®
NEUROLOGY BOARD REVIEW MANUAL
PUBLISHING STAFF
PRESIDENT, PUBLISHER
Bruce M.White
EXECUTIVE EDITOR
Debra Dreger
SENIOR EDITOR
Miranda J. Hughes, PhD
EDITORIAL ASSISTANT
Melissa Frederick
SPECIAL PROGRAMS DIRECTOR
Barbara T.White
PRODUCTION MANAGER
Neuromuscular Junction
Abnormalities: Case Studies
Series Editor:
Raymond K. Reichwein, MD
Assistant Professor of Neurology, Division of Neurology, Pennsylvania
State University College of Medicine, Hershey, PA
Consulting Editor and Contributing Author:
Milind J. Kothari, DO
Associate Professor of Neurology, Director, Neurology Residency
Training Program, Division of Neurology, Pennsylvania State
University College of Medicine, Hershey, PA
Suzanne S. Banish
PRODUCTION ASSISTANTS
Tish Berchtold Klus
Christie Grams
ADVERTISING/PROJECT COORDINATOR
Patricia Payne Castle
Table of Contents
Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ii
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Case Patient 1 Presentation. . . . . . . . . . . . . . . . . . . . . . . 1
Pathophysiology of Myasthenia Gravis . . . . . . . . . . . . . . 3
NOTE FROM THE PUBLISHER:
This peer-reviewed publication has been
developed without involvement of or
review by the American Board of Psychiatry and Neurology.
Diagnostic Testing for Myasthenia Gravis . . . . . . . . . . . . 4
Treatment of Myasthenia Gravis . . . . . . . . . . . . . . . . . . . 5
Myasthenic and Cholinergic Crisis . . . . . . . . . . . . . . . . . 8
Lambert-Eaton Myasthenic Syndrome. . . . . . . . . . . . . . . 8
Endorsed by the
Association for Hospital
Medical Education
The Association for Hospital Medical Education
endorses HOSPITAL PHYSICIAN for the purpose of presenting the latest developments in
medical education as they affect residency programs and clinical hospital practice.
Botulism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Summary Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Cover Illustration by Jean Gardner
Copyright 2000, Turner White Communications, Inc., 125 Strafford Avenue, Suite 220, Wayne, PA 19087-3391, www.turner-white.com.
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means,
mechanical, electronic, photocopying, recording, or otherwise, without the prior written permission of Turner White Communications, Inc.
The editors are solely responsible for selecting content. Although the editors take great care to ensure accuracy, Turner White
Communications, Inc., will not be liable for any errors of omission or inaccuracies in this publication. Opinions expressed are those of the
authors and do not necessarily reflect those of Turner White Communications, Inc.
Neurology Volume 5, Part 1 i
NEUROLOGY BOARD REVIEW MANUAL
Preface
B
oard certification in neurology has become
increasingly important. The process of certification requires both residency training and successful completion of the American Board of Psychiatry
and Neurology certification examination.
The Hospital Physician Neurology Board Review Manual
is a series of quarterly publications designed to aid in
the preparation for the written part of the board examination. Each volume consists of four publications
focusing on selected topics. Space does not permit an
exhaustive review; however, Volume 5 targets several of
the more commonly encountered conditions or topics
in neurology. Topics included in Volume 5 are:
• Part 1—Neuromuscular Junction Abnormalities
• Part 2—Epilepsy
• Part 3—Peripheral Neuropathy
• Part 4—Headache
Board examination candidates will find this manual
to be a concise review of some of the essential and wellrecognized aspects of these topics. The case-based format presents the information in a logical fashion,
including clinical presentation, differential diagnosis,
diagnostic evaluation, and management.
This manual has been developed without the involvement of or review by the American Board of Psychiatry and Neurology. It is based on the Series Editor’s, Consulting Editor’s, and Contributing Author’s
clinical experience, awareness of new developments in
the field of neurology, and knowledge of the basic
components of education contained in our residency
training program. This board review manual program
is not comprehensive and should be viewed as a supplement to other preparatory material for board certification. The Editors wish all candidates success on the
examination.
Raymond K. Reichwein, MD
Assistant Professor of Neurology
Division of Neurology
Pennsylvania State University College of Medicine
Hershey, PA
ii Hospital Physician Board Review Manual
®
NEUROLOGY BOARD REVIEW MANUAL
Neuromuscular Junction
Abnormalities: Case Studies
Series Editor:
Consulting Editor and Contributing Author:
Raymond K. Reichwein, MD
Assistant Professor of Neurology
Division of Neurology
Pennsylvania State University College of Medicine
Hershey, PA
Milind J. Kothari, DO
Associate Professor of Neurology
Director, Neurology Residency Training Program
Division of Neurology
Pennsylvania State University College of Medicine
Hershey, PA
I. INTRODUCTION
Myasthenia gravis (MG) is an autoimmune disorder
that affects the neuromuscular junction at the postsynaptic level. Although the cause of the disorder is unknown, the role of immune responses (circulating antibodies directed against the nicotinic acetylcholine
receptor) in its pathogenesis is well established. The
disorder is characterized by fluctuating, fatigable weakness of muscles under voluntary control; some patients
may experience symptoms only late in the day or after
exercise. Because this disorder is quite treatable, prompt
recognition is crucial.
The prevalence of MG in the United States is roughly 14.2 cases per 1 million.1 Although MG may present
at any age, it has a bimodal peak of age at onset. In
women, the onset usually occurs between 20 and
40 years of age; among men, the onset is usually at 40 to
60 years of age. Familial occurrence of MG is rare; however, first-degree relatives do have a higher incidence of
other autoimmune diseases.2
During the past decade, our understanding of the
disease has improved substantially, leading to new
modalities of treatment with a substantial reduction in
the mortality and morbidity. This review focuses on MG
(clinical features, electrodiagnostic testing, and treatment) and also briefly discusses other disorders that
affect the neuromuscular junction (Lambert-Eaton
myasthenic syndrome [LEMS], botulism). Two case patients are presented to illustrate different aspects of
management of these diseases.
II. CASE PATIENT 1 PRESENTATION
Patient 1 is a 36-year-old woman with a 6-month history of intermittent horizontal diplopia and difficulty
swallowing. She indicates that her symptoms worsen as
the day progresses. She also has drooping of the left
eyelid at times and also reports some headaches. She
reports difficulty with swallowing liquids, including
occasional gagging, and easily gets fatigued. She
denies any sensory problems. Her examination reveals
mild left eyelid ptosis that worsens with sustained
upward gaze. Her neck flexors/extensors are normal
in strength. The remainder of her neurologic examination is unremarkable.
• Based on the clinical history and examination, the
most common signs and symptoms of MG in patient
1 are all of the following EXCEPT:
A) Intermittent diplopia
B) Difficulty swallowing
C) Eyelid ptosis
D) Headaches
Neurology Volume 5, Part 1 1
Neuromuscular Junction Abnormalities: Case Studies
Table 1. Clinical Features of Myasthenia Gravis
History
Onset of fluctuating ptosis or diplopia that worsens with
repeated use and improves with rest
Onset of fluctuating dysarthria, dysphagia, dysphonia with
or without ocular symptoms, or generalized weakness
that worsens with repeated use and improves with rest
Persistent ocular symptoms (1–2 yr) do not exclude the
diagnosis of MG, but persistent limb weakness with no
development of ocular-bulbar weakness makes the diagnosis of MG unlikely (unless test results are positive)
Physical examination
Weakness referable to ocular, bulbar, or limb muscle
Limb weakness prominent in proximal flexor groups
Normal muscle tone and bulk
Normal reflexes and sensation
Induction of muscle weakness with exercise when
weakness is subtle
Adapted with permission from Pourmand R: Myasthenia gravis. Dis
Mon 1997;43:82.
DISCUSSION
The correct answer is D. Headaches are not typically
associated with MG. Patient 1 also had migraine
headaches. In this case, the ocular dysfunction and difficulty swallowing (dysphagia) are typical of MG; the
fatigue is also indicative of MG. Patient 1’s difficulty with
liquids indicates a neurologic cause for her dysphagia
rather than a mechanical cause, which would involve
solids rather than liquids. It is important to assess for eyelid ptosis using sustained upward gaze to elicit the deficit.
Clinical Features of Myasthenia Gravis
The initial symptoms of MG typically involve the ocular muscles in about 60% of patients; virtually all patients have ocular involvement within 2 years of onset of
MG.3 The eyelid ptosis may be unilateral or bilateral.
Extraocular muscle weakness may also present in an
asymmetrical fashion. Patients with mild diplopia may
initially attempt using eyeglasses or changing their eyeglass prescription to correct their problem. The diplopia usually manifests on convergence or upward gaze.
Ptosis may occur with reading or long periods of driving. Myasthenic weakness may mimic third, fourth,
and sixth cranial nerve palsies as well as an intranuclear
ophthalmoplegia. Unlike third nerve palsies, MG never
affects pupillary function.
2 Hospital Physician Board Review Manual
Difficulty chewing, speaking, and swallowing may also
be the initial presenting symptoms but are less frequent
than ocular symptoms.3 Some patients may experience
severe fatigability and weakness of mastication, and are
unable to keep their jaw closed after chewing. Myasthenic speech is often nasal (from weakness of the soft
palate) and slurred (from weakness of the tongue, lips,
and face); there is no difficulty with fluency of language.
Patients also may state they have fatigue and fluctuating weakness. The weakness worsens after exercise
and typically improves with rest; the distinguishing clinical feature of MG is pathologic fatigability. In mild disease, neck flexor weakness may be the only finding. In
general, upper extremity weakness is more common
than lower extremity weakness. Patients may state they
have difficulty reaching with their arms, getting up
from a chair, or going up and down stairs. A key point
to remember is that if a patient has generalized limb
weakness without ocular involvement, the diagnosis of
MG should be questioned. Table 1 summarizes the
clinical features of MG.2 Cognition, sensory function,
or autonomic function is not abnormal because the
disorder is limited to the neuromuscular junction.
Examination of a patient with possible MG is directed at assessing muscle strength and demonstrating
pathologic fatigability. A few maneuvers that may be
used to elicit MG symptoms include having the patient
look up for several minutes (to elicit ptosis or extraocular weakness), count aloud to 100 (to elicit nasal or
slurred speech), or repetitively move their proximal
muscles (to elicit fatigue).4 The remainder of the neurologic examination is usually normal.
Differential Diagnosis of Myasthenia Gravis
Before diagnosing MG, it is necessary to exclude
other conditions that may present with somewhat similar features. Thyroid disease is a common disorder to
rule out. Also, patients with MG may have a coexistent
autoimmune disorder. Other forms of neuromuscular
junction disorders, acquired myopathies, and motor
neuron disease should be excluded. Mitochondrial
myopathy, thyroid ophthalmopathy, and other cranial
neuropathies should be considered in a patient with
ocular MG. Table 2 summarizes the different conditions that should be excluded; distinguishing clinical
and laboratory features are also summarized. 2 In some
patients, MG may be induced by certain drugs including some antiarrhythmic agents, D-penicillamine, and
antimalarial agents.5 There are also many classes of
drugs that can lead to worsening of MG symptoms
(Table 3).
Neuromuscular Junction Abnormalities: Case Studies
Table 2. Neurologic Disorders That Can Mimic Myasthenia Gravis*
Disease
Clinical Features
Diagnostic Test
Progressive external
ophthalmoplegia
Progressive ptosis and ophthalmoplegia
Electrocardiography
Fixed weakness
Muscle biopsy
Amyotrophic lateral sclerosis
Asymmetric muscle weakness and atrophy
Electromyography
Fasciculation and hyperreflexia
Nerve conduction velocities
Normal eye movements
Lambert-Eaton myasthenic syndrome
Proximal, symmetric hip and shoulder
weakness
Paresthesia
Repetitive nerve stimulation
Anti-Hu and anti–calcium
channel antibodies
Dry mouth
Hyporeflexia
Periodic paralysis
Polymyositis, dermatomyositis
Intermittent generalized limb weakness
after exertion or intake of highcarbohydrate food
Proximal, symmetric limb weakness
with or without skin rash
Potassium level during attack
Muscle biopsy
Serum creatine kinase
Electromyography
Muscle biopsy
Guillain-Barré syndrome
Ascending, symmetric limb weakness
and areflexia
Nerve conduction velocities
and F wave
Cerebrospinal fluid study
Botulism
Generalized limb weakness
Repetitive nerve stimulation
Pupillary dilatation
Hyporeflexia
Multiple sclerosis
Bilateral internuclear ophthalmoplegia
Magnetic resonance imaging of head
Upper motor neuron signs
Cerebrospinal fluid study
Adapted with permission from Pourmand R: Myasthenia gravis. Dis Mon 1997;43:80.
*These conditions should be considered in a patient with possible myasthenia gravis.
III. PATHOPHYSIOLOGY OF MYASTHENIA GRAVIS
The neuromuscular junction is composed of the
nerve terminal, the synaptic cleft, and the highly organized postjunctional folds on the muscle membrane.
The nerve terminal is the site of synthesis and storage
of the neurotransmitter acetylcholine (which is released in discrete quanta). When a nerve action potential depolarizes the presynaptic terminal, voltagedependent calcium channels are activated allowing an
influx of calcium, which results in a release of acetylcholine from the presynaptic terminal. The acetylcholine diffuses across the synaptic cleft and binds to
acetylcholine receptors (AChR) on the postsynaptic
membrane resulting in an end-plate potential. This
normal process is altered in patients with MG and with
LEMS 6 (Figure 1).
The pathophysiology of MG is now well understood.
The condition is caused by sensitized T-helper cells and
an IgG-directed attack on the nicotinic acetylcholine
receptor of the neuromuscular junction.7 Various experimental studies support this hypothesis: (1) antibodies are present in most patients with MG; (2) antibodies
can be passively transferred to animals, yielding experimental myasthenia; (3) removal of these antibodies
leads to recovery; and (4) animals immunized with an
acetylcholine receptor produce antibodies that can
Neurology Volume 5, Part 1 3
Neuromuscular Junction Abnormalities: Case Studies
Table 3. Drugs Reported to Exacerbate or Induce
Myasthenia Gravis
Antibiotic
Agents
Cardiovascular
Agents
Others
Ampicillin
Procainamide
Phenytoin
Ciprofloxacin
Propafenone
Trimethadione
Erythromycin
Quinidine
Trihexyphenidyl
Permission to electronically reproduce this table
Aminoglycosides
Verapamil
Chloroquine
not granted by copyright holder.
D-Penicillamine
Imipenem
Acebutolol
Pyrantel
Oxprenolol
Corticosteroids
Practolol
Interferon alfa
Propranolol
Mydriatics
Timolol eye drops
Adapted from Wittbrodt ET: Drugs and myasthenia gravis. An update.
Arch Intern Med 1997;157(4):405.
provoke an autoimmune disease (experimental autoimmune MG), which closely resembles the naturally
occurring disease.7
IV. DIAGNOSTIC TESTING FOR MYASTHENIA
GRAVIS
The diagnosis of MG is usually straightforward and is
based on the following: (1) recognition of the clinical
pattern of disease (see Section II.), (2) detection of
acetylcholine receptor antibodies, (3) electrodiagnostic
studies, and (4) Tensilon test findings.
LABORATORY AND RADIOGRAPHIC STUDIES
Certain laboratory studies should be performed to
exclude other disorders in the differential diagnosis of
MG; these studies are summarized in Table 4. The most
sensitive and specific test for MG is the presence of
acetylcholine receptor antibodies (AChR-Ab), although
not all patients with MG have positive AChR-Ab titers.
False-positive results do occur but are rare.8 Approximately 90% of patients with generalized MG have positive antibody titers, compared with 45% to 65% of
patients with ocular MG.9,10 It is important to note that
the degree of positivity does not correlate with the disease severity.11,12 Tests for striational muscle antibodies
may be useful in late-onset MG to exclude the possibility of a thymoma.2
Approximately 20% of patients with MG have a thymoma, whereas about 70% have thymic hyperplasia.13
To exclude thymoma, all patients with MG should have
4 Hospital Physician Board Review Manual
a computed tomography (CT) scan of the chest performed with contrast. A routine chest radiograph may
also be performed but should not be done in place of
the CT chest scan.
PHARMACOLOGIC STUDIES
Edrophonium chloride (Tensilon) is a short-acting
acetylcholinesterase inhibitor. During a Tensilon test,
the patient should be connected to a cardiac monitor,
and atropine must be available at the bedside in case
the patient develops bradycardia. A total dose of 10 mg
of edrophonium may be used. A small test dose (2 mg)
is injected intravenously and, if after 1 minute there is
no improvement in ptosis, the remainder of the dose
should be slowly given. The effects of edrophonium are
short lasting (usually < 10 minutes). For the outcome to
be considered positive for MG, there must be unequivocal improvement of strength (ie, ptosis that improves).
The patient may experience cholinergic side effects,
such as increased salivation, tearing, muscle fasciculations, or abdominal cramps.
ELECTRODIAGNOSTIC STUDIES
The electrophysiologic evaluation of MG (Table 5)
involves routine nerve conduction testing, repetitive
nerve stimulation, exercise testing, and in certain
instances, single-fiber electromyography (EMG).4
Findings of routine nerve conduction studies in
patients with MG are typically normal; if the findings
are abnormal, one should question the diagnosis of
MG. Repetitive nerve stimulation (RNS) is then performed and should demonstrate a decrement of
greater than 10% to be considered positive (Figure 2).
The yield of the test increases if proximal nerves (spinal
accessory, facial) are stimulated, limb temperature is
increased,14 or the test is conducted after exercise of the
appropriate muscle.
Exercise testing should be done with all RNS studies;
often the decrement is enhanced after exercise (Figure 2).
Single-fiber EMG is used to measure the relative firing
of adjacent muscle fibers from the same motor unit.
The variation in firing between these fibers is called jitter, which is increased in patients with MG. Although
single-fiber EMG is the most sensitive test for demonstrating neuromuscular transmission (> 95%), it is not
specific, and results may be abnormal in various neuropathic or myopathic disorders.3,15,16 Thus, the electrophysiologic studies should always be interpreted in the
context of the clinical setting.3
CASE PATIENT 1 FOLLOW-UP
Patient 1 had an increased serum AChR-Ab titer of
Neuromuscular Junction Abnormalities: Case Studies
Nerve
ACh
VGCC-Ab
AChR-Ab
Receptor
Muscle
NORMAL
MG
LEMS
Figure 1. Schematic of the neuromuscular junction. (Left) Normal muscle end-plate membrane. (Middle) In patients with acquired
myasthenia gravis (MG), the muscle end-plate membrane is distorted, and the normal folded pattern is lost. Acetylcholine receptors
(AChR) are lost from the tips of the folds, and AChR antibodies (AChR-Ab) are attached to the postsynaptic membrane. (Right) In
Lambert-Eaton myasthenic syndrome (LEMS), antibodies against the voltage-gated calcium channel (VGCC-Ab) on the nerve terminal
interfere with release of acetylcholine (ACh). In botulism, the findings are similar to those with LEMS. Reproduced with permission
from Sanders DB, Howard JF: Disorders of neuromuscular transmission. In Neurology in Clinical Practice. Bradley WG, Daroff RB, Fenichel
GM, Marsden CD, eds. Newton, MA: Butterworth-Heinemann, 1996:1986.
22.3 nmol/L (normal < 0.2 nmol/L). A CT scan of her
chest revealed a thymoma. Electrodiagnostic studies
demonstrated normal nerve conduction. Using RNS at
3 Hz, there was a 37% decrement of the spinal accessory nerve and a 12% decrement of the facial nerve. The
patient underwent immunosuppressive therapy and
was referred for thymectomy.
ence of other systemic illnesses. The goal of therapy is
to achieve remission, so that the patient is symptom free
and not taking medication. Most patients do become
symptom free but need to continue taking a low-dose
immunosuppressive medication. Table 6 summarizes
the various oral preparations used in treating patients
with MG.
• Appropriate therapy for patient 1 includes:
A) Pyridostigmine (Mestinon)
B) Intravenous immunoglobulin
C) Plasmapheresis
D) Thymectomy
E) All of the above
The correct answer is E. All are accepted treatments
for a patient with MG. Some treatments are used for
acute management and other modalities are for longterm management. Treatment is discussed in the following section (Section V.).
ACETYLCHOLINESTERASE INHIBITORS
This class of medication remains the first line of therapy in symptomatic patients. The most common agent
used is pyridostigmine (Mestinon). These agents effectively increase the amount of neurotransmitter (acetylcholine) available at the postsynaptic junction. The
optimal dose varies from patient to patient. In general,
an awake patient is given 30 mg (0.5 tablets) every 4
to 6 hours; the dose is titrated depending on clinical
symptoms and patient tolerance. The drug has a short
half-life of approximately 3 to 6 hours. The major
side effects are those of cholinergic excess: abdominal
cramping, increased salivation, and diarrhea. If the patient receives too much medication, increased weakness (cholinergic crisis) may develop. A long-acting
form (Mestinon Timespan 180 mg) is usually used
when the patient has problems during sleep or awakens with weakness and/or ptosis. The Timespan form
is not recommended for use during the day. Neostigmine has a shorter but more pronounced effect and
can be administered orally, parenterally, or even
intranasally.17
V. TREATMENT OF MYASTHENIA GRAVIS
There is no distinct protocol for the treatment of
MG; physicians need to decide when aggressive management must be undertaken. In general, the rate of
progression, distribution of muscle weakness, and severity of symptoms are the most important considerations
for immediate treatment. Other factors that may influence long-term treatment include age, sex, and pres-
Neurology Volume 5, Part 1 5
Neuromuscular Junction Abnormalities: Case Studies
Table 4. Laboratory Studies for the Differential
Diagnosis of Myasthenia Gravis
Table 5. Electrophysiologic Evaluation of Myasthenia
Gravis
Acetylcholine receptor antibody (AChR-Ab) > 0.2 nmol/L*
Routine motor and sensory nerve conduction testing
is performed in at least 2 nerves, preferably in one upper
and one lower extremity nerve. Compound muscle action
potential (CMAP) amplitudes should be normal. If CMAP
amplitudes are low or borderline, distal stimulation should
be repeated immediately after 10 seconds of exercise to
exclude a presynaptic neuromuscular junction (NMJ) disorder (ie, Lambert-Eaton myasthenic syndrome).
Antinuclear antibody (ANA)
Antistriated muscle antibodies
Complete blood count
Erythrocyte sedimentation rate
Liver and renal profiles
Rheumatoid factor
Serum electrolyte levels
Thyroid function
*Not all patients with myasthenia gravis have positive AChR-Ab titers.
False-positive results can occur but are rare.
IMMUNOSUPPRESSIVE THERAPY
Because MG is an autoimmune condition, the mainstay of treatment involves attacking the immune system.
Immunosuppressive agents should be tailored to the
individual patient; often, combination therapy is more
efficacious (allowing for reduced dose and fewer side
effects) than monotherapy.18 The more commonly used
immunosuppressive agents (eg, azathioprine, prednisone) are listed in Table 6. The potential side effects of
the major immunosuppressive agents are summarized
in Table 7.
Corticosteroids
As a general rule, most patients with MG require
steroid therapy at some point in their disease. Steroids
may potentially reduce the AChR-Ab titer in patients
with MG.19 The typical dose of prednisone is 1 mg/kg
per day, administered as a single daily dose. It is very
important, however, to begin treatment with a low dose
of prednisone and then gradually titrate the dose up.
Patients may experience transient worsening of their
MG symptoms during the first 2 to 3 weeks of prednisone therapy. The dose may be increased by 5 mg
every 4 to 7 days until clinical benefit is achieved or the
dose of 1 mg/kg of body weight is reached. Typically,
patients improve 6 to 8 weeks after initiating therapy.
Once a therapeutic dose is achieved, the patient should
remain on this dose for approximately 2 months. The
regimen is then changed to alternate-day therapy, and
once the patient is stabilized, the dose may be slowly
tapered by approximately 5 mg each month. It is not
uncommon for patients to relapse after the medication
has been tapered off.
6 Hospital Physician Board Review Manual
Repetitive nerve stimulation (RNS) and exercise testing.
Perform slow RNS (3 Hz) on at least one proximal and one
distal motor nerve, preferably in weak muscles. If any substantial decrement (> 10%) is present, repeat RNS to ensure the
decrement is reproducible. If there is no substantial decrement at baseline, then exercise the muscle for 1 minute and
repeat RNS at 1, 2, 3, and 4 minutes to reveal any decrement
secondary to postexercise exhaustion. If at any time a substantial decrement is present, exercise the muscle for 10 seconds and immediately repeat RNS to reveal any postexercise
facilitation (repair of the decrement).
Needle electromyography (EMG) of distal and proximal
muscles, especially weak muscles, will reveal unstable or short,
small, polyphasic motor unit action potentials in patients with
moderate-to-severe MG. Recruitment is normal or early.
Needle EMG must exclude severe denervating disorders or
myotonic disorders, which may display an abnormal decrement on RNS.
Single-fiber EMG (SF-EMG). If the results from the previous
tests are normal or equivocal in a patient strongly suspected
of having MG, perform SF-EMG in the extensor digitorum
communis and, if necessary, one other weak muscle, to reveal
increased jitter and blocking. Normal SF-EMG results in a clinically weak muscle exclude a NMJ disorder.
Adapted with permission from Preston DC, Shapiro BE: Electromyography and Neuromuscular Disorders: Clinical-Electrophysiologic
Correlations. Boston, MA: Butterworth-Heinemann, 1998:506.
Most patients generally require long-term, low-dose
prednisone therapy to maintain remission. However,
patients should be informed of potential side effects of
corticosteroids including obesity, osteoporosis, cataracts,
hypertension, hyperglycemia, steroid myopathy, and
electrolyte imbalances (Table 7); appropriate precautionary measures should be followed to avoid side
effects. Thus, patients may need to take antacids, calcium supplements, or other therapy to prevent problems
that steroids may cause. Patients with diabetes who typically take oral agents may require insulin therapy when
taking corticosteroids.
Neuromuscular Junction Abnormalities: Case Studies
Azathioprine
Azathioprine (Imuran) is now the most commonly
used drug in patients with MG.2 The drug is used to
allow tapering of the corticosteroid dose and to reduce
some of the side effects from corticosteroids. However,
most patients taking azathioprine will not show reduction of their corticosteroid side effects for about 4 to
6 months and sometimes longer. The typical starting
dose of azathioprine is 50 mg daily for the first week
(test dose), and then the dose is titrated up to a maximum of 2 to 3 mg/kg per day in divided doses. Azathioprine also causes side effects (Table 7). The most
common side effects are neutropenia and liver function
abnormalities; thus, a CBC and liver profile should be
done routinely in patients receiving azathioprine.
Rarely, an acute hypersensitivity reaction develops when
therapy begins, which is why a test dose is used for the
first week. The long-term effects are not well known, but
there is some concern about an increased risk of malignancy.20
2 mV
2 ms
A
15%
B
2%
C
27%
D
30%
E
Cyclosporine
Cyclosporine (Sandimmune) is a powerful immunosuppressant that inhibits T-cell activation. This agent is
usually used in someone who cannot tolerate azathioprine or who has not responded to prednisone/azathioprine therapy. The usual starting dose of cyclosporine is
3 mg/kg per day, which is titrated up to approximately
5 to 6 mg/kg per day. A blood level (trough) should be
checked periodically. The most important side effects are
nephrotoxicity and hypertension.
Cyclophosphamide
In general, cyclophosphamide (Cytoxan) is used
only when the other agents have failed or are not tolerated by the patient. The dose of cyclophosphamide is
approximately 2 to 5 mg/kg per day. Hemorrhagic cystitis can occur as well as other side effects (Table 7).2
Plasma Exchange (Plasmapheresis) and Intravenous
Immunoglobulin
Plasmapheresis is an effective therapy but is transient
in its response. It is particularly useful in myasthenic crisis or in preparation for surgery. For example, patient 1
underwent 3 consecutive days of plasmapheresis before
thymectomy. The goal of plasmapheresis is to remove
the circulating immune complexes and AChR-Ab.
Patients usually undergo a course of 5 to 6 exchanges
during a 2-week period. There are risks involved with
plasmapheresis including fluid imbalance, hypercoagulation, and the more common problem of vascular
access.21
31%
F
6%
Figure 2. Repetitive nerve stimulation (3 Hz) of the ulnar nerve
at the wrist, recording over the abductor digiti minimi muscle.
Maximal percentage decrement is noted at the right of the tracings. (A) Baseline; (B) immediately after 10 seconds of exercise
(postexercise facilitation); (C–E) 1, 2, and 3 minutes after 60 seconds of exercise (postexercise exhaustion); and (F) immediately
after 10 seconds of exercise again (postexercise facilitation and
repair of the decrement). Adapted with permission from Preston
DC, Shapiro BE: Electromyography and Neuromuscular Disorders:
Clinical-Electrophysiologic Correlations. Boston, MA: ButterworthHeinemann, 1998:507.
The administration of intravenous immunoglobin
(IVIG) serves as an alternative therapy to plasmapheresis and is especially helpful when vascular access
is a problem. The exact mechanism of IVIG is not well
understood, although several have been postulated.22
IVIG is given as a dose of 2 g/kg over 2 to 5 days. It is
relatively safe; however, it has a few side effects including headache, chills, and fever.3 Usually, premedication
with acetaminophen and diphenhydramine alleviates
these side effects. Other, more rare side effects include
aseptic meningitis and renal failure.3
Neurology Volume 5, Part 1 7
Neuromuscular Junction Abnormalities: Case Studies
Table 6. Drugs Commonly Used to Treat Myasthenia Gravis
Class
Drug
Route of Admission
Preparation
Acetylcholinesterase
inhibitors
Pyridostigmine
Oral, parenteral
Tablets (60 mg), controlled release
tablets (180 mg), syrup (60 mg/5 mL),
ampules (5 mg/mL)
Neostigmine
Oral, parenteral, intranasal
Tablets (15 mg), ampules (0.25–1 mg/mL),
nebulized solution (60 mg/mL; 1 puff =
4 –6 mg)
Prednisone
Oral
Tablets (1–50 mg), syrup (5 mg/5 mL)
Corticosteroids
Prednisolone
Parenteral
Ampules (20–50 mg/mL)
Cytotoxic
Azathioprine
Oral
Tablets (50 mg)
Cyclosporine
Cyclosporine
Oral
Capsules (25–125 mg), syrup (100 mg/mL)
Adapted with permission from Evoli A, Batocchi AP, Tonali P: A practical guide to the recognition and management of myasthenia gravis. Drugs
1996;52:665.
Thymectomy
There is general agreement that a thymectomy
should be performed in patients with MG who are
younger than 60 years.3 Thymectomy should be
performed only in a patient who is medically stable.
There has been some recent controversy regarding the
surgical approach; in general, the median sternotomy
approach is preferred, which allows for maximal exposure and removal of all thymic tissue at the time of
surgery.13 Clinical improvement of MG symptoms is
typically delayed by 6 to 12 months after thymectomy.
It is suggested that patients with MG who have had
thymectomy receive influenza vaccines, pneumonia
vaccines, and other prophylactic therapy to decrease
infection. If the patient has a thymoma, it should be
removed.3
weakness, causing cholinergic crisis. If the crisis is not
recognized early, respiratory collapse can develop or
the patient can aspirate because of increasing bulbar
weakness.
Myasthenic or cholinergic crisis must be managed
aggressively, although they may be very difficult to distinguish. As a rule, it is safer to assume that the patient
has myasthenic crisis. Table 8 outlines the protocol for
managing a patient with crisis. Some have suggested
using the Tensilon test (ie, edrophonium) to distinguish these two conditions; however, it is very difficult in
a patient in severe distress. If symptoms worsen after
edrophonium, then the patient has cholinergic crisis. If
symptoms improve after edrophonium, then the
patient has myasthenic crisis.
VII. LAMBERT-EATON MYASTHENIC SYNDROME
VI. MYASTHENIC AND CHOLINERGIC CRISIS
Myasthenic crisis is defined as the sudden worsening
of respiratory function with profound weakness; it is a
neurologic emergency that rarely occurs. The initial
presentation of MG may be that of crisis, or a patient
with known MG may also develop crisis. Death rarely
occurs after crisis because of early recognition, effective
therapy, and modern intensive care units. Crisis has various causes, including concurrent infection or the addition of new medication that exacerbates MG (Table 3).
Cholinergic crisis occurs more frequently and can
sometimes be a neurologic emergency. In response to
worsening weakness, patients frequently increase their
acetylcholinesterase inhibitor dose; however, excess doses
of acetylcholinesterase inhibitor can lead to increased
8 Hospital Physician Board Review Manual
GENERAL PRINCIPLES
LEMS is the most common presynaptic disorder of
neuromuscular transmission (Figure 1). The disorder
was initially described as a paraneoplastic condition but
has been reported with other autoimmune conditions.
Associated conditions may include thyroid disease, pernicious anemia, vitiligo, celiac disease, type I diabetes,
rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, and scleroderma.23 LEMS usually presents after
40 years of age, although the primary autoimmune
form of LEMS may occur in younger adults or, very
rarely, in children.
Typically, patients with LEMS present with progressive generalized weakness that is more prominent in the
Neuromuscular Junction Abnormalities: Case Studies
Table 7. Potential Side Effects of Immunosuppressive Drugs Used to Treat Myasthenia Gravis
Azathioprine
Cyclosporine
Cyclophosphamide
Prednisone
Allergy
Nephrotoxicity
Nausea and vomiting
Obesity
Nausea and vomiting
Hypertension
Bone marrow suppression
Easy bruising
Thrombocytopenia
Hepatotoxicity
Alopecia
Osteoporosis
Leukopenia
Gingival hypertrophy
Hemorrhagic cystitis
Cataracts
Increased risk for infection
Hirsutism
Hyponatremia
Hirsutism
Alopecia
Increased risk for infection
Pulmonary fibrosis
Acne
Pancreatitis
Tremor
Hyperpigmentation
Increased risk of carcinoma
Fluid retention
Hypertension
Hyperglycemia
Necrosis of the femoral head
Steroid myopathy
Electrolyte imbalances
Adapted with permission from Pourmand R: Myasthenia gravis. Dis Mon 1997;43:96.
lower extremities, in contrast to MG which typically
involves upper extremity weakness. The presentation is
similar with either the primary autoimmune form or
with the secondary paraneoplastic form of LEMS.
LEMS may be associated with other paraneoplastic
disorders including cerebellar ataxia or primary sensory neuropathy. An important presenting feature that
distinguishes LEMS from MG is the involvement of the
autonomic nervous system. Patients with MG do not have
autonomic nervous system dysfunction. However, patients with LEMS can have autonomic dysfunction. Approximately 6% of patients may present with dry mouth,
dry eyes, constipation, and erectile dysfunction.23 Bulbar
symptoms (dysphagia, dysarthria) are usually mild, if
present, which can help distinguish LEMS from MG.
On physical examination, there is usually weakness
of proximal muscles resulting in a waddling gait. The
weakness of LEMS may mimic some myopathies,
with the patient having difficulty arising, walking, or
climbing stairs. Fatigue is a prominent symptom.
Often, one notes improvement in strength that
occurs after a few seconds of voluntary contraction
(facilitation). The deep tendon reflexes are diminished or absent.
The pathogenesis of LEMS is quite well understood
and involves the production of an IgG antibody directed against the voltage-gated calcium channel (VGCC)
on the presynaptic membrane (Figure 1).4 Although
the most common malignancy associated with LEMS is
small-cell lung carcinoma (SCLC), other malignancies
include renal cell carcinoma, lymphoma, and adenocarcinoma of the lung.23
DIAGNOSIS
Early in its course, the diagnosis of LEMS may be difficult. Other neurologic conditions that should be considered in the differential diagnosis are inflammatory
myopathies, MG, and chronic inflammatory demyelinating polyneuropathy. Sometimes a patient with LEMS
may be considered hysterical or depressed because of an
atypical presentation. The VGCC antibody test is helpful
in the diagnosis of LEMS; however, these antibodies are
also present in 20% to 40% of patients with SCLC who
do not have LEMS.24 Thus, a positive VGCC antibody
test result is not diagnostic of LEMS; clinical and electrodiagnostic studies are usually required to confirm
the diagnosis.
The electrophysiologic features are diagnostic in a
patient with LEMS. The routine nerve conduction studies demonstrate normal sensory nerve action potentials
and low-amplitude motor nerve responses. RNS (3 Hz)
usually demonstrates a decrement similar to that seen
with MG. However, on fast RNS (50 Hz or 10 seconds of
exercise), the compound muscle action potential shows
a marked increase of about 200% or even greater
(Figures 3 and 4).4
TREATMENT
The main treatment for LEMS is to treat the underlying malignancy. Thus, an extensive search should
be undertaken for a possible malignancy if none is
evident. If no cancer is found on initial screening,
studies should be repeated every 6 months until the
tumor becomes evident. Pharmacologic treatment
with 3,4-diaminopyridine has been shown to improve
Neurology Volume 5, Part 1 9
Neuromuscular Junction Abnormalities: Case Studies
Table 8. Protocol for Managing Myasthenic or
Cholinergic Crisis*
2 mV
2 ms
Secure the airway and monitor vital signs
Measure respiratory function with vital capacity, negative
inspiratory flow, blood gases
Intubate if the vital capacity is less than 1 L
Discontinue all acetylcholinesterase inhibitors
Monitor the patient in the intensive care unit
Rule out or treat concurrent infection
Perform plasma exchange (plasmapheresis), 5 to 6 courses
within 2 weeks
May restart low dose of acetylcholinesterase inhibitors after
24–48 hours
*It is difficult to distinguish myasthenic and cholinergic crisis. It is safer
to assume that patients have myasthenic crisis.
Adapted with permission from Pourmand R: Myasthenia gravis. Dis
Mon 1997;43:99.
acetylcholine release, but pyridostigmine does not
improve release.25 In some cases, plasmapheresis in
conjunction with immunosuppressive agents is beneficial.23
Figure 3. Exercise testing in patients with Lambert-Eaton myasthenic syndrome, with the median nerve stimulated supramaximally at the wrist and the abductor pollicis brevis muscle recorded. (Top) Baseline. (Bottom) Immediately after 10 seconds of
maximal voluntary exercise. Note marked increase in the amplitude of the motor response (postexercise facilitation). Adapted
with permission from Preston DC, Shapiro BE: Electromyography
and Neuromuscular Disorders: Clinical-Electrophysiologic Correlations.
Boston, MA: Butterworth-Heinemann, 1998:512.
VIII. BOTULISM
GENERAL PRINCIPLES
This condition is caused by the exotoxin of the bacterium Clostridium botulinum. The exotoxin results in a
decrease in acetylcholine release at the presynaptic level.
There are currently 5 categories of botulism: classic (food
borne), infant, wound, hidden (adult form of infant botulism), and inadvertent.26 There are many strains of botulism; however, types A, B, and E are commonly associated with clinical disease.26 The condition often begins
with gastrointestinal dysfunction (nausea, vomiting, and
abdominal pain) followed by visual problems and
dysarthria. Rapidly progressive descending weakness
usually follows, resulting in quadriparesis. In approximately 50% of patients,4 the pupils are often paralyzed,
and most patients have significant autonomic dysfunction (ileus, decreased salivation). The two main conditions that should be considered in the differential diagnosis are MG and Guillain-Barré syndrome (GBS). MG
does not present in such a rapid manner, and there is no
autonomic dysfunction. GBS usually has prominent sensory symptoms associated with the weakness. The elec-
10 Hospital Physician Board Review Manual
2 mV
100 ms
Figure 4. Rapid repetitive nerve stimulation (50 Hz) in LambertEaton myasthenic syndrome.Note the marked increment (> 250%)
in the amplitude of the compound muscle action potential. Adapted
with permission from Preston DC, Shapiro BE: Electromyography
and Neuromuscular Disorders: Clinical-Electrophysiologic Correlations.
Boston, MA: Butterworth-Heinemann, 1998:511.
trophysiologic results for botulism are similar to those for
LEMS. The main treatment for botulism is supportive
care with special attention to the respiratory status.
Antitoxin may be administered but may be associated
with severe allergic reactions.26
Neuromuscular Junction Abnormalities: Case Studies
CASE PATIENT 2
Presentation
Patient 2 is a 48-year-old man who develops dysphagia after dinner. During the next few hours, he develops diplopia, dysarthria, and facial weakness followed
by respiratory compromise. He is admitted to the intensive care unit. On physical examination, he has sluggishly reactive pupils, facial weakness, depressed gag
reflex, and proximal muscle weakness. His deep tendon
reflexes are absent.
Discussion
• Which of the following should be considered in the
differential diagnosis of patient 2?
A) MG
B) GBS
C) Organophosphate poisoning
D) Botulism
E) All of the above
The correct answer is E. Patient 2’s presentation is
suggestive of a rapidly progressive paralytic disorder. All
of the conditions listed as possible answers may present
in such a fashion. Patient 2 was diagnosed with GBS
and underwent plasmapheresis. After 2 exchanges, he
continued to worsen.
• Which of the following tests would be most useful
for patient 2 at this point?
A) Lumbar puncture
B) Drug toxicology screen
C) Electrodiagnostic studies
D) Lyme titer
E) Acetylcholine receptor antibodies
The correct answer is C. Electrodiagnostic studies
(electromyography/nerve conduction velocity [(EMG/
NCV)] would provide the most useful information by
indicating evidence of a demyelinating polyneuropathy
or possibly a disorder of neuromuscular transmission.
Patient 2’s EMG/NCV results showed the following: all
sensory responses were normal and all motor responses
were markedly reduced in amplitude with normal latencies. These EMG/NCV results suggest a differential
diagnosis of myopathy, motor neuron disease/polyradiculopathy, or neuromuscular junction transmission
disorder.
• What should be the next step for patient 2?
A) RNS
B) Single-fiber EMG
C) Evaluation for lung cancer
D) Muscle biopsy
The correct answer is A. Given the results of the
nerve conduction studies, RNS should be performed to
determine if there is a problem at the neuromuscular
junction. Slow RNS (3 Hz) was performed over the
ulnar nerve and showed a 15% decrement. Furthermore, 50-Hz RNS was also performed and showed a
250% increment. These results are highly suggestive of
a presynaptic disorder of neuromuscular transmission.
On further questioning, patient 2 revealed that he had
eaten some canned fruit earlier, which had spoiled;
analysis of his stool demonstrated C. botulinum type B.
He was treated with antitoxin and showed slight clinical
improvement over the next few days.
IX. SUMMARY POINTS
• Ptosis or diplopia is the initial presenting symptom
of myasthenia gravis (MG) in approximately 66% of
patients. Weakness confined to the ocular muscles
occurs in approximately 10% of patients, and the
remaining patients have generalized involvement
after about 2 years.
• The hallmark of MG is pathologic fatigability. The
examination should show fatigable weakness in various muscle groups, especially the ocular muscles. Provocative maneuvers may be used to elicit such abnormalities (eg, persistent upward gaze with exercise).
• Acetylcholine receptor antibodies can be found in
the serum of most patients with MG. However, lack
of serum antibodies does not exclude the diagnosis
of MG. The amount of antibody does not correlate
with the severity of the disease.
• The response to edrophonium is very reliable in a
patient with ocular muscle weakness. Electrodiagnostic studies, including repetitive nerve stimulation,
are extremely useful in demonstrating abnormalities
of neuromuscular transmission. Single-fiber electromyography is very sensitive but not very specific.
• Treatment of MG may be a life-long process in some
patients. The goal is to achieve remission. Patients
may become worse during episodes of infection.
Appropriate monitoring should be undertaken
during immunosuppressive therapy to avoid side
effects. Thymectomy should be performed in a
patient younger than 60 years.
• It is often very difficult to distinguish between myasthenic and cholinergic crisis. However, crisis should
be considered a neurologic emergency, and the
patient should be treated for possible myasthenic
crisis using a specific protocol.
• Lambert-Eaton myasthenic syndrome (LEMS) has
Neurology Volume 5, Part 1 11
Neuromuscular Junction Abnormalities: Case Studies
distinctive clinical features that distinguish it from
MG. Electrodiagnostic studies with fast repetitive
nerve stimulation are very helpful in making a diagnosis. In these patients, an aggressive search for an
underlying malignancy should be done.
• Botulism has electrodiagnostic features similar to
LEMS. A careful history may help confirm the
diagnosis. Often patients may be misdiagnosed with
Guillain-Barré syndrome.
REFERENCES
1. Phillips LH 2nd: The epidemiology of myasthenia gravis.
Neurol Clin 1994;12:263–271.
2. Pourmand R: Myasthenia gravis. Dis Mon 1997;43:65–109.
3. Massey JM: Acquired myasthenia gravis. Neurol Clin 1997;
15:577–595.
12. Drachman DB, Adams RN, Josifek LF, Self SG: Functional activities of autoantibodies to acetylcholine receptors and the clinical severity of myasthenia gravis. N Engl
J Med 1982;307:769–775.
13. Wilkins KB, Bulkley GB: Thymectomy in the integrated
management of myasthenia gravis. Adv Surg 1999;32:
105–133.
14. Keesey JC: AAEE Mini-monograph #33: electrodiagnostic approach to defects of neuromuscular transmission.
Muscle Nerve 1989;12:613–626.
15. Bertorini TE, Stalberg E, Yuson CP, Engel WK: Singlefiber electromyography in neuromuscular disorders: correlation of muscle histochemistry, single-fiber electromyography, and clinical findings. Muscle Nerve 1994;
17:345–353.
16. Sanders DB, Stalberg EV: AAEM mini-monograph #25:
single-fiber electromyography. Muscle Nerve 1996;19:
1069–1083.
4. Preston DC, Shapiro BE: Electromyography and Neuromuscular Disorders: Clinical-Electrophysiologic Correlations.
Boston: Butterworth-Heinemann, 1998.
17. Ricciardi R, Rossi B, Nicora M, et al: Acute treatment of
myasthenia gravis with intranasal neostigmine: clinical
and electromyographic evaluation. J Neurol Neurosurg
Psychiatry 1991;54:1061–1062.
5. Penn AS, Low BW, Jaffe IA, et al: Drug-induced autoimmune myasthenia gravis. Ann N Y Acad Sci 1998;841:
433–449.
18. Evoli A, Batocchi AP, Tonali P: A practical guide to the
recognition and management of myasthenia gravis.
Drugs 1996;52:662–670.
6. Sanders DB, Howard JF: Disorders of neuromuscular
transmission. In Neurology in Clinical Practice, 2nd ed.
Bradley WG, Daroff RB, Fenichel GM, Marsden CD,
eds. Newton, MA: Butterworth-Heinemann, 1996:
1983–2001.
19. Kaplan I, Blakely BT, Pavlath GK, et al: Steroids induce
acetylcholine receptors on cultured human muscle:
implications for myasthenia gravis. Proc Natl Acad Sci
U S A 1990;87:8100–8104.
7. Preston DC: Myasthenia gravis. In Office Practice of
Neurology. Samuels MA, Feske S, eds. New York, NY:
Churchill Livingstone, 1996:562–567.
8. Phillips LH 2nd, Melnick PA: Diagnosis of myasthenia
gravis in the 1990s. Semin Neurol 1990;10:62–69.
9. Vincent A, Newsom-Davis J: Acetylcholine receptor antibody as a diagnostic test for myasthenia gravis: results in
153 validated cases and 2967 diagnostic assays. J Neurol
Neurosurg Psychiatry 1985;48:1246–1252.
10. Limburg PC, The TH, Hummel-Tappel E, Oosterhuis
HJ: Anti-acetylcholine receptor antibodies in myasthenia
gravis. Part 1. Relation to clinical parameters in 250 patients. J Neurol Sci 1983;58:357–370.
11. Lindstrom JM, Seybold ME, Lennon VA, et al: Antibody
to acetylcholine receptor in myasthenia gravis. Prevalence, clinical correlates, and diagnostic value. Neurology
1976;26:1054–1059.
20. Confavreux C, Saddier P, Grimaud J, et al: Risk of cancer
from azathioprine therapy in multiple sclerosis: a casecontrol study. Neurology 1996;46:1607–1612.
21. Kuks JB, Das PC: Plasma exchange in myasthenia gravis.
Int J Artif Organs 1998;21:188–191.
22. Howard JF Jr: Intravenous immunoglobulin for the treatment of acquired myasthenia gravis. Neurology 1998;51
(6 Suppl 5):S30–S36.
23. Levin KH: Paraneoplastic neuromuscular syndromes.
Neurol Clin 1997;15:597–614.
24. Jones HR: Lambert-Eaton Myasthenic Syndrome. In
Office Practice of Neurology. Samuels MA, Feske S, eds. New
York, NY: Churchill Livingstone, 1996:567–571.
25. Sanders DB, Howard JF Jr, Massey JM: 3,4-Diaminopyridine in Lambert-Eaton myasthenic syndrome and
myasthenia gravis. Ann N Y Acad Sci 1993;681:588–590.
26. Cherington M: Clinical spectrum of botulism. Muscle
Nerve 1998;21:701–710.
Copyright 2000 by Turner White Communications Inc., Wayne, PA. All rights reserved.
12 Hospital Physician Board Review Manual