III.

Neuromuscular Junction
i. Myasthenia gravis
OCULAR MYASTHENIA
contributed by Amir Ali Ahmadi and Jason Barton, University of British Columbia, January 2009
EPIDEMIOLOGY
Myasthenia gravis is the most common disorder of the neuromuscular junction. It has a prevalence of about 50-
400 per million. It has no racial or geographic predilection (1) and may occur at any age. Neonatal form are
rarely encountered, and the clinical course in children and infants differ from that in adults (2). Before age 40
the disease is more common in women (1). Purely ocular myasthenia, which tends to start at a slightly later age
than generalized myasthenia, is more common in men (1) (3). There appears to be increased likelihood of ocular
myasthenia in theChinese population (4).

SYMPTOMS AND SIGNS

Patients with myasthenia have weakness without atrophy, pain, sensory loss or reflex changes. The two classic
features of myasthenic weakness are variability, in that weakness changes over minutes or days, or even shifts
between different muscles, and fatigability, which means that the weakness worsens with repeated use and
improves with rest.

Weakness particularly affects bulbar, facial and extra-ocular muscles. Up to two thirds of patients initially
present with diplopia or ptosis (3, 5), and nearly all will have diplopia or ptosis at some point. One fourth of
patients present with bulbar symptoms such as nasal slurred speech, or difficulty chewing and swallowing. Limb
involvement is the initial complaint in a minority, about 14-27%. The symptoms of myasthenia are often better
upon awakening or after rest and will be worse after prolonged use of affected muscle later in the course of the
day (6). Among the different symptoms, only two have been studied for their predictive value for myasthenia:
presence of food remaining in mouth after swallowing and speech becoming unintelligible during prolonged
speaking. Neither normal swallowing nor normal speech rules out myasthenia gravis (6).

Fluctuating, asymmetric external ophthalmoplegia with ptosis and weak eye closure is virtually
diagnostic of ocular myasthenia. However, many ocular myasthenics are misdiagnosed initially. While any
ocular motility disturbance that spares the pupil and is atypical for a single nerve palsy readily suggests
myasthenia, weakness patterns that fit neuropathic patterns can also be produced by myasthenia (7, 8). It is
important to attend to details suggesting variability and fatigue, such as weakness worsened by activity,
improved by rest, and varying daily, hourly or weekly. A diurnal pattern with worse symptoms in the evening is
not uncommon. A patient who has been diagnosed with different ocular motor deficits by different physicians
on different days may well have myasthenia.

Although it can occur with other myopathic processes, combined weakness of the extra-ocular muscles, levator
palpebrae superioris and orbicularis oculi suggests myasthenia. In one survey, 10% of ocular myasthenics had
ptosis, 90% had diplopia and ptosis, and 25% also had weakness of the orbicularis oculi (9).

Ocular signs in myasthenia represent a combination of peripheral paresis and secondary central compensatory
or adaptive mechanisms. Some paretic signs are highly indicative of myasthenia, particularly when they reflect
excessive fatigue or variability, but compensatory signs can occur with any type of peripheral ocular weakness.

An old but widely accepted classification system for myasthenia gravis is the Osserman Classification:
 OSSERMAN CLASSIFICATION OF MYASTHENIA GRAVIS

class I Ocular: purely ocular without generalized symptoms

class
Mild: slow progression, drug responsive, no crisis
IIa

class
Moderate: severe skeletal and bulbar involvement without crisis, less satisfactory drug response
IIb

class rapid progression of severe symptoms with respiratory crisis and poor drug response. High
Severe:
III incidence of thymoma, High Mortality

class Late
similar to III but more time, High Mortality
IV severe:

Lid weakness
Fatigue and variable paretic features:
In 90% of patient some degree of ptosis will accompany diplopia (10). It may be unilateral or bilateral, usually
asymmetric initially. It is typically variable and fatigable, sometimes only apparent towards the end of the day.
On exam, lid signs of fatigue include ptosis that worsens with repeated eye opening or prolonged upgaze for a
minute. (See video myasthenic lid nystagmus.) To elicit Cogan’s lid twitch sign (11), the eyes are closed or
placed in downgaze, allowing the levators to rest. When the patient opens their eyes and looks straight ahead
again, the rested lid will elevate well, only to droop again over the next few seconds as fatigue sets in. As with
many myasthenic signs, Cogan’s lid twitch has sometimes been reported with other ocular motor disorders
(12). Lid hopping, the fluttering of a ptotic lid during lateral pursuit or sustained upgaze, is a sign of variability
(13). In paradoxical reversal of ptosis (14), the droop switches from one eye to the other during the course of
a day, with rest, or after edrophonium.
 Myasthenia
gravis, ptosis
and impaired
elevation OD.A
59 year old man
with prior
thyroid disease.
Note the
moderate left
hypertropia in
primary
position.This
pattern mimics a
superior
divisional III
nerve palsy.
(N.B. pupils are
pharmacological
ly dilated.)

Secondary adaptive features:

A unilateral ptosis may appear mild because of partial compensation: the true extent of ptosis can be revealed
by covering the ptotic eye and observing a gradual increase in ptosis behind the cover over several
minutes.Enhancement of ptosis (15) or seesaw ptosis (10) is a similar feature: manual lifting of a ptotic lid
eliminates the need for compensation, and the relaxation unmasks a ptosis in the other lid, which had appeared
normal because it had shared in the central compensation directed at the more severe ptosis of the other eye, as
per Hering’s law (16). This sign of adaptation can also be found in patients with other causes of asymmetric
ptosis.

Occasionally, a myasthenic patient has apparent lid retraction rather than ptosis. While this can reflect co-
existentthyroid orbitopathy in some (17, 18), lid retraction can be a sign of central compensation. In response
to unilateral or asymmetric ptosis, innervation to both lids increases (Hering’s law): this may cause the less
affected lid to retract, which may appear more dramatic than the mild ptosis of the more affected lid (16, 19, 20).
As with enhancement of ptosis, manual lifting of the ptotic lid will result in disappearance of the retraction,
confirming that it was compensatory in origin. Likewise, the initial lid elevation in Cogan’s lid twitch can be
transiently excessive (11): resting the levator briefly increases its strength and unmasks the increased innervation
from central adaptation, causing the lid to overshoot on upgaze. Last, prolonged upgaze may cause a post-tetanic
facilitation leading to lid retraction in rare patients (21), but should suggest Lambert-Eaton syndrome first (22).

Extraocular muscles
The dynamics of eye movements show a complex mix of peripheral paretic and central adaptive effects (28).
Quantitative measures have been variable, some finding mild slowing of saccades (29) or quick phases of
optokinetic nystagmus (30), but others finding slightly faster saccades than with other ocular palsies (31-33).
Overall, the characteristics of eye movements do not adequately distinguish myasthenic weakness from other
types (34), except that saccades of CPEO are much slower than those in myasthenia (31, 32). Most ocular
myasthenics with diplopia also have ptosis (9), but exceptions are not infrequent. Patients with extraocular
weakness are usually aware of diplopia, but some complain of blurred vision. Noting that this blurriness worsens
over the day and is eliminated by covering either eye will clarify the issue.

Any pattern of ocular weakness can occur, from single muscle paresis to complete external ophthalmoplegia. It
can mimic both peripheral palsies, such as IV palsy (7), VI palsy, and partial III palsy (8), and central ocular
motor disorders, including unilateral or bilateral internuclear ophthalmoplegia (23-25) (See Video myasthenia
gravis – ocular weakness.), one-and-a-half syndromes (26) and double elevator palsy. An upgaze palsy with
intact Bell’s phenomenon can even occur, despite the fact that this usually suggests a supranuclear disorder)
(27). Though any muscle may be affected, the medial rectus, inferior rectus and superior oblique may be
more frequently involved (13).

Fatigue and variable paretic features:

While initial saccades may be nearly normal, fatigue from repetition eventually causes saccades to slow and
even truncate their amplitude (35). Intra-saccadic fatigue of twitch fibres causes abrupt decelerations during a
single saccade, so that after a fast start the eye slows down and drifts to its final position (28, 36), sometimes in
a stuttering fashion (37). (See Video myasthenic intrasaccadic fatigue.) If the tonic fibres are also paretic, the
eye may even stop short of its goal. The peak velocity of a truncated saccade is excessive, giving the appearance
of an abnormally rapid small saccade. Eye movement recordings can show moment-to-moment saccadic
variability in either velocity profiles (36) or the relation of peak velocity to amplitude: this ‘saccadic jitter’ is
diagnostic of myasthenia in about 40% of myasthenics (38).

There are no proven protocols for measuring ocular motor fatigue (33, 34), but qualitative results suggest one
sign may be increased variability of saccadic trajectories (36). Sustained gaze may cause a decrease in saccadic
amplitude, but may not be specific for myasthenia (39). Fatigue and complex saccadic trajectories have also
been reported in Guillain-Barre•L syndrome (37).

Fatigue of the tonic fibres causes ‘quiver’ eye movements, in which saccades are followed by slow drifts back
to center, because the tonic fibres cannot sustain the eccentric position (40). This tonic fatigue can also cause a
gaze-paretic nystagmus after prolonged gaze (41-43).

Secondary adaptive features:

While large saccades are often hypometric in myasthenia, compensatory increases in innervation may lead to
excessive force for small saccades, causing hypermetric small saccades (31). Dissociated gaze-evoked
nystagmus can represent compensatory changes for paresis in the other eye (43), sometimes only emerging after
administration of cholinergic agents (42).

Internal ocular muscles

There are reports of anisocoria that disappeared with anticholinesterase medication (44, 45) but given the normal
variability of anisocoria, such observations are not conclusive. These reports also claimed sluggish pupil light
reactions with improvement on cholinesterase inhibitors (44, 45), which may be supported by quantitative
demonstrations of reduced velocities of pupil constriction (46). There are isolated reports of fatigue of pupil
constriction to prolonged light stimulation (47), abnormal pupil cycle times (48), and accommodation fatigue
that improved with edrophonium (49, 50). These findings are subtle and require instrumentation to detect: as a
rule, obvious pupil or accommodative weakness should suggest a condition other than myasthenia.

Facial Muscles
Facial weakness often coexists with ocular weakness in myasthenia, but can occur in isolation. Fatiguable
weakness of the orbicularis oculi can cause afternoon ectropion of the lower lid. Examination may show failure
to bury the lashes with forceful lid closure, or the ‘peek sign’ indicating orbicularis fatigue (51): on lid closure
to command, the orbicularis muscle may be normal, but as the patient continues to try keeping the eyes forcefully
closed the lids separate, sometimes showing a rim of sclera. With profound orbicularis fatigue, the cornea may
become visible. In severe cases of orbicularis weakness, there may be exposure keratitis, but this is rare.
Orbicularis oris weakness may cause difficulty with whistling, sucking through straw or blowing up a balloon.
On examination the patient may not be able to prevent the escape of air through the pursed lips when examiner
compresses the expanded cheeks. Laughing can reveal ‘myasthenic sneer’ (52).

Mild myasthenic weakness of the orbicularis oculi: Note in this patient with left ptosis, that forced closure of the lids leaves
slightly more of the left lid visible, indicating associated weakness of the orbicularis on the left.

Oropharyngeal Muscles
Tongue weakness can caused slurred speech or swallowing problems. It is assessed by having the patient push
their tongue against their cheek. Slurred speech developing towards the end of a conversation is a fatigable sign.
Weakness of the masseter muscles causes difficulty chewing due to poor jaw closure. Dysphagia can be due to
weakness of the tongue or the posterior pharynx or soft palate; the latter can be associated with nasal dysarthria
and nasal regurgitation of liquid (6). Esophageal smooth muscles are not involved.

Axial Muscles
Myasthenia rarely presents with axial muscle weakness alone, but in generalized disease there can be weakness
of neck flexors causing head droop, vocal cord paresis causing hoarseness, or respiratory muscle weakness
causing dyspnea. The latter is a particular serious problem, as many patients who die do so from respiratory
failure.

Limb Muscles
Weakness affects proximal muscles mainly and is often asymmetric. There can be difficulty in raising the arms
to get items off high shelves, or maintaining raised arms, as when shampooing the hair. Leg weakness can cause
trouble climbing stairs, walking for long distances, or getting up out of low chairs.

PATHOPHYSIOLOGY
There are congenital and acquired forms of myasthenia. Congenital myasthenias are a rare group of disorders,
often presenting in newborns and infants, due to a variety of inherited genetic defects inpre- and post-synaptic
defects affecting the neuromuscular junction (53). Some such as familial infantile myasthenia and familal limb
girdle myasthenia are autosomal recessive, others such as slow channel syndrome are autosomal dominant or
sporadic. Most are apparent from birth, though the slow channel syndrome may present in adulthood. Extra-
ocular muscle dysfunction is frequent but unlikely to be the sole manifestation. Sophisticated electrophysiology
is required for diagnosis. Congenital myasthenia must be distinguished from neonatal myasthenia, in which the
infant of a myasthenic mother has transient weakness because of placental transfer of antibodies.

Acquired myasthenia is an autoimmune disease. Antibodies directed against acetylcholine receptors of the post-
synaptic membrane are responsible for the disease. Evidence for this includes the detection of such antibodies
in the serum of 80%-90% of myasthenic patients (54), immunoglobulin G deposition at the neuromuscular
junction (55), development of experimental myasthenia in animals given immunoglobulin derived from the
serum of myasthenic patients, and improvement of the disease with therapies that reduce serum antibodies (56).

In the 10- 20% of myasthenic patients without antibodies to the acetylcholine receptor, it is postulated that there
may be antibodies to other proteins at the neuromuscular junction. Antibodies against muscle-specific
kinase (MuSK)have been found in 30% of these ‘sero-negative’ myasthenic patients. MuSK is a tyrosine kinase
receptor that is required for the development and maintenance of postsynaptic membrane at the neuromuscular
junction. The pathogenicity of MuSK antibodies in myasthenia remains controversial because these antibodies
do not produce an myasthenic disorder in animal models (57).

Acetylcholine receptor antibodies are polyclonal and differ across patients. They cause weakness by reducing
the likelihood of acetylcholine released into the synaptic gap interacting with the receptor. This may be
accomplished through at least 5 different mechanisms:

 (a) binding of acetylcholine receptor and either altering its function or preventing acetylcholine binding to
acetylcholine receptor,
 (b) endocytosis and accelerating degradation of acetylcholine receptor, by cross-linking and dimerization
of receptors,
 (c) decreased folding of the post-synaptic membrane,
 (d) increased gap between the pre-synaptic nerve terminal and the post-synaptic muscle membrane
 (e) complement destruction of the post-synaptic surface (55).
The reduction in interactions between acetylcholine and its receptor is reflected in smaller amplitudes of the
graded excitatory post-synaptic potentials (EPSP). These need to summate to exceed a certain threshold to trigger
the action potential that causes muscle contraction. The process of neuromuscular transmission has a
significant safety factor, in that these end-plate potentials are usually far larger than the level needed to trigger
action potentials (58). However, in myasthenia the smaller end-plate potentials make generation of the action
potential less reliable. Failure results in weakness. Furthermore, the normal decline in the acetylcholine released
per impulse that occurs with repeated use results in even greater likelihood of failed transmission in the
myasthenic. This is manifest clinically as fatigable weakness (59).
There are several hypotheses about why the extraocular muscles are so frequently affected in myasthenia gravis
(60):

 a) Mild weakness in ocular muscles is easier to notice than limb weakness, since any small ocular
misalignment will cause double vision (60).
 b) Compensation for mild weakness is better in limb than in extra-ocular muscles. Extraocular muscles
do not have the proprioceptive receptors of other skeletal muscle, but rather there are palisade endings
associated with extrafusal muscle fibres, which may not allow for rapid adjustment for mild variations in
muscle power (61).
 c) The extraocular muscles have a higher firing frequency than other skeletal muscle (400 to 500 Hz) and
up to 70% of ocular motor neurons are already at threshold in primary gaze, making them much more
susceptible to transmission defects at the neuromuscular junction.
 d) Extraocular muscles have anatomic characteristics that make them more susceptible to neuromuscular
transmission block. Their post-synaptic membranes have less prominent synaptic folds with fewer
acetylcholine receptors and sodium channels. This reduces the safety factor for neuromuscular transmission
(62) (63). Also, in the 20% of extraocular muscles that are multi-innervated fibres, force generation is directly
proportional to the membrane depolarisation generated by the end-plate potential: hence any reduction in this
potential will reduce muscle contraction (64). Such muscles do not have a safety factor.
 e) There are both fetal and adult isoforms of the acetylcholine receptor. The acetylcholine receptor is a
pentameric protein with different adult and fetal isoforms. The fetal isoform is composed of two alpha
subunits, a beta, a delta, and a gamma. Adult receptors contain an epsilon subunit instead of a gamma. Limb
muscles normally express only the adult form, but extraocular muscles express both (65-67). There is some
evidence that the antibodies in ocular myasthenia bind a mixture of fetal and adult isoforms more strongly
(68).
 f) The immune response in extraocular muscles differs from limb muscles. In rodent models, complement
regulatory proteins are expressed at lower levels in extraocular muscles, and hence the injury from a
complement-mediated disease like myasthenia is more severe in these muscles (69). Other autoimmune
differences between ocular and generalized myasthenia are described. The level of acetylcholine receptor
antibodies in patients with ocular myasthenia is lower (70), and T cell responses to acetylcholine receptor
epitopes of ocular myasthenia patients are lower than that of generalized patients (71).
The reasons for frequent ptosis may differ from this list of explanations for vulnerability of extraocular
dysfunction. Palpebral muscles are more similar histologically to other skeletal muscles than extraocular
muscles. They are fatigue-resistant and their fibres are singly innervated, not multi-innervated. Also, they do not
express the fetal isoform of the acetylcholine receptor (66). The simple explanation again may be that they are
constantly active during waking hours, which make them more prone to fatigue (64).

DIFFERENTIAL DIAGNOSIS
Most commonly the clinician is faced with a problem of differentiating ocular myasthenia from other common
peripheral or central neuropathic conditions, such as the ocular motor palsies.

It must also be remembered that there are other disorders that affect the neuromuscular junction. Lambert-
Eaton myasthenic syndrome affects mainly adults, and causes weakness that improves with repetitive activity.
Involvement of the eyes is usually subtle and infrequent, but include lid retraction after prolonged upgaze (22).
Toxins that impair neuromuscular transmission can mimic myasthenia. Botulism is important: clues are
gastrointestinal symptoms of nausea and vomiting, and autonomic signs of dilated pupils and urinary retention,
and affected friends or family. The toxins of kraits, cobras, coral snakes and sea snakes block acetylcholine
receptors, and intoxication with organophosphate insecticides causes a cholinergic crisis, presenting as a
combination of autonomic and neuromuscular signs

When severe and diffuse, ocular myasthenia may resemble the symmetric total external ophthalmoplegia, ptosis
and orbicularis oculi weakness seen with chronic progressive external ophthalmoplegia (CPEO) (72).
Features pointing to CPEO rather than myasthenia include a slow, progressive symmetric course without
fluctuation and slow saccades (31, 32). Increased jitter on single-fibre EMG can occur with both myasthenia and
CPEO (73). Ragged red fibres on muscle biopsy and deletions on mitochondrial DNA analysis confirm the
diagnosis of CPEO.

Graves ophthalmopathy may mimic myasthenia gravis but lid retraction is seen instead of ptosis. Ptosis in
patients with Graves suggests coexistent myasthenia (10).

DIAGNOSTIC TESTS
Diagnosis of ocular myasthenia gravis is usually made based on clinical grounds. Laboratory tests can help
confirm the diagnosis but have their limitations. For one, all tests are more sensitive in generalized myasthenia
than in ocular myasthenia; hence a negative result in the latter is not very useful. Attention to clinical signs
of variability in weakness over time and between office visits may ultimately provide diagnostic information
that is more useful than these tests.

Edrophonium Test
Edrophonium and neostigmine are acetycholinesterase inhibitors that slow the degradation of acetylcholine and
increase its efficacy at the neuromuscular junction. With the intravenous edrophonium test, a test dose of 2mg
is first given; if no adverse effects occur over the next minute, a further 3-4mg is given, and more, up to 10 mg
total or when benefit is observed (74). In ocular myasthenia, only 2-3 mg is needed to show improvement in
ptosis or extraocular signs (75). Pediatric doses are 1mg for those under 34kg and 2mg for those above (76).
Atropine should be available in case of bradycardia, hypotension, or syncope. The effect begins within about
30-40 seconds and lasts about 8-10 minutes (76). Side effects of tearing, salivation, sweating, abdominal cramps,
and nausea often occur and help confirm that the systemic presence of the drug. Cardiac dysrhythmia and asthma
are contraindications. Placebo control can be used if the endpoint is not obvious, but a vague endpoint usually
means an inconclusive result (74). Intramuscular neostigmine can allow observation over a period of 30-60
minutes, including orthoptic measurements (77).

Improved ptosis is the most reliable sign: reported sensitivities are 92% and specificities of 97% (10, 78-80).
Diplopia fails to respond in about a third of patients (9), and longstanding myasthenia may not respond at all.
For extraocular muscles, the Lancaster red-green test or Hess screen can help assess ocular alignment (77, 81,
82). However, alignment can paradoxically worsen with edrophonium in up to 25% of patients with myasthenia,
as well as in patients with other ocular motor palsies (81, 83). The major problem is that changes in alignment
may not only reflect increased strength but also increased weakness after edrophonium (74), which occurs in
both normal and non-myasthenic weakness. Measuring edrophonium effect is thus best done by assessing
strength of a single muscle rather than changes in the relative strength of two muscles.

Myasthenia gravis, fatigue and edrophonium response of right ptosis. Right ptosis is shown in primary (upper row) and
upgaze (lower row).

Start of testing After 30 seconds of prolonged upgaze 2 minutes after edrophonium

False positive results occur with other neuromuscular, neuropathic, and central conditions, including Lambert-
Eaton syndrome, botulism, brainstem gliomas and other tumours (84-87).

Myasthenia can also be diagnosed from qualitative changes with edrophonium. Saccadic hypermetria may be
induced as the resolution of weakness unmasks a central adaptation that has increased the neural pulse to the
weak muscle (88).
 Myasthenia
gravis,
edrophonium test:
saccadic
waveforms.Record
ing of horizontal
saccades. Top solid
trace right eye
position before 2mg
i.v. edrophonium,
bottom trace is
same eye after
edrophonium.
Dotted traces are
position of the
target.Before the
drug, saccades are
hypometric. After
the drug, saccadic
amplitude is
increased with
pronounced
hypermetria,
unmasking central
adaptation to the
peripheral
weakness. Another
saccade with intra-
saccadic fatigue is
evident as well
(arrow).

Laboratory measures can quantify the effect of edrophonium on (34). Edrophonium increases intraocular
pressure in myasthenia, reflecting improved muscle tone (89-92). This is only a moderately useful test, with
sensitivity and specificity of 82% (34). Eye recording studies show that edrophonium increases the amplitude,
peak velocity and frequency of optokinetic quick phases (30) and saccades (33, 34). Saccadic duration decreases
in myasthenia also (93). In contrast, in patients with non-myasthenic palsies, edrophonium increases saccadic
duration (93) and decreases peak velocities of saccades in patients with non-myasthenic palsies (33) . With
criteria adjusted to yield specificities equal to sensitivities, these saccadic tests have accuracy rates of between
80 and 97% (34).

Almost all of the above studies assessed patients whose diagnoses were known: thus the results were superfluous.
In real life the tests are more important when the diagnosis is uncertain. There are few prospective studies in this
kind of situation. In patients in whom the diagnosis was established later, one study claimed good accuracy for
optokinetic testing (30) and another for saccade testing, using a criterion of 10% increase in amplitude (39).
Ice and Rest Tests
These two tests are more simple procedures, which can be done in the office with relative ease. They have not
been as extensively studied as the edrophonium test, and their sensitivity and the specificity have been
determined by relatively small sample sizes. The inter-observer reliability is also unknown. Some studies have
demonstrated a high correlation between the results of these tests in patients later determined to have myasthenia
by the other more standardized tests (80, 94).

The ice test involve placing a surgical glove containing ice or filled with cotton on a ptotic eyelid for
approximately two to five minutes and noting whether improvement occurs in the degree of ptosis (95, 96).

The rest test involves letting a patient rest with eyes closed for 15 minutes, then re-examining lid and extraocular
function immediately on awakening (94). Improved function can be taken as a sign of fatigable weakness. The
rest test can potentially be used in lieu of the edrophonium test in patients with contraindications to that
medication.

Myasthenia
gravis, sleep test:
saccadic
waveforms.Record
ing of horizontal
saccades. Dotted
traces are position
of the target.Top
solid trace is
horizontal position
of the right eye at
the start of testing.
Bottom trace is
same eye after 15
minutes of rest with
the eyes closed.
Before the ‘nap’,
saccades are slow
and hypometric.
The arrow in the top
graph indicates
intrasaccadic
fatigue: the saccade
begins with a rapid
phase which
suddenly gives way
to a slower phase
with shallower
slope when fast-
twitch fibers
fatigue. After,
amplitudes and
velocity are
improved.
Antibody testing
There are three different forms of circulating acetylcholine receptor antibodies: binding, modulating and
blocking. The binding acetylcholine receptor antibody has sensitivity of 75%-80% for generalized myasthenia.
However, the sensitivity drops significantly in ocular myasthenia to about 50% (9, 97-101), although some ocular
myasthenics with normal antibody titres will develop low positive titres after several months (97). The test for
acetylcholine receptor antibodies has the highest specificity of all tests for ocular myasthenia, around 95-100%
(102).

Testing for modulating acetylcholine receptor antibodies increases the diagnostic yield, but mainly in generalized
myasthenia, but at the cost of slightly lower specificity (10). Testing for blocking acetylcholine receptor
antibodies is of little use: it is positive only in 1% of myasthenics with a negative assay for binding acetylcholine
receptor antibodies.

Although rare (54), false positive assays for acetylcholine receptor antibodies can occur in other autoimmune
conditions, such as systemic lupus erythematosus, rheumatoid arthritis, autoimmune liver disease, thyroid
ophthalmopathy, thymoma, and patients taking D- penicillamine (101, 103), and other neurological conditions
such as amyotrophic lateral sclerosis and Lambert Eaton syndrome. Abnormal titres can also occur in unaffected
family members of myasthenic patients (97).

While there is not a significant correlation between the antibody titre and clinical severity in different patients,
the titre of an individual patient does appear to correlate over time with the severity of their own disease and
their response to treatment (101).

Antibodies against MuSK have been found in 30% of seronegative myasthenics. However, MUSK antibodies
are far less likely in seronegative patients with only ocular myasthenia (104). Given the high cost of testing for
MuSK antibodies there is probably little need to use this test in ocular myasthenia (10).

Repetitive Nerve Stimulation

Repeated stimulation of a motor nerve at 2-5Hz normally leads to a gradual reduction in the amount of
acetylcholine released from the pre-synaptic terminal, but in healthy subjects the amount still comfortable
exceeds the limit needed to generate an end-plate potential that will trigger an action potential (62). In
myasthenia, though, this might fail, leading to a decrease in the amplitude of the compound muscle action
potential of 10% or more, generally by the fourth or fifth response. Repetitive stimulation is positive in 95% of
patients with generalized myasthenia, but may miss up to 50% of patients with ocular myasthenia (9, 105).
Recent reviews suggests that the sensitivity of this test is only 11-39% , though its specificity is 89-98% (10,
80). Also, in ocular myasthenia, some note that abnormal repetitive stimulation result in a limb muscle does not
necessarily imply that the disorder will generalize clinically (10).

Single Fibre Electromyography

Each motor nerve supplies several muscle fibres, which comprise a ‘motor unit’. Single-fibre EMG measures
the synchronicity of the firing of two muscle fibres in the same motor unit, which is usually high. If
neuromuscular transmission is faulty, this synchronicity will deteriorate and become more variable (‘jitter’)
with occasional failure of one unit to fire (‘blocking’). Although technically difficult, single-fibre EMG is one
of the most useful tests for myasthenia. When applied to a symptomatic muscle in generalized myasthenia,
sensitivity is over 90% (106). For ocular myasthenia the frontalis is used (107) with about 85% sensitivity (73,
80), compared to 63% sensitivity for jitter in limb muscles in ocular myasthenia (108). Estimates of specificity
of frontalis jitter for ocular myasthenia range from 63% to 90% (80, 107).
ASSOCIATED DISORDERS
All myasthenic patients should have a CT scan of the chest to rule out thymoma. About 7-26% of patient
with myasthenia gravis have such a tumour (109, 110). These patients have higher mortality rates and greater
morbidity. As many as 65-70% of myasthenic patients have thymic hyperplasia (111). Antibodies directed
against striated muscle may correlate with thymoma: the sensitivity is 84% and the specificity is 56-77% (98,
109, 110). Assuming that 12% of patient s with myasthenia have thymoma, this means that only a third of those
with a positive test have thymoma, though 97% of those with a negative test will not have it. These antibodies
may be generated by an immunologic cross-reaction with antigens in the thymic tumour, specifically to
neurofilaments containing titin epitopes. Anti-titin antibodies supposedly have 100% specificity (110).

Autoimmune thyroid disease is common and hyper- or hypothyroidism can precede or follow myasthenia.
About 25% of patients with normal levels of thyroid hormone will have antithyroid antibodies (17, 18).
Conversely, 8% of patients with Graves’ disease have anti-acetylcholine receptor antibodies (103).

Myasthenic patients with thymoma may be at increased risk for other autoimmune processes (112), including
rheumatoid arthritis, thyroiditis, polymyositis, pernicious anemia, thrombocytopenia, and polymyositis (113),
and non-thymic cancers (112). Rarer associations include Lambert-Eaton syndrome (114) and opsoclonus (115).

MANAGEMENT
The two goals of treatment of ocular myasthenia are to minimize symptoms and to reduce the rate of
progression to generalized myasthenia. Management also includes avoidance of medications that worsen
neuromuscular transmission (116-118). Most frequently reported (118)are aminoglycoside antibiotics, beta-
blockers (119, 120), and chloroquine. Other drugs that may worsen myasthenia are other antibiotics, anti-
arrhythmics, calcium channel blockers (121), some anticonvulsants, and intravenous iodinated contrast (122).
Sometimes these drugs can unmask myasthenia in a previously normal subject (116). Penicillamine may induce
autoantibodies, causing an iatrogenic myasthenic syndrome (116, 118).

Cholinesterase Inhibitors
These drugs bind to the acetylcholinesterase residing in the neuromuscular junction, preventing the degradation
of acetylcholine and increasing the likelihood of interaction between this neurotransmitter and its receptor. These
drugs provide only symptomatic treatment, and probably do not alter the likelihood of progression (123).
Pyridostigmine is the most commonly used of these drugs. Oral Pyridostigmine is started at 15-60 mg every 6
hours and can be increased to 90-120 mg every 4 hrs if necessary. A long-acting, 180-mg slow-release
preparation can be used overnight. The drug•fs onset of action is 30-45 minutes with peak action at 2 hours. In
mild cases, 30-60 mg every 6-8 hours is often effective (124). Ninety percent of patients benefit from these
drugs, although mildly so in half (125). Cholinesterase inhibitors are more effective for ptosis than for diplopia
(9, 10).

Relative contraindications include asthma, arrhythmias, and prostatic hypertrophy. The main side effects stem
from autonomic muscarinic hyperactivity, including hypotension, bradycardia, excess salivation, abdominal
cramps, and diarrhea (117). The major risk is cholinergic crisis, in which excess acetylcholine increases
weakness due to a depolarization block. This can be difficult to differentiate from myasthenic weakness, and
inadvertently worsened by increasing the dose. The safest course is to admit the patient to an intensive care unit,
stop all medications temporarily, consider ventilatory support, and treat with plasmapharesis or intravenous
immunoglobulin.

Corticosteroids
Corticosteroids are the most commonly used immunomodulatory treatment for myasthenia gravis (124),
particularly in patients whose symptoms have not been controlled by acetylcholinesterase inhibitors. A review
of five retrospective studies of corticosteroids in ocular myasthenia concluded that these achieved good results
in 72-96% of patients (126). Limited evidence from randomized controlled trials suggests that corticosteroid
treatment offers significant short-term benefit in myasthenia gravis compared with placebo (127).

A review of several retrospective studies suggests that prednisone or other immunomodulatory therapy in the
first year after diagnosis of ocular myasthenia reduces the rate of generalization, from 34-70% to 9-13%,
regardless of antibody status (128). Others claim that 2 years of low-dose prednisone reduces generalization
from 33% to 7% (75). However, there no controlled trials yet on this issue (123).

Since corticosteroids may transiently worsen myasthenic symptoms initially, most physicians start patients at
a low dose (129), for example 10-20 mg daily increased by 5-10 mg every 3 days until ptosis and diplopia are
significantly improved or a maximum of 60-80 mg/day is reached. After symptoms have stabilized for a month,
daily prednisone can be reduced by 5-10mg every 2 weeks until reaching a dose of 20mg/day, following which
the rate of reduction is slowed. Most patients will require some maintenance dose for years and intermittent
increases with relapses.

Other Immunosuppressive Agents

While these can be used when steroids are ineffective or cause significant side effects, there are few controlled
trials investigating their efficacy (123).

Azathioprine is metabolised to 6-mercaptopurine which in turn inhibits T-cell development (124). It can take 3
to 12 months for induction of its effect and 2-3 years to reach peak efficacy, so prednisone is often used
concomitantly initially. Its peak theraputic level is reached at 2-3 years of treatment. A randomised controlled
trial demonstrated that azathioprine reduces corticosteroid requirement and is as effective as corticosteroids in
long-term treatment of myasthenia (117, 130). For ocular myasthenia, a study of 23 patients suggested that it
was helpful when combined with low-dose prednisone in 91% of this group (125). About 35-55% of patients
with generalized myasthenia on azathioprine develop either gastrointestinal (nausea, vomiting, and elevated liver
enzymes) or haematological side effects (131). Complete blood count and liver enzymes should be monitored
monthly. An acute hypersensitivity reaction with fever, abdominal pain and myalgia mandates immediate
cessation of the drug. Contraindications include diabetes mellitus and hepatitis.

Other immunosuppressive agents are rarely used but are available for patients intolerant of or refractory to
azathioprine and prednisone are problematic (124, 128).

Cyclosporine A has been used in a few reports (132, 133). Like azathioprine, it requires 3-9 months to achieve
a therapeutic response. A third of patients may develop nephrotoxicity or hypertension, which require cessation
of therapy. It is recommended that renal function be monitored monthly for the first 3 months and liver enzymes
monthly for the duration of treatment.

Mycophenolate mofetil is becoming more popular (134-137). It has a strong safety profile and no major organ
toxicity or mutagenic effect. Its adverse effects include vomiting, diarrhea, leukopenia, and sepsis. Complete
blood counts are done weekly for the first month, biweekly for the following 2 months, and monthly thereafter.

Tacrolimus has been used in one report (138). It inhibits helper T cell activation. Tacrolimus is 10-100 times
more potent than cyclosporine and less nephrotoxic. Hyperglycemia is a known dose-dependent complication.

Thymectomy
This is indicated in any patient with a known thymoma, but is often used in patients with progressive generalized
disease regardless of the status of the gland (139). It can induce remission in 10-30% and improves up to 80%
of patients with generalized myasthenia (140, 141). There is little data on thymectomy for ocular myasthenia.
One retrospective review of thymectomy in 61 patients with ocular myasthenia reported remission in 31 patients,
improvement in 12 patients, no change in 1 patient, and worsening in two patients, with one post-operative death.
12 patients had thymomas (142). Without a control group, it is difficult to know how this compares with medical
management. Some clinicians limit the use of thymectomy in ocular myasthenia gravis to those with severe signs
(143). Some claim it offers no benefit (125), while others claim significant improvement in 80% of patients who
fail to respond or relapse with drug therapy (144). A decline in acetylcholine receptor antibodies following
thymectomy with clinical improvement has been documented in some ocular myasthenics (128).

Plasmapharesis and Intravenous Immunoglobulin (IVIG)

Short-term immunomodulation can be achieved with plasmapharesis and intravenous immunoglobulin in the
patient with life-threatening myasthenic crisis, and therefore are not relevant to ocular myasthenia. Improvement
starts in the first week and can last for 4 to 6 weeks.

Symptomatic relief
Physical adaptive therapies can also be used for symptomatic treatment, with varying success. An eye patch
solves any diplopia. Prisms are difficult to use because the weakness fluctuates. Most patients find lid
crutches for ptosis too awkward, and relief of ptosis may unmask a more troublesome diplopia. Strabismus
surgery can rarely be considered in longstanding cases where careful documentation has revealed no change in
ocular alignment over months or years.

PROGNOSIS
A key question is whether a patient with ocular myasthenia will develop generalized disease. Studies suggest
that about 50% will do so within 6 months, and 70 to 80% over the following years. with 94% doing so within
the first 3 years (1, 3, 75). Progression to generalized myasthenia can occur after 3 years but at a very low rate
(125). About 10% achieve complete remission, sometimes at a late date (145).

Electrophysiological findings of subclinical disease in limb muscles do not predict generalization (3). A positive
test for acetylcholine receptor antibodies may increase the likelihood of generalization, but the titre level is not
predictive (75).

Anticholinesterase medications do not change the likelihood of generalization (1). Whether predisone,
thymectomy, or other immunosuppression do so is not yet clear. Retrospective reviews have suggested that
steroids and azathioprine may reduce the rate of generalization by as much as 75% (125, 146). There is too little
data to determine if thymectomy makes a difference (125, 144).