REVIEW ARTICLE
Myasthenia Gravis
Milind J. Kothari, DO
Myasthenia gravis (MG) is a chronic neuromuscular
disorder that can lead to various degrees of neurologic
dysfunction. Initial patient presentation may be a
diagnostic dilemma to the family physician unfa-
miliar with testing methods for and the treatment
and care of patients with MG. The author focuses
on the clinical features, electrodiagnostic testing, and
treatment of patients with MG.
M yasthenia gravis (MG) is an autoimmune dis-
order that affects the neuromuscular junction
(NMJ) 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 estab-
lished. The disorder is characterized by fluctuating, fati-
gable weakness of muscles under voluntary control.
Some patients may have symptoms only late in the day
or after physical exertion (eg, exercise). As this disorder
is highly treatable, prompt recognition is crucial. During
the past decade, significant progress has been made in
our understanding of the disease, leading to new treat-
ment modalities and a significant reduction in mor-
bidity and mortality. With prompt intervention, the
patients overall quality of life is also improved.
Physiology of Neuromuscular Transmission
The NMJ 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 syn-
thesis and storage of the neurotransmitter acetylcholine,
which is released in the discrete quanta. The quanta are
located in three separate stores: primary (immediately
available), secondary (mobilization store), and tertiary
From Pennsylvania State University College of Medicine in Hershey.
Address correspondence to Milind J. Kothari, DO, Professor of Neu-
rology, Pennsylvania State University College of Medicine, 500 Uni-
versity Drive, MC H037, Hershey, PA 17033-2360.
E-mail: mkothari@psu.edu
Kothari Review Article
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(reserve store). When a nerve action potential depolar-
izes the presynaptic terminal, voltage-dependent cal-
cium channels are activated, allowing an influx of calcium
that results in a release of acetylcholine from the presy-
naptic terminal. The acetylcholine diffuses across the
synaptic cleft and binds to acetylcholine receptors (AchR)
on the postsynaptic membrane, resulting in an end-plate
potential (EPP).
Under normal circumstances, the EPP always rises
above the threshold level, resulting in a muscle
fiberaction potential. The amplitude of the EPP above
the threshold value needed to generate a muscle
fiberaction potential is called the safety factor. For
patients who have a disorder of neuromuscular trans-
mission, this safety factor is reduced.
During repetitive nerve stimulation (RNS), all mea-
surements are made on the compound muscle
fiberaction potential, the sum of the individual muscle
fiberaction potentials generated in a muscle. For patients
with NMJ disorders, RNS will cause a depletion of quanta
and reduce the amplitude of the EPP. With a reduced
safety factor, the EPP of some muscle fibers will fall
below the threshold level and an action potential will
not be generated. This reduction of action potentials
accounts for the decremental response when performing
RNS studies in the neurophysiology laboratory.
Etiology
The pathophysiology of MG is now well understood. The
condition is caused by sensitized T-helper cells and an
immunoglobulin antibody G (IgG)directed attack on the
nicotinic acetylcholine receptor of the NMJ.1 A variety of
experimental studies1 support this hypothesis:

acetylcholine receptor antibodies are present in most
patients with MG;

acetylcholine receptor antibodies can be transferred
passively to animals producing experimental autoim-
mune MG;

removal of acetylcholine receptor antibodies leads to
recovery;
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Patients with mild diplopia may initially seek the

Table 1 help of an optometrist, requesting eyeglasses or a change
Neurologic Conditions Mimicking Myasthenia Gravis in lens prescription to correct the problem. Diplopia usu-
ally manifests when the patient has visual convergence
Condition Signs and Symptoms
or upward gaze.
Amyotrophic lateral sclerosis Asymmetric muscle Myasthenic weakness may mimic third, fourth, and
weakness and sixth cranial nerve palsies as well as an internuclear oph-
atrophy thalmoplegia. Unlike third nerve palsies, MG never
Botulism Generalized limb affects pupillary function.
weakness Difficulty chewing, speaking, or swallowing may
Guillain-Barr syndrome Ascending limb also be the cause for initial presentation, but the occur-
weakness rence of these symptoms is less frequent than the afore-
Inflammatory muscle disorders Proximal symmetric
mentioned ocular symptoms.4 Some patients may have
limb weakness severe fatigability and weakness during mastication,
being unable to keep the jaw closed after chewing. Myas-
Lambert-Eaton syndrome Proximal symmetric
limb weakness thenic speech is often nasal (from weakness of the soft
palate) and slurred (from weakness of the tongue, lips,
Multiple sclerosis Bilateral
internuclear
and face), though there is no difficulty with language
ophthalmoplegia fluency.
Patients also may complain of fatigue and fluctu-
Periodic paralysis Intermittent
generalized muscle ating weakness. The weakness worsens after exertion
weakness 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

animals immunized with an acetylcholine receptor than lower extremity weakness. Patients may complain
begin producing acetylcholine receptor antibodies, of difficulty when reaching with their arms, getting up
which can provoke an autoimmune disease (ie, exper- from a chair, or going up and down stairs. A key point
imental autoimmune MG) closely resembling the nat- to remember is that if a patient has generalized limb
urally occurring disease. weakness without ocular involvement, the diagnosis of
MG should be questioned. As the disorder is limited to
Epidemiology the NMJ, no abnormality of cognition, sensory function,
The prevalence of MG in the United States is roughly or autonomic function is present. Further, it is not
14.2 cases per 1 million people.2 Although MG may uncommon for a patient with MG to exhibit symptoms
appear at any age, it has a bimodal peak of age at onset. of depression.5
In women, the onset usually occurs between 20 and Examination of a patient with MG therefore is
40 years of age; among men, the onset is usually at 40 to directed at muscle strength and demonstrating pathologic
60 years of age. Familial occurrence of MG is rare, though fatigability. A few maneuvers that may be used are
first-degree relatives do have a higher incidence of other having the patient look up for several minutes (examining
autoimmune disease.3 for ptosis or extraocular weakness), counting aloud to 100
(listening for nasal or slurred speech), or by repetitively
Clinical Features testing the proximal muscles.6 The results for the
Although the initial symptoms of MG typically involve remainder of the neurologic examination are usually
the ocular muscles in approximately 60% of patients, normal.
virtually all patients will have ocular involvement within
2 years of disease onset.4 Differential Diagnosis
Ptosis, which is very common and may occur while Before diagnosing MG, it is necessary to exclude other
the patient is reading or during long periods of driving, conditions that may appear with somewhat similar fea-
may be unilateral or bilateral. Extraocular muscle weak- tures. Thyroid disease is a common disorder to rule out.
ness may also present asymmetrically. Also, patients with MG may have a coexistent autoim-

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Table 2
Medications That Induce or Exacerbate Myasthenia Gravis*

Anti-infective Agents Cardiovascular Agents Other Agents

Aminoglycosides Acebutolol hydrochloride Chloroquine

Ampicillin sodium Oxyprenolol hydrochloride Corticosteroids

Ciprofloxacin hydrochloride Practolol d-penicillamine

Erythromycin Procainamide hydrochloride Interferon
(INF-
)

Imipenem Propafenone hydrochloride Mydriatics

Kanamycin sulfate Propranolol hydrochloride Phenytoin sodium

Pyrantel Quinidine Trihexyphenidyl hydrochloride

Timolol maleate Trimethadione

Verapamil hydrochloride

*Adapted from Wittbrodt ET. Drugs and myasthenia gravis: An update [review]. Arch Intern Med. 1997;157:399-408.

mune disorder. Other forms of NMJ disorders, acquired
myopathies, and motor neuron disease should be
excluded. In a patient with ocular MG, mitochondrial
myopathy, thyroid ophthalmopathy, and other cranial
neuropathies should be considered. Table 1 summarizes
the conditions that should be excluded prior to diag-
nosis of MG.
In some patients, MG may be induced by certain
drugs, including some antiarrythmics, D-penicillamine,
and antimalarials.7 In addition, many classes of drugs can
lead to worsening of the symptoms present in patients
with MG (Table 2).
Diagnostic Testing
A quick bedside technique for diagnosing MG is the ice
test.8,9 For a patient with ptosis, a small cube of ice is
placed over the eyelid for about 2 minutes. Improve-
ment of the ptosis after this procedure suggests a dis-
order of neuromuscular transmission.
Laboratory Studies
Certain studies should be performed to exclude other
disorders that are in the differential diagnosis. Physi-
cians who suspect their patients have MG should order
the laboratory studies listed in Figure 1.
The most sensitive and specific test for MG is the
presence of acetylcholine receptor antibodies (AchR-Ab).
Not all patients who have MG have positive AchR-Ab
titers, however. False-positive results do occur but are
rare.10 Whereas 45% to 65% of patients with ocular MG
have positive antibodies, approximately 90% of patients
with generalized MG have positive antibodies.11,12 An
important point when reviewing results with patients is
to note that the degree of positivity for the test results
does not correlate with the severity of disease.13,14
Three laboratory studies are commercially avail-
able and may be used when testing for the presence of
AchR-Ab (ie, binding, modulating, and blocking). The
binding antibody is the most common initial screening
study. Patients with very mild disease, or those in the
early stages, may be seronegative. Acetylcholine
receptormodulating antibodies are detected using cul-
tured human cells. This laboratory study should be done
for patients who test negative for the binding antibodies.
The assay for the blocking antibody, which uses
bungarotoxin, is rarely administered. Tests for stria-
tional muscle antibodies may be useful in late-onset
MG to exclude the possibility of a thymoma.3
A more recently available commercial test is the
muscle-specific receptor tyrosine kinase (MuSK).15 This
assay is most useful when testing patients who have
MG but are AchR-Ab negative.
Radiographic Studies
Approximately 20% of patients with MG have a thy-
moma present, whereas about 70% have thymic hyper-
plasia.16 To exclude this abnormality, all patients with
MG should have a computed tomography (CT) scan of

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Electrodiagnostic Studies
The electrophysiologic evaluation of MG involves routine
 Antibody tests:
nerve-conduction testing, repetitive nerve stimulation,

Acetylcholine-receptor antibody (AchR-Ab) titer
exercise testing, and, in certain instances, single-fiber
electromyelogram (EMG). As a general rule, test results

Antistriated muscle antibodies
are normal for patients with MG when routine nerve-con-

Antinuclear antibody (ANA) duction studies are done. If the results of the nerve-con-
 Complete blood count (CBC) duction studies are abnormal, physicians should question
the diagnosis of MG. Then, RNS is done; the results
 Erythrocyte sedimentation rate (ESR)
should demonstrate a greater than 10% decrement to be
 Liver and renal profiles considered positive (Figure 2). The yield of the test
 Rheumatoid factor (RF) increases if proximal nerves are stimulated (eg, spinal
accessory, facial), limb temperature is increased,17 or the
 Electrolyte panel
test is conducted following exercise of the appropriate
 Thyroid function studies: muscle(s). Exercise testing should be done with all RNS

Thyroid-stimulating hormone (TSH) studies because the decrement is often enhanced fol-

Triiodothyronine (T3)
lowing exercise (Figure 2).
Single-fiber EMG is used to measure the relative

Thyroxine (T4) firing of adjacent muscle fibers from the same motor
unit. The variation in firing between these fibers is called
jitter. For patients with MG, increased jitter is seen.
Figure 1. Laboratory studies that should be ordered by physi- Although single-fiber EMG is the most sensitive test for
cians prior to diagnosing patients with myasthenia gravis. demonstrating neuromuscular transmission (95%), it is
not specific; the results may be abnormal in a variety of

the chest done with contrast. Routine chest radiography

may be done but should not be done in place of the CT Table 3
scan of the chest. Medications Commonly Used to Treat
Myasthenia Gravis
Pharmacologic Studies
Medication Starting Dosage
Edrophonium chloride (Tensilon) is a short-acting acetyl-
choline esterase inhibitor. During this test, the patient Azathioprine 50 mg test dose; increase
should be hooked up to a cardiac monitor. Also, atropine up to 3 times daily
must be available at the bedside in the event of brady-
Cyclophosphamide 25 mg daily; increase as
cardia. A total of 10 mg of edrophonium may be used. needed
A small test dose (2 mg) is injected intravenously and if,
after 1 minute, there is no improvement in strength, the Cyclosporine 25 mg twice daily;
increase as needed
remainder of the dose should be given slowly. The
effects of the edrophonium usually last fewer than Mycophenolate mofetil 250 mg twice daily;
10 minutes. increase as needed
For the test results to be considered positive, there Prednisone 5 mg daily; increase dose
must be an unequivocal improvement of strength (eg, by 5 mg every 5 days until
ptosis that improves). The patient may have cholinergic a dose of 40 mg to 60 mg
daily is reached
side effects such as increased salivation, eye tearing,
muscle fasciculations, or abdominal cramps. If patients Pyridostigmine bromide 30 mg to 60 mg every
report a subjective improvement of overall strength or a 4 hours during waking
hours or 180 mg at
reduction in fatigue, the test results should not be con- bedtime
sidered positive. Such premature diagnoses frequently
lead to unnecessary neuromuscular consultations.

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neuropathic or myopathic disorders.4,18,19 An important
point is that the electrophysiologic studies should always
be interpreted in the context of the clinical setting.4
Treatment
There is no distinct protocol for the treatment of patients
who have MG. Physicians need to decide when aggres-
sive management must be undertaken. In general, the rate
of disease progression and distribution of weakness as
well as severity are the most important considerations
when developing a treatment plan. Other factors that
may influence long-term treatment would be age, sex,
and the presence (or absence) of other systemic illness.
The goal of therapy is to achieve remission, which is
to have the patient symptom-free and not taking main-
tenance medication. In general, most patients do become
symptom-free, but they need to stay on a low-dose
immunosuppressive medication. Table 3 summarizes the
oral preparations used in treating patients with MG.
Acetylcholinesterase Inhibitors
This class of medication remains the first line of therapy
in symptomatic patients. The most common agent used
is pyridostigmine bromide. Acetylcholinesterase
inhibitors effectively increase the amount of neuro-
transmitter (ie, acetylcholine) available at the NMJ. The
optimal dose of pyridostigmine varies from patient to
patient. In general, a patient is started on 30 mg (half
tablet) every 4 to 6 hours while awake and the dosage is
titrated depending on clinical symptoms and patient tol-
erability.
Pyridostigmine has a short half-life of approximately
3 to 6 hours. The possible adverse effects are those of
cholinergic excess: abdominal cramping, increased sali-
vation, and diarrhea. If patients receive too much of this
medication, increased weakness may develop (ie, cholin-
ergic crisis).
When the patient has problems during sleep or
awakens with weakness or ptosis, a long-acting form of
pyridostigmine bromide (Mestinon Timespan tablets) is
usually prescribed at 180 mg daily. This long-acting form
is not recommended for use throughout the day, however.
Neostigmine has a shorter but more pronounced effect.
It can be administered orally, parenterally, or even
intranasally.20
Immunosuppressive Therapy
As MG is an autoimmune condition, the mainstay of
treatment involves attacking the immune system. The
more common immunosuppressive agents are listed in
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REVIEW ARTICLE
2 mV
A 2 msec
15%
B
2%
C
27%
D
30%
E
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 decrement is noted at the right of the trac-
ings. (A) Baseline reading; (B) Immediately after 10 seconds
of exertion (postexercise facilitation); (C) 1 minute after 60 sec-
onds of exertion (postexercise exhaustion); (D) 2 minutes after
60 seconds of exertion (postexercise exhaustion); (E) 3 min-
utes after 60 seconds of exertion (postexercise exhaustion);
(F) Immediately after 10 seconds of exertion again (postexer-
cise facilitation and repair of the decrement). (Reprinted from
Electromyography and Neuromuscular Disorders: Clinical-Elec-
trophysiologic Correlations. Preston DC, Shapiro BE. Neuro-
muscular junction disorders, p 507, Copyright 1997, with per-
mission from Elsevier.)
Table 3. When using any of these agents, careful moni-
toring of the complete blood cell count (CBC), electrolyte
panel, and the liver and renal profiles is essential. The
doses may need to be adjusted according to the patients
white blood cell count.
 Steroid TherapyAs a general rule, most patients
with MG require steroid therapy at some point during
treatment. Steroids may potentially reduce the AchR-
Ab titer in patients with MG.21
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The typical dosage of prednisone is 1 mg per kilo-
gram of body weight daily, administered as a single oral
dose. It is important to start patients on a low dose of
prednisone and gradually titrate the dose up. Patients
may have transient worsening of MG symptoms during
the first 2 to 3 weeks of prednisone therapy. Patients
should be warned of these potential adverse effects at
the initial stages of therapy and reassured that they will
have benefits in 6 to 8 weeks after therapy is initiated.
The drug is usually started at 5 mg daily and may be
increased by 5 mg every 4 to 7 days until a clinical ben-
efit is achieved or 1 mg per kilogram of body weight is
reached. Once a therapeutic dose is achieved, the patient
should remain on this dose for about 2 months. Then a
regimen to switch to alternate-day therapy should be
instituted. Once the patients condition is stabilized, the
dosage may be slowly tapered downward. In general, the
dose should be tapered downward by 5 mg every month.
It is not uncommon for patients to relapse after the
steroids have been tapered offanother hazard they
should be alerted to in advance of a change in dosage.
Most patients who have MG generally require long-term
low-dose prednisone therapy to maintain remission of
symptoms.
Patients should also be informed in advance of other
adverse effects not relating to their current symptoms of
MG: acne, bruising (occur easily and difficulty in healing),
cataracts, imbalances on electrolyte panel test results, hir-
sutism, hyperglycemia, hypertension, necrosis of the
femoral head, obesity, osteoporosis, and steroid-induced
myopathy. Patients with type 2 diabetes mellitus who
are taking oral agents to control symptoms of MG may
require insulin therapy to treat diabetes symptoms during
this period. Appropriate precautionary measures should
be followed to avoid any of the aforementioned adverse
effects.
 AzathioprineThe most commonly used drug to
treat patients with MG is now azathioprine.3 It allows
tapering of steroid dosage and reduces some of the
adverse effects of steroid therapy. Commonly, the
patient will not have clinical benefit from azathioprine
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 mg to 3 mg per kilogram
of body weight daily in two or three divided doses.
The most common adverse effects are neutropenia
and liver function abnormalities. Thus, results from reg-
ular CBC counts and liver profile tests should be rou-
tinely followed for patients receiving azathioprine therapy.
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Rarely, an acute hypersensitive reaction develops
when initiating this treatment modality. Therefore, a
test dose is commonly used during the first week of
treatment. Although the long-term effects of azathio-
prine are not well known, some concern has been raised
about an increased risk of malignancy.22
 CyclosporineA powerful immunosuppressant that
inhibits T-cell activation is cyclosporine. This agent is
usually prescribed for patients who have failed to
respond to combination therapy with prednisone
and azathioprine and those who cannot tolerate aza-
thioprine.
The standard starting dose for cyclosporine is 25 mg
twice daily and titrated up to a maximum of approxi-
mately 3 mg to 6 mg per kilogram of body weight. How-
ever, immunosuppressive therapy should always be
tailored to the individual patient; combination therapy
is often more efficacious (ie, allowing for reduced dosage
and fewer adverse effects) than monotherapy.23
While patients are receiving this treatment, their
blood levels (troughs) of cyclosporine should be checked
periodically. The most important adverse effects are
nephrotoxicity and hypertension.
 CyclophosphamideIn general, cyclophosphamide
is used only when other agents have failed or are
not well tolerated by the patient. Cyclophosphamide
therapy may be started at 25 mg daily and gradually
increased up to a maximum of approximately 2 mg to
5 mg per kilogram of body weight daily.
An increased incidence of hemorrhagic cystitis
accompanies the use of this medication in some patients.
 Mycophenolate MofetilA novel immunosup-
pressive agent for treatment of MG that has already
been shown to be of benefit in transplantation
medicine is mycophenolate mofetil. Recent open-
label trials in patients with MG have shown this med-
ication to provide significant benefit.24-27
The standard daily dosage for this medication is
1 g to 2 g. Patients may be started at 250 mg of mycophe-
nolate mofetil twice daily, and the dosage can be titrated
upward as needed. When starting this agent, the
patients CBC count should be checked every week for
the first month of treatment, every 2 weeks for the next
6 to 8 weeks, and monthly thereafter.
Currently, this agent is considered a useful alterna-
tive treatment modality for patients who have severe
MG. This medication should also be considered for use
in treatment when standard immunosuppressive agents
fail.
Kothari Review Article

Plasmapheresis
Plasma exchange, or plasmapheresis, is an effective
means of therapy but is transient in its response. This
technique is particularly useful when treating patients in
myasthenic crises or those in preparation for surgery.
The goal of this therapeutic intervention is to remove
the circulating immune complexes and AchR-Ab.
Patients usually undergo a 2-week course of 5 to
6 exchanges.
Risks involved in this treatment include fluid imbal-
ance and hypercoagulation. However, a more common
problem for patients is the difficulties that may arise as
a result of physicians using vascular access procedures
to do this therapeutic procedure.28
Intravenous Immunoglobulin Therapy
The administration of intravenous immunoglobulin
(IVIG) serves as an alternate mode of therapy to plasma-
pheresis. This procedure is especially helpful when vas-
cular access is a problem.
The exact mechanism of action of IVIG therapy on
MG is not well understood, though several options have
been suggested.29 Intravenous immunoglobulin is given
as a dose of 2 g per kilogram of body weight over 2 to
5 days.
Intravenous immunoglobulin therapy is a relatively
safe treatment method and has few adverse effects,
though headache, chills, and fever have been reported in
some patients. 4 Usually, premedication with
acetaminophen and diphenhydramine alleviates these
symptoms. Other rare adverse events include aseptic
meningitis and renal failure.4
Surgical Intervention
There is general agreement that a thymectomy should be
done in patients with MG only if those patients are med-
ically stable and aged 60 years or younger. If a patient has
a thymoma, it should clearly be removed.4
There has been some controversy recently as to which
surgical approach is better. In general, a median ster-
notomy is preferred and allows for maximal exposure to
ensure that all thymic tissue is removed at the time of
surgery.30
Clinical improvement is typically delayed by
6 months to 1 year after surgery.
Myasthenic Crisis
Rarely, the initial presentation of a patient with MG may
occur when that patient is in myasthenic crisis. Alterna-
tively, a patient with known MG may reach a crisis.
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A myasthenic crisis is defined as the sudden wors-
ening of respiratory function and/or profound muscle
weakness. Recognition and treatment of myasthenic
crisis is a neurologic emergency. With early recognition,
effective therapy, and modern intensive care units, mor-
tality from such crises is now a rare occurrence.
Crisis can occur as a result of a variety of causes,
including concurrent infection or the addition of new
medications that are known to exacerbate MG or worsen
its symptoms (see Table 2).
Frequently, in response to worsening weakness,
patients decide to take progressively more acetyl-
cholinesterase inhibitors without consulting their physi-
cians, not realizing that excessive acetylcholinesterase
treatment can by itself lead to increased muscle weakness
(ie, cholinergic crisis). If this condition is not recognized
early, the patient usually has respiratory collapse or aspi-
rates from increasing bulbar weakness.
Patients with myasthenic or cholinergic crisis must
be treated aggressively. However, it is frequently difficult
to distinguish cholinergic crisis from myasthenic crisis.
Some have suggested administering the edropho-
nium test to distinguish between the two types of crisis.
In other words, if there is a worsening of symptoms after
the edrophonium test is done, the diagnosis should be
cholinergic crisis; if there is improvement, myasthenic
crisis. However, it is difficult to administer this test to
patients in acute distress. As a general rule, immediately
treat the patient for the more severe of the two conditions,
myasthenic crisis.
Comment
The purpose of this article was to provide a better under-
standing of MG for family physicians. This understanding
should lead to better physician interactions with the con-
sulting neurologist. Family physicians should play an
active role in the diagnosis and management of patients
with MG.
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