti-epileptic action is brief, it should never be
given alone but always in combination with a long-acting AED such
as phenytoin. However, there are some situations in which this
sequence is not effective or the patient is severely apneic or hypoxic;
as a result, enough time cannot be allowed for the conventional
anticonvulsants to work. In this circumstance, diazepam may be very
useful (0.25 to 0.40 mg/kg up to 20 mg by slow IV infusion) to control
clinical seizure activity. Endotracheal intubation is very often required
at this stage, and hypotension is a potential problem.
b. Another benzodiazepine, lorazepam (Ativan), is also effective in this
circumstance. Initially 0.05 to 0.10 mg/kg to a maximum dose of 4
mg is given over about 2 minutes. If seizures are not controlled,
another 4 mg may be given in a similar fashion. Respiratory
depression may occur, but overall the drug seems reasonably safe.
c. Midazolam (Versed) is a short-acting benzodiazepine that may also
be useful in the management of tonic-clonic status epilepticus. A
slow IV infusion of 0.2 mg/kg may be given (at about 1 mg/minute),
followed by a constant infusion of 0.2 mg/kg/hour. Monitoring by
EEG is useful if the constant infusion is used.
d. Either diazepam, lorazepam, or midazolam may be used, but only
one benzodiazepine should be administered to the same patient
during a given attack of status epilepticus.
7. Phenobarbital is generally considered an effective drug for control of
generalized tonic-clonic status epilepticus. It is the drug of choice in
neonates.
a. Dosage. Phenobarbital should be given IV if possible, 10 mg/kg in
children and 90 to 120 mg in adults, either as the initial drug or as
the second-line drug if phenytoin fails to control the seizures. This
may be repeated every 10 to 15 minutes to a maximum dose of
about 25 mg/kg in children and 1,000 mg in adults.
b. Respiratory depression is common with barbiturates, particularly
when given IV; they should be given only when the facilities are
available for emergency endotracheal intubation. In patients who
received phenobarbital as the first-line drug, phenytoin may be used
as the second (see sec. V.C.5.c.(5)).
8. General anesthesia or pentobarbital-induced coma is the last resort for
the control of tonic-clonic status epilepticus. In addition to controlling the
muscular movements, these act as AEDs and will often terminate the
most resistant forms of status epilepticus. Long-acting AEDs should
always be given before general anesthesia is administered. Use of
pentobarbital requires the availability of continuous EEG monitoring to
document the production of a burst suppression pattern on the EEG. For
dosage regimen, see Chap. 1, sec. VII.D.6.g.
D. Myoclonic epilepsy. The term myoclonus is used to describe several different
types of abnormal involuntary movements characterized by single or repetitive
jerks of a body part. The phenomenon of myoclonus may be a symptom of a
disease that involves numerous parts of the nervous system. However, some
types of myoclonus are associated with paroxysmal discharges of the EEG,
suggesting that it is epileptic in nature. Other types have no associated EEG
abnormality, and these are not generally felt to be epileptic in nature. The latter
variety includes many biochemical disorders, such as uremia and hepatic
failure; nocturnal myoclonus, occurring as a person is about to fall asleep;
myoclonus seen in some spinal cord lesions; and palatal myoclonus, which is
thought to be caused by disease of the central tegmental tract of the brainstem.
Action myoclonus, seen occasionally as a sequel to hypoxic brain damage or
encephalitis, sometimes has associated EEG spikes and sometimes does not (see
Chap. 15).
1. Infantile spasms
a. Description. Infantile spasms are defined as massive flexor (rarely
extensor) spasms of the extremities and trunk that begin in infancy,
usually between the ages of 4 and 9 months, and are associated with
hypsarrhythmia. There are two varieties of infantile spasms: cryptogenic
and symptomatic. In the cryptogenic variety, etiology is unknown, and the
infant is normal neurologically up until the onset of the spasms, with
developmental regression typically occurring thereafter. Brain computed
tomography (CT) scanning and magnetic resonance imaging (MRI) are
normal, at least at the onset. Possible etiologies in the symptomatic group
include developmental brain abnormalities (particularly lissencephaly),
congenital infections, neurocutaneous syndromes (e.g., tuberous sclerosis),
complications of labor and delivery, and a variety of metabolic diseases.
Infants in this category are usually abnormal developmentally and
neurologically prior to onset of spasms. Both types of infantile spasms are
characterized by generalized flexor spasms of the neck, trunk, and
extremities. The attacks occur in bouts several times a day, occurring
sometimes as often as 50 times/day, often during periods of drowsiness.
b. The diagnosis depends on the characteristic appearance of spells in an
infant between the ages of 4 and 9 months, although occasionally the onset
can be earlier or later (up to 2 years). The EEG shows an abnormality that
is referred to as hypsarrhythmia (generalized asynchronous spikes and
high-voltage slow, sharp activity), which is highly characteristic of this
disorder. Diagnostic evaluation should include a search for a metabolic,
infectious, or structural abnormality, which may be the cause of the
spasms.
c. The prognosis with infantile spasms is poor, particularly if there is an
earlier onset, if there is delayed development prior to the onset of the
seizures, or if there is evidence of a structural abnormality by CT or MRI.
Many patients die in childhood owing to complications of the chronic
underlying neurologic disease.
d. Treatment (Table 6-6)
TABLE 6-6. Treatment of Infantile Spasms
1. Adrenocorticotropic hormone (ACTH) may have some effect on the
course of infantile spasms in that it may control the seizures and
improve the EEG. However, there is no evidence that treatment with
ACTH will alter the ultimate outcome. ACTH, 20 to 40 units IM, is given
daily. If the initial response is good, a 2- to 3-week course of treatment
is often all that is necessary. Up to 6 to 8 weeks of treatment or a higher
dosage may be necessary if the initial response is less favorable. A
repeat course of treatment is recommended if there is relapse after
ACTH is stopped. It is important to monitor blood pressure, stool for
blood, electrolytes, and infectious symptoms and signs. Chickenpox
exposure should be treated with zoster immune globulin (ZIG) as soon
as possible.
2. Valproic acid is sometimes effective in controlling myoclonus. The
dosage is discussed in sec. V.A.1.d.(2). If used, it must be understood
that the likelihood of serious liver toxicity is greater in infants than in
older patients and especially if the infant is also developmentally
delayed or is receiving additional AEDs. In children below the age of 2
years, valproate should not be used in combination with another drug.
The suspicion or documentation of an underlying metabolic disorder
might be a contraindication to the use of valproate. This is especially
true if the underlying disorder involves mitochondrial enzyme function.
Carnitine should be supplemented in infants and young children who are
in relatively high-risk categories for serious liver toxicity. The carnitine
dosage ranges from 50 to 100 mg/kg/day to a maximum of 3 g/day.
3. Clonazepam, a benzodiazepine derivative that is related to diazepam,
may be useful in the treatment of various types of myoclonus. It is
started at 0.01 to 0.03 mg/kg/day PO and is gradually increased to 0.1
to 0.2 mg/kg/day, divided into 3 doses.
4. Diazepam is occasionally effective in infantile spasms in dosages of
about 1 to 2 mg PO q3h.
5. A ketogenic diet can be used in combination with any of these drugs.
6. Acetazolamide can also be used in combination with any of these
therapies discussed, with the exception of the ketogenic diet.
2. Benign myoclonus of infancy. The seizure pattern is similar to that seen in
infantile spasms, but there are no neurodevelopmental or EEG abnormalities.
The cause is not known. Treatment is not necessary, and outcome is good.
3. Juvenile myoclonic epilepsy (J ME). The seizure pattern has a genetic basis
and is carried in chromosome number 6. It usually begins between 12 and 18
years of age and typically consists of myoclonic jerks, which usually occur on
awakening or shortly thereafter. The arms are involved to a greater degree
than the legs. Consciousness may or may not be altered. Absence and
generalized tonic-clonic seizures may also occur. Patients are otherwise
normal neurologically. The EEG shows generalized repetitive spike and
spike-wave discharges. Valproate is the drug of choice and is usually effective.
Alcohol and sleep deprivation are potent triggers of seizures in this syndrome,
and patients should be aware of this.
4. Other types of myoclonic epilepsy
a. Description. Myoclonic seizures may be seen in a wide variety of static,
metabolic, and degenerative diseases, such as Lafora disease, various
lipidoses, and subacute sclerosing panencephalitis.
b. Diagnosis. Diagnostic studies will be determined by the underlying cause
or causes suspected.
c. Prognosis will vary with the underlying illness.
d. Treatment
1. Valproate may be effective in controlling the variety of seizure patterns
seen in this syndrome with its associated slow spike-and-wave EEG
abnormality.
2. Primidone is the second-line drug and should be tried next if valproate
is not effective.
3. Clonazepam and diazepam may be useful to control the myoclonus
(see sec. V.D.1.d.(3) and sec. V.D.1.d.(4)).
E. Febrile seizures
1. Description. Uncomplicated febrile seizures are defined as brief generalized
seizures in a child, usually between the ages of 6 months and 5 years, who is
febrile prior to the seizure in the absence of CNS infection or other defined
cause. Children who have had prior afebrile seizures are excluded from this
category. If the definition of uncomplicated febrile seizures is strictly followed, it
is possible to separate out a group of children who have a good prognosis:
a. The child should be between 6 months and 5 years of age.
b. There should be a clear history of fever prior to the onset of the seizure.
c. The seizure should have no focal features.
d. The seizure should be short, usually less than 10 minutes in duration.
e. The child should be normal neurologically and developmentally, before and
after the seizure.
f. There should be no family history of afebrile epilepsy.
g. Usually such seizures are over by the time the family can bring the child to
the emergency department, and therapy is rarely required.
h. Lumbar puncture should be normal, free of any evidence of infection.
i. Routine laboratory studies, including electrolytes, glucose, calcium,
phosphate, magnesium, and BUN, are all normal.
j. When the possibility of lead poisoning exists, a lead level may also be
determined.
2. Prognosis. If the above criteria are satisfied, the neurologic outcome is
excellent, and the parents may be so advised. Overall, there is approximately a
30% to 40% recurrence rate of uncomplicated febrile seizures. The recurrence
risk is higher if the initial seizure occurs prior to 1 year of age. If, however, the
above criteria are not strictly satisfied, one is not dealing with an uncomplicated
febrile seizure disorder and prognosis will vary, depending on the underlying
condition. In such a patient, there may be recurrence of seizure activity with or
without fever, and treatment with AEDs may be necessary as described in sec.
V.C and Table 6-4. Risk factors that may indicate a greater likelihood of a
patient having afebrile seizures include neurologic or developmental
abnormality, prolonged or partial seizure pattern, and a family history of
afebrile epilepsy.
3. Treatment. By definition, little or no therapy is required to control a single
uncomplicated febrile convulsion.
a. Control of fever
1. Tepid baths.
2. Acetaminophen, 5 to 10 mg/kg/dose q4h PO or PR.
3. Nonsteroidal antiinflammatory drugs are effective in reducing
temperature in febrile children. Ibuprofen suspension (Pedia-Profen),
100 mg/5 mL can be used in infants 6 months and older. The dosage
ranges from 5 to 10 mg/kg q6h, up to a maximum daily dose of 40
mg/kg.
4. Aspirin may contribute to the pathogenesis of Reye syndrome, and
it should not be prescribed routinely, especially in children with
chickenpox or those suspected of having influenza.
b. Seizure control is rarely necessary due to the self-limited nature of
uncomplicated febrile convulsion.
c. Prophylactic therapy. In selected patients with recurrent febrile seizures,
prophylactic therapy is necessary. Phenobarbital is rarely used because of
its side effects and lack of efficacy in a significant number of patients.
Diazepam has been shown to be effective in preventing recurrences if
given immediately at the onset of fever and continued until the patient has
been afebrile for 24 hours. Children who experience a seizure immediately
at the onset of fever should be given diazepam in anticipation of fever,
depending on prodromal symptoms and signs. The recommended dosage
is 0.33 mg/kg PO q8h, or the drug may be administered rectally 0.5 mg/kg
as a gel (Diastat).
VI. Partial (focal) seizures
A. Description. The term partial (focal) seizures refers to seizures that arise from a
particular focal region of the brain. A partial seizure may
1. Remain partial.
2. Spread to involve neighboring regions of cortex (jacksonian seizure).
3. Proceed to a generalized convulsion.
B. Diagnosis. In any seizure episode, it is the onset of the spell that determines
whether or not it is a partial seizure. Since any area of the cerebral cortex may be
involved with focal epileptic discharges, nearly every variety of human experience
can be imitated by a seizure. Often, in fact, the nature of the behavior or the
experience that precedes a generalized convulsion gives a clue to the focus from
which the seizure emanated.
1. The disturbance of cortical function that precedes a generalized convulsion is
referred to as the aura. By definition, an aura occurs only in partial epilepsy
and is of strong differential value in diagnosing a patient who has had a
generalized convulsion. Thus, occurrence of an aura confirms the diagnosis of
a partial seizure with spread to a secondarily generalized convulsion.
2. A postictal (Todd) paralysis also suggests a partial seizure. This distinction
is crucial, since partial seizures represent focal brain disease, whereas
generalized seizures usually do not.
3. In a patient with partial seizures, a careful search for the underlying disease
process always should be made. A history of the exact nature of the partial
seizures or the aura of secondarily generalized seizures may provide valuable
information regarding the location of the abnormality. A focal or lateralizing
EEG abnormality also may be helpful.
4. Classification. Partial seizures are usually divided into two major categories:
simple and complex.
a. Simple partial seizures consist of elementary sensations, simple
movements, or speech disturbances. These disturbances may be motor,
sensory, or autonomic. Examples of partial motor seizures are localized,
repetitive movements of a body part, masticatory movements, speech
arrest, adversive postures, or tonic postures. Sensory seizures may be
somatic, visual, auditory, gustatory, vertiginous, or abdominal, and
autonomic attacks may initiate nausea, vomiting, or diaphoresis. These
seizures are thought to originate in the areas of the cortex that are known to
subserve movement or sensation for the particular body parts involved.
There is no impairment of consciousness.
b. Complex partial seizures (formely known as temporal lobe, psychomotor,
and temporo-limbic seizures) refer to apparently integrated purposeful
activity, sometimes with amnesia and psychic phenomena, such as
hallucinations, dj vu (factitious familiarity with an unfamiliar environment),
jamais vu (factitious unfamiliarity with a familiar environment), paranoid
feelings, forced thinking, and affective disturbances. This group of disorders
has been referred to as psychomotor epilepsy, which is thought to arise
often from abnormalities in the limbic cortex (i.e., orbital frontal or temporal
lobes). Most cases of temporal lobe epilepsy begin between the ages of
10 and 30 years. Cases that begin after the age of 30 years should raise
the question of brain tumor, primary or secondary. In younger children,
temporal lobe epilepsy may be difficult to distinguish from absence
seizures. However, the presence of an aura and postictal confusion in the
former often helps to make the distinction clinically. The EEG is often
helpful, particularly if it shows the typical 3-second spikes and slow-wave
pattern of typical absence seizures. A normal EEG interictally is of no help
in making the distinction.
5. A partial seizure pattern unique to the pediatric patient is rolandic or benign
childhood epilepsy with centrotemporal spikes. It usually begins between 5
and 10 years of age, although earlier or later onset is possible. Patients
typically have nocturnal seizures predominantly involving facial and
oropharyngeal muscles. Seizures may also occur while the patient is awake.
The EEG shows characteristic central-midtemporal (rolandic) spikes, which
typically are more common or are only present during sleep. The EEG
background is normal. Patients are otherwise normal, and an anatomic
abnormality is not identified if diagnostic criteria are met. Remission during
adolescence or sooner can be expected. Not all children with benign focal
epilepsy of childhood require treatment in spite of the impressive EEG
abnormality that accompanies the syndrome. Children should be treated if
seizures recur frequently, are prolonged, or occur randomly through the day
rather than just typically at night.
C. Evaluation includes:
1. A careful history and physical examination with special reference to evidence
of old strokes, congenital anomalies, remote infections, head trauma,
cranial surgery, and neoplasm (particularly cancer of the breast, lung, colon,
kidney, and melanoma).
2. EEG. (If the routine EEG is normal, activation procedures may be used,
including sleep, hyperventilation, and photic stimuli. Occasionally, special
recording methods are used, such as nasopharyngeal or sphenoidal leads, in
an attempt to record abnormalities in the temporal lobe areas that are far from
the standard scalp electrodes.) Ambulatory or simultaneous EEG-video
monitoring might be necessary.
3. An MRI is the imaging method of choice, and CT scan should be bypassed
except in the emergency setting.
4. Lumbar puncture, with special reference to cell count, cytology, syphilis
serology, and protein in selected patients.
5. Chest x-ray.
6. CBC.
7. Erythrocyte sedimentation rate.
8. Stool guaiac.
9. Serum electrolytes.
10. Serum calcium, magnesium, and phosphate.
11. Liver function tests (aspartate aminotransferase [AST], alanine
aminotransferase [ALT], total bilirubin, and alkaline phosphatase).
12. Urinalysis.
13. BUN and serum creatinine.
14. Blood glucose.
15. Further studies, including arteriography, may be required if the screening
studies discussed are abnormal, requiring further evaluation of a particular part
of the nervous system.
16. In children with partial seizures, there is less likelihood of a serious underlying
brain disease than in adults, and thus the evaluation is sometimes less
extensive. If the evaluation is negative, treatment may be started, but careful,
frequent follow-up examinations are necessary because the primary disease
process may become obvious only some time after the epilepsy begins.
D. Prognosis. The outlook depends on the underlying condition; even if the primary
disease is benign (e.g., mesial temporal sclerosis) or no primary disease can be
found, these seizures are generally much more difficult to treat than primary
generalized seizures. In the case of complex partial seizures, interictal behavioral
abnormalities are a common accompaniment of the disease. Whether these
psychiatric syndromes (e.g., schizophrenialike illness, hypergraphia, and
hyper-religiosity sometimes seen in patients with temporal lobe epilepsy) are due
to the same primary disease that caused the epilepsy is unknown at the present
time. However, it is generally agreed that AEDs have little or no effect on the
interictal behavior disorders seen in these patients. Many require
antipsychotic drugs for the control of these disorders, and the prognosis for a
normal life in these patients is poor. In partial seizures with simple symptoms,
there is no concomitant psychiatric illness, but the seizures themselves may be
very difficult to control without reaching drug toxicity.
E. Treatment
1. Medical. The drug treatment of partial seizures is the same as that for
generalized tonic-clonic convulsions (see Table 6-4). Gabapentin, topiramate,
lamotrigine, tiagabine, and felbamate can also be effect-ive in reducing seizure
frequency. They are used mainly as adjunctive agents.
An important principle of treatment is that partial seizures, even when
continuous (epilepsia partialis continua), are not an emergency and
should not be treated as such. It is also important to remember that control is
difficult, and rapid control of focal phenomena is rarely, if ever, required. Thus
one should proceed cautiously and methodically through the choices of drugs
shown in Table 6-4, making sure not to produce unacceptable side effects in
an effort to control small focal abnormalities.
2. Surgical. Occasionally, partial seizures are impossible to control medically,
and surgical intervention is necessary. Some patients will require surgical
removal of the offending focus. Other surgical treatments for medically
resistant seizure patients include cortexectomy and partial corpus callosotomy.
However, results in these extraordinarily severe cases are variable, so that
surgical treatment should be reserved for medical failures and should not be
used as a first-line form of therapy. Exceptions to this rule are patients with
partial seizures caused by a surgically removable lesion, vascular malformation
(e.g., arteriovenous malformation, cavernous hemangioma), or congenital
anomaly. Such procedures require sophisticated pre-operative evaluation and
intraoperative electrocorticography and should be performed at specialized
centers where such techniques are routinely employed.
Some neurosurgeons believe that the behavioral abnormalities sometimes
seen in complex partial seizure patients can be reversed by removal of the
epileptogenic focus. However, this is not a generally accepted notion, and at
present only medically uncontrollable seizures are an indication for surgery.
VII. Neonatal seizures
A. Description. Neonatal seizures refer to seizure activity during the first 30 days of
life. Unlike those in the older patient, seizures in the newborn are often subtle and
more difficult to diagnose. Common manifestations of neonatal seizures include:
1. Tonic eye deviation, rapid eye movements, or both.
2. Repetitive eyelid blinking.
3. Facial grimacing.
4. Fragmentary clonic movements of single extremities.
5. Tonic posturing of a single extremity.
6. Apnea, often associated with other seizure activity but sometimes the sole
manifestation of the seizure.
7. Generalized tonic-clonic seizures, which do occur but are uncommon.
B. The diagnosis rests on the clinician's ability to recognize the symptoms, which
are often only fragmentary movements that may be epileptic in nature. Treatment
of the seizure itself is rarely an emergency unless respirations are compromised. It
is more important to diagnose the patient's condition rapidly, so appropriate
therapy can be initiated promptly. Speed is important because several types of
neonatal seizures may result in irreversible cerebral damage. The common
causes of neonatal seizures are the following:
1. Prenatally determined problems, such as developmental brain
malformations, infections, or maternal abuse of drugs.
2. Metabolic abnormalities
a. Hypoglycemia, which usually occurs within the first few hours of birth. In
babies who are small for their gestational age, are premature, have diabetic
mothers, or are septic, one should suspect possible hypoglycemia.
Hypoglycemia in the term infant can be defined as a blood glucose level
below approximately 35 mg/dL within the first 72 hours and 45 mg/dL
thereafter. In the low-birth-weight infant, hypoglycemia is defined as a blood
glucose level below approximately 25 mg/dL. Many pediatricians will start
early feedings or an intravenous glucose infusion as prophylaxis against
hypoglycemia. Also, blood glucose should be monitored frequently in
high-risk groups, since hypoglycemia can produce irreversible cerebral
damage. It is obviously better to prevent neonatal hypoglycemic seizures
than to treat them once they occur.
b. Hypocalcemia
1. Early-onset hypocalcemia (within the first 3 days of life) is commonly
seen in babies with low birth weight, in premature infants, and in babies
who are small for their gestational age. There is often a history of
pregnancy complicated by toxemia, perinatal distress, or mechanical
birth trauma.
2. Late-onset hypocalcemia (after the third day of life) is thought to be due
to the high phosphate load the infant receives in the first few days of life.
The serum calcium level is usually below 7.5 mg/dL in both early- and
late-onset hypocalcemia.
c. Hypomagnesemia presents much the same picture as hypocalcemia and
is found in the same high-risk groups, but it is less common.
Hypomagnesemia and hypocalcemia may coexist, and both must be
treated.
d. Pyridoxine dependency usually produces seizures within minutes or hours
after birth, but there are recent reports of atypical cases with later onset.
e. Biotinidase deficiency and treatment with biotin, 5 to 10 mg/day, should
be considered in infants with unexplained seizures, especially if they are
refractory to standard drugs. It is not necessary to wait for the result of the
serum biotinidase assay before starting biotin.
f. Other metabolic abnormalities, including aminoacidurias and drug
withdrawal (infants of drug dependent mothers).
3. Both intrauterine and postnatally acquired CNS infections may produce
seizures in the first month of life. The evaluation should include routine CSF
examination and antibody titers for toxoplasmosis, rubella, cytomegalovirus,
and herpesvirus.
4. Perinatal complications resulting in severe asphyxia or mechanical trauma.
5. Genetic factors can be important in the newborn, resulting in the syndrome of
benign familial neonatal convulsions. Seizure onset is usually on day 2 or 3 of
life. Seizures tend to be brief and of mixed types. Remission occurs in the
majority of patients by 6 weeks of age, and neurodevelopmental outcome is
usually good, although a number of patients have had later epilepsy and
learning difficulties. This unique syndrome is linked to the long arm of
chromosome 20.
C. Treatment (Table 6-7). Once blood is drawn and sent to the laboratory for
analysis, therapy is begun at once. The sequence shown in Table 6-7 is
self-explanatory. The use of short-acting drugs such as diazepam is no more
effective than maximum doses of phenobarbital and phenytoin.
TABLE 6-7. Treatment of Neonatal Seizures
VIII. Discontinuation of medication in patients with seizures. There are
no fixed rules concerning discontinuation of medication in patients with seizures. Most
neurologists would consider stopping drugs only after a long (4 to 5 years) seizure-free
interval, but a shorter interval is also acceptable if the patient is in a relatively low-risk
category. In children, it is reasonable to attempt to discontinue treatment after 2
seizure-free years. When this is done, drugs should be tapered slowly over several
months. During the period of tapering, the patient must be considered at risk for a
seizure, and recommendations regarding daily activities are made accordingly.
A. Factors that favor a bad prognosis (i.e., make it more likely that seizures will
recur):
1. Development abnormalities, such as mental retardation.
2. Abnormal neurologic examination.
3. Long duration of epilepsy before control.
4. Partial seizures.
5. Combination of seizure types.
6. Significant EEG abnormality.
7. Onset in adolescence, such as J ME.
B. Factors not associated with increased risk of recurrence
1. Number of seizures before control.
2. Age at discontinuation of medications.
3. Family history of epilepsy.
IX. Daily activities in patients with seizures. Certain activities are of particular
potential risk in patients with seizures because of potential harm to either the patient or
others. There are no rigid guidelines for the restriction of such activities as swimming,
skiing, or driving an automobile.
A. In general, people with epilepsy should not swim alone or climb to excessive
heights, but these restrictions probably apply to everyone, especially children.
B. Children should be allowed to ride bicycles, but not in traffic, and they should
wear a protective helmet (as should everyone).
C. Driving. In some localities, the law requires that a physician report any knowledge
of seizures to officials responsible for issuing driver's licenses. In other places, this
is not required and in fact may represent a breach of confidence between the
physician and patient. It is strongly recommended that physicians become familiar
with the local or state laws that apply to this issue. Detailed information about the
laws in each state regarding the legal rights of seizure patients may be obtained
from the Epilepsy Foundation of America, 4351 Garden City Drive, Landover, MD
20785; (301) 459-3700. From a purely medical point of view, most neurologists
would consider patients to be functionally normal if they are seizure-free for 1
year and are reliably taking the prescribed anticonvulsant regimen. In patients in
whom the seizures are not associated with loss of consciousness or change in
cognitive function, driving may be considered safe as long as the patient is
capable of operating a motor vehicle during a seizure.
X. Paroxysmal conditions resembling epilepsy. A number of paroxysmal
disorders exist that may be related to epilepsy, either by virtue of their clinical similarity
and possible confusions in diagnosis or by virtue of their possible, although unproved,
true epileptic nature. It is important to diagnose these syndromes correctly, since some
have specific therapies of their own, a few of which may actually conflict with AED
therapy.
A. Narcolepsy
1. Description
a. Narcolepsy is defined as a group of disorders characterized by some or all
of the following characteristics:
1. Sleep attacks (irresistible episodes of sleep).
2. Cataplexy (sudden attacks of loss of postural tone sparing
consciousness, often stimulated by emotional experiences, e.g.,
laughter, passion, fear).
3. Sleep paralysis (total paralysis that lasts a few minutes, usually on
awakening from sleep but sometimes just before falling asleep).
4. Hypnagogic hallucinations (vivid visual or auditory hallucinations, or
both, just as the person is falling asleep).
5. The EEG may show the characteristic phenomenon of sleep-onset rapid
eye movement (REM) sleep. The physiology of normal sleep is
reviewed in Chap. 1 sec. IX.
b. The essential abnormality in narcolepsy is thought to be defective
activity of the reticular activating system (RAS). Some patients with
narcolepsy will slip uncontrollably from the waking state directly into REM
sleep (so-called sleep-onset REM), and it is believed that, as a result of this
process, the rest of the syndrome evolves. For example, sleep paralysis
and cataplexy are merely components of the paralysis that occurs during
normal REM sleep (as already noted), and hypnagogic hallucinations are
merely dreams, normally occurring in the REM sleep state.
c. Patients with narcolepsy are most likely to fall asleep in situations that
would normally produce drowsiness (i.e., postprandial and during
boredom), presumably because of an underactive RAS, and are unable to
maintain the waking state under stress. Patients who have more severe
narcolepsy will, of course, fall asleep at inappropriate times, such as while
driving a car.
d. Studies of accident-prone drivers have revealed a much higher than
expected number of narcoleptics. The relation between emotional
experiences and cataplexy is unknown, but it is thought to be mediated
through the RAS also.
2. The diagnosis depends on a characteristic history and the typical EEG
pattern, although the latter will not occur in every episode of sleep. Thus, a
normal sleep EEG does not rule out narcolepsy. Conversely, sleep-onset REM,
found incidentally in asymptomatic patients, should not lead to treatment for
narcolepsy. However, it should be considered in patients with hypersomnia,
whether or not the other associated abnormalities are found. The EEG may be
helpful if positive (i.e., if it shows sleep-onset REM); however, the diagnosis
can be made legitimately with a normal EEG if the history is sufficiently
characteristic.
It is possible to confuse narcolepsy with epilepsy, particularly if the sleep
attacks come on very suddenly. However, a history of an irresistible tendency
to sleep and the associated abnormalities should permit proper diagnosis by
history alone.
3. Prognosis. The outlook for narcolepsy is generally good, and the patient
usually responds dramatically to drug therapy.
4. Treatment. There is no single treatment for all the elements of narcolepsy.
Individual patients must be treated for their predominant symptoms, sometimes
combining drugs to attain adequate relief from the entire complex.
a. Sleep attacks, hypnagogic hallucinations, and sleep paralysis
1. Amphetamines are known to suppress REM sleep. It is not known
whether this characteristic of these agents is the reason for their
effectiveness in narcolepsy. However, it is clear that amphetamines are
often useful in controlling sleep attacks and are sometimes useful in
controlling hypnagogic hallucinations and sleep paralysis.
a. Many problems are associated with chronic use of amphetamines.
For example, many narcoleptics abuse these agents, constantly
raising the dosage as their tolerance develops. Other patients find
that under treatment they are less aware of an oncoming sleep
attack, and this places them at even greater risk for accidents. Since
amphetamines interfere with normal sleep, these patients often
require increasingly higher doses during the day to protect against
an even greater tendency for sleep attacks.
b. Side effects of amphetamine use include a syndrome of irritability,
paranoid ideation, and psychosis. Furthermore, these agents are
relatively contraindicated in patients with coronary artery disease
and hyperthyroidism.
c. Dosage. Despite their drawbacks, when used carefully,
amphetamines are still the best treatment of the major
manifestations of narcolepsy. Whichever amphetamine preparation
is used, therapy should begin with low dosages and be gradually
increased until a satisfactory therapeutic effect is obtained. Some
commonly used agents are as follows:
i. Methylphenidate (Ritalin), 20 to 200 mg/day PO, divided into 2 or
3 doses.
ii. Methamphetamine hydrochloride (Fetamin), 20 to 200 mg/day
PO, divided into 2 or 3 doses.
iii. Dextroamphetamine sulfate (Dexedrine), 20 to 200 mg/day PO,
divided into 2 or 3 doses.
2. Monoamine oxidase (MAO) inhibitors often have a striking
therapeutic effect.
a. Serious side effects, such as orthostatic hypotension, hypertension,
edema, and impotence are common, requiring discontinuance of the
medication in a large number of patients.
b. MAO inhibitors cannot be given in combination with dibenzepin
derivatives (e.g., tricyclic antidepressants, doxepin, carbamazepine),
sympathomimetics (e.g., amphetamines), or food with high tyramine
content (e.g., cheese, sour cream, Chianti wine, sherry, beer, pickled
foods).
c. Withdrawal of MAO inhibitors may result in insomnia, hallucinations,
and serious depression, with suicidal thoughts and severe anxiety.
For this reason, they are recommended only when amphetamines
cannot be used and the symptoms of narcolepsy are unbearable.
Even then the drug should be administered only under strict
supervision.
d. Dosage. Some commonly available MAO inhibitors and their
recommended dosages are as follows:
i. Phenelzine sulfate (Nardil), 15 to 75 mg/day PO, divided into 3
or 4 doses.
ii. Tranylcypromine sulfate (Parnate), 10 to 30 mg/day PO,
divided into 2 doses.
iii. Pargyline hydrochloride (Eutonyl), 25 to 200 mg/day PO in a
single dose.
iv. Isocarboxazid (Marplan), 10 to 30 mg/day PO in a single dose.
b. Cataplexy. Amphetamines and MAO inhibitors have little effect on
cataplexy. However, it has been shown that the tricyclic antidepressants
may be particularly effective in the relief of this symptom. Furthermore, they
are effective in much lower dosages than are required for the treatment of
depression; this suggests a separate mechanism for their effect in this
syndrome. Imipramine (Tofranil), 50 to 100 mg/day PO, divided into 1 of 3
doses is commonly used in the management of cataplexy.
c. Sleep attacks and cataplexy. Theoretically, the combination of a tricyclic
antidepressant and an amphetamine is dangerous, since the latter causes
a release of catecholamines at the neuronal synapse; the former blocks
reuptake of the catecholamine neurotransmitter. This combination could
therefore produce hypertensive episodes, but actually one may generally
use imipramine (25 mg tid) together with methylphenidate (5 to 10 mg
tid) without difficulty and with good control of both sleep attacks and
cataplexy. Tricyclic antidepressants should not be used in
combination with an MAO inhibitor.
B. Migraine (see also Chap. 2). Because of its paroxysmal attacks of neurologic
symptoms, usually followed by headache, migraine has some relation to epilepsy.
However, the differential diagnosis between the 2 conditions usually is not difficult.
In one situation, brainstem or basilar artery migraine, loss of consciousness may
occur due to vasomotor changes consequent to transient brainstem ischemia, and
this may imitate epilepsy. Under certain rare circumstances, the cerebral ischemia
due to vasopasm may actually trigger bona fide convulsions, usually in a patient
with known epilepsy. On the other hand, some patients with migraine have
associated paroxysmal EEG abnormalities. Some of these patients experience
relief of their headaches when treated with anticonvulsants, so that a trial of
phenytoin or phenobarbital is often warranted in these patients. (See Chap. 2 for
the details of diagnosis and treatment of migraine.)
C. Paroxysmal abdominal pain (abdominal epilepsy). A syndrome of paroxysmal
abdominal pain occurs in children for which no gastrointestinal or intraabdominal
cause can be found. Some of these patients will respond to conventional AED
therapy, a fact that has led some physicians to believe that this pain is caused by
an epileptic syndrome. Thus, in a child with recurrent apoplectic episodes of
abdominal pain in which a thorough medical evaluation has revealed no cause, it
is probably reasonable to perform an EEG and conduct a therapeutic trial of an
AED. As these patients mature, many will develop migraine, further emphasizing
relationship between migraine and epilepsy.
D. Breath holding spells
1. Description. Breath holding or reflexive apneic spells usually begin during the
first 2 years of life, but rarely before 6 months of age. A precipitating factor,
such as fear, pain, anger, or frustration, leads to a brief bout of crying, during
which the breath is held in expiration. Cyanosis then develops, which may be
followed by loss of consciousness and a brief generalized convulsion. The
exact mechanism for this type of spell and its physiologic consequences are
not known, but the brief convulsion that is sometimes seen is presumably
caused by cerebral hypoxia.
2. Treatment consists of reassuring patients and giving them advice on how to
protect the child during a spell. There is no doubt that behavioral influences
can lead to an increase in the frequency of spells, and parents should be
advised of this possibility.
3. Differential diagnosis. It is important to distinguish between breath holding
spells and true epilepsy because the prognosis and treatment differ. AEDs are
not indicated in the treatment of breath holding spells, and they are not
effective in terminating the attacks. The spells almost always terminate by the
age of 5 years, and they have no relation to the later development of epilepsy.
E. Hypercyanotic attacks
1. Description. In patients with cyanotic congenital heart disease, particularly
tetralogy of Fallot, sudden episodes of increased cyanosis may occur and be
followed by loss of consciousness and perhaps a convulsion. The mechanism
for these attacks may be spasm of the already small infundibulum (right
ventricular outflow tract). The pulmonary circulation, which is already
compromised, is decreased further, and the blood becomes even poorer in
oxygen than it is normally. Then cerebral anoxia increases suddenly, and loss
of consciousness and, possibly, convulsions result.
2. The treatment is repair of the anomaly or at least surgical creation of an
aortopulmonary shunt (Blalock-Taussig operation) until definitive repair is
technically possible. No anticonvulsants are required. Treatment of the acute
attack is administration of oxygen in as high a concentration as can be
obtained.
F. Shuddering attacks. Sudden, brief shuddering or shivering movements may
occur in infants and children, often with flexion of the trunk and extremities, but
without alteration of consciousness. Patients and their EEGs are normal. A cause
is not known and treatment is not necessary.
G. Cardiovascular syncope. Syncope is loss of consciousness due to an acute
decrease in cerebral blood flow. If it is prolonged, seizure-like activity may occur,
particularly in patients with known epilepsy. If the period of cerebral hypoperfusion
persists, a bonafide seizure may occur. This phenoment, called convulsize
syncope, is not epilepsy and should not be treated as such. The causes of
syncope are protean, but they must always be ruled out when the patient suffers
from episodic loss of consciousness, with or without convulsions. It is important to
make this distinction because the treatment of cardiovascular syncope varies
significantly from the treatment of epilepsy. In fact, phenytoin, a commonly used
anticonvulsant, is strongly contraindicated in syncope caused by heart block. Thus
cardiovascular syncope must be carefully excluded before the patient is treated for
epilepsy.
1. The major causes of syncope are the following:
a. Heart block.
b. Arrhythmias (usually ventricular tachycardia or ventricular fibrillation).
c. Carotid sinus hypersensitivity.
d. Vasovagal attacks.
e. Aortic stenosis.
f. Asymmetric septal hypertrophy.
g. Drugs (e.g. vasodilators, anti-hypertensives, diuretics, alcohol)
2. Diagnosis
a. The diagnosis is not difficult to make if the attack is observed, since in
cardiovascular syncope there is hypotension, whereas epilepsy alone
does not produce hypotension. The heart rate may be very slow (as in heart
block, carotid sinus hypersensitivity, or vasovagal syncope) or very rapid
and weak or absent altogether (as in tachyarrhythmias).
b. If an attack is not observed, the differential diagnosis between
cardiovascular syncope and epilepsy can be very difficult. Also, whenever
there is doubt concerning the mode of onset of the attacks, particularly in
elderly patients, cardiovascular syncope should be considered, and several
days of Holter ECG monitoring should be performed. This, of course, will
not entirely rule out very infrequent arrhythmias or episodes of heart block,
but it is the best procedure available.
3. Treatment. Carotid sinus massage may be performed under controlled
circumstances, and a detailed cardiologic evaluation is often useful to exclude
significant aortic valvular disease or asymmetric septal hypertrophy. No AED
therapy is required and is, in fact, contraindicated in heart block.
H. Conversion disorders and dissociative states (hysteria) (see Chap. 9) may
present a difficult problem in two ways when it occurs in a patient with apparent
seizures.
1. Hyperventilation may result in a loss of consciousness and tetany, simulating
epilepsy. This condition can be remedied by using a rebreathing bag for acute
therapy. It is not really an epileptic phenomenon.
2. Non-epileptic seizures, also known as pseudoseizures, hysterical seizures, or
psychogenic seizures may be very difficult to distinguish from true epilepsy.
Furthermore, many patients with non-epileptic seizures also have authentic
epileptic seizures. The normal EEG is of some help, but, as stated previously,
many patients with bona fide epilepsy display repeatedly normal EEGs, thus
making this an inadequate criterion. Prolonged ambulatory EEG monitoring,
when available, may be helpful, and if an episode is recorded, the distinction
between epileptic and nonepileptic events can be made. An experienced
clinician can sometimes distinguish a poor imitation of a true seizure, but when
the patient is able to imitate a seizure accurately, there is no practical method
of distinguishing psendoseizures from real ones.
One helpful criterion is whether the patient is incontinent or not. It is said that
all persons are incontinent during a tonic-clonic convulsion unless their
bladders are empty. Thus patients who have multiple attacks will certainly be
incontinent during some of them, whereas many patients with non-epileptic
seizures are never incontinent. However, this criterion is of no help in patients
who are incontinent or in patients with conversion attacks that mimic absence
or partial seizures, which do not show incontinence as a part of the bona fide
seizure pattern.
I. Malingering. Seizures imitated by malingerers pose a problem similar to that of
other non-epileptic seizures. Imitations of generalized seizures are very rarely
associated with incontinence, even less so than in psychogenic seizures. The only
way for physicians to distinguish other forms of imitations is to use their
experience with respect to the appearance of real epilepsy. However, even the
most experienced observer can be misled, and occasionally malingerers are
treated with AEDs. Again, recording an event with prolonged EEG monitoring can
be helpful.
J . Tic douloureux (see Chap. 2). Trigeminal neuralgia and some other neuralgialike
syndromes have certain characteristics in common with epilepsy. They occur
intermittently, usually with an apoplectic onset, and may respond to AEDs,
particularly phenytoin and carbamazepine. It is rare, however, that they actually
pose a difficult differential diagnosis from true epilepsy.
K. Paroxysmal vertigo (see Chap. 4). Several syndromes of paroxysmal vertigo
exist that may be confused occasionally with epilepsy, namely, benign positional
vertigo (Brny vertigo) and Mnire syndrome. Usually these two syndromes
can be distinguished from epilepsy on the basis of history and physical
examination. The former may have a clear history of positional exacerbation of
vertigo, and the patient will experience vertigo and nystagmus if the head is
positioned properly during the neurologic examination. The latter shows episodes
of vertigo that are usually associated with concomitant hearing loss in the affected
ear. Although the hearing loss will fluctuate with the attacks of vertigo, over time
decreased hearing will be noted, and this can be documented by neurologic
examination and audiometry. Vertigo may be a manifestation of complex partial
seizures but is usually associated with some clouding of consciousness or change
in mental state during the vertiginous episodes.
Selected Readings
Annegers J F, Hauser WA, Coan SP, Rocca WA. A population based study of seizures after traumatic
brain injuries.
N Engl J Med 1998;338:20.
Callaghan N, Garrett A, Goggin T. Withdrawal of anticonvulsant drugs in patients free of seizures for two
years. N Engl J Med 1988:318:942.
Camfield C, et al. Outcome of childhood epilepsy: a population-based study with a simply predictive
scoring system for those treated with medication. J Pediatrics 1993;122:681.
The Felbamate Study Group in Lennox-Gastaut Syndrome. Efficacy of felbamate in childhood epileptic
encephalopathy (Lennox-Gastaut syndrome). N Engl J Med 1993;328:29.
J ones KL, et al. Pattern of malformations in the children of women treated with carbamazepine during
pregnancy. N Engl J Med 1989;320:1661.
Kumar A, Bleck TP. Intravenous midazolam for the treatment of refractory status epilepticus. Crit Care
Med 1992;20:483.
Lucus MJ , Levens KJ , Cunningham FG. A comparison of magnesium sulfate with phenytoin for the
prevention of eclampsia. N Engl J Med 1995;333:201.
Motte J , et al. Lamotrigine for generalized seizures associated with the Lennox-Gastaut syndrome. N
Engl J Med 1997;377:1807.
Pellock J M, ed. New antiepileptic drugs in childhood epilepsy. Semin Pediatr Neurol 1997;4:1.
Ronen GM, et al. Seizure characteristics in chromosome 20 benign familial neonatal convulsions.
Neurology 1993;43:1355.
Rosman NP, et al. A controlled trial of diazepam administered during febrile illnesses to prevent
recurrences of febrile seizures. N Engl J Med 1993;329:79.
Salbert BA, Pellock J M, Wolf B. Characterization of seizures associated with biotinidase deficiency.
Neurology 1993;43:1351.
Shinnar S, et al. Discontinuing antiepileptic medication in children with epilepsy after two years without
seizures. N Engl J Med 1985;313:976.
Thurston J H, et al. Prognosis in childhood epilepsy. N Engl J Med 1982;306:831.
CHAPTER 7. BRAIN DEATH AND PERSISTENT VEGETATIVE STATE
Manual of Neurologic Therapeutics
CHAPTER 7. BRAIN DEATH AND PERSISTENT
VEGETATIVE STATE
Thomas M. Walshe III
Brain death
Persistent vegetative state
I. Brain death
A. Definition
1. Medical definition. The criteria for brain death have become established in
the last 20 years and brain death is accepted along with the traditional
definition of death based on cessation of the circulation and asystole.
a. Advances in intensive care technology have made it possible to maintain
perfusion and oxygenation in patients who have lethal brain damage. Brain
death indicates the death of the person whose whole brain is dead despite
adequate cardiac and respiratory function.
1. Brain death occurs in acute anoxia, as in cardiorespiratory arrest or
prolonged hypotension, that devastates the brain but spares the less
sensitive organs so that they can be revived.
2. Brain tumor, head trauma, and stroke may also cause complete
destruction of the brain but allow artificial maintenance of the other
organs.
b. The basic pathology of brain death (the so-called respirator brain) is
widespread necrosis and edema without inflammatory reaction.
Transtentorial (temporal lobe) and cerebellar tonsillar herniations occur.
Brain swelling causes increased intracranial pressure and an absence of
cerebral blood flow.
c. The clinical recognition of brain death allows the possibility for the
brain-dead patient to provide high-quality organs for transplantation.
Moreover, the high cost of intensive medical care makes it desirable to
diagnose the brain-dead patient as early as possible.
2. Legal definition. The legal definition of death is taken from Black's Law
Dictionary, which states that death is defined by physicians as a total
stoppage of the circulation of the blood and a cessation of the animal and vital
functions consequent thereupon, such as respiration, pulsation, etc. The
acceptance of brain death as a definition of death of the person has become
generalized since the original definition in 1968. Numerous authorities have
determined the validity and accepted the criteria.
a. In 1972, the American Neurological Association accepted brain death as a
definition of death. Scrupulous application of the criteria is essential to
establishing the diagnosis of brain death. It is advisable to underdiagnose
brain death when the clinical data are questionable.
B. Criteria
1. Exclusions
a. Before the criteria can be applied, the diagnostic and therapeutic
measures needed to correct the underlying illness must have been
undertaken.
b. If there is suspicion of intoxication with central nervous system (CNS)
depressants, the diagnosis of brain death cannot be made.
1. Blood levels of drugs do not always correlate with mortality in drug
overdose. The criteria for brain death can be applied only when drug
levels have been allowed to drop to therapeutic or lower levels for an
adequate time. Longer periods of observation are necessary in patients
intoxicated at the onset of coma.
2. The signs suggesting brain death do not persist for more than 36
hours in most cases of uncomplicated drug intoxication. Careful
neurologic observation reveals gradually increasing reflex activity in
such cases, which indicates improvement. Usually, the earliest reflex to
return is the pupillary light response. If the patient continues to improve,
oculocephalic, corneal, and other reflexes return. The
electroencephalogram (EEG) may be isoelectric in some cases of drug
overdose but usually shows fast activity superimposed on generalized
slowing.
3. Endogenous toxins from renal, hepatic, or other organ failure also
preclude making the diagnosis of brain death.
4. Paralytic agents when used in severely ill patients may produce such
profound weakness that the cranial reflexes are absent. Brain wave and
cerebral blood flow are preserved in such cases.
c. Hypothermia of less than 90F (32C) also precludes the application of the
criteria for brain death. Hypothermia occurs in patients with brain death, but
the temperature is usually higher than 90F (32C), and the hypothermia is
not found initially.
d. Patients with cardiogenic shock cannot be judged by the criteria. Blood
pressure must be above 90 mm Hg systolic to use the criteria.
e. The diagnosis of brain death is specific. It does not apply to patients
existing in a persistent vegetative state or to other severe degrees of
brain damage. Decisions concerning these patients need to be based on
other criteria.
2. Standard of practice. The specific criteria for brain death are usually
established by individual hospitals and reflect the local laws. Local practice is
based on the general criteria presented in Table 7-1. A history and an
examination that establish the diagnosis of an untreatable structural brain
lesion are necessary for the diagnosis of brain death. In general, the criteria
are attempts to define signs that indicate that there is no nervous system
function above the spinal cord.
TABLE 7-1. Criteria for Brain Death
3. Duration. The diagnosis of brain death usually is not even considered for
several hours after the onset of artificial support. The original Harvard ad hoc
committee recommended that the signs be consistent for 24 hours, but recent
analysis of brain death cases shows that many patients with proved brain
death suffer cardiac arrest before the 24-hour waiting period is over. Therefore,
if the signs are clear and there is no suspicion of drug intoxication or other
exclusions, the diagnosis can be made if the syndrome persists for at least 6
hours in an adult. When the history and examination are unequivocal, a single
examination is sufficient. Making the diagnosis before cardiac decompensation
and arrest occur provides the highest quality of organs for transplantation (see
sec. I.B.8).
4. Reflex activity
a. The pupils are often dilated but may be in midposition in brain death. The
most helpful reflex signs in diagnosing brain death are fixed pupils and
absent corneal, oculocephalic, and vestibular reflexes. Gag, cough, and
respiratory reflexes are also absent.
b. Spinal cord reflex activity persists in as many as two thirds of patients with
angiographically proved brain death. The presence of these reflexes
indicates a functional spinal cord but does not exclude brain death.
Although they are usually absent, the deep tendon reflexes may persist in
brain death. Spinal cord reflexes must be separated from decerebrate and
decorticate postures, which would exclude the diagnosis of brain death.
c. Induced movements and muscle tone do not always preclude the
diagnosis of brain death unless there is movement of the face. The full
decerebration posture is inconsistent with brain death, but partial
movements resembling decerebration do not indicate brain survival.
Spontaneous movement may also occur in brain death, but the movements
are never voluntary or complex. Simple random jerks of the limbs are the
most commonly observed movements in brain death.
d. The snout reflex, jaw jerk, abdominal reflexes, and plantar responses
also may persist and are not indicative of brain survival.
5. EEG
a. The EEG is a very helpful test in the diagnosis of brain death, although it is
not mandatory. In the absence of drug intoxication, patients who have an
isoelectric EEG for 12 to 24 hours do not survive.
b. Because of the high gains needed, it is necessary to use leads to monitor
external movement and the EEG. An electrode on the right hand serves to
measure external movement; since there is no muscle activity, there will be
no muscle artifact. The study is run at standard gains, and again at twice
standard gains, for at least 30 minutes to ensure the absence of brain
waves. There should be no EEG response to pain or other stimuli.
c. When any brain wave is present, the diagnosis of brain death cannot
be made.
6. Absent cerebral blood flow. A persistent absence of cerebral blood flow
determined by radionuclide angiography is diagnostic of brain death. However,
a conventional angiogram is seldom necessary when clinical observation
and EEG are available. Funduscopy that shows sludging of blood in the retinal
veins (boxcars) is clinical evidence of absent cerebral blood flow.
7. The diagnosis of brain death in an infant under 1 year old requires the
conclusive diagnosis of untreatable brain damage. Otherwise the same criteria
apply. In infants under 2 months, 48 hours should elapse before brain death is
diagnosed; 24 hours is recommended as the wait for infants between 2 months
and 1 year.
8. Physician responsibility. The psychosocial implications of death are
always difficult for both the physician and the patient's family. The difficulty is
compounded with patients in whom there are superficial signs of survival.
a. Once the diagnosis has been determined, the physician should carefully
explain the meaning of the syndrome to the patient's family. To
prevent confusion and misunderstanding, the physician should be sure that
the family realizes that the person is dead before stopping organ
maintenance or suggesting organ donation. There are times when the
family rejects the presence of brain death on ethical or other grounds.
Counseling and communication with the family will prevent unpleasant
misunderstandings. The respiratory and cardiac systems are very unstable
in the brain-dead patient. The controversy when unresolvable will not
persist and the traditional signs of death will soon become manifest. It may
in some cases be proper to wait for cardiac arrest when there is extreme
resistance in the family to accept the reality of brain death.
b. The clinical record must reflect the decision-making process and should
document the signs carefully. Two physicians, neither of whom is a member
of the transplantation team, should agree on the diagnosis in the record.
C. Summary
1. The diagnosis of brain death is made by a physician on the basis of the
observation of a number of clinical signs that indicate absence of brain
function.
2. The EEG corroborates the diagnosis and is done when possible.
3. Documentation of absent cerebral blood flow is confirmatory but usually not
necessary.
4. Death is declared and documented in the record before organ maintenance is
stopped.
5. Careful explanation to the family is of paramount importance.
II. Persistent vegetative state
A. Description. Patients who do not meet the criteria for brain death but who are
severely brain-damaged cannot be managed as those with brain death, even if
they remain permanently unconscious. Some patients appear permanently asleep
(comatose) without even the outward appearance of consciousness. Others
appear to be awake and have a sleep-wake cycle; they are, however, unable to
experience the environment or to respond to stimuli in any way. Patients in the
latter group are said to be in a vegetative state, and when it lasts for more than a
month it is called a persistent vegetative state (PVS). Because the diagnosis is not
as intuitive as in patients who are permanently comatose, a set of criteria has
been established for PVS. The management for PVS and permanent loss of
consciousness is the same.
B. Diagnosis
1. The criteria for defining PVS are the following:
a. History of extensive destruction of brain from any cause.
b. Abnormal computed tomographic (CT) or magnetic resonance imaging
(MRI) scan showing loss of brain substance.
c. Absence of sedative, toxic, or systemic complications that alter the level of
awareness.
d. Wakeful state with periods of sleep.
e. Absent awareness of environment and self.
f. Absent ability to communicate.
g. Only reflex or random motor activity to stimulus.
h. Spontaneous pulse, respiration, and blood pressure.
i. Duration of at least 1 month.
2. The PVS may follow trauma, cardiac arrest, or drug overdose or may present
as an end stage of chronic degenerative disease.
3. A careful neurologic examination performed by an experienced physician is
necessary to establish the absence of any awareness of environment or ability
to react with more than reflex responses.
4. A CT scan is used in identifying destructive brain lesions and in establishing a
neurologic diagnosis. When a CT scan is not sufficient, angiography or other
radiographic tests should be used.
5. The patient must be observed for a sufficient time to establish the permanence
of the syndrome. At least 1 month (and longer in children) is needed to show
that there is no improvement. Serial neurologic examinations should document
failure to improve even minimally.
6. The patient's state should be determined only when there are no concomitant
medical or toxic conditions. The diagnosis of PVS cannot be made when the
patient either has an acute illness or is on medication that impairs the mental
state.
C. Prognosis
1. The neuropathology usually involves destruction of the neocortex,
hippocampus, and basal ganglia. There is relative sparing of the brainstem.
2. In cases of nontraumatic coma, it is not possible to predict which patients will
enter the PVS. There are, however, several unfavorable signs which, when
observed early, are suggestive of poor outcome.
a. Absent motor responses at admission.
b. Absent normal responses at 1 day.
c. Poor motor responses at 3 days despite awakening at 1 day .
d. Persistent roving conjugate eye movements at 1 week.
e. Persistent coma at 1 week.
f. The vegetative state at 1 week.
3. Patients with head trauma have a slightly better chance of recovery than
patients with anoxic-ischemic injury when the unfavorable signs exist.
4. Recovery from the PVS seldom occurs. Most patients die of medical
complications, and those who live for long periods do not regain the functions
of a social human being. Decisions on the degree of care should be based on
the availability of medical resources, the wishes of the patient when known,
and the wishes of the family. When there is a small possibility that the
diagnosis is not PVS, vigorous treatment should be pursued until the diagnosis
is clear. If the family insists on vigorous treatment when the diagnosis is clearly
PVS, the physician should comply by providing chronic medical care in a
proper chronic care facility. PVS patients do not require an intensive care
setting and in most there is no need for mechanical ventilation.
D. Management
1. Feeding by artificial means is not necessary, since the patient has no
awareness of nutrition. The decision should be made considering the wishes of
the family.
2. Proper care of bowel and bladder is needed to reduce nursing demands. A
urinary catheter may be needed as a convenience.
3. It is not mandatory to treat infection, renal failure, cardiac failure, or other
medical problems in a permanently vegetative patient. The patient should not
be put on a respirator.
4. When the physician or nursing staff cannot comply with the wishes of the
family, it is best to transfer the patient to the care of those who feel comfortable
with the family's wishes. When there is no way to resolve conflict between the
family and the medical staff, the court may appoint a guardian.
5. It is best to identify a single family member (next of kin or legal guardian) with
whom to make plans. That person can involve other family members as is
appropriate to the structure of the family. At times a meeting between the
family and the medical team is helpful in establishing an acceptable plan.
Selected Readings
Ad Hoc Committee of the American Encephalographic Society. Cerebral death and the
electroencephalogram: report of the ad hoc committee of EEG criteria for determination of cerebral death.
JAMA 1969;209:1505.
ANA Committee on Ethical Affairs. Persistent vegetative state: report of the American Neurological
Association Committee on Ethical Affairs. Neurology 1993;33:386.
Ashwal S, Schneider S. Brain death in children, 2. Pediatr Neurol 1987;3:69.
Bates D, et al. A prospective study of nontraumatic coma: methods and results in 310 patients. Ann
Neurol 1977;2:211.
Benzel EC, Mashburn J P, Conrad S, Modling D. Apnea testing for the determination of brain death: a
modified protocol. Technical note. J Neurosurg 1992;76:1029.
Cranford RE, Smith HL. Some critical distinctions between brain death and the persistent vegetative
state. Ethics Sci Med 1979;6:199.
Dougherty J H, et al. Hypoxic-ischemic brain injury and the vegetative state: clinical and neuropathologic
correlation. Neurology 1981;31:991.
Howsepian A. The 1994 Multi-Society Task Force consensus statement on the persistent vegetative
state: a critical analysis. Issues Law Med 1996;12:3.
Korein J , ed. Brain death: interrelated medical and social issues. Ann NY Acad Sci 1978;315:1.
Korein J , Maccario M. On the diagnosis of cerebral death: a prospective study on 55 patients to define
irreversible coma. Clin Electroencephalogr 1971;2:178.
Levy DE, et al. Factors influencing the recovery from non-traumatic coma. Ann Intern Med 1981;94:293.
Mohandas A, Chou SN. Brain death: a clinical and pathological study. J Neurosurg 1971;35:211.
Ott B. Defining and redefining death. Am J Crit Care 1995;4:476.
Pius XII. The prolongation of life. The Pope Speaks 1958;4:393.
Report of the committee on irreversible coma and brain death. Trans Am Neurol Assoc 1977;102:192.
Report of the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and
Behavioral Research. Deciding to forego life-sustaining treatment. Washington, DC: Government Printing
Office, March 1983.
Ventura MG, Masser PG. Defining death: developments in recent law. Crit Care Clin 1985;1:397.
Walker AE, Didmond EL, Moseley J . The neuropathological findings in irreversible coma. J Neuropathol
Exp Neurol 1975;34:295.
Wilson K, Gordon L, Selby J B Sr. The diagnosis of brain death with Tc-99 HMPOA. Clin Nucl Med
1993;18:428.
CHAPTER 8. INFECTIOUS DISEASES
Manual of Neurologic Therapeutics
CHAPTER 8. INFECTIOUS DISEASES
Stephen M. Sagar and Dawn McGuire
Bacterial meningitis
Tuberculous infection of the CNS
Brain abscess
Subdural empyema
Spinal epidural abscess
Neurosyphilis
Other spirochetal infections
Fungal infections of the CNS
Viral meningitis
Viral encephalitis
Rabies
Poliomyelitis
Slow viruses and progressive multifocal leukoencephalopathy
Toxoplasmosis
Amebic meningoencephalitis
Herpes zoster (shingles)
Acquired immunodeficiency syndrome (AIDS)
Cysticercosis
I. Bacterial meningitis
A. Diagnosis
1. Indications for lumbar puncture (LP)
a. Examination of the cerebrospinal fluid (CSF) is the only means of making a
definite diagnosis of meningitis and identifying the infecting organism.
Untreated bacterial meningitis is virtually 100% fatal within hours to days.
Because of the urgency of starting specific therapy, it is imperative to
examine a sample of CSF as soon as possible.
b. Identification of an organism in a parameningeal or systemic source of
infection is not adequate to guide therapy. In more than 25% of cases,
blood cultures fail to yield an organism.
c. All material for bacteriologic examination should generally be obtained prior
to beginning antibiotic therapy. However, positive bacteriologic culture can
frequently be obtained up to 4 hours after the first dose of antibiotics, and
bacterial antigens can be detected in CSF up to several days after initiation
of therapy. When radiologic studies need to be performed prior to LP,
antibiotic therapy should not be delayed. When brain imaging is not
mandatory, however, most clinicians would perform an expeditious LP and
obtain all other bacteriologic cultures before administering the first dose of
antibiotics.
d. Risks of LP. Diffusely elevated intracranial pressure occurs in nearly all
cases of bacterial meningitis and is not in itself a contraindication to LP. In
the presence of a mass lesion, however, withdrawal of CSF from the
lumbar space and the continuing leak of CSF through the dural defect can
cause a pressure difference between the supra- and infratentorial
compartments. This can lead to downward herniation of brain. Although
the risk is real, delay in diagnosing bacterial meningitis is fatal far
more often than is an imprudent LP. Therefore, the risks and benefits of
LP must be carefully weighed in each case.
1. In the presence of a known intracranial mass lesion, such as tumor,
abscess, or hemorrhage, LP can be especially hazardous.
2. Papilledema or retinal hemorrhages rarely occur in uncomplicated
bacterial meningitis. A computed tomography (CT) evaluation should
precede LP.
3. A clear history of a progressive focal neurologic deficit preceding the
onset of meningitis suggests the presence of an abscess, tumor,
subdural fluid collection, or other mass lesion. A CT scan should
precede LP.
4. Certain complications of bacterial meningitis (cortical vein thrombosis
with venous infarction of the brain, arterial infarction, subdural
empyema, subdural effusion, disseminated intravascular coagulation
[with a bleeding diathesis]) may increase the risks of LP but usually
occur later in the course rather than at presentation.
5. Skin or soft tissue infection in the area through which the needle must
pass is a contraindication to LP.
6. Signs of possible herniation such as altered pupillary responses, new
focal neurologic deficits, rapidly declining mental status, or Cushing
reflex (hypertension and bradycardia) must be evaluated
radiographically prior to LP. Evidence of shift of midline structures,
obliteration of CSF pathways, or frank herniation is an absolute
contraindication to LP.
7. Seizures, isolated cranial nerve palsies, focal neurologic signs, ataxia,
and depressed mental status all can occur early in the course of
bacterial meningitis in the absence of a mass lesion. These symptoms
alone do not increase the risk of LP but should be evaluated
radiographically prior to LP.
e. It is a good practice to have a secure IV in place when the LP is performed.
Hyperosmolar agents can then be infused if necessary, and antibiotics can
be begun immediately on obtaining the CSF sample.
f. Alternatives to LP. The LP may be deferred while emergency radiologic
studies are performed to confirm or exclude the presence of a mass lesion.
As discussed in 1.c, an initial dose of antibiotics should be administered
immediately.The CSF may be obtained by a ventricular tap through an
open fontanel in an infant or by means of a burr hole in children and adults.
This procedure should be performed only by an experienced neurosurgeon,
and it carries its own high risks. Furthermore, ventricular fluid is not entirely
equivalent to subarachnoid fluid. In some cases of meningitis, the
ventricular fluid may be sterile and may result in a falsely negative CSF
culture. In rare instances (limited almost entirely to pediatric practice), when
the diagnosis of bacterial meningitis seems indisputable on clinical grounds,
when the infecting organism may be predicted with a high degree of
confidence, and when the patient is at significant risk of herniation,
antibiotics may be started without obtaining a sample of CSF. In these
instances, blood cultures are taken and LP is performed 8 to 24 hours after
both antibiotics and antiedema therapy are initiated. By following this
procedure, the risk of LP is lessened, and the CSF formula may still be
purulent, allowing the diagnosis to be confirmed. If the appropriate antibiotic
is chosen, however, there is little chance of culturing an organism from the
CSF.
2. Technique for LP
a. Preparing the patient
1. A blood glucose should be drawn within 15 minutes of beginning the
procedure.
2. To minimize the patient's anxiety, the procedure is explained to the
patient, and all steps are described during the procedure.
3. Positioning the patient:
a. Whenever possible, the LP is performed with the patient lying on his
or her side with knees and hips flexed. The patient may be left
relatively relaxed while being prepped and draped, and only when
the physician is prepared to introduce the needle are the patient's
hips and back maximally flexed. Care must be taken to avoid airway
obstruction when flexing the neck of an infant; risk of respiratory
compromise is especially high in infants with cyanotic heart disease.
b. The L3L4 interspace is palpated at the level of the superior iliac
crests, and any scoliosis or abnormalities of the spine are noted.
c. If the puncture cannot be performed with the patient lying on his or
her side, it may be done with the patient in a sitting position, leaning
forward onto a table. It is essential that the patient's spine be
perfectly vertical. The CSF pressure cannot be measured accurately
in this position; however, once puncture of the dura is achieved, the
patient can be carefully repositioned in the lateral decubitus position
and the opening pressure obtained. In patients with severe scoliosis
or vertebral body degeneration, LP under fluoroscopy may be
required.
4. Preparing the skin
a. Wash the patient's back with iodine-soaked sponges; begin at the
site of the proposed puncture and wash in concentric circles. Wash
with iodine 2 or 3 times, and then wash with alcohol-soaked sponges
3 times, taking care to wash off all the iodine.
b. To avoid introducing iodine into the subarachnoid space on the LP
needle, change gloves before proceeding.
c. Cover the patient with a sterile drape.
b. Introducing the needle
1. Have all of the equipment for the puncture ready before introducing the
needle (i.e., LP needle, stop-cock attached to a manometer and
appropriately positioned, and 3 or 4 sterile tubes with stoppers).
a. Choice of spinal needle: The newer atraumatic needles (i.e., the
Sprotte 22-gauge spinal needle) reduce the incidence of
postlumbar puncture headache while maintaining accurate
transduction of CSF pressure and adequate CSF flow rate.
2. Anesthetize the skin with a small wheal of lidocaine or procaine at the
exact site of the proposed puncture. The skin wheal is painful and
should be raised slowly with an intradermal injection of 0.1 to 0.2 mL of
anesthetic. An additional 0.2 to 0.5 mL may be injected into deeper
layers of the dermis, but there is no need to inject anesthetic deep into
the muscle because this is usually more painful than the single passage
of a 22-gauge needle.
3. Introduce a 22-gauge LP needle, with the stylus in place, through the
skin in the center of the skin wheal. Direct the bevel of the needle with
its flat surface parallel to the long axis of the patient's spine; thus, the
needle will spread, rather than cut, the dural fibers that run
longitudinally. Direct the needle tip 10-15 degrees cephalad (more or
less toward the umbilicus), and introduce the needle slowly but steadily
until the needle is felt to pierce a tough membrane or is thought to be
near the dura. At this point, the needle is introduced in steps of 2 to 3
mm, and the stylus is removed between each step to check for CSF
return. Once CSF return is obtained, the needle is introduced 1 to 2 mm
farther, and the bevel is turned perpendicular to the long axis of the
spine. Care must be taken not to introduce the needle too far because
puncture of the venous plexus anterior to the spinal canal is the most
common cause of a traumatic tap.
4. If CSF return cannot be obtained at the L3L4 interspace, the L2L3 or
L4L5 space may be tried. After repeated LPs, a patient may develop a
persistent CSF leak, keeping CSF pressure so low that it will not flow
through a 22-gauge needle unless the patient's head is elevated.
5. Each time the stylus is withdrawn, be ready to attach the stop-cock and
manometer to the needle as quickly as possible to minimize
unnecessary CSF loss and obtain an accurate opening pressure.
c. Collecting the CSF
1. Measure the CSF pressure by allowing fluid to flow into the manometer.
Evidence that the needle is properly positioned in the subarachnoid
space includes good respiratory variation of the fluid level in the
manometer. The patient should be as relaxed as possible; the legs and
hips can be extended slightly from the maximally flexed position when
the pressure is measured.
2. Collect the fluid into at least 3 sterile tubes. One scheme is as follows:
a. Tube No. 1: Collect 2 mL for protein and glucose. This tube is
centrifuged, and the sediment is used for microscopic examination.
b. Tube No. 2: Collect 1 to 2 mL for bacteriologic culture.
c. Tube No. 3: Collect 1 mL for cell count and 1 mL for serology.
Additional CSF may be needed for CSF cytology, fungal or
mycobacterial cultures, and large volumes of 7 to 10 mL increase the
diagnostic yield. Polymerase chain reaction (PCR) assays (i.e.,
varicella-zoster virus, herpes simplex virus, Mycobacterium
tuberculosis bacillus, cytomegalovirus, and J C virus) generally
require only 1 mL volumes each.
3. If the opening pressure is high, there is little advantage in collecting
less fluid in an attempt to minimize the risk of herniation. Much of the
danger from the LP is from leakage of CSF through the dural defect
created by the needle.
4. In virtually all cases of bacterial meningitis, the CSF pressure is found to
be elevated. Thus, the patient should be observed closely (no less often
than every 15 minutes for the next 4 hours) and hyperosmolar agents
administered if the patient shows evidence of neurologic deterioration.
5. If the patient's condition deteriorates during the performance of the LP
or if the patient is considered to be at a high risk of herniation, the stylet
is replaced into the needle and the needle is left in place. Mannitol, 1.0
to 1.5 g/kg, is infused over 20 to 30 minutes, and high-dose steroid
therapy is begun with dexamethasone (Decadron), 10 mg, given by
rapid IV infusion. After the mannitol has been infused, the needle is
withdrawn.
d. Withdrawal of the needle. Cases have been reported in which nerve roots
were trapped by an LP needle when the stylet was replaced; the root was
avulsed as the needle was withdrawn. When the needle is withdrawn, the
stylet should not be in place.
e. Examination of the CSF
1. CSF formula (Table 8-1). The CSF formula in bacterial meningitis will
be purulent (elevated cell count, predominantly polymorphonuclear
leukocytes), with low glucose (less than 40 mg/dL) and elevated protein
(more than 50 mg/dL) concentrations. However, in the following cases
the CSF profile can be misleading:
TABLE 8-1. The Cerebrospinal Fluid Formula
a. In a partially treated bacterial meningitis.
b. Early in overwhelming infection, especially with Streptococcus
pneumoniae, where there can be a poor polymorphonuclear
response.
c. When the patient is markedly leukopenic or immunosuppressed.
d. When meningitis is caused by bacteria that induce a lymphocytic
rather than a neutrophilic CSF profile, e.g., Listeria monocytogenes,
Treponema pallidum, Borrelia burgdorferi, Leptospira interrogans.
2. Microscopic examination. The following examinations are performed,
as indicated, on the sediment of fresh, centrifuged CSF:
a. Gram stain.
b. Acid-fast bacilli (AFB) stain. The greater the volume of CSF
examined, the higher the yield of this procedure. Therefore, the CSF
sediment may be concentrated by allowing 4 or 5 drops of CSF to
dry sequentially on one area of a slide.
c. India ink preparation is not as good a screening test for
Cryptococcus species as is Gram stain, in which the organisms
appear as large, gram-positive cocci. When Gram stain suggests
fungus, India ink can be used to identify the cryptococcal capsule.
Identification of cryptococcal antigen titers in CSF by latex
agglutination is the most sensitive means of detecting cryptococcal
meningitis.
d. Wet smear for fungi and amebae.
e. Examination of polymorphonuclear cells with polarized light to look
for keratin fragments. These fragments indicate chemical meningitis,
secondary to the spillage of the contents of a dermoid cyst or
craniopharyngioma.
3. Bacteriologic examination
a. Routine cultures for bacteria. CSF is smeared on a blood agar
plate or a chocolate agar plate or slant or is inoculated into a nutrient
broth. It is essential to inoculate all cultures as soon as possible after
the LP.
b. If indicated, fluid may be cultured for mycobacteria, fungi, and
amebae.
4. Special studies
a. Meningitis due to Neisseria meningitidis, Haemophilus influenzae,
and S. pneumoniae may be rapidly diagnosed, even in the absence
of a positive Gram stain, by documentation of the presence of
specific bacterial antigens in the CSF. The latex particle
agglutination and coagglutination tests have replaced
counterimmunoelectrophoresis for rapid detection in CSF.
b. Serologic test for syphilis (STS). Peripheral blood serology should
be used as a screening test for syphilis and the CSF serology
examined only when the peripheral serology is positive or there is
clinical suspicion of central nervous system (CNS) syphilis. If such
suspicion is present, a negative serum STS does not rule out
neurosyphilis.
c. Viral isolation studies, viral antibody titers, or, if available, PCR
assays as indicated based on clinical suspicion.
d. Immunoassays for fungal antigens. Latex particle agglutination
for cryptococcal antigen is more sensitive than Gram's stain or India
ink preparation for the diagnosis of cryptococcal meningitis.
Complement fixation tests can be obtained from the State
Department of Health Laboratory when coccidioidomycosis or
histoplasmosis is suspected.
e. PCR for Mycobacterium tuberculosis in CSF (TB Amplicor) is more
sensitive (60%) and specific (100%) than combined Ziehl-Neelsen
staining and culture for the diagnosis of tuberculous meningitis.
3. Additional studies
a. Once the presumptive diagnosis of bacterial meningitis has been made, the
patient is reassessed for factors that may have increased the risk of
meningitis. These factors include:
1. Recent head trauma with skull fracture, usually basilar, giving
organisms access to the intracranial cavity.
2. The presence of a CSF leak, usually due to head trauma and involving
a defect in the cribriform plate.
3. Recent intracranial surgery.
4. Meningomyelocele.
5. Immune deficiency. Patients with defects in cell-mediated immunity,
including transplant recipients, are especially susceptible to intracellular
parasites such as Listeria. Patients with poor humoral immunity or who
have been splenectomized are at risk for infection with encapsulated
organisms. Neutropenic patients are at increased risk for infection with
Pseudomonas aeruginosa and the Enterobacteriaceae.
6. The presence of a parameningeal focus of infection: sinusitis, otitis
(usually chronic), mastoiditis, osteomyelitis of the skull, occult brain
abscess, and infected pilonidal sinuses.
7. A source of systemic sepsis, especially endocarditis.
b. Routine tests in all patients with presumptive bacterial meningitis:
1. Hematologic
a. CBC with differential.
b. Examination of a peripheral blood smear.
2. Metabolic
a. BUN and creatinine.
b. Blood glucose.
c. Electrolytes.
d. Urinalysis.
e. If nephrotoxic drugs are to be used, a baseline creatinine clearance
(Cl
cr
) is obtained.
3. Radiologic
a. Chest x-ray.
b. An MRI or CT scan (with bone windows) of the head to seek a
possible parameningeal focus of infection.
4. Blood, urine, and throat cultures.
c. Special studies for special circumstances:
1. When there is evidence of a CSF leak, and in all cases of recurrent
meningitis without an obvious cause, a radioactively labeled tracer or a
dye solution is injected into the subarachnoid space, and pledgets are
placed in the nasal cavity or ear canal. The pledgets are then examined
over time to document CSF rhinorrhea or otorrhea. Glucose oxidase test
strips are not a reliable means of detecting CSF leaks.
2. In neonatal meningitis, the mother is examined for signs of infection.
Amnionitis, endometritis, maternal urinary tract infections, and
septicemia are known to predispose to neonatal meningitis. A
knowledge of the identity and antibiotic sensitivity of maternal perinatal
infections may help to guide therapy for the neonate.
B. General medical care of a patient with bacterial meningitis
1. Systemic complications
a. Shock
1. Septic shock, if present, should be treated with volume replacement and
pressors, as indicated.
2. Shock associated with hemorrhagic infarction of the adrenals
(Waterhouse-Friderichsen syndrome) is an uncommon complication
of meningococcal meningitis. It is associated with severe purpura and
fulminant meningococcemia. In a patient with bacterial meningitis and
shock, emergency treatment with replacement doses of corticosteroids
is warranted until the patient has stabilized and the medical situation
has been better evaluated.
3. Disseminated intravascular coagulation (DIC) may accompany septic
shock. In a recent prospective study, DIC complicated bacterial
meningitis in more than 8% of patients, occurring predominantly in the
first week of illness.
4. Adult respiratory distress syndrome (ARDS), or shock lung, is
another consequence of microcirculatory failure, causing severe
hypoxemia and refractory pulmonary edema. ARDS was seen in 3.5%
of patients in a prospective study of complications of bacterial
meningitis, with 100% mortality.
b. Volume status. Because of the likely presence of brain swelling and
increased CSF pressure in CNS infection, care is taken not to overhydrate
the patient. If the patient is not hypotensive, approximately 1,200 to 1,500
mL of normal saline is adequate daily fluid intake in adults, and about 1,000
mL/m
2
body surface area is adequate in children. The volume of fluid in
which the antibiotics are administered and any oral intake are included in
this total. These restrictions may be gradually relaxed as the infection
responds to therapy, especially if the CSF pressure is decreasing. Solutions
that contain more than 50% free water (e.g., 5% dextrose-water, D/W)
should not be administered, except in small volumes when they are used to
dissolve the antibiotics.
c. Fever. Salicylates, acetaminophen, and baths in tepid water may all be
used to lower body temperature. Patients usually become afebrile within 2
to 5 days of initiation of appropriate antibiotic therapy. If fever persists or
recurs, reassessment, including repeat LP, is indicated. Inadequate drug
therapy and complications such as cortical venous thrombophlebitis,
subdural empyema, or extra-cerebral metastatic infection must be
considered, as well as drug fever. A syndrome of fever, arthritis, and
pericarditis is seen in about 10% of patients with meningococcal meningitis,
usually beginning 3 to 6 days after initiation of therapy.
d. Isolation. Patients with meningococcal infections or meningitis of unknown
etiology are placed under respiratory precautions for the first 24 hours of
antibiotic therapy or until meningococcal disease has been ruled out.
Precautions may be necessary in patients with bacterial infections that have
broad drug resistance to prevent the organisms from infecting other
susceptible patients.
2. Treatment of predisposing factors
a. Parameningeal infections are treated concurrently with meningitis, with
surgical drainage if necessary.
b. Foci of systemic sepsis may require more prolonged antibiotic therapy
than the meningitis (e.g., infective endocarditis, osteomyelitis, and wound
infection).
c. Minor CSF leaks need not be repaired until after the CNS infection is under
control.
C. Systemic antibiotic therapy of bacterial meningitis
1. General principles
a. Patients are hospitalized for the entire course of treatment, and the entire
course of antibiotics is administered parenterally. LP should not await CT
except in the presence of coma, focal neurologic findings, papilledema, or
rapidly deteriorating mental status. In such cases, blood cultures are
obtained and empiric antibiotic treatment is begun immediately, based on
the most likely pathogens (Table 8-2). Optimal treatment requires
antibiotics with bactericidal, not merely bacteriostatic, drug effect in CSF.
Empiric therapy must be modified, if indicated, once CSF cultures and
antibiotic susceptibility test results are available. H. influenzae vaccination
and the widespread emergence of antibiotic resistant strains of other CNS
pathogens have altered the epidemiology of bacterial meningitis and
necessitated new therapeutic recommendations.
TABLE 8-2. Initial Therapy of Bacterial Meningitis
b. The minimum duration of antibiotic therapy necessary is unknown, but in
meningitis with the common organisms S. pneumoniae, H. influenzae, and
N. meningitidis, the practice is to treat at full dose of parenteral antibiotics
for at least 10 days and at least 7 days after the patient becomes afebrile. If
any surgery is performed near the end of therapy, the antibiotics are
continued at least 72 hours after surgery. In infections with less sensitive
organisms (e.g., enteric gram-negative organisms, L. monocytogenes,
group B streptococci), or after trauma or surgery, when pockets of
organisms can infect poorly perfused tissues, it is reasonable to prolong the
duration of antibiotic therapy to 2 to 3 weeks or longer.
c. In complicated cases, when the organism is relatively difficult to treat
(e.g., enteric gram-negative rods, Listeria, Staphylococcus aureus), an LP
should be performed about 72 hours after initiation of antibiotic therapy.
The CSF cell count, differential cell count, protein, and glucose are
determined, and the CSF is examined microscopically and cultured
appropriately to document that it has been sterilized. An LP at the
conclusion of therapy has not proved useful in predicting those patients
who will relapse.
d. In meningeal infections with organisms that are relatively sensitive to
antibiotics with good CSF penetration (e.g., streptococcal species, N.
meningitidis, and H. influenzae), the CSF should be sterile within 24 hours
of beginning therapy, and the differential cell profile should be
predominantly mononuclear. (The CSF protein level may continue to be
high and the CSF glucose may remain low for 2 weeks or longer despite
curative therapy.) Other organisms, especially gram-negative rods, may
continue to be cultured from the CSF for as long as 72 hours after the
initiation of therapy. Persistence of the infecting organism in the CSF
beyond the expected interval, however, may imply a need to change
antibiotics or to add intrathecal antibiotics. It may also indicate the presence
of an occult parameningeal focus of infection seeding the CSF.
e. Drug toxicity. In the treatment of bacterial meningitis, the highest doses of
drugs that can be tolerated are generally used, and often the patients have
underlying hepatic, renal, or hematologic disease. Therefore, the patient
must be observed carefully for the development of drug toxicity.
f. Antibiotics that penetrate poorly into the CSF are avoided in the treatment
of bacterial meningitis, including the tetracyclines and the first- and
second-generation cephalosporins.
2. Pharmacology of antibiotics used in the chemotherapy of bacterial
meningitis
a. Chloramphenicol
1. Pharmacokinetics. Half-life =1.5 to 3.5 hours. The CSF concentration
is 30% to 80% of plasma concentration. The drug is inactivated primarily
in the liver by glucuronidation, and the inactive metabolites are excreted
in the urine. Therefore, the dosage does not have to be decreased in
renal failure but should be decreased in severe hepatic insufficiency.
2. Dosage
a. Chloramphenicol is not recommended for use in neonates. It is not
bactericidal to enteric bacilli, and risk of side effects is high in infants
under 1 month of age.
b. Infants over 1 month old: 50 mg/kg/day IV, divided into 2 doses at
12-hour intervals.
c. Children: 100 mg/kg/day IV, divided into 4 doses at 6-hour intervals.
d. Adults: 4 to 6 g/day IV, divided into 4 doses at 6-hour intervals.
3. Toxicity
a. Hypersensitivity reactions include rash, fever, angioedema,
stomatitis, and idiosyncratic bone marrow suppression with
pancytopenia. Aplastic anemia occurs in fewer than 1 in 40,000, but
it is irreversible. It occurs usually after prolonged exposure or on a
second exposure.
b. Dose-related and reversible bone marrow suppression occurs with
plasma drug levels of 25 g/mL or higher. Recovery usually occurs
about 12 days after the drug is stopped.
c. Gray baby syndrome and cardiovascular collapse occur in
premature infants and neonates with inadequate hepatic
glucuronyltransferase activity.
4. Precautions
a. Bone marrow function must be checked frequently. The CBC,
differential, platelet count (or peripheral smear), serum iron, total iron
binding capacity (TIBC), and reticulocyte count should be checked 3
times weekly. The first sign of bone marrow suppression is increased
serum iron and increased saturation of TIBC.
b. Extreme care must be used if the drug is given to children less than
1 month old.
c. If used in combination with penicillin, the first dose of penicillin is
given at least 30 minutes before the first dose of chloramphenicol,
and succeeding doses of the two drugs should not be given within 30
minutes of each other.
d. Chloramphenicol penetrates the CSF and reaches levels sufficient to
be bactericidal against H. influenzae, S. pneumoniae, and N.
meningitidis. However, it is not recommended against
penicillin-resistant S. pneumoniae because of the higher CSF drug
concentrations needed for bactericidal activity against this organism.
Similarly, bactericidal levels against most enteric gram-negative rods
are not achieved after intravenous administration, and
chloramphenicol is not adequate treatment for these organisms.
b. The penicillins
1. Penicillin G
a. Pharmacokinetics. Penicillin G is excreted primarily by the kidney
and partially in bile. The half-life is approximately 30 minutes in
adults but is 3 hours in neonates less than 1 week old. The half-life
increases in renal failure. In meningitis, CSF levels are variable,
ranging between 5% and 30% of concentrations in blood, and are
generally therapeutic.
b. Dosage
i. Neonates: 50,000 to 100,000 units/kg/day IV, divided into 2
doses.
ii. Infants: 250,000 units/kg/day IV, divided into 4 to 6 doses.
iii. Children: 12 10
6
units/day, divided into 6 doses.
iv. Adults: 24 10
6
units/day IV, divided into 6 doses.
v. In renal failure (Cl
cr
<10 mL/minute): Children: same doses as
above. Adults: 2 10
6
units q4h IV.
c. Toxicity
i. Hypersensitivity reactions include rash, fever, eosinophilia,
angioedema, anaphylaxis, serum sickness, and encephalopathy.
ii. Seizures can occur with high doses or intrathecal use.
iii. Penicillin G is available as a sodium or potassium salt, and it may
create a significant salt load in infants or in patients with heart or
renal failure.
iv. Precautions. Potassium salt has 1.7 mEq of potassium per 10
6

units.
2. Ampicillin
a. Pharmacokinetics. Half-life =1.5 hours. Ampicillin is excreted
primarily by the kidneys; therefore, the dosage must be reduced in
renal failure. Penetration into CSF is similar to that of penicillin G.
b. Dosage
i. Neonates: 50 to 100 mg/kg/day IV, divided into 2 doses.
ii. Infants 2 weeks to 2 months old: 100 to 200 mg/kg/day IV,
divided into 3 doses.
iii. Infants over 2 months old and children: 300 to 400 mg/kg/day
IV divided into 4 doses.
iv. Adults: 12 g/day IV, divided into 4 to 6 doses.
v. In renal failure (adults): 2 to 3 g given at the following intervals:
Cl
cr
(mL/min) Dosage interval
80 q6h
5080 q6h
1050 q9h
<10 q12h
c. Hypersensitivity reactions are the same as with penicillin G. An
ampicillin rash does not necessarily represent hypersensitivity and in
itself does not preclude continuation of the drug, its future use, or the
use of other penicillins.
3. The broad-spectrum penicillins, carbenicillin, ticarcillin, piperacillin,
mezlocillin, and azlocillin, are antibiotics similar in pharmacokinetics
and antibacterial action to ampicillin, except that they have greater
activity against P. aeruginosa, Proteus strains, and Enterobacter.
a. Dosage
i. Carbenicillin:
Neonates during the first week of life and infants weighing less
than 2,000 g: 400/mg/kg/day IV, divided into 4 doses.
Infants after the first week of life if weight is greater than 2,000 g:
400 to 600 mg/kg/day IV, divided into 6 to 12 doses.
Adults: 24 to 36 g/day IV, divided into 12 doses.
ii. Ticarcillin:
Neonates: 200 to 450 mg/kg/day IV, divided into 4 to 6 doses
(the package insert and Physicians' Desk Reference have
detailed instructions for computing the dosage in neonates).
Infants: 300 mg/kg/day IV, divided into 6 doses.
Children and adults: 200 to 300 mg/kg/day IV, divided into 6 to
12 doses.
iii. Piperacillin, mezlocillin, and azlocillin:
Children: 75 mg/kg IV q4h, up to 24 g/day.
Adults: 240 to 360 mg/kg/day IV, divided into 6 doses.
iv. In renal failure
Cl
cr
(mL/min) Dosage interval
>100 q4h
5080 q4h
1050 q68h
<10 q812h
b. Toxicity is similar to that of penicillin G; abnormal platelet
aggregation with bleeding diathesis has been reported with
carbenicillin and ticarcillin.
c. Precautions. Carbenicillin and ticarcillin contain 5.2 mEq/g of
sodium. Since ticarcillin is administered at a lower dosage than
carbenicillin, it is to be preferred when a large sodium load must be
avoided. Piperacillin (1.85 mEq/g), mezlocillin (1.85 mEq/g), and
azlocillin (2.17 mEq/g) are even lower in sodium, but there is less
experience with their use in gram-negative meningitis than with
either carbenicillin or ticarcillin. None of the broad-spectrum
penicillins is to be used alone in the treatment of gram-negative
meningitis, especially Pseudomonas, since antibiotic resistance
commonly develops during monotherapy. An aminoglycoside is
usually added.
4. Oxacillin
a. Pharmacokinetics. Half-life =0.5 to 1.0 hour. Oxacillin is excreted
by the kidneys and liver. Penetration into CSF is similar to that of
penicillin G.
b. Dosage
i. Neonates, 1 week old: 50100 mg/kg/day IV, divided into 2 to 3
doses.
ii. Neonates, 2 to 4 weeks old: 100 to 200 mg/kg/day IV, divided
into 2 to 3 doses.
iii. Infants and children: 200 mg/kg/day IV, divided into 4 to 6
doses.
iv. Adults: 12 g/day IV, divided into 4 to 6 doses.
v. In renal failure: Dosage adjustment is usually unnecessary, but
some clinicians limit dosage to 1 g IV q46h if the Cl
cr
is less than
10 mL/minute.
c. Toxicity is the same as for penicillin G; interstitial nephritis has also
been reported.
5. Nafcillin
a. Pharmacokinetics. Half-life =30 minutes. Ninety percent is
excreted in bile. Penetration into CSF is similar to that of penicillin G.
b. Dosage. Same as for oxacillin.
c. Toxicity. Same as for oxacillin.
c. Aminoglycosides
1. Pharmacokinetics
a. Penetration into CSF with systemic administration is very low in the
presence of a normal blood-brain barrier and variable but low with
inflamed meninges. Levels in CSF are higher in neonates.
Aminoglycosides are excreted unchanged in the urine primarily by
glomerular filtration.
b. Half-life
i. Streptomycin: 2 to 3 hours.
ii. Gentamicin: 2 hours.
iii. Tobramycin: 1.5 to 3.0 hours.
iv. Kanamycin: 3 to 4 hours.
v. Amikacin: 2 hours.
vi. Netilmicin: 2 hours.
c. Serum drug levels achieved after a given dose may vary widely
among individuals.
2. Dosage
a. Systemic gentamicin, tobramycin, and netilmicin
i. Premature and term infants younger than 1 week: 5
mg/kg/day IV, divided into 2 doses.
ii. Neonates older than 1 week: 7.5 mg/kg/day IV, divided into 3
doses.
iii. Infants and adults: 5 mg/kg/day IV, divided into 3 doses.
iv. In renal failure: 1.0 to 1.3 mg/kg qxh, where x =serum
creatinine value 8.
b. Systemic kanamycin and amikacin
i. All ages: 15 mg/kg/day, divided into 2 doses.
ii. In renal failure: 7 mg/kg qxh, where x =serum creatinine value
9.
c. Intrathecal gentamicin and tobramycin
i. Neonates: 1 mg q24h.
ii. Adults: 4 to 8 mg q24h.
3. Toxicity
a. Vestibular disturbance is dose-related and occurs more readily in
the presence of inflamed meninges. The labyrinthine disorder
typically occurs in four stages:
i. A prodrome of 1 to 2 days of headache.
ii. An acute stage of nausea, vomiting, and vertigo, lasting 1 to 2
weeks.
iii. A chronic labyrinthitis, with gait ataxia as the main symptom,
lasting about 2 months.
iv. Gradual compensation, by means of visual and proprioceptive
cues, so that balance can be maintained except when the eyes
are closed. Recovery can take 12 to 18 months and might be
incomplete.
b. Hearing dysfunction occurs less readily than vestibular dysfunction
and is also dose-related. Older patients are more susceptible.
Tinnitus is often the first symptom, and audiometry shows a
high-tone hearing loss as the first sign, gradually progressing to
involve the lower tones. Tinnitus persists as long as 2 weeks after
the drug is stopped.
c. The aminoglycosides are weak neuromuscular blockers, an effect
that has no importance in patients with normal pulmonary function.
However, it can be important in patients with myasthenia gravis,
chronic obstructive pulmonary disease, or acute respiratory failure
and in the immediate postoperative period when other
neuromuscular blockers may still be active.
d. Nephrotoxicity. Acute tubular necrosis with impaired glomerular
filtration can occur and is associated with prolonged therapy and
high trough aminoglycoside concentrations. Dehydration, shock,
oliguria, and concurrent administration of other nephrotoxic drugs
may potentiate the renal toxicity.
e. Hypersensitivity reactions. Rash, eosinophilia, blood dyscrasia,
exfoliative dermatitis, stomatitis, fever, lymphadenopathy, and
anaphylaxis are unusual reactions of therapy.
f. Intrathecal use is frequently associated with paresthesia of the legs
and, occasionally, transverse myelitis or spinal arachnoiditis.
Injection of excessive amounts of aminoglycoside into the ventricles
has produced seizures, encephalopathy, and death.
4. Precautions
a. Follow renal function and urinalysis at least twice weekly.
b. Observe the patient carefully for any sign of vestibular or auditory
dysfunction.
c. Serum drug levels vary widely among individuals on a given dose
of aminoglycoside. Thus, serum drug levels should be measured just
before and 0.5 to 1.0 hour after a dose is given, once a steady-state
concentration is achieved, and at least weekly thereafter if the renal
function is normal. Levels should be obtained more frequently if the
renal function is abnormal. If direct injection of the drug into the CSF
is indicated, the CSF level should be checked before the second
dose and before every other dose thereafter.
i. Therapeutic peak drug levels of gentamicin and tobramycin are 6
to 8 g/mL (20 to 25 g/mL for kanamycin and amikacin).
ii. Trough levels should be less than 1 g/mL for gentamicin and
tobramycin (less than 6 g/mL for kanamycin and amikacin) to
prevent excessive accumulation of drug.
d. If maximum doses are to be used or a prolonged course is
anticipated, a baseline audiogram should be obtained before
initiation of therapy and at any sign of hearing loss.
e. If an aminoglycoside must be used in patients with respiratory
disease or neuromuscular disease affecting respiration, respiratory
function is checked before beginning therapy, after the first dose,
and then as indicated. In myasthenia, depending on severity,
respiratory function may need to be checked as often as every 4
hours. Neuromuscular blockade can be counteracted with
intravenous calcium or an anticholinesterase agent (neostigmine or
pyridostigmine).
5. Synergistic action with penicillins. Gram-negative rods such as
Pseudomonas or Proteus species may be sensitive both to a
broad-spectrum penicillin or third-generation cephalosporin and to an
aminoglycoside. The aminoglycosides work synergistically with these
b-lactam antibiotics, and combination therapy is warranted in
treating meningitis caused by gram-negative rods. In neonatal
Streptococcus agalactiae meningitis, IV gentamicin may be added to
penicillin until susceptibility testing is completed and clinical
improvement is observed. Thereafter, penicillin alone may be used.
d. Macrolides
1. Erythromycin
a. Pharmacokinetics. Half-life =1.5 to 2.0 hours. Erythromycin is
excreted in the bile. There is no need to decrease the dosage in
renal failure. Penetration into CSF is similar to that of penicillin G.
b. Dosage
i. Neonates: 20 mg/kg, divided into 2 doses.
ii. Children: 40 to 50 mg/kg/day IV, divided into 4 doses.
iii. Adults: 4 to 8 g/day IV, divided into 4 doses.
c. Toxicity
i. Hypersensitivity reactions include rash, fever, eosinophilia, and
cholestatic jaundice (with the estolate form).
ii. Intravenous use frequently causes phlebitis.
iii. High-tone hearing loss has been reported.
d. Precautions. If used IV, infuse over 0.5 to 1.0 hour in 250 mL of
solution.
2. Azithromycin is the only new generation macrolide used for IV
antibiotic treatment. It is active against b-lactamase-producing H.
influenzae; overall resistance rate of S. pneumoniae is 5% to 7%. Most
methicillin-resistant S. aureus is also resistant to azithromycin.
a. Pharmacokinetics. Half-life =11 to 14 hours, but tends to increase
with multiple doses, up to about 50 hours. Elimination is primarily
hepatic, and caution should be used in patients with liver failure.
b. Azithromycin has not been studied systematically in meningitis, and
CSF penetration studies have not been published. The IV dose for
severe pneumonia is 500 mg/day.
3. Vancomycin has assumed a new importance with the increase in
B-lactam-resistant S. pneumoniae, and should be used, in
combination with ceftriaxone, in patients with a CSF Gram stain
consistent with S. pneumoniae.
a. Pharmacokinetics. Half-life =6 hours. Levels in CSF with inflamed
meninges are similar to those with penicillin. Vancomycin is excreted
by the kidneys, so the dosage must be adjusted in renal
insufficiency.
b. Dosage
i. Premature infants and neonates: 6 to 15 mg/kg/day IV, divided
into 4 doses.
ii. Children: 44 mg/kg/day IV, divided into 2 or 3 doses.
iii. Adults: 2 g/day IV, divided into 2 doses.
c. Toxicity
i. Hypersensitivity reactions include rash, fever, and anaphylaxis.
ii. High-tone hearing loss, which is unusual with plasma
concentrations less than 30 g/mL.
iii. Nephrotoxicity.
d. Precautions
i. Concurrent administration with other oto- or nephrotoxic drugs
should be avoided.
ii. Follow renal function at least twice weekly.
iii. Serum drug levels should be obtained just before and 1 hour
after a dose is given, 24 hours after initiation of therapy, and at
least weekly (more frequently if renal function is deteriorating).
e. Peak range is 15 to 35 g/mL at steady state.
f. Trough levels should be less than 10 g/mL. When maximum doses
are to be used, obtain a baseline audiogram, and repeat it at any
sign of hearing loss.
e. Cephalosporins
1. The third-generation cephalosporins ceftriaxone, cefotaxime, and
ceftizoxime achieve concentrations in the CSF 10 to 30 times the mean
bactericidal concentration for many pathogens. They are widely used in
bacterial meningitis.
2. In general, these agents are effective for meningitis caused by N.
meningitidis, S. pneumoniae, and H. influenzae (including some
b-lactamase producing strains) as well as against many enteric
gram-negative rods, including most strains of Escherichia coli and
Klebsiella. These agents are therefore useful for the initial therapy of
acute meningitis in nonimmunosuppressed hosts, both children and
adults. However, with the increase in cephalosporin-resistant strains of
S. pneumoniae, initial combination therapy with vancomycin is
recommended pending susceptibility testing results. The
third-generation cephalosporins are not active against Listeria, S.
aureus, or anaerobic bacteria, so they must be used in conjunction with
other agents for the initial therapy of neonatal meningitis, in
postneurosurgical patients and immunosuppressed hosts, and in cases
where Pseudomonas is a likely pathogen.
3. Ceftazidime, unlike the other third-generation cephalosporins listed,
has activity against Pseudomonas. Its use should be reserved for
cases where Pseudomonas is suspected.
4. Toxicity. Cephalosporins are generally well tolerated, but
hypersensitivity reactions (typically rash or fever) occur.
Penicillin-allergic patients may or may not have allergy to
cephalosporins. Bone marrow suppression occurs rarely. Diarrhea is
relatively common with third-generation cephalosporins. Nephrotoxicity
has been reported with concomitant administration of cephalosporins
and aminoglycosides or furosemide.
5. Ceftriaxone
a. Pharmacokinetics. Half-life =6 to 9 hours. Excretion is 60% renal
and 40% hepatic.
b. Dosage
i. : 80 to 100 mg/kg/day IV divided into 4 doses.
ii. : 4 to 6 g/day IV divided into 2 or 3 dosages.
iii. The dosage requires adjustment in the presence of combined
renal and hepatic insufficiency.
c. The clinical experience in treating bacterial meningitis with
ceftriaxone is greater than that with other cephalosporins. Many
clinicians regard it as the agent of choice for the initial treatment of
meningitis of unknown etiology and in the treatment of organisms
known to be sensitive, especially enteric gram-negative rods.
Vancomycin should be added where CSF Gram's stain is consistent
with S. pneumoniae.
6. Cefotaxime
a. Pharmacokinetics. Half-life =1 hour. Excretion is renal.
b. Dosage
i. Children: 200 mg/kg/day IV divided into 6 doses.
ii. Adults: 12 g/day IV divided into 6 doses. The dosage must be
adjusted in renal failure.
c. Cefotaxime is almost as active against pneumococci as penicillin.
Like ceftriaxone, it can be used alone in the initial treatment of
bacterial meningitis in immunocompetent adults.
7. Ceftizoxime
a. Pharmacokinetics. Half-life =1.4 to 1.8 hours. Excretion is renal.
b. Dosage
i. Children: 600 mg/kg/day IV divided into 3 doses.
ii. Adults: 9 to 12 g/day IV divided into 3 doses. The dosage must
be adjusted in renal failure.
8. Ceftazidime
a. Pharmacokinetics. Half-life =0.9 to 1.7 hours. Excretion is renal.
b. Dosage
i. Children: 90 to 150 mg/kg/day IV divided into 3 doses.
ii. Adults: 6 to 12 g/day IV divided into 3 doses. The dosage must
be adjusted in renal failure.
c. Although the spectrum of action and pharmacokinetics of ceftazidime
are similar to those of the other third-generation cephalosporins used
to treat meningitis, it has enhanced activity against Pseudomonas.
Because of the potential for development of drug resistance during
therapy, most experts favor using ceftazidime in combination with an
aminoglycoside for Pseudomonas meningitis. Cures with
monotherapy have been reported.
g. Aztreonam has a monocyclic b-lactam nucleus that confers stability
against b-lactamase-producing gram-negative aerobes, including
Pseudomonas. It has been used successfully as monotherapy in
gram-negative meningitis in an open-label trial and can be used in
penicillin-allergic patients.
1. Pharmacokinetics. Half-life =1.7 to 2.0 hours. Excretion is renal, and
dosage must be adjusted in renal failure.
2. Dosage
a. Infants: 90 to 120 mg/kg/day IV divided into 3 or 4 doses.
b. Children older than 2 years: 150 to 200 mg/kg/day IV divided into 3
or 4 doses.
c. Adults: 3 to 8 g/day IV divided into 3 or 4 doses.
3. Toxicity. Aztreonam is generally well tolerated. Eosinophilia is common;
rash, diarrhea, and abnormal liver function tests occur occasionally.
Thrombocytopenia and seizures have been reported rarely.
3. Initial choice of antibiotics
a. Identification of the infecting organism must be made, and the drug
sensitivities determined. Until this information is available, the initial choice
of antibiotics is guided by the following factors:
1. Gram stain. If a high-quality Gram stain shows an identifiable organism
in abundance, the patient is treated for that organism. In addition,
coverage should be given for other likely infecting organisms given the
age of the patient. S. pneumoniae should be treated initially with a
combination of ceftriaxone or cefotaxime and vancomycin, until
cephalosporin sensitivity of the strain is known.
2. Age of the patient. In the absence of complicating conditions (e.g.,
immunologic disease, recent intracranial surgery or head trauma), the
epidemiology of infection changes with the age of the patient.
a. Neonatal meningitis generally originates from 2 sources:
i. Infections acquired during delivery, which usually appear within
the first week of life; the pathogenic organisms are those found in
the female genital tract, such as enteric gram-negative bacilli,
group B streptococci, and L. monocytogenes.
ii. After about 1 week of age, meningitis is more often a result of
systemic sepsis from respiratory, skin, or umbilical infections, and
the predominant organisms are S. aureus, group B streptococci
(S. agalactiae), and organisms present in hospital nurseries, such
as Pseudomonas and Proteus species. Opportunistic pathogens
such as Flavobacterium septicum or Salmonella species must
also be considered.
iii. The temporal division is not sharp, however, because neonates
may develop delayed infections from organisms presumably
acquired during delivery, and hospital-acquired organisms may
cause infection within the first days of life. Consequently, the first
2 months of life may be considered as a unit.
b. Children and adolescents
i. After the age of 2 months, the child loses the protection of
maternal antibodies and becomes susceptible to the common
organisms that cause childhood meningitis, primarily H.
influenzae and N. meningitidis. There are rare cases of
gram-negative or staphylococcal infection, which are usually
associated with surgery, trauma, or systemic sepsis. The
incidence of H. influenzae meningitis peaks at the age of 1
year, then drops off steadily as most children develop antibodies
to the group B capsular antigen, either naturally or through
vaccination.
ii. With widespread vaccination, H. influenzae meningitis is much
less common, leaving meningococcus as the most common
agent from ages 2 to 18 years.
c. Adults. After the age of 18 years, most adults have developed
immunity to Meningococcus, and Pneumococcus becomes the
leading cause of bacterial meningitis. With its many type-specific
capsular antigens and lack of cross-immunity among types, no
permanent immunologic protection can develop against the
Pneumococcus, and resistance to penicillins and cephalosporins is a
growing worldwide problem. Virtually all other bacterial meningitis in
adults occurs in the setting of some predisposing condition, such as
trauma, surgery, or immunosuppression. Elderly and debilitated
patients, including alcoholics, are at increased risk for infection with
gram-negative rods, particularly E. coli. In addition, cases of H.
influenzae meningitis are being recognized more frequently among
older adults, and at least 20% of the strains are b-lactam resistant.
3. Predisposing factors
a. Head trauma. Closed head injury, with skull fractures or defects in
the cribriform plate, can give bacteria access to the subarachnoid
space. Usually the meningitis occurs within 2 weeks of injury, and
Pneumococcus is the infecting organism. With open head injuries
and delayed onset of meningitis, a wide variety of organisms,
including gram-negative bacilli and staphylococci, may invade the
CNS. Meningitis associated with CSF rhinorrhea is due to
Pneumococcus in a high percentage of patients, even long after
trauma.
b. Parameningeal infections. Sinusitis, chronic otitis, and mastoiditis
may lead to the development of meningitis, which is due to
Pneumococcus in most cases, less commonly to H. influenzae, and
occasionally to S. aureus. It should be emphasized that the
presence of an organism in a parameningeal focus of infection
does not guarantee that organism to be the etiology of the
meningitis, and the initial antibiotic is not chosen on that basis
alone. Any organism that infects the ears or sinuses should be
covered by the initial therapy; but unless there is confirmation by a
strongly diagnostic CSF Gram stain, other likely organisms must be
covered as well.
c. Postneurosurgical meningitis. The organism is introduced at
surgery or shortly thereafter, before healing of the incision. Most
often it is a skin organism or one of the wide variety of organisms
acquired in the hospital environment. Consequently, broad-spectrum
coverage is necessary until an organism can be identified.
Staphylococcus epidermidis is an especially common pathogen
infecting intraventricular shunts.
d. Anatomic defects. Meningomyeloceles, midline dermal sinus tracts
including pilonidal sinuses, and tumors of the head and neck that
invade the skull and meninges may give organisms access to the
subarachnoid space. Thus, these conditions are sought in all
patients with meningitis caused by unusual organisms. In the
presence of these defects, initial antibiotic coverage must include
staphylococci, streptococci, and enteric gram-negative organisms in
addition to the common organisms for the particular age group.
e. Evidence of systemic sepsis. Purpuric or petechial skin lesions
may point to a diagnosis of meningococcemia, and bacilli often can
be seen in or cultured from such lesions. However, staphylococcal
septicemia, acute bacterial endocarditis, and, rarely, septicemia with
enteric gram-negative organisms may produce similar skin lesions.
Pneumonia may accompany meningitis and is often the primary
infection, with meningitis occurring as a consequence of septicemia.
J ust as with sinus and ear infections, however, initial therapy should
not be chosen purely on the basis of the respiratory pathogen.
f. Underlying systemic illness
i. Splenectomy and sickle cell anemia predisposes to
pneumococcal sepsis and meningitis.
ii. Navahos and individuals with the HLA-B12 haplotype may be
at increased risk of H. influenzae B infection.
iii. Systemic malignancy, especially hematologic malignancy,
induces vulnerability to a much wider range of organisms than
that affecting the normal host, especially if the WBC count is
depressed. Patients with malignancy and a normal peripheral
WBC count are most often infected with Cryptococcus, but
Listeria should also be considered, along with the more usual
pathogens such as Pneumococcus. When the WBC count falls
below 2,700, gram-negative rod meningitis becomes more likely.
iv. Transplant recipients and other patients on
immunosuppressive therapy, as well as patients with renal
failure, are susceptible to infection with fungus, enteric
gram-negative rods, and hospital-acquired pathogens such as
Pseudomonas, Acinetobacter, and Serratia species. Dialysis
patients are particularly likely to become infected with skin
organisms, such as staphylococci and streptococci.
v. Patients with acquired immunodeficiency syndrome (AIDS)
are susceptible to infections with Toxoplasma, fungi (especially
Cryptococcus), herpesviruses, and mycobacteria. Patients with
AIDS may have simultaneous CNS infections with more than one
pathogen (see sec. XVII).
g. Epidemiology. In nonhospitalized patients, knowledge of community
epidemics helps determine the appropriate therapy. In hospitalized
patients with malignancy, immunosuppression, or anatomic defects
that predispose to the development of meningitis with unusual
organisms, initial antibiotic therapy should cover the organisms
known to be present in the patient's hospital environment. Thus one
must take into account antibiotic sensitivities of hospital flora in
choosing a therapeutic regimen. Broad-spectrum antibiotic coverage
should be used if there is any doubt about the infecting organism,
particularly in patients with inadequate host defenses or with
hospital-acquired infections.
b. Recommendations for initial antibiotic therapy (see Table 8-2)
1. Neonatal meningitis (in infants younger than 2 months)
a. Ampicillin, 50 to 100 mg/kg/day IV, divided into 2 doses, and one
of the following:
i. Gentamicin, 5.0 mg/kg/day IV or IM, divided into 2 doses in
premature infants and in term infants in the first week of life; or
7.5 mg/kg/day IV or IM, divided into 3 doses in neonates after the
first week of life; or
ii. Amikacin, 15 mg/kg/day, divided into 2 doses if
gentamicin-resistant organisms are common in the hospital
nursery.
b. Alternative. Ampicillin, 50 to 100 mg/kg/day IV divided into 2
doses, and ceftriaxone, 100 mg/kg/day divided into 2 doses.
c. For penicillin-allergic patients. Vancomycin, 6 to 15 mg/kg/day
divided into 4 doses, and one of the following:
i. Gentamicin or amikacin in the same dosage as in (a)(i) or (a)(ii),
or
ii. Tobramycin, 3.0 to 4.5 mg/kg/day IV divided into 3 doses.
2. Infants and children (over 2 months old)
a. Ampicillin, 300 to 400 mg/kg/day IV, in 4 or 6 divided doses, and
one of the following:
i. Chloramphenicol, 50 to 100 mg/kg/day IV, in 4 divided doses, or
ii. A third-generation cephalosporin (e.g., ceftriaxone, 100
mg/kg/day IV).
b. Alternative. Chloramphenicol, 50 to 100 mg/kg/day IV, divided into
4 doses, and erythromycin, 25 to 50 mg/kg/day, divided into 4
doses.
3. Adults (community-acquired meningitis)
a. Ampicillin, 12 g/day IV, divided into 4 or 6 doses. If
ampicillin-resistant strains of H. influenzae are common in a
particular area, it is reasonable to add ceftriaxone, 4 to 6 g/day IV
divided into 2 doses.
b. Alternative. Chloramphenicol, 4 g/day IV, divided into 4 doses,
and erythromycin, 4 g/day IV, divided into 4 doses.
4. Patients with basilar skull fractures or CSF leaks. Treatment is the
same as in (5).
5. Postneurosurgical infection
a. Vancomycin
i. Premature infants and neonates: 6 to 15 mg/kg/day IV, divided
into 4 doses.
ii. Children: 44 mg/kg/day IV, divided into 2 or 3 doses.
iii. Adults: 2 g/day IV, divided into 2 doses and
b. Ceftazidime
i. 50 to 100 mg/kg IV every 8 hours in premature infants.
ii. Children: 90 to 150 mg/kg/day IV divided into 3 doses.
iii. Adults: 6 to 12 g/day IV divided into 3 doses. The dosage must
be adjusted in renal failure.
c. Alternatives:
i. Erythromycin, 20 mg/kg/day IV, divided into 2 doses, in
neonates; 40 to 50 mg/kg/day IV, divided into 4 doses, in
children; 4 to 8 g/day IV, divided into 4 doses, in adults; and
gentamicin 5 mg/kg/day IV divided into 2 doses; or
ii. Vancomycin, 2 g/day IV divided into 2 doses, and gentamicin (5
mg/kg/day IV divided into 2 doses), tobramycin (same dosage
as gentamicin), or amikacin (15 mg/kg/day IV divided into 2
doses).
6. Underlying immunosuppression or malignancy
a. Ampicillin
i. Neonates: 50 to 100 mg/kg/day IV, divided into 2 doses.
ii. Infants 2 weeks to 2 months old: 100 to 200 mg/kg/day IV,
divided into 3 doses.
iii. Infants over 2 months old and children: 300 to 400 mg/kg/day
IV divided into 4 doses.
iv. Adults: 12 g/day IV, divided into 4 to 6 doses. In renal failure,
adjust dose as in C.2.b.(2)(b)(v).
b. Ceftazidime
i. 50 to 100 mg/kg IV every 8 hours in premature infants
ii. Children: 90 to 150 mg/kg/day IV divided into 3 doses.
iii. Adults: 6 to 12 g/day IV divided into 3 doses. The dosage must
be adjusted in renal failure.
c. Alternative. Erythromycin (or vancomycin) and gentamicin (see
sec. (5)(b)(i) and sec. (ii) for dosage).
c. Antibiotic therapy of bacterial meningitis of known etiology
1. As soon as the identification of the infecting organism has been made
and its antibiotic sensitivity is known, the broad-spectrum coverage is
changed to the optimum antibiotic available for the pathogen (Table
8-3). This antibiotic is continued for the remainder of the course.
TABLE 8-3. Antibiotic Therapy of Bacterial Meningitis of Known Etiology
2. The third-generation cephalosporins are a major improvement in the
therapy of gram-negative meningitis. However, resistance is common
among strains of Enterobacter, Pseudomonas, and Serratia.
a. The suggested initial therapy of meningitis caused by an
unidentified gram-negative rod is as follows:
i. Systemic aminoglycoside: gentamicin, tobramycin, or
netilmicin, 5 to 6 mg/kg/day IV; or amikacin, 15 to 20 mg/kg/day
IV, when gentamicin-resistant Pseudomonas strains are a
possibility; and
ii. Intralumbar or intraventricular aminoglycoside: gentamicin
or tobramycin, 5 to 10 mg/day IV, or amikacin, 20 to 25 mg/day
IV, and
iii. Systemic cephalosporin: ceftriaxone, 4 to 6 g/day IV divided
into two doses, or an equivalent cephalosporin.
b. Once antibacterial sensitivities are known, the antibiotics can be
adjusted. For Enterobacter and Pseudomonas infections, the
combination of a broad-spectrum penicillin (carbenicillin, ticarcillin,
piperacillin, mezlocillin, or azlocillin) or ceftazidime, 6 to 12 g/day IV,
divided into 3 doses, plus an aminoglycoside administered both IV
and intrathecally is the therapy of choice (see 2.c.(2)(c) for dosage).
c. Trimethoprim-sulfamethoxazole has been used in treating
gram-negative meningitis with some success, but experience with its
use is limited. It may have a role in the treatment of unusual
pathogens and in treating patients allergic to the standard antibiotics.
The dosage in adults is 15 to 20 mg/kg/day IV divided into 4 doses.
d. Aztreonam, 3 to 8 g/day IV divided into 3 or 4 doses, has also been
used successfully in treating gram-negative meningitis.
3. H. influenzae presents a special problem in antibiotic choice. An
increasing proportion (one third or greater) of isolates in the United
States are resistant to ampicillin by virtue of their ability to produce
b-lactamase, which confers resistance to ampicillin. As a consequence,
hospitals in which ampicillin-resistant H. influenzae has been recovered
from spinal fluid use a third-generation cephalosporin, such as
ceftriaxone or cefotaxime, or chloramphenicol as the first-line drug for H.
influenzae meningitis. A direct assay of b-lactamase activity of fluenzae
meningitis. A direct assay of b-lactamase activity of the isolate is a more
reliable indication of ampicillin sensitivity than is the standard disk
inhibition method. There have been only rare reports of H. influenzae
isolates that are resistant to chloramphenicol.
D. Intrathecal antibiotic therapy of bacterial meningitis
1. Rationale. Because of the relatively low CSF drug concentrations obtained
with some antibiotics, there have been many attempts to treat CNS infections
with direct subarachnoid injections. This procedure is used to expose the
organisms in the meninges and CSF to higher concentrations of antibiotics
than can be achieved with systemic administration alone.
2. There are several problems with the intrathecal approach.
a. Many drugs are toxic to the CNS when they come in contact with the
surface of the brain or spinal cord in high concentrations. For example,
penicillin and its derivatives cause seizures and encephalopathy. Also,
many drugs, when injected into the lumbar subarachnoid space, have been
reported to cause paresthesia, radiculopathies, or transverse myelitis, and
there have been reports of arachnoiditis following repeated intrathecal
administration of drugs.
b. Drugs do not diffuse freely throughout the CSF. When administered into
the lumbar space, they reach negligible concentration in the ventricles and
relatively low concentrations in the basilar cisterns. The more hydrophilic
the molecule, the more freely it diffuses in CSF.
c. Patients with CNS infections may have blocks in CSF flow at various
levels, limiting drug access to some parts of the subarachnoid space.
d. The concentration of antibiotic in the CSF varies widely from patient to
patient following a given intrathecal dose and can be affected by the
dynamics of CSF flow as well as the presence of hydrocephalus.
3. Aminoglycoside antibiotics can be injected safely into the subarachnoid
space. They may, however, produce paresthesia in the extremities and eighth
cranial nerve damage, especially in high concentrations. Nevertheless, in
reasonable doses, these drugs can be used safely for a brief course of
intrathecal therapy. Techniques of administration are as follows:
a. Intralumbar. An LP is performed in the usual manner, and 5 to 10 mL of
CSF is removed for analysis, including drug level measurement, cell count,
protein, sugar, and culture. The drug to be administered is dissolved either
in 5 or 10 mL of sterile saline without bacteriostatic preservative or in CSF
and is slowly injected through the LP needle.
b. Intracisternal. Drugs may be injected into the basilar cistern by those
skilled in the technique of cisternal puncture. The advantage over lumbar
injection is that higher levels of antibiotic may be achieved at the base of
the brain and over the convexity. This technique is essentially the same as
intralumbar injection, but the drug is injected over 1 minute to minimize the
time the needle remains in the cistern, where it can potentially damage the
medulla. Cisternal puncture is not recommended for repeated
administration of drugs and should be undertaken only by those with
considerable experience with the technique.
c. Intraventricular. An indwelling catheter that connects one lateral ventricle
to a small silicone rubber reservoir (Ommaya reservoir) may be implanted
surgically. The self-sealing reservoir can be repeatedly punctured
percutaneously, thereby giving ready access to the intraventricular space,
either for the sampling of CSF or the injection of drugs. Very high drug
levels may be achieved in the ventricles, and adequate levels are reached
in the cisternal and lumbar CSF. With aminoglycosides, a 5-mg dose
injected intraventricularly may yield therapeutic drug levels (4 to 6 g/mL)
throughout the CSF for as long as 24 hours after injection. The
disadvantages of this method of administration are that the patient is
subjected to a neurosurgical procedure with its possible complications, and
the devices can become plugged, disconnected, or infected during use.
Drug administration using the reservoirs requires meticulous aseptic
technique.
4. Precautions to be taken with intrathecal antibiotic administration
a. Measure the CSF drug level with each dose to ensure that antibiotic is not
accumulating excessively in the CSF.
b. Follow the CSF protein and cell count for signs of a CSF block (greatly
elevated protein) or chemical meningitis (increasing CSF white cell count,
often with polymorphonuclear leukocytes predominating, and increasing
protein).
c. Culture the CSF with each injection. An increasing cell count may indicate
iatrogenic CNS infection as well as chemical meningitis.
d. Be aware of the possibility of blockages of CSF flow, denying the antibiotic
access to regions of the subarachnoid space that may harbor loculated
infections. A radioactively labeled colloid may be injected into the ventricle
to determine the patency of CSF pathways by radiologic methods. In
patients with obstructive hydrocephalus, combined intraventricular
administration of antibiotic through a drainage catheter and intralumbar
administration may be required.
5. Indications for intrathecal therapy. Intrathecal therapy is reserved for those
patients in whom systemic therapy alone is not likely to be curative. In these
patients, the organism requires higher drug levels than are attainable in CSF
by intravenous administration. Definite indications for the use of intrathecal
antibiotic administration have not been defined, but it should be limited to
certain rare situations.
a. Gram-negative meningitis
1. If the bacteria are sensitive to ampicillin or a third-generation
cephalosporin, these drugs achieve bactericidal concentrations in the
CSF with intravenous administration. Experience has shown them to be
adequate as single agents against most susceptible pathogens. Strains
of Pseudomonas, Serratia, Acinetobacter (mima, herellea), and some
Proteus species are usually resistant to these antibiotics. Some
clinicians would use an aminoglycoside administered systemically and
intrathecally as part of the initial therapy when these organisms are
suspected. If IV therapy is used initially, repeat LP should be performed
in patients who do not improve after 24 hours. If culture remains positive
for gram-negative bacilli, intrathecal or intraventricular therapy should be
considered.
2. If the organism is resistant to ampicillin and the cephalosporins, or if the
infection fails to respond adequately to a full course of therapy, an
aminoglycoside may be used both systemically and intrathecally, in
combination with an appropriate broad-spectrum penicillin.
3. The indications for intraventricular administration of an aminoglycoside
via an Ommaya reservoir are not established. In the absence of good
evidence for the superiority of the ventricular route, it is reasonable to
begin with intralumbar therapy and resort to intraventricular therapy only
for:
a. Highly resistant organisms (as determined by the minimal
bactericidal concentration of the antibiotic used).
b. Infections that fail to respond to intralumbar therapy.
c. Patients with known block to CSF flow that prevents drugs
administered into the lumbar subarachnoid space from reaching the
basilar cisterns.
b. Staphylococcal meningitis. Bacitracin in doses of 5,000 to 10,000 units
may be injected into the subarachnoid space in the treatment of meningitis
due to penicillinase-producing S. aureus. However, this therapy is indicated
only in moribund patients and those failing to respond to systemic
administration of oxacillin or nafcillin in high doses. The technique of
administration is the same as that for the aminoglycosides.
c. Enterococcal meningitis (Streptococcus faecalis) is a rare disease, at
times occurring in neonates or as a complication of surgery or bacterial
endocarditis. Although usually sensitive to ampicillin in vitro, this organism
requires combined therapy with penicillin and an aminoglycoside to cure
serious infections. Consequently, the combination of penicillin G and
gentamicin is administered systemically. Intrathecal gentamicin may be
added if response to intravenous therapy is inadequate. Ampicillin-resistant
strains are treated with vancomycin; however, vancomycin-resistant
enterococci (VRE) are now being reported in some hospitals. Synercid, the
first in a new class of antibiotics (streptogramins), is in investigational use
for systemic VRE; its efficacy in meningitis has not been characterized.
E. Corticosteroid therapy of bacterial meningitis
1. Infants and children. Dexamethasone, 0.15 mg/kg body weight q6h for the
first 4 days of antibiotic therapy, has been shown to reduce the risk of hearing
loss and other neurologic sequelae in infants and children with bacterial
meningitis. Therefore, many experts recommend its routine use in meningitis in
nonimmunosuppressed children and in infants older than 2 months.
Administration early in treatment is essential, preferably at the same time, or
just before the first dose of antibiotic.
2. Adults. Some experts recommend the routine use of antiinflammatory doses
of corticosteroids (prednisone, 40 to 80 mg/day or equivalent) in
nonimmunosuppressed adults with bacterial meningitis. There are no
placebo-controlled studies verifying the efficacy of this practice. Adults with
high concentrations of bacteria in CSF and evidence of increased intracranial
pressure may benefit most.
3. High-dose corticosteroids are used for the therapy of cerebral edema
associated with severe meningitis (see sec. I.H.1).
4. Maintenance doses of corticosteroids are administered if there is a suspicion of
adrenal necrosis (Waterhouse-Friderichsen syndrome) (see sec. I.B.1.a.(2)).
F. Prophylactic treatment of contacts: Meningococcal disease
1. Choice of contacts for treatment. Patients with meningococcal disease are
infectious and can spread the organism to others by the respiratory route until
they have been on antibiotics for 24 hours. About 3 per 1,000 family members
of index cases will develop meningococcal disease. Others will become
asymptomatic carriers and can expose other susceptible people to the
organism. Therefore, it is recommended that the following groups be treated
with antibiotics when an index case is diagnosed:
a. Family and household members.
b. Others in contact for prolonged periods with an index case. This does not
include acquaintances or school classmates.
c. Hospital staff members on whom the patient has breathed directly. There is
no need to treat any hospital personnel who have merely been in the room
with the patient.
2. Treatment. The current recommendations for prophylactic therapy are as
follows:
a. If the organism is known to be sensitive to sulfonamides, the preferred
antibiotic is sulfadiazine, 1 g PO q12h for 2 days in adults, 500 mg PO
q12h in children ages 1 to 12 years, and 500 mg/day PO in infants.
b. When the drug sensitivity of the organism is unknown or when it is known to
be sulfadiazine-resistant, the preferred drug is rifampin, 600 mg PO q12h
for 4 doses in adults, 10 mg/kg q12h for 4 doses in infants and children
over 1 month of age, and 5 mg/kg q12h for 4 doses in infants under 1
month of age. The alternative in adults is minocycline, 200 mg PO, then
100 mg PO q12h for 5 doses (not to be used in children).
c. Secondary cases of meningococcal disease usually occur within 4 days of
the index case. Therefore, one should not await results of antibiotic
sensitivity testing before treating those at risk but should treat all close
contacts of the index case immediately on diagnosis. However, both
rifampin and minocycline have significant side effects (GI upset and
dizziness), so only those at real risk should be treated prophylactically.
Neither drug should be used during pregnancy.
d. Close contacts (e.g., those who have had oral contact with the patient,
hospital personnel whose mucosa has been exposed to infected
secretions) should be treated with procaine penicillin G, 600,000 units IM
q8h for 6 doses, then penicillin V, 500 mg PO q8h for 8 days.
3. A quadrivalent meningococcal vaccine (groups A, C, Y, W135) is
immunogenic in adults and in children over 2 years of age. Its use should be
considered in close household contacts of index cases as an adjunct to
chemoprophylaxis and in asplenic children or those with complement
deficiencies. It should be used only when the meningococcal type is known
early during the index infection, as the vaccines require 5 days to confer
protection. Serogroup B, for which there is not yet a vaccine, causes most of
the sporadic meningococcal disease in the United States. In epidemics of
meningococcal disease, the Centers for Disease Control (CDC) should be
consulted concerning the use of the vaccine.
4. Children younger than 6 years of age who are household or day-care
contacts of patients with H. influenzae meningitis should receive rifampin, 20
mg/kg PO qd for 4 days.
G. Shunt infections. Infections of shunts that are implanted for the treatment of
hydrocephalus make up a special category of postneurosurgical infections. These
infections are usually acquired at surgery. Consequently, the spectrum of
organisms is the same as that of other neurosurgical infections. Staphylococci
(especially S. epidermidis), streptococci, and anaerobes are the organisms in the
vast majority of infections; gram-negative enteric bacteria are unusual but
significant pathogens. Meningococcus and Pneumococcus are rare causes of
shunt infections. The initial antibiotic coverage is the same as that for the other
postneurosurgical infections already discussed.
1. Diagnosis. CSF obtained by LP grows the infecting organism in only about
three fourths of shunt infections. Thus, the blood, surgical wound (if it is fresh),
urine, and fluid obtained from a direct puncture of the shunt-valve reservoir, in
addition to the lumbar CSF, are cultured. Peritonitis may occur with
ventriculoperitoneal shunt infections, and the ascitic fluid may yield the
organism.
2. The treatment of a shunt infection is as follows:
a. Surgical removal of the shunt.
b. Appropriate systemic antibiotic coverage (see sec. I.C.3.b.(5)).
c. Once the shunt is removed, the infection usually responds to systemic
antibiotics, and there is no need for intrathecal therapy. However, when
constant ventricular drainage is required after shunt removal, antibiotics can
be instilled through the drainage cannula with little added morbidity.
H. Complications of bacterial meningitis
1. Increased intracranial pressure (ICP) is common in bacterial meningitis.
a. Etiology. Increased ICP usually occurs because of impaired CSF
absorption due to accumulation of fibrin and inflammatory cells around the
arachnoid villi and resolves with treatment of the infection. In addition,
increased ICP can occur through 2 other mechanisms: hydrocephalus and
brain edema. The latter is typically a diffuse process caused by bacterial
and leukocyte products that increase capillary permeability (vasogenic
edema) and compromise the integrity of cell membranes (cytotoxic edema).
Brain edema may also be focal, secondary to arteritis or cortical venous
thrombophlebitis with ischemia and brain infarction.
b. Treatment. The pressure generally returns rapidly to normal as the
infection responds to therapy. If the patient is afebrile, awake, and alert,
without focal signs, it can safely be assumed that the increased CSF
pressure has resolved. The therapy for increased ICP in association with
meningitis is conservative. There is no need to treat intracranial
hypertension per se unless there are signs of severe generalized brain
edema or localized mass effect with risk of herniation. Bradycardia in
association with elevated blood pressure, the Cushing reflex, may signal
increased ICP; however, hypotension and shock more commonly
accompany increased ICP.
1. If the patient is doing well clinically, avoid repeated LPs.
2. Fluid balance. Avoid overhydrating the patient or administering large
amounts of free water. In adults with adequate perfusion, 1,500 mL of
normal saline per day is sufficient, including the volume of fluid in which
the antibiotics are administered. In children, one third to one half
maintenance with half-normal saline in 5% D/W is recommended. When
patients can regulate their own fluid intake, they should be limited to
less than 2,000 mL of total daily intake (PO plus IV) until the CSF
pressure is no longer elevated. In patients receiving mannitol, normal
saline (309 mOsm/L) should be used for all IV fluids, including, where
possible, diluents for medications.
3. Steroids are administered in high doses initially and then rapidly
tapered once the infection is under control. One protocol consists of
dexamethasone (Decadron), 10 mg IV for the first dose, then 4 to 6 mg
IV q6h until the infection is under control. The dose is then tapered to
zero over 5 to 10 days, assuming the total course is less than 3 weeks.
If high doses are given for longer than 2 weeks, more gradual tapering
is necessary, since the risk of adrenal insufficiency increases. The usual
precautions necessary with high-dose steroid administration (i.e., the
monitoring of blood glucose and stool guaiacs and concern for masked
infection) are followed. Steroids begin to exert an effect only after 12 to
16 hours.
4. Hyperosmolar agents. When using hyperosmolar agents, the
physician must guarantee a patient urinary system; in comatose
patients, a Foley catheter is required. Both mannitol and glycerol are
associated with hyperosmolar, hyperglycemic, nonketotic coma in
diabetics. Blood glucose and serum electrolytes should be followed
frequently in diabetics and at least every other day in nondiabetics.
a. Mannitol, 1.0 to 1.5 g/kg, may be given for acute increased ICP
where there is danger of transtentorial herniation. Doses of 0.25-0.5
g/kg may be repeated twice at 4-hour intervals, to cover the period
before steroids take effect. In children, 0.25-1.00 g/kg may be given
over 1030 minutes. Smaller doses may be as effective as larger
ones and may be given more often, if necessary. Some data show
that after mannitol is given, a rebound increase in ICP occurs. In
meningitis, this effect can be minimized by using steroids and by
treating the infection. The serum osmolality should be checked
immediately after administration of each dose and should not be
allowed to rise above 320 mOsm/liter. The goal of therapy is
controlled hyperosmolality, not hypovolemia.
b. Furosemide (0.5 mg/kg) can be used as an adjunct to mannitol to
decrease ICP. It facilitates removal of sodium and water from brain
and reduces CSF formation.
2. Seizures are a common manifestation of meningitis, especially in infants and
children, and generally do not affect prognosis. Epilepsy is uncommon (3% to
7%) after recovery. However, seizures may also signal more serious
complications of meningitis, including:
a. Bacterial encephalitis.
b. Cortical vein thrombosis with venous infarction.
c. Subdural effusion or empyema.
d. Infectious vasculitis.
e. Brain abscess (rare as a complication, except in neonates).
f. Metabolic abnormalities. Hyponatremia from the syndrome of inappropriate
antidiuretic hormone (SIADH) secretion is a particularly common
complication of meningitis.
3. Hydrocephalus
a. Communicating hydrocephalus may complicate bacterial meningitis due
to obstruction of CSF flow by thickened and fibrotic meninges. Usually the
site of obstruction is at the base of the brain. This syndrome may occur
early or late in the course of the infection and should be suspected if the
patient's mental status fails to return to normal as the infection clears or
deteriorates after initial improvement. This condition is not a medical
emergency and may resolve spontaneously without shunting. The same
considerations apply in deciding whether, and when, a shunt should be
implanted as with other cases of communicating hydrocephalus (see Chap.
3).
b. Noncommunicating hydrocephalus rarely occurs as a complication of
meningitis and is due to partial or complete obstruction of CSF flow at the
aqueduct of Sylvius or at the fourth ventricular outlet.
1. Total obstruction of ventricular outflow is rare. It usually causes coma,
which can mistakenly be assumed to be due to the infection itself.
However, total obstruction of ventricular outflow is an emergency and
will rapidly lead to death unless it is corrected. The presence of coma,
bilateral Babinski signs, and paralysis of upward gaze should
suggest the diagnosis, which can be confirmed by CT scan or MRI.
Papilledema is not necessarily present. Since this syndrome generally
occurs early, when the CSF is still infected, the acute treatment is
constant ventricular drainage rather than shunting. After the CSF is
sterile, a ventriculoperitoneal or ventriculoatrial shunt may be placed.
2. Partial obstruction at the aqueduct or fourth ventricular outflow is not
an emergency, but it requires careful observation for signs of total
obstruction.
4. Subdural effusion. Infants less than 1 year of age are subject to the
accumulation of sterile collections of fluid in the subdural space as a
complication of bacterial meningitis (most often H. influenzae).
a. The diagnosis is made by transillumination of the skull or CT scanning,
and it is confirmed by tapping the subdural space percutaneously through
the patent fontanel.
b. Treatment is aimed at maintaining normal ICP. Repeated percutaneous
aspiration of the fluid is usually adequate, and the fluid ceases to
reaccumulate after the infection is treated. Subdural taps are not indicated if
there are no signs or symptoms of increased ICP and no focal neurologic
deficits. The membrane that surrounds the effusion may have to be excised
surgically in rare cases if the fluid continues to reaccumulate after repeated
taps.
5. Subdural empyema is a rare complication of meningitis.
a. Description. Subdural empyema is suggested by the development of
papilledema, persistently increased ICP, persistent fever, focal signs, or
seizures.
b. The diagnosis can be made by CT scan or MRI. The EEG and technetium
brain scan are of little value in the diagnosis of this condition, and LP is
dangerous.
c. Treatment is immediate and aggressive surgical drainage. Appropriate
stains and cultures are performed at surgery, and appropriate antibiotic
therapy is continued for at least 1 week postoperatively.
6. Persistent fever during the treatment of bacterial meningitis suggests one of
several conditions: an occult focus of infection requiring surgical drainage or
prolonged antibiotic therapy (e.g., osteomyelitis, an occult abscess either in the
brain or elsewhere, or subdural effusion), drug fever, or inadequate antibiotic
therapy.
7. Persistent neurologic deficit
a. A focal neurologic deficit may indicate destruction of brain tissue by
encephalitis or infarction, or the presence of a mass lesion, such as a
subdural effusion or empyema. Brain abscess complicating meningitis is
rare after the neonatal period.
b. Cranial nerve palsies may occur but usually resolve. Hearing deficits are
the most commonly persistent cranial nerve abnormalities. Children should
be evaluated with brainstem auditory evoked responses or audiometry.
c. Venous thrombosis occurs as a result of cortical vein thrombophlebitis.
The only known treatment is antibiotics to prevent progression of the
process. Anticoagulation is of no known benefit.
d. Vasculitis is relatively common, especially in children, and usually resolves
with appropriate antibiotic therapy. However, with involvement of the large
arteries at the base of the brain, stroke and permanent neurologic deficit
can occur.
8. Medical complications
a. Bacterial meningitis may lead to SIADH with hyponatremia and increased
risk of seizures.
b. Systemic sepsis may lead to DIC, shock, ARDS, and metastatic abscess
formation (see sec. I.B).
c. Antibiotics used in high doses, as is necessary for meningitis, subject the
patient to their associated risks (see sec. I.C).
d. The risks associated with steroids and hyperosmolar agents have been
discussed (see sec. I.H.1.b(4)).
II. Tuberculous infection of the CNS
A. Diagnosis
1. Tuberculous meningitis. Any subacute febrile meningitis with a low spinal
fluid sugar content is tuberculous meningitis until proven otherwise (Adams R.
N Engl J Med 1974;290:1130). The diagnosis of tuberculous meningitis must
often be made before culture results become available because
Mycobacterium tuberculosis requires at least 4 weeks to grow in vitro. The
diagnosis is suggested by the clinical symptoms (fever, headache, lethargy,
vomiting, and cranial nerve palsies), is supported by evidence of active
pulmonary disease (present in only about one third of cases, usually miliary) or
by a positive purified protein derivative (PPD) (present in about 50% of cases),
and is confirmed by observing acid-fast organisms on a Ziehl-Neelsen-stained
CSF sample or by detection of myocobacterial DNA by PCR (TB Amplicor).
Where available, CSF C-reactive protein (C-RP) detection and a CSF
adenosine deaminase (ADA) activity measurement of more than 5 IU/L are
60% to 90% sensitive and 75% to 100% specific for TB meningitis, and can be
used for rapid diagnosis. Nuchal rigidity is not often seen early in the disease.
The CSF usually shows a lymphocytic pleocytosis with a low glucose;
however, polymorphonuclear predominance can be seen early in the disease.
The protein is nearly always elevated, frequently leading to the formation of a
clot, or pellicle, on standing. The diagnostic yield of the CSF in the absence of
PCR, CSF ADA, or C-RP determination can be augmented in various ways:
a. The probability of growing the organism is directly related to the quantity of
CSF cultured. Consequently, 7 to 15 mL of CSF should be removed for
culture with each diagnostic LP.
b. Concentration of the organisms will aid in microscopic identification by the
AFB smear.
1. The pellicle can be smeared and is an excellent source of the organism.
2. The CSF can be centrifuged and the sediment smeared if no pellicle
forms.
c. Chemical and immunologic tests, including enzyme-linked immunosorbent
assay (ELISA) and latex particle agglutination, have been either technically
difficult or unreliable, or both.
d. Repeated CSF examinations may show a characteristic pattern of falling
sugar, rising protein, and rising or stable cell count. An initially normal
CSF does not rule out tuberculous meningitis.
2. Other CNS complications. Tuberculosis may also infect the brain
parenchyma, producing diffuse encephalitis or a focal tuberculoma, with or
without meningeal involvement. In the absence of meningitis or tuberculosis in
other organs, the diagnosis may be extremely difficult and often is made only
after tissue biopsy. M. tuberculosis also may invade blood vessels and cause a
CNS vasculitis with associated brain infarction.
B. Treatment
1. Antibiotics
a. First-line drugs
1. Isoniazid (INH) is effective, is relatively nontoxic, and penetrates the
meninges well. However, organisms resistant to isoniazid, as well as
multiple drug-resistant strains, are increasingly common and
constitute an important and growing public health hazard. The dosage in
adults is 5 mg/kg/day in a single oral dose. In children, the dosage is 10
to 20 mg/kg/day. The total daily dose should not exceed 300 mg. All
patients over 6 years old should receive pyridoxine, 50 mg/day, to
prevent pyridoxine deficiency syndromes, which include neuropathy,
encephalopathy, seizures, and anemia (see Chap. 14).
2. Rifampin, 600 mg/day PO in adults and 10 to 20 mg/kg/day PO in
children, not to exceed 600 mg/day.
3. Pyrazinamide, 15 to 30 mg/kg/day PO in both children and adults,
divided into 3 or 4 doses. The maximum daily dose is 2 g.
4. Ethambutol, 15 to 25 mg/kg/day PO in both adults and children. The
maximum daily dose is 2.5 g.
b. Second-line drugs for use in cases of resistant organisms or patient
sensitivity to first-line drugs:
1. Streptomycin, 15 mg/kg/day (maximum 1 g/day) in adults and 20 to 40
mg/kg/day in children as a single daily IM injection. Because of eighth
nerve and renal toxicity, the maximum dose should not be administered
for more than 12 weeks.
2. Ciprofloxacin, 750 mg PO bid. Ciprofloxacin penetrates into the CSF
well.
3. Ethionamide, 0.5 to 1.0 g daily PO divided into 2 to 4 doses.
Penetration into CSF is excellent, but GI, liver, and CNS toxicity are
common.
c. Antibiotic regimen
1. For the first 2 months and until antibiotic sensitivity is known, four
drugs are recommended:
a. Isoniazid, 300 mg/day, and
b. Rifampin, 600 mg/day, and
c. Pyrazinamide, 15 to 30 mg/kg/day, and
d. Streptomycin, 15 mg/kg/day IM, or
e. Ethambutol, 15 to 20 mg/kg/day.
2. The regimen is adjusted after antibiotic sensitivities are known. Many
clinicians reduce the regimen to 2 drugs (generally isoniazid and
rifampin) after 2 to 3 months of therapy.
3. The minimum necessary duration of therapy is unknown, but patients
with tuberculous meningitis are typically treated for 6 months to 1 year.
In general, tuberculosis is treated 50% longer in patients with
concurrent human immunodeficiency virus (HIV) infection.
4. The CDC recommends that therapy be monitored until patient
compliance can be demonstrated. Noncompliant patients may have
antibiotics administered under medical supervision on a twice weekly
schedule:
a. Isoniazid, 15 mg/kg (maximum 900 mg), twice per week, and/or
b. Rifampin, 600 mg, twice per week, and/or
c. Pyrazinamide, 50 to 70 mg/kg, twice per week, and/or
d. Ethambutol, 50 mg/kg, twice per week.
2. Steroids. Some have advocated the use of systemic, or even intrathecal,
steroids in tuberculous meningitis. The aim is to inhibit the inflammatory
response and thereby prevent some of the complications of infection, which
result as much from the inflammation and granuloma formation as from direct
destruction by the bacteria. A 20-year retrospective study from Egypt indicated
a significant reduction in mortality among patients with TB meningitis treated
with dexamethasone. There is no evidence that the efficacy of
antimycobacterial therapy is compromised by adjuvant corticosteroids.
a. Theoretical indications for the use of steroids in addition to
antituberculous chemotherapy are as follows:
1. To reduce elevated ICP due to brain swelling.
2. To reduce inflammatory exudate in the subarachnoid space and
associated risk of obstructive hydrocephalus or spinal block.
3. To decrease vascular inflammation (arteritis) of the vessels at the base
of the brain and associated risk of infarction.
b. Patients with a normal mental status and no neurologic deficit probably
would not benefit from steroid therapy.
c. Clinical indications for steroid use are:
1. Deterioration in level of consciousness.
2. Progressive focal neurologic signs. Findings should be elevated
radiographically when possible.
d. The dosage of steroids for increased ICP is the same as for increased
pressure of other types: dexamethasone, 10 mg IV as a first dose, then 4 to
6 mg IV q6h (adults and children). Mannitol may also be used in acute
situations. Prednisone, 60 or 80 mg/day, or its equivalent, is usually chosen
as an antiinflammatory agent. The high dose is generally maintained for 2
to 3 weeks and is then slowly tapered over about 1 month.
3. Contacts of the patient should be treated prophylactically according to the
recommendations of the American Thoracic Society (see Selected
Readings ).
4. Tuberculomas are treated medically with regimens identical to those used for
tuberculous meningitis. Indications for surgical excision include diameter
greater than 2 cm, elevated ICP due to edema around the lesion that is
refractory to medical therapy, intractable epilepsy, lack of response to
appropriate antibiotics, and situations where the diagnosis is in question.
Biopsy of tuberculomas has been reported to cause tuberculous meningitis and
should be carried out with caution.
5. Follow-up and complications
a. Repeat LPs are performed at 1 month, 6 months, and 2 years after
beginning therapy if the patient is clinically stable. The appearance of a new
neurologic sign or symptom should prompt an LP or other diagnostic tests
as indicated.
b. The major late neurologic complication of tuberculous meningitis is
hydrocephalus. Treatment depends on the site and degree of the CSF
block (see Chap. 3).
c. Relapses. The main reason for relapse is noncompliance with treatment.
Inadequate therapy has caused an alarmingly high incidence of organisms
resistant to multiple drugs. At the first indication of a relapse, the patient
is hospitalized, the antibiotic sensitivity of the organism is rechecked, and,
pending those results, appropriate changes in the drug regimen are made.
These changes might include the administration of the drugs under
supervision, as well as substitution or addition of alternative drugs.
6. Toxicity of antituberculous chemotherapy
a. Isoniazid
1. Hepatic. About 10% of patients on isoniazid develop elevated serum
glutamic-oxaloacetic transaminase (SGOT) levels. Usually, the SGOT
returns to normal even if isoniazid is continued. True hepatitis occurs in
only 1% of cases. It can occur months after beginning therapy and can
produce jaundice, permanent liver damage, and even death. The risk of
developing hepatitis increases with age, is not dose-dependent, and
may occur principally in rapid acetylators of isoniazid.
2. Neurologic. Pyridoxine deficiency syndromes, including neuropathy,
anemia, encephalopathy, and seizures, may occur if pyridoxine
supplementation is not provided. This does not occur in children under
the age of 6 years. Optic atrophy occurs rarely.
3. Psychiatric. Euphoria, mania, and frank psychosis can occur. These
generally do not represent pyridoxine deficiency.
4. Hypersensitivity reactions are rare.
5. Precautions
a. Provide pyridoxine supplementation at a dose at least one tenth the
isoniazid dose for patients over 6 years of age.
b. Evaluate monthly for symptoms of hepatitis. Perform liver function
tests at baseline and when symptoms suggest hepatotoxicity.
c. Isoniazid may precipitate phenytoin (Dilantin) toxicity by interfering
with that drug's metabolism.
b. Streptomycin
1. Neurologic. Eighth cranial nerve damage (vestibular and hearing
disturbances) limits the maximum dose of streptomycin that can be
used. Doses of 1 g/day or less are reliably tolerated for 2 to 3 months.
2. Renal. As with all aminoglycosides, dose-related renal impairment may
occur, but in the absence of preexisting renal disease, doses of
streptomycin up to 1 g/day are tolerated.
3. Hypersensitivity reactions are unusual.
4. Precautions
a. Renal function is checked prior to use, and the dosage is adjusted
accordingly.
b. Evaluate monthly for symptoms and signs of labyrinthine
dysfunction. If administered to pregnant women, streptomycin
may cause congenital deafness in the fetus.
c. Ethambutol
1. Neurologic. Visual changes with optic nerve dysfunction can occur at
doses higher than 15 mg/kg/day. However, this problem usually
reverses if the drug is withdrawn promptly. The most sensitive indicators
are tests of color vision and visual acuity.
2. Precautions. Evaluate monthly for visual symptoms.
d. Rifampin
1. GI upset is common with rifampin administration.
2. Hypersensitivity reactions, thrombocytopenia, hepatocellular injury,
and skin eruptions are rare.
3. Drug interactions. Rifampin increases the rate of hepatic metabolism
of many drugs, including warfarin, anticonvulsants, and
estrogen-containing contraceptives.
4. Precautions. Patients should be warned that rifampin turns the urine,
tears, and sweat orange. Soft contact lenses can be permanently
discolored.
e. Pyrazinamide
1. Hepatic. Hepatocellular toxicity occurs in about 15% of patients at a
dose of 3 g/day. Fatal hepatic necrosis rarely occurs.
2. GI upset is common.
3. The drug may precipitate attacks of gout and may exacerbate diabetes
mellitus.
4. Hypersensitivity reactions are relatively common.
5. Precautions. Evaluate monthly for symptoms of hepatitis. Perform liver
function tests at baseline and when symptoms suggest hepatotoxicity.
f. Ciprofloxacin
1. Neurologic. CNS toxicity is rare, but seizures, psychosis, and tremors
have been reported.
2. GI upset occurs occasionally.
3. Hypersensitivity reactions are relatively common.
4. Precautions. Ciprofloxacin, like all quinolones, is contraindicated in
children and should not be given to pregnant women.
g. Ethionamide
1. Hepatic. Hepatocellular toxicity occurs in about 5% of patients taking
the drug; diabetics appear to be at higher risk.
2. Neurologic. Reversible CNS toxicity, with depression, drowsiness,
tremor, and olfactory disturbances, may occur. Seizures are rare.
3. GI upset is common.
4. Severe postural hypotension can occur.
5. Precautions. Evaluate monthly for symptoms of hepatitis. Liver function
tests should be performed at baseline and when symptoms suggest
hepatotoxicity.
III. Brain abscess
A. Diagnosis
1. Clinical presentation. Brain abscess generally manifests itself as the
subacute progression of focal neurologic signs, headache, and altered mental
status. Seizures occur in 25% to 50% of patients. Systemic signs of infection,
such as fever and peripheral leukocytosis, are present only in about half of
patients. The erythrocyte sedimentation rate usually is elevated.
2. There may be evidence for a contiguous or systemic source of infection.
3. Differential diagnosis may include brain tumor, chronic subdural hematoma,
chronic meningitis, or viral encephalitis. Signs of meningeal irritation are
usually absent or mild. However, if the abscess ruptures into the ventricular
system, the ensuing ventriculitis and meningitis produce marked meningeal
signs.
4. The definitive diagnosis is often made only at surgery, although a characteristic
CT scan or MRI in the appropriate clinical setting may strongly suggest the
diagnosis.
B. Localizing the lesion
1. A CT scan and MRI are highly reliable in localizing abscesses. Furthermore, in
the appropriate clinical setting, the typical ring-enhancing lesion (i.e., a thin,
usually regular, contrast-enhancing ring around a low-density center) is
relatively specific for brain abscess. Cystic tumors or infarcts with rims of
neovascularization can give a similar appearance, but the CT absorption
values of their centers are generally higher than those of abscess. The CT
scan and MRI can also distinguish between an unencapsulated area of brain
infection (cerebritis) and an encapsulated abscess.
2. Arteriography is relatively poor in localizing brain abscess.
3. An LP may be hazardous when a brain abscess is present, and the CSF rarely
discloses the organism responsible for infection. Examination of the CSF can
help rule out bacterial meningitis, but in most patients the history and
examination will distinguish abscess from meningitis.
4. Skull x-rays or CT scan. All patients with suspected brain abscess should
have complete skull x-rays or CT scan with bone windows early in their course
to search for parameningeal infection. Adequate views of the mastoids and
sinuses are essential, since brain abscess due to sinusitis usually occurs
adjacent to the infected sinus. Frontal or ethmoidal sinus infections are
associated with abscesses in the frontal lobe, while either frontal or temporal
abscesses complicate maxillary and sphenoid sinusitis. Abscess associated
with mastoiditis or otitis commonly occurs in the temporal tip or cerebellar
hemisphere.
C. Pathophysiology. Brain abscess formation involves two stages.
1. Initially, a diffuse and poorly marginated area of infection is associated with
edema and destruction of brain tissue. During this cerebritis stage, the CT
scan shows a nonspecific low-density area that enhances diffusely with IV
contrast material. At this stage, the infection is curable with antibiotic
therapy alone and is not amenable to surgical therapy.
2. Over a period of 4 to 9 days, the center of the infection turns into semiliquid
pus and necrotic brain tissue. Once this stage is reached, the infection may not
be curable by medical therapy alone. Gradually, encapsulation by gliotic
tissue occurs and a free abscess forms. A CT scan with contrast or MRI
demonstrates the characteristic ring lesion.
D. Treatment
1. Surgery. The traditional treatment of brain abscess is drainage of the abscess
cavity, either by needle aspiration or by total excision.
a. Presently, the best surgical treatment for abscess is controversial, and
there are advocates of aspiration, defenders of total surgical excision, and
advocates of minimally invasive neuroendoscopic treatment. With the
advent of CT-guided stereotactic biopsy and intraoperative ultrasound, an
abscess in virtually any area of the brain can be aspirated relatively safely.
For deep lesions, stereotactic aspiration is the procedure of choice.
However, a superficial lesion in a readily accessible area (e.g., the frontal
tip) should be considered for complete excision because this eliminates the
risk of recurrence.
b. For patients at risk from increased ICP, immediate surgery is necessary to
reduce mass effect, either by aspiration or complete excision.
2. Medical therapy
a. Antibiotics. Preoperatively, the patient is started on appropriate antibiotics
(see sec. III.D.4.d). The pus from the abscess is Gram-stained and cultured
for aerobic and anaerobic bacteria and for fungi. The results of these
studies guide postoperative antibiotic choice. Antibiotics are continued for
at least 4 weeks postoperatively, and the entire course is given parenterally
and in meningeal doses.
b. Antiedema therapy. Patients in immediate danger of herniation are treated
with mannitol, 1.0 to 0.5 g/kg IV over 20 to 30 minutes. Patients with severe
brain edema may be treated with high-dose steroids. Generally,
dexamethasone, 16 to 24 mg/day, is given in 4 to 6 divided doses
preoperatively and for several days postoperatively. If the patient is stable,
the dexamethasone dose is tapered over 1 to 2 weeks. There is no
evidence that steroids lead to spread of the local infection of brain.
However, steroids may reduce contrast enhancement on CT scan and lead
to the false impression of a reduction in abscess size. There is
experimental evidence that steroids interfere with the formation of an
abscess wall and diminish antibiotic penetration into the abscess; as a
result, routine use is not recommended.
c. Anticonvulsants, such as phenytoin, are used in patients with abscesses
involving the cerebral cortex.
3. Antibiotic therapy alone is used in selected patients:
a. In patients with cerebritis only.
b. In patients with multiple abscesses or surgically inaccessible lesions.
c. In patients who are poor surgical candidates and who are not in immediate
danger from increased ICP. A CT scan should be performed and the
therapy assessed weekly. If no shrinkage is noted by 4 weeks, surgical
treatment should be considered. Abscesses larger than 3 cm are
generally refractory to medical therapy alone.
4. Initial selection of antibiotics
a. The most common sources of brain abscess are the following:
1. Direct spread of infection from a contiguous source
a. Otitis.
b. Paranasal sinus infection.
c. Meningitis (rare).
d. Orbital cellulitis.
2. Hematogenous spread
a. Congenital heart disease with a right-to-left shunt or systemic
arteriovenous fistula.
b. Pulmonary infection.
c. Bacteremia from other extracranial infections or from dental or other
procedures.
3. Traumatic
a. Penetrating head trauma.
b. Intracranial surgery.
b. Any possible source of infection is cultured, and a Gram stain is done. As
with meningitis, one cannot assume that the abscess is infected with the
same organism that is obtained from the presumed source of infection.
Moreover, many brain abscesses contain multiple organisms, particularly
anaerobes. As a result, the organism or organisms recovered from a brain
abscess cannot be predicted from the clinical situation with the degree
of confidence that is possible with meningitis.
c. It is not known whether the ability of an antibiotic to penetrate into the CSF
is as important in the therapy of brain abscess as it is in the therapy of
meningitis. One might expect, however, that in the cerebritis stage there are
organisms in areas of the brain with a relatively intact blood-brain barrier;
therefore, drugs that penetrate the blood-brain barrier are preferred.
d. Recommended empiric therapy
1. Sinusitis and congenital heart disease. Penicillin G, 16 to 24 million
units/day IV divided into 6 doses, or ampicillin, 12 g/day IV divided into 6
doses; and metronidazole, 30 mg/kg/day divided into 4 doses.
2. Otitis media, mastoiditis, and lung abscess. Penicillin or ampicillin,
as in sec. III.D.4.d(1), and ceftriaxone, 4 to 6 g/day IV divided into 2
doses, and metronidazole.
3. Posttraumatic and postsurgical. Oxacillin (or nafcillin), 10 to 12 g/day
IV, divided into 6 doses, and ceftriaxone.
4. Unknown source. Same as in sec. III.D.4.d.(2). If there is evidence of
Pseudomonas infection, an anti-Pseudomonas penicillin (e.g.,
carbenicillin or ticarcillin) and ceftazidime can be used.
IV. Subdural empyema
A. Diagnosis. In adults, subdural empyemas occur most commonly in association
with ear or sinus infection. They occur less commonly after head trauma or
intracranial surgery and, rarely, in association with meningitis or bacteremia. Fever
and peripheral leukocytosis may not be present initially. Clinical deterioration can
be extremely rapid, with progression from mild hemiparesis to coma and death
within hours. Surgical treatment should not be delayed because a patient
appears clinically stable. In children, subdural empyema occurs most frequently
as a complication of meningitis.
1. MRI is the preferred method of detecting subdural fluid collections.
2. CT scan may miss small collections of fluid adjacent to the skull, but it is
otherwise reliable.
3. In infants, the diagnosis can be made by transillumination of the skull and
subdural tap.
4. LP is potentially hazardous and is contraindicated when a subdural empyema
is suspected.
B. Treatment
1. Surgery. Immediate surgical drainage is indicated, followed by a course of
high-dose antibiotics determined by the results of the Gram stains and cultures
performed at surgery.
2. Antibiotics. The patient receives one preoperative dose of antibiotic. The
appropriate regimen is chosen according to the clinical situation and guided by
the same principles as in treatment of brain abscess (see sec. III.D.4.d).
3. The customary duration of postoperative antibiotics is 3 weeks. The presence
of a focus of infection such as osteomyelitis dictates a longer course.
4. Increased ICP may be treated, as in brain abscess, using mannitol initially
and, if more than a few hours of therapy are necessary, steroids.
V. Spinal epidural abscess
A. Diagnosis
1. Clinical presentation. The presence of a spinal epidural abscess is suggested
by the onset of severe back pain and local tenderness, followed within a few
days by radiculopathy and later by myelopathy. In acute cases, the patient is
febrile and has an elevated WBC count and erythrocyte sedimentation rate. In
chronic cases, however, the patient may lack systemic signs of sepsis. It is
crucial to make the diagnosis in the early stages, before spinal cord
compression occurs. Older age and degree of compression of the thecal sac
are risk factors for poor outcome.
2. Bacteriology. The most common infecting organisms are S. aureus, enteric
gram-negative rods, and aerobic streptococci. Anaerobic organisms are
uncommon causes of spinal epidural abscess.
3. Diagnostic tests
a. MRI, if available on an emergency basis, is excellent for localizing epidural
abscess.
b. Myelography can also localize the abscess and, if coupled with CT
scanning, is extremely sensitive for areas of osteomyelitis. Moreover,
myelography provides an opportunity to obtain a CSF sample.
c. A CSF sample can be helpful in providing evidence for a coexistent
bacterial meningitis. Moreover, the infecting organism can be cultured from
CSF in many cases. If a CSF sample is to be obtained, care should be
taken to avoid the involved area so as not to pass the spinal needle
through the abscess and induce meningitis. If necessary, CSF can be
obtained by lateral cervical or cisternal puncture.
d. Cultures. As in other CSF infections, blood, urine, and any clinically
apparent focus of infection are cultured prior to institution of antimicrobial
therapy. The most common associated infection is vertebral osteomyelitis.
B. Treatment
1. Surgery. The infection is drained as soon after diagnosis as possible. Either
acute or chronic epidural abscesses can lead to paralysis within hours.
Acute abscesses contain semiliquid pus that can be drained easily. Chronic
abscesses are composed of granulation tissue, which can be removed
surgically. In either case, appropriate cultures and stains for aerobic and
anaerobic bacteria as well as fungi should be performed at the time of surgery.
2. Antibiotics. A single dose of antibiotic may be given preoperatively. The
postoperative antibiotic therapy is determined by the results of stains and
cultures done at the time of surgery. Initially, oxacillin, 2 g IV (40 mg/kg in
pediatric patients), or vancomycin (in penicillin-allergic patients), 1 g IV (20
mg/kg in children), should be given. If a gram-negative infection is suspected,
gentamicin, 1 mg/kg IV or IM, or ceftriaxone, 2 g IV, is given as well. The
antibiotics are continued for 3 to 4 weeks unless there is evidence of vertebral
osteomyelitis, in which case a 6- to 8-week course is indicated.
3. Steroids. Although there are no firm data supporting the use of steroids in
spinal epidural abscess, high-dose steroids may be used in an attempt to
minimize spinal cord edema. Dexamethasone, 10 mg IV, can be given
preoperatively, followed by 4 to 6 mg IV, IM, or PO q6h postoperatively. This
dose is continued for 7 to 10 days, followed by a 10- to 14-day steroid taper.
VI. Neurosyphilis
A. Diagnosis. The incidence of syphilis increased dramatically in the 1980s and
continues to rise. The chief goal of detection and treatment of early syphilis is to
prevent disability from tertiary disease, including CNS complications. Neurologic
symptoms rarely appear earlier than the secondary stage. However, treponemes
reach the CNS early in infection, and CSF is consistent with an aseptic meningitis
in up to one third of asymptomatic patients. It is crucial to identify and treat
patients in the primary and early secondary stages, before major damage can
occur.
1. In primary syphilitic chancres, in secondary skin lesions, and, very rarely,
in CSF or fluid from the anterior chamber of the eye, treponemes can be
identified by dark-field examination. This provides hard evidence of active
infection.
2. Treponema pallidum cannot be cultured routinely, and if the dark-field
examination does not yield a diagnosis, one must rely on serologic tests. When
the clinical presentation suggests neurosyphilis, both a nontreponemal
serologic test for syphilis (STS) and a serum fluorescent treponemal antibody
absorption test (FTA-ABS) should be performed. Where available, reverse
transcriptase PCR to detect T. pallidum in CSF is highly sensitive for detecting
low numbers of treponemes (see Selected Readings ).
a. Serologic tests for syphilis (STS, nontreponemal tests). The Venereal
Disease Research Laboratory (VDRL), Hinton, rapid plasma reagin,
Kolmer, and Kahn tests all depend on detecting, in the patient's serum or
CSF, antibodies to lipoidal substances in the treponemal cell wall or
resulting from the treponeme-host interaction.
1. These tests are inexpensive and can be used in mass screening
programs.
2. These tests are less sensitive than the treponemal tests in detecting
early evidence of infection, but after they become positive, they are the
earliest of the serologic tests to revert to negative after treatment. Thus
the effectiveness of therapy or the possibility of reinfection can be
evaluated, based on the antibody titers obtained.
3. In late neurosyphilis, the serum STS may be negative in as many as
one third of cases. A negative serum STS does not rule out
neurosyphilis. The CSF STS may be positive despite a negative
peripheral blood serology, but even a negative CSF STS does not
absolutely rule out the diagnosis of neurosyphilis in an appropriate
clinical setting. Rarely, an initially negative CSF STS may become
positive during treatment.
4. Biologic false-positive STS tests are common and are associated with
old age, pregnancy, and rheumatic and inflammatory disease (e.g.,
systemic lupus erythematosus and bacterial endocarditis). A positive
STS should be confirmed by a more specific treponemal test.
b. Treponemal tests
1. The FTA-ABS depends on the presence of antibodies that are specific
for T. pallidum.
a. It is the most sensitive serologic test routinely available, being the
first to turn positive after infection and the last to revert to negative
after therapy. The FTA-ABS may remain positive indefinitely, even
with adequate therapy, so that it cannot be used to judge the
adequacy of therapy or possible reinfection.
b. The FTA-ABS is much more expensive than the STS. It should be
performed only when specifically indicated (e.g., in the evaluation of
possible tertiary syphilis) and not as a routine screening procedure.
c. A positive FTA-ABS rules out a biologic false-positive STS.
d. Of patients with late neurosyphilis, 5% to 10% have a negative
FTA-ABS, so even this test may not completely rule out
neurosyphilis.
e. The clinical significance of a positive CSF FTA-ABS is not known.
Therefore, a CSF FTA-ABS is not useful for diagnostic purposes.
B. Asymptomatic neurosyphilis is defined as an abnormal spinal fluid in the
absence of neurologic disease but in the presence of serologic evidence of
syphilis. It can occur as early as the primary stage, but progression to
symptomatic neurosyphilis is preventable with adequate therapy.
1. Diagnosis
a. An LP is performed in all patients with inadequately treated syphilis beyond
1 year duration, even in the absence of neurologic signs and symptoms.
Moreover, all patients previously treated for primary or secondary syphilis
should undergo LP if they are possible treatment failures, as suggested by
a persistently high or rising STS titer.
b. The fluid is analyzed for cells, protein, and STS. The diagnosis of
neurosyphilis is confirmed by a positive CSF STS, but the cell count is the
best indicator of disease activity. The significance of a positive CSF STS
in the setting of a normal CSF profile is unclear.
c. In HIV-infected patients with a positive serum STS, an LP should be
performed, even if treatment for primary or secondary syphilis has been
documented. Conventional therapy might not be adequate to treat early
syphilis in such patients, and the index of suspicion for neurosyphilis must
be high. However, nonspecific CSF abnormalities are common at all stages
of HIV disease and complicate interpretation.
2. Treatment
a. Penicillin is the drug of choice and is effective in preventing progression to
symptomatic disease in immunocompetent patients. There are several
possible regimens, but only high-dose aqueous penicillin G achieves
treponemicidal drug levels in CSF:
1. Aqueous penicillin G, 4 million units IV q4h for 14 days, or
2. Procaine penicillin G, 2.4 million units/day IM, plus probenecid, 500
mg PO qid for 14 days, or
3. Benzathine penicillin G, 2.4 million units IM weekly for 3 doses.
b. Alternative therapy for penicillin-allergic patients has not been well
studied. The following are the usual recommendations:
1. Tetracycline, 500 mg PO qid for 30 days, or
2. Erythromycin, 500 mg PO qid for 30 days.
3. Follow-up examination
a. The patient is seen and the CSF examined approximately every 3 to 6
months for the first year, and the serum STS is checked. In 12 to 24
months, the STS should revert to negative or achieve a low stable titer. A
normal CSF profile 1 year after treatment indicates cure.
b. Indications for retreatment
1. Failure of the CSF cell count to revert to normal within 6 months; protein
level should be falling but may not be normal at 6 months.
2. Some clinicians consider a rising CSF STS titer or one that has not
decreased by more than one dilution by the end of the first year as an
indication for retreatment.
C. Symptomatic neurosyphilis
1. Diagnosis
a. When T. pallidum invades the CNS, several types of disease may result:
1. Meningeal and vascular
a. Cerebromeningeal: diffuse or focal (gumma).
b. Cerebrovascular.
c. Spinal meningeal and vascular.
2. Parenchymatous
a. Tabes dorsalis.
b. General paresis.
c. Optic atrophy.
b. The diagnosis must often be based on clinical grounds because in late
neurosyphilis both the peripheral and CSF STS, less commonly the
FTA-ABS, might be negative. The CSF must be abnormal, with increased
WBCs and elevated protein, to make the diagnosis of meningovascular
syphilis or general paresis. Rarely, T. pallidum can be visualized in the CSF
by dark-field examination. The CSF is occasionally normal in tabes dorsalis,
particularly in longstanding disease.
2. Antibiotic therapy
a. Adequate therapy for late neurosyphilis is unknown, and clinical
progression can occur despite massive doses of antibiotics. It is possible
that some of the manifestations of late neurosyphilis are caused by
autoimmune mechanisms rather than by direct infection.
b. The preferred treatment for neurosyphilis is high-dose parenteral
penicillin.
1. Aqueous penicillin G, 12 to 24 million units/day IV, divided into 6
doses for 14 days, or
2. Procaine penicillin G, 2.4 million units IM daily, plus probenecid, 500
mg PO qid for 14 days.
3. Either program should be followed by weekly injections of benzathine
penicillin G, 2.4 million units IM, for 3 weeks.
c. In patients who are allergic to penicillin, alternatives are not well
studied, and optimal doses and duration of therapy are not known. Rational
programs include:
1. Tetracycline, 500 mg PO qid for 30 days, or
2. Erythromycin, 500 mg PO qid for 30 days, or
3. Chloramphenicol, 1 g IV q6h for 6 weeks, with bone marrow function
followed carefully and the dosage adjusted accordingly (see sec.
I.C.2.a), or
4. Ceftriaxone, 2 g IV or IM daily, for 14 days.
3. Steroids have no proven effect in the treatment of late neurosyphilis.
Prednisone, 40 mg daily, or its equivalent may decrease the CSF cell count,
but there is no evidence that it affects the outcome of therapy or the long-term
disability. Steroids are clearly indicated for syphilitic uveitis and syphilitic
involvement of the inner ear with a hearing deficit and labyrinthine dysfunction.
In these diseases, it is customary to administer prednisone, 80 mg every other
day.
4. Follow-up
a. The CSF should be examined weekly during treatment to document a
falling WBC count. Most clinicians continue treatment beyond the usual
duration if the CSF cell count is not falling. After treatment, the patient is
seen every 3 to 6 months for the first year. At each visit, the serum STS is
checked, and an LP is performed at least every 6 months. If the patient is
stable after 1 year, with a normal CSF cell count and a falling or fixed low
value of the CSF protein, yearly return visits are sufficient, with a final LP 2
years after treatment.
b. As in asymptomatic neurosyphilis, if the therapy is effective, the CSF cell
count is normal within 6 months after treatment. The CSF protein may be
elevated for a longer time and may never return to normal, but it should
plateau at a fixed low level.
c. The STS may be positive for the life of the patient in both the serum and the
CSF. In either case, the CSF STS titer is of limited help in following the
patient, the CSF cell count and clinical course being the essential data
on which therapy is based.
5. Complications of neurosyphilis
a. Communicating hydrocephalus due to blockage of CSF flow at the base
of the brain may follow neurosyphilis. Hydrocephalus should always enter
into the differential diagnosis when general paresis progresses despite
antibiotic therapy. The treatment is ventricular shunting.
b. Lightening pains complicating tabes dorsalis have a poor prognosis.
Phenytoin and carbamazepine may be tried, but often they are of no
benefit.
c. Charcot joints.
d. Perforating ulcers.
e. Parenchymal or meningeal gummas.
f. Spinal pachymeningitis.
D. Congenital neurosyphilis
1. The diagnosis of congenital syphilis is often difficult to make, since the
neonate's serum STS and FTA-ABS and even the CSF STS may be positive
because of passively transferred maternal antibody in the absence of infection
in the child. Long-bone x-rays to detect metaphysitis and other bony lesions
may aid in diagnosis.
a. The newborn's IgM FTA-ABS can be tested, and the total IgM in the cord
blood can be measured to aid in the diagnosis. However, if the mother
acquired syphilis late in pregnancy, serology may be negative in both
mother and infant.
b. An LP is performed in all infants at risk of congenital syphilis. Cells in the
CSF without another cause must be considered diagnostic of congenital
neurosyphilis in the appropriate setting. However, up to about 1 month of
age, CSF in the healthy newborn may contain a mildly elevated WBC count
(30 to 40 cells) and protein (up to 150 mg/dL).
c. Treatment. Some experienced clinicians recommend that congenital
secondary syphilis be treated with a regimen effective for neurosyphilis.
Aqueous penicillin G, 250,000 units/kg/day IV for at least 10 days, will
achieve treponemicidal drug levels in CSF.
E. Jarisch-Herxheimer reaction
1. The J arisch-Herxheimer reaction is a febrile response that is believed to be
caused by a release of large amounts of treponemal products into the
circulation within the first 24 hours of therapy. It is characterized by fever,
chills, myalgia, headache, tachycardia, tachypnea, elevated WBC count, and
decreased blood pressure. During the reaction, the rash of secondary syphilis,
if present, may worsen. It is a common occurrence on initiation of antisyphilitic
therapy, usually beginning about 2 hours after the first dose of antibiotics,
peaking at about 7 hours, and resolving in 24 hours.
2. The standard therapy is hydration and antipyretics. It is important that the
J arisch-Herxheimer reaction not be confused with an allergic reaction to
penicillin. Some physicians administer a dose of steroids with the initiation of
therapy for secondary or tertiary syphilis in an attempt to prevent this reaction.
VII. Other spirochetal infections
A. Lyme disease is caused by B. burgdorferi, a spirochete that is transmitted by
ixodid ticks, including the deer tick. Disease is endemic along the Atlantic coast of
the United States and in some parts of the West and Midwest. The disease is also
common in western Europe. The prevalence of infected ticks appears to be
increasing; this, along with increased recognition of the signs and symptoms, has
made Lyme disease the most commonly reported tick-borne disease in the United
States.
1. Description
a. Stage 1. The illness begins with a flulike syndrome, in some cases
associated with an expanding ringlike skin rash with central clearing
(erythema chronicum migrans). The tick itself is pinhead size, so the tick
bite may not be apparent on clinical examination.
b. Stage 2. After several weeks or months, a fluctuating meningoradiculitis
may occur, with headache, stiff neck, and cranial nerve or spinal root
involvement. In the United States facial nerve palsy, often bilateral, is the
most common focal sign, but in Europe a polyradiculopathy involving spinal
roots is more common. Cardiac involvement may also occur at this stage.
c. Stage 3 is usually associated with arthritis, involving predominantly large
joints. However, CNS complications can occur months to years after initial
infection, including seizures, encephalopathy, dementia, ataxia, and a
demyelinating syndrome that may mimic multiple sclerosis.
2. Diagnosis
a. With neurologic involvement in stages 2 and 3, CSF examination usually
reveals a lymphocytic pleocytosis with elevated protein.
b. Serum IgG antibody titers to B. burgdorferi are generally high with active
nervous system disease. The CSF serology is usually positive in stage 2
disease, but, like syphilis, it may be negative in tertiary Lyme disease.
Demonstration of intrathecal production of anti-B. burgdorferi antibody is
the most sensitive test for neuroborreliosis.
c. Because of cross-reacting antigens, patients with Lyme disease may have
a false-positive syphilis serology. Conversely, false-positive Lyme
serologies may be found in syphilis, leptospirosis, and relapsing fever.
Western blot should be used to confirm positive or equivocal serologic
(ELISA) results.
3. Treatment
a. Early disease and in patients with isolated seventh cranial nerve palsy
and normal CSF
1. Doxycycline, 100 mg PO bid.
2. Tetracycline, 500 mg PO qid, or minocycline, 100 mg PO bid, for 21 to
30 days.
3. Amoxicillin, 500 mg PO tid (20 mg/kg/day divided into 3 doses in
children), plus probenecid, 500 mg PO tid, is used for pregnant or
lactating women, children under 8 years old, and patients allergic to
tetracyclines, for 21 to 30 days.
4. Erythromycin, 250 mg PO qid (30 mg/kg/day PO divided into 4 doses
for children), is an alternative for penicillin-allergic patients, for 21 to 30
days.
b. Patients with abnormal CSF, polyradiculopathy, or parenchymal CNS
disease are treated with high-dose parenteral penicillin.
1. Penicillin G, 20 to 24 million units/day IV in 6 divided doses for 2 to 3
weeks, is standard.
2. The alternative is ceftriaxone, 2 g IV daily (75 to 100 mg/kg/day in
children) for 14 days, or cefotaxime, 2 g IV q8h for 14 days.
3. Chloramphenicol, 250 mg IV q6h for 14 days, has been used
successfully in penicillin-allergic patients.
c. Patients may experience a Jarisch-Herxheimer reaction at the initiation of
therapy. This can be treated as in syphilis (see sec. VI.E).
B. Brucellosis is caused by several Brucella species, which are small,
gram-negative coccobacilli. The disease occurs in meat packers and those
exposed to unpasteurized milk or cheese.
1. Description
a. Early disease is usually self-limited and resembles a flulike illness, but it
might be associated with an acute lymphocytic meningitis.
b. Late disease may produce a chronic meningoencephalitis.
Radiculopathies, myelitis, or encephalomyelitis might dominate the clinical
picture.
2. Diagnosis
a. The CSF demonstrates a lymphocytic pleocytosis with elevated protein.
The glucose may be low or normal. The CSF pressure may also be
elevated.
b. Brucella can be cultured from blood or CSF in a significant proportion of
patients.
c. The diagnosis is generally made by serology. Peripheral agglutination titers
in active infections are usually greater than 1:160. Positive CSF
agglutination titers are confirmatory of neurologic involvement.
3. Treatment
a. Rifampin is administered in combination with either a third-generation
cephalosporin, trimethoprim-sulfamethoxazole, or doxycycline.
Prolonged therapy, for 6 weeks up to 1 year, is required. The duration
depends on the clinical response and repeat CSF examinations.
b. For acutely ill patients, parenteral therapy in doses used for the treatment of
acute meningitis may be required. For chronic therapy, oral
trimethoprim-sulfamethoxazole or doxycycline is preferred over a parenteral
cephalosporin.
c. The most widely used chronic regimen consists of rifampin, 600 mg PO
daily, and trimethoprim-sulfamethoxazole, 160 mg PO qid.
C. Leptospirosis is caused by L. interrogans. The majority of cases involve a
self-limited flulike syndrome, often with conjunctival suffusion and muscle
tenderness, that occurs during the initial leptospiremic phase of disease. A
minority of infections produce more severe illness (Weil disease), usually
affecting the liver or kidney. Neurologic involvement is an uncommon complication
of the immune phase of disease and can be seen about 2 weeks into the illness.
Acute aseptic meningitis, myelitis, encephalitis, and cranial nerve palsies may
occur, with spontaneous recovery in weeks to months. Exceptionally, CNS
involvement is fatal. Leptospirosis generally occurs from contact with the urine of
infected animals, and human disease is most common in farm workers,
veterinarians, and pet owners. The disease is relatively common in the tropics, but
in the United States it occurs with significant frequency only in southern states and
along the west coast.
1. Diagnosis. Leptospira can be cultured from the CSF during the first 10 days of
illness. However, the diagnosis is generally based on the clinical situation and
detection of a fourfold rise in serum agglutination titers between acute and
convalescent serum. A single titer of greater than 1:200 supports the
diagnosis.
2. Treatment. Antibiotic therapy is administered if the diagnosis is made within
the first 5 days of illness. Antibiotics are not likely to benefit patients who
present with immune phase neurologic involvement.
a. Penicillin G, 1 million units IV q6h for 7 to 10 days, is commonly used.
b. The alternative drug for penicillin-allergic patients has not been defined,
but doxycycline, erythromycin, or chloramphenicol is a reasonable
alternative.
VIII. Fungal infections of the CNS
A. Description. The usual clinical picture is that of chronic meningitis; however,
intraparenchymal fungal infections may occur with symptoms that resemble
bacterial brain abscess. Fungal infection of the CNS may occur in
immunocompetent hosts, but risk is highest in hosts with compromised immune
function due to cancer, lymphoma, immunosuppressive therapy, or AIDS. Specific
antifungal therapy can be curative even in immunocompromised hosts. The vast
majority of cases of fungal meningitis in this country are caused by Cryptococcus
neoformans, Coccidioides immitis, and Candida albicans. Aspergillus species,
Histoplasma capsulatum, and Blastomyces rarely involve the CNS. Phycomycetes
(mucormycosis) produce a characteristic rhinocerebral syndrome with or without
associated meningeal inflammation. Nocardia and Actinomyces, although not true
fungi, can infect the CNS and behave clinically as fungal pathogens. Each of these
organisms has its distinctive features, but the basic approach to their therapy is
similar (Table 8-4).
TABLE 8-4. Antifungal Therapy
B. Amphotericin B
1. Clinical usefulness. Amphotericin B is an effective agent, both in vitro and in
vivo, against virtually all known fungi, although resistance to the drug has been
reported.
a. Almost universal toxicity from the drug accompanies its use, ranging from
fever and rigors to renal failure. A new IV liposomal formulation of
amphotericin B is being used as an alternative to conventional amphotericin
B and appears to be both effective and somewhat better tolerated, with less
associated nephrotoxicity. Side effects of amphotericin B are as follows:
1. Dose-related effects
a. Short-term systemic effects
i. Fever, chills.
ii. Nausea, vomiting.
iii. Anorexia, malaise, headache.
iv. Hypotension.
b. Renal toxicity
i. Impaired glomerular function; decreased glomerular filtration rate
and Cl
cr
. This may progress to oliguric renal failure.
ii. Impaired tubular function; distal renal tubular acidosis;
hypokalemia, which may be severe.
c. Anemia secondary to bone marrow suppression.
d. Local toxicity
i. Intravenous administration: phlebitis.
ii. Intrathecal injection: paresthesia, nerve palsies, back pain,
paraplegia, chemical meningitis, arachnoiditis, and CSF blocks.
iii. Intracisternal injection: hydrocephalus.
iv. Intraventricular injection: ventriculitis, encephalopathy, seizures,
and death.
2. Idiosyncratic effects
a. Shock.
b. Thrombocytopenia.
c. Acute liver failure.
d. Seizures.
e. Cardiac arrest, ventricular fibrillation.
b. Clinically, the most important toxic effects are renal. About 50% of patients
receiving a total of 4 g and 85% of those receiving 5 g of amphotericin B
are left with permanent renal insufficiency of clinical significance. Usually,
the dosage of amphotericin administered to a given patient is limited by
renal toxicity, which often occurs at a dosage of 0.5 to 0.7 mg/kg/day.
Hypokalemia is common and requires close monitoring and potassium
replacement as necessary. It is recommended that amphotericin B be used
according to a strict protocol (see sec. VIII.K for guidelines for the use of
amphotericin B).
c. Prolonged courses of therapy at potentially toxic doses are necessary to
treat fungal meningitis. However, relapse can occur even when the drug is
continued until the patient is clinically well and the CSF is normal.
d. The drug levels in the CSF associated with intravenous use are extremely
low, and this probably accounts for the relapse rate. Injection of the drug
directly into the subarachnoid space has been used, analogous to the use
of intrathecal or intraventricular aminoglycosides in gram-negative
meningitis, and the problems are similar (see sec. I.D).
1. Intralumbar injections do not deliver high concentrations of drug to the
basilar cisterns, the main site of most fungal infections, and virtually no
drug enters the ventricles. Furthermore, subarachnoid blocks to CSF
flow are common in fungal meningitis, complicating the problem of
distribution of drug through the subarachnoid space.
2. Amphotericin B produces irritative side effects when injected into the
subarachnoid space. Intrathecal injection frequently gives temporary
paresthesia, but progressive arachnoiditis, subarachnoid blocks, and
transverse myelitis have occurred as well. A single intraventricular
injection of 1 mg has produced encephalopathy and death within hours.
Risks of repeated intraventricular injection include all the potential
complications of Ommaya reservoirs.
e. Even when fungal infection is cured, the inflammatory reaction induced by
the fungus may lead to spinal block, hydrocephalus, and cranial nerve
palsies. The meninges over the convexities can become severely thickened
and cause bilateral mass effect with risk of herniation.
2. Systemic therapy. Despite its toxicity, amphotericin B remains the first-line
drug in essentially all fungal infections of the CNS. Its detailed use is described
in the guidelines for the use of amphotericin B (see sec. VIII.K). A low dose is
given initially and increased incrementally to the maximum tolerated daily dose,
or to a maximum of 0.7 to 1.5 mg/kg/day. The usual adult dosage is 50
mg/day. During chronic administration, renal function is followed closely, and
the dosage is decreased if the serum creatinine begins to rise above 3.5
mg/dL. In the absence of hard data on the necessary dosage of amphotericin,
various modifications of this approach have been suggested in an attempt to
minimize the toxicity and discomfort associated with the daily administration of
amphotericin B at high doses. These include:
a. Administration of twice the daily dose on an alternate-day basis. The
advantage of this program is that fewer total injections are given, so
phlebitis is less of a problem, and on the days during which patients do not
receive the drug, they are free of fever, anorexia, and other debilitating
effects of the drug. Nephrotoxicity is not reduced.
b. Determination of the minimal inhibitory concentration (MIC) of drug in
the patient's serum against the fungus isolated, and adjustment of the daily
dose of amphotericin B to achieve a serum drug level that is twice the MIC.
This generally results, for Cryptococcus species, in a dosage of 0.5 to 1.0
mg/kg/day. However, there are no data, to show that serum levels of
amphotericin B correlate with clinical effectiveness.
3. Intrathecal therapy
a. Indications. Subarachnoid administration should be considered in the
following settings:
1. In patients who have failed to respond to systemic therapy or who
relapse after a full course of systemic therapy.
2. In patients who are moribund at the initiation of therapy.
3. In severely immunosuppressed patients.
4. In patients with coccidioidal meningitis.
b. Routes of subarachnoid injection
1. Intraventricular. If subarachnoid therapy is used, intraventricular
injection of amphotericin B by means of an Ommaya reservoir and
indwelling intraventricular cannula constitutes the most reliable route of
therapy. This is the preferred method at most institutions.
2. Intracisternal injections of amphotericin B are used routinely at some
centers, but this approach is not recommended unless the injections are
done by a person very experienced in the technique.
3. Intralumbar. The drug, suspended in a solution heavier than CSF, such
as 10% D/W, can be injected into the lumbar space. Then the patient is
placed in the Trendelenburg position for a period of time so that the drug
can flow by gravity to the basilar cisterns. However, there is no wide
experience with this technique.
c. The patency of CSF pathways from the site of injection to the base of the
brain must be demonstrated before initiation of subarachnoid therapy and
repeatedly throughout the course of therapy if there is any indication of a
block to CSF flow.
C. Fluorocytosine (5-FC) is active against Cryptococcus, Candida, Aspergillus, and
Torulopsis; however, not all strains of these fungi are sensitive to the drug, and
resistance may develop during therapy. Therefore, 5-FC sensitivity must be
documented in each case in which the drug is used. Fluorocytosine has not
been demonstrated to be effective when used alone against life-threatening
infections. The following uses can be recommended (see dosage guidelines in
sec. VIII.L):
1. In cryptococcal disease, 5-FC and amphotericin B are synergistic in their
action, and combination therapy suppresses the appearance of 5-FC-resistant
organisms. Recommended therapy for AIDS patients is induction with the
combination of amphotericin B (0.7 mg/kg/day) and 5-FC (100 mg/kg/day). If
the patient is moribund at the initiation of therapy, fails to respond to this
regimen, or relapses after the therapy has been completed, the addition of
subarachnoid therapy can be considered. The hematologic toxicity of 5-FC
may be treatment limiting in AIDS patients.
2. There is insufficient experience with fungal disease other than cryptococcosis
to know whether the combination of 5-FC plus amphotericin B, at a lower
dosage of 0.5 mg/kg/day, is as effective as amphotericin B at a maximum
dosage in treating organisms that are sensitive to 5-FC. In severe infections
with sensitive organisms and in moribund patients, 5-FC should be added to
full-dose amphotericin B (0.7 mg/kg/day), the latter given both systemically and
by a subarachnoid route.
3. After the patient has received a course of amphotericin B or amphotericin B
plus 5-FC, 5-FC may be given alone to prolong the course of therapy.
4. Fluorocytosine is secreted by the kidneys. When given in combination with
amphotericin B, renal dysfunction induced by amphotericin may result in
progressively increasing serum levels of 5-FC. It is important, therefore, to
monitor serum levels of 5-FC and to maintain serum concentrations in the 60
to 80 g/mL range.
D. Ketoconazole has activity against coccidioidomycosis, histoplasmosis, and
Candida infection. It is administered orally and penetrates poorly into the CSF, so
that therapeutic levels against fungi are not reached at the usual oral dosage of
400 to 800 mg/day. Higher dosages have produced therapeutic responses in a
few patients with coccidioidal meningitis. The major toxicity is nausea and
hepatocellular dysfunction, which rarely can progress to fatal hepatic necrosis.
E. Fluconazole
1. Fluconazole has been used as both initial treatment and maintenance therapy
in cryptococcal meningitis.
a. Currently, it is recommended at a dosage of 200 to 400 mg/day PO as
maintenance or suppressive therapy in cryptococcal disease in AIDS
patients.
b. In patients with mild disease, it can be used as initial therapy for
cryptococcal meningitis at a dosage of 400 mg/day for 10 to 12 weeks.
2. In an uncontrolled study of coccidioidal meningitis, fluconazole (400 mg/day)
was associated with a 70% response rate in previously untreated patients.
3. Side effects. Fluconazole is generally well tolerated but is occasionally
associated with GI upset and, rarely, with hepatitis or allergic reactions.
F. Duration of therapy. The duration of therapy necessary to cure fungal infections
of the CNS is unknown. In many patients the infection is probably never cured, in
the sense that every organism is not eliminated and viable organisms remain.
There are cases of cryptococcal meningitis in which the India ink stain remains
positive for months after therapy is stopped but the patient remains clinically well.
1. If the patient responds clinically to the initial therapy, that regimen should be
continued:
a. For at least 6 weeks. Four weeks of therapy may suffice in a carefully
selected subset of patients who meet all of the following criteria: meningitis
without neurologic signs; no underlying systemic disease or
immunosuppressive therapy; pretreatment CSF cell count greater than 20
g/mL; serum cryptococcal antigen titer less than 1:32; and after 4 weeks
of therapy, a negative CSF India ink preparation and CSF cryptococcal
antigen titer less than 1:8.
b. For 1 month after the last positive CSF culture.
c. Until there is no evidence of active CNS infection:
1. A stable or improving neurologic examination, or
2. A normal or only mildly elevated, stable CSF cell count.
d. Until there is no evidence of active systemic infection.
e. Until drug toxicity precludes further therapy.
2. The need for prolonging therapy
a. Persistently positive CSF cultures or positive India ink preparations in
cryptococcal disease require prolonging therapy. A persistently elevated
CSF protein is not in itself an indication for prolonging therapy. A lifelong
course of antifungal therapy is generally administered to AIDS patients with
cryptococcal meningitis (see sec. XVII).
b. In cryptococcal disease, failure of the serum or CSF antigen titer to fall by
more than two dilutions during therapy carries a poor prognosis and should
lead to prolonged treatment.
c. Coccidioidal antigens may also be measured in the CSF, but their relation
to prognosis has not been as clearly evaluated as it has for cryptococcal
antigens.
d. Oral 5-FC may be given alone after the course of combination therapy or
after amphotericin B alone has been completed. Since there are
presumably few viable organisms present, 5-FC resistance is less likely to
develop.
e. Some experts recommend the administration of subarachnoid amphotericin
B weekly for life in coccidioidomycosis.
f. The subarachnoid injection of amphotericin B may be continued, either
alone or in combination with oral 5-FC, even after systemic amphotericin B
has been stopped because of renal toxicity.
G. Use of steroids
1. Elevated CSF pressure. In fungal meningitis, as in other infections of the
CNS, high-dose steroids are used for the treatment of elevated CSF pressure
due to brain swelling or focal infection of brain parenchyma. Hydrocephalus
should be ruled out by CT scan or MRI in all such cases. Serial LPs or
continuous lumbar drainage should be considered in patients with persistently
elevated ICP.
2. Hydrocortisone may be injected along with intrathecal amphotericin B in an
attempt to minimize local irritative effects (see sec. VIII.K).
H. Fungal meningitis is associated with an impressive granulomatous response at the
base of the brain and at the lining of the ventricles. This can obstruct CSF flow and
cause hydrocephalus. If hydrocephalus occurs late, after the CSF is sterile, a
ventriculoatrial or ventriculoperitoneal shunt can be placed. If the CSF is still
infected, constant ventricular drainage must be used; or, if the CSF block is
outside the ventricular system and the hydrocephalus is not life threatening,
definitive treatment may be deferred until the CSF can be sterilized.
I. Intraparenchymal fungal infections of the CNS. Fungi can invade the
parenchyma of the brain and cause abscess or granuloma formation. This process
may occur with or without an associated meningitis. Aspergillus is the organism
that most typically causes focal intraparenchymal disease, but any fungus that
infects the CNS may cause intraparenchymal infection, including Cryptococcus,
Candida, and Mucor. The prognosis for intraparenchymal disease is worse than
that for meningeal involvement alone. The diagnostic approach and treatment are
similar to those for bacterial brain abscess, with surgical excision of accessible
lesions. If the etiologic agent is known or strongly suspected preoperatively,
antifungal therapy in the maximum tolerated dosages should be started 48 hours
before surgery. Multiple or inaccessible lesions may have to be treated medically,
in which case the dosage of amphotericin B is pushed to its maximum, and 5-FC
is added if the organism is sensitive. Intraparenchymal lesions caused by C.
neoformans often can be treated medically and followed with serial CT scans, in a
manner similar to the treatment of focal bacterial cerebritis (see sec. III.D.3). A
focal invasive cryptococcal cerebritis, with unusually inflammatory histopathology,
has been observed in patients previously treated for cryptococcal meningitis. CSF
cryptococcal antigen titers may be misleadingly low and CSF noninflammatory.
Patients present with seizures, mental status changes, and focal deficits.
Response to reinduction therapy, in the few patients reported, has been uniformly
good.
J . Actinomyces and Nocardia species are acid-fast organisms with properties that
are intermediate between those of bacteria and fungi. When they infect the CNS, it
is usually by causing brain abscess, with symptoms of an expanding mass lesion.
Spinal cord abscess and meningitis can also occur. Rarely, an intracranial epidural
abscess complicates cranial osteomyelitis. Unlike the fungi, these organisms
respond to antibacterial drugs. Single abscesses may require surgical excision.
The drugs of choice are as follows:
1. Actinomycetes
a. Penicillin G, 24 million units/day in adults and 200,000 units/kg/day in
children in 12 divided doses for at least 8 weeks. The optimum duration of
therapy is not known, but some would prolong treatment for 5 months.
b. In penicillin-allergic patients, erythromycin, 4 g/day IV in adults and 50
mg/kg/day IV in children in 4 divided doses.
2. Nocardia species
a. Trimethoprim-sulfamethoxazole, 15 to 20 mg/kg/day IV (trimethoprim
dose, administered as a solution containing trimethoprim and
sulfamethoxazole in a ratio of 1:5), divided into 4 doses. The drugs should
be dissolved in at least 75 mL of 5% D/W immediately before administration
and infused slowly over 1.0 to 1.5 hours. With renal impairment (Cl
cr
15 to
30 mL/minute), halve the dose. The drug should not be used if Cl
cr
is less
than 15 mL/minute.
b. Cycloserine, 15 mg/kg/day PO in 4 divided doses, in combination with
sulfamethoxazole for severe disease, moribund patients, multiple
intracranial abscess, or failure to respond to sulfamethoxazole alone.
K. Guidelines for the use of amphotericin B
1. Intravenous administration
a. Initial doses. When beginning treatment with amphotericin B, it is prudent
to start with a small dose and build up to full therapeutic doses over 5 to 10
days. The first dose is generally 1 mg. Each succeeding dose is doubled
until 16 mg/day is reached, and thereafter the dose is increased in
increments of 10 mg until the full therapeutic dose, usually 50 mg/day, is
reached. If therapy is interrupted for more than 10 days, the procedure is
repeated. In life-threatening fungal infections, the full therapeutic dose must
be achieved more rapidly. In that case, a 1-mg test dose is administered. If
that dose is tolerated, a dose of 0.2 mg/kg is administered, and succeeding
daily doses are increased in 0.2 mg/kg increments.
b. The infusion mixture is administered through a central catheter over 4 to 6
hours. The rate of infusion may be varied according to the severity of the
side effects encountered. Generally, the immediate side effects tend to
diminish with repeated doses.
c. Amphotericin B can produce acute hyperkalemia during and immediately
following the infusion, so that patients receiving high doses, especially
those with renal insufficiency, may require hourly monitoring of serum
potassium levels. Chronically, the distal tubular toxicity of amphotericin B
can produce both sodium and potassium wasting. Some clinicians replete
patients with up to 300 mEq/day of sodium. Serum potassium should be
monitored and dietary potassium supplemented as required.
d. Monitoring of drug toxicity. Renal and bone marrow function are closely
observed during therapy. The following tests are performed before initiating
therapy and at least twice a week while systemic amphotericin B is being
administered:
1. CBC.
2. Peripheral blood smear, platelet count, or both.
3. Reticulocyte count.
4. BUN or creatinine.
5. Serum electrolytes.
6. Bilirubin.
7. SGOT.
8. Alkaline phosphatase.
9. Urinalysis.
e. The maximum dosage is 1.5 mg/kg/day IV. Typically, adults receive 50
mg/dose. Tolerance of more than 1.0 mg/kg/day is uncommon. Dosage
reduction is recommended when plasma creatinine rises over 3.5 mg/dL.
Adequate hydration must be maintained to minimize azotemia.
2. Intrathecal administration
a. Premedicate the patient with an antiemetic and perform an LP in the usual
manner. With each dose, CSF is removed and the cell count, protein,
sugar, and culture are checked to monitor the progress of the therapy.
Fungal antigen titers, if available, are checked weekly.
b. The first dose should be 0.025 mg dissolved in 5 mL of CSF.
Hydrocortisone, 5 to 15 mg, may be added to the injection to reduce side
effects. A dose is given every other day and is increased slowly by
0.025-mg increments with each dose until the maximum dose of 0.5 mg is
achieved. At that point, the frequency of administration is decreased to
twice a week.
L. Guidelines for the use of 5-FC. Fluorocytosine is well absorbed when taken PO,
and CSF concentration reaches 80% to 100% that of serum.
1. The dosage is 75 to 150 mg/kg/day divided into four doses.
2. In renal failure, the frequency of doses (25 to 40 mg/kg) must be reduced as
follows:
Cl
cr
(mL/min) Dosage interval
100 q6h
4025 q12h
2512 q24h
12 q48h
3. The sensitivity of the organism being treated must be checked at the initiation
of therapy and at least monthly thereafter.
4. Serum levels should be monitored regularly, especially in the presence of
decreased renal function. The therapeutic concentration is 50 to 100 g/mL.
5. Toxicity
a. GI upset, with anorexia, nausea, vomiting, and diarrhea, is the most
frequent untoward effect.
b. Hepatic. Elevation of SGOT and alkaline phosphatase may occur, possibly
in association with hepatic necrosis. Liver function should, therefore, be
checked weekly during therapy.
c. Hematologic. Anemia, leukopenia, or thrombocytopenia may occur. These
reactions are dose-dependent and occur primarily in azotemic patients.
Because of the renal toxicity of amphotericin B, the combination of 5-FC
and amphotericin B is especially likely to lead to bone marrow dysfunction.
Fluorocytosine may be especially myelosuppressive in AIDS patients.
Blood counts are checked at least twice weekly in all patients during
therapy with 5-FC.
IX. Viral meningitis
A. Description. Viruses often infect the subarachnoid space and leptomeninges, with
little or no parenchymal involvement of the CNS. The clinical syndrome is that of
an acute febrile illness, with headache, meningismus, and often vomiting. The
neurologic signs are sparse. There may be lethargy, irritability, mild drowsiness,
isolated transient cranial nerve dysfunction, or minor reflex changes. Seizures,
aside from febrile convulsions, or any severe and persistent neurologic deficits
imply an encephalitic component to the illness. There may be associated findings
of systemic viral infection, and these may help to identify the etiologic agent.
The total duration of the illness is 10 to 14 days, and the course is benign, without
significant sequelae in more than 90% of cases. About 10% of patients require
prolonged convalescence, and rarely there are permanent residual deficits, usually
spasticity or intellectual impairment. Death from aseptic meningitis is exceedingly
rare. A careful history may reveal evidence of concurrent viral illness in family
members or other contacts of the patient.
B. Etiology. The most common single agent is mumps, especially where mumps
vaccine use is limited, but the enteroviruses, primarily Coxsackievirus and
echovirus, constitute the most common viral group that infects the meninges.
Lymphocytic choriomeningitis (LCM), herpesviruses, and arthropod-borne
viruses are less frequently identified. HIV can cause both acute and chronic
aseptic meningitis but far more commonly causes asymptomatic CSF
abnormalities. A similar clinical picture can be produced by certain nonviral
agents. Leptospirosis is an unusual cause of the syndrome in the United States,
and mycoplasmosis is a rare cause. All other agents account for less than 1% of
cases of aseptic meningitis in the United States.
C. Diagnosis. The most important clinical problem in aseptic meningitis is to verify
that the CSF is indeed aseptic (i.e., no bacterial, mycobacterial, or fungal agent is
causing the infection). Leptospires and mycoplasmas, although bacteria, are
included in the causes of aseptic meningitis, since they do not grow on the usual
culture media, and they cause a benign neurologic disease that is
indistinguishable from viral illness. The CSF profile is lymphocytic, with normal
glucose, but very early in the course the CSF may have a polymorphonuclear
predominance. A repeat LP 8 to 24 hours after the first will show a shift to
lymphocytic predominance in these cases. Identification of the specific infecting
organism is useful in confirming the diagnosis and for epidemiologic purposes, but
it has no therapeutic importance.
D. Treatment consists of supportive measures. There is no known specific therapy.
E. Complications
1. Hydrocephalus. There are reported cases of hydrocephalus following mumps
meningitis. Mumps, and possibly other viruses, can cause an ependymitis
throughout the ventricular system. The resultant scarring can lead to
aqueductal stenosis as a late complication, and ventriculoatrial or
ventriculoperitoneal shunting is required.
2. Residual neurologic deficits occur rarely.
X. Viral encephalitis
A. Description. Viral encephalitis is usually an acute febrile illness. It is often
associated with headache, meningismus, and behavioral change or depressed
mental status. Examination of the CSF usually reveals a lymphocytic pleocytosis
and elevated protein, but indices may be normal early on. Infection of cortical
neurons may cause seizures or focal deficits. Coma may occur. The disease is
more prolonged than aseptic meningitis, lasting 2 weeks to several months. There
is significant mortality during the acute illness (about 10% for all cases of clinically
recognized viral encephalitis), and there is a high incidence of permanent and
disabling sequelae.
B. Etiology. The most common etiologic agents identified in this disease are
mumps, herpes simplex virus 1 (HSV-1), and arboviruses. Enteroviruses are
unusual causes of encephalitis, as are varicella and Epstein-Barr viruses and
mycoplasma. Rabies encephalitis is rare in the United States. The prognosis
depends on the etiologic agent.
1. Herpes simplex is the most common cause of sporadic, focal encephalitis in
the United States. Mortality is 10% to 40%, with a corresponding high
incidence of serious residual deficits. Most infections are due to HSV-1 and
characteristically produce destructive lesions of the inferior frontal and
anterior temporal lobes. Hence dementia, personality disorders, memory loss,
and aphasia are common sequelae of infection. Culture of the CSF usually
does not yield virus. A CT scan or MRI showing inflammation and edema in the
characteristic areas or an EEG with periodic sharp wave activity temporally on
a background of focal or diffuse slowing should prompt empiric treatment with
intravenous acyclovir. Brain biopsy remains the gold standard of diagnosis.
Successful therapy depends on a high index of suspicion leading to early
diagnosis. Immunosuppressed patients may have a markedly decreased
inflammatory response in the brain, associated with a misleadingly
insidious clinical course. CT may be negative; MRI with coronal images
through the temporal lobes may aid diagnosis, as may CSF PCR.
2. The arboviruses have a variable prognosis.
a. Eastern equine encephalitis is the most severe, with a 70% to 90%
incidence of death or disabling sequelae.
b. The morality from western equine encephalitis and St. Louis
encephalitis is 2% to 20%. The disease is usually benign, although it may
be severe in younger children and the elderly.
c. California encephalitis (including the La Crosse virus) and Venezuelan
equine encephalitis generally cause benign infections; death and disability
are unusual.
3. Encephalitis caused by mumps or lymphocytic choreomeningitis (LCM) virus is
benign except in rare instances.
4. Neonatal viral encephalitis may occur and has a poor prognosis. Neonatal
encephalitis due to herpes simplex virus 2 (HSV-2) is usually a fulminant,
generalized, and rapidly fatal disease. Unlike in adult HSV-1 encephalitis, the
yield of CSF viral culture in neonatal HSV-2 encephalitis is high.
C. Treatment
1. Edema. In viral encephalitis, the CSF pressure may be very high, and focal
areas of infection with edema, vascular engorgement, or hemorrhage may act
as a mass lesion. Herniation can occur. Osmotic agents may be used in acute
situations, and high-dose steroids may be used over the longer run (see sec.
I.H). There is experimental evidence that steroids can potentiate the spread of
herpes in nervous tissue, so steroids should not be used in viral encephalitis
without definite indications. In addition, since much of the edema is cytotoxic,
steroids may be of limited benefit.
2. Seizures resulting from viral encephalitis may be extremely difficult to control,
but their treatment is identical to that of seizures of other etiologies (see Chap.
6).
3. Specific antiviral therapy
a. Herpes simplex encephalitis. Acyclovir, 10.0 to 12.5 mg/kg IV q8h, is
administered immediately on making the diagnosis of herpes simplex
encephalitis. The patient should be adequately hydrated, and each dose
should be slowly infused over 60 minutes to prevent the drug from
precipitating in the renal tubules. The optimum duration of therapy is
unknown, but 10 to 14 days is common.
1. Pharmacokinetics. Acyclovir is excreted by the kidney and has a
half-life of about 3 hours with normal renal function. The dosage must
be reduced in renal insufficiency. Concentrations in CSF reach about
50% of plasma levels.
2. Toxicity. Acyclovir is generally well tolerated, but local irritation,
nausea, and headache can occur with IV infusion. About 1% of patients
receiving intravenous acyclovir develop encephalopathy, which can be
difficult to distinguish from the underlying encephalitis. Abnormal bone
marrow and hepatic function have been reported in
immunocompromised patients.
3. Because the diagnosis of herpes simplex encephalitis is often unclear
on clinical grounds, the precise indications for the use of acyclovir are
undefined. The lack of toxicity of acyclovir has led to its use in many
clinical circumstances where the diagnosis of herpes simplex
encephalitis is entertained, but where definite proof from viral culture or
brain biopsy is lacking.
4. Acyclovir is less toxic and more effective than vidarabine (Ara-A) for the
therapy of herpes encephalitis.
b. CMV infections. Cytomegalovirus can cause ventriculitis, encephalitis,
myelitis, polyradiculopathy, and retinitis in immunocompromised hosts. It is
a common pathogen in transplant recipients and AIDS patients.
1. Ganciclovir (DHPG) has broad-spectrum antiviral activity against
herpesviruses but has achieved widest clinical use in CMV infections. It
has demonstrated efficacy in CMV retinitis and is used, although without
documented effect, in CMV encephalitis and myelitis. Improvement of
CMV polyradiculitis has been demonstrated in a few cases.
a. Dosage. Ganciclovir, 5.0 mg/kg IV q12h, is infused over 1 hour. The
dosage must be adjusted in renal insufficiency. The total duration of
therapy is generally 14 to 30 days, depending on the clinical
response. In AIDS patients, maintenance therapy at a dosage of 5
mg/kg/day or 6 mg/kg/day, 5 days/week, may have to be
administered for life to prevent relapse.
b. Pharmacokinetics. Ganciclovir is excreted by the kidney and has a
plasma half-life of 3 to 4 hours. CSF levels reach 38% those in the
plasma.
c. Toxicity. The toxicity is dose-related and is directed primarily at
rapidly dividing cells. Inhibition of spermatogenesis, bone marrow
suppression, and GI reactions are common. Encephalopathy is
uncommon.
2. Foscarnet has a spectrum of antiviral activity similar to that of
ganciclovir. It is effective in CMV retinitis and can be used as a
second-line agent in patients with ganciclovir-resistant CMV causing
nervous system disease.
a. Dosage is 60 mg/kg IV q8h for 14 days, infused over 1 hour by
infusion pump only. In AIDS patients, maintenance therapy, 90 to
120 mg/kg/day IV, is recommended, administered as a 2-hour pump
infusion. Oral ganciclovir has been successful as maintenance
therapy in CMV retinitis and is a reasonable alternative.
b. Pharmacokinetics. Foscarnet is excreted by the kidney and has a
plasma half-life of 3.3 hours. Levels in CSF reach 40% of those in
plasma.
c. Toxicity. Renal toxicity is dose limiting in up to 23% of patients.
Derangements of calcium, potassium, phosphate, and magnesium
levels can occur. The dosage must be adjusted in renal failure.
Acute overdose can cause seizures or cardiac arrhythmias and
is potentially fatal.
XI. Rabies is transmitted to humans by animal bites and causes severe brainstem
encephalitis with high mortality. The usual incubation period in humans is 30 to 60 days
for bites on the extremities, but incubation periods as long as 6 months have been
reported. Bites on the face and neck can have an incubation period as short as 2
weeks. The clinical disease usually begins with personality change and a period of
excitement. Then focal neurologic signs, especially those referable to the brainstem,
develop. The characteristic hydrophobia is caused by dysphagia and hyperirritability of
the respiratory tract and pharynx. Death results from respiratory failure or cardiac
arrhythmia; the latter is associated with myocarditis in some cases. In rare cases, the
clinical syndrome may begin with ascending paralysis of the Guillain-Barr type. The
disease is nearly 100% fatal during the acute stage; however, with intensive respiratory
support and nursing care, complete recovery has been reported. Rabies vaccine and
antiserum should be administered to anyone with an animal bite sustained in an
unprovoked attack. Foxes, bats, and skunks are the major animal reservoirs in the
United States.
XII. Poliomyelitis. A special form of viral infection of the CNS is caused by
enteroviruses that target the anterior horn cells of the spinal cord. The clinical picture is
one of an acute febrile illness with lower motor neuron paralysis. Fortunately,
immunization has made infection with poliovirus rare. Cases continue to be reported
sporadically, either secondary to poliovirus in nonimmunized individuals or, rarely,
secondary to other enteroviruses. The treatment is purely supportive.
XIII. Slow viruses and progressive multifocal leukoencephalopathy
A. Jakob-Creutzfeldt (JC) disease and its new variant,
Gerstmann-Straussler-Scheinker disease, fatal familial insomnia, and kuru
are among the transmissible spongiform encephalopathies. It is hypothesized that
the infectious agent is a self-replicating protein or proteinaceous infectious
particle (prion). Competing hypotheses suggest that the agent is a small virus,
perhaps with the prion protein as a receptor, or a nucleic acid (virion) associated
with a protein. Kuru, once endemic in part of Papua New Guinea, was spread
mainly by ingestion of infected human brain tissue and is now rare. J C disease
has a worldwide distribution and is a subacutely progressive dementing illness,
usually beginning in the sixth or seventh decades and progressing relentlessly to
coma and death. Ataxia and myoclonus are striking features clinically. The CSF is
normal, but the EEG is distinctive and characterized by periodic triphasic sharp
wave complexes or, less commonly, intermittent burst-suppression high-voltage
activity. So-called new-variant J C disease, reported in Great Britain, occurs at an
average age of 27, and presents with psychiatric or sensory symptoms before
changes in cognition. Ataxia and myoclonus are also common. EEG is abnormal
more variable. Ingestion of tissues from cows with the bovine form of scrapie,
bovine spongiform encephalopathy (mad cow disease), has been implicated as
the key risk factor for this disease, and animal experiments indicate infectivity
across species. There is no known specific therapy, and J C disease is uniformly
fatal (see Chap. 3).
B. Subacute sclerosing panencephalitis is a syndrome that typically occurs in
childhood but has been reported up to the age of 34 years. It is almost always the
result of persistent, variably defective measles virus, but rarely may be caused by
rubella. The first symptoms are personality change and intellectual deterioration,
followed by the development of myoclonic seizures, ataxia, and visual impairment.
There are reports of spontaneous remissions, but only after permanent damage
has occurred to the brain. Usually, the disease progresses to death in a matter of
months or a few years. The CSF may contain a few lymphocytes, but, most
importantly, it contains a highly elevated gamma globulin with elevated titers of
antimeasles antibodies. Oral isoprinosine and intraventricular interferon-a have
been used in a small series, with neurologic improvement in a few patients. A
multicenter international trial is underway.
C. Progressive multifocal leukoencephalopathy (PML) is caused by the
papovavirus J C or, rarely, SV-40. The disease usually begins with focal neurologic
signs and symptoms and progresses in many patients within a few months to
global impairment and death. The virus causes demyelination of white matter in
the brain (leukoencephalopathy), with a marked absence of inflammatory
response or edema. Although J C virus is ubiquitous and anti-J C antibodies are
found in the majority of individuals, active disease is seen only in patients with
disorders of cellular immunity. Most cases are seen among AIDS patients, but
transplant recipients and patients with lymphoma are also at risk. There is no
proven effective therapy. In AIDS patients, stabilization or remission has been
reported with antiretroviral therapy for HIV-1. Improved cellular immunity and a
decrease in HIV-1 proteins permissive for J C viral replication probably play a role
in such cases. A controlled clinical trial of IV or intraventricular cytosine
arabinoside failed to demonstrate efficacy in AIDS patients with PML compared
with antiretroviral therapy alone. Interferon-a, cydofovir, and the topoisomerase
inhibitor topotecan each have been associated with clinical and radiographic
improvement in a few patients.
XIV. Toxoplasmosis
A. Description. Toxoplasma gondii is an intracellular parasite that infects humans
and animals. Infection is usually asymptomatic, but it can cause several varieties
of disease. In North America and parts of Europe, its role as a common
opportunistic CNS pathogen in AIDS (see sec. XVII) has diminished markedly
since the widespread use of trimethoprim-sulfamethoxazole for prophylaxis of
Pneumocystis carinii pneumonia (PCP).
1. Congenital toxoplasmosis classically causes a syndrome of choreoretinitis,
retardation, and intracranial calcifications, often associated with microcephaly,
hepatosplenomegaly, jaundice, and rash. Any of the components of the
syndrome may be missing in a given patient.
2. Acquired toxoplasmosis usually occurs in a host with defective cellular
immunity and may produce encephalitis, meningitis, or, most commonly, an
intracerebral mass lesion. Spinal cord abscess and myositis have been
reported. Definitive diagnosis requires identification of the organisms in a
tissue biopsy.
B. Diagnosis. Serologic tests for toxoplasmosis are generally not helpful in the
diagnosis of acute infections, since at least 40% of the population has IgG
antibodies directed against Toxoplasma. In immunocompetent individuals, a
fourfold rise in titers is indicative of active infection. In AIDS patients, such a rise is
rarely seen. However, the measurement of a baseline anti-Toxoplasma IgG titer at
the time of diagnosis of AIDS may aid the diagnosis of active toxoplasmosis in the
appropriate clinical setting. It should be emphasized that anti-Toxoplasma titers
can be nondetectable in some AIDS patients with cerebral toxoplasmosis,
particularly if low dilutions are not used in the assay; therefore, negative titers
argue against, but do not rule out, toxoplasmosis. When brain biopsy is
necessary to establish the diagnosis, MRI is more sensitive than CT scanning in
disclosing surgically accessible lesions. Toxoplasma brain abscesses are
characteristically multiple and ring-enhancing with contrast. While single,
nonenhancing, and diffusely enhancing toxoplasma lesions are also seen, other
diagnoses such as lymphoma should be considered, and early brain biopsy is
reasonable. A trial of 10 days to 2 weeks of anti-Toxoplasma therapy is
appropriate in an AIDS patient with positive anti-Toxoplasma antibody titers
and brain lesions consistent with toxoplasmosis. If lesions do not regress
radiographically, brain biopsy should be considered.
C. Treatment. Prompt treatment of the acquired disease often results in a cure. The
congenital disease is treated only in an attempt to prevent progression of the
disease; the CNS damage that is present at birth is irreversible. There is a high
spontaneous remission rate of acquired toxoplasmosis in immunocompetent
individuals, but active CNS disease is an indication for treatment. AIDS patients
should have lifelong maintenance therapy to prevent relapse. The recommended
therapy is as follows:
1. Sulfadiazine, 100 mg/kg/day (maximum 8 g/day), in combination with
pyrimethamine, 1 mg/kg/day, up to 100 mg/day. A 100- to 200-mg loading
dose of pyrimethamine should be given. Trimethoprim, a folate antagonist
similar to pyrimethamine, cannot be used in place of pyrimethamine because it
has no activity against toxoplasmosis.
2. Folinic acid (Leucovorin), 10 mg/day, may be given to counteract the
hematologic toxicity of pyrimethamine.
3. Toxicity from sulfadiazine and pyrimethamine is common. Problems leading to
discontinuation of therapy include hypersensitivity reactions and bone marrow
suppression. Patients with AIDS who are taking azidothymidine (AZT) may
require a reduction in AZT dosage to prevent synergistic bone marrow toxicity.
4. The optimum duration of therapy is unknown. Radiographic reevaluation is
performed after 10 days to 2 weeks of therapy to document regression of
lesions. Patients with AIDS are usually treated for life. Maintenance therapy
with pyrimethamine, 25 to 50 mg/day, folinic acid, 5 mg/day, and sulfadiazine,
1 to 2 g/day, is standard; pyrimethamine, folinic acid, and clindamycin, 600
mg/day can also be used. The role of prophylaxis in AIDS patients with positive
Toxoplasma serology has not been defined; however, PCP prophylaxis with
antibiotics also active against T. gondii has been linked to the observed decline
in CNS toxoplasmosis in HIV-1-seropositive patients.
5. Alternative regimens. Pyrimethamine alone or in combination with
clindamycin, 1,200 to 2,400 mg/day in 4 divided doses, is used in sulfa-allergic
patients.
XV. Amebic meningoencephalitis. Naegleria, a genus of free-living amebas
commonly present in warm freshwater, can cause an acute meningoencephalitis with
purulent CSF and hemorrhagic brain lesions. They can be identified as mobile, large
organisms on a wet preparation of fresh CSF. There is no known effective therapy. All
forms of antibiotic therapy, including metronidazole (Flagyl),
sulfamethoxazole-trimethoprim, amphotericin B, and assorted antibacterial agents, have
been tried.
XVI. Herpes zoster (shingles) is caused by reactivation of latent varicella-zoster
virus chronically resident in dorsal root and cranial nerve ganglia. Fifty percent of cases
involve thoracic dermatomes, with pain and paresthesia preceding the vesicular
eruption. When the seventh cranial nerve is involved, there is a lower motor neuron
facial palsy, and the vesicles may appear in the external auditory canal or the tympanic
membrane (Ramsay Hunt syndrome).
A. Patients with symptomatic herpes zoster, especially young patients, have an
increased incidence of immunodeficiency states, particularly HIV infection and
lymphoma. Such conditions should be sought by physical examination and
appropriate blood testing.
B. Steroids should be avoided in the acute period and, if possible, should be
decreased or discontinued if their use preceded the infection.
C. Treatment of pain may be difficult both acutely and chronically (postherpetic
neuralgia). Carbamazepine, desipramine, or local application of capsaicin cream
may be of value in a minority of patients. The treatment of chronic pain is
discussed in Chap. 9.
D. Acyclovir, 5 mg/kg IV q8h for 7 days, hastens the healing of cutaneous lesions
and decreases the duration of acute pain. However, the incidence and severity of
postherpetic neuralgia are unaffected by antiviral therapy. Immunocompromised
patients should be treated with acyclovir in an effort to prevent dissemination of
the infection.
E. Nonimmune contacts of patients with cutaneous lesions of herpes zoster are at
risk for primary infection with the virus (chickenpox).
XVII. Acquired immunodeficiency syndrome (AIDS) is a multisystem
infection by the human immunodeficiency virus 1 (HIV-1). Neurologic disease affects
one half to two thirds of patients and can occur at any stage of the infection, but is more
common in the setting of late-stage AIDS. A variety of mechanisms have been
implicated in primary neurologic complications of HIV disease, including neurotoxic
effects of both viral products and the immune response to the virus. For example, the
cytokine tumor necrosis factor a (TNF-a) is neurotoxic in vitro and has been implicated
in the pathogenesis of HIV-associated injury to brain, spinal cord, and peripheral nerve.
However, nervous system injury in HIV is multifactorial, and the roles of host factors as
well as neurovirulence of various viral strains remain to be characterized. Maximal
suppression of viral load with aggressive therapy has been associated with
marked improvement in cognition, even with antiretrovirals that do not cross the
blood-brain barrier. This suggests that brain viral burden may be less of a factor than
is systemic viral load and the immune activation or dysregulation caused by infection.
Secondary complications are due to opportunistic infections and neoplasms, as well
as neurotoxic side effects of therapy.
A. Primary HIV infection of the nervous system. HIV is a neurotrophic as well as
lymphotrophic member of the lentivirus subfamily of retroviruses, all of which
target the nervous system of the host. HIV has been isolated from the CSF and
brain of AIDS patients with various neurologic syndromes, and the synthesis of
HIV-specific immunoglobins within the blood-brain barrier has been demonstrated.
HIV has also been isolated from the CSF of asymptomatic seropositive patients,
including those with normal CSF. HIV enters the nervous system early, causing
apparently latent infection in brain macrophages; the virus is found only rarely
in neurons or other parenchymal cells.
1. Acute infection. Although the initial CNS infection is usually asymptomatic,
neurologic disease might be the first manifestation of HIV and can occur at the
time of seroconversion when immunologic indices are normal.
a. An acute, reversible encephalopathy may occur. Confusion, memory loss,
and disorder of mood are seen.
b. Acute aseptic meningitis, with headache, stiff neck, photophobia, and
arthralgias, may occasionally be accompanied by a maculopapular rash.
c. Isolated cranial neuropathies, particularly Bell palsy, acute ascending or
transverse myelitis, and inflammatory polyneuropathy resembling
Guillain-Barr syndrome, have also been reported early in infection.
2. Chronic infection
a. HIV-associated cognitive-motor complex, or AIDS dementia complex,
occurs in about 20% of AIDS patients, typically in the setting of severe
immunosuppression. There is a progressive subcortical dementia,
sometimes associated with loss of balance or leg weakness. Early on, the
symptoms may be mistaken for depression, since difficulties with
concentration and memory, apathy, and psychomotor retardation are
common presentations. A treatable affective disorder must be carefully
ruled out. Mania, organic psychosis, and, rarely, catatonia might occur.
Seizures can occur, attributable only to HIV infection, but this must be a
diagnosis of exclusion after appropriate clinical and radiologic evaluation.
Grasp reflexes and other frontal release signs, tremor, cog-wheel rigidity,
long tract signs (e.g., extensor plantar responses), clumsy fine-motor
movements, and myoclonus are common. In patients with AIDS dementia,
brain imaging may be unremarkable. AIDS dementia is a clinical, not a
radiographic, diagnosis. Abnormal radiographic HIV encephalitis might
be seen in patients with normal cognition. Typically, however, CT scan
reveals diffuse cortical atrophy and enlarged ventricles, and MRI might
show multifocal or diffuse increase in white matter signal on T2-weighted
images. On pathologic examination, white matter pallor is the most
common finding. Multinucleated giant cellssyncytia of infected
macrophagesare pathognomonic for HIV encephalitis; perivascular
mononuclear cuffing is a more common, though nonspecific, finding.
b. Recurrent or chronic meningeal irritation may be associated with cranial
neuropathies, particularly of the fifth, seventh, and eighth cranial nerves.
c. HIV-associated myelopathy (vacuolar myelopathy) clinically and
pathologically resembles the combined systems degeneration of vitamin B
12
deficiency. There is a usually painless spastic paraparesis and dorsal
column sensory loss (loss of proprioception and vibration sense),
sometimes associated with incontinence, that progresses over weeks to
months. Coexistent HIV-associated cognitive impairment may be seen, and
coexistent peripheral neuropathy can complicate the neurologic
examination. Vitamin B12 deficiency, neurosyphilis, human T-cell
lymphotropic virus type 1 myelopathy, and spinal cord tumor should
be ruled out.
d. Peripheral neuropathies (Table 8-5) are common, multifactorial in
etiology, and poorly understood. Some probably represent
immune-mediated injury; others (particularly progressive lumbosacral
polyradiculopathy) can represent secondary infection. Toxic neuropathies,
or exacerbations of preexisting HIV-associated neuropathies, are common
with a number of the antiretroviral agents and with chemotherapeutic
agents used to treat Kaposi sarcoma.
TABLE 8-5. Peripheral Neuropathies Associated With HIV Infection
e. Lumbosacral polyradiculopathy, while occasionally a self-limited
complication of HIV disease, often represents a treatable, potentially lethal
complication of opportunistic infection with CMV.
1. Description. Patients present with a subacute onset of leg weakness
with or without back and radicular pain. Bowel and bladder involvement
often follows early on. Deep tendon reflexes in the lower extremities are
depressed or absent, and there may be perianal anesthesia.
2. Diagnosis. Electromyography and nerve conduction studies can aid in
diagnosis. Unlike many other AIDS-associated diseases, CSF
examination can be relatively specific, i.e., a high WBC count (more
than 500 WBCs/L) with polymorphonuclear predominance is often, but
not always, seen. Protein is usually elevated, and glucose can be
normal or low. CSF should be sent for CMV culture and, if available,
PCR for CMV; however, therapy should be begun empirically prior
to culture results because improvement is usually seen only when
therapy is initiated early. CMV culture is positive only in about one half
to two thirds of cases.
3. The differential diagnosis includes lymphomatous meningitis, VZV,
and neurosyphilis; therefore, CSF evaluation should include a
high-volume (10 to 20 mL) sample for cytology and a CSF VDRL. In
addition, a mass in the cauda equina or conus medullaris must be
ruled out radiographically. A careful evaluation for CMV retinitis or
other organ involvement should be undertaken; however, CMV
polyradiculopathy can be seen in the absence of other CMV disease, as
well as presenting during therapy of CMV disease in other organs.
4. Treatment is with ganciclovir or foscarnet; in some patients, combined
chemotherapy may be warranted (see sec. X.C.3.b). Resistant
organisms have been reported.
3. The CSF in HIV infection
a. Seropositive patients, even in the absence of neurologic disease, often
have a mild to moderate CSF mononuclear pleocytosis, elevated protein,
and mildly decreased glucose concentration (but more than 35 mg/dL).
b. There is no association between the degree of pleocytosis and the ability to
culture HIV from the CSF or between positive CSF HIV culture and
neurologic complications.
c. Despite the common, nonspecific CSF abnormalities seen in HIV infection,
patients who have neurologic signs and symptoms, CD4 (helper T
cell) counts below 200, and the triad of CSF pleocytosis, elevated
protein, and low CSF glucose are likely to have a treatable
opportunistic infection.
d. Thus far there have been no uniformly convincing biologic markers in CSF
that can be recommended for diagnosing AIDS dementia or vacuolar
myelopathy; they remain clinical diagnoses of exclusion. High viral load in
CSF is sometimes, but not always, associated with more severe AIDS
dementia.
4. Anti-HIV chemotherapy. Federal guidelines on the use of antiretroviral
therapy have recently been released (see Selected Readings ); however, for
many experienced clinicians, the optimum time for initiation of therapy and the
conditions under which it should be initiated, particularly in asymptomatic
patients, remain controversial. Of the 15 available antiretroviral agents in use
for HIV-1 treatment, only 3 will be described.
a. Azidothymidine (zidovudine), the first antiretroviral drug to be approved
for HIV, specifically inhibits retroviral reverse transcriptase. AZT is now
used typically in combination with at least one other nucleoside analog and
a protease inhibitor. Indications, if any, for AZT monotherapy are undefined.
AZT alone is of clear benefit in the AIDS encephalopathy in children.
Clinical trials have demonstrated some benefit in cognitive function in
adults, but follow-up has been limited to 16 weeks.
1. The dosage is 200 mg 6 times/day PO or 1.5 mg/kg q48h IV. The
dosage may require adjustment if bone marrow depression occurs.
Lower doses may be equally effective for long-term use with less bone
marrow suppression.
2. Pharmacokinetics. The drug is metabolized in the liver, and the
glucuronidated metabolite is excreted by the kidneys. The serum
half-life is about 1 hour, and penetration into the CSF is excellent.
3. Toxicity. Bone marrow suppression is common. It is generally
dose-related and reversible. Myelotoxicity is potentiated by vitamin B
12

or folate deficiency or by concurrent therapy with other cytotoxic drugs.
Headache and mild behavioral abnormalities may also occur. Myopathy
is an uncommon complication and often improves on discontinuation or
lower dose therapy.
4. Drug interactions. Probenecid, cimetidine, lorazepam, and
indomethacin interfere with the clearance of AZT and may potentiate its
toxicity.
b. Didanosine (ddI) and zalcitabine (ddC) also inhibit retroviral reverse
transcriptase and have activity against HIV-1.
1. Indications. Each is now used in combination antiretroviral therapy,
typically with a protease inhibitor (PI) and another nucleoside analog.
Didanosine monotherapy was shown to be comparable to AZT in
improving neurologic function in children.
2. Dosage
a. Didanosine: patients over 75 kg, 300 mg bid; 50 to 75 kg, 200 mg
bid; 35 to 49 kg, 125 mg bid.
b. Zalcitabine: 0.75 mg tid.
3. Toxicity. Both drugs can cause pancreatitis (which may be fulminant
with ddI); painful peripheral neuropathy, especially with higher dosages
and after prolonged therapy, is fairly common with both drugs and
usually resolves 2 to 6 weeks after discontinuation. Among the newer
nucleoside analogs, 3TC and D4T also have been associated with
peripheral neuropathy in some patients, but the frequency and relative
risk is not well defined. The newer antiretroviral agents, including
nonnucleoside reverse transcriptase inhibitors and PIs, have increased
the complexity of antiretroviral therapy and, in many cases, its clinical
efficacy. Dramatic remissions of severe HIV-associated cognitive
impairment with protease inhibitors have been observed. Thus far, the
PIs do not appear to be associated with peripheral neuropathy or other
toxic nervous system side effects.
B. Opportunistic infections of the CNS. Patients with AIDS are at increased risk of
CNS infection with toxoplasmosis, cryptococcosis, tuberculosis, progressive
multifocal leukoencephalopathy, CMV, and herpes zoster; CNS aspergillosis,
candidiasis, and nocardiosis are sometimes seen. Whether HIV increases the risk
of neurosyphilis remains controversial. Patients with AIDS do not have a greatly
increased risk of acute bacterial meningitis or bacterial brain abscess.
1. The treatment for these infections in HIV-infected individuals is the same as for
other patients, except that prolonged courses of therapy might be required.
After the acute course of therapy for cryptococcal meningitis, tuberculous
meningitis, or CNS toxoplasmosis is complete, most clinicians continue therapy
with appropriate antibiotics at a reduced dosage (generally on a once or twice
per week schedule).
2. T. gondii was the most common opportunistic pathogen affecting the CNS in
AIDS until widespread use of drugs active against this parasite for PCP
prophylaxis. For example, the reported incidence of CNS toxoplasmosis in
AIDS patients at the Piti-Salptrire Hospital in France dropped from 19% to
6% between 1986 and 1993. Toxoplasmosis may present as a focal mass
lesion or, less commonly in AIDS patients, a meningoencephalitis. Seizures
are common. The CSF is not helpful in diagnosis, and LP may be
contraindicated (see sec. I.A.1.d). Definitive diagnosis requires biopsy of
accessible lesions. However, therapy is often administered empirically, based
on CT scan or MRI findings (see sec. XIV).
3. Cryptococcal meningitis typically presents as a subacute meningitis. Cell
count, protein, and glucose in the CSF can be normal in up to 20% of cases,
but CSF cryptococcal antigen is detected in 90% to 95%. India ink preparation
is an inadequate screen for cryptococcal meningitis. Patients who present
with significantly altered mental status have up to 25% mortality. A focal
invasive cryptococcal encephalitis, with unusually marked inflammation of
parenchyma, may complicate cryptococcal meningitis, even after apparently
successful treatment. It should be suspected in patients with a history of
cryptococcal meningitis who present with seizures, focal neurologic deficits,
and radiographic findings suggestive of cerebritis, i.e., focal enhancement of
cerebral sulci and adjacent cortex with underlying edema. Controlled clinical
trials have shown benefit of induction therapy with amphotericin (0.7
mg/kg/day) and flucytosine (100 mg/kg/day) followed by consolidation and
long-term maintenance therapy with fluconazole (400 mg/day). A newer azole,
itraconazole, has been used successfully as maintenance therapy. In patients
with elevated intracerebral pressure, the use of serial LPs or continuous
lumbar drainage of CSF may lessen morbidity and mortality.
4. CNS infection with C. albicans and C. immitis, as well as more common fungi,
occurs with increased frequency in AIDS.
5. It is common practice to treat all immunocompromised patients, including those
with AIDS, with a 10-day course of acyclovir for cutaneous varicella-zoster
eruptions (shingles).
6. There is no available effective therapy for progressive multifocal
leukoencephalopathy. Experimental therapies include interferon-a, cydofovir,
and topotecan. Based on clinical trial results demonstrating poor efficacy,
cytarabine (Ara-C), IV or intraventricular, cannot be recommended.
7. Herpesviruses. The treatments of infections with herpes simplex virus (see
sec. IX), CMV (see sec. IX), and varicella-zoster virus (see sec. XVI) have been
discussed. Although the optimum duration of therapy for these infections has
not been established in AIDS, it is customary to administer more prolonged
courses of antiviral therapy than are used in immunocompetent hosts. HSV
encephalitis can present with a more insidious course in AIDS patients than in
the immunocompetent, probably because of reduced inflammatory response.
CSF may be bland, and CT may be unrevealing. PCR for HSV in CSF as well
as MRI with coronal views through the temporal lobes may help establish the
diagnosis. The diagnosis should be considered in immunocompromised
patients with acute or subacute mental status changes and focal neurologic
deficits. VZV (zoster) is an important and underdiagnosed nervous system
disease with protean manifestations. VZV can cause a CNS vasculitis that may
wax and wane, and vessels may rarely be markedly abnormal without frank
infarction. Typically, however, ischemic or hemorrhagic strokes, both
superficial and deep, are seen and are highly suggestive of VZV, particularly if
white matter is disproportionately involved. VZV myelitis may also occur, and
can present acutely or insidiously. Arteritis affecting peripheral nerves can
cause mononeuritis multiplex, polyneuropathy, or polyradiculopathy. A current
or recent zosteriform rash is not required for the diagnosis, and is often
absent by history or on exam.
C. Focal brain lesions. Patients who are HIV-positive frequently present with the
subacute onset of diffuse or focal neurologic signs or with seizures. When CT
scan discloses one or more low-intensity, ring-enhancing lesions in the brain, the
differential diagnosis is broad and includes toxoplasmosis, lymphoma,
tuberculoma, fungal abscess, stroke, and bacterial abscess or metastatic cancer
given the appropriate clinical setting. Kaposi sarcoma and bacillary angiomatosis
rarely involve the brain. More than one pathologic process may be involved, and
radiographic presentations of these diseases (e.g., contrast patterns and edema)
can vary. Nonenhancing white matter lesions with no associated edema or mass
effect are suggestive of either PML or HIV encephalitis. However, pathologic
diagnoses cannot be made radiographically. Because it is not realistic to
perform brain biopsies of all such lesions, an empiric approach must be
developed.
1. An MRI is more sensitive than CT scanning in detecting brain lesions in AIDS.
2. One reasonable approach is based on the distinction between single and
multiple lesions.
a. Multiple contrast-enhancing lesions, or lesions with mixed enhancement
patterns, are treated empirically with anti-Toxoplasma therapy (see sec.
XIV). Patients who deteriorate during therapy or who fail to respond both
clinically and radiographically are considered for brain biopsy.
b. Accessible solitary lesions are biopsied unless highly suggestive of
toxoplasmosis (e.g., a cortical or deep-gray ring-enhancing lesion). Up to
25% of toxoplasmic abscesses present as single lesions on CT.
3. Some clinicians recommend treating all AIDS patients with focal brain lesions,
regardless of number or pattern of enhancement, with therapy for
toxoplasmosis, providing Toxoplasma serology is positive. Patients with
negative serology and those who fail to respond to therapy are biopsied.
4. The bone marrow suppressive effects of therapy for toxoplasmosis may require
a reduction in dose of AZT or other marrow-suppressive drugs.
D. Neoplasms. Patients with HIV infection are at increased risk for primary CNS
lymphoma, lymphomatous meningitis, and, rarely, involvement of the brain with
Kaposi sarcoma. The management of CNS lymphoma is discussed in Chap. 11.
XVII. Cysticercosis is the most common parasitic CNS disease. Infestation of the
CNS with larvae of the pork tapeworm Taenia solium is acquired by ingesting food
contaminated by tapeworm eggs.
A. Description. The infection may be asymptomatic or may cause one of several
neurologic syndromes: epilepsy, hydrocephalus, stroke, chronic basilar
meningitis, dementia, encephalitis, and acute chemical meningitis. Spinal
cord or retinal involvement is rare. Focal progressive neurologic deficits
associated with intraparenchymal cysts may occur. The parasite is endemic to
Mexico, Central and South America, eastern Europe, China, and Southeast Asia.
Patients with cerebral cysticercosis do not necessarily have signs of intestinal
infection with tapeworm; i.e., their stools may not contain ova or parasites, and
peripheral blood eosinophilia is uncommon.
B. The diagnosis is suggested by the epidemiology and by a CT scan showing
either punctate calcifications or fluid-filled parenchymal cysts. Contrast
enhancement occurs in active lesions, i.e., when larvae die and evoke
inflammation and edema. Intraventricular cysts, which can cause life-threatening
hydrocephalus, usually are not seen on CT; MRI is more sensitive in this setting.
The diagnosis may be strengthened by a positive immunoblot for anticysticercosis
antibodies in serum or CSF and confirmed by brain biopsy, if necessary. Patients
and family members should have stool examinations for evidence of
tapeworm and treatment where appropriate, since reinfection can occur.
C. Treatment
1. Praziquantel, 50 mg/kg/day PO in 3 divided doses for 14 days, will kill
surviving larvae in patients with active infestation. Praziquantel may cause
headache, dizziness, and GI upset. Hypersensitivity reactions are rare.
2. Albendazole, 15 mg/kg/day in 3 divided doses for 21 days, has compared
favorably in treatment of parenchymal and subarachnoid neurocysticercosis.
An 8-day course of albendazole is as effective as a longer course and has
been used successfully in ventricular, subarachnoid, and racemose
cysticercosis.
3. Patients with active neurocysticercosis who respond to chemotherapy develop
an acute inflammatory reaction to the dying organisms. This reaction may
produce headache, seizures, increased ICP, or focal neurologic deficits. Most
are self-limited and can be managed with analgesia and anticonvulsants as
necessary. More severe reactions will respond to corticosteroids (e.g.,
dexamethasone, 8 mg IV or PO q8h), but there is evidence that corticosteroids
decrease the plasma level of praziquantel and may increase albendazole
levels. Steroids are not used routinely but should be used in the setting of
increased ICP, intraventricular cysts, or high intraparenchymal cyst burden.
Steroids may also be of use in the acute, encephalitic form of
neurocysticercosis and in chemical meningitis.
4. There is no indication for chemotherapy of inactive neurocysticercosis, as
the larvae are dead. Edema or enhancement of the cyst on CT scan or MRI is
taken as evidence of active disease.
5. There are only limited indications for surgical excision of cysts: when the
diagnosis is in doubt, rapidly enlarging fourth ventricle cysts, or incipient
herniation. Even with obstructive hydrocephalus due to intraventricular cysts,
ventricular shunting without excision of the cysts is usually effective.
Selected Readings
Bacterial Meningitis
Carson D, Serpell M. Choosing the best needle for diagnostic lumbar puncture. Neurology 1996;47:33.
Durand ML, Calderwood SB, Weber DJ , Miller SI, Southwick FS, Caviness VS J r., Swartz MN. Acute
bacterial meningitis in adults. N Engl J Med 1993;328:21.
Fong IW, Tomkins KB. Review of Pseudomonas aeruginosa meningitis with special emphasis on
treatment with ceftazidime. Rev Infect Dis 1985;7:604.
Lentnek AL, Williams RR. Aztreonam in the treatment of gram-negative bacterial meningitis. Rev Infect
Dis 1991;13 [Suppl 7]:S586.
McIntyre PB, Berkey CS, King SM, Schaad UB, Kilpi T, Kanra GY, Perez CM. Dexamethasone as
adjunctive therapy in bacterial meningitis. A meta-analysis of randomized clinical trials since 1988. JAMA
1997;278(11):925.
Pfister HW, Feiden W, Einhaupl KM. Spectrum of complications during bacterial meningitis in adults:
results of a prospective clinical trial. Arch Neurol 1993;50:575.
Quagliarello VJ , Scheld WM. Treatment of bacterial meningitis. N EnGl J Med 1997;336(10):708.
Tunkel AR, Wispelwey B, Scheld WM. Bacterial meningitis: recent advances in pathophysiology and
treatment. Ann Intern Med 1990;112:610.
Tuberculous Meningitis
American Thoracic Society and the Centers for Disease Control. Treatment of tuberculosis and
tuberculosis infection in adults and children. Am Rev Respir Dis 1986;134:355; 1987;136:482.
Bonington A, Strang J I, Klapper PE, et al. Use of Roche Amplicor Mycobacterium tuberculosis PCR in
early diagnosis of tuberculous meningitis. J Clin Microbiol 1998;36(5):1251.
Girgis NI, Sultan Y, Farid Z, Monsour MM, Erian MW, Hanna LS, Mateczun A. Tuberculosis meningitis,
Abbassia Fever HospitalNaval Medical Research Unit No. 3, Cairo, Egypt, from 1976 to 1996. Am J
Trop Med Hyg 1998;58(1):28.
Brain Abscess
Mampalam TJ , Rosenblum ML. Trends in the management of bacterial brain abscesses: a review of 102
cases over 17 years. Neurosurgery 1988;23:451.
Mathisen GE, J ohnson J P. Brain abscess. Clin Infect Dis 1997;24(4):763.
Spinal Epidural Abscess
Khanna RK, Malik GM, Rock J P, Rosenblum ML. Spinal epidural abscess: evaluation of factors
influencing outcome. Neurosurgery 1996;39(5):958.
Neurosyphilis and Other Spirochetal Diseases
Al Deeb S, Yaqub BA, Sharif HS, Phadke J G. Neurobrucellosis: clinical characteristics, diagnosis, and
outcome. Neurology 1989;39:498.
Centurion-Lara A, Castro C, Shaffer J M, Van Voorhis WC, Marra CM, Lukehart SA. Detection of
Treponema pallidum by a sensitive reverse transcriptase PCR. J Clin Microbiol 1997;35(6):1348.
Dans PE, Cafferty L, Otter SE, J ohnson RJ . Inappropriate use of the cerebrospinal fluid Venereal Disease
Research Laboratory (VDRL) test to exclude neurosyphilis. Ann Intern Med 1986;104:86.
Dorfman DH, Glaser J H. Congenital syphilis presenting in infants after the newborn period. N Engl J Med
1990;323:1299.
Gourevitch MN, Selwyn PA, Davenny K, Buono D, Schoenbaum EE, Klein RS, Friedland GH. Effects of
HIV infection on the serologic manifestations and response to treatment of syphilis in intravenous drug
users. Ann Intern Med 1993;118:350.
Halperin J J . Nervous system Lyme disease. J Neurol Sci 1998;153(2):182.
Hook EW, Marra CM. Acquired syphilis in adults. N Engl J Med 1992;326:1060.
Steere AC. Lyme disease. N Engl J Med 1989;321:586.
Fungal Infections
Dismukes WE, Cloud G, Gallis HA, et al. Treatment of cryptococcal meningitis with combination
amphotericin B and flucytosine for four as compared with six weeks. N Engl J Med 1987;317:334.
Galgiani J N, Catanzaro A, Cloud GA, Higgs J , Friedman BA, Larsen RA, Graybill J K. Fluconazole therapy
for coccidioidal meningitis. Ann Intern Med 1993;119:28.
Schwartz MN. Chronic meningitis: many causes to consider. N Engl J Med 1987;317:957.
van der Horst CM, Saag MS, Cloud GA, et al. Treatment of cryptococcal meningitis associated with the
acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Disease Mycoses Study
Group and AIDS Clinical Trials Group. N Engl J Med 1997;337(1):15.
Viral Infections
Brown P. The risk of bovine spongiform encephalopathy (mad cow disease) to human health. JAMA
1997;278:1008.
Case Records of the Massachusetts General Hospital, Case 15-1998 (subacute sclerosing
panencephalitis). N Engl J Med 1998;338(20):1448.
Collaborative DHPG Treatment Study Group. Treatment of serious cytomegalovirus infections with
9-(1,3-dihydroxy-2-propoxymethyl) guanine in patients with AIDS and other immunodeficiencies. N Engl J
Med 1986;314:801.
Corey L, Spear PG. Infections with herpes simplex viruses. N Engl J Med 1986;314:686.
Whitley RJ . Viral encephalitis. N Engl J Med 1990;323:242.
Yalaz K, Anlar B, Oktem F, et al. Intraventricular interferon and oral isoprinosine in the therapy of
subacute sclerosing panencephalitis. Neurology 1992;42:488.
Acquired Immunodeficiency Syndrome (AIDS)
Antinori A, Ammassari A, DeLuca A, et al. Diagnosis of AIDS-related focal brain lesions: a
decision-making analysis based on clinical and neuroradiologic characteristics combined with polymerase
chain reaction assays in CSF. Neurology 1997; 48:687.
Report of the NIH panel to define principles of therapy of HIV infection. Ann Intern Med 1998;128
(12):1057.
Filippi CG, Sze G, Farber SJ , Shahmanesh M, Selwyn PA. Regression of HIV encephalopathy and basal
ganglia signal intensity abnormality at MR imaging in patients with AIDS after the initiation of protease
inhibitor therapy. Radiology 1998;206(2):491.
Gray F, Belec L, Lesis MC, et al. Varicella-zoster virus infection of the central nervous system in the
acquired immunodeficiency syndrome. Brain 1994;117(5):987.
Hollander H, McGuire D, Burack J H. Diagnostic lumbar puncture in HIV-infected patients: analysis of 138
cases. Am J Med 1994;96:223.
McGuire D. Neurological aspects of AIDS. Medicine 1996;24(9):131.
McGuire D, So YT. Neurologic dysfunction in HIV: intracranial disorders. In: Cohen PT, Sande M,
Volberding P, eds. AIDS knowledge base. Boston: Little, Brown and Company, 1998.
Schiff D, Rosenblum MK. Herpes simplex encephalitis (HSE) and the immunocompromised: a clinical and
autopsy study of HSE in the settings of cancer and human immunodeficiency virus-type 1 infection. Hum
Pathol 1998;29(3):215.
Cysticercosis
Del Brutto OH, Sotelo J . Neurocysticercosis: an update. Rev Infect Dis 1988;10:1075.
Garg RK. Drug treatment of neurocysticercosis. Natl Med J India 1997;10(4):173.
Takayanagui OM, J ardim E. Therapy for neurocysticercosis: comparison between albendazole and
praziquantel. Arch Neurol 1992;49:290.
CHAPTER 9. NEUROPSYCHIATRIC DISORDERS
Manual of Neurologic Therapeutics
CHAPTER 9. NEUROPSYCHIATRIC DISORDERS
George B. Murray
Depression
Hysteria
Pain
Neuropsychiatric features of medical and neurologic illness
I. Depression. The most common serious psychiatric disorder found in general
medical practice is depression. It is primarily a disorder of affect, but it can influence the
cognitive sphere as well. The causes of depression are unknown, although there are
theories ranging on a spectrum from purely psychosocial stress events to a purely
biochemical transmitter dysfunction. In a lifetime, 20% of females and 11% of males can
expect a clinical depression.
A. Classification. Many attempts have been made to classify depression, but not
everyone agrees to such classifications. The two most prevalent classifications are
reactive versus endogenous depression and primary versus secondary
depression.
1. Reactive depression is thought to result primarily from psychosocial stress,
as, for example, a grief reaction, whereas endogenous depression is thought to
be more a result of specific biologic dysfunction.
2. Primary depression is that usually seen by a psychiatrist or general
practitioner in which there is no other medical or surgical illness involved. The
primary depression may take on the somatic cloak of fatigue, gastrointestinal
symptoms, or other more generalized medical illness. Secondary depression
follows some other medical or surgical illness, but this does not necessarily
imply that the medical or surgical illness caused the depression.
B. Diagnosis
1. Major depression. Since 1980 with the publication of the Diagnostic and
Statistical Manual, 3rd edition (DSM-III), there has been more or less solid
agreement on the criteria for making the diagnosis of major depression. Those
criteria are outlined in Table 9-1.
TABLE 9-1. Major Depression Criteria
a. A handy mnemonic for these criteria is: SIG E CAPS. This is to signify a
prescription for depression of energy capsules. The initials stand for a
disorder of one of the criterion symptoms.
Ssleep disorder
Ilack of interest
Gguilty feelings
Eloss of energy
Clack of concentration or thinking disorder
Aloss of appetite or weight loss
Ppsychomotor retardation or agitation
Ssuicidal reflection or thoughts of death
Thus, if the physician finds that the patient has been in a depressed mood,
has a loss of interest, or has been anhedonic for at least 2 weeks, and has
a minimum of 5 of these symptoms, then a major depression is probably
the diagnosis. Notice that the diagnosis is a clinical decision and not made
by various paper-and-pencil tests.
b. Laboratory studies are sometimes helpful but are not used often in
general clinical practice.
1. The dexamethasone suppression test (DST) was touted as a method
for diagnosing endogenous depression. It has been largely abandoned
by clinicians interested in depression. It is now used most often in
academic studies on depression. The result of the DST is considered
abnormal if cortisol levels are higher than 5 g/dL in blood samples
drawn 8, 12, and 16 hours after a single midnight dose of 1 mg of
dexamethasone.
2. The thyroid-releasing hormone (TRH) test has also been used in
testing patients thought to be clinically depressed. About one half of
depressed patients fail to show a rise above 7 U/mL of
thyroid-stimulating hormone after administration of TRH.
3. Blood levels of antidepressants are not drawn regularly as, for
example, are blood levels in the use of anticonvulsants. However, there
are levels that correspond approximately to therapeutic doses. They are
generally used when one does not see a therapeutic benefit with a
specific antidepressant.
c. Approximately 90% of patients with major depressive disorders show some
form of sleep alteration. Endogenous and nonendogenous forms of major
depressive disorder show characteristic sleep electroencephalogram (EEG)
patterns. Patients with endogenous depression can be distinguished from
those with nonendogenous depression on the basis of short rapid eye
movement (REM) sleep latencies, i.e., sleep-to-REM latencies of less than
62 minutes.
2. So-called masked depression is often difficult to diagnose. Some patients
present with several somatic manifestations, but usually one is the cardinal
complaint, such as fatigue, weakness, anorexia, insomnia, headache,
dizziness, constipation, abdominal pain, or chronic pain. Usually these patients
must be evaluated for their specific somatic complaint before depression can
be absolutely diagnosed. However, the ultimate proof of masked depression
consists of extinction of the somatic complaint with antidepressant treatment.
Often, clinically ill patients will have a major depression that increases the pain
or complaint of the somatic illness. On treating the depression in this setting,
one often notes improvement in the patient's suffering due to the somatic
illness.
3. Minor depression is listed in the Diagnostic and Statistical Manual, 4th edition
(DSM-IV), but only as a depressive disorder not otherwise specified. It still
remains strongly rooted in the research diagnostic criteria of Feigner. The
criteria for diagnosis are similar to those of major depression except for the
requirement of depressed mood or anhedonia for the same 2-week period and
only 2 of the symptoms represented in SIG E CAPS (see sec. I.B.1.a).
4. Dysthymia (formerly known as depressive neurosis) consists of a chronic
disturbance of mood involving depressed mood for most of the day, more days
than not, for at least 2 years. In addition, during these periods of depressed
mood there must be at least two of the following associated symptoms:
a. Poor appetite or overeating
b. Insomnia or hypersomnia
c. Low energy or fatigue
d. Low self-esteem
e. Poor concentration or difficulty making decisions
f. Feelings of hopelessness
People with dysthymia may have a superimposed major depression (double
depression). In a lifetime 8% of females and 5% of males can expect an
episode of clinical dysthymia. It is also quite common that people with
dysthymia have a personality disorder, the most common of which are
borderline, histrionic, narcissistic, avoidant, and dependent personality
disorders. Dysthymia in these people with personality disorders is
sometimes called characterologic depression. The ICD-10 Classification of
Mental and Behavioral Disorders describes it as including depressive
neurosis, depressive personality disorder, neurotic depression, and
persistent anxiety depression.
5. Bipolar disorder (manic-depressive illness). The essential features of
bipolar disorder is one or more manic episodes. A manic episode is a distinct
period during which the predominant mood is either elevated, expansive, or
irritable with various associated symptoms, such as flight of ideas, pressure of
speech, and grandiosity. For such a disorder to be called bipolar, there must
be at least one episode of major depression. There are many subcategories of
bipolar disorder, and the phenomenon of rapid cycling is not rare. Because of
the complexity, a psychiatrist should be involved in the management of such
patients. Mania can also be seen independently of depression and therefore is
not part of bipolar disorder. Secondary mania is not infrequently seen following
certain medications, head injury, or complex partial seizure.
6. Pseudodementia of depression is the syndrome in which dementia is
mimicked or caricatured by a major depression. Pseudodementia is not a
diagnosis; it is a descriptive term. A physician who sees a fair number of
Alzheimer patients will undoubtedly encounter some with an apparent
dementia who, in fact, will have the pseudodementia of depression. It is also
possible that people with Alzheimer disease may have a minor or major
depression comorbidly. The only absolute way one can determine whether
some patients have dementia or pseudodementia is to treat the patient with
suspected pseudodementia for depression, and as the depression clears, the
patient's cognitive findings return to baseline. See Chap. 3 for more clues for
distinguishing dementia from the pseudodementia of depression.
C. Treatment. There are three major treatment modalities for major depression:
psychotherapy, medication, and electroconvulsive therapy (ECT). Treatment of
major depression is generally satisfactory, but refractory depressions are not
uncommon in many patients. Research is now showing that dysthymia seems to
respond to psychopharmacologic intervention.
1. Psychotherapy. More emphasis was placed on psychotherapeutic treatment
of depression in earlier years. Still few studies show the efficacy of
psychotherapy in the resolution of major depression. The most common types
of therapy used are insight-oriented, cognitive, and various subtypes of the
two. Cognitive therapy seems to be very helpful in minor depression.
2. Medication. Many medically oriented psychiatrists feel that medication is the
sine qua non of treatment, along with brief supportive psychotherapy. Most
presently available drugs are polycyclic antidepressants. Table 9-2 gives a
summary of antidepressants available and dosages.
TABLE 9-2. Antidepressant Drugs
3. Dosage of polycyclic antidepressants. To minimize side effects with these
medications, it is generally better to begin treatment at low dosages, usually 25
to 50 mg at bedtime, with protriptyline being an exception (see Table 9-2).
About 2 days later the dosage can be increased to about 100 mg, and then
about 3 days later to about 150 mg. If the patient shows side effects (e.g.,
orthostatic hypotension), one should maintain the dosage at the same level for
several more days before increasing. If the side effects are too bothersome,
change to another polycyclic. A single bedtime dose is usually helpful in
compliance; however, some antidepressants, such as fluoxetine or
protriptyline, may be too energizing to give all in the evening. In elderly
patients, even lower starting doses (e.g., 25 mg/day) and slower rates of
dosage acceleration may be required (see Table 9-2).
4. Side effects. The most common side effects seen with these medications are
a variety of anticholinergic effects (e.g., dry mouth, urinary retention,
aggravation of glaucoma, constipation). Sedation may be a problem or a
desired therapeutic effect depending on the patient's needs. Different
medications are high or low in sedative potency. Antidepressant medications
do have the potential, save fluoxetine, for producing cardiac arrhythmias. They
can lengthen the QT interval, thereby increasing the vulnerable period for
serious ventricular arrhythmia. As a matter of course, these medications are
very rarely prescribed prior to 4 weeks after myocardial infarction. Any question
with regard to their use in patients with cardiovascular disease should be
discussed with a cardiologist.
5. Monoamine oxidase inhibitors (MAOIs) are being used more than previously.
In some patients, they are used as a first-line medication, especially if
someone in the patient's family has had success with an MAOI. A diet to
eliminate tyramine must be followed while on these medications.
6. Lithium. Although lithium's primary use is in bipolar disorder, it is also used in
unipolar depression as an adjunct in stabilizing the person's mood. It is now
also being used in low dose added to antidepressant for refractory depression.
Other compounds are frequently used for mood stabilization also, mainly
carbamazepine (Tegretol), divalproex sodium (Depakote), which is
FDA-approved for this indication, and, less so, lamotrigine (Lamictal) and
gabapentin (Neurontin).
7. Alprazolam (Xanax) is included here because of the putative antidepressive
qualities of this benzodiazepine. It has been used especially in patients soon
after myocardial infarction.
8. Suicide is always a possibility in severe depression. If suicide is strongly
suspected, it is prudent to get psychiatric consultation. Overdosage of
polycyclic antidepressants is a common cause of suicide attempts.
9. Mania. The usual treatment for mania is to start a neuroleptic along with
lithium. Secondary mania, if secondary to partial seizure, often cools down to
normalcy on carbamazepine. Valproate and clonazepam have also been
effective in secondary mania.
II. Hysteria
A. Description. There are many meanings of the word hysteria.
1. There are at least six major ways that the word is used:
a. Hysterical conversion reaction.
b. Hysterical personality.
c. Hysteria as a form of repetitive somatizing behavior (Briquet syndrome).
d. As a contagious group process.
e. To connote a process in psychoanalytic theory.
f. As a layperson's term for exaggerated behavior or exaggerated symptoms.
2. In neurology, the term is usually used to describe conversion reactions and/or
dissociative reactions. All physicians after adequate workup have encountered
various conversions or dissociations such as paralyses, anesthesias,
movement and gait disorders, urinary retention, pain syndromes, seizures,
visual loss, amnesia, fugue states, and unresponsive states.
B. Histrionic personality disorder used to be known in psychiatry as hysterical
personality disorder, but because of the rather pejorative quality of the historical
concept of the wandering uterus, the term was changed from hysterical to
histrionic in 1980. A personality style is made up of traits that are enduring
patterns of perceiving, relating to, and thinking about the environment and oneself.
When these traits are inflexible and maladaptive and cause either significant
impairment in social or occupational functioning or subjective distress, they
constitute a personality disorder.
1. Diagnosis. According to DSM-IV, the histrionic personality disorder is seen as
a pattern of excessive emotionality and attention seeking beginning by early
adulthood. For the diagnosis to apply, patients must have at least five of the
following eight characteristics:
a. Are uncomfortable in situations in which they are not the center of attention.
b. Conduct interactions with others characterized by inappropriate sexually
seductive or provocative behavior.
c. Display rapidly shifting and shallow expression of emotions.
d. Use physical appearance to draw attention to themselves on a consistent
basis.
e. Have a style of speech that is excessively impressionistic and lacking in
detail.
f. Manifest self-dramatization, theatricality, and exaggerated expression of
emotion.
g. Display suggestibility, i.e., can be easily influenced by others or
circumstances.
h. Consider relationships to be more intimate than they actually are.
2. Management features. People with the histrionic personality disorder are
commonly seen in medical practice. Histrionic patients are seen by generalists,
internists, neurologists, and all other medical and surgical specialists. It should
be borne in mind that most people with conversion disorder do not have a
histrionic personality disorder.
C. Somatization disorder, also known as Briquet syndrome, describes a syndrome
of recurrent and multiple somatic complaints of several years' duration for which
medical attention has been sought but that are apparently not due to any physical
disorder. This diagnosis is primarily made in women. The onset occurs before age
35. It is never monosymptomatic and often includes a history of excessive surgical
operations. It is the best studied syndrome in the whole field of hysteria. It is
estimated to occur in 1% to 2% of the female population. If this diagnosis is
suspected, psychiatric referral is strongly suggested.
D. Conversion reaction
1. Description
a. The term conversion reaction was coined by Freud in 1893 to describe a
condition with qualities of excitation attached to certain unbearable ideas,
which are transmuted into some bodily form of expression. Limb
anesthesias, pseudoseizures, and tunnel vision are all fairly common
examples of this. Conversion phenomena differ from malingering, since in
conversion the patient does not have conscious control over the
symptom. Most adult patients with conversion reactions are women, and
the average age is about 40 years.
b. LaBelle indifference is sometimes present. This is not to be confused
with stoicism.
c. Many entities thought to be conversion reactions have turned out later to be
organic conditions. In a review of 6 studies, the rate varied from 13% to
30%.
2. Diagnosis. There are 4 important factors in diagnosing conversion disorder.
a. Physical functioning is lost or altered, suggesting a physical disorder.
b. Psychological factors are judged to be etiologically related to the symptom
because of a temporal relationship between the symptom and a
psychosocial stressor that is apparently related to a psychological conflict.
c. The person is not conscious of intentionally producing the symptom.
d. The symptom is not a culturally sanctioned response pattern and cannot,
after appropriate investigation, be explained by a known physical disorder.
3. Pseudoseizure, once called hysterical seizure, is referred to by some as
psychogenic seizure. The relationship between hysteria and epilepsy is
notoriously confusing. A true pseudoseizure, as distinguished from
malingering, is an apparent seizure with a subjective change in consciousness
without ictal discharge. Three cautions are necessary:
a. If it is a true conversion symptom, then the symptomatology must not be
under the patient's control and a secondary gain must be discoverable.
b. The surface EEG is not very helpful in detecting ictal discharge in deeper
limbic structures; therefore, a surface EEG with no spiking evident does
not, in fact, categorically rule out true seizure.
c. Pseudoseizures are most common in patients with true epilepsy. The most
difficult to distinguish cases are those patients who have pseudoseizures
and complex partial seizures. Implanted electrodes in limbic structures have
shown that what were once called pseudoseizures often are true seizures.
The importance of making the distinction is obvious in the treatment. Holter
monitor EEG has proved a useful, albeit not infallible, tool for understanding
pseudoseizures.
4. Treatment. There is no standard treatment for conversion disorder.
a. In some few patients, direct confrontation may be helpful, but this is
discouraged unless the physician is quite sure of a very healthy, positive
doctor-patient relationship. The use of hypnosis has been used sometimes
with great efficacy but, again, a positive outcome is not assumed.
b. A sodium Amytal interview has often been helpful and in some cases
clearly makes the diagnosis.
c. Probably the most used and most helpful treatment is to suggest to patients
that they will gradually recover and that there is nothing seriously wrong,
and to allow patients to save face by not confronting them with a
psychoanalytic explanation for the conversion reaction.
E. Dissociative disorders. The essential feature of dissociation is a sudden,
temporary alteration in the integrative functions of consciousness, identity, or
motor behavior. Often the layperson will speak of a dissociation of consciousness
as being spaced. Important personal events cannot be recalled. A sudden
temporary alteration in identity or integrative functions may result in the forgetting
of one's usual identity and a totally or partially new identity will be assumed. This
brings with it a feeling of unreality.
An alteration in motor behavior is exemplified by a psychogenic fugue. One can be
so overwhelmed by unconscious material that consciousness may be impaired in
a psychogenic stupor or psychogenic unresponsiveness. All of these are
characterized by attempts to escape from excessive tension and anxiety by
separating off some parts of personality function from the rest.
1. Psychogenic amnesia. Usually this disorder is observed in adolescents and
young adults and rarely in the elderly. It is often found in young people in the
military.
a. Amnesia begins suddenly and usually follows a severe psychosocial stress.
It can be seen in posttraumatic stress disorder.
b. Psychogenic amnesia is almost always anterograde.
c. Malingering is one of the diagnoses that should be excluded, although it
can be difficult to do so.
d. Hypnosis, a sodium Amytal interview, or both may be helpful.
2. Psychogenic fugue. The essential feature here is a sudden, unexpected
travel away from home or customary work locale often with an assumption of a
new identity and an inability to recall one's previous identity. Elements of
disorientation and perplexity may exist, and in recovery there is often no
recollection of the events.
a. There have been some dramatic psychogenic fugues reported in the media.
In most cases, however, the fugue is less elaborate and consists of little
more than brief, apparently purposeful travel. Any new identity is usually
partial.
b. Little is known of elements such as age of onset, complications,
prevalence, sex ratio, or family pattern in this entity.
c. J ust as in psychogenic amnesia, a differential diagnosis must include
multiple personality, cursive epilepsy of complex partial seizure, and
malingering.
d. There is no standard treatment for this entity. Clear diagnosis and
reassurance usually give the best results.
3. Depersonalization disorder is sometimes referred to as self-estrangement.
The major diagnostic point is the occurrence of one or more episodes of feeling
outside of one's personality, an experience that causes social or occupational
impairment.
a. It is estimated that 30% to 70% of young adults may have
depersonalization without significant impairment.
b. Many people have mild depersonalization. This is not infrequent with the
use of marijuana or during acute stresses (e.g., earthquake).
c. Often the experience of one's self-identity is altered by some perception or
experience (e.g., finding out that one is homosexual at a party), and the
reality of one's identity is lost or skewed.
d. These patients are not psychotic because they have intact reality testing,
but the feelings of unreality are ego-dystonic.
e. Derealization is frequently present, where one feels that the perception of
his or her surroundings are not as real as they usually appear.
f. Onset after the age of 40 is rare.
g. The course is generally chronic and marked by remissions and
exacerbations.
III. Pain. All physicians come in contact with acute and chronic pain in their practice.
Pain control has become a much more sophisticated area in medical practice in the last
20 years.
A. In general, pain is categorized and managed into two areas: acute and chronic
pain.
1. It is always of primary importance to try to find the cause of any pain, so that it
can be addressed before other treatments are started.
2. Specific treatment of specific types of pain is preferable if it can be
determined (e.g., carbamazepine for trigeminal neuralgia).
3. For generalized pain, it is a rule of thumb that treatment starts with mild
nonnarcotics and then moves up the scale to more potent narcotics depending
on the pain and the patient's comfort. Table 9-3 lists the major analgesics used
in common practice along with their duration of action and the efficacy of their
mode of delivery.
TABLE 9-3. Oral and Parenteral Narcotic Analgesics for Severe Pain
4. Placebos are sometimes used as a diagnostic tool, but this use is actually not
very helpful, since over 33% of people will have a positive placebo response.
The response in an individual can vary in the same person at different times.
The postulated mechanism of action of the placebo effect is that the placebo
activates a descending pain modulation system, which in part involves release
of endogenous opiates. Placebo effects also appear to be influenced by the
doctor-patient relationship, the significance of the placebo treatment to the
patient, and setting of the treatment.
5. There are many ancillary techniques used in the management of pain,
especially in trying to alleviate chronic pain. In these ancillary techniques, the
disciplines of anesthesia, neurosurgery, and psychiatry play a major role. Such
techniques as the use of epidural morphine, nerve blocks, behavioral
conditioning, neurosurgical lytic lesions, and cingulotomy are usually available
at larger medical centers. Gabapentin has been helpful in central thalamic
pain, e.g., Djrine-Roussy syndrome.
B. Acute pain. Most physicians can effectively treat acute pain in their practice.
1. The tolerance of pain differs in individuals according to the attention drawn to
it, the person's personality, and the possible psychiatric state of the patient.
2. In the treatment of acute pain, especially in the hospitalized patient, there is
little propensity for the patient to become addicted to a narcotic, whereas
narcotic addiction is not uncommon in chronic pain.
C. Chronic pain is usually defined as pain that persists for about 6 months or more.
It may be due to nonmalignant or malignant conditions and is usually distinguished
from the continuous pain of the terminally ill.
1. In chronic pain, it appears that the limbic system has a larger role than in
acute pain. Suffering, as distinct from nociception and pain, enters the chronic
picture. It is thought that the paleospinothalamic tract, having multiple
connections in the limbic system, plays an important role in chronic pain and
that the fast-tracking neospinothalamic tract has a lesser role.
2. In any assessment of pain, whether acute or chronic, there are 3 factors that
should always be considered:
a. The astute use of anatomic dermatome reference points.
b. Identification of pain of the deafferentation type.
c. The assessment of the suffering and pain behavior components in the
patient.
3. Deafferentation pain is chronic pain that follows direct injury to the peripheral
or central nervous system.
a. Forms
1. Reflex sympathetic dystrophy.
2. Phantom limb.
3. Causalgia.
4. Postherpetic neuralgia.
5. Thalamic pain.
b. Descriptions
1. Causalgia is a burning or searing sensation.
2. Dysesthesia feels like pins and needles, numbness, or tingling.
3. Formication feels like insects crawling on the skin.
4. Hyperpathia is the painful response to a light touch of a shirt or a
breeze. This pain responds poorly to known therapies and in general
narcotics are not the answer. Usually a referral to a pain center is
needed.
4. Psychiatric factors in chronic pain. One of the major difficulties in the
treatment and management of chronic pain is that there is usually much more
to the patient's presentation than just pain alone, even though that is the only
thing the patient will talk about. Psychiatric factors can influence the volume
or gain on the pain of any lesion. This can be seen on any Sunday when
professional football players are injured after a particularly savage hit and then
they return two or three plays later. If they had been hit that way standing on a
street corner, their subsequent behavior might include a day or two in bed. This
psychological decrease in volume on pain is well known in combat veterans
also. The following factors usually increase the volume of pain:
a. Depression. Since in chronic pain the suffering component is more evident
than in acute pain, where the nociceptive component is more stark, we
presume that the limbic system has a regulatory influence on the intensity
of felt pain. If the patient has a major depression, any gloominess,
dysphoria, or irritability from that depression will amplify any painful
sensation that is felt. Some pain specialists feel that almost all chronic pain
is the result of severe depression.
Diagnosing depression in the chronic pain patient is the first step. Polycyclic
antidepressants have an analgesic quality that is relatively mild over and
above their antidepressant quality.
b. Anxiety. Many people with chronic pain may be anxious or even fearful,
which influences the chronic pain they suffer. Although benzodiazepines
are helpful in the anxious patient, for chronic pain patients small doses of
nonsedating, high-potency neuroleptics tend to decrease anxiety and fear
greatly and often are instrumental in reducing narcotic analgesics. When
the clinician sees fearfulness, the use of haloperidol, 0.5 mg bid, may be
quite helpful in chronic pain control.
c. Psychogenic pain. When no physical findings adequately account for the
pain and there appear to be psychological factors that could be causal, the
patient is said to suffer from psychogenic pain. There should be a temporal
relationship between the onset of pain and a secondary gain. As an
example, a naval aviator who previously had a terrifying carrier landing may
find that he has an excruciating headache in the briefing room prior to his
next scheduled flight. Another psychological factor could be that the
patients get support from those around them that they would not get without
the pain.
d. Personality disorder. Chronic pain can be the arena where manipulation
occurs through the distorted personality. The antisocial personality disorder,
the dependent personality disorder, and the borderline personality disorder
are probably the most bothersome of personality disorders with regard to
pain behavior. The focus of the doctor-patient interaction will always be the
pain or narcotic analgesics and not the distortion of personality that the
patient has. It may be important to get psychiatric confirmation of
personality disorder in these cases.
IV. Neuropsychiatric features of medical and neurologic illness
A. Psychosis is occasionally found in patients who have dementing illness, basal
ganglia disease, or stroke. The two major expressions of psychosis are delusion
and hallucination.
1. A delusion is a firm, fixed belief without any objective evidence for that belief.
A patient may have a near-delusion, i.e., an overvalued idea. This does not
strictly mean that the patient has psychosis, but there is some reason why he
or she is investing this idea with much greater affect.
2. Hallucinations can be visual, auditory, olfactory, or somatosensory. Olfactory
and dermatologic sensory hallucinations are not unusual; the most common
are auditory and visual. Auditory hallucinations are more often seen with
delusions, whereas visual hallucinations are often seen alone and often
secondary to organic lesions.
3. Treatment. After a metabolic disorder, seizure disorder, fever, or any other
entity that might produce delusion or hallucination has been ruled out,
treatment can be initiated. The usual treatment is with neuroleptics. We tend to
prefer high-potency, low-dosage haloperidol. Small doses, 0.5 to 2.0 mg, are to
be tried first, since most of these patients will have impaired brain to begin
with. Visual hallucinations are usually well taken care of, auditory hallucinations
not quite as well as visual, and delusions may not be able to be eradicated
totally but usually show much less intensity on neuroleptics.
B. Obstreperous behavior can be seen either with or without psychosis.
1. Cause. One must search for a possible known cause of obstreperous
behavior, such as a medical side effect, a partial seizure, or the patient's acting
on a delusional system. Usually there is no known cause of this behavior.
2. Treatment. The most common treatment of obstreperous behavior is, again,
with neuroleptics, using the lowest dosage possible. There has been some
success with innovative treatments, i.e., carbamazepine, divalproex sodium,
and trazodone at low dosages.
C. Stroke. About 400,000 people per year suffer thromboembolic stroke.
Neuropsychiatric features are common in stroke.
1. Depression is common with stroke. One study found that 27% of stroke
patients had major depression and 20% had minor depression within 2 weeks
of the stroke. Six months later that 47% rose to 60% depressed, all untreated.
Those stroke patients who are treated for their depression do much better in
rehabilitation. It has been shown that 60% of stroke patients with depression
have their stroke in the left anterior hemisphere. Treatment by antidepressants
of poststroke depression has been successful with both nortriptyline and
trazodone. Recently, some success has been seen in poststroke depression
with the faster acting psychostimulants.
2. Subcortical dementia is a mildly controversial entity that can be seen in
stroke patients. Not infrequently these patients are thought to have major
depression when in fact they have only apathy. This apathy has been
successfully treated with psychostimulants, such as methylphenidate or
dextroamphetamine in low dosage.
3. Post stroke a patient may develop nonconvulsive partial seizures wherein the
only symptomatology may be delusions, hallucinations, or both.
D. Basal ganglia disease is looked on today in a more holistic manner, i.e., concern
is not merely with the motor problems but with neuropsychiatric features of the
disease.
1. Parkinson disease patients may have delusions, hallucinations, or
depression. It is important to judge clinically whether these may be secondary
to the medication that the patient is using. Depression has been seen in as
many as 41% of parkinsonian patients, and most of these patients have a
history of cognitive impairment while they are in major depression. More than
50% of patients will reveal depressive symptomatology during the evolution of
the disease. Nortriptyline is effective in treating this depression;
electroconvulsive therapy is also quite effective in Parkinson disease and has
improved the quality of motor movement as well.
2. Huntington disease also shows an inordinate amount of depression, with a
suicide rate much higher than that in other basal ganglia diseases.
E. Multiple sclerosis causes fatigue with its patchy demyelination. Depression in
multiple sclerosis patients has been estimated to be between 14% and 27%.
Patients benefit from tricyclic antidepressant use. Amantadine has been helpful in
reducing fatigue. Lability of mood has been estimated to be about 18% in multiple
sclerosis patients and generally responds to low-dose neuroleptics.
F. Alzheimer disease can be accompanied by depression, delusions, hallucinations,
and obstreperousness. In a study of 120 outpatients with probable Alzheimer
disease, 13% had major depression, 30% had minor depression, 7% had
hallucinations, and 4% had delusions. One third of the patients had no other
neuropsychiatric diagnosis besides Alzheimer disease.
Selected Readings
Bouckoms AJ , Masand P, Murray GB, Stern TA, and Tesar GE. Chronic nonmalignant pain treated with
long-term oral narcotic analgesics. Ann Clin Psychiatry 1992;4:185.
Cummings J L. Subcortical dementia: neuropsychology, neuropsychiatry and pathophysiology. Br J
Psychiatry 1986;149:682.
Cummings J L. Organic psychosis. Psychosomatics 1988;29:16.
Devinsky O, Putnan F, Grafman J , Bromfield E, and Theodore WA. Dissociative states and epilepsy.
Neurology (NY) 1989;39:835.
Diagnostic and statistical manual of mental disorders, 4th ed. (DSM-IV). Washington, DC: American
Psychiatric Association, 1993.
Foley KM. The treatment of cancer pain. N Engl J Med 1985;313:84.
Ford C. The somatizing disorders: illness as a way of life. New York: Elsevier, 1983.
Freeman MP, Stoll AL. Mood stabilizer combinations: a review of safety and efficacy. Am J Psychiatry
1998;155:12.
Gates J R, Ramani V, Whalen S, and Loewenson R. Ictal characteristics of pseudoseizures. Arch Neurol
1985;42:1188.
Gold PW, Goodwin FK, Chrousos GP. Clinical and biochemical manifestations of depression. N Engl J
Med 1988;319:348.
Hyman SE, Cassem NH. Pain. In: Rubenstein E, Federman DD, eds. Scientific American medicine:
current topics in medicine. New York: Scientific American, 1989:1.
Kotila M, Waltimo O. Epilepsy after stroke. Epilepsia 1992:33:495.
Larson EW, Richelson E. Organic causes of mania. Mayo Clin Proc 1988;63:906.
Lesser RP. Psychogenic seizures. Psychosomatics 1986;27:823.
Masand P, Murray GB, Pickett P. Psychostimulants in post-stroke depression. J Neuropsychiatry
1991;3:23.
Richelson E. Synaptic pharmacology of antidepressants: an update. McLean Hosp J 1988;13:67.
Schiffer RB, Kurland R, Rubin A, and Boer BA. Evidence for atypical depression in Parkinson's disease.
Am J Psychiatry 1988;145:1020.
Signer S, Cummings J L, Benson DF. Delusions and mood disorders in patients with chronic aphasia. J
Neuropsychiatry 1989;1:40.
Starkstein SE, Robinson RG. Affective disorders and cerebral vascular disease. Br J Psychiatry
1989;154:170.
Starkstein SE, Mayberg HS, Berthier ML, et al. Mania after brain injury: neurological and metabolic
findings. Ann Neurol 1990;27:652.
Thase ME, Greenhouse J B, Frank E, et al. Treatment of major depression with psychotherapy or
psychotherapy-pharmacotherapy combinations. Arch Gen Psychiatry 1997;54(11):1009.
World Health Organization. The ICD-10 classification of mental and behavioural disorders. Geneva, 1992.
CHAPTER 10. STROKE
Manual of Neurologic Therapeutics
CHAPTER 10. STROKE
Richard C. Hinton
Ischemic strokes
Hemorrhagic strokes
Cerebrovascular disease usually may be distinguished from other neurologic disorders
by the sudden or very rapid development of symptoms that are almost always focal. At
times, however, other conditions such as seizure equivalents, hemorrhage into a tumor,
or, rarely, demyelinating disease may be mistaken for cerebrovascular disease. A
completed stroke is suspected when there is persistence of the neurologic deficit for
longer than 24 hours. When the deficit completely disappears after a period of 24 hours
or longer, the term reversible ischemic neurologic deficit (RIND) has been applied. A
transient ischemic attack (TIA) refers to a transient neurologic deficit lasting less than 24
hours with complete return to normal. If appropriate therapy is to be administered, the
precise nature of the underlying cerebrovascular disease must first be understood
and clarified with the clinical examination and diagnostic studies.
Stroke can be conveniently divided into two categories: ischemic strokes, including
embolic and thrombotic strokes, and hemorrhagic strokes, such as primary
intracerebral hemorrhage and subarachnoid hemorrhage (usually the result of leakage
from a cerebral aneurysm or vascular malformation). Successful prevention of stroke
may be possible with the identification of important risk factors, such as hypertension,
atrial fibrillation, smoking, and perhaps myxomatous degeneration of the mitral valve.
Hyperlipidemia may also be a risk factor for cerebrovascular disease, although probably
not as strong as in coronary artery disease. Antiphospholipid antibodies such as the
lupus anticoagulant and anticardiolipin antibodies may also be risk factors for
cerebrovascular disease, and deficiencies of clotting inhibitory factors such as
antithrombin III, protein S, and protein C have also at times been implicated.
In this chapter, guidelines for treatment of the various types of stroke are presented.
However, it should be stated that controversies exist among clinicians, particularly in the
use of anticoagulants and antiplatelet agents for cerebral ischemia. Therefore, these
guidelines must be applied with caution and tailored to the individual patient. Although a
general orientation to the clinical picture for each variety of stroke is provided, a detailed
description is beyond the scope of this manual.
I. Ischemic strokes. The clinician is most commonly confronted with two types of
ischemic stroke: primary thrombotic occlusion of a vessel and occlusion of a vessel
by material from a distant source (embolism). Primary thrombotic occlusion usually
occurs in a vessel already partially occluded by atherosclerosis, such as the carotid
artery or the basilar artery. The heart is the most common source of embolic material,
e.g., mural thrombus formation in the setting of atrial fibrillation or myocardial infarction,
patent foramen ovale, prosthetic valves, septic and bland emboli in bacterial
endocarditis, marantic (nonbacterial) endocarditis, Libman-Sacks endocarditis, and
atrial myxoma. Less commonly, embolism arises from ulcerated atherosclerotic plaque
in the aortic arch or at the origin of the great vessels. Although the carotid arteries are
subject to primary thrombosis, often symptoms are the result of embolism to the
intracranial vessels, so-called local embolism. Rare causes of ischemic stroke include
cerebral vein thrombosis, paradoxical embolism, polycythemia vera, meningovascular
syphilis, arteritis secondary to tuberculosis, arteritis in association with collagen vascular
disease, giant cell arteritis, Takayasu arteritis, moyamoya, fibromuscular dysplasia,
subclavian steal, and dissecting aortic aneurysm.
A. Description. Although not invariable, the neurologic deficit associated with
embolism characteristically begins suddenly, with a maximum deficit occurring at
the onset; preceding TIAs may occur but are less common than in primary
thrombosis. Preceding TIAs are common with thrombotic strokes. This type of
stroke also may progress over hours or days, and the neurologic deficit fluctuates
or changes in a stepwise fashion with a series of sudden events, the so-called
stroke-in-evolution.
1. Middle cerebral artery syndrome. Middle cerebral artery occlusions are
usually embolic, and middle cerebral artery stenosis with or without thrombotic
occlusion is less common. When the entire territory of the middle cerebral
artery is affected, the resulting clinical picture includes contralateral hemiplegia
and hemianesthesia; contralateral homonymous hemianopia with impairment
of conjugate gaze in the direction opposite the lesion; aphasia with
language-dominant (usually left) hemispheral involvement; and apractognosia,
asomatognosia, and anosognosia, with nondominant hemispheric involvement.
When middle cerebral branch occlusions occur, which is often the case,
incomplete syndromes result: nonfluent or Broca aphasia with contralateral
lower-face and arm weakness from upper-division middle cerebral artery
occlusion, Wernicke aphasia with lower-division middle cerebral artery
occlusion, and others.
2. Anterior cerebral artery syndrome. Anterior cerebral artery occlusion, also
usually embolic, may lead to paralysis of the opposite foot and leg,
contralateral grasp reflex, gegenhalten rigidity, abulia, gait disorder,
perseveration, and urinary incontinence. Occlusion of the stem of the anterior
cerebral artery is often inconsequential because of collateral flow through the
anterior communicating artery. However, when both anterior cerebral arteries
arise from a common stem, occlusion can result in a severe deficit involving
the territories of both arteries.
3. Carotid artery syndrome. Carotid occlusive disease can produce symptoms
in two ways: by hypoperfusion secondary to stenosis or occlusion, and, as
already mentioned, by providing a source of embolic material (artery-to-artery
emboli, or local embolism). Even when the artery is only mildly stenotic,
ulceration of the atheromatous plaque can be a nidus for thrombus formation
and thus a potential source for embolism. However, there is uncertainty as to
whether there is a significant risk from these ulcerated plaques in the
absence of severe stenosis of the vessel. While occlusion of the carotid artery
is occasionally asymptomatic, symptomatic occlusion most commonly
produces deficits that involve all or part of the middle cerebral artery
territory, although other clinical presentations are possible:
a. Because of variations in the origins of cerebral vessels, the territory
supplied by the anterior cerebral artery and at times the posterior cerebral
artery may be involved. When the internal carotid artery is severely
narrowed and collateral flow is compromised, the most distal regions
supplied by the middle cerebral, anterior cerebral, and, at times, the
posterior cerebral arteries (the so-called border zones, or watershed )
may be affected. These zones represent the areas of collateralization
among the 3 arteries. The damage in this situation typically produces
weakness or paresthesias in the contralateral arm and, if more
extensive, the face and tongue.
b. Carotid artery disease is responsible for approximately 50% of the cases of
transient unilateral loss of vision (transient monocular blindness or
amaurosis fugax). This is usually the result of platelet emboli from
atheromatous plaques in the carotid system. Occlusion of the central retinal
artery or one of its branches, with persistent total or partial loss of vision, is
less commonly caused by carotid artery disease. Nevertheless, carotid
artery disease should be excluded in this case.
c. The presence of prominent facial pulses, reversed flow in the
ophthalmic artery, or low retinal artery pressure by
ophthalmodynamometry usually signifies severe stenosis or occlusion of
the ipsilateral internal carotid artery.
4. Posterior cerebral artery syndrome. The posterior cerebral artery may be
occluded by embolus or thrombosis, and this can result in various
combinations of the following neurologic signs: contralateral homonymous
hemianopia (often upper quadrantanopia), memory loss, dyslexia without
dysgraphia, color anomia, mild contralateral hemiparesis, contralateral
hemisensory loss, and ipsilateral third nerve palsy, with contralateral
involuntary movements, hemiplegia, or ataxia.
5. Vertebrobasilar artery syndrome. While not as common as anterior
circulation ischemia, the basilar and vertebral arteries are vulnerable to
atherosclerosis and thrombosis as well as embolism.
a. Occlusion of branches of the basilar artery usually results in unilateral
pontine or cerebellar dysfunction or both. Depending on the level of
involvement, clinical features include combinations of ipsilateral ataxia;
contralateral hemiplegia with sensory loss; ipsilateral horizontal gaze palsy,
with contralateral hemiplegia (the opposite of that seen in hemispheric
lesions); ipsilateral peripheral seventh nerve lesion; internuclear
ophthalmoplegia; nystagmus, vertigo, nausea, and vomiting; deafness and
tinnitus; and palatal myoclonus and oscillopsia.
b. Occlusion or severe stenosis of the basilar artery itself usually gives
rise to bilateral clinical signs, such as quadriplegia, bilateral conjugate
horizontal gaze palsies, coma, or the de-efferented (locked-in) syndrome.
These same signs may be produced by bilateral vertebral artery disease or
unilateral disease when one vertebral artery is the dominant source of
blood supply.
c. Damage to structures in the medulla may be the result of occlusion or
stenosis of the intracranial vertebral arteries or posteroinferior
cerebellar artery. This leads to various symptom complexes; the best
known of these is the lateral medullary syndrome, consisting of nystagmus,
vertigo, nausea, vomiting, dysphagia, hoarseness, impaired sensation on
the ipsilateral side of the face, ipsilateral ataxia, ipsilateral Horner
syndrome, and impairment of pain and thermal sense over the contralateral
side of the body.
6. Cerebellar infarction. Early in its course, cerebellar infarction usually
produces dizziness, nausea, vomiting, direction-changing nystagmus, and
ataxia. There is often heel-to-shin or finger-to-nose ataxia. Over 1 to 3 days,
there may be resultant edema of the cerebellum manifested by such signs of
brainstem compression as conjugate gaze palsy, ipsilateral fifth nerve
dysfunction, and ipsilateral facial nerve palsy. The disorder may then progress
rapidly to coma and death. Patients with these clinical signs should always be
evaluated thoroughly and observed for several days, since the complication of
brainstem compression can be remedied by surgical decompression of the
posterior fossa.
7. Lacunar infarction. A special type of vascular disease is characterized by
hyaline thickening of the small penetrating arteries of the brain
(lipohyalinosis) and is most commonly seen in patients with diabetes mellitus
and hypertension. Occlusion of these vessels results in small, deep, often
cystic infarcts referred to as lacunar infarcts. These infarcts are often
asymptomatic but may cause certain clinical syndromes, such as pure motor
stroke, pure sensory stroke, clumsy hand-dysarthria syndrome, homolateral
ataxia and crural paresis, pure motor hemiparesis with contralateral paralysis
of lateral gaze and internuclear ophthalmoplegia, sensorimotor lacuna, ataxic
hemiparesis, and others. This diagnosis may be suspected when the
electroencephalogram (EEG) is normal and the clinical symptoms fit one of
these syndromes. While primary occlusion of these small arteries is the usual
mechanism, the arteries may also be the target of embolism, and at times the
origin of the affected small vessel is occluded by atherosclerotic plaque in the
large vessel from which it arises.
B. Diagnosis. While careful history taking and physical examination may give a fairly
accurate clinical impression, certain diagnostic tests are often necessary. For
instance, it is imperative to distinguish hemorrhage from infarction.
Therefore, diagnostic studies should be arranged early in the course to chart an
appropriate course of therapy.
1. A computed tomography (CT) scan is usually the first test to perform
because it easily distinguishes hemorrhage from infarction in almost every
case. It may occasionally fail to detect hemorrhagic infarction.
2. Magnetic resonance imaging (MRI) is even more sensitive than CT scanning
in detection of early cerebral infarction. It is not as accurate as CT for the
identification of acute hemorrhage and thus not as useful as an emergency
procedure. Special MR techniques are now generally available to image
cerebral vessels (MR angiography). Although not as accurate as cerebral
angiography, MR angiography nevertheless can be a valuable noninvasive
technique in the evaluation of the cerebral vasculature, provided the clinician is
aware of its limitations.
3. Lumbar puncture (LP). Examination of the cerebrospinal fluid (CSF) is
important in the unlikely event that CT scan or MRI is not available, since blood
appears in the CSF of most patients with intracerebral hemorrhage and all
patients with subarachnoid hemorrhage. Small intraparenchymal hemorrhages
that do not communicate with the subarachnoid space will not yield positive
CSF early. The same is often true of hemorrhage into an area of infarction
(hemorrhagic infarction), which is usually the result of an embolus. In these
situations, the CSF may become hemorrhagic after 48 hours due to seepage of
blood into the ventricular system or subarachnoid space. Diagnostic confusion
may arise when bleeding into the CSF is induced by needle insertion at
LPthe so-called traumatic tap. If four to six tubes of CSF are collected
successfully, traumatic taps usually show a diminishing number of RBCs in
each successive tube, whereas true hemorrhage produces a more uniform
RBC count in each tube. Moreover, when blood has been present in the CSF
for approximately 6 hours or longer, the supernatant CSF will appear
xanthochromic after centrifugation.
4. Noninvasive evaluation of the carotid arteries. Several noninvasive tests
are currently available to evaluate the carotid circulation, including
oculoplethysmography, ultrasound carotid imaging, and Doppler evaluation.
The most sophisticated of these, duplex scanning, combines ultrasound
real-time imaging with a Doppler probe. The newer machines provide a very
sophisticated Doppler analysis and are rather accurate in detecting significant
disease at the carotid bifurcation; these are less accurate with disease above
this area and, of course, offer little in the evaluation of the vertebrobasilar
system or intracranial circulation. A newer ultrasound technique, called
transcranial Doppler, allows a Doppler spectral analysis of some of the
intracranial arteries, thus providing an indirect assessment of the velocities in
these arteries. This has some utility in the identification of intracranial stenoses
and is of particular value in the evaluation of vasospasm secondary to
subarachnoid hemorrhage. It is also under investigation for use in the
evaluation of other conditions, including cerebral death, migraine, and vascular
malformations, and in the detection of cerebral embolism.
5. Angiography. Digital subtraction angiography uses a computerized
subtraction technique that allows visualization of the arteries with either an
intravenous injection of contrast material or a small dose of intraarterial
contrast. This digital technique often minimizes the amount of contrast
necessary to obtain definitive images. With the intravenous route, more dye is
given and, compared to the intra-arterial route, side effects are more
pronounced, including allergic reactions, pulmonary edema, and acute renal
failure. In the past, digitalized venous imaging was employed as a screening
test for detection of large vessel occlusive disease, but noninvasive MR
angiography is now the preferred procedure when available. Intra-arterial
angiography is the most definitive test and is necessary at times, particularly
when surgery is contemplated. In experienced hands, the associated risk is
small, especially when the femoral or brachial approach is used. Nevertheless,
there is always some potential risk of stroke or dissection of the catheterized
artery, and this procedure must be utilized judiciously and only when the
information obtained will be crucial in planning treatment. Iodine-based dyes
should be used cautiously or not at all in patients with impaired renal function
and are contraindicated in diabetics on metformin.
6. The EEG is usually abnormal in cortical cerebral infarctions, with slowing over
the area of infarction. When it is normal, it may support a clinical impression of
lacunar infarction.
7. Brain scan often shows increased uptake in the area of infarction, but often it
does not become positive for 4 to 5 days or longer. Moreover, the
disphosphonate scan seems to give positive evidence of infarction more often
than does the conventional technetium scan. In most circumstances,
radionuclide brain scan is an outmoded procedure.
8. Metabolic imaging studies. Positron emission tomography (PET) and single
photon emission computed tomography (SPECT) are methods for imaging
and, in the case of PET, measuring various aspects of brain metabolism.
These techniques are valuable in assessing a transient ischemic episode in
which there is no anatomic lesion or in an early stroke prior to the development
of an infarction, which is not visible by CT scan or MRI. Currently, neither PET
nor SPECT is widely available.
9. Laboratory tests. When cerebral embolism is accompanied by fever and an
increased sedimentation rate, infective endocarditis or, less commonly,
atrial myxoma, should be considered. Serial blood cultures would be
important when infective endocarditis is suspected. In a younger patient, a
hypercoagulable screen is sometimes in order, which might include protein C
activity, protein S activity, antithrombin III activity, and antiphospholipid
antibody studies.
10. Echocardiography is positive in virtually all patients with left atrial myxoma
and is useful in the evaluation of valvular heart disease. However, in searching
for an embolic source, a newer technique, transesophageal
echocardiography, is more accurate in the detection of mural thrombi and
valvular vegetations. It is also very sensitive in the detection of patent foramen
ovale when paradoxical embolism is suspected. Although some degree of
patency of the foramen ovale is relatively common, whether a minor degree of
patency represents a significant risk for stroke remains to be determined.
Transesophageal echocardiography has also been useful in detecting embolic
sources in the great vessels in the form of ulcerated plaque and mural
thrombus.
11. When no source for embolism has been discovered, Holter monitor may at
times reveal unsuspected intermittent atrial fibrillation.
C. Medical treatment
1. General precautions
a. Rapid lowering of blood pressure should be avoided in the first 10 days
unless it is critically high (persistent diastolic pressure higher than 120 mm
Hg), and of course hypotension should be reversed. The patient might be
kept in the horizontal position for a few days, with the feet slightly elevated,
especially for stenotic lesions.
b. Vomiting is common in the early stages of some types of stroke,
particularly vertebrobasilar strokes and hemorrhages. If vomiting occurs,
nasogastric suction is instituted together with intravenous fluid and
electrolyte maintenance; close attention must be given to the control of
nasopharyngeal secretions. Patients who are dysphagic must also be
maintained on intravenous fluids.
c. Intravenous solutions that contain excessive amounts of free water (such
as 5% dextrose-water, D/W) may increase cerebral edema and are
contraindicated. A solution of 5% dextrose and 0.45% normal saline is
preferable.
d. Inactivity can itself be a problem. Antiembolic stockings, although of
doubtful efficacy in preventing thrombophlebitis, are usually worn, and a
footboard is placed at the foot of the bed. Intermittent compression devices
that promote venous flow in the legs are available and may be effective.
With prolonged inactivity, the patient should be turned q23h to prevent
decubitus ulcers.
e. Within 24 to 48 hours of completion of the stroke, passive range-of-motion
exercises are begun 3 to 4 times a day to prevent the development of
contractures.
2. Anticoagulants. The most commonly used anticoagulants for cerebrovascular
disease are the coumarin agents and heparin. These drugs should not be
given to noncompliant patients or to those who cannot be followed closely with
clotting tests. They are contraindicated in patients with bleeding diatheses,
active peptic ulcer disease, uremia, or severe liver disease, and in patients
who are at risk of falling frequently.
a. Coumarin agents. Either bishydroxycoumarin (average maintenance dose,
75 mg/day) or warfarin (maintenance dose, 2 to 15 mg/day) may be used
for oral long-term anticoagulant therapy. These agents alter synthesis of the
vitamin Kdependent clotting factors (II, VII, IX, and X) and result in
production of biologically inactive forms.
1. Dosing. Although prolongation of the prothrombin time (PT) may be
achieved in 48 hours or so, this is merely a reflection of the short
half-life of factor VII, and the patient's intrinsic clotting mechanism is still
very much intact. It is usually 5 days or longer before the other factors
reach their lowest levels and adequate therapeutic anticoagulation is
achieved. For this reason, a loading dose at the commencement of
therapy is unnecessary, and a daily maintenance dose, such as
warfarin, 10 mg/day, may be started. Daily PT determinations are made,
and the dosage is adjusted to maintain the PT level at 16 to 19 seconds
(although variations from one laboratory to another may dictate a
different value).
Once the PT has been controlled and the patient has been discharged
from the hospital, the PT should be determined no less frequently than
every 2 to 3 weeks. Other drugs that may augment or antagonize the
effect of the coumarin agents are always kept in mind.
2. Side effects. Besides hemorrhagic complications, coumarin agents may
enhance the release of atheromatous plaque emboli. These may be
manifest clinically by purple toes, livedo reticularis, and other ischemic
signs in the extremities. Tissue necrosis may occur with coumarin usage
in patients with hereditary or acquired deficiencies of protein C or its
cofactor, protein S.
Coumarin effects can be reversed in 6 to 12 hours after the
intravenous injection of 50 mg of vitamin K, provided that the liver is
functioning properly. Rapid reversal of coumarin effects can be achieved
by administering fresh-frozen plasma IV, starting with 15 to 20 mL/kg,
followed by one third the dose at 8- to 12-hour intervals.
b. Heparin combines with a circulating plasma cofactor, antithrombin III, and
neutralizes not only thrombin but also some other serine proteases of the
coagulation system. Two forms of heparin are now available: unfractionated
heparin and low molecular weight heparin.
1. With unfractionated heparin, 2 methods of administration can be used.
In most cases a continuous infusion by syringe pump of 800 to 1,000
units per hour of heparin is begun. If a rapid effect is necessary, this
infusion may be preceded by an IV bolus of 2,500 to 5,000 units. An
alternative method calls for an initial IV bolus of 4,000 to 5,000 units,
followed by repeated bolus injections of 4,000 to 5,000 units q4h. The
continuous infusion is probably safer and more easily controlled than the
repeated boluses of heparin. Either the Lee-White whole-blood clotting
time or the activated partial thromboplastin time (PTT) may be used to
adjust the heparin dose to maintain the prolonged clotting time, which
should not exceed twice that of the control. If the continuous infusion
method is used, the clotting tests can be performed approximately 4
hours after a bolus of heparin has been given. Coagulation tests are
performed at least once a day.
2. Preparations of low molecular weight heparin are now available.
These have been released mostly for prevention of deep vein
thrombosis following surgery, although they are currently being used by
some for other thrombotic conditions including stroke. The available
preparations include enoxaparin (prefilled syringes of 30 mg/0.3 mL or
40 mg/0.4 mL). Maintenance dose is 30 mg b.i.d. subcutaneously.
Therepeutic dose for deep vein thrombosis is 1 mg/kg b.i.d.
subcutaneously; dalteparin (prefilled syringes of 2,500 units/0.2 mL and
5,000 units/0.2 mL). Maintenance dose 2,500 units subcutaneously
once a day. Therapeutic dose for deep vein thrombosis 5,000 units
subcutaneously once a day; the heparanoid danaparoid sodium (750
anti-Xa units twice daily subcutaneously [0.6 mL =750 units]).
Compared to unfractionated heparin, these agents have a more
selective effect on factor Xa, are at least equally effective in thrombus
inhibition, may have less hemorrhagic side effects, and appear to be
less likely to cause heparin-induced thrombocytopenia. It is
unnecessary to follow anticoagulation studies such as the PTT with
these low molecular weight heparins.
3. Side effects
a. Hemorrhage. Hemorrhagic areas on the patient's skin or
microscopic hematuria might indicate excessive anticoagulation. In
case of hemorrhagic side effects, the effects of unfractionated
heparin can be reversed in minutes by intravenous administration
of protamine, given in a 2 mg/mL solution (5 mL of a 1% solution
are mixed with 20 mL of saline). The protamine is injected slowly IV,
with no more than 50 mg given in any 10-minute period. If the
protamine is needed just after a dose of heparin has been given, the
amount of protamine required may be calculated by assuming that 1
mg of protamine will neutralize approximately 90 USP units of
heparin of beef lung origin or 115 USP units of heparin derived from
intestinal mucosa; however, the package insert for heparin should be
checked because preparations vary. The quantity of protamine
required to neutralize the heparin decreases rapidly after heparin
administration. For instance, the requirements after a half hour has
elapsed are approximately half the amount required immediately
after the heparin is given. If 4 hours or more has passed, no
protamine is given, since an overdose of protamine may produce a
hemorrhagic state. Side effects include hypotension, bradycardia,
dyspnea, and flushing.
As with unfractionated heparin, protamine may also be used to
reverse hemorrhagic complications with low molecular weight
heparins, but the anticoagulant effect is only partially reversed (60%
to 75%) in this case.
b. Heparin-induced thrombocytopenia (HIT) is an uncommon side
effect of heparin. The nonimmunologic HIT type I is without clinical
significance, generally occurs in the first few days of heparin therapy,
and is associated with a 10% to 30% decrease in platelet counts.
The more serious immune-mediated HIT type II occurs usually from
3 to 14 days after initiation of heparin, usually results in platelet
counts of 30,000 to 60,000 (but as low as 5,000), and is associated
with serious thromboembolic events (both venous and arterial) in
35% to 50% of patients. Confirmation of HIT II may be easily
obtained by a heparin-associated antibody assay. HIT II is much
more common with bovine preparations than with porcine heparin
and is least common with the low molecular weight heparins. As a
precaution, platelet counts should be performed daily on the fourth
through the eleventh day after starting heparin. If heparin is
continued beyond this time, then platelet counts should be
performed weekly for 1 month, then once a month for more
prolonged usage. If HIT II occurs, heparin should be discontinued
and a coumarin agent should be started or continued. Some other
agent with immediate anticoagulation properties should be
administered. A direct thrombin inhibitor such as hirudin, synthetic
analogs of hirudin, or argetroban would be ideal; however, these
agents have not yet been approved by the FDA in this country.
Danaparoid may have the least cross-reactivity (20%) with heparin
and can be administered for this indication with an initial bolus of
2,500 units IV followed by 400 units/hour during hours 1 to 4, 300
units/hour during hours 5 to 8, and 150 to 200 units/hour for the next
7 days or until platelet counts rise above 100,000. Dalteparin also
appears to have low cross-reactivity with unfractionated heparin and
has been suggested as treatment for HIT II. Other agents with
potential benefit for HIT II include immunoglobulin G-IV (0.4 g/kg IV
followed by repeated treatments at 24 and 48 hours) and
recombinant tissue factor pathway inhibitors (TFPIs).
c. Osteoporosis and calcium oxalate urinary stones are complications
of prolonged heparin usage and can be detected by appropriate
laboratory studies.
3. Thrombolytic agents. Thrombolytic agents are now commonly used in the
acute management of stroke. These may be delivered intravenously as well as
intra-arterially. Recanalization rates for intravenous thrombolytic agents are
generally quoted in the 30% to 40% range, while higher rates in the range of
60% to 70% are achieved with intra-arterial delivery. Although these agents
have the ability to lyse clots with the potential for significant clinical
improvement, they are also potentially very hazardous in terms of hemorrhagic
risk. It is advised that any physician or center using these agents adopt strict
treatment guidelines, including exclusion and inclusion criteria, preset orders,
and an algorithm for blood pressure control. The ability to obtain emergency
CT scanning is essential, and it is also recommended that neurosurgery
backup be available in the event of life-threatening intracerebral hemorrhage.
a. Intravenous recombinant tissue plasminogen activator (rt-PA) is the
only FDA-approved drug for the acute treatment of stroke. The dose is 0.9
mg/kg intravenously, with 10% being given as a bolus and the remainder
infused over 1 hour. The drug must be administered within 3 hours of onset
of symptoms (if the patient awakens with a neurologic deficit or is unable to
give an accurate description of onset of symptoms, the time of onset is
assumed to be the last time the patient was known to have been
asymptomatic). The drug should not be given to patients displaying early
signs of massive infarction on CT scan, and of course patients on
anticoagulants or with bleeding diatheses would be excluded. Patients with
sustained blood pressures greater than 185/110 should not receive the
drug until the blood pressure has been stabilized below these values.
Detailed guidelines for intravenous rt-PA administration are provided in
Guidelines for Thrombolytic Therapy for Acute Stroke: A Supplement to the
Guidelines for the Management of Patients with Acute Ischemic Stroke, a
consensus statement from the Stroke Council of the American Heart
Association (see Suggested Readings). Included in these guidelines for
thrombolytic therapy are inclusion and exclusion criteria as well as an
algorithm for blood pressure control using labetalol.
b. Thrombolytic agents may also be delivered intra-arterially via a
microcatheter placed directly into the occluding thrombus. Although this
route of delivery is more effective in terms of the thrombolytic effect, it
remains to be seen whether or not this route of administration is safer.
While all of the available thrombolytic agents have been used intra-arterially
in the treatment of acute stroke, urokinase appears to be the most
commonly employed agent. To date, a randomized multicenter trial of
intra-arterial urokinase has not been undertaken, although the drug is
commonly used in this fashion at centers where interventional
neuroradiology is available. A trial is currently underway with intra-arterial
prourokinase, a more fibrin-specific form of urokinase. Most centers using
urokinase in this fashion require that a patient be treated within 6 hours of
onset of symptoms for strokes in the anterior circulation but extend this time
to 24 hours for basilar artery occlusions. Since urokinase has not so far
been approved by the FDA for use in this manner, centers wishing to give
intra-arterial urokinase are advised to use the drug under a study protocol
with approval by a local investigational review board.
c. If excessive hemorrhage occurs secondary to thrombolytic agents, the
thrombolytic effect may be reversed or minimized by giving up to 10 bags of
cryoprecipitate. Also 1 unit of single donor platelets is recommended by
some. Of course, for significant blood loss, packed red cell transfusions
may be necessary.
4. Antiplatelet agents. Many drugs interfere with platelet function and might
serve as antiplatelet agents, but the experience is greatest with aspirin,
dipyridamole, and sulfinpyrazone. Ticlopidine has been demonstrated to be
at least as effective as aspirin in preventing stroke in both men and women.
There is even some suggestion that it might be more effective in general than
aspirin. Clopidogrel, another platelet IIb/IIIa receptor inhibitor similar to
ticlopidine, was shown in one study to have a marginal benefit over aspirin in
the prevention of strokes. Because the risk of hemorrhagic side effects may be
smaller with antiplatelet agents, they may be tried as alternative forms of
therapy in patients in whom the coumarin agents and heparin are
contraindicated.
a. Dosage
1. Experimental evidence suggests that aspirin is more effective in lower
doses because of a selective inhibition of thromboxane A
2
. In the Dutch
trial of aspirin in TIAs, 30 mg of aspirin daily was no less effective in the
prevention of subsequent vascular events than 283 mg/day, and many
physicians feel 81 mg/day to be ideal. Nevertheless, based on results
from earlier studies, some still advocate a higher dosage of aspirin such
as 325 mg/day or higher.
2. Dipyridamole (Persantine), 50 mg PO t.i.d., and sulfinpyrazone
(Anturane), 200 mg PO t.i.d., have not been demonstrated to be
effective in the treatment of cerebrovascular disease either alone or in
combination with aspirin. However, recently a large European study
(European Stroke Prevention Study [ESPS]) found the combination of
aspirin and dipyridamole (200 mg slow-release b.i.d.) to be significantly
more effective than either agent alone.
3. The usual dosage of ticlopidine (Ticlid) is 250 mg b.i.d.
4. The recommended dose of clopidogrel is 75 mg once daily.
b. Side effects
1. Although the side effects of aspirin are numerous, the major ones at
this dosage are gastrointestinal (e.g., gastric irritation and aggravation of
peptic ulcer disease).
2. Side effects with dipyridamole are uncommon but include headache,
dizziness, nausea, flushing, weakness or syncope, mild GI distress, and
skin rash.
3. Sulfinpyrazone, a uricosuric agent, can lead to urolithiasis and upper
gastrointestinal (GI) disturbances, with aggravation of peptic ulcer
disease, skin rash, anemia, leukopenia, agranulocytosis, and
thrombocytopenia. It may augment the effect of the coumarins.
4. The most common side effect of ticlopidine is GI distress such as
diarrhea, although neutropenia and aplastic anemia have been
described; for this reason the manufacturer recommends a complete
blood count (CBC) determination every 2 weeks for the first 3 months of
usage. Skin rash is another potential complication of ticlopidine.
5. Side effects of clopidogrel include GI distress as well as skin rash.
Neutropenia appears to be much less likely with clopidogrel than with
ticlopidine. Thrombotic thrombocytopenic purpura has also been
described with ticlopidine.
5. Choice of therapeutic agent. The choice of therapeutic agents in cerebral
ischemia is a source of great controversy, partly because of the difficulties
involved in conducting meaningful clinical trials.
a. Unfractionated heparin has not been proven to be efficacious in the acute
treatment of stroke, although some studies suggest a benefit. There are
very few reported trials using the low molecular weight heparins in the
treatment of stroke, but one study from Hong Kong reported a benefit at 6
months in patients treated with nadroparin within 48 hours of onset of
symptoms.
b. Warfarin has been shown to be quite effective in preventing stroke in
patients with atrial fibrillation and is considered by many to be the treatment
of choice for cardioembolism in general. (See Selected Readings for more
extensive reviews.)
c. A number of clinical trials with the antiplatelet agents have been
completed. In the Canadian Cooperative Platelet-Inhibiting Drug Trial,
aspirin, 1,200 mg/day, was significantly effective in reducing the risk of
continuing TIAs, stroke, and death, but only in men. Sulfinpyrazone had no
therapeutic effect. In the Aspirin in Transient Ischemic Attack Study
conducted in the United States, aspirin failed to achieve statistical
significance against placebo in reducing subsequent continuing TIAs,
cerebral or retinal infarction, or death, although it appeared superior to
placebo in certain subgroups, such as those with multiple TIAs, and
particularly in those with carotid lesions on the side appropriate to the
symptoms. Prospective studies of healthy male physicians in both the
United States and Britain failed to show a protective effect of aspirin for
cerebrovascular events, and in fact in both studies there was an increased
number of hemorrhagic strokes in the aspirin group. In a double-blind trial
with dipyridamole in patients with TIAs, there was no beneficial effect over
that of placebo with regard to subsequent TIAs, stroke, or death. So, as
with the antithrombin agents, there is some uncertainty over the
effectiveness of the antiplatelet agents in the treatment of cerebral
ischemia. Note that the dose of aspirin used in the Canadian trial was large
(i.e., 1,200 mg/day), whereas in vitro evidence suggests that lower dose
aspirin (i.e., 300 mg/day) may be more effective. As mentioned, in the
Dutch trial of aspirin in TIAs, 30 mg/day of aspirin was no less effective than
283 mg/day. In the recently reported International Stroke Trial (IST), aspirin
offered a very small but significant benefit over placebo in the treatment of
acute ischemic stroke. In the Ticlopidine-Aspirin Stroke Study (TASS) trial
(Hass et al.) of patients with transient or mild persistent focal cerebral
ischemia, the incidence of subsequent fatal or nonfatal stroke was 21%
lower in the ticlopidine-treated patients (10% compared to 13%). However,
side effects were more common in the ticlopidine-treated group such as
diarrhea, skin rash, and neutropenia. In the Clopidogrel versus Aspirin in
Patients at Risk of Ischemic Events (CAPRIE) study, clopidogrel was only
slightly more effective than aspirin for stroke, but the side effect of
neutropenia appeared to be much less than in the case of ticlopidine. As
previously stated, the ESPS study demonstrated the combination of aspirin
and dipyridamole to be more effective than either agent alone.
d. Thrombolytic agents. Three large multicenter trials of intravenous
streptokinase in the treatment of stroke were discontinued because of
excessive mortality from intracerebral hemorrhage. In the European
Cooperative Acute Stroke Studies (ECASS) of intravenous rt-PA (tissue
plasminogen activator) in Europe, there was no difference in primary
endpoints in the intention-to-treat (ITT) analysis, although the target
population (excluded major protocol violators) analysis revealed a
significant difference in favor of rt-PA on the modified Rankin at 3 months.
Patients had to be treated within 6 hours of onset of symptoms, and the
dosage of rt-PA was 1.1 mg/kg. The rate of parenchymal intracerebral
hemorrhage was increased almost threefold in the rt-PA group in both
analyses, and there was a significant increase in intracerebral
hemorrhage-related deaths in the ITT group (6.3% versus 2.4%).
In contrast to ECASS, the National Institute of Neurological Diseases and
Stroke (NINDS)-sponsored intravenous rt-PA trial in the United States
reported a more favorable outcome in those treated with rt-PA. The patients
were required to be treated within 3 hours of onset of symptoms, and the
dosage of rt-PA was 0.9 mg/kg. Compared to the placebo group, there was
a 12% absolute (32% relative) increase at 3 months in the number of
patients with minimal or no disability in the rt-PA group. There was also an
11% absolute (55% relative) increase at 3 months in the number of patients
with an NIHSS score of 0 or 1. Similar positive results were present for the
modified Rankin and Glasgow Outcome Scale. Symptomatic hemorrhage
was present in 6.4% of those treated with rt-PA compared to 0.6% of
controls. In spite of an increased risk of intracerebral hemorrhage and the
fact that there was a mortality of 60% at 3 months in the patients with
symptomatic intracerebral hemorrhage, there was no difference in mortality
at 3 months between the treatment groups. Unfortunately, the side effect of
intracerebral hemorrhage is unpredictable, and in a post hoc analysis of the
NINDS study, only 2 variables were associated with increased risk of
symptomatic intracerebral hemorrhage: severity (National Institutes of
Health stroke scale greater than 20) and early CT evidence for extensive
ischemia.
e. Although platelet aggregation may initiate the clotting process, theoretically,
inhibition of the thrombin system would seem to be of paramount
importance in symptomatic individuals with severe arterial stenoses or other
underlying risks for thrombus formation, such as atrial fibrillation. In these
situations, there is sludging and turbulence with accumulation of
proaggregatory substances and thrombin, and the therapeutic effect of the
antiplatelet agents may be overwhelmed in this setting. Furthermore,
microscopic platelet plugs pose little threat to the brain, although the retina
may be damaged. Macroscopic fibrin thrombi represent the greatest danger
to the cerebral circulation and are responsible for the more serious types of
stroke, such as middle cerebral artery occlusion. For these reasons and
based on prior experience, many clinicians have in the past utilized
anticoagulation with heparin and the coumarin agents. Now, thrombolytic
agents have been introduced into the therapeutic arena, and they are
rapidly assuming a dominant role in the acute management of stroke. As
mentioned, rt-PA is the only drug approved by the FDA for the acute
treatment of stroke.
6. With these points in mind, the following guidelines are offered for medical
management of cerebral ischemia, although they are by no means universally
accepted. Once a major stroke is complete, the patient is often severely
incapacitated and little can be accomplished with treatment. Therefore, early
detection and treatment are critical. It should be emphasized that patients with
severe and permanent deficits need not be treated aggressively, and the larger
the area of infarction, the greater the danger of anticoagulants in making the
ischemic area hemorrhagic.
a. Acute neurologic deficit with resolution (TIA). This is the ideal stage in
which to intervene and prevent a subsequent completed stroke. The
mechanism of the stroke must be clarified before an appropriate treatment
plan can be formulated. If a large or medium vessel stenotic lesion is
detected or if cardioembolism is suspected, heparin is given according to
the guidelines in sec. I.C.2.b, followed by gradual anticoagulation with
warfarin. If carotid endarterectomy is contemplated, heparin is continued
until the time of surgery. In the case of small vessel occlusive disease
(lacunar disease), some clinicians would initially place the patient on
antiplatelet therapy and use anticoagulation only if this form of therapy
failed. Others would anticoagulate in the same fashion outlined above for
large and medium vessel stenotic lesions.
b. Acute persistent neurologic deficit. In the first few hours of presentation,
the neurologic deficit may be fixed or may fluctuate (stroke-in-evolution). Of
course, some of these deficits will clear completely with time and fulfill the
criteria for TIA. If the time elapsed from onset of symptoms is 3 hours or
less, some stroke experts advocate the intravenous administration of rt-PA
assuming that the inclusion criteria mentioned in sec. I.C.3 have been met.
They stress that in the NINDS trial of intravenous rt-PA, the drug was
effective regardless of the type of ischemic stroke. However, other equally
respected experts emphasize the importance of documenting occlusion of a
major vessel before subjecting a patient to the risk of thrombolytic therapy.
They reason that in the absence of occlusion of a major vessel, such
exposure to risk is unwarranted, since lacunar strokes often have a more
favorable outcome regardless of the type of treatment given. Nevertheless,
not all lacunar strokes are associated with a good functional outcome and
intravenous rt-PA must be considered. In centers where interventional
neuroradiology is available, intra-arterial urokinase results in a higher
incidence of recanalization. Arteriography in this case is also useful in
clarifying the mechanism of ischemia. While the drug is usually given only
within the first 6 hours after onset of ischemia in the anterior circulation, this
therapeutic window is often extended to 24 hours in the case of basilar
artery occlusion.
If the patient presents after the above time windows for thrombolytic
therapy, heparin can be considered according to the guidelines in sec.
I.C.2.b. If carotid endarterectomy is indicated, then heparin is generally
continued until the time of surgery. As in the setting of TIA, some experts
would recommend antiplatelet therapy and not anticoagulation for lacunar
disease.
c. Subacute and chronic stages of stroke. After the acute setting, a
decision must be made regarding long-term anticoagulation versus
antiplatelet therapy. If a significant underlying condition exists that could
predispose the patient to experience further ischemic events, then it seems
prudent to consider long-term anticoagulation with one of the coumarin
agents, assuming that no contraindications exist. Examples of serious
underlying conditions include middle cerebral artery stenosis, basilar artery
stenosis, and atrial fibrillation. For lacunar disease, antiplatelets might be
more appropriate.
D. Surgery. Carotid endarterectomy is the most commonly performed surgical
procedure for ischemic cerebrovascular disease. It should be performed at centers
where an acceptably low morbidity with the procedure has been achieved. Surgery
may also be effective in the rare cases of symptomatic extracranial vertebral artery
disease, subclavian steal, and aortic arch disease. As mentioned previously,
posterior fossa decompression can be lifesaving in the case of massive cerebellar
infarction and brainstem compression. The procedure of anastomosing the
temporal artery to the middle cerebral artery has not been shown in a multicenter
study to be any more effective than medical management for patients with such
lesions as middle cerebral artery stenosis or intracranial carotid artery stenosis.
Carotid endarterectomy has now been shown to be superior to medical
management in symptomatic patients with lesions of 70% or greater
stenosis, provided there are no serious medical contraindications to surgery. It
should be cautioned that some centers have reported unacceptably high morbidity
and mortality figures with the procedure, and carotid endarterectomy can be
recommended only in centers where low morbidity and mortality have been
achieved. One source of morbidity with carotid endarterectomy is the shunt, which
may dislodge a loosely adherent clot at the time of placement. Some centers feel
that this risk can be minimized with the use of intraoperative EEG monitoring; in
this case, the shunt is used only when EEG abnormalities persist after
cross-clamping of the artery. Surgery for complete carotid occlusion must be
performed within 24 hours or so if lasting patency is to be achieved.
1. Transient ischemic attacks. Carotid endarterectomy is indicated for
hemispheric TIAs in the carotid territory in patients with severe stenosis of 70%
or greater (usually corresponds to a lumen diameter of 2 mm or less). Some
controversy exists among clinicians and surgeons regarding patients with
lesser degrees of stenosis but with ulceration of the plaque seen on
angiogram. In these patients, other potential sources of embolism, such as the
heart or great vessels, must be considered.
2. Completed stroke and stroke-in-evolution. When carotid artery disease
leads to massive infarction of a cerebral hemisphere, surgical results are poor.
However, carotid endarterectomy is indicated when there is less than
maximum damage and the potential for an acceptable recovery exists.
Potential surgical lesions include severe stenosis of 70% or greater and
possibly lesser degrees of stenosis with an ulcerated plaque. Although
coexisting asymptomatic stenosis or occlusion of the contralateral carotid
artery may be present, in most cases this would not alter the decision to
operate on the symptomatic side.
The timing of the surgical procedure is another source of controversy. In the
past, there was concern that sudden restoration of blood flow to an area of
infarction might result in a more serious hemorrhagic infarct, and often surgery
was delayed for days or weeks. However, many surgeons are comfortable with
operating immediately, and early surgical intervention could potentially prevent
a more serious stroke. If the blood pressure is maintained in the normal range
at surgery and postoperatively, the hemorrhagic complication is rare.
3. Asymptomatic stenosis. After a number of earlier studies with conflicting
results, the Asymptomatic Carotid Atherosclerosis Study (ACAS) trial showed a
benefit of carotid endarterectomy compared to medical management for
asymptomatic patients with carotid artery stenosis of 60% or greater. However,
in this study, the cumulative risk of stroke in the nonsurgical group was only
11% after 5 years. Therefore, the endarterectomy should be reserved for
asymptomatic patients who are expected to survive for some length of time.
Moreover, the procedure should be performed at centers where a complication
rate of less than 3% has been achieved for asymptomatic carotid stenosis.
4. When a surgical carotid lesion is present but severe coexisting medical
illness precludes an operation, anticoagulants or antiplatelet agents should be
administered according to the guidelines in sec. I.C.2.
5. For stenotic lesions not accessible by carotid endarterectomy (e.g.,
cavernous carotid stenosis), anticoagulants or antiplatelet agents would be
selected on an individual basis according to the severity of the lesion and the
suitability of the individual patient for anticoagulation. However, in patients in
whom there is a major contraindication to anticoagulation or in whom TIAs
occur despite adequate anticoagulation, an extracranial-intracranial bypass
graft could be considered.
E. Antiedema agents
1. Corticosteroids have not been shown to be effective in cerebral infarction or
cerebral hemorrhage, although there is some evidence that they are effective
in reducing cerebral edema in other conditions. In spite of this evidence, some
clinicians feel they should be given when there are signs of increased
intracranial pressure, such as obtundation, coma, or signs of herniation. In this
situation, dexamethasone is given in an initial bolus of 10 mg IV or IM, followed
by 4 mg IV or IM q46h.
2. Osmotic agents such as mannitol or glycerol are probably more effective in
reducing intracranial pressure. It is important to keep in mind that these agents
may have only a transient benefit, and there is some evidence that a rebound
increase in cerebral edema may occur when they are discontinued, particularly
with mannitol. Mannitol is of particular value when an immediate reduction in
intracranial pressure is necessary. The dosage of mannitol is usually 0.5 to 1.5
g/kg IV. The dosage of glycerol is 1 g/kg PO q6h.
3. High-dose barbiturates have been administered in patients in whom all other
measures have failed, although this treatment cannot be recommended based
on the available evidence at this point in time. Guidelines for barbiturate coma
are outlined in Chap. 1, sec. VII.D.6.
F. Anticonvulsants. Some patients with cerebral infarction develop seizures, but
this is often a late complication. Anticonvulsants are generally withheld until there
is evidence of seizure activity.
G. Vasodilators. In spite of evidence that cerebral blood flow is increased by amyl
nitrate, papaverine, isoxsuprine, acetazolamide, carbon dioxide, and other agents,
these agents do not seem to alter the course of ischemic strokes favorably.
Indeed, some physicians feel that the resultant vasodilatation from these agents
reduces perfusion to the area of ischemia (so-called intracerebral steal).
H. Other therapeutic agents. Some agents such as clofibrate have been tried in
brief clinical trials in the treatment of stroke, but they have not been clearly shown
to be of value. Prostacyclin, a potent platelet aggregator and vasodilator, has not
been shown in clinical trials to be of benefit. Clinical trials with volume expanders,
such as low molecular weight dextran or hydroxyethyl starch, have produced
mixed results, and a final verdict concerning these agents must await further
clinical trials. The same is true of pentoxifylline, which increases red blood cell
(RBC) deformability, and naloxone, an opiate receptor antagonist. Clinical trials in
stroke and cardiac arrest with barbiturates have failed to show any beneficial
effect. The influx of calcium into ischemic neurons seems to be an important
determinant in cell death. Although studies with nimodipine, a calcium channel
inhibitor, have produced mixed results, theoretically this drug might be of benefit.
Glutamate N-methyl-d-aspartate (NMDA) receptor antagonists have been
suggested as treatment for cerebral ischemia and are currently under
investigation.
I. In the recovery phase, in which some degree of improvement almost always
occurs, speech, occupational, and physical therapy are beneficial.
II. Hemorrhagic strokes. The most common varieties of hemorrhagic stroke are
intracerebral hemorrhage secondary to hypertension or amyloid angiopathy and
subarachnoid hemorrhage secondary to ruptured saccular aneurysm or arteriovenous
malformation. Other, less common causes of hemorrhage are anticoagulants, bleeding
diatheses, trauma, hemorrhage into a primary or metastatic brain tumor, idiopathic
subarachnoid hemorrhage, and rupture of a mycotic aneurysm. Rare causes include
carotid cavernous arteriovenous fistulas, hemorrhage after vasopressor drugs,
hemorrhage on exertion, encephalitis, vasculitis, and pituitary apoplexy.
A. Intracerebral hemorrhage
1. Description. It is the small penetrating arteries that are damaged by
hypertension and give rise to hypertensive intracerebral hemorrhage. As a
consequence, the hemorrhage almost always arises in the following locations
in decreasing order of frequency: putamen, thalamus, pons, and cerebellum.
Hemorrhage secondary to anticoagulants, bleeding diatheses, or trauma often
involves other areas of the brain, such as the frontal, temporal, or occipital
lobessites that are rarely involved with hypertensive hemorrhage.
Amyloid angiopathy has recently been recognized as a relatively common
cause of hemorrhage in the elderly; these hemorrhages tend to be lobar in
location in contrast to hypertensive hemorrhages, and they may be recurrent or
multiple. The onset of intracerebral hemorrhage is abrupt, and the stroke
usually evolves gradually over minutes or hours without the stepwise
progression seen in thrombotic strokes.
a. Putaminal hemorrhage. When first seen, patients with putaminal
hemorrhage often present a clinical picture that is almost indistinguishable
from that of middle cerebral artery occlusion, with contralateral hemiplegia,
hemianesthesia, homonymous hemianopsia, aphasia (if the dominant
hemisphere is involved), and hemineglect, anosognosia, and the like, with
nondominant hemispheral involvement. There is usually a greater alteration
of the state of consciousness in patients with hemorrhage. Smaller
hemorrhages produce more restricted deficits, whereas larger ones may
produce coma and signs of herniation.
b. Thalamic hemorrhage produces contralateral hemiparesis or hemiplegia
with contralateral hemianesthesia. The sensory loss may be
disproportionately greater than the motor deficit. Unusual eye signs provide
a clue to the diagnosis of thalamic hemorrhage. Often there is restriction of
upward gaze, at times with forced downward deviation of the eyes; skew
deviation of the eyes is common. The eyes may even be deviated
conjugately away from the side of the lesion (so-called wrong-going eyes).
As in putaminal hemorrhage, massive hemorrhage in the thalamus leads to
coma and signs of herniation.
c. Pontine hemorrhage usually results in early coma, pinpoint pupils that
react to light, and bilateral decerebrate posturing. The eyes are often in
midposition, with impaired or absent response to caloric testing. More
restricted hemorrhages in the pons, although uncommon, may produce
deficits that resemble those seen in pontine infarction.
d. Cerebellar hemorrhage may be diagnosed early with a careful clinical
evaluation. Patients typically develop sudden dizziness and vomiting, along
with marked truncal ataxia. On examination they are unable to stand or
walk because of the ataxia. They are often perfectly alert early in the
course. Frequently there are signs of compression of the ipsilateral pons,
such as paresis of lateral conjugate gaze to the side of the lesion, ipsilateral
facial weakness, and diminished corneal reflex on the affected side.
Untreated, these patients progress rapidly to coma and death from
brainstem compression. It is critically important to make the diagnosis early
because surgical evacuation of the hematoma can be lifesaving.
2. Diagnosis. Clinical guidelines for the diagnosis of intracerebral hemorrhage
are provided in sec. II.A.1.
a. Lumbar puncture. Almost all cerebellar and pontine hemorrhages produce
bloody CSF, as do most hemorrhages in the putamen and thalamus. Some
of the small hemorrhages in the putamen and thalamus may not show
blood in the CSF early; however, as previously mentioned, the CSF is
almost always positive within 48 hours. Lumbar puncture is usually safe,
but with mass effect there is always the threat of herniation, and this is a
particular hazard in cerebellar hemorrhage. In this case lumbar puncture
would be indicated only if CT scan was not available.
b. A CT scan is usually available and is the procedure of choice to confirm the
diagnosis of intracerebral hemorrhage and to determine the extent of
damage. Before the advent of CT scans, angiography would often show an
avascular mass in the region of hemorrhage.
3. Treatment
a. General measures. The same general measures listed for ischemic stroke
(see sec. I.C.1) apply to the management of intracerebral hemorrhage with
the exception of blood pressure control. In the patient with intracerebral
hemorrhage, efforts are made to maintain the blood pressure in the normal
range.
b. Antiedema agents. Patients with intracerebral hemorrhage may have
considerable cerebral edema, and if drowsiness or evidence of herniation is
present, antiedema agents, such as steroids, mannitol, or glycerol, are
given in the dosages discussed in sec. I.C.4.
As mentioned, steroids such as dexamethasone have not been shown to
be effective in patients with intracerebral hemorrhage, and osmotic agents
such as mannitol or glycerol are more effective in reducing cerebral edema.
It is important to keep in mind that the osmotic agents are of transient
benefit and when discontinued a rebound effect might ensue. They are of
particular value when given just before decompressive surgery or as a
last-resort effort to reverse herniation.
c. Surgery. Evacuation of a hematoma in an accessible location, such as the
cerebellum, putamen, thalamus, or temporal lobe, might be lifesaving, and
this type of emergency surgery must be considered if the condition of the
patient does not stabilize and signs of herniation begin to appear. However,
when the patient's condition is stable and the hemorrhage is not life
threatening, it is not clear that emergency evacuation of the clot is any more
beneficial than conservative, nonsurgical management.
d. Anticonvulsants may be withheld until there is evidence of seizure activity.
e. Clotting abnormalities. In patients with hemorrhage secondary to clotting
abnormalities or anticoagulant therapy, appropriate measures are taken to
reverse the abnormality (e.g., platelets for thrombocytopenia, fresh-frozen
plasma and vitamin K for coumarin agents, and protamine for heparin).
B. Subarachnoid hemorrhage
1. Description
a. Aneurysmal rupture. Subarachnoid hemorrhage is most commonly the
result of rupture of a saccular aneurysm, which is a defect in the internal
elastic lamina or the arterial wall that occurs at sites of arterial bifurcation or
branching. The majority of patients who experience rupture are between the
ages of 35 and 65 years. Associated conditions include polycystic kidneys,
Marfan syndrome, Ehlers-Danlos syndrome, and coarctation of the aorta.
Other types of aneurysms occur along the trunk of the internal carotid,
vertebral, or basilar arteries, and these are described in terms of their
morphology as fusiform, globular, or diffuse. These aneurysms may cause
symptoms by compressing local structures or thrombosis, but they seldom
rupture. A rare cause of subarachnoid hemorrhage is rupture of a mycotic
aneurysm, the result of septic embolism. Unfortunately, aneurysms are
usually asymptomatic until they rupture.
1. Typically there is a sudden onset of severe headache, usually the
worst headache the patient has ever experienced. The patient may lose
consciousness, and while this event may herald the onset of coma, the
patient often reawakens somewhat confused. At times, the loss of
consciousness is sudden and unaccompanied by headache. The event
often occurs during physical exertion, such as during sexual intercourse.
Although patients with ruptured cerebral aneurysms usually have
supportive clinical signs, their examination may be perfectly normal
early, and a high index of suspicion is in order for patients with severe
headache of sudden onset.
2. On examination, signs of meningeal irritation are common, as is
low-grade fever.
3. Subhyaloid hemorrhages are often seen on funduscopic examination.
4. The hemorrhage may be only subarachnoid, or blood may dissect into
the brain parenchyma itself, causing focal neurologic deficits.
5. Infarction early in the course may also result from compromise of blood
flow or thrombosis in the arteries involved by the aneurysm.
6. Clinical localization of the aneurysm is usually difficult, although
certain signs may be helpful: pain behind the eye and dysfunction of the
second to sixth cranial nerves with cavernous carotid artery aneurysms;
hemiplegia, aphasia, and so on with middle cerebral artery aneurysms;
third nerve palsy with aneurysm at the juncture of the posterior
communicating and internal carotid arteries; abulia or weakness of the
lower limb with anterior communicating artery aneurysms; and
involvement of the lower cranial nerves with basilar and vertebral artery
aneurysms.
7. Focal neurologic deficits that occur a few days after the initial
hemorrhage, either transient or permanent, are usually caused by
vasospasm resulting from the presence of blood in the subarachnoid
space.
8. Hydrocephalus may occur as an early or late complication of
subarachnoid hemorrhage and may require shunting.
b. Arteriovenous malformations (AVMs) are usually brought to clinical
attention because of seizures or hemorrhage, although large ones may
shunt enough blood to result in ischemia of the surrounding brain.
Symptoms are most likely to occur in childhood or young adulthood. Since
AVMs commonly extend from the surface into the brain parenchyma,
hemorrhage from these malformations is often a combination of
intracerebral and subarachnoid hemorrhage. A chronic headache is a
common complaint prior to hemorrhage, and the presence of a bruit over
the eyeball, carotid artery, or mastoid of a young patient strongly suggests
the presence of a cerebral AVM. Other vascular malformation may occur
including telangiectasias, cavernous angiomas, and venous angiomas. MRI
is particularly useful in separating these types of malformations, and this
has some clinical importance since hemorrhage with venous angiomas and
possibly telangiectasias is probably rare. However, it has recently become
apparent that cavernous angiomas pose some risk of hemorrhage,
although not as great as in the case of AVMs, and these malformations
have a characteristic appearance on MRI.
In any large series of patients with subarachnoid hemorrhage, a
considerable number will have no demonstrable lesion. At least some of
these result from rupture of so-called cryptic AVMs, which are too small to
be detected angiographically. Spinal AVMs must be considered in young
patients with subarachnoid hemorrhage and no demonstrable cerebral
lesion. Also, a bruit may sometimes be heard over the spine in these
patients.
2. Diagnosis
a. Whenever a subarachnoid hemorrhage is suspected, a CT scan is the
diagnostic procedure of choice. In most but not all cases, the subarachnoid
blood is seen on CT. The CT scan can also provide information about
cerebral edema, parenchymal hemorrhage, ventricular hemorrhage, and
hydrocephalus. The finding of a large, localized collection of subarachnoid
blood may identify the site of hemorrhage.
b. Examination of CSF. An LP is indicated only if the CT scan is not available
or is nondiagnostic. The risk of herniation or of inducing rehem-orrhage by
the LP must be considered. Bloody CSF on LP examination will always be
found with subarachnoid hemorrhage. Traumatic tap can usually be ruled
out according to the guidelines in sec. I.B.3.
c. Skull x-rays may show calcification in an AVM and occasionally in an
aneurysm but are not routinely ordered.
d. Angiography. Many physicians would perform angiography shortly after
admission, since early surgery (in the first 24 to 48 hours) is now probably
the treatment of choice for ruptured cerebral aneurysms in patients with
minor neurologic impairment. For more severely impaired patients,
angiography might be delayed, unless diagnostic confusion exists between
ruptured aneurysm or AVM and hypertensive intracerebral hemorrhage and
particularly when any type of decompressive surgery is necessary.
e. If no lesions are demonstrated by cerebral angiography and no localizing
neurologic signs are present, an aneurysm is not completely ruled out
because at times these lesions are obliterated initially by thrombosis only to
appear on angiography at a later time as the clot dissolves. For this reason,
a repeat angiogram is usually performed after a few weeks. A rare cause
for subarachnoid hemorrhage is a spinal AVM, and if there are any clinical
findings consistent with this, such as a bruit over the spine or localized
collections of blood along the spine on imaging studies, spinal angiography
might be indicated, although these lesions are also demonstrable by MRI.
3. Treatment. Surgery is the treatment of choice for suitable patients whose
aneurysms are surgically accessible. In the preoperative period, therapeutic
efforts are directed to prevention and treatment of the two most important
complications: recurrent hemorrhage and vasospasm. Arteriovenous
malformations may or may not be amenable to surgery. Since there is risk of
recurrent hemorrhage from AVMs, although less than that for aneurysms, the
following preoperative measures apply in the early period after bleeding.
a. Preoperative measures
1. General precautions
a. Elevation of blood pressure is avoided if possible. If hypertension
exists, antihypertensive drugs are used to maintain the blood
pressure in the normal range.
b. Sedation with phenobarbital or diazepam is instituted to prevent
excitement and elevation of the blood pressure.
c. Seizures are a complication and raise the blood pressure, so
prophylactic anticonvulsants are given. Phenobarbital is an
effective anticonvulsant (starting dosage, 30 mg PO t.i.d.) and may
serve a dual purpose as sedative and anticonvulsant.
d. To prevent straining with bowel movements, stool softeners are
given, such as dioctyl sodium sulfosuccinate (Colace), 100 mg PO
t.i.d.
e. The room is darkened and noise minimized.
f. While hypertension is to be avoided preoperatively, if there is
evidence of reduced intravascular volume, volume expansion is
probably important and can be accomplished according to the
guidelines in sec. II.B.3.a.(4)(b). Caution is in order preoperatively,
as the artificial colloids such as hetastarch may alter the coagulation
mechanism with prolongation of the PT, PTT, and the bleeding time.
2. Antifibrinolytic agents. It is thought that lysis of the clot formed at the
point of bleeding is partly responsible for recurrent hemorrhage from
aneurysms and AVMs. This provides some rationale for the use of
antifibrinolytic agents; indeed, most studies suggest the considerable
efficacy of these agents in preventing rebleeding. However, clinicians
are now trying to avoid using these agents because of a higher risk of
both venous and arterial thrombotic complications. Nevertheless, in the
case of ruptured aneurysm when surgery must be delayed for a
prolonged period of time, their use must be considered.
e-Aminocaproic acid (Amicar), 30 to 36 g/day, may be given IV. This is
usually prepared by mixing 30 to 36 g in 1 L of 5% dextrose and 0.45%
normal saline or a similar solution. The mixture is infused over 24 hours
with a microdrop apparatus. Alternatively, the drug may be administered
in a dosage of 4 g PO q3h. The drug is continued until the time of
surgery or for 6 weeks if surgery is contraindicated. Complications
include nausea, cramps, diarrhea, dizziness, tinnitus, conjunctival
suffusion, nasal stuffiness, headache, skin rash, thrombophlebitis, and
pulmonary embolus.
3. Antiedema agents. Corticosteroids, mannitol, or glycerol may be given
if there are signs of increased intracranial pressure, as discussed in sec.
I.C.4.
4. Management of vasospasm. Vasospasm may be responsible for
drowsiness or focal neurologic signs, but these signs do not usually
occur until 2 to 3 days after the initial hemorrhage and peak in
occurrence at about 7 days. The spasm is thought to result from the
release of vasoactive compounds such as serotonin, catecholamines,
peptides, and endothelin.
a. Intravenous isoproterenol and nitroglycerin have been used in an
effort to dilate the cerebral vessels. Both have produced variable
results.
b. Volume expansion as a measure to increase cerebral perfusion
may be the most effective therapy for vasospasm. Hypervolemic
volume expansion is accomplished by administering 5% albumin or
other plasma fraction solutions IV. As an alternative, artificial colloids
such as hetastarch may be given IV. A word of caution is in order
when administering the artificial colloids preoperatively because they
may alter the coagulation mechanism with transient prolongation of
the PT, PTT, and bleeding time. Hypervolemia is relatively
contraindicated in patients with reduced cardiac output or congestive
heart failure. The therapy is monitored via a central venous catheter,
adjusting the central venous pressure to 8 to 12 mm Hg or the
pulmonary capillary wedge pressure to 12 to 16 mm Hg.
Hypervolemia may be combined with phlebotomy and hemodilution
to achieve a hematocrit of 30% to 35%. If spasm is still a problem
even after hypervolemia, the blood pressure can be raised with
hypertensive agents such as intravenous dopamine, phenylephrine,
and dobutamine. This therapy is much safer once the aneurysm has
been clipped, since the risk of rebleeding is probably increased as
the blood pressure is raised.
c. Dilation of vasospastic segments of cerebral vessels has been
successfully performed in certain selected cases using
transluminal balloon angioplasty.
d. Slow-channel calcium inhibitors have been proposed for the
treatment of vasospasm, and one such agent, nimodipine, is
available for this purpose. It appears to have some effect in reducing
mortality if given early before vasospasm appears. The dosage is 30
to 60 mg PO q4h. The most undesirable side effect is hypotension,
and this is of course to be avoided in the presence of vasospasm.
Intravenous nicardipine, another dihydropyridine calcium channel
inhibitor, was shown in one clinical trial to significantly reduce
symptomatic and angiographic vasospasm and to result in improved
clinical outcome. Nicardipine is administered by slow continuous
infusion at a concentration of 0.1 mg/mL. In the original study, a
dose of 0.15 mg/kg/hour was used. However, a later study
suggested that 0.075 mg/kg/hour was equally effective and
minimized the potential side effects of hypotension, pulmonary
edema, and azotemia.
b. Surgery. Patients who undergo surgery for ruptured aneurysms generally
fare somewhat better than those who are treated medically because of the
sharp reduction in the incidence of rebleeding with surgery. The decision to
operate is made with the guidance of the neurosurgeon and depends to a
certain extent on his or her preferences. However, certain generalizations
can be made.
1. Contraindications. Surgery is not usually performed on patients in
coma or with severe neurologic deficits because of the high mortality
and low potential for recovery.
2. Timing. In the past, surgery was usually delayed for 10 days or so after
the hemorrhage, provided that significant vasospasm was not present.
Recently, multicenter studies have reported encouraging results with
early aneurysm surgery in the first 24 to 48 hours for patients not
severely impaired. It appears that surgery can be performed at this
stage without worsening vasospasm, since vasospasm is usually a later
development. With early surgery, the subarachnoid space is irrigated to
remove the blood, and this is felt to reduce the threat of vasospasm;
some centers are even instilling tissue plasminogen activator to dissolve
the adherent clot after the aneurysm is securely clipped.
3. Procedures. Various procedures have been devised for dealing with
aneurysms surgically (e.g., clipping the neck of the aneurysm, wrapping
it with muscle, coating it with plastic, and occluding the internal carotid
artery in the neck), the most common of which is clipping the neck of
the aneurysm.
a. Block resection or ligation of the major arteries is done for AVMs,
although the importance of the involved vessels in supplying blood to
critical areas of the brain often precludes this form of therapy. When
this is the case, embolic procedures may be used, employing such
material as gelfoam and Silastic balls.
b. Balloon occlusion. Giant aneurysms of the intracranial carotid
artery are usually not amenable to surgery. Angiographic techniques
now allow balloon occlusion of the aneurysm in many patients. At
times the neck of the lesion can be occluded, sparing the parent
vessel. In other patients the carotid artery must be occluded. In such
cases, a test occlusion is performed with the patient awake. If any
signs of ischemia develop, the procedure is stopped. An
extracranial-intracranial bypass procedure is done, and the occlusion
can be performed safely a few days later.
c. Radiotherapy. Conventional x-ray irradiation of AVMs in an attempt
to induce hyalinization and occlusion of the involved vessels has
been used in the past with little success. However, radiotherapy
using a proton beam has enabled more accurate focusing of the
beam and has produced more satisfactory results. A new device that
has also been effective for this purpose, the gamma knife, allows
precise focusing of gamma rays from a cobalt source.
d. Shunt. Hydrocephalus can occur as an early or late complication of
subarachnoid hemorrhage and may require a shunt procedure.
e. Embolization. In patients in whom aneurysmal surgery is
contraindicated, embolization procedures employing such materials
as platinum coils have been quite effective at inducing thrombosis in
the aneurysm. When surgery is contraindicated, the preoperative
measures already listed are continued for approximately 6 weeks,
after which time activity is gradually increased.
Selected Readings
Ackerman RH. Non-invasive diagnosis of carotid disease. In: Siekert RG, ed. Cerebrovascular survey
report for Joint Council Subcommittee on Cerebrovascular Disease: National Institute of Neurological and
Communicative Disorders and Stroke and National Heart and Lung Institute. Rochester, NY: Whiting,
1980:190.
Ackerman RH. Non-invasive diagnosis of carotid disease in the era of digital subtraction angiography.
Neurol Clin 1983;1:263.
Allen GS, et al. Cerebral arterial spasm: a controlled trial of nimodipine in patients with subarachnoid
hemorrhage. N Engl J Med 1983;308:619.
Aspirin as a therapeutic agent in cardiovascular disease. Special Writing Group. Circulation 1993;87:659.
Barnett HJ M. Aspirin in stroke prevention: an overview. Stroke 1990;21(Suppl 4):40.
The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of low-dose warfarin
on the risk of stroke in patients with non-rheumatic atrial fibrilation. N Engl J Med 1990;323:1505.
Bousser MG, et al. AICLA controlled trial of aspirin and dipyridamole in the secondary prevention of
athero-thrombotic cerebral ischemia. Stroke 1983;14:5.
Canadian Cooperative Study Group. A randomized trial of aspirin and sulfinpyrazone in threatened
stroke. N Engl J Med 1978;299:53.
Candelise L, et al. A randomized trial of aspirin and sulfinpyrazone in patients with TIA. Stroke
1982;13:175.
Caplan LR. Stroke. Stoneham, UK: Butterworth-Heinemann, 1993.
CAPRIE Steering Committee. A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk
of ischaemic events. Lancet 1996;348(9038):1329.
Cerebral Embolism Study Group. Immediate anticoagulation of embolic stroke: a randomized trial. Stroke
1983;14:668.
Cerebral Embolism Study Group. Brain hemorrhage and management options. Stroke 1984;15:779.
Curling OD, et al. An analysis of the natural history of cavernous angiomas. J Neurosurg 1981;75:702.
The Dutch TIA Trial Study Group. A comparison of two doses of aspirin (30 mg vs. 283 mg a day) in
patients after a transient ischemic attack or minor ischemic stroke. N Engl J Med 1991;325:1261.
European Stroke Prevention Study 2. Efficacy and Safety Data. The ESPS 2 Group. J Neurol Sci
1997;151(Suppl):S1.
Executive Committee for the Asymptomatic Carotid Atherosclerosis Study: endarterectomy for
asymptomatic carotid artery stenosis. JAMA 1995;273:1421.
Fields WS, et al. Controlled trial of aspirin in cerebral ischemia. Stroke 1977;8:301.
Fields WS, et al. Controlled trial of aspirin in cerebral ischemia: II. Surgical group. Stroke 1978;9:309.
Genton E, et al. Platelet-inhibiting drugs in the prevention of clinical thrombotic disease. N Engl J Med
1975;293:1174.
Guidelines for the management of aneurysmal subarachnoid hemorrhage. A statement for healthcare
professionals from a special writing group of the Stroke Council, American Heart Association. Circulation
1994;90:2592.
Guidelines for the management of patients with acute ischemic stroke. A statement for healthcare
professionals from a special writing group of the Stroke Council, American Heart Association. Circulation
1994;90:1588.
Guidelines for carotid endarterectomy. A multidisciplinary consensus statement from the ad hoc
committee, American Heart Association. Circulation 1995;91:566.
Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen
activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study (ECASS). JAMA
1995;274:1017.
Haas S. Impact of the European consensus statement on the clinical acceptance of low molecular weight
heparin. Clin Appl Thromb Hemost 2(Suppl 1):S35.
Hass WK, et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of
stroke in high-risk patients. N Engl J Med 1989;321:501.
Haley EC J r, Kassell NF, Torner J C, et al. A randomized trial of two doses of nicardipine in aneurysmal
subarachnoid hemorrhage. A report of the Cooperative Aneurysm Study. J Neurosurg 1994;80:788.
International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomised trial of
aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke.
Lancet 1997;349:1569.
Kay R, Sing Wong K, Yu YL, et al. Low-molecular-weight heparin for the treatment of acute ischemic
stroke. N Engl J Med 1995;333:1588.
NACENT Collaborators. Beneficial effects of carotid endarterectomy in symptomatic patients with
high-grade carotid stenosis. N Engl J Med 1991;325:445.
The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue
plasminogen activator for acute ischemic stroke. N Engl J Med 1991;333:1581.
Nibbelink DW, Torner J C, Henderson WG. Intracranial aneurysms and subarachnoid hemorrhage: a
cooperative study. Antifibrinolytic therapy in recent onset subarachnoid hemorrhage. Stroke 1975;6:622.
Origitano TC, et al. Sustained increased cerebral blood flow with prophylactic hypertensive hypervolemic
hemodilution (Triple-H therapy) after subarachnoid hemorrhage. Neurosurgery 1990;27:729.
Petty GW, et al. Complications of long-term anticoagulation. Ann Neurol 1988;23:570.
Sorenson PS, et al. Acetylsalicylic acid in the prevention of stroke in patients with reversible cerebral
ischemic attacks: a Danish cooperative study. Stroke 1983;14:15.
Steering Committee of the Physicians' Health Study Research Group. Final report on the aspirin
component of the ongoing Physicians' Health Study. N Engl J Med 1989;321:129.
Swedish Cooperative Study. High dosage acetylsalicylic acid after cerebral infarction. Stroke
1987;18:325.
Weitz J I. Low-molecular-weight heparins. N Engl J Med 1997;337:688.
Zeumer H, Freitag HJ , Zanella F, et al. Local intra-arterial fibrinolytic therapy in patients with stroke:
urokinase versus recombinant tissue plasminogen activator (rt-PA). Neuroradiology 1993;35:159.
CHAPTER 11. NEOPLASMS
Manual of Neurologic Therapeutics
CHAPTER 11. NEOPLASMS
Howard D. Weiss
Introduction
Treatment
Brain tumors in adults
CNS tumors in childhood
Spinal cord tumors
Neurologic complications of radiation therapy
I. Introduction
A. Classification. Figure 11-1 presents a classification of the most common
neoplasms of the CNS and their sites of predilection.
FIG. 11-1. Most common CNS tumors and their sites of predilection.
B. Prevalence. Brain tumors are not rare. Each year over 100,000 adults in the
United States will be diagnosed with a primary or metastatic brain tumor. Brain
tumors also occur in children and young adults and are the second leading cause
of cancer death in persons under 30.
C. Genetic syndromes. The cause of most brain tumors is unknown. There are
several hereditary disorders associated with neural tumors, the most well known of
which are:
1. von Hippel-Lindau syndrome: hemangioblastoma, pheochromocytoma, renal
cell carcinoma (chromosome 3p).
2. Neurofibromatosis type 1: neurofibroma, optic glioma, neurofibrosarcoma
(chromosome 17q).
3. Neurofibromatosis type 2: acoustic neuroma, meningioma, spinal nerve root
neurofibroma (chromosome 22q).
4. Tuberous sclerosis: subependymal giant cell astrocytoma, hamartoma
(chromosome 16p).
D. Symptoms. Cerebral neoplasms produce subacute and progressive neurologic
signs and symptoms. The patient's symptoms are determined by the size,
location, and rate of growth of the tumor, as well as the degree of peritumor
cerebral edema.
1. Increased intracranial pressure occurs with many cerebral neoplasms and
can cause headache. The headaches may be mild, and are often bilateral or
diffuse, without localizing value. The early morning headache and nausea
usually thought to be associated with increased intracranial pressure is a
pattern seen in only a small proportion of cases. Recurrent headache in an
adult not previously prone to headaches should always raise the suspicion of
an occult intracranial mass lesion.
2. Focal clinical manifestations (e.g., hemiparesis, ataxia, aphasia, visual loss)
depend on the location of the lesion and the extent of the surrounding brain
edema. Tumors in relatively silent regions of the brain commonly present with
change in personality or behavior rather than focal signs or symptoms
(Table 11-1).
TABLE 11-1. Tumors That Can Present Without Conspicuous Focal Signs on
Routine Neurologic Examination
3. Seizures. Generalized convulsions or focal seizures (or both) occur in about
one third of patients with tumors in the supratentorial compartment. Seizures
are more likely to accompany slowly growing tumors than highly malignant
ones.
4. Occasionally, hemorrhage into a highly vascular tumor can produce a sudden
change in neurologic status that can be mistaken for a stroke syndrome.
Glioblastoma multiforme and brain metastases from choriocarcinoma,
melanoma, and anaplastic lung cancer are the tumors most likely to bleed
spontaneously.
E. Diagnosis. Once a brain tumor is suspected on clinical grounds, brain imaging
studies are undertaken to confirm its presence and exact location.
1. Magnetic resonance imaging (MRI) without and with a contrast agent
such as gadolinium is the most sensitive diagnostic study for detecting
intracranial mass lesions. MRI is particularly useful for visualizing the
brainstem and other posterior fossa structures that are not well seen on
computed tomography (CT). The contrast agent helps differentiate between the
borders of the tumor and surrounding edema, and facilitates detection of small
lesions that might otherwise be missed.
2. CT scan without and with contrast reveals most brain tumors and, like MRI,
allows assessment of accompanying cerebral edema, midline shift, and
ventricular compression or obstructive hydrocephalus. CT is the procedure of
choice in patients who cannot undergo MRI (e.g., pacemaker or other metallic
implants) or when the patient's inability to lie perfectly still would degrade the
MRI images.
Small tumors that are not causing mass effect or edema can evade detection
on MRI or CT if contrast is not administered.
3. Differential diagnosis. Enhancing cerebral infarcts, brain abscesses, large
demyelinating plaques, and intracranial granulomas can be easily mistaken for
neoplasms on MRI or CT. Brain imaging studies cannot predict the
histopathology of brain tumors with complete accuracy and do not obviate the
need for tissue diagnosis in most cases.
4. Cerebral angiography has become less important in the diagnosis and
localization of intracranial tumors since the development of the CT scan and
MRI.
5. Lumbar puncture (LP) may reveal increased opening pressure or other
nonspecific findings such as elevated cerebrospinal fluid (CSF) protein. LP is
potentially dangerous in patients with intracranial mass lesions, and is not part
of the routine preoperative evaluation of patients with CT scan or MRI evidence
of brain tumor. The major exception to this dictum is in patients suspected of
having neoplastic meningitis. In these cases, the diagnosis is confirmed by
demonstrating malignant cells on cytologic examination of the CSF, and 1 or
more LPs may be necessary.
II. Treatment. Despite their diverse locations and histologic features, brain tumors
have several medical management issues in common.
A. Tumor-related brain edema
1. Corticosteroids. Steroid therapy is initiated prior to tissue diagnosis in
symptomatic patients with CT or MRI studies revealing an intracranial mass
lesion with surrounding edema. High-dose corticosteroids can reduce
tumor-associated cerebral edema, thereby lowering intracranial pressure and
palliating focal deficits. The use of corticosteroids has had a major beneficial
impact on the preoperative and postoperative management of patients with
brain tumor.
a. Mechanism of action. Most brain tumors (primary or metastatic) cause
vasogenic edema in the surrounding brain parenchyma. If the edema is
considerable or widespread, it can produce a marked increase in
intracranial pressure, causing neurologic deficits by compressing nearby
structures. The symptoms of many patients may be more a reflection of
cerebral edema than destruction of brain parenchyma by tumor. The
mechanism by which steroids act to reduce cerebral edema is probably
related to stabilization of the capillary endothelial junction and reduction of
cerebrovascular permeability.
b. Clinical effects. Improvement in focal neurologic signs and symptoms of
intracranial hypertension begins within 24 to 48 hours of starting steroids in
most patients with primary or metastatic brain tumors. The maximum
degree of improvement is usually obtained by the fourth or fifth day,
although improvement might continue for several weeks.
c. Choice of corticosteroid. Response is independent of the corticosteroid
selected (e.g., dexamethasone, methylprednisolone, prednisone,
hydrocortisone), provided that equivalent doses are used. Dexamethasone
has been the most widely used steroid for treating cerebral edema, due to
its relatively low mineralocorticoid (salt-retaining) side effects.
d. Initial dosage. The use of steroids in brain tumor patients was derived from
empirical observations, and most clinical studies have employed different
dosages in steroid administration. Although the information regarding
optimal dosage is largely anecdotal, several guidelines have been
established:
1. There is a clear dose dependency of clinical response to corticosteroids.
The great majority of patients with brain tumors who respond favorably
to steroids do so with dexamethasone, 4 to 6 mg given PO or
parenterally 4 times a day. This is a large dose of steroid
(dexamethasone, 20 mg/day, is roughly equivalent to prednisone, 130
mg/day).
2. Administering dexamethasone in daily divided doses seems to be
necessary because some patients begin to suffer recurrent symptoms if
there is a prolonged interval between doses.
e. Megadoses. Critically ill patients or those who do not have a favorable
response to the standard dexamethasone doses (4 to 6 mg q.i.d.) should
be treated with even more massive dosages (e.g., 25 mg q.i.d.). The risk of
serious side effects is increased with these dosages, but in seriously ill
patients the favorable response may be lifesaving and allow time for more
definitive therapies (e.g., surgical decompression or radiotherapy) to be
undertaken.
f. Side effects. The complications and side effects of steroid therapy in brain
tumor patients are similar to those that occur in any other group of patients.
The physician must be vigilant for glucose intolerance, oral candidiasis or
other infections, gastric irritation, adrenal suppression, steroid myopathy,
osteoporosis, and psychiatric side effects. Serum glucose should be
regularly monitored to detect steroid-induced hyperglycemia. The use of H2
blockers to minimize gastric irritation is indicated for many patients. Oral
candidiasis should be promptly diagnosed and treated with clotrimazole
troches (Mycelex) or fluconazole. Fear of inducing side effects is seldom a
good reason for withholding steroid therapy from patients who are seriously
ill with brain tumor.
g. Duration of treatment. Steroids can be successfully tapered and
discontinued without recurrent neurologic symptoms in patients who have
responded well to definitive therapy (e.g., surgical decompression or
radiation therapy). Unfortunately, many patients with incompletely treated
tumors are steroid-dependent and will experience recurrent cerebral
edema and clinical deterioration when the dosage is tapered below a critical
level. Higher steroid dosages should be reinstituted in these patients, and
most will improve again, although some will never return to their previous
level of function. Many patients with malignant primary or metastatic brain
tumors remain steroid-dependent to maintain some degree of neurologic
function during their last months of life.
B. Surgical therapy of intracranial tumors. Many factors influence the decision for
advising surgical intervention.
1. Histologic confirmation. Despite the recent advance in radiologic diagnostic
techniques, there is still no absolutely reliable substitute for histologic
diagnosis. Patients who are suspected of harboring an untreatable malignant
glioma are still occasionally found to have an occult metastasis, treatable
meningioma, lymphoma, or brain abscess. Direct histologic confirmation
provides the basis for determining the prognosis and need for radiotherapy or
chemotherapy.
2. Restoration of impaired neurologic function. If the preoperative neurologic
deficit is due to direct infiltration and destruction of brain tissue by tumor,
surgical resection cannot be expected to improve the situation. Conversely, to
the extent that the deficits are linked to pressure-related phenomena, they may
be surgically reversible. Surgical resection can be palliative, even in cases in
which total resection is not possible, by providing an internal decompression.
Patients with benign brain tumors that cannot be totally resected may be given
many additional years of productive life by repeated decompressions at
appropriate intervals.
3. Possibility of cure. The complete removal of the brain tumor and permanent
prevention of tumor recurrence can be achieved in many extraaxial tumors
(e.g., meningiomas, schwannomas, pituitary adenomas). Very few intra-axial
tumors can be resected completely or cured surgically.
4. Surgical risks. The patient's general condition and the presence of concurrent
systemic illness (e.g., heart disease, pulmonary disease, disseminated cancer)
will influence the risks of anesthesia and neurosurgery for brain tumor. The
major neurosurgical consideration for operative risk is the location of the tumor.
Deliberate resection or inadvertent compression, retraction, or
devascularization of the brain can produce irreversible deficits. Adverse
anatomic location can render surgical removal of benign tumors hazardous and
complete resection impossible. This is particularly true for tumors in the
hypothalamic and third ventricle region, brainstem tumors, tumors of the clivus
and foramen magnum, and tumors that are intimately involved with major
vascular channels (e.g., carotid artery or sagittal sinus). Conversely, tumors in
relatively silent areas (e.g., anterior frontal lobe, cerebellar hemisphere,
anterior temporal lobe) can be widely resected with relatively little risk of
iatrogenic neurologic impairment. The size of the tumor also affects the
anticipated operative risk. Resection of large tumors requires more extensive
manipulation of adjacent normal structures, thereby increasing the risk of an
adverse outcome.
5. Operative techniques. Stereotactic devices have helped the neurosurgeon
localize the lesion more rapidly and reliably. The use of intraoperative
magnification and the operating microscope allows stereoscopic visualization
of otherwise inaccessible structures and has played a major role in reducing
the morbidity and mortality of brain tumor surgery. The most common
approach to tumors in and around the hemispheres is a craniotomy. A portion
of skull overlying the tumor is removed en bloc, thereby allowing adequate
access to the intracranial compartment. The bone flap is then replaced at the
end of the procedure for protective and cosmetic reasons. Newer
CT-monitored techniques have increased the safety of stereotactic biopsy of
brain lesions without craniotomy or direct tumor exposure. Stereotactic biopsy
is indicated for (a) deep mass lesions inaccessible to surgical resection or (b)
when no preoperative neurologic symptoms are present and the risks of
craniotomy outweigh the benefits. Many brain lesions are not homogeneous,
and stereotactic biopsy may yield tissue samples that are nondiagnostic or
not representative of the tumor as a whole. In general, extensive tumor
resection is the surgical procedure of choice, as it offers the greatest
likelihood of an unequivocal diagnostic specimen, lowers intracranial pressure
(often with improved postoperative neurologic status), and enhances the
likelihood that adjunctive therapies such as radiation or chemotherapy will be
effective.
6. Operative complications
a. Hemorrhage. Intracerebral hemorrhage after craniotomy can occur in or
away from the operative field, often due to traction of an adjacent artery or
vein. Postoperative hemorrhage is usually venous in origin and extrinsic to
the brain itself (subdural or extradural). Evacuation of the extracerebral
collections may be necessary if it produces obtundation or focal deficit.
Hemorrhage is also a potential complication of stereotactic brain biopsy.
b. Brain edema usually is present prior to surgery and may be severely
aggravated during surgery by mechanical retraction, venous compression,
brain manipulation, and overhydration. Patients should receive
corticosteroids for several days prior to craniotomy to reduce preoperative
cerebral edema. Intraoperative use of osmotic agents such as IV mannitol
may be necessary to reduce cerebral edema.
c. Infection. The risk of wound infection is increased in lengthy operations
and procedures in which foreign materials (e.g., shunt tubing,
chemotherapy polymers) are implanted. Most infections are by cutaneous
or airborne pathogens (e.g. gram-positive cocci, most notably
staphylococci). The routine use of prophylactic antibiotics in brain tumor
surgery is not recommended.
d. Seizures. Supratentorial operations carry a risk of causing focal or
generalized seizures. The likelihood of seizures depends on the location
and histology of the tumor as well as operative complications. When
postoperative seizures develop, they usually do so within the first month
after surgery. The following guidelines seem appropriate:
1. All patients with a history of seizures prior to surgery should be
maintained on a proper anticonvulsant regimen during and after surgery.
2. Prophylactic anticonvulsant therapy is not routinely warranted for all
patients with brain tumor. Most studies of prophylactic anticonvulsant
therapy have shown postoperative seizure rates to be similar for treated
and untreated patients. There is an increased incidence of
anticonvulsant side effects due in patients undergoing radiation and on
steroid therapy. There is an increased risk of Stevens-J ohnson
syndrome in the setting of steroid taper, radiation, and phenytoin or
carbamazepine therapy.
3. Falx and parasagittal meningiomas carry the highest risk of
postoperative seizures. In these cases, prophylactic anticonvulsant
therapy should be given before surgery and continued at least 4 months
thereafter.
e. Communicating hydrocephalus. Leakage of blood into the CSF pathways
during surgery can result in impairment of CSF absorption in the arachnoid
villi, producing a communicating hydrocephalus. This is usually a
self-limited problem and only seldom requires relief by a lumbar puncture or
shunt. This is in contrast to tumors that block CSF flow in the third or fourth
ventricles causing obstructive hydrocephalus. In this situation ventricular
shunting is often an important part of the surgical management to alleviate
dangerous intracranial hypertension.
f. Neuroendocrine disturbances. The syndrome of inappropriate antidiuretic
hormone secretion (SIADH) will occasionally occur after brain surgery.
Electrolytes should be monitored in the postoperative period, as the
retention of free water results in hyponatremia and severe cerebral edema.
Rigorous fluid restriction will correct the fluid and electrolyte disturbance.
SIADH seldom lasts for more than a week or two postoperatively.
Surgery in the region of the hypothalamic-pituitary axis can result in various
degrees of panhypopituitarism, diabetes insipidus, or both.
III. Brain tumors in adults
A. Overview. The majority of adult primary cerebral neoplasms arise from cells of
glial origin (astrocytes, oligodendrocytes, or ependymal cells). Tumors derived
from astrocytes are by far the most common adult gliomas.
Several grading systems for classifying these tumors have been used, looking at
cellularity, nuclear atypia, mitoses, endothelial proliferation, and necrosis.
B. Malignant glioma
1. Incidence. The most common primary brain tumor in adults is malignant
glioma, which includes anaplastic astrocytoma and glioblastoma
multiforme. Both are invasive malignant tumors with hypercellularity, vascular
proliferation, and pleomorphism. The distinction is based largely on the
presence of tumor necrosis in glioblastoma.
There are approximately 5,000 new cases of this disorder each year in the
United States. The age of peak incidence is 45 to 55 years, and men are more
frequently afflicted than women, in a ratio of 3:2. The tumor may arise in any
portion of the cerebral hemispheres, with the frontal and temporal lobes being
the most frequent sites. The cerebellum, brainstem, and spinal cord are rare
sites for malignant glioma in adults.
2. Prognosis. Malignant gliomas are rapidly growing anaplastic tumors, with a
uniformly fatal prognosis. The median survival is only 27 months for anaplastic
astrocytoma and 8 months for glioblastoma multiforme. Although these tumors
are highly invasive within the central nervous system (CNS), they seldom
metastasize outside of the nervous system. Age is an important prognostic
indicator. Patients younger than 45 survive significantly longer than patients
over 65, regardless of therapy. Patients presenting with personality change or
impaired functional status have a worse prognosis than patients without these
findings.
3. Surgical therapy. The surgical treatment of choice is craniotomy followed by
extensive resection of the largest volume of tumor possible. This is the most
reliable method for obtaining adequate histologic samples and results in
internal decompression of the swollen brain. Patients with malignant gliomas
treated with extensive surgical resection do better postoperatively, require less
long-term steroid therapy, and survive longer than patients who have
undergone only partial excision or biopsy.
Although malignant gliomas often appear relatively well circumscribed on CT or
MRI examination, the tumor invariably infiltrates into adjacent lobes or across
cerebral commissures. Therefore, although the neurosurgeon may
optimistically report gross total removal of the tumor, malignant gliomas will
always recur, usually within months. Unfortunately, surgery is never curative in
these cases.
4. Radiation therapy
a. Dosage and fields. Malignant glioma is not a radiosensitive tumor.
Nevertheless, studies performed in the 1970s showed that patients who
received a full course of postoperative radiation therapy survived longer
than patients who did not. The median survival following surgery and
radiation therapy for glioblastoma multiforme is approximately 40 weeks.
Current practice involves a localized field approach with 4,500 cGy to the
area surrounding the tumor plus additional coned-down radiation to the
tumor bed (e.g., 2,000 cGy), divided in a total of 25 to 30 fractions.
b. Brachytherapy. Since 80% of malignant gliomas recur within the original
tumor margins, investigational efforts have explored providing high-dose
focal therapy (stereotactic I-125 or Ir-192 implants) to the tumor and its
borders. The role of brachytherapy has not been defined, but this technique
may prolong survival in selected patients.
c. Complications of radiation therapy. The incidence of radiation-induced
brain damage is thought to be small if standard doses are used. However,
as many as 40% of malignant glioma patients who survive for more than 18
to 24 months after whole-brain radiation therapy develop progressive
cognitive impairment, cerebral atrophy, and white matter changes on CT or
MRI as a delayed complication (see VI.A).
Radiation can cause an increase in cerebral edema. Steroids are continued
throughout radiation therapy and can be slowly tapered during the last few
weeks of treatment if the patient's condition is clinically stable. All patients
suffer loss of hair as a result of therapy, although in many instances the hair
regrows over the next few months. Perhaps the greatest morbidity that
most patients suffer as a result of cranial irradiation is the extra 5 to 6
weeks during which they must either remain in the hospital or return each
day for treatment. In view of the poor prognosis of glioblastoma, this is an
important consideration.
d. Value of radiotherapy. Although radiation is not curative, it does
ameliorate symptoms and lengthen short-term survival. These modest
benefits justify the continued use of postoperative cranial irradiation in
malignant glioma (Table 11-2).
TABLE 11-2. Results of Various Treatment Programs for Malignant Glioma
5. Chemotherapy
a. The failure of surgery and radiation therapy to alter the grim prognosis has
led to clinical trials of antineoplastic agents in malignant glioma. Progress in
finding effective chemotherapy has been impeded by problems in drug
delivery to the brain, neurologic and systemic toxicity, and tumor resistance.
b. Lipid-soluble drugsthe nitrosoureas. Small, lipid-soluble molecules
that can cross the normal blood-brain barrier, such as the nitrosoureas,
may have the best chance of attaining sufficient concentration for
chemotherapeutic effectiveness in all areas of the tumor. A large
randomized study demonstrated modest increases in median survival (from
36 to 51 weeks) and long-term survivors (24% at 18 months) for patients
receiving intravenous carmustine (BCNU) in addition to surgery and
radiation therapy. Trials of intracavitary implantation of slow-release
carmustine-impregnated polymer wafers (Gliadel) demonstrated
prolongation of survival without the systemic side effects associated with
chemotherapy in patients with recurrent malignant glioma. This is a novel
therapeutic approach that may also be beneficial as a primary treatment for
newly diagnosed cases.
c. Other agents, including procarbazine, oral lomustine (CCNU), etoposide,
vincristine, and streptozotocin have been studied. The combination of
procarbazine, lomustine, and vincristine has been employed with modest
clinical benefit.
d. Recommendation for chemotherapy. Chemotherapy (e.g., BCNU,
CCNU) is not recommended routinely for all patients with malignant glioma.
The data indicate that adjuvant chemotherapy is only marginally effective in
prolonging survival or improving quality of life. The additional morbidity of
chemotherapy is justified only in younger patients with minimal neurologic
deficits.
e. Immunotherapy. Immunotherapy offers the theoretic promise of specific
antitumor cytotoxicity with little or no damage to normal brain. Studies
involving active immunization with irradiated autologous tumor cells,
adoptive immunotherapy (intratumoral or IV injection of immune cells),
humoral immunomodulators (e.g., interferons), monoclonal antibody
therapy, and gene therapy are all in the experimental stage.
6. Recurrent glioma. Weeks to months after treatment with surgical resection,
radiation therapy, and chemotherapy, patients will develop worsening
neurologic symptoms and CT/MRI evidence of recurrent glioma. The tumors
tend to recur at or within a few centimeters of their original site. Reoperation
can debulk the tumor, thereby reducing the mass effect, lowering the patient's
steroid requirements, and temporarily improving quality of life for a few months.
Intracavitary implantation of carmustine-implanted polymer wafer can be
considered at reoperation. At times it is difficult to distinguish recurrent tumor
from radiation necrosis, as both can cause mass effect and surrounding
edema. An area of radiation necrosis would be hypometabolic on a single
proton emission computed tomography scan, whereas an area of malignant
tumor recurrence would be hypermetabolic.
7. Referral for research protocols. Many medical centers are actively studying
new cytotoxic drugs and other experimental approaches for recurrent
malignant gliomas (e.g., chemotherapy, interstitial brachytherapy,
hyperthermia, immunotherapy). Patients in relatively good neurologic condition
should be offered the option of referral to one of these research centers. The
prospective data gathered at these institutions will one day result in an
improved outlook for patients with malignant glioma.
B. Supratentorial astrocytomas in adults
1. Biology. Astrocytomas of the cerebral hemisphere occur less commonly in
adults than malignant glioma and account for only 10% of adult primary brain
tumors. Although these neoplasms are referred to as low grade or
histologically benign, they continue to grow and dedifferentiate, ultimately
shortening life.
2. Presentation. Patients with these tumors will typically present with a transient
neurologic event (e.g., a seizure), a normal neurologic examination, and brain
MRI or CT studies revealing a nonenhancing supratentorial lesion with minimal
mass effect. Cerebral infarction, multiple sclerosis plaque, vasculitis, and
progressive multifocal leukoencephalopathy could also produce similar brain
imaging study abnormalities and must be considered in the differential
diagnosis.
3. Surgery. Because these tumors may remain clinically dormant for many years,
some experts advocate waiting until the lesion has progressed before advising
any treatment. Most would agree that the treatment of choice is biopsy and
extensive surgical resection if the lesion is in an area that is surgically
accessible. These tumors have an infiltrative growth pattern, and only rarely
can complete excision be achieved, although the amount of residual
postoperative tumor correlates with prognosis. Stereotactic biopsy can miss
areas of anaplasia and lead to misdiagnosis.
4. Radiation therapy. Postoperative radiation therapy (5,500 cGy to the tumor
bed) might modestly delay tumor recurrence, but it is unclear as to whether
long-term (10-year) survival is increased or whether the benefit outweighs the
risk of delayed post-radiation cognitive impairment (see sec. VI.A). Prospective
studies are underway to determine whether radiation therapy should be
routinely administered.
5. Prognosis. The prognosis for supratentorial astrocytoma is highly variable.
Statistics taken from a large heterogeneous series of cases suggest a median
survival of 5 to 8 years after surgery, and the range in survival time is quite
great. Some patients die within the first year, whereas a small number survive
for more than 10 years without further symptoms. The vast majority of patients
eventually suffer recurrence and progressive neurologic symptoms. In many
cases, this represents a malignant dedifferentiation of the tumor to
glioblastoma multiforme.
Patients in whom the recurrent tumor is in a surgically accessible location often
benefit substantially from repeated craniotomy and tumor resection.
Antineoplastic chemotherapy has not been useful in the management of
astrocytoma but may have a role in tumors that have dedifferentiated to
malignant glioma.
6. Favorable variants. A small minority of astrocytomas, including subependymal
giant cell astrocytoma, pilocytic astrocytoma, and pleomorphic
xanthoastrocytoma, have a reduced capacity for invasion and limited potential
for growth and anaplastic progression. These lesions have a much more
favorable long-term prognosis with resection alone than other astrocytic
neoplasms.
C. Oligodendrogliomas
1. Biology. This is an uncommon neoplasm, appearing on CT or MRI as a
partially calcified, variably enhancing mass. The clinical presentation and
natural history of these lesions are similar to that of astrocytoma.
2. Treatment. Surgical resection is appropriate to establish a diagnosis, but the
role of early radiation therapy is unresolved. Radiotherapy may be reasonably
deferred in indolent cases until there is progression clinically or radiologically.
3. A small subset of anaplastic oligodendrogliomas behave very aggressively
and may even metastasize in the meninges or systemically. These tumors are
much more sensitive to antineoplastic chemotherapy than other malignant
gliomas, and several year survival is possible with treatment. The potential for
palliation of this rare tumor underscores the importance of accurate tissue
diagnosis in patients with brain tumor.
D. Primary central nervous system lymphoma
1. Epidemiology. Primary central nervous system lymphoma (PCNSL) is a
non-Hodgkin B-cell tumor, occurring in the absence of systemic lymphoma.
There is an greatly increased risk of these tumors in immunosuppressed
hosts, e.g., autoimmune deficiency syndrome (AIDS) patients and organ
transplant recipients. Three percent of AIDS patients will develop PCNSL
either prior to AIDS diagnosis or during their subsequent course. Although
uncommon, the incidence of PCNSL has also been increasing in the
immunocompetent population, with an average age at diagnosis of 60 and a
slight male preponderance.
2. Clinical features. There are 4 distinct clinical presentations of primary CNS
lymphoma.
a. Solitary or multiple discrete intraparenchymal brain tumors causing
change in personality or focal deficits are the most common clinical
presentations. The tumors are multifocal in nearly half the cases and may
be mistaken for cerebral metastases of occult origin.
b. Diffuse meningeal or periventricular infiltration is the second most
common clinical presentation. This can occur simultaneously with discrete
intraparenchymal mass(es).
c. Retinal or vitreous infiltration can antedate (or follow) the development of
brain or meningeal lesions. Slit-lamp examination should be a routine part
of monitoring patients with primary CNS lymphoma.
d. Involvement of the spinal cord with discrete intramedullary tumor nodules
can rarely occur.
3. Radiologic features can be distinctive. The lesions of PCNSL are usually
periventricular and may involve deep structures such as the basal ganglia.
They enhance diffusely with contrast and generally lack ring enhancement or
significant peritumoral edema (unlike most brain tumors or abscesses).
4. Diagnosis in immunocompetent patients. Surgical cure is not possible for a
tumor characterized by invasion and multicentricity. Stereotactic biopsy or CSF
cytology (including immunocytologic studies) are diagnostic procedures of
choice in patients with multifocal or diffuse meningeal disease. Steroids
should be avoided if possible in the prebiopsy treatment of patients
suspected of having PCNSL. Steroids cause tumor lysis, producing dramatic
clinical and radiologic improvement, but obscure the ability to make a definitive
diagnosis by biopsy. Other CNS diseases, such as sarcoidosis, may also
present with enhancing masses that resolve with steroids. Histologic
confirmation of malignant lymphoma must be obtained before cytotoxic therapy
can be considered.
5. Diagnosis and management of intracranial mass lesions in patients with
AIDS. Intracranial mass lesions are common consequences of human
immunodeficiency virus (HIV) infection and usually caused by opportunistic
infections (most commonly toxoplasmosis, but also cryptococcal abscesses
and cryptococcomas, tuberculous abscess and tuberculoma, Nocardia
abscesses, syphilitic gummas, Candida abscesses, etc.) or by neoplasm
(most commonly PCNSL, but also metastatic tumors).
a. Toxoplasmosis is the most common cause of cerebral mass lesions in
adults with AIDS in the United States, affecting 10% to 15% of these
patients. Empiric treatment for toxoplasmosis without biopsy confirmation
can be initiated in AIDS patients with a positive Toxoplasma serology and in
patients with multiple lesions. Patients treated presumptively require careful
clinical and radiologic monitoring over the ensuing 2 weeks. Ninety percent
of patients with toxoplasmosis will improve by day 14. Failure to respond
warrants consideration for additional diagnostic studies such as stereotactic
biopsy.
b. A solitary lesion accompanied by a negative Toxoplasma serology in an
HIV infected patient warrants stereotactic brain biopsy rather than waiting
for the results of 2 weeks empiric toxoplasmosis therapy.
c. Opportunistic CNS infections including toxoplasmosis are less common in
HIV-infected children. Proceeding directly to biopsy may be appropriate in
this group of patients.
6. Treatment of PCNSL in immunocompetent patients. Clinical improvement
with steroids and radiation therapy is usually very dramatic but temporary. The
median survival with radiation alone is only 18 months. Neuraxis dissemination
occurs in 60% and systemic lymphoma in 10% of patients who survive over 1
year after radiation for PCNSL. Several recent studies have established the
sensitivity of PCNSL to chemotherapy. One regimen employing IV
methotrexate and intrathecal methotrexate (via intraventricular reservoir)
before radiation therapy, with postirradiation high-dose cytarabine, prolonged
median survival to 42 months.
7. Treatment of PCNSL associated with AIDS. The prognosis in
AIDS-associated PCNSL is dire, partly because these patients may succumb
to opportunistic infections rather than PCNSL. Radiation therapy prolongs
survival to several months, but chemotherapy is probably best reserved for
immunocompetent patients.
D. Meningiomas
1. Biology. Meningiomas are histologically benign tumors that arise from
arachnoidal cells. They are the second most common primary intracranial
tumors in adults. Their peak incidence is in the fourth and fifth decades, and
unlike other primary brain tumors, meningiomas occur more commonly in
women than in men (in a ratio of 2:1).
a. Cytogenetic analysis has demonstrated multiple deletions on chromosome
22 in most patients with meningioma.
b. Progesterone and estrogen receptors are present in many meningiomas
and may have functional importance in the growth of these tumors.
2. Location. The anatomic distribution of meningioma parallels that of the
arachnoid villi: the cerebral convexities (50%--parasagittal, falx, or lateral
convexity) or base (40%--olfactory groove, sphenoid wing, or suprasellar).
Meningiomas of the foramen magnum, posterior fossa, or ventricular system
are relatively uncommon. Far less common in the spinal canal than
intracranially, meningiomas nevertheless account for 25% of primary spinal
tumors, occurring most frequently in the thoracic region.
3. Radiologically on CT or MRI meningiomas show well-defined extra-axial
lesions that enhance homogeneously after IV contrast and may be calcified.
4. Surgery. Meningiomas are well-circumscribed, slow-growing tumors. They
may infiltrate the dura, dural sinuses, or bone but generally do not invade the
underlying brain parenchyma. Complete surgical removal and surgical cure are
often possible in meningiomas of the dural convexity, falx, lateral sphenoid
wing, frontal base, and posterior fossa.
5. Prognosis. The prognosis is generally favorable, and prolonged survival after
surgical resection is the rule rather than the exception. Nevertheless, the rate
of tumor recurrence and life expectancy may vary, depending on the location of
the tumor and whether complete surgical resection is possible.
In a large series of patients with meningioma, a macroscopically complete
removal of the tumor was achieved in about 60% of cases. There was a 10%
rate of tumor recurrence in the patients with complete tumor removal, probably
due to residual untreated nests of tumor; and the average time that elapsed
between primary operation and confirmation of recurrence was 4 to 5 years
(range 1 to 13 years). Many of these patients benefited from a second tumor
resection. In the group of patients in whom the resection of intradural tumor
was frankly incomplete, there were clinical recurrences in about 40% of cases.
However, there were many satisfactory results even in this group: 25%
survived more than 10 years after only partial resection.
6. Histology. The major histologic subtypes of meningiomas are
endotheliomatous, transitional, and angioblastic. The prognoses of these
tumors are similar. The rare hemangiopericytoma and malignant meningioma
are biologically more aggressive and recur with significantly higher frequency
and after shorter intervals than the other types of meningiomas.
7. Radiation therapy may be indicated for some patients with progressive
neurologic deficits due to recurrent meningioma in whom further surgical
therapy is inadequate or contraindicated. Retrospective studies have
suggested prolonged survival and delayed recurrence rates for selected
patients with subtotally resected meningioma who have undergone local
radiation therapy.
8. Incidental meningioma. With the advent of CT and MRI, meningiomas are
being discovered serendipitously in patients who are being evaluated for
unrelated problems (e.g., head trauma, stroke). The size and location of the
tumor, the presence or absence of mass effect and edema, and the age of the
patient help to determine proper management. Meningiomas with considerable
surrounding edema can justifiably be removed after the first evaluation. Small
asymptomatic tumors without mass effect can be followed clinically and with
serial CT scans. Surgical resection is not indicated unless there is evidence of
progression.
E. Acoustic schwannoma
1. Incidence. Schwannomas, tumors of the Schwann cells of peripheral nerves,
commonly occur in the intracranial cavity, originating from the acoustic nerve at
the cerebellopontine angle. Schwannomas are the most common
cerebellopontine angle tumors, but meningiomas, gliomas, and
cholesteatomas also may occur in this location.
Acoustic schwannomas account for 8% of all brain tumors. They occur mainly
in middle adult life and are rare in childhood. About 5% to 10% of patients with
acoustic schwannoma have the central form of von Recklinghausen
neurofibromatosis. In these patients, the acoustic tumors are often bilateral and
may be associated with multiple cranial and spinal schwannomas,
meningiomas, and gliomas.
2. Clinical features. The earliest symptoms of acoustic schwannoma are caused
by impairment of the acoustic nerve (deafness, tinnitus, and unsteadiness),
with trigeminal dysfunction (loss of corneal reflex, facial numbness), facial
weakness, and ataxia occurring later. Isolated vertigo is an extremely
uncommon first symptom. MRI with contrast is the diagnostic procedure of
choice and can detect even small intracanalicular tumors.
3. Treatment
a. Surgery. Schwannomas are slow growing, and symptoms are usually
present for months to years before the diagnosis is made. The tumors are
usually encapsulated and compress but do not invade the adjacent neural
tissue. Tumors less than 2 cm in diameter can usually be completely
removed. Complete removal is seldom possible with large tumors. Serious
surgical morbidity also has been directly related to the size of the tumor,
being less than 5% for tumors smaller than 2 cm in diameter, and more
than 20% for tumors greater than 4 cm in diameter. If left untreated, these
tumors ultimately cause increased intracranial pressure and brainstem
compression. This underscores the importance of early diagnosis and
treatment to reduce the morbidity and mortality of this disease.
The surgical approach varies with the size of the tumor, the presence or
absence of functional hearing, and the expertise of the surgical team.
Recent advances in diagnostic and surgical techniques have resulted in
improved ability to resect these tumors completely. Anatomic preservation
of the adjacent facial nerve is usually possible, although permanent facial
paralysis occurs postoperatively in many cases. Preservation of functional
hearing after surgery can be expected in only a small proportion of cases.
b. Standard radiotherapy has not been of value in the treatment of
incompletely resected acoustic schwannomas. Stereotactic radiosurgery
(the gamma knife, i.e., multiple highly collimated beams of gamma
irradiation focused on the tumor) shows promise for treating elderly patients
or patients with serious medical conditions that would increase the risk of
surgery. Gamma knife radiosurgery may be an effective alternative to
surgery in treating patients with small to medium sized acoustic neuromas.
F. Sellar and parasellar masses include pituitary adenomas, meningiomas,
craniopharyngiomas, metastatic tumors, nasopharyngeal tumors, and
nonneoplastic lesions such as sarcoidosis and aneurysms. Pituitary adenomas
are the most common sellar tumors.
1. Classification. Pituitary adenomas can be classified on a functional
(endocrine) or anatomic basis.
a. Functional classification
1. Nonfunctioning (null cell) adenomas.
2. Hypersecreting adenomas. From late adolescence through adulthood
the frequency of adenoma is prolactinoma >nonsecreting adenoma >
growth hormone-secreting adenoma >corticotropin-secreting adenoma
>glycoprotein-secreting adenoma.
b. Anatomic classification
1. Microadenomas (less than 10 mm in diameter).
2. Diffuse adenomas (surrounded by dura but with some suprasellar or
parasellar extension).
3. Invasive adenomas (infiltrating dura, bone, or brain).
2. Clinical and laboratory features of pituitary adenomas. Laboratory studies
of anterior pituitary function should be obtained including prolactin, growth
hormone, thyroid function, cortisol levels, follicle-stimulating hormone,
luteinizing hormone, and testosterone.
a. Microadenomas will be asymptomatic unless they are hypersecreting
tumors.
1. Hyperprolactinemia can be determined by measurement of morning
basal prolactin levels. Levels greater than 100 ng/mL (normal value is
less than 15 ng/mL) almost always indicate a tumor. Levels between 15
and 100 ng/mL can be due to a pituitary tumor but are more often
caused by medications (e.g., phenothiazines, antidepressants,
estrogens, metoclopramide) or disorders that interfere with normal
hypothalamic inhibition of prolactin secretion. Once a microprolactinoma
is detected, only about 5% of patients will subsequently develop
macroadenomas.
2. Hyperprolactinemia sometimes will cause no symptoms. In women it
usually causes amenorrhea or galactorrhea (or both). Perhaps one
fourth of all women with secondary amenorrhea and galactorrhea have
prolactin-secreting pituitary tumors. In men, the earliest symptoms of
hyperprolactinemia are impotence and loss of libido. Gynecomastia and
galactorrhea are much later manifestations in men.
b. Macroadenomas. Larger tumors compress the adjacent normal pituitary
gland and can produce variable degrees of hypopituitarism; gonadotropin
deficiency is usually seen before the development of corticotropin
deficiency. Extension of tumor above the sella turcica will compress the
optic chiasm. This causes progressive visual loss that often starts as a
bitemporal superior quadrant-anopia. Advanced cases will invade the
cavernous sinus, third ventricle, hypothalamus, or temporal lobe. Most
macroadenomas come to medical attention because of visual loss or due to
headache.
c. Tumors that secrete adrenocorticotropic hormone (ACTH) or growth
hormone are usually diagnosed while they are relatively small because the
striking endocrine disturbances (Cushing disease or acromegaly) lead to
early detection.
d. Pituitary apoplexy. Perhaps 5% of cases present with sudden progression
of symptoms resulting from acute hemorrhage, tumor necrosis, or both.
This syndrome, known as pituitary apoplexy, may lead to rapid visual loss,
subarachnoid hemorrhage, and impairment of consciousness. Pregnancy,
head trauma, acute hypertension, and anticoagulation predispose to
pituitary apoplexy.
3. Diagnosis. MRI provides sagittal as well as coronal and axial views, and
serves to demonstrate the relationship of tumor to the optic chiasm, cavernous
sinus, and hypothalamus. MRI can distinguish pituitary tumor from aneurysm.
4. Treatment of pituitary adenomas depends on the size of the tumor and the
associated endocrine or visual disturbances.
a. Surgery. Signs of significant extrasellar extension, such as involvement of
the optic chiasm or cranial nerves, are indications for surgery in
nonsecretory adenomas. Prolactic secreting tumors respond well to medical
therapy (sec. 4.C.) and seldom require surgery. Transsphenoidal surgery
has a much lower operative morbidity and mortality than the transcranial
approach. With the use of the operating microscope, it is possible to dissect
and remove both microadenomas and larger tumors while preserving a
normal pituitary gland.
The prognosis for visual recovery is best when the history of impairment
has been brief. The endocrine status after surgery is also improved
occasionally (e.g., fertility might return in 70% of patients).
During surgery for pituitary tumors, patients are treated with corticosteroids
as prophylaxis against adrenal insufficiency. The degree of pituitary
impairment is reassessed postoperatively so that appropriate replacement
therapy can be administered if indicated. Diabetes insipidus can occur after
surgery, but it is usually transient.
b. Postoperative irradiation. Radiation therapy has proved to be a useful
adjunct in significantly reducing the rate of postoperative recurrence in
cases in which complete resection is not possible. In one series of patients,
the recurrence rate was decreased from 42% to 13% by postoperative
irradiation. Current practice is to administer 5,000 to 6,000 cGy over 5 to 6
weeks. The field size is determined by the radiographic and surgical
findings.
Stereotactic radiosurgery might have a role in treating small tumors
(particularly those causing acromegaly or Cushing disease) that have
recurred despite microsurgery.
c. Medical treatment with dopamine agonists. Dopamine is the
hypothalamic neurotransmitter that normally inhibits prolactin secretion from
pituitary cells. Bromocriptine, a synthetic dopamine agonist, reduces high
prolactin levels and may induce shrinkage of tumor with relief of mechanical
symptoms.
Pharmacologic therapy with bromocriptine should be the initial treatment for
patients with a prolactinoma, and in most cases surgery can be avoided. In
hyperprolactinemia with amenorrhea and galactorrhea, the symptoms are
reversed in over 80% of women treated with bromocriptine, and fertility is
restored. Another dopamine agonist, carbergoline, has also been approved
by the FDA for treatment of prolactinomas. This drug has a longer half-life
and greater potency than bromocriptine.
There is some apprehension about letting a patient with a prolactinoma
become pregnant for fear of precipitating symptomatic tumor growth (during
normal pregnancy, pituitary volume may double). Fortunately, this
complication is uncommon, occurring in only 1% of women with
microadenomas but in 25% with macroadenomas. Bromocriptine appears
to be safe in pregnancy and can be reinstituted if this occurs. Nevertheless,
surgery is usually recommended for patients with macroadenomas who
desire pregnancy.
d. The somatostatin analog octreotide may decrease the size of growth
hormone-secreting pituitary tumors. Growth hormone-secreting adenomas
should be resected surgically. Octreotide can be used as an adjunct to
surgery or as primary treatment in selected cases.
G. Cerebral metastases. Metastasis to the brain parenchyma or meninges is a
common complication of systemic cancer. Approximately 15% to 20% of patients
dying of cancer will have brain metastasis at the time of autopsy. The frequency of
brain metastases varies considerably with the histology of the cancer.
Bronchogenic carcinoma, breast carcinoma, renal cancer, and malignant
melanoma are the cancers most likely to metastasize to the brain. Hematologic
malignancies such as Hodgkin disease or chronic lymphocytic leukemia rarely
cause parenchymal brain metastasis. When neurologic signs and symptoms
develop in a patient with cancer, a variety of potential diagnoses in addition to
cerebral metastasis must be considered (Table 11-3).
TABLE 11-3. Common Neurologic Complications of Cancer
1. Intraparenchymal metastases
a. Clinical features. The formation of a solid mass lesion is the most common
type of cerebral metastasis. Metastases reach the brain by hematogenous
spread. The frequency of metastasis in these structures is roughly in
proportion to the blood flow to the region (cerebral hemispheres >
cerebellum >brainstem). These lesions cause symptoms through increased
intracranial pressure, destruction of brain tracts, cerebral edema, or
seizures (similar to primary brain tumors). Headaches, intellectual or
behavioral changes, focal weakness, and unsteadiness are the most
common presenting signs. In about 40% of cases of brain metastasis, a
solitary lesion will be seen on CT scan; in the remaining 60%, multiple
tumors are seen. MRI with contrast is more sensitive for demonstrating
small tumors and may show multiple lesions when only one is seen on
contrast-enhanced CT.
b. Cancer presenting as brain metastasis. In patients with a known history
of malignancy, the development of neurologic signs or symptoms prompts
immediate investigation for evidence of CNS metastases. However,
occasionally brain metastasis will be the initial clinical manifestation of a
systemic cancer. The possibility of metastasis from an occult primary tumor
therefore must be considered in every patient with brain tumor.
Thorough general physical examination and routine screening tests (e.g.,
urinalysis, stool guaiac, CBC, liver function tests, chest x-ray) always
should be performed before craniotomy for a (presumed) primary brain
tumor. Since virtually all parenchymal brain metastases are hematogenous
in origin, the lung is likely either the site of the underlying tumor or involved
metastatically. CT of the chest and abdomen is the most useful diagnostic
test in patients suspected of having a brain metastasis of unknown origin in
whom the routine laboratory tests and chest x-ray are negative. Further
search for a primary tumor is seldom fruitful if there no other clues on
history or physical examination.
c. Corticosteroids. High-dose corticosteroids are useful in palliating
symptoms from cerebral metastases by reducing brain edema. Steroids
should be started if the CT or MRI scan shows mass effect or edema, and
continued through the course of surgery or radiation therapy. Megadoses
of dexamethasone (e.g., 25 mg q6h) may palliate intractable headaches or
progressive deficits when standard doses (4 to 6 mg q6h) fail (see sec.
II.A.1).
d. Surgery for solitary metastasis. If the brain metastasis is solitary and is in
a relatively accessible location (e.g., frontal lobe, nondominant temporal
lobe, cerebellum), total surgical excision is sometimes possible. Surgery
should be reserved for patients with a solitary metastasis who do not have
extensive systemic disease or for patients in whom the histology of the
CNS abnormality is in some doubt. Recent randomized studies reveal that
surgery provides symptomatic relief and longer survival in patients with
solitary metastasis compared to radiation therapy alone.
It is uncertain whether whole-brain radiation should be administered to
patients following resection of solitary brain metastasis. The risks of
radiation toxicity in long-term survivors may outweigh the benefits, but this
issue has not been resolved.
e. Radiotherapy. Cancer patients with multiple cerebral metastases and
those with solitary metastases who are not candidates for surgery should
undergo cranial irradiation. This is one of the few instances in which
radiotherapy is justified without a histologic diagnosis of the lesion. The
presence of intracerebral metastases is documented on CT scan before
starting radiotherapy. The radiation dose is generally 2,500 to 5,000 cGy,
delivered to the whole brain over 2 to 4 weeks. Stereotactic radiosurgery
using the gamma knife or linear accelerator is being used in patients
with both newly diagnosed and recurrent disease. These techniques deliver
a very high dose of radiation to a very limited well-defined area of tissue in
a single treatment fraction. There are many potential advantages to these
techniques and trials comparing radiosurgery plus whole-brain irradiation
versus whole-brain irradiation alone for patients with multiple metastases
are now underway.
f. Radiosensitive cancers such as breast cancer, choriocarcinoma, testicular
cancer, and lymphoma have better response rates than resistant tumors
such as melanoma, colon cancer, or renal cancer. However, most patients
who complete the course of cranial irradiation experience at least some
relief of symptoms. The 6-month survival rate in this group is 33%; the
1-year survival rate is 10%. Death is usually due to aggressive uncontrolled
systemic disease rather than brain metastasis. A small group of patients
with stable systemic disease will have a prolonged survival.
g. Patients who suffer recurrent cerebral metastasis after standard
radiotherapy who have stable systemic disease may be candidates for
stereotactic radiosurgery or surgical decompression.
h. Systemic chemotherapy. Systemic anticancer chemotherapy has not
proved useful in the treatment or prevention of cerebral metastases. For
example, brain metastases often continue to grow despite shrinkage of
pulmonary or hepatic metastases in patients undergoing chemotherapy.
The difficulty has probably been related to the inability of most drugs to
cross the blood-brain barrier in sufficient concentrations to be effective.
2. Meningeal carcinomatosis and meningeal lymphoma
a. Incidence. Infiltration of the leptomeninges by neoplastic cells (meningeal
carcinomatosis or neoplastic meningitis) is a common complication of
cancer. Meningeal carcinomatosis occurs most often in cases of stage 4
non-Hodgkin lymphoma, small cell lung cancer, breast cancer, malignant
melanoma, gastrointestinal neoplasms, and acute leukemias. The
development of neoplastic meningitis in patients with solid tumors is
typically accompanied by widespread systemic metastasis. Meningeal
involvement is so common in acute lymphoblastic leukemia and
transformed cell lymphomas that patients with these neoplasms are given
prophylactic CNS treatment.
b. Clinical features. The neurologic signs of meningeal carcinomatosis are
caused by focal infiltration of cranial nerves (e.g., diplopia, facial palsy),
spinal nerve roots (e.g., radicular pain and radicular sensorimotor
symptoms), or cerebral symptoms (headache, change in mental status).
The diagnosis of neoplastic meningitis should be considered in any patient
who presents with neurologic signs or symptoms attributable to multiple
anatomic sites within the neuraxis.
Approximately one third of patients with meningeal carcinomatosis will have
concomitant parenchymal brain metastases.
c. Diagnosis
1. The diagnosis of meningeal carcinomatosis is confirmed by cytologic
demonstration of malignant cells in the CSF. Malignant cells are not
found in the CSF in tumors that are strictly intraparenchymal, but only
when the meninges are invaded. CSF protein is often elevated, and
CSF glucose is sometimes diminished in meningeal carcinomatosis, but
these are nonspecific abnormalities. The CSF may show a modest
pleocytosis or be relatively acellular.
2. Although the majority of initial lumbar punctures are abnormal in
patients with neoplastic meningitis, serial lumbar punctures may be
required to cytologically identify malignant cells in the spinal fluid.
3. MRI or CT scan of the brain can be helpful in suggesting the diagnosis
of meningeal carcinomatosis if contrast enhancement of the basal
cisterns is seen. However, in most cases CNS brain imaging studies are
unrevealing or just show mild hydrocephalus. MRI with gadolinium of the
lumbar spine or myelography may reveal tumor nodules in the nerve
roots of the cauda equina in many patients with meningeal
carcinomatosis.
4. The clinician must keep a high index of suspicion and obtain one or
more CSF cytology specimens to make an early diagnosis of meningeal
carcinomatosis.
d. Treatment. Because of the widespread dissemination of malignant cells
within the CSF, effective therapy must target the entire neuraxis. The
current approach to treatment of meningeal carcinomatosis is local
radiation delivered to bulky or symptomatic sites of disease combined with
serial intrathecal administration of methotrexate, cytosine arabinoside,
or thiotepa. Some patients require whole-brain radiation, especially when
a concomitant intraparenchymal metastasis is suspected. Typical doses for
intrathecal treatment are as follows: methotrexate, 12 mg; cytosine
arabinoside, 50 mg; or thiotepa, 10 mg administered biweekly.
Chemotherapeutic agents for intrathecal use must be injected using
preservative-free diluents. The preservatives in bacteriostatic diluents can
cause severe CNS complications.
e. Duration of treatment. When clinical and CSF cytologic improvement
occur, the response is generally seen after the first two to four doses of
intrathecal chemotherapy. Intrathecal therapy is then continued until the
CSF is devoid of malignant cells, after which 2 or more booster doses are
given. Monthly maintenance therapy is subsequently given for 6 months to
1 year (or until time of relapse).
f. Method of subarachnoid injection. Repetitive intrathecal administration of
chemotherapy by lumbar puncture is uncomfortable and results in
unpredictable distribution of drug through the neuraxis. After multiple LPs,
the opening pressure is often very low (due to CSF leakage), and it is often
difficult to determine whether the drug is actually administered into the
subarachnoid space. A surgically implanted subcutaneous reservoir
attached to an intraventricular catheter (Ommaya reservoir) can be used
for the direct installation of chemotherapy as well as sampling CSF.
However, even direct intraventricular installation of chemotherapy does not
ensure uniform drug distribution throughout the CSF.
CSF flow imaging using 111-indium diethylenetriamine penta-acetic acid
injected through the Ommaya reservoir allows detection of ventricular outlet
obstruction or abnormalities of flow in the spinal canal or over the
convexities that might impair clearance of drug and cause increased
toxicity.
g. Technique for making intraventricular injections using the Ommaya
reservoir
1. The patient should be placed in a slight Trendelenburg position to
facilitate gravitational force for specimen collection.
2. The scalp is shaved over the reservoir and the surrounding skin
carefully cleaned and draped to maintain sterility.
3. The reservoir is punctured obliquely with a small-bore (23- or 25-gauge)
butterfly needle to facilitate self-sealing. Local anesthesia is not
necessary and should not be used.
4. CSF is obtained by gravity for cell count, cytologic examination, culture,
etc.
5. Using sterile technique, the syringe containing the medication is
attached. The drug is slowly injected over several minutes. The volume
of fluid injected should be less than the volume removed.
6. The reservoir capacity is 1.4 mL, and it should be flushed with 2 to 3 mL
of CSF or preservative-free normal saline. With proper handling, well
over 100 punctures can be made into the Ommaya reservoir without
evidence of leakage. The procedure is relatively painless although
transient dizziness, headache, or nausea can occur after injections.
Infection occurs in more than 10% of patients with Ommaya reservoirs
placed for therapy of neoplastic meningitis and is usually manifested by
tenderness, fever, meningismus, or persistent headache. Most patients
can be treated with systemic antibiotics (with or without intrathecal
antibiotics) without removal of the catheter.
h. Side effects. Oral leucovorin is administered with intrathecal methotrexate
to prevent systemic myelosuppression. A transient chemical meningitis
occurs in a small proportion of patients within 12 hours of drug
administration. Delayed neurotoxicity is the major side effect of
intraventricular chemotherapy, especially when combined with whole-brain
radiotherapy. Many patients who survive for more than a year will develop a
progressive leukoencephalopathy with cognitive dysfunction and spasticity.
i. Prognosis. Early and vigorous treatment is often successful in reversing
neurologic symptoms and prolonging life in patients with leukemia,
lymphoma, or breast cancer. Approximately 50% of patients with meningeal
carcinomatosis from breast cancer and more than 80% of patients with
meningeal lymphoma or leukemia show considerable clinical improvement.
Patients with lung cancer or melanoma seldom have a favorable clinical
response. A course of intrathecal chemotherapy and radiotherapy involves
considerable patient morbidity. This treatment should be reserved,
therefore, for patients whose general condition and prognosis warrants very
aggressive therapy.
The disease is inexorably progressive and leads to death within weeks from
neurologic dysfunction in patients who are untreated or fail to respond to
treatment.
3. Skull metastasis. Metastatic disease to the convexity of the skull is common
but usually asymptomatic, requiring no specific therapy. Metastasis to the base
of the skull causes specific clinical syndromes due to compression of cranial
nerves:
a. Orbital metastasis presents with supraorbital pain, proptosis, and
ophthalmoplegia.
b. Parasellar metastasis causes unilateral frontal headache,
ophthalmoplegia, and sensory loss over the forehead.
c. Jugular foramen metastasis affects cranial nerves IX, X, and XI, causing
retro-auricular pain, dysphagia, and unilateral palatal weakness.
d. Occipital condyle metastasis causes unilateral occipital pain and
ipsilateral hypoglossal palsy.
e. CT with bone windows is very helpful in evaluating metastatic lesions of
the skull base. MRI may not visualize the lesions well, although a
contrast-enhancing soft tissue mass is often seen. In patients with known
systemic cancer and positive neuroimaging studies, focal radiation therapy
is administered to palliate the symptoms.
IV. CNS tumors in childhood. Cancer is the second leading cause of death in
children between 1 and 15 years of age. Brain tumors are the second most common
type of cancer in children. The majority of childhood brain tumors arise in the posterior
fossa or sellar region. Early diagnosis may be difficult because tumors in these locations
produce relatively nonfocal neurologic signs and symptoms.
A. Cerebellar astrocytoma
1. Incidence. The most common brain tumor in childhood is cerebellar
astrocytoma. These tumors generally are slow growing and may have an
excellent prognosis.
2. Clinical picture. Cerebellar astrocytomas occur most frequently in children
between 5 and 10 years of age. In younger children, the only signs may be
irritability, vomiting, and an enlarging head (due to obstructive hydrocephalus).
More commonly, the presenting symptoms are incoordination and ataxia.
3. Surgery. Cerebellar astrocytomas occasionally occupy the vermis, but most
often they are located in the cerebellar hemisphere. At least one half of these
tumors have an associated cyst, and the neoplastic mass is sometimes
confined inside a relatively small mural nodule. When this occurs, surgical
excision of the nodule is curative.
Subsequent tumor recurrence is uncommon in patients who have gross total
tumor removal, even after decades of follow-up. Thus, successful removal of
an astrocytoma of the cerebellum often results in a complete and permanent
cure. These patients require follow-up clinical evaluation and serial MRI or CT
scans to promptly identify evidence of tumor recurrence. Further surgery or
radiation therapy may be indicated in patients with recurrent tumor.
B. Brainstem gliomas account for approximately 15% of childhood primary brain
tumors and can be divided into 2 main groups:
1. Diffuse intrinsic brainstem gliomas present with cranial nerve palsies, ataxia,
and long tract signs. On MRI diffuse infiltrative enlargement of the pons and/or
rostral medulla is seen. These tumors cannot be resected and are not sensitive
to radiation or chemotherapy. The prognosis for survival is very poor.
2. Focal brainstem gliomas are smaller and more sharply demarcated from
normal tissue, often occurring in a dorsally exophytic location in the floor of the
fourth ventricle, the cervicomedullary junction, or midbrain tectum.
Histologically these lesions are usually low-grade gliomas and often have an
indolent clinical course; they have a favorable prognosis after surgery.
C. Medulloblastoma
1. Incidence. Medulloblastoma is the second most common brain tumor in
childhood. The tumor occurs mainly between the ages of 2 and 10 years.
However, about 30% of cases of medulloblastoma occur during adolescence
and early adulthood.
2. Clinical picture. Medulloblastoma is a primitive neuroectodermal tumor
(PNET) arising from multipotential cells in the cerebellum. The majority of
tumors originate in the midline of the cerebellum, occupying the vermis and
fourth ventricle. Initial clinical features therefore are often due to
noncommunicating hydrocephalus and increased intracranial pressure. In older
(over age 6) age groups, medulloblastoma is more likely to occupy a lateral
lobe, and signs of cerebellar involvement (staggering gait, ataxia) are more
prominent.
3. Metastasis. Medulloblastomas that arise from the vermis often fill the cavity of
the fourth ventricle and infiltrate into the brainstem. The tumor may also spread
en plaque over the surface of the cerebellum. Infiltration of the subarachnoid
space, with metastatic spread of medulloblastoma through the CSF pathways
(to the spinal cord, base of the brain, or cerebral hemisphere), is present in
25% of cases at the time of diagnosis.
4. Surgery. Because of the unfavorable location, invasiveness, and metastatic
potential of medulloblastoma, complete surgical resection with cure is rarely
achieved. Nevertheless surgery is indicated in all patients to provide the
correct histologic diagnosis, to resect the tumor mass to the greatest extent
possible, and to reestablish the patency of the CSF pathways. In some cases a
ventricular shunt may be necessary for decompressive purposes.
5. Radiotherapy. Unlike most other primary brain tumors, medulloblastoma is a
highly radiosensitive neoplasm. It is now recognized that irradiation of the
entire neuraxis (spine and brain) is necessary in all cases, due to the marked
propensity of medulloblastoma to metastasize by way of CSF.
The current trend in treatment has been to increase the radiation to the
maximum tolerable dose: 5,000 to 6,000 cGy to the local tumor, and 3,600 cGy
to the brain and spinal cord, with reduced doses for children under 3 years of
age.
6. Prognosis. Children younger than 4 years at diagnosis have a lower survival
rate than older children. Complete or near-complete surgical resection
favorably affects outcome. Patients with localized disease and extensive
surgical resection have a 5-year disease-free survival rate of 60% after
craniospinal irradiation. The majority of patients in the latter category have
presumably been permanently cured of medulloblastoma. Over 80% of the
long-term survivors have no serious neurologic disability and lead normal lives.
Patients with disseminated disease have a survival rate of less than 40% at 5
years after craniospinal irradiation.
7. Chemotherapy. Medulloblastoma has biologic features that make the tumor
susceptible to chemotherapy: the tumor is rapidly growing and highly
radiosensitive. The use of adjuvant chemotherapy with CCNU, vincristine,
cyclophosphamide, procarbazine, mechlorethamine, or cisplatin can
substantially improve the survival in patients with disseminated disease at the
time of diagnosis. Multicenter trials are now underway to determine optimal
chemotherapy regimens, whether all children with medulloblastoma should
receive adjuvant chemotherapy, and management of patients with recurrent
tumor.
8. Neurocognitive sequelae of craniospinal irradiation can be significant,
particularly for younger children. Adjuvant chemotherapy may allow the doses
of craniospinal irradiation to be reduced, thereby decreasing the incidence of
side effects.
D. Ependymoma
1. Biology. Ependymomas, tumors derived from ependymal cells, are a common
brain tumor in childhood. About 70% of childhood ependymomas arise in the
fourth ventricle, 20% in the lateral ventricles, and 10% in the region of the
cauda equina. The median age of onset in these sites is 2, 6, and 13 years,
respectively. Ependymomas also occasionally occur in adults, the spinal cord
and lateral ventricles being the sites of predilection. The majority of
ependymomas are histologically benign, although a small number are
malignant PNETs, referred to as ependymoblastomas.
2. Surgery. The treatment of ependymoma begins with the most extensive
surgical resection possible. Unfortunately, ependymomas in the fourth ventricle
are often attached to the floor of the medulla, making total removal impossible.
These tumors often have produced ventricular obstruction and hydrocephalus
by the time of diagnosis and a ventricular shunt may be necessary.
3. Radiotherapy. Ependymomas almost invariably recur after surgery, regardless
of their initial site or completeness of excision. Postoperative radiation
therapy (4,500 to 6,000 cGy over 4 to 6 weeks) prolongs survival significantly.
The 5- to 10-year survival rates after surgery and radiotherapy are around 70%
for histologically benign ependymomas that have been totally resected.
Subtotally resected tumors have a poorer prognosis (30% to 40% at 5 years).
Like medulloblastomas and other PNETs, ependymoblastomas have a
tendency to metastasize through the CSF. In these cases, irradiation of the
entire neuraxis may reduce the risk of tumor seeding elsewhere in the CNS
and thereby improve the survival rate. Multicenter treatment trials are
evaluating the role of chemotherapy in ependymoblastoma.
E. Craniopharyngioma
1. Incidence. Craniopharyngioma is a tumor that originates from squamous cell
nests in the region of the pituitary stalk. This tumor occurs in both childhood
and adulthood and accounts for about 3% of all brain tumors.
2. Clinical picture. Craniopharyngiomas can cause symptoms by compressing
the optic chiasm or tracts, by depressing pituitary or hypothalamic function, and
by increasing the intracranial pressure. Calcification is seen in or above the
sella turcica in more than 80% of children and 40% of adults with
craniopharyngioma.
3. Surgery. Craniopharyngiomas are biologically and histologically benign, but
their intimate relation to vital neural and neuroendocrine structures presents a
formidable obstacle to complete surgical resection. With the use of the
operating microscope, smaller tumors can be completely removed. However,
the realities of unavoidable operative morbidity detracts from the success of
surgical cure. Most of the completely resected patients are morbidly obese due
to lack of hypothalamic control of appetite and virtually all have
panhypopituitarism. Even when the surgeon believes that the tumor was
completely removed, follow-up serial MRI studies are needed, as recurrent
tumor will develop in 20% to 30% of cases within a few years of surgery.
Larger (over 5 cm diameter) craniopharyngiomas can only be partially resected
even in expert hands.
4. Radiotherapy. Postoperative radiation therapy can substantially delay (and
in some instances eliminate) tumor recurrence in cases of incomplete surgical
resection. Recent series report greater tumor control (of more than 10 years
duration in the majority of patients) after subtotal resection and postoperative
radiotherapy.
Stereotactic radiosurgery is being evaluated as a potentially more effective and
less neurotoxic approach than standard radiation therapy.
F. Tumors of the pineal region
1. Clinical picture. Tumors that arise in the pineal region occur mainly during
adolescence and early adult life. These tumors usually produce symptoms by
compressing the midbrain tectum (causing Parinaud syndrome) or obstructing
the aqueduct of Sylvius (causing noncommunicating hydrocephalus). Pineal
tumors can also encroach anteriorly to involve the hypothalamus (diabetes
insipidus, precocious puberty) or optic pathways.
2. Histology. Several biologically and histologically distinct tumors can arise from
the pineal region to produce this clinical picture. The germinoma (also referred
to as pinealoma or atypical teratoma) is the most common pineal tumor,
accounting for more than 50% of cases. Germinomas arise from primitive
midline germ cells in the pineal or hypothalamic regions. Other germ cell
tumors, including teratomas and embryonal carcinomas, occasionally occur in
this region; and tumors of the pineal parenchyma (the pineocytoma and
pineoblastoma), glial tumors (astrocytoma, ganglioneuroma), and
epidermoid cysts account for the remainder of these tumors.
3. Treatment. Ventricular shunting is usually the initial treatment for the signs and
symptoms of increased intracranial pressure due to obstructive hydrocephalus.
Cerebrospinal fluid a-fetoprotein and plasma b-human chorionic
gonadotropin levels may be elevated in patients with germ cell tumors. In this
situation, radiation may be considered empirically because germ cell tumors
are highly radiosensitive. Otherwise, surgical exploration and complete
resection of the tumor should be attempted if possible.
Malignant pineal region tumors can metastasize through the CSF. Cytologic
examination of the CSF is important in planning treatment. Spinal irradiation is
administered in addition to cranial irradiation if there is evidence of spinal
seeding. Chemotherapy might have a role in the palliation of tumors that have
recurred after surgery and radiation therapy.
V. Spinal cord tumors. Tumors originate less commonly in the spinal region than in
the brain in both adults and children, accounting for only 10% of all primary tumors of
the CNS. These tumors are seldom fatal, unlike their intracranial counterparts, but they
are extremely disabling. Prompt recognition and treatment can do much to relieve the
morbidity.
A. Spinal neoplasms
1. Clinical features. If the lesion is extramedullary (e.g., not growing within the
spinal cord parenchyma), the tumor will often produce symptoms by
compression or destruction of nerve roots or bone before the spinal cord itself
becomes involved. Conversely, intramedullary tumors often produce
manifestations of disturbed spinal cord function from the outset. The clinical
picture in individual cases depends on the transverse level of the tumor
(cervical, thoracic, lumbar, sacral, or cauda equina), the topography of the
tumor, peculiarities in the local blood supply to the spinal cord, and the speed
of compression.
2. Diagnosis
a. The diagnosis of intraspinal tumor is suggested by radiologic evidence of
bony erosion of the pedicles and intervertebral foramina (e.g., by a
schwannoma) or bony destruction (e.g., by metastatic cancer or
lymphoma).
b. MRI with contrast enhancement has become the noninvasive modality of
choice for evaluation of the spinal cord, epidural space, and paraspinous
structures.
c. Myelography, using a water-soluble agent, combined with high-resolution
CT imaging of the spine provides detailed anatomic information. These
studies localize the tumor and enable the physician to deduce whether the
tumor is intramedullary, extramedullary-intradural, or extradural.
Myelography is occasionally followed by rapid clinical deterioration due to
increased spinal cord compression. Fortunately, with the advent of MRI,
myelography is seldom necessary in detecting spinal tumors.
B. Primary intraspinal tumors. The relative incidence of primary intra-spinal tumors
by histologic type differs quite markedly from that of intra-cranial tumors (Table
11-4).
TABLE 11-4. Relative Incidence of Primary Intraspinal Neoplasms
1. Schwannoma
a. Clinical features. The most common primary intraspinal tumor is the
schwannoma. Schwannomas are extramedullary-intradural tumors
composed of Schwann cells, which can arise from spinal nerves at any
level (cervical, thoracic, lumbar, or cauda equina) and most often arise from
a posterior (sensory) nerve root. The most common initial symptom
therefore is pain in a radicular distribution.
Schwannomas grow slowly, and pain may be present for years before the
correct diagnosis is made, especially when in the relatively spacious
lumbosacral region. Schwannomas of nerve roots in the relatively tight
cervical region are more likely to compress the spinal cord early in their
course.
b. Treatment. Spinal schwannomas usually can be completely excised and
cured by surgery. In some cases, the tumor grows through the
intravertebral foramen to form an extraspinal mass (dumbbell tumors),
and a second operation is often necessary to remove the extraspinal
portion of these tumors. Fortunately, a high degree of clinical recovery
can be expected because the diagnosis is generally made before the spinal
cord has been extensively damaged by pressure.
c. Recurrence of schwannoma is likely only in cases in which total extirpation
is impossible, as in very large tumors or tumors with extradural extension.
2. Meningiomas
a. Clinical features. Meningiomas are the second most common primary
intraspinal tumor. Spinal meningiomas have a marked propensity to occur
in the thoracic spinal cord, and they are rare below the midlumbar level.
Like schwannomas, meningiomas are slow-growing
extramedullary-intradural tumors. The clinical picture usually evolves slowly
over months to years before the diagnosis is made.
b. Treatment. Spinal meningiomas usually can be completely removed
surgically. The neurologic deficits are at least partially reversible, and the
patient is thus cured of the disease. However, complete resection is often
technically quite difficult to achieve without damaging the spinal cord,
especially in tumors located anterior to the cord. In these cases, it may
prove impossible or unwise to attempt complete tumor removal.
c. Recurrence is likely in patients with partially resected tumors, but it does
not become clinically evident for months or years.
3. Astrocytomas and ependymomas
a. Clinical features. The most common intramedullary spinal tumors are the
gliomas, which are composed mainly of ependymomas and astrocytomas.
The ependymomas predominate in the cauda equina and lumbar region;
the astrocytomas, in the cervical region. Spinal gliomas are slow-growing
tumors, and a history of deficits of several years duration is commonplace.
b. Surgery. Most spinal gliomas are invasive as well as expansive;
unfortunately, complete surgical resection is possible in less than 20% of
cases. Most intramedullary spinal tumors can be decompressed by
means of a laminectomy, partial resection, and opening of the dura mater.
Moreover, approximately 60% of intramedullary spinal tumors are also
associated with syringomyelia; in these cases its cavity should be opened
to allow drainage.
These procedures are likely to produce some recovery of neurologic
function if the tumor has not caused irreversible damage to the spinal cord.
The prognosis depends on the growth rate of the tumor, and in many
patients the deficits progress slowly over several years.
c. Radiotherapy. Postoperative radiotherapy to the spinal cord is thought to
delay the onset of recurrent neurologic symptoms and is therefore
recommended for patients with partially resected intraspinal glioma. The
spinal cord tolerance to irradiation is less than that of the brain, and the
maximum permissible tissue dose is 3,500 to 4,500 cGy, depending on the
field size.
C. Metastatic spinal tumors
1. Biology. Metastatic tumors can reach the spinal cord by direct spread from an
involved vertebra, by extension of tumor through an intervertebral foramen
from a paraspinal mass, or (uncommonly) by direct hematogenous spread to
the extradural fat. Therefore, metastatic neoplasms of the spine are almost
always contained in the extradural space.
2. Prevalence. Metastasis to the spinal cord occurs in approximately 10% of
patients with metastatic cancer. The tumors that are most likely to spread to
the spinal canal are multiple myeloma, lymphomas, and cancers of the
lung, breast, prostate, kidney, and sarcomas. A favorable outcome depends
on early diagnosis and treatment.
3. Clinical features
a. Prodromal phase. Perhaps 90% of patients with cancer who develop
spinal cord compression pass through a prodromal phase, which is
characterized by severe back pain, radicular pain, or both. This pain
precedes the onset of spinal cord compression by weeks to months in
nearly all cases. Patients without pain are unlikely to have epidural spinal
cord compression.
b. Stage of pain without neurologic deficit. It is difficult to predict in a
patient with back pain from bone metastasis whether epidural disease is
present and at what point neurologic deficit will ensue. Unremitting back
pain is always considered a serious symptom in a cancer patient. Although
cancer patients may have pain of benign musculoskeletal origin, evidence
of metastatic tumor (e.g., lytic or blastic lesions in the vertebrae, a
paravertebral soft tissue mass, or a positive bone scan) should be
sought diligently in cancer patients with back pain or radicular pain or both.
MRI or CT-myelography will be necessary to evaluate for epidural
involvement. If epidural tumor is found, a course of local radiotherapy or
chemotherapy or both, depending on the histology of the primary neoplasm,
might effectively relieve the pain and prevent eventual myelopathy due to
spinal cord compression.
c. Stage of spinal compression. The stage of spinal cord compression
usually begins with subtle weakness and/or numbness in the legs.
Hesitancy or urgency may lead to painless urinary retention with overflow.
The tempo of neurologic progression is usually quite rapid, over the next
few days the patient becomes completely paraplegic. Metastatic lung
cancers, renal carcinoma, and lymphomas are said to produce the most
rapid progression to paraplegia. Thus, spinal cord compression is an
emergency.
The earliest signs and symptoms of spinal cord compression should
promptly lead to spinal MRI with gadolinium enhancement or, if not
available, CT myelography.
3. Prognosis. Early diagnosis is of paramount importance. The most important
prognostic factor is the severity of the neurologic deficit at the time of
diagnosis. Patients who begin treatment when still ambulatory are likely to
remain ambulatory. Patients who are nonambulatory are unlikely to regain
ambulation.
4. Treatment
a. Steroids. There is experimental and clinical evidence that administration of
very high doses of corticosteroids relieves local spinal edema and, in some
instances, may have a significant oncolytic effect. Current practice is to
start very large doses of cortico-steroids (e.g., dexamethasone, 100 mg
then 25 mg q6h) as soon as the diagnosis of spinal cord compression from
metastatic tumor is suspected. This very large dose is continued for several
days and then reduced, often allowing the clinician to buy time while
awaiting results of more definitive therapy (radiotherapy or surgery).
b. Radiotherapy. Most oncologists have realized that spinal epidural
compression by radiosensitive tumors such as lymphomas could be
managed effectively by radiotherapy without surgery. Recent data reveal
that radiotherapy alone is as effective as decompressive laminectomy
followed by radiotherapy in treating epidural spinal compression, regardless
of the underlying histology (e.g., prostate, lung, breast, or renal cancer).
After both forms of treatment, the overall improvement rate was 40% to
50% and the duration of clinical remission was similar. Consequently the
additional morbidity of surgery is not warranted in most patients with spinal
epidural compression. Patients with rapidly progressing neurologic deficits
(weakness evolving over 48 hours) did as well or better when treated with
irradiation alone as laminectomy-treated patients.
c. Surgery. The majority of epidural metastases arise from the vertebral body
and remain anterior to the spinal cord. The standard posterior
laminectomy surgical approach to epidural metastasis does not allow
adequate resection of tumor or decompression of the spinal cord in most
cases. Consequently it is not surprising that laminectomy has no added
benefit to radiation therapy in most cases. Laminectomy can be considered
in patients with cord compression who have no tissue diagnosis of cancer
(unknown primary tumor), in the occasional patient with a posteriorly
placed metastasis, or in patients who relapse after radiation therapy.
Conversely, direct anterior resection and procedures to stabilize the spine
can be very beneficial for patients with epidural metastases and
progressive myelopathy. This surgical approach is more complex and
carries greater surgical morbidity than laminectomy. Consequently, patients
with advanced cancer who are poor surgical risks would not be candidates
for anterior resection.
VI. Neurologic complications of radiation therapy
A. Delayed cerebral radiation necrosis can occur following radiation therapy to
intracranial as well as extracranial neoplasms (e.g., nasopharyngeal or sinus
cancers). This complication is related to the radiation dose, fraction size, and
duration of therapy. Delayed radiation necrosis usually occurs within the portals of
radiation, with most cases presenting 6 months to several years after the last dose
of radiation. Interstitial brachytherapy carries a high risk of radiation necrosis in the
surrounding brain.
1. Cerebral necrosis after radiotherapy is being recognized more commonly
now, particularly as the number of patients surviving more than a year or two
after treatment increases.
2. Clinical features. The symptoms of cerebral radionecrosis are those of an
expanding mass. MRI or CT cannot always differentiate between recurrent
tumor versus radiation necrosis. Positron emission tomography (PET) is very
helpful in distinguishing tumor recurrence from necrosis, but it is not generally
available.
3. Treatment. High-dose steroids can temporarily palliate the symptoms of
delayed cerebral radiation necrosis. Surgical exploration and removal of the
enlarging necrotic mass are necessary in many cases.
B. Ventricular dilatation and cerebral atrophy. A syndrome of progressive
dementia, apathy, gait disturbance, and incontinence of urine can occur in patients
who have received whole-brain irradiation for brain metastasis. CT or MRI scans
reveal ventricular dilatation, cerebral atrophy, and periventricular white matter
abnormalities without recurrent tumor or focal mass effect from necrotic brain. The
symptoms begin 6 to 36 months (median 1 year) after treatment. Administration of
relatively high daily fractions of radiation increases the risk of CNS injury and
should be avoided in the treatment of good-risk patients with brain metastasis. In
some cases, the cause of neurologic decline may be secondary to communicating
hydrocephalus, perhaps from radiation-induced obliteration of pacchionian
granulations. In this situation ventricular shunting offers potential palliation.
C. Radiation-induced myelopathy
1. Lhermitte sign. A sudden electric shock sensation precipitated by neck
flexion commonly occurs after radiation therapy for neck or upper respiratory
tract tumors. This usually begins a few months after treatment and gradually
abates within several months. The Lhermitte sign is not the harbinger of
subsequent progressive spinal cord dysfunction following radiation therapy.
2. Chronic progressive radiation myelopathy
a. Clinical features. A chronic progressive myelopathy, with ascending
paresthesias, predominantly spinothalamic sensory loss, spastic paresis,
and sphincter dysfunction, can occur between 6 and 36 months (mean 12
months) after radiation therapy to the mediastinum, cervical, or head and
neck region.
b. High radiation doses and overlapping ports increase the risk of
radiation-induced myelopathy. The spinal cord is much more sensitive to
the toxic effects of radiation than the brain. Individual variations in
susceptibility to radiation damage may also be a factor.
c. Diagnosis. The differential diagnosis includes spinal epidural tumor, an
intramedullary spinal metastasis, meningeal carcinomatosis, necrotizing
carcinomatous myelopathy (a paraneoplastic syndrome), and radiation
myelopathy. Myelography and MRI in radiation myelopathy may be normal
or show an atrophic or swollen spinal cord. The CSF is usually normal.
d. Treatment. There is no known effective therapy for chronic progressive
radiation myelopathy. A course of high-dose steroids is often administered,
particularly if the spinal cord appears swollen, but this produces transient
benefit, if any.
D. Radiation-induced brachial plexopathy can occur following radiation therapy for
breast cancer or Hodgkin disease. Radiation with large doses per fraction (e.g.,
4,500 cGy in 15 fractions) is more likely to cause this problem than treatment with
small doses per fraction (e.g., 5,400 cGy in 30 fractions).
1. Clinical features. Tingling and numbness in the fingers and weakness in the
hand or arm are the initial symptoms, beginning 1 to 5 years after radiotherapy
to the region of the brachial plexus. The signs are usually referable to the
upper brachial plexus (C5C6 dermatomes). Pain evolves only later in the
course and is seldom the predominant symptom. The symptoms and signs
slowly worsen, rendering the hand useless in many cases.
2. Differential diagnosis. Radiation-induced plexopathy must be distinguished
from metastatic tumor infiltrating the brachial plexus. Tumor infiltration usually
presents with severe pain followed by weakness and sensory loss in a lower
brachial plexus distribution (C7T1 dermatomes). CT or MRI of the brachial
plexus is useful but cannot always distinguish radiation fibrosis from tumor
infiltration.
3. Treatment. Surgical exploration of the brachial plexus is necessary in some
cases for diagnosis and treatment. Neurolysis or neurolysis plus omental
grafting does not stop the progression of deficits in radiation-induced brachial
plexopathy but may produce pain relief.
E. Neurotoxicity of antineoplastic chemotherapy is commonly encountered and
can be the dose-limiting factor in many situations.
1. Vinca alkaloids. Peripheral neuropathy is a very common side effect of the
Vinca alkaloids, particularly vincristine. Nearly all patients treated with several
courses of vincristine lose deep tendon reflexes. Continued treatment causes
paresthesias and distal hypalgesia (small fiber neuropathy) that can followed
by motor and proprioceptive loss (large fiber neuropathy). Autonomic
neuropathy, including ileus and orthostatic hypotension, can also occur.
Patients with preexisting neuropathy (e.g., diabetes or hereditary neuropathies)
are particularly prone to the neurotoxic effects of Vinca alkaloids. The signs
and symptoms usually resolve slowly over many months after the
chemotherapy is completed.
2. Cisplatin commonly causes a neuropathy affecting large sensory fibers,
resulting in sensory ataxia due to loss of vibratory sensation and
proprioception. Ototoxicity and vestibulopathy can also be caused by cisplatin.
The development of neurotoxicity correlates with the total cumulative dose and
the dose per treatment. Unlike other chemotherapy-induced neuropathies,
cisplatin neuropathy can worsen for months after treatment is completed
before stabilizing and improving.
3. Paclitaxel causes a small fiber sensory neuropathy that can progress to large
fiber motor and sensory loss with continued treatment. In some patients the
symptoms do not progress and may even resolve despite continued treatment.
In others a severe peripheral neuropathy may be a dose-limiting effect.
4. Neuroprotective agents that prevent peripheral neuropathy, such as nerve
growth factors, are being actively investigated and may be available in the
future.
Selected Readings
Review Articles
Black P McL. Brain tumors. N Engl J Med 1991;324:14711476, 15551564.
Clouston PD, et al. The spectrum of neurologic disease in patients with systemic cancer. Ann Neurol
1992;31:268273.
Malignant Gliomas
Brem H, et al. Placebo-controlled trial of intraoperative controlled delivery by biodegradable polymers of
chemotherapy for recurrent gliomas. Lancet 1995;345: 10081012.
Committee on Health Care Issues, American Neurological Association. Chemotherapy for malignant
gliomas. Ann Neurol 1989;25:88.
Meckling S, et al. Malignant supratentorial glioma in the elderly: is radiotherapy useful? Neurology
1996;47:901905.
Primary Central Nervous System Lymphoma
DeAngelis LM. Primary central nervous system lymphoma: a new clinical challenge. Neurology
1991;41:619621.
Evaluation and management of intracranial mass lesions in AIDS. Neurology 1998;50:2126.
Meningiomas
Black P McL. Meningiomas. Neurosurgery 1993;32:643657.
Pituitary Adenomas
Shimon I, Melmed S. Management of pituitary tumors. Ann Int Med 1998;129: 472483.
Cerebral Metastasis
Patchell RA, et al. A randomized trial of surgery in the treatment of single metastasis to the brain. N Engl
J Med 1990;322:494500.
Vecht CJ , et al. Treatment of single brain metastasis: radiotherapy alone or combined with surgery? Ann
Neurol 1993;33:583590.
Radiosurgery
Kondziolka D, et al. Stereotactic radiosurgery using the gamma knife: indications and results. The
Neurologist 1997;3:4552.
Meningeal Carcinomatosis
Lesser GJ . Neoplastic meningitis. The Neurologist 1996;2:1124.
Pineal Region Tumors
Edwards M, et al. Pineal region tumors in children. J Neurosurg 1988;68:689.
Spinal Tumors
Byrne TN. Spinal cord compression from epidural metastasis. N Engl J Med 1992;327:614619.
Neurotoxicity of Chemotherapy
Gilbert MR. Neurotoxicity of cancer chemotherapy. Neurologist 1998;4:4353.
CHAPTER 12. TRAUMA: SEVERE HEAD INJ URY, SPINAL CORD INJ URY
Manual of Neurologic Therapeutics
CHAPTER 12. TRAUMA: SEVERE HEAD INJURY, SPINAL
CORD INJURY
Robert L. Martuza and J ean-Valery C.E. Coumans
Severe Head Injury

Background

Diagnosis

Initial medical management

Quick neurologic examination for the severely injured patient

Detailed neurologic evaluation

Ancillary tests

Emergency treatment

Neurosurgical treatment

Nonoperative injuries

Medical treatment

Delayed complications of head injury
Spinal Cord Injury

Mechanisms of injury

Immediate care of the spinal cord injured patient

Care of the neural lesion

Diagnosis of spinal cord injury

Treatment

Complications

Rehabilitation
Severe Head Injury
I. Background
A. Severe head injury is a problem of enormous magnitude. In adults, automobile
and work-related accidents and, in children, accidents at play and falls account for
most cases. Although methods of treating head injury have improved (e.g., nursing
care, intracranial pressure [ICP] and vital sign monitoring techniques, control of
brain edema, and expeditious imaging of intracranial mass lesions) and mortality
has decreased, a substantial number of patients are left with varying degrees of
disability. Even patients with only mild to moderate head injuries may have
significant physical or neuropsychological deficits. Since many of these patients
are unable to return to work, the economic consequences of head injury are
staggering.
B. Classification. Brain injury can be categorized as primary or secondary. Primary
brain injury is damage that occurs as a result of the initial insult and is
pathologically described as diffuse axonal injury. Secondary injury compounds
primary injury and occurs as a result of intracranial complications (e.g., intracranial
hematoma, brain edema, infections) or extracranial complications that affect
delivery of oxygen and nutrients to the brain (e.g., pneumonia, pulmonary
thromboembolism, hemodynamic instability). Each of these sequelae alone or in
combination can lead to the demise of the patient. These complications must be
diagnosed and treated vigorously because the additive effect they have on the
primary brain lesion increases the neurologic damage and resultant disability.
C. Initial management. The final outcome following head trauma is related to the
extent of parenchymal injury, the age of the patient, and the neurologic function at
the time definitive therapy is instituted. Since only the last parameter is under
partial control of the emergency room physician, it is essential that expeditious
treatment be planned from the time of the accident and that evaluation and
treatment proceed rapidly. Treatment should begin with a well-trained emergency
medical team that is responsible for transporting severely injured patients.
Whenever possible, the physician should be in contact with the emergency
medical team to provide guidance regarding the need for intubation, intravenous
volume expanders, or mannitol prior to the injured patient's arrival at the hospital.
On arrival at the emergency room, the patient's respiratory pattern, skin color,
pulse, pupil size, and level of consciousness should be quickly determined. This
requires no diagnostic equipment and should take only a few seconds. Sedation
and neuromuscular blockade should be avoided as they mask the neurologic
examination. The clinical tempo of the examination should be assessed, as
deterioration during transport from the scene will mandate an especially efficient,
rapid evaluation. The primary physician should determine how many doctors,
nurses, and other personnel are available to help and assign appropriate tasks. A
neurosurgeon should be consulted in all cases of severe head injury.
II. Diagnosis
A. History. The ambulance team may provide information about the accident.
Occasionally, a neurologic event such as a seizure, stroke, or subarachnoid
hemorrhage may be witnessed as having preceded a motor vehicle accident, and
the diagnostic possibilities will differ from the usual head injury. The neurologic
state of the patient when first found is important to determine the rate and direction
of change of neurologic function. Such details and the current state of the
neurologic examination in the hospital will determine the pace of the remaining
evaluation.
B. Neurologic evaluation. If the patient is deteriorating rapidly, the neurologic
evaluation should take only a few minutes; if the patient is stable, a more detailed
examination is possible. It is useful to summarize the patient's presenting clinical
status in the form of the Glasgow Coma Scale (GCS) score (Table 12-1). This
simple score can be used quickly to define the severity of the injury and to
estimate prognosis. Prior to assessing neurologic function, however, the basics of
life support and resuscitation must be performed.
TABLE 12-1. Glasgow Coma Scale
a
III. Initial medical management for trauma patients. In head-injured patients, the
first priority is physiologic resuscitation.
A. Airway. An adequate airway is the first priority. It is essential for life. Additionally,
hypoxia suppresses cerebral function and hypercarbia increases ICP. Together,
these 2 factors make the neurologic examination prognostically inaccurate. If a
patient is responsive and can protect his or her own airway, nothing further need
be done. But the patient who is deteriorating or who is unresponsive will need to
be intubated. When in doubt, it is best to intubate the patient, as hypocarbia is the
most effective way to decrease ICP rapidly, thereby preventing secondary brain
injury. Additionally, neuronal oxygenation is required to help prevent further cell
injury or death. Generally, endotracheal intubation is used. With severe head
injury there is a very high incidence of associated cervical spine injury. If the
patient is hemodynamically and neurologically stable, and breathing
spontaneously, it is wise first to do a lateral cervical spine radiograph with
someone pulling the arms downward to exclude a cervical spine fracture; all seven
cervical vertebrae and the cervicothoracic junction must be visualized. If a fracture
is present, hyperextension of the neck, which is often necessary for intubation, can
cause spinal cord damage, and nasotracheal intubation or fiberoptic intubation (if
readily available) is preferred. If the patient is unstable and there is no time for a
cervical spine x-ray, a spine fracture should be assumed to be present until proved
otherwise, and nasal or fiberoptic intubation should be utilized. A word of caution
is in order: In the presence of severe facial or basal skull fractures, nasal passage
of any tubes may be difficult or dangerous. In emergency situations it is
sometimes necessary to perform a tracheostomy or a cricothyroidotomy, the latter
technique having the advantage of speed and less blood loss. Proper placement
of the endotracheal tube should be confirmed with auscultation, capnography, and
x-ray.
B. Breathing. Once the patient is intubated, it is reasonable initially to use 100%
oxygen. For the average adult, a rate of 12 to 14 breaths per minute at a volume
of 750 to 1,000 mL is sufficient. Difficulty with ventilation can be due to a tension
pneumothorax, sometimes requiring emergent decompression before radiographic
confirmation can be obtained. A chest x-ray and arterial blood gases should be
checked as soon as possible.
C. Circulation. Severe head injury is often associated with loss of cerebrovascular
autoregulation. Hypotension becomes equivalent to hypoxia, and brain function
cannot be adequately assessed. It is essential to replace blood volume and to
maintain an adequate blood pressure. An attempt is made to place a large-bore IV
catheter in a nontraumatized extremity (an IV line placed in a severely injured limb
will result in extravasation of replacement fluid into the soft tissues). If a peripheral
IV cannot be inserted easily, a subclavian or jugular vein catheter is placed, or an
expeditious antecubital or saphenous cutdown is performed. Generally, a
subclavian catheter is preferable to a jugular line because it is less likely to
interfere with further diagnosis and treatment of cervical spine or neck injuries.
Blood is removed and sent for the following studies: CBC, prothrombin time,
partial thromboplastin time, platelets, blood urea nitrogen (BUN), blood sugar,
toxic screen, and clot to the blood bank for typing and cross-matching. A chest
x-ray should be checked after all subclavian and internal jugular line insertions to
confirm placement.
The loss of cerebral autoregulation and the normal blood-brain barrier makes the
brain more susceptible to edema, especially in the face of fluid resuscitation. Once
the intracranial capacity to accommodate an increase in volume due to edema is
overcome, ICP will quickly rise. For this reason, careful fluid resuscitation is
crucial. If the patient has no evidence of hemodynamic instability, an attempt is
made to maintain a normovolemic state. Although traditionally these patients were
kept at two thirds maintenance fluid, recent evidence suggests that euvolemia may
provide better perfusion pressures to the brain while not increasing ICP. If
hypotension is a problem, cautious volume reexpansion should be performed. If
systemically indicated, packed RBCs are given. It is most advantageous to keep
the hematocrit greater than 30% for neuronal oxygenation. If blood products are
not required, the debate still exists as to whether to supply crystalloid salts or
colloids. Recent evidence indicates that crystalloid fluids are adequate and should
not unduly increase ICP.
D. Shock. If shock is present, its cause must be found in concert with volume
administration.
1. Hemorrhagic shock. Even the most severe head injury only rarely is the
cause of hemorrhagic shock. Such cases may be seen with serious
transections of major scalp arteries, with penetrating lesions of the major
cerebral venous sinuses, or, rarely, in infants with open cranial sutures where a
significant percentage of blood volume can collect intracranially. However, it
must be emphasized that these circumstances are unusual and the presence
of shock suggests an associated injury with blood loss into the chest,
abdomen, pelvis, retroperitoneum, or thigh. Physical examination and
radiologic studies are needed, routinely including plain films of the chest,
cervical spine, and pelvis. A bladder catheter is inserted. Peritoneal lavage or
abdominal computed tomographic (CT) scan may be necessary to exclude
intraabdominal hemorrhage. Chest tube or chest CT scan may be necessary to
rule out intrathoracic hemorrhage.
2. Spinal shock. Spinal injury must be excluded. Spinal shock is basically an
acute sympathectomy and causes hypotension with a slow pulse rate.
Intravascular volume expansion with or without the use of a-adrenergic agents
or atropine is usually effective treatment.
E. Airway, breathing, and circulation (ABCs) are first priorities. Patients with mild
injuries might require none of the previously mentioned treatments, whereas
patients with severe injuries might require all of them. However, all trauma patients
need consideration of these basics of care. If other physicians are present, they
may attend to these matters while the neurologist or neurosurgeon is evaluating
neurologic function. If the neurologist or neurosurgeon is the only physician
present, the ABCs must be covered first; only then can a detailed neurologic
evaluation be performed.
IV. Quick neurologic examination for the severely injured patient. A
patient with an initial GCS of 8 or less is defined as having a severe head injury. As
indicated by the GCS, 3 parts of the physical examination are most useful for
establishing rapid diagnostic and prognostic criteria. In true neurologic emergencies,
this abbreviated examination may be all that is possible prior to operative intervention.
A. The level of consciousness is the most sensitive indicator of overall brain
function and can be broken down into 2 components: alertness and content.
Alertness reflects the level of brainstem ascending reticular activating system
(ARAS) function, whereas content reflects the level of cortical function. It is a
nonspecific indicator and can be severely altered by alcohol, toxins, hypotension,
hypoxia, or trauma of the brainstem or cortex. The highest level of environmental
awareness should be described. Brief descriptive phrases are more useful than
terms such as stupor and coma and allow for comparison of serial examinations.
B. Eyes. Because the pathways involved in pupillary function and eye movements
traverse large areas of the brain, eye signs are the second most important part of
the neurologic examination.
1. The size, shape, and reactivity of each pupil (direct and consensual) should be
noted. Pupillary size is a balance between sympathetic pupillodilatory and
parasympathetic pupilloconstrictor drives.
a. A sluggishly reactive or dilated pupil suggests the possibility of cerebral
herniation with compression of the third nerve on the tentorial edge.
Because of their superficial location on the third nerve, parasympathetic
pupilloconstrictor fibers are compromised before fibers controlling medial
rectus function. This can be helpful in distinguishing compression due to
herniation from associated local ocular trauma in which pupil and
oculomotor function are equally affected. Progression from a normal
pupillary examination to a unilaterally sluggish or dilated pupil is a cardinal
indicator of herniation and mandates prompt aggressive intervention.
b. Pinpoint pupils that are still reactive can occur with pontine lesions by
segmentally compromising sympathetic tone. A unilateral Horner
syndrome can result from interruption of the sympathetic system anywhere
along its course and in the setting of trauma should raise suspicion to the
possibility of carotid artery dissection or cervical spine injury. The presence
or absence of facial anhidrosis can help to localize the injury relative to the
level of the carotid bifurcation. Toxins and metabolic insults only rarely
affect pupillary function. Heroin overdose, however, should be considered
in comatose patients with bilateral meiosis.
2. Spontaneous eye movements should be noted. If they are full, further testing
is not necessary. Conjugate lack of movement to one side may represent a
visual field defect, parietal neglect, or an injury to a cortical brainstem gaze
center. Tonic conjugate deviation of the eyes can be indicative of a seizure.
Unilateral lack of movement implies nerve damage intracranially or
intraorbitally or an orbital fracture with muscle entrapment. If spontaneous eye
movements are not full and the patient is unresponsive, the doll's-head
maneuver, ice water calorics, or both are performed (see Chap. 1). In the
traumatized patient, a cervical fracture must be excluded with a full cervical
spine series before performing the doll's-head maneuver, and otoscopy should
be done before caloric testing.
3. The corneal reflex (afferent fifth cranial nerve, efferent seventh cranial nerve)
is tested on each eye with a wisp of cotton. This reflex is often preserved even
in rather deep levels of coma. A unilateral facial palsy may obscure the reflex,
but the eye will roll superiorly (Bell phenomenon) or a contralateral blink will
be noted. Loss of this reflex carries serious prognostic implications, especially
when associated with other signs of brainstem dysfunction.
C. Motor function. Mortality figures based on the GCS have been shown to correlate
particularly well with best motor response. In the severely injured patient, fine
testing of various muscle groups is not the immediate objective. Spontaneous
movements of each limb are noted. If none are present, movements are elicited
verbally or with the application of noxious stimuli to the chest or proximal limb, and
the highest level of response is recorded. Purposeful movement is considered a
coordinated response to a verbal command or noxious stimuli. Flexor posturing
(decorticate) generally implies injury to the cerebral hemisphere or their
peduncles. Extensor posturing (decerebrate) generally implies unopposed
spinocerebellar tone secondary to injury between the pontine and midbrain levels.
Flaccid extremities suggest intoxication, drug overdose, or medullary spinal cord
injury. Focal weakness may represent local extremity or nerve injury, whereas a
hemiplegia more likely reflects spinal, brainstem, or higher cortical dysfunction.
D. Changes in the examination suggesting any of the 4 types of herniation
syndromes must be recognized. When attributable to a discrete mass lesion,
each of these herniation syndromes may represent a true neurosurgical
emergency. Each syndrome can be associated with systemic hypertension,
bradycardia, and irregular respiration (Cushing response), a non-specific
indicator of increased ICP.
1. The uncal herniation syndrome of rostrocaudal deterioration is caused by
masses that compress the hemisphere laterally and push the inferomedial part
of the ipsilateral temporal lobe (uncus) through the tentorial incisura,
compressing the midbrain. Progressive agitation may be a subtle sign of
herniation, but it is nonspecific. The ipsilateral oculomotor nerve is compressed
early, giving rise to pupillary dilatation and fixation. Complete ophthalmoplegia
follows along with contralateral hemiparesis, due to pressure on the ipsilateral
cerebral peduncle. Consciousness deteriorates, often precipitously, secondary
to compromise of the midbrain ARAS. Another neighboring anatomic structure
that may be affected is the posterior cerebral artery, compression of which
gives rise to hemorrhagic infarction of the posterior temporal and occipital
lobes. Less commonly (about 10%), the contralateral peduncle is crowded
against the opposite tentorial edge, producing a hemiparesis ipsilateral to the
lesion and initial pupillary change (Kernohan notch phenomenon). If herniation
is prolonged for more than a few minutes, irreversible brainstem damage
occurs due to pressure on and stretching of the vasculature with consequent
hemorrhagic infarction (Duret hemorrhages).
2. Central herniation syndrome. Like the uncal herniation syndrome, central
herniation involves a transtentorial descent of brain matter with herniation
rostrocaudally through the incisural notch. Clinically, it may be difficult to
interpret, as it has few localizing signs other than progressive loss of
consciousness. Unlike in uncal herniation, the entire diencephalon (including
the thalamus, hypothalamus, and basal nuclei) is the region at risk, and it may
actually buckle up against the midbrain. Hemorrhage and edema of the
diencephalon are classic, with vascular compression of the posterior cerebral
and anterior choroidal arteries. High ICP is almost certain, with compression of
subarachnoid cisterns and the cerebral aqueduct preventing egress of
cerebrospinal fluid (CSF). This tends to worsen herniation.
3. Cerebellar herniation syndrome. Lesions in or around the cerebellum
compress the pons from the rear or distort the medulla as the cerebellar tonsils
are forced downward through the foramen magnum. The heralding features of
this often rapidly progressing syndrome are cerebellar ataxia, unilateral or
bilateral sixth cranial nerve dysfunction (lateral gaze), diminishing level of
consciousness, and the presence of Babinski signs. Gaze palsy to the side of
the offending mass, followed by small but reactive pupils (pontine pupils), loss
of all horizontal eye movement, and tetraparesis may then occur. Medullary
failure with disordered respiration and apnea soon follow. This syndrome can
progress very rapidly because the amount of excess space in the posterior
fossa is less than in the supratentorial regions; thus, expanding masses are not
well tolerated in this region.
4. Subfalcial (cingulate) herniation. Expanding lesions in one frontal lobe may
herniate under the rigid falx cerebri. This herniation usually has no clinical
expression and is noted only on CT scan or at autopsy, unless the herniating
mass compromises the anterior cerebral arteries and produces unilateral or
bilateral leg weakness and abulia from inferior medial frontal lobe damage.
E. Once the quick neurologic examination of the severely injured patient is
completed, a decision must be made as to whether to proceed to surgery (e.g.,
persistent shock from continuing abdominal hemorrhage), to CT scanning or other
diagnostic tests, or to a more detailed neurologic examination. Although further
examination is desirable, the overall stability of the patient must be considered,
and careful prioritizing is mandatory for the patient's well-being.
In the absence of other extracranial life-threatening injuries, surgical intervention
without first obtaining a CT scan is rarely indicated. The availability of extremely
rapid new-generation CT scanners, coupled with the possibility of a false or
incompletely localizing neurologic examination, usually warrants temporizing
patients with signs of intracranial hypertension with hyperventilation, mannitol, and
diuretics long enough to obtain a scan. We generally prioritize a CT section
through the level of suspected injury and then proceed to the operating room while
awaiting reconstruction of the remaining images. One situation in which it may be
justified to proceed directly to surgery is when a patient has a rapidly progressing
uncal herniation syndrome localizing to the side of a squamous temporal bone
fracture that traverses the middle meningeal groove.
V. Detailed neurologic evaluation
A. Cerebral hemispheres. Once the level of consciousness is determined, a
comprehensive mental status examination should be performed. Evaluation of
new memory formation and recall of recent and past events is particularly
important. Amnesia is a common sequela of head injury and may be retrograde
(loss of recall of events immediately preceding the injury) or antegrade (loss of
recall of events after the injury).
B. Cranial nerves
1. Olfactory. Testing of the sense of smell requires patient cooperation. A
response to alcohol or ammonia reflects irritation of the nasal mucosa
(trigeminal nerve). Although the olfactory bulb or nerve may be injured in
ethmoid or orbital fractures, it is most frequently affected in patients with
severe concussion. Up to one third of patients recover the sense of smell
spontaneously.
2. Optic nerve and chiasm. Visual acuity, visual fields, and visual neglect should
be tested. Ophthalmoscopy should evaluate the cornea, lens, media, retina,
and optic disc. Papilledema is uncommon in the acute setting. Subhyaloid
hemorrhage may be due to nontraumatic subarachnoid hemorrhage. Retinal
vein stasis suggests intracranial hypertension. Optic nerve and (more rarely)
chiasmal lesions occur in approximately one half of orbit fractures. The nerve
most often is affected at the level of the optic foramen. Chiasmal damage
usually follows serious trauma; however, optic nerve damage may be caused
by more trivial injuries. Chiasmal lesions are sometimes associated with
hypothalamic damage, which can cause diabetes insipidus. Unilateral optic
nerve damage results in deafferentation of the pupillary light reflex. This
engenders a defective direct light reflex, but an intact consensual reflex (the
so-called Marcus Gunn syndrome or deafferented pupil). Visual-evoked
responses may be used to evaluate optic nerve function as well.
Surgery is sometimes helpful in decompressing the optic nerve from bone
fragments. Ophthalmologists also frequently advocate the use of high-dose
methylprednisolone, in a protocol similar to that used for spinal cord injury, for
optic nerve injury. The prognosis for return of vision is poor.
3. The oculomotor, trochlear, and abducens nerves might be affected within
the orbit or at the superior orbital fissure in sphenoidal fractures. The sixth
(abducens) nerve can be affected by a fracture at the apex of the petrous bone
or by torsion, secondary to increased ICP, at the level of its passage into the
cavernous sinus (Dorello canal). Due to its long intracranial course, the sixth
nerve is frequently affected by intracranial trauma. Pupillary and extraocular
movement abnormalities might be produced by brainstem, particularly
midbrain, contusion, and diplopia might be caused by orbital trauma and
consequent misalignment of the visual axis.
4. Trigeminal nerve. The skin in each of the 3 divisions should be tested with a
pin to differentiate a peripheral branch injury from a more central lesion. In
most cases the trigeminal nerve is affected in its extracranial course, with the
maxillary branch being the most frequently damaged. The gasserian ganglion
can be damaged in basilar skull fractures or penetrating injuries. In the
presence of trigeminal nerve injury, other neighboring structures (cavernous
sinus; third, fourth, and sixth cranial nerves; and the carotid artery) are usually
affected.
5. Facial nerve. An injury of the motor cortex or internal capsule produces a
contralateral lower facial palsy sparing the frontalis muscle, which has bilateral
cortical innervation. A brainstem injury, however, produces an ipsilateral palsy
of the entire face and is usually associated with an alteration of consciousness
and other brainstem signs. A peripheral facial nerve injury also causes an
ipsilateral palsy but without other central signs. Although the facial nerve can
be injured extracranially, it is more frequently damaged in its intrapetrosal
course. Paresis (incomplete lesion) has a better prognosis than paralysis
because the latter often reflects anatomic transection of the nerve. Delayed
onset may be a result of hemorrhage or edema within the canalicular portion of
the nerve, and it may be amenable to treatment. Whether to decompress the
nerve surgically is controversial; medical treatment with glucocorticoids has
been suggested. To differentiate physiologic nerve impulse blockage from
actual axonal degeneration, electric testing is required.
a. Percutaneous nerve excitability testing may be done at the bedside and
is simple to perform. It can detect evidence of axonal degeneration earlier
than can electromyography.
b. Electromyography (EMG) is a useful tool for detecting evidence of axonal
regeneration. It is important to determine whether the lesion is situated
proximally or distally to the geniculate ganglion because the surgical
approach is easier in the latter case.
c. Evoked responses can be used to evaluate the blink reflex. This can be
done using visual stimuli (afferent limb, second cranial nerve; efferent limb,
seventh cranial nerve) or tactile stimuli (afferent limb, fifth cranial nerve;
efferent limb, seventh cranial nerve, which is the corneal reflex). The
integrity of the facial nerve and its brainstem connections can be evaluated
in this way without the necessity for patient cooperation.
d. The Schirmer test is based on the fact that the greater petrosal nerve
leaves the facial nerve at the level of the geniculate ganglion. Thus, a strip
of filter paper is left in the lower conjunctival sac, and the wetting by tears is
compared between the 2 sides. Normally, the lacrimal gland can wet a
minimum of 2 to 3 cm of the paper in 5 minutes, whereas the denervated
gland will wet only a few millimeters.
6. Vestibulocochlear nerve
a. Vestibular branch. Posttraumatic dizziness and vertigo are discussed in
Chap. 4.
b. The cochlear branch often is damaged in temporal bone fractures, usually
in conjunction with the vestibular branch, and is heralded by the presence
of CSF otorrhea or hemotympanum. Whenever such a lesion is suspected,
audiometry should be performed as soon as the patient's condition permits.
Brainstem auditory-evoked responses may be used to evaluate the
cochlear nerve and its central nervous system (CNS) connections in
patients who are unable to cooperate.
1. Posttraumatic tinnitus may result from injuries to the cochlear nerve,
labyrinth, and blood vessels supplying the inner ear. There is no reliable
treatment for traumatic tinnitus.
2. Hearing loss is usually mixed at the onset, with both conductive and
sensorineural components.
a. In conductive hearing loss, the sound is impeded from reaching the
receptor organ due to tympanic rupture, hemorrhage in the middle
ear, or disorganization of the ossicular chain. The conductive
component tends to resolve spontaneously in many patients by
resorption of edema and hemorrhage, except in cases of ossicular
chain disruption. An otology consultation is indicated.
b. Sensorineural hearing loss results from direct injury to the receptor
organ, the cochlear nerve, or its neural connections. The prognosis
in this type of hearing loss is poor.
7. Injury to the glossopharyngeal, vagus, spinal accessory, and hypoglossal
nerves is usually associated with severe basilar skull fracture. Most patients
do not recover from this type of injury.
C. Cerebellar testing. Unilateral dysmetria or ataxia may indicate cerebellar injury.
Nystagmus may also be present, but associated vestibular injury can be
confusing. A worsening level of consciousness in the presence of cerebellar signs
or gaze palsy may indicate an expanding posterior fossa mass. The potential for
apnea and death is ever present, and an expeditious CT scan is indicated.
D. Motor testing. The quick neurologic evaluation may miss an associated spinal,
brachial plexus, or peripheral nerve injury. Detailed testing of all muscle groups
should exclude these problems. Additionally, neurologic worsening from the time
of the initial examination might be detected. Muscle strength should be graded as
follows:
5 Normal
4 Overcomes gravity plus some resistance
3 Overcomes gravity but not added resistance
2 Moves horizontally but cannot overcome gravity
1 Trace movement
E. Sensory testing. Pin, light touch, and position sense should be tested to
anatomically localize any central or peripheral deficit. An injury initially thought to
be a complete motor and sensory deficit on one or both sides may, on more
detailed testing, demonstrate some preservation of light touch, vibration, or
position sensibility, suggesting an anterior spinal cord syndrome.
F. Reflexes. The presence of extensor plantar responses, hyperreflexia, or ankle
clonus suggests an upper motor neuron injury. These signs take time to develop
and may not be present in the acute setting. Depressed reflexes are less specific
and may be due to an overall depression of neurologic function, spinal shock,
metabolic insults, or peripheral nerve damage. Priapism is commonly seen
following acute spinal cord injury. It results from a loss of the adrenergic
innervation required for detumescence.
G. Traumatic carotid and vertebral artery dissection and/or thrombosis.
Occasionally, the carotid artery is injured in the neck during trauma and may
develop an intimal tear resulting in dissection, thrombosis, or both; an ipsilateral
Horner syndrome is often present. It may also be injured in or above the
cavernous sinus. The vertebral artery may be damaged in a similar manner in
fracture dislocations of the neck. Physical examination may not be very sensitive
for detecting arterial dissections, and cerebral angiogram or magnetic resonance
angiography may be necessary. The clinical syndromes associated with great
vessel thrombosis are covered in Chap. 10.
H. Injury list. After the ABCs, the general examination, and either the quick or
detailed neurologic examination, a list of definite and possible injuries should be
made, with the most serious injury at the top. Ancillary studies should be planned
to achieve a definite diagnosis for each problem, and the patient should generally
be placed under the primary care of the specialist treating the most threatening
organ injury.
VI. Ancillary tests
A. Nervous system
1. Cervical spine x-rays. The lateral view is the most useful and should
generally be taken with someone pulling the arms toward the feet to ensure
that all 7 cervical vertebrae and the cervicothoracic junction are visualized. The
stiff cervical spine collar should not be removed until the cervical spine series
is cleared. Fractures, displacement, and perispinal edema all suggest injury.
Anteroposterior (AP) views may demonstrate a unilateral jumped facet not
appreciated on the lateral view. The odontoid view is essential. With oblique
views, the x-ray tube should be angled rather than the patient's neck turned. If
an adequate set of cervical spine films cannot be obtained (especially in the
unresponsive or unreliable patient, or in the patient with neck pain), a spinal
fracture must be assumed to be present until further studies are done. The CT
scanning, intubation, and surgery may need to be done with the patient
maintained in cervical immobilization.
2. The CT scan has revolutionized trauma care and is the single most important
neurologic study in the acutely head-injured patient. The CT scan is omitted
only in mild head injuries where the history is not significant for loss of
consciousness and there is no abnormality on neurologic examination. Rarely,
in rapidly evolving deficits where surgery is immediately necessary and the
neurosurgeon is nearly certain of the location of the lesion, the CT scan may
be deferred. In this latter situation, a postoperative CT scan is obtained.
Portable CT scanners can be used intraoperatively, allowing the surgeon to
confirm the completeness of a hematoma evacuation prior to leaving the
operating room. They also allow critically ill patients to be scanned without
leaving the intensive care unit.
a. Intracranial hematomas can be differentiated by their shape and location.
1. An epidural hematoma is biconvex and is bound by the dural insertion
at the cranial sutures. Only occasionally can high arterial pressures
result in violation of the suture lines.
2. A subdural hematoma is not bound by normal sutures and can cover
most of the hemisphere but does not cross the interhemispheric fissure.
Of note, it may not be radiographically possible to distinguish epidural
from subdural hematoma.
3. Parenchymal hemorrhages can occur anywhere.
4. Subarachnoid hemorrhage is common in severe head injury and
usually appears as a serpiginous density in the sulci, fissures, and basal
cisterns and can track into the ventricular system.
b. Contusions may appear as areas of increased, decreased, or normal
density. They are most common at the temporal and frontal tips and may be
associated with significant swelling.
c. Increased ICP. Subfalcial herniation, obliteration of the basal cisterns with
early temporal lobe herniation, or compressed ventricles suggest increased
ICP.
d. Intracranial air indicates a sinus injury, penetrating wound, or
compound fracture. Foreign bodies should be noted. Associated orbital,
facial, and soft-tissue injuries should be noted.
3. MRI
a. Head injury. Magnetic resonance imaging (MRI) has replaced CT
scanning as the study of choice for evaluating subacute and chronic head
injury.
1. In subacute injury, MRI is superior for evaluating both hemorrhagic and
nonhemorrhagic contusions, petechial shearing injuries commonly seen
in the brainstem and white matter adjacent to the corpus callosum, and
extra-axial fluid collections.
2. In chronic injury, parenchymal abnormalities, correlating with the
patient's clinical state, are best visualized with MRI. Encephalomalacia
is identified by increased signal on T2 resulting from increased tissue
water content. Again, extra-axial fluid collections, such as isodense
chronic subdural hematomas (isodense by CT criteria), are readily
diagnosed with MRI.
3. In the acute setting, CT remains superior to MRI. Although MRI may
give a better anatomic picture in some cases, it physically isolates the
acutely traumatized patient from lifesaving modalities and personnel.
However, MRI is utilized when the patient's clinical condition does not
correlate with CT findings and for circumventing problems with bone
artifact in the posterior fossa. The evolution of the MRI appearance of
hemorrhage is characteristic and corresponds to the metabolic
degradation of hemoglobin (Table 12-2).
TABLE 12-2. Evolution of the MRI Appearance of Hemorrhage
b. Spinal cord injury. With the advent of MRI-compatible halo tong systems,
MRI is now the preferred method for evaluating acute, subacute, and
chronic traumatic spinal cord injuries. Assessment of soft tissues by MRI is
superior to both myelography and myelography/CT, while obviating the
dangers of lumbar puncture in a patient who potentially has a spinal block
or associated intracranial mass lesion. Transport of a patient to MRI in the
presence of an acute spinal cord injury is hazardous and should be
supervised by a physician, preferably a neurosurgeon.
4. Cerebral angiography is indicated in the emergency evaluation of intracranial
hemorrhage that might be attributable to an aneurysm or arteriovenous
malformation, when there is the possibility that a penetrating injury has
traversed a major cerebral artery resulting in a traumatic aneurysm, or when
carotid or vertebral artery dissection is suspected.
5. Skull x-rays are used infrequently to assess fracture of the cranial vault. A CT
scan appropriately windowed for bone provides essential information regarding
the possibility of fractures, whereas windowing for soft tissue demonstrates the
integrity of the underlying parenchyma. However, facial x-rays can be quite
useful for assessing sinus injuries and orbital and facial fractures. However, if
time permits, three-dimensional reconstruction of CT scan images provides the
most detail.
6. Thoracic and lumbar spine x-rays are not done routinely. Local pain,
tenderness, or the presence of neurologic abnormality dictates their use. In
patients with an altered mental status, however, lateral thoracic and lumbar
spine x-rays are part of the standard radiographic evaluation.
7. Nuclear brain scanning, electroencephalography (EEG), and
echoencephalography have little use in the current management of head
trauma. Lumbar puncture is generally contraindicated. Even if subarachnoid
hemorrhage is suspected, CT scan is the procedure of choice.
B. Chest injuries occur in 3% of all patients with severe head injuries. A chest x-ray
may reveal rib fractures, a pneumothorax, a hemothorax, a lung contusion, or an
injury to the diaphragm. Neurogenic pulmonary edema can be caused by cerebral
or spinal injuries. Thoracic spine fractures may be associated with a widened
mediastinum, suggesting an aortic tear and requiring angiography.
C. Abdomen. Intraabdominal injuries occur in 4% of patients with severe head
injuries. A KUB (a plain film of the kidneys, ureters, and bladder) and lateral
decubitus film may show intraabdominal air or fluid or retroperitoneal hemorrhage,
but CT is much more accurate and reliable. Generally, IV and oral contrast are
needed and should be given after a head CT has been performed, since contrast
can confound the interpretation of hemorrhage.
D. Kidneys. Hematuria or retroperitoneal injury on abdominal films requires an
intravenous pyelogram. Whenever possible, this should be done after the
noncontrast head CT scan, since the contrast might make a cerebral contusion
look like a consolidated hematoma.
E. Extremities. X-rays should be taken of any limb where a fracture is suspected.
VII. Emergency treatment
A. Severe head injuries should not be managed alone. A neurosurgeon and other
specialists should be involved as early as possible. A dedicated nurse should be
with the patient at all times.
B. The ABCs must be instituted and monitored with frequent measurement of vital
signs.
C. Deteriorating neurologic function despite adequate oxygenation and blood
pressure suggests elevated ICP from a hematoma or cerebral edema. Treatment
should include hyperventilation to achieve a PCO
2
of 28 to 30 mm Hg, elevation of
the head to decrease venous pressure, and administration of mannitol (1 g/kg) as
an IV bolus with furosemide (0.5 mg/kg). Prevent jugular kinking or compression,
which can raise intracranial venous pressures. These measures are only
temporary and will allow time either for CT scanning to achieve a definite
diagnosis or to proceed to the operating room.
D. Phenytoin (Dilantin) may be given to prevent seizures. A loading dose of 15
mg/kg is given at a rate not in excess of 50 mg/minute IV with appropriate cardiac
monitoring.
E. Disseminated intravascular coagulation may occur in as many as half of
patients with severe brain injuries, as the brain has very high levels of tissue
thromboplastin. The likelihood of its occurrence is proportional to the amount of
brain tissue injury. This is particularly serious in massive injuries associated with
gunshot wounds. Diffuse bleeding from puncture sites and lacerations may require
the administration of fresh-frozen plasma before the results of clotting studies are
obtained. If administration of several units of fresh-frozen plasma does not permit
clotting, 10 units of platelets are given empirically. Coagulopathy may also account
for a fraction of the spat hematomas (late or delayed) seen in the head-injured
patient.
F. Steroids. Because steroids have not been shown to favorably alter outcome in
head-injured patients and have associated potential deleterious side effects, their
routine use in head injury is not recommended.
VIII. Neurosurgical treatment
A. Epidural hematoma
1. Description. Epidural hematoma is a collection of blood situated between the
skull and dura. It most commonly occurs in association with a temporal bone
fracture that traverses the middle meningeal groove. Because the dura
becomes adherent to the skull with age, epidural hematoma is seen rarely in
the elderly. Early recognition of this true neurosurgical emergency can lead to
a lifesaving operation.
a. Lucid interval. Classically, after an initial short period of unconsciousness
on impact, there is a lucid interval followed by progressive impairment of
consciousness and contralateral hemiparesis. In more than 50% of
patients, however, there is no lucid interval, and unconsciousness is
present from the moment of the injury. Extreme headache is usual,
resulting from the stripping of the dura from the inner table of the skull, and
is usually progressive when there is a lucid interval.
The lucid interval suggests minimal initial parenchymal damage. This
interval represents the time elapsed between the initial traumatic
unconsciousness and the beginning of diencephalic derangement produced
by transtentorial herniation. The length of the lucid interval is variable. An
absent or short lucid interval suggests that the bleeding is brisk and
probably arterial.
b. Hemiparesis. The focal neurologic deficit generally is contralateral
hemiparesis, due to the effect of the expanding mass on the origin of the
corticospinal tract. Hemiparesis ipsilateral to the clot may also occur due to
compression of the contralateral cerebral peduncle against the tentorial
edge (Kernohan notch).
c. Seizures can occur but are more common with parenchymal injuries.
d. Herniation. Unilateral pupillary dilatation is an indication of transtentorial
herniation.
2. Diagnosis. The classic history of initial loss of consciousness, followed by a
lucid interval and later by progressive obtundation and hemiparesis, is highly
suggestive of epidural hematoma. When a linear skull fracture is seen across
the middle meningeal groove in plain skull x-rays, a CT scan is the next step.
Sometimes, however, herniation has already begun by the time the patient
reaches the emergency room and exploratory burr holes are necessary.
3. Pathophysiology. Epidural hematoma usually results from low-speed, blunt
head injury, as from falls or impacts with objects, and it is almost always
associated with linear skull fracture. In the majority of patients, the bleeding
vessel is the middle meningeal artery, vein, or both. The middle meningeal
vessels are injured when the fracture line crosses the middle meningeal groove
in the temporal squama. Classically, there is little associated underlying
parenchymal injury.
4. Treatment. In this situation, time should not be wasted on unnecessary tests.
a. In herniating patients, emergency treatment with intubation,
hyperventilation, and mannitol is instituted, and the patient is taken to
surgery.
b. If at all possible, and only if it can be done very quickly, a CT scan should
be performed first to exclude other lesions instead of or in addition to an
epidural hematoma.
B. Subdural hematoma
1. Description. Subdural hematoma is a collection of blood between the dura
and the underlying brain and is present in 10% to 15% of patients with severe
head injuries. Depending on the time interval between the injury and the onset
of symptoms, subdural hematomas are clinically divided into acute (up to 24
hours), subacute (1 to 10 days), and chronic (more than 10 days). About half of
cases (mostly the acute subdural hematomas) are associated with skull
fracture. Subdural hematoma can be located anywhere in the cranial cavity,
but it is most frequently over the convexity. About 20% of subdural hematomas
are bilateral and may be caused by birth injury, bleeding diathesis, or blunt
trauma without fracture.
2. Pathophysiology. Cortical veins going to the dura or dural sinuses, or
vascular tears in contusions and lacerations, are the most common sites of
bleeding. They are often associated with cerebral contusions and edema. The
CT scan may show mass effect and midline shift in excess of the thickness of
the hematoma due to the associated brain injury.
3. Specific types of subdural hematomas
a. Acute subdural hematomas are frequently the result of high-speed
impacts, such as automobile accidents. Associated severe primary brain
damage is the rule. The ultimate outcome is related to age, neurologic
function at the time of surgery, time course from injury to operation, and the
amount of underlying parenchymal injury. Overall mortality is about 50%.
Nonremitting coma from the moment of impact is suggestive of acute
subdural hematoma. The distinction between an acute subdural hematoma
and an epidural hematoma is often difficult or impossible to make on clinical
grounds.
b. Subacute subdural hematomas are suspected when, after several days
of headache or diminished alertness, deterioration of consciousness
develops. In all other respects, this type of hematoma resembles the acute
variety.
c. Chronic subdural hematomas. In contrast to the other hematomas,
chronic subdural hematomas may follow trivial trauma, at times unnoticed
by the patient or not witnessed by family or friends. A gradual drift into
stupor or coma, occasionally preceded by headaches, is common. Mental
changes can be prominent and simulate dementia, psychiatric disorders, or
drug toxicity. In infants, chronic subdural hematoma is most common
between 2 and 6 months of age and often is caused by accidental or
inflicted head injury (i.e., shaken baby syndrome). In this age group, the
clinical picture is one of increasing ICP with vomiting, lethargy, and
irritability; an increasing head circumference; and a bulging fontanel.
Seizures are common as well. In cases of suspected abuse, one must look
carefully for associated retinal hemorrhages and long-bone fractures.
Rotational acceleration can easily tear the superior cortical veins as they
enter the superior sagittal sinus. Brain atrophy associated with aging,
prolonging the trajectory of these veins, probably makes them more
susceptible to rupture. This would explain the significant proportion of cases
of chronic subdural hematoma in elderly and alcoholic patients following
minor degrees of head injury or with no antecedent trauma. In nonfatal
cases, the evolution is toward encapsulation of the clot in a progressively
more fibrous capsule, lined with vascular granulation tissue. The dural or
parietal layer of this capsule is much thicker than the arachnoidal or visceral
layer. The contents of the hematoma vary from thick and tarry dark fluid
with fragments of dissolving clot at the onset to thinner and clearer fluid at
later stages. These contents are thought to increase in volume due to
transudation of plasma and small hemorrhages from the highly vascular
lining membranes. As the interval lengthens from the time of injury, the CT
density of the hematoma changes from hyperdense to isodense to
hypodense relative to brain. At the isodense stage, a sizable hematoma
may not be detected by CT scanning unless IV contrast is administered to
enhance the vascular chronic membrane. This is one reason why MRI has
supplanted CT as the study of choice for evaluating subacute and chronic
subdural hematoma. If MRI is not available, contrast CT, nuclear brain
scanning, or arteriography can help to secure the diagnosis.
4. Treatment
a. Acute subdural hematoma. Surgical treatment is usually necessary.
Acute intraoperative and postoperative cerebral edema often requires ICP
monitoring and aggressive treatment.
b. Chronic subdural hematoma
1. In reliable patients for whom good follow-up is possible, small chronic
subdural hematomas may be followed by serial neurologic examinations
and CT scans. Many such patients can be managed successfully
without surgery, and the lesion resolves spontaneously.
2. In patients with severe or progressive deficits or in individuals who
cannot be followed reliably, surgical treatment is recommended. Burr
holes under local or general anesthesia can be used for drainage of fluid
when the CT scan shows a hypodense collection; this treatment often
results in a permanent resolution of the hematoma. In a few patients,
repeat drainage via burr hole(s) is necessary. In patients with
hyperdense CT collections, or where burr hole drainage is ineffective,
craniotomy and evacuation of the solid clot are needed.
3. Children with open fontanels. The head is shaved and prepared with
iodine. An 18- to 22-gauge short-beveled subdural needle with a stylet is
introduced at the lateral corner of the anterior fontanel at least 3 cm
from the midline. If the fontanel is small, the needle is introduced
through the coronal suture. The needle is advanced slowly until the dura
is punctured, and it is secured by the examiner's finger against the
scalp. The stylet is then removed and fluid allowed to drain. Suction
should not be used on the needle. Subdural taps are repeated as
often as is necessary to relieve symptoms or signs of increased ICP. If
repeated subdural taps have failed and further treatment is necessary,
temporary shunting procedures and, occasionally, craniotomy might be
indicated.
C. Intracerebral hematoma
1. Description. The term intracerebral hematoma refers to hemorrhage larger
than 5 mL within the brain substance (smaller hemorrhages are called
punctate or petechial). The symptoms vary with the location of the
hematoma. In the absence of prolonged initial unconsciousness, there may be
a lucid interval with progressive headaches, and progressive contralateral
hemiparesis might occur if the hematoma is in the appropriate site. Stupor that
progresses to coma will develop if the diencephalon is displaced by the mass
effect. Occasionally, a lucid interval with later deterioration suggests a spat
(late) hematoma, despite absence of evidence for hemorrhage on an earlier
CT scan. Approximately 13% of spat hematomas occur because of a
coagulopathy; the etiology of the remaining 87% is unclear.
2. Diagnosis. A CT scan is the most useful study for demonstrating acute
intracerebral hematoma.
3. Pathophysiology. Intracerebral hematomas are frequently located in the
temporal and frontal lobes. Traumatic cerebellar hematomas are rare.
4. Treatment. For small hemorrhages, treatment consists of observation and
supportive measures. Careful attention to blood pressure should be
maintained, as hypertensive episodes can lead to rehemorrhage. Large
intracerebral hematomas in eloquent areas of the brain may be treated with
hyperventilation, mannitol, and steroids with ICP monitoring in an effort to
avoid surgery. Surgery is indicated for large accessible hematomas in patients
with serious neurologic derangement and mass effect or in those with
neurologic deterioration or ICP elevation despite medical therapy. Temporal
lobe hematomas are especially dangerous, as uncal herniation can lead to
rapid progression to coma and death.
D. Intraventricular hemorrhage
1. Description. Intraventricular hemorrhage may occur following trauma or
subarachnoid hemorrhage. In most patients, the CT scan shows blood density
in the occipital horns. In others, small amounts of blood might block the
aqueduct or fourth ventricle, or larger amounts might occlude the lateral
ventricles at the foramen of Monro, causing acute hydrocephalus.
2. Pathophysiology. If no parenchymal injury is present, intraventricular
hemorrhage might be associated with headache but no neurologic dysfunction.
The block of CSF outflow leads to increasing obstruction without lateralizing
signs. Lateral rectus weakness or diminished upgaze may be noted. At this
stage, deterioration can proceed rapidly to respiratory arrest and death.
3. Minor hemorrhage without hydrocephalus will resolve spontaneously; for larger
hemorrhages, an external ventriculostomy is generally necessary and is
usually placed under local anesthesia in one or both frontal horns. This allows
for CSF drainage and ICP monitoring. After several days, when the blood
clears, the ventriculostomy drains are removed, and in many patients a
permanent shunt is not necessary.
E. Skull fractures without underlying hematomas may be closed (skin intact) or
open (laceration overlies fracture). Closed fractures usually need no further
treatment unless they are depressed and represent a local mass lesion or
represent a significant cosmetic defect. Surgical elevation is then necessary. In
contrast, open fractures almost always need neurosurgical care, since the dura
may be lacerated and bacteria, dirt, and other foreign substances may lead to
delayed infection. A CT scan is done and neurosurgical exploration, debridement,
and repair are performed. Prolonged antibiotics are generally not necessary.
1. Description. Basal skull fractures may be anterior, suggested by raccoon
eyes or CSF rhinorrhea, or posterior, suggested by the Battle sign or CSF
otorrhea. Skull x-rays or CT scan may show an air-fluid level or opacification of
the mastoid air cells or the frontal, ethmoidal, or sphenoidal sinuses. Anterior
basal skull fractures involving the anterior or middle fossa often injure the
olfactory nerve, whereas posterior fractures most often injure the facial and
vestibulocochlear nerves as they course through the petrous bone. Leakage
of CSF frequently accompanies basal skull fractures. To differentiate blood
from bloody CSF rhinorrhea, one can check the fluid for glucose and chloride
content. The CSF is normally hyperchloremic with respect to serum, and
glucose should be about two thirds of the simultaneous serum glucose. Mucus
and tears are low in glucose. CSF can also be distinguished from mucus,
tears, or blood by the presence of b
2
-transferrin. The halo test is less reliable
(a drop of blood-tinged CSF on a cloth sheet should form a double ring
resembling a halo).
2. Treatment. The presence of any skull fracture suggests a significant impact,
and all patients should be admitted to the hospital. Uncomplicated patients are
monitored and may be treated with analgesics (acetaminophen, 650 mg PO
q4h, and/or codeine, 30 to 60 mg PO q4h; aspirin and other nonsteroidal
antiinflammatory drugs are avoided because of their potential inhibition of
platelet function). These patients can be discharged the next day. More
complicated patients are admitted for variable lengths of time. Most CSF leaks
will stop spontaneously with head elevation. Profuse or persistent leaks require
continuous lumbar drainage or surgical repair to prevent meningitis.
F. Scalp lacerations in the absence of an underlying fracture may be debrided,
irrigated, and sutured. If a fracture is present, a penetrating injury must be
excluded. Treatment for tetanus must be given (see Chap. 16). Prophylactic
antibiotics are used for contaminated wounds.
IX. Nonoperative injuries. The initial concern of the physician dealing with head
trauma is the exclusion of an expanding mass lesion such as an epidural or subdural
hematoma. This concern is justified by their immediate threat to life and function and the
availability of a specific treatment, namely, surgery. Yet traumatic hematomas are
present in the minority of cases of head injury. The most common problems following
head injury are concussion, contusion, and cerebral edema.
A. Concussion
1. Description. A concussion is reversible physiologic change in nervous system
function without a gross anatomic abnormality. The 10-second knockout punch
in boxing is a classic example. Consciousness is lost or impaired, and
retrograde or anterograde amnesia (or both) may occur. Generally, no focal
deficit is present. More severe concussion, as from a high-speed motor vehicle
accident, may be associated with neurologic impairment for more extended
periods of time, with recovery evolving through a period of restlessness and
agitated confusion to gradually increasing periods of rational behavior until
normality returns. In children, the syndrome often consists of lethargy,
irritability, pallor, and vomiting.
2. Pathophysiology. Rotational acceleration, provoked by sudden head motion,
induces a swirling movement of the hemispheres around the relatively fixed
diencephalon. This instantaneously deranges the function of the ARAS and
results in loss of consciousness. Linear acceleration and deceleration,
producing complex intracerebral pressure changes, also may be operative in
certain cases. The typical concussion involves no grossly observable anatomic
abnormality. The CT scan is normal, although subtle changes may be seen on
MRI. Derangement at a cellular level may be present, accounting for the
immediate neurologic impairment, the potential for delayed cerebral edema,
and the cumulative effects noted in boxing and the long-term effects seen in
the postconcussion syndrome.
B. Contusion
1. Description. The term contusion refers to bruised necrotic cortex and white
matter, with variable amounts of petechial hemorrhages and edema.
Subarachnoid bleeding of variable magnitude is common. The clinical state in
brain contusion is similar to that of concussion, but brain contusion is usually
more severe and has associated focal neurologic deficits.
2. Pathophysiology. Contusion may result from direct bruising of the brain at the
site of impact (coup), fragments of bone under depressed fractures, or injury at
the pole opposite the impact (contrecoup). The orbital surface of the frontal
lobes and the frontotemporal junction of the hemispheres often are affected
due to violent displacements of the brain against bony irregularities of the
orbital roof or the lesser sphenoid wing.
3. Treatment. Most contusions are amenable to medical treatment; however, it
must be recognized that extensive contusions with edema may represent focal
mass lesions, and surgery must be considered when a noneloquent damaged
area (frontal or temporal tip) is a potential threat to life or other neurologic
function.
C. Cerebral edema
1. Description. Edema represents an excess accumulation of water within the
brain tissue and is seen on the CT scan as a hypodense area with associated
mass effect. Cerebral edema can be associated with any of the operative or
nonoperative posttraumatic lesions already discussed and often represents a
cause of progressive neurologic worsening or even death from uncontrollable
elevated ICP.
2. Pathophysiology. Several hypotheses have been studied regarding the
causes of cerebral edema. These include:
a. Obstruction to venous outflow from mass lesions with elevated ICP.
b. Cellular metabolic derangement associated with dysregulation of the
normal sodium-, potassium-, and water-pumping mechanisms.
c. Breakdown of the blood-brain barrier. In head trauma it is not certain which
of these factors is the most critical, and all may be present to a variable
extent.
X. Medical treatment. Once a surgically treatable mass lesion has been excluded,
medical measures are instituted. The patient who is stunned for a few seconds but who
has no loss of consciousness and has a normal neurologic examination may be
discharged in the care of a reliable friend or relative who is willing to make frequent
observations of the patient over the next 24 hours. It is advisable to discharge patients
with a head trauma sheet that describes potential signs and symptoms of delayed
neurologic dysfunction. The patient with loss of consciousness (even if transient) or with
severe headaches is observed further in the hospital. Often an overnight stay will
suffice. For those with more severe and persistent impairment of neurologic function,
admission to an intensive care unit is generally necessary, and the following measures
are instituted.
A. Airway. Although the airway was initially considered when the patient arrived in
the emergency ward, it must continually be assessed. The patient who did not
require intubation may become less responsive or may not be able to protect the
airway, and intubation may be needed. Soft cuff endotracheal tubes may be left in
place for 1 week or more without difficulty. A nasotracheal tube is often better
tolerated. Frequent suctioning with sterile technique is essential. If intubation is
required for a week or more, due to persistent coma or because of copious
secretions or other pulmonary problems, tracheostomy is advisable.
B. Breathing. If the patient does not have evidence of elevated ICP, normal
ventilatory levels are appropriate. Episodes of acute neurologic deterioration are
most quickly treated by hyperventilation using a hand-controlled Ambubag. For
patients with persistent elevation of ICP, hyperventilation may be necessary to
achieve and maintain a normal ICP. Acutely lowering PCO
2
to below 25 mm Hg is
avoided because a paradoxical rise in ICP secondary to tissue ischemia-induced
vasodilatation can result. Chronically lowering PCO
2
to less than 28 mm Hg is
usually avoided. The PO
2
should be kept higher than 90 mm Hg. Positive
end-expiratory pressure (PEEP) may be needed to normalize PO
2
. If PEEP is kept
less than 10 mm H
2
O, it is generally safe, but rises in ICP can be produced even
at these levels.
C. Circulation. An arterial line is helpful for the patient with persistent coma and
provides continuous blood pressure monitoring and multiple intermittent blood gas
determinations. In the presence of head trauma, normal mechanisms of cerebral
autoregulation are often inoperable, and extremes of blood pressure should be
avoided. Hypotension can cause worsening of neurologic function or even
ischemic stroke. Mean arterial pressures of less than 90 mm Hg require the
placement of a central venous pressure catheter to guide volume replacement to
avoid exacerbation of cerebral edema from fluid overload. In patients with a history
of cardiac disease, a pulmonary artery catheter may be preferable. Phenylephrine
(Neo-Synephrine), dopamine, or another appropriate pressor as a continuous IV
drip may be necessary for blood pressure support. Hypertension is also potentially
hazardous and can cause an elevation in ICP and hemorrhage into contused
brain. A systolic pressure greater than 170 mm Hg adds little to cerebral perfusion
and should be avoided. If agitation is the cause, sedation may suffice. A new mass
lesion or hydrocephalus should be excluded as the cause of new-onset
hypertension. Labetalol, 5 to 10 mg IV, may be used. Nitroprusside or nitroglycerin
should be infused IV only if ICP is not a problem or if it can be closely monitored,
since either drug can elevate ICP. If intravascular volume expansion is required,
colloid or crystalloid may be employed. Generally, an isotonic crystalloid salt
solution is used for gentle rehydration, with bolus colloid infusion (i.e., blood or
albumin) for acute hydration.
D. Intracranial pressure. Elevated ICP from cerebral edema, extensive contusion,
or hematomas not amenable to surgery is the most common serious problem
associated with severe head injury. Intracranial pressure monitoring devices allow
the physician to react quickly to increased pressure in an attempt to prevent
secondary tissue injury from pressure-induced ischemia. Patients who are
responsive and can be followed adequately by the neurologic examination usually
do not require ICP monitoring. Those in coma (GCS less than 8), however,
generally require some form of monitoring of ICP. A number of systems are
available. An intraventricular catheter provides accurate pressure monitoring and
allows CSF to be drained to relieve sudden episodes of elevated ICP.
Disadvantages of the catheter include risk of hemorrhage from insertion through
traumatized brain, the potential for worsening midline shifts, and the risk of
ventriculitis. Both epidural and subdural monitors are also available. The simplest
and most widely used are the fiberoptic subdural device, which once placed
requires no further calibration, and the open bolt connected to a strain gauge.
Newer strain gauge models are also currently in clinical trials, and these may offer
additional advantages. Although small amounts of CSF can be drained through
the open bolt system, the effect is usually negligible. Due to compartmentalization
of the brain, it should be recognized that a fiberoptic or bolt ICP measurement in
the frontal region can be normal, yet the patient may develop progressive temporal
lobe herniation. Therefore, clinical evaluation still should predominate whenever
possible.
Although transient ICP elevation may be associated with neurologic deterioration,
persistent elevations of about 18 mm Hg result in diminished cerebral perfusion
pressure (CPP =mean arterial blood pressure mean ICP; see Chap. 1) and may
be associated with a worse neurologic outcome. Treatment should be
accompanied by a continuous monitoring of CPP and include the following
sequential measures:
1. Elevate the head of the bed. This should be part of the general care of the
head-injured patient. It promotes venous drainage and often will suffice to
decrease the ICP. Avoidance of jugular compression also allows for improved
venous drainage.
2. Ventricular drainage. If a ventricular catheter is present, the venting of a small
amount of fluid is the quickest method to lower ICP. Too much drainage may
cause ventricular collapse and catheter blockage. If the catheter is not present,
it may be needed if other methods fail to decrease ICP.
3. Hyperventilation with an Ambubag will quickly lower ICP and may suffice to
stop a transient ICP elevation or will buy time to institute other measures.
Prolonged hyperventilation should be avoided.
4. Mannitol appears to enhance circulation by decreasing ICP as well as by a
direct effect on cerebral perfusion in the microcirculation. Acute elevations of
ICP are effectively treated with 100 to 200 mL of 20% mannitol. The effect is
not immediate, but results are usually seen within 20 minutes and last for 2 to 6
hours. Some patients require 100 mL q4h to maintain an ICP of less than 15 to
20 mm Hg, in which case serum electrolytes and osmolarity should be checked
frequently and hyperosmolarity (more than 310 mOsm) should be avoided.
5. Furosemide (0.5 mg/kg, or 20 to 40 mg for the average adult) can be given IV
in concert with mannitol for acute episodes to hasten the reduction of ICP.
6. Barbiturates. If the listed measures have been ineffective, 50 to 100 mg of
pentobarbital can be given as an IV bolus and repeated qh as needed to
maintain ICP below 15 to 20 mm Hg. Arterial pressure, ICP, cardiac output,
and pulmonary capillary wedge pressures should be monitored. The most
common complication of barbiturate therapy is hypotension, which can occur
despite maintenance of adequate blood volume and cardiac output. CPP must
be carefully followed. Lowering of systolic blood pressure below 80 mm Hg
should be avoided and limits the usefulness of barbiturates in some patients.
The major disadvantage of barbiturate therapy is that the neurologic
examination is suppressed or even nullified. Indeed, pentobarbital-induced
coma with a burst suppression EEG pattern is often the endpoint of barbiturate
therapy. However, the pupils usually remain small unless herniation is present.
Therapy is continued with daily laboratory examination of pentobarbital levels
until the ICP has been kept below 15 to 20 mm Hg for 24 hours. The
barbiturates are then weaned, which may require 1 to 2 days for full reversal of
drug effect.
In addition to the effect on ICP, barbiturates may provide cerebral protection by
blocking free-radical production, thus decreasing brain damage caused by
these agents, and by decreasing cerebral metabolic oxygen consumption.
7. If a sudden marked rise in ICP has caused neurologic deterioration or has
required most or all of the above measures, a repeat CT scan should be done
to exclude a newly developed hemorrhage or hydrocephalus.
8. Steroids have not been shown to favorably alter outcome in most head-injured
patients and may in fact have a deleterious effect secondary to steroid-related
side effects.
E. Urinary drainage. In the acute setting with vascular instability or when osmotic
diuretics are being used, a continuous bladder catheter is needed. In patients with
hematuria, a catheter should not be inserted prior to obtaining a urethrogram.
Foley catheters should be discontinued as soon as possible in favor of a condom
catheter or intermittent catheterization to reduce urinary infection.
F. A nasogastric tube is useful to evacuate stomach contents in the acute setting
and later to administer antacids, medicines, and nutrition.
G. Nursing care should include adequate hand and foot restraints to prevent
self-injury or pulling out of tubes, frequent turning (q23h) of the patient to prevent
decubitus ulcers, and sterile endotracheal suctioning of secretions. Therapy to
prevent flexion contractures is also crucial.
H. Fluids and electrolytes
1. Maintenance intravenous administration of 0.45% sodium chloride in 5%
dextrose-water (D/W) or its equivalent supplemented with potassium chloride,
20 to 40 mEq/L, is utilized with the rate dependent on the ICP and on frequent
measurements of serum electrolytes, osmolarity, and BUN. It is desirable to
keep osmolarity above 290 mOsm and sodium above 140 mOsm for the first
week after a severe injury to prevent exacerbation of cerebral edema. For
intravascular volume expansion, colloid or crystalloid may be utilized, and
packed red blood cells should always be considered if hematocrit is less than
30%.
2. Diabetes insipidus may result from acute transection of the pituitary stalk or
from elevated ICP compromising the stalk or its vasculature. Diagnosis is
made by documenting a high-volume, hyponatremic urinary output in the
presence of serum hypernatremia and hypertonicity. It is necessary to exclude
diuresis due to mannitol or other diuretics or to fluid overload. Treatment
initially consists of adequate fluid replacement, followed by pitressin or
desmopressin (DDAVP), a synthetic substitute with less of an effect on blood
pressure.
3. Inappropriate antidiuretic hormone secretion may also be noted and may
be due to hypothalamic injury. The ensuing hyponatremia in the presence of
concentrated urine may aggravate cerebral edema, depress neurologic
function, or precipitate seizures. Usually, restriction of free water will suffice for
treatment. Occasionally, furosemide diuresis is necessary. Only in rare severe
cases is hypertonic saline administration necessary.
I. Nutrition. In the acute setting, nutrition is not a consideration, but serious trauma
increases metabolic needs and decreases the immune response so that total
parenteral nutrition should be started as soon as is feasible. If gastrointestinal
function is adequate, a soft flexible nasogastric tube is used. If not, intravenous
alimentation is given. The goal is an intake of 2,500 kcal/day or approximately
150% of the patient's baseline needs.
J . Seizures. Prophylaxis of seizures in a patient who has not had a seizure is
controversial; however, the development of a seizure can acutely elevate ICP, and
early posttraumatic seizure prophylaxis with phenytoin (5 mg/kg/day) is given at
most centers. Acute seizures are treated as described in Chap. 6.
K. Gastrointestinal ulceration is common in patients with severe head trauma and
may be aggravated by steroids. H
2
blockers, ranitidine (150 mg q12h), and
antacids are utilized to neutralize gastric pH. Generally, ranitidine is preferable to
cimetidine, as it has fewer encephalopathic side effects. Gastroprotective agents
such as sucralfate, 1 g PO q.i.d., are also recommended. The use of sucralfate
may be associated with a lower incidence of pneumonia as compared to H
2

blockers, as it does not promote bacterial colonization of the stomach.
L. A bowel regimen is required in comatose patients and should include stool
softeners, rectal disimpaction if necessary, and enemas if required.
M. Pneumatic compression boots (airboots) are used routinely in the immobilized
patient in an attempt to protect against lower-extremity deep venous thrombosis
and the associated risk of pulmonary thromboembolism.
XI. Delayed complications of head injury
A. Posttraumatic epilepsy
1. Description. A proportion of head-injured patients will develop posttraumatic
seizures, which can be classified as immediate (occurring at the time of or
within a few minutes of injury), early (occurring within the first week), or late
(occurring after the first week). Care must be exercised to ensure that the
process is truly epileptic, distinguishing it from other paroxysmal disorders such
as vasovagal syncope and anxiety attacks. The incidence of posttraumatic
epilepsy varies markedly with the mode of injury (i.e., whether the injury was
penetrating or blunt).
a. The overall incidence of posttraumatic epilepsy in penetrating injuries is
about 50%. Factors that influence the likelihood of seizures are the extent
of the lesion, as measured by neurologic deficit (e.g., hemiparesis),
infection, and the location of the lesion (lesions around the rolandic region
have the highest propensity for becoming epileptogenic).
b. Blunt injuries are more common in nonmilitary settings. The incidence of
posttraumatic epilepsy in this group is about 5%, with exacerbating factors
including hemorrhagic contusion or dural tear from a depressed skull
fracture.
2. Pathophysiology. Immediate seizures do not necessarily predispose to
subsequent seizures. They are generally a nonspecific reaction to head trauma
but may represent an intracranial hematoma. Early seizures reflect the initial
brain damage and are more common in children, provided that the injury is
relatively minor. Moreover, early seizures are a well-recognized antecedent of
later seizures. In addition to the occurrence of early seizures, depressed skull
fractures and intracranial hematomas are associated with a high incidence of
late posttraumatic seizure.
3. EEG. In most cases of blunt head injury, the EEG cannot help to determine
which individuals will develop posttraumatic epilepsy. However, its predictive
capacity is much better following penetrating injuries. Early tracings habitually
show alpha suppression and focal theta or delta slowing unilaterally or
generally.
4. Pattern of seizures. Although some early seizures tend to begin focally, most
seizures (early and late) are generalized from the onset. The epilepsy remits
(the criterion of remission being the occurrence of a 2-year seizure-free period)
in 50% to 75% of cases.
5. Treatment
a. When to treat. If traumatic unconsciousness has been brief and there is no
hematoma, parenchymal injury, or neurologic deficit, no treatment is given.
In patients with cerebral contusion, prolonged unconsciousness, and
hematoma, many clinicians administer phenytoin prophylactically for a
1-week period (loading dose of 15 mg/kg, or 1,000 mg in adults, over the
first 24 hours; then a maintenance dosage of 5 mg/kg, or 300 to 400 mg,
daily in adults IV or by means of a nasogastric tube). Blood levels should be
checked periodically (see Chap. 6).
b. Length of treatment. Current data do not support the prophylactic use of
anticonvulsants for longer than 1 week in patients who have not
experienced seizure activity. If immediate seizure activity was present or
the patient is at high risk, a 1- to 3-month course of anticonvulsants may be
continued. For patients who develop posttraumatic epilepsy, a carefully
tailored regimen should be instituted with one or more of the many existing
anticonvulsants. Although phenytoin is effective in reducing seizure activity
in the immediate posttraumatic period, it is often not the most appropriate
drug for prolonged use. It is also important to avoid stopping
anticonvulsants abruptly after prolonged use, since this may be associated
with the recurrence of seizures. Anticonvulsants may be gradually
discontinued over 2 to 3 months.
B. Postconcussion encephalopathy. See Chap. 3.
C. Infection. Meningeal and encephalic infection may occur after head injury,
especially after compound and basilar fracture. These are discussed in Chap. 8.
D. Leakage of CSF is a common complication of basilar skull fracture. It will often
stop spontaneously. When it does not, continuous lumbar drainage may decrease
the pressure sufficiently to allow the tear to seal. If this fails, the location of the
dural tear must be found and surgically repaired. Radionuclide-labeled materials
placed in the CSF may be used to help localize the site of the leak.
Spinal Cord Injury
Since World War II, the creation of centers that specialize in spinal cord injuries has
improved their treatment.
I. Mechanisms of injury
A. Automobile accidents, falls, sports (e.g., diving), industrial accidents, and gunshot
and stab wounds are all causes of spinal cord injury. Most of the lesions are in the
lower cervical cord (C4C7, T1) and the thoracolumbar junction (T11T12, L1).
The thoracic spinal cord is less frequently affected.
B. Factors that set spinal cord injuries apart from cranioencephalic injuries are:
1. The high concentration of important neural tracts and centers in a structure of
relatively small diameter.
2. The position of the cord within the vertebral column.
3. Peculiarities of the spine such as canal size.
4. Presence of osteophytes.
5. Variability of vascular supply.
C. Table 12-3 demonstrates the anatomic relationships of the cervical spinal
segments to the corresponding vertebral bodies, nerve roots, and neurologic
functions. Note that roots C2C7 exit superior to their respective vertebral bodies,
whereas all other nerve roots of the spinal cord exit inferior to the vertebral body.
TABLE 12-3. Relationship of Spinal Segments, Vertebral Bodies, Nerve Roots,
and Their Functions
D. The effects on neural tissue are most important in spinal injuries. The cord and
roots are injured by the following 4 mechanisms:
1. Compression by bone, ligaments, extruded disc material, foreign body, and
hematoma. The most severe damage is caused by bony compression,
compression from a posteriorly displaced vertebral body fragment, and
hyperextension injuries.
2. Stretching of tissues. Overstretching that causes disruption of tissue usually
follows hyperflexion. The stretch tolerance of the cord may decrease with age.
3. Edema. Cord edema soon appears and produces further impairment of
capillary circulation and venous return, compounding the primary injury.
4. Circulatory disturbances are the result of compression by bone or other
structures of the anterior or posterior spinal arterial systems.
II. Immediate care of the spinal cord injured patient. The aim is to prevent
further damage to the spinal cord by all possible means. A certain number of spinal cord
injuries are worsened by improper handling of the patient in this stage or by the effects
of hypotension or hypoxia on already compromised neural tissue.
A. Move the patient carefully if a spinal lesion is suspected.
B. Place the patient on a firm, flat surface for transport. If a cervical lesion is
suspected, someone should be assigned to ensure stability of the patient's head
during movements. Many sophisticated modalities now exist for transferring the
patient with minimal spinal disturbance.
C. Pillows, rolled blankets, or sandbags may be used at the patient's sides to prevent
lateral displacements.
D. Cover the patient with blankets to avoid loss of body heat.
E. Transfer the patient to an acute care hospital or to a center that specializes in
spinal cord injuries.
III. Care of the neural lesion
A. Spinal cord concussion
1. Description. Spinal cord concussion is a state of transient loss of cord function
due to trauma with or without associated fracture or dislocation. Immediate
flaccid paralysis occurs. Recovery is complete in a matter of minutes to hours.
2. Pathophysiology. Violent pressure waves propagated through deep tissues
are believed to transiently change the normal properties of tracts and neuronal
groups.
3. Treatment. Fracture or unstable dislocation must be excluded. If recovery is
complete, no further treatment is necessary. If recovery plateaus with a
persistent deficit, a compressive lesion must be excluded.
B. Spinal cord contusion and transection. In these conditions, there is some
discernible anatomic change of the spinal cord, although there may be functionally
complete transection with few pathologic changes. The cord is rarely completely
severed. Delayed loss of neurologic function can occur early or late. The early
losses are usually caused by spinal cord edema or by hemorrhagic necrosis of
central gray matter. This can lead to a neurologic deficit extending to a higher level
than the initial injury. However, one must always exclude delayed hematoma, disc
fragment, or an unrecognized fracture as other treatable causes. Because time is
so crucial, immediate exploration for treatable lesions is mandatory. If complete
paralysis and sensory loss are present for longer than 48 hours, the chances for
functional recovery are minimal, and the spinal cord changes are assumed to be
anatomic rather than physiologic.
1. In cord contusion, early changes include edema, petechial hemorrhages,
neuronal changes, and an inflammatory reaction. At later stages, the cord may
be reduced to a fibrotic structure, and the pathologic changes may extend
above and below the damaged segment. Late deficits are usually a result of
the formation of intramedullary cysts or syringomyelic cavities. The neurologic
syndromes that result from spinal cord injury are varied, but a few are well
established.
2. Complete functional cord transection
a. Spinal shock. At first there is immediate flaccid paralysis and sensory loss
below the level of the lesion. In the immediate postinjury period of
neurogenic shock, priapism is often present in males, and the
bulbocavernosus reflex is lost. After this initial period of several hours, the
bulbocavernosus reflex will return, but most other reflexes remain absent
through the period of spinal shock. This state usually lasts for 3 to 6 weeks,
but sepsis, malnutrition, or other complications can prolong it for months.
b. Increasing reflex activity. Spinal shock is replaced by gradual return and
an eventual increase of reflex activity. In cervical lesions there is an initial
tendency to flexion that later is followed by extension. The presence of
internal stimuli, such as urethritis, cystitis, and decubitus ulcers, provokes
flexor spasms, which if repeated tend to fix the posture in flexion. The mass
reflex is the most dramatic manifestation of increased flexion activity. It
consists of contraction of the abdominal muscles, triple flexion of the lower
limbs, profuse perspiration, piloerection, and automatic urination in
response to stimuli below the lesion.
c. Sensation. In incomplete lesions there is usually some recovery of
sensation after a variable interval of time. Complete lesions show no
recovery.
d. Pains. Radicular pain due to root involvement might be present for weeks
or months. More frequently, however, a more severe type of pain,
commonly described as a dysesthetic burning, occurs below the lesion
level. This pain lasts longer and might be resistant to narcotics. Note that
pain, whatever its nature, is markedly influenced by the patient's emotional
state.
e. Autonomic disturbances
1. Temperature regulation. Sweating is decreased or absent below the
level of the lesion if it is above T9T10. If the lesion is above C8, all
thermoregulation is lost. It is not uncommon to see wide fluctuations of
body temperature, especially in response to sepsis. The profuse sweats
seen in these patients are reflexive in nature and are triggered by
impulses from the bladder or rectum (distention). Hyperhidrosis is
another manifestation of this hyperreflexic state.
2. Blood pressure regulation. Orthostatic hypotension is caused by a
lack of reflex contraction of the capacitance vessels in response to
postural changes. If the patient is tilted up, a precipitous drop in blood
pressure occurs, which may lead to unconsciousness. Episodes of
paroxysmal hypertension also occur, usually in response to a distended
bladder or rectum. Since these episodes can be precipitated by painful
stimulation below the level of the lesion, adequate anesthesia must be
used for all procedures, even if they only involve insensate body parts.
3. Bladder regulation. Disturbances of bladder function and its result,
chronic renal failure, are the most common causes of death in these
patients (for details on neurogenic bladder, see Chap. 17).
a. First stage. Immediately following cord damage, reflex bladder
function, as with other reflexes in spinal shock, is abolished. There is
marked atony and overdistention of the bladder, and overflow
voiding occurs. This stage can last for days to weeks, depending on
the same factors operative in spinal shock (e.g., age, associated
diseases, malnutrition, sepsis).
b. The second stage varies according to the location of the lesion. In
lesions above the lumbosacral segments, reflex bladder function
returns, and an automatic or reflex bladder develops. Initially, the
detrusor contractions are weak, and the volume of urine voided is
small, although subsequent emptying becomes more complete.
Bladder distention may be heralded by flushing, headache, nasal
congestion, and other signs that the patient learns to recognize as
representing bladder fullness.
The establishment of satisfactory reflex micturition depends on
avoidance of both infection and overdistention during the initial stage
of bladder atony. If the lesion is at the level of the conus medullaris
or cauda equina, the bladder is called autonomic (i.e., deprived of
voluntary and reflex activity). Detrusor contractions mediated by the
intramural autonomic plexus are not effective, and voiding is never
complete (as in the automatic or reflex type). Intravesical pressure is
high, dribbling may occur, and there is a large residual volume. If the
external sphincter is surgically severed, the bladder may be emptied
by abdominal compression.
c. In the third stage of reconditioning, the patient with an autonomic
bladder, having learned the signals of bladder distention, is able to
trigger micturition by such acts as abdominal pressure.
d. Bowel dysfunction goes through the same three stages. Initially,
the bowel is distended and atonic, and peristalsis is abolished.
Return of bowel sounds and passage of flatus signal the beginning
of the second stage. Once peristalsis begins, reflex or automatic
evacuation may be accomplished if the stool is kept soft (by stool
softeners or bulk-producing agents) and if there is no fecal
impaction. Reflex evacuation may be triggered by abdominal
compression or by the insertion of a suppository. In the autonomic
type, the sphincter is patulous and rectal incontinence develops.
Reconditioning of the bowels is easier than reconditioning of the
bladder.
Gastric atony and distention can be dramatic during the first stage of
bowel dysfunction. To prevent overdistention and potential gastric
perforation in the spinal cord injured patient, who may not sense the
overdistention, a nasogastric tube should be placed for drainage.
f. Sexual dysfunction varies, depending on the severity of the process.
3. Anterior cord syndrome is characterized by paralysis and loss of pain
sensation below the level of the lesion; there is some preservation of touch,
vibratory, and position senses, which run in the posterior columns of the spinal
cord. An extruded anterior disc fragment is a treatable cause that must be
excluded.
4. Central cord syndrome is characterized by a greater motor deficit in the arms
than in the legs, and there are variable sensory deficits. The greater
predilection for the arms (versus the legs) may be explained by anterior horn
cell damage in the cervical cord and by involvement of the more medially
placed fibers of the corticospinal tract in the lateral columns. Anatomically,
lumbar and sacral tracts run more laterally and are therefore relatively spared
from a centrally placed lesion. This syndrome is most commonly seen in
hyperextension injuries in patients with spondylosis, therefore being mainly a
disease of the elderly. Recovery of hand function is usually incomplete.
5. Brown-Squard syndrome results from damage to one half of the cord, with
resulting ipsilateral weakness, proprioceptive and vibratory loss, segmental
anesthesia at the level of the lesion, and contralateral loss of pain and
temperature sensation. This syndrome is most common with penetrating spine
injuries.
IV. Diagnosis of spinal cord injury
A. Shortly after the patient's arrival at the hospital, a detailed neurologic
examination is carried out and recorded (see sec. V under Severe Head
Injury ).
B. The spine is examined carefully for deformities, swelling, tenderness, and
limitation of movement, particularly in the neck. Be careful not to move the spinal
elements unduly until fracture has been ruled out.
C. Radiologic examination should include all areas of the spine where injury is
questioned. Lateral and anteroposterior projections are performed. In the cervical
region, open-mouth view of the odontoid and oblique projections of the spine is
necessary. Cautious, supervised flexion and extension views may be indicated. If
the plain x-rays do not adequately show a suspected lesion, CT scanning may be
necessary for clarifying bony injury. If a neurologic deficit is present, MRI is
preferable to other diagnostic modalities, as it is superior for demonstrating both
extrinsic and intrinsic spinal cord pathology. If MRI is not available, the instillation
of contrast material (nonionic, water-soluble contrast media) by C1C2 puncture
may augment CT scanning.
V. Treatment. The best results have been achieved in special centers where large
numbers of spinal cord injured patients are seen. The treatment is determined by the
interval of time that has elapsed since the injury, the presence of associated problems,
the level and completeness of the injury, and the specific bony abnormalities present, if
any. The need for an airway, ventilation, and treatment of associated injuries is
self-evident and is similar to the precautions noted in the discussion under Severe
Head Injury. Although many medical treatments for spinal cord injury are currently in
clinical trials, one treatment has become widely accepted. Based on the National Acute
Spinal Cord Injury Study, a methylprednisolone protocol has been adopted at most
centers. The administration consists of methylprednisolone, 30 mg/kg IV bolus dose
over 15 minutes, followed by 5.4 mg/kg/hour maintenance dose to begin 45 minutes
after the bolus. If begun within 3 hours, the infusion should be continued for 23 hours. If
begun between 3 and 8 hours after the injury, the infusion should last 47 hours. If the
8-hour window has been missed, methylprednisolone should not be used. Prophylaxis
for peptic ulcer disease is mandatory. On a cellular basis, methylprednisolone probably
acts by inhibiting lipid peroxidation and secondary increase in arachidonic acid.
A. Acute surgery. Posterior decompressive laminectomy is not advocated at the
present time except in rare instances. Current indications for surgery are as
follows:
1. Open reduction of dislocation, with or without fracture in the cervical region,
if traction and manipulation have failed.
2. Cervical fractures with partial cord lesions, in which a bony fragment
remains compressing the anterior aspect of the cord despite adequate traction.
3. Cervical injuries with partial cord lesions, in which no bony fragment can be
seen but extruded disc material is suspected of compressing the cord. MRI,
myelography, or CT scan might be necessary to demonstrate this condition.
4. Depressed fragments of the neural arch.
5. Compound injuries, with foreign bodies or bone fragments in the spinal canal.
6. Partial cord lesions, with gradual worsening of the neurologic examination
or worsening after initial improvement despite maximal conservative
management. A hematoma must be suspected. Repeat MRI prior to surgery is
advisable if quickly available.
B. Treatment of the vertebral injury. After achieving initial cardiorespiratory
stability, the correct radiographic diagnosis is essential, and treatment is guided
accordingly. When traction is needed, either cranial tongs or a halo-traction
apparatus can be used to apply force along the longitudinal axis of the cervical
spine. An MRI-compatible system should be employed, as MRI will often be
necessary at some point in the treatment course of the patient. In general, greater
weights are needed for lower cervical spine fractures. A useful guideline for the
initial weight is to place 5 lb per level above the injury (e.g., for a fracture at C5,
one would use 25 lb). Traction weights should be placed by an experienced
person. Weight should be added under fluoroscopic guidance, or a lateral cervical
spine x-ray should be checked with each weight change. Attention to ligamentous
instability is necessary to prevent overdistraction with subsequent cord stretching
and injury. For thoracic or lumbar fractures, traction is usually not helpful.
1. Cervical injuries
a. Atlanto-occipital dislocation. Injury at this level is usually fatal due to
vertebral artery injury or direct medullary compromise. The rare patient who
survives to reach the hospital may have little or no neurologic deficit.
Traction can cause further distraction and neurologic deficit. If ventilation is
compromised, tracheostomy may be required, since head manipulation is
treacherous. Occipitocervical fusion is needed.
b. A Jefferson fracture usually results from a blow to the vertex of the head,
causing a bilateral fracture through the posterior arch of C1.
Radiographically, the open-mouth view should be diagnostic. If the patient
survives, pain may be present, but often there is no neurologic deficit, in
part because the nature of the C1 disruption widens the spinal canal. In
most instances, these fractures will heal with halo-vest fixation.
Occasionally, an occipital-C1-C2 fusion is needed.
c. Atlanto-axial injuries are conveniently divided into 4 groups.
1. Ligamentous injuries. Open-mouth views may show an intact
odontoid, but lateral views demonstrate an abnormal separation of the
odontoid from C1 anteriorly (normal predental space should be less than
3 mm in adults and 5 mm in children). Cautious flexion and extension
views demonstrate hypermobility. Spontaneous healing will always be
unstable, and early C1-C2 fusion is required.
2. Odontoid tip fracture (type 1). Fracture through the bone will usually
heal spontaneously following halo-vest stabilization.
3. Fractures through the odontoid base (type 2) may compromise the
blood supply to the odontoid, leading to nonunion. Surgical stabilization
and fusion is recommended in most cases.
4. Fractures involving the C2 body (type 3) will usually heal adequately
with halo-vest immobilization.
d. A hangman fracture refers to a bilateral pedicle disruption of the arch of
C2 with associated C2C3 dislocation. It is usually the result of a
hyperextension injury, such as when a passenger in a motor vehicle
accident strikes his or her chin on the dashboard. Most such fractures heal
following immobilization. Alternatively, surgical stabilization and fusion can
be helpful.
e. Locked (or jumped) facets may be unilateral or bilateral. Unilateral injuries
often cause partial (less than 50%) compromise of the spinal canal. Root
injury with or without cord injury may be seen. Locked facets are seen as a
vertebral subluxation on the lateral x-ray and are often first detected on the
anteroposterior x-ray by noting a rotation in the normal vertical alignment of
the spinous processes. Oblique films confirm the facet dislocation. Traction
frequently will relocate the unilateral locked facet, especially at higher
cervical levels. It is advisable to obtain an MRI scan prior to the reduction,
as reducing locked facets in the presence of an acutely herniated disc can
exacerbate the cord injury. In this setting, surgical excision of the herniated
disc followed by reduction is indicated. For lower cervical segments,
surgical intervention may be needed to achieve reduction. In contrast,
bilateral jumped facets are usually associated with spinal injury and are
more easily realigned with traction. Essentially all facet disruptions remain
unstable due to associated ligamentous injury and often easily redislocate,
necessitating fusion.
f. A flexion teardrop fracture refers to a wedge-shaped fracture of the edge
of the anterior vertebral body. It is often associated with disruption of the
interspinous and other posterior ligaments, causing instability. Frequently,
significant neurologic deficit is present from anterior impingement of the
spinal cord by the disrupted body.
g. Dislocations through the disc space are generally unstable and will not
fuse spontaneously. Surgical fusion is needed. In contrast, dislocations
caused by a fracture through the vertebral body will usually fuse after an
adequate period of immobilization.
2. Thoracic injuries. Because of the buttressing effect of the rib cage, most
thoracic injuries are relatively stable. Traction is not helpful. Surgery is needed
if misalignment is severe or if further future angulation is expected. However,
less severe misalignment might be tolerated and will heal with bed rest and
immobilization with a form-fitted plastic jacket.
3. Thoracolumbar injuries are often associated with a burst of the vertebral
body with significant bone displacement into the canal compressing the conus
or cauda equina. If the deficit is incomplete, surgery to decompress the spinal
canal and to promote realignment and fusion will often result in neurologic
improvement.
C. General nursing care
1. Bladder care. The aim of bladder care is to obtain a patient-controlled reflex
bladder that is free of infection. To accomplish this, the technique of
intermittent, sterile, no-touch catheterization has yielded the best results. Also,
maintenance of an acidic urine with ascorbic acid, 1 g q.i.d., helps prevent
infection and urinary calculi.
Although urine production is decreased for the first day or so after injury, we
intermittently catheterize patients 2 to 3 times daily, depending on residual
volumes, from the outset to decrease the risk of urinary infection (see Chap. 17
for details).
Difficulty with urine storage can be improved by the use of medications that
promote bladder neck contractility, such as phenylephrine, and by reducing
spasticity with agents such as oxybutynin chloride (Ditropan). Difficulty with
bladder emptying can be ameliorated with cholinergic drugs such as
bethanechol, which promote bladder contractions, or by relaxing the external
sphincter with anti-spasticity agents such as baclofen.
2. Bowel care. The aim of bowel care is to obtain a patient-controlled reflex
evacuation. The initial stage of bowel distention is treated by rectal tube or
enemas. Later, when peristalsis returns, bulk-producing agents, such as
psyllium hydrophilic mucilloid (Metamucil), or stool softeners, such as dioctyl
sodium sulfosuccinate (Colace), are used. As the bowel becomes more active,
suppositories replace enemas. The patient should be examined frequently for
fecal impaction.
3. Skin care. Blankets and sheets are drawn tight and smooth, and the patient is
put on a mattress or foam pad placed on a hard, flat surface. The patient
should be turned q2h, day and night. In specialized centers, continuously
rotating beds are utilized to protect pressure points and to facilitate care. In
cases of vertebral injury, beds that do not offer spinal support should not be
employed.
4. Nutrition. A high-calorie, high-protein diet is essential. If the patient is unable
to eat, supplements are given parenterally or by means of a nasogastric tube.
Fluid and electrolyte balance should be watched closely.
5. Pain control. Acute pain is treated with aspirin, propoxyphene (Darvon), and
codeine. Sedative drugs (e.g., barbiturates, benzodiazepines) can be used to
control anxiety. In patients with partial cord function, both barbiturates and
benzodiazepines theoretically can interfere with function by enhancing
g-aminobutyric acid-mediated inhibition. Phenytoin, carbamazepine, and
amitriptyline have all been employed for dysesthetic pain associated with cord
injuries. Chronic pain is best treated in conjunction with a pain service.
6. Psychiatric care. Early contact with experienced psychiatric health care
personnel is arranged.
VI. Complications
A. Urinary calculi are related to improper urinary drainage, infection, and
hypercalciuria due to prolonged immobilization. Prevention is accomplished by
acidifying the urine, promoting a high urine output, avoiding infection, and
mobilizing the patient early.
B. Decubitus ulcers are heralded by an area of redness in the pressure points. The
incidence of decubiti has fallen dramatically since World War II, attesting to the
better nutritional state and nursing care these patients receive. Body casts that
cover pressure points are contraindicated unless applied by skilled therapists for
the treatment of flexion contractures of the extremities. Small decubiti often heal
spontaneously, provided that they are scrupulously cleaned and kept dry. Larger
lesions may require plastic surgery (see Chap. 17, sec. V).
C. Muscle spasms can be greatly diminished if their precipitating factors are kept to
a minimum (e.g., urethritis, cystitis, decubiti, rectal or vesical distention). Also, they
tend to ameliorate spontaneously after the second year.
Drugs used for the treatment of spasticity include diazepam, baclofen, and
dantrolene sodium. If drug treatment is ineffective, intrathecal injection of phenol
may be necessary (for details, see Chap. 15, sec. II.D.). Intrathecal baclofen
pumps are becoming increasingly employed for the treatment of spasticity in
patients with preserved voluntary muscle control. Rhizotomy is reserved for
exceptionally severe cases and is rarely done.
D. Contractures occur in plegic extremities. Proper prophylaxis includes the early
use of range of motion exercises and splinting.
E. Deep venous thrombosis occurs commonly in spinal cord injury patients. The
onset of tachycardia, dyspnea, chest pain, or hypotension can indicate a
pulmonary embolus.
All patients with uninjured lower extremities should be fitted with prophylactic
elastic stockings and pneumatic compression devices. Additional benefit may be
gained from the administration of subcutaneous heparin in patients without CNS
hemorrhage.
F. Atelectasis and pneumonia occur in patients who are unable to deep-breathe
and cough. Spinal cord injury patients should be treated with postural drainage,
assistive coughing, chest percussion, and, when possible, incentive spirometry.
Routine tracheostomy care should be employed, including the use of humidified
air and suctioning to facilitate the removal of secretions.
VII. Rehabilitation
A. Physiotherapy. Massage and passive movements are started as soon as
possible. Later, special exercises are devised for the development of certain
muscle groups necessary for independence. Specialists in rehabilitation medicine
or spinal cord injury rehabilitation should be consulted for the design and
maintenance of these programs.
B. Vocational therapy prepares patients for future gainful employment while at the
same time shifting their attention away from the disability. Multiple devices are
available that permit a wide range of activities for these patients.
C. Sports. Wheel-chair basketball, archery, bowling, road racing, swimming, and bag
punching are available. Special hunting seasons are set for paraplegics.
D. Psychiatric therapy is nearly always indicated and may be essential for suicidal
or excessively depressed patients.
Selected Readings
Annegers J F, et al. Seizures after head trauma: a population study. Neurology (NY) 1980;30:683.
Becker DP, Gudeman SK. Textbook of head injury. Philadelphia: WB Saunders, 1989.
Braakman R, et al. Megadose steroids in severe head injury. Results of a prospective double-blind clinical
trial. J Neurosurg 1983;58:326.
Bracken MB, et al. A randomized controlled trial of methylprednisolone or naloxone in the treatment of
acute spinal cord injury. N Engl J Med 1990;322:1405.
Bracken MB, et al. Methylprednisolone or naloxone treatment after acute spinal cord injury: one year
follow-up data. J Neurosurg 1992;76:23.
Bracken MB, et al. Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48
hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury
Randomized Controlled Trial. National Acute Spinal Cord Injury Study. JAMA 1997;277(20):1597.
Chesnut RM, et al. Early and late systemic hypotension as a frequent and fundamental source of cerebral
ischemia following severe brain injury in the Traumatic Coma Data Bank. Acta Neurochir (Suppl)
1993;59:121.
Ducker TB, et al. Complete sensorimotor paralysis after cord injury: mortality, recovery, and therapeutic
implications. J Trauma 1979;19:837.
Eisenberg HM, et al. High-dose barbiturate control of elevated intracranial pressure in patients with
severe head injury. J Neurosurg 1988;69:15.
Gomori J M, et al. Variable appearances of subacute intracranial hematomas on high-field spin-echo MR.
Am J Neuroradiol 1987;8:1019.
Hsiang J K, et al. Early, routine paralysis for intracranial pressure control in severe head injury: is it
necessary? Crit Care Med 1994;22:1471.
Kaufman HH, et al. Delayed and recurrent intracranial hematomas related to disseminated intravascular
clotting and fibrinolysis in head injury. Neurosurgery 1980;7:445.
Levin HS, et al. Long-term neuropsychological outcome of closed head injury. J Neurosurg 1979;50:412.
Miner ME, et al. Disseminated intravascular coagulation fibrinolytic syndrome following head injury in
children: frequency and prognostic implications. J Pediatrics 1982;100:687.
Muizelaar J P, et al. Adverse effects of prolonged hyperventilation in patients with severe head injury: a
randomized clinical trial. J Neurosurg 1991;75:731.
Schmoker J D, et al. An analysis of the relationship between fluid and sodium administration and
intracranial pressure after head injury. J Trauma 1992;33:476.
Schwartz ML, et al. The University of Toronto head injury treatment study: a prospective, randomized
comparison of pentobarbital and mannitol. Can J Neurol Sci 1984;11:434.
Simon RH, Sayre J T. Strategy in head injury management. Norwalk, CT: Appleton and Lange, 1987.
Sonntag VKH. Management of bilateral locked facets of the cervical spine. Neurosurgery 1981;8:150.
Temkin NR, et al. A randomized, double blind study of phenytoin for the prevention of post-traumatic
seizures. N Engl J Med 1990;323:497.
Tranmer BI, et al. Effects of crystalloid and colloid infusions on intracranial pressure and computerized
electroencephalographic data in dogs with vasogenic brain edema. Neurosurgery 1989;25(2):173.
Wald SL, Shackford SR, Fenwick J . The effect of secondary insults on mortality and long-term disability
after severe head injury in a rural region without a trauma system. J Trauma 1993;34:377.
Wilkins RH, Rengachary SS, eds. Neurosurgery, vol. 2, part 8. New York: McGraw-Hill, 1996;2601.
Young B, et al. Failure of prophylactically administered phenytoin to prevent early posttraumatic seizures.
J Neurosurg 1983;58:231.
CHAPTER 13. DEMYELINATING DISEASES
Manual of Neurologic Therapeutics
CHAPTER 13. DEMYELINATING DISEASES
Daniel B. Hier
Multiple sclerosis (MS)
Optic neuritis
Acute disseminated encephalomyelitis
Acute transverse myelitis
I. Multiple sclerosis (MS)
A. Diagnosis
1. No specific laboratory test is currently available to confirm the diagnosis of MS.
The diagnosis generally rests on 2 features of the illness:
a. A history of fluctuations in the clinical course--either well-defined
exacerbations and remissions or lesser variations in a progressive downhill
course.
b. A physical examination consistent with that of multiple lesions in the white
matter of the central nervous system (CNS).
2. The spinal fluid is abnormal in about 90% of patients, and about 50% of
patients have a cerebrospinal fluid (CSF) pleocytosis with more than 5
lymphocytes. Pleocytosis tends to be more marked early and during acute
exacerbations in the course of MS.
a. Nearly 75% of patients have elevated CSF gamma globulins, with
immunoglobulin G (IgG) making up more than 12% of the CSF total protein.
Mild elevations of total CSF protein are common, but elevations over 100
mg/dL are unusual. A variety of CSF indices are useful in the diagnosis of
MS, including the IgG/albumin ratio, the IgG synthetic rate, and the IgG
index. Caution must be exercised in interpreting these IgG indices because
they are abnormal in a large number of inflammatory diseases other than
MS.
b. By utilizing high-resolution electrophoresis of concentrated CSF,
oligoclonal bands of IgG can be demonstrated in 85% to 95% of patients
with definite MS. However, oligoclonal bands of IgG also occur in
neurosyphilis, subacute sclerosing panencephalitis, fungal meningitis, and
progressive rubella panencephalitis. Nevertheless, this test often is useful
in confirming the diagnosis of MS because it is frequently abnormal early in
the course of the disease. The test is available from commercial
laboratories.
c. An increase in CSF myelin basic protein may confirm an acute attack of
MS. Elevated values (more than 9 ng/mL) suggest active demyelination.
However, myelin basic protein levels may also be increased in transverse
myelitis, optic neuritis, or radiation-induced demyelination. This test is not
generally useful in confirming the initial diagnosis of MS. It is also available
from commercial clinical laboratories.
d. Lumbar puncture has not been shown to have any adverse effect on the
course of the disease, and it should be performed diagnostically in all
suspected cases.
3. Pattern shift visual-evoked responses are abnormal in approximately 80% of
patients with definite MS and 50% of patients with probable MS. In as many as
50% of MS patients, visual-evoked responses reveal a clinically unsuspected
lesion of the optic pathways.
4. Brainstem auditory-evoked responses are abnormal in about 50% of
patients with definite MS and 20% of patients with probable MS. Unsuspected
lesions of the auditory pathways are found in about one third of MS patients.
5. Somatosensory-evoked responses are abnormal in about 70% of patients
with either probable or definite MS. Clinically unsuspected lesions of the
somatosensory pathways are detected in about one half of patients with MS.
6. Magnetic resonance imaging (MRI) is more sensitive than computed
tomographic (CT) scanning in detecting CNS demyelination. The MRI is more
sensitive than evoked potentials and is probably as sensitive as CSF
examination in the diagnosis of MS. When the MRI shows white matter lesions
in the setting of abnormal CSF and evoked potentials, the diagnosis of MS is
almost unequivocal.
a. Normal MRI in suspected MS. Although the brain MRI may be normal in
MS, this is an uncommon finding. In patients with an initial neurologic event
consistent with CNS demyelination and a normal MRI, the 5-year risk of MS
is less than 5%. Conversely, patients with a first neurologic event consistent
with demyelination and multiple white matter brain lesions on MRI have a
5-year risk of MS of about 60%.
b. The MRI as a marker of disease severity in MS. The MRI burden
(number and size of white matter lesions on MRI) correlates weakly with
clinical status in MS. The MRI also can detect attacks of demyelination that
have no obvious clinical correlate. Nonetheless, MRI remains an excellent
measure of disease severity and progression.
7. Differential diagnosis. Other diseases affecting CNS white matter may
resemble MS clinically or radiologically. Care must be taken to exclude these
conditions before confirming a diagnosis of MS:
a. Certain tumors (especially lymphomas and gliomas of the hemispheres,
brainstem, and spinal cord).
b. Certain malformations (Arnold-Chiari and platybasia).
c. Spinal cord compression due to spondylosis, herniated intervertebral disk,
and epidural tumor.
d. Degenerations including spinocerebellar, motor neuron disease, familial
spastic paraparesis, hereditary ataxias, and subacute combined
degeneration of the spinal cord.
e. Vasculitis including polyarteritis, isolated angiitis of the nervous system, and
systemic lupus erythematosus.
f. Behet disease.
g. Human T-cell lymphotropic virus type 1-associated myelopathy.
h. Neurosarcoidosis.
i. Postinfectious and postvaccinial encephalomyelitis.
j. Human immunodeficiency virus (HIV) encephalopathy.
k. Vitamin B
12
deficiency.
l. Adult-onset adrenoleukodystrophy.
8. If the neurologic symptoms in a case of suspected MS are limited to the spinal
cord, brainstem, or posterior fossae, MRI is useful in excluding cord
compression, tumors, or malformations. Features that cast doubt on the
diagnosis of MS include completely normal CSF, completely normal MRI of
brain and spinal cord, neurologic signs and symptoms that can be explained by
a focal lesion, or absences of fluctuations in the clinical course.
9. The hot-bath test is an antiquated procedure for diagnosis of MS. Persistent
deficits have been reported in some patients after testing. We do not
recommend use of this test.
B. Prevalence and etiology. Prevalence and incidence of MS vary with latitude,
increasing with distance from the equator. In industrialized northern hemisphere
countries, the annual incidence of MS is approximately 3/100,000 with a
prevalence of 60/100,000. Epidemiologic studies suggest that the prevalence of
MS has been rising for the past 40 years. The cause of MS is unknown. One
hypothesis is that some environmental factor, possibly a limited group of viruses,
acts early in life to initiate the disease process in a genetically susceptible group of
individuals.
C. Prognosis. After the patient has been diagnosed as having MS, the physician
must correct any misconceptions the patient may have about the nature and
prognosis of the illness. The course is highly variable.
1. A review of 146 persons treated at the Mayo Clinic over a 60-year period
revealed a 25-year mortality of about 26% compared with 14% in the general
population. After 25 years, two thirds of the survivors were still ambulatory.
2. Approximately 20% of patients have benign MS. These patients do progress
over time and generally have mild signs and symptoms. Remaining cases are
classified as relapsing-remitting, progressive-relapsing, primary-progressive,
and secondary-progressive. Prognosis is best with the benign forms and worse
with the progressive forms. About 50% develop chronic progressive MS. Poor
prognostic signs include motor or coordination symptoms at onset or older age
at onset. Predominance of sensory symptoms is usually associated with a
benign course.
3. A decreased risk of exacerbations has been found during pregnancy.
However, exacerbations increase immediately post partum.
D. Treatment
1. Therapy aimed at halting the progression of MS
a. Ineffective treatments. Diets based on either restriction or
supplementation with linoleic acid are not of proven benefit. Long-term
therapy with adrenocorticotropic hormone (ACTH) or corticosteroids
(intrathecally or systemically administered) does not alter the course of MS.
Hyperbaric oxygen is of unproven benefit.
b. Two b-interferons have been approved for the treatment of ambulatory
patients with relapsing-remitting MS.
1. Dosage. The recommended dosage of interferon b-1b (Betaseron) is 8
million IU SC every other day. In a 2-year study, incidence of new
attacks was reduced by 34% in treated patients. Efficacy data beyond 2
years of treatment are not currently available. Safety data beyond 3
years are not currently available. Current recommendations are to treat
patients for 2 years and then reevaluate therapy. Adverse reactions to
interferon b-1b include injection site reactions (85%), injection site
necrosis (5%), and flulike symptoms (76%). Flulike symptoms tend to
abate with time. Depression, anxiety, confusion, and suicide attempts
occurred in some of the interferon b-1b trial patients. Neutropenia and
elevation of liver transaminases occurred in some patients.
Interferon b-1a (Avonex) is given as a dose of 6 million units
intramuscularly per week. In a 2-year study, the incidence of
exacerbations was reduced by 31%. Skin reactions are generally absent
with interferon b-1a; flulike symptoms may occur.
2. Contraindications include hypersensitivity to interferon b or human
albumin.
3. Laboratory monitoring (complete blood count, or CBC, with
differential, blood chemistries including liver enzymes, and platelet
count) is recommended before onset of treatment and at 3-month
intervals during treatment.
Neutralizing antibodies occur with prolonged use of interferon b. After 2
years of therapy, approximately 38% of patients on interferon b-1b and
22% of patients on interferon b-1a have detectable neutralizing
antibodies. The presence of the these antibodies correlates with loss of
interferon b activity and disease relapse. Titers of neutralizing can be
obtained from reference laboratories.
4. Glatirmer acetate (Copaxone) is a mixture of synthetic polypeptides
designed to mimic myelin basic protein. In a 2-year study, exacerbation
frequency of MS was reduced by 29%. Glatirmer acetate is given daily
at a dose of 20 mg SC. Glatirmer acetate is generally well tolerated.
Current recommendations for relapsing-remitting MS are to initiate
treatment with either an interferon b or glatirmer acetate. Therapy is
considered a failure if there are severe side effects, 3 or more attacks
per year, or steady disease progression. With treatment failure, one of
the alternative drugs should be considered.
2. Treatment of acute exacerbations
a. Deterioration in the neurologic status of a patient with MS may be due to a
new attack of demyelination or, less commonly, intercurrent infection
(especially of the urinary tract), electrolyte imbalance, fever, drug
intoxication, or conversion reaction. When doubt exists, demonstration of
lymphocytes in the CSF might support the diagnosis of acute
demyelination.
b. Intravenous methylprednisolone has largely replaced ACTH or oral
prednisone as treatment for acute attacks of MS. Controlled studies have
shown intravenous methylprednisolone to be superior to placebo for acute
exacerbations of MS. Intravenous methylprednisolone is also probably
more effective than either ACTH or oral prednisone for acute
exacerbations.
1. Response rate. More than 85% of patients with relapsing-remitting MS
show improvement with intravenous methylprednisolone; less than 50%
of patients with chronic progressive MS will improve with such
treatment.
2. Dosage. Methylprednisolone is administered intravenously at a dosage
of 250 to 500 mg q12h for 3 to 7 days, followed by oral prednisone at a
dosage of 60 to 80 mg daily for 7 days. The prednisone is then tapered
10 mg every 4 days over a 1-month period.
3. Complications of methylprednisolone therapy
a. Fluid retention and hypokalemia might occur. Electrolytes are
checked regularly. Potassium is replaced if necessary. Fluid
retention and associated hypertension can be controlled with
diuretics.
b. As prophylaxis against gastric irritation and hemorrhage,
treatment with either antacids or cimetidine (Tagamet) is
recommended.
c. Restlessness, anxiety, and insomnia generally diminish with
lorazepam (Ativan) 0.5 to 1.0 mg daily, or flurazepam, 15 to 30 mg at
bedtime. Depression, psychosis, or euphoria may occur, especially
in the presence of extensive cerebral lesions.
d. Psychosis is best managed with the assistance of a psychiatrist. A
major tranquilizer, e.g., risperidone (Risperdal) 0.5 to 2.0 mg,
coupled with reduction of methylprednisolone dosage, is usually
effective in controlling psychosis. Psychosis may require cessation of
corticosteroids in some patients sensitive to these drugs. If these
patients remain in relapse, they may require treatment with
alternative immunosuppressant drugs such as cyclophosphamide.
e. Infection and sepsis are occasional complications and require
prompt treatment with appropriate antibiotics. When the patient has
a positive tuberculin test, concurrent treatment with an
antituberculous drug is indicated.
f. Osteoporosis and vertebral body collapse do not generally
complicate short courses of corticosteroids.
c. Oral corticosteroids may also be effective in shortening acute attacks of
MS. Prednisone may be used in less severe exacerbations of MS when
hospitalization is unnecessary. However, the decision to use oral
prednisone in place of intravenous methylprednisolone must be made with
some caution; in a placebo-controlled study of optic neuritis, intravenous
methylprednisolone followed by oral prednisone proved superior to either
oral prednisone or placebo.
1. Dosage. The selection of dosage is somewhat arbitrary. An acceptable
regimen is the following:
Days 1 to 10: prednisone, 60 mg daily.
Days 11 to 13: prednisone, 50 mg daily.
Days 14 to 16: prednisone, 40 mg daily.
Days 17 to 19: prednisone, 30 mg daily.
Days 20 to 22: prednisone, 20 mg daily.
Days 23 to 25: prednisone, 10 mg daily.
Days 26 to 28: prednisone, 5 mg daily.
2. Concurrent antacid or cimetidine therapy is recommended. Potassium
supplementation and diuretic therapy are generally not necessary.
E. Complications of MS
1. Weakness. Physical therapy is of benefit when weakness is due to lack of use,
but it does not strengthen muscles weakened by CNS demyelination. This
therapy maintains range of motion, assists in gait training, and boosts patient
fitness and morale.
2. Spasticity
a. Physical therapy is of little benefit in diminishing spasticity.
b. Baclofen (Lioresal) is the drug of choice in the treatment of spasticity due
to MS. It is highly effective in reducing painful flexor and extensor spasms
and is somewhat less effective in reducing baseline spasticity or
hyperreflexia. Its major side effect is drowsiness, which generally
diminishes with continued use. Confusion may occur at higher dosages,
especially if cognitive impairment is present. Unlike dantrolene, use of
baclofen is not associated with increased weakness. However, some very
weak patients cannot tolerate the loss in spasticity that is important in
permitting them to bear weight. The usual starting dosage is 5 to 10 mg
t.i.d., which may be gradually increased to 20 mg q.i.d.
Baclofen is now available for intrathecal administration by either bolus
therapy or continuous implanted pump therapy. Intrathecal baclofen may be
effective in refractory cases of spasticity when oral medication fails. A
clinically significant improvement in spasticity after bolus injection is
generally obtained before pump implantation. Continuous infusion rates
vary between 12 and 2,000 g/day intrathecally.
c. Tizanidine (Zanaflex) is new a
2
-adrenergic receptor agonist that is
effective against spasticity in MS. The usual starting dose is 4 mg. The drug
can be titrated slowly to higher dosages at 2- to 4-mg increments up to a
maximum of 36 mg/day.
d. Diazepam (Valium) may reduce spasticity in some patients. Its mechanism
of action is believed to be central. Side effects include drowsiness and
fatigue. The usual effective dosage is 5 to 50 mg daily.
e. When baclofen, tizanidine, and diazepam and are ineffective, dantrolene
(Dantrium) may be tried. Dantrolene always produces increased
weakness because its mechanism of action involves decoupling of
excitation-contraction in muscle. The drug has proved useful in only a few
patients with spasticity, but in responsive individuals the improvement can
be dramatic. Dosage can be initiated at 25 mg daily and gradually
increased to a maximum of 400 mg daily over several weeks. Dantrolene
may produce hepatitis, and its use is contraindicated in the presence of
hepatic disease. Thus, liver function must be monitored regularly. Other
side effects include drowsiness, dizziness, and diarrhea. Because
dantrolene is a potentially toxic drug, its use should be discontinued unless
a therapeutic effect can be demonstrated. Intrathecal baclofen may be an
alternative to dantrolene in some patients.
f. Intrathecal phenol, anterior rhizotomy, and peripheral nerve block are
considered only if spasticity or flexor spasms are refractory to drug
treatment and make the patient uncomfortable. These procedures are
reserved for patients with longstanding paraplegia, since relief of spasticity
is accompanied by further paralysis.
1. Intrathecal injection of 5% to 20% phenol in glycerol has been used
widely to relieve spasticity. The procedure can be performed easily
without general anesthesia. A radiopaque dye is added to the phenol
solution, and the procedure is done under fluoroscopic control on a
myelography table. Spasticity is relieved by the production of a flaccid
paralysis that lasts for 3 to 12 months. Sensory loss usually
accompanies the paralysis and can lead to pressure sores. Also,
bladder and bowel sphincter dysfunction commonly occurs.
2. In patients with normal bowel and bladder function, anterior rhizotomy
is probably the procedure of choice. Irreversible weakness is produced,
but sensory loss and urinary retention are avoided. Alternatively,
peripheral nerve block with phenol may relieve spasticity without
risking bladder or bowel dysfunction.
3. Tremor and ataxia. About 70% of patients experience cerebellar intention
tremor or ataxia at some time during their illness.
a. Mild degrees of tremor or ataxia are often improved by weighting the
affected limbs. Tremors of the head and trunk are particularly resistant to
treatment.
b. Thalamotomy remains a rarely used procedure for cerebellar tremor.
c. Propranolol (40 to 160 mg daily), diazepam (5 to 15 mg daily), primidone
(500 to 1,500 mg daily), or clonazepam (0.5 to 2.0 mg daily) may be tried
for the tremor, although results are often unsatisfactory.
4. Pain. Shooting or lancinating pains that affect the pelvic girdle, shoulders, and
face are common features of MS. Facial pain that is indistinguishable from
trigeminal neuralgia occurs in about 3% of patients, and most bilateral
trigeminal neuralgia is caused by MS.
a. These neuritic pains, regardless of location, often respond to
carbamazepine, 400 to 1,200 mg daily. Alternatively, gabapentin
(Neurontin) 900 to 2,700 mg daily in divided dosages, may relieve neuritic
pains in some patients.
b. In drug-refractory cases, surgical management is recommended (see
Chap. 9).
c. Baclofen, 10 to 20 mg t.i.d., is also effective for the neuritic pains of MS
and may be useful in refractory cases of trigeminal neuralgia.
d. Burning pains or uncomfortable dysesthesias may improve with tricyclic
antidepressants such as imipramine, 25 to 100 mg daily.
5. Bladder, bowel, and sexual dysfunction are common. In patients with either
urinary retention of incontinence, correctable anatomic lesions must be
excluded.
a. Rational therapy of bladder dysfunction depends on urodynamic
(cystometric) studies. Bladder dysfunction is often complex in MS. About
33% of patients have difficulty retaining urine, about 20% have difficulty
emptying the bladder, and 50% have a mixture of retention and emptying
difficulties.
b. When failure to store urine is due to uninhibited involuntary detrusor
contractions, propantheline, 7.5 to 15.0 mg q.i.d. or tolterodine (Detrol),
2 mg PO b.i.d., might abolish incontinence. However, some of these
patients may develop urinary retention that requires intermittent
catheterization.
c. Failure to store urine associated with both involuntary detrusor contractions
and sphincter incompetence may require a urinary diversion procedure,
an indwelling catheter, or an external drainage appliance (condom
catheter).
d. In patients with failure to empty the bladder, anatomic obstructions should
be corrected. In cases of functional obstruction at the bladder neck,
a-sympathetic blocking agents may be of value, e.g., tamulosin (Flomax)
0.4 to 0.8 mg/day or doxazosin (Cardura) 1 to 8 mg/day. If there are weak
contractions of the detrusor muscle, bethanechol (Urecholine), 10 to 25
mg q.i.d., may be of benefit. Other patients show improved voiding with
either the Crede or Valsalva maneuver. The remaining patients will require
either indwelling catheters, intermittent catheterization, or urinary diversion
procedures.
e. A penile prosthesis may restore potency in men whose impotence is
secondary to MS. Some will obtain erections with intracavernous injections
of alprostadil (Caverject) 10 to 20 g or intraurethral suppositories of
alprostadil (Muse) 250 to 1,000 g.
6. Psychiatric complications include depression, euphoria, emotional lability,
and psychosis.
a. Reactive depressions that occur soon after diagnosis are often relieved by
sympathetic, supportive psychotherapy.
b. Depressions related to increasing disability are best managed by
providing the patient with a positive therapeutic regimen, including physical
therapy.
c. Depression related to cerebral lesions may be resistant to treatment.
However, antidepressant drugs are sometimes of benefit.
d. Euphoria tends to occur late in the course of MS, and it is associated with
signs of generalized intellectual deterioration and extensive cerebral
demyelination. Psychosis is a relatively rare complication, usually related
to high-dose corticosteroid therapy. Treatment with an appropriate major
tranquilizer such as risperidone 0.5 to 2 mg is generally effective.
7. Fatigue is a common complaint in MS, affecting up to 90% of patients.
Amantadine (Symmetrel), 100 mg PO bid, may relieve fatigue in some
patients. Patients unresponsive to amantadine may respond to pemoline
(Cylert), 37.5 mg PO every morning or fluoxetine (Prozac) 10 to 40 mg daily.
8. Heat sensitivity is common in MS. Neurologic deterioration may occur in hot
weather or during febrile illnesses. Management consists of aggressive
treatment of intercurrent illnesses and liberal use of air conditioning during hot
weather.
9. Seizures occur in about 5% of patients with MS. They are generally easily
controlled with either phenytoin, 200 to 400 mg daily, or carbamazepine, 600
to 1,800 mg daily.
II. Optic neuritis
A. Diagnosis. The term optic neuritis (ON) refers to the abrupt (usually over 2 to 3
days) loss of vision that results from optic nerve demyelination. When the optic
nerve head is visibly inflamed or swollen, the term papillitis is used. Other cases
are classified as retrobulbar neuritis, in which visual acuity is diminished in the
affected eye. There may also be a central scotoma. Pain in the eye is common.
Loss of color vision (achromatopsia) is common.
1. Differential diagnosis. A variety of other illnesses may resemble the
symptoms and clinical features of demyelinative ON:
a. Vascular: giant cell arteritis, temporal arteritis, retinal ischemia, central
retinal artery occlusion, and ischemic optic neuropathy.
b. Neoplastic: pituitary adenoma, intrinsic optic nerve tumors, and
compressive tumors of the optic nerve.
c. Hereditary: Leber optic atrophy.
d. Nutritional: vitamins B
1
and B
12
deficiency.
e. Inflammatory: retinitis, meningitis, encephalitis, and choroiditis.
f. Toxic and drug-related optic neuropathy.
g. Papilledema due to pseudotumor cerebri.
h. Pseudopapilledema due to tumor, vascular disease, inflammatory disease,
metabolic disorders, and retinal lesions.
2. Laboratory tests. When the diagnosis is in doubt, a more extensive evaluation
may be needed, including MRI of brain and orbits with gadolinium
enhancement; cerebral angiography; CSF examination for infection,
inflammation, or neoplasm; CT scan of orbits with contrast infusion; or
fluorescein angiography of the retinal vessels.
3. When the authenticity of the patient's complaints is doubted (conversion
reaction or malingering), the demonstration of abnormal pattern shift
visual-evoked potential can be useful in confirming the diagnosis of ON.
B. Relation of ON to MS. Forty percent of MS patients have at least one attack of
ON. In 10% to 15% of MS patients, ON is the first symptom of demyelination. As
with MS, CSF pleocytosis and increased CSF IgG may occur in ON, but with a
lesser frequency.
C. The prognosis for spontaneous recovery of vision is quite good. About 50% of
patients have recovery of vision within 1 month; 75%, within 6 months. Neither
pain in the orbit (70% of cases) nor papillitis (20% of cases) alters the prognosis
for recovery.
D. Treatment
1. Recent studies indicate that oral prednisone, retrobulbar injection of
corticosteroids, and injection of ACTH are not effective treatments for ON. In a
placebo-controlled study, intravenous methylprednisolone followed by
prednisone speeded recovery of vision when compared to placebo. At 6
months, however, vision was only marginally better than in the placebo group.
Oral prednisone alone was not superior to placebo.
2. Indications. Despite the generally favorable prognosis for spontaneous
recovery of vision, some neurologists continue to choose to treat ON with
intravenous methylprednisolone. Others reserve treatment for either bilateral
ON or unilateral ON with poor vision in the contralateral eye. Current guidelines
suggest administering intravenous methylprednisolone at a dosage of 250 mg
q6h for 3 days, followed by oral prednisone at a dosage of 1 mg/kg for 11 days.
3. Patients must be carefully observed for complications, which include
gastrointestinal hemorrhage, infection, hypertension, fluid retention,
hypokalemia, and psychosis. Concurrent antacid therapy is recommended.
III. Acute disseminated encephalomyelitis
A. Description. Acute disseminated encephalomyelitis is an uncommon
demyelinating disease of the brain and spinal cord. Pathologically, it closely
resembles experimental allergic encephalomyelitis, with extensive demyelination
and perivascular infiltrates of lymphocytes. Most cases develop 4 to 6 days after
the viral exanthem of measles, chickenpox, smallpox, or rubella (postinfectious
encephalomyelitis) or 10 to 15 days after vaccination against smallpox or rabies
(postvaccinial encephalomyelitis). Acute disseminated encephalomyelitis in
children must be distinguished from Reye syndrome (a nondemyelinative
postinfectious encephalopathy).
B. Diagnosis. Acute disseminated encephalomyelitis is a monophasic self-limited
disease of varying severity. In mild cases, there may be only headache, stiff neck,
fever, and confusion. In more severe cases, however, convulsions, quadriplegia,
cerebellar ataxia, multiple cranial nerve palsies, sensory loss, and coma may
occur in varying combinations. An MRI is useful in demonstrating widespread
white matter lesions. A CSF examination shows changes consistent with aseptic
meningitis.
C. Prognosis. Mortality is 10% to 20% in postmeasles encephalomyelitis and as high
as 30% to 50% in postvaccinial encephalomyelitis. Approximately 25% to 50% of
survivors are left with severe neurologic sequelae.
D. Treatment. Uncontrolled studies have shown that corticosteroids reduce the
severity of the illness. Dosages of methylprednisolone similar to those used for
acute MS are recommended. One protocol is to administer methylprednisolone,
500 mg IV q12h for 3 days, followed by oral prednisone, 60 to 80 mg/day for 7
days, followed by a taper of 20 mg each week. Anticonvulsants may be needed to
control seizures. Mannitol may be administered for cerebral edema. Vigorous
supportive measures are indicated because many patients make good or excellent
recoveries.
IV. Acute transverse myelitis
A. Description. Acute transverse myelitis is a common complication of MS.
Transverse myelitis also occurs as an idiopathic illness, a postvaccinial illness, a
postinfectious illness, or as a complication of HIV infection, systemic lupus
erythematosus, syphilis, or Borrelia burgdorferi infection. Most patients present
with leg weakness associated with a sensory level and sphincter disturbance.
Back pain is common.
B. The diagnosis of transverse myelitis is largely clinical. Imaging of the cervical and
thoracic spinal cord is essential to rule out spinal cord compression, infarction, and
neoplasm. The spinal cord is best imaged by either MRI with gadolinium
enhancement or myelography if MRI is unavailable. Brain MRI is useful in
determining the likelihood of coexisting MS. The CSF should be examined for
changes to exclude infection or neoplasm; however, CSF changes are similar in
myelitis due to MS and idiopathic transverse myelitis.
C. Prognosis. Idiopathic transverse myelitis and postvaccinial and postinfectious
transverse myelitis are monophasic self-limited illnesses of varying severity.
Prognosis for recovery is often good.
D. Treatment. If transverse myelitis is due to an infection (e.g., B. burgdorferi, human
immunodeficiency virus, syphilis) or a connective tissue disease (e.g., systemic
lupus erythematosus), then treatment is that of the underlying condition. If the
transverse myelitis is due to MS or is idiopathic, postvaccinial, or postinfectious,
then the attack is treated as if it were an attack of acute MS with intravenous
methylprednisolone followed by oral prednisone (see sec. I.D).
Selected Readings
Diagnosis and Prognosis of Multiple Sclerosis
Berger J R, Sheremata WA. Persistent neurological deficit precipitated by hot bath test for multiple
sclerosis. JAMA 1983;249:1751.
Chiappa KH. Pattern shift visual, brainstem auditory, and short-latency somatosensory-evoked potentials
in multiple sclerosis. Neurology (Minneap) 1980;30:110.
Koopmans RA, et al. Benign versus chronic progressive multiple sclerosis: magnetic resonance imaging
features. Ann Neurol 1989;25:74.
Miller DH, Morrissey SB, McDonald WI. The prognostic significance of brain MRI at presentation with a
single episode of suspected demyelination: a five year follow-up study. Neurology 1992;42:427.
Nelson LM, et al. Risk of multiple sclerosis exacerbation during pregnancy and breast-feeding. JAMA
1988;259:3441.
Paty DW, et al. MRI in diagnosis of MS: a prospective study with comparison of clinical evaluation,
evoked potentials, oligoclonal banding, and CT. Neurology 1988;38:180.
Percy AK, et al. Multiple sclerosis in Rochester, Minn.: a 60-year appraisal. Arch Neurol 1971;25:105.
Rudick RA, et al. Multiple sclerosis: the problem of incorrect diagnosis. Arch Neurol 1986;43:578.
Spencer W. Suspicion of multiple sclerosis: to tell or not to tell? Arch Neurol 1988;45:441.
Troiano R, et al. Effect of high-dose intravenous steroid administration on contrast-enhancing computed
tomographic scan lesions in multiple sclerosis. Ann Neurol 1984;15:257.
Willoughby EW. Serial magnetic resonance scanning in multiple sclerosis: a second prospective study in
relapsing patients. Ann Neurol 1989;25:43.
Wolinsky J S. Multiple sclerosis. Curr Neurol 1993;13:167.
Drug Therapy of Multiple Sclerosis
Barnes D, et al. Randomised trial of oral and intravenous methylprednisolone in acute relapses of multiple
sclerosis. Lancet 1997;349:902.
Calabresi PA, et al. Interferon beta results in immediate reduction of contrast-enhanced MRI lesions in
MS patients followed by weekly MRI. Neurology 1997;48:1446.
Chrouso GA, et al. Side effects of glucocorticoid treatment: experience of the optic neuritis treatment trial.
JAMA 1993;269:2110.
Compston A. Methylprednisolone and multiple sclerosis. Arch Neurol 1988;45:670.
Duquette P, et al. Interferon beta-1b is effective in relapsing remitting multiple sclerosis: clinical results of
a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993;43:655.
Hauser SL, et al. Intensive immunosuppression in progressive multiple sclerosis: a randomized,
three-arm study of high-dose intravenous cyclophosphamide, plasma exchange, and ACTH. N Engl J
Med 1983;308:173.
IFNB Multiple Sclerosis Study Group. Neutralizing antibodies during treatment of multiple sclerosis with
interferon beta-1b. Neurology 1996;47:889.
J ohnson KP, et al. Copolymer 1 reduces relapse rates and improves disability in relapsing-remitting
multiple sclerosis: multicenter trial. Neurology 1995;45:1268.
Kappos L, et al. Cyclosporine versus azathioprine in the long-term treatment of multiple sclerosis: results
of the German Multicenter Study. Ann Neurol 1988;23:56.
Killian J M, et al. Controlled pilot trial of monthly intravenous cyclophosphamide in multiple sclerosis. Arch
Neurol 1988;45:27.
Menken M. Consensus and controversy in neurologic practice: the case of steroid treatment in multiple
sclerosis. Arch Neurol 1989;46:322.
Rudick RA, et al. Management of multiple sclerosis. N Engl J Med 1997;337:1604.
Weiner HL, Hafler PA. Immunotherapy of multiple sclerosis. Ann Neurol 1988;23:211.
Cerebrospinal Fluid in Multiple Sclerosis and Neuroimaging
Caroscio J T, et al. Quantitative CSF IgG measurements in multiple sclerosis and other neurological
diseases: an update. Arch Neurol 1983;40:409.
Farlow MR, et al. Multiple sclerosis: magnetic resonance imaging, evoked responses, and spinal fluid
electrophoresis. Neurology (Minneap) 1986;36:828.
Farrell MA, et al. Oligoclonal bands in multiple sclerosis: clinical-pathologic correlation. Neurology
(Minneap) 1985;35:212.
Gerson B, et al. Myelin basic protein, oligoclonal bands, and IgG in cerebrospinal fluid as indicators of
multiple sclerosis. Clin Chem 1981;27:1974.
J ohnson KP. Cerebrospinal fluid and blood assays of diagnostic usefulness in multiple sclerosis.
Neurology (Minneap) 1980;3:106.
Mushlin AI, et al. The accuracy of magnetic resonance imaging in patients with suspected multiple
sclerosis. JAMA 1993;269:3134.
Schapira K. Is lumbar puncture harmful in multiple sclerosis? J Neurol Neurosurg Psychiatry
1959;22:238.
Weakness and Spasticity in Multiple Sclerosis
Barnes MP, et al. A double-blind, placebo-controlled trial of tizanidine in the treatment of spasticity
caused by multiple sclerosis. Neurology 1994;44:S70.
Becker WJ , et al. Long-term intrathecal baclofen therapy in patients with intractable spasticity. Can J
Neurol Sci 1995;22:208.
Coffey RJ , et al. Intrathecal baclofen for intractable spasticity of spinal origin: results of a long-term
multicenter study. J Neurosurg 1993;78:226.
Duncan GW, Shahani BT, Young RR. An evaluation of baclofen treatment for certain symptoms in
patients with spinal cord lesions. Neurology (Minneap) 1976;26:441.
Gelenberg AJ , Poskanzer DC. The effects of dantrolene sodium on spasticity in multiple sclerosis.
Neurology (Minneap) 1973;23:1313.
Lenman J AR. A clinical and experimental study of the effects of exercise on motor weakness in
neurological disease. J Neurol Neurosurg Psychiatry 1959;22:182.
Levine I, et al. Diazepam in the treatment of spasticity: a preliminary quantitative evaluation. J Chronic Dis
1969;22:57.
Liversedge LA, Maher RM. Use of phenol in relief of spasticity. Br Med J 1960;2:31.
Selker R, Greenberg A, Marshall M. Anterior rhizotomy for flexor spasms and contractures of the legs
secondary to multiple sclerosis. Ann Surg 1965;162:298.
Bladder, Bowel, and Sexual Dysfunction in Multiple Sclerosis
Betts CD, Dmellow MT, Fowler CJ . Urinary symptoms and the neurological features of bladder
dysfunction in multiple sclerosis. J Neurol Neurosurg Psychiatry 1993;56:245.
Blaivas J G. Management of bladder dysfunction in multiple sclerosis. Neurology (Minneap) 1980;30:12.
Hinson J L, Boone TB. Urodynamics and multiple sclerosis. Urol Clin North Am 1996;23:475.
Massey EW, Pleet A. Penile prosthesis for impotence in multiple sclerosis. Ann Neurol 1979;6:451.
O'Riordan J I, et al. Do alpha-blockers have a role in lower urinary tract dysfunction in multiple sclerosis? J
Urol 1995;153:1114.
Peterson T, Pedersen E. Neurodynamic evaluation of voiding dysfunction in multiple sclerosis. Acta
Neurol Scand 1984;69:402.
Tarabulcy E. Bladder disturbances in multiple sclerosis and their management. Mod Treat 1970;7:941.
Vas CJ . Sexual impotence and some autonomic disturbances in men with multiple sclerosis. Acta Neurol
Scand 1969;45:166.
Psychological and Neuropsychological Complications of Multiple Sclerosis
Beatly WW, et al. Anterograde and retrograde amnesia in patients with chronic progressive multiple
sclerosis. Arch Neurol 1988;45:611.
Krupp LB, et al. Fatigue in multiple sclerosis. Arch Neurol 1988;45:435.
Peyser J M, et al. Cognitive function in patients with multiple sclerosis. Arch Neurol 1980;37:577.
Rosenberg GA, Appenzeller O. Amantadine, fatigue, and multiple sclerosis. Arch Neurol 1988;45:1104.
Schiffer RB. The spectrum of depression in multiple sclerosis. Arch Neurol 1987;44:596.
Weinshenker BG, et al. A double-blind, randomized, crossover trial of pemoline in fatigue associated with
multiple sclerosis. Neurology 1992;42:1468.
Tremor and Ataxia in Multiple Sclerosis
Cooper IS. Relief of intention tremor of multiple sclerosis by thalamic surgery. JAMA 1967;199:689.
Goldman MS, Kelly PJ . Symptomatic and functional outcome of stereotactic ventralis lateralis
thalamotomy for intention tremor. J Neurosurg 1992;77:223.
Hewer RL, Cooper R, Morgan H. An investigation into the value of treating intention tremor by weighting
the affected limb. Brain 1972;95:579.
Pain in Multiple Sclerosis
Albert M. Treatment of pain in multiple sclerosis: a preliminary report. N Engl J Med 1969;280:1395.
Chakravorty B. Association of trigeminal neuralgia with multiple sclerosis. Arch Neurol 1966;14:95.
Houtchens MK, et al. Open label gabapentin treatment for pain in multiple sclerosis. Multiple Sclerosis
1997;3:250.
Moulin DE. Pain syndromes in multiple sclerosis. Neurology (Minneap) 1988;38:1830.
Optic Neuritis
Beck RW, et al. A randomized controlled trial of corticosteroids in the treatment of optic neuritis. N Engl J
Med 1992;326:581.
Bradley WG, Whitty CWM. Acute optic neuritis: prognosis for development of multiple sclerosis. J Neurol
Neurosurg Psychiatry 1968;31:10.
Compston DAS, et al. Factors influencing the risk of multiple sclerosis developing in patients with optic
neuritis. Brain 1978;101:495.
Feinsod M, Hoyt WF. Subclinical optic neuropathy in multiple sclerosis. J Neurol Neurosurg Psychiatry
1975;38:1109.
J acobson DM. Optic neuritis in the elderly: prognosis for visual recovery and long-term follow-up.
Neurology (Minneap) 1988;38:1834.
Miller DH, et al. The early risk of multiple sclerosis after optic neuritis. J Neurol Neurosurg Psychiatry
1988;51:1569.
Optic Neuritis Study Group. The 5-year risk of multiple sclerosis after optic neuritis. Neurology
1997;49:1404.
Rizzo J F, Lessell S. Risk of developing multiple sclerosis after uncomplicated optic neuritis: a long-term
prospective study. Neurology (Minneap) 1988;38:185.
Acute Disseminated Encephalomyelitis
Alvord EC. Acute disseminated encephalomyelitis and allergic neuroencephalopathies. In: Vinken PJ ,
Bruyn GW, eds. Handbook of clinical neurology, vol 9. Amsterdam: North-Holland, 1970;500.
J ohnson RT, Griffin DE, Gendelman HE. Post-infectious encephalomyelitis. Semin Neurol 1985;5:180.
Kesselring J , et al. Acute disseminated encephalomyelitis: MRI findings and the distinction from multiple
sclerosis. Brain 1990;113:291.
Pasternak J F, deVivo DC, Prensky AL. Steroid-responsive encephalomyelitis in childhood. Neurology
(Minneap) 1980;30:481.
Scott T F. Post-infectious and vaccinial encephalitis. Med Clin North Am 1967;51:701.
Selling B, Meilman E. Acute disseminated encephalomyelitis treated with ACTH. N Engl J Med
1955;253:275.
Transverse Myelitis
Ropper AH, Poskanzer DC. The prognosis of acute and subacute transverse myelop-athy based on early
signs and symptoms. Ann Neurol 1978;4:51.
Tyor WR. Post-infectious encephalomyelitis and transverse myelitis. In: J ohnson RT, Griffin J W, eds.
Current therapy for neurologic disease, 4th ed. St. Louis: Mosby-Year Book, 1993.
CHAPTER 14. TOXIC AND METABOLIC DISORDERS
Manual of Neurologic Therapeutics
CHAPTER 14. TOXIC AND METABOLIC DISORDERS
Stephen M. Sagar
Liver disease
Endocrine disorders
Renal failure
Pulmonary disorders
Hyponatremia
Acute intermittent porphyria (AIP)
Heavy metal poisoning
Carbon monoxide poisoning
Acetylcholinesterase (AChE) inhibitor poisoning
Alcohol
Opiates
Barbiturates
Poisoning with nonbarbiturate CNS depressants
Amphetamines
Polycyclic antidepressants
Salicylate intoxication
Hyperthermia
Nutritional deficiency and excess
I. Liver disease
A. Hepatic encephalopathy is an acute, reversible global derangement of mental
function that occurs in the presence of portosystemic shunting. The syndrome is
characterized by depressed mental status, asterixis, and electroencephalogram
(EEG) slowing. Elevated blood concentrations of ammonia and other nitrogenous
substances may be pathogenic.
1. Elimination of predisposing factors
a. Avoid use of sedatives, tranquilizers, and analgesics.
b. Correct fluid and electrolyte disturbances.
1. Hypokalemia and alkalosis increase renal ammonia production and may
worsen hepatic encephalopathy. These conditions should be corrected
promptly. Potassium-wasting diuretics should be avoided.
2. Intravascular volume must be maintained to prevent prerenal azotemia
and to maintain adequate liver perfusion.
3. Hyponatremia associated with hepatic encephalopathy must be treated
promptly but cautiously, as the overly aggressive correction of
hyponatremia can lead to central pontine myelinolysis (see sec. V.C and
sec. V.D).
c. Infection is a common precipitant of hepatic encephalopathy. Moreover, the
patient may fail to manifest fever or other systemic signs of sepsis.
Therefore, a careful search for occult infection, especially peritonitis, should
be conducted.
d. Acute inflammation (e.g., pancreatitis) and trauma, including surgery, may
also precipitate hepatic encephalopathy.
2. Supportive measures
a. Patients in coma require an indwelling urinary catheter, skin care, and
careful attention to fluid balance.
b. Deeply comatose patients may require tracheal intubation to protect the
airway.
3. Dietary protein restriction
a. When the diagnosis of hepatic coma is first made, the patient should be
placed on a protein-free diet until neurologic function shows definite
improvement.
1. The patient may be fed by mouth, nasogastric tube, or parenterally,
depending on the mental status.
2. Enough calories (at least 500 kcal/day in adults) should be provided to
inhibit proteolysis; 1,500 mL of 10% dextrose-water (D/W) provides 600
kcal. If possible, a nasogastric tube is used for feedings, in which case a
mixture of 10% or 20% D/W and lipids may be administered in sufficient
quantity to provide 1,500 to 2,000 kcal/day.
3. The administration of standard, commercially available
hyperalimentation mixtures containing amino acids is contraindicated in
hepatic encephalopathy. Experimental regimens of special amino acid
mixtures or of a-keto precursors of essential amino acids (HepatAmine)
are of no proven benefit.
b. Cathartics are used to eliminate dietary protein in the gut. Magnesium
citrate, 200 mL of the commercial solution, or sorbitol, 50 g in 200 mL
water, may be administered PO or through a nasogastric tube.
c. Gastrointestinal (GI) bleeding may deliver a large protein load to the gut
and thereby precipitate hepatic coma.
1. The GI bleeding is treated as vigorously as possible; one should bear in
mind the high surgical mortality of patients with severe liver disease.
2. Blood in the stomach is aspirated continuously through a nasogastric
tube.
3. The gut is purged with an enema followed by cathartics. Repeated
doses of sorbitol, 50 g in 200 mL water, are given to produce at least
one loose bowel movement q4h as long as the bleeding persists.
d. Adequate vitamin supplementation is provided, with daily doses of folate, 1
mg; vitamin K, 10 mg; and multivitamins.
e. As the patient improves, a diet of 20 g of protein per day is provided, and
the daily protein intake is then increased by 10 g every 2 to 3 days until the
patient's maximum protein tolerance is reached. In outpatients, it is
impractical to maintain a protein intake of less than 50 g/day.
4. Decrease gut ammonia absorption. Bacteria in the large bowel produce a
significant quantity of nitrogenous products.
a. Neomycin, a poorly absorbed antibiotic, will decrease the number of
bacteria in the gut. The dosage for adults is 1 g q.i.d. given PO or by
retention enema if necessary. With chronic administration, neomycin can
produce hearing loss and renal impairment. Colitis, overgrowth of the bowel
by Candida, and malabsorption are other possible complications of
neomycin therapy.
b. Lactulose (a synthetic disaccharide that cannot be digested in the upper GI
tract), 30 to 50 mL (0.65 g/mL) t.i.d. PO, by gastric tube, or by retention
enema, will acidify the stool and minimize ammonia absorption from the
gut. Lactulose may be used in patients who are unable to tolerate
neomycin, and it may also be used on a long-term basis. Some patients will
respond to neomycin but not to lactulose; occasionally, some will respond
to lactulose but not to neomycin.
c. Flumazenil (Romazicon), an inverse agonist of the benzodiazepine
receptor, 1 to 3 mg, by intravenous infusion, may temporarily reverse some
of the neurologic effects of hepatic encephalopathy.
5. Monitoring therapy
a. Clinically
1. Hepatic encephalopathy can be divided into 5 stages:
a. Stage 1 (subclinical encephalopathy). The patient is asymptomatic or
has nonspecific complaints and deficits can be found only by
detailed neuropsychological testing.
b. Stage 2 (precoma). Mild confusion and mental slowness without
asterixis or EEG abnormalities.
c. Stage 3 (impending coma). Disorientation, drowsiness, asterixis, and
possible mild EEG slowing.
d. Stage 4. The patient is asleep most of the time and is confused
when aroused; there is asterixis and EEG slowing.
e. Stage 5 (coma). The patient responds only to pain; there is
hypotonia and marked EEG slowing.
2. In mild stages of encephalopathy, a handwriting chart and tests of
constructional ability (e.g., drawing a clock or constructing a star with
match sticks) are sensitive indicators of clinical status.
b. Blood ammonia levels correlate poorly with stage of encephalopathy.
c. EEG. In deeper stages of hepatic encephalopathy, the degree of EEG
slowing has an excellent correlation with the patient's clinical status.
Abnormalities of the visual-evoked response have also been shown to have
a similar correlation. However, these tests are no better than the clinical
examination.
d. Cerebrospinal fluid (CSF) glutamine concentrations correlate with the
presence and degree of hepatic encephalopathy and can be useful
diagnostically. However, there is no indication for performing serial lumbar
punctures to monitor therapy.
7. Chronic management
a. Low-protein diet. Dietary protein is limited to the lowest practical and
tolerable level (usually 50 g/day). Vitamin supplementation is provided with
folate, multivitamins, and vitamin K. There is some evidence that in
zinc-deficient patients, supplementation with oral zinc sulfate 600 mg/day
improves function.
b. The patient should have at least one bowel movement each day.
c. Chronic use of neomycin is limited by its toxicity, but 500 mg PO
b.i.d.q.i.d. can usually be tolerated for a few weeks or even months. The
patient must be followed closely for evidence of diminished hearing or
impaired renal function. Alternatives to neomycin include metronidazole,
800 mg q.d., and rifaximin, 1,200 mg q.d. Lactulose, 10 to 30 mL PO t.i.d.,
is safer than neomycin and is equally effective in most cases. However, it is
unpalatable to many patients.
d. As a last resort, surgical exclusion of the colon from the bowel may be
done. However, the operation carries a high morbidity and mortality rate.
B. Acquired chronic hepatocerebral degeneration (ACHD)
1. Description. The cardinal features of ACHD are dementia, dysarthria,
cerebellar ataxia, tremor, spastic paraparesis, and choreoathetosis. It typically
develops in patients who are subject to recurrent bouts of hepatic
encephalopathy.
2. Treatment
a. There is no specific treatment for ACHD, and it is preventable only through
appropriate management of the underlying liver disease. It is possible, but
has not been proved, that prevention of bouts of hepatic encephalopathy
prevents the progression of irreversible central nervous system (CNS)
damage.
b. Choreoathetosis might respond to neuroleptics (see Chap. 15), and the
behavioral abnormalities might respond to protein restriction.
c. The dopamine receptor agonist bromocriptine is administered at an initial
dosage of 2.5 mg/day PO in 3 or 4 divided doses. The dosage may be
increased by 2.5 mg about every 3 days until toxicity supervenes or until a
dosage of 15 mg/day is reached. The major benefit is reported to be in
mental status.
C. Acute liver failure. With acute hepatocellular failure, there is a severe CNS
dysfunction. Unless the liver disease reverses itself, coma and death occur. Efforts
to decrease blood ammonia concentrations, including protein restriction and
administration of neomycin or lactulose, are commonly expended but have not
been shown to improve the outcome. Elevated intracranial pressure (ICP) may be
life threatening in fulminant hepatic failure and may be treated with mannitol (see
Chap. 12, sec. X.D). In addition, hypoglycemia may contribute to the
encephalopathy and must be vigorously treated with intravenous dextrose.
D. Hepatolenticular degeneration (Wilson disease) is an autosomal recessive
disorder of copper metabolism. It leads to cirrhosis of the liver and cerebral
dysfunction; movement disorders, tremor, and personality changes are the usual
neurologic manifestations. The therapy is discussed in Chap. 15, sec. IV.E.1.c.
E. Reye syndrome
1. Description
a. Epidemiology. Reye syndrome is an increasingly rare multisystem disease
that occurs almost exclusively in children between the ages of 2 and 12
years. It is associated with viral infection, and the majority of cases are
related to either influenza B or chickenpox. Salicylate use has been
circumstantially associated with Reye syndrome; consequently,
acetaminophen or ibuprofen is preferred over aspirin as an antipyretic in
childhood.
b. Clinical course. Reye syndrome is characteristically preceded by a
relatively benign viral illness. Typically, as the viral illness is resolving, there
is an abrupt onset of vomiting and lethargy. This is followed to varying
degrees by agitation and delirium, which may progress to coma within
hours. Mild cases occur, without profound changes in mental status. At the
other extreme, death can result from brain swelling.
c. Clinical stages
1. Stage 1. Drowsiness and vomiting with or without hyperventilation.
2. Stage 2. Delirium with hyperventilation.
3. Stage 3. Delirium recedes, and there is increasing lethargy, progressing
to coma; dilated, reactive pupils; and decorticate posturing (i.e., the
flexor posture of the upper extremities and extensor posture of the lower
extremities).
4. Stage 4. Coma with unreactive pupils and decerebrate posturing (i.e.,
extensor postures of both upper and lower extremities).
5. Stage 5. Brain death.
d. Laboratory abnormalities
1. Liver function abnormalities
a. Serum glutamic-oxaloacetic transaminase (SGOT) and serum
glutamic-pyruvic transaminase (SGPT) are elevated at least 3 to 4
times above normal.
b. Bilirubin is either normal or only mildly elevated.
c. The prothrombin time (PT) is moderately prolonged.
d. Blood ammonia is very high (up to 1,000 g/dL) during the early
stages of the illness, but then it falls to normal values whether or not
the coma resolves.
2. CSF
a. There are no cells, and the protein is normal.
b. After coma develops and the brain swells, the CSF pressure
becomes elevated.
3. Hypoglycemia is common in children under 5 years of age.
4. Acid-base disturbances
a. Respiratory alkalosis is frequent.
b. Metabolic acidosis, with an anion gap and elevated lactate levels,
develops in severe cases.
5. Muscle enzymes. Creatine kinase (CK) and aldolase are elevated, with
CK fractionation yielding primary muscle (MM) and heart (MB)
isozymes.
2. Diagnosis
a. The diagnosis is generally made on the basis of the stereotypical clinical
presentation and pattern of laboratory findings.
b. Routine liver biopsy is not necessary, but it confirms the diagnosis in
questionable cases. The pathognomic finding in the liver is microvesicular
fatty infiltration.
c. The differential diagnosis includes salicylate intoxication, hepatic
encephalopathy from any cause, CNS infection, and, in young infants,
inborn metabolic errors involving amino acid, organic acid, and carnitine
metabolism.
d. Because Reye syndrome is now so rare, all patients presenting with a
Reye-like illness should be screened for inborn errors of metabolism. Green
and colleagues (J Pediatrics 1988;113:156) present a useful scheme for
screening and workup of these children. The following situations are
especially suggestive of underlying genetic metabolic disease:
1. Children younger than 3 years of age, especially if there has been
developmental delay.
2. Children of any age who have experienced a prior Reye-like episode.
3. A family history of a similar illness.
4. A history in the patient or family of near-miss or actual sudden infant
death.
5. Unexplained lactic acidosis.
e. Inborn errors of metabolism that can mimic Reye syndrome include:
1. Disorders of fatty acid oxidation, especially medium-chain acyl
coenzyme A dehydrogenase deficiency.
2. Organic acidurias.
3. Disorders of the urea cycle.
4. Carnitine deficiency.
5. Disorders of pyruvate metabolism.
6. Glycerol kinase deficiency.
7. Disorders of fructose metabolism.
3. Prognosis
a. The chance of surviving Reye syndrome diminishes progressively with an
increasing depression of the mental status. The mortality of those in coma
has been reported to range from 10% to 80%.
b. The maximum elevation of blood ammonia is a good prognostic indicator. If
ammonia does not rise above 300 g/dL, the survival rate is virtually 100%.
4. Laboratory evaluation
a. Patients with Reye syndrome should have the following evaluation:
1. Blood glucose.
2. Complete cell count (CBC) and differential cell count.
3. Blood urea nitrogen (BUN) or creatinine and urinalysis.
4. Electrolytes, including calcium and phosphorus.
5. Arterial blood gases and pH.
6. Complete liver function tests, including SGOT (or SGPT), lactic acid
dehydrogenase (LDH), alkaline phosphatase, total and direct bilirubin,
total protein, and albumin.
7. Prothrombin time (PT).
8. Blood ammonia.
9. Salicylate level and screening of blood and urine for toxic substances,
unless drug ingestion can be absolutely ruled out by history.
10. Lumbar puncture is best performed early, prior to elevation of ICP.
11. All children, especially those under 2 years of age and those with
recurrent symptoms, should have serum and urine amino acid profiles
performed and urine screened for organic acids.
b. If the diagnosis is confirmed, the hemoglobin, PT, and blood sugar must be
followed q48h during the first 72 hours. Ammonia, SGOT, and electrolytes
must be followed at least daily. Arterial blood gases are drawn as indicated.
c. There is no therapeutic indication for attempting to identify the associated
virus.
5. Acute management
a. Maintain vital functions.
1. Vital signs are monitored closely, and complications of coma are
avoided. Reye syndrome is a prime indication for placing the patient in
an intensive care unit.
2. The airway is protected with a cuffed endotracheal tube if the patient is
stuporous or comatose. Respirator support may be required. The
arterial PO
2
is kept above 100 mm Hg, a value higher than is usually
required, because of abnormalities of mitochondrial respiration that
occur in Reye syndrome.
3. Maintain body temperature below 37C (98.6F) with a cooling blanket.
Do not use salicylates.
b. Treat possible hypoglycemia.
1. A blood glucose is drawn before administering IV fluids; the blood
glucose is followed closely and maintained between 150 and 200
mg/dL.
2. In children under 5 years of age and in all patients in coma, glucose, 1
to 2 mL/kg of 50% D/W is given on admittance.
3. A constant infusion of a glucose-containing solution (e.g., 10% dextrose
in 0.45% saline) is maintained.
4. The addition of insulin to intravenous glucose solutions in the ratio of 1
unit of insulin to 10 g of glucose is used in some centers in an attempt to
inhibit mobilization of free fatty acids. There are no studies
demonstrating benefit from this regimen, and blood insulin levels are
known to be greatly elevated in patients with Reye syndrome without the
exogenous administration of insulin. If insulin is given, however, albumin
should be added to the solution to prevent the insulin from sticking to
glass. Alternatively, insulin may be administered as an IV bolus q4h,
with careful monitoring of blood glucose with Dextrostix immediately
before and 30 minutes after each insulin dose.
c. Treat complications of the abnormal liver function.
1. Hypoprothrombinemia may lead to hemorrhagic complications and
requires vigorous treatment. Vitamin K (10 mg IM) may have to be given
as often as q6h. If the PT cannot be corrected to within 2 seconds of
control with vitamin K, the administration of fresh-frozen plasma in
sufficient quantities is required.
2. Hyperammonemia is treated with measures similar to those used in
hepatic encephalopathy.
a. No protein is administered for the first 72 hours of the illness.
b. If GI bleeding occurs, the gut is kept free of blood by gastric lavage
and catharsis.
c. After about 72 hours, the ammonia level will return to normal,
whether or not the patient's mental status improves.
d. Treat brain swelling.
1. Fluids are restricted to 1,200 mL total fluids/day/m
2
body surface area.
The urine output, urine specific gravity, electrolytes, and serum
osmolality are monitored at least daily.
2. Monitoring devices for ICP are useful in patients in stage 3 or worse and
in patients who are deteriorating rapidly. The use of these devices
allows the precise and continuous monitoring of ICP during the first 2 to
4 days of illness, when the patient is at high risk from brain swelling.
They are used in conjunction with an arterial catheter to monitor
systemic blood pressure, and an intense effort is made to maintain
cerebral perfusion pressure (mean arterial blood pressure ICP)
greater than 50 mm Hg.
3. For acute increases in ICP, controlled hyperventilation is often effective.
The PCO
2
is generally maintained at 30 mm Hg and the patient
hyperventilated to 25 mm Hg for a rise in ICP. Hyperventilation should
be implemented at the first sign of a pressure wave and continued until
the CSF pressure falls. Paralysis with pancuronium bromide (Pavulon),
0.1 to 0.2 mg/kg IV, will help control the PCO
2
and thus ICP. For
paralyzed patients, continuous EEG monitoring will monitor for seizure
activity.
4. If hyperventilation fails to provide adequate control of ICP, mannitol,
0.25 mg/kg, is given by IV infusion over 20 minutes and repeated as
necessary. The serum osmolality should be maintained in the range of
300 to 320 mOsm/L to prevent large rebound rises in ICP following
each mannitol dose.
5. When all other measures to control CSF pressure fail and the patient is
progressing to stage 4 (i.e., the onset of decerebrate posturing),
barbiturate coma using pentobarbital may be used according to the
protocol in Chap. 1, sec. VII.D.6.
6. The role of corticosteroids in Reye syndrome has not been defined.
There is no firm evidence for their clinical benefit, but many centers use
high doses of dexamethasone to attempt to control the brain swelling
associated with Reye syndrome.
e. Treat seizures.
1. Prophylactic anticonvulsant therapy is recommended for all patients with
Reye syndrome who have significant mental status depression.
a. Phenytoin (Dilantin) is preferred over phenobarbital because large
loading doses have less effect on mental status and respirations.
Valproic acid should be avoided because of its hepatotoxicity.
b. Dosage. Therapy is initiated with a loading dose of approximately 15
mg/kg given IV or PO. If given IV, the usual precautions necessary
for the intravenous administration of phenytoin are followed (Chap.
6). The maintenance dosage is 5 mg/kg/day IV or PO.
Anticonvulsants are continued until the patient's mental status
returns to normal.
2. The therapy of seizures, once they occur in Reye syndrome, follows the
principles listed in Chap. 6.
f. Hemodialysis, peritoneal dialysis, and exchange transfusion have all been
tried for the treatment of Reye syndrome. None is recommended.
II. Endocrine disorders. Virtually all hormone disorders have associated neurologic
signs and symptoms, often as the cardinal features of the syndrome. In most of these
disorders, the therapy is correction of the underlying endocrine disorder. The exceptions
are hyperthyroidism and pheochromocytoma, for which beta and alpha blockers,
respectively, are used to control the manifestations of the autonomic nervous system
while definitive therapy is being pursued.
III. Renal failure
A. Uremic encephalopathy
1. Description. The clinical features of uremic encephalopathy are nonspecific
and cannot be distinguished from those of other metabolic encephalopathies.
There is a global defect of cerebral function, beginning with difficulty in
concentration and subtle personality changes, progressing to confusion and
then to drowsiness, stupor, and coma. Asterixis is prominent when higher
cortical function becomes affected and before coma supervenes. Generalized
major motor (grand mal) seizures may occur during the stages of stupor and
coma.
2. Diagnosis
a. The EEG shows low-voltage slowing in early stages, with the development
of generalized paroxysmal slowing in late stages.
b. The CSF is normal, with the possible exception of a mild elevation of the
protein.
c. The more rapid the progression of the renal failure, the greater the severity
of the encephalopathy for a given BUN or creatinine level.
3. Treatment
a. The underlying renal disease is treated.
b. Incapacitating mental changes or the development of asterixis is an
indication for dialysis.
B. Seizures
1. Etiology. In renal failure, generalized seizures may occur as a result of any of
several mechanisms:
a. Uremic encephalopathy.
b. Water intoxication with hyponatremia.
c. Hypocalcemia.
d. Hypomagnesemia.
e. Hypertensive encephalopathy.
f. Dialysis disequilibrium syndrome.
2. Treatment
a. Treatable underlying metabolic problems are managed appropriately.
b. Seizures that result from uremic encephalopathy are in themselves an
indication for dialysis.
c. Seizures that do not respond to metabolic correction or dialysis are treated
in the same manner as seizures in other situations. As a general rule,
anticonvulsants are metabolized in the liver, so dosages for dialysis
patients are similar to those for patients with normal renal function.
However, some extra precautions may be necessary.
1. Phenytoin dosages do not have to be modified in the presence of renal
failure, but absorption of oral phenytoin may be erratic. Consequently,
the patient must be observed frequently for signs of clinical toxicity.
Blood levels of phenytoin may be helpful, but the percentage of
phenytoin not bound to plasma proteins is higher in renal failure than in
normal renal function. Therefore, in severe uremia the therapeutic range
of plasma phenytoin concentration is 5 to 10 g/mL. Measurements of
free (unbound) phenytoin concentration or salivary concentration are
helpful (therapeutic range, 1 to 2 g/mL). Also, the half-life of phenytoin
may be shortened in renal failure, so a t.i.d. dosage schedule is
recommended.
2. Phenobarbital can be used in diminished dosages in renal failure. The
blood level must be measured frequently to adjust the dosage, and a
supplemental dose following dialysis may be required.
3. Diazepam (Valium), up to 10 mg IV, or lorazepam, 2 to 4 mg IV, may be
used for emergency seizure control when seizures threaten vital
functions or when status epilepticus occurs. Benzodiazepines have only
a temporary effect (20 to 30 minutes), so that more definitive therapy
must be undertaken during this time to provide long-lasting seizure
control (see Chap. 6, sec. V.C.5.c(6)).
4. Valproic acid may be given in the usual dosages to uremic patients and
is particularly useful in the control of generalized myoclonic and
tonic-clonic seizures. The therapeutic range of plasma concentration in
uremia is somewhat lower than in normal renal function, although the
exact range has not been established.
5. Carbamazepine (Tegretol) may be used in renal failure in the usual
dosages, and the therapeutic range of plasma concentration (4 to 12
g/mL) is the same as in normal renal function.
6. Ethosuximide (Zarontin) may also be used in the usual dosages and
with the usual therapeutic range (40 to 100 g/mL). It is dialyzable,
however, so a supplemental postdialysis dose is necessary.
7. Of the newer anticonvulsants, both gabapentin (Neurontin) and
topiramate (Topamax) are renally excreted and are dialyzable. The
doses must be reduced by 50% to 75% in renal failure and the drugs
should be administered immediately post dialysis. The dose of
lamotrigine (Lamictal) may have to be reduced by 20% in renal failure;
tiagabine (Gabatril) can be used at the usual doses.
d. Hemodialysis patients may have seizures during or up to 8 hours after
dialysis, due to the disequilibrium syndrome.
1. The risk of seizures may be reduced by decreasing the rate and
duration of dialysis and increasing its frequency.
2. Hemodialysis patients should be on prophylactic anticonvulsants.
Phenytoin, 100 mg t.i.d., is the usual regimen in adults.
C. Uremic neuropathy
1. Description. Uremia causes a distal sensorimotor neuropathy that affects the
legs before the arms. The neuropathy is often painful, with burning feet, and
can be incapacitating.
2. Treatment
a. Neuropathy resolves with correction of the underlying renal disease or renal
transplantation. Chronic hemodialysis is much less effective than renal
transplantation.
b. The neuropathic pain of uremic neuropathy may respond to carbamazepine
(Tegritol), 400 to 1,200 mg/day PO in divided doses; clonazepam
(Clonopin), beginning with a dosage of 0.5 mg PO t.i.d. and increasing in
0.5-mg increments every 2 to 3 days until relief is obtained, toxicity
supervenes, or a total dose of 20 mg/day is reached; or gabapentin
(Neurontin), 300 mg q.d. Addition of a low dose of a tricyclic antidepressant
may also be of benefit.
D. Neurologic complications of hemodialysis
1. Seizures and the disequilibrium syndrome are discussed in sec. III.B.
2. Subdural hematoma
a. There is an increased incidence of subdural hematoma among patients
undergoing chronic hemodialysis. Possible predisposing factors are
anticoagulation, rapid shifts in brain size, hypertension, and minor head
trauma. In dialysis patients, subdural hematomas are frequently bilateral.
b. The treatment of subdural hematoma is surgical drainage. Because of the
osmotic and volume shifts that occur between body compartments during
hemodialysis, it is not safe to defer surgical treatment and follow the patient
clinically (as one might do with other patients with chronic subdural
hematomas). During the postoperative period, the patient is managed with
peritoneal dialysis to minimize rapid osmotic shifts and to avoid systemic
anticoagulation.
3. Headache
a. Migraine may be made worse by uremia. Its treatment in the presence of
renal failure is identical to that of other forms of migraine headaches (see
Chap. 2, sec. II.B.2.a; see also sec. VI.B.1).
b. The dialysis disequilibrium syndrome produces headache during and for up
to 8 hours after dialysis. Ergot or sumitriptan may be tried in the same
manner as for migraine therapy.
c. Persistent headache suggests the presence of subdural hematoma.
4. Vitamin deficiency
a. All chronic hemodialysis patients should be on supplemental multivitamins,
including folate, thiamine, and pantothenic acid.
b. Attempts to treat uremic neuropathy with various vitamins have been
unsuccessful.
5. Muscle cramps during or immediately following hemodialysis may cause
severe pain. Quinine sulfate, 320 mg PO at the beginning of each dialysis, has
been reported to be beneficial and safe.
E. Neurologic complications of renal transplantation
1. CNS infections (see Chap. 8).
2. CNS malignancy, including primary CNS lymphoma (see Chap. 11).
3. Cyclosporine neurotoxicity. Of patients taking cyclosporine, 15% to 20%
develop an action tremor, which is generally not troublesome. A small
percentage, however, develop some mixture of encephalopathy, cerebellar
signs, and spinal cord dysfunction. Some of these patients have a
leukoencephalopathy on imaging studies. The syndrome is usually reversible
with discontinuation of cyclosporine or a reduction in dosage. Seizures,
sometimes in association with hypomagnesemia, have been associated with
cyclosporine use and cease with a reduction in dosage.
IV. Pulmonary disorders. Both hypercapnia and hypoxemia are associated with
encephalopathy. The treatment is the same as for underlying lung disease.
V. Hyponatremia
A. Description
1. Sodium is the primary extracellular cation and the chief determinant of the
osmolarity of the extracellular fluid, including the blood plasma. Consequently,
hyponatremia and hypoosmolarity generally coexist. Exceptions include the
circumstances in which the sodium concentration is artifactually lowered
(hyperlipidemia and hyperproteinemia) or in which an osmotic agent other than
sodium makes up a significant portion of the serum solute content, producing
hyponatremia with normal or elevated serum osmolality (e.g., hyperglycemia or
the exogenous administration of osmotic agents, such as mannitol and
glycerol).
2. In the absence of exogenously administered osmotic agents:
Serum osmolarity (mOsm/L) =2 [sodium (mEq/L)
+potassium (mEq/L)] +BUN (mg/dL)/3 +blood glucose (mg/dL)/18
3. The hypoosmolar state may be asymptomatic, or it may cause a metabolic
encephalopathy: confusion and agitation, progressing to lethargy and then to
seizures and coma. Psychosis with hallucinations can occur, and asterixis may
be seen.
4. Symptoms usually do not appear unless the serum sodium is lower than 125
mEq/L; seizures generally occur only when the sodium level drops lower than
115 mEq/L. The more rapid the development of the hyponatremia, the more
severe the symptoms for a given sodium concentration.
B. Differential diagnosis
1. Loss of sodium out of proportion to water
a. Renal sodium wasting
1. Salt-losing nephropathy.
2. Diuretics.
3. Hypoadrenocorticism.
b. Cerebral salt wasting after subarachnoid hemorrhage or head trauma.
2. Retention of water out of proportion to sodium
a. Syndrome of inappropriate antidiuretic hormone (SIADH) secretion
1. Bronchogenic oat cell carcinoma and other malignant tumors with
ectopic vasopressin (antidiuretic hormone) production.
2. CNS disease: stroke, head trauma, infection, tumors, acute intermittent
porphyria, and hydrocephalus.
3. Pulmonary disease: tuberculosis, pneumonia, lung abscess, and chronic
obstructive airway disease.
4. Unknown etiology.
5. Drugs: chlorpropamide, vincristine, cyclophosphamide, phenothiazines,
barbiturates, tricyclic antidepressants, clofibrate, acetaminophen,
carbamazepine. In the elderly, tricyclic antidepressants and
carbamazepine are frequent offenders.
6. Guillain-Barr syndrome
b. Beer drinking.
c. Oliguric renal failure with overhydration with hypotonic fluids.
d. Edematous states
1. Hepatic cirrhosis.
2. Congestive heart failure.
e. Psychogenic polydipsia.
f. Hypothyroidism.
3. Shifts in water between body compartments
a. Hyperglycemia.
b. Exogenous administration of osmotic agents: mannitol, glycerol.
c. Hypoadrenocorticism.
d. Sick cell syndrome.
4. Pseudohyponatremia
a. Hyperlipemia.
b. Hyperproteinemia.
C. Correction of hyponatremia
1. Acute hyponatremia (less than 24 hours duration) is potentially life threatening
and requires vigorous treatment. On the other hand, the overly rapid correction
of hyponatremia, especially chronic hyponatremia, is associated with central
pontine myelinolysis. The optimum rate of correction in various clinical
circumstances is not clear, but several guidelines can be suggested.
2. Chronic asymptomatic hyponatremia is surprisingly well tolerated. The serum
osmolality should be corrected at a rate of 5 mEq/L/day or less, relying on
water restriction as the major mode of therapy.
3. In chronic symptomatic hyponatremia in which seizures occur, the sodium
should be corrected to 120 mEq/L at a rate no more rapid than 12 mEq/L/day.
At that point, slower correction should be undertaken.
4. In acute hyponatremia, whether symptomatic or asymptomatic, the serum
sodium should be corrected to 120 mEq/L at a rate of 12 mEq/L/day. Further
correction should be no more rapid than 6 mEq/L/day.
5. In all situations, one must be careful not to overcorrect to serum osmolalities
above normal.
D. Specific situations
1. Dilutional hyponatremia occurs most frequently as an iatrogenic disease in
patients, especially women, who are volume-depleted and who are
administered intravenous hypotonic fluids.
a. The clinical picture is one of volume depletion with a low urine sodium
concentration.
b. The treatment consists of the replacement of volume and sodium deficits. A
water diuresis will then ensue, and the serum sodium will return to normal.
In mild cases, a liberalization of the sodium content of the diet or a
reduction of dosage in a diuretic agent may be adequate therapy. Only
when the patient is symptomatic or the serum sodium is less than 120
mEq/L is intravenous isotonic saline given.
2. Water retention
a. Patients may retain water out of proportion to sodium in oliguric renal
failure, hypothyroidism, and, very rarely, psychogenic polydipsia.
1. The treatment in most cases is to restrict the water intake to the amount
of calculated insensible losses (800 mL/day in a normothermic adult)
until the sodium is within the normal range.
2. In rare circumstances in which the patient has symptoms of severe
water intoxication, it may be necessary to administer hypertonic saline in
the form of 3% sodium chloride to raise the serum sodium to a level
greater than 125 mEq/L. This should generally be done with the aid of a
central venous pressure (CVP) line; furosemide (Lasix) may be
administered if volume overload occurs.
b. SIADH
1. Description. SIADH occurs in a variety of circumstances (see sec.
V.B.2.a). The pathophysiology of the hyponatremia involves both water
retention with volume expansion and sodium wasting. The patient is
normovolemic or mildly hypervolemic but is not edematous.
2. Diagnosis. The following criteria must be met to verify the diagnosis:
a. Serum hyponatremia and hypoosmolality.
b. Renal sodium wasting. Generally, with a normal sodium intake, the
urine sodium concentration is greater than 25 mEq/L in the presence
of SIADH. Occasionally, when the patient is sodium-restricted and a
steady state has been reached, the urine sodium may be lower.
c. The urine osmolality is inappropriately high for the serum osmolarity.
d. The patient is not volume-depleted.
e. Normal renal function.
f. Normal adrenal function.
3. In asymptomatic and mildly symptomatic cases, water restriction is the
treatment of choice. The patient's daily fluid intake is restricted to
calculated insensible losses until the serum sodium is within normal
limits. The water intake may then be limited to daily maintenance levels.
4. In severe hyponatremia from SIADH, the serum sodium can be
corrected to 120 mEq/L within 12 to 24 hours by the infusion of
hypertonic saline.
a. A catheter to monitor CVP is placed, and an infusion of 3% saline is
begun at a rate of about 100 mL/hour.
b. The CVP is carefully monitored and doses of furosemide, 1 mg/kg
IV, are administered to control intravascular volume and prevent
congestive heart failure.
c. Serum sodium and potassium and urine potassium are monitored
hourly. Potassium chloride is added to the saline infusion to replace
diuretic-induced potassium losses.
5. The inciting cause of SIADH should be eliminated if possible (i.e.,
offending drugs are discontinued, bulk tumor is removed if possible, or
CNS and pulmonary infections are treated appropriately).
6. Chronic SIADH
a. The therapy of chronic SIADH is water restriction. However, water
restriction is extremely unpleasant for the patient, so various means
may be used to allow a more liberal water intake.
b. Dietary sodium supplementation allows greater water intake, but it
may lead to congestive heart failure in the presence of compromised
cardiac or renal function.
c. Lithium carbonate is effective, but alternative therapies offer fewer
side effects.
d. Demeclocycline, 300 mg PO t.i.d., will cause a partial renal diabetes
insipidus and allow liberalized fluid intake.
e. Phenytoin acts centrally to inhibit ADH release, but in practice it has
been of no benefit in the management of SIADH of CNS origin.
f. Oral furosemide, 40 mg QD has been reported effective in the
chronic treatment of SIADH. (g) Oral urea (30 g/day) as a single
daily dose is effective but should be avoided in patients with peptic
ulcer disease.
c. Subarachnoid hemorrhage. Many patients develop hyponatremia, often
with volume contraction, after subarachnoid hemorrhage. Efforts to define
the etiology of this condition have failed. The term cerebral salt wasting has
been applied, as some patients undergo natriuresis. The serum and urine
electrolyte abnormalities of cerebral salt wasting are indistinguishable from
those of SIADH; but, unlike SIADH, the patient is volume-depleted and
responds to fluid and sodium repletion. Central venous pressure
measurement or radioisotope dilution studies to measure plasma volume
may be required to make the distinction. However, the pathophysiology
may be complex, as SIADH also contributes to hyponatremia in some
patients with subarachnoid hemorrhage. Whatever the etiology, fluid
restriction is dangerous in patients with subarachnoid hemorrhage, and
these patients should be treated with infusions of isotonic saline to maintain
plasma volume.
VI. Acute intermittent porphyria (AIP)
A. Description. Acute intermittent porphyria is an autosomal dominant disease of
porphyrin metabolism manifested by recurrent attacks of abdominal pain and
neurologic dysfunction. It results from a deficiency of porphobilinogen (PBG)
deaminase (formerly called uroporphyrinogen I synthetase).
1. Symptoms rarely appear until puberty, and in most cases they begin in the
second to fourth decade of life. Females outnumber males in symptomatic
cases, and asymptomatic carriers of the defect exist.
2. Acute attacks are usually heralded by abdominal pain and constipation
followed by neurologic disease. Peripheral neuropathy (which may progress to
quadriplegia and respiratory paralysis), cranial nerve palsies, psychosis,
depression, confusion, coma, and seizures might all occur during an acute
attack. Attacks can leave the patient with residual peripheral nerve or
psychiatric dysfunction. Even with optimum management, a severe acute
attack of AIP carries a significant mortality.
B. Diagnosis. During acute attacks of AIP, and usually between attacks as well,
patients have elevated urinary excretion of d-aminolevulinic acid (d-ALA) and
PBG. The latter can be detected by the Watson-Schwartz test. The definitive test
for this disease is to compare the activity of PBG deaminase in the patient's
erythrocytes with that of relatives. Family members with this disease have enzyme
levels that are about half those of unaffected family members. No definite sporadic
cases of AIP have ever been documented.
C. The neurologic manifestations of hereditary coproporphyria and variegate
porphyria and their treatment are similar to AIP, although their chemical
manifestations differ.
D. Prophylaxis against acute attacks. The mainstay of management of this disease is
the avoidance of factors known to precipitate acute attacks. Asymptomatic family
members are identified by erythrocyte PBG deaminase levels, so appropriate
measures can be taken to keep them in the asymptomatic class.
1. Drugs. The most common precipitant of an acute attack of AIP is the
administration of a drug that induces hepatic d-ALA synthetase activity. Drugs
may be divided into the following 4 classes, according to their ability to induce
d-ALA synthetase.
a. Drugs that are definitely known to precipitate attacks and must be avoided
in porphyrics whenever possible:
1. Anticonvulsants: barbiturates, phenytoin, methsuximide (Celontin),
primidone, trimethadione.
2. Tranquilizers: chlordiazepoxide (Librium), meprobamate (Miltown),
isopropyl meprobamate (Soma).
3. Sedatives: barbiturates, glutethimide (Doriden), methyprylon (Noludar).
4. Antibiotics: sulfonamides, griseofulvin (Fulvicin, Grifulvin), dapsone.
5. Alcohol.
6. Others: ergots, dichloralphenazone (Midrin), pyrazolone compounds
(aminopyrine, antipyrine, isopropyl antipyrine, dipyrone), imipramine
(Tofranil), eucalyptol, tolbutamide (Orinase), chlorpropamide, synthetic
estrogens and progestins.
b. Drugs that have been shown experimentally to induce d-ALA synthetase
and that should be avoided whenever possible:
1. Anticonvulsants: mephenytoin (Mesantoin), phensuximide (Milontin),
valproic acid.
2. Antibiotics: chloramphenicol, rifampin.
3. Others: 2-alkyloxy-3-methylbenzamide, clonidine.
c. Drugs demonstrated to be safe in AIP:
1. Analgesics: salicylates, opiates (morphine, methadone, codeine,
propoxyphene [Darvon], meperidine [Demerol]), acetaminophen.
2. Sedatives: chloral hydrate, bromides.
3. Autonomic drugs: atropine, hyoscine.
4. Antihypertensives: reserpine, guanethidine, propranolol.
5. Antihistamines: diphenhydramine (Benadryl), meclizine (Bonine,
Antivert), promethazine (Phenergan).
6. Tranquilizers: phenothiazines including chlorpromazine (Thorazine).
7. Antibiotics: penicillins, aminoglycosides, tetracycline, nitrofurantoin
(Furadantin), methenamine mandelate (Mandelamine).
8. Others: ascorbic acid, B vitamins, digoxin, neostigmine (Prostigmin),
succinylcholine, ether, nitrous oxide, corticosteroids.
d. For drugs not listed, there is inadequate evidence on which to base a
judgment.
2. Hormones. Estrogen, progesterone, and testosterone have been shown to
induce d-ALA synthetase activity.
a. Pregnancy has been reported to precipitate acute attacks and therefore
carries an increased risk in the presence of AIP.
b. Exogenous administration of estrogens and oral contraceptives has been
reported to precipitate acute attacks and, with the exception discussed in
sec. III.D.2.c, should be avoided in these patients.
c. Some women with AIP experience regular, cyclic attacks, usually mild,
during the few days immediately preceding menstruation. Oral
contraceptives have been successfully used to prevent these cyclic attacks
and should be tried in women with this syndrome. Oral contraceptives do
not prevent attacks and are contraindicated in patients who do not have this
rare cyclic syndrome. A long-acting luteinizing hormone-releasing hormone
agonist has been reported to prevent attacks in a single patient with this
syndrome.
d. Corticosteroids can be used safely.
3. Infections. Although fever and leukocytosis may occur as a manifestation of an
acute attack of AIP, they are more often manifestations of infection. Infections
in these patients must be diagnosed and treated promptly.
4. Starvation and dieting. A high-carbohydrate intake can suppress the induction
of liver d-ALA synthetase activity. Conversely, d-ALA synthetase activity rises
during periods of low-carbohydrate intake, and starvation can precipitate an
acute attack. Thus, these patients should be maintained on a relatively
high-carbohydrate diet, ingesting over half their calories as carbohydrates.
E. Treatment of the acute attack
1. Suppression of porphyrin synthesis
a. High-carbohydrate intake. The patient is provided with 450 to 600 g of
carbohydrate daily, either PO or parenterally, during the attack. Especially if
parenteral glucose solutions are used, the serum electrolytes are followed
closely because of the frequent association of SIADH with porphyria.
b. Hematin, like carbohydrate, lowers hepatic d-ALA synthetase levels. In
several reports, it has shown promising results when administered
parenterally to patients with attacks of AIP. A freshly prepared hematin
solution is administered IV at a dosage of 80 to 100 mg daily in adults. To
avoid phlebitis, hematin should be administered through a central venous
catheter or infused into a large peripheral vein slowly over 15 to 20 minutes.
2. Management of complications of the acute attack
a. Abdominal pain
1. Chlorpromazine is highly effective for the abdominal pain. It probably
works through the autonomic nervous system to control the disordered
intestinal motility. Doses must be titrated for the individual patient to
avoid oversedation. A dose of 50 mg IM may be repeated q34h as
needed.
2. Opiates may be added to chlorpromazine as necessary. One must be
careful not to depress respiration excessively in patients with severe
neuropathies and respiratory compromise.
3. Fecal disimpaction is frequently necessary.
b. Respiratory failure and bulbar paralysis may require tracheal intubation,
respiratory support, or gastric feeding.
c. Psychosis. Chlorpromazine or other phenothiazines may be used safely to
control the psychiatric manifestations. Acute and chronic depression may
occur; patients should be evaluated for suicide risk.
d. Seizures. Because of the many drugs that cannot be used in these patients,
including barbiturates, hydantoins, and succinimides, the treatment of
seizures can be extremely difficult.
1. If the seizures are associated with an acute attack, diazepam, 5 mg IV,
or lorazepam, 2 to 4 mg IV, may be sufficient, although repeated
intravenous doses may be required until the attack is aborted.
2. Clonazepam in low doses (i.e., 0.5 to 1.0 mg PO t.i.d.) is probably safe
for chronic administration, although high doses may exacerbate AIP.
Blood levels therefore should be closely monitored and maintained in
the middle of the therapeutic range. Gabapentin is also probably safe.
3. Triple bromides are the only other alternative. Bromide has a narrow
therapeutic index. Serum levels should be maintained in the range of 60
to 90 mg/dL. The effective dosage is in the range of 3 to 5 g/day.
4. Hyponatremia, hypocalcemia, and hypomagnesemia should be
diagnosed and treated promptly.
e. Labile hypertension or postural hypotension may accompany the autonomic
nervous system disorders associated with AIP. The labile hypertension
usually requires no treatment, although both reserpine and guanethidine
are known to be safe if needed. Postural hypotension requires careful
maintenance of intravascular volume.
3. Chemical abnormalities. Several endocrinologic abnormalities occur in
association with AIP.
a. The oral glucose tolerance test frequently is abnormal during an acute
attack, but it usually requires no treatment.
b. The free thyroxine and protein-bound iodine might be elevated, but these
do not require specific therapy.
c. Patients often have type IIA hyperlipoproteinemia that persists between
attacks and, in the absence of information to the contrary, may be treated
like any other case of hyperbetalipoproteinemia.
VII. Heavy metal poisoning
A. Lead
1. Sources of exposure. The most common cause of lead poisoning in children is
residential remodeling. Inorganic lead is present in paintsboth interior paints,
which still line the walls of many older buildings, and modern exterior paints.
The organic lead compound tetraethyl lead is a gasoline additive, which is
present in high concentrations in the atmosphere around tanks used to store
gasoline and in dirt collected from urban areas near heavily traveled
intersections or expressways.
2. Clinical manifestations of lead toxicity
a. Encephalopathy
1. Epidemiology. Lead encephalopathy occurs in children who ingest large
amounts of lead salts. It occurs only rarely in adults and only in those
exposed to tetraethyl lead, which is lipid soluble and reaches high levels
in the CNS. In children, it is usually accompanied by pica, and it is most
common between the ages of 1 and 3 years. Lead encephalopathy is
more common in summer than in winter.
2. Signs and symptoms. The usual symptoms of lead encephalopathy are
personality change, lethargy, and irritability progressing to somnolence
and ataxia, and finally, seizures, coma, and death. In children, acute
episodes of lead encephalopathy may recur, superimposed on a state of
chronic lead intoxication.
3. Prognosis. The mortality of acute lead encephalopathy is less than 5%
in the best of hands, but 40% of victims are left with permanent and
significant residual neurologic deficits, which may include dementia,
ataxia, spasticity, and seizures.
b. Lead colic is the most common manifestation of lead poisoning in adults.
The patient is anorectic and constipated, and often has nausea and
vomiting. There is abdominal pain but no tenderness. Characteristically, the
patient presses on the abdomen to relieve the discomfort. Lead colic
generally accompanies lead encephalopathy in children.
c. Neuromuscular form. Slowing of motor nerve conduction velocity is an early
sign of lead poisoning in children; symptomatic neuropathy is rare. In
adults, however, symptomatic neuropathy is common in lead poisoning.
Typically, lead neuropathy is predominantly motor, but paresthesias and
sensory changes may occur. Extensors are weakened before flexors, and
the most used muscle groups (usually the extensors of the wrist) are
involved earliest.
d. It is suspected that chronic low-level lead exposure in children causes an
attention deficit disorder with hyperactivity.
3. Diagnosis
a. Physical examination. The only characteristic physical finding of lead
poisoning is the presence of lead lines around the gum margins. These
occur in a minority of cases and only in patients with poor dental hygiene.
b. Blood smear. In chronic lead exposure, there is usually a microcytic anemia
that may be superimposed on an iron deficiency anemia. Basophilic
stippling is seen in a minority of cases, and the bone marrow may show
ringed sideroblasts.
c. Urine. There is proximal renal tubular dysfunction associated with lead
toxicity, with glycosuria, phosphaturia, and aminoaciduria.
d. X-rays. Lead lines may be seen in the long bones. In children who have
recently ingested lead-containing paint, radiopaque flecks may be seen in
the abdomen.
e. Laboratory evidence of increased body lead burden
1. The serum lead level is the most useful screening test, although it does
not reflect the total body lead burden accurately. Lead levels that are
measured on capillary blood (obtained from a finger stick) are subject to
contamination by lead on the skin. Consequently, a cleanly obtained
venous specimen is preferred. The 24-hour urinary lead excretion test
has the same limitations as the serum lead level test.
2. An ethylenediaminetetraacetic acid (EDTA) test measures total body
lead burden more accurately than does a single serum or urinary level
test. However, this test is dangerous in children with high lead burdens
because EDTA may mobilize lead from the tissues and precipitate
encephalopathy. Therefore, it should not be performed in a child who
has a serum lead level higher than 70 g/dL or who has symptoms of
early encephalopathy.
The test is performed by administering calcium EDTA in either 1 or 3
doses of 25 mg/kg IV at 8-hour intervals. A 24-hour urine specimen is
collected, and the total lead excreted in 24 hours is measured. A
positive test consists of greater than 500 mg of lead excreted per 24
hours, or greater than 1 mg of lead excreted per 24 hours per milligram
of EDTA administered.
3. Several tests measure the toxic effects of lead on porphyrin metabolism.
These tests are generally the most sensitive measures of lead toxicity.
a. d-ALA dehydratase activity in erythrocytes is the most sensitive test
of lead poisoning, but it is not readily available.
b. Urinary or serum d-ALA levels higher than 20 mg/dL are indicative of
lead toxicity.
c. Urinary coproporphyrin excretion greater than 150 mg/24 hours is
indicative of lead toxicity.
d. Erythrocytic protoporphyrin (EP) levels higher than 190 g/dL of
whole blood are diagnostic of lead poisoning in the absence of either
iron deficiency or erythropoietic protoporphyria, both of which may
also elevate EP levels.
4. Treatment
a. Encephalopathy. For lead encephalopathy caused by the ingestion of
inorganic lead, chelation therapy with EDTA and dimercaprol, or British
antilewisite (BAL), is instituted immediately.
1. The immediate medical needs of the patient, which may include seizure
control and protection of the airway, are attended to.
2. A urine flow of 350 to 500 mL/m
2
/day is established. Overhydration,
especially with free water, endangers the patient with increased ICP and
should be avoided.
3. Dimercaprol is given at a dosage of 500 mg/m
2
/day by deep
intramuscular injection in divided doses q4h for children under 10 years
of age. The adult dosage is 3 mg/kg/day in divided doses q4h.
4. Beginning 4 hours after the initial dimercaprol injection, simultaneous
injections of dimercaprol and EDTA are given in separate sites. The
dosage for EDTA is 1,500 mg/m
2
/day IM in divided doses q4h for
children under 10, and 12.5 mg/kg/day for adults. In adults, EDTA may
be administered as a continuous IV infusion of a solution of EDTA in 5%
D/W at no greater concentration than 0.5%. The maximum adult dose is
7.5 g/day.
5. The usual course of therapy is 5 days.
6. Because of the danger of vomiting with dimercaprol, food is withheld for
the first 3 days and then is given only if the patient is fully alert and
without GI upset. Iron therapy is not administered simultaneously with
dimercaprol. Electrolytes, including calcium and phosphate levels, are
measured daily. SIADH frequently accompanies lead encephalopathy.
7. Increased ICP is managed with osmotic agents. The role of steroids is
unclear. There is some evidence of an adverse interaction of EDTA and
steroids, so some experts avoid their concurrent use.
8. Side effects of chelation therapy
a. Dimercaprol may produce lacrimation, blepharospasm, paresthesias,
nausea, vomiting, tachycardia, and hypertension. Its use is
contraindicated in the presence of glucose 6-phosphate
dehydrogenase deficiency.
b. EDTA may produce renal injury, cardiac conduction abnormalities,
and electrolyte disorders. Renal function, calcium, and electrolytes
are followed daily, and urine output is carefully monitored and
maintained.
c. The intramuscular injection of EDTA is painful. It is commonly mixed
with procaine at a final concentration of 0.5%.
b. Lead colic and lead neuropathy in adults
1. These conditions require immediate attention but are not emergencies.
The cornerstone of therapy is removal of the patient from the offending
environment and elimination of sources of future lead exposure.
2. In patients who are very symptomatic and in those with serum lead
levels of 100 g/dL or greater (or EP levels higher than 190 g/dL whole
blood), a course of chelation therapy with dimercaprol plus EDTA is
given and followed with a course of oral penicillamine or succimer (see
sec. VII.A.4.c).
3. In mildly symptomatic patients without markedly elevated serum lead or
erythrocytic protoporphyrin levels, a course of oral penicillamine or
succimer is probably adequate.
4. Lead colic responds acutely to calcium gluconate, 1 g IV, repeated as
necessary.
c. Long-term therapy
1. A 5-day course of dimercaprol plus EDTA usually removes about 50%
of the soft-tissue stores of lead and reduces the serum lead level by a
corresponding amount. After chelation therapy is stopped, however,
lead may be mobilized from bone, again raising the soft-tissue and
serum lead concentrations. Consequently, the serum lead should be
checked every few days after completion of a course of chelation
therapy, and another course given if the serum lead rises above 80
g/dL. Some patients may require 3 or 4 courses of chelation therapy.
2. Succimer (dimercaptosuccinic acid) has been approved by the Food
and Drug Administration (FDA) for the oral therapy of lead intoxication.
The drug is administered at a dosage of 30 mg/kg/day or 1,050 mg/m
2

in 3 divided doses for 5 days. The dosage is then reduced to 20
mg/kg/day or 700 mg/m
2
in 2 divided doses for 14 more days. It is
important to treat concurrent iron deficiency. Adverse effects can include
GI upset, allergic rashes, and elevated liver enzymes. The drug has a
bad odor, which reduces patient compliance. The capsules may be
opened and the drug sprinkled on juice or a food vehicle.
3. Penicillamine is not approved by the FDA for use in lead poisoning, and
its precise role is not well defined. It was widely used prior to the
introduction of succimer to promote the further excretion of lead
following a course of dimercaprol plus EDTA. Its use now is reserved for
patients who require oral chelation therapy but who cannot tolerate
succimer. It is administered PO at a dosage of 600 mg/m
2
/day in a
single dose. It should be administered on an empty stomach, at least 2
hours apart from meals. The therapy must be continued for 3 to 6
months. Toxic reactions to penicillamine include nephrotic syndrome,
optic neuritis, and blood dyscrasias.
d. Tetraethyl lead can be absorbed through the respiratory tract and, unlike
inorganic lead salts, can produce encephalopathy in adults. The usual
treatment is chelation therapy with dimercaprol plus EDTA, although there
is not strong evidence of its effectiveness. Serum lead levels and EP
concentrations are not helpful in treating acute poisoning with tetraethyl
lead; both diagnosis and therapy must be based on clinical findings.
e. Asymptomatic lead exposure in children. The Centers for Disease Control
recommends that children at high risk for lead poisoning be screened with
serum lead levels every 6 months. The management is based on the serum
lead level:
1. Serum lead level less than 10 g/dL requires only continued routine
screening.
2. Serum lead level of 10 to 20 g/dL may require more frequent screening
and discussion with the family about eliminating potential sources of
environmental lead.
3. Serum lead level of 20 to 45 g/dL (the upper limit is set at 40 g/dL in
some clinics) demands an evaluation of the patient's medical status,
with particular attention to nutrition and possible anemia or iron
deficiency, and vigorous efforts to remove the patient from
environmental lead exposure. Many clinics would institute a course of
oral chelation therapy with succimer.
4. Serum lead level of 45 to 69 g/dL requires a full medical evaluation,
removal from the source of exposure, and immediate chelation therapy
with succimer or EDTA.
5. Serum lead level of 70 g/dL or greater requires immediate inpatient
chelation therapy with EDTA plus dimercaprol.
B. Mercury
1. Sources of exposure
a. Mercury salts and mercury vapor are potential environmental toxins in the
chemical, paint, and paper industries, especially in chlorine production.
Mercury vapor and dust are absorbed through the skin and lungs, and
ingested mercury salts are absorbed from the gut. Elemental liquid mercury
is poorly absorbed from the GI tract unless it is finely divided.
b. Organic mercury compounds pose the greatest threat to the CNS.
1. Phenolic and methoxymethyl mercury are degraded to inorganic
mercury in the body and are metabolized as inorganic mercury salts.
2. Alkyl mercury, primarily methyl and ethyl mercury, is produced as a
waste product in the plastics and agricultural fungicide industries. It is
well absorbed through skin and is highly lipid-soluble, reaching high
concentrations in the CNS.
2. Clinical manifestations
a. Acute mercury poisoning from a brief exposure to a large amount of
mercury produces stomatitis and a metallic taste; a sensation of constriction
of the throat; ulcers on the tongue and palate; GI upset with nausea,
vomiting, and bloody diarrhea; abdominal pain; acute renal failure; and
circulatory collapse. The CNS manifestations include lethargy, excitement,
hyperreflexia, and tremor.
b. Chronic inorganic mercury poisoning produces stomatitis and a metallic
taste, loss of appetite, a blue line along the gingival margin, hypertrophied
gums, tremor, chorea, ataxia, nephrotic syndrome, and erythrism (a
syndrome of personality change, shyness, and irritability). Pink disease, or
acrodynia, occurs in infants. It is characterized by irritability, insomnia,
stomatitis, loss of teeth, hypertension, and erythema.
c. Organic mercury intoxication produces fatigue, apathy, memory loss,
emotional instability, ataxia, dysarthria, tremor, dysphagia, paresthesias,
and, characteristically, constriction of the visual fields. This may progress to
seizures, coma, and death. Organic mercury also crosses the placenta and
can produce retardation and paralysis in the offspring of asymptomatic
mothers. Renal lesions with proximal tubular dysfunction also occur.
3. Diagnosis and treatment
a. Acute mercury poisoning must be diagnosed by the history of exposure and
the clinical picture. The aims of therapy are to remove unabsorbed mercury
from the GI tract, chelate mercury that has already been absorbed, and
prevent acute renal failure.
1. Emesis or gastric lavage is used to empty the stomach, which is then
rinsed with a proteinaceous solution (egg white, albumin, or skim milk)
or charcoal. Because of the locally corrosive nature of mercury salts, the
trachea is intubated if the patient is not fully alert.
2. Sodium formaldehyde sulfoxylate may decrease mercury absorption by
chemically reducing mercuric salts to the less soluble form of metallic
mercury; 250 mL of a 5% solution may be instilled into the duodenum.
3. Dimercaprol can be given at a dosage of 4 to 5 mg/kg IM q4h, with no
dose exceeding 300 mg. After the first 24 hours, the frequency of doses
is reduced to q6h for 2 to 3 days and then q8h for the remainder of a
10-day course. N-Acetyl-d,l-penicillamine may be the best chelating
agent for mercury compounds, but it is not generally available.
4. Intravenous fluids are administered to maintain urine flow, and mannitol,
1 g/kg IV, is given if the patient is oliguric. Dialysis may be necessary if
the kidneys have shut down and the patient is severely intoxicated.
Electrolyte management might be difficult due to the diuresis induced by
mercury salts, with sodium and potassium losses as well as volume
depletion.
b. Chronic inorganic mercury poisoning generally does not present the severe
emergency that acute poisoning presents. Removal from exposure and a
course of dimercaprol or penicillamine (see sec. VII.B.3.a.(3)) are the
cornerstones of therapy. Total body sodium, potassium, and intravascular
volume may need to be repleted.
c. Alkyl mercury poisoning is most often a chronic process. There is an
enterohepatic circulation of alkyl mercury, so excretion can be promoted by
binding the mercury compound in the small intestine with an unabsorbable
resin. Cholestyramine, 16 to 24 g/day in divided doses, may be given
together with enough of an osmotic cathartic (e.g., sorbitol) to prevent
constipation. The dosage of cholestyramine in children has not been
established.
C. Arsenic
1. Sources of exposure. The primary cause of arsenic poisoning today is
pesticide ingestion, either accidentally in children and agricultural workers or
intentionally through suicide or homicide. Arsenic-containing rat poison is no
longer in widespread use, but it might still be stored in some homes and farms.
Occasionally, iatrogenic poisoning occurs from arsenic-containing antiparasitic
agents used in the treatment of trypanosomiasis (e.g., tryparsamide,
carbarsone, and senite).
2. Clinical manifestations
a. Acute poisoning. Acutely, arsenic produces capillary endothelial damage
with leakage, especially in the splanchnic circulation. Nausea, vomiting,
abdominal pains, and muscle cramps also occur. With somewhat larger
doses, intravascular hemolysis can occur, which can lead to acute renal
failure. Abnormalities are present on the electrocardiogram, and stomatitis
appears. With lethal doses, a sequence of shock, coma, and death occurs
in 20 to 48 hours.
b. Chronic poisoning. GI symptoms are less prominent than with acute
poisoning, but weight loss, anorexia, nausea, and diarrhea or constipation
may occur. Neurologic toxicity may be manifested by a sensorimotor
neuropathy, excessive salivation and sweating, and encephalopathy. The
last, in its early stages, consists of fatigue, drowsiness, headache, and
confusion, but it may progress to seizures, coma, and death. Rarely, there
may be increased CSF protein and a mild pleocytosis along with fever, so
the picture might be mistaken for an infectious process. Dermatologic signs
can be diagnostic, with characteristic arsenical keratoses and transverse
lines in the nails (Mees lines). Hepatic and renal damage may occur.
3. Diagnosis
a. Acute arsenic intoxication must be recognized by a history of ingestion and
by the clinical presentation. In acute intoxication, the urinary arsenic
excretion may be extremely high.
b. Chronic arsenic poisoning
1. Chronic arsenic poisoning is suggested by the clinical picture, especially
the dermatologic manifestations.
2. The upper limits of normal urinary arsenic excretion are not sharply
defined, but levels higher than 0.1 mg/L are suggestive of abnormally
high exposure. Concentrations of arsenic in the nails or hair that are
greater than 0.1 mg/kg are indicative, but not diagnostic, of arsenic
poisoning. Individuals who are chronically exposed to arsenic may
harbor large amounts in their tissues and excrete large amounts without
developing symptoms of toxicity.
3. With chronic arsenic ingestion, there is increased urinary
coproporphyrinogen III, but normal urinary d-ALA excretion.
4. Treatment
a. Removal from exposure and elimination of unabsorbed arsenic from the GI
tract by the use of emesis or gastric lavage and osmotic cathartics are the
initial steps.
b. Dimercaprol is an effective chelating agent for arsenic. The usual course
consists of 4 to 5 mg/kg IM q4h for 24 hours, followed by the same dose
q6h for 2 to 3 days, followed by tapering doses to complete a 10-day
course. Neuropathy may require months to resolve.
c. Fluid and electrolyte disturbances must be rapidly repaired, and
intravascular volume must be protected with electrolyte and albumin
solutions. Pressors may be required in cases of acute poisoning.
d. The abdominal pain of acute arsenic poisoning may be severe and require
large doses of narcotics.
D. Antimony
1. Sources of exposure. Antimony poisoning is rare but may occur from ingestion
of acidic food that is stored in improperly made enamelware or from
parasiticidal drugs (e.g., tartar emetic) used in the therapy of leishmaniasis,
schistosomiasis, and filariasis.
2. The clinical manifestations are similar to those of arsenic poisoning (see sec.
VII.C.2).
3. The treatment is identical to that of arsenic poisoning, including use of
dimercaprol (see sec. VII.C.4).
E. Thallium
1. Sources of exposure. Thallium is the primary ingredient of some depilatories
and rat poisons. Poisoning usually occurs as a result of accidental ingestion of
these materials.
2. Clinical manifestations. Alopecia is the hallmark of thallium intoxication.
Neurologic manifestations are prominent: ataxia, chorea, restlessness, and
hallucinations, progressing to coma and death. Blindness, facial paralysis, and
peripheral neuropathy may occur. Nausea, vomiting, constipation, and liver
and renal damage may also occur.
3. Treatment
a. Removal from exposure and elimination of unabsorbed thallium from the GI
tract with emesis or gastric lavage and catharsis are the primary modes of
therapy.
b. Prussian blue (potassium ferric hexacyanoferrate) may be introduced by
tube into the duodenum and may decrease thallium absorption. The dosage
is 250 mg/kg given over 24 hours in 2 to 4 divided doses.
VIII. Carbon monoxide poisoning
A. Clinical manifestations
1. Carbon monoxide is the most common cause of death by poisoning in the
United States. The acute manifestations of carbon monoxide inhalation are
those of hypoxia without cyanosis. The textbook cherry-red appearance is
uncommon. The earliest neurologic dysfunction is lethargy, which may
progress to coma. Retinal hemorrhages may occur. As hypoxia becomes more
severe, brainstem functions fail. Cardiac ischemia and acute myocardial
infarction may occur.
2. The patient might recover completely from the acute episode, if rescued in
time, or be left with residual neurologic dysfunction. Characteristically, the
basal ganglia are the most vulnerable structures. The patient might also
recover completely from the acute intoxication only to succumb to a massive
subacute demyelination of the cerebral white matter that begins 1 to 3 weeks
after exposure.
B. Diagnosis
1. The history is usually sufficient to give the diagnosis. The cherry-red
appearance might also give a clue. Generally, if the patient has inhaled smoke
or flame, rather than air contaminated by carbon monoxide, the damage to the
respiratory epithelium by heat or oxides of nitrogen is of more immediate
concern than carbon monoxide poisoning.
2. Many blood gas laboratories can measure carbon monoxide saturation of
blood. (Note that venous blood is adequate for carbon monoxide
determinations.) In the absence of lung disease or a right-to-left shunt, SaO
2
,
while the patient is breathing 100% oxygen, will give an estimate of the carbon
monoxide saturation. The PaO
2
is of no use in estimating carbon monoxide
saturation because it will not be affected by the combination of hemoglobin
with carbon monoxide.
C. Treatment
1. The primary therapy for carbon monoxide intoxication is to remove the patient
from exposure as rapidly as possible and to administer 100% oxygen. Any
patient with symptoms of hypoxia or carbon monoxide saturation greater than
about 40% should be observed in the hospital for at least 48 hours and
maintained on supplemental oxygen until the carbon monoxide concentration
falls below 20%. For severely poisoned patients, hyperbaric oxygen
administration (if a chamber is available) or exchange transfusion may be of
benefit.
2. Any maneuvers that reduce the tissue demand for oxygen should be
undertaken. Patients are kept at rest and tranquilized if they are hyperactive
from encephalopathy or other causes. Hyperthermia is treated vigorously.
3. Fire victims frequently inhale both carbon monoxide and cyanide (a product of
combustion of many plastics and synthetic materials). Although
methemoglobin-forming agents such as amyl nitrite and sodium nitrite are
routinely used to treat cyanide poisoning, they reduce the oxygen-carrying
capacity of the blood and should probably be avoided when carbon monoxide
levels are high.
4. Residual movement disorders are common after severe carbon monoxide
poisoning. Choreoathetosis, myoclonus, and a parkinsonian syndrome can
occur. These disorders are treated symptomatically in the same manner as
movement disorders of other etiologies (see Chap. 15). For parkinsonism
associated with carbon monoxide intoxication, direct-acting dopamine agonists
(bromocriptine, pergolide) may be more effective than L-dopa.
5. There is no known treatment for or specific means of preventing the delayed
massive demyelination that sometimes follows carbon monoxide poisoning.
IX. Acetylcholinesterase (AChE) inhibitor poisoning
A. Source of exposure. The usual source of AChE inhibitors is organophosphorous
insecticides. Acute poisoning may occur through ingestion, inhalation, or
absorption through the skin. Chronic poisoning produces chronic peripheral
neuropathy. Its only treatment is discontinuation of exposure to the toxin.
B. Clinical manifestations of acute AChE inhibitor poisoning are a combination of
local effects, systemic muscarinic and nicotinic effects, and CNS toxicity.
1. Local effects
a. Inhalation exposure produces symptoms referable to the eyes, mucous
membranes of the nose and pharynx, and the bronchial smooth muscle.
Pupillary constriction, conjunctival congestion, watery nasal discharge,
wheezing, and increased respiratory secretions are all prominent.
b. Ingestion of AChE inhibitors produces anorexia, nausea, vomiting,
abdominal cramps, and diarrhea.
c. Skin exposure produces localized swelling and muscle fasciculations.
2. Muscarinic effects include salivation, sweating, lacrimation, bradycardia, and
hypotension. Severe poisoning produces involuntary urination and defecation.
3. Nicotinic effects referable to the neuromuscular junction include muscle
fatigue, weakness, and fasciculations that progress to paralysis. The most
immediate life-threatening effect of AChE inhibitor intoxication is respiratory
paralysis, which is especially dangerous when combined with bronchospasm
and copious bronchial secretions.
4. CNS toxicity is manifested by confusion, ataxia, dysarthria, and diminished
deep tendon reflexes, which may progress to seizures and coma.
C. Diagnosis
1. The clinical presentation and a history of exposure are the key elements of
diagnosis.
2. Some clinical laboratories assay AChE activity in plasma and erythrocytes.
Although the normal range for AChE activity is broad, patients with significant
systemic AChE inhibitor toxicity all have extremely low levels.
D. Treatment
1. Exposure is terminated by removal of the patient from contaminated air,
washing the skin copiously with water, or gastric lavage as indicated.
2. The airway must be protected, especially if gastric lavage is required, and
respiratory assistance must be provided if necessary. Frequent suctioning of
respiratory secretions is required.
3. Circulatory collapse is treated with maintenance of fluid volume and pressors
as necessary.
4. Seizures are treated by the usual methods (see Chap. 6).
5. Muscarinic effects can be blocked with atropine in large doses. Therapy should
begin with 2 mg IV and then be repeated q35min. until muscarinic symptoms
disappear and bradycardia is reversed. If the patient is alert, doses of atropine
may then be given PO as required. Intravenous doses will need to be repeated
every few hours in comatose patients.
6. Reversal of peripheral AChE may be achieved with pralidoxime for the
proportion of the enzyme that has not irreversibly bound the inhibitor. The
initial dose for adults is 1 g, infused IV over 2 or more minutes. If improvement
is not noted within 20 minutes, the dose is repeated.
The earlier pralidoxime is administered in the course of intoxication, the greater
its effect. It may need to be repeated q812h. Pralidoxime does not reach CNS
AChE, and compounds that do so are not available in the United States.
X. Alcohol
A. Acute intoxication
1. Pharmacokinetics of ethyl alcohol
a. Ethanol is completely absorbed from the GI tract within 2 hours. It is
absorbed less rapidly if there is food in the stomach at the time of ingestion.
b. Ethanol is metabolized by the liver, and it is more rapidly metabolized in
those who drink regularly and heavily than in occasional drinkers.
c. The rate of ethanol metabolism is approximately 7 to 10 g/hour, which
represents about 1 oz of 90-proof spirits or 10 oz of beer per hour.
d. The lethal blood level of alcohol is about 5,000 mg/L. In a 70-kg man, this
represents about 1 pint of 90-proof spirits distributed throughout total body
weight.
e. The toxicity from a dose of ethanol depends on the maximum blood ethanol
level, the rapidity with which that level is obtained, the patient's prior
experience with alcohol, and the presence of other drugs.
2. Management of acute alcohol intoxication
a. In mild intoxication, the most important aspect of management is to see that
patients can get home safely, without endangering themselves and others
by attempting to drive. Analeptics, such as caffeine, amphetamines, and
theophylline, do not help sober up the patient or improve driving
performance.
b. Moderate intoxication with alcohol poses no danger to patients if they are
merely observed until ready to make their own way home. If there has been
ingestion within the preceding 2 hours, emesis, gastric lavage, and
catharsis may be used to prevent further absorption. As with mild
intoxication, analeptics are of no use.
c. The chief danger in severe ethanol intoxication is respiratory depression.
As long as adequate supportive care is provided before significant hypoxia
occurs, the outlook is excellent. Within 24 hours, the alcohol will be
metabolized.
1. The blood alcohol level may be measured directly or estimated by
measuring the serum osmolarity. Each 100 mg/L of blood ethanol raises
the serum osmolarity by approximately 2 mOsm/L.
2. Tracheal intubation and respiratory support are provided at the earliest
sign of respiratory depression. Respiratory support should be continued
until the patient is fully awake.
3. Gastric lavage is performed if there is a possibility of alcohol or other
drug ingestion within the preceding 2 hours. If the patient is not fully
awake, the trachea is protected with a cuffed endotracheal tube before
gastric lavage is undertaken.
4. Frequently, life-threatening ethanol ingestion is accompanied by
ingestion of other CNS depressants. This possibility should be
considered if the patient's mental status is depressed out of proportion
to the blood ethanol level or if unexpected neurologic signs are present.
5. Fluids are given to maintain adequate blood pressure and urine output,
but there is no need to induce a forced diuresis.
6. If the patient is suspected of being a chronic alcoholic or of having
severe liver disease, blood is drawn for determination of glucose and
electrolytes, and thiamine, 50 mg IV and 50 mg IM, and glucose, 25 to
50 g by IV push, are administered immediately in the event of
complicating Wernicke encephalopathy or hypoglycemia.
7. Chronic alcoholics are frequently potassium-depleted and may require
replacement with potassium chloride. Acid-base balance is maintained,
and alcoholic ketoacidosis is either ruled out or treated appropriately
with intravenous glucose and fluids.
8. If the blood ethanol level is extremely high (more than 7,000 mg/L),
peritoneal dialysis or hemodialysis may be justified to reduce the
ethanol level rapidly.
9. Although fructose administration hastens ethanol metabolism, its risk
does not justify the benefit obtained.
B. Ethanol withdrawal
1. Mild withdrawal syndrome
a. Clinical manifestations of mild ethanol withdrawal are anxiety, weakness,
tremulousness, sweating, and tachycardia.
b. Treatment
1. In the absence of other intercurrent illness, such as coronary artery
disease or infection, these patients may be treated at home if the social
situation is appropriate.
2. Patients are given thiamine, 50 mg IM, and a prescription for
multivitamins if they are malnourished. They are instructed to maintain
adequate hydration and food intake during the period of withdrawal.
3. A benzodiazepine tranquilizer minimizes the symptoms of withdrawal. In
general, one may begin with chlordiazepoxide, 25 to 50 mg PO q4h for
the first 48 to 72 hours, and then taper the dosage over 5 to 7 days.
Diazepam is equally effective. The initial dosage is 5 to 10 mg PO
q46h.
2. Moderate and severe withdrawal syndromes
a. Patients who are febrile, irrational, hallucinating, or extremely agitated must
be hospitalized until the severe manifestations of ethanol withdrawal have
resolved.
b. General medical therapy
1. These patients frequently are dehydrated, and total body potassium is
depleted. Those deficits are replaced with appropriate electrolyte
solutions. Vascular collapse may occur, but it usually responds to
rigorous volume replacement.
2. Ethanol withdrawal is often precipitated by an intercurrent illness, often
infection. Such illnesses must be detected and treated appropriately.
3. Chronic alcoholics are subject to bleeding disorders from liver disease
or thrombocytopenia. Consequently, acetaminophen, 600 mg or 1.2 g
PO or per rectum, is preferred to aspirin for the treatment of
hyperthermia.
4. The patient is usually magnesium-depleted. There is no good evidence
that replacing magnesium has any effect on the course of the
withdrawal syndrome, but many physicians elect to administer
magnesium if the patient is admitted early in the course of withdrawal.
Magnesium sulfate may be given in a 50% solution, 1 to 2 mL IM, or the
same amount may be mixed with IV electrolyte solutions.
5. Severe liver disease may result in hypoglycemia, and starvation may
result in ketoacidosis. Consequently, glucose is administered early,
either as a bolus of 25 to 50 g (if the patient is comatose) or as a
dextrose-plus-electrolyte solution.
6. Thiamine, 50 mg IV and 50 mg IM, is always administered to chronic
alcoholics prior to glucose because of the risk of Wernicke
encephalopathy.
c. Tranquilization. The benzodiazepines are the preferred drugs for sedation
in alcohol withdrawal.
1. Diazepam and chlordiazepoxide are essentially identical in their
therapeutic effect when used in equipotent doses. Both have a
prolonged duration of action (12 to 36 hours), are well absorbed PO, are
erratically absorbed when administered IM, and have a rapid and
predictable effect when given IV. The primary danger from both drugs is
excessive CNS depression after repeated doses, due to the cumulative
effect of successive doses given within 24 hours of each other.
Respiratory arrest may occur occasionally with rapid intravenous
injection of either drug, but the risk is minimized with small doses.
2. Dosages. Diazepam may be administered IV in 2.5-mg or 5-mg doses
q5min until the patient is calm, and then 5 to 10 mg PO or by slow
intravenous injection q26h as necessary. Chlordiazepoxide may be
used in an identical manner, chlordiazepoxide, 12.5 mg, being
equivalent to diazepam, 2.5 mg.
3. The most important aspects of managing alcohol withdrawal with
intravenous benzodiazepines are frequent observation of the patient to
prevent cumulative toxicity and avoidance of large doses (diazepam,
approximately 5 mg, or chlordiazepoxide, approximately 25 mg) in any
one intravenous injection. It is essential that each patient be individually
titrated with tranquilizer and repeatedly reevaluated rather than being
put on a fixed dosage schedule.
d. Withdrawal seizures
1. Description. Ethanol withdrawal seizures occur between 12 and 30
hours after cessation of regular ethanol ingestion, are generalized major
motor convulsions, and are usually brief and one or two in number.
Ethanol withdrawal seizures can be prolonged, however, and status
epilepticus may occur. The interictal EEG is normal, and except for
periods of drug withdrawal, the patient is not predisposed to unprovoked
seizures.
2. The diagnosis of ethanol withdrawal seizure can be made only if the
seizure fits the typical clinical pattern and there is no other possible
cause. Seizures from other causes are likely to be precipitated by
ethanol withdrawal and should be treated appropriately (see Chap. 6).
3. Treatment
a. Phenytoin may partially protect against ethanol withdrawal seizures.
Assuming patients have not been taking an antiepileptic, they can be
given a 1-g loading dose, either IV as a single dose infused over 20
to 30 min, or PO divided into 2 or 3 doses given 1 to 2 hours apart.
Then patients are maintained on 300 mg/day PO or IV for 3 days,
and the dosage is tapered over about 1 week after the risk of
withdrawal seizures has passed. Ethanol withdrawal seizures are not
an indication for long-term anticonvulsant therapy.
b. Experts differ over the indications for phenytoin prophylaxis of
withdrawal seizures. Some would administer phenytoin to all patients
seen during the first 24 hours of withdrawal from heavy ethanol use.
Others would limit its use to those with a history of withdrawal
seizures or with an underlying seizure disorder.
c. If a patient is seen after a withdrawal seizure has occurred, it is
reasonable merely to observe the patient without therapy as long as
other causes (particularly head trauma, subdural hematoma,
metabolic derangement, and CNS infection) for the seizure have
been ruled out. The probability is high that the seizure either will not
recur or, if it does recur, will be brief. Some would argue that the risk
involved in phenytoin use is sufficiently low that it should be used in
this situation until the patient is out of danger.
d. If the patient is allergic to phenytoin, carbamazepine is the
alternative. Barbiturates should be avoided, as they may potentiate
the respiratory depressant effects of benzodiazepines used to treat
withdrawal symptoms.
C. Wernicke encephalopathy
1. Description
a. Wernicke encephalopathy is a thiamine deficiency disease that occurs in
chronic alcoholics or patients with chronic malnutrition. It has an acute
onset, and its cardinal manifestations are confusion and memory loss,
nystagmus, extraocular movement deficits (most often unilateral or bilateral
sixth nerve palsies), and ataxia, occurring in any combination. Drowsiness,
stupor, and even coma may occur.
b. With prompt treatment, the ocular abnormalities usually clear within days,
but about one fourth of patients will be left with Korsakoff psychosis, in
which the ability to form new memories is impaired far out of proportion to
other higher cortical functions. Any patient with an appropriate
predisposition who has any sign of ataxia, confusion, or extraocular
movement abnormality should be treated for Wernicke encephalopathy.
2. The diagnosis is usually obvious clinically, but it can be confirmed with
erythrocyte transketolase levels. The blood sample must be drawn before the
administration of thiamine to be diagnostic.
3. The treatment is parenteral thiamine. The dosage required is not known, but it
is customary to give 50 to 100 mg IV and IM immediately and then 50 mg/day
PO or IM for 3 days thereafter. Except for extremely rare immediate
hypersensitivity reactions to commercial thiamine preparations, the drug
causes no toxicity.
4. The administration of glucose before thiamine in a severely thiamine-deficient
patient may precipitate Wernicke encephalopathy. It is therefore recommended
that thiamine be given before glucose in any patient in whom thiamine
deficiency is a possibility, including patients with coma of unknown cause.
5. Patients at risk for Wernicke encephalopathy should be treated with
multivitamins, including vitamin B complex, along with thiamine.
XI. Opiates
A. Overdose
1. Description. Depressed mental status, respiratory depression, and pinpoint
pupils are the typical symptoms of acute opiate poisoning. The body
temperature may be subnormal, the blood pressure may be low, and the limbs
and jaw are generally flaccid. With very high doses, convulsions and
pulmonary edema may occur.
2. Emergency treatment is directed at respiratory depression.
a. Patients who are cyanotic, have a respiratory rate below 10/minute, or
cannot protect their own airway are intubated with an orotracheal or
nasotracheal tube and given respiratory assistance with positive pressure
ventilation.
b. Naloxone (Narcan), an opiate antagonist, is given in 0.4-mg increments by
rapid intravenous injection until the patient is respiring normally or until a
total of 10 mg has been given, at which point the diagnosis must be called
into question. Several aspects of the pharmacology of narcotic antagonists
should be kept in mind:
1. The duration of action of naloxone is only 1 to 4 hours, depending on
the dose, which is shorter than the duration of commonly available
opiates. Therefore, after the action of an opiate is reversed with
naloxone, patients require close observation in the event that they
relapse into coma. Repeated doses of naloxone may be required,
especially in methadone intoxication, because of the long duration of
action of methadone (24 to 36 hours).
2. Paradoxically, opiate addicts are more sensitive to narcotic antagonists
than are patients who are not tolerant of opiates. Therefore, narcotic
antagonists are administered in small intravenous doses (naloxone, 0.4
mg) repeated q23min until the desired effect is achieved or until a total
of 10 mg has been given.
3. When given to opiate addicts, narcotic antagonists may precipitate
severe acute withdrawal within minutes of intravenous injection if given
in sufficient doses. Once the antagonist is administered, the withdrawal
syndrome will be extremely resistant to reversal by the administration of
opiates until the effect of the antagonist has waned. Furthermore, in
narcotic addicts, one should not attempt to reverse all of the narcotic
effects immediately with naloxone. Rather, the aim is to return patients'
spontaneous respirations and restore level of consciousness to the point
where they can protect their own airway and make spontaneous
postural adjustments in bed.
4. Narcotic antagonists, including naloxone, have an emetic effect.
Therefore, in comatose patients, the trachea is protected by a cuffed
endotracheal tube.
B. Acute opiate withdrawal
1. Although many of the symptoms of opiate withdrawal are dramatic, the only
potentially dangerous manifestation is dehydration due to nausea, vomiting,
sweating, and diarrhea, combined with failure to take in oral fluids.
Consequently, the essential aspect of management of severe narcotic
withdrawal is the administration of appropriate electrolyte solutions to maintain
intravascular volume and electrolyte balance.
2. At any point in the course of the syndrome, as long as a narcotic antagonist
has not been administered, the symptoms may be rapidly relieved by narcotic
administration. For example, morphine sulfate may be administered by
intravenous injection in small incremental doses of 2 to 5 mg q35min until the
desired effect is achieved.
3. Clonidine, an a-adrenergic agonist and antihypertensive agent, administered
as a single dose of 5 g/kg, will alleviate the symptoms of opiate withdrawal.
The patient may then be treated with a 2-week course of clonidine, beginning
with a dosage of 0.1 mg q46h, as necessary to prevent withdrawal symptoms;
the dosage is adjusted to a maximum of 1.2 mg/day or until oversedation or
hypotension supervenes.
XII. Barbiturates
A. Acute intoxication. Barbiturates do no direct damage to the nervous system, so
every patient who reaches medical attention before the development of CNS
damage from hypoxia or shock has the potential to recover completely with
adequate supportive therapy.
1. Initial evaluation of the patient
a. A classification of the level of barbiturate intoxication is useful in
determining the prognosis.
1. Class 0. Patients who are asleep but can be aroused to purposeful
activity.
2. Class I. Patients who are unconscious but withdraw from noxious stimuli
and whose muscle stretch reflexes are intact (the corneal reflex may be
depressed).
3. Class II. Patients who are unconscious and do not respond to painful
stimuli, but who retain muscle stretch reflexes and have no respiratory
or circulatory depression.
4. Class III. Patients who are unconscious with loss of some or all reflexes,
but with spontaneous respirations and normal blood pressure.
5. Class IV. Patients with respiratory depression, cyanosis, or shock.
b. A complete history of the events surrounding the ingestion is obtained. In
particular, the ingestion of alcohol, other sedatives, or tranquilizers along
with barbiturates is common, accounting for neurologic depression that is
out of proportion to the dose or serum level of barbiturate taken.
c. The initial laboratory evaluation of patients in classes III and IV should
include:
1. Hemogram (hematocrit, WBC count, and differential).
2. Creatinine, BUN, or both.
3. Electrolytes.
4. Glucose.
5. Chest x-ray.
6. Urinalysis.
7. Arterial blood gases.
8. A screen of the serum and urine for toxic substances.
d. Serum barbiturate levels are helpful, but they must be interpreted in the
context of the clinical situation.
1. A high barbiturate level confirms the diagnosis of barbiturate
intoxication.
2. Prognostically, the serum level correlates with the duration of coma
(Table 14-1). However, the usual method of measuring barbiturates
does not distinguish between the different varieties of barbiturates, so
the level must be interpreted with a knowledge of the compound
ingested.
TABLE 14-1. Serum Levels of Commonly Used Barbiturates
3. The drug level may not correlate with the clinical status of the patient in
several situations:
a. In mixed ingestions, the patient's nervous system may be more
depressed than would be predicted from the barbiturate level.
b. Patients who take barbiturates habitually, either therapeutically or as
drugs of abuse, can tolerate much higher levels of barbiturates than
those who have no tolerance for the drug.
c. CNS stimulants (analeptic agents) may temporarily elevate a
patient's mental status.
2. Supportive therapy. The lowest mortality reported (0.8%) was achieved at a
Scandinavian center that employed only supportive measures in the treatment
of barbiturate intoxication.
a. Respiration. Patients in class IV require immediate endotracheal intubation
and respiratory assistance. Patients in classes 0 to III require a cuffed
endotracheal tube if gastric lavage is to be undertaken, if the cough reflex is
absent, or if there is any doubt as to the adequacy of respirations.
Arterial blood gases must be monitored closely to maintain the PO
2
greater
than 80 mm Hg (SO
2
more than 94%). The minimum necessary
concentration of inspired oxygen is used to prevent the development of
oxygen toxicity. In the absence of underlying lung disease, room air should
suffice. In class III patients, care must be exercised in administering oxygen
without respiratory assistance because removal of the hypoxic drive to
ventilation may lead to more pronounced hypoventilation.
b. Cardiovascular. Hypotension occurs in barbiturate poisoning from
decreased intravascular volume, from hypoxia with acidosis, and, at
extremely high doses, from the direct myocardial depressant effects of
barbiturates. The decreased intravascular volume is caused by dehydration
and the escape of fluid from the capillaries because of increased capillary
permeability, which results from both barbiturate toxicity and hypoxia. The
venous pooling of blood that follows may impair cardiac output further.
1. The chief therapy of hypotension consists of correction of hypoxia, if it
exists, and replacement of vascular volume. A CVP line is placed, and
volume-expanding solutions are infused at about 20 mL/min until the
CVP reaches 2 to 6 cm H
2
O.
a. The initial liter of volume replacement may be in the form of a 5%
albumin solution because it will not only expand intravascular volume
rapidly but will also bind some of the circulating barbiturates.
However, this latter effect is significant only for long-acting and
intermediate-acting compounds.
b. An isotonic electrolyte solution may be used after the initial liter of
albumin is infused.
2. Pressors may be required in patients with severe intoxication in which
the blood pressure does not respond to volume replacement. In general,
the pressor chosen is infused at a rate that is sufficient to maintain
systolic blood pressure at about 90 mm Hg, but the urine output is the
ultimate guide. In cases of ingestion of long-acting and
intermediate-acting barbiturates, which are excreted primarily in the
urine, dopamine is the pressor of choice.
c. Other supportive measures
1. Frequent turning, attention to skin care, and other supportive measures
are necessary for comatose patients.
2. Frequent suctioning of intubated patients, pulmonary physical therapy,
and prompt antibiotic treatment of respiratory infections are also
required.
3. Removal of unabsorbed drug from the GI tract is helpful only if the patient is
seen within 3 hours of ingestion. The only exceptions are the rare patients who
ingest large amounts of barbiturates and develop a resultant ileus. Because of
their intestinal hypomotility, these patients retain unabsorbed drug in the gut for
many hours.
a. Emesis should be induced only in patients with mild ingestion who are
awake and able to protect their own airways from aspiration.
b. Gastric lavage may be undertaken in patients who are seen within 3 hours
of ingestion, but it should be performed only with a cuffed endotracheal
tube in place.
c. After the stomach is evacuated, if bowel sounds are present, an osmotic
cathartic may be administered.
1. Sorbitol, 50 g mixed with about 200 mL of water, or magnesium citrate,
200 mL of the standard commercial solution, may be used.
2. Activated charcoal will bind barbiturates and may be given along with
the cathartic; the usual dose is 30 g.
4. Removal of absorbed barbiturate from the body
a. Both forced diuresis and, in the case of phenobarbital, alkalinization of the
urine hasten excretion of barbiturates. However, these methods pose risks
of volume and sodium overload and have failed to improve outcome.
Therefore, they are not generally recommended.
b. Hemodialysis is more effective for removing intermediate- and long-acting
barbiturates than short-acting compounds. The indications for its use are:
1. Renal or hepatic insufficiency severe enough to prevent the elimination
of the drug.
2. Shock or prolonged coma that does not respond to conservative
management.
3. Ingestion of a lethal dose of drug (3 g of a short-acting or 5 g of a
long-acting barbiturate).
4. A serum drug level predictive of prolonged coma (approximately 3.5
mg/dL for short-acting barbiturates or 8 mg/dL for phenobarbital).
5. Complications of barbiturate intoxication result primarily from prolonged coma,
but pneumonia and bladder infections are encountered frequently. Acute renal
failure due to acute tubular necrosis or to nontraumatic rhabdomyolysis can
also occur.
6. Psychiatric evaluation and care are provided to all patients who ingest
overdoses of drugs intentionally.
B. Barbiturate withdrawal. Acute barbiturate withdrawal presents a clinical picture that
is strikingly similar to that of alcohol withdrawal, with tremor, delirium, and seizures
being prominent. Symptoms may be aborted by the intravenous administration of
barbiturates. Pentobarbital may be given in 25-mg increments q510min until
symptoms abate.
In contrast to ethanol withdrawal, the seizures associated with withdrawal from
short-acting barbiturates are often severe. Intravenous barbiturate is the treatment
of choice. Diazepam is generally effective, but the combination of barbiturate and
diazepam frequently produces respiratory depression. After the acute symptoms
are under control, the patient may be withdrawn from barbiturates gradually. As
with ethanol withdrawal, careful attention is directed to fluid and electrolyte
balance, antipyresis, and prevention of infectious complications.
XIII. Poisoning with nonbarbiturate CNS depressants
A. The basic therapy of acute intoxication with all CNS depressants is similar to that
of barbiturate intoxication. The respiratory and cardiovascular systems must be
stabilized, unabsorbed drug is removed by lavage and catharsis, and the
elimination of the drug from the body is speeded by whatever techniques are
feasible for each drug.
B. Individual drugs
1. Glutethimide
a. Description. Glutethimide (Doriden) overdose carries high mortality. The
characteristic fluctuating course is probably caused by delayed absorption
of drug as a result of paralytic ileus. The signs are similar to those of
barbiturate intoxication, except that the drug also possesses anticholinergic
activity, producing dilated pupils.
b. Treatment is primarily supportive, and elimination of the drug may be
hastened by forced diuresis. Hemodialysis against a lipid-containing dialysis
should be employed if the patient has renal failure, fails to respond to
conservative measures, or has ingested a potentially lethal dose (more than
10 g total or blood level higher than 3 mg/dL).
2. Chloral hydrate and ethchlorvynol
a. Description. Chloral hydrate (Noctec) and ethchlorvynol (Placidyl)
intoxications resemble barbiturate intoxication, except that chloral hydrate
may produce constricted pupils.
b. The treatment is identical to that of barbiturate overdose. Hemodialysis is
effective in eliminating both drugs and should be used with the same
indications as with barbiturate overdose.
3. Benzodiazepines
a. Description. Diazepam and chlordiazepoxide taken alone PO generally do
not produce life-threatening intoxication in medically sound patients.
Respiratory depression is of significance only in patients with intrinsic lung
disease or in cases of mixed ingestions.
b. Treatment of benzodiazepine intoxication consists of eliminating
unabsorbed drug from the GI tract and supporting these patients until they
awaken.
XIV. Amphetamines
A. Acute toxicity
1. Description. Acute amphetamine toxicity produces psychosis, hyperpyrexia,
hypertension, dilated pupils, vomiting, and diarrhea. Life-threatening effects of
severe intoxication include cardiac arrhythmias, seizures, coma, and
respiratory arrest. The lethal dose in children is about 5 mg/kg; in adults, it is
about 1.5 g. The serum half-life is a matter of days, so toxic symptoms might
persist for longer than a week.
2. Treatment
a. Sedation with neuroleptics controls psychotic manifestations.
Chlorpromazine, 50 mg PO or IM, may be given initially and q30min until
the patient is calm. Then it is given q46h as necessary.
b. Hyperpyrexia can be controlled with a cooling blanket and vigorous wetting
with towels soaked in tepid water.
c. Arrhythmias are treated with appropriate drugs.
d. Seizures are a short-term problem if no irreversible CNS damage occurs
from hypoxia or cardiac arrest. They should be treated with the usual
measures (see Chap. 6).
e. Unabsorbed drug is removed with emesis, lavage, catharsis, or all three, as
appropriate. Lavage may be of benefit even several hours after ingestion.
f. Acidification of the urine hastens the excretion of amphetamines and should
be employed in the event of severe intoxication. Ammonium chloride may
be administered PO or IV at a total dosage of 8 to 12 g/day, and the urine
pH is checked frequently. Ammonium chloride is contraindicated in shock,
systemic acidosis of any cause, and hepatic failure or portosystemic
shunting.
g. Severe hypertension is best treated with an alpha-blocking agent, such as
phentolamine (Regitine). Moderate hypertension responds to
chlorpromazine.
B. Chronic amphetamine abuse should be treated psychiatrically. Acute
amphetamine withdrawal produces no medical complications, so there is no need
to taper doses. After sudden cessation of habitual amphetamine ingestion, a
prolonged sleep generally occurs, requiring only observation and maintenance of
hydration.
C. Cocaine intoxication is clinically similar to amphetamine overdose, and the
supportive treatment is identical. Cocaine has a much shorter half-life than
amphetamines, and it is metabolized rapidly by the liver. Consequently, forced
diuresis or acidification of the urine is of no benefit. Seizures, stroke, subarachnoid
hemorrhage, and cardiovascular collapse can occur as a result of cocaine
intoxication.
D. Phencyclidine (PCP) intoxication produces agitation and psychosis associated
with hypertension, tachycardia, and hyperthermia. Cerebellar ataxia and
nystagmus may be prominent. Supportive care is provided as necessary. The
bizarre behavior is managed with a quiet environment, benzodiazepines, and
neuroleptics. Phencyclidine has a prolonged biological half-life, up to 50 hours, so
that prolonged treatment may be required. There is an enterohepatic recirculation
of phencyclidine, so gastric aspiration and cholestyramine administration hasten
elimination of the drug, as may forced diuresis. Acidification of the urine is of no
value.
XV. Polycyclic antidepressants
A. The acute toxic effects of polycyclic antidepressants resemble atropine poisoning,
with hyperpyrexia, dilated pupils, hypertension, tachycardia, and dryness of the
skin and mucous membranes. The life-threatening manifestations are coma,
seizures, cardiac arrhythmias, and cardiac conduction defects.
B. Supportive therapy
1. The initial emergency treatment is the same as for any overdose: stabilization
of respiratory and cardiac status and elimination of unabsorbed drug from the
GI tract.
2. Cardiac conduction defects and arrhythmias are prominent in tricyclic
intoxication. The patient should be on a cardiac monitor, a temporary
transvenous pacemaker should be readily available, and the patient should be
placed in an intensive or coronary care unit. Lidocaine is effective for
ventricular arrhythmias. Propranolol should be used with extreme care if a
conduction defect is present.
3. Hyperpyrexia can be controlled with a cooling blanket or by vigorous rubdowns
with towels soaked in tepid water. Chlorpromazine may increase the
effectiveness of hypothermic methods.
4. Severe hypertension responds to the administration of an alpha blocker such
as phentolamine.
C. Physostigmine is reported to antagonize the CNS toxicity of tricyclics and other
anticholinergics.
1. Physostigmine injection may serve as a diagnostic test to confirm
anticholinergic ingestion. Physostigmine, 1 mg, is injected SC, IM, or slowly IV,
which will produce peripheral cholinergic signs within 30 minutes if no
anticholinergics have been ingested. These signs include bradycardia,
salivation, lacrimation, and pupillary constriction. In a patient who has ingested
anticholinergics, the injection will produce no significant effect.
2. For the treatment of anticholinergic overdose, 1-mg doses of physostigmine
are injected IM or slowly IV at 20-minute intervals until 4 mg has been
administered or cholinergic signs appear.
3. Indications. Physostigmine is most effective against the toxic delirium of
anticholinergic overdose. It will occasionally awaken a comatose patient.
However, physostigmine is itself toxic, so its use should be reserved for
patients with life-threatening complications of tricyclic overdose: respiratory
depression, intractable seizures, or severe hypertension.
4. Side effects. If excessive physostigmine is administered, cholinergic side
effects may in themselves exert harmful effects. Excessive respiratory
secretions, salivation, and bronchospasm can interfere with pulmonary
function. Vomiting, abdominal cramps, and diarrhea can also occur. Excessive
cholinergic effects may be counteracted with atropine (see sec. IX.D.5).
Physostigmine at toxic doses or administered rapidly IV can cause seizures.
5. The duration of action of physostigmine is only 1 to 2 hours, whereas tricyclics
persist over 24 hours. Therefore, the patient must be monitored and repeated
doses are administered as necessary.
D. Tricyclic antidepressants are cleared mainly by the kidneys, so forced diuresis is
effective. Dialysis is of no additional benefit except in renal failure.
XVI. Salicylate intoxication
A. Description
1. In the United States salicylate is the medicine that most frequently produces
clinically significant intoxication. The most common source is aspirin, but
sodium salicylate and oil of wintergreen are also common causes.
a. Aspirin. Adult aspirin tablets contain 325 mg of aspirin, whereas children's
tablets contain 80 mg. Some so-called extra-strength aspirin tablets contain
as much as 750 mg.
b. Oil of wintergreen contains methyl salicylate in a concentration of about 0.7
g/mL. It is highly toxic, and 1 or 2 tsp can be a fatal dose for a small child.
2. The toxic dose of salicylate is about 250 mg/kg in a healthy person. Lower
doses of both methyl salicylate and aspirin can be intoxicating in a person who
is dehydrated or in renal failure.
3. Pharmacokinetics
a. Salicylates are well absorbed from the GI tract, over 50% of a therapeutic
dose being absorbed within 1 hour of ingestion. Poisoning has occurred
from oil of wintergreen from cutaneous absorption.
b. Once absorbed, aspirin is rapidly hydrolyzed to salicylic acid.
c. Salicylic acid is variably bound to albumin. At toxic levels, the serum
albumin binding sites are 100% saturated.
d. Salicylic acid is excreted both unchanged and as its glucuronidated product
in the urine. Salicylic acid has a pK
a
of about 3, so it can be trapped in the
alkaline solution. Thus, alkalinization of the urine can increase salicylic acid
excretion by as much as five-fold.
4. Signs and symptoms of toxicity
a. Central nervous system abnormalities dominate the clinical picture.
1. The earliest signs are tinnitus and impaired hearing.
2. Agitation progressing to delirium, stupor, and coma results from severe
intoxication.
3. Seizures can occur as a direct effect of salicylate toxicity or as a
secondary manifestation of hypoglycemia or effective hypocalcemia
(see sec. XVI.A.4.b).
4. Salicylates in toxic doses stimulate respiration and produce hyperpnea,
usually with tachypnea and respiratory alkalosis.
5. With extremely high doses, respiratory depression occurs.
b. Metabolic derangements
1. Salicylates interfere with carbohydrate metabolism.
a. Hypoglycemia may occur in young children.
b. The brain uses glucose inefficiently and may experience a relative
hypoglycemia, even with a normal blood glucose.
c. Mild to moderate hyperglycemia is common.
2. In severe intoxication, metabolic acidosis occurs with an increased
anion gap and organic aciduria.
3. The organic aciduria, with or without glycosuria, produces an osmotic
diuresis, which in turn produces dehydration.
4. The respiratory alkalosis, when prolonged, has secondary effects on
electrolyte metabolism.
a. There is renal sodium and potassium wasting. The hypokalemia
renders the metabolic acidosis unresponsive to alkali therapy until
the potassium is repleted.
b. The respiratory alkalosis produces decreased unbound serum
calcium levels, which can lead to tetany and seizures.
5. SIADH has been reported in association with salicylate poisoning.
c. Effects on blood clotting
1. Salicylate in toxic concentrations exerts an antiprothrombin effect, with
prolongation of the PT and diminished factor VII activity.
2. Salicylates interfere with platelet function, even in nontoxic doses.
3. Salicylates are locally irritating to the gastric mucosa and can lead to GI
hemorrhage.
d. Hepatotoxicity might elevate the liver enzymes, which can lead to confusion
with Reye syndrome in children or with hepatic encephalopathy in adults.
e. Noncardiac pulmonary edema has been reported.
B. Diagnosis
1. Salicylate intoxication occurs frequently in 3 groups:
a. Children under 5 years of age, as a result of accidental ingestion.
b. Adolescents and young adults, as a result of intentional ingestion.
c. Unintentional overdose in patients taking salicylates for rheumatic disease.
2. The diagnosis is obvious with an adequate history of ingestion; however, it is
frequently masked by chronic therapeutic overdose if the physician is unaware
that the patient is taking salicylates.
3. The diagnosis is considered in patients with mental status changes,
hyperpnea, and respiratory alkalosis, with or without superimposed metabolic
acidosis.
4. Serum salicylate levels confirm the diagnosis. A level higher than 30 mg/dL
may produce early symptoms of salicylism; mental changes and hyperpnea
occur at levels higher than 40 mg/dL. With chronic ingestion, blood levels
correlate poorly with the clinical status of the patient but will nevertheless serve
to make or to rule out the diagnosis.
5. The ferric chloride test serves as a rapid screening test for the presence of
salicylic acid.
a. A few drops of a 10% solution of ferric chloride are added to 3 to 5 mL of
acidified urine. A purple color indicates a positive result.
b. The test is extremely sensitive, so a positive result is not diagnostic of
salicylate intoxication.
c. Ferric chloride reacts only with salicylic acid, not with aspirin. Therefore, it
cannot be used to test for the presence of aspirin in gastric contents.
d. Phenothiazines react with ferric chloride, but they tend to give a pink rather
than a purple color.
e. Acetoacetic acid, present in ketosis, will react with ferric chloride. Its
presence may be excluded, however, if the urine is boiled and acidified
before the ferric chloride is added.
6. The initial laboratory evaluation of a patient with salicylate intoxication should
include the following:
a. Serum salicylate level is of prognostic importance and gives a baseline
value with which to judge the effects of therapy.
b. Patients with intentional overdoses should have blood or urine (or both)
screened for the presence of other toxic substances.
c. CBC, including platelet count.
d. Stool and gastric contents are tested for the presence of occult blood.
e. Arterial blood gases and pH.
f. BUN (or creatinine), electrolytes, calcium, and phosphorus.
g. Liver function tests, including SGOT, LDH, alkaline phosphatase, total
bilirubin, total protein, and albumin.
h. Prothrombin time and partial thromboplastin time.
i. Chest x-ray.
j. ECG, giving particular attention to signs of hypokalemia or hypocalcemia.
k. Urinalysis with specific gravity. If the serum sodium is low and SIADH is a
possibility, urine sodium concentration and osmolality are measured.
C. Acute management
1. Routine emergency measures for the treatment of drug intoxications
a. Protect the airway and support respiration, if necessary.
b. Empty the GI tract of unabsorbed drug.
1. Forced emesis is used if the patient is alert.
2. Gastric lavage is performed after tracheal intubation with a cuffed
endotracheal tube if patients are stuporous, in coma, or unable to
protect their own airway.
3. Activated charcoal is given as 200 to 300 mL of a thick suspension to
bind unabsorbed salicylates.
4. Cathartics are administered after the charcoal has been given.
2. Fluid and electrolyte management is used to treat shock, to maintain urine
output, and to restore electrolyte and acid-base balance.
3. Alkalinization of the urine by the infusion of sodium bicarbonate hastens the
excretion of salicylic acid. However, in practice the technique has no value.
a. In elderly patients and those with abnormal hearts, the risks of increased
sodium load are not justified by the expected benefits of alkalinization of the
urine.
b. In patients with metabolic acidosis, the urine cannot be alkalinized except
with massive and dangerous quantities of alkali.
c. In patients with respiratory alkalosis and alkalemia, the administration of
alkali is contraindicated.
4. Hypoglycemia
a. In young children, after blood has been drawn, 50% D/W (0.5 mL/kg IV) is
administered immediately.
b. Only glucose-containing fluids are used for maintenance.
5. Hemorrhagic complications
a. In severe salicylate poisoning, vitamin K, 50 mg IV, is given after an initial
PT has been measured. The vitamin K is repeated as necessary to
maintain a normal PT.
b. If bleeding occurs or if the PT is found to be longer than twice the control
value, fresh-frozen plasma or concentrates of clotting factors (Konyne) are
given.
c. Platelet transfusion might be required to achieve control of hemorrhage
because the patient's own platelets will have a disordered function.
d. In comatose patients, antacids and histamine antagonists may be given by
nasogastric tube in an effort to prevent gastric hemorrhage.
6. Tetany may be treated with the intravenous infusion of calcium gluconate in
1-g doses, repeated as often as necessary.
7. Seizures
a. Hypoglycemia and hypocalcemia are treated appropriately (see sec.
XVI.C.4 and sec. XVI.C.6). Other metabolic causes of seizures, such as
hyponatremia and hypoxia, must also be considered.
b. Seizures that occur as a direct toxic effect of salicylate are a poor
prognostic sign, generally indicating the necessity for hemodialysis to
hasten elimination of the salicylate. Diazepam, given IV, or muscle
paralysis and respiratory support may be used for the temporary control of
seizures until the salicylate level is lowered.
8. Fever can be treated with tepid water baths.
9. Methods to hasten the elimination of salicylates
a. Forced diuresis is of little benefit, and the patient should not be subjected to
a larger fluid load than necessary to achieve a reasonable urine output.
b. Alkalinization of the urine is discussed in sec. XVI.C.3. Despite its theoretic
advantages, it has no practical use in salicylate poisoning.
c. Peritoneal dialysis is about as efficient as the normal kidneys in eliminating
salicylate from the blood. Its primary use is in the setting of renal failure.
The addition of albumin to the dialysis solution hastens the elimination of
salicylate, but there is no evidence that its benefit outweighs the expense
and added complexity of the dialysis.
d. Hemodialysis is the most efficient means available for the elimination of
salicylate. The generally accepted indications for hemodialysis are:
1. Salicylate level higher than 70 mg/dL or known absorption greater than
5 g/kg.
2. Profound coma with respiratory failure.
3. Severe metabolic acidosis.
4. Renal failure.
5. Failure to respond to conservative therapy.
XVII. Hyperthermia
A. Pathophysiology. Rises in body temperature may be due to excessive heat gain,
insufficient heat loss, or both.
1. Excessive heat gain
a. Exercise.
b. High ambient temperatures.
c. Increased metabolic rate.
d. Release of pyrogens (e.g., by infection).
e. Neuroleptic malignant syndrome (see sec. XVII.B.4).
2. Defective heat loss
a. Excessively warm clothing.
b. Increased humidity.
c. Low wind velocity.
d. Advanced age.
e. Anticholinergic drugs (e.g., phenothiazines, tricyclic antidepressants).
f. Sympathetic autonomic failure with decreased or absent sweating due to:
1. Elevated body temperatures.
2. Spinal cord transection above T1.
B. Categories of heat disorders
1. Heat cramps
a. Description. Muscle or abdominal cramps associated with exercise in warm,
ambient environments are commonly seen.
b. Treatment. Rest and oral electrolyte replacement are usually adequate.
2. Heat exhaustion (heat prostration, exertional heat injury)
a. Description. Heat exhaustion is marked by moderately elevated body
temperatures (i.e., 39.5C to 42.0C) and a neurologic syndrome
characterized by headache, piloerection, hyperventilation, nausea,
vomiting, unsteady gait, and confusion. Sweating remains intact in patients
with heat exhaustion, so the skin is wet and cool.
b. Treatment. Patients should be admitted to the hospital for treatment
because some may progress to heat stroke. Rest and parenteral
rehydration are usually adequate to reverse the syndrome.
3. Heat stroke
a. Description. When body temperatures rise high enough, CNS mechanisms
for control of heat loss might fail. When this occurs, there is a very rapid
further rise in body temperature, which is a life-threatening medical
emergency. Such patients might be diaphoretic or have hot, dry skin
(sweating having failed) and elevated body temperatures (higher than 41C,
ranging as high as 43C). The level of consciousness becomes deranged,
often quite suddenly, so that patients can deteriorate rapidly from confusion
or delirium to deep coma, often with seizures. Cerebral edema occurs,
which can lead to widespread cerebral ischemia and eventually brain death.
Other abnormalities include circulatory failure, disseminated intravascular
coagulation, severe dehydration, and hepatic necrosis. Electrolyte
abnormalities, most commonly respiratory alkalosis and hypokalemia, are
common.
b. Treatment
1. Surface cooling should be started immediately. The most effective
means is to use evaporative cooling by spraying the naked patient with
tepid water and using a powerful fan to maintain a flow of air over the
patient's body. Alternatively, immersion in ice or cold water may be
used.
2. Intravenous fluids should be administered with care, as typically the
patient is normovolemic but has redistributed fluid to peripheral,
vasodilated tissues. With cooling, fluid will redistribute and cardiac
output will be restored.
3. A bladder catheter should be placed and urinary output carefully
monitored.
4. Isoproterenol via constant infusion (1 g/minute) may be used to
increase cardiac output.
5. Avoid a-adrenergic drugs (e.g., norepineprhine) that produce
vasoconstriction and thus retard heat loss.
6. Avoid anticholinergic drugs (e.g., atropine) that retard the return of
sweating.
7. Monitoring of ICP using a dural bolt might be necessary if
consciousness does not return promptly.
8. Treat increased ICP as outlined in Chap. 1, sec. VII.D.
9. Seizures may be treated with phenytoin or phenobarbitol as outlined in
Chap. 6.
10. If disseminated intravascular coagulation develops, heparin, 1,000
units/hour by constant infusion, may be used.
4. Neuroleptic malignant syndrome (NMS)
a. Description. NMS is characterized by hyperthermia, muscular rigidity, and
altered mental status. It occurs in patients taking neuroleptic medications
or, rarely, in association with withdrawal of L-dopa or other dopaminergic
agonists.
1. Although a preponderance of reported cases have occurred with the use
of potent neuroleptics such as haloperidol, the syndrome has been
associated with virtually all dopamine receptor antagonists and
dopamine-depleting agents (e.g., reserpine).
2. NMS may occur immediately after the first dose of a neuroleptic or in a
patient who has been taking neuroleptics for many years. Many cases
are associated with a rapid increase in dose.
3. Laboratory abnormalities may include an elevated serum creatine
kinase, elevated white blood cells, and abnormal liver function tests.
The CSF is normal, and the EEG shows generalized slowing. The CT
scan and MRI are normal.
4. Life-threatening complications of NMS include respiratory failure
secondary to muscular rigidity and renal failure secondary to
myoglobinuria.
b. Prevention. NMS is commonly precipitated by dehydration, fever, or
environmental exposure to high temperatures in patients taking
neuroleptics. These precipitants should be especially avoided in patients
taking neuroleptics or dopamine-depleting agents.
In addition, withdrawal of dopamine agonists, including carbidopa-L-dopa
(Sinemet), should be carried out gradually.
c. Treatment
1. Immediate withdrawal of all neuroleptic medications (including those
administered as antiemetics) or dopamine-depleting agents (e.g.,
reserpine, tetrabenazine) is essential at the earliest sign of NMS. In
cases associated with withdrawal of dopamine agonists (e.g., L-dopa,
bromocriptine, pergolide), reinstitution of dopaminergic therapy and
more gradual withdrawal should be undertaken.
2. The mainstay of management is supportive care.
a. Rehydration and maintenance of adequate urine flow.
b. Lowering of body temperature with antipyretics, cooling blanket, or
tepid water bath as required.
c. Protection of the airway by endotracheal intubation as required.
d. In unusual cases, respirator support with muscular paralysis might
be required to maintain ventilation in the face of extreme muscular
rigidity.
3. The direct-acting muscle relaxant dantrolene is widely used in severe
cases of NMS, although there are no systematic studies documenting its
benefit. Muscle relaxation may facilitate nursing care and aid in lowering
body temperature. In addition, to the extent that muscle rigidity
contributes to muscle necrosis and myoglobinuria, muscle relaxation
can help prevent renal failure. However, it is clear that muscular rigidity
is not the only cause of muscle damage in NMS and that hyperthermia
may persist in spite of muscle paralysis. Dosages of dantrolene
employed have varied from 1 to 10 mg/kg/day IV or by nasogastric tube
given in 4 divided doses. Hepatic toxicity occurs with dosages above 10
mg/kg/day.
4. The dopamine agonist bromocriptine has also been widely used and
has theoretical support. However, there are no systematic studies
documenting its benefit in NMS. Dosages employed have varied from
2.5 to 10.0 mg IV or by nasogastric tube q46h.
5. Electroconvulsive therapy has shown effectiveness in anecdotal reports.
Its role in the treatment of NMS is undefined.
d. Prognosis. Although mortality rates from NMS as high as 15% to 20% are
quoted in the literature, it is clear that with adequate supportive care the
mortality is much less. To prevent relapse of NMS, neuroleptic medications
must not be reinstituted until the syndrome has resolved completely.
Patients may require sedation with benzodiazepines in the meantime. After
resolution of all clinical signs of NMS, neuroleptics may be cautiously
reinstituted. NMS is not an allergic reaction to neuroleptics, and the
occurrence of NMS is not an absolute contraindication to neuroleptic use.
XVIII. Nutritional deficiency and excess
A. Vitamin deficiency
1. Thiamine
a. Description
1. Thiamine deficiency is associated with chronic alcohol abuse (see sec.
X.C) and with severe nutritional deficiency, as occurs in patients on
long-term parenteral nutrition.
2. The acute syndrome of thiamine deficiency in adults, known as
Wernicke encephalopathy, is characterized by nystagmus and
limitations of extraocular movements, gait ataxia, and mental confusion.
b. Prevention
1. Patients receiving parenteral nutrition should have thiamine
supplementation of 2 to 10 mg/day, depending on carbohydrate intake.
2. Chronic alcoholics and other chronically malnourished patients should
receive supplementation with thiamine, 50 mg PO daily, as well as with
daily multivitamins.
3. Hemodialysis patients should all receive regular thiamine
supplementation.
c. Treatment
1. Acute Wernicke encephalopathy is an emergency (see sec. X.C).
2. Patients are administered thiamine, 50 mg IV and 50 mg IM,
immediately. They then receive thiamine, 50 mg IM daily for 3 days, and
long-term supplementation with thiamine, 50 mg IM or PO daily.
3. Patients should also be supplemented with vitamin B complex, either
PO or parenterally as appropriate.
2. Cobalamin (vitamin B
12
) deficiency (pernicious anemia)
a. Description
1. Cobalamin deficiency is usually associated with an acquired defect in
intestinal absorption of the vitamin due to intrinsic factor deficiency.
Rarely, patients on highly restricted diets (so-called vegans) develop
cobalamin deficiency from inadequate intake of the vitamin. There are
rare inborn errors of metabolism that affect cobalamin absorption or
transport, or the activity of its target enzymes that duplicate various
aspects of cobalamin deficiency. These syndromes generally present in
early childhood. Finally, the recreational use or occupational exposure
to the anesthetic gas nitrous oxide can duplicate all of the clinical
features of cobalamin deficiency.
2. The classic picture of cobalamin deficiency consists of megaloblastic
anemia, subacute combined degeneration of the spinal cord
(demyelination of the posterior columns and corticospinal tracts), optic
neuropathy (termed tobacco amblyopia, since it is more common in
smokers) and mental status changes. Any of these can occur in
isolation. There is increasing recognition that personality change and
dementia may be the only manifestation of cobalamin deficiency,
mandating more aggressive screening. The administration of folate to
cobalamin-deficient patients may predispose to the development of
neurologic signs prior to hematologic abnormalities. Cobalamin and
folate deficiency both cause elevations of plasma homocystine
concentrations and may be a risk factor for cerebrovascular disease.
b. Diagnosis
1. Serum cobalamin. Some patients become symptomatic even with serum
cobalamin concentrations in the low-normal range (150 to 250 pmol/L).
2. Elevated serum concentrations of methylmalonic acid and total serum
homocysteine help substantiate the diagnosis in questionable cases.
These tests are expensive; their role in the screening of patients with
nonspecific neuropsychiatric symptoms or signs and borderline or
low-normal serum cobalamin levels is undefined.
3. Intrinsic factor deficiency can be confirmed by a Schilling test. Some
patients may absorb free cobalamin normally and have a normal
standard Schilling test, but absorb cobalamin poorly from food. These
cases can be diagnosed by administering the oral cobalamin with egg
white (the food Schilling test).
4. The presence of antiintrinsic factor or antiparietal cell antibodies
confirms the diagnosis of pernicious anemia.
c. Treatment
1. All patients suspected of cobalamin deficiency should have therapy
initiated immediately after serum has been drawn for the determination
of cobalamin concentration. Cobalamin administration does not
invalidate the Schilling test.
2. Cyanocobalamin or hydroxycobalamin, 1,000 g IM, is administered
daily for 5 to 10 days, then weekly for 4 dosages, and then monthly for
the remainder of the patient's life. Lower doses may suffice, but
clinicians generally use high doses for neurologically symptomatic
patients. There is evidence that hydroxycobalamin is more effective than
cyanocobalamin in patients with optic nerve involvement.
3. Hematologic measurements (hemoglobin, mean corpuscular volume,
and reticulocyte count) and serum cobalamin levels are followed
periodically to verify the therapeutic response.
4. Severely anemic patients may develop hypokalemia as the anemia is
corrected; in these patients the serum potassium concentration should
be measured regularly over the first 2 weeks of therapy.
5. Folate administration can cause neurologic deterioration in
cobalamin-deficient patients. Therefore, folate should be withheld until
cobalamin stores are repleted (1 to 2 weeks of daily cobalamin
injections).
3. Pyridoxine (vitamin B
6
)
a. Description
1. Pyridoxine deficiency syndromes are rare. They occur predominantly in
adults administered drugs that antagonize the action of pyridoxine, most
notably the antituberculous agent isoniazid. Other drugs that can induce
pyridoxine deficiency include hydralazine, cycloserine, penicillamine,
and pyrazinamide. Purely dietary deficiency of pyridoxine is extremely
rare.
2. Pyridoxine deficiency produces a symmetric, distal sensory and motor
neuropathy. Rarely, seizures and encephalopathy occur.
b. Treatment
1. Adults taking isoniazid, 300 mg daily, should be supplemented with
pyridoxine, 50 mg daily.
2. Symptomatic pyridoxine deficiency due to isoniazid is treated with
pyridoxine, 100 to 200 mg IM or PO daily for 2 weeks, followed by
supplementation with 50 mg daily.
3. Nutritional pyridoxine deficiency, in the absence of pyridoxine
antagonists, requires doses of 2.5 to 5.0 mg daily.
4. The excessive ingestion of pyridoxine can produce a sensory
neuropathy, so that doses in excess of those necessary to correct the
deficiency should be avoided.
5. Pyridoxine is a cofactor for the decarboxylation of L-dopa, so pyridoxine
supplementation of patients taking L-dopa will decrease the
antiparkinsonian effect of the L-dopa. Pyridoxine-free multivitamin
preparations are available for such patients. Patients taking L-dopa in
combination with a decarboxylase inhibitor (e.g., Sinemet) may take
pyridoxine if indicated, since the decarboxylase inhibitors block the
action of pyridoxine on L-dopa metabolism.
4. Vitamin E (a-tocopherol)
a. Description
1. Vitamin E is a fat-soluble vitamin; deficiency states therefore occur with
chronic malabsorption syndromes. This can occur in association with
hereditary disorders such as abetalipoproteinemia, with intestinal
resections, and with hepatobiliary disease.
2. Clinical manifestations include peripheral neuropathy, ataxia, and
proximal muscle weakness. The syndrome resembles spinocerebellar
degeneration.
b. Treatment
1. Dosage. In adults, 60 to 75 units of vitamin E, PO or IM, generally
suffices. Dosage should be adjusted to achieve plasma vitamin E levels
within the normal range.
2. Excessive doses of vitamin E have been reported to produce a
reversible myopathy.
3. It may be necessary to supplement other fat-soluble vitamins (vitamins
A, D, and K) as well.
B. Hypervitaminoses
1. Description. The administration of excessive doses of vitamins therapeutically
and the ingestion of megadoses of vitamins by food faddists have introduced
syndromes of hypervitaminosis into medicine.
a. Pyridoxine toxicity produces a predominantly sensory neuropathy.
b. Hypervitaminosis E can cause myopathy.
c. Hypervitaminosis A is associated with benign intracranial hypertension.
2. The treatment of these conditions is cessation of vitamin supplementation. The
sensory neuropathy of pyridoxine intoxication and the myopathy of
hypervitaminosis E are both reversible. Benign intracranial hypertension
associated with hypervitaminosis A resolves over several weeks once the
vitamin excess is corrected, although permanent visual loss can occur.
Selected Readings
Hepatic Encephalopathy
Cordoba J , Blei AT. Treatment of hepatic encephalopathy. Am J Gastroenterol 1997;92:1429.
Green A, Hall SM. Investigation of metabolic disorders resembling Reye syndrome. Arch Dis Child
1992;67:1313.
Green CL, Blitzer MG, Shapira E. Inborn errors of metabolism and Reye syndrome: differential diagnosis.
J Pediatr 1988;113:156.
Hou J -W, Chou S-P, Wang T-R. Metabolic function and liver histopathology in Reye-like illness. Acta
Pediatr 1996;85:1053.
Riordan SM, Williams R. Treatment of hepatic encephalopathy. N Engl J Med 1997;337:473.
Renal and Electrolyte Disorders
Diringer MN. Management of sodium abnormalities in patients with CNS disease. Clin Neuropharmacol
1992;15:427.
Harrington MR. Cerebral salt wasting syndrome: a review. Neurosurgery 1996;38:152.
Laureno R, Karp BI. Myelinolysis after correction of hyponatremia. Ann Intern Med 1997;126:57.
Acute Intermittent Porphyria
Crimlisk HL. The little imitator-porphyria: a neuropsychiatric disorder. J Neurol Neurosurg Psychiatry
1997;62:319328.
Kappas A, Sassa S, Galbraith RA, Nordman Y. The porphyrias. In Scriver CR, Beaudet AL, Sly WS, Valle
D., eds. The metabolic and molecular bases of inherited disease, 7th ed. New York: McGraw-Hill,
1995;21032160.
Heavy Metal Poisoning
Angle CR. Childhood lead poisoning and its treatment. Annu Rev Pharmacol Toxicol 1993;32:409.
Chao J , Kikano GE. Lead poisoning in children. Am Fam Physician 1993;47:113.
Mortensen ME, Walson PD. Chelation therapy for childhood lead poisoning: the changing scene in the
1990s. Clin Pediatr 1993;32:284.
Carbon Monoxide Poisoning
Ilano AL, Raffin TA. Management of carbon monoxide poisoning. Chest 1990;97:165.
Drug and Alcohol Intoxication
Brust J CM. Neurological aspects of substance abuse. Boston: Butterworth-Heineman, 1993.
Brust J CM. Acute neurologic complications of drug and alcohol abuse. Neurol Clin 1998;16:503.
Hyperthermia
Caroff SN, Mann SC. Neuroleptic malignant syndrome. Med Clin North Am 1993;77:185.
Rosebush P, Stewart TA. Prospective analysis of 24 episodes of neuroleptic malignant syndrome. Am J
Psychiatry 1989;146:717.
Tek D, Olshaker J S. Heat illness. Emerg Med Clin North Am 1992;10:299.
Nutritional Deficiency
Green R, Kinsella LJ . Current concepts in the diagnosis of cobalamin deficiency. Neurology
1995;45:1435.
Malinow MR. Plasma homocyst(e)ine and arterial occlusive diseases: a mini-review. Clin Chem
1994;40:173.
Savage DG, Lindenbaum J . Neurological complications of acquired cobalamin deficiency: clinical
aspects. Bailliere's Clin Haematol 1995;8:657.
Shevell MI, Rosenblatt DS. The neurology of cobalamin. Can J Neurol Sci 1992;19:472.
Victor M, Adams RD, Collins GH. The Wernicke-Korsakoff syndrome and related neurological disorders,
2nd ed. Philadelphia: FA Davis Company, 1989.
CHAPTER 15. MOVEMENT DISORDERS
Manual of Neurologic Therapeutics
CHAPTER 15. MOVEMENT DISORDERS
Robert D. Helme
Motor control systems
Pyramidal and parapyramidal pathway dysfunction
Cerebellar dysfunction
Basal ganglia dysfunction
Tremor
Asterixis
Myoclonus
Hyperekplexia
Restless legs syndrome
I. Motor control systems. The rational management of movement disorders
requires an understanding of the anatomic and physiologic substrate necessary for
normal movement. Benefit from therapeutic maneuvers is often limited by our
rudimentary, but steadily improving, knowledge of human anatomy and physiology.
A. Pyramidal system. Motor control is effected by upper motor neurons that arise
in sensorimotor areas of the cerebral cortex, descend in the posterior limb of the
internal capsule, cerebral peduncle, and pyramidal tract and then decussate in the
medulla before entering the contralateral corticospinal tract to influence the lower
motor neurons of the brainstem and spinal cord directly or through local
interneurons. To this pyramidal system are added local feedback systems in the
spinal cord whereby the alpha motor neuron is influenced through the gamma
loop, sensory input from the same and nearby segmental levels, and a variety of
segmental reflexes controlling actions such as postural support, stepping and
flexor withdrawal. This pyramidal system arises from much of the posterior frontal
lobe, the sensory strip of the parietal lobe, and other areas of sensorimotor cortex.
An important component of this system is the supplementary motor cortex where
premovement signals are generated.
B. A parapyramidal system also arises in part from the same motor areas as the
pyramidal system and acts on the lower motor neuron through multisynaptic
pathways through the red nucleus (rubrospinal system), tectum (tectospinal
system), and reticular formation of pons and medulla (reticulospinal system).
The fourth major parapyramidal system is the Vestibulospinal system, which has
its major input from vestibular, reticular, and cerebellar sources.
The neurotransmitters specific to these systems are not well characterized
although glutamate, glycine, and acetylcholine appear to be important.
C. The extrapyramidal system, centered on the basal ganglia, influences motor
control through these pyramidal and parapyramidal pathways, generally by means
of input into the motor areas of the cerebral hemisphere via the thalamus and
supplementary motor cortex (see sec. IV). The cerebellum influences the same
pathways, especially through the vestibulospinal systems and through relays in
the thalamus that innervate the same motor areas of the cerebral cortex (see sec.
III).
II. Pyramidal and parapyramidal pathway dysfunction. The clinical effect of
lesions in the descending motor control system can best be summarized as paralysis
and spasticity.
A. Paralysis may be complete (plegia) or partial (paresis), and may be manifest only
as loss of hand and foot dexterity. There is no chemotherapy that will improve
paralysis. Physical therapy is of benefit because it provides retraining of the
remaining neuromuscular apparatus and prevents contracture.
B. Spasticity is characterized by increased limb tone in proportion to the velocity of
muscle stretch, which results in clasp-knife rigidity, exaggerated tendon jerks with
clonus and reflex spread, and extensor or Babinski responses in the lower
extremities. Spasticity predominates in antigravity muscles; flexors of the arms
and extensors of the legs. It may be manifested only as loss of dexterity. Flexor
spasms are also a common manifestation of spasticity that result from unopposed
stimulation of cutaneous afferent impulses to the spinal cord. The initial approach
to patients with spasticity is to determine how much spasticity interferes with and
contributes to their functional state. The presence of pain in association with flexor
spasms also needs to be assessed. Basic management requires attention to
positioning, avoidance of noxious stimulation, and a daily stretching program.
C. Chemotherapy of spasticity
1. Pharmacokinetics. The major chemotherapeutic agents of use in spasticity
are benzodiazepines, baclofen, dantrolene, and tizanidine (Table 15-1).
TABLE 15-1. Drugs Useful for Spasticity
a. Benzodiazepines appear to act in the spinal cord, enhancing postsynaptic
effects of g-aminobutyric acid (GABA), which increases presynaptic
inhibition. The site of action is a receptor near the GABA receptor. These
drugs also act at brainstem sites. The major benzodiazepine drug used is
diazepam (Valium).
b. Baclofen (Lioresal), an analog of GABA, is thought to act through a
bicuculline-insensitive GABA receptor to produce inhibition. It also reduces
gamma efferent activity and thus reduces spindle bias.
c. Diazepam and baclofen are useful for reducing spasticity associated with
primary afferent stimulation but are not of major benefit for neuronal
activation of pyramidal and parapyramidal pathways. These pyramidal and
parapyramidal pathways probably utilize the excitatory neurotransmitters
aspartate and glutamate or the inhibitory neurotransmitter glycine.
d. Dantrolene sodium (Dantrium) acts to suppress calcium release from the
sarcoplasmic reticulum of the muscle fiber and thus interferes with
excitation-contraction coupling. It follows that dantrolene sodium will
produce benefit only in proportion to an increasing degree of weakness.
e. Tizanidine affects spinal polysynaptic reflexes by agonist activity at
noradrenergic a
2
receptors. This impairs excitatory amino acid release from
spinal interneurons and inhibits facilitatory coerulospinal pathways.
2. Dosage. Because the drugs act at different sites, it is possible to use
combination therapy with doses low enough to avoid major side effects. In
using these drugs one should realize that spasticity may be necessary for gait
training in the rehabilitation of a patient with an upper motor neuron lesion.
Without rigid legs, splinting may be useless. These drugs are not of proven
benefit in treating the spasticity of motor neuron disease or stroke; trials have
been done predominantly in patients with intrinsic spinal cord disease, multiple
sclerosis, and cerebral palsy. Recommendations for use of the 3 major drugs
are as follows:
a. Diazepam (Valium) is used in relatively high dosages, starting with 2 mg
t.i.d. and increasing, as tolerated, to 60 mg/day. There is no absolute
maximum dosage. Common side effects include weakness, sedation, and
dizziness. Paradoxical insomnia, anxiety, and hostility may be serious
long-term side effects and more often than not limit its use. Narrow-angle
glaucoma is an uncommon contraindication. Alcohol use should be limited.
Transitory hepatic dysfunction and blood dyscrasias have been
encountered. Particular care is required in initiating and terminating therapy
in patients on anticoagulant medication.
b. Baclofen (Lioresal) is used particularly in patients with painful flexor
spasms. The starting dosage is 5 mg b.i.d., which is increased as tolerated
every 3 days to 80 to 120 mg/day. It is mostly excreted through the renal
system. Intrathecal baclofen has been shown to be effective when
administered in doses between 50 and 100 g using a programmable drug
pump. Epidural infusions have also been used successfully in limited
studies. Common side effects of both oral and intrathecal medication are
weakness, sedation, dizziness, gastrointestinal (GI) symptoms, tremor,
insomnia, headache, and hypotension. Serious side effects include
personality disturbance and hallucinations. The drug should be withdrawn
gradually. Epilepsy is a relative contraindication to its use. Alcohol use
should be limited. Nocturnal dosage may be preferred. Hepatic dysfunction
may occur. Intrathecal overdose may be managed by cerebrospinal fluid
(CSF) drainage.
c. Dantrolene sodium (Dantrium) produces weakness proportional to relief of
spasticity and is therefore more useful in wheelchair-bound paraplegic
patients. It may be more useful in spasticity of cerebral origin than the other
drugs listed. Its use in ambulatory patients may cause unacceptable
weakness. The starting dosage is 25 mg/day, which is increased as
tolerated over about 4 weeks to 400 mg/day. Common side effects include
weakness, sedation, dizziness, diarrhea, and reduced glomerular filtration
rate. Nausea is generally transient. A serious side effect is hepatotoxicity,
especially with dosages above 200 mg/day in older patients, and liver
function must be monitored during treatment. Half of the drug's metabolism
occurs in the liver by the hepatic microsomal mixed oxidase system. Use of
the drug is therefore contraindicated in patients with preexisting liver
disease. Care should also be used in prescribing the drug to patients with
severe cardiac or pulmonary disease.
d. Tizanidine (Zanaflex), an a
2
agonist, in dosages up to 36 mg/day, is
equivalent in its antispastic effects to baclofen. It is started at 2 mg/day and
increased by 4 mg every week. Side effects include weakness,
hypotension, sedation, and dry mouth. A slow-release form may allow
once-daily dosage. It is not available in the United States.
e. Other chemical treatment modalities that may be useful in patients with
spasticity who do not respond to the benzodiazepines, baclofen,
dantrolene, and tizanidine are the following:
1. Clonidine (Catapres), either oral or transdermal, may benefit some
patients.
2. A combination of phenytoin (Dilantin), 300 mg/day, together with
chlorpromazine (Thorazine), 300 mg/day.
3. Vigabatrin (Sabril), an anticonvulsant that is a g-amino acid
transaminase inhibitor, 2 g/day, may be tried.
D. Other treatments
1. Intrathecal treatments with alcohol or phenol might be useful in alleviating
painful spasms in the lower extremities. However, this maneuver is likely to
produce incontinence, so it can be utilized only in patients who have already
lost bladder and bowel function. Botulinum toxin (Botox) may be used in
some patients with spasticity that is producing proportionately more
dysfunction than weakness (see sec. IV.G). It is likely to enhance nursing care.
It can be used for conditions such as cerebral palsy, adductor spasm from
multiple sclerosis, and stroke.
2. Peripheral nerve blockade might be necessary for relief of severe spasticity
in some patients. It is tried first with local anesthetic. If this is successful in
relieving the spasticity, a longer lasting nerve block may be produced with
alcohol or 5% phenol injection.
3. Selective posterior rhizotomy has been used, usually in the context of
spasticity associated with cerebral palsy. More major rhizotomies are
occasionally indicated.
4. Physical therapy is of paramount importance in the spastic patient in that
contracture must be prevented if useful function is ever to be regained.
Postural adjustments, topical cooling, close splinting (second skin), and
range-of-motion exercises are the mainstay of treatment. Noxious stimuli of
somatic and visceral structures should always be minimized.
5. Transcutaneous electrical nerve stimulation may occasionally be of benefit.
6. Cerebellar, dorsal column, and other forms of electrical brain stimulation are
used in a few specialized centers, but there is no convincing evidence of
benefit.
7. Orthopedic procedures are of benefit in selected patients.
III. Cerebellar dysfunction
A. Description. The anatomy and cellular physiology of the cerebellum are well
known, largely because of its relatively simple design. Input comes from all levels
of the central nervous system (CNS). Vestibular and spinal cord sensory input is
especially important, as are descending frontal motor relays. Output is directed to
the pyramidal system through the ventrolateral and ventroanterior nuclei of the
thalamus and to the brainstem parapyramidal systems, especially the lateral
vestibulospinal tract. Lateral regions of the cerebellum are involved with control of
distal extremity coordination, and midline regions are involved with axial
coordination and gait. Cerebellar or cerebellar tract dysfunction is evident clinically
as hypotonia, incoordination (dysmetria, dyssynergia, and
dysdiadochokinesia), and dysfunction of eye movements, equilibrium, and
gait. Disordered eye movements are very common, particularly gaze paretic
nystagmus. Other, nonmotor roles such as autonomic, sensori-perceptual,
emotional, and cognitive functions have been attributed to the cerebellum. The
neurotransmitter systems in the cerebellar outflow systems are unknown, and
medical therapy generally is ineffective in diseases involving the cerebellum, even
if the cause is known. The commonest causes of cerebellar intention tremor are
multiple sclerosis, head trauma, ischemia, and degenerative disease.
B. Treatment
1. Therapy should first be directed to the underlying cause of the syndrome if it
can be identified.
2. Physical therapy is the mainstay of treatment. Frenkel exercises, isometric
rhythmic stabilization, resistive gait and balance, and mobile walking aids have
been utilized with partial success. Limb weights up to a few hundred grams
may reduce the intention tremor of cerebellar disease.
3. Scoliosis may require orthopedic surgical intervention.
4. Destructive lesions of the ventrolateral thalamus (i.e., in the area of the
thalamus that relays to cortical motor control systems) may alleviate cerebellar
intention tremor and the so-called rubral or cerebellar outflow tremor (a tremor
that combines the features of parkinsonian tremor and cerebellar tremor, which
is thought to be due to lesions in the cerebellar outflow system). Recently,
chronic high-frequency stimulation of the ventral intermediate nucleus of the
thalamus has been advocated.
5. Medication
a. Physostigmine, administered as 1-mg tablets, has been reported to be of
some benefit in some patients with inherited cerebellar ataxia at dosages
approaching 8 mg/day.
Acetazolamide (Diamox) is useful for some of the episodic ataxic
syndromes.
b. 5-Hydroxytryptophan, 10 mg/kg/day, has been suggested to partially
alleviate dysarthria and postural disequilibrium.
c. The cerebellar syndrome may be associated with other abnormalities in
motor control, which may themselves be amenable to treatment.
IV. Basal ganglia dysfunction
A. Description
1. The anatomic arrangement of the basal ganglia suggests that extrapyramidal
function is mediated primarily through a series of closed loops (Fig. 15-1).
Afferents come to the small neurons of the neostriatum (caudate and putamen)
from the cerebral cortex, either directly or through connections with the
centromedian nucleus of the thalamus. Efferent axons from the large neurons
of the neostriatum pass to the cerebral cortex by way of sequential connections
in the globus pallidus and ventroanterior and ventrolateral nuclei of the
thalamus, influencing ipsilateral cortical motor centers and thus contralateral
motor function. The direct striatopallidal pathway facilitates cortically initiated
movements whereas the indirect pathway involving the subthalamic nucleus
suppresses potentially conflicting and unwanted motor patterns. Lesions in
both the pallidum and thalamus are able to oppose movement disorders
induced by nigrostriatal system degeneration. The neurotransmitters of these
pathways are not all known, but it seems clear that GABA and glutamate are of
major importance in projection pathways and acetylcholine in intrinsic striatal
neurons.
FIG. 15-1. Simplified outline of connections between the basal ganglia and
motor areas of the cerebral cortex. The afferent pathways are largely excitatory
(+) in nature. The efferent pathways are largely inhibitory (). The globus
pallidus interna (I) (efferent connections not shown) can be considered to have
the same projections as the substantia nigra (sn) reticularis (R). X, globus
pallidus externa; SP, substance P, a neuromodulator in the striatonigral
projection; E, enkephalin, a neuromodulator in the putamen pallidal projection;
C, substantia nigra compacta. Thalamic nuclei: ventroanterior (VA),
ventrolateral (VL), and centromedianum (CM).
2. An important modulatory system is the nigro-neostriatal projection, which
utilizes dopamine as a neurotransmitter at terminals situated on dendrites of
neurons in the neostriatum. Dopamine-containing neurons are stimulatory in
the direct striatopallidal pathway and inhibitory in the indirect pathway. An
understanding of the synthesis and metabolism of dopamine is therefore
essential to the successful management of extrapyramidal disorders (Fig.
15-2). The afferent systems that influence the perikarya of dopaminergic
neurons in the pars compacta of the substantia nigra are not well documented,
except for axons of the direct striatopallidal pathway that contain GABA as
neurotransmitter and substance P as neuromodulator. There may also be a
striatonigral cholinergic pathway. Enkephalin acts as a modulator in the
GABA-ergic indirect striatopallidal pathway. Other peptides, such as
somatostatin, cholecystokinin, and neuropeptide Y, may also modulate neural
activity in the striatum. In addition, reciprocal connections exist between the
striatum and the subthalamus, prerubral nucleus, and mesencephalon (part of
which contains 5-hydroxytryptamine as a neurotransmitter). From this outline it
is clear that drugs that influence cholinergic and dopaminergic systems would
be expected to have an influence on motor control by the basal ganglia.
FIG. 15-2. Major synthetic and metabolic pathways for dopamine: PAH,
phenylalanine hydroxylase; TH, tyrosine hydroxylase; DDC, dopa
decarboxylase (actually L-aromatic amino acid decarboxylase); MAO,
monoamine oxidase; COMT, catechol-o-methyltransferase. The amino acids
must compete with other neural amino acids for absorption at the level of the
gastrointestinal epithelium and blood-brain barrier vascular endothelium. The
peripheral circulation DDC inhibitors facilitate the use of lower L-dopa dosages,
but it must be noted that conversion to dopamine requires active neuronal
uptake in a reduced population of dopamine-containing neurons. There is an
efficient reuptake mechanism for released dopamine that leads to
intraneuronal metabolism of dopamine by MAO. Extraneuronal dopamine is
metabolized by COMT. 1, phenylalanine; 2, tyrosine; 3,
dihydroxyphenylalanine (DOPA); 4, dopamine; 5, 3-methoxytyramine; 6,
dihydroxyphenylacetic acid; 7, homovanillic acid.
3. The pathways for synthesis and metabolism of dopamine in the striatum are
well characterized and summarized in Fig. 15-2. The action of released
dopamine on striatal neurons is mediated by at least 2 of the 6 known
dopamine receptors, known as D1 and D2. Activation of D1 receptors leads to
production of cyclic adenosine monophosphate, whereas D2 receptor
activation does not. D2 receptors probably exist in high- and low-affinity states
on striatal neurons and terminals of corticostriatal afferents.
4. Movement disorders produced by dysfunction of the basal ganglia may be
classified as those resulting in diminished activity (akinesia or bradykinesia),
typified by Parkinson disease and other causes of so-called parkinsonism, and
those that result in overactivity (hyperkinesia or dyskinesia), typified by
Huntington chorea. Hyperkinetic movements produced by basal ganglia
disorders include chorea, athetosis, ballismus, dystonias, and probably tics.
These movements are generally abolished by sleep and enhanced by anxiety
and excitement. Action tremors, myoclonus, and startle (hyperekplexia) are
usually included with these disorders but their genesis lies outside the basal
ganglia. There are a variety of pathological disorders and medications that may
produce features of under- and/or overactivity as described in the text.
B. Parkinson disease
1. Description. Parkinson disease is a movement disorder of unknown cause
that primarily affects the pigmented, dopamine-containing neurons of the pars
compacta of the substantia nigra. Experience with parkinsonism induced by
neurotoxins, particularly N-methyl-phenyl-1,2,3,6-tetrahydropyridine (MPTP),
has implicated free radical generation in the pathogenesis of the disease (see
Fig. 15-2). Familial cases do occur, which suggests that genetic predisposition
to the effect of toxins may be a factor in pathogenesis. The lifetime risk for
family members is raised approximately 10-fold. Clinically, Parkinson disease
is characterized by the slow development of bradykinesia, increased tone,
resting tremor, and loss of postural reflexes. Slowness in initiation and
execution of voluntary movements is noted, particularly with such movements
as walking, rolling over in bed, fine finger dexterity, and writing (micrographia).
Patients have decreased facial expression, monotonous low volume speech,
and decreased blinking. Posture is stooped, and gait is shuffling, with poor arm
swing and reduced postural balance often associated with festination. The
abnormal tone is referred to as lead-pipe and cogwheel rigidity. Most
characteristic, and often present early in the course of the disease, is an
asymmetric, coarse (3 to 7 cps), resting tremor characterized as pill rolling.
Tremor, however, disappears with complete muscle relaxation. A symmetric
action tremor of 5 to 12 cps might also be present. A useful clinical
classification of severity of Parkinson disease is that introduced by Hoehn and
Yahr (Table 15-2).
TABLE 15-2. Staging of Parkinson Disease
Late motor and behavioral complications of Parkinson disease are common.
Late motor disabilities include increasing postural instability, unusual breathing
patterns, and brief freezing patterns, all of which are essentially unresponsive
to treatment. The presence of oculogyric crisis is associated with
postencephalitic Parkinson disease and antipsychotic drug ingestion. It is often
difficult to decide whether there is a concurrent dementia in long-term patients
because of difficulty with communication. In one series, over 30% of patients
were demented after 6 years of treatment. This is important in the assessment
of individual patients because mildly demented patients are likely to have
adverse behavioral side effects such as confusion, agitation, hallucinations,
delusions, and psychosis when treated with medication.
It is important to recognize other symptoms of Parkinson disease not so much
because they are treatable but in order to avoid unnecessary investigation.
Before the advent of treatment with L-dopa, two thirds of patients died within 7
years; the benefits of treatment on longevity are controversial and are currently
being reexamined. The diagnosis is usually not a problem in the 50- to
60-year-old person with slow onset of the typical features. A history of
encephalitis lethargica is now a very rare cause of newly diagnosed disease.
The pathology in idiopathic cases consists of loss of neurons from the
substantia nigra and other pigmented brainstem nuclei with consequent gliosis
and the formation of Lewy bodies in remaining neuronal perikarya. Whether the
disease is a generalized tissue defect is still uncertain.
2. Differential diagnosis. Most causes of parkinsonism, such as head trauma,
drug ingestion, and carbon monoxide, cyanide, and manganese poisoning, are
usually obvious; normal-pressure hydrocephalus and J akob-Creutzfeldt
disease may not be. A vascular cause for parkinsonism is not disputed,
although not all elements of Parkinson disease will be present. Alzheimer
disease may also have associated parkinsonism. Tumor and syphilis are very
rare causes of parkinsonism. The degenerative diseases with parkinsonism as
a major feature are sometimes referred to as parkinsonism-plus syndromes
and are listed in Table 15-3. Striatonigral degeneration, olivopontocerebellar
degeneration, and Shy-Drager syndrome may be classified within the
syndrome of multiple systems atrophy where the symptom complex presents
predominantly with parkinsonism, cerebellar dysfunction, or autonomic
insufficiency, respectively. This sporadic rare disease has been associated
with neuronal and oligocyte tubular inclusions which, however, are not
pathognomic for the disease. It is not uncommon for these syndromes to be
recognized after a course of L-dopa treatment has been shown to be
ineffective, although patients with diffuse Lewy body disease may respond well
initially. Treatment is symptomatic for the complications that may arise from
associated system degeneration.
TABLE 15-3. Parkinsonism-Plus Syndromes
3. Treatment of Parkinson disease is based on considerations of the benefits of
restoring function and arguments for neuroprotection of dopamine-containing
neurons. No drug therapy for peptide deficiencies has been described to date.
The object is either to increase available dopamine or dopamine agonist in the
neostriatum or to reduce cholinergic activity with anticholinergic agents. Choice
of therapy depends on the age of the patient and the degree of disability.
Indeed, no therapy may be the best choice early in the disease. There is no
argument that L-dopa is the most effective treatment for Parkinson disease but
motor fluctuations will eventually occur in the great majority of patients so
treated. In general an L-dopa preparation is the treatment of first and only
choice in older patients; in middle aged patients L-dopa is usually preferred as
the initial therapy and a dopamine agonist is added as L-dopa starts to be
associated with side effects; and a dopamine agonist may be preferred in
young adults where later supplementation by small (100-mg) doses of L-dopa
is often found to provide the best outcome. The major indication for use of
L-dopa is the incapacity of bradykinesia. The drug is administered with a
peripherally acting dopa decarboxylase inhibitor to reduce side effects such as
nausea and vomiting, cardiac arrhythmias, and postural hypotension. In the
past, these side effects have often limited the rapid buildup to therapeutic
efficacy. Most physicians introduce L-dopa therapy when symptoms start to
interfere with quality of life.
a. Carbidopa-L-dopa (Sinemet) (carbidopa, 10-mg, L-dopa, 100 mg;
carbidopa, 25 mg, L-dopa, 100 mg; or carbidopa, 25 mg, L-dopa, 250 mg)
has had the widest use. Carbidopa is a peripheral dopa decarboxylase
inhibitor that increases the amount of L-dopa available for action within the
CNS (see Fig 15-2). The usual starting dosage is carbidopa, 25 mg, and
L-dopa, 100 mg, t.i.d., given just after a meal to avert nausea. Thirty
milligrams of carbidopa daily is ineffective as a peripheral dopamine
decarboxylase inhibitor and precludes the use of Sinemet 10-100 as a
starting dose if administered t.i.d. The dosage is increased by 1 tablet per
day, every 3 or 4 days, as tolerated, over about 4 weeks. The final dosage
should be kept to a minimum compatible with a useful life for the patient.
This is usually less than 1 g/day of L-dopa. Improvement should be obvious
2 weeks after commencing treatment. A slow-release form of Sinemet
(Sinemet CR) is available but is usually not needed until symptom
fluctuation becomes apparent.
b. Benserazide-L-dopa (Prolopa, Madopar) (benserazide, 50 mg; L-dopa,
100 mg) is administered in the same way as carbidopa-L-dopa. The greater
amount of dopa decarboxylase inhibitor (i.e., 50 mg of benserazide versus
25 mg of carbidopa) may be better tolerated in some patients, especially if
nausea is a problem. A slow-release form of Prolopa (Madopar HBS), in
which the preparation floats on gastric contents, is used in some countries
but is not available in the United States. Madopar CR is also available in
some countries.
c. Carbidopa and benserazide. In some countries, carbidopa and
benserazide are available as separate preparations and may allow better
individual dosage adjustment in terms of the L-dopa/decarboxylase ratio.
d. Response to therapy. Approximately 80% of patients are improved
significantly by L-dopa therapy, but there appears to be no way to predict
which patients are responsive. Long-term studies suggest that there is a
decline in benefit from L-dopa after the first 2 to 3 years of treatment, such
that after 5 or 6 years, only 25% to 50% of patients have maintained their
initial improvement. Wide swings in motor performance were not seen
before the introduction of L-dopa therapy and are less frequent in patients
with late age onset disease. The initial dosage regimen of L-dopa appears
not to affect the incidence of the on-off phenomenon or end-of-dose
wearing-off effect but may be implicated in the development of peak dose
dyskinesia. Long-term treatment reduces mortality, although it appears that
dementia often emerges as a problem in long-term survivors. Some studies
have reported depression in over 20% of patients before treatment was
begun. Latent depression may become overt as a patient begins to become
more mobile with L-dopa therapy, and suicidal tendencies have been
reported. Tricyclic medication, selective serotonin reuptake inhibitors
(SSRIs), but not nonspecific MAO inhibitors, may be used concurrently with
L-dopa to treat depression.
e. Dose-related side effects
1. Peak dose dyskinesias. Fluctuations in motor performance early in the
disease are less apparent than might be expected from the short
half-life of the drug. This is probably because of storage and slow
release from dopamine-containing neurons in the brain. However, high
dosages of L-dopa preparations result in peak dose dyskinesias, often
before the end of the first year of treatment in younger patients. These
side effects become more severe and more generalized with time, and
almost 75% of patients have them after 6 years of treatment. Peak dose
dyskinesias occur 20 to 90 minutes after taking medication and are
clinically similar to the tardive dyskinesias seen with antipsychotic drug
therapy. They are usually choreiform, although dystonic, ballistic, or
myoclonic movements may occur. The abnormal movements respond to
a gradual reduction in dosage over a few days, as do less troublesome
side effects such as dry mouth, blurred vision, and postural hypotension.
Vitamin supplementation in patients receiving L-dopa without a dopa
decarboxylase inhibitor should not contain vitamin B
6
because this will
counteract the beneficial effect of the drug.
2. End-of-dose wearing-off phenomenon is another dose-related side
effect that becomes more prominent in patients on long-term therapy.
This effect may be correlated with low plasma concentrations of L-dopa.
The usual approach to this problem is to administer smaller doses of
L-dopa more frequently. Late afternoon drug failure may respond to
domperidone (Motilium) and cisapride (Prepulsid). Fluctuations in
response to L-dopa may also be reduced by slow-release preparations
that allow for a steady state of receptor stimulation. These agents
appear to be moderately effective. As might be anticipated, they are
associated with the slow onset of drug effectiveness in the morning and
are used in conjunction with regular preparations, especially with the
morning's first dose.
Some patients may be disciplined enough to use liquid L-dopa, which
needs to be prepared fresh each day from crushed L-dopadopa
decarboxylase tablets (1 g L-dopa), ascorbic acid (2 g), and tap water (1
L). This preparation is then taken every 60 to 90 minutes during the day.
Other medicines used for the wearing-off phenomenon include
dopamine agonists, amantadine, selegiline, and anticholinergics, but
none can be regarded as being entirely satisfactory.
Another approach to the problem of dose-related side effects has been
the use of a low-protein diet to diminish competition for absorption of
phenylalamine and tyrosine, particularly at the bloodbrain barrier. This
is generally achieved with a diet containing 0.8 g of protein per kilogram
of body weight, delivered at equal intervals through the day or
concentrated in the evening meal. Many older people are already
receiving a protein input at this level.
3. Biphasic dose response. Some patients are aware of dys-kinesias of
brief duration that occur shortly after taking their first dose of medication
in the morning, which resolves only to be followed 1 to 2 hours later by
the onset of severe dystonic spasms, particularly in the lower
extremities. These spasms can often be limited by a further dose of
L-dopa. Baclofen, 5 to 40 mg/day, has also been used to treat this
condition. These patients often progress to the on-off phenomenon.
4. The most troublesome side effects are nausea and vomiting, even
when the drug is administered in minimal doses with or after meals. Mild
antinauseants such as trimethobenzamide hydrochloride (Tigan), 25
mg t.i.d.; domperidone (Motilium), 10 to 20 mg 30 minutes before
L-dopa; anticholinergics; or antihistamines may be useful in this
situation.
5. Vivid dreaming is often reduced by avoiding the last dose of L-dopa
preparation at night.
6. Anxiety, agitation, confusion, delusions, visual hallucinosis, and
psychosis usually respond quickly (within a day or so) to lowered
dosage, although in rare cases it may take weeks to resolve completely.
Hallucinations may be treated with clozapine (Clozaril) commencing at
6.25 mg nocte increasing slowly to a maximum of 50 mg/day. The most
important but reversible side effect to be monitored with weekly (for 18
weeks) and then monthly blood counts is agranulocytosis, but postural
hypotension, delirium, sedation, and sialorrhea might also be
troublesome. Clozapine has also been reported to be helpful in
smoothing motor fluctuations and for treating tremor. Recently,
ondansetron (Zofran), a 5-HT-3 antagonist used to treat severe emesis
caused by chemotherapy and radiotherapy, has been shown to be
useful for hallucinations at a dose of 12 to 24 mg/day. Side effects
include headache, hiccups, and xerostermia.
7. Euphoria, mania, and hypersexuality can also occur with L-dopa
preparations. Another atypic neuroleptic drug belonging to the
thienobenzodiazepine class, olanzapine (Zyprexa), may also be helpful
beginning with 2.5 mg daily gradually increasing to 10 mg daily. The
medication, which is supplied in 2.5-, 5.0-, 7.5-, and 10-mg tablets, is
taken once daily.
8. Other side effects include flushing, orthostatic hypotension, and
premature ventricular contractions. Orthostatic hypotension may be
treated by elevation of the head of the bed, antigravity stockings, and
9-a-fludrocortisone, 0.1 to 0.2 mg/day. Hypertension can occur with
treatment. Minor transient changes can occur in liver function tests and
hematologic parameters. Abrupt cessation of therapy should be
avoided, as it may lead to a picture resembling neuroleptic malignant
syndrome with fever, muscular rigidity, and coma. Midrodine, an alpha
agonist, 20 to 40 mg/day has also been recommended recently for the
treatment of postural hypotension.
f. Dose-unrelated side effects
1. The on-off phenomenon becomes a likely side effect with extended
duration of therapy and is not seen in the absence of L-dopa therapy.
This disability occurs in about 50% of patients treated for 5 or more
years. The on-off effect consists of periods of unpredictable severe
akinesia, hypotonia, and apprehension of rapid onset and termination,
which last from 30 minutes to a few hours and which are unrelieved by
further doses of L-dopa. The cause is unknown, although off episodes,
like end-of-dose akinesia, have been correlated with low plasma
concentration of L-dopa in some studies. However, maintaining constant
L-dopa plasma levels with intravenous drug administration does not
always abolish clinical fluctuations. Recently, it has been proposed that
L-dopa may itself have inhibitory effects on motor activity. Whether it is
this function of L-dopa, accumulation of functioning dopamine
metabolites, decreased storage capacity of the dopaminergic neurons,
or pharmacodynamic fluctuations in receptor activity that underlies
non-dose-related side effects in advanced disease is currently unknown.
Administration of an L-dopa preparation q2h may help to partially
smooth out these effects. Sinemet, for example, can be cut in quarters
with a razor blade to allow smaller doses to be administered. L-Dopa
methyl ester is an experimental drug that may prove to be of benefit in
this distressing condition. A drug holiday for up to 1 week has also been
advocated in the past for treatment of on-off effects but is of little or no
benefit.
2. Treatment. The main treatment of the on-off phenomenon is
subcutaneous apomorphine (Apomine) by injection or infusion. This
medication is administered at least 24 hours after the introduction of
domperidone (Motilium), 20 mg t.i.d., to eliminate the inevitable
vomiting that occurs without its use. The dose, initially commenced at
1.5 mg, is titrated for benefit up to 7 mg. A satisfactory result will
produce a clinical improvement within 10 minutes that will last for up to
50 minutes. The medication reduces the time that a patient spends in
the off state but does not reduce the frequency of on-off spells. Nasal,
rectal, and sublingual apomorphine may be of benefit in some patients.
The dose of domperidone can be reduced after a stable dose of
apomorphine has been achieved. Dry mouth, headache, and yawning
are among the more common side effects.
3. The contraindications to L-dopa therapy are relatively few. They
include narrow-angle glaucoma (most glaucoma cases are of the
chronic, wide-angle type), previous melanoma, although this has been
questioned, and concurrent use of MAO inhibitors. Caution should be
used in patients who have cardiac arrhythmias or recent myocardial
infarction or for whom surgery is planned.
c. Dopamine agonists
1. There is consensus that dopamine agonists active at D2 receptors are
effective as adjunctive treatments but are not as good as L-dopa for
primary symptom control. Because they are not converted to dopamine,
reduce dopamine neuron firing, act as free radical scavengers, and
induce enzymes that metabolize free radicals, they may also be
neuroprotective if the dopamine toxicity theory is correct. Because
dopamine agonists rarely produce motor fluctuations, a case to use
them can be made in young and middle-aged patients, and in patients
who develop dyskinesias. The Achilles heel of these medications is their
predilection for producing behavioral side effects, especially visual
hallucinations and delirium. Table 15-4 describes key features of several
dopamine agonists that are finding wider use. It is still not clear as to
whether these medications differ widely in their clinical effect. Side
effects otherwise include postural hypotension; abdominal bloating;
nausea, vomiting, and constipation; dry mouth; fatigue; sedation; nasal
stuffiness; and erythromelalgia. In future it should be possible to avoid
ergot-based medications as they have been associated with the rare
syndromes of pleural and retroperitoneal fibrosis.
TABLE 15-4. Dopamine Agonists Used for Parkinson Disease
2. Bromocriptine mesylate (Parlodel) is the most used dopamine
receptor agonist. It may permit up to a 30% reduction of L-dopa dosage.
Bromocriptine has effects at postsynaptic sites and modulatory effects
on L-dopa-induced dopamine receptor binding at presynaptic
autoreceptors. The initial dosage of bromocriptine is 2.5 mg/day, and
this is slowly increased over several weeks. Maximum therapeutic
benefit is often of slow onset, and the dosage can be held at low levels
(e.g., 12 mg/day) for several months before full effectiveness is noted.
The maximum dosage is 30 to 50 mg/day usually given b.i.d. to t.i.d.
Extensive first-pass metabolism occurs in the liver. Side effects are
more prominent at higher doses. Early side effects include nausea,
which may be treated with domperidone, vomiting, and postural
hypotension.
3. More recently developed ergot analogs have been shown to have a
similar overall benefit as bromocriptine. Pergolide mesylate (Permax),
active at D1 and D2 receptors, has undergone extensive evaluation.
The mean effective dosage is usually about 2 to 4 mg/day. The starting
dosage is 0.1 mg/day. Cardiac arrhythmias may be more prevalent with
this drug. It is better used together with a small dose of L-dopa for
maximum benefit. Hypersensitivity to this or other ergot derivatives is a
contraindication to its use. The side effect profile is similar to that for
bromocriptine.
Other dopamine agonists include the short-acting medicines ropinirole
and pramipexole (Mirapex) and the long-acting medicine cabergoline
(see Table 15-4).
d. Combined therapy. Many middle-aged patients are now successfully
managed by using an L-dopa preparation initially and then adding a
dopamine agonist such as bromocriptine in low dosage. A typical regimen
would be Sinemet 25-100 initially t.i.d. for 3 months and then adding
bromocriptine, 2.5 mg/day, increasing over 3 months to 2.5 mg t.i.d. Many
other variations on this approach are in clinical use. The hope is that there
will be fewer side effects with this strategy, particularly dyskinesias and
motor fluctuations.
e. Anticholinergics are said to be useful early in the disease when tremor is
the most prominent problem. They are now being used much less as
first-line therapy.
1. Commonly used agents and the usual dosages include:
a. Ethopropazine (Parsidol), 10 to 20 mg t.i.d.
b. Benztropine (Cogentin), 0.5 to 4.0 mg b.i.d.
c. Biperiden (Akinetin), 1.0 to 2.0 mg t.i.d.
d. Trihexyphenidyl hydrochloride (Artane), 1.0 to 5.0 mg t.i.d.
2. Other anticholinergics used to treat Parkinson's disease include
orphenadrine (Disipal) and procyclidine (Kemadrin). The maximum
dose of these agents is determined by observation of the onset of side
effects. The dosage is gradually increased to the tolerated maximum.
For example, it may be possible to give up to 400 mg/day of
ethopropazine.
3. Side effects. Common well-tolerated side effects of anticholinergic
drugs include dry mouth, blurred vision, and dizziness. Other, more
serious side effects include acute confusion, constipation, urinary
retention, and precipitation of untreated glaucoma. The deleterious
effects on cognitive function are reversed when dosage is reduced, but
this must be done very slowly over several weeks. Abrupt cessation of
anticholinergic medication can lead to worsening symptoms. This may
mislead the clinician into thinking these drugs are of continuing benefit
when in fact they are no longer necessary. It is not advisable to
introduce a tranquilizer for cognitive side effects. Constipation responds
to a gentle laxative. Bladder neck obstruction in men may require
surgical intervention. If glaucoma is being managed appropriately,
anticholinergic agents can still be used.
e. Amantadine hydrochloride (Symmetrel) and amphetamines may act by
increasing endogenous dopamine release at the nerve terminal in the
neostriatum.
1. Amantadine hydrochloride is used in an initial dosage of 100 mg/day
and increased to 100 mg t.i.d. The benefit obtained is short-lived, and
intermittent use has been advocated. It may be helpful for the
wearing-off phenomenon. Prominent side effects are depression,
congestive cardiac failure, pedal edema, livedo reticularis, urinary
retention, and an acute confusional state, especially with visual
hallucinations. The drug is excreted unmetabolized in the urine. This
drug may also be effective through its anticholinergic properties and is
more useful for treating tremor.
2. Amphetamine has been used in the past for treatment of oculogyric
crises. Side effects generally preclude its use. Methylphenidate is said
to be helpful as an analgesic for headache and burning pain and for
sensory symptoms, including unpleasant tingling, numbness, and
formications.
3. A new approach to the treatment of Parkinson disease that has not yet
been fully evaluated is the use of catechol-O-methyltransferase
inhibitors, which reduce competition for L-dopa transfer into the brain by
limiting the production of these dopa analogs. Two medicines of this
type currently undergoing trials include entacapone and tolcapone.
Hepatitis pathology has recently been reported with tolcapone.
4. Neuroprotection. The effect of treatments on the course of Parkinson
disease remains controversial. The view that oxidative stress
contributes to the pathogenesis of the disease, possibly through the
metabolism of dopamine, has lead to a number of therapeutic
approaches that attempt to ameliorate this possibility. They include the
introduction of L-dopa preparations as late as possible in the course of
the disease, the use of dopamine agonists to reduce dopamine turnover
and facilitate free radical metabolism, and the use of selegiline, an
MAO-B inhibitor that may reduce the generation of free radicals by
MAO.
f. Selegiline (Eldepryl) is the principal MAO-B inhibitor used so far. It also
inhibits neuronal dopamine uptake and has been shown to be useful in the
treatment of Parkinson disease alone and as an adjunct to L-dopa therapy.
Selegiline also acts to induce superoxide dismutase and catalase, which
increases free radical elimination. The dosage of selegiline is 100 g/kg/day
after a loading dose of 10 mg daily for 1 week. The usual regimen is one
5-mg tablet in the morning and one 5-mg tablet at noon with meals. At 30
mg/day, the drug inhibits both MAO-A and MAO-B. It is metabolized to
amphetamine, which may be responsible for part of the euphoric effect. Its
place in the treatment of Parkinson disease is still controversial, but it is
probably best regarded as an L-dopa-sparing agent that also prolongs the
effect of L-dopa in patients with end-of-dose failure. It has been reported to
be associated with increased mortality in one UK study but this has been
criticized on methodologic grounds. Many physicians continue to use it
before any other medications are started in presymptomatic patients
because of its putative neuroprotective effect, a benefit that has now been
shown in more than one study. The drug should not be used in combination
with meperidine, other MAO inhibitors, or antidepressants, particularly
SSRIs, as a serotonergic syndrome might be precipitated. This syndrome is
characterized by delirium, autonomic signs (fever, sweating, diarrhea), and
neuromuscular manifestations (ataxia, hyperreflexia, myoclonus). Serotonin
syndrome is caused by a combination of decreased presynaptic serotonin
uptake and decreased synaptic cleft metabolism. Signs resolve within hours
once the inciting agents are withdrawn. Occasionally, treatment with a
serotonin antagonist such as cyproheptadine (Periactin), methysergide
(Deseril), or propranolol (Inderal) is warranted.
Methylenedioxymethamphetamine (Ecstasy) can also precipitate the
serotonin syndrome.
g. Tolcapone (Tasmar) inhibits plasma catachol-O-methyl transferase, thus
prolonging the half-life of levodopa, increasing the time available for the
drug to cross the blood-brain barrier. It is therefore useful to treat the
wearing off of levodopa/carbidopa in patients with advanced Parkinson
disease. The medication is available in 90-, 100-, and 200-mg tablets. The
initial dose is 100 mg PO t.i.d., increasing slowly as necessary. The
levodopa dose may need to be decreased. The first dose of the day should
be taken with the first dose of levodopa/carbidopa, with the second and
third doses spaced six and twelve hours later. The drug should not be
combined with an MAO inhibitor and doses of other drugs which depend on
COMT metabolism (e.g., methyldopa, dobutamine, apomorphine,
isoproteronol) may have to be lowered. In patients on oral anticoagulants,
prothrombin time should be monitored since the effect of tocopon on oral
anticoagulants has not been adequately studied.
h. Propranolol (Inderal) may on occasion be used for action tremor, a
common accompaniment of Parkinson disease (see sec. V.C.3.c.(1) for
dosage). It is also said to be useful for pain that is not associated with
dystonia.
i. Botulinum toxin A (Botox) has been used to treat equinovarus and claw
dystonia in patients who have these conditions and where other medical
therapies have not helped (see sec. IV.G).
j. Surgery
1. Ventrolateral thalamotomy has been used in patients with severe
unilateral tremor, not controlled with drugs, who have the intellectual
capacity for gainful employment. Bilateral thalamotomy has led to
severe speech defects. Ventral pallidotomy may be useful for
bradykinesia and tremor, and is coming back into favor in some centers.
It has been claimed that prior surgery reduces the frequency of
L-dopa-induced dyskinesias. Neurostimulation of the nucleus ventral
intermedius of the thalamus is also under trial.
2. Transplantation of catecholamine-containing tissue from adult and
neonatal sources into the basal ganglia of a few patients with Parkinson
disease resulted in clinical improvement and has led to the trial of this
therapy in a number of coordinated centers. Tissues transplanted have
included adrenal medulla (with very limited success) and neonatal
substantia nigra. Reports to date suggest that any benefits from this
procedure are unpredictable, and it is unlikely that it will become the
preferred form of therapy in any but a very small number of patients.
The next wave of local treatment to improve dopaminergic activity is
likely to be focused on ex vivo gene therapy.
k. Nonpharmacologic treatment programs. There is little direct evidence of
the value of nonpharmacologic treatments apart from the value of
socialization on psychological well-being. However, a general fitness
program is wise for all older people. Speech therapy appears to be of
limited benefit, although some patients speak more clearly if given cues
such as that of a metronome. The occupational therapist can provide aids
as required, and physical therapy can teach patients useful tricks to help
initiate movement and gait. These rely on the following principles: breaking
movements into small components, performing each submovement at a
conscious level, performing one movement at a time, and using cues to
assist movement initiation and execution. Patients must expect inaccuracy
for faster movements.
l. Compliance. The occasional patient appears to have no benefit from any
medical therapy. It is usually wise to admit such patients to the hospital and
begin therapy again under strict supervision. A review of the patient may
also eventually reveal a parkinsonism-plus syndrome.
C. Huntington chorea (see also Chap. 3, sec. III.A.4)
1. Description. Huntington chorea is an inherited autosomal dominant dementing
disease for which, in adult-onset cases, the associated movement disorder
typifies relative overactivity of the dopaminergic system. Chorea and athetosis
may be considered together, since the two commonly coexist in this and in
other extrapyramidal syndromes that predominantly affect the striatum. Indeed
severe chorea is virtually indistinguishable from athetosis. There does not
appear to be a distinct anatomic substrate for these involuntary movement
patterns. Hypotonia, with consequent pendular reflexes, is a frequent
concomitant of chorea. Chorea refers to rapid, jerky, semipurposive
movement, usually of the extremities; athetosis describes slower, less
purposeful, continuous sinuous movements. Childhood onset of Huntington
chorea may be associated with parkinsonism. Dysarthria is frequently present.
The other key features of Huntington chorea are progressive emotional and
personality changes and dementia. Depression is common, with suicide an
outcome in approximately 5% of cases.
2. Differential diagnosis. Presymptomatic and prenatal early detection of
Huntington chorea is now available through testing for the genetic defect, a
repeated replication sequence on chromosome 4. Catastrophic sequelae, such
as suicide or psychiatric hospitalization, has proven to be uncommon (less
than 1%). Other diseases of the basal ganglia that may result in similar
movements are benign inherited chorea, senile chorea, neuroacanthosis, and
Lesch-Nyhan syndrome in childhood; and acquired conditions such as seen
with Sydenham chorea of acute rheumatic fever and with other acute infections
including diphtheria, whooping cough, rubella, and encephalitis; oral
contraceptives and, rarely, pregnancy; thyrotoxicosis; cerebrovascular disease
(posthemiplegic athetosis); cerebral palsy including kernicterus; mercury
poisoning; and drugs, particularly antipsychotics, anticonvulsants, lithium, and
antiemetics; and diseases that may present as parkinsonism or
choreoathetosis (see sec. IV.E). Management of these movement disorders is
the same, in principle, as for Huntington chorea.
3. Treatment (Table 15-5). Treatment of the primary defect in Huntington chorea
is not yet feasible. Controlled trials of agents that attempt to reverse oxidative
stress are underway with remacemide and coenzyme Q. Pharmacologic
treatment with dopamine depletion or receptor blockade is helpful in the early
stages of Huntington chorea.
TABLE 15-5. Drugs Commonly Used for Movement Disorders
a. Haloperidol (Haldol), 1 to 4 mg q.i.d. The side effects of neuroleptic
medication, apart from those on movement at D2 receptors, should be
borne in mind when using drugs of this class. They include postural
hypotension and other anticholinergic side effects, sedation, and
neuroleptic malignant syndrome.
b. Chlorpromazine (Thorazine), 50 mg t.i.d.
c. Tetrabenazine (Nitoman). See sec. IV.B.3.d.(2)(a).
d. Reserpine (Serpasil), 0.5 mg q.i.d., has been used in Sydenham chorea.
e. Propranolol (Inderal), in high dosage, may be useful for action tremor,
which may be a component of the disorder.
f. Dantrolene sodium (Dantrium) has been used for the chorea associated
with hemiatrophy.
Sodium valproate (Epilim), 200 mg t.i.d., may also be tried. Corticosteroids
are indicated in Sydenham chorea when severe and laboratory parameters
suggest active inflammation.
D. Disease presenting with parkinsonism or choreoathetosis. A group of
uncommon diseases may manifest themselves with either choreoathetosis or
parkinsonism as the primary movement disorder. At autopsy, these diseases
demonstrate widespread pathology in the basal ganglia, usually in a distribution
that does not clearly implicate any of the specific connections previously
discussed. These diseases should be considered in the differential diagnosis of
any patient having symptoms of parkinsonism or choreo-athetosis alone.
Management includes treatment of both the underlying disease and the movement
disorder. However, it is intuitively apparent that parkinsonism secondary to a
lesion of the neostriatum is unlikely to respond to L-dopa if the postsynaptic
elements for neurotransmission in that system have been destroyed by the
disease process.
1. Wilson disease
a. Description. Wilson disease is a rare inherited autosomal recessive
disorder that has its onset between the ages of 10 and 40 years. It is
characterized by progressive liver and neurologic disease, Kayser-Fleischer
rings of the cornea, and occasional renal dysfunction. The neurologic
presentation has been subdivided into 2 major categories. Younger patients
have rapid progression of either athetosis or rigidity and dystonia with a
characteristic fixed grin. Myoclonus also can occur, and this form of the
disease is more difficult to treat. Adults are more likely to have a benign
course, with tremor (action and intention), dysarthria (which may have
spastic, cerebellar, and hypokinetic components), and dysphagia as
prominent symptoms. This form of the disease is more amenable to
treatment. Asterixis (see sec. VI) may occur concomitantly with progressive
hepatic dysfunction.
b. The diagnosis is established by documenting the Kayser-Fleischer ring by
slit-lamp examination, establishing disordered liver function, and evaluating
copper metabolism. Useful screening tests include serum copper and
ceruloplasmin levels (both are decreased in Wilson disease) as well as
urinary excretion of copper (increased). The cerebrospinal concentration of
copper and urinary excretion of copper are useful tests for monitoring
treatment. Liver biopsy may help to establish cirrhosis and may show an
increased liver copper concentration.
Heterozygotes are defined by measurement, over several days, of fecal
excretion of intravenously administered radiolabeled copper or by
demonstration of intermediate increases in liver copper concentration.
Imaging of lucencies in the basal ganglia may be observed but do not
preclude a response to therapy.
c. Treatment
1. D-Penicillamine (Cuprimine), 250 mg t.i.d. between meals, retards the
progression of the disease in most patients with the late-onset form but
may exacerbate symptoms when introduced. Medication is continued for
life, but dosage may be reduced during pregnancy. Total drug
withdrawal can be fatal. Toxic reactions are more common with dosages
exceeding 2 g/day. Acute sensitivity reactions occur in one third of
patients. Reported side effects include nausea and vomiting, ageusia,
rashes, adenopathy, arthralgia, leukopenia, thrombocytopenia, and
Goodpasture's syndrome. The nephrotic syndrome and optic
neuropathy have been reported following treatment with the d,l isomer.
Optic neuropathy may improve with pyridoxine, 100 mg daily. Acute
sensitivity responses can be treated with corticosteroids. Ageusia may
respond to zinc sulfate. The drug is teratogenic in animals. Onset of
benefit may be delayed for some months following institution of therapy.
2. A diet low in copper (1.5 mg/day) may decrease the requirement for
penicillamine. Food such as shellfish, liver, mushroom, nuts, and
chocolate should be avoided.
3. Some authors have suggested that zinc sulfate or acetate containing 25
mg of elemental zinc administered q4h between meals and before bed
is a useful, and essentially harmless, first-line therapy for Wilson
disease that reduces copper absorption and may delay the onset of the
need to use drugs such as D-penicillamine. It is also used in conjunction
with D-penicillamine and may be continued satisfactorily after
D-penicillamine has been stopped because of side effects.
4. Triethylenetetramine dihydrochloride (Trientine) has been suggested
for use in patients with serious toxic reactions to penicillamine. The
dosage is 400 to 800 mg t.i.d. before meals.
5. Ammonium tetrathiomolybdate is a promising treatment for Wilson
disease that does not appear to be associated with initial worsening of
the syndrome, as is frequently seen with penicillamine.
6. Treatment of metabolic acidosis may help the neurologic disease in
those patients with renal tubular acidosis.
7. Liver transplantation has been advocated on occasion for this disease.
8. Symptomatic treatment of the movement disorder is outlined in sec.
IV.D.3.
2. Calcification of the basal ganglia and dentate nucleus commonly occurs in
the elderly and may account in part for the frequency of mild abnormal
movements in that population. When calcium deposition is severe, a major
progressive movement disorder may result that is manifested either as
parkinsonism or as choreoathetosis.
a. The differential diagnosis depends on the history and examination as well
as on evaluation of the chemical data outlined in Table 15-6.
TABLE 15-6. Differential Diagnosis of Calcification in the Basal Ganglia
b. Treatment. In the presence of hypocalcemia (as in postsurgical
hypoparathyroidism, idiopathic hypoparathyroidism, or
pseudohypoparathyroidism), the progress of the movement disorder
appears to be arrested by restoring serum levels to the normal range
through use of vitamin D (50,000 to 100,000 units/day) and calcium
supplements. Serum chemistries should be monitored regularly to avoid
vitamin D intoxication. Regression of the movement disorder is rare, except
perhaps in idiopathic hypoparathyroidism. In striatopallidodentate
pseudocalcification (Fahr disease), the serum chemistries are normal, and
no treatment is recommended. Calcification also occurs rarely in
hyperparathyroidism and pseudopseudo-hypoparathyroidism
(normocalcemic pseudohypoparathyroidism).
3. In Hallervorden-Spatz disease, iron-containing pigments are deposited in the
globus pallidus and pars reticularis of the substantia nigra. The disease is
manifested in childhood as progressive parkinsonism or choreoathetosis,
occasionally with other motor control system abnormalities. Iron-chelating
agents are not useful in reversing the pigmentary deposits. The movement
disorder is treated as outlined in sec. IV.D.3.
4. Ataxia-telangiectasia is a rare hereditary disease with variable elements of
hyperkinesis, myoclonus, nystagmus, and dystonia. The diagnostic clinical
features are difficulty in generating horizontal eye movements and the
conjunctival telangiectasia. This disease can occur in adults without immune
deficiency and has a variable phenotype. Choreoacanthocytosis is another rare
syndrome that is predominantly hyperkinetic in type.
5. Other diseases that may rarely be associated with parkinsonism or
hyperkinesis include infections such as encephalitis, AIDS, and syphilis;
immunologic diseases such as systemic lupus erythematosus; stroke, tumor,
vascular malformations, and consequences of traumatic injury including
subdural hematoma.
E. Hemiballismus. The flinging, rotatory movements of hemiballismus usually arise
following lesions of the subthalamus, particularly hemorrhage. Even without
therapy, the symptoms often resolve to a considerable degree over a period of a
few weeks. Initial pharmacologic approaches include reserpine or tetrabenazine
for acute disability, then phenothiazines or haloperidol. Clozapine (Clozaril, 50
mg/day) may be helpful in cases resistant to other medications. The most effective
treatment for chronic severe hemiballismus is probably ventrolateral thalamotomy.
F. Idiopathic dyskinesias and dystonias constitute a group of movement disorders
that may be divided, for convenience, into generalized and segmental types.
Dystonia is a persistent attitude or posture produced by co-contraction of agonist
and antagonist muscles and may be considered an extreme form of athetosis.
Large axial and limb muscles are involved. The prototype disorder in the
generalized group is dystonia musculorum deformans; other inherited dystonias
are very rare. Dystonia may be secondary to a variety of neurologic conditions
including cerebral hypoxia, encephalitis, trauma, medication, poisons such as
manganese, and disorders that give rise to parkinsonism and choreoathetosis.
The segmental dystonias include torticollis, retrocollis, writer's cramp and other
craft-associated dystonias, Meige facial dystonia, and blepharospasm.
1. Treatment
a. Medical treatment of the idiopathic dyskinesias and dystonias, whether
generalized or segmental, is generally unsatisfactory. Systemic drugs used
include anticholinergics (especially high-dose ethopropazine), followed by
diazepam, haloperidol, tetrabenazine, and lithium.
b. Botulinum toxin type A (Botox) may be used to treat segmental dystonia.
The dosage is site- and patient-dependent and should be administered by
someone familiar with its use. Botulinum toxin acts by binding in a
noncompetitive manner to presynaptic cholinergic terminals, thus leading to
functional denervation and muscle weakness. It has been particularly
effective for blepharospasm, spasmodic torticollis, hemifacial spasm, and
spasmodic (adductor) dysphonia, with 90% success rates reported.
Because of weakness, injection of zygomaticus should be avoided when
injecting patients with hemifacial spasm. Weakness induced by botulinum
toxin is reversible. Patients with apraxia of eye opening do poorly.
Task-related dystonias such as writer's cramp respond less well. Botulinum
toxin may also be of benefit in jaw-closing dystonia and patients with
functional impairment due to spasticity rather than weakness in pathologies
as diverse as head injury, stroke, and multiple sclerosis. Care must be
taken only to inject symptomatic muscle with the minimum amount of toxin
so as to preserve as much power as possible while dampening the
dystonia. This may require electromyographic (EMG) control. The effect on
the dystonia may not be apparent for several days, and it will recur in
approximately 3 months, requiring reinjection. The activity of botulinum
toxin varies in preparations from different sources. The preparation in the
United States is approximately fivefold more active than that from the
United Kingdom. The actual dose used varies from as low as 2 units for
small intrinsic muscles of the hand and vocal adductor muscles to as much
as 150 units for a large muscle such as tibialis posterior. A standard dose
for blepharospasm might be 20 units. Treatment failure may lead to a
second injection. Late treatment failure may be associated with increased
antibody production. In this situation, botulinum F toxin might be helpful.
Treatment failure can occur with or without weakness. Relative
contraindications to its u se include myasthenia gravis and concomitant
administration of aminoglycosides.
c. Some patients with dystonia may respond to closely applied splints (second
skin) such as can be fashioned from Lycra garments.
d. Spinal cord stimulation has been reported to be useful in some groups
but must currently be considered experimental.
2. Dystonia musculorum deformans is a hereditary progressive dystonia seen
most commonly in J ewish families. Treatment is generally not very effective.
L-dopa (Sinemet 10-100) has been used successfully in some patients who are
thus classified as having DOPA-responsive dystonia. Mild parkinsonism occurs
in some of these patients and/or their relatives. Ventrolateral thalamotomy is
effective in a few selected patients. Orthoses may be useful.
3. Spasmodic torticollis is an example of an idiopathic segmental dystonia
involving the musculature of the neck. It is usually a sporadic condition but has
been reported in families. The anatomic substrate of the disorder is unknown.
The movements can be brief and repetitive, as in a dyskinesia, or sustained, as
in a dystonia.
If medical therapy is unsuccessful, behavioral modification techniques may be
used, including sensory and positional feedback therapy. Patients often learn
that adoption of particular limb postures help control the movement even
before that movement is fully executed. In the past, definitive treatment was a
surgical lesion of the motor fibers involved, i.e., section of the spinal accessory
fibers and intradural section of C1C3 anterior nerve roots. The spontaneous
partial remission rate has been reported to be as high as 33% in 3 years.
4. Some focal dystonias occur following relatively minor injury. The
pathogenesis is obscure.
5. Paroxysmal choreoathetosis and dystonia are rare clinical phenomena that
may be familial, sporadic, or acquired as seen occasionally in demyelinating
disease.
a. The familial phenotype is quite variable. Attacks may be induced by startle
or movement. Choreoathetosis is usually asymmetric and generally lasts
only a few seconds to minutes, and responds to carbamazepine and
phenytoin in its kinesogenic form.
b. Paroxysmal nonkinesogenic dystonia may be precipitated by alcohol,
emotion, or fatigue and may last for hours. It responds to treatment with
clonazepam. In some cases it is a prelude to Parkinson disease.
G. Drug-induced extrapyramidal syndromes
1. Medications can produce symptoms and signs of under- and/or overactivity of
the basal ganglia.
a. With the introduction of the phenothiazines, drug-induced extrapyramidal
symptoms became common. Phenothiazines, butyrophenones, and
other more recently developed neuroleptic drugs act primarily as
dopamine receptor blockers, predominantly at D2 receptors in the limbic
system, in the treatment of psychotic disorders. They produce a number of
drug-induced extrapyramidal symptoms. (Table 15-7).
TABLE 15-7. Severity of Induced Parkinsonism and Dystonic Reactions
with Commonly Used Antipsychotic Drugs
b. Similar drugs are also widely used as antinauseants including
prochlorperazine (Compazine) and metoclopramide (Maxolon). These
drugs may also result in extrapyramidal symptoms, although this is less
likely with metoclopramide.
c. Catecholamine analogs and depleting drugs such as methyldopa,
tetrabenazine, and reserpine also produce extrapyramidal syndromes.
d. Other medications that rarely cause an extrapyramidal syndrome include
diltiazem, captopril, vincristine, valproate, phenytoin, lithium, and cytosine
arabinoside.
e. Long-term therapy with L-dopa has also seen the introduction of another
group of patients with drug-induced extrapyramidal syndromes of the
dyskinetic type (see sec. IV.C).
2. Reversal. Drug-induced movements are best reversed by stopping or reducing
the dosage of medication.
3. The abnormal movements produced include the following:
a. Acute idiosyncratic dyskinesia and dystonia may occur within the first
few days of treatment with neuroleptic medication.
1. Dyskinesia refers to rapid, brief involuntary movements that may take
the form of chorea, athetosis, or ballismus (see sec. IV.B.3.d).
2. Dystonia may occur with the first dose of neuroleptic medication. It
consists of long-duration, slow, contorting movements of axial,
appendicular, or eye muscles (oculogyric crisis). Muscles most
commonly affected are those of the neck, trunk, and proximal
extremities. Respiratory muscles might also be affected. Acute dystonia
can be treated with a parenteral anticholinergic agent, such as
benztropine (Cogentin), 1 mg IM or IV, or with diphenhydramine
(Benadryl), 50 mg IV. In general, this should be followed by oral
medication for the next 48 hours. Paradoxically, oral antihistamines
have been documented as a cause of dystonic reactions. It is usually
possible to stop the offending drug.
b. Parkinsonism. Dose-related akinesia, rigidity, and tremor (3 to 5 cps)
might occur between a few days and 4 weeks after initiation of treatment.
This state can persist for many months after cessation of therapy with
antipsychotic medications. Treatment consists of:
1. Decreasing the antipsychotic drug dosage or
2. Adding anticholinergic medication:
a. Benztropine (Cogentin), 0.5 to 4.0 mg b.i.d.
b. Biperiden (Akineton), 1.0 to 2.0 mg t.i.d.
c. Trihexyphenidyl hydrochloride (Artane), 1.0 to 5.0 mg t.i.d.
The half-life of benztropine is longer than that of biperiden, which
has a longer half-life than trihexyphenidyl hydrochloride. The
anticholinergic drugs may partially reverse the antipsychotic effects
of the primary drug. They are not necessary for all patients and are
rarely required for more than 2 or 3 months. There is no indication
for prophylactic use. Theoretically, L-dopa and dopamine receptor
agonists should be of benefit, but they nearly always produce a
coincident confusional state.
c. Akathisia is a dose-related side effect of antipsychotic drugs that usually
occurs during the first few days of treatment and may be present in up to
20% of patients. The term refers to the restlessness seen in these patients.
They are literally unable to sit still and appear intensely anxious. The
etiology is obscure, and the treatment is withdrawal of antipsychotic
medication. Initiation of treatment with the lowest possible dose of
medication and recognition of the syndrome, thus preventing escalating
doses of antipsychotic medication, are the two major factors in
management. Anticholinergic medication is only partially effective. Other
medications reported to be effective in alleviating symptoms include
benzodiazepines, alpha antagonists, clonidine, and amantadine. Late-onset
akathisia occurs rarely and is less responsive to medication.
d. Tardive (late) dyskinesias
1. Description. Tardive dyskinesias usually occur more than 1 year after
continuous neuroleptic medication. The prevalence might be as high as
20% of patients and probably exceeds that figure in the elderly,
especially women. Tardive dyskinesia is said to occur more frequently in
patients who have manifested acute reactions to neuroleptic
medications and who have an underlying affective disorder. Tardive
dyskinesias might include facial and limb chorea, athetosis, dystonia,
and akathisia. The involuntary movements of the tardive dyskinesias are
often restricted to movements involving the head and neck, such as
chewing and tongue thrusting (orobuccal dyskinesia). The movements
occasionally involve the muscles of respiration.
2. Treatment of tardive dyskinesias depends on either stimulating the
cholinergic mechanism or decreasing dopaminergic activity. Another
approach is the use of drugs active in the GABA system, which has a
striatonigral projection. Further dopamine receptor blockade achieved
by increasing the dosage of antipsychotic drug might help the disorder
in the short term, but eventual dosage reduction becomes necessary. It
is important that antipsychotic medication be used in as low a dose as
possible. Anticholinergic drugs should be used sparingly in patients with
tardive dyskinesia, as they can exacerbate the problem, although they
probably do not increase the initial risk of developing the signs of the
disorder.
The symptoms may fluctuate and take months or years to resolve
following drug withdrawal; approximately 50% are reversible within 5
years, but some might never resolve. Fortunately, most do not continue
to progress once a plateau of activity is reached. Treatment of tardive
dyskinesia and dystonia is difficult, and many medicines have been
advocated. J udicious use of drug holidays in the administration of
neuroleptic medication has not proved beneficial and may be associated
with increased risk.
a. Tetrabenazine (Nitoman) depletes central biogenic monoamine
stores. Treatment is started with one half of a 25-mg tablet; this
dosage is increased slowly to a maximum of 200 mg/day.
Parkinsonism, drowsiness, and depression are common side effects.
Anxiety, choking attacks, insomnia, and akathisia have been
reported. Concurrent use of an MAO inhibitor is contraindicated.
(Tetrabenazine is not licensed for use by the U.S. Food and Drug
Administration.)
b. Reserpine (Serpasil) depletes central biogenic monoamine stores
much like tetrabenazine. Treatment is started with 0.25 mg PO daily
and increased slowly to 2 to 4 mg/day. Orthostatic hypotension is a
major problem, during which time the patient must be warned to rise
slowly with careful monitoring of blood pressure. Tolerance usually
develops in 1 to 2 weeks.
c. Other drugs that have been tried in this syndrome with variable
success include baclofen, valproic acid, diazepam, alpha
antagonists, amantadine, clonidine, and carbidopaL-dopa.
H. Tics
1. Description. Tics may be defined as quick, coordinated repetitive movements,
in contrast to the irregular and nonrepetitive quasi-purposeful jerky movements
of chorea. Tics may be defined as simple or multiple and as acute, subacute,
and chronic.
a. Five percent of children develop tics, the vast majority of which disappear
by adolescence. Tics may occur as adverse reactions to stimulants, anoxic
brain injury, and viral encephalitis.
b. The most dramatic tic is the multiple chronic tic syndrome known as Gilles
de la Tourette syndrome. In this disease, tics are first noted between the
ages of 2 and 13 years and intermittently worsen over the lifetime of the
individual. It is more common in males. Patients develop involuntary grunts,
whistles, and cough and may develop echolalia. In about half the cases,
uncontrolled use of offensive language (coprolalia) develops. Other
associated neuropsychiatric symptoms include those of attention deficit
hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD).
These disorders may respond to desipramine and clonidine (ADHD) and
fluoxetine and clomipramine (OCD). Tics may be voluntarily suppressed in
the early stages of the disease.
2. Treatment
a. Haloperidol (Haldol) is the treatment of choice; however, success is limited
by the frequent side effects of drug treatment. The starting dosage is 0.5
mg t.i.d.; the maximum dosage, determined by observation of the onset of
side effects (e.g., sedation, hypotension, and parkinsonism), is usually
between 8 and 16 mg q.i.d. There have been rare reports of leukopenia.
b. Pimozide (Orap), an oral dopamine receptor blocking drug related to
haloperidol, will sometimes be effective when haloperidol fails. The starting
dosage is 1 to 2 mg daily, increasing gradually to 7 to 16 mg daily.
c. Clonidine (Catapres), an a-2-adrenergic agonist, helps in half of patients
on haloperidol with recurrence of the tics. Clonidine is started at 0.1 mg/day
and gradually increased to as high as 2.0 mg/day. Maximum improvement
may not be seen for 6 months. Behavioral symptoms are more responsive
than tics. Sedation, fatigue, and postural hypotension are the main side
effects. The drug should not be withdrawn rapidly because of the possibility
of rebound hypertension.
d. Tetrabenazine has been reported to be useful in young patients.
e. The dopamine and 5-hydroxytryptamine antagonist risperidone
(Risperidol) 0.5 to 9 mg/day, has been reported to be helpful in recent trials.
f. The calcium channel blocking drugs nifedipine, flunarizine, and verapamil
have also been used for this disorder.
g. Botulinum toxin A (Botox) has been used for dystonic tics. Behavioral
approaches to tic control include habit reversal, self-monitoring, and
relaxation (see sec. IV.G.1.b).
V. Tremor
A. Description. Tremor may be defined as an involuntary, regular, and repetitive
shaking of a body part around a fixed point. The anatomic substrate of most
tremors is unknown, but progress has been made in physiologic classification.
B. Classification (Table 15-8). Tremors may be classified according to the following
criteria: distribution, rate, amplitude, and relationship to voluntary movement.
There may be tremor at rest (see sec. IV), tremor with sustained posture (action
tremor), or intention tremor (see sec. III).
TABLE 15-8. Characteristics of Major Tremor Syndromes
C. Action tremor
1. Description. The most common group of tremors to be managed are action
tremors, which are usually of high frequency (7 to 12 cps) and low amplitude.
They may be asymmetric. Action tremors may be induced in normal individuals
under appropriate postural conditions, such as movements requiring extremes
of precision or power (physiologic tremor). The tremor is increased in states of
fatigue, anxiety, weakness, hypercapnia, drug and alcohol withdrawal, and
some metabolic and endocrine conditions (hypoglycemia, uremia, severe
hepatic disease, thyrotoxicosis, and heavy-metal intoxication). Drugs that
exaggerate the physiologic tremor include catecholamines (including
amphetamine), theophylline, caffeine, lithium, tricyclic antidepressants,
steroids, antipsychotic drugs, and sodium valproate. It may be familial. When
it first appears in the elderly, it is known as senile tremor. Otherwise, if there
is no demonstrable cause, it is known as essential tremor. The diagnosis of
essential tremor does not preclude the later development of Parkinson
disease.
2. Mechanism. The anatomic substrate of action tremor is not clear. It appears
that peripheral mechanisms are involved in the genesis of both physiologic
tremor and that associated with thyrotoxicosis. In addition, central mechanisms
are also involved in essential, familial, and senile tremors. Action tremors are
usually synchronous on EMG analysis but may be alternating as seen in
Parkinson disease.
3. Treatment (see Table 15-3)
a. Tranquilizers may be used for anxiety-induced tremors. Diazepam
(Valium), 6 to 15 mg daily in divided doses, would be appropriate.
b. A single dose of alcohol will reduce an action tremor for 3 to 4 hours; its
therapeutic effect begins within 10 minutes of ingestion.
c. b-Adrenergic antagonists
1. Propranolol (Inderal), 40 to 240 mg daily in divided doses, will usually
reduce action tremors within 48 hours of initiation of treatment. A useful
starting dosage is 20 mg b.i.d. Extensive first-pass metabolism occurs in
the liver. Propranolol is contraindicated in asthma and
insulin-dependent diabetes; side- effects include congestive cardiac
failure, intensification of atrioventricular heart block, and bradycardia.
Other side effects include hypotension, nausea, diarrhea, insomnia, and
hallucinations.
2. For patients with asthma, metoprolol (Lopressor), a cardio-selective
beta blocker, is preferred. The starting dosage is 50 mg b.i.d.,
increasing to 100 mg b.i.d. This treatment is usually less effective than
propranolol.
3. When patient compliance is a problem, the water-soluble, long-acting,
nonselective beta blocker nadolol (Corgard) may be used. Since it is
long-acting, a single daily dose of 40 to 80 mg may be used, making it
more convenient than the shorter acting drugs. Because of its water
solubility, nadolol crosses the blood-brain barrier poorly. In some
patients, however, it reduces action tremor, thus indicating that the
effects of beta blockade may be on the peripheral rather than the central
nervous system.
d. Primidone (Mysoline), 25 to 500 mg PO in divided doses, may improve
action tremors. Some now consider primidone to be the drug of first choice
for treating these tremors. The mechanism of action is unknown. Acute
toxicity with this drug may be severe. It should be introduced very slowly to
avoid vomiting and ataxia.
e. Nimodipine (Nimotop) at a dose of 30 mg q.i.d. has also recently been
used to treat action tremor successfully.
f. Botulinum toxin A (Botox) has been used as a method of last resort to
treat essential tremor of the limbs and head (see sec. IV.G).
g. Ventrolateral thalamotomy has been of benefit in severe action tremor
and in congenital rubral and cerebellar intention tremor of the limbs, but not
in head tremors.
D. Orthostatic tremor is an unusual tremor variant manifested as unsteadiness
while standing but steadiness while walking. Little is found on examination.
However, a rapid (16 cps) tremor of synchronous or, occasionally, alternating type
is seen in the lower limbs when under conditions of load. Treatment consists of
low-dose clonazepam (Clonopin), 0.5 to 1.0 mg/day.
VI. Asterixis may be considered a variant of tremor in which the rate of limb flexion
and extension is irregular and usually slow. The EMG indicates that this disorder arises
from temporary loss of tone in the outstretched limb. The anatomic substrate is
unknown, although it has been seen in patients with focal lesions due to vascular
disease. This disorder arises in metabolic diseases (renal, pulmonary, and hepatic), in
Wilson disease, and with some drugs including metoclopramide, hypoglycemics, and
anticonvulsants. Treatment is that of the underlying disorder.
Palatal myoclonus consists of rapid, rhythmic involuntary movements of the soft palate.
The pathogenesis is sometimes due to lesions in the central tegmental tract. In this
situation cerebellar signs are often present and sleep does not interrupt the tremor.
Clonazepam (Clonopin) 0.25 to 3 mg/day and valproic acid (Epilim) 200 to 1,000
mg/day may be helpful.
VII. Myoclonus
A. Description. The term myoclonus refers to the rapid, irregular, jerking movements
commonly appreciated as night start, which interrupts the steady drift into sleep.
The anatomic substrate for myoclonus is not known as there is usually diffuse
neuronal loss in cerebrum and cerebellum, including the dentate nucleus.
Aminergic mechanisms in the raphe nuclei have been implicated. Physiologically it
often appears to be temporally related to an epileptiform slow wave on the
electroencephalogram. The myoclonic jerk is followed by a transient inhibition of
normal postural mechanisms. Myoclonus has many causes and is characterized
by (a) brief, shocklike contractions, the EMG of which resembles, but is often
shorter than, the EMG of a normal muscle contraction, and (b) the stimuli that
induce the myoclonus. For example, intention myoclonus is found in patients with
hypoxic brain damage; this type of myoclonus has brief, shocklike contractions.
B. Treatment. Acquired causes of myoclonus include infections (encephalitis,
meningitis, syphilis, toxoplasmosis); metabolic conditions (hypoxia, uremia,
hepatic encephalopathy), poisons and drug intoxications (imipramine, penicillin,
chlorambucil, L-dopa, lithium, MAO inhibitors, piperazines, thallium), and
neuroblastoma. Treatment is directed at the underlying condition. Some
dementias have associated myoclonus that is resistant to treatment. These
include J akob-Creutzfeld disease, Alzheimer disease, Lewy body disease, Wilson
disease, progressive poliodystrophy in children, and subacute sclerosing
panencephalitis. Progressive myoclonic epilepsy is described in Chap. 6.
Unfortunately, specific treatment of myoclonus is generally unsatisfactory.
Occasionally, the following drugs are effective:
1. Clonazepam (Clonopin), 7 to 12 mg daily in divided doses, starting with 1.5
mg daily and increasing over 4 weeks.
2. Valproic acid (Epilim) in gradually increasing doses (up to 1,600 mg/day) has
been useful in posthypoxic myoclonus.
3. Piracetam, 18 to 24 g/day, has been reported as useful adjunctive therapy in
myoclonus.
4. 5-Hydroxytryptophan (5-HTP), 150 to 1,600 mg PO daily divided into 2 to 4
doses, with and without carbidopa, has been used in the treatment of
posthypoxic myoclonus with some success. A suggested protocol is 5-HTP,
100 mg, and carbidopa, 25 mg, increasing every second day to the maximum
tolerated dose, usually around 3 g/day. Gastrointestinal upset is a common
problem but often can be managed with antiemetics. Euphoria and mania may
occur at higher doses. A sclerodermalike illness has been reported as a
complication.
5. Tetrabenazine has been shown to be useful in spinal myoclonus.
VIII. Hyperekplexia, or familial startle disease, is an autosomal dominant disorder
characterized by an exaggerated startle reaction to sudden unexpected auditory or
tactile stimuli. It is caused by a point mutation in the a
1
subunit of the glycine receptor.
Clonazepam (Clonopin) is the treatment of choice. Stiff man syndrome is a chronically
progressive condition of stiffness and rigidity in axial and then proximal limb muscles
making voluntary movement and ambulation difficult (Frankenstein gait). A fixed spinal
deformity is common. Episodic spasms may be precipitated by sudden movement,
jarring noise, and emotional upset. EMG shows continuous motor unit activity that is
abolished by intravenous administration of diazepam. An autoimmune pathogenesis is
suspected and antibodies to the enzyme glutamic acid decarboxylase is found in two
thirds of the cases. First line treatment consists of corticosteroids and plasmapheresis.
IX. Restless legs syndrome is characterized by unusual sensations in the
muscles and bones of the lower legs that occur at rest, most frequently at night, and
that disappear on movement. The etiology and pathogenesis are usually unknown,
although the syndrome may be seen in patients with chronic renal failure. Restless legs
syndrome may also be seen in association with periodic movements during sleep,
and the treatment of the 2 syndromes is the same. Both cause insomnia. Treatments
have included anticonvulsants (clonazepam and carbamazepine), dopaminergic
agents (L-dopa and bromocriptine), clonidine, and opioids (see Chap. 16, sec.
XVIII.H).
Selected Readings
Freeman TB. From transplants to gene therapy for Parkinson disease. Exp Neurol 1997;144:47.
Hoehn MM, Yahr MD. Parkinsonism: onset, progression, and mortality. Neurology 1967;17:427.
Penn RD. Medical and surgical treatment of spasticity. Neurosurg Clin North Am 1990;1(3):719.
Stern MB, ed. The changing standard of care in Parkinson disease. Current concepts and controversies.
Neurology 1997;49[Suppl 1].
Tasker RR, Lang AE, Lozano AM. Pallidal and thalamic surgery for Parkinson disease. Exp Neurol
1997;144:35.
CHAPTER 16. DISEASES OF NERVE AND MUSCLE
Manual of Neurologic Therapeutics
CHAPTER 16. DISEASES OF NERVE AND MUSCLE
Thomas M. Walshe III
Electrophysiologic tests
Muscle biopsy
Nerve biopsy
General principles on the chronic use of corticosteroids
Muscular dystrophy
Myotonia and myotonic dystrophy
Polymyositis
Trichinosis
Rhabdomyolysis
Glycogen storage diseases
Carnitine deficiency
Episodic muscle weakness and the ion channel diseases
Myasthenia gravis
Lambert-Eaton myasthenic syndrome (LEMS)
Botulism
Tetanus
Malignant hyperthermia and neuroleptic malignant syndrome
Neuropathy
Motor system disease
Disorders of muscle, of the myoneural junction, of the peripheral nerve, or of the motor
neuron improve with specific therapy when the underlying pathophysiology is
understood. When there is no specific therapy, however, the management controls
symptoms, retards progression, increases the time of remission, and improves the
quality of the patient's life. The treatment plan of neuromuscular disorders requires the
skills of physicians, physical therapists, social workers, and other providers. The
severity and progression of the disease dictates the complexity of the management
plan.
I. Electrophysiologic tests are used to support the clinical diagnosis, to assess
the severity, and to monitor the progression or improvement in neuromuscular diseases.
There are 4 parts in the neurophysiologic evaluation of a patient with a neuromuscular
disorder.
A. Motor conduction velocity in large myelinated fibers can be calculated by
recording the time a standard current takes to produce a twitch when the distance
between the stimulus and the reacting muscle is known. Nerves in the upper and
lower extremities as well as the facial nerve can be tested.
Nerve conduction velocity can remain normal for up to 7 days following section of
a nerve, and denervation changes might not appear for 10 to 21 days following
section. Most patients with axonal neuropathies (e.g., nutritional) have slightly
reduced conduction velocity, but the reduction may be so slight that it is only in the
low-normal range. Neuropathies that affect myelin early (and show segmental
demyelination pathologically) reduce nerve conduction velocities. Acute
inflammatory demyelinating polyneuropathy (AIDP), diphtheria,
Charcot-Marie-Tooth disease, metachromatic leukodystrophy, and entrapments
often show definite slowing. When the nerve is completely degenerated, there is
no way to measure nerve conduction velocity.
B. Sensory conduction velocity reflects the time it takes for an evoked potential to
be recorded at a site that is distal along a nerve. In the upper extremity, the
median, ulnar, and radial nerves can be tested easily. In the lower extremity, the
sural, saphenous, deep peroneal, and lateral femoral cutaneous nerves are
accessible. In addition, neural action potentials can be recorded by stimulating a
mixed nerve. Changes in amplitude and conduction time of the neural action
potential (whether from a sensory or mixed nerve) are useful in the evaluation of
nerve entrapment syndromes, axonal neuropathies, or demyelinating
neuropathies.
C. Late responses
1. The Hoffman reflex (H reflex) is an electrical equivalent to a deep tendon
reflex that assesses both sensory and motor function. It can be elicited only
from the soleus muscle in adults. A submaximal stimulus is applied to the tibial
nerve, by which it follows the IA afferent fibers to the spinal cord, where it
synapses with the motor neurons and causes a direct motor response and a
delayed or H-reflex response. The H reflex may be absent or prolonged in
neuropathy when other conduction studies are normal. S1 radiculopathy also
prolongs the H reflex. Patients with AIDP frequently have an abnormal H reflex.
2. The F response can be measured in both upper and lower extremities. It is
elicited by supramaximal stimulation to a nerve, so the impulses travel
antidromically in the efferent parts of the nerve. There is no synapse. In normal
patients, the F response and the H reflex vary with the height of the patient.
Abnormal late response latency may occur in neuropathy or radiculopathy
even when the other studies are in the normal range. The F response is not
sensitive in identifying radiculopathy.
D. Magnetic stimulation can be used instead of electrical stimulation to study nerve
conduction. The present technology does not provide adequate stimulus
localization to warrant routine use, although it has been used in the diagnosis of
radiculopathy.
E. The electromyogram (EMG) assesses the electrical characteristics of muscle.
Signs of denervation include fibrillations, positive sharp waves, reduced
interference pattern, and polyphasic units; such signs may support the suspicion
of neurogenic disease.
Primary muscle disorders have nonspecific and variable EMG patterns, usually
with reduced amplitude. Myotonia and myasthenia gravis show distinct EMG
patterns, which are described in sec. VI and sec. XIII, respectively.
F. The neurophysiologic studies are valuable to the clinician to separate different
classes of disease and to make specific diagnoses.
1. Nerve conduction studies
a. Separate the axonal neuropathies from the demyelinating neuropathies.
b. Identify entrapments of single nerves.
2. EMG
a. Identifies denervation of muscle in motor neuron disease, radiculopathy,
and other denervation.
b. Identifies myasthenia gravis or Lambert-Eaton syndrome.
c. Adds support to the clinical impression of the presence of a myopathy and
specifically identifies myotonia.
II. Muscle biopsy is safe and may resolve a diagnostic problem, allowing specific
diagnosis and treatment of myopathy. Whenever there is a clinical syndrome that
indicates an abnormality of muscle, a muscle biopsy should be considered.
A. Disorders with a specific appearance on muscle biopsy
1. Progressive muscular atrophy and dystrophy.
2. Localized or diffuse inflammatory disease of muscle.
3. Systemic disease that is suspected to be vasculitis or collagen-vascular in
nature.
4. The state of denervation in the muscle after injury to nerves and vessels of a
limb.
5. To diagnose congenital and metabolic myopathies.
B. Ideally, the neuropathologist responsible for making the diagnosis should be
present when the biopsy is done to ensure that the correct muscle is sampled and
that the sample is handled correctly. The studies to be performed are set up in
advance, and the specimen is fixed in the operating room. The specimen must be
suitable for light and electron microscopy, and histochemical stains of frozen
sections are essential on frozen specimens. Muscle biopsies taken from an area
tested with an EMG needle are often uninterpretable due to the needle trauma.
III. Nerve biopsy is done when a specific etiology is suspected. However, the
diagnosis can usually be made by other means. Painful dysesthesia is an occasional
complication of sural nerve biopsy.
A. Nerve biopsy may be pathognomonic in:
1. Sarcoidosis.
2. Metachromatic leukodystrophy.
3. Amyloidosis.
4. Polyarteritis nodosa.
5. Leprosy.
6. Hereditary neuropathies.
B. In the majority of cases of peripheral neuropathy nerve biopsy yields nonspecific
information and is not used routinely. Electron microscopy is essential for
separating axonal degeneration from segmental demyelination.
IV. General principles on the chronic use of corticosteroids.
Corticosteroid therapy requires careful thought about its indications, and once started it
requires careful observation of the patient. The complications and adverse responses to
corticosteroids are time- and dose-related. Therefore, long-term corticosteroid therapy is
best avoided unless it produces a definite advantage.
As a general rule, other therapeutic agents are tried before corticosteroids are begun. In
neuromuscular diseases, however, there are few choices, and a corticosteroid is often
needed. When possible, less hazardous agents should be used to allow the lowest
possible dose of corticosteroid.
A. Complications during corticosteroid use. Iatrogenic Cushing syndrome,
diabetes mellitus, osteoporosis, activation of tuberculosis, hypertension,
psychosis, and increased susceptibility to infection are seen in some patients
treated with corticosteroids. Also, some patients treated with high doses of
corticosteroid for long periods have a tendency for gastric ulceration and bleeding.
B. Considerations in stopping corticosteroid. Three problems might arise when
corticosteroids are stopped.
1. Suppression of the adrenal gland (hypothalamic-pituitary-adrenal axis) occurs
regularly when the duration of therapy is longer than 1 week with dosages
equivalent to prednisone, 20 to 30 mg/day in divided doses. Complete recovery
may take up to 1 year. With doses closer to the physiologic level, suppression
may not occur for a month.
Patients who have been treated with pharmacologic doses of corticosteroids
usually need no replacement therapy, but they may require steroid coverage
during acute illness or other stress.
2. Steroid withdrawal symptoms (anorexia, nausea, vomiting, lethargy,
headache, fever, arthralgia, myalgia, or weight loss) may occur after chronic
treatment is discontinued. Symptomatic treatment and small doses (10 mg) of
cortisol for several weeks may help.
3. Acute exacerbation of the underlying disease is a major concern when
steroids are stopped. Very gradual reduction of the dosage helps to prevent
acute flare-ups.
C. Choice of drugs
1. Prednisone is the standard short-duration oral corticosteroid used in the
treatment of neuromuscular disorders. Prednisone (and cortisone) are
activated in the liver, and in severe liver failure the active parenteral forms
(prednisolone or cortisol) are given.
2. Corticosteroids are preferred to adrenocorticotropic hormone (ACTH)
because they can be given PO and the dose is more precise. With
corticosteroids, adrenal gland function does not determine the blood level of
hormone, and there are fewer side effects. Although ACTH does not suppress
the adrenal gland, neither does short-acting corticosteroid therapy used on
alternate days.
D. Treatment course
1. Corresponding dosages of various corticosteroids are given in Table 16-1.
Corticosteroids can be given in divided daily doses, a single morning dose, or a
morning dose every other day. In short treatment courses of less than 1 month,
the dosage schedule does not matter. In chronic treatment, divided daily doses
produce iatrogenic Cushing syndrome, adrenal suppression, and increased
susceptibility to infection.
TABLE 16-1. Common Corticosteroid Drugs
2. Daily therapy. The short-acting corticosteroids used chronically as a single
morning dose produce less suppression of the adrenal gland, but they do not
prevent iatrogenic Cushing syndrome. The therapeutic effect of a single
morning dose is the same as divided doses in most illnesses. Thus, when
chronic daily therapy is required, the single-dose schedule is preferred.
3. Alternate-day corticosteroid therapy (twice the daily dose given on alternate
days) helps to prevent suppression of adrenal function and iatrogenic Cushing
syndrome. There is some evidence that it also prevents increased
susceptibility to infection.
Most neuromuscular diseases respond favorably to alternate-day
therapy. In early-morning single-day therapy and alternate-day therapy,
long-acting corticosteroids (e.g., dexamethasone) are not suitable because
they do not allow a sufficient period of low steroid level in the blood to prevent
side effects.
4. To change from a daily dose to the alternate-day plan, merely increase the
dosage gradually on one day, while reducing the dosage by the same amount
on the alternate day. At the same time, in the case of divided daily doses, the
frequency of the dose is reduced until the whole dose is given in the morning.
V. Muscular dystrophy
A. Description
1. A dystrophy is a chronic inherited myopathy characterized by progressive
muscular weakness and loss of muscle bulk. Pathologically, the number of
muscle fibers is reduced, and the remaining fibers are variable in size. Loss of
muscle bulk from defects in the nerve or motor neuron, usually called atrophy,
shows a different pathologic change. There are several types of dystrophy
(Table 16-2).
TABLE 16-2. Types of Muscular Dystrophy
a
2. The rate of progression and the severity vary with both the type of dystrophy
and the individual case. The Duchenne dystrophies are usually the most
severe, and the majority of these patients die by the age of 20 years. Patients
with other dystrophies survive into adulthood. Those with mild, restricted
dystrophies may live a near normal life.
3. The pathophysiology of many of the muscular dystrophies remains unknown.
However, recent investigations suggest that a defect in the muscle cell
membrane is the underlying abnormality. A deletion mutation at the Xp21 locus
(on the short arm of the X chromosome) is the cause of Duchenne or Becker
muscular dystrophy. The gene product, dystrophin, is absent in the muscle
membrane of patients with Duchenne dystrophy and is reduced in amount or is
of altered molecular weight in patients with Becker dystrophy, a less severe
variant. There are several genetically determined families of abnormal proteins
that are related to abnormal muscle molecular physiology in the dystrophies.
The molecular pathophysiology of the slowly progressive dystrophies (FSH,
limb-girdle) is gradually being worked out and more specific identification of
subtypes is now possible.
B. Diagnosis
1. The history and signs of muscle weakness and wasting in a child or young
adult suggest the diagnosis. However, there are no absolute clinical criteria for
separating neurogenic atrophy from dystrophy. Separation of the various
dystrophies is made by the distribution of muscle involvement, speed of
progression, and other clinical characteristics (see Table 16-2). Table 16-3 lists
some differences that might be useful in distinguishing atrophy and dystrophy.
TABLE 16-3. Separation of Neurogenic from Myopathic Disorders
2. Muscle biopsy is helpful in diagnosing dystrophy and identifying certain
benign congenital myopathies (e.g., central core, nemaline) that may resemble
dystrophy. The muscle biopsy is taken from an involved muscle, but not one
that is severely weak. The deltoid or gastrocnemius is often used in patients
with dystrophy, but the rectus abdominis may be a better choice because there
is less of a problem with postoperative immobilization, which causes disuse
weakness.
3. DNA analysis on blood by polymerase chain reaction may demonstrate a
defect in up to 70% of patients with Duchenne or Becker muscular dystrophy.
The test can be done on cultured tissue from a fetus also. Dystrophin assay on
muscle biopsy can distinguish the Duchenne and Becker variants from each
other and from other myopathies in which dystrophin is normal. Although the
combination of the two tests is highly reliable in making the diagnosis, most
clinicians omit the biopsy if a deletion is found on the blood test. Dystrophin
analysis separates Duchenne from Becker dystrophy.
C. Treatment
1. Mild cases need no therapy early in the course. Careful motor assessment at
6- to 12-month intervals is usually enough.
2. In severe cases, especially in patients with Duchenne dystrophy, the family
must be made aware of the natural history of the disease.
a. Knowledge that faithful compliance with therapeutic directions helps to
prolong the patient's independence should encourage the family to help.
However, when the disease is obviously progressing, there often is
disappointment. Thus, it is important to maintain a guarded hope for
stabilization so the physical program will be maintained.
b. Since many dystrophy patients are children, a treatment plan should
include education and meeting social needs. For example, children can
usually remain in normal schools until they cannot climb stairs easily. In
Duchenne dystrophy, however, the intelligence quotient (IQ) is often
reduced (many are below 90), and earlier transfer to special schools might
be indicated.
c. The goal of therapy is more than keeping the patient ambulatory. The
patient who must spend most of the time concerned with the disease
misses the purpose of therapy. The family and the patient should be
encouraged to maintain as normal a life as possible for as long as possible.
3. Prednisone (0.75 mg/kg/day) can improve strength in Duchenne dystrophy,
but potential risks outweigh benefits so routine treatment is not recommended.
Steroid treatment should be considered in acute situations, such as sudden
worsening of respiratory function due to pneumonia or atelectasis. Boys
treated with steroid need to keep a low-fat, low-sodium diet to prevent weight
gain. If exposed to chickenpox, the steroid-treated boy should receive zoster
immune globulin.
4. Physical treatment
a. Intensive physical therapy is begun early to prevent contractures. The
family and patient are instructed in home exercises. Physical therapy is
accepted better before contracture and deformity occur.
b. Goals are to maintain good alignment in the weight-bearing joints and to
prevent contractures. Flexion contractures are common around hips,
ankles, and knees, since the flexors are often slightly less involved than the
extensors. Bracing the feet at night is a simple measure which delays
contracture of the ankles.
c. Range-of-motion exercises, instruction in proper positioning in bed and in a
chair, frequent changes of position, and early use of splints, when
necessary, help to prevent contractures that make nursing care difficult and
impede ambulation.
d. There is no evidence that exercise retards the progression of muscular
dystrophy. Most children are maximally active by nature without a planned
exercise program. Physical therapy can help to advise about specific
methods to optimize function provide bracing and teach flexibility exercises.
5. Respiratory care
a. Swallowing and respiratory difficulty occur in severe, generalized
dystrophy and in pharyngeal dystrophy. Respiratory decompensation is
usually a gradual process and occurs late in the course.
b. Pulmonary function tests often are abnormal, even in patients with
superficially normal respiratory reserve. Patients are encouraged to develop
diaphragmatic breathing by using blow bottles or playing wind instruments
(e.g., harmonica). Breathing exercises, taught by a therapist, are also
helpful.
c. Later in the course of the disease, intermittent positive pressure breathing
and postural drainage may become necessary.
d. A rising PCO
2
in patients without pulmonary infection is usually a bad
prognostic sign in dystrophy because about 80% of severe muscular
dystrophy patients die from respiratory causes. Muscular dystrophy patients
are rarely intubated late in the course of illness.
6. Gait maintenance
a. Obesity is treated vigorously to improve the patient's ability to walk and to
prevent hypoventilation.
b. Patients are asked to walk for a least 3 hours each day; if they are not
ambulatory, they are instructed to stand for 3 hours in divided periods (30
minutes q34h).
c. As the disease progresses, independent ambulation can be maintained with
crutches, braces, and surgical procedures. The wheelchair is avoided as
the primary means of mobility until ambulation is impractical.
d. Patients may become weaker during acute illnesses, but bed rest usually is
contraindicated because weakness invariably follows prolonged bed rest,
and such weakness might become permanent.
7. Preventive therapy/genetic counseling. When the inheritance of a disease is
known, it is often possible to predict the probability of the disease's occurring in
offspring of affected parents. An important aspect in the care of muscular
dystrophy is advising the family about recurrence rates in future generations.
a. Sex-linked recessive disorders (Duchenne dystrophy)
1. Inheritance. A known carrier can be told that there is one chance in two
of producing a dystrophic male or a carrier female. However, about one
third of patients have no prior family history.
2. Carrier detection. The serum creatine kinase (CK) will be elevated in
approximately half of obligate carriers. The enzymes should be checked
at least 3 times, 10 days apart, since levels may fluctuate. It is best to
avoid excessive exercise prior to the test because this may result in
confusion if the serum enzyme levels are elevated. A normal result does
not exclude the possibility of the carrier state. Sixty to sixty-five percent
of families have Duchenne muscular dystrophy/Becker muscular
dystrophy mutations associated with intragenic deletions of the
dystrophin gene. Once an affected male is diagnosed, the carrier status
can be determined by detecting the same deletion in 1 of the 2
dystrophin alleles of a female at risk. In other cases, restriction fragment
length polymorphism linkage analysis can be used. Carrier detection is
accurate in 85% to 90% of girls tested.
3. Prevention. Several choices are open to couples who carry the
abnormal gene:
a. Voluntary sterilization, contraception, or fertilization and implantation
of an egg from a noncarrier with the husband's sperm.
b. In utero determination of the disorder with abortion of all affected
males.
4. Spontaneous mutation occurs in one third of Duchenne dystrophy
patients. The more normal children a woman has before a dystrophic
child is born, the smaller the probability that she is a carrier. If the
mother of a dystrophic child is not a carrier, the chance of her having
another dystrophic child is small.
b. Autosomal dominant disorders (facioscapulohumeral [FSH]
dystrophy, myotonic dystrophy, and late distal dystrophy)
1. Inheritance. Although the typical halting FSH dystrophy is usually an
autosomal dominant trait, there are cases that are clinically similar that
are autosomal recessive or sex-linked.
The severity of the disease varies. The affected person has one chance
in two of having an affected offspring when there is autosomal dominant
inheritance.
2. There are no carriers.
3. Prevention is by contraception. Artificial insemination from a
nonaffected male or egg donation from a nonaffected female may be
used to produce normal offspring.
c. Autosomal recessive disorders (limb-girdle)
1. Inheritance. Both parents must have the trait before the offspring are
affected. If both parents are carriers, 1 in 4 children will have the
disease, 2 in 4 will be carriers, and 1 will not be affected at all.
2. Prevention. Contraception and avoidance of consanguineous marriage
can help prevent these diseases.
VI. Myotonia and myotonic dystrophy
A. Description
1. Thinning of the muscles of the face and neck causes an expressionless
countenance, with poor movement of the mouth. The patients have ptosis and
the muscles of the hands and forearms are thinned.
2. On contraction and relaxation the muscles feel stiff. Percussion myotonia may
be elicited in the muscles or the tongue. The myotonia usually is not severe.
3. The myotonia of myotonic dystrophy and congenital myotonia (Thomsen
disease) are treated with the same drugs. In congenital myotonia without
dystrophy, the myotonia is usually much more severe. Myotonia is also seen in
hyperkalemic periodic paralysis. The myotonia in Thomsen disease is
considered to be caused by an abnormality in the chloride channel.
4. The EMG shows a decremental pattern without a plateau on repetitive
stimulation as well as the characteristic myotonic irregular-pattern
afterpotentials.
5. Hypogonadism, cataracts, mental retardation, and esophageal dysfunction are
often associated problems.
6. The disease is usually an autosomal dominant trait, and it may appear from
early infancy to adulthood.
B. Treatment
1. Drugs that act on the muscle cell membrane are used for myotonia.
a. Phenytoin (Dilantin), 5 mg/kg/day PO, is effective and has fewer cardiac
side effects than the other agents. It is the usual first choice.
b. Procainamide, up to 50 mg/kg/day PO, divided into 3 or 4 doses.
c. Quinine, 5 to 10 mg/kg/day PO, divided into 6 doses.
d. Corticosteroids have been used in severe cases (see sec. IV).
e. Diazepam (Valium) has no effect.
2. Respiratory care. Intercostal myotonia may interfere with regular breathing
and present respiratory complications, even when there is little myotonia in the
limbs. Patients with myotonic dystrophy often have oropharyngeal dysfunction
and may develop aspiration pneumonia.
3. Treatment of the dystrophy depends on its severity. Usually the weakness is
much more of a problem than the myotonia, and often the myotonia needs no
therapy.
VII. Polymyositis
A. Description
1. Polymyositis is an inflammatory autoimmune muscle disease that causes
weakness and fatigue. The natural history of the disease varies, relapsing and
remitting when treated and occasionally improving spontaneously. Cancer,
cardiac involvement, older age of onset, and delay of treatment are each
associated with a poor prognosis. Other organ systems are also involved in
polymyositis. Interstitial lung disease is one of the most common
complications.
2. The clinical features of polymyositis are variable, but proximal muscle
weakness is the rule. The disease is occasionally acute and may progress in
weeks to complete disability. Some patients have a subacute course that
evolves over several months; those with acute onset may have associated
myoglobinuria. The face is often spared, and muscle atrophy is a late sign.
Pharyngeal muscle involvement may produce dysphagia, but speech usually
remains normal. Also, the posterior neck muscles are often weak. Some
patients develop an erythematous skin eruption on the dorsum of the hands,
proximal digits, knees, or elbows, or a purple discoloration and edema of the
eyelids. Some patients also develop sclerodactyly. Patients with skin
involvement are said to have dermatomyositis, but the therapeutic approach is
the same as for polymyositis. Cardiac involvement occurs in up to 30% of
patients.
B. Diagnosis
1. Muscle enzymes (CK, transaminase, and aldolase) are usually elevated, but
they may be normal in some cases.
2. The erythrocyte sedimentation rate does not correlate reliably with the
activity of the disease.
3. The EMG is nonspecific, but it usually suggests a primary myopathic process
with brief, small-amplitude polyphasic motor units. However, positive sharp
waves, fibrillations, and high-frequency repetitive discharges are also
frequently seen.
4. Muscle biopsy shows an inflammatory infiltrate and necrosis of muscle fibers
in about 85% to 90% of patients. Often several biopsies must be taken to get a
diagnostic specimen.
5. Differential diagnosis
a. Other diseases that may be confused initially with polymyositis are:
1. Paroxysmal myoglobinuria.
2. Parasitic myositis.
3. Polymyalgia rheumatica.
4. Muscular dystrophy.
5. Thyrotoxic and other endocrine myopathies.
6. Diabetic amyotrophy.
b. Appropriate study and muscle biopsy usually distinguish these diseases
from polymyositis.
c. Relation to cancer. Polymyositis has been linked to occult cancer, but
recent reports have refuted the high incidence of occult cancer in patients
with polymyositis. However, patients with true polymyositis, rather than
muscle wasting from cachexia, have a 20% incidence of cancer. Patients
with dermatomyositis and those who have evidence of denervation on EMG
may have a higher incidence of cancer.
C. Treatment
1. Corticosteroids
a. Corticosteroids have been found to benefit patients with polymyositis,
although no controlled trials have been done. Mortality is not affected by
corticosteroids, but remission is more rapid, and there is less morbidity
when corticosteroids are used. Corticosteroids are usually used in
combination with either methotrexate or azathioprine.
b. Patients who have had disease of acute onset for a short time are most
likely to benefit from corticosteroid therapy. However, those with chronic
polymyositis and atrophy may not improve with steroid therapy. In chronic
cases, when there is no improvement in 2 months, there will usually be no
success with corticosteroids (see sec. VII.C.2.b).
c. Dosage
1. The usual beginning dosage of prednisone is 60 to 100 mg PO every
morning until improvement occurs; then the dosage may be reduced to
40 mg and maintained for several months.
2. Dosage reduction. After the initial treatment, the prednisone dosage is
reduced slowly by 5 to 10 mg every 3 to 7 days to prevent flare-up of the
disease. The dosage is kept at around two thirds of the original dosage
for several more months. As the dosage is reduced, each change
represents a larger percent change. Therefore, as the dosage is
decreased, longer intervals are needed to prevent a relapse. In 6 to 12
months, most patients can be dropped to a maintenance level (15 to 20
mg every morning) and kept there. If the disease remains quiescent,
alternate-day corticosteroid therapy (30 to 40 mg every other day) is
recommended for most patients. If exacerbation occurs, high dosages
are resumed and maintained until signs of improvement occur.
Response to therapy and relapse can be monitored in most cases by
muscle enzyme determination.
3. Attempts at steroid withdrawal should be made after the first 24
months of therapy, since activity of the disease often subsides after 2
years. Most cases are quiescent after 8 years.
4. Low doses of corticosteroids are not useful in bringing active
polymyositis into remission.
d. Steroid myopathy. The occurrence of steroid-induced myopathy in
patients with chronic polymyositis can complicate therapy. Steroid
myopathy should be suspected if the patient's weakness seems to increase
while muscle enzymes and EMG remain unchanged. Increased type II
muscle fiber atrophy on muscle biopsy is also suggestive of steroid-induced
myopathy. Women with polymyositis seem to be more susceptible to
steroid-induced myopathy, so lower doses of prednisone should be used
when possible. Biopsy usually is not needed for confirming the diagnosis of
steroid-induced myopathy; it is usually sufficient to reduce the dose of
steroid, and if improvement follows, one can assume that the weakness
was from the drug. Management requires reduction of steroids to a
maintenance level and observation for a rise in muscle enzymes. If the
enzymes rise and further deterioration occurs, high-dose cortico-steroid
therapy is restarted.
e. Follow-up. The muscle enzymes (serum glutamic-oxaloacetic
transaminase [SGOT], CK, and aldolase) are useful indicators of disease
activity, although in some cases all the enzymes or all but one may remain
normal. The enzyme levels may fall for several weeks before clinical
improvement is seen, and they may rise before weakness occurs in a
relapse.
2. Immunotherapy
a. Indications. Immunosuppressive drugs may be of benefit in chronic
progressive polymyositis in patients who are not improved by corticosteroid
therapy and in those who have intolerable complications of steroid therapy.
b. Immunosuppressive drugs may allow a smaller dosage of corticosteroid,
or they may be effective if used alone.
1. Methotrexate
a. Dosage. Up to 75% of steroid-resistant patients respond when
methotrexate is added to corticosteroid therapy. The drug must be
given IV over 20 to 60 minutes. In patients with normal liver and
kidney function, the starting dosage is 0.4 mg/kg per treatment, and
it is increased to a maximum of 0.8 mg/kg per treatment in 2 to 3
weeks.
b. Frequency. Methotrexate is given weekly at the onset. As
improvement occurs, the frequency is reduced to biweekly and then
triweekly. When improvement is maximal, monthly doses are given
for 10 to 24 months. Cortico-steroids may be reduced as
improvement occurs.
c. Toxicity of methotrexate includes stomatitis and gastrointesintal (GI)
complaints, which usually subside with reduction of the dosage.
Leukopenia and hepatic toxicity may occur and, when severe,
require that the drug be stopped.
2. Azathioprine (Imuran), 1.5 to 2.0 mg/kg PO, is used in patients with
polymyositis, either alone or with prednisone. Over the short term, there
seems to be little benefit in adding azathioprine to prednisone.
Azathioprine may be of use in long-term treatment, in patients who fail
on prednisone, or in patients who do not tolerate prednisone. When
used, the dosage is gradually increased until the white blood cell count
(WBC) becomes depressed, and that dosage is continued until
remission of the myositis occurs. Major side effects are bone marrow
suppression, anorexia, nausea, vomiting, and jaundice.
3. Other therapeutic measures
a. Intravenous immunoglobulin G (IVIG) has been used in some cases of
polymyositis but there is not yet convincing evidence that it is better than
corticosteroids. In human immunodeficiency virus (HIV)-related myositis
and in cases refractory to steroids, IVIG is an option that has brought
improvement in some cases. It may be used in some patients to avoid the
adverse effects of steroid treatment. Plasma exchange is another
second-line treatment for myositis.
b. Bed rest is essential in acute cases.
c. As the patient improves, physical therapy is indicated for range-of-motion
exercises.
d. Patients with chronic weakness may benefit from braces and other
physical measures.
VIII. Trichinosis
A. Description
1. Incidence. In the United States, there are less than 100 recorded cases per
year of infestation with Trichinella spiralis, a nematode that affects skeletal
muscle.
2. The clinical syndrome varies as the parasite moves from the GI tract, through
the lymphatics, to the bloodstream, and finally as it ends as an encapsulated
embryo in the skeletal muscle. Nausea, vomiting, and diarrhea may occur
acutely, with a low-grade fever. Fatigue and edema of the eyelids and face are
common. Myalgia and muscle tenderness occur later. Occasionally, isolated
muscle weakness may produce a focal sign (e.g., diplopia), but weakness is
generalized and mild. Eosinophilia is present early, and muscle biopsy often
demonstrates the parasite.
3. Disease course. Onset of the syndrome is usually within 2 to 3 days of
ingestion of the parasite, and improvement begins at 4 weeks. By 2 months,
symptoms are usually gone. The disease is seldom fatal, and its severity
depends on the size of the inoculum.
4. Etiology. Undercooked game animals are the most common source of
infection (pigs are now rarely fed uncooked garbage, so there is less trichinosis
in the pig population). Bear and walrus have been implicated as sources of
trichinosis.
B. Treatment
1. Corticosteroids can be used to improve the symptoms. Prednisone, 60 mg in
the first 24 to 48 hours, may be given, with subsequent reduction to 20 mg/day
for 7 to 10 days or until the patient improves.
2. Thiabendazole, 25 mg/kg b.i.d. PO for 7 to 10 days, relieves the acute
symptoms in some patients. Also, it acts to destroy the capsule of the
Trichinella embryo. Side effects occur in about half of patients treated with
thiabendazole and include anorexia, nausea, vomiting, dizziness, lethargy,
headache, and elevation of liver enzymes. Mebendazole is another
broad-spectrum antihelminthic used in trichinosis. The dose is 200 to 400 mg
t.i.d. for 3 days, increasing to 400 to 500 mg t.i.d. for 10 days.
IX. Rhabdomyolysis
A. Description. Any process that disrupts the muscle cell can lead to the release of
myoglobin and other muscle protein into the plasma. Major associated conditions
include trauma, strenuous exercise, heat stroke, polymyositis, alcohol ingestion,
licorice ingestion, McArdle disease, diabetic acidosis, and hyperkalemia. There
are also familial cases (Myer-Betz disease) in which myoglobinuria may follow
exercise or infection. Three major complications of rhabdomyolysis might occur
that require treatment:
1. Respiratory distress from weakness of respiratory muscles is a rare problem.
2. Hyperkalemia might occur because of the necrosis of muscles and may lead
to lethal cardiac arrhythmia.
3. Acute renal failure occurs when plasma myoglobin concentration is high.
4. Treatment is strict bed rest, osmotic diuresis for prevention of renal failure,
and maintenance of electrolyte balance.
X. Glycogen storage diseases
A. McArdle disease (deficient muscle phosphorylase)
1. Description. Pain and stiffness on physical exertion in young adults is the
mark of deficient muscle phosphorylase. Blood lactate does not rise following
exercise, and weakness and wasting are rare. When the stiffness is severe,
shortening of the muscles may occur. The EMG of the shortened muscles
shows physiologic contracture with electrical silence; muscle glycogen is
elevated on biopsy.
2. Treatment
a. The amount of exercise is reduced automatically by the patient, and that
alone may provide relief in the early stages.
b. Ingestion of glucose or fructose (20 to 45 g t.i.d.) might increase exercise
tolerance, but the treatment can lead to obesity.
c. Drugs that raise the concentration of free fatty acids may be used,
including:
1. Fenfluramine, 20 mg b.i.d.
2. Isoproterenol, 10 to 20 mg daily.
d. Glucagon has been used to produce hyperglycemia, and it may increase
tolerance in some patients.
B. Pompe disease (acid maltase deficiency)
1. Description. Pompe disease usually occurs in the first few months of life; it is
associated with an enlarged heart from cardiomyopathy and hypotonia. Death
usually occurs before 12 months, and diagnosis is made on muscle biopsy. An
adult form exists.
2. Treatment. No definitive treatment is available, although there have been
reports of improvement with a high-protein, high-fat diet. Some investigators
have attempted bone marrow transplant to improve the disorder.
C. Phosphofructokinase deficiency
1. Description. The clinical picture is very similar to McArdle disease, but there is
less pain associated with the stiffness. There are very few cases studied, but
the inheritance seems to be autosomal recessive, since both parents generally
leave low phosphofructokinase in muscle.
2. Treatment. There is no accepted method of treatment.
XI. Carnitine deficiency
A. Description. There are two primary genetic carnitine deficiency syndromes. Both
are inherited in an autosomal recessive manner.
1. The systemic form generally is manifested early in life as a recurrent illness
similar to Reye syndrome, with episodes of acute encephalopathy,
hypoglycemia, hyperammonemia, elevated liver enzymes, and prolonged
prothrombin time. These episodes can be precipitated by caloric deprivation,
as might occur during an ordinary acute febrile illness. Patients with systemic
carnitine deficiency have low levels of carnitine in liver, muscle, and serum,
although the latter is variable.
2. The myopathic form presents as a progressive myopathy with variable
degrees of weakness. Encephalopathic episodes do not occur, and there is no
liver involvement. Carnitine levels are normal in serum and liver but reduced in
muscle.
B. Treatment with carnitine (d,l-carnitine, 2 g/day PO) is indicated, but not all
patients will respond favorably.
XII. Episodic muscle weakness and the ion channel diseases
A. Familial hypokalemic periodic paralysis
1. Description
a. Familial hypokalemic periodic paralysis is transmitted as an autosomal
dominant trait. The disease is 3 times more common in males, and it
usually appears in the late teens or early 20s. Genetic study has shown an
abnormality in the gene that regulates the calcium ion channel. Numerous
mutations have been identified to cause the problem.
b. The onset is usually sudden with weakness of all 4 limbs. However, the
muscles of respiration and swallowing usually are spared. The distribution
of weakness may be asymmetric.
c. The attacks often occur in the morning and when untreated last from 1 to
36 hours. The muscles are weak and flaccid, and the deep tendon reflexes
may be absent. Heavy carbohydrate ingestion or vigorous exercise followed
by rest may precipitate attacks. Cold weather also may precipitate attacks.
d. The serum potassium level is usually between 2 and 3 mEq/L. Other
laboratory tests are normal.
e. The EMG shows decreased muscle excitability. Muscle biopsy during
attacks may reveal large vacuoles in the affected muscle fibers.
f. Hyperaldosteronism and thyrotoxicosis may be associated with episodic
weakness and hypokalemia. Hyperthyroidism occurs with episodic
weakness in Asians.
2. Treatment
a. Acute attack. High doses of potassium are given either PO (10 to 15 g of
potassium chloride mixed in fluid) or IV in a potassium chloride solution (40
to 60 mEq in 500 mL of 5% dextrose-water [D/W] infused over several
hours) to reverse the acute attack.
b. Prophylaxis
1. High-potassium, low-carbohydrate, and low-sodium diet.
2. Spironolactone (Aldactone), 100 mg PO daily or b.i.d.
3. Thiamine hydrochloride, 50 to 100 mg daily.
4. Treatment of hyperthyroidism when present.
5. Dichlorphenamide, 25 to 50 mg PO t.i.d., or acetazolamide (Diamox),
250 to 500 mg PO q46h, to cause a mild metabolic acidosis.
B. Familial hyperkalemic periodic paralysis
1. Description
a. Hyperkalemic periodic paralysis affects females and males equally, and it is
transmitted as an autosomal dominant trait. Onset is usually during
childhood. Recent genetic data suggest that there are several mutations
that affect the sodium channels either to disrupt excitation or to increase
excitability of the muscle.
b. The attacks are milder and shorter (30 to 90 minutes) than in hypokalemic
paralysis. Respiratory muscles are spared, but trunk and proximal limb
muscles are involved. Mild myotonia may be present clinically in the
tongue, hands, and eyelids.
c. The EMG shows hyperirritability between attacks and myotonic-like
discharges during attacks. Serum potassium level is either high or high
normal.
2. Treatment
a. Acute attack
1. Most attacks are of short duration and require no specific therapy.
2. Attacks can be stopped with IV infusion of 10% calcium gluconate, 10
to 20 mL.
b. Prophylaxis
1. Acetazolamide, 250 mg PO q.i.d., or dichlorphenamide, 25 to 50 mg
t.i.d.
2. Chlorothiazide, 50 to 100 mg PO daily.
XIII. Myasthenia gravis
A. Description. Weakness and progressive fatigue with exercise are the hallmarks of
generalized myasthenia gravis. However, diplopia may be the only symptom of
ocular myasthenia, and the pupil is never involved. Muscle wasting may occur
late, but it is not prominent. The course is variable and marked with remissions
and exacerbations, which makes evaluation of the therapy difficult. Most patients
reach maximum severity of their disease within 1 year, but a few progress over
several years. Classification into several general groups helps to predict the
course and to determine the type of therapy. Choice of therapy depends on the
individual case; some respond easily to a single modality, whereas others require
all modalities used in tandem or together.
1. Group I. About 14% of patients have ocular myasthenia only.
2. Group IIA. Mild generalized myasthenia with ocular signs.
3. Group IIB. Moderately severe generalized myasthenia, with mild bulbar and
ocular involvement.
4. Group III. Acute severe myasthenia, with bulbar and respiratory complications.
Tracheostomy is required.
5. Group IV. Late severe myasthenia, usually developing from other groups
within 2 years.
B. Diagnostic tests
1. Edrophonium (Tensilon) test
a. Initial diagnosis. When there is a defect that is easily observed, such as
grip strength, neck power, extraocular muscle function, ptosis, diplopia,
swallowing, vital capacity, and occasionally changes on EMG, edrophonium
chloride can cause transient improvement and support the diagnosis of
myasthenia gravis. The edrophonium test is not used in patients with
respiratory distress.
1. For best results a placebo control is used, and the trial is done
double-blind. The placebo can be nicotinic acid (100 mg/10 mL of
saline), which gives a systemic response, or saline alone. Atropine (0.4
mg) is often used both as a control and to protect against excessive
muscarinic side effects, such as:
a. Excessive sweating.
b. Excessive salivation.
c. Lacrimation.
d. Diarrhea.
e. Abdominal cramps and nausea.
f. Incontinence of stool and urine.
g. Bradycardia.
h. Hypotension.
i. Small pupils (less than 2 mm).
2. Edrophonium, 10 mg, is used in the adult (0.2 mg/kg in children). To
begin, 2 mg is infused into a secure IV line, and the patient is observed
for excessive muscarinic side effects. If there are no severe effects, the
remaining drug is infused in about 30 seconds.
3. The patient is observed for improvement. The duration of action is 2 to
20 minutes; however, occasionally, in patients treated with prednisone,
it may be longer (up to 2 hours). The clinical improvement should
coincide with the drug's expected duration of action.
b. Smaller doses of edrophonium (1 mg) are used to diagnose cholinergic
crisis. If there is no improvement, more drug is infused 1 mg at a time, up to
5 mg. Improvement is judged clinically, as in the diagnostic test.
Respiratory function must be assessed carefully before the test; if
edrophonium causes apnea, facilities for tracheal intubation must be at
hand.
c. Evaluation of oral anticholinesterase therapy can be done in some
patients by infusing edrophonium, 2 mg, 1 hour after the last oral dose and
watching for improvement and side effects. If there is improvement and
there are no increased side effects, the oral dose is increased by 25% to
50%. If there is no change in the patient's power but there are mild side
effects, the dose is kept the same. When the side effects are prominent and
the patient's power is worse following the edrophonium, the oral dose is
reduced by 25 to 50%.
2. Neostigmine test. If the duration of the action of edrophonium is too short to
permit evaluation of the patient's response, the anticholinesterase neostigmine
(Prostigmin) may be used. Neostigmine, 0.04 mg/kg, is injected IM and
reaches its maximum activity in 1 to 2 hours. The effect is gone at 3 to 4 hours.
Pretreatment with atropine can prevent muscarinic side effects.
3. EMG. If a nerve is stimulated at 3 to 10 impulses/second repeatedly and an
EMG is recorded, the amplitude of contraction is temporarily diminished in
myasthenia gravis. When myasthenia patients are relaxed so that several
muscles (at least one of which is proximal) are rested, 95% will show a
pathognomonic EMG pattern. In myasthenia, a decrement in response is
followed by a plateau or an increment, whereas in other disorders that may
show a decrement (myotonia, poliomyelitis, amyotrophic lateral sclerosis,
neuropathies, and McArdle disease), the decrement is continuous. Single-fiber
EMG recording often shows abnormalities characteristic of neuromuscular
junction disease.
4. Acetylcholine receptor antibody assay is positive in 50% of patients with
ocular myasthenia and in 80% to 90% of patients with generalized myasthenia.
The antibody level reflects the severity of disease in untreated patients.
5. Evaluation of thymus
a. About 75% of patients with myasthenia gravis have abnormal thymus
glands. The most common abnormality is hyperplasia, but 15% have
thymoma.
b. CT scan of the mediastinum is highly reliable in identifying thymoma. CT
scan is sometimes normal in patients with thymic hyperplasia.
C. Treatment
1. General measures
a. Patients with generalized myasthenia should be hospitalized and kept at
rest while anticholinesterase medication is begun.
b. Contraindicated medications. Drugs that have mild neuromuscular
blocking effects and sedatives, which may cause respiratory depression,
are contraindicated. Common drugs of this type are:
1. Quinine.
2. Quinidine.
3. Procainamide.
4. Propranolol.
5. Lidocaine.
6. Aminoglycoside antibiotics.
7. Polymyxin.
8. Viomycin.
9. Colistin.
10. Morphine.
11. Barbiturates.
12. Other tranquilizers.
c. The goals of therapy in myasthenia vary with the severity of the illness.
Improvement in strength or increased time spent out of the hospital are
goals in more severe cases. However, complete remission can occur with
steroid therapy.
d. Thyroid abnormalities occur in association with myasthenia gravis, and
antithyroid antibodies and antimuscle antibodies have been detected in
some myasthenics. However, no clinical correlation between the
abnormalities and these antibodies has been made. In thyrotoxic patients,
thyrotoxic myopathy is more common than myasthenia gravis. However, in
patients with myasthenia, thyrotoxicosis must be treated before the
myasthenia gravis will improve.
e. Ephedrine, 25 mg t.i.d., or other stimulant drugs occasionally improve
strength in patients on anticholinesterase therapy.
2. Respiratory care
a. Acute generalized myasthenia is a medical emergency, and even when
the patient appears to have normal respiratory function, rapid
decompensation can occur. Thus, myasthenics with generalized disease
are kept under close observation in an intensive care unit until treatment is
seen to be effective.
b. Measurement of maximum voluntary ventilation (patient breathes as
rapidly and as deeply as possible for 15 seconds while expired gases are
collected and analyzed) gives the best indication of effects of myasthenia
on respiratory muscles. Measurement of vital capacity with a hand
spirometer is also a satisfactory way of following respiratory function.
c. Ocular myasthenia (group I) is a benign illness. It is not associated with
respiratory failure.
3. Anticholinesterase therapy remains the initial choice when myasthenia is
diagnosed. It is used in conjunction with corticosteroid therapy to treat the
disease definitively.
a. Pharmacology
1. Anticholinesterase drugs inhibit the destruction of acetylcholine and
allow its accumulation at the synapse. Therefore, the effects of the drug
are limited to the cholinergic synapse. The motor end-plate is the
primary therapeutic target, but autonomic cholinergic synapses are also
affected and produce side effects. The drugs used do not cross the
blood-brain barrier, so there are insignificant central effects. The
parasympathetic postganglionic effects predominate because the
ganglionic sites are less sensitive to inhibition. Both the dose of drug
given and the level of activity at the synapse determine the degree of
the parasympathetic activity.
2. Side effects may be reduced by avoiding factors that increase
parasympathetic activity (e.g., motion). Atropine, 0.4 to 0.8 mg PO, may
be useful in reducing side effects in certain circumstances, but chronic
use is usually not helpful because of atropine toxicity. However, patients
should have atropine on hand for occasional use.
3. Smaller doses of anticholinesterase, taken more frequently, or doses
taken with food to delay absorption may help to reduce side effects. The
patient often becomes tolerant of the side effects with prolonged
therapy.
4. The common anticholinesterase drugs are listed in Table 16-4.
TABLE 16-4. Anticholinesterase Drugs Commonly Used for Myasthenia
Gravis
b. Administration
1. The oral dosage and frequency of administration depend on the
severity of the disease and the patient's sensitivity to the drug. Therapy
is by trial and error initially, but a usual starting dosage is
pyridostigmine (Mestinon), 60 mg q4h, or its equivalent (see Table
16-4). The use of liquid dosage forms allows an individualized program.
a. If one anticholinesterase drug is ineffective, usually the others will be
also. Side effects may be less bothersome with one preparation, but
there is no way of determining which will be tolerated best.
b. Patients should be instructed to observe and record their response
to the drug so that adjustments can be made.
2. Parenteral therapy might be required during an acute attack, after
surgery, or if dysphagia is a problem. Supplementary subcutaneous
injection of anticholinesterase 1 hour before meals may improve
dysphagia. The parenteral dose is one thirtieth the oral dose for
neostigmine and pyridostigmine.
4. Crisis (acute weakening in a myasthenic)
a. Myasthenic crisis. Changes in the absorption of medication or the
natural worsening of the disease may cause increased weakness,
requiring an increase of anticholinesterase drugs.
b. Cholinergic crisis
1. Anticholinesterase drugs can occupy the same receptors as
acetylcholine, and an excess of anticholinesterase will reduce
neuromuscular transmission. The curarelike effect of
anticholinesterase drugs gives them a bell-shaped
dose-response curve and creates a serious hazard in therapy.
2. A slight decrease in neuromuscular transmission can produce
severe weakness in the myasthenic patient. The clinical
syndrome is much like that of a myasthenic crisis. Many patients
might give a history of recent cholinergic side effects, suggesting
excessive anticholinesterase therapy.
3. If the patient is treated with atropine, the warning side effects
might not occur, and increased weakness will be the only sign of
toxicity.
4. Chronic use of anticholinesterase medication damages the
synapse, and some patients become refractory to the medication.
Usually, after a time off the medication (often with respiratory
support), the patient again responds to anticholinesterase
medication.
c. Treatment of crisis
1. Crisis is an emergency and requires intensive care. The patient's
respiratory function must be maintained, and if respiratory (or
swallowing) dysfunction is present, elective endotracheal
intubation is done before emergency intubation is necessary.
When the airway is secure, diagnosis of the type of crisis can
continue.
2. The edrophonium test can be used in the nonapneic patient, and
if unequivocal improvement occurs, the anticholinesterase
dosage can be increased while the patient remains under close
observation. In severe cases, the patient is unable to cooperate,
so improvement with edrophonium is seldom consistent.
3. When there is doubt about the result of the edrophonium test, all
anticholinesterase medications are stopped for 72 hours. The
patient may be followed with serial edrophonium tests until a
definite improvement is seen. At that time, longer acting drugs
may be started.
4. Often less medication is required following crisis because the
patient is more sensitive to the drugs.
d. Patient education. Patients are taught not to increase the dosage of
anticholinesterase in response to increased weakness. They should
be aware that the smallest possible amount of drug is best and that a
full-strength dosage might be too much.
5. Immunotherapy background
a. Myasthenia gravis is an autoimmune disease in which circulating
IgG antibody is activated against the acetylcholine receptor on the
motor end-plate. Animals immunized with purified acetylcholine
receptor protein develop experimental myasthenia identical to the
human disorder.
b. Myasthenia gravis seems to occur with high frequency in 2 separate
age groups. The peak incidence in one group is at age 30, and
women are more commonly affected. In the other group, peak
incidence occurs at age 70, and both sexes are equally affected.
Most of the younger patients have thymic germinal centers, whereas
the older patients have atrophied thymuses or thymomas. The
younger group responds better to treatment with anticholinesterase
drugs and thymectomy but varies in response to corticosteroid. The
older group often benefits from corticosteroid therapy and less
commonly from anticholinesterase drugs or thymectomy.
6. Corticosteroid therapy
a. Indications
1. Failure of anticholinesterase medication to allow an acceptable
level of function without excessive side effects. Most patients with
generalized myasthenia are treated with steroids unless there is
a major contraindication.
2. To improve the patient's strength preoperatively in preparation for
thymectomy.
3. Failure of remission following thymectomy.
4. Rarely in pure ocular myasthenia when diplopia is disabling.
b. High-dose corticosteroid therapy
1. Prednisone, 60 to 100 mg daily, may produce increased
weakness about 5 days after onset of therapy. Anticholinesterase
drugs or in severe cases plasmapheresis can be used to control
steroid-induced exacerbation. Improvement begins at about 12
days. High-dose corticosteroids are as effective as ACTH, and
with prolonged treatment longer remissions can be obtained.
2. High dosages are maintained until improvement is sustained (for
about 2 weeks). There are seldom relapses after the first 2 weeks
of therapy, and anticholinesterase drugs are gradually withdrawn
over 1 month. About three fourths of patients have a significant
improvement following corticosteroid treatment.
3. The corticosteroids are then gradually reduced to 5 to 15 mg
daily (or the equivalent alternate-day dosage) over several
months. Then the maintenance dosage is continued. Some
patients might be able to stop the maintenance dosage without
relapse.
4. Care must be taken early in the treatment to protect the patient
from respiratory complications or aspiration. The incidence of
such problems is smaller in corticosteroid treatment than in
treatment with ACTH.
5. Dexamethasone, 20 mg daily for 10 days and then repeated for
a second course, has been highly successful. Improvement or
remission occurs in most patients and continues for 3 months or
longer after the drug is stopped. Generally the higher the dosage
of steroid used, the greater the remission rate. Dexamethasone is
not often used as the first treatment, but it may be needed if
prednisone treatment at lower dosages fails.
c. Low-dose corticosteroid therapy
1. By starting with a low-dose alternate-day program (25 mg of
prednisone on alternate days) and gradually increasing the
dosage by 12.5 mg every third dose until the total dosage
reaches 100 mg on alternate days, or until optimal results occur,
the initial period of worsening is avoided.
2. Improvement may not occur for 6 to 7 weeks of therapy with
low-dose treatment, and therapy should be continued for 3
months before being abandoned.
3. If relapse occurs after withdrawing or reducing the
corticosteroids, the full dosage should be resumed.
7. Other immunotherapy
a. Plasmapheresis
1. Plasmapheresis is directed to removing the harmful antibody
that causes myasthenia gravis. Patients with severe generalized
myasthenia gravis who are resistant to other modes of therapy
may improve transiently after plasmapheresis. The improvement
following plasmapheresis may last for months in a few patients,
but repeated exchanges are usually needed to maintain the
improvement. The best results are achieved by using steroid,
immunosuppressive, and plasmapheresis together.
2. Plasmapheresis is done using a blood component separator. The
technique varies from center to center but usually begins with an
initial exchange of 10 to 20 L over several weeks. If the initial
series is successful, it is followed by a chronic program in which 2
L is exchanged weekly for several weeks, and then the
exchanges are done as needed to continue the improvement.
3. The fluid removed during plasmapheresis is replaced with normal
saline or, in large exchanges, with serum albumin or fresh-frozen
plasma after removal of the cryoprecipitate factors.
4. Iron replacement usually is needed. The transient hypocalcemia
that follows exchange is usually not clinically significant.
5. Plasmapheresis should be employed only in centers where
adequate experience with the technique is available.
b. Azathioprine (2.5 mg/kg) is added following plasma exchange to
sustain improvement especially in elderly patients. Benefit appears
in 3 to 4 months. In adults the dose is gradually increased to 50 mg
t.i.d. Some patients who fail to improve on steroids improve on
azathioprine. The blood count and liver function need to be
monitored frequently. The drug is best tolerated after meals. If the
WBC drops to below 3,500 the dose is reduced and then gradually
increased. Cyclophosphamide and cyclosporin have been used in
myasthenia when other modalities failed.
c. Intravenous immunoglobulin G (IVIG)
1. Myasthenia gravis improves after IVIG for weeks or months. It
can be used in conjunction with other immunotherapy to initiate
treatment in generalized myasthenia when plasma exchange is
not possible. The dose is 0.4 g/kg/day for 3 to 5 days. The rate of
administration should be slow to avoid adverse effects. The major
problems are mild and include hemolytic anemia, arthralgia,
cramps, myalgia, nausea, vomiting, chills, fever, pallor, malaise,
headache, anxiety, itching, urticaria, hypertension, hypotension,
dyspnea. Anaphylaxis has been reported and in high doses
aseptic meningitis has occurred.
8. Surgical therapy
a. Patients without thymoma
1. The thymus has been implicated in the etiology of myasthenia
gravis. In 1939, a thymic cyst was removed from a patient, with
coincidental improvement in the patient's myasthenia gravis.
Since that time it has been found in young patients with
generalized myasthenia that removal of the thymus often leads to
a lasting remission. Also, as many as 90% of selected patients
who have a thymectomy experience a remission or sustain
improvement for 5 years. Many of these patients need less
anticholinesterase medication, and some can discontinue it
entirely.
2. With continued reduction of operative morbidity and mortality,
many authorities advocate thymectomy in all young patients early
in their course, especially when anticholinesterase medications
do not produce optimum improvement with minimum side effects.
Young patients who have the disease for a short time improve
most rapidly, and pathologically the thymus shows absent or few
germinal centers. Patients with pure ocular myasthenia do not
undergo thymectomy.
b. Patients with thymoma. Mortality in patients with thymoma is much
higher than in those without it, and removal of the thymoma might
not improve myasthenia. Radiation therapy is used when the
thymoma cannot be removed completely. About 30% of patients with
thymoma have myasthenia, and 10% of myasthenic patients have
thymoma.
c. Surgical approach. There is some debate about the best approach
for removal of the thymus.
1. Median sternotomy. The classic approach is through a median
sternotomy, and the method is safe in experienced hands.
2. Transcervical approach
a. The transcervical approach sacrifices the excellent exposure
of the sternotomy, but it reduces the postoperative morbidity
when successful.
b. Hemorrhage, pneumothorax, and fragmentation of the gland
with incomplete removal may complicate the transcervical
approach and necessitate an unplanned open procedure.
3. The procedure with which the surgeon is most comfortable is the
best choice, but when uncomplicated, the transcervical approach
results in the least morbidity.
9. Postoperative treatment of the myasthenia patient
a. Tracheostomy is performed by many surgeons if there is:
1. Oropharyngeal weakness.
2. Previous myasthenic crisis.
3. Previous history of respiratory complications.
4. Vital capacity less than 2,000 cm
3
.
b. In patients without tracheostomy, the nasotracheal tube is left in
place for 48 hours after surgery.
c. After thymectomy, the patient might show marked improvement for
12 to 24 hours.
1. In the immediate postoperative period, no anticholinesterase
drugs are given, and the patient is kept slightly underdosed to
reduce excess secretions.
2. The medication is changed from the parenteral to the oral form as
soon as possible. It is increased to the optimal dosage level
gradually (36 to 48 hours).
3. Care must be taken not to overdose the patient, since previous
doses of anticholinesterase drugs may be excessive after
thymectomy.
d. Sedatives and weak neuromuscular blockers must be used with
extreme caution if the patient is not intubated.
10. Treatment of myasthenia in pregnancy
a. During pregnancy, myasthenic patients may become worse,
improve, or remain unchanged. When change occurs, it is usually in
the first trimester or post partum.
b. Abortion. Therapeutic abortion is not indicated because it may
cause worsening of the myasthenia. Spontaneous abortion is
common during the first trimester in women with myasthenia gravis.
c. Labor in myasthenic mothers is usually shorter than in normal
mothers. Intramuscular anticholinesterases are used during labor.
d. Local or regional anesthetics are preferred to general anesthesia,
and caution is required with sedatives.
e. Cesarean section is done only for obstetric indications.
f. Contraception. The neurologist and obstetrician must help the
myasthenic woman formulate plans for long-range family planning.
Voluntary sterilization or contraception should be suggested when
the myasthenia is severe.
11. Neonatal myasthenia
a. Description. Congenital myasthenia gravis is very rare, but neonatal
myasthenia occurs in about 20% of babies born to myasthenic
mothers. The condition is transitory and is usually gone in 24 to 36
hours. However, it may persist for weeks. Signs include masklike
face, poor sucking, difficulty swallowing, regurgitation, and
respiratory distress. Symptoms usually begin within 3 days of birth,
but they sometimes do not appear for 10 days.
b. Treatment. Symptomatic treatment to prevent aspiration, provide
nutrition, and maintain respiration is most important.
Anticholinesterase drugs may be needed for a short time.
Neostigmine, 1 to 2 mg PO (parenteral dose is one thirtieth the oral
dose) q4h, or pyridostigmine, 4 to 10 mg PO, is recommended for
infants.
XIV. Lambert-Eaton myasthenic syndrome (LEMS)
A. Description. A myasthenia-like syndrome (LEMS) occurs with carcinoma (usually
oat cell carcinoma of the lung). The syndrome is associated with generalized
muscle weakness but, unlike that of myasthenia gravis, the weakness improves
when the muscle is exercised. Patients with LEMS also often demonstrate
autonomic symptoms, such as dry mouth, and neuropathic elements, such as
absent reflexesfeatures that do not occur with myasthenia gravis. An EMG is
helpful in differentiating the syndrome from true myasthenia gravis. It is now clear
that about half of cases of LEMS occur without underlying carcinoma. The
pathogenesis of LEMS involves an immune attack on the presynaptic aspect of
the neuromuscular junction. There is an LEMS autoantibody test available.
B. Treatment
1. Removal of the tumor, when possible, may resolve the syndrome.
2. 3,4-Diaminopyridine, 18 to 25 mg PO q.i.d., has been used to improve
neuromuscular function in patients with LEMS.
3. Plasmapheresis used in conjunction with prednisone and azathioprine has
been used to provide symptomatic improvement.
4. IVIG in doses of 1 g/kg/day for 2 days produces a transient improvement. It
may be repeated monthly or less often to continue the remission.
XV. Botulism
A. Description. Botulism is an intoxication caused by the exotoxin of Clostridium
botulinum, an anaerobic, gram-positive, spore-forming rod that may contaminate
foods.
1. As in tetanus, the toxin rather than the bacterial infection produces the illness.
Botulinum toxin is a powerful presynaptic blocker of acetylcholine release.
There are 6 antigenically distinct toxins (A, B, C, D, E, and F) but only A, B,
and E are associated with human illness.
2. The clinical syndrome is one of progressive muscle weakness, often
beginning in the extraocular or pharyngeal muscles and becoming generalized.
Also, GI complaints may be prominent. There are no sensory signs; dilated
unreactive pupils are seen regularly, but the patient remains alert. Dry,
erythematous mucous membranes are also common.
3. The diagnosis is confirmed when the disorder appears in a mouse injected
either with serum from the patient or with an aliquot of the suspected food.
4. The course is usually rapid, with symptoms appearing within 18 hours of
ingestion of the toxin. A more rapid onset is associated with more severe
courses.
5. The prognosis in treated patients is about 80% survival. Patients whose cases
are not generalized usually do very well. Those who are over 20 years old and
those with type A toxin have a slightly higher mortality.
6. A syndrome of botulism occurs in young infants due to colonization of the gut
by Clostridium with subsequent absorption of toxin. The course is subacute to
chronic.
B. Treatment
1. Antitoxin. Therapy against the toxin is begun as soon as possible.
a. Specific typing of the toxin can be done, but treatment is usually started
with trivalent (A, B, E) antitoxin.
b. The antitoxin is horse serum, so skin testing and precautions for
anaphylaxis are necessary; 10,000 units of antitoxin are administered IV in
one dose.
c. Approximately 15% to 20% of botulism patients will have minor allergic
reactions to the antitoxin that may require treatment with antihistamines or
corticosteroids. However, some patients have severe reactions, so
provision for emergency endotracheal intubation should be made before the
antitoxin is given.
2. Emetics, cathartics, and enemas are used with caution to eliminate any toxin
that remains in the GI tract.
3. Respiratory care. Maintenance of respiratory function is the most important
aspect in treating severe cases of botulism.
a. Patients who appear to have mild symptoms (diplopia and mild weakness)
may rapidly develop respiratory failure, so respiratory function must be
monitored frequently in all patients until there are signs of improvement.
b. If vital capacity falls to 1,000 cm
3
, elective intubation is considered. Severe
dysphagia also requires nasogastric or endotracheal intubation to prevent
aspiration.
XVI. Tetanus
A. Description. Tetanus is an intoxication that results from infection with Clostridium
tetani, a gram-positive coccus that enters through a wound.
1. An exotoxin causes the neuromuscular irritability and the syndrome of
tetanus.
2. Clinical features. The major presenting feature of generalized tetanus is
muscle rigidity and discomfort in the jaws, neck, and lower back. The
symptoms, which may be mild at the onset, progress over hours or days to a
state of muscular hyperirritability and spasm that may involve the respiratory
and pharyngeal muscles. Convulsive seizures are common.
3. Tetanus can be localized to the area surrounding the wound rather than
generalized. Often the jaw is involved early in both localized and generalized
tetanus (lockjaw).
4. The prognosis is good in localized tetanus, but mortality reaches 50% in
patients with generalized disease, despite therapy.
B. Treatment
1. Treatment directed against the toxin. The major emphasis is on
neutralization of the toxin. Some patients with tetanus may have no C. tetani in
their wound cultures, and other (20%) may have no wound visible at the time of
onset.
a. Human hyperimmune globulin is the antitoxin of choice; 3,000 to 10,000
units are given IM or IV, although lower doses can be effective. A single
dose is adequate. Toxin already fixed in the neural tissues will not be
eliminated by antitoxin, but circulating toxin will be neutralized by it.
2. Therapy directed against the bacteria
a. The area of the wound is surgically excised and drained.
b. Cultures of the wound are taken, but they do not always grow the
organisms.
c. Penicillin is the antibiotic of choice: procaine penicillin, 1.2 million units IM
or IV q6h for 10 days.
d. For patients unable to take penicillin, tetracycline, 500 mg PO or IV q6h for
10 days, may be substituted.
3. General measures
a. The treatment of tetanus, like that of any paralyzed patient, includes care of
skin, bladder, bowel, fluid management, nutrition, and respiration.
Prevention of aspiration pneumonia and pain is particularly important.
b. Spasms of generalized tetanus are painful and interfere with respiration. A
dark, quiet room will help reduce the spasms. Sedation is important in
controlling the spasms, and the patient should be kept asleep. Diazepam,
in dosages determined by the patient's response (2 to 10 mg IV q412h), is
safe and effective. Meprobamate, barbiturates, and chlorpromazine have
also been used with success. Diazepam may cause respiratory and
cardiac arrest in a few patients if used with barbiturates, so the
combination should be avoided.
c. Neuromuscular blockers are helpful when the other methods fail to
reduce the muscle spasm that interferes with swallowing or respiration. The
patient must be artificially ventilated when neuromuscular blockers are
used. It is not safe to try to give a dose of neuromuscular blocker to stop
spasm in the extremities while preserving respiratory function. Pancuronium
(Pavulon), succinylcholine, and other blocking agents may be useful when
the patient is intubated. Sedation should be maintained or increased when
blockers are used because it is extremely unpleasant for the patient to be
awake and paralyzed. Intrathecal baclofen infusion has been used to
control spasms.
d. Autonomic dysfunction (hypertension, hypotension, hyperpyrexia, and
cardiac arrhythmia) is common. Treatment is directed at the symptoms.
4. Prophylaxis
a. All persons, beginning at 2 months of age, should be immunized against
tetanus toxin. Initial immunization is tetanus toxoid, 0.5 mL in 3 injections
4 weeks apart. Booster injections are required every 10 years.
b. In acute injuries, thorough washing and debriding are necessary.
1. In fresh, clean wounds, the toxoid course should be completed if it has
not been completed already. If the initial immunization is complete, a
booster dose of toxoid is given if the patient has not had one in the past
10 years.
2. In wounds that are dirty or infected, toxoid booster is given if none
has been received for 5 years. Human antitoxin (250 units IM), in
addition to the toxoid, is given to patients who have not received earlier
immunization. Contracting tetanus does not confer immunity, and the
series of toxoid injections is required in these persons.
XVII. Malignant hyperthermia and neuroleptic malignant syndrome
A. Description. Exposure to various inhalation anesthetics, muscle relaxants (e.g.,
succinylcholine, curare, pancuronium), or stress alone may, in susceptible
individuals, result in sudden release of calcium from the sarcoplasmic reticulum
with resultant intense muscle contraction. Susceptibility is inherited as an
autosomal dominant trait. The resultant clinical syndrome may begin during
anesthesia or in the several hours thereafter. A similar syndrome may occur after
exposure to certain neuroleptic drugs (neuroleptic malignant syndrome). If the
syndrome is untreated, the mortality is nearly 100%. The common symptoms, in
their usual order of appearance, are:
1. Tachycardia.
2. Acidosis.
3. Tachypnea.
4. Cardiac arrhythmias.
5. Muscle stiffness.
6. Rise in body temperature.
B. Treatment. Early recognition is important. As soon as the characteristic clinical
syndrome is noted:
1. Discontinue anesthesia or neuroleptic drugs.
2. Initiate surface cooling with ice packs applied to the body or immersion in ice
or cold water.
3. Initiate core cooling with cool oral fluids and reestablish electrolyte balance
with oral and intravenous fluids, 1 to 2 L over 3 to 4 hours.
4. Administer dantrolene, 1 mg/kg, by rapid IV infusion, and repeat as necessary
until symptoms subside (up to a maximum of 10 mg/kg). Dantrolene, 1 to 2
mg/kg PO q.i.d., may be required for a few days thereafter to prevent
recurrence. Dantrolene blocks the release of calcium from the sarcoplasmic
reticulum, thus relieving the underlying pathologic alteration causing the
syndrome. High intravenous doses of dantrolene may cause enough muscle
weakness to precipitate respiratory failure.
C. Prophylaxis
1. In patients with known propensity toward malignant hyperthermia,
inhalation anesthetics, neuroleptics, and muscle relaxants should be avoided if
possible.
2. If possible, in patients with a known family history of malignant
hyperthermia, anesthesia, neuroleptics, and muscle relaxants should not be
administered until a muscle biopsy is performed to determine susceptibility.
Muscle from susceptible people contracts in vitro on exposure to
concentrations of caffeine, halothane, or suxamethonium that cause only
minimal changes in normal muscle.
3. A history of anesthesia without an attack of malignant hyperthermia does not
exclude susceptibility in patients with a positive family history. Such patients
may suffer attacks of malignant hyperthermia on subsequent exposures to the
known precipitating factors.
XVIII. Neuropathy
A. Description
1. Peripheral neuropathy of various types (polyneuropathy [PN], entrapment
neuropathy [EN], mononeuritis multiplex [MNM]) is a symptom that may be
associated with many etiologies and diseases.
2. There are also several neuropathies that are primarily neurologic such as the
hereditary (Charcot-Marie-Tooth disease) or the inflammatory
(Landry-Guillain-Barr disease) neuropathies. The first step in management of
a neuropathy is to diagnose the underlying disease or cause (Table 16-5). The
details of therapy depend on the underlying illness, the severity of the
neuropathy, and the rate of progression. Patients with acute progressive motor
neuropathy require observation in the hospital, whereas those with chronic
neuropathy can be treated as outpatients.
TABLE 16-5. Genetic Tests Available for Nerve and Muscle Disorders.
3. Polyneuropathy. Symmetric loss of sensory function, motor function, or both
usually begins in the feet in polyneuropathy. Deep tendon reflexes may be
diminished early, especially in the ankles; later, reflexes may be absent. Some
neuropathies affect the proximal nerves early (diabetic amyotrophy), and these
may be confused with myopathy.
4. Mononeuropathy is the asymmetric dysfunction of one or more large nerves.
There is usually pain, and the cranial nerves can be affected. The cranial
nerves may also be involved in polyneuropathies. The pathology of
mononeuropathy and mononeuropathy multiplex is usually disruption of the
vasa nervorum. In the polyneuropathies, the mechanism is often unknown;
however, axonal degeneration occurs in some, and in others the myelin
sheaths undergo segmental demyelination.
B. Diagnosis
1. The differentiation of chronic polyneuropathy from primary disease of muscle
and other conditions that cause weakness is seldom a problem. However,
identifying the cause of the neuropathy is difficult.
2. Muscle enzymes are normal in polyneuropathy.
3. Abnormal nerve conduction studies support the diagnosis of peripheral
neuropathy, although normal studies do not exclude it. Mononeuropathy
usually shows decreased conduction in the affected nerve, but other nerves
are normal. Nerve conduction studies can identify multifocal conduction block
motor neuropathy, which can be confused with ALS based on the clinical
findings.
C. Acute idiopathic demyelinating polyradiculoneuritis (AIDP)
(Landry-Guillain-Barr-Strohl syndrome)
1. Description
a. Incidence. Persons of all ages are affected in AIDP, but the highest
incidence is in persons between the ages of 50 and 74. The syndrome may
follow a mild viral illness by 1012 days or appear without prodrome. It is
also associated with HIV infection and AIDS.
b. The earliest signs are motor weakness, paresthesias, and pain,
progressing from lower extremities to upper extremities.
c. The cranial nerves are affected in 75% of cases. The facial nerve is
involved in half of those with cranial neuropathy, and of those with facial
palsies, it is bilateral in about 80%.
d. Autonomic disorders (cardiac arrhythmia, hypotension, hypertension,
hyperpyrexia, and tachycardia) occur frequently and account for almost half
of fatalities.
e. CSF protein is usually high. Cell counts in CSF are always below 70
lymphocytes/g and usually lower than 20/g.
f. Nerve conduction velocities are reduced in 90% of patients.
2. Prognosis. Patients with normal nerve conduction studies have the best
prognosis.
a. The disease progresses over 7 to 21 days. Patients with more rapid
progression usually need respiratory support. Improvement follows the
progressive period by 10 to 14 days, and recovery continues for 6 to 36
months.
b. Most patients recover enough to leave the hospital in 75 days or less.
Atelectasis, aspiration, pneumonia, pulmonary abscess, venous
thrombosis, and pulmonary embolus are serious complications of the
paralysis. Despite these complications, overall mortality is only 5% with
modern intensive care.
c. Recovery is complete in about half of patients, and most of the remainder
have only mild abnormalities. Severe disability occurs in about 10% to 15%
of patients.
3. Treatment. The neuropathologic defect is an autoimmune inflammatory
perivascular mononuclear infiltrate that may involve the entire peripheral
nervous system. Both axonal degeneration and segmental demyelination
occur. The major emphasis in management is supportive care to prevent
complications, since given time most patients improve spontaneously.
a. Plasma exchange used within 7 days of onset seems to shorten the
recovery time in about two thirds of patients with severe Guillain-Barr
syndrome. The usual course is 3 to 5 exchanges every other day.
b. Intravenous immunoglobulin, 0.4 g/kg, given in 1,000 mL of saline over 6
to 8 hours, is used in patients in whom plasma exchange fails to provide
benefit.
c. Corticosteroids are of little benefit in the acute disorder.
d. Respiratory care. The most important consideration is maintaining
adequate respiration. Patients should be followed closely, with
measurement of vital capacity, and endotracheal intubation is performed
when the vital capacity drops to 25% to 30% of normal. (Normal vital
capacity in males =25 cm
3
height in centimeters; females =20 cm
3

height in centimeters; children =200 cm
3
age in years.) When bulbar
muscles are involved, feeding is done by intravenous administration,
nasogastric tube, or gastrostomy.
e. Prophylactic anticoagulation is indicated in paralyzed patients.
Subcutaneous heparin in low doses (5,000 units q12h) or warfarin helps to
prevent thromboembolic complications of immobilization. Infants and small
children need not be anticoagulated, since they can be easily mobilized.
f. Fecal impaction is a painful problem that occurs in bedridden patients.
Thus, suppositories and enemas should be used from the outset, before
problems arise.
g. Physical therapy. Bed rest is indicated in the acute phase of the illness
until improvement begins.
1. Positioning. Careful positioning of the patient in bed prevents bed
sores and compression of nerves. A firm foundation or bedboard is
necessary, and flexed positions are avoided for prolonged periods.
Frequent (q2h) change of the patient's position is necessary to prevent
pressure sores. A water mattress or egg crate mattress is useful in
reducing pressure sores.
2. Prevention of contractures
a. Range-of-motion exercises prevent the connective tissues from
shortening, which is a natural tendency. A short, passive
range-of-motion program twice daily is started early in the course of
the illness. However, as improvement occurs, most types of
intensive physical therapy can be used.
b. A footboard is necessary to prevent gastrocnemius and Achilles
tendon contractures. Pillows under the shoulders should be avoided
because they may promote kyphosis. Allowing the patient
periodically to lie face down helps to prevent flexion contractures of
the hips.
c. If contractures begin to form, stretching range-of-motion exercises
may relieve them. Once contractures are fully formed, however,
surgical release is necessary.
3. Edema. Paralyzed extremities lack the normal muscle tone that keeps
edema from occurring. Edema makes the skin less resistant to pressure
necrosis, infection, or mild trauma. Edema may be painful when it forms
rapidly.
a. Intermittent elevation of the extremities (above the level of the heart)
may help to prevent edema and reduce edema that is already
present.
b. Intermittent compression of edematous extremities for 60 to 90
minutes twice daily, followed by massage and elevation, is useful.
c. Ace bandages applied tightly to the trunk and unwrapped for 10 to
15 minutes 3 times a day or a pressure stocking can be used to
prevent edema.
4. Pain. Myalgia and arthralgia are common in acute polyradiculoneuritis.
a. Mild analgesics are usually effective (aspirin, 600 mg q34h), but
occasionally codeine (30 to 60 mg q4h) or morphine (5 to 10 mg IM) is
needed. Narcotics cause respiratory depression and constipation.
b. Heat applied before range-of-motion exercises and warm baths (Hubbard
tank) may reduce pain.
5. Later phase of therapy. Maximum development of residual function is the
goal of late therapy.
a. Restorative surgical procedures may increase function.
b. A brace can be used to maintain the limb (often the foot) in good position,
but it cannot overcome a fixed deformity. A brace must be strong enough to
function but light enough to allow easy ambulation. The weight of the brace
is especially important in the patient with weakness of hip flexion. A brace
that allows controlled motion is usually more comfortable than one that
allows no motion.
c. Management of physical therapy is done with the help of trained physical
therapists and, if available, a competent physiatrist.
k. Autonomic syndrome. Occasionally, paroxysmal hypertension, headache,
sweating, anxiety, and fever occur in patients with acute polyradiculoneuritis.
Phenoxybenzamine (20 to 60 mg in divided doses) has been used to relieve
this syndrome. Also, diabetes insipidus and the syndrome of inappropriate
antidiuretic hormone secretion have been reported to occur in patients with
acute polyradiculopathy. In these patients, observation of the urinary output,
the state of hydration, and serum and urine electrolytes allows prompt therapy
when needed.
D. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is similar
to AIDP in its clinical features except that it has a relapsing remitting or
progressive course lasting at least 2 months. Many patients do not recover fully.
1. Some patients have primarily motor dysfunction with evidence of multifocal
conduction block on electrophysiologic study. This entity, which is a
demyelinating neuropathy, resembles motor neuron disease and sometimes
has elevated antibody titers to gangliosides. Treatment with cyclophosphamide
has resulted in improvement in some cases.
2. There are several diseases associated with a syndrome similar to CIDP.
Human HIV infection, systemic lupus erythematosus, and plasma cell
dyscrasia are only a few. Hereditary demyelinating neuropathies are also a
consideration, especially in children.
3. Treatment begins with a specific diagnosis and management of an underlying
disorder if found. In the idiopathic cases, one can try corticosteroids, plasma
exchange, and azathioprine. The plan depends on the severity of the disease
and the availability of experienced plasma exchange technicians.
a. Corticosteroids. Prednisone is started at 100 mg/day; this dosage is
continued for 2 to 4 weeks and with improvement is gradually changed to
100 mg every other day. The dosage must be maintained for 3 to 6 months
without improvement before steroid failure can be assumed. Most patients
with CIDP who respond to steroids require maintenance dosages of 5 to 20
mg every other day for life.
b. Plasma exchange (2 exchanges per week for 3 weeks) is added to the
corticosteroid if there is no improvement in the first week or two.
c. Azathioprine (50 mg t.i.d.) is used in patients who do not respond to
corticosteroids in the first 3 to 4 weeks and in patients who receive plasma
exchange as initial treatment. It is also started concurrently with
corticosteroids in severe progressive cases. Monitor liver function and
blood counts.
d. Intravenous immunoglobulin treatment has been effective in patients
with refractory disease. Its use as the only treatment remains in question.
The usual dosage is 0.4 g/kg given in 1,000 mL of saline IV over 6 to 8
hours.
E. Other chronic neuropathies. The treatment of chronic neuropathy associated
with a systemic disease begins with control or cure of the underlying disease or
condition. Management of the residual deficit is aimed at keeping patients
functional and optimizing their motor and sensory function. Braces and splints help
with the distal weakness. Sensory neuropathy interferes with gait subtly, causing a
feeling of dizziness, which on questioning is a sense of imbalance, especially
when other modalities of sense are also compromised.
1. Neuropathy associated with deficiency diseases (see sec. XVIII.A.2)
a. Alcoholic polyneuropathy probably results from multiple vitamin
deficiencies or from thiamine deficiency. Alcohol by itself is also responsible
for the neuropathy. Adequate diet supplemented with multivitamins and
thiamine (50 to 100 mg PO daily) is the usual method of treatment. Most
patients improve in several months, but severe cases may take up to a year
to improve.
b. Pyridoxine deficiency occurs in patients treated with isoniazid. It may
cause a mild sensorimotor neuropathy and optic neuritis. A preparation of
isoniazid-vitamin B
6
combination prevents the neuropathy. Pyridoxine
toxicity also causes a sensory neuropathy.
c. Folic acid deficiency may occur with chronic phenytoin administration or in
persons with a low folate intake. Folic acid, 1 mg every morning, prevents
the neuropathy, but it may make the seizure disorder less responsive to
phenytoin.
d. Niacin deficiency by itself probably does not cause peripheral neuropathy,
but pellagra patients with peripheral neuropathy have multiple vitamin
deficiencies.
2. Diabetes mellitus
a. Polyneuropathy. Diabetes mellitus is the most common cause of
neuropathy in developed parts of the world. The polyneuropathy associated
with diabetes is usually mixed but is often primarily sensory. Pain in both
legs and feet is a routine complaint and can be disablingly severe.
1. Control of hyperglycemia may improve diabetic polyneuropathy.
Treatment of the pain requires several approaches. Physical measures,
such as warm compresses, massage, and whirlpool baths, may be
temporarily helpful. Also, rest may help, and mild analgesics, such as
aspirin, are often used.
2. Narcotics are not generally used for neuropathic pain because they are
often ineffective and tolerance causes the dose to escalate. Phenytoin,
300 to 400 mg daily, may help, but if improvement does not occur in 10
to 14 days, therapy should be stopped. Amitriptyline 50 to 200 mg QHS
in gradually increasing doses improves neuropathic pain. The side
effects are dry mouth (universal), constipation, impotence, urinary
retention (rare), and supraventricular tachyarrhythmia. Tegretol also
reduces the painful neuropathy in doses of 600 to 1,200 mg q.d. in
divided dosage. Gradual increase of the dose avoids the adverse
effects, which are GI distress, dizziness, somnolence, and a general
feeling of discomfort. The WBC and liver function tests (LFT) need to be
followed monthly until the dose is stable and the patient has been safely
on the drug for 6 to 10 months. Gabapentin 300 mg q.i.d. is an
alternative to the others. The adverse effects are minimal, which makes
it attractive; the efficacy is being determined by its current use.
b. Autonomic neuropathy is common in diabetes and causes decreased
sweating, orthostatic hypertension, nocturnal diarrhea, fecal incontinence,
constipation, urinary incontinence or retention, and impotence. Delayed
gastric emptying can also occur, causing difficulty in controlling the blood
sugar.
1. Orthostatic hypotension may improve with pressure stockings or
mineralocorticoid (Florinef, 0.1 mg daily). Ephedrine (up to 25 mg t.i.d.)
is also helpful in some patients.
2. Diarrhea may be intermittent and may resolve spontaneously.
Denatured tincture of opium, 5 to 10 drops q.i.d., or another
antidiarrheal is often helpful.
3. When fecal incontinence is a problem, an enema each morning cleans
the bowel and allows the patient relative safety, using only a pad.
4. Treatment of urinary problems is discussed in Chap. 14.
c. Mononeuritis. The cranial nerves are frequently involved, particularly the
oculomotor nerve. Diabetic oculomotor nerve palsy is usually painful. As a
rule, there is sparing of the pupila sign that helps to distinguish it from a
posterior communicating artery aneurysm. Large peripheral nerves can also
be involved, causing a pain syndrome. The pain is treated with analgesics,
and often narcotics are required. This pain usually subsides spontaneously
in a few days, and in the case of third nerve palsy, the deficit improves in 1
to 4 months. An eye patch circumvents the diplopia until improvement is
complete.
3. Neuropathy associated with toxic diseases (see sec. XVIII.A.3). Removal
from exposure and, when possible, direct removal of the toxin is the treatment
for all toxic conditions.
a. Chronic arsenic toxicity causes a painful mixed motor and sensory
polyneuropathy.
1. The treatment is dimercaprol (BAL) oil suspension. However,
dimercaprol is contraindicated in hepatic insufficiency, and acute renal
failure may occur during therapy. Alkalinization of the urine helps to
prevent breakdown of dimercaprol-metal complexes and protects the
kidney. Other side effects are hypertension, nausea, vomiting, and
headache. Reduction of dosage reduces the side effects.
2. For chronic arsenic poisoning, dimercaprol, 2.5 mg/kg, is given q.i.d.
for 2 days, b.i.d. on the third day, and then daily by deep IM injection for
10 days. Dimercaprol therapy is thought to decrease the duration of the
illness, but it has no effect on the recovery rate.
b. The sensorimotor neuropathy of lead intoxication is treated with
ethylenediaminetetraacetic acid (EDTA). EDTA can cause renal failure, and
daily urinalysis is indicated during therapy. If hematuria, proteinuria, or
epithelial cell casts increase during treatment, the drug should be stopped.
1. EDTA is usually given IM, 0.04 g/kg b.i.d. The prognosis depends on
the amount of exposure and the degree of impairment. Early treatment
results in the best prognosis.
2. Penicillamine, 25 mg/kg daily in divided doses, also has been used to
remove lead from the body in chronic intoxication.
c. Mercury intoxication neuropathy is predominantly a motor disorder. It can
also be treated with dimercaprol, but it is usually treated with EDTA
(Calcium Disodium Versenate). Mercury poisoning causes dementia, which
may not be reversible.
4. Neuropathy associated with drugs (see sec. XVIII.A.4)
a. Nitrofurantoin (Furadantin), 400 mg daily for 2 weeks, has produced
decreased conduction velocities in all patients tested. The polyneuropathy
is primarily sensory at the onset, with pain and paresthesias. However, the
polyneuropathy is reversible when the drug is stopped.
b. Vincristine is consistently associated with peripheral polyneuropathy, and
the neurotoxicity is the dose-limiting factor. Absent Achilles tendon reflex is
the earliest sign that accompanies paresthesias in the fingers and toes.
However, the cranial nerves may also be affected. The neuropathy usually
improves within several months after the drug is stopped.
c. Phenytoin is occasionally associated with a mild polyneuropathy, which is
thought to be related to folate deficiency.
d. Isoniazid causes vitamin B
6
(pyridoxine) deficiency with polyneuropathy.
5. Entrapment neuropathy
a. Carpal tunnel syndrome is the most common entrapment. It is the result
of compression of the median nerve by the volar ligament.
1. Description. Pain and tingling in the hand are the usual early signs, and
retrograde distribution of the pain may cause arm and shoulder pain in
some patients. There may be no objective neurologic signs, and nerve
conduction studies may be normal, but usually median nerve conduction
is slowed across the wrist. Often, the earliest objective sign is failure to
appreciate textures. Later, clear deficits of sensation with muscle
wasting occur in the distribution of the median nerve.
2. Associated disease. A variety of diseases are associated with carpal
tunnel syndrome (see sec. XVIII.A.1). Thus, before surgery is
undertaken, underlying diseases that are treatable should be controlled.
3. Treatment
a. The treatment is usually surgical release at the site of entrapment.
b. When the symptoms are mild and there are no objective signs of
nerve damage, conservative measures may be enough. For
example, splinting the wrist at night may relieve carpal tunnel
symptoms, especially in the transient syndrome seen in pregnancy.
c. Injection of corticosteroid into the volar ligament may relieve the
symptoms temporarily. In some cases, remission may last for
several years. If nerve conduction is slow, however, surgery is
usually required.
b. Pronator syndrome. The median nerve might also be entrapped as it
passes into the forearm between the two heads of the pronator teres
muscle. Pain is reported in front of the elbow and at the wrist. Also,
weakness in apposition of the thumb and hypesthesia on the radial side of
the index finger have been reported. However, this condition is rare.
Treatment is surgical release.
c. The ulnar nerve may be entrapped at the wrist or in the palm, but most
commonly entrapment occurs at the elbow. Paresthesia of the fourth and
fifth fingers is a common symptom. Weakness of the hand with atrophy of
the first interosseous muscle and the hypothenar eminence is less
common, and weakness of abduction of the fifth finger may be the only
sign. When entrapment is at the elbow, therapy is surgical transposition of
the nerve anteriorly.
d. The radial nerve is entrapped very rarely, and most isolated radial palsies
are caused by direct trauma.
1. Description. Weakness of finger extension without weakness of wrist
extension has been attributed to entrapment of the radial nerve at the
level of the supinator muscle. The extensor carpi ulnaris is weak, but the
extensor carpi radialis is normal, so that weakness of finger extension
occurs with radial deviation of the hand. Sparing of the extensor carpi
radialis occurs because the branch of the radial nerve to the carpi
radialis leaves proximal to the entrapment point.
2. The onset of entrapment is slow as opposed to the sudden onset seen
in the common traumatic palsies.
3. Treatment is surgical release, but splints and physical therapy
constitute the only therapy for traumatic lesions. Most patients with
traumatic radial palsy recover in several months.
e. The lateral cutaneous nerve of the thigh may be entrapped between the 2
folds of the inguinal ligament. The syndrome produced is known as
meralgia paresthetica, which is characterized by paresthesia, pain, or
numbness in the lateral part of the thigh. There may be objective signs of
decreased sensation in the region of numbness.
1. The etiology varies, but trauma, use of a corset or truss, and other
external mechanical compressions around the waist have been
implicated. Intrapelvic tumor and acute abdominal enlargement from
ascites or pregnancy have also been implicated.
2. Treatment is unnecessary if there is no pain. Evaluation for a definite
etiology must be done, and if pain is severe, injection of local anesthetic
into the nerve at the anterior iliac spine may help. Resection of the
nerve is rarely necessary.
f. The posterior tibial nerve may be entrapped under the flexor retinaculum,
behind and inferior to the medial malleolus at the tarsal tunnel. The patient
complains of pain or numbness in the sole of the foot; walking and standing
increase the pain. A tender tibial nerve may be found behind the medial
malleolus, and dorsal extension and pronation of the foot may provoke
pain. The syndrome is rare, but it can occur following previous trauma.
Treatment is surgical release.
6. Leprosy
a. Description. In underdeveloped parts of the world, leprosy is a common
cause of neuropathy. Mycobacterium leprae, an acid-fast rod, causes a
predominantly sensory neuropathy.
1. Lepromatous leprosy is extensive, diffuse, and symmetric, involving
skin and peripheral nerves.
2. Tuberculoid leprosy is less extensive, with fewer skin lesions that are
sharply demarcated, but the neurologic involvement is more severe. The
nerves are often enlarged.
b. Treatment. Free treatment and hospitalization are available at the U.S.
Public Health hospitals at San Francisco, California; Carville, Louisiana; or
Staten Island, New York. Most cases require less than 2 months of
hospitalization.
1. The drug of choice is dapsone, 50 to 100 mg PO daily for adults and 1
mg/kg for children. When there is no clinical evidence of activity and no
acid-fast rods are seen on skin smears, treatment is continued for 18
months in tuberculoid leprosy and for 10 years in lepromatous leprosy.
Patients who have features of both types are treated for lepromatous
leprosy. Note that dapsone by itself can cause polyneuropathy.
2. Rifampin is a more effective agent and is used in many parts of the
world. However, it has not been released for use in leprosy by the Food
and Drug Administration (FDA). Patients who relapse on dapsone alone
are often given rifampin in addition.
3. Reactional states. During therapy, tender inflamed subcutaneous
nodules (erythema nodosum leprosum) may appear acutely. These
nodules appear in groups and last 1 week or longer, and new groups
occur as the older ones regress. Fever, myalgia, and other systemic
symptoms also occur with these nodules. Treatment is with analgesics
and antipyretics. Corticosteroids may be needed in some severe cases,
and dapsone is continued.
4. Treatment of household contacts. Dapsone, 50 mg twice weekly or
25 mg daily for 2 to 3 years, is recommended for close contacts.
7. Plasma cell dysplasia may be associated with a severe progressive sensory
and/or motor neuropathy. The detection of a monoclonal spike on the serum
protein electrophoresis of a patient with a neuropathy may lead to the
diagnosis of multiple myeloma, amyloidosis, Waldenstrm macroglobulinemia,
cryoglobulinemia, lymphoma, or, most commonly, monoclonal gammopathy of
undetermined significance (MGUS). In some patients with osteosclerotic
myeloma, a characteristic syndrome of polyneuropathy, organomegaly,
endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) occurs.
Even when the underlying disease cannot be treated (e.g., MGUS), the
neuropathy might improve with plasma exchange or intravenous
immunoglobulin.
8. Multifocal motor neuropathy with conduction block is an immune-mediated
motor neuropathy that may mimic motor neuron diseases. Some patients have
demonstrable antibodies against gangliosides (e.g., anti-GM1 or
anti-asialo-GM1), but the diagnosis depends on finding conduction block on
nerve conduction studies. This disorder is important to recognize because it is
treatable with intravenous immunoglobulin in 0.4 g/kg given in 1,000 mL of
saline over 6 to 8 hours, every 6 to 12 weeks.
F. Neuropathy in HIV infection. About 15% of patients with AIDS develop a distal
symmetric axonal neuropathy. There is often pain and sensory loss in the feet.
There is no response to immunotherapy, but the pain sometimes responds to
carbamazepine, tricyclics, gabapentin, and nonnarcotic analgesics. HIV patients
also have mononeuritis multiplex caused by nerve infarction. Treatment with
antivirals (zidovudine, didanosine, dideoxycytidine) also causes axonal
neuropathy. AIDP and CIDP in HIV infection often have a CSF pleocytosis greater
than in idiopathic cases. Reduction of the viral load reduces the incidence of the
neuropathy. Do protease inhibitors cause neurologic complications? Painful
HIV-related neuropathy with vasculitis on biopsy has responded to corticosteroids.
Without biopsy the vasculitis can't be diagnosed but in cases that are refractory to
treatment either a biopsy or a short trial of steroid is an option.
G. Idiopathic facial palsy (Bell palsy)
1. Description. Acute idiopathic facial palsy is a mononeuropathy of the seventh
cranial nerve.
a. Isolated unilateral facial weakness is the most common feature, but pain,
hyperacusis, and ageusia may occur in some cases. In about 70% of
patients the deficits improve completely, in 13% there is minimal deficit, and
in 16% there is significant facial weakness.
b. In 85% of untreated patients who improve, the initial change appears within
3 weeks. The other 15% show signs of improvement within 3 to 6 months.
c. Patients older than 60 years of age, those with a complete lesion, and
those with hypertension and diabetes mellitus are at risk of not recovering
completely. When the EMG shows signs of denervation, the prognosis for
complete recovery is worse.
2. Treatment. Corticosteroid therapy is recommended. Since most patients
recover without treatment, however, there is some controversy about the
necessity for therapy. Prednisone, 60 mg PO every morning for 5 days, then
reduced gradually over 10 to 14 days, is standard and usually safe treatment.
Evidence shows that the recovery time is shorter when steroids are used. If
used, corticosteroids should be started as soon after the onset as possible,
since the suspected effect of the drug is reduction of facial nerve edema.
3. Complications. Facial spasm is occasionally a late complication of Bell palsy,
and it is often refractory to medical treatment. Anxiety usually makes the
twitches worse, and mild sedatives may help to relieve them (diazepam, 5 to
10 mg q.i.d., or phenobarbital, 30 to 60 mg t.i.d.). Phenytoin is occasionally
helpful (300 mg PO every morning), but if no effect is seen in 10 to 14 days,
the drug should be stopped.
H. Restless legs syndrome
1. Description. The restless legs syndrome is a rare condition in which an
unpleasant creeping sensation occurs deep in the legs (and occasionally in the
arms). The problem occurs when the patient is at rest, so it interferes with
sleep. The person is compelled to move the legs around to avoid the
unpleasant feeling. The calf and pretibial areas are the usual sites of
discomfort, and it is often bilateral. It may be intermittent, lasting several
minutes or hours, and there is no pain. The cause of the syndrome is unknown,
but it has been associated with iron deficiency anemia, cancer, and pregnancy.
It is found in some families as an autosomal dominant trait.
2. Treatment
a. The underlying condition is treated.
b. Clonazepam, 0.5 mg t.i.d.
c. Diazepam, 20 to 40 mg/day, helps occasionally.
d. Carbamazepine, 200 mg t.i.d.
e. Clonidine, 0.1 mg t.i.d.
f. Sinemet, 10/100 mg t.i.d.
g. Bromocriptine, 2.5 mg t.i.d.
XIX. Motor system disease
A. Description. Neuronal degeneration confined to the anterior horn cell and motor
neurons in the cerebral cortex is called motor system disease. The course of
motor system disease varies, depending on the age of the patient and the parts of
the motor system that are involved. There are several distinct forms of motor
system disease.
1. Amyotrophic lateral sclerosis (ALS) is the most common form of motor
system disease. Its etiology is unknown, but it is easily recognized by atrophy,
weakness, spasticity (from degeneration of upper motor neurons), and
absolute lack of sensory signs. It usually occurs sporadically, but occasionally
it may be found in families as a dominant trait. The gene for familial ALS codes
for superoxide dismutase (SOD), an important endogenous antioxidant, raising
the possibility that oxidative stress might lead to anterior horn cell death in
some forms of ALS. Males are affected more than females, and the onset is
usually in middle age with rapid progression.
Before making the diagnosis, treatable disease, such as spinal cord
compression, must be sought. Imaging study of the spinal cord is necessary
unless clear involvement of spinal and brainstem nuclei indicates a diffuse
localization. Neurophysiologic study identifies diffuse denervation and will
identify conduction block neuropathy that mimics motor neuron disease.
Abdominal reflexes and bladder function are usually normal. The degenerative
process may be localized only in the brainstem, in which case it is called
progressive bulbar palsy. In Guam and the Kii Peninsula of J apan, an
exceptionally high incidence of ALS has been reported.
2. Progressive muscular atrophy resembles ALS, but without involvement of
the upper motor neurons. Tendon reflexes are almost always absent, although
spinal cord and brainstem neurons may be involved. This is a very rare form of
motor system disease, with an earlier onset and slower progression than ALS.
Some forms of progressive muscular atrophy are hereditary, either as
dominant or recessive traits. There is an infantile form, Werdnig-Hoffman
disease, that is manifested as a floppy infant. A juvenile variety with proximal
distribution is called Kugelberg-Welander disease.
3. Primary lateral sclerosis is an extremely rare form of motor neuron disease,
in which the spinal motor neurons are spared but the upper motor neurons
degenerate, resulting in spasticity. The pathology of this disease is not fully
known. The progression is slow, and it is usually not fatal. The disorder may be
found in families, and the patient's kin may demonstrate other degenerative
disorders.
B. Prognosis. Patients who have motor system disease with only spinal involvement
usually die within 3 to 5 years. Those who have bulbar involvement (alone or with
spinal disease) usually die within 2.5 years. Occasionally, the progression of this
form of the disorder seems to slow down; some patients are reported to have lived
for 10 to 15 years with the spinal form of the disease. Thus, these cases may be
cited when discussing the prognosis of the illness with patients and their family.
Physical disability is usually complete earlier in bulbar cases (several months)
than in spinal cases (up to 4 years). However, progressive muscular atrophy and
primary lateral sclerosis, as they progress, often develop into the complete
syndrome of ALS. Patients with the juvenile form of progressive muscular atrophy
(Kugelberg-Welander disease) may live for 20 to 40 years after diagnosis.
C. Treatment
1. Emotional
a. The psychological management of any terminal illness must be
individualized. The general approach described for ALS can be modified to
be of use in other terminal illnesses as well. When the mind is spared and
patients can feel that they are becoming more disabled from one visit to
another, there is a particularly severe sense of helplessness. Thus,
frequently physicians will tend to avoid these patients and appear only
during catastrophe, when certain tangible action can help. However, the
management of ALS requires more availability and more support on the
part of physicians than diseases that are directly treatable.
b. When patients realize the severity of the illness, a massive reorganization
of their life must be undertaken. Also, once they realize that death is
inevitable, a variety of reactions will occur. For example, patients might
become depressed, with a sense of uselessness and hopelessness, and
increased dependence on the family and physician might follow. Self-pity
and low self-esteem might also contribute to the depression. The physician
can help in these situations by being appropriately available and by serving
as a listener for patients to express their feelings. At times, antidepressant
medication (amitriptyline hydrochloride [Elavil], 100 to 300 mg at bedtime) is
useful, but it should not be used as a substitute for the doctor-patient
relationship.
Some patients react with denial of depression and present a front of
pseudogaiety. In this case, the physician can help by being receptive to the
patient's underlying fears and anxieties and by not participating in the
process of denial.
c. Initial denial gives way to feelings related to job, family, religion, finances,
self-esteem, physical incapacity, and emotional vulnerability. Dying patients
have a fear of pain and abandonment, as well as anxiety about desertion of
their family and concern about other responsibilities. These are subjects
about which patients may wish to talk with the physician. A psychiatric
consultant or social worker may be needed if the neurologist is unable to
provide enough time.
d. In general, the physician should avoid offhand reassurances and superficial
denial of the illness. It does not help to commiserate with patients, to grieve
with them, or to provide false hope. Instead, the physician should represent
a warm, compassionate, personal force who is willing to help the patient.
Patients should be included in all major discussions and decisions
regarding their illness, and they are encouraged to remain as active as
possible. Also, members of the patient's family need support and accurate
information to allow them to adjust to the change in their lives with more
ease.
e. Patients with chronic progressive illness leave many questions unasked.
The physician should provide opportunities for patients to acquire the
knowledge they want and at the rate at which it is needed. It is best to tell
the truth about the prognosis. Many answers need to be repeated and
expanded as the illness progresses. Predicting the time of death is not
possible and should be avoided, but patients should be advised to arrange
their affairs just in case. When direct questions about death are asked,
pleading ignorance is not sufficient. Turn the question back to the patients
and allow them to express their feelings about the condition.
f. There is often a point in a chronic illness at which patients become angry.
The anger may be directed at the family, physician, or hospital. The
physician must allow patients to express this hostility and refrain from
counterattack, thus maintaining the therapeutic alliance. The family and
hospital staff must also be aware of the process behind the patient's anger.
2. Medical therapy. Riluzole. The FDA has approved riluzole, an excitatory
amino acid inhibitor. The drug interferes with glutamate release and activity
and stabilizes the inactivated sodium channels. The efficacy seen in clinical
trials suggests that the drug retards progression of the disease especially in
bulbar ALS. The dose is 50 mg q12h fasting. Monthly follow-up of liver
function, complete blood count, and disease progression is necessary in the
beginning, then at 3-month intervals. Patients progress despite the treatment
and the drug should not be presented as a cure but rather as a possible means
to delay the inevitable progression. As many as 20% drop out of treatment
from adverse effects. There are a number of treatment trials using neurotrophic
factors, e.g., ciliary neurotrophic factor (CNTF), brain-derived neurotrophic
factor (BDNF), or superoxide dismutase inhibitors in motor neuron disease. In
addition to their scientific benefit, participation in a drug trial can act as a sign
to patients that an attempt is being made to help them. Throughout the disease
tangible signs of help are useful to give patients a thread of hope in the
supportive program. Many become depressed and desperate. Suicide is
uncommon in these patients, perhaps because the weakness caused by the
disorder renders them incapable of performing the act.
3. Treatment of weakness
a. The treatment of weakness in ALS is purely mechanical. For example, a
neck brace can help when neck muscles are too weak to hold the head up,
and wrist splints occasionally improve grip in patients with weakness of
wrist extension.
b. Motorized and mechanical appliances (wheelchair, lifts, hospital beds) help
to maintain maximal independence.
c. Bracing is usually not done to preserve gait in ALS. However, in cases of
juvenile motor neuron disease (Kugelberg-Welander disease), bracing
might be indicated because the progression is very slow.
d. Physical therapy helps to minimize disuse atrophy and prevent
contractures. Fatigue should be avoided, and strength should be used for
necessary activities of daily living rather than in useless attempts to build
up the muscles.
e. Muscle cramps are common and may be prevented with phenytoin, 300
mg daily, or diazepam, 2 to 10 mg t.i.d. Warmth and massage are helpful in
releasing the cramps.
4. Most patients with motor system disease can be treated at home during most
of their illness, with help from a visiting nurses association or other community
agencies. It is expensive to keep these patients in acute care facilities.
However, if the family is not able to manage the patient, placement in a chronic
care facility for terminal care is necessary.
5. In following patients with motor system disease, body weight, ability to cough,
vital capacity, and difficulty swallowing are evaluated to measure change and
to anticipate problems.
Selected Readings
General
Dalakas M. Pharmacologic concerns of corticosteroids in the treatment of patients with immune-related
neuromuscular diseases. Neurol Clin 1990;8(1):93.
Kurtz LA, Scull SA. Rehabilitation for developmental disabilities. Pediatr Clin North Am 1993;40(3):629.
McCabe ER. Genetic screening for the next decade: application of present and new technologies. Yale J
Biol Med 1991;64(1):9.
McGee SR. Muscle cramps. Arch Intern Med 1990;150(3):511.
Newsom-Davis J , Mills KR. Immunological associations of acquired neuromyotonia (Isaacs' syndrome):
report of five cases and literature review. Brain 1993;116(Pt 2):453.
Thornton CA, Griggs RC. Plasma exchange and intravenous immunoglobulin treatment of neuromuscular
disease. Ann Neurol 1994;35(3):260.
Muscular Dystrophies
Bieber FR, Hoffman EP, Amos J A. Dystrophin analysis in Duchenne muscular dystrophy: use in fetal
diagnosis and in genetic counseling. Am J Hum Genet 1989;45:362.
Brown RH J r. Dystrophin-associated proteins and the muscular dystrophies. Annu Rev Med 1997;48:457.
Fenichel GM, et al. Long term benefit from prednisone therapy in Duchenne muscular dystrophy.
Neurology 1991;41:1874.
Hardiman O, et al. Neuropathic findings in oculopharyngeal muscular dystrophy: a report of seven cases
and a review of the literature. Arch Neurol 1993;50(5):481.
Harris SE, Cherry DB. Childhood progressive muscular dystrophy and the role of physical therapy. Phys
Ther 1974;54:4.
Love DR, et al. Dystrophin and dystrophin-related proteins: a review of protein and RNA studies.
Neuromusc Disord 1993;3(1):5.
Miller G, Wessel HB. Diagnosis of dystrophinopathies: review for the clinician. Pediatr Neurol 1993;9(1):3.
Sarnat HB, O'Connor T, Byrne PA. Clinical effects of myotonic dystrophy on pregnancy and the neonate.
Arch Neurol 1976;33:459.
Wessel HB. Dystrophin: a clinical perspective. Pediatr Neurol 1990;6(1):3.
Polymyositis
Amato AA, Barohn RJ . Idiopathic inflammatory myopathies. Neurol Clin 1997;15(3): 615.
Barwick DD, Walton J N. Polymyositis. Am J Med 1963;35:646.
Bromberg MB. The role of electrodiagnostic studies in the diagnosis and management of polymyositis.
Compr Ther 1992;18(4):17.
Bunch TW. Polymyositis: a case history approach to the differential diagnosis and treatment. Mayo Clin
Proc 1990;65(11):1480.
Bunch TW, et al. Azathioprine with prednisone for polymyositis: a controlled clinical trial. Ann Intern Med
1980;92:365.
Chwalinska-Sadowska H, Maldykowa H. Polymyositis-dermatomyositis: 25 years of follow-up of 50
patients' disease course, treatment, prognostic factors. Mater Med Pol 1990;22(3):213.
Dalakas MC. Clinical, immunopathologic, and therapeutic considerations of inflammatory myopathies.
Clin Neuropharmacol 1992;15(5):327.
Falasca GF, Reginato AJ . The spectrum of myositis and rhabdomyolysis associated with bacterial
infection. J Rheumatol 1994;21(10):1932.
Mastaglia FL, Phillips BA, Zilko P, Treatment of inflammatory myopathies. Muscle 1997;20(6):651.
Targoff IN. Autoantibodies in polymyositis. Rheum Dis Clin North Am 1992;18(2):455.
Villalba L, Adams EM. Update on therapy for refractory dermatomyositis and polymyositis. Curr Opin
Rheumatol 1996;8(6):544.
Periodic Paralysis
Griggs RC, Ptacek LJ . The periodic paralyses. Hosp Pract (Off Ed) 1992;27(11):123.
Gutmann L, Phillips LH. Myotonia congenita. Semin Neurol 1991;11(3):244.
Hudson AJ , Ebers GC, Bulman DE. The skeletal muscle sodium and chloride channel diseases. Brain
1995;118(Pt 2):547.
Stedwell RE, Allen KM, Binker LS. Hypokalemic paralyses: a review of the etiologies, pathophysiology,
presentation, and therapy. Am J Emerg Med 1992;10(2):143.
Myasthenia Gravis
Bain PG, et al. Effects of intravenous immunoglobulin on muscle weakness and calcium channel
autoantibodies in the Lambert-Eaton myasthenic syndrome. Neurology 1996;47(3):678.
Bleck TP. Tetanus: pathophysiology, management, and prophylaxis. Dis Mon 1991;37(9):545.
Cooper J D. Current therapy for thymoma. Chest 1993;103 [Suppl 4]:334S.
Dau PC, Denys EH. Plasmapheresis and immunosuppressive drug therapy in the Eaton-Lambert
syndrome. Ann Neurol 1982;11:570.
Dowell VR J r. Botulism and tetanus: selected epidemiologic and microbiologic aspects. Rev Infect Dis
1984;[Suppl 1]:S202.
Gajdos P, Chevret S, Clair B, Tranchant C, Chastang C. Myasthenia Gravis Clinical Study Group. Clinical
trial of plasma exchange and high-dose intravenous im-munoglobulin in myasthenia gravis. Ann Neurol
1997 J un;41(6):789.
Hambleton P. Clostridium botulinum toxins: a general review of involvement in disease, structure, mode of
action and preparation for clinical use. J Neurol 1992;239(1):16.
Lang B. Effects of intravenous immunoglobulin on muscle weakness and calcium channel autoantibodies
in the Lambert-Eaton myasthenic syndrome. Neurology 1996;47(3):678.
Richardson J P, Knight AL. The prevention of tetanus in the elderly. Arch Intern Med 1991;151(9):1712.
Schreiner MS, Field E, Ruddy R. Infant botulism: a review of 12 years' experience at the Children's
Hospital of Philadelphia. Pediatrics 1991;87(2):159.
Sutton DN, et al. Management of autonomic dysfunction in severe tetanus: the use of magnesium
sulphate and clonidine. Intensive Care Med 1990;16(2):75.
Thomas CE, Mayer SA, Gungor Y. Myasthenic crisis: clinical features, mortality, complications, and risk
factors for prolonged intubation. Neurology 1997 May; 48(5): 1253.
Facial Paralysis
Adour KK. Medical management of idiopathic (Bell's) palsy. Otolaryngol Clin North Am 1991;24(3):663.
Adour KK, Wingerd J . Idiopathic facial paralysis (Bell's palsy): factors affecting severity and outcome in
446 patients. Neurology (Minneap) 1974;44:1112.
Bauer CA, Coker MD. Update on facial nerve disorders. Otolaryngol Clin North Am 1996;29(3):445.
Collin J R, Leatherbarrow B. Ophthalmic management of seventh nerve palsy. Aust N Z J Ophthalmol
1990;18(3):267.
Murr AH, Benecke J E J r. Association of facial paralysis with HIV positivity. Am J Otol 1991;12(6):450.
Peitersen E. The natural history of Bell's palsy. Am J Otol 1982;4:107.
Neuropathy
Bosch EP, Smith BE. Peripheral neuropathies associated with monoclonal proteins. Med Clin North Am
1993;77(1):125.
Chaudhry V, Corse AM, Cornblath DR, et al. Multifocal motor neuropathy: response to human immune
globulin. Ann Neurol 1993;33(3):237.
Dyck PJ , et al. Plasma exchange in polyneuropathy associated with monoclonal gammopathy of
undetermined significance. N Engl J Med 1991;325(21):1482.
Gorson KC, Allam G, Ropper AH. Chronic inflammatory demyelinating polyneuropathy: clinical features
and response to treatment in 67 consecutive patients with and without a monoclonal gammopathy,
Neurology 1997;48(2):321.
Gracey DR, et al. Respiratory failure in Guillain-Barr syndrome: a six-year experience. Mayo Clin Proc
1982;57:742.
Guillain-Barr Syndrome Study Group. Plasmapheresis and acute Guillain-Barr syndrome. Neurology
1985;35:1096.
J enkins D, et al. Leprotic involvement of peripheral nerves in the absence of skin lesions: case report and
literature review. J Am Acad Dermatol 1990;23(5, Pt 2):1023.
Latov N. Pathogenesis and therapy of neuropathies associated with monoclonal gammopathies. Ann
Neurol 1995;37 [Suppl 1]:S32.
Leneman F. The Guillain-Barr syndrome: definition, etiology, and review of 1100 cases. Arch Intern Med
1966;118:139.
Levinson AI. The use of IVIG in neurological disease. Clin Rev Allergy 1992;10(12):119.
Mollman J E. Neuromuscular toxicity of therapy. Curr Opin Oncol 1992;4(3):540.
Shevell M, et al. Congenital inflammatory myopathy. Neurology 1990;40(7):1111.
Simpson DM, Olney RK. Peripheral neuropathies associated with human immunodeficiency virus
infection. Neurol Clin 1992;10(3):685.
Soueidan SA, Dalakas MC. Treatment of autoimmune neuromuscular diseases with high-dose
intravenous immune globulin. Pediatr Res 1993;33[Suppl 1]:S95.
Van der Mechae FGA, Schmitz PIM, the Dutch Guillain-Barr Study Group. A randomized trial comparing
intravenous immune globulin and plasma exchange in Guillain-Barr syndrome. N Engl J Med
1992;326(17):1123.
Motor System Disease
Agre J C, Rodriguez AA, Tafel J A. Late effects of polio: critical review of the literature on neuromuscular
function. Arch Phys Med Rehab 1991;72(11):923.
Bensimon G, Lacomblez L, Meininger VA. Controlled trial of riluzole in amyotrophic lateral sclerosis.
ALS/Riluzole Study Group. N Engl J Med 1994;330(9):585.
Doble A. The pharmacology and mechanism of action of riluzole. Neurology 1996;47(6 Suppl 4):S233.
Lacomblez L, Bensimon G, Leigh PN, Guillet P, Meininger V. Dose-ranging study of riluzole in
amyotrophic lateral sclerosis. ALS/Riluzole Study Group II. Lancet 1996; 347(9013):1425.
Mackay RP. Course and prognosis in amyotrophic lateral sclerosis. Arch Neurol 1963;8:117.
Miller RG, Bouchard J P, Duquette P, et al. Clinical trials of riluzole in patients with ALS. ALS/Riluzole
Study Group II. Neurology 1996;47(4 Suppl 2):S86.
Parry GJ , Sumner AJ . Multifocal motor neuropathy. Neurol Clin 1992;10(3):671.
Practice advisory on the treatment of amyotrophic lateral sclerosis with riluzole: report of the Quality
Standards Subcommittee of the American Academy of Neurology. Neurology 1997;49(3):657.
Smith RA, Norris FH. Symptomatic care of patients with amyotrophic lateral sclerosis. JAMA
1975;234:715.
Williams DB. Motor neuron disease (amyotrophic lateral sclerosis). Mayo Clin Proc 1991;66:54.
CHAPTER 17. PROBLEMS ASSOCIATED WITH CHRONIC NEUROLOGIC DEFICITS
Manual of Neurologic Therapeutics
CHAPTER 17. PROBLEMS ASSOCIATED WITH CHRONIC
NEUROLOGIC DEFICITS
Thomas M. Walshe III and Howard D. Weiss
Treatment of dysphagia
Bladder dysfunction
Bowel dysfunction
Management of tracheostomy
Decubitus ulcer
Sexual Dysfunction
Neurologic disease causes deficits in motor, sensory, and autonomic function that
require special management to optimize the patient's recovery. The deficits are
managed by specialists in rehabilitation, surgery, gastroenterology, and respiratory
medicine, among others, but the neurologist and generalist will be increasingly
responsible for getting the patient to the proper specialist and continuing the
management plans set up by the consultants. The care of a severely impaired
neurologic patient rests on the daily effort of chronic care providers who supply the
basic needs of the patient's life. The staff in the nursing homes and other chronic care
settings become adept at providing the services to the patient but, again, the primary
neurologist must be able to competently oversee their activity and offer appropriate
advice.
In mild stable cases of motor dysfunction, almost normal existence is possible with
proper bracing or other rehabilitation. However, in disorders that cause severe deficits
that are motor-, sensory-, or coordination-related, management is aimed at maximizing
the remaining function and avoiding complications.
In progressive disorders, the management is adjusted to the tempo and severity of the
illness. For example, malignant brain tumor or bulbar amyotrophic lateral sclerosis
(ALS) becomes fatal rapidly and rehabilitation is of limited help, but an understanding of
the prognosis and care of the secondary symptoms provides a real benefit to patients
and their families. The following sections describe the management of the ancillary
problems seen in disabled neurologic patients. The guidelines discussed can be applied
with slight modification regardless of the underlying neurologic process.
I. Treatment of dysphagia. Weakness, spasticity, or both of the pharynx and
tongue cause dysphagia and a lethal tendency to aspirate secretions and foods.
A. The use of a feeding tube, through a percutaneous endoscopic gastrostomy
(PEG), cervical esophagostomy, or jejunostomy, is required when the deficit is
expected to be prolonged. If the patient improves in months the gastrostomy is
easy to remove. In chronic care settings a good alternative to tube feeding for
some patients who are prone to dysphagia but able to swallow most foods is
careful oral feeding. Many stroke patients have dysphagia but are able to eat (one
of the few pleasures remaining to those in an institution or otherwise disabled) with
proper preparation of the food and attention to the feeding. Elderly patients
aspirate small amounts routinely; after a stroke or other deficit, many will have
serious difficulty but can continue to eat as the deficit improves. It is better to try all
ways to provide adequate, safe nutrition (even allowing an occasional episode of
aspiration) by mouth in an alert patient before a feeding tube is placed. However,
comatose patients and those with severe dysphagia for all forms of oral nutrition
require feeding by tube as the only alternative to maintain nutrition and hydration.
Of course, patients who have a dysphagia from an illness with a good prognosis
(e.g., inflammatory neuropathy) should have a tube early in their course.
Nasogastric tubes have been used temporarily for feeding, but they are
uncomfortable, cause pressure necrosis of the nares when used chronically, and
allow aspiration. If a nasogastric tube is used, the smallest possible diameter is
best; the soft rubber pediatric tubes are large enough even for adults. The
nasogastric tube should not be used for more than a few days. The cervical
esophagostomy may be useful in severely dysphagic patients who are ambulatory
because the patient can insert the tube during feedings and the ostium can be
covered with a dressing at other times. Patients with severe weakness or ataxia of
the upper extremities are usually unable to feed themselves, so percutaneous
endoscopic gastrostomy is the method of choice. However, multiple abdominal
procedures, especially gastric operations, make gastrostomy more dangerous
than cervical esophagostomy.
The use of feeding tubes in patients with severe progressive dementia poses a
dilemma since the patient has no sense of hunger and may suffer fatal aspiration if
fed by mouth. Some patients will starve to death (and become dehydrated) if they
are allowed to eat ad lib. The patients who feed on the suck reflex have a high rate
of aspiration. In our experience it has been possible for the chronic care providers
to feed the patients as best as possible without a feeding tube. The complications
are clearly understood and accepted by the providers and families; if not the
patient is tube-fed without appreciable improvement in the quality or length of life.
Most chronic care providers are reluctant to use feeding tubes in severely
demented patients.
B. Care of a gastrostomy is simple: 10 to 14 days after the tube is inserted, a
well-defined fistula is established, and the tube can be changed easily. A 22F or
24F Foley catheter or special gastrostomy tube may be used.
C. Tube feedings with commercial products (e.g., Sustacal or Sustagen) are
calculated to deliver the desired amount of calories each day.
1. The caloric need is higher for active patients and ranges from 1,200 to 2,400
kcal/day. The liquid foods are usually concentrated to deliver 1 kcal/mL. If they
cause diarrhea, they may need to be diluted. To avoid clogging of the tube,
each feeding is followed with water.
2. Tube feeding is best started with about one half the total desired calories
diluted in water. A gradual increase in concentration (and calories) averts
diarrhea and malabsorption. Before administering a feeding, the tube is
aspirated to ensure that the previous feeding was absorbed. Small volumes
are given at first at frequent intervals (q12h). The maximum volume given is
about 200 mL (150 mL of food followed by 50 mL of water).
3. Large volumes may cause vomiting and aspiration, although larger individuals
might require more volume. If the patient needs more water, small volumes
may be given between feedings. Also, blended food mixed with milk or water
may provide more bulk and prevent the feeling of hunger in patients with a
gastrostomy. Some patients do best with continuous feeding at 60 to 70
mL/hour.
D. If aspiration of saliva and nasal secretions is a problem, a cuffed endotracheal
tube is necessary. Anticholinergic drugs or tricyclic antidepressants might reduce
salivation and prevent drooling, and in some cases the patient may be able to
swallow the reduced volume of secretions safely. Ligation of the trachea above the
tracheostomy might be necessary to prevent chronic aspiration of secretions and
food.
E. The decision to undertake palliative surgery such as gastrostomy and
tracheostomy depends on the general level of function of the patient. Patients
with progressive illnesses are often not treated with tracheostomy late in the
illness, when respiratory failure threatens. Patients with stable illnesses of
brainstem or cervical spinal cord often benefit from it.
II. Bladder dysfunction. Spinal cord trauma is the most prevalent cause of
severe neurogenic bladder dysfunction, but other spinal cord conditions, such as
multiple sclerosis, spinal cord tumor, ruptured disk, and tabes dorsalis, produce
problems with micturition. In addition, disorders of peripheral nerves, such as diabetes
mellitus and herpes zoster, may cause hyporeflexive bladder. Neurologic disease
affecting higher centers, such as Parkinson disease, frontal lobe tumors, and
cerebrovascular disease, may also cause abnormal micturition. During each incident, a
cystometrogram is necessary to define the type of bladder dysfunction so that
appropriate therapy can be attempted. Early urologic consultation together with a
cystometrogram is needed to define structural abnormalities.
A. Normal bladder function. The anatomy and physiology of the bladder are
arranged to allow storage of urine until it can be conveniently excreted.
1. The majority of the detrusor muscle derives its innervation via
parasympathetic fibers (S2S4). The area of the trigone, however, is
innervated by sympathetic fibers (T11L2). (Ascending fibers provide
appropriate feedback control.)
a. Both somatic sensory fibers and parasympathetic ascending fibers leave
the bladder to converge at the S2S4 levels. There are also some
ascending sympathetic fibers that synapse at the T9L2 levels. The lateral
spinothalamic tracts and the fasciculus gracilis carry the ascending fibers to
higher centers.
b. The corticospinal tracts carry motor fibers to the external sphincter and
pelvic floor muscles, which are under voluntary control. The primitive
micturition reflex is at the S2S4 level via parasympathetic efferent fibers.
2. To maintain continence of urine, the urethral pressure must be higher than
the vesical pressure. The muscles of the urogenital diaphragm and urethra
may be either flaccid or spastic in neurologic disease. If they are flaccid there
is little outflow obstruction, and incontinence is common even with low bladder
pressure. If the muscles of the urogenital diaphragm and urethra are spastic,
ureteral reflux and high volumes of residual urine occur unless there is a high
bladder pressure to overcome the resistance. Optimal function requires a
balance between the bladder and the urogenital musculature. In neurologic
disease, the balance among urethral pressure at the bladder neck, external
sphincter and pelvic muscle tension, and detrusor pressure is disturbed, which
can cause incomplete or unexpected voiding.
3. Micturition is the result of reflex and voluntary activity. In the normal bladder,
a pressure of 30 to 40 cm H
2
O causes reflex reduction of urethral pressure and
consequent micturition. As the bladder fills, wall tension increases but
intravesicular pressure remains constant. At low volumes, a normal person
feels the bladder filling, and when it reaches 100 to 200 mL the urge to void
occurs. Voluntary control of the external sphincter and pelvic floor muscles
helps to maintain continence, but there is also reflex inhibition of the detrusor,
so pressure is kept constant. In normal persons, the maximum bladder
capacity is 400 to 450 mL, and at this point the detrusor contracts and all of the
urine is expelled. Initiation of micturition when the bladder is full is caused
mostly by reflex. The latency between the decision to void and the initiation of
flow is inversely related to the bladder volume.
B. Goals for management of the neurogenic bladder
1. Protect the kidneys from hydronephrosis and infection by reducing residual
urine and reflux up the ureters.
2. Relieve incontinence.
3. Maintain an acceptable functional capacity so voiding occurs only q46h.
C. Hyperreflexive bladder management (lesions above S2S4). The hyperreflexive
bladder is characterized by many subthreshold, uninhibited detrusor contractions,
reduced capacity, and spontaneous voiding with a strong stream. Chronic spinal
cord lesions above S2S4 cause a hyperreflexive bladder in which the patient has
no sensation of bladder fullness. In these patients, the bladder empties by reflex
action when a critical volume is reached. If the urogenital diaphragm muscles are
coordinated with the reflex detrusor contraction, complete spontaneous voiding
occurs. However, if the urethral pressure is too high, there is reflux into the
ureters; and if the urethral pressure is too low, there is incontinence. In lesions that
are higher (i.e., in the cortex, posterior hypothalamus, midbrain, or anterior pons),
there may be a sensation of urgency and frequency without dysuria. Dyssynergy
between the muscles of the urogenital diaphragm and the detrusor causes
incontinence during small reflex contractions. In this case, instillation of ice water
into the bladder will produce reflex micturition. Cystitis can cause bladder
hyperreflexia because of irritation of nerve endings in the bladder wall, and
hyperactivity can occur in obstructive bladder disease (prostatic hypertrophy
usually), even without neurologic disease.
1. When a patient is incontinent with a hyperreflexive bladder or has an acute
spinal cord injury with resolving spinal shock, intermittent catheterization is
started. To avoid infection, an experienced person (or team) should perform
the catheterization in the early stages.
a. Volume intake. The patient is given large volumes of fluid either PO,
through a nasogastric tube, or IV, and the bladder is drained q24h. High
volume intake reduces the risk of infection and calculus formation.
b. Bladder training is begun (see sec. II.C.2), and as the patient begins to
void on his or her own (usually by reflex), the frequency of catheterization is
reduced until the patient voids by reflex and carries an acceptable residual
volume (i.e., less than 100 mL). It usually takes less than 90 days for most
patients with a complete spinal cord lesion to become catheter-free.
Approximately 10% to 20% fail to improve because of either a very small
bladder capacity or excessive bladder hyperreflexia. If intermittent
catheterization fails, an indwelling catheter is placed or other methods are
used to maintain continence.
c. Incomplete spinal cord lesions have the most rapid and complete return
of reflex micturition. Some patients might require chronic intermittent
catheterization in addition to reflex voiding.
2. Bladder training. Intermittent catheterization prevents excess bladder
distention. Bladder training helps to prevent bladder contracture, conditions a
regulated reflex pattern, and causes the patient to take notice of bladder
function.
a. Regular attempts at initiating the voiding reflex should be made. In
patients with a complete sensory level below the waist, the best means of
beginning the reflex varies. Squeezing the glans penis, scratching the
scrotum, pulling the pubic hair, tapping over the bladder, and (most often
successful) deep digital stimulation of the rectum are useful methods.
b. High volume intake keeps the urine dilute and helps prevent infection.
However, once a patient is trained, fluid volume must be adjusted so
voiding is not inconveniently frequent.
c. Observance of intake and output ensures fluid balance.
d. External compression of the bladder (Crede maneuver) helps reduce
residual volume and, with triple voiding, increases the total amount voided.
e. Alternation of the patient's position increases the total volume voided.
3. Drug therapy. The use of drugs is limited because chronic use causes toxicity.
a. Bethanechol chloride (Urecholine), a cholinergic agonist, may increase
detrusor activity and facilitate reflex voiding. It has few cardiac side effects
and an effect localized on the urinary cholinergic circuit. The dosage is 10
to 50 mg q46h PO or 5 to 10 mg q46h SC.
b. When small bladder volumes cause excessive reflex activity and urgency
incontinence, reduction in the reflex may increase the time between
voidings.
1. Propantheline bromide (Pro-Banthine) is an anticholinergic agent that
reduces detrusor reflex activity in dosages of 15 mg PO q.i.d.
Oxybutynin (Ditropan) has an atropine-like effect on smooth muscle
and is also useful to relax the detrusor. The dose is 5 mg b.i.d. or t.i.d.
Anticholinergic drugs are most useful in partial spinal cord lesions or
higher lesions to reduce urgency and frequency. The anticholinergic
drugs may, however, increase residual volume and paradoxically cause
more frequency because of reduced functional capacity. Increased
residual volume also increases the risk of infection, which may lead to
chronic cystitis or even pyelonephritis. Thus, these drugs are
discontinued if the residual volume is increased to more than 15% of the
voided volume.
2. Tricyclic antidepressants (150 mg at bedtime) may act to increase
bladder capacity through their anticholinergic activity.
c. Phenoxybenzamine, an a-adrenergic blocking agent, acts on the proximal
urethra and reduces urethral pressure. Residual volume may be reduced
when it is given in dosages of 20 to 40 mg t.i.d. The specific a
1
blockers
have replaced phenoxybenzamine and are useful in some patients
especially if there is prostatic hypertrophy. Prazosin, trazosin, and
tamsulosin (a
1a
) are available. Tamsulosin has no antihypertensive
effecta benefit in some cases. The need for bladder neck resection may
be averted when a blockers are effective.
d. Propranolol (Inderal), a b-adrenergic blocker, increases urethral resistance
and may be helpful when incontinence is caused by uninhibited
contractions that overcome the urethral pressure. Usual doses are 20 to 40
mg q.i.d. or more.
e. Drugs to reduce spasticity of the pelvic floor may reduce residual volume
and allow more complete voiding. Dantrolene sodium (Dantrium) has not
been systematically tested, but baclofen (Lioresal), used for bladder
training, has been reported to reduce residual urine volume.
4. Surgical therapy
a. When medical measures fail to allow reflex voiding or there is high bladder
pressure with reflux of urine into the ureters causing hydronephrosis,
bladder neck resection or external sphincterotomy will reduce both
resistance to flow and bladder pressure. Removal of prostate or urethral
valve obstruction also may be necessary to allow adequate reflex voiding.
b. Other procedures are available to increase the voiding pressure, reduce
capacity, increase capacity, or divert the urinary stream. Urologic
consultation is needed in all of these cases.
c. When a hyperreflexia is severe and the bladder is contracted so there is
low functional capacity, an alcohol block of the cauda equina or anterior
and posterior rhizotomy of T12S5 will cause it to become hypotonic.
However, these procedures can only be done in paraplegics, and they
cause impotence. The major indication is to spare the kidneys from
hydronephrosis and recurrent pyelonephritis.
D. Hyporeflexive bladder management. The hyporeflexive bladder is characterized
by very low pressure, no contractions, high capacity, high residual volume, and
poor stream. There is absent or decreased sensation of fullness. It is associated
with lesions at either the S2S4 level or on the peripheral nerves and roots.
Transient urinary retention may follow lumbar puncture or, more commonly,
lumbar myelography. Men with prostate enlargement are particularly susceptible
to retention. Intermittent catheterization q46h will keep the bladder drained, but
occasionally bethanechol chloride (10 to 25 mg PO q68h) is needed. The
retention usually resolves spontaneously in 24 to 48 hours.
1. Chronic intermittent catheterization done by the patient on a timed schedule
is effective in keeping the bladder empty. Also, it can be done, if necessary,
using nonsterile technique without danger of serious infection. Patients can
carry the catheter with them in a pocket or purse. Often patients with ataxia,
upper extremity weakness, excessive adduction spasticity in the legs, or
dementia are not able to catheterize themselves and require the help of a
caregiver or an alternative method.
2. The use of external bladder compression (Crede maneuver) and contraction
of abdominal muscles may allow the patient to void sufficiently to reduce
residual urine to an acceptable volume (usually less than 15% of voided
volume). Since the patient may not perceive bladder fullness, regular attempts
at voiding at specific times are important. In patients with weak abdominal
muscles, a lumbosacral corset helps to increase intra-abdominal pressure.
3. Drug therapy
a. Incomplete lesions in which there is diminished reflex activity may improve
with bethanechol chloride, 10 to 25 mg PO q8h. If the oral dose is
ineffective, subcutaneous injection may be useful.
b. The a
1
blockers (see II.C.3.c) may reduce urethral pressure so that voiding
is more complete (20 to 40 mg t.i.d.).
4. Surgical therapy
a. Bladder neck resection reduces physiologic obstruction and allows more
complete emptying of the bladder.
b. Relief of obstruction from prostate transurethral resection of the prostate
(TURP) or urethral valves may also reduce residual volume.
E. Incontinence. Overflow incontinence occurs in hypotonic bladders, and higher
volume reflex incontinence occurs in hyperreflexive bladders. The easiest method
to control incontinence is to keep the bladder empty by voiding every hour or at a
rate that prevents either overflow or urgency. The patient starts at a frequent rate
and determines which rate is adequate.
1. For the incontinent male, several appliances are available.
a. The penile sheaths or condom collecting devices are useful for both
temporary and chronic use. The device is attached around the shaft of the
penis with cement or tape, and it can be left in place for up to 12 hours. A
reservoir bag can be strapped to the leg and be hidden by clothing. Many
males with bladder dysfunction use a condom device when they are in
public. Frequent changes of the condom (q68h) and local care to the penis
usually prevent skin breakdown. However, if ulceration or maceration of the
skin of the penis occurs, the device should be removed, the area kept dry,
and a bland ointment used to help with healing. In hospitalized patients, a
diaper can be used instead of the device to allow the penis to heal.
Condom devices promote urinary tract infection in bedridden patients,
especially if the distal part of the condom becomes obstructed and urine
pools in the condom. There are several types of penile sheaths available
and the patient should be given the chance to try the single-and
double-component varieties to see which he prefers.
b. The Cunningham clamp is a device designed to occlude the urethra
mechanically by external compression of the penis. However, the clamp
should be released frequently to prevent pressure necrosis of the penis or
urethra. This old-fashioned device should not be used in patients who do
not have tactile sensation of the penis.
2. Surgically implanted prosthetic devices to provide sphincteric effect are
available. These devices are useful in patients with hyporeflexive and
hyperreflexive bladders.
3. Electrodes placed in the S2S4 area of the spinal cord have produced detrusor
contraction in some cases of hyporeflexive bladder.
4. Incontinence in the female is difficult to control with medication if the bladder
volume is large or the bladder is hyperreflexive. An indwelling catheter may be
the only way to keep the patient dry. If the bladder volume is small and the
patient can use intermittent catheterization, a pad may be sufficient between
catheterizations.
5. Chronic indwelling catheters should be avoided if possible.
a. The catheter is inserted, using strict aseptic technique.
1. Teflon catheters have less chance of accumulating mineral deposits;
therefore, they can be changed less frequently.
2. The standard rubber catheter is changed every 7 to 10 days.
3. A Foley balloon-type catheter is less desirable for chronic use
because the balloon may cause bladder irritation and pressure damage.
In women, the Foley catheter is usually necessary because there is no
effective way of securing a straight catheter. In males, a straight
catheter taped to the penis can be substituted for the balloon type.
b. In all cases, the drainage system should remain closed, and the reservoir
should never be raised above the bladder to prevent reflux into the
bladder. A disinfectant may be added to the reservoir.
c. Irrigation of the bladder is done through a double-lumen catheter
perfused q.i.d. or t.i.d. with a volume that is equal to the bladder capacity.
Any sterile solution is suitable. A citric acid solution (e.g., Renacidin) helps
to prevent calcium salts from aggregating on the catheter, and solutions of
acetic acid or neomycin are also available. When the patient is ambulatory,
continuous irrigation may be stopped by clamping the inflow tube.
d. Catheter size. A 16F catheter or smaller is optimal. Large catheters are
associated with urethral abscess in men, but in women the urethra will
dilate if larger catheters are used. If a balloon catheter is used, 5-mL
volume in the balloon is sufficient. In males, the catheter should be taped to
the abdomen to prevent extreme angulation, causing pressure necrosis at
the penoscrotal junction.
e. Drainage of the upper urinary tracts is facilitated by:
1. Early ambulation or wheelchair activity.
2. Frequent changes of position.
3. Elevation of the head of the bed.
f. High fluid intake helps to prevent infection and calculus formation. Intake
of 3,000 to 4,000 mL of fluid each day is indicated for persons with
indwelling catheters in place, unless there is a strong medical
contraindication to this fluid load.
F. Stone prevention
1. Chronically bedridden patients have a high incidence of renal calculi. Good
nutrition and high fluid volume are important to prevent stones. If
hypercalciuria is present, a reduction in the amount of dietary calcium may help
to prevent stone formation.
2. Acidification of the urine helps to prevent infection as well as to keep mineral
salts in solution. Thus, most patients with bladder dysfunction, especially those
with indwelling catheters, should have their urine acidified to prevent
precipitation of mineral deposits and help prevent infection.
a. Cranberry juice lowers the pH irregularly but is useful in some cases as an
adjunct to other agents; 250 mL t.i.d. has been used.
b. Ascorbic acid, 250 mg PO q.i.d., will lower urine pH if there is no infection
present. Methenamine mandelate (Mandelamine), 1 g PO q.i.d., will lower
urine pH if there is no infection present; 1 g PO q.i.d., used with ascorbic
acid, is useful in keeping urine acidified when infection is present. It also
has bactericidal action.
G. Urine infection
1. It is not necessary to treat asymptomatic, chronic urinary infection rigorously
while a catheter is in place. Acidification of the urine and use of suppressive
agents, such as methenamine mandelate, 1 g q.i.d., methenamine
hippurate (Hiprex), 1 g b.i.d., or sulfisoxazole (Gantrisin), 1 g q.i.d., are
sufficient to keep the bacterial count as low as possible. The standard
treatment has become trimethoprim and sulfamethoxazole double strength
(160 mg/800 mg q.d) (Bactrim DS and others). Allergy to sulfa may limit the
use. Other broad-spectrum antibiotics are also used when necessary.
Prevention of ureteral reflux is critical to protect the upper tracts from infection.
2. When acute infection occurs or the patient becomes febrile, specific therapy
is necessary. If the patient is on intermittent catheterization, a Teflon catheter
is inserted and kept in place until the infection is under control. If the patient is
on continuous drainage, the old catheter is replaced and specific antibiotics are
used. However, frequent aseptic change of the catheter may be necessary.
Although the urine may never become sterile, the goal of therapy is to
eradicate the bacteria in the tissue and upper tracts. Bladder urine may remain
infected.
III. Bowel dysfunction
A. Fecal impaction occurs in patients with a variety of illnesses, but it is especially
common with neurologic disease. Adequate investigation for bowel obstruction is
necessary in persistent cases.
1. Predisposition
a. Bedridden patients.
b. Elderly patients, especially those with a history of fecal impaction or
constipation.
c. Patients with abdominal weakness from neuromuscular, neuropathic, spinal
cord, or other disorders.
d. Patients receiving narcotics or other drugs that reduce bowel motility (e.g.,
anticholinergics).
e. Dehydrated patients (e.g., those on glycerol, mannitol, or alumina gels).
2. Signs and symptoms
a. Having the urge to defecate but being unable to do so is a common
complaint in fecal impaction.
b. Frequent watery stools.
c. Crampy abdominal pain.
d. Bowel obstruction with air-fluid levels seen on abdominal x-rays.
e. A hard mass in the rectum or an abdominal mass that moves easily with
palpation.
3. Treatment
a. Adequate hydration softens the stool and prevents impaction. Patients
who do not ask for liquids (dementia, coma, etc.) are most prone to the
problem.
b. Drugs such as dioctyl sulfosuccinate (Colace) also increase stool water
and soften stools.
c. Natural laxatives (e.g., whole bran, prunes, etc.) in the diet are useful to
keep the stool soft. The bulk-forming laxatives (Metamucil and others) are
helpful also.
d. Oral mineral oil, 30 mL PO daily or b.i.d. for several days, helps to move
impactions.
e. Saline laxatives. Milk of magnesia (MOM) and others are useful PO 60 mL
q.d. or by enema. MOM in oil is particularly effective. The stimulant
laxatives are not usually necessary but drugs like bisacodyl are available.
The program needs to be developed by the patient or caregivers beginning
with the least complex maneuvers until a successful routine is established.
Comatose and vegetative patients can be given programmed bowel care to
control the spontaneous defecation which creates an unpleasant
environment for the nursing staff.
f. Digital removal of the impaction or removal through a sigmoidoscope is
necessary when other measures fail.
B. Fecal retention and incontinence
1. Paralyzed patients often have no problem with fecal incontinence or
constipation, even when bladder dysfunction is severe.
2. Diarrhea may precipitate fecal incontinence in an otherwise controlled patient.
When diarrhea is controlled, the bowel is often continent.
3. Bowel training is necessary in some patients.
a. Regular enemas or a suppository is utilized each day until a bowel pattern
is established.
b. Regular attempts at defecation should be made, using an abdominal
corset if necessary. Attempts to open the bowel after meals involve use of
the gastrocolic reflex to improve evacuation.
c. Maintenance of a soft stool, using adequate hydration, prunes, bran
cereals, and stool softeners (dioctyl sulfosuccinate, 100 mg t.i.d.), helps to
promote bowel function.
d. An abdominal corset may help to increase intra-abdominal pressure in
patients with weak abdominal muscles.
e. In severe idiopathic polyradiculitis (Landry-Guillain-Barr syndrome),
and other self-limited conditions, regular enemas and suppositories are
often necessary until the patient can contract the abdominal muscles.
Vacuetts suppositories are very useful when the stool is soft; they release
carbon dioxide, increase pressure in the lumen of the bowel, and help
stimulate reflex defecation.
f. Avoid constipating medications, such as narcotics.
4. Patients with chronic fecal incontinence (e.g., diabetics) can be helped
occasionally.
a. Use of denatured tincture of opium (5 to 10 drops b.i.d.) may reduce
motility of the bowel.
b. A regular morning enema to cleanse the bowel may allow the patient to go
through the day with only a pad, with little risk of an unexpected loss of
stool.
c. Biofeedback techniques have been used to train some patients to use the
external sphincter and the other voluntary muscles to maintain fecal
continence. There is not a consensus as to its efficacy.
d. Surgical interventions
1. Sphincteroplasty and gracilis muscle transposition have each been used
with success in some patients with failure to close the sphincter. The
injection of fat perianally has also been used. The injections are
temporary but last for months in some cases.
2. The Malone antegrade continence enema is used in children but seems
applicable to adults with severe fecal incontinence. A continent
cecostomy is created surgically through the appendix or otherwise and
that opening allows the insertion of a catheter and a daily large-volume
enema to flush the bowel from above. The patient is in control of the
bowel contents and can get through the day with a pad.
IV. Management of tracheostomy
A. Placement
1. Acute respiratory distress is managed by endotracheal intubation in an
intensive care unit. Tracheostomy can be done as an elective procedure if
improvement is not expected to occur within 7 to 10 days.
2. Indications. Patients with neuromuscular, motor system, or brainstem lesions
often require tracheostomy to:
a. Maintain airway.
b. Prevent aspiration.
c. Permit deep suctioning.
d. Reduce dead space and reduce the work of breathing.
B. Complications
1. Overall mortality is 1.6% in adults and 1.4% in children. Hemorrhage and a
displaced tube are the most common causes of death. Death rarely occurs as
a late complication unless there is obstruction or detachment of the tube from
the ventilator.
2. Causes of obstruction
a. Secretions harden and occlude the lumen of the tube, especially when
inadequate humidity is administered or the tube is not changed frequently.
b. In metal tubes, the cuff is separate from the tube, and it may slip down and
occlude the lumen.
c. If the tracheostomy is low in the neck, the cannula may obstruct at the
carina. If a tube is used that is too long, it may intubate only a single
bronchus. Postintubation auscultation and chest x-ray will identify this
complication.
d. Trauma. Injured mucosa causes collection of tissue debris and granulation
at the lumen of the tube, which may obstruct it.
3. Hemorrhage
a. Acute postoperative hemorrhage around the wound may be life threatening.
b. Later, hemorrhage caused by erosion of the mucosa or erosion into an
artery or vein, causing massive hemorrhage, may be fatal because of
aspiration or exsanguination.
4. Subcutaneous or mediastinal emphysema usually needs no treatment;
however, if it is excessive, change of the tube position and repair of the rent
might be indicated. At times pneumothorax may follow subcutaneous
emphysema, and appropriate x-rays of the chest should be obtained in all
patients with subcutaneous or mediastinal air.
5. Infection
a. Wound infections.
b. Chronic tracheitis. Culture of bacteria in the secretions of a
tracheotomized patient is not enough to diagnose infection. Most patients
with tracheostomies harbor a number of potential pathogens.
C. Choice of tube
1. Metal tubes usually have an outer cannula that remains in the trachea and an
inner cannula that can be removed and cleaned. Metal tubes have no built-in
cuff, but one can be added. These tubes are used for permanent
tracheostomies. Patients with chronic tracheostomies can be instructed in
self-management of these tubes at home if they have arm function.
2. Valved tubes are also metal. They are used so the patient can speak. At night
a nonvalved inner cannula can be inserted.
3. Plastic tubes are becoming more popular and are used for tracheostomy
when a cuff is necessary. However, the whole tube must be changed when
secretions accumulate. Most neurologic patients require a cuff, since protection
against aspiration is an important consideration.
D. Management of the cuffed tube
1. Choice of a low-pressure, high-volume cuff helps to prevent pressure necrosis
of the trachea.
2. The cuff is never inflated to an arbitrary volume. The volume is determined by
leakage of air around the cuff. When positive pressure ventilation is used, the
cuff is inflated until no leakage is heard around the cuff, and then several
milliliters is withdrawn until there is a slight leak.
3. The cuff will cause pressure necrosis unless it is deflated for 5 to 10 minutes
q12h. Also, if a high-volume, low-pressure cuff is used, there is less chance of
necrosis. When aspiration is a problem, the patient is placed in the
Trendelenburg position, or at least supine, when the cuff is deflated. Note that
suctioning above the cuff is necessary before it can be deflated.
4. The patient requires adequate fluid intake, and when a plastic cuffed tube is
used, hydration in the form of aerosol is necessary to keep the patient's
secretion thin. The room humidity should be kept high and the room
temperature warm. A tracheostomy mask is useful to deliver warm humidified
air to the patient.
5. Frequent suction of secretions keeps the accumulation on the tube to a
minimum. Instillation of 5 to 10 mL of sterile saline might help when secretions
are very thick.
6. Postural drainage helps to remove secretions from the bronchi.
7. Speech is possible with any tracheostomy if the tube is occluded and the cuff is
deflated.
8. Tracheostomy wounds close spontaneously in several days when the tube is
removed. If healing is slow, taping the edges of the wound together or using a
bandage with petroleum jelly to make an airtight seal will speed healing. In a
few cases, the tracheostomy must be closed surgically.
9. Once artificial respiration is not necessary, the tracheostomy can be allowed to
close unless aspiration or prophylactic use (as in severe myasthenia) requires
continuation. Occlusion of the tracheostomy, with the patient breathing through
the mouth for several minutes, increasing to hours, tests the need for a
tracheostomy. In many cases, patient comfort without the tracheostomy is
basis enough to remove it, despite the blood gases and other parameters.
10. In chronic aspiration, the upper trachea can be ligated and the tube left in
place. Then the patient can take fluids and food by mouth.
11. Otolaryngology consultation is helpful in management of a chronic
tracheostomy.
E. Changing the tracheostomy tube
1. Plastic tubes must be changed every 5 to 10 days. Metal tubes can be cleaned
daily and changed less frequently.
2. The orifice at the neck communicates with the trachea and is well formed after
about 3 to 5 days postoperatively. If the tube is changed earlier, a surgeon
should do it.
3. Gentle, firm pressure slips the tube into place and usually causes a cough
reflex.
4. It is best to use the same size tube with each change. There is a tendency for
staff members to use a smaller tube at each change because the larger tubes
are not as easily inserted. However, if progressively smaller tubes are used
there will be a point at which the orifice is not adequate and surgical dilatation
is needed.
V. Decubitus ulcer
A. Prevention
1. Neurologic patients who are paralyzed, those with sensory deficits or
incontinence, and those who are fed by others are highly susceptible to
pressure necrosis of the skin. The single cause of decubitus ulcers is the
failure of the normal repositioning of the body to avoid constant pressure on an
area of the skin. The most important preventive measures are frequent
turning of the patient and frequent changing of the patient's posture. In
quadriplegic patients, the Stryker frame is useful, and the patient can be
rotated easily q12h. Careful turning and positioning will prevent decubitus
ulcer in these patients. Thus, prevention of decubitus ulcer depends on the
quality of nursing care.
2. Protection of bony prominences (e.g., heels, ischial tuberosities, and sacral
areas) from pressure and other trauma is necessary. In infants with chronic
compensated hydrocephalus, care must be taken to shift the enlarged head
and keep it protected; otherwise decubitus ulcer will occur.
3. Sheepskin, water mattress, and other soft material helps to protect the skin.
However, cushions in donut shape can cause ischemia of the central area and
actually promote decubitus ulcer formation.
Scrupulous protection from fecal and urinary incontinence is also of prime
importance.
4. The patient's skin should be kept dry, and urinary incontinence must be
controlled. Frequently changed diapers can be used to keep the patient dry
without using an indwelling catheter.
5. Use of bland ointment, such as petroleum jelly, in areas exposed to dampness
may help to prevent maceration of the skin.
6. Good nutrition is important to maintain healthy skin.
7. If edema forms, the skin becomes thin and vascularity decreases. Aggressive
treatment of dependent edema in a paralyzed limb and special protection of it
will help to prevent skin breakdown.
B. Treatment of established pressure sores
1. Pressure must be removed from the area of skin that is involved. As long as
pressure is maintained, the ulcer will fail to heal and may progress no matter
what else is done. The area of the ulcer is gently scrubbed with saline or
hydrogen peroxide and mechanically debrided if there is necrotic tissue
present. Wet-to-dry dressings are useful for large necrotic ulcers until there is a
fresh area of granulation tissue. In exudative wounds dextranomer beads or
paste (Debrisan) can dry the wound and facilitate healing. The paste is
changed twice a day and not allowed to fully dry. Calcium alginate dressings
(Sorbsan) have been even more successful than enzyme preparations in some
hands. Once the ulcer begins to granulate the wet dressings are discontinued
to allow healing. Also, lytic enzyme ointment (e.g., Biozyme, Elase, Penafil,
and Travase) can be applied to the necrotic ulcer or in solution with a
wet-to-dry dressing, which may be enough to debride the lesion. The enzyme
is applied 2 or 3 times daily, and the ulcer is washed before application.
Hydrogels (e.g., K-Y J elly) are as effective as enzyme preparations in some
cases. After debridement the area is kept dry, using a light 4 4 in. dressing or
other lightly applied bandage while it heals.
2. Petroleum jelly or zinc oxide can be used as an occlusive dressing. A paste
of magnesium aluminum gel can be made by pouring off the supernatant liquid
of a bottle of antacid. This paste can be applied to the ulcer and will dry,
forming a crust that protects the area. Application 3 times a day is adequate.
3. Capillary circulation is thought to be defective in patients with pressure
sores. A moist environment and gentle massage around the ulcer might
improve circulation and promote healing.
4. Patients with poor nutrition or anemia have more difficulty healing. Increased
intake of protein is indicated.
5. In severe deep ulcers with undermined edges, surgical debridement and
skin grafting may be necessary.
In patients with established wounds, special beds (Clinitron and others) that
reduce pressure will facilitate healing.
6. Infection in decubitus ulcer is usually not a contributing cause of the ulcer, but
in severe undermined ulcers septicemia and death can occur. Topical
antibiotics are not useful in these cases.
7. Op-Site is a synthetic material that is permeable to both oxygen and water. It
has been used as a film to cover decubitus ulcers and seems to increase the
healing rate. The film is applied over the ulcer and left in place until there is
fluid leakage through it. Initially, changes are needed frequently, but as healing
progresses changes may be weekly. Cellulitis is a very rare complication.
8. Large ulcers usually require surgical debridement. Some centers have maggot
therapy available to debride large necrotic wounds. The creatures are
contained in a special bandage placed over the wound and allowed to devour
the dead tissue over a period of days. The treatment is very effective. Blowfly
larvae are used.
VI. Sexual Dysfunction
A. Introduction. Sexual performance and enjoyment depend on a complex interplay
of psychologic, neurologic, endocrine, vascular, and anatomic factors. The
evaluation and treatment of patients with sexual dysfunction requires expertise in
several disciplines of medicine.
1. History. Many patients and physicians are reluctant to discuss sexual
difficulties. The nature and duration of the patient's problem must be clarified.
The strength of the patient's sexual desire must be assessed. Severely
reduced sexual drive is a common manifestation of chronic physical illness but
might also reflect depression, medication effects, alcohol or drug abuse,
endocrine disturbances, sexual inhibition, or lack of an appropriate partner.
The partner's sexual functioning and expectations must also be assessed to
gain accurate insight into the patient's problem.
2. Examination. General physical examination, urologic or gynecologic
examination, neurologic examination, vascular examination, and psychologic
assessment are all part of the evaluation of the patient with sexual dysfunction.
B. Impotence. Impotence is the inability to have an erection that is sufficient for
sexual intercourse.
1. Physiology of penile erection. Penile erection is a reflex phenomenon
controlled by the autonomic nervous system. The afferent parasympathetic
fibers originate in the sacral spinal cord (segments S2, S3, S4) and travel via
the pelvic nerves to the penis. Sympathetic fibers to the pelvic organs originate
from the lower thoracic and lumbar cord and travel via the pudendal and pelvic
nerves or along blood vessels. The stimuli that activate the erection reflex
include psychic sexual arousal, local stimulation of the genital region, or
interoceptive signals arising from the bowel or bladder. These signals trigger
local release of nitric oxide (NO), which activates enzymes that increase levels
of cyclic guanosine monophosphate (cGMP) thereby producing smooth muscle
relaxation in the corpus callosum. The increased arterial blood flow dilates the
sinusoidal erectile tissues, allowing increased capacity for storing blood. The
expanded sinusoids compress the draining veins to reduce outflow and further
trap blood within the penis. Eventually a steady state is reached whereby the
rate of arterial inflow and venous outflow are equal, and the penis stops
enlarging but remains rigid.
2. Psychogenic impotence. It was once thought that the majority of impotent
men were suffering from emotional disturbances that inhibited the erection
reflex. Recent studies reveal that most impotent men have an organic
disorder, although emotional problems commonly exacerbate the physical
condition.
a. Clinical features. Depression, anxiety, phobias, and partner problems are
common causes of impotence. Although psychologic factors can inhibit the
erection reflex, erections might still occur under specific circumstances.
Thus, the patient may report that he awakens in the morning with a full
erection, is potent with some sexual partners but not others, or is able to
obtain a full erection by masturbation.
b. Diagnosis. Psychogenic impotence is a diagnosis of exclusion. In
uncertain cases a nocturnal penile tumescence study can be helpful. During
the night most men experience several erections associated with REM
sleep. The test involves attaching an apparatus to the penis that can
measure penile circumference (and with more sophisticated devices, penile
rigidity) during a night's sleep. The test is not infallible. There are some
patients with neurogenic erectile dysfunction who will have normal
nocturnal erections. Therefore, a normal nocturnal penile tumescence study
is highly suspicious, but does not prove unequivocally that impotence is
psychogenic.
c. Psychotherapy. Psychotherapy must be directed at the specific factors
that impair the patient's sexual performance (e.g., stress management,
depression, performance anxiety, marital discord, etc.). The specific
experience and personal style of the therapist are the most important
predictors of successful psychotherapy.
3. Neurogenic causes of impotence
a. Autonomic neuropathies. Autonomic neuropathies are a common cause
of impotence. Diabetes mellitus is often associated with autonomic
neuropathy, with impotence occurring in 10% to 25% of young diabetics
and over 50% of older diabetics. There is a strong correlation between
neurogenic bladder abnormalities (as demonstrated on cystometrogram)
and impotence. Other disorders of the autonomic nervous system
commonly associated with impotence include alcoholic polyneuropathy,
primary amyloidosis, Shy-Drager syndrome, familial dysautonomia, and
acute pandysautonomia.
b. Multiple sclerosis (MS). Neurogenic impotence is common in patients with
multiple sclerosis and does not necessarily correlate with the severity of
general neurologic disability. Perhaps two thirds of men with MS complain
of erectile dysfunction, ranging from incomplete or transitory erections to
complete impotence. In a recent study of 29 men with erectile dysfunction
and multiple sclerosis, only 3 were found to have a purely psychogenic
cause. Fatigue and lack of libido are also common complaints in MS.
c. Spinal cord trauma
1. Clinical features. Disorders of sexual function have been carefully
studied in patients with spinal cord injuries. The level and degree of
spinal trauma are important in determining residual sexual function.
Most men with transection of the cervical or thoracic cord will retain the
ability to have erections. These erections can occur spontaneously
during a flexor spasm or at other inappropriate times, but not in
response to psychic stimuli unless the cord lesion is incomplete.
Men with lesions of the lumbosacral cord or cauda equina are less likely
to have erections.
2. Treatment. Counseling by physicians who are familiar with the
problems of sexual activity in paraplegics and tetraplegics enables some
of these patients to resume intercourse. Fertility is usually impaired in
severely spine-injured men, but it is possible to obtain semen from these
patients for artificial insemination.
d. Brain disorders. There have been reports of impotence associated with
temporal lobe tumors or trauma. Some patients with temporal lobe epilepsy
are described as hyposexual, and the relation between psychogenic
factors and impotence is not clear in these cases. However, successful
treatment of temporal lobe seizures may reverse the hyposexuality.
Since the introduction of L-dopa, many previously impotent men with
Parkinson disease have been able to resume sexual activity. On rare
occasions, L-dopa or dopamine agonist therapy results in elderly men
becoming hypersexual.
e. Endocrine impotence. In general, the endocrine disorders that affect
potency do so by impairing sexual drive rather than causing a direct effect
on the erection reflex. Addison disease, Cushing syndrome,
hypopituitarism, hypothyroidism, acromegaly, hypogonadism, Klinefelter
syndrome, and myotonic muscular dystrophy have all been associated with
decreased libido and potency. Prolactin-secreting pituitary adenomas in
men often present in association with impotence. In large series of men
with erectile dysfunction, the number of patients whose impotence is due to
endocrine disorder is quite small.
f. Vascular impotence. Adequate blood flow to the penis is necessary to
initiate and maintain erection. Thus, atheromatous narrowing of the
abdominal aorta or iliac arteries can lead to impotence. Bruits, intermittent
claudication, and diminished pulses are often found in these patients.
g. Venous leakage from the penis is an uncommon, but surgically correctable,
cause of impotence.
C. Medication and drug-induced sexual dysfunction. Many commonly used drugs
can interfere with sexual function in men and women, resulting in loss of libido,
impotence, or impaired orgasm.
1. Antihypertensive medications have been reported to interfere with sexual
function in a substantial number of cases, and this may result in
noncompliance by the patient. The thiazide diuretics, sympatholytics (e.g.,
clonidine, methyldopa), and beta blockers (e.g., propranolol, metoprolol,
pindolol) commonly cause sexual dysfunction. Angiotensin-converting enzyme
(ACE) inhibitors (e.g., captopril, enalapril) and calcium channel blockers (e.g.,
verapamil) are antihypertensive medications that may have a lower incidence
of causing sexual dysfunction.
2. The H
2
receptor antagonists (e.g., cimetidine, ranitidine) increase prolactin
secretion and can cause loss of libido and impotence. Famotidine and
nizatidine are newer drugs in this category that can also cause sexual
dysfunction in some patients.
3. Neuroleptic drugs (e.g., haloperidol, chlorpromazine, perphenazine,
thiothixene, etc.) and tricyclic antidepressants (e.g., amitriptyline, imipramine,
desipramine, nortriptyline, etc.) may impair sexual function due to their
anticholinergic and sympatholytic activity. The antidepressant trazodone can
cause priapism. Fluoxetine has been associated with decreased libido and
impotence.
4. Monoamine oxidase inhibitors (e.g., phenelzine) can cause anorgasmia in
men and women.
5. Central nervous system depressants, including sedatives, antianxiety drugs,
marijuana, alcohol, and heroin, can all decrease libido, impair erection, and
inhibit ejaculation.
D. Treatment. The underlying disorder causing erectile dysfunction might not be
correctable, but several effective treatment modalities are available to enable the
patient to resume satisfactory sexual intercourse.
1. Sildenafil has revolutionized the treatment of impotence by providing a safe,
effective, oral medication for improving erectile dysfunction. The drug is not a
direct vasodilator but rather works by inhibiting the phosphodiesterase that is
responsible for degrading cGMP in the corpus cavernosum. In patients
receiving sildenafil, when sexual stimulation causes local release of NO, the
increased levels of cGMP in the corpus cavernosum enhance smooth muscle
relaxation and increase inflow of blood, resulting in firmer and more sustained
penile erection. Sildenafil is not an aphrodisiac and has no effect in the
absence of sexual stimulation. Sildenafil has been shown to enhance erections
in men with a broad range of organic and psychogenic disorders, including
diabetes, spinal cord injury, radical prostatectomy, medication-induced
impotence, cardiac disease, and MS. For most patients the dose is 50 mg to
be taken 30 minutes to 3 hours before sexual activity. Elderly patients and
patients with hepatic or renal dysfunction may have relatively increased plasma
levels of sildenafil and should be given 25 mg. Sildenafil can potentiate the
hypotensive effects of nitrates and should not be used in patients taking these
medications.
2. Intracavernous injections. Drugs that relax smooth muscle, such as
papaverine, phentolamine, and prostaglandin E
1
, can be injected directly
into the corpus cavernosum to induce erection in many patients with impaired
potency of diverse etiologies. The injections are made with a very fine needle
and are nearly painless. Papaverine and phentolamine are commonly used in
combination. The dose of medication necessary to produce erection has to be
carefully titrated in each patient. Erection begins 5 to 10 minutes after injection
and lasts for 30 minutes to 2 hours, with partial detumescence after
ejaculation. Priapism, usually after the first injection, has been the most serious
complication and requires emergency treatment. Penile scarring and infection
due to multiple injections have not been common problems. Sildenafil has
largely replaced the need for intracavernous injection therapy.
3. Vacuum devices have been manufactured to draw blood into the penis. When
an adequate erection has been produced, it can be maintained by placement
of a constricting band around the penis.
4. A variety of surgical implants that are placed directly into the corpora
cavernosa have been devised, including permanently rigid and inflatable penile
prostheses. Sensation and ejaculation are not adversely affected by the
implant. The best candidate for an implant is a relatively healthy patient with
organic impotence that cannot be palliated medically. Patient satisfaction rates
have been over 90% in several recent series of men with penile implants.
Selected Readings
Fecal Incontinence
Hirsh T, Lembo T. Diagnosis and management of fecal incontinence in elderly patients. Am Fam
Physician 1996;54(5):15591564, 15691570.
Ko CY, Tong J , Lehman RE, Shelton AA, Schrock TR, Welton ML. Biofeedback is effective therapy for
fecal incontinence and constipation. Arch Surg 1997;132 (8):829833.
Koyle MA, Kaji DM, Duque M, Wild J , Galansky SH. The Malone antegrade continence enema for
neurogenic and structural fecal incontinence and constipation. J Urol 1995;154(2 Pt 2):759761.
Ouslander J G, Schnelle J F. Incontinence in the nursing home. Ann Intern Med 1995;122(6):438449.
Patankar SK, Ferrara A, Larach SW, Williamson PR, Perozo SE, Levy J R, Mills J . Electromyographic
assessment of biofeedback training for fecal incontinence and chronic constipation. Dis Colon Rectum
1997;40(8):907911.
Schell SR, Toogood GJ , Dudley NE. Control of fecal incontinence: continued success with the Malone
procedure. Surgery 1997;122(3):626631.
Shafik A. Perianal injection of autologous fat for treatment of sphincteric incontinence. Dis Colon Rectum
1995;38(6):583587.
Sheldon CA, Minevich E, Wacksman J , Lewis AG. Role of the antegrade continence enema in the
management of the most debilitating childhood recto-urogenital anomalies. J Urol 1997;158(3 Pt
2):12771279.
Feeding Tubes
Amann W, Mischinger HJ , Berger A, et al. Percutaneous endoscopic gastrostomy (PEG). Eight years of
clinical experience in 232 patients. Surg Endosc 1997; 11(7):741744.
Britton J E, Lipscomb G, Mohr PD, Rees WD, Young AC. The use of percutaneous endoscopic
gastrostomy (PEG) feeding tubes in patients with neurological disease. J Neurol 1997;244(7):431434.
Norton B, Homer-Ward M, Donnelly MT, Long RG, Holmes GK. A randomised prospective comparison of
percutaneous endoscopic gastrostomy and nasogastric tube feeding after acute dysphagic stroke. Br
Med J 1996;312(7022):1316.
Sheiman SL. Tube feeding the demented nursing home resident. J Am Geriatr Soc
1996;44(10):12681270.
Wanklyn P, Cox N, Belfield P. Outcome in patients who require a gastrostomy after stroke. Age Ageing
1995;24(6):510514.
Neurogenic Bladder Dysfunction
Kohler-Ockmore J , Feneley RC. Long-term catheterization of the bladder: prevalence and morbidity. Br J
Urol 1996;77(3):347351.
Tracheostomy
Eibling DE, Snyderman CH, Eibling C. Laryngotracheal separation for intractable aspiration: a
retrospective review of 34 patients. Laryngoscope 1995;105(1):8385.
Evans J M, Andrews KL, Chutka DS, Fleming KC, Garness SL. Pressure ulcers: prevention and
management. Mayo Clin Proc 1995;70(8):789799.
Koh WY, Lew TW, Chin NM, Wong MF. Tracheostomy in a neuro-intensive care setting: indications and
timing. Anaesth Intensive Care 1997;25(4):365368.
Lissoni A. Tracheostomy and mechanical ventilation in ventilatory failure of patients with neuromuscular
disease. Monaldi Arch Chest Dis 1995;50(3):232234.
Neri M, Donner CF, Grandi M, Robert D. Timing of tracheostomy in neuromuscular patients with chronic
respiratory failure. Monaldi Arch Chest Dis 1995;50(3):220222.
Pfeiffer G, Winkler G, Neunzig P, Wolf W, Thayssen G, Kunze K. Long-term management of acute
respiratory failure in metabolic myopathy. Intensive Care Med 1996;22(12):14061409.
Richard I, Giraud M, Perrouin-Verbe B, Hiance D, Mauduyt de la Greve I, Mathe J F. Laryngotracheal
stenosis after intubation or tracheostomy in patients with neurological disease. Arch Phys Med Rehab
1996;77(5):493496.
Soudon P. Tracheal versus noninvasive mechanical ventilation in neuromuscular patients: experience
and evaluation. Monaldi Arch Chest Dis 1995;50(3):228231.
Decubitus Ulcer
Bascom PB, Tolle SW, Cassel CK. Caring for the terminally ill. Hosp Pract (Off Ed) 1996;31(5):7578,
8284, 89.
Day A, Dombranski S, Farkas C, et al. Managing sacral pressure ulcers with hydrocolloid dressings:
results of a controlled, clinical study. Ostomy Wound Manage 1995;41(2):5254, 56, 58 passim.
Isenberg J S, Ozuner G, Restifo RJ . The natural history of pressure sores in a community hospital
environment. Ann Plast Surg 1995;35(4):361365.
Levine J M, Totolos E. Pressure ulcers: a strategic plan to prevent and heal them. Geriatrics
1995;50(1):3237.
Martin SJ , Corrado OJ , Kay EA. Enzymatic debridement for necrotic wounds. J Wound Care
1996;5(7):310311.
Remsburg RE, Bennett RG. Pressure-relieving strategies for preventing and treating pressure sores. Clin
Geriatr Med 1997;13(3):513541.
Sayag J , Meaume S, Bohbot S. Healing properties of calcium alginate dressings. J Wound Care
1996;5(8):357362.
Sherman RA. A new dressing design for use with maggot therapy. Plast Reconstr Surg
1997;100(2):451456.
Sexual Dysfunction
Drugs that cause sexual dysfunction. Med Lett 1987;29:65.
Kirkeby HJ , et al. Erectile dysfunction in multiple sclerosis. Neurology 1988;38:1366.
Masters WH, J ohnson VE. Human sexual inadequacy. Boston: Little, Brown and Co., 1970.
Masters WH, J ohnson VE. Human sexual response. Boston: Little, Brown and Co., 1966.
Mooney TO, et al. Sexual options for paraplegics and quadriplegics. Boston: Little, Brown and Co., 1975.
Sidi AA, et al. Intracavernous drug induced erections in management of male erectile dysfunction. J Urol
1986;135:704.
Weiss HD. The physiology of human penile erection. Ann Intern Med 1972;76:793.
Yeates WK. Ejaculation and its disorders. Arch Ital Urol Nefrol Androl 1990;62(1):137.
Appendix. PATIENT INFORMATION GUIDE
Manual of Neurologic Therapeutics
Appendix. PATIENT INFORMATION GUIDE
Acoustic Neuroma
Acoustic Neuroma Association (ANA)
P.O. Box 12402
Atlanta, GA 30355
Contact Person: Lois Lowery
Phone: 404-237-8023
Fax: 404-237-2704
Email: anausa@aol.com
Alcoholism
National Clearinghouse for Alcohol and Drug Information (NCADI)
P.O. Box 2345
Rockville, MD 20847-2345
Contact Person: Information Specialist
Toll Free: 800-729-6686
Fax: 301-468-6433
Email: info@prevline.health.org
Alzheimer Disease
Alzheimer's Association
919 North Michigan Avenue, Suite 1000
Chicago, IL 60611-1676
Toll Free: 800-272-3900
Phone: 312-335-8700
Fax: 312-335-1110
Alzheimer's Disease Education and Referral Center (ADEAR)
P.O. Box 8250
Silver Spring, MD 20907-8250
Toll Free: 800-438-4380
Fax: 301-495-3334
Email: adear@alzheimers.org
Web Site: http://www.alzheimers.org/adear
The Alzheimer's Foundation (AF)
8177 South Harvard
M/C-114
Tulsa, OK 74137
Phone: 918-481-6031
Amyotrophic Lateral Sclerosis (ALS)
The Amyotrophic Lateral Sclerosis Association (ALSA)
21021 Ventura Boulevard, #321
Woodland Hills, CA 91364
Contact Person: Michael Havlicek, President & CEO
Phone: 818-340-7500
Fax: 818-340-2060
Forbes Norris MDA/ALS Center
California Pacific Medical Center
2324 Sacramento Street, Suite 150
San Francisco, CA 94115
Phone: 415-923-3604
Fax: 415-673-5184
Les Turner Amyotrophic Lateral Sclerosis Foundation (LTALSF)
3325 Main Street
Skokie, IL 60076
Contact Person: Claire Owen
Phone: 847-679-3311
Fax: 847-679-9109
Anorexia Nervosa
Anorexia Nervosa and Related Eating Disorders, Inc. (ANRED)
P.O. Box 5102
Eugene, OR 97405-0102
Contact Person: Bradley Rubel
Phone: 541-344-1144
National Association of Anorexia Nervosa and Associated Disorders
P.O. Box 7
Highland Park, IL 60035
Phone: 847-831-3438
Aphasia
National Aphasia Association (NAA)
P.O. Box 1887
Murray Hill Station
New York, NY 10156-0611
Toll Free: 800-922-4622
Phone: 212-340-6025
Arthrogryposis Multiplex Congenita
National Support Group for Arthrogryposis Multiplex Congenita (AVE.S)
P.O. Box 5192
Sonora, CA 95370
Contact Person: Mary Anne Schmidt
Phone: 209-928-3688
Email: Ave.s@sonnet.com
Web Site: http://www.sonnet.com/Ave.s
Ataxia
Ataxia Telangiectasia Children's Project
398 West Camino Gardens Boulevard, Suite 104
Boca Raton, FL 33432
Contact Person: Brad Margus
Phone: 407-395-2621
Fax: 407-395-2640
Email: bradmargus@delphi.com
Web Site: http://www.med.jhu.edu/ataxia
National Ataxia Foundation (NAF)
750 Twelve Oaks Center
15500 Wayzata Boulevard
Wayzata, MN 55391
Phone: 612-473-7666
Fax: 612-473-9289
Email: naf@mr.net
Web Site: http://www.ataxia.org/
Attention Deficit Disorder
Children and Adults with ADD (CHADD)
National Office
499 NW 70th Avenue, Suite 101
Plantation, FL 33317
Toll Free: 800-233-4050
Fax: 954-587-4599
Web Site: http://www.chadd.org/
Autism
Autism Research Institute
4182 Adams Avenue
San Diego, CA 92116
Contact Person: Barnard Rimland, Ph.D.
Phone: 619-281-7165
Fax: 619-563-6840
Web Site: http://www.autism.com/ari
Autism Society of America
7910 Woodmont Avenue, Suite 650
Bethesda, MD 20814-3015
Toll Free: 800-3AUTISM
Phone: 301-657-0881
Fax: 301-657-0869
Web Site: http://www.autism-society.org/
Therapeutic Nursery for Autistic Children
New Bellevue 21 South
Bellevue Hospital Center
462 First Avenue at 27th Street
New York, NY 10016-9198
Contact Person: Richard Perry, M.D.
Phone: 212-562-4504
Fax: 212-562-4973
Batten Disease
Batten Disease Support and Research Association (BDSRA)
2600 Parsons Avenue
Columbus, OH 43207
Contact Person: Lance J ohnston
Toll Free: 800-448-4570
Email bdsral@aol.com
Web Site: http://www.bdsra.org/
Children's Brain Disease Foundation (CBDF)
350 Parnassus Avenue, Suite 900
San Francisco, CA 94117
Phone: 415-863-8640
Fax: 415-863-3452
Institute for Basic Research in Developmental Disabilities (IBRDD)
1050 Forest Hill Road
Staten Island, NY 10314
Phone: 718-494-5151
Fax: 718-494-2258
Behet Disease
American Behet's Disease Association (ABDA)
1671 Summit Avenue
St. Paul, MN 55105-1815
Toll Free: 800-723-4238
Phone: 612-645-9475
Web Site: http://medhlp.netusa.net/agsg/agsg28.htm
Bell Palsy
American Academy of OtolaryngologyHead and Neck Surgery (AAO-HNS)
Communications Department
One Prince Street
Alexandria, VA 22314-3357
Phone: 703-836-4444
Fax: 703-683-5100
Web Site: http://www.entnet.org/
Benign Essential Blepharospasm
Benign Essential Blepharospasm Research Foundation, Inc. (BEBRF)
P.O. Box 12468
Beaumont, TX 77726-2468
Contact Person: Mary Smith
Phone: 409-832-0788
Fax: 409-832-0890
Birth Defects
March of Dimes Birth Defects Foundation (MDBDF)
1275 Mamaroneck Avenue
White Plains, NY 10605
Contact Person: The Resource Center
Toll Free: 800-367-6630
Fax: 717-825-1987
Blindness
Research to Prevent Blindness (RPB)
645 Madison Avenue, 21st Floor
New York, NY 10022-1010
Contact Person: Thomas Furlong
Phone: 212-752-4333
Fax: 212-688-6231
Brain Injury
Brain Injury Association, Inc.
1776 Massachusetts Avenue NW, Suite 100
Washington, DC 20036
Contact Person: I & R Coordinator
Toll Free: 800-444-6443
Phone: 202-296-6443
Fax: 202-296-8850
Brain Trauma Foundation
523 East 72nd Street
New York, NY 10021
Contact Person: Peter Quinn
Phone: 212-772-0608
Fax: 212-772-0357
Head Injury Hotline (The Phoenix Project)
P.O. Box 84151
Seattle, WA 98144
Contact Person: Constance Miller
Phone: 206-621-8558
Fax: 206-623-4251
Email: brain@headinjury.com
Web Site: http://www.headinjury.com/
The Perspective Network
P.O. Box 1859
Cumming, GA 30128-1859
Contact Person: Dena Taylor
Toll Free: 800-865-6302
Fax: 770-844-6898
Email: dktaylor@tbi.org
Web Site: http://www.tbi.org/
Brain Tumor
American Brain Tumor Association
2720 River Road, Suite 146
Des Plaines, IL 60018
Toll Free: 800-886-2282
Phone: 847-827-9910
Fax: 847-827-9918
Email: abta@aol.com
Web Site: http://www.abta.org/
Brain Tumor Foundation for Children, Inc.
2231 Perimeter Park Drive, Suite 9
Atlanta, GA 30341
Contact Person: Elaine Allman
Phone: 770-458-5554
Fax: 770-458-5467
Brain Tumor Information Service (of the Neuro Information Foundation)
919 North Michigan Avenue, Suite 3100
Chicago, IL 60611
Contact Person: G. J . Djohrmann
Phone: 312-684-1400
Fax: 312-280-9475
Children's Brain Tumor Foundation
274 Madison Avenue, Suite 1301
New York, NY 10016
Contact Person: Susan L. Weiner, Ph.D., Executive Director
Phone: 212-448-9494
Fax: 212-448-1022
Web Site: http://www.childrensneuronet.org/
National Brain Tumor Foundation (NBTF)
785 Market Street, Suite 1600
San Francisco, CA 94103
Contact Person: Patient Services Department
Toll Free: 800-934-2873
Fax: 415-284-0209
Cerebral Palsy
United Cerebral Palsy Association (UCPA)
1660 L Street NW, Suite 700
Washington, DC 20036
Toll Free: 800-872-5827
Phone: 202-776-0406
Fax: 202-776-0414
Charcot-Marie-Tooth Disease
Charcot-Marie-Tooth Association (CMTA)
Crozer Mills Enterprise Center
601 Upland Avenue
Upland, PA 19015
Contact Person: Patricia Dreibelbis
Toll Free: 800-606-CMTA
Phone: 610-499-7486
Fax: 610-499-7487
Email: CMTAssoc@aol.com
Coma
Coma Recovery Association, Inc.
570 Elmont Road, Suite 104
Elmont, NY 11003
Contact Person: Florence Manginaro
Phone: 516-355-0951
Fax: 516-355-0961
Cornelia de Lange Syndrome
Cornelia de Lange Syndrome Foundation, Inc.
60 Dyer Avenue
Collinsville, CT 06022-1273
Contact Person: J ulie Mairono
Toll Free: 800-223-8355
Fax: 860-693-6819
Cushing Syndrome
National Cushing's Association (NCA)
4645 Van Nuys Boulevard, #104
Sherman Oaks, CA 91403
Contact Person: Andrea Hecht
Phone: 818-788-9235
Depression
National Depressive and Manic-Depressive Association
730 North Franklin, Suite 501
Chicago, IL 60610-3526
Contact Person: Mike Maloney
Toll Free: 800-826-3632
Fax: 312-642-7243
National Foundation for Depressive Illness
P.O. Box 2257
New York, NY 10116
Contact Person: Peter Ross
Toll Free: 800-248-4344
Fax: 212-268-4434
Down Syndrome
National Down Syndrome Congress (NDSC)
1605 Chantilly Drive, Suite 250
Atlanta, GA 30324-3269
Toll Free: 800-232-6372
Fax: 404-633-2817
National Down Syndrome Society (NDSS)
666 Broadway, 8th Floor
New York, NY 10012-2317
Contact Person: Information & Referral Specialist
Toll Free: 800-221-4602
Phone: 212-460-9330
Fax: 212-979-2873
Web Site: http://www.ndss.org/
Office of Research Reporting, National Institute of Child Health and Human
Development (NICHHD)
National Institutes of Health
31 Center DriveMSC 2425
Building 31/2A32
Bethesda, MD 20892-2425
Phone: 301-496-5133
Fax: 301-496-7101
Web Site: http://www.nichd.nih.gov/
Dysautonomia, Familial
Dysautonomia Foundation (DF)
20 East 46th Street, Room 302
New York, NY 10017
Contact Person: Lenore Roseman
Phone: 212-949-6644
Fax: 212-682-7625
Dyslexia
The Orton Dyslexia Society (ODS)
8600 LaSalle Road, Suite 382
Chester Building
Baltimore, MD 21286-2044
Contact Person: Susan Brickley
Toll Free: 800-222-3123
Phone: 410-296-0232
Fax: 410-321-5069
Dystonia
Dystonia Medical Research Foundation (DMRF)
One East Wacker Drive, #2430
Chicago, IL 60601-2001
Toll Free: 800-377-DYST
Phone: 312-755-0198
Fax: 312-803-0138
Email: dystfndr@aol.com
Web Site: http://www.dystonia-foundation.org/
WE MOVE (Worldwide Education and Awareness for Movement Disorders)
Mount Sinai Neurology
One Gustave L. Levy Place, Box 1052
New York, NY 10029
Contact Person: J udith Blazer, M.D., Executive Director
Toll Free: 800-437-MOV2
Phone: 212-241-8567
Fax: 212-987-7363
Email: wemove@smtplink.mssm.edu
Web Site: http://www.wemove.org/
Epilepsy
Epilepsy Foundation of America (EFA)
4351 Garden City Drive
Landover, MD 20785-4951
Toll Free: 800-EFA-1000
Phone: 301-459-3700
Fax: 301-577-4941
Email: postmaster@efa.org
Web Site: http://www.efa.org/
Gaucher Disease
National Gaucher Foundation (NGF)
11140 Rockville Pike, Suite 350
Rockville, MD 20852-3106
Contact Person: Sharon Adams
Toll Free: 800-925-8885
Phone: 301-816-1515
Fax: 301-816-1516
Web Site: http://www.gaucherdisease.org/
Genetics
Alliance of Genetic Support Groups (AGSG)
35 Wisconsin Circle, #440
Chevy Chase, MD 20815-7015
Contact Person: J oan Weiss
Phone: 301-652-5553
Fax: 301-654-0171
Center for Genetic Studies in Inherited Neurological Disorders
Division of Neurology, Box 2900
Bryan Research Building
Duke University Medical Center
Durham, NC 27710
Toll Free: 800-283-4316
Fax: 919-684-6514
Web Site: http://wwwchg.mc.duke.edu/index.html
National Society of Genetic Counselors (NSGC)
233 Canterbury Drive
Wallingford, PA 19086-6617
Contact Person: Bea Leopold
Phone: 610-872-7608, mailbox #7
Fax: 610-872-1192
Email: nsgc@aol.com
Guillain-Barr Syndrome
Guillain-Barr Syndrome Foundation International (GBSFI)
P.O. Box 262
Wynnewood, PA 19096
Contact Person: Estelle Benson
Phone: 610-667-0131
Fax: 610-667-7036
Email: gbint@ix.netcom.com
Web Site: http://www.webmast.com/gbs
Headache
American Association for the Study of Headache (AASH)
875 Kings Highway, Suite 200
Woodbury, NJ 08096
Contact Person: Linda McGillicuddy
Phone: 609-845-0322
Fax: 609-384-5811
Email: lmgillicuddy@aash.ccmail.compuserve.com
American Council for Headache Education (ACHE)
875 Kings Highway, Suite 200
Woodbury, NJ 08096-3172
Contact Person: Linda McGillicuddy
Phone: 609-845-0322
Fax: 609-384-5811
Email: lmcgillicuddy@ache.ccmail.compuserve.com
Web Site: http://www.achenet.org/
National Headache Foundation (NHF)
428 West St. J ames Place, 2nd Floor
Chicago, IL 60614-2750
Contact Person: Suzanne Simons
Toll Free: 800-843-2256
Phone: 312-388-6399
Fax: 312-525-7357
Web Site: http://www.headaches.org/
Huntington Disease
Harvard Brain Tissue Resource Center (HBTRC)
McLean Hospital
115 Mill Street
Belmont, MA 02178-9106
Toll Free: 800-272-4622
Hereditary Disease Foundation (HDF)
1427 7th Street, Suite 2
Santa Monica, CA 90401
Contact Person: Ellen Robinson
Phone: 310-458-4183
Fax: 310-458-3937
Email: 75051.3604@compuserve.com
Web Site: http://www.hdfoundation.org/
Huntington's Disease Society of America (HDSA)
140 West 22nd Street, 6th Floor
New York, NY 10011-2420
Contact Person: Marilyn Wolff
Toll Free: 800-345-HDSA
Phone: 212-242-1968
Fax: 212-342-2443
Email: curehd@hdsa.ttisms.com
Web Site: http://www.hdsa.org/
Huntington Society of Canada (HSC)
13 Water Street North
P.O. Box 1269
Cambridge, Ontario, Canada N1R 7G6
Phone: 519-622-1002
Fax: 519-622-7370
Hydrocephalus
Guardians of Hydrocephalus Research Foundation (GHRF)
2618 Avenue Z
Brooklyn, NY 10011-2420
Contact Person: Kathy Soriano
Toll Free: 800-458-8655
Fax: 718-743-1171
Hydrocephalus Association (HA)
870 Market Street, Suite 955
San Francisco, CA 94102
Contact Person: J ennifer Henerlau
Phone: 415-776-4713
Web Site: http://www.hydroassoc.org/
National Hydrocephalus Foundation (NHF)
1670 Green Oak Circle
Lawrenceville, GA 30243
Contact Person: Ann Marie Liakos, Executive Director
Phone: 770-995-9570
Fax: 770-995-8982
Email: annliakos@aol.com
Joseph Machado Disease
International J oseph Diseases Foundation, Inc.
P.O. Box 2550
4047 First Street, Suite 107
Livermore, CA 94551-2550
Phone: 510-371-1287
Fax: 510-371-1288
Language Disorders
American Speech-Language-Hearing Association (ASLHA)
10801 Rockville Pike
Rockville, MD 20852
Toll Free: 800-638-8255
Fax: 301-571-0457
Email: irc@asha.org
Web Site: http://www.asha.org/
Learning Disabilities
Learning Disabilities Association of America (LDAA)
4156 Library Road
Pittsburgh, PA 15234-1349
Contact Person: J ean Petersen
Phone: 412-341-1515
Fax: 412-344-0224
National Center for Learning Disabilities (NCLD)
381 Park Avenue South, Suite 1420
New York, NY 10016
Phone: 212-545-7510
Fax: 212-545-9665
Leukodystrophy
United Leukodystrophy Foundation (ULF)
2304 Highland Drive
Sycamore, IL 60178
Contact Person: Ron Brazeal
Toll Free: 800-728-5483
Phone: 815-895-3211
Fax: 815-895-2432
Email: ulf@ceet.niu.edu
Web Site: http://www.ulf.org/
Lowe Syndrome
Lowe Syndrome Association (LSA)
222 Lincoln Street
West Lafayette, IN 47906
Contact Person: Kaye McSpadden
Phone: 317-743-3634
Malignant Hyperthermia
Malignant Hyperthermia Association of the U.S. (MHAUS)
32 South Main Street
P.O. Box 1069
Sherburne, NY 13460-1069
Contact Person: Cindy Reandeau
Toll Free: 800-986-4287
Phone: 607-674-7901
Fax: 607-674-7910
Email: mhaus@norwich.net
Maple Syrup Urine Disease
Maple Syrup Urine Disease Family Support Group (MSUDFSG)
1854 Agape Court
East Earl, PA 17519
Contact Person: Dawn Marie Hahn
Phone: 717-445-5961
Mental Health
National Alliance for the Mentally Ill
200 North Glebe Road, Suite 1015
Arlington, VA 22203-3754
Contact Person: Kerry Flynn
Phone: 703-524-7600
Fax: 703-524-9094
National Institute of Mental Health (NIMH)
Information Resources and Inquiries Branch
5600 Fishers Lane, Room 7C-02
Rockville, MD 20857
Panic Disorders Info: 800-64PANIC
Depression Info: 800-421-4211
Phone: 301-443-4513
Fax: 301-443-0008
Fax on Demand: 301-443-5158
Email: nimhinfo@nih.gov
Web Site: http://www.nimh.nih.gov/
National Mental Health Association (NMHA)
1021 Prince Street
Alexandria, VA 22314-2971
Phone: 703-684-7722
Fax: 703-684-5968
Web Site: http://www.nmha.org/
Mental Retardation
The ARC of the United States
500 East Border Street, Suite 300
Arlington, TX 76010
Contact Person: Alan Abeson, Ed.D., Executive Director
Phone: 817-261-6003
TTY: 817-277-0553
Fax: 817-277-3491
Email: thearc@metronet.com
Web Site: http://thearc.org/
Moebius Syndrome
Moebius Syndrome Foundation
16265 Felten Lane
Blackwater, MO 65322
Contact Person: Vicki McCarrell
Phone: 816-834-3406
Email: vmccarrell@vax1.rain.gen.mo.us
Mucopolysaccharidoses/Mucolipidoses
Mucopolysaccharidoses (MPS) Society
17 Kraemer Street
Hicksville, NY 11801
Contact Person: Marie Capobianco
Phone: 516-931-6338
Multiple Sclerosis
Center for Neurologic Study (CNS)
11211 Sorrento Valley Road, Suite H
San Diego, CA 92121
Contact Person: Gayle Bresnahan
Phone: 619-455-5463
Fax: 619-455-1713
Web Site: http://www.cnsonline.org/
Multiple Sclerosis Association of America (MSAA)
706 Haddonfield Road
Cherry Hill, NJ 08002
Contact Person: J ohn Hodson
Toll Free: 800-833-4672 and 800-LEARN MS
Phone: 609-488-4500
Fax: 609-661-9797
National Multiple Sclerosis Society (NMSS)
733 Third Avenue
New York, NY 10017-3288
Toll Free: 800-344-4867 (FIGHT MS)
Phone: 212-986-3240
Fax: 212-986-7981
Email: info@nmss.org
Web Site: http://www.nmss.org/
Muscular Dystrophy
Muscular Dystrophy Association (MDA)
3300 East Sunrise Drive
Tucson, AZ 85718
Contact Person: Program Services Department
Phone: 520-529-2000
Fax: 520-529-5300
Email: mda@mdausa.org
Web Site: http://www.mdausa.org/
Muscular Dystrophy, Fascioscapulohumeral
Fascioscapulohumeral Society, Inc. (FSH Society)
Three Westwood Road
Lexington, MA 02173
Contact Person: Carol Perez
Phone: 617-860-0501
Fax: 617-860-0599
Web Site: http://www.fshsociety.org/
Myasthenia Gravis
The Myasthenia Gravis Foundation of America (MGF)
222 South Riverside Plaza, Suite 1540
Chicago, IL 60606
Contact Person: Abigail McCulloch
Toll Free: 800-541-5454
Fax: 312-258-0461
Myoclonus
Moving Forward
2934 Glenmore Avenue
Kettering, OH 45409
Contact Person: Pauline Dill
Phone: 513-293-0409
Myoclonus Research Foundation (MRF)
200 Old Palisade Road, Suite 17D
Fort Lee, NJ 07024
Contact Person: Theodora Mason
Phone: 201-585-0770
Fax: 201-585-8114
Myositis
Myositis Association of America, Inc. (MAA)
1420 Huron Court
Harrisonburg, VA 22801
Contact Person: Betty N. Curry
Toll Free: 540-433-7686
Fax: 540-432-0206
Email: maainfo@shentel.net
Web Site: http://www.myositis.org/
The National Myositis Association
P.O. Box 890
Cooperstown, NY 13326
Contact Person: Karan Zopatti
Toll Free: 800-821-7356
Fax: 540-432-0206
Narcolepsy
American Sleep Disorders Association (ADA)
1610 14th Street NW, Suite 300
Rochester, MN 55901
Contact Person: J erry Barrett, Executive Director
Phone: 507-287-6006
Fax: 507-287-6008
Email: asda@millcomm.com
Web Site: http://www.asda.org/
Narcolepsy Network
P.O. Box 42460
Cincinnati, OH 45242
Contact Person: Robert Cloud
Phone: 513-891-3522
National Sleep Foundation
1367 Connecticut Avenue NW, Suite 200
Washington, DC 20036
Fax: 202-785-2880
Email: natsleep@haven.ios.com
Web Site: http://www.sleepfoundation.org/
Neurofibromatosis
National Neurofibromatosis Foundation (NNF)
95 Pine Street, 16th Floor
New York, NY 10005
Phone: 212-344-6633
Fax: 212-747-0004
Email: nnff@aol.com
Web Site: http://www.nf.org/
Neurofibromatosis, Inc. (NF, Inc.)
8855 Annapolis Road, Suite 110
Lanham, MD 20706-2924
Contact Person: Mary Ann Wilson
Toll Free: 800-942-6825
Fax: 301-577-0016
Email: NFINC@gnn.com
Web Site: http://www.nfinc.org/
Neuropathy
The Neuropathy Association
P.O. Box 2055
Lenox Hill Station
New York, NY 10021
Contact Person: Mary Ann Donovan
Toll Free: 800-247-6968
Fax: 212-305-3986
Email: info@neuropathy.org
Web Site: http://www.neuropathy.org/
Obsessive-Compulsive Disorder
Obsessive-Compulsive Foundation (OCF)
P.O. Box 70
Milford, CT 06460-0070
Contact Person: J ames Broatch, M.S.W.
Phone: 203-878-5669
Developmental Recording: 203-874-3843
Fax: 203-874-2826
Email: jhs28a@prodigy.com
Web Site: http://www.ocfoundation.org/
Pain
American Chronic Pain Association (ACPA)
P.O. Box 850
Rocklin, CA 95677
Contact Person: Penney Cowan
Phone: 916-632-0922
Fax: 916-632-3208
National Chronic Pain Outreach Association (NCPOA)
7979 Old Georgetown Road, Suite 100
Bethesda, MD 20814-2429
Phone: 301-652-4948
Fax: 301-907-0745
Email: NCPOA1@aol.com
Palsy, Progressive Supranuclear
The Society for Progressive Supranuclear Palsy, Inc. (SPSP, Inc.)
J ohns Hopkins Outpatient Center, Suite 5065
601 North Caroline Street
Baltimore, MD 21287
Contact Person: Elaine Stiles
Toll Free: 800-457-4777
Phone: 410-955-2954
Fax: 410-614-9260
Paralysis
American Paralysis Association (APA)
500 Morris Avenue
Springfield, NJ 07081
Toll Free: 800-225-0292
Phone: 201-379-2690
Fax: 201-912-9433
The Miami Project to Cure Paralysis
1600 NW 10th Avenue, R-48
Miami, FL 33136
Contact Person: Maria Amader, R.N., C.R.R.N.
Phone: 305-243-6001
Fax: 305-243-4427
Email: mpinfo@miamiproj.med.miami.edu
Web Site: http://www.miamiproject.miami.edu/
Parkinson Disease
American Parkinson Disease Association, Inc.
1250 Hylan Boulevard, Suite 4B
Staten Island, NY 10305
Contact Person: G. Maestrome D.V.M.
Toll Free: 800-223-2732
Phone: 718-981-8001
Fax: 718-981-4399
Email: apda@admin.con2.com
Web Site: http://neuro-chief-e.mgh.harvard.edu/parkinsonsweb/Main/PDmain.html
National Parkinson Foundation, Inc.
1501 NW 9th Avenue
Bob Hope Road
Miami, FL 33136-1494
Toll Free: 800-327-4545
Fax: 305-548-4403
National Parkinson Foundation, West Coast Office (NPF)
15840 Ventura Boulevard, Suite 215
Encino, CA 91436
In CA: 800-400-8448
Outside CA: 800-522-8855
Phone: 818-981-2233
Fax: 818-981-7392
Parkinson's Action Network
822 College Avenue, Suite C
Santa Rosa, CA 95404
Contact Person: Dyann Bucy
Toll Free: 800-850-4726
Fax: 707-544-2363
Email: parkactnet@aol.com
Parkinson's Disease Foundation (PDF)
William Black Medical Building
710 West 168th Street
New York, NY 10032
Phone: 212-923-4700
Fax: 212-923-4778
The Parkinson's Institute
1170 Morse Avenue
Sunnyvale, CA 94089-1605
Contact Person: Carol Marchi
Toll Free in CA: 800-655-2273
Toll Free in US: 800-786-2978
Fax: 408-734-8522
United Parkinson Foundation (UPF)
833 West Washington Boulevard
Chicago, IL 60607
Contact Persons: J udy Rosner/J eanne Lee
Phone: 312-733-1893
Fax: 312-733-1896
Email: upf_itf@msn.com
Polio/Postpolio Syndrome
International Polio Network (IPN)
4207 Lindell Boulevard, Suite 110
St. Louis, MO 63108-2915
Phone: 314-534-0475
Fax: 314-530-5070
Polio Survivors Association (PSA)
12720 Lareina Avenue
Downey, CA 90242
Contact Person: Richard Daggett
Phone: 310-862-4508
Porphyria
American Porphyria Foundation (APF)
P.O. Box 22712
Houston, TX 77227
Contact Person: Desiree Lyon
Phone: 713-266-9617
Fax: 713-871-1788
Web Site: http://www.enterprise.net/apf
Post-Traumatic Stress Disorders
National Center for Post-Traumatic Stress Disorder
VA Medical Center (116D)
White River J unction, VT 05009
Contact Person: Fred Lerner, D.L.S.
Phone: 802-296-5132
Fax: 802-296-5135
Web Site: http://www.ncptsd.org/
Prader-Willi Syndrome
Prader-Willi Syndrome Association
2510 South Brentwood Boulevard, Suite 220
St. Louis, MO 63144
Contact Person: Russell Myler
Toll Free: 800-926-4797
Fax: 314-962-7869
Email: PWSAUSA@aol.com
Web Site: http://www.pwsausa.org/
Pseudotumor Cerebri
The Pseudotumor Cerebri Society (PTC)
1319 Butternut Street, Apt. 3
Syracuse, NY 13208
Contact Person: Pamela Ingram
Phone: 315-464-3937 or 315-423-8278
Fax: 315-464-5006
Email: ingramp@vax.cs.hscsyr.edu
Rare Disorders
National Organization for Rare Disorders (NORD)
P.O. Box 8923
New Fairfield, CT 06812-8923
Contact Person: J oy E. Yacolucci, Information Services
Toll Free: 800-999-6673
Phone: 203-746-6518
Fax: 203-746-6481
Email: orphan@NORD-RDB.com
Web Site: http://www.NORD-RDB.com/~orphan
Reflex Sympathetic Dystrophy Syndrome
Reflex Sympathetic Dystrophy Syndrome Association of America (RSDSA)
116 Haddon Avenue, Suite D
Haddonfield, NJ 08033
Phone: 609-795-8845
Fax: 609-795-8845
Web Site: http://www.rsds.org/
Rehabilitation
National Easter Seal Society, Inc.
230 West Monroe, Suite 1800
Chicago, IL 60606
Contact Person: Information and Referral
Toll Free: 800-221-6827
Fax: 312-726-1494
Web Site: http://www.easter-seals.org/
National Institute on Disability and Rehabilitation Research (NIDRR)
Department of Education
330 C Street SW, Room 3060
Washington, DC 20202-2572
Phone: 202-205-8134
Fax: 202-205-8515
National Rehabilitation Information Center (NARIC)
8455 Colesville Road, Suite 935
Silver Spring, MD 20910-3319
Toll Free: 800-346-2742
TTY: 301-495-5626
Fax: 301-587-1967
Web Site: http://www.naric.com/
Restless Legs Syndrome
Restless Legs Syndrome Foundation, Inc. (RLS)
304 Glenwood Avenue
Raleigh, NC 27603-1407
Contact Person: LeNoir Thackston
Phone: 919-834-0821
Fax: 919-832-4273
Web Site: http://www.rls.org/
Rett Syndrome
International Rett Syndrome Association (IRSA)
9121 Piscataway Road, Suite 2B
Clinton, MD 20735
Contact Person: Kathy Hunter
Toll Free: 800-818-7388
Fax: 301-856-3336
Reye Syndrome
National Reye's Syndrome Foundation (NRSF)
P.O. Box 829
Bryan, OH 43506
Contact Person: Sandi Nelson
Toll Free: 800-233-7393
Phone: 419-636-2679
Fax: 419-636-3366
Shy-Drager Syndrome
Shy-Drager Syndrome Support Group
1607 Silver SE
Albuquerque, NM 87106
Contact Person: Dorothy Trainor Kingsbury
Toll Free: 800-SDS-4999
Smell and Taste (Chemosensory) Disorders
Smell and Taste Center
Hospital of the University of Pennsylvania
3400 Spruce Street
Philadelphia, PA 19104-4283
Phone: 215-662-6580
Fax: 215-349-5266
Sotos Syndrome
Sotos Syndrome Support Association (SSSA)
Three Danada Square East, #235
Wheaton, IL 60187
Email: sssa@well.com
Web Site: http://www.well.com/user/sssa
Spasmodic Dysphonia
National Spasmodic Dysphonia Association
P.O. Box 203
Atwood, CA 92811-0203
Spasmodic Torticollis
National Spasmodic Torticollis Association (NSTA)
P.O. Box 424
Mukwonago, WI 53149-0424
Toll Free: 800-487-8385
Fax: 414-662-9887
Spina Bifida
Spina Bifida Association of America (SBAA)
4590 MacArthur Boulevard NW, Suite 250
Washington, DC 20007-4226
Contact Person: Larry Pencak
Toll Free: 800-621-3141
Phone: 202-944-3285
Fax: 202-944-3295
Email: spinabifda@aol.com
Web Site: http://www.sbaa.org/
Spinal Injuries/Spine and Back Care
Back Association of America
P.O. Box 135
Pasadena, MD 21123-0135
Contact Person: Margaret Hill
Phone: 410-255-3633
Fax: 410-255-7338
Kent Waldrep National Paralysis Foundation
16415 Addison Road, Suite 550
Dallas, TX 75248
Contact Person: Ken Peters
Toll Free: 800-925-2873
Phone: 214-248-7100
Fax: 214-248-7313
National Spinal Cord Injury Association (NSCIA)
8300 Colesville Road, Suite 551
Silver Spring, MD 20910
Contact Person: Bernadette Mauro
Toll Free: 800-962-9629
Phone: 301-588-6959
Fax: 301-588-9414
Email: nscia2@aol.com
National Spinal Cord Injury Hotline
2200 Kernan Drive
Baltimore, MD 21207
Contact Person: J ulie Hammond
Toll Free: 800-526-3456
Fax: 410-448-6627
Email: SCIHOTLINE@aol.com
Web Site: http://www.pva.org/psa/closehotline.html
North American Spine Society
6300 North River Road, Suite 500
Rosemont, IL 60018-4231
Contact Person: Eric Muehlbauer
Phone: 847-698-1630
Fax: 847-823-8668
Email: nassman@aol.com
Web Site: http://www.spine.org/
Paralyzed Veterans of America (PVA)
801 18th Street NW
Washington, DC 20006
Toll Free: 800-424-8200
Phone: 202-872-1300
Spinal Cord Society (SCS)
Wendell Road
Fergus Falls, MN 56537
Phone: 218-739-5252
Fax: 218-739-5262
Spinal Muscular Atrophy
Families of Spinal Muscular Atrophy
P.O. Box 196
Libertyville, IL 60048-0196
Contact Persons: Marilyn Naiditch/Audrey Lewis
Toll Free: 800-886-1762
Fax: 847-367-7623
Email: sma@interaccess.com
Web Site: http://www.abacus96.com/fsma/
Stroke
American Heart Association National Center
7272 Greenville Avenue
Dallas, TX 75231-4596
Toll Free: 800-AHA-USA-1
Fax: 214-369-3685
Web Site: http://www.amhrt.org/
American Occupational Therapy Association (AOTA)
4720 Montgomery Lane
P.O. Box 31220
Bethesda, MD 20824-1220
Phone: 301-652-2682
Fax: 301-652-7711
National Stroke Association (NSA)
96 Inverness Drive East, Suite I
Englewood, CO 80112-5112
Toll Free: 800-STROKES
Phone: 303-649-9299
Fax: 303-649-1328
Stroke Club International (SCI)
805 12th Street
Galveston, TX 77550
Contact Person: Ellis Williamson
Sturge-Weber Syndrome
National Congenital Port Wine Stain Foundation (NCPWSF)
125 East 63rd Street
New York, NY 10021
The Sturge-Weber Foundation (SWF)
P.O. Box 418
Mount Freedom, NJ 07970-0418
Contact Person: Karen Ball
Toll Free: 800-627-5482
Phone: 201-895-4445
Fax: 201-895-4846
Email: crs0590@inforamp.net
Web Site: http://www.sturge-weber.com/
Sudden Infant Death Syndrome
National Sudden Infant Death Syndrome Resource Center
2070 Chain Bridge Road, Suite 450
Vienna, VA 22182
Phone: 703-821-8955
Fax: 703-821-2098
Syringomyelia
American Syringomyelia Alliance Project (ASAP)
P.O. Box 1586
Longview, TX 75606-1586
Contact Person: Patricia Williams
Toll Free: 800-ASAP-282
Email: 102563.3507@compuserve.com
Web Site: http://www.dataprompt.com/syringo.html
Tardive Dyskinesia/Tardive Dystonia
Tardive Dyskinesia/Tardive Dystonia National Association (TDNA)
P.O. Box 45732
Seattle, WA 98145-0732
Phone: 206-522-3166
Fax: 206-522-3166
Tay-Sachs
Late Onset Tay-Sachs Foundation
1303 Paper Mill Road
Erdenheim, PA 19038
Contact Person: Marc P. Fishbein
Toll Free: 800-672-2022
Fax: 215-537-0708
Email: 72624.3502@compuserve.com
Web Site: http://www.lotsf.org/
National Foundation for J ewish Genetic Diseases (NFJ GD)
250 Park Avenue, Suite 1000
New York, NY 10177
Phone: 212-371-1030
Fax: 212-319-5808
National Tay-Sachs and Allied Diseases Association (NTSADA)
2001 Beacon Street, Suite 204
Brookline, MA 02146
Contact Person: Debra Gutter, Executive Director
Toll Free: 800-906-8723
Fax: 617-277-0134
Tinnitus
American Tinnitus Association (ATA)
P.O. Box 5
Portland, OR 97207-005
Contact Person: Barbara Tabachnick
Phone: 503-248-9985
Fax: 503-248-0024
Email: tinnitus@ata.org
Web Site: http://www.ata.org/
Tourette Syndrome
Tourette Syndrome Association, Inc. (TSAI)
42-40 Bell Boulevard
Bayside, NY 11361-2820
Contact Person: Sue Levi-Pearl
Toll Free: 800-237-0717
Phone: 718-224-2999
Fax: 718-279-9596
Email: tourette@ix.netcom.com
Web Site: http://www.tsa-usa.org/
Tourette Syndrome Foundation of Canada (TSFC)
3675 Keele Street, Suite 203
Toronto, Ontario, Canada M3J 1M6
Contact Person: Rosie Wartecher
Toll Free: 800-361-3120
Phone: 416-636-2800
Fax: 416-636-1688
Tremor
International Tremor Foundation (ITF)
833 West Washington Boulevard
Chicago, IL 60607
Contact Persons: J udy Rosner/J eanne Lee
Phone: 312-733-1893
Fax: 312-733-1896
Email: UPF_ITF@MSN.COM
Trigeminal Neuralgia
Trigeminal Neuralgia Association (TNA)
P.O. Box 340
Barnegat Light, NJ 08006
Contact Person: Claire Patterson
Phone: 609-361-1014
Fax: 609-361-0982
Web Site: http://www.tna-support.org/
Tuberous Sclerosis
National Tuberous Sclerosis Association (NTSA)
8181 Professional Place, Suite 110
Landover, MD 20785
Contact Person: Barbara Witten
Toll Free: 800-225-6872
Phone: 301-459-9888
Fax: 301-459-0394
Email: ntsa@aol.com
Vestibular Disorders
Vestibular Disorders Association (VEDA)
P.O. Box 4467
Portland, OR 97208-4467
Contact Person: J erry Underwood
Toll Free: 800-837-8428
Phone: 503-229-7705
Fax: 503-229-8064
Email: veda@teleport.com
Web Site: http://www.teleport.com/~veda
Williams Syndrome
Williams Syndrome Association (WSA)
P.O. Box 297
Clawson, MI 48017-0297
Contact Person: Anne Tipton
Phone: 810-541-3630
Fax: 810-541-3631
Email: mailto:wsa%20office@aol.com
Web Site: http://www.williams-syndrome.org/
Wilson Disease
Wilson's Disease Association (WDA)
P.O. Box 75324
Washington, DC 20012-5324
Contact Person: Ascher Sellner
National Center for the Study of Wilson's Disease (NCSWD)
432 West 58th Street, Suite 614
New York, NY 10019
Phone: 212-523-8717
Fax: 212-523-8708