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CLINICAL MANIFESTATIONS OF MYASTHENIA GRAVIS

Norah S. Lincoff, MD
Buffalo, New York

Myasthenia Gravis (MG) is an autoimmune disorder


of neuromuscular transmission in which acetylcholine
receptor antibodies attack the postsynaptic membrane of
the neuromuscular junction. Reduction in the number of
acetylcholine receptors and structural damage to the
membrane impair synaptic transmission from motor
axons to muscle and result in the weakness and
fatigability that characterize this disease. The muscle
weakness worsens with exertion or sustained activity.
MG can weaken any striated voluntary muscles, and may
produce life-threatening symptoms such as dysphagia
and respiratory failure. Fortunately therapeutic advances
have increased patients' survival and life expectancy
(1-4).
DEMOGRAPHICS:
The prevalence of MG is now felt to be as high as 50
to 125 cases per million population, or roughly 25,000
people in the United States (2). The disease can begin at
any age, but the peak incidence occurs in the third
decade in women (average age of onset 28), and in the
fifth decade in men (average age of onset 42). The
overall female to male ratio is 3:2 (5). Neonatal MG
results from the passive transfer of anti-acetylcholine
receptor antibodies from an affected mother to her
newborn infant, and produces symptoms in about one in
seven babies born to mothers with MG. The symptoms
are usually transient and appear within the first 72 hours
of life. The mean duration of neonatal MG is 18 days,
and may require short-term treatment with assisted
ventilation, IV prostigmine and/or oral mestinon.
CLINICAL FEATURES OF PATIENTS WITH MG
A physiologist by the name of Thomas Willis was the
first to describe the clinical features of MG in 1672
(6-8). The main features of MG are muscle weakness
and fatigability.
The extra-ocular muscles and
periorbital muscles are affected most frequently.
Patients will often present with ptosis, and/or diplopia
with or without other systemic symptoms of fatigue,
muscle pain or weakness. At initial presentation, 75% of
patients with MG have only ptosis and /or diplopia, but
only 15% of all patients will remain exclusively ocular
myasthenics. Fifty percent of ocular myasthenics do not
have measurable acetylcholine receptor antibody titers
(9,10), but 60% of all myasthenics develop systemic
features such as proximal muscle weakness or difficulty
with speech and swallowing within two years after the
onset of ocular symptoms. On the other hand, during the
course of systemic MG, 90% of patients develop
neuro-ophthalmologic signs (11).
Sixty five percent of patients with MG have thymic
hyperplasia, and 15% actually have a thymoma (12). It
is believed that the myoid cells in the thymus gland can
differentiate and express acetylcholine like receptor
autoantigens, and that the B-lymphocytes in the gland
can produce acetylcholine specific receptor antibodies
(5). Because of this belief that the thymus gland is likely
a site of autosensitization, it is now recommended that

all patients with thymomas and all patients under 65


years of age with thymic hyperplasia undergo
thymectomy (14,15). Though 15-20% of myasthenics
go into permanent remission, spontaneously, it is
believed that an additional 20% will go into remission
following thymectomy. For those who do not go into
remission following thymectomy, a substantial
percentage show marked improvement in their disease
state, with less need for maintenance medication.
Myasthenia coexists with many other autoimmune
diseases including thyroid disease (hyperthyroidism 5%,
all thyroid disease states 9-18%), rheumatoid arthritis,
ankylosing spondylitis, aplastic and pernicious anemias,
systemic lupus erythematosis, ulcerative colitis, sarcoid,
pemphigus, Sjogrens disease, diabetes mellitus, and
autoimmune hepatitis (5). A few patients have been
reported to have acquired MG after bone marrow
transplantation. Many drugs are known to exacerbate
MG including: neuromuscular blocking agents,
antibiotics (especially aminoglycosides), quinine,
quinidine, chloroquine, procainamide, calcium channel
blockers, phenytoin, lithium, antidepressants, Beta
blockers (including ophthalmic glaucoma drops), and
others (16).
OCULAR SIGNS IN MG
The levator palpebrae superioris is the most
frequently affected muscle in MG, and its weakness
results in ptosis, with or without the Cogan's lid twitch
(2). Though ptosis may first be noticed in one eye, it
almost always becomes bilateral with time. Ptosis may
be absent on awakening in the morning, and usually
becomes more pronounced as the day proceeds. Ptosis
can be partial or complete and the levator usually
fatigues easily with prolonged upgaze, causing the ptosis
to worsen. Many patients with severe ptosis adopt a
chin-up position so as to peek under their lids, and some
require a lid crutch. An elevated brow on one side is
also a common finding in these patients; there is
sometimes associated lid retraction. If one elevates the
more ptotic lid in a patient with MG, the opposite lid
will often drop because of Herring's law of equal
innervation (seesaw phenomenon or enhanced ptosis).
Though ptosis may be an isolated finding in MG, it is
often seen in association with orbicularis weakness.
Having the patient perform forced lid closure tests this.
The examiner then either looks for the "peek sign" as the
muscles weaken, or forcibly attempts to open the
patient's lids manually.
The extraocular muscles that rotate the globe are the
second most common group of muscles affected in MG
and their involvement causes diplopia, ophthalmoplegia,
and nystagmus. One or more of the muscles may be
affected either partially or completely and, in severe
cases, complete external ophthalmoplegia can occur.
The most frequently involved muscles are the medial
rectus, inferior rectus and superior oblique. Patients
with unilateral ptosis may not notice diplopia until their
lid is elevated during their examination. Some patients

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will squint one eye shut in order to avoid diplopia. The


ophthalmoparesis may mimic or present as a comitant or
incomitant strabismus, an isolated cranial nerve palsy, a
gaze palsy, as an internuclear ophthalmoplegia, or as
convergence insufficiency.
The onset should be
painless, though many patients develop headache, which
is felt to be secondary to sustained muscle contraction in
an attempt to elevate the lid or to fuse. Occlusion of one
eye by a patch or black contact lens almost always
alleviates this symptom.
Pupillary dysfunction in MG has been reported in the
literature, but clinically it is a rare finding. The most
common reported finding has been mydriasis, anisicoria
and pupillary sluggishness that improved with treatment
with Tensilon or prostigmine. Fatigue of the pupillary
response has also been reported (17,18). Involvement of
the iris sphincter muscle is the presumed cause for these
findings.
SYSTEMIC SIGNS IN MG
Patients with generalized MG can present with
weakness and fatigability of any striated skeletal muscle
group. Physical examination may reveal weakness that
is generalized, apparent only in certain muscles, or
present primarily after sustained effort (1). The most
commonly involved muscles outside of the lids and
extraocular muscles, include the facial muscles, neck
flexors, triceps, and quadriceps. The limbs are usually
more affected in a proximal distribution. Weakness of
the jaw or pharyngeal muscles can lead to dysphagia,
and weakness of the diaphragm can lead to respiratory
failure.
On neurological examination: Reflexes,
coordination, sensation, bladder and bowel function
should be unaffected in patients with presumed MG.
Patients with facial muscle involvement may present
with a "snarling expression", nasal speech or dysphonia.
Involvement of the muscles of mastication, jaw muscles
or bulbar muscles results in trouble chewing,
swallowing, and again trouble with speech. Patients
with severe weakness have trouble controlling their
saliva, and sometimes have to manually hold their jaw to
speak, or chew their food (slack jaw/hanging jaw).
Proximal limb weakness is best assessed on
presentation with timed forward arm abduction (5
minutes or best effort) (1). Patients may complain of
difficulty with simple tasks requiring them to lift their
arms, such as combing or brushing their hair, shaving or
applying makeup.
The clinical severity of their disease can be graded
(1,3):
Grade 1: focal disease
Grade 2: generalized disease that is either mild or
moderate
Grade 3: severe generalized disease
Grade 4: myasthenic crisis with life-threatening
impairment of respiration
Since a simple URI in patients with MG can trigger a
crisis, all patients suspected of having generalized MG
should undergo forced vital capacity testing (FVC), and
peak respiratory force testing through a pulmonary
service to rule out respiratory muscle involvement. A
myasthenic patient is said to be in "crisis" when
difficulty with respiration or swallowing, requiring

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assistance, occurs. Approximately 16% of myasthenics


experience crisis (19). A FVC below 1 liter usually
indicates the need for ventilatory assistance. These
patients are usually treated in the ICU with plasma
exchange or intravenous gamma globulin (IVIG)
(20-23).
MANAGEMENT AND TREATMENT
The suspicion of MG, whether purely ocular or
systemic, requires a multi-disciplinary approach to
assure appropriate work-up and treatment.
The
diagnosis must be established firmly before treatment is
initiated because therapy entails a major commitment to
medical and often surgical measures(1).
As an
ophthalmologist trained in neuro-ophthalmology, I
always involve a neurologist, neuro-muscular specialist
or neuro-immunologist early in the care of my patients
who I suspect are suffering from MG. These consultants
help to establish the diagnosis and evaluate the severity
of the MG, and also search for associated conditions and
masqueraders of myasthenia. They are also usually
more comfortable and familiar with the treatment of
patients who need increasing doses of anti-cholinesterase
agents and prednisone or the initiation of
immunosuppressive drugs such as Imuran, Cyclosporine
A, Cytoxan, and CellCept (24-28).
Protocol for Evaluation and Treatment of MG:
Clinical suspicion
Confirmation of the diagnosis with a Tensilon test
(29) and/or Sleep test (30)
Serology (AChR antibodies in serum) (31)
Repetitive nerve stimulation (EMG) looking for a
decremental response (32)
CT of the chest to R/O a thymic abnormality
Pulmonary function testing to assess ventilatory
function
Treatment / Medical treatment trials (5,33):
Anticholinesterase agents: Pyridostigmine (Mestinon)
60mg Q 6 hours to 120mg Q 3hrs
Occlusion therapy with patch or black contact lens
for diplopia. Prism can also be tried in certain cases.
Immunosuppressive agents: Prednisone 20mg QD
(increase by 5mg Q 2-3 days up to 60 mg (then
alternate day therapy).
Caution patients that they may suffer a transient
initial exacerbation.
Azathioprine 50mg QD (CBC monitoring necessary)
Cyclosporine 2.5mg/kg BID (serum level monitoring
necessary)
Thymectomy
Plasmapheresis 5 exchanges over a 5-10 day period
to decrease AChR antibody titers during
exacerbations
IVIG 1-2 gm/kg IV to downregulate autoantibody
production during an exacerbation
MASQUERADERS OF MG / DDX (34,35)
1. Lambert-Eaton Syndrome (LES) (35,36):
Neuromuscular disease associated with carcinoma.
Patients often report difficulty with walking and
arising from a seated position because of weakness of
their trunk and pelvic muscles. Ptosis, diplopia, and
difficulty with swallowing and speaking are less

common than in MG. Other findings include decreased


reflexes, parasthesias, and autonomic dysfunction (i.e.
dry mouth, constipation and erectile dysfunction).
2. Guillain-Barre Syndrome (38): An inflammatory
demyelinating polyneuropathy that is usually post
infectious, post surgical or following vaccination.
Common features include ascending relatively
symmetric limb weakness, areflexia, sensory
symptoms, and oropharyngeal and facial weakness.
Ptosis rare (5-10%) and does not fatigue. Diplopia
secondary to ophthalmoplegia is also rare (15%). An
elevated CSF protein is common. Respiratory failure
is usually associated with severe limb weakness and
paralysis.
3. Botulism: A presynaptic neuromuscular disorder
caused by a toxin that interferes with the release of
ACh at the motor terminal. Patients often present
with constitutional symptoms such as nausea,

vomiting, and dysphagia. Generalized weakness of


the proximal muscles is common. Ophthalmologic
findings inclu d e d ip lop ia secondary to
ophthalmoplegia, poorly reactive pupils, and ptosis.
4. Bilateral midbain/brainstem lesions: Patients present
ataxic, areflexic, with signs of external
ophthalmoplegia. Alteration in wakefulness and
coma are common.
5. Chronic progressive external ophthalmoplegia with
skeletal myopathy (CPEO): This mitochondrial
disorder usually presents with bilateral ptosis,
followed by symmetric progressive ophthalmoplegia.
Patients usually do not suffer from diplopia.
Generalized skeletal muscle weakness, and facial
weakness can be seen. Ataxia is seen in about 20%
of patients.

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