749

Update on Ocular Myasthenia Gravis

Meabh O’Hare, MBBCh, BAO1 Christopher Doughty, MD1

1 Department of Neurology, Brigham & Women’s Hospital, Boston Address for correspondence Meabh O’Hare, MBBCh, BAO,
Department of Neurology, Brigham and Women’s Hospital, 60
Semin Neurol 2019;39:749–760. Fenwood Rd, Boston, MA 02115 (e-mail: mohare1@partners.org).

Abstract Myasthenia gravis is an antibody-mediated autoimmune disorder of the post-synaptic

Keywords neuromuscular junction resulting in fluctuating, fatigable weakness. Most patients first
► ocular myasthenia present with extraocular symptoms (diplopia and/or ptosis), and in 15% of cases
gravis symptoms will remain restricted to only the extraocular muscles (ocular myasthenia
► ptosis gravis [OMG]). The history and clinical examination are of the utmost importance in

Downloaded by: Collections and Technical Services Department. Copyrighted material.

► diplopia correctly identifying OMG patients, as supportive serologic or electrodiagnostic
► neuromuscular studies are frequently nondiagnostic. In this review, we outline a diagnostic approach
junction to OMG (focusing on key clinical features), discuss therapeutic options, and highlight
► acetylcholine recent developments in the understanding of OMG.
receptor antibody

Myasthenia gravis (MG) is an antibody-mediated autoimmune
disorder affecting the postsynaptic neuromuscular junction,
resulting in fluctuating weakness that worsens with exertion
and improves with rest.1 Extraocular symptoms—diplopia
and/or ptosis—are among the initial presenting complaints
in up to 85% of MG patients,2,3 and are the only symptoms
present at disease onset in up to 50%.3 The majority of these
patients will go on to develop generalized muscular weakness
(generalized myasthenia gravis [GMG]), but in approximately
15% of cases, the disease remains restricted to the ocular
muscles (ocular myasthenia gravis [OMG]).2,4 Ocular muscles,
for the purpose of defining OMG, include the extraocular
muscles controlling eye movements (i.e., the superior, inferior,
medial, and lateral recti, and the superior and inferior obli-
ques), the levator palpebrae, and the orbicularis oculi.5
Certain unique challenges are presented in making the
diagnosis of OMG, as it is common for supportive tests such
as serologic or electrophysiologic studies to be nondiagnostic
when disease is restricted to the extraocular muscles. The
clinician must rely heavily on the history and clinical exami-
nation in making the diagnosis. Therefore, the importance of
recognizing classic OMG features and avoiding common diag-
nostic pitfalls cannot be overemphasized. In this review, the
authors outline a diagnostic approach to OMG focusing on
simple bedside exam maneuvers and discuss treatment strat-
egies suitable for affected patients. New developments in the
understanding of OMG are highlighted, including discussion of
lipoprotein receptor-related protein-4 (LRP-4) antibody-asso-
ciated OMG, the emerging phenomenon of checkpoint inhibi-
tor induced myasthenia gravis, and the controversy regarding
the role of early immunotherapy in potentially reducing the
risk of generalization in OMG.
Pathophysiology
The underlying pathophysiology of MG relates to disruption
of the normal structure and function of the neuromuscular
junction (NMJ).6 In the healthy state, an action potential (AP)
reaching a motor nerve terminal results in Ca2þ entry via
P/Q-type Ca2þ channels. Synaptic vesicles containing acetyl-
choline (ACh) then fuse with the presynaptic membrane,
releasing their contents. ACh interacts with acetylcholine
receptors (AChRs) on the postsynaptic membrane, resulting
in cation-specific channel opening that generates a localized
end-plate potential (EPP). Normally, this EPP is more than
sufficient to activate postsynaptic voltage-gated Naþ chan-
nels and trigger a muscle fiber AP, resulting in intracellular
Ca2þ release and muscle fiber contraction.6,7 This built-in
redundancy wherein the EPP amplitude exceeds that re-
quired to trigger an AP is termed the “safety factor.”6
A healthy postsynaptic NMJ is a highly organized, tightly
folded structure with acetylcholine receptors (AChRs) densely
concentrated at the apices of these folds, and voltage-gated
Naþ channels concentrated in the troughs (►Fig. 1). Structural

Issue Theme Neuro-Ophthalmology; Copyright © 2019 by Thieme Medical DOI https://doi.org/

Guest Editor, Sashank Prasad, MD Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0039-1700527.
New York, NY 10001, USA. ISSN 0271-8235.
Tel: +1(212) 584-4662.
750 Update on Ocular Myasthenia Gravis O’Hare, Doughty
Fig. 1 Electron microscopy of the neuromuscular junction (stained
for AChR). (A) Normal individual. (B) A patient with moderately severe
GMG. The NMJ in myasthenia demonstrates deficiency of AChR
staining as well as degeneration of the postsynaptic architecture.
Reproduced from: Engel129 with permission. AChR, acetylcholine
receptors; GMG, generalized myasthenia gravis; NMJ, neuromuscular
junction.
proteins including low-density lipoprotein receptor-related
protein 4 (LRP-4) and muscle-specific receptor tyrosine kinase
receptor (MuSK) are required for the normal clustering of
AChRs.6 The structural organization of the NMJ is critical for
the coupling of the EPP to AP generation.6 In healthy NMJs, the
quantity of ACh released from the presynaptic membrane
progressively decreases under conditions of sustained activity
(a normal phenomenon termed “synaptic rundown”). Howev-
er, due to the normal built-in safety factor, EPPs remain large
enough to trigger an AP. In MG, disruption of normal NMJ
function results in a loss of the safety factor, meaning that
some EPPs are of insufficient amplitude to trigger a muscle
fiber AP. The decremental muscle response with sustained
neural activity manifests clinically as the characteristic fatiga-
bility seen in this condition.7
In MG, a number of pathogenic autoantibodies have been
identified, targeting different components of the NMJ. Anti-
bodies targeting the AChR (AChR Abs) are most common and
result in complement-mediated destruction of the postsyn-
aptic membrane.8 In addition, AChR Abs block the action of
ACh and cause crosslinking of AChRs, thereby increasing the
rates of receptor degradation.6,8,9 The pathogenic mecha-
nism of anti-MuSK Abs, which are primarily immunoglobu-
lin G4 (IgG4) subtype Abs that do not fix complement,8 is less
clear. However, MuSK is known to be critical for the mainte-
nance of both pre- and postsynaptic structure and function,
and anti-MuSK Abs appear to impair normal MuSK activity,
leading to decreased ACh release, as well as loss of normal
AChR clustering.10 Antibodies directed at LRP-4 result in
impaired NMJ function owing to interference with MuSK
activation and signaling, as well as complement fixation and
postsynaptic membrane destruction.11
It is important to be aware that a significant proportion of
OMG patients have no detectable antibodies against these
targets, and the pathophysiology underlying these cases
remains unclear. Many of these “seronegative” cases may
Seminars in Neurology Vol. 39 No. 6/2019
represent false negative testing in patients that harbor an
autoantibody that is not detected by conventional means. For
example, the diagnostic yield of AChR Abs testing is significant-
ly increased by using a cell-based assay, rather than the typical
radioimmunoprecipitation technique.12,13 Others may have
novel autoantibodies that have not yet been described. Recent-
ly, antibodies directed against cortactin (a postsynaptic protein
required for clustering of AChRs) have been identified in 24% of
double seronegative OMG patients.14 The pathogenicity and
specificity of cortactin antibodies remains to be determined.15
The primary site of AChR Ab production is the thymus
gland, which plays a key role in MG pathogenesis.8,9 The
thymus is the site of normal T-cell maturation, and is critical
in the establishment of central immune tolerance.9 Normally
the thymus undergoes involution in adulthood,9 but 70% of MG
patients have evidence of thymic follicular hyperplasia,16 and
Downloaded by: Collections and Technical Services Department. Copyrighted material.
about 15% have thymoma.17 The prevalence of thymic pathol-
ogy in patients with purely ocular symptoms has not been
clearly described. Thymomas are more commonly identified in
late-onset MG (i.e., >50 years old), and are strongly associated
with both AChR Ab seropositivity and generalized disease.8
The presence of antibodies targeting components of striated
muscle (including titin and ryanodine receptors)8 is also
predictive of thymoma, particularly in younger patients.18
It is not entirely clear why MG involves extraocular
muscles so prominently.19 Extraocular muscles may be
more prone to fatigability due to their rapid firing rate.
Motor end plates within extraocular muscles may also
have physiologic characteristics that confer increased sus-
ceptibility to the effects of MG, such as lower concentration
of AChRs and the presence of multiterminal muscle fibers
which lack secondary synaptic folding.19,20 In addition,
complement regulatory genes are expressed differently in
extraocular muscles, which may make their NMJs more
susceptible to complement-mediated tissue injury.19
Clinical Presentation and Examination
Findings
The estimated incidence of MG is approximately 10 cases per
million person-years, with a prevalence of about 80 cases per
million people.21 The age of onset of MG is bimodal in women
(peaking in the 30s and then in the 70s) but is unimodal in
men (peaking in the 70s).21 A similar distribution is seen in
OMG.22 OMG is slightly more common in men, with a male:
female ratio of about 3:2.22
Patients with OMG complain of drooping of the eyelids
and/or doubling or blurring of their vision. Fatigability of
these symptoms is a key feature – patients often describe
feeling best first thing in the morning and worst in the
evening, and may report improvement after rest or napping.
Diplopia can take a variety of forms, such as vertical, hori-
zontal, oblique, or any combination of these. Diplopia that
varies in character over time is highly suggestive of MG.
On examination, ophthalmoplegia of any combination of
extraocular muscles may be found, including any isolated
extraocular muscle. OMG can accordingly be confused with
disorders such as neuropathies of cranial nerves III, IV, or VI;

Fig. 2 In this patient with bilateral ptosis due to ocular myasthenia
gravis, taping up the right eyelid has resulted in worsening ptosis of
the left eyelid, to the point of complete eye closure (“curtain sign”).
internuclear ophthalmoplegia; or vertical gaze palsy. An es-
sential differentiating feature is ophthalmoplegia that fatigues
or changes in character. Fatigability should be sought on
examination even if patients do not volunteer it, with the
caveat that it is not specific to MG. Sustained upward gaze may
provoke or exacerbate ptosis or diplopia,23 and persistent gaze
in the direction in which diplopia is most symptomatic may
also provoke or exacerbate symptoms.24 Examining the eyes at
different times during the patient encounter may reveal
changing patterns of extraocular weakness. In cases of mild
ophthalmoplegia, the alternate crosscover test or Maddox rod
testing can be helpful in demonstrating a subtle phoria that
worsens with sustained gaze.
Ptosis can be bilateral or unilateral; unilateral ptosis that
alternates between sides is particularly suggestive of MG
(►Fig. 2).25 Because of the equal bilateral innervation to the
levator palpebrae muscles (Hering’s law), passively raising a
seemingly unilateral ptotic eyelid may sometimes unmask
subtle ptosis on the other side (a phenomenon called the
“curtain sign”).26,27 Weakness of orbicularis oculi, leading to
weak or incomplete eye closure (the “peek sign”), is also very
common in OMG.28 Strength of other facial, bulbar, or limb
muscles should be carefully examined, as weakness of any of
these would indicate GMG.
Bedside assessments of pupillary function are normal in
MG, which can help to distinguish it from other causes of
complex ophthalmoparesis, including third nerve involve-
ment. However, pupillometric studies in patients with MG
have demonstrated subtle subclinical changes in the velocity
of the pupillary response,29,30 as well as fatigability of the
pupillary response (as demonstrated by a reduction in the
oscillatory rate of hippus, following sustained light expo-
sure31), and fatigability of the accommodation reflex, indi-
cating minor involvement of intrinsic ocular muscles.32
Differential Diagnosis
A broad differential diagnosis should be considered for
patients presenting with symptoms and signs suggestive of
OMG, particularly those with ambiguous exam findings and
negative diagnostic testing. As discussed further below, ab-
normalities on electrodiagnostic testing are nonspecific, and
Update on Ocular Myasthenia Gravis O’Hare, Doughty 751
should not be overrelied upon. Common differential consider-
ations are outlined in ►Table 1. Careful examination of pupil-
lary function and eye closure is particularly important; as
discussed above, pupillary involvement should automatically
prompt consideration of a cranial nerve III palsy rather than
MG as the cause of ophthalmoplegia/ptosis. Conversely, weak-
ness of eye closure in association with ophthalmoplegia makes
MG more likely, as it is not seen with cranial nerve III, IV, or VI
palsies or with thyroid ophthalmopathy. Given that intracra-
nial mass lesions such as tumors or aneurysms can mimic OMG
through effects on cranial nerves or their nuclei, imaging of the
brain is sometimes necessary in cases of diagnostic uncertain-
ty.33 Decompensated underlying strabismus (e.g. caused by
congenital esophoria or IV nerve palsy) can also mimic OMG, as
patients often report symptoms that worsen with fatigue;
however, serial examinations in these cases do not demon-
Downloaded by: Collections and Technical Services Department. Copyrighted material.
strate dynamic changes in the pattern of ocular misalignment.
It is also important to inquire about exposure to certain
drugs that can induce MG. Historically, D-penicillamine
(used in the treatment of rheumatoid arthritis) was known
to induce AChR Ab-positive MG in up to 7% of treated
patients.34,35 In contemporary practice, MG is now increas-
ingly being recognized as a complication of immune check-
point inhibitors (ICPis). These medications are being
increasingly used to upregulate the immune system to target
a variety of malignancies. ICPis can lead to off-target im-
mune-related adverse events (irAEs) affecting essentially any
system in the body. The incidence of MG after ICPi use has
been estimated at 0.12 to 0.2%.36,37 This can present as
isolated OMG, but more commonly patients with ICPi-relat-
ed MG present with more severe generalized symptoms,
frequently requiring ventilator support.36–38 ICPis have also
been reported to provoke severe exacerbations in those with
known myasthenia gravis, even patients previously with
only OMG,39 or in pharmacologic remission.40
Symptoms of ICPi-associated MG typically begin after the
first or second cycle of treatment, a median of 5 weeks after
initiation of treatment.36–38 In addition, ICPis can induce
myositis, which commonly involves bulbar and oculomotor
muscles, making the distinction from MG challenging. More-
over, overlap of MG and myositis frequently occurs.36,41
When overlap is suspected, a decremental response to
slow repetitive nerve stimulation and positive AChR Abs
suggest MG, whereas an elevated creatine kinase (CK) sug-
gests myositis. Cases of MG with or without myositis are
sometimes accompanied by concurrent myocarditis,36 so
screening with troponin levels, electrocardiogram, and/or
echocardiography may be considered in those with respira-
tory symptoms or an elevated CK.42 A major difference
between ICPi-associated MG and idiopathic MG is that the
illness may be monophasic; initial treatment with pyridos-
tigmine and corticosteroids (or intravenous immunoglobu-
lins [IVIg] or plasma exchange in severe cases) may result in
symptom resolution without the need for corticosteroid-
sparing agents. If initial symptoms are restricted to OMG or
only mild generalized weakness, the American Society of
Clinical Oncology (ASCO) guidelines allow for consideration
of restarting the ICPi once symptoms have resolved.42
Seminars in Neurology Vol. 39 No. 6/2019
752 Update on Ocular Myasthenia Gravis O’Hare, Doughty

Table 1 Mimics of ocular myasthenia gravis

Disease Distinguishing features

Thyroid ophthalmopathy Thyroid eye disease (also known as Grave’s orbitopathy) can cause variable
ophthalmoplegia but typically does not cause ptosis or weakness of orbicularis
oculi. It may be associated with proptosis or periorbital edema.120 In some cases,
thyroid ophthalmopathy and OMG can coexist.
Mitochondrial myopathies Chronic progressive external ophthalmoplegia (CPEO) causes bilateral, sym-
metric ptosis and severe restriction of eye movements. Despite the degree of
ophthalmoparesis, diplopia is often absent.121 Associated findings indicative of
cerebellar and/or retinal pathology may also be seen when CPEO occurs in the
context of Kearns–Sayre syndrome.122
Cranial neuropathies Any process affecting cranial nerves III, IV, and/or VI can be confused with OMG.
Intracranial mass lesions (including the cavernous sinus), brainstem infarction,
trauma, infection, and Miller–Fisher variant acute inflammatory demyelinating
polyneuropathy can all affect multiple cranial nerves and thereby mimic OMG.
Pupillary involvement is not seen with MG and accordingly should raise a
high degree of concern for an alternative pathology, especially a compressive

Downloaded by: Collections and Technical Services Department. Copyrighted material.

lesion affecting cranial nerve III.
Oculopharyngeal muscular dystrophy (OPMD) OPMD causes progressive bilateral ptosis which may be asymmetric. Retrospec-
tively identifying an insidious onset (e.g. in old photographs) can be helpful.
Ophthalmoparesis occurs but diplopia is less common. Patients often also
experience dysarthria and dysphagia.123
Myotonic dystrophy Myotonic dystrophy (most commonly type 1) can cause bilateral ptosis and
some degree of ophthalmoparesis. Grip or percussion myotonia is usually evident
on exam, as is weakness of neck flexion and distal limb muscles. Other features
include dysphagia, dysarthria, cataracts, and cardiac arrhythmias.124
Congenital myasthenic syndromes Congenital myasthenic syndromes are rare genetic disorders resulting in NMJ
dysfunction. Some may present in adulthood, mimicking seronegative autoim-
mune MG and should be considered if usual MG treatment is ineffective.125
Congenital myopathies Certain congenital myopathies (centronuclear myopathy and core myopathies)
can present in adulthood with prominent ophthalmoplegia and/or ptosis.
Prominent bulbar symptoms typically accompany the extraocular weakness, as
well as frequent respiratory involvement.126
Decompensated phoria An underlying tendency toward mild ocular misalignment is common, and
typically overcome by compensatory mechanisms. These mechanisms can
decompensate over time, leading to episodes of blurred or double vision.127
Convergence insufficiency Convergence insufficiency can cause symptomatic diplopia due to an inability to
maintain binocular fusion with near vision. This is often a primary idiopathic
condition, but can occur as a consequence of traumatic, ischemic, neurode-
generative or metabolic insults.128

Abbreviations: MG, myasthenia gravis; NMJ, neuromuscular junction; OMG, ocular myasthenia gravis.

Diagnosis and Testing overestimates given inherent limitations of the case-

An overview of the diagnostic approach is illustrated in
►Fig. 3. Although serologic and electrophysiologic testing
play an important role in the diagnosis of MG, it is important
to recall that serologic studies are frequently negative in
OMG, and typical electrodiagnostic findings can be nonspe-
cific. Accordingly, a number of simple bedside maneuvers,
listed below, have an important role in the evaluation of
patients with suspected OMG:
• The “ice test”: applying ice to a ptotic eyelid results in
temporary improvement in ptosis due to the enhance-
ment of neuromuscular transmission at cold tempera-
tures (►Fig. 4).43 Ice should be applied for at least
2 minutes, and an improvement of at least 2 mm in ptosis
is considered a positive result.44 Pooled estimates of
sensitivity and specificity for this test have been reported
as 94 and 97%, respectively45; however, these are likely
control design of the included studies. One retrospective
cohort study (in which the ice test was routinely per-
formed on all patients presenting with ptosis) reported
sensitivity of 92% and specificity of 79% for OMG.46
• The “rest test”: the patient lies down in a dark room with
eyes closed for 30 minutes. The test is positive if this results
in an objective improvement in ptosis or ophthalmopare-
sis.47 A single case–control study reported very high sensi-
tivity and specificity for this test (99 and 91%, respectively).45
• Cogan’s lid twitch: this sign is provoked by asking the patient
to gaze downwards (thus resting the levator palpebrae), and
then make a saccade back to the primary position. The upper
eyelid briefly overshoots into retraction before then settling
into the ptotic position.48 In one cohort of patients with
isolated ptosis (bilateral or unilateral), sensitivity and speci-
ficity of Cogan’s lid twitch for OMG were 50 and 91.7%,
respectively, with false positives seen in levator dehiscence
and mitochondrial myopathy.49 A false positive Cogan’s lid

Seminars in Neurology Vol. 39 No. 6/2019

 Update on Ocular Myasthenia Gravis O’Hare, Doughty 753

Downloaded by: Collections and Technical Services Department. Copyrighted material.

Fig. 3 Suggested diagnostic algorithm for suspected OMG. AChR, acetylcholine receptors; CMAP, compound muscle action potential; GMG,
generalized myasthenia gravis; LRP, lipoprotein receptor-related protein; MRI, magnetic resonance imaging; MuSK, muscle-specific receptor
tyrosine kinase receptor; OMG, ocular myasthenia gravis; RNS, repetitive nerve stimulation; SFEMG, single-fiber electromyogram.

twitch has also previously been reported with parasellar
meningiomas50 and dorsal midbrain gliomas.51
• The forced eyelid closure test (Bienfang’s test): this is a
modification of the Cogan’s lid twitch in which sustained
voluntary contraction of the orbicularis oculi for 5 to
10 seconds (to ensure a period of complete levator palpe-
brae relaxation) that enhances the appearance of a transient
upward lid twitch when eyes are reopened.52 In one study,
sensitivity was 94% and sensitivity was 91% for the diagnosis
of OMG. False positives were seen in Lambert–Eaton myas-
thenic syndrome (LEMS) and decompensated phoria.52
Serologic Testing
AChR Ab positivity is the most specific diagnostic test for
OMG–in cases with suggestive symptoms and signs, the
specificity is estimated to be 98 to 100%.45 False positives
have been reported in cases of motor neuron disease and LEMS,
as well as in asymptomatic patients with other autoimmune
diseases, or thymoma.53 The sensitivity of serologic testing,
however, is poor in OMG. While as many as 90% of GMG
patients are AChR Ab positive, only about 50% of those with
OMG will test positive.45,54–59 Different AChR subtypes have
been identified: binding, modulating, and blocking AChR Abs.
Binding Abs are the most important of these, but testing for
modulating Abs in addition leads to slightly increased test
sensitivity.53,60 AChR blocking Abs are of lower clinical utility,
as they are not detected in isolation.53,60
Approximately 40 to 50% of generalized MG patients
negative for AChR Abs will test positive for anti-MuSK
Abs,61–63 with a female predominance.63 Bulbar, neck, and

Seminars in Neurology Vol. 39 No. 6/2019

754 Update on Ocular Myasthenia Gravis O’Hare, Doughty
Fig. 4 This patient with ocular myasthenia gravis has baseline asymmetric bilateral ptosis (A). After application of the ice pack (B), the ptosis
objectively improves (C). (Images courtesy Sashank Prasad, MD).
respiratory involvement are prominent features seen in this
phenotype.58,61,62 Initial descriptions of the clinical pheno-
type associated with anti-MuSK seropositivity suggested
that extraocular muscles were less commonly affected,61,64
but more recent reports indicate at least some ocular in-
volvement in the majority of cases.58 However, anti-MuSK
Abs are only rarely found in isolated OMG (detected in 5% of
one OMG cohort56).
Anti-LRP-4 Abs have been detected in about 20% of
“double-negative” MG (i.e., negative for both AChR and
MuSK Abs),65 although estimates of LRP-4 seropositivity
vary widely between studies (range: 2–50%).66–68 Clinically,
anti-LRP-4 MG tends to present with milder symptoms than
AChR-positive MG, frequently with isolated ocular involve-
ment.65 In one cohort of patients with double-negative OMG,
27% were LRP-4 positive.65 MG antibody assays do not
routinely include LRP-4 antibodies, so sending this separate
test in seronegative OMG patients may be useful. LRP-4
antibodies are not specific to MG – they have been detected
in up to 23% of patients with motor neuron disease,69,70 as
well as in cases of LEMS and neuromyelitis optica.65
Edrophonium (“Tensilon”) Testing
The interpretation of this test requires an objective, measur-
able deficit (most commonly ptosis or ocular misalignment)
which should improve after IV administration of edropho-
nium (an acetylcholinesterase inhibitor with rapid onset and
offset71). False positive results have been reported in motor
neuron disease, LEMS, and central lesions including brain-
stem glioma and pineal germinoma.72–74 Edrophonium test-
ing has largely been supplanted by serologic testing given the
small associated risk of bradycardia and bronchospasm;
testing requires cardiac monitoring and atropine available
at the bedside.72
Electrodiagnostic Studies
Given the high specificity of serologic testing, electrodiag-
nostic testing is most useful in seronegative cases of sus-
pected OMG. When testing for MG, slow repetitive nerve
stimulation (RNS) at 2 to 5 Hz is used (►Fig. 5). Changes in
the resulting compound muscle action potential (CMAP)
with each stimulation are measured.75 Although RNS at
Seminars in Neurology Vol. 39 No. 6/2019
Downloaded by: Collections and Technical Services Department. Copyrighted material.
this rate results in a depletion of the presynaptic ACh
vesicles, the safety factor present in healthy NMJs results
in stable CMAP amplitudes. In MG, however, repetitive
stimulation results in EPPs that dip below the threshold
required to generate each all-or-nothing muscle fiber AP,
so summative CMAPs decrease in amplitude with repetitive
stimulation. Typically the first CMAP is compared with the
fourth or fifth CMAP, and a decrement of >10% is considered
a positive test.75,76 Repetitive nerve stimulation (RNS) has
relatively low sensitivity for OMG (with abnormalities
detected in about 30% of cases).45,77 RNS test sensitivity is
improved by focusing the study on muscles that are clinically
weak, so testing orbicularis oculi offers higher yield in
suspected OMG.78
After 1 to 2 seconds of RNS, ACh is mobilized from
a secondary store, increasing the EPP and resulting in stabi-
lization or slight improvement of the CMAP decrement.76 In
MG, exercise of muscles also leads to fatigability and more
profound decrement of the CMAP amplitude.76 A decremen-
tal response to slow RNS can also be seen in other conditions,
such as LEMS, motor neuron disease, and other neuropathic
conditions.77 RNS should therefore always be performed in
conjunction with routine nerve conduction studies and
electromyography to ensure these other conditions are not
missed.76 RNS is also technically demanding; any movement
of the patient, recording electrodes, or nerve stimulator can
artifactually create the false impression of a decremental
response (►Fig. 5).77
Single-fiber electromyography (SFEMG) is the most sen-
sitive test for OMG (abnormal in about 95% of OMG patients if
more than one muscle tested79,80), leading some to argue
that it should be used in place of RNS in suspected OMG
cases.75 However, SFEMG is not available at all centers, is
highly operator dependent, and requires close patient coop-
eration.76 Variability in the AP interval between two muscle
fibers in the same motor unit, termed “jitter,” is the key
abnormality detected on SFEMG in MG. Abnormal jitter is not
specific to NMJ disorders; it is seen in a wide range of nerve
and muscle disorders, and must be interpreted in the appro-
priate clinical context.
Finally, in cases where serologic and electrodiagnostic
testing is nondiagnostic, but significant clinical suspicion for

Fig. 5 (A) 3-Hz repetitive nerve stimulation in a patient with myasthenia
gravis results in a >10% decrement in amplitude when comparing the first
and fifth compound muscle action potential (CMAP). (B) Following
10 seconds of sustained voluntary contraction of the muscle, the test is
repeated and less decrement (“repair”) is observed. This phenomenon of
transient improvement (“postexercise facilitation”) occurs because maxi-
mal voluntary contraction leads to calcium accumulation in the pre-synaptic
nerve terminal, facilitating ACh release and thereby counterbalancing the
depletion of ACh vesicles. (C) At a more delayed time point following
exertion (i.e., 3 minutes after 60 seconds of exercise), the decremental
CMAP response is more pronounced—a phenomenon termed “postexercise
exhaustion.” (D) Repetitive stimulation can be technically challenging.
Here, artefactual decrement in sequential CMAPs is demonstrated; this can
occur as a result of patient, electrode, or stimulator movement. True
pathophysiologic decrement leads to a characteristic “U-shaped” pattern of
sequential CMAPs, as is seen in panels A and C, whereas artefactual
decrement leads to a more haphazard, random pattern.
Update on Ocular Myasthenia Gravis O’Hare, Doughty 755
OMG remains, an empiric trial of pyridostigmine can be
considered. A symptomatic response to this can help support
a clinical diagnosis of OMG. Serologic testing should also be
repeated in 6 to 12 months, as some patients initially
categorized as seronegative will develop detectable circulat-
ing antibodies on repeated testing.81
Additional Testing
All patients diagnosed with MG (OMG or GMG) should
undergo screening imaging to evaluate for thymoma, typi-
cally with computed tomography (CT) or magnetic reso-
nance imaging (MRI) of the chest.82 Other autoimmune
diseases are frequently comorbid in patients with MG.
Thyroid disease is most common among these, affecting up
to 22% at presentation.83 It is therefore reasonable to obtain
screening thyroid function tests at the time of diagnosis.
Downloaded by: Collections and Technical Services Department. Copyrighted material.
Risk of Conversion to Generalized
Myasthenia
The clinical course over the first 3 years seems to be critical in
determining the long-term manifestations of the disease.84
About 15% of patients initially presenting with ocular symp-
toms will remain purely ocular, while about 85% will general-
ize.2,4,85 The vast majority of this generalization occurs within
the first year of symptoms. One large case series demonstrated
that 87% of generalization occurs in the first year and 94% in the
first 3 years.84 However, a recent case series using a more
restricted definition of OMG—isolated ocular symptoms for
>24 months—still demonstrated a rate of progression to GMG
of 21% at a median of 83 months (range, 24–158 months).56
Risk factors for the development of generalized symptoms
include female gender and seropositivity, with a much greater
risk of generalization in MuSK-positive cases than in AChR-
positive cases.56,86 A retrospective cohort study of 101 OMG
patients (not treated with any form of immunosuppression)
identified that significant predictive factors for generalization
included seropositivity, thymic hyperplasia, and the presence
of comorbidities including other autoimmune diseases.87
Electrodiagnostic evidence of subclinical generalized dis-
ease has been examined as a risk factor for clinical generali-
zation of OMG. One prospective study of 39 OMG patients
within 4 months of symptom onset showed that SFEMG
abnormalities of the extensor digitorum communis (EDC)
were common, occurring in 70% of cases. A higher percentage
of the patients with abnormal SFEMG converted to GMG (57
vs. 18%), although this did not reach statistical significance.88
Subsequent larger retrospective studies have confirmed the
high rate of subclinical SFEMG abnormalities in OMG
patients (occurring in 68–82% of cases) but have shown no
predictive value of these findings.89,90
Patients with OMG that do not generalize tend to have a
benign clinical course, with ocular symptoms typically reach-
ing peak severity within the first 1 to 3 years.2 In a retrospec-
tive review of 78 OMG cases, 54 cases remained purely ocular
over the follow-up period (mean duration, 8.3 years); of these,
54% went into remission (defined as the absence of disability,
with or without pharmacologic treatment), 33% showed
Seminars in Neurology Vol. 39 No. 6/2019
756 Update on Ocular Myasthenia Gravis O’Hare, Doughty
clinical improvement, and 13% remained stable.83 However,
patients who do not achieve minimal manifestations of disease
status do report reduced quality of life, and more severe ocular
symptoms at onset correlate with an increased likelihood of an
unfavorable response to therapy.91
Treatment
While OMG symptoms of ptosis and diplopia can be trouble-
some and even disabling for the patient, they are usually not
life-threatening. Therefore the role of aggressive immuno-
modulating therapies is debated in this population. However,
balanced with this concern is the understanding that a
significant proportion of OMG patients will develop gener-
alized symptoms, with some data suggesting a possible
reduction in the rate of generalization with the early use
of immunotherapies.83,92–95 Additional recent observational
data also suggest that early initiation of immunosuppressive
therapy is associated with a greater likelihood of successful
resolution of symptoms. Those treated with corticosteroids
 steroid-sparing agents within 12 months of symptom
onset were twice as likely to show complete resolution of
ophthalmoparesis, with a median time to resolution of
4 months (compared with 14 months in the delayed treat-
ment group).96 Randomized data to support a specific treat-
ment approach are sparse, so a tailored approach based on
patient preference, treatment goals, and the anticipated side
effect burden may be most appropriate.97
Nonpharmacologic Treatment Options
In patients with mild symptoms (e.g., incomplete ptosis),
starting with a conservative, nonpharmacologic approach is
reasonable and avoids potential side effects from medica-
tions. For patients with symptomatic diplopia, the most
simple and cost-effective intervention is to patch one eye.
For those resistant to wearing a patch, one occlusive contact
lens can be used. Alternatively, customized prisms can be
helpful if the degree of misalignment is relatively stable.98
Strabismus surgery can be performed but typically only in
patients with stable ocular misalignment for at least
6 months.98,99 In one retrospective series describing nine
OMG patients managed with strabismus surgery, five
patients achieved single-vision postoperatively, and four
patients required a second surgery.100 Ptosis can be treated
with eyelid supports (either crutches inserted into glasses
frames or taping of the eyelid),98,101 although there is an
associated risk of exposure keratopathy.98 Ptosis surgery can
be performed in cases of longstanding, stable myasthenic
ptosis, but there is a high rate of ptosis recurrence with need
for repeat surgery. Exposure keratopathy is again a risk.98,102
Pharmacologic Treatment Options
Pyridostigmine
Pyridostigmine is an acetylcholinesterase inhibitor which
prolongs the duration of action of ACh at the NMJ.103 Dosing
is started at 30 mg two to four times per day which can be
increased gradually up to 60 to 90 mg four to five times per
Seminars in Neurology Vol. 39 No. 6/2019
day.33,101 Pyridostigmine is a purely symptomatic interven-
tion with no effect on the natural history of the disease.101
Unfortunately, only 20 to 40% of OMG patients will exhibit a
satisfactory response to pyridostigmine monotherapy.101 Side
effects range from unpleasant (diarrhea, increased salivation,
urinary urgency) to more dangerous (e.g. bronchospasm in
those with underlying obstructive lung disease).101
Corticosteroids
In patients with persistent symptoms despite pyridostig-
mine, corticosteroids are commonly used as the next line of
therapy, typically prednisone/prednisolone.33 Corticoste-
roids exert their therapeutic effect in MG by reducing anti-
body production and inhibiting CD4 þ T cell activation.101 Up
to 80% of OMG patients will show significant symptomatic
improvement with corticosteroids.101 Data from a retrospec-
Downloaded by: Collections and Technical Services Department. Copyrighted material.
tive cohort study suggests that the rate of achieving complete
remission from ocular symptoms may be higher in those
treated with steroids compared to pyridostigmine alone (70
vs. 21%). However, at a median dose of 20 mg of prednisone
daily, this was associated with a relatively high incidence of
adverse events including new-onset glucose intolerance or
diabetes in 67%, new or worsening hypertension in 20%,
weight gain in 42%, and new or worsening osteoporosis in
20%, despite appropriate calcium and vitamin-D supplemen-
tation.59 Although hampered by poor accrual of participants,
the recently completed randomized placebo-controlled
EPITOME (Efficacy of Prednisone for the Treatment of Ocular
Myasthenia) trial demonstrated that minimal manifestations
status could be reached within 16 weeks for five out of six
prednisone-treated OMG patients in comparison to zero of
five on placebo, with comparably low rates of mild adverse
events.57
Expert consensus generally favors starting at low doses of
prednisone and slowly uptitrating (e.g., 5 mg increments
every 5 days) until significant symptom resolution is
seen.33,103,104 The maximum dose of steroids required for
symptom control is typically lower in OMG than in
GMG.96,103 The median prednisone dose required for treat-
ment response in the EPITOME trial, for example, was 15 mg
daily.57 After symptom control is achieved, the dose is
tapered over several weeks to the minimum effective
dose.33,103,104 For certain patients – those prioritizing rapid
symptomatic resolution, and at lower risk of side effects –
higher starting doses of 0.5 mg/kg/day can be prescribed,
followed by a slow taper once symptoms improve.97
Other Immunotherapeutic Agents
When corticosteroids are ineffective (as seen in up to 24% of
OMG patients92), when side effects limit their use, or when
contraindications preclude their use entirely, additional
immunosuppressive agents, such as azathioprine, mycophe-
nolate mofetil, or methotrexate can be considered. These
medications may be introduced when patients require high
doses of steroids or have difficulty weaning, or they can be
started at the same time as steroid therapy (especially in
selected patients at higher risk for steroid-induced
complications).

A placebo-controlled randomized trial has shown that
using azathioprine as an adjunct to steroids in generalized
MG leads to lower maintenance steroid doses, increased
remission rates, lower relapse rates, and decreased side
effects.105 Specifically for OMG, azathioprine used alone or
in combination with prednisone is effective in improving
symptoms in the majority of patients (91% positive response
reported with azathioprine and prednisone combination
therapy in a nonrandomized trial).83 Azathioprine is typical-
ly better tolerated than long-term steroid therapy,101 but
careful monitoring is required as some side effects can be
life-threatening. Complete blood count and liver function
testing must be followed, as leukopenia, thrombocytopenia,
and liver function test abnormalities can result.101 Those
with mutations in the thiopurine methyltransferase gene are
at increased risk of azathioprine-induced myelosuppres-
sion.103 In addition, azathioprine confers a three-fold in-
creased risk of developing nonmelanomatous skin
cancers.106 Mycophenolate mofetil has also been shown to
be safe and well-tolerated as a steroid-sparing agent in
OMG,107 but a randomized placebo-controlled trial in GMG
showed no benefit.108 Gastrointestinal complaints are the
most prominent side-effect of mycophenolate,107 and mye-
losuppression or hepatotoxicity are rarely seen.103 Metho-
trexate has been compared to azathioprine in GMG and
shown to have similar efficacy and tolerability.109
Although commonly considered as rescue therapy in
generalized disease, IV immunoglobulins and plasmaphere-
sis are typically not required for OMG. Eculizumab, a biologic
agent targeting the terminal complement protein C5 is now
available for use in AChR positive GMG. However, the lack of
data in OMG and seronegative patients110 preclude its use at
present in the OMG population.
Thymectomy
Thymectomy is required for those patients with thymoma, but
has also been shown to result in better clinical outcomes and
reduced corticosteroid requirements in nonthymomatous
AChR seropositive GMG.111,112 Thymectomy may be particu-
larly effective in those early in their disease course with
significant follicular hyperplasia.8 The role of thymectomy in
nonthymomatous OMG remains highly controversial,113,114
given the potential for significant morbidity associated with
this invasive procedure. Some retrospective data suggest a
high rate of OMG remission following thymectomy (defined
variably as being asymptomatic either off medications or on
low doses of immunosuppression), particularly when surgery
is performed within the first 12 months of symptoms.115,116 A
2017 meta-analysis examining outcomes of thymectomy spe-
cifically in nonthymomatous OMG concluded that complete
stable remission (defined as being asymptomatic for >1 year of
all pharmacologic treatment5) was achieved in about 50% of
cases.114 Significant heterogeneity of the data included in this
meta-analysis precludes definitive conclusions. In addition,
the AChR Ab seropositivity status is lacking in the majority of
included reports, and data on complication rates was not
reported in the meta-analysis.117 Despite the lack of random-
ized prospective data supporting this practice, thymectomy
Update on Ocular Myasthenia Gravis O’Hare, Doughty 757
may be considered for AChR Ab seropositive OMG patients
who have failed medical therapy.85,103
Does Immunomodulatory Therapy Improve Outcomes in
OMG?
Retrospective data suggest that in addition to treating OMG
symptomatically, immunomodulatory therapy may alter the
natural history of the disease and reduce the risk of develop-
ing GMG. However, there is a lack of randomized controlled
data to support this theory. The natural tendency of the
disease to improve or remit spontaneously (i.e., with no
treatment) in a minority of cases should also be noted.118
Multiple retrospective case series have noted that OMG
patients treated with immunosuppression (including cortico-
steroids, azathioprine, and thymectomy) are significantly less
likely to develop GMG.83,92–95 In one illustrative retrospective
Downloaded by: Collections and Technical Services Department. Copyrighted material.
series by Kupersmith, outcomes of OMG patients treated with
steroids were compared to those treated with pyridostigmine
alone.92 All patients with symptomatic extraocular symptoms
not responsive to pyridostigmine alone were offered predni-
sone (in the absence of any contraindications to steroid use),
and the majority of patients treated with steroids started them
within 6 months of symptom onset. GMG developed in 50% of
the untreated group (mean conversion time 0.22 years from
OMG symptom onset; range, 0.1–0.8 years) versus 14% of the
treated group (mean conversion time, 5.8 years; range,
2.5–10.5 years). This suggests that steroid treatment may
impact the natural history of OMG by both delaying the
conversion to GMG and reducing the incidence of conversion.
However, the retrospective nature of the data supporting
this theory makes it hard to draw firm conclusions, and the
role of immunosuppression in preventing secondary gener-
alization remains controversial.119 The difficulty of inter-
preting nonblinded retrospective studies to assess treatment
effect is illustrated by the case series reported by Galassi et al
which indicated that 0% of untreated OMG patients
developed secondary generalization versus 24.8% of treated
patients.56 This finding can presumably be attributed to a
lower risk of disease progression in mild OMG cases that
were not symptomatic enough to warrant treatment, rather
than any causal effect from the treatment itself.
Conclusion
OMG is an autoimmune disease affecting the neuromuscular
junction of the extraocular muscles, resulting in a characteristic
presentation with fluctuating, fatigable diplopia and ptosis.
Supportive diagnostic tests, including serologic and electro-
diagnostic studies, can help confirm the diagnosis; however,
the sensitivity of these tests is much lower when myasthenia is
restricted to the ocular form. Therefore, the diagnosis of OMG
frequently remains purely clinical. The physical examination of
patients with OMG is accordingly of fundamental importance,
both in establishing a positive diagnosis and ruling out potential
mimics. Treatment of OMG encompasses a range of nonphar-
macologic, symptomatic, and immunomodulatory options, and
is best tailored to the individual patient based on severity of
symptoms, treatment goals, and comorbidities.
Seminars in Neurology Vol. 39 No. 6/2019
758 Update on Ocular Myasthenia Gravis O’Hare, Doughty
References
1 Jayam Trouth A, Dabi A, Solieman N, Kurukumbi M, Kalyanam J.
Myasthenia gravis: a review. Autoimmune Dis 2012;2012:874680
2 Grob D, Brunner N, Namba T, Pagala M. Lifetime course of
myasthenia gravis. Muscle Nerve 2008;37(02):141–149
3 Bever CT Jr., Aquino AV, Penn AS, Lovelace RE, Rowland LP.
Prognosis of ocular myasthenia. Ann Neurol 1983;14(05):516–519
4 Evoli A, Tonali P, Bartoccioni E, Lo Monaco M. Ocular myasthenia:
diagnostic and therapeutic problems. Acta Neurol Scand 1988;
77(01):31–35
5 Jaretzki A III, Barohn RJ, Ernstoff RM, et al; Task Force of the
Medical Scientific Advisory Board of the Myasthenia Gravis
Foundation of America. Myasthenia gravis: recommendations
for clinical research standards. Neurology 2000;55(01):16–23
6 Ruff RL, Lisak RP. Nature and action of antibodies in myasthenia
gravis. Neurol Clin 2018;36(02):275–291
7 Thanvi BR, Lo TCN. Update on myasthenia gravis. Postgrad Med J
2004;80(950):690–700
8 Berrih-Aknin S, Le Panse R. Myasthenia gravis: a comprehensive
review of immune dysregulation and etiological mechanisms.
J Autoimmun 2014;52:90–100
9 Sommer N, Tackenberg B, Hohlfeld R. Chapter 5 The immuno-
pathogenesis of myasthenia gravis. In: Engel AG, ed. Handbook
of Clinical Neurology. New York, NY: Elsevier; 2008:169–212
10 Mori S, Kubo S, Akiyoshi T, et al. Antibodies against muscle-
specific kinase impair both presynaptic and postsynaptic func-
tions in a murine model of myasthenia gravis. Am J Pathol 2012;
180(02):798–810[published Online First: 2011/12/07]
11 Shen C, Lu Y, Zhang B, et al. Antibodies against low-density
lipoprotein receptor-related protein 4 induce myasthenia gravis.
J Clin Invest 2013;123(12):5190–5202
12 Rodríguez Cruz PM, Al-Hajjar M, Huda S, et al. Clinical features
and diagnostic usefulness of antibodies to clustered acetylcho-
line receptors in the diagnosis of seronegative myasthenia
gravis. JAMA Neurol 2015;72(06):642–649
13 Jacob S, Viegas S, Leite MI, et al. Presence and pathogenic
relevance of antibodies to clustered acetylcholine receptor in
ocular and generalized myasthenia gravis. Arch Neurol 2012;69
(08):994–1001
14 Cortés-Vicente E, Gallardo E, Martínez MÁ, et al. Clinical character-
istics of patients with double-seronegative myasthenia gravis and
antibodies to cortactin. JAMA Neurol 2016;73(09):1099–1104
15 Gallardo E, Martínez-Hernández E, Titulaer MJ, et al. Cortactin
autoantibodies in myasthenia gravis. Autoimmun Rev 2014;13
(10):1003–1007
16 Marx A, Müller-Hermelink HK, Ströbel P. The role of thymomas in
the development of myasthenia gravis. Ann N Y Acad Sci 2003;
998(01):223–236
17 Marx A, Pfister F, Schalke B, Saruhan-Direskeneli G, Melms A,
Ströbel P. The different roles of the thymus in the pathogenesis of
the various myasthenia gravis subtypes. Autoimmun Rev 2013;
12(09):875–884
18 Romi F, Skeie GO, Aarli JA, Gilhus NE. Muscle autoantibodies in
subgroups of myasthenia gravis patients. J Neurol 2000;247(05):
369–375
19 Kaminski HJ, Li Z, Richmonds C, Ruff RL, Kusner L. Susceptibility
of ocular tissues to autoimmune diseases. Ann N Y Acad Sci 2003;
998:362–374
20 Kaminski HJ, Maas E, Spiegel P, Ruff RL. Why are eye muscles
frequently involved in myasthenia gravis? Neurology 1990;40
(11):1663–1669
21 Carr AS, Cardwell CR, McCarron PO, McConville J. A systematic
review of population based epidemiological studies in myasthenia
gravis. BMC Neurol 2010;10:46–46. Doi: 10.1186/1471-2377-10-46
22 Peragallo JH, Bitrian E, Kupersmith MJ, et al. Relationship between
age, gender, and race in patients presenting with myasthenia
gravis with only ocular manifestations. J Neuroophthalmol
2016;36(01):29–32
Seminars in Neurology Vol. 39 No. 6/2019
23 Kee HJ, Yang HK, Hwang J-M, et al. Evaluation and validation of
sustained upgaze combined with the ice-pack test for ocular
myasthenia gravis in asians. Neuromuscul Disord 2019;29(04):
296–301
24 Osher RH, Glaser JS. Myasthenic sustained gaze fatigue. Am J
Ophthalmol 1980;89(03):443–445
25 Pourmand R. Myasthenia gravis. Dis Mon 1997;43(02):65–109
26 Averbuch-Heller L, Poonyathalang A, von Maydell RD, Remler BF.
Hering’s law for eyelids: still valid. Neurology 1995;45(09):
1781–1783
27 Pelak VS, Galetta SL. Ocular myasthenia gravis. Curr Treat
Options Neurol 2001;3(04):367–376
28 Osher RH, Griggs RC. Orbicularis fatigue: the ‘peek’ sign of
myasthenia gravis. Arch Ophthalmol 1979;97(04):677–679
29 Lepore FE, Sanborn GE, Slevin JT. Pupillary dysfunction in
myasthenia gravis. Ann Neurol 1979;6(01):29–33
30 Yamazaki A, Ishikawa S. Abnormal pupillary responses in myas-
thenia gravis. A pupillographic study. Br J Ophthalmol 1976;60
(08):575–580
Downloaded by: Collections and Technical Services Department. Copyrighted material.
31 Dutton GN, Garson JA, Richardson RB. Pupillary fatigue in
myasthenia gravis. Trans Ophthalmol Soc U K 1982;102(Pt
4):510–513
32 Cooper J, Pollak GJ, Ciuffreda KJ, Kruger P, Feldman J. Accommo-
dative and vergence findings in ocular myasthenia: a case
analysis. J Neuroophthalmol 2000;20(01):5–11
33 Sussman J, Farrugia ME, Maddison P, Hill M, Leite MI, Hilton-
Jones D. Myasthenia gravis: Association of British Neurologists’
management guidelines. Pract Neurol 2015;15(03):199–206
34 Andonopoulos AP, Terzis E, Tsibri E, Papasteriades CA, Papape-
tropoulos T. D-penicillamine induced myasthenia gravis in
rheumatoid arthritis: an unpredictable common occurrence?
Clin Rheumatol 1994;13(04):586–588
35 Drosos AA, Christou L, Galanopoulou V, Tzioufas AG, Tsiakou EK.
D-penicillamine induced myasthenia gravis: clinical, serological
and genetic findings. Clin Exp Rheumatol 1993;11(04):387–391
36 Suzuki S, Ishikawa N, Konoeda F, et al. Nivolumab-related
myasthenia gravis with myositis and myocarditis in Japan.
Neurology 2017;89(11):1127–1134
37 Kao JC, Brickshawana A, Liewluck T. Neuromuscular complica-
tions of programmed cell death-1 (PD-1) inhibitors. Curr Neurol
Neurosci Rep 2018;18(10):63
38 Makarious D, Horwood K, Coward JIG. Myasthenia gravis: An
emerging toxicity of immune checkpoint inhibitors. Eur J Cancer
2017;82:128–136
39 Cooper DS, Meriggioli MN, Bonomi PD, Malik R. Severe exacer-
bation of myasthenia gravis associated with checkpoint inhibitor
immunotherapy. J Neuromuscul Dis 2017;4(02):169–173
40 Lau KH, Kumar A, Yang IH, Nowak RJ. Exacerbation of myasthenia
gravis in a patient with melanoma treated with pembrolizumab.
Muscle Nerve 2016;54(01):157–161
41 Shah M, Tayar JH, Adbel-Wahab N, Suarez-Almazore ME. Myosi-
tis as an adverse event of immune checkpoint blockade for
cancer therapy. Semin Arthritis Rheum 2018;48(04):736–740
42 Brahmer JR, Lacchetti C, Schneider BJ, et al; National Comprehen-
sive Cancer Network. Management of immune-related adverse
events in patients treated with immune checkpoint inhibitor
therapy: American Society of Clinical Oncology Clinical Practice
Guideline. J Clin Oncol 2018;36(17):1714–1768
43 Sethi KD, Rivner MH, Swift TR. Ice pack test for myasthenia
gravis. Neurology 1987;37(08):1383–1385
44 Kubis KC, Danesh-Meyer HV, Savino PJ, Sergott RC. The ice test
versus the rest test in myasthenia gravis. Ophthalmology 2000;
107(11):1995–1998
45 Benatar M. A systematic review of diagnostic studies in myas-
thenia gravis. Neuromuscul Disord 2006;16(07):459–467
46 Fakiri MO, Tavy DL, Hama-Amin AD, Wirtz PW. Accuracy of the
ice test in the diagnosis of myasthenia gravis in patients with
ptosis. Muscle Nerve 2013;48(06):902–904

47 Odel JG, Winterkorn JM, Behrens MM. The sleep test for myas-
thenia gravis. A safe alternative to Tensilon. J Clin Neurooph-
thalmol 1991;11(04):288–292
48 Cogan DG. Myasthenia gravis: a review of the disease and a
description of lid twitch as a characteristic sign. Arch Ophthal-
mol 1965;74:217–221
49 Van Stavern GP, Bhatt A, Haviland J, Black EH. A prospective study
assessing the utility of Cogan’s lid twitch sign in patients with isolated
unilateral or bilateral ptosis. J Neurol Sci 2007;256(1,2):84–85
50 Moorthy G, Behrens MM, Drachman DB, et al. Ocular pseudo-
myasthenia or ocular myasthenia ‘plus’: a warning to clinicians.
Neurology 1989;39(09):1150–1154
51 Ragge NK, Hoyt WF. Midbrain myasthenia: fatigable ptosis, ‘lid
twitch’ sign, and ophthalmoparesis from a dorsal midbrain
glioma. Neurology 1992;42(04):917–919
52 Apinyawasisuk S, Zhou X, Tian JJ, Garcia GA, Karanjia R, Sadun AA.
Validity of forced eyelid closure test: a novel clinical screening test for
ocular myasthenia gravis. J Neuroophthalmol 2017;37(03):253–257
53 Howard FM Jr, Lennon VA, Finley J, Matsumoto J, Elveback LR.
Clinical correlations of antibodies that bind, block, or modulate
human acetylcholine receptors in myasthenia gravis. Ann N Y
Acad Sci 1987;505:526–538
54 Sommer N, Melms A, Weller M, Dichgans J. Ocular myasthenia
gravis. A critical review of clinical and pathophysiological
aspects. Doc Ophthalmol 1993;84(04):309–333
55 Vaphiades MS, Bhatti MT, Lesser RL. Ocular myasthenia gravis.
Curr Opin Ophthalmol 2012;23(06):537–542
56 Galassi G, Mazzoli M, Ariatti A, Kaleci S, Valzania F, Nichelli PF.
Antibody profile may predict outcome in ocular myasthenia
gravis. Acta Neurol Belg 2018;118(03):435–443
57 Benatar M, Mcdermott MP, Sanders DB, et al; Muscle Study
Group (MSG). Efficacy of prednisone for the treatment of ocular
myasthenia (EPITOME): A randomized, controlled trial. Muscle
Nerve 2016;53(03):363–369
58 Evoli A, Alboini PE, Iorio R, Damato V, Bartoccioni E. Pattern of
ocular involvement in myasthenia gravis with MuSK antibodies.
J Neurol Neurosurg Psychiatry 2017;88(09):761–763
59 Bhanushali MJ, Wuu J, Benatar M. Treatment of ocular symptoms
in myasthenia gravis. Neurology 2008;71(17):1335–1341
60 Sanders DB, Andrews PI, Howard JF, Massey JM. Seronegative
myasthenia gravis. Neurology 1997;48(Suppl 5):40S–45S
61 McConville J, Farrugia ME, Beeson D, et al. Detection and
characterization of MuSK antibodies in seronegative myasthenia
gravis. Ann Neurol 2004;55(04):580–584
62 Evoli A, Tonali PA, Padua L, et al. Clinical correlates with anti-
MuSK antibodies in generalized seronegative myasthenia gravis.
Brain 2003;126(Pt 10):2304–2311
63 Guptill JT, Sanders DB, Evoli A. Anti-MuSK antibody myasthenia
gravis: clinical findings and response to treatment in two large
cohorts. Muscle Nerve 2011;44(01):36–40
64 Sanders DB, El-Salem K, Massey JM, McConville J, Vincent A.
Clinical aspects of MuSK antibody positive seronegative MG.
Neurology 2003;60(12):1978–1980
65 Zisimopoulou P, Evangelakou P, Tzartos J, et al. A comprehensive
analysis of the epidemiology and clinical characteristics of anti-
LRP4 in myasthenia gravis. J Autoimmun 2014;52:139–145
66 Higuchi O, Hamuro J, Motomura M, Yamanashi Y. Autoantibodies
to low-density lipoprotein receptor-related protein 4 in myas-
thenia gravis. Ann Neurol 2011;69(02):418–422
67 Zhang B, Tzartos JS, Belimezi M, et al. Autoantibodies to lipopro-
tein-related protein 4 in patients with double-seronegative
myasthenia gravis. Arch Neurol 2012;69(04):445–451
68 Pevzner A, Schoser B, Peters K, et al. Anti-LRP4 autoantibodies in
AChR- and MuSK-antibody-negative myasthenia gravis. J Neurol
2012;259(03):427–435
69 Tzartos JS, Zisimopoulou P, Rentzos M, et al. LRP4 antibodies in
serum and CSF from amyotrophic lateral sclerosis patients. Ann
Clin Transl Neurol 2014;1(02):80–87
Update on Ocular Myasthenia Gravis O’Hare, Doughty 759
70 Rivner MH, Liu S, Quarles B, et al. Agrin and low-density
lipoprotein-related receptor protein 4 antibodies in amyotrophic
lateral sclerosis patients. Muscle Nerve 2017;55(03):430–432
71 Meriggioli MN, Sanders DB. Myasthenia gravis: diagnosis. Semin
Neurol 2004;24(01):31–39
72 Seybold ME. The office Tensilon test for ocular myasthenia
gravis. Arch Neurol 1986;43(08):842–843
73 Dirr LY, Donofrio PD, Patton JF, Troost BT. A false-positive
edrophonium test in a patient with a brainstem glioma. Neurol-
ogy 1989;39(06):865–867
74 Fierro B, Croce G, Filosto L, Carbone N, Lupo I. Ocular pseudo-
myasthenia: report of a case with a pineal region tumor. Ital J
Neurol Sci 1991;12(06):593–596
75 AAEM Quality Assurance Committee. American Association of
Electrodiagnostic Medicine. Practice parameter for repetitive nerve
stimulation and single fiber EMG evaluation of adults with sus-
pected myasthenia gravis or Lambert-Eaton myasthenic syndrome:
summary statement. Muscle Nerve 2001;24(09):1236–1238
76 Preston DC, Shapiro BE. Electromyography and Neuromuscular
Downloaded by: Collections and Technical Services Department. Copyrighted material.
Disorders: Clinical-Electrophysiologic Correlations. 3rd ed. New
York, NY: Saunders; 2012
77 Howard JF Jr. Electrodiagnosis of disorders of neuromuscular
transmission. Phys Med Rehabil Clin N Am 2013;24(01):
169–192
78 Zambelis T, Kokotis P, Karandreas N. Repetitive nerve stimula-
tion of facial and hypothenar muscles: relative sensitivity in
different myasthenia gravis subgroups. Eur Neurol 2011;65(04):
203–207
79 Sanders DB, Howard JF Jr. AAEE minimonograph #25: Single-
fiber electromyography in myasthenia gravis. Muscle Nerve
1986;9(09):809–819
80 Padua L, Caliandro P, Di Iasi G, Pazzaglia C, Ciaraffa F, Evoli A.
Reliability of SFEMG in diagnosing myasthenia gravis: sensitivity
and specificity calculated on 100 prospective cases. Clin Neuro-
physiol 2014;125(06):1270–1273
81 Vincent A, Newsom-Davis J. Acetylcholine receptor antibody as a
diagnostic test for myasthenia gravis: results in 153 validated
cases and 2967 diagnostic assays. J Neurol Neurosurg Psychiatry
1985;48(12):1246–1252
82 Priola AM, Priola SM. Imaging of thymus in myasthenia gravis:
from thymic hyperplasia to thymic tumor. Clin Radiol 2014;69
(05):e230–e245
83 Sommer N, Sigg B, Melms A, et al. Ocular myasthenia gravis:
response to long-term immunosuppressive treatment. J Neurol
Neurosurg Psychiatry 1997;62(02):156–162
84 Grob D, Arsura EL, Brunner NG, Namba T. The course of myas-
thenia gravis and therapies affecting outcome. Ann N Y Acad Sci
1987;505:472–499
85 Gilhus NE. Myasthenia Gravis. N Engl J Med 2016;375(26):
2570–2581
86 Mazzoli M, Ariatti A, Valzania F, et al. Factors affecting outcome
in ocular myasthenia gravis. Int J Neurosci 2018;128(01):15–24
87 Wong SH, Petrie A, Plant GT. Ocular myasthenia gravis: toward a
risk of generalization score and sample size calculation for a
randomized controlled trial of disease modification. J Neuro-
ophthalmol 2016;36(03):252–258
88 Weinberg DH, Rizzo JF III, Hayes MT, Kneeland MD, Kelly JJ Jr.
Ocular myasthenia gravis: predictive value of single-fiber elec-
tromyography. Muscle Nerve 1999;22(09):1222–1227
89 Rostedt A, Saders LL, Edards LJ, Massey JM, Sanders DB, Stålberg
EV. Predictive value of single-fiber electromyography in the
extensor digitorum communis muscle of patients with ocular
myasthenia gravis: a retrospective study. J Clin Neuromuscul Dis
2000;2(01):6–9
90 Guan YZ, Cui LY, Liu MS, Niu JW. Single-fiber electromyography
in the extensor digitorum communis for the predictive prognosis
of ocular myasthenia gravis: a retrospective study of 102 cases.
Chin Med J (Engl) 2015;128(20):2783–2786
Seminars in Neurology Vol. 39 No. 6/2019
760 Update on Ocular Myasthenia Gravis O’Hare, Doughty
91 Suzuki S, Murai H, Imai T, et al. Quality of life in purely ocular
myasthenia in Japan. BMC Neurol 2014;14(01):142
92 Kupersmith MJ. Ocular myasthenia gravis: treatment successes
and failures in patients with long-term follow-up. J Neurol 2009;
256(08):1314–1320
93 Mee J, Paine M, Byrne E, King J, Reardon K, O’Day J. Immunotherapy
of ocular myasthenia gravis reduces conversion to generalized
myasthenia gravis. J Neuroophthalmol 2003;23(04):251–255
94 Monsul NT, Patwa HS, Knorr AM, Lesser RL, Goldstein JM. The
effect of prednisone on the progression from ocular to
generalized myasthenia gravis. J Neurol Sci 2004;217(02):
131–133
95 Kupersmith MJ, Moster M, Bhuiyan S, Warren F, Weinberg H.
Beneficial effects of corticosteroids on ocular myasthenia gravis.
Arch Neurol 1996;53(08):802–804
96 Europa TA, Nel M, Heckmann JM. Myasthenic ophthalmoparesis:
Time To resolution after initiating immune therapies. Muscle
Nerve 2018;58(04):542–549
97 Guidon AC, Hobson-Webb LD. On the double: early immuno-
therapy speeds recovery of ocular myasthenic weakness. Muscle
Nerve 2018;58(06):743–744
98 Haines SR, Thurtell MJ. Treatment of ocular myasthenia gravis.
Curr Treat Options Neurol 2012;14(01):103–112
99 Morris OC, O’Day J. Strabismus surgery in the management of
diplopia caused by myasthenia gravis. Br J Ophthalmol 2004;88
(06):832
100 Peragallo JH, Velez FG, Demer JL, Pineles SL. Long-term follow-up
of strabismus surgery for patients with ocular myasthenia
gravis. J Neuroophthalmol 2013;33(01):40–44
101 Evoli A, Batocchi AP, Minisci C, Di Schino C, Tonali P. Therapeutic
options in ocular myasthenia gravis. Neuromuscul Disord 2001;
11(02):208–216
102 Carter SR, Meecham WJ, Seiff SR. Silicone frontalis slings for the
correction of blepharoptosis: indications and efficacy. Ophthal-
mology 1996;103(04):623–630
103 Kerty E, Elsais A, Argov Z, Evoli A, Gilhus NE. EFNS/ENS Guide-
lines for the treatment of ocular myasthenia. Eur J Neurol 2014;
21(05):687–693
104 Sanders DB, Wolfe GI, Benatar M, et al. International consensus
guidance for management of myasthenia gravis: executive sum-
mary. Neurology 2016;87(04):419–425
105 Palace J, Newsom-Davis J, Lecky B; Myasthenia Gravis Study
Group. A randomized double-blind trial of prednisolone alone or
with azathioprine in myasthenia gravis. Neurology 1998;50(06):
1778–1783
106 Pedersen EG, Pottegård A, Hallas J, et al. Risk of non-melanoma
skin cancer in myasthenia patients treated with azathioprine.
Eur J Neurol 2014;21(03):454–458
107 Chan JW. Mycophenolate mofetil for ocular myasthenia. J Neurol
2008;255(04):510–513
108 Sanders DB, Hart IK, Mantegazza R, et al. An international, phase
III, randomized trial of mycophenolate mofetil in myasthenia
gravis. Neurology 2008;71(06):400–406
109 Heckmann JM, Rawoot A, Bateman K, Renison R, Badri M. A
single-blinded trial of methotrexate versus azathioprine as
steroid-sparing agents in generalized myasthenia gravis. BMC
Neurol 2011;11:97
110 Gilhus NE. Eculizumab: a treatment option for myasthenia
gravis? Lancet Neurol 2017;16(12):947–948
Seminars in Neurology Vol. 39 No. 6/2019
111 Wolfe GI, Kaminski HJ, Aban IB, et al; MGTX Study Group. Ran-
domized trial of thymectomy in myasthenia gravis. N Engl J Med
2016;375(06):511–522 (Erratum in: Randomized Trial of Thymec-
tomy in Myasthenia Gravis. [N Engl J Med 2017])
112 Wolfe GI, Kaminski HJ, Aban IB, et al; MGTX Study Group. Long-
term effect of thymectomy plus prednisone versus prednisone
alone in patients with non-thymomatous myasthenia gravis: 2-
year extension of the MGTX randomised trial. Lancet Neurol
2019;18(03):259–268
113 Gilbert ME, De Sousa EA, Savino PJ. Ocular Myasthenia Gravis
treatment: the case against prednisone therapy and thymecto-
my. Arch Neurol 2007;64(12):1790–1792
114 Chavis PS, Stickler DE, Walker A. Immunosuppressive or surgical
treatment for ocular myasthenia gravis. Arch Neurol 2007;64
(12):1792–1794
115 Roberts PF, Venuta F, Rendina E, et al. Thymectomy in the
treatment of ocular myasthenia gravis. J Thorac Cardiovasc
Surg 2001;122(03):562–568
116 Liu Z, Feng H, Yeung SC, et al. Extended transsternal thymectomy
Downloaded by: Collections and Technical Services Department. Copyrighted material.
for the treatment of ocular myasthenia gravis. Ann Thorac Surg
2011;92(06):1993–1999
117 Zhu K, Li J, Huang X, et al. Thymectomy is a beneficial therapy for
patients with non-thymomatous ocular myasthenia gravis: a
systematic review and meta-analysis. Neurol Sci 2017;38(10):
1753–1760
118 Oosterhuis HJ. The natural course of myasthenia gravis: a long
term follow up study. J Neurol Neurosurg Psychiatry 1989;52
(10):1121–1127
119 Wong SH, Plant GT, Cornblath W. Does treatment of ocular
myasthenia gravis with early immunosuppressive therapy
prevent secondarily generalization and should it be offered to
all such patients? J Neuroophthalmol 2016;36(01):98–102
120 Bartley GB, Gorman CA. Diagnostic criteria for Graves’ ophthalm-
opathy. Am J Ophthalmol 1995;119(06):792–795
121 Richardson C, Smith T, Schaefer A, Turnbull D, Griffiths P. Ocular
motility findings in chronic progressive external ophthalmople-
gia. Eye (Lond) 2005;19(03):258–263
122 Butler IJ, Gadoth N. Kearns-Sayre syndrome. A review of a
multisystem disorder of children and young adults. Arch Intern
Med 1976;136(11):1290–1293
123 Emery AE. The muscular dystrophies. Lancet 2002;359(9307):
687–695
124 Machuca-Tzili L, Brook D, Hilton-Jones D. Clinical and molecular
aspects of the myotonic dystrophies: a review. Muscle Nerve
2005;32(01):1–18
125 Garg N, Yiannikas C, Hardy TA, et al. Late presentations of
congenital myasthenic syndromes: How many do we miss?
Muscle Nerve 2016;54(04):721–727
126 North KN, Wang CH, Clarke N, et al; International Standard of Care
Committee for Congenital Myopathies. Approach to the diagnosis of
congenital myopathies. Neuromuscul Disord 2014;24(02):97–116
127 Evans BJ. Optometric prescribing in decompensated heteropho-
ria. Optometry in Practice 2008;9:63–78
128 Arnoldi K, Reynolds JD. A review of convergence insufficiency:
what are we really accomplishing with exercises? Am Orthopt J
2007;57:123–130
129 Engel AG. Morphologic and immunopathologic findings in
myasthenia gravis and in congenital myasthenic syndromes.
J Neurol Neurosurg Psychiatry 1980;43(07):577–589