Although the cause of myasthenia gravis is still unknown, its patho-

genesis appears clear: immunologic attack on synaptic receptors in

muscle causes receptor deficiency, decreased miniature endplate poten-
tials, and decrements in the compound action potentials evoked from
muscles on repetitive stimulation of peripheral nerves. In addition to the
involvement of skeletal muscle, some MG patients may manifest subtle
alterations of the function of heart, lung, smooth muscle, and CNS,
indicating that this is truly a systemic disorder. Modern therapy involves
adjusting treatment to the needs of individual patients. Anticholinester-
ases, calcium, ephedrine, potassium, and germine partially correct the
defect in neuromuscular transmission; prednisone, ACTH. cytotoxic
drugs, antilymphocyte serums, gamma globulin, thoracic duct drainage,
plasmapheresis, and thymectomy partially modify the abnormalities of the
immune system.
MUSCLE a NERVE 1:190-205 1978
DlAGNOSlS AND MANAGEMENT
BERNARD M. PATTEN, MD, FACP
I n the last five years, significant research advances have
taken place which have promoted our understanding
of myasthenia gravis (MG). As a consequence, MG has
been identified not only as a disorder of skeletal muscle
but also as one of the foremost examples of autoim-
mune disease in man. In addition, subtle alterations of
heart, lung, smooth muscle, and central nervous system
have been described that indicate that MG is truly a
systemic disorder. Our new understanding of methods
to modify this condition has permitted, in most cases, a
dramatic improvement in the prognosis of MG and has
given us a number of effective tools for management.
This article presents the current concepts of MG in
a review of the clinical characteristics and the current
methods of diagnosis and management of this disease.
CLINICAL FEATURES
The single most important clinical feature of MG is
weakness of skeletal muscle worsened by exercise and
relieved by rest. Without this feature there can be no
diagnosis. This weakness with easy fatigability is the
-
Fromthe Department of Neurology, Baylor College of Medicine. Houston.
TX
Acknowledgments Dr Yadollah Harati read, criticized. and corrected the
manuscript Terry Tomkins organized the tables and typed the drafts This
work was supported by a grant from the South Texas Chapter of the
Myasthenia Gravis Foundation. a grant Irom the Muscular Dystrophy
Associations of America, Inc , a gift from Rosalie and J oe Eisenberg of San
Antonio, TX, and a gift from Dorothy and Leon Williams of Brownwood, TX
Address reprint requests to Dr Patten at the Department of Neurology,
Baylor College of Medicine, Houston. TX 77030
Received for publication March 3, 1978
only constant in the disease-and all other features are
variable. For instance, the weakness is usually worse in
the afternoon and evening, though some patients are
weaker in the mornings when they first awake. Usually
the muscles supplied by the cranial nerves are the first
and the most severely affected, with resultant diplopia,
ophthalmoplegia, dysphagia, dysphonia, dyspnea, and
dysmimia. Then the disease may involve proximal
lower- and upper-extremity muscles. I n rare instances,
however, proximal muscles weaken first. The involve-
ment of individual muscles may be symmetric but
often is asymmetric, with the dominant leg and arm
usually weaker than their nondominant counterparts.
MG can also present as weakness in a single muscle, for
example, the external rectus or superior oblique in one
eye; .or as a single complaint, for example, jaw ptosis
from inability to close the mouth. Rarely, it presents as
a symptom seemingly unrelated to the neuromuscular
system, for example, burning eyes from exposure ker-
atitis (from incomplete eye closure during sleep) or sore
throat on waking (from mouth-breathing during
sleep).
The disease may affect people at any age and of
either sex. It varies in severity from mild nonprogressive
disease involving eyes only (ocular form), to severe
cases that may be rapidly fatal, such as the acute
fulminant form usually afflicting older men.
PHYSICAL SIGNS
No two myasthenic patients look alike or have the same
signs or symptoms. The classic appearance of the
patient with moderately severe disease is unmistakablc
(fig. 1). However, the more subtle early presentations
190 Diagnosis and Management of MG MUSCLE & NERVE May/Jun 1978
Figure 1. Typical facial appearance of myasthenia. Note
that the corners of the mouth do not rise despite the
patient's best effort to smile. Left ptos~s IS almost
complete, and the forehead is wrinkled and the eyebrows
elevated to try to compensate for this.
are just as important and should not be missed (fig. 2).
Detailed examination of individual muscles often
shows excessive fatigue and weakness, which should
alert the physician to the presence of neuromuscular
disease.
In uncomplicated MG, aside from weakness and
fatigability of the involved muscles, there are few
physical signs. Trigrooved tongue, though common,
is not specific for MG since it can be found in
amyotrophic lateral sclerosis. However, the appearance
and disappearance of trigrooved tongue with treat-
ment is a way of distinguishing MG from other neu-
romuscular conditions associated with this sign. Deep
tendon reflexes are usually hyperactive, sometimes
with clonus. If a reflex is repeatedly elicited, the jerk
may decrease progressively until it disappears.
There is increasing interest in those clinical obser-
vations that suggest the disorder involves much more of
the body than just skeletal muscle dysfunction. Evi-
dence is slowly accumulating that points to involve-
Figure 2. This woman might look normal even to the
experienced physician. Note, however, the failure of the
corners of the mouth to rise when she smiles and the
slight droop of the left eyelid with the attempt to
compensate by elevation of the outside margin of the left
eyebrow. She complained of easy fatigability of six-
months duration. The only finding on examination,
besides the mild ptosis, was weakness of the deltoids. At
operation. the surgeon removed a hyperplastic thymus
within which was a golf-ball-sized rnvasive thymoma. This
patient illustrates the importance of thymectomy even in
those who have mild myasthenia.
ment of the central nervous system in this disorder. In
my experience, a small percentage of patients will have
transient signs usually considered indicative of CNS
dysfunction, such as Hoffrnann sign, cross adductor
reflexes, and unilateral or bilateral Babinski signs.
These usually disappear as the disease comes under
therapeutic control. The presence of abnormal reflexes
in myasthenia gmvis should not cause undue concern.
Angiograms and myelograms are not needed to evalu-
ate these findings. We already know that MG is
associated with normal contrast studies. Of course,
persistent signs of central nervous dysfunction, es-
pecially when associated with cerebellar signs or optic
neuritis, should point to the possibiIity that the patient
Diagnosis and Management of MG MUSCLE & NERVE May/J un 1978 191
has the overlap syndrome-in which clinical and labo-
ratory features of myasthenia gravis and multiple
sclerosis coexist in the same patient at the same time.77
I have been impressed that some patients with
myasthenia complain of decreased intellectual ability,
emotional lability, and insomnia, all of which improve
with treatment. Abnormal sleep with decreased rapid
eye movement time has been reported recently. 75 MG
patients have a higher than normal frequency of
seizures.
Transitory trigeminal anesthesia,? anosmia,j
ageusia,% as well as muscle stiffness are found in
myasthenia.gO These findings suggest another group of
abnormalities (little understood and as yet not investi-
gated) which involve central cholinergic transmission.
The presence in human MG5? and in experimental
autoimmune MG in rabbits?* of cholinergic receptor
antibodies, which are produced locally in the central
nervous system and circulate in the cerebrospinal fluid,
may help to explain the observations that suggest a
concomitant disorder in the central nervous system.
EVIDENCE FOR SYSTEMIC INWLVEMENT
Myocardial abnormalities exist in myasthenia. In one
recent series, over 40% of myasthenic patients had
prolonged Q-T intervals on electrocardiogram (ECG)
and about 20% had sinus tachycardia or bundle-
branch block. l 2 Kinetocardiograms may show para-
doxical systolic outward movements indicative of myo-
cardial dyskinesis,6' and one autopsied patient had
myocardial necrosis. I
Smooth-muscle involvement has been documented
less commonly. Intestinocolonic measurements in 84
patients confirm gut involvement in MG; interestingly,
these smooth-muscle defects improve after thymec-
tomy. 9s
Direct pupillary responses to light and the deriva-
tive curves (velocity and acceleration) of pupillary
reactions can be recorded by infrared video pupillogra-
phy. Analysis of the pupillary responses showed a
reduction in amplitude, maximal velocity, and maxi-
mal acceleration of pupillary constriction in the my-
asthenic patients compared with normals.'"' On the
other hand, changes in pupillary dilation were mini-
mal. Abnormal values returned toward normal within
5 min after intravenous injection of 5 mg of edro-
phonium hydrochloride.lo1 These results suggest that
the iris sphincter is commonly involved in myasthenia.
Some myasthenia have cold hands and feet and
red shiny skin around the nail beds and over the elbows
and knees-changes reminiscent of those of der-
matomyositis but less severe. Lung abnormalities are
also present in some. Severe bronchial asthma was
present in 4% of my own patients. Other patients may
have alterations of length-tension characteristics of the
alveoli and episodic large (e.g., 2-liter) changes in
functional residual capacity.69 Alternate-day pred-
nisone may be associated with a small reduction in
respiratory function during the off day.68
There appears to be an increased risk of cancer,
especially in patients who have not had thymectomy.
In a recent series, 126 neoplasms were found among
1,556 myasthenic patients (8%).74 The period of highest
risk followed the onset of disease in those who had not
undergone thymectomy. Of all neoplasms, one-half
occurred within the first 5 years of disease-more than
two-thirds within the first 10 years. Colorectal cancer
was the most common primary finding in myasthenic
men. Breast cancer was the most common primary
neoplasm in myasthenic women, with 20% of the
breast cancers present bilaterally. Risk of cancer in-
creases with the severity of the myasthenia and de-
creases 2 years following thymectomy. A relationship
between decreased peripheral lymphocyte counts, in-
creased severity of myasthenia, and increased inci-
dence of neoplasm was also observed in this series.74
IgA levels are low in some myasthenic patients who
have not had thymectomy, but may rise after the
procedure. Since IgA deficiency has been shown to be
correlated with predisposition to cancer,8 thymectomy-
induced increases in IgA levels may be one mechanism
accounting for cancer risk decreases after
These subtle abnormalities of central nervous sys-
tem, heart, smooth muscle, and lung, as well as this
significant increase in the incidence of malignant
neoplasms, suggests that myasthenia is a more complex
disorder than one that simply involves skeletal muscle.
CLINICAL CLASSIFICATION
Table 1 lists the modified Osserman classification of
MG currently in use worldwide by myasthenia special-
ists. Table 2 lists another classification of MG. Each
type in the table-2 list can be modified by describing
the severity (mild, moderate, severe), the time course
(acute, subacute, chronic), and any associated disease
that might have a significant effect on the prognosis.
Thus, a 22-year-old woman with generalized my-
asthenia of two-years duration would be classified as
subacute, moderate adult type I MG. A 65-year-old
man with sudden onset and rapid progression of MG to
respiratory impairment would be classified as having
acute, severe adult type I1 MG. This classification
(table 2), though more complex, is more exact and has
important clinical implications. For instance, the
young woman described above would be likely to have
HL-A8 tissue antigen and a hyperplastic thymus, and
would probably respond well to thymectomy and
anticholinesterase therapy. The middle-aged man
192 Diagnosis and Management of MG MUSCLE & NERVE May/J un 1978
would be likely not to have HL-A8, but he might have
HL-A2, and he has a high chance (approximately 60%)
of having a thymoma. In his case, response to anti-
cholinesterases would probably be disappointing, but
prednisone treatment might result in dramatic im-
provement.
EVIDENCE FOR IMMUNE SYSTEM DYSFUNCTION
This material was reviewed in this journal in a recent
two-part article by Si mp~on. ~ . ~~
LABORATORY CONFIRMATIOM OF CLINICAL MG
El oct mphyr i ol ~y. The clinical diagnosis of MG is
often confirmed by observing the electrical responses of
a muscle to repetitive supramaximal stimulation of its
motor nerve.72 At a frequency of 3 Hz,1R*19,71,7b the
voltages of motor action potentials are fairly consistent
in normal adults. The fifth response may be slightly
smaller than the first, at 3-Hz stimulation, but the
decrement is less than 8%. Although the muscle voltage
response to a single-nerve stimulus is usually normal in a
myasthenic person, even in severely affected muscle,
the response to repetitive nerve stimulation at low rates
(two to five per second) usually is distinctly abnormal
(greater than 8% decrement). There is a progressive
decrease in voltage beginning with the second re-
sponse, almost always reaching a minimal level at the
fifth response, after which voltages may increase
slightly (fig. 3). The short-term decrement at two to
three stimuli per second is thought to be related to the
kinetics of acetylcholine release from the motor-nerve
ending,l but that type of EMG abnormality is not
exclusive to MG. It also occurs in partially curarized
normal muscle and has been identified in a few
patients with amyotrophic lateral sclerosis.6z This dec-
rement simply indicates that the neuromuscular safety
margin has been reduced by one of several possible
rnechani ~ms.~~ In some MG patients, low rates of
stimulation (2-5 Hz) may cause an early abnormal
increment or facilitation (40% or more), with or
without preceding initial decrements, as is typical of
and greater in patients with the facilitating myasthenic
syndrome described by Lambert and Eat~n. ~
The characteristic feature of the myasthenic state,
postactivation exhaustion, is not found in partially cura-
rized normal muscle. It is disclosed by eliciting a brief
intense activity of the neuromuscular apparatus either
by nerve faradization, 30-100 Hz for 2-10 sec, or by
maximum voluntary contraction for 15 sec. Immedi-
ately thereafter, a 3-Hz nerve stimulation (given
intermittently as bursts of three stimuli every 30 sec)
shows a transient facilitation of neuromuscular trans-
mission that is followed by a neuromuscular block that
increases to maximum 2 to 4 min after exercise and
recovers slowly and more or less completely. In mildly
Or in patients presenting a diagnostic
problem, the decrement with 3-Hz nerve stimulation
Table 1. Clinical classification of myasthenia gravis a
GROUP /-Ocular Myasthenia
Involvement of ucular muscles only, with ptosis and diplopia
Very mild, no mortality
A Mild Generalized
GROUP //-Generalized Myasthenia
Slow onset, frequently ocular, gradually spreading to skele
tal and bulbar muscles Respiratory system not involved
Response to drug therapy good Low mortality rate
~~
0. Moderate Generalized
Gradual onset with frequent ocular presentation, progress-
ing to more severe generalized involvement of the skeletal
and bulbar muscles. Dysarthria, dysphagia, and poor mas-
tication more prevalent than in mild generalized MG. Respi-
ratory muscles not involved. Response to drug therapy less
satisfactory and the patients activities restricted, but mor-
tality rate low.
C. Severe Generalized
Acute Fulminating: Rapid onset of severe bulbar and
skeletal muscle weakness with early involvement of
respiratory muscles. Progression of disease usually
complete within six months. Percentage of thymomas
highest in this group. Response to drug therapy less
satisfactory and the patients activities restricted, but
mortality rate low.
Late Severe: Severe myasthenia gravis develops at least
two years after onset of Group I or Group I1symptoms.
Progression of MG may be either gradual or sudden.
Second highest percentage of thymomas. Response to
drug therapy and prognosis poor.
aModffied from Osserman KE Myasthenia Gram New Yor k, Grune 8
Stratton, I958
may be slight or absent in the rested muscle, but the
postactivation exhaustion phenomenon can be seen
clearly.
A test has been devised by Desmedt and Borenstein
to permit a more sensitive delineation of subclinical
myasthenic involvement. I9 It combines forearm ische-
mia (cuff around the upper arm) with stimulation of
the ulnar nerve below the cuff at 3 Hz continuously
for 4 min. A myasthenic patient may develop distinct
decrement during 4 min, with the circulation still
occluded, whereas normal subjects maintain ampli-
tude. This phenomenon, occasionally helpful in in-
creasing the percentage of positive diagnoses,72 is
characteristic of MG but is not found in all muscles nor
in all myasthenic patients. For practical purposes, the
ischemic test can be used in the ulnar-supplied muscles
of women patients with the criterion that decrements
exceeding 10% are diagnostic of myasthenia. In men,
decrements of as much as 23% in the ulnar muscles of
normal subjects occasionally appear. Thus, decrements
Diagnosis and Management of MG MUSCLE & NERVE May/J un 1978 193
~
Table 2. Myasthenic syndromes.
Type of MG Characteristics Type of MG Characteristics
NEONATAL
Present in about 12% of children born FAMILIAL II
OCULAR
ADULT I
ADULT I1
to myasthenic mothers. Starts within
72 hr of birth; may last 3 to 47 days
(average 18 days), then disappears.65
Responds to anticholinesterasez7 and
exchange transfusion.22 Anti-AChRAb
present. 64
Only involves eyes; antibody (anti-
AChRAb) against the acetylcholine re-
ceptor, if present, is usually low
titer.2.54 Ocular MG may respond to
prednisoneao and/or anticholines-
terase and in rare instances may be
associated with thymoma.70
Usually women under 40 but may start
at any age, including childhood. Thy-
mic hyperplasia and HL-A8 often pres-
ent.70 Anti-AChRAb present. Re-
sponds to thymectomy. anticholines-
terases, and prednisone. Incidence of
thymoma lower than in adult type II.
Usually men over 40. HLA-A2 often
present.70 Anti-AChRAb present. Ae-
sponds better than type 1 to steroid27
and worse than type I to thymectomy
and anticholinesterases. Incidence of
thymoma higher than in adult type 1.70
Starts at birth but does not disappear
as the neonatal does. May be familial.
No anti-AChRAb present. No re-
sponse to thymectomy but does re-
spond to anticholinesterases. Poor
response to prednisone.
Identical to adult I or I1except family
history is positive.
TRUE CONGENITAL
FAMILIAL I
in men should exceed 25% to be indicative of a
pathologic synaptic function.21
Temperature is important in neuromuscular trans-
mission. It is now clear that cooling a myasthenic
muscle by only a few degrees considerably reduces the
amount of decrement and neuromuscular block. Con-
versely, warming a cool myasthenic muscle to body
temperature (37" C ) increases the decrement. I n any
patient undergoing EMG testing, i t is unsafe to assume
that the temperature is within normal range, since
distal muscles often have temperatures as low as 29'-
30' C. This effect of temperature is illustrated in figure
4 A and B, in which the electrical and mechanical
responses of the adductor pollicis muscle of a moder-
ately severe generalized myasthenia are recorded at 35"
C and 28" C, respectively. The decrement is consider-
able at 35" C and the force output is below normal. At
28' C the same muscle demonstrates much less decre-
ment in the electrical responses and the force output is
DRUG-INDUCED
DRUG-AGGRAVATED
EATON-LAMBERT
ENGEL'S DISEASE
Positive family history. Any age, either
sex, mild, no progression, some re-
sponse to anticholinesterase. No re-
sponse to thymectomy or prednisone.
Anti-AChRAb absent.
Type caused by drug working through
an antibody-mediated reaction, e.g ,
Mysoline, penicillamine. 17.56.57
Any type where neuromuscular trans-
mission is compromised by drugs,
e.g., curare, quinine, quinidine,
Mg ++, procainamide, Inderal. ami-
noglycoside antibiotics, lithium, strep-
tomycin, colistin, linocin, tetracycline.
Often adults; often, but not neces-
sarily, associated with cancer. Re-
flexes tend to be absent and bulbar
muscles tend to be spared. Anti-
AChRAb absent. May respond to
guanidine or anticholinesterases.
First described by Andrew Engel and
colleagues. The hallmarks of this new
syndrome are repetitive muscle action
potentials from a single nerve stimulus,
decreased quanta1 content of the end-
plate due to a decreased store of
quanta, very small nerve terminals,
small amounts of postsynaptic acetyl-
choline receptor and absence of end-
plate acetylcholinesterase. Clinically,
the patient looks like a mild non-
progressive congenital myasthenic ex-
cept there is no response to anticholi-
nesterases.25 Anti-AChRAb absent.
more than four times larger, though still not normal.
Therefore, even in routine testing for myasthenia, the
electromyographic examination should be conducted
in a warm room, the patient should be kept covered as
much as possible, and distal muscles should be warmed
to body tern perat u re. 2n
These routine tests for the diagnosis of MG are
based on thc characteristic neuromuscular blocking
that occurs in this disease. Another technique that also
measures neurornuscular blocking in a more sensitive
way is single fiber electromyography (SFEMG). With
this method, recordings can be made either with
voluntary activation or with electrical stimulation." In
voluntary activation, an electrode is positioned in the
muscle to record activity from two individual muscle
fibers belonging to the same motor unit. The temporal
variability in the recorded muscle action potential
from the two fibers, termedjilter, is primarily caused by
a variation in the neuromuscular transmission time in
194 Diagnosis and Management of MG MUSCLE & NERVE May/J un 1978
Figure 3. Electromyographic tracings in myasthenia
gravis. The median nerve was stimulated via surface
electrodes placed at the wrist, and the electrically
evoked muscle action potential was recorded from the
thenar muscles. Note that at the stimulus rate of 2
impulses per second the amplitudes of the action
potentials decline, reaching a nadir at the fiffh
potential, and then tend to rise. This finding is
diagnostic for myasthenia gravis. Note also that at the
stimulus rate of 20 impulses per second there is no
decrement and only a steady increase in the
amplitude of the evoked muscle action potential, a
finding seen in mild myasthenia or in some muscles in
some myasthenic patients as they improve with
treatment. It had previously been considered that a
neurosis was the cause of the patients weakness and
easy fatigability.
Figure 4. SFEMG jitter recordings from the extensor digitorum communis muscle of a patient with
myasthenia gravis. The oscilloscope sweep is triggered by the first action potential, and the interval
variability between the single-fiber action potentials (the neuromuscular jitter) fs seen as a variable position
of the second potential. In the upper row, 70 action potentials are superimposed. In the lower row, the
oscilloscope sweep is moved downwards. In (A) normal jitter, in (I) increased jitter but no impulse
blockings, and in (C) increased jitter and occasional blockings. (Reprinted with permission from Sti l berg ,
Trontelj JL( Schwartz MS: Single muscle fiber recordings of the jitter phenomenon in patients with
myasthenia gravis and in members of their families. Ann NY Acad Sci 274:789-202. 7976.)
Diagnosis and Management of MG MUSCLE & NERVE May/Jun 1978 195
A 3- Dv44-l I
figure 5. Effect of local cooling on the myasthenic
neuromuscular failure. Woman, age 20 years. with severe
generalized myasthenia gravis. In both A and 3. upper
trace is the isometric myogram and lower trace is the
belly tendon electric response of the adductor pollicis
muscle during stimulation of the ulnar nerve at lO/sec.
Note better performance at the intramuscular
temperature of 28 C compared to 35 C. (Reprinted with
permission from Borenstein S. Desmedt JE: Temperature
and weather correlates of myasthenic fatigue. Lancet
2:63-66. 1974.)
the two motor endplates involved. When neuromuscu-
lar transmission is disturbed, jitter increases and, with
more severe defects in transmission impulse, blocking
occurs (fig. 5). Increased jitter and impulse blockings
are found in myasthenia and are correctable with
anticholinesterase medication. The value of this pro-
cedure for the routine diagnosis of MG has not been
proved. The machine required for such testing is more
expensive than the routine electromyograph and, as
yet, SFEMG is only available in a few centers. In-
creased jitter is common in amyotrophic lateral scle-
rosis and other neuromuscular diseases, so that the
specificity of the findings needs to be further defined.
Despite these difficulties, SFEMG will probably play
an increasingly useful role in neuromuscular research
and in the evaluation of routine cases as more elec-
tmmyographers learn to use this technique. Mean-
while, the most commonly used laboratory test
involving activation of muscle by repetitive supramaxi-
ma1 stimulation of its motor nerve will remain the test
of choice for confirming the clinical diagnosis of my-
asthenia.
Ozdemir and Young, using electromyographic test-
ing in 80 patients with unquestionable myasthenia, 40
patients with other neuromuscular diseases, and 40
normal subjects, have discovered some general princi-
ples that govern diagnostic yield in repetitive-stimula-
tion studies of neuromuscular transmi~sion.~ They
found a positive test (greater than 8% decrement) in at
least one muscle in 76 (95%) of the MG patients. Two
patients who had no decrement had pure ocular
myasthenia; the other two with negative tests had
clearcut moderate generalized myasthenia. When only
one muscle was tested, a positive diagnostic test was
obtained in 59% of the cases if the recording was made
from an intrinsic hand muscle; whereas, if only the
deltoid was tested, a positive result was obtained in
82% of the cases. The presence of decremental response
could not be predicted on the basis of clinical involve-
ment because many clinically normal muscles showed
decrements, and some muscles with severe clinical
involvement did not show abnormalities. The conclu-
sions reached by these researchers are that several
muscles (including the deltoid) should be tested in
individual patients, and the presence of a positive
finding in any one muscle does confirm the clinical
diagnosis. However, they also concluded that failure to
demonstrate decrements does not exclude the diag-
nosis, since even severely involved typical myasthenia
may have normal findings on electromyographic exam-
i nati ~n. ~
Phrrnucologlc Thsts. Tensilon test. Edrophonium chlo-
ride (Tensilon) as a test for diagnosis is given in an
initial intravenous (I V) dose of 2 mg, which is followed
by an additional 8 mg if there is no change within 60 sec.
Often the injection produces an unequivocal improve-
ment in muscle strength, but sometimes the test is not
clearly interpretable-it should always be preceded by
a saline control to identify placebo reactions. Because
edrophonium has muscarinic side effects, one can
premedicate with atropine or use a more sophisticated
placebo control, such as 50 mg of intravenous nicotinic
acid. Edrophonium is also sometimes used in those
patients who respond unsatisfactorily to anti-
cholinesterase medication, to assess the effect of a
proposed increase in medication. If after a 2-mg dose
IV the patient becomes weaker, then he is overdosed; if
he becomes stronger, he is underdosed. The danger of
this test is that a given patient at some point in time
may be underdosed with respect to one muscle group
and overdosed with respect to another. It would be a
grave error, for instance, to increase the dose of an
anticholinesterase in a patient whose arms became
stronger after edrophonium but whose respiratory
function, measured by vital capacity, declined. This
can happen easily if vital capacity is not routinely and
repeatedly measured in all patients with MG who have
changing medication needs or show a poor response to
treatment.
There is another danger in the use of the
edrophonium test. The time at which this test is
l B 6 Diagnosis and Management of MG MUSCLE & NERVE May/Jun 1978
performed in relation to the time of peak action of the
anticholinesterase the patient is already taking can
present serious problems. The peak anticholinesterase
time can be estimated from the stated usual action of
the drug, but that is not always applicable to all
myasthenic patients; for some, drug absorption might
be accelerated or delayed. Edrophonium given on
either side of the anticholinesterase peak might suggest
underdosage, but at the peak the patient could be
optimally dosed or even overdosed. Raising the base-
line anticholinesterase on the basis of this response
would result in overdosing.
A different kind of problem with the edrophonium
test is the rare syncopal reaction, in which the
patient suddenly collapses immediately after injec-
tion but recovers rapidly without treatment or residua.
Wealways have an AmbuB bag and a mouth airway
immediately available when performing the edro-
phonium test, but as yet we have not had to use these
for this reaction.
In general, we have found the edrophonium test of
little value in the day-to-day regulation of anti -
cholinesterase dosage. If the patient is so precariously
positioned in relation to his disease that he needs such
careful adjustment of anticholinesterase dosage, prob-
ably he is relatively refractory to that therapy so even
the most sophisticated adjustment of dose will be of
little avail. Under such conditions, a switch to another
therapy such as prednisone is needed (see below).
When it is necessary to adjust the anticholines-
terase dose, instead of edrophonium we use clinical
judgment in deciding whether the patient needs more
or less drug. Clues as to the patients real needs include
an increase in strength 20 min after the last dose and a
fall in performance just before the next dose is due. I n
this situation, it is likely that the patient needs more
drug. Having made the clinical decision regarding the
patients needs, we act accordingly and observe the
effect of the action over the following two to three days.
If the patient worsens, then werevise ourjudgment and
do the opposite ofwhat we did originally. If the patient
improves, we then decide to hold fast or continue on
course, depending on the functional status of the
patient.
Curare test. Myasthenic patients can be 10 to 100
times more sensitive than normal persons to the neu-
romuscular blocking action of curare and other drugs
such as gallamine, pancuronium, and ether, which
bind reversibly to the acetylcholine receptor (AChR).
The excessive sensitivity of patients with MG to curare
is the basis for the diagnostic use of curare in the two
types of curare tests: systemic and regional.
The systemic curare test is most often used in our
hospital to rule out myasthenia in a patient whose
clinical presentation is atypical and who has had no
decrements on the repetitive-stimulation studies. The
patient is told that he will receive several medicines via
intravenous infusion-some may worsen myasthenia,
some may improve it, and some may have no effect. An
intravenous infusion is then installed and kept open
with normal saline. Detailed measurements are made
of hand grips, ptosis, eye movements, head and leg
holding times against gravity, and vital capacity. If the
patient is clinically weak, it is also a good idea to follow
some task that the patient can barely accomplish and
some task that the patient just barely cannot accom-
plish, so that any changes that occur in these bor-
derline functions will be clearcut. The dose of curare is
one-tenth that of the curarizing dose; this amounts to
0.1 ml of the standard solution of d-tubocurarine
(3 mg/ml) per 40 lbs of body weight. This amount is
drawn into a tuberculin syringe, then placed into a
larger syringe with enough normal saline added to
make a total solution of 4 ml. Thus, each 0.5 ml of the
mixture will have 1 /80 ( 1 /10 X 1 /8) of the curarizing
dose. Then, three injections of 0.5 ml normal saline are
given every 2 min through the intravenous line, and the
clinical measurement of muscle strength repeated to
obtain baseline information. Then, 0.5 ml of the curare
solution is injected every 2 min and the measurements
are repeated each time. The injections of the curare
solution are stopped when the full 8/80 (1110) of the
curarizing dose has been given or when the patient has
shown unequivocal worsening. Usually sensitivity to
curare at doses up to 5/80 indicates the presence of
myasthenia. Sensitivity to curare at doses above 5/80
may be seen in some otherwise normal people and, of
course, failure to show sensitivity, although against the
diagnosis of MG, does not entirely exclude this disease.
In fact, negative tests have been known to occur in
purely ocular myasthenia and in generalized my-
asthenia in remission. Unfortunately, the possibility of
severe respiratory complications of systemic curare
administration to myasthenic patients (we have seen
respiratory arrest after injection of only 1/80 of the
curarizing dose) requires that someone in the group
performing the test know how to intubate and ventilate
the patient with the AmbuB bag. Anesthesiology
standby is expensive, so it is better if the neurologist
himself is expert at intubation and ventilation. The
systemic curare test can be terminated with pyridostig-
mine (Mestinon), and patients who have had positive
tests should be under close nursing observation for at
least 10 hr.
The indications for the regional curare test are
similar to those for the systemic curare test and the
same precautions should be followed. The test is done
by applying a blood pressure cuff around thc arm to be
Diagnosis and Management of MG MUSCLE 8, NERVE May/Jun 1978 197
tested. A scalp-vein needle, pointing distally, is inserted
into a superficial forearm vein; the arm is elevated for 1
min; and the cuff is inflated to about 250 mm Hg or at
least 100 mm Hg above systolic pressure. The arm is
then lowered and a solution of 0.2 mg d-tubocurarine
in 20 ml of 0.9% NaCl is injected rapidly. The cuff
remains inflated for 6.5 min after the start of the
injection, to allow for adsorption of the d-tubocurarine
onto the motor endplates. Repetitive nerve stimula-
tions at 3 per second are then done with limb ischemia
and after the cuff is released. A decrement of greater
than 10% is considered a positive test and, if present,
usually appears early and may persist for an hour or
longer. Whether this test can be used, as has been
claimed, to measure response to thymectomy or to
uncover systemic myasthenia in patients who have
ocular involvement only, must await further evalua-
ti ~n. ~'
Pupillometric testing. Infrared video pupillography
measures pupillary response to light and velocity as
well as acceleration of pupillary reactions before and
after intravenous edrophonium. This tool may provide
objective measures of myasthenia in the future, but the
exact role of this test in present clinical practice has yet
to be determined.'"'
Audiometric testing. Fatigability of the stapedius is
increased in some patients with myasthenia and can
be measured objectively. Pure tone audiograms, tym-
panometry, and acoustic reflex tests can be used to
distinguish cholinergic from myasthenic crises. Con-
tinuation of these investigations is needed to determine
the clinical importance of these observation^.^^'.^^
Oculo,yraphy. Rapid eye movements, having high
velocity and low amplitude, are common in my-
asthenic patients and can be observed clinically. They
are called quiuer movements and are probably patho-
gnomonic of MG. These voluntary saccades can be
studied by elect roocu lograp h y. 4 ~ 1 3 ~ 1 0 2 Despite the 1 i m -
ited range of eye movements, maximum velocities of
20" and 40' saccades in myasthenic patients are usual,
whereas maximum velocities in patients with other
types of ophthalmoplegia are significantly lower. Some
myasthenics have hypermetric and high-velocity small-
amplitude saccades; these are the clinically observed
quiver movements characteristic of myasthenia. l 3
Naturally, modification of these abnormalities with
edrophonium and quantitative assessment with
oculography and computer-assisted plotting of ampli-
tude-velocity relationships improve the sensitivity of
this test. Incidentally, in myasthenia, the preserva-
tion of saccades with high initial velocities, even in the
presence of severe ophthalmoplegia, suggests that
muscle fibers generating rapid movements during sac-
cades (fast twitch fibers) can be relatively spared when
the muscle fibers responsible for maintenance of ex-
centric gaze (tonic fibers) are severely affected. This
relative sparing of faster twitch fibers may explain the
relative sparing of distal muscles in myasthenia, since
distal muscles have a greater percentage of fast twitch
fibers than proximal muscles.
MANAGEMENT OF MG
A complete understanding of the therapies available
for myasthenia and the effective role of each in the
management of this disease is the cornerstone of
successful treatment of this condition. Naturally, good
rapport, a sympathetic ear, and %hour availability
are important aids in treating MG, as worry can have
such an adverse effect on the patient's condition. But
these measures can never substitute adequately for
effective control of the disease. Success in management
also depends on the patient's full understanding of his
condition, of the things to avoid that make myasthenia
worse, and of the reasons for and goals of the therapies.
Myasthenic Hazards. Atropine. J udicious use of atropine
to reduce rnuscarinic side effects when treating with
anticholinesterases can benefit some patients, but
masking those side effects removes a signal to the
patient of excessive dosage. Atropine should not be
used in those newly treated myasthenic patients who
are just learning the benefits and side effects of anti-
cholinesterase medications.
Antzarrhythmic drugs. Of the antiarrhythmic drugs,
quinidine is potentially dangerous in myasthenia. One
personally observed myasthenic patient treated for
cardiac arrhythmia had an exacerbation of weakness
because of quinidine administration. Diphenylhydan-
toin (DilantinB), used in the therapy of cardiac ar-
rhythmia to decrease membrane excitability and also
used as an anticonvulsant, could conceivably have a
similar effect and thus should be used with caution-
yet, Schwab and Osserman, two clinicians with very
extensive experience with myasthenic patients, never
observed any weakness attributable to anticonvulsants
(personal communication). Quinine, sometimes used
as a muscle relaxant, and also occasionally self-admin-
istered in the form of tonic water, can also be de-
leterious. Because the quinine in tonic water may
decompensate a myasthenic patient, that drink is
prohibited routinely. (In the past, quinine has been
used as a provocative test for latent symptoms of MG.)
Theoretically, procainamide, because of its depressive
action on membrane excitability, might cause weak-
ness in some myasthenic patients. The beta-receptor
blocking agent propranolol (Inderal @ ) used for digi-
talis intoxication, high blood pressure, and some ar-
rhythmias, has been associated with sudden worsening
of myasthenia.4"
198
Diagnosis and Management of MG
MUSCLE 8, NERVE May/J un 1978
Antibiotics. The neuromuscular blockade caused by
certain antibiotics is not simply related to dose or route
of administration. Some antibiotics that have had
adverse neuromuscular effects in humans are neo-
mycin, streptomycin, dihydrostreptomycin, gen-
tamicin, kanamycin, polymyxin, bacitracin, and
colistin.36,58,82,96,1W A myasthenic syndrome secondary to
certain antibiotics has been reported in nonmyasthenic
persons. The syndrome usually occurs immediately
after surgery and is probably caused by the antibiotic-
induced presynaptic impairment of acetylcholine
mobilization within or released from the axonal
terminal. However, the clinical event usually is associ-
ated with other factors that impair the safety of
neuromuscular transmission, such as ether anesthesia,
curariform and depolarizing muscle-relaxing agents,
hypocalcemia, and chronic or acute renal dis-
Calcium is the most effective agent for partially
reversing antibiotic-induced weakness in almost all
cases: cholinesterase inhibitors, such as neostigmine
and edrophonium, are also effective but to a lesser
extent and, again, are not effective in all cases.1o1
Pregnancy. The stress of gestation, labor, and deliv-
ery should be avoided.
Heat. Sunbathing, hot showers or baths, and work
on warm days may suddenly worsen the condition.
Unexplained severe weakness in the mornings remitted
in one case (personally observed) when the patient was
told to take a tepid bath instead of her usual hot one.
Another patient became so weak during a hot shower
that she was unable to shut off the water, unable to
stand, and then developed severe respiratory distress.
The adverse effect of heat on neuromuscular transmis-
sion, as demonstrated by Desmedt and Borenstein,O is
the probable mechanism for the clinical deterioration
in warm environments and for the preference of some
of these patients for cold drinks, ice cream, sunglasses,
and colder climate^.^
Emotional upsets. MG patients should try to main-
tain a calm philosophic outlook on life, avoiding stress
and paying reasonable attention to the rules of good
health, including adequate rest, recreation, diet, and
sleep.
ease. I5.29.58.IOO
Drug Therapy. The pharmacologic approach to treat-
ing MG is twofold. One is to enhance function at the
neuromuscular junction in order to correct the relative
deficiency of acetylcholine action with drugs acting
directly on the transmission process. The other is to
suppress the abnormal immune basis of the disease in
those tissues responsible for the altered immune state.
The former is symptomatic thcrapy, whereas the latter
is an attack on an early step in the pathogenesis of the
disease.
Drugs directly improving neuromuscular transmission. Of
the agents that improve neurornuscular transmission,
the anticholinesterase drugs are the most commonly
used, especially pyridostigmine or sometimes neostig-
mine (and occasionally ambenonium) for mainte-
nance therapy. Edrophonium is used as a short-acting
diagnostic agent. These drugs have greatly improved
the length of survival and the life quality of many
myasthenic patients, although a significant number
sooner or later do not respond adequately. By tem-
porarily inhibiting acetylcholinesterase at the neu-
romuscular junction, they enhance the action of
acetylcholine at that site.
Other agents that can improve neuromuscular
transmission in MG, but much less effectively, include
guanidine, calcium,5I and ephedrine. They act by
increasing the presynpatic release of acetylcholine.
The veratrum alkaloids were used successfully in the
1930s in myasthenia but were apparently discarded
because of the cardiovascular and emetic side effects. A
semisynthetic derivative, germine monoacetate, that is
free of hypotensive, bradycardic, and emetic effects has
been tested more recently with encouraging results in
preliminary trials on some myasthenic patients. The
basic mechanism of action of this agent is the produc-
tion, especially in the muscle itself but also in motor
axons, of repetitive electrical activity after a single
normal action potential.
In using anticholinesterases, our practice has been
to become familiar with one drug and use i t in all cases.
Weuse Mestinon because i t has fewer cholinergic side
effects, a smoother time course of action, and is avail-
able in 60-mg tablets, as a syrup with 60 mg in each 5
ml, in an intramuscular form (1 mg IM equals about
30 mg orally), and in 180-mg timespan tablets for
sustained release at night. Mestinon is usually initiated
at doses of 30-60 mg four times daily; then the dose,
rate of administration, and time of administration are
adjusted by trial and error to achieve maximum bene-
fit. If the patient is having weakness at night or on
awakening in the morning, the 180-mg Mestinon
timespan may be added at bedtime. Some patients
report the excretion of undissolved timespan tablets in
their stool; also, regular Mestinon is sometimes poorly
ab~0rbed.l ~ The proppr maintenance dose depends on
the individual patients requirements; we have had
sonx who do well on 30 mg twice daily, and some who
require 19 g daily in divided doses. The proper dose of
medicine is whatever amount is needed to control the
symptoms.
Drugs modf i i ng immune mechanisms in myasthtnia
grauis. ACTH and ad renocort icosteroids- Bot h
Diagnosis and Management of MG
MUSCLE & NERVE May/J un 1978 199
ACTH35.'%6737and corticosteroidsg.'0.16,26,~3,45.49.55.98 are
beneficial in many patients with MG. The usefulness
of ACTH is limited by its tendency to produce exacer-
bations of weakness in the early stage of treatment,
often requiring management of the patient in an
intensive-care facility.
Those most experienced with ACTH administra-
tion in myasthenia recommend a paired course: 100
units, intramuscularly or intravenously, each day for 10
days, then a 5-day (not longer than 7 to 10 days) rest
period, and then another 10-day course.34 After a single
or paired course, patients are improved clinically to a
variable degree-maximally, about a week after the
end of the course-and for a variable time, usually six
weeks to six months (mean, two to three months).34@
Frequently, during ACTH administration there is a
marked increase in weakness, variably beginning with
the first 5 days (usually the 2nd and 3rd day), and most
marked by the 6th or 7th day of therapy, with some
recovery toward the end of the 10-day per i ~d. ~~, ~ The
patient may become unable to chew, swallow, talk, or
breathe and thus will require assisted mechanical
ventilation, nasogastric-tube feeding, and round-the-
clock nursing care to survive this profound weakness.
Four theoretic explanations for the induced weakness
in patients concomitantly receiving ACTH and anti-
cholinesterase are: (1) the patient has undergone rapid
remission, and thus anticholinesterase is at an overdose
level; (2) there is an adverse interaction between
ACTH and the anticholinesterase; (3) the ACTH alone
has a transient adverse effect on neuromuscular trans-
mission; or (4) ACTH releases (from lymphoid, adre-
nocortical, or other cells) harmful substances that act
adversely, alone or in conjunction with anticholines-
terase, on neuromuscular transmission. But this
ACTH-induced weakness has occurred even in a pa-
tient not concomitantly receiving anticholinesterase
drugsLU]
At present weuse ACTH only in those patients who
do not respond to thymectomy, oral corticosteroids, or
anticholinesterases. Strangely enough, patients unre-
sponsive to these treatments may respond to ACTH
and can be maintained on weekly or monthly injec-
tions. Although oral corticosteroids are effective in the
therapy of MG, the particular indications for the use of
these agents have not been firmly established. Most
types of MG may be expected to benefit fmm oral
corticosteroids, with older men responding better than
younger women. Some advocate corticosteroid use in
ocular myasthenia, particularly if anticholinesterases
have been ineffective and if the ocular myasthenia
significantly impairs the patient's life or Others
are skeptical about using corticosteroids in ocular
myasthenia because the side effects may be too high a
price to pay for the benefits obtained. When to use
corticosteroid therapy has also been a moot question.
Genkins thinks that the use of corticosteroids prior to
thymectomy impairs the response to thymectomy (per-
sonal communication), while J ohns uses these agents
to prepare the patient for thymectomy? Also, there is
controversy about the concomitant administration of
anticholinestera~es~~ as well as whether the cor-
ticosteroids should be initially given on a daily basis46
or on alternate days.26
A reasonable approach to treatment that works for
me is as follows. Oral prednisone is used as the agent of
choice because it is cheap, effective, and available in
50-mg tablets. Prednisone has a short half-life, so that
alternate-day therapy does not interfere with the pitui-
tary-adrenal axis. All patients with generalized auto-
immune MG with or without thyrnomas are candi-
dates for prednisone therapy if they have been given an
adequate trial of anticholinesterases and are still not
leading a life that is satisfactory to them. Patients with
ocular myasthenia, in general, are not candidates for
therapy unless their ocular symptoms interfere with
their work, for example, neurosurgeons or entertainers.
Before prednisone therapy is initiated, the patient
should be admitted to the hospital and the physician
who is managing the patient should be familiar with
the following important points.
Refractory response-Early investigators of cor-
tisone's effect on MG often noted a worsening of the
patient's condition and development of a refractory
response to the anticholinesterase drug during the
period of initial corticosteroid adrninistrati~n.~~~~~~~~
The reason for this worsening is not known, but it has
been ascribed to an adverse interaction between cor-
ticostemids and anticholinesterase drugs at the neu-
romuscular junction, similar to that which has been
demonstrated in the rat.7R Various regimens have been
designed to avoid this initial worsening, but the one
that seems simplest and most effective is to gradually
increase the dose of prednisone from 25 mg orally every
other day to 100 mg every other day over a period of
one month.sR On this regimen, patients usually do not
experience weakness; rather they experience a progres-
sive increase in strength on the day they take the
prednisone, with a return toward baseline strength on
the day they do not take the prednisone. When pred-
nisone is given initially in daily doses, exacerbation of
myasthenic weakness occurs in about 40% of pa-
tients. ' 0,46955 In one series, exacerbations began between
the 1st and 21st day of therapy, with a mean of 5 days.'5
The duration of increased muscle weakness lasted from
one hour to 20 days, with a mean of 6 days. In 80% of
patients exacerbations were mild to moderate in sever-
ity, while in 20% they were so severe that brief respira-
200 Diagnosis and Management of MG MUSCLE 8 NERVE May/J un 1978
tory support was required. Age, sex, duration of illness,
timing, degree, or duration of exacerbation cannot be
used to predict the ultimate response to prednisone.
Patients who become weak may develop a refractory
response to anticholinesterase drugs during the period
of increased weakness, a finding also reported in an-
other series in which methylprednisone was used in-
stead of prednisone. l o
Initial weakening with the induction of cortico-
steroid therapy has been demonstrated in rat nerve-
muscle preparations in which corticosteroid abolished
anticholinesterase drug-potentiated single-twitch ten-
sion amplitude and caused subsequent refractory re-
sponse in corticosteroid-treated animals to the poten-
tiating effect that normally results from increasing
doses of cholinesterase inhibitor^.'^Our policy has been
to avoid these periods of worsening by enforcing rest
and by using an alternate-day regimen with gradual
build-up in prednisone dosage. Moderate (and some-
times marked) reduction of requirements for cho-
linesterase inhibitors often occurs during the initial
month of therapy and manifests itself initially as
cramps, muscle twitches, and occasional diarrhea on
the afternoon of the day the patient takes the pred-
nisone. Consequently, anticholinesterases may have to
be reduced as rapidly as can be tolerated in order to
avoid cholinergic weakness. Some patients can be
withdrawn from the anticholinesterases as they con-
tinue to improve. We observe the patient in the hospital
until he is steadily improving, and then manage him
with frequent outpatient contacts (often by telephone)
to adjust the dosage of the medicines. During the next
few months, the on-off day difference gradually dimin-
ishes until the patient is better on both days.
Maintenance prednisone therapy-The aim of
therapy is to maintain normal functional status with
use of the lowest possible dose (given in the safest
possible way). Therefore, when the patient has been
functionally normal for two to three months, the
prednisone dosage may be decreased by 5 mg each
month until the lowest dose that will maintain the
patient's health is reached.
Prednisone regimens-As in other conditions re-
sponding to prednisone, compared with other time
schedules alternate-day therapy is the best-tolerated
regimen (that is, fewest side effects) and also the least
effective in controlling the disease. When myasthenia
does not improve with alternate-day therapy, once-a-
day therapy should be tried with the patient taking the
entire day's dose in the morning. Those patients whose
condition does not improve with daily therapy should
be tried on round-the-clock therapy, in which one-
quarter of the daily dose is taken every 6 hr.
Side effects-Side effects of therapy are numerous
and include fluid retention, aggravation of diabetes,
change in facial and body fat (cushingoid appearance),
hypertension, cataracts, demineralization of bone, hy-
pokalemia, gastrointestinal bleeding, and sleep distur-
bance. The occurrence of some of these side effects can
be minimized by a high-protein, low-carbohydrate,
and low-sodium diet, potassium chloride supplementa-
tion, the use of antacids, and the use of supplements
with vitamin D and calcium. Cataracts are removed
surgically.
Dexamethasone-Dexamethasone (20 mg/day or-
ally for 10 days) has considerable promise as a therapy
in MG since it has produced the greatest duration and
incidence improvement compared to methylpred-
nisolone and predni ~one.~ However, alternate-day dex-
amethasone is not recommended because the long
half-life of the drug suppresses the pituitary axis and
may lead to side effects in those patients who need
long-term therapy.
Thymoctomy. There are two major problems with the
prednisone therapy of MG: side effects, and the ten-
dency for the symptoms to recur as the prednisone dose
is reduced. Because of these problems, and until a more
effective therapy is available for MG, thymectomy
remains the treatment of choice for all types of autoim-
mune myasthenia except perhaps for those cases of
ocular myasthenia which have been proved to be purely
ocular by a systemic or regional curare test.
The value of thymectomy has been reaffirmed
55,57963-74984,85 but, regrettably, a randomized prospectivc
study comparing patients treated medically with those
subjected to thymectomy has not been done. In the
absence of such a study, historic controls using com-
puter-assisted retrospective matches for age, sex, sever-
ity, and duration of disease confirm the impression of
early investigators that in the surgically treated group
improvement is greater and mortality is less than in the
medically treated control group. I ' Thymectomy may
benefit myasthenic patients of either sex with any
severity or duration of disease. There is some evidence,
however, that when thymectomy is performed earlier,
the symptoms and signs are fewer, the removed thymus
is more normal by histologic criteria, and the prognosis
is better-although individual exceptions to this
abound. Results are poor in patients with thymoma,
but these patients will usually benefit from post-
thymectomy prednisone or cytotoxic therapy. Re-
sponses to thymectomy cannot be predicted in
individual cases. Some patients may be remarkably
improved the day of surgery or one or two days
thereafter. In fact, a previous ptosis may be replaced by
lid retraction and the myasthenic snarl may be re-
repeatedly by numerous studieshl 1,24,28,29,05,38,39,42.46-48,50.-
Diagnosis and Management of MG MUSCLE & NERVE May/J un 1978 201
placed by a grimace, with surgery alone (ix., no
anticholinesterases). This initial dramatic change in
the myasthenia quickly fades and has no relation to
ultimate outcome. I t is important to recognize this so
that anticholinesterase dosage can be appropriately
rcduced to prevent cholinergic overdosage. I n most
patients, the response to thymectomy is delayed, in
some cases for as long as seven years after operation.
Improvement is so gradual that it is often appreciated
only in retrospect that the condition improved after
surgery. Possible benefits to be expected from thymec-
tomy include: (1) increased chance for remission, (2)
better control of disease, (3) reduced requirement for
medication, (4) decreased chance of thymoma, and (5)
decreased chance of systemic cancer.
When thymectomy is called for, patients previously
treated with corticosteroids must receive them just
before, during, and after surgery, to prevent relative
adrenal insufficiency, shock, and possible death. Our
practice has been to give 100 mg of hydrocortisone in
each liter of intravenous infusion just before, during,
and for two days after surgery. The patient may receive
three to five liters of solution during that time (ix., a
total corticosteroid dose of 300-500 mg). We also
administer 100 mg of intramuscular hydrocortisone
just prior to surgery in case of inadvertent omission of
corticosteroid in the intravenous infusion.
The choice of a transverse cervical or a median
sternotomy incision is best judged by the surgeon, and
the current controversy concerning which approach is
bestM seems unjustified because the mortality (which
should be zero or close to zero by either approach) and
the results are similar for both operations. Thymus
location is variable; the thymus may be found from one
hilum of the lung to another and from the base of the
skull to the diaphragm. Given this anatomic variation,
the occurrence of small implants of thymus in medi-
astinal and pericardial fat, and the finding that thymic
hormone activity recovers toward normal one year
after even the most meticulous dissections (personal
observation), it appears that complete thymectomy is
impossible and is not needed for a good result.
Cytotoxlc Therapy. Immunosuppressive treatment of
MG is effective and safe if carefully monitored, and
offers the possibility of c~re.~ Our practice has been to
use cyclophosphamide (Cytoxin) in doses of 100 mg
daily in those patients who have severe myasthenia
unresponsive to other therapy or who have severe side
effects from corticosteroids. Usually, there is a response
within the first two weeks of therapy even in patients
who have invasive thymomas. Concurrently admin-
istered anticholinesterases and corticosteroids are grad-
ually reduced as the patient improves.
Gamma Globulln. Some patients may benefit from 10-
20 ml human gamma globulin injected IM every three
weeks. On this regimen, patients, particularly those
over 55 years old, have had excellent results permitting
reduction of maintenance prednisone dosage.37 The
mechanism of gamma globulins action is unclear, but
suppression of endogenous IgG synthesis or competi-
tive binding to the AChR preventing the action of anti-
AChR antibody (AChRAb) may be important.
Thoraclc Duct Drainage. Thoracic duct drainage, effec-
tive in immunosuppression used for renal transplanta-
tion patients, also has a use in MG treatment. The
operation is minor,5b although it can be technically
difficult. The lymphatic fluid is drained into a bottle
via a plastic tube. Large amounts of immunoglobulins
and lymphocytes are removed, and fluid and protein
losses have to be replaced. Patients improve within 48
hr but relapse when the procedure is discontinued. Of
interest, retransfusion of cell-free lymph from the
drainage worsens the mya~theni a,~~ and an IgG anti-
body, which decreases a-bungarotoxin binding to the
AChR, has been isolated from this lymph. This pro-
cedure may be useful in severe myasthenics who are
refractory to other therapies.
Antilymphocyto and Antithymocyte Sera. These sera
prepared in goats have been reported to be effective in
some pati ent~.~J ~ At present, their use is experimental.
Plarmaphererir. Plasma exchange may be followed by
a short-term (three-week) remission,B1 and clinical im-
provement is associated with a decrease in serum anti-
AChRAb. This procedure requires considerable pa-
tient and professional time and is expensive. In most
patients long-term benefit can only be achieved by
concurrent use of corticosteroid and/or immunosup-
pressive (i.e., cyclophosphamide 2-3 mg/kg or
azathioprine 1-2 mg/kg) treatment.
Summary of Suggorted Managemont of MG. Treatments
are tailored to suit the needs of the individual patient,
but in general all myasthenic patients are initially
treated with anticholinesterase therapy; the dose is
adjusted to achieve maximum benefit. Those not re-
sponding well to anticholinesterases are treated with
prednisone or with whatever other therapy appears
needed to bring the disease under sufficient control so
that thymectomy can be performed. After thymec-
tomy, doses of medicines are reduced slowly as benefits
accrue. I n our experience, the sternal-splitting pro-
cedure is tolerated well by most patients. The manage-
ment of ocular myasthenia depends on the patients
202 Diagnosis and Management of MG MUSCLE & NERVE May/J un 1978
situation and desires. Generally, we prefer to patch one
eye of the patient with ocular myasthenia who does not
respond to anticholinesterases rather than subject him
to the long-term side effects of corticosteroids or to the
risk of thymectomy. Some patients, however, need
effective control of ocular myasthenia for occupational
reasons, in which cases we act accordingly. Immu-
nosuppressants are reserved for severe myasthenics
(usually with invasive thymoma) who are not respond-
ing to cholinesterase inhibitors or prednisone or in
whom side effects are intolerable. Therapies, such as
thoracic duct drainage and plasmapheresis, are re-
served for patients who wish to explore additional,
more experimental methods of treatment.
_____
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