Myasthenia Gravis and Lambert-Eaton Myasthenic Syndrome - Continuum December 2016

Review Article
Myasthenia Gravis
Address correspondence to
Dr Michael W. Nicolle, London
Health Sciences Centre,
University Hospital,
339 Windermere Rd,
London, ON N6A 5A5, Canada,
mnicolle@uwo.ca.
and Lambert-Eaton
Relationship Disclosure:
Dr Nicolle has given
expert medical testimony
Myasthenic Syndrome
in court cases for the
Canadian Medical
Michael W. Nicolle, MD
Protective Association.
Unlabeled Use of
Products/Investigational ABSTRACT
Use Disclosure:
Dr Nicolle discusses the Purpose of Review: This article discusses the pathogenesis, diagnosis, and management of
unlabeled/investigational autoimmune myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS).
use of azathioprine, Recent Findings: Recognition of new antigenic targets and improved diagnostic methods
mycophenolate, and
rituximab for the treatment
promise to improve the diagnosis of MG, although the clinical phenotypes associated with
of myasthenia gravis and newer antibodies have not yet been defined. Future therapies might specifically target
Lambert-Eaton myasthenic the aberrant immune response. The apparent increase in the prevalence of MG is not
syndrome and the use of
3,4-diaminopyridine for the fully explained. Results of a long-awaited trial of thymectomy support the practice of
treatment of Lambert-Eaton performing a thymectomy under specific conditions.
myasthenic syndrome. Summary: The current treatment options are so effective in most patients with MG or
* 2016 American Academy LEMS that in patients with refractory disease the diagnosis should be reconsidered. The
of Neurology.
management of MG is individualized, and familiarity with mechanisms, adverse effects,
and strategies to manage these commonly used treatments improves outcome. Patient
education is important. LEMS, frequently associated with an underlying small cell lung
cancer, is uncommon, and the mainstay of treatment is symptomatic in most patients.
Continuum (Minneap Minn) 2016;22(6):19782005.
INTRODUCTION treatments in MG and LEMS. 1 The

Immune myasthenia gravis (MG) is the neuromuscular junction includes the pre-
best delineated of human autoimmune synaptic nerve terminal, basal laminaY
diseases. Fatigable weakness is the hall- containing synaptic cleft, and postsyn-
mark of both MG and Lambert-Eaton aptic muscle fiber endplate.
myasthenic syndrome (LEMS). The ex- Nerve depolarization allows calcium
panding repertoire of antibody assays influx through nerve terminal voltage-
has improved the diagnosis of MG and gated calcium channels (VGCCs). This
may allow treatments to be tailored to results in release of acetylcholine into
specific antibodies. Management options the synaptic cleft. Acetylcholine binds
for MG include symptomatic as well as to its receptor (acetylcholine receptor
immunosuppressive and immunomodu-
[AChR]), opening AChR channels and
latory treatments and, in select circum-
producing an influx of cations, mostly
stances, thymectomy. LEMS is uncommon
sodium, at the endplate. Depolarization
and often occurs as a paraneoplastic
disorder with an underlying small cell of the muscle membrane produces an
lung cancer. endplate potential, which, if of suffi-
cient amplitude, results in an all or none
NEUROMUSCULAR JUNCTION AND muscle fiber action potential and even-
NEUROMUSCULAR TRANSMISSION tually muscle movement. An excess of
Understanding normal neuromuscular released acetylcholine and AChRs at the
transmission is important to appreciate muscle endplate provides a safety fac-
the rationale for diagnostic tests and tor of neuromuscular transmission.
1978 www.ContinuumJournal.com December 2016
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

KEY POINTS
Acetylcholine binds to its receptor tran- in a decrement with low-frequency re- h The function of
siently and either diffuses out of the petitive nerve stimulation studies and acetylcholine at the
neuromuscular junction or is hydro- weakness clinically. Second, during neuromuscular junction is
lyzed by acetylcholinesterase, anchored high-frequency (20 Hz to 50 Hz) stimu- influenced by several other
in the basal lamina. This terminates the lation or after brief (10 seconds) maximal key proteins, which are
effects of nerve depolarization. voluntary contraction, intracellular cal- now known to be targets
of the autoimmune
AChR localization at the neuromus- cium is increased in the presynaptic nerve
response in some patients
cular junction and its function are in- terminal, increasing acetylcholine release. with myasthenia gravis.
fluenced by several other proteins at the Maximal voluntary contraction mimics
h Antibodies against the
muscle endplate. Agrin, secreted by the high-frequency stimulation, as the nerve
most common antigenic
nerve terminal, interacts with muscle- fires at approximately 20 Hz during a target in myasthenia
specific tyrosine kinase (MuSK) via its maximal contraction. The increased in- gravis, the acetylcholine
coreceptor, low-density lipoprotein tracellular calcium may overcome defec- receptor, are found in
receptor-related protein 4 (LRP4). The tive neuromuscular transmission; in 85% of patients with
resultant MuSK-LRP4 complex results in MG, this results in postexercise repair generalized myasthenia
the activation and clustering of AChRs at on repetitive nerve stimulation studies, gravis and 50% of
patients with ocular
the neuromuscular junction. MuSK also and in LEMS, this results in facilitation or
myasthenia gravis and
anchors acetylcholinesterase at the syn- increment after high-frequency stimu- disrupt neuromuscular
aptic basal lamina. In MG, antibodies lation or maximal voluntary contraction. transmission through
against the AChR or other neuromuscu- This also explains the return of a deep several mechanisms.
lar junction targets reduce the number, tendon reflex after maximal voluntary
function, or clustering of AChRs at the contraction in LEMS. Third, longer pe-
neuromuscular junction. In LEMS, anti- riods of exercise result in less well
bodies against the VGCC inhibit calcium understood pre- and postsynaptic ef-
influx into the nerve terminal and re- fects, which also worsen neuromuscular
duce acetylcholine release into the syn- transmission and cause postexercise
aptic cleft after nerve depolarization. exhaustion as is seen in repetitive nerve
Three other phenomena during nor- stimulation studies or fatigable weak-
mal neuromuscular transmission are ness, which is seen clinically.
important to understand; these phenom-
ena are seen electrophysiologically and MYASTHENIA GRAVIS
clinically in MG and LEMS. First, during MG is a disorder where neuromuscular
low-frequency (2 Hz to 5 Hz) stimulation, transmission is disrupted as a result of an
acetylcholine release gradually declines autoimmune attack on postsynaptic anti-
as presynaptic stores are depleted, with genic targets, producing weakness of ske-
a nadir at the fourth or fifth stimulation letal muscles. The clinical hallmark of the
in a train of stimuli. In healthy individ- weakness is its variability and fatigability.
uals, this never reaches significance be-
cause of the safety factor. However, when Pathophysiology
the amount of acetylcholine available for In MG, antibodies against proteins at
release is diminished (as in LEMS) or the the neuromuscular junction interfere
number of available AChRs is reduced with neuromuscular transmission. Anti-
(as in MG), muscle fiber depolarization bodies against the most common anti-
may fail. If this fails at a single fiber, this is genic target in MG, the AChR, are found
detected on single fiber EMG as blocking in 85% of patients with generalized MG
or is detected as jitter if the endplate and 50% of patients with ocular MG and
potential amplitude is sufficient to pro- disrupt neuromuscular transmission
duce a delayed muscle fiber depolariza- through several mechanisms. They can
tion. When many fibers fail, this results reversibly block acetylcholine binding,
Continuum (Minneap Minn) 2016;22(6):19782005 www.ContinuumJournal.com 1979

Myasthenia Gravis and LEMS
KEY POINTS
h In more than one-half of cross-link adjacent cell surface AChRs the pathogenesis of MG.9 Although not
the remaining patients resulting in their internalization into the a hereditary disorder in the mendelian
who have acetylcholine muscle cell, or, for some immunoglo- sense, about 3% to 5% of patients with
receptorYnegative bulin subclasses, cause complement MG will have a family member with im-
generalized myasthenia fixation and destruction of the neuro- mune MG, similar to the data from more
gravis, antibodies target muscular junction.2,3 A mixture of anti- than 800 patients in the authors MG
other proteins at the
bodies with each of these mechanisms clinic.10 The prevalence of other autoim-
neuromuscular junction.
The first described
occurs in an individual patient, although mune disorders, especially thyroid, is
and still most prevalent complement-fixing antibodies are likely increased in patients with MG and their
are antibodies against the most common. family members, occurring in 13% to 30%
muscle-specific In more than one-half of the remain- of patients with MG compared with 5% to
tyrosine kinase. ing patients who have AChR-negative 8% in the general population.11,12 This
h The frequent pathologic generalized MG, antibodies target other suggests a genetic influence to autoim-
involvement of the proteins at the neuromuscular junction. mune diseases, of which MG is one of
thymus, especially with The first described and still most prev- the least frequent.
thymic hyperplasia, in alent are antibodies against MuSK. Anti-
some forms of myasthenia Epidemiology
MuSK antibodies are mostly of the
gravis supports the rationale
nonYcomplement-fixing IgG4 subclass Studies show significant heterogeneity
for its removal in select
circumstances, as shown and disrupt neuromuscular transmission in the incidence and prevalence of MG,
by a recent international by interfering with LRP4/MuSK interac- in part because of geographic and ethnic
clinical trial. tion, reducing AChR clustering at the variation. However, recent evidence sug-
h The different ways of muscle endplate.4 More recently, anti- gests that MG is increasingly common,
classifying myasthenia bodies against LRP4, agrin, and cortactin especially in the elderly.13 The incidence
gravis are useful when have been described.5 The significance of of MG ranges between 9 to 30 out of
considering the sensitivity these antibodies is less well delineated. 1 million, and the prevalence ranges
of diagnostic tests as well Pathologic thymic involvement, either from 100 to 140 out of 1 million. How-
as management options. ever, recent studies have shown a pre-
thymic hyperplasia or a thymoma, is
h Congenital myasthenic found in the majority of patients with valence of more than 200 in 1 million.7,14
syndromes are genetic AChR MG.6 Thymic hyperplasia occurs in Women are more likely to have MG than
disorders with a mutation men in the first 5 decades of life whereas
50% to 80% of postpubertal juvenile
in a presynaptic, synaptic,
cases and early-onset adult cases of AChR men are more likely to be diagnosed
or postsynaptic protein
involved in neuromuscular MG.6 Thymic hyperplasia is uncommon with MG after the age of 50.9 Ocular MG
transmission. in MuSK MG and less common in sero- is more common in patients with prepu-
negative and late-onset MG, where the bertal juvenile MG, especially in people of
thymus is often normal, atrophic, or a Asian descent and in men with late-onset
thymoma is found.6,7 The hyperplastic MG. MuSK MG is more frequent in
thymus is a significant source of anti-AChR younger women and possibly in the
antibodies.6,8 A thymoma is found in nonwhite population.
10% to 20% of patients with MG, and MG
occurs in 30% to 50% of thymoma cases. Classification
Although the etiology for MG remains MG can be classified in several ways,
unknown, some subsets of AChR MG are each of which is useful when consider-
associated with specific human leuko- ing diagnostic tests, therapeutic options,
cyte antigen (HLA) determinants, and and prognosis.15,16
subsets of MuSK MG are associated with Age at onset. Congenital myasthenic
other HLA determinants. A recent syndromes are genetic disorders with a
genome-wide association survey in white mutation in a presynaptic, synaptic, or post-
patients with AChR MG showed associa- synaptic protein involved in neuromus-
tion with specific loci that might influence cular transmission. Congenital myasthenic

KEY POINTS
syndromes are not discussed in detail in age 65, although it is often not re- h Neonatal myasthenia
this article but are considered in the cognized and is most commonly mis- gravis is a self-limited
differential diagnosis of immune MG. diagnosed as a stroke. 13,14,16 disorder that occurs after
Neonatal MG occurs after the transpla- Thymic pathology. The likelihood the transplacental
cental transmission of AChR or MuSK and type of thymic pathology is associ- transmission of
antibodies and had been said to occur in ated with age at onset, clinical manifes- acetylcholine receptor or
muscle-specific tyrosine
about 10% to 15% of babies of mothers tations, and serologic status. Thymic
kinase antibodies.
with MG. However, it may be less fre- hyperplasia is present in 50% to 80% of
quent now, and in more than 50 mothers patients with AChR-positive early-onset h Juvenile myasthenia
makes up 10% to 15%
that the author has managed through MG, is less common in late-onset MG, and
of most series of patients
pregnancy, not a single case of neonatal is rare in MuSK MG.6Y8 The benefits of with myasthenia gravis
MG has occurred. The antibody- thymectomy in MG are presumed to and is arbitrarily defined
producing cells are not transmitted, so relate to the removal of a hyperplastic as an age of onset of
neonatal MG is a self-limited disorder. thymus. A thymoma, found in 10% to less than 18, excluding
Juvenile myasthenia makes up 10% to 20% of all cases of MG, is more com- congenital myasthenic
15% of most series of patients with MG mon with onset after 40 years of age, syndromes and neonatal
myasthenia gravis.
and is arbitrarily defined as an age of where it occurs in 25% to 35% of cases.17
onset of less than 18, excluding congen- Thymomatous MG is usually more severe h Thymic hyperplasia is
ital myasthenic syndromes and neonatal and less likely to be ocular.18 A thymoma present in 50% to 80%
of patients with acetyl-
MG. Cases of prepubertal onset are more is usually discovered at the time of MG
choline receptorYpositive
likely to be seronegative, have a benign diagnosis although can present later. The early-onset myasthenia
clinical course, a higher prevalence of vast majority of thymomatous MG cases gravis, is less common in
ocular and mild generalized disease, and have positive AChR antibodies, so AChR late-onset myasthenia
are more common in Asians. Postpubertal negativity essentially rules out a thy- gravis, and is rare in
juvenile MG has similar rates of seropos- moma.19,20 A report of a possible medi- muscle-specific tyrosine
itivity and thymic hyperplasia compared astinal abnormality on a CT chest in a kinase myasthenia gravis.
to early-onset adult MG. patient negative for AChR will almost h A thymoma, found in
Early-onset MG is variably defined as always turn out to be something other 10% to 20% of all cases
age at onset after 18 years but before 40 than a thymoma. Patients with AChR- of myasthenia gravis, is
more common with onset
to 60 years of age, with 50 being the positive thymoma without clinical mani-
after 40 years of age,
most common age cutoff. A cutoff age of festations of MG have been described. where it occurs in 25% to
45 years was suggested by a cluster However, a careful history and examina- 35% of cases.
analysis of patients with MG that con- tion will almost always reveal features
h Given their high specificity,
sidered age at onset and thymic hy- suggesting MG, or the patient will even- if either acetylcholine
perplasia.15 Women outnumber men in tually develop MG.20 A thymoma is receptor or muscle-specific
early-onset MG. This is an important almost never found in MuSK MG. tyrosine kinase antibodies
classification as the likelihood of thymic Serologic status. Serologic status is are positive, a diagnosis
hyperplasia and of response to thymec- arguably the most important classifica- of myasthenia gravis
tomy in nonthymomatous MG is greater tion. Given their high specificity, if either is certain.
in early-onset MG. Patients with MuSK MG AChR or MUSK antibodies are positive, a
are also more likely to have an early onset. diagnosis of MG is certain. The specificity
Late-onset myasthenia gravis. Late- of antibodies against agrin, LRP4, or cor-
onset MG includes patients with onset tactin is less well defined. As described
after 50 years of age who are more often previously, when AChR antibodies are neg-
men and have ocular MG. In late-onset ative, an underlying thymoma is very rare,
MG, a thymoma is more common than and thymic hyperplasia is less frequent. In
thymic hyperplasia. Evidence exists for MuSK MG the thymus is usually normal,
an increasing prevalence of MG in the the disease may be more severe, and pa-
elderly, especially those older than tients are less responsive to pyridostigmine

KEY POINTS
h When antibodies are or IV immunoglobulin (IVIg).21 In the 5% periods is sometimes spontaneously
negative in myasthenia to 10% of patients with immune MG who described. However, patients commonly
gravis, especially when are negative for all known antibodies, the may not remember previous symptoms
patients do not respond diagnosis of MG must always be ques- unless asked specifically. They may have
to treatment as expected, tioned, especially when patients do not been told that previous symptoms were
the diagnosis should respond to treatment. because of a transient ischemic attack or
be reconsidered.
Clinical manifestations and severity. Bells palsy, so a careful history of both
h The way in which a About 50% to 60% of patients present ini- current and previous symptoms is impor-
history of fatigue is elicited
tially with isolated ocular involvement, tant. The patient with unilateral ptosis
is important; direct
most of whom will generalize. Fifteen who had a previous episode of self-
questioning about
worsening weakness at percent to 25% of patients have only limited ptosis on the opposite side
the end of the day may ocular involvement throughout their almost certainly has MG.
falsely suggest a diagnosis course (ocular MG).22,23 Ocular MG is Although characteristic for MG, fati-
of myasthenia gravis. more likely seronegative for AChR anti- gability should be distinguished from
h Most patients (50% to bodies and rarely positive for MuSK. fatigue. The way that a history of fatigue
85%) with myasthenia The role for thymectomy in ocular MG is is elicited is important. An unprompted
gravis present with ocular less certain, and sensitivities of most history of significant fluctuation given by
symptoms with or without diagnostic tests are lower than in gener- the patient is the most specific. Less
generalized weakness. alized MG. Generalized MG includes directed questions (eg, Are there times
About 50% to 60% of
patients with weakness outside of the when your weakness is better or worse?)
patients with myasthenia
gravis present with isolated
ocular muscles, many of whom will also are more useful than asking directly
ocular involvement, have ocular manifestations. The Myas- whether the weakness is worse at the
although many of these thenia Gravis Foundation of America, end of the day. No matter what the cause
(50% to 60%) develop Inc classification is used mostly for for weakness, direct questions will often
generalized weakness research studies but is useful when elicit a history suggesting fatigable weak-
often within the first considering the management options ness and will result in MG being inap-
3 years after onset.
for MG.3 propriately considered in the differential.
Taking the history. When taking the Ocular symptoms. Most patients
history, it is useful to have the patient (50% to 85%) with MG present with
describe what they mean by weakness. A ocular symptoms with or without gener-
history more suggestive of pain, lack of alized weakness. About 50% to 60% of
energy, exhaustion, diffuse nonspecific patients with MG present with isolated
fatigue, or somnolence may not be con- ocular involvement, although many of
sistent with MG. The prevalence of ob- these (50% to 60%) develop generalized
structive sleep apnea is higher in patients weakness often within the first 3 years
with MG; therefore, somnolence secondary after onset. Ocular involvement in-
to a sleep disorder may coexist with MG.24 cludes ptosis, diplopia, or a combina-
The distinguishing clinical feature in tion of these.
MG is fatigable weakness. Fluctuation in Ptosis can be unilateral and, if bilateral,
symptoms is characteristic, although not is usually asymmetric. Persistently sym-
universal, and can occur over short or metric ptosis is more suggestive of a
longer periods of time. Worsening at myopathic etiology, especially chronic
the end of the day is common, although progressive external ophthalmoplegia.
some patients experience worse symp- MG is one of few disorders that can cause
toms first thing in the morning. The complete unilateral (or rarely bilateral)
patient who has no ptosis first thing in ptosis or a history of ptosis alternating
the morning and whose eyes are sides over time.
completely closed at night almost cer- Many patients describe diplopia. Milder
tainly has MG. Fluctuation over longer involvement may produce blurred vision

KEY POINT
or a halo around objects instead. Resolu- move their jaws to chew. Fatigable dysar- h Distal weakness, which is
tion of these symptoms when one eye is thria is also common. Complete aphonia sometimes surprisingly
covered suggests subtle diplopia, although is extremely rare in MG. Laryngeal in- asymmetric, occurs in
many patients have not attempted this. volvement with stridor is rare but can be about 5% of patients with
Persistent diplopia with one eye covered life-threatening. Neck weakness can af- myasthenia gravis.
suggests an ophthalmic or functional fect flexors, extensors, or both. Although
cause. Monocular vision is not affected flexor weakness is more common, MG
in MG, and abnormalities in monocular should be considered in the differential
vision require an ophthalmologic assess- of patients presenting with a head drop.
ment. Photophobia, with worsening of MG is painless, although sometimes
either ptosis or diplopia in bright lights, patients can develop secondary myofas-
is not uncommon although the reasons cial pain including neck and shoulder
for this are unclear. Some patients are so pain with a head drop without recog-
troubled by this that they wear dark nizing that weakness is the cause for
sunglasses. Patients with LEMS rarely, if this pain.
ever, present with ocular symptoms.25 Respiratory involvement in MG usu-
Generalized weakness. The weak- ally occurs associated with significant
ness experienced by patients with MG bulbar weakness. Exertional dyspnea is
can involve any striated muscle but char- nonspecific and can occur in elderly pa-
acteristically affects some muscles more tients with comorbidities or in any patient
than others. The reasons for this are not after deconditioning or weight gain. More
clear given that antibodies can access useful for diagnosis is orthopnea, which
any neuromuscular junction. Bulbar suggests diaphragm weakness, although
weakness can affect almost any of the this too is not specific for MG. Some
craniobulbar striated muscles. Facial weak- patients describe almost instantaneous
ness is often not recognized subjectively. dyspnea on bending over, presumably
Some patients describe difficulties keep- secondary to the abdominal contents
ing water out of their eyes in the shower pushing against a failing diaphragm.
or while swimming. Dysphagia when Extremity weakness in MG almost
consuming solids or liquids is common always occurs along with ocular and bul-
and can occur because of facial (labial), bar manifestations, although isolated
tongue, masseter, or pharyngeal weak- limb-girdle weakness occurs in about
ness. The temperature dependency of 5% of patients with MG. Extremity weak-
neuromuscular transmission means that, ness affects proximal arms more than legs
rarely, patients will describe more diffi- and is usually symmetric. Patients may
culty swallowing hot liquids than cold. describe increasing difficulties with the
Having patients point to where food gets prolonged use of their arms over their
stuck is useful. Localization below the heads. However, fatigable weakness of
sternal notch implies esophageal involve- the arms, of which the patient may be
ment and is not typical for MG. Nasal unaware, may be found on examination.
regurgitation when swallowing is some- Less common manifestations include
times described in MG. Clearing the distal or asymmetric weakness, which
throat or coughing after eating, even in happens in about 5% of patients with
the absence of subjective dysphagia, sug- MG. This almost always occurs later in
gests possible aspiration, which is often the course of the disease in patients
silent. Fatigable weakness of chewing is with more characteristic ocular, bulbar,
also suggestive of MG, with jaw closure and proximal extremity weakness. Distal
much more affected than jaw opening. weakness can produce a finger drop,
When severe, patients may manually which can sometimes be surprisingly

KEY POINTS
h The diagnosis of asymmetric and even focal within a hand suspected, the examiner should look for
myasthenia gravis is and, very rarely, a footdrop.26 the characteristic and fatigable weakness.
made based on clinical Muscle-specific tyrosine kinase. When To examine a patient for suspected
suspicion, the history and considered as a group, clinical differences fatigable ptosis, the examiner should hold
neurologic examination, exist between patients with AChR and the test object up for at least 60 seconds
and is then supported by MuSK MG. However, significant overlap and watch for obvious worsening. Re-
electrophysiologic and
occurs with the clinical manifestations of peated blinking, which mimics a brief max-
serologic studies.
AChR MG so that predicting MuSK anti- imal voluntary contraction, may transiently
h Myasthenia gravis can body positivity in an individual patient is improve neuromuscular transmission
produce any pattern of
difficult. Patients with MuSK antibodies and mask fatigable ptosis. As the differ-
pupil-sparing extraocular
muscle involvement, are more likely to be female, have early- ential for unilateral ptosis is different
including sixth or third onset MG, and have more severe disease, than for bilateral, looking for enhanced
cranial nerve palsy especially affecting bulbar and respiratory ptosis in the patient with what appears
or internuclear muscles. Rarely is MuSK MG purely ocu- to be unilateral ptosis can be useful.
ophthalmoplegia mimics. lar. Patients with MuSK MG may be more Manual elevation of the obviously ptotic
likely to be oligosymptomatic or mono- eyelid may bring on fatigable ptosis on
symptomatic. Isolated dysphagia, a head the opposite side as the patient is less
drop, or dyspnea without other bulbar reliant on the compensatory use of the
weakness is uncommon in AChR MG frontalis muscle, which may have ob-
but occasionally occurs in MuSK MG scured ptosis on the less affected side.
(Case 11-1). The specificity and sensitivity of the
Cogan eyelid twitch sign (twitching of
Diagnosis the upper eyelid seen when the eyes are
The diagnosis of MG is made based on moved from downgaze back to the
clinical suspicion, the history and neuro- primary position) is widely variable; the
logic examination, and is then supported author does not find this sign useful in
by electrophysiologic and serologic stud- diagnosing MG.
ies. Few diagnostic tests are infallible and The first step when assessing diplo-
some, such as single fiber EMG, are not pia is to establish that it is binocular. If
specific for MG. Undue reliance on diag- monocular (two objects persist when
nostic tests when the clinical picture does one eye is covered), an ophthalmic or
not fit may lead to a false diagnosis of functional origin is likely. MG can pro-
MG.27 Although diagnostic tests in pa- duce any pattern of pupil-sparing extra-
tients with mild, especially ocular, MG ocular muscle involvement, including
may be normal, if no objective support sixth or third cranial nerve palsy or inter-
exists for the diagnosis on at least one nuclear ophthalmoplegia mimics. Down-
test in a patient with significant weakness, gaze is less affected in MG. Although
other diagnoses should be considered. objective limitations in extraocular mus-
Clinical. The biggest delay in diagno- cle movement may be present, usually
sis often results from failure to consider the weakness is subtle and not appreci-
MG in the differential. MG is uncommon, ated by the examiner. It is important for
and most non-neurologists are not famil- the examiner to ask the patient to report
iar with its clinical features. Patients who double vision when assessing the extra-
report significant weakness the previous ocular muscles. Complete symmetric oph-
day but have no objective weakness the thalmoplegia, especially if early in the
next morning are often labeled as func- course, is very uncommon in MG and
tional. Most elderly patients with MG more suggestive of chronic progressive
are first diagnosed as having a stroke or external ophthalmoplegia. Although
transient ischemic attack. Once MG is ptosis can take 60 seconds to fatigue,

KEY POINTS
h Although ptosis can take
Case 11-1 60 seconds to fatigue,
A 47-year-old woman presented for evaluation of a possible myopathy. While diplopia usually appears
fishing 3 years earlier, she had developed a painless head drop after leaning within 15 to 30 seconds
over a railing for several hours. This symptom had improved but several days of sustained gaze.
later, after a sudden forced flexion of her neck, her head drop returned and
h A single breath count, in
persisted. Initially she was thought to be functional and was referred to a
which the patient counts
chiropractor, which did not help her condition. Shortly after, she developed
out loud at approximately
severe orthopnea and had to sleep in a chair, and she also developed acute
2 Hz from full inspiration
dyspnea on bending over. She required bilevel positive airway pressure (BiPAP)
until he or she needs to
for her dyspnea and developed severe pulmonary hypertension. Her symptoms
take a breath, correlates
became worse at the end of the day. On questioning she reported dysphagia.
roughly with the forced
Studies done prior to her visit included concentric needle EMG that showed vital capacity in
increases in spontaneous activity with 1+ positive sharp waves in paraspinal pulmonary function
and trapezius muscles. Repetitive nerve stimulation of ulnar, axillary, and facial studies.
nerves was reported as normal. Single fiber EMG in extensor digitorum
communis was also reported as normal.
On examination at age 47, she had no diplopia or ptosis. She had mild facial
and severe neck flexor and extensor weakness and moderate fatigable deltoid
and triceps weakness with equivocal hip flexor weakness. Repeat nerve
conduction studies and EMG showed 1+ fibrillation potentials and numerous
myopathic motor unit potentials in the cervical paraspinals, trapezius, and deltoid
muscles. Repetitive nerve stimulation of the median nerve was normal, but a
40% decrement was seen in spinal accessory studies. Single fiber EMG in
orbicularis oculi showed abnormal jitter in 14 of 21 fiber pairs with blocking in
four of the 14. Acetylcholine receptor antibodies were negative, and the CT chest
showed no thymic abnormalities.
She was treated with pyridostigmine, prednisone, and azathioprine but
worsened and required IV immunoglobulin (IVIg). She improved, although she
required several more treatments over the next 2 years, improving after each
treatment. When testing for muscle-specific tyrosine kinase (MuSK) antibodies
became available 2 years after presentation, the patient was found to be positive.
She slowly improved, and at follow-up 5 years later, she was off pyridostigmine
and prednisone and remained on azathioprine alone. Her dyspnea improved, and
she was able to sleep supine, although she remained on BiPAP for severe
obstructive sleep apnea.
Comment. This case demonstrates the characteristic features of MuSK
myasthenia gravis with female predominance, prominent bulbar and respiratory
weakness, and atypical findings on electrophysiologic studies with abnormalities
much more frequent in bulbar and proximal muscles. Frequently, patients with
MuSK myasthenia gravis either do not respond or may even worsen after
treatment with pyridostigmine.
diplopia usually appears within 15 to whether the patient can speak in full
30 seconds of sustained gaze. sentences. A single breath count, in which
In any patient who reports dysphagia or the patient counts out loud at approxi-
other significant bulbar weakness, bed- mately 2 Hz from full inspiration until he
side testing of swallowing is best left to a or she needs to take a breath, correlates
speech and language pathologist with roughly with the forced vital capacity in
experience in assessing patients with MG. pulmonary function studies. Counting to
A simple bedside assessment of re- 20 or more suggests that significant re-
spiratory function involves observing spiratory involvement is unlikely. During

KEY POINTS
h The tests used to diagnose the single breath count the examiner be objectively assessed. Ideally, the
myasthenia gravis include should listen for fatigable dysarthria. edrophonium test should be done dou-
repetitive nerve The dysarthria in MG is bulbar and can ble blinded, with syringes of saline or
stimulation and single usually be readily distinguished from edrophonium drawn up by a third per-
fiber EMG. dysarthria in other disorders that might son, and the response to each assessed by
h Routine nerve conduction be mistaken for MG. both patient and examiner blinded to
studies and needle EMG When assessing fatigable limb weak- what is being administered. As there is
are usually normal in ness in patients with possible MG, the often a subjective element to the inter-
patients with myasthenia
author prefers the hands-on method, in pretation of this test, by blinding the
gravis but should almost
which the patient contracts repeatedly edrophonium test, the risk of examiner
always be done first as
myopathic or neurogenic for at least five contractions against resis- and patient bias is reduced. In the ice
conditions may confuse tance. The examiner then looks for grad- pack test, crushed ice in a plastic bag is
the interpretation of ual worsening in power with the last few applied over a ptotic eyelid for 2 to
repetitive nerve stimulation contractions. With profound weakness 5 minutes and then removed.30 PreY
and single fiber EMG. at baseline, demonstrating additional and postYice pack test eyelid positions
h Reduced motor fatigue is difficult. Others prefer to are then compared, ideally by a blinded
amplitudes on motor assess power of a single contraction examiner looking at photographs.
nerve conduction study followed by the patient exercising (eg, Electrophysiologic studies. The tests
is suggestive of clapping hands over the head 20 times) used to diagnose MG include repetitive
Lambert-Eaton
and then reassessing power. The hands-on nerve stimulation and single fiber EMG.1
myasthenic syndrome.
technique allows a better assessment of Routine nerve conduction studies and
h Abnormalities on needle the pattern of fatigue to differentiate from needle EMG are usually normal in pa-
EMG, including fibrillation
nonorganic fatigue, which is often sudden tients with MG but should almost always
potentials, positive
sharp waves, and
with tremulous recruitment. Muscles eas- be done first as myopathic or neurogenic
myopathic motor unit ily assessed for fatigue include deltoids, conditions may confuse the interpreta-
potentials, can be seen in triceps, and hip flexors. It is more tion of repetitive nerve stimulation and
some patients with difficult to convincingly demonstrate fa- single fiber EMG. Reduced motor ampli-
myasthenia gravis, tigue in distal muscles, which are easily tudes on motor nerve conduction study
especially in patients with overcome in normal individuals. Limb is suggestive of LEMS. Both LEMS and
muscle-specific tyrosine
weakness in MG is almost always proximal amyotrophic lateral sclerosis may also
kinase myasthenia gravis.
and symmetric and affects arms more than produce a decrement on repetitive nerve
legs. In the arms, involvement of deltoids stimulation and an abnormal single fiber
and triceps is typical for MG, whereas EMG. Denervation on needle EMG sug-
myopathies more commonly cause weak- gests motor neuron disease. However,
ness of deltoids and biceps. abnormalities on needle EMG, including
The quantitative myasthenia gravis test fibrillation potentials, positive sharp waves,
and similar scales incorporate measures and myopathic motor unit potentials,
of ocular, bulbar, respiratory, and ex- can be seen in some patients with MG, es-
tremity strength and fatigue.28 Although pecially in patients with MuSK MG.31
used mostly for research trials, the When a diagnosis of MG is serologi-
quantitative myasthenia gravis test score cally proven, electrophysiologic testing
can be used in clinical practice to follow may not be necessary. However, repet-
patients during treatment. itive nerve stimulation is a useful exten-
The ice pack and edrophonium tests sion of the clinical examination when
have similar sensitivities and specific- determining whether the patients symp-
ities.29 Increasing difficulties in obtain- toms are secondary to MG. However,
ing edrophonium means that this test is many muscles, including extraocular and
rarely done. If performed, there must be a most bulbar and leg muscles, are not
clear end point (usually ptosis) that can accessible for repetitive nerve stimulation

KEY POINT
studies. Normal repetitive nerve stimula- fiber EMG is higher in proximal or h Although highly sensitive,
tion results in a weak muscle suggests bulbar muscles. and sometimes the only
that the weakness is not related to MG. Single fiber EMG provides no addi- positive diagnostic test in
Patients with MG who have what appears tional diagnostic information when the ocular myasthenia gravis,
to be severe weakness should have at diagnosis has been established serolog- abnormalities on single
least one objective abnormality on diag- ically or if a significant decrement is seen fiber EMG are nonspecific
and can be seen in many
nostic testing, particularly electrophysi- on repetitive nerve stimulation, both of
other myopathic or
ologic testing. which have a higher specificity for MG. As neurogenic conditions.
Repetitive nerve stimulation can be single fiber EMG is most useful when all Single fiber EMG results
performed in several different nerve- other tests are negative, it is used mostly should always be
muscle pairs. Sensitivities are higher to diagnose ocular MG. Studies of orbi- correlated with the
in proximal muscles. If accessible, the cularis oculi or frontalis are more sensi- clinical presentation.
weakest muscles should be studied. With tive than distal muscles. Although highly
oculobulbar and mild proximal arm sensitive, an abnormal single fiber EMG
weakness, normal studies in a distal is not specific for MG, and results need
hand muscle do not exclude MG. Useful to be correlated with the clinical features
proximal nerve-muscle pairs are facial to (Figure 11-1). The performance and in-
nasalis or orbicularis oculi, spinal acces- terpretation of single fiber EMG requires
sory to trapezius, axillary to deltoid, and an experienced electromyographer. One
sometimes radial to extensor forearm of the reasons for a false diagnosis of MG
muscles. In the leg, studies of the fibular is undue reliance on abnormal single
(peroneal) nerve to tibialis anterior are fiber EMG studies without considering
possible, but for technical reasons it is specificity. Single fiber EMG can be ab-
not possible to study proximal leg mus- normal in a wide range of neurogenic
cles. In ocular MG, the sensitivity of and myopathic conditions including con-
repetitive nerve stimulation is low genital myasthenic syndromes, LEMS,
(approximately 20%) but in generalized progressive external ophthalmoplegia,
MG, the sensitivity is higher (approxi- and amyotrophic lateral sclerosis.32Y34
mately 80%), providing that studies of Abnormalities on single fiber EMG can
symptomatic or proximal muscles are persist for at least a year after botuli-
done. In MuSK MG the yield of both num toxin injection, especially with re-
repetitive nerve stimulation and single peated injections, and can be found in
FIGURE 11-1 Single fiber EMG showing A, jitter at more than 200 sec; B, jitter at
more than 700 sec and blocking in more than 60% of muscle fiber
action potentials.

KEY POINTS
h The acetylcholine receptor muscles remote from the injection site or MuSK as well as in other disorders,
antibody titer does not so that an abnormal single fiber EMG including amyotrophic lateral sclerosis.42
correlate well with clinical must always be considered with caution It is uncertain whether a specific clinical
severity in an individual after botulinum toxin.35 phenotype is associated, although early
patient, and it is not useful Serologic studies. Although the sen- evidence suggests that LRP4 is found
to follow antibody sitivity of antibody testing is low in some in ocular as well as in mild to moderate
levels serially.
situations (eg, ocular MG), the specific- generalized MG.42
h Novel antigenic targets ity for the diagnosis of MG is very high Even more recently, antibodies against
have been recently
(more than 99% for AChR antibodies).29,36 agrin or cortactin have been reported in MG.
discovered in patients
In the right clinical context, positive anti- Their pathogenic relevance and associated
with myasthenia gravis.
bodies confirm a diagnosis of MG. Posi- clinical phenotype are uncertain21,45,46
h Positive serologic tests in tive AChR antibodies also correlate with Although often used as a diagnostic
myasthenia gravis both
thymic pathology (either thymic hyper- criterion in published studies of MG,
confirm the diagnosis as
well as help guide plasia or a thymoma), whereas MuSK especially ocular MG, a frequent diag-
management options. antibodies, for the most part, do not.15 nostic pitfall is overreliance on response
h Response to treatment, Thus, knowledge of the serostatus guides to treatment. This false-positive response
especially to pyridostigmine investigations and treatment options. is especially common with pyridostigmine
and IV immunoglobulin, AChR antibodies are present in approx- and IVIg (Case 11-2) for several reasons,
may be useful as a imately 50% of patients with ocular MG including a placebo effect, especially in
diagnostic test but only and 85% of patients with generalized patients with pseudo-MG. Many patients
when supported by MG.29 A small percentage of initially with nonspecific fatigue pursue an Inter-
clinical features and, AChR-negative patients may become se- net diagnosis leading to a self-diagnosis
preferably, other objective
ropositive, usually in the first year.37 More of MG. Improvement with treatment is
diagnostic tests.
recent improvements in the assay using taken to confirm the diagnosis of MG,
clustered AChRs in cell-based assays re- even when all other diagnostic tests are
veal positive AChR antibodies in 50% of negative. Some patients come to the
previously seronegative patients. This neurologist well versed in the symptoms
assay is more demanding technically and of MG, and asking about specific details
is not yet widely available.7,38 The AChR of each symptom is essential to help
antibody titer does not correlate well with patients differentiate what is occurring
clinical severity in an individual patient, from what they have read about. Subjec-
and it is not useful to follow antibody tive response to treatment should only be
levels serially.39 Negative AChR antibodies used to diagnose MG if it is unequivocally
make a thymoma extremely unlikely.15,40 and objectively verified. IVIg may pro-
MuSK antibodies are found in approx- duce a nonspecific sense of well-being,
imately 40% (range of 0% to 70%) of the independent of its specific benefits in
15% AChR-negative generalized MG MG. Finally, some disorders in the differ-
group but are rarely positive in patients ential for immune MG may also respond
with ocular MG.21,37,41 The range of MuSK to symptomatic treatments including
sensitivities may reflect geographic and congenital myasthenic syndromes, mito-
ethnic variation as MuSK is more com- chondrial myopathies, and LEMS. If in
mon in the nonwhite population.14,21,42,43 doubt, with the patients consent, a
More recently, LRP4 antibodies have blinded trial of active therapy versus
been found in a small number (approxi- placebo can sometimes establish whether
mately 18%) of patients who are negative the benefit is biological (Case 11-2).
for AChR and MuSK,42 although other Ancillary investigations. A CT chest
studies suggest a lower frequency.44 Their is indicated in patients with AChR MG,
role in MG is less certain as they may oc- although many neurologists will arrange
cur in patients who are positive for AChR one in all MG patients. Its main indication

Case 11-2
A 45-year-old woman was referred for a neurologic consultation after
receiving a diagnosis of myasthenia gravis (MG) made by her internist 1 year
earlier and because of ongoing symptoms despite treatment. Her symptoms
included a hoarse voice with aphonia after prolonged talking, dysphagia for
solids and liquids with choking, weakness of jaw muscles when chewing, facial
weakness, exertional dyspnea without orthopnea, and a head drop. No diplopia or
ptosis had occurred. In addition, the patient had described generalized
exhaustion, fatigue, and daytime somnolence. Because of her extremity
weakness, she would often fall to the ground and could not work. She had read
extensively about MG. She had thought that pyridostigmine had made a huge
difference in her symptoms. Despite continued use of pyridostigmine, she had
worsened and had become unable to walk. Prednisone and azathioprine had
been started by her previous physician, and she was also being treated with IV
immunoglobulin (IVIg), which she had continued on a monthly basis thereafter. Both
the patient and her previous physician had perceived significant benefit after IVIg,
although it had caused headaches requiring narcotics. Because of worsening
weakness, her frequency of IVIg treatments had been increased to every
2 weeks prior to referral for the second opinion.
On examination, she had blepharospasm but no objective weakness. All
investigations were normal including repetitive nerve stimulation (several times),
single fiber EMG, CT chest, acetylcholine receptor (AChR) (several times)
antibodies, and muscle-specific tyrosine kinase (MuSK) antibodies. A speech and
language pathology consultation did not show any objective evidence of
dysarthria or dysphagia consistent with MG.
When suggested by the neurologist, she agreed to an n-of-1 (ie, double
blinded trial of treatment in a single patient) placebo versus IVIg trial in which she
would receive IVIg or placebo every 3 weeks for a total of three treatments of each,
with each treatment received in randomized order and with a standardized
objective clinical and electrophysiologic assessment at each visit. Both she and the
neurologist were blinded to the treatment received. After the fourth scheduled
treatment, she asked for the trial to be stopped as she was convinced that IVIg
produced significant improvement (as well as a headache requiring narcotics) on
each of the three occasions that she felt she had received it. No significant changes
in the clinical examination were noted by the neurologist, and no changes in the
quantitative MG scoring or any abnormalities on repetitive nerve stimulation
were noted with any of the four treatments. When the neurologist was
unblinded to her treatment, she had received placebo each of the three times
she felt that she had improved and had received IVIg on the occasion she
perceived no benefit. She chose not to continue follow-up with the neurologist as
she disagreed with his opinion that she did not have MG. She sought a second
opinion with another neurologist. Despite being told again by that neurologist
that her condition was not MG, 3 years later she continued to be treated with
pyridostigmine, prednisone, azathioprine, and IVIg every 2 to 4 weeks, prescribed
by her first physician for a myasthenialike syndrome.
Comment. This case demonstrates the perils of accepting a patients response
to treatment as definitive evidence that the diagnosis is MG. Ultimately, response
is often subjective and, if it is the only diagnostic clue, may lead to a false-positive
diagnosis of MG.
is to look for a thymoma, although it can plasia is a pathologic diagnosis made at

be difficult to distinguish focal hyperplasia the time of thymectomy. A normal thy-
from a small thymoma.47 Thymic hyper- mus in a young, healthy control can look

KEY POINT
h Vitamin B12 deficiency enlarged, and a normal or small thymus Differential Diagnosis
or thyroid disease may on CT may still be hyperplastic.47 Thymic With a characteristic history of fluctuat-
produce nonspecific hyperplasia can occur in other autoim- ing weakness and an appropriate pattern
symptoms that can mune conditions including systemic lupus of weakness, a clinical diagnosis of MG
complicate the erythematosus and autoimmune thyroid often seems secure. However, many
management of disease. If considering thyroid eye disease, patients report worsening of their weak-
myasthenia gravis if
looking for enlarged extraocular muscles ness at the end of the day even when the
not recognized.
on a CT or MRI of the orbits is useful. ultimate diagnosis is not MG, and some
The prevalence of other autoimmune conditions can mimic the symptoms and
diseases is increased in MG. Without sug- signs of MG.
gestive clinical features, the yield of Ocular. Ocular MG is often more dif-
screening for most autoimmune diseases ficult to diagnose than generalized MG,
is low. However, the routine determina- and the sensitivity of diagnostic tests is
tion of vitamin B12 and thyroid levels is lower. Many conditions can mimic ocu-
useful as vitamin B12 deficiency or thy- lar MG (Table 11-1).27 Ophthalmologic
roid disease may produce nonspecific conditions, including levator dehiscence or
symptoms that can complicate the man- a decompensated phoria, are common
agement of MG if not recognized. eventual diagnoses when ocular MG is
TABLE 11-1 Differential for Myasthenia Gravis
Generalized Myasthenia
Anatomic Ocular Myasthenia Gravis Gravis
Ophthalmic Thyroid eye disease, levator Not applicable
dehiscence, phoria, tropia
Central nervous Blepharospasm, brainstem Amyotrophic lateral sclerosis,
system lesion (eg, multiple sclerosis, Parkinson disease/parkinsonism
ischemia, mass lesion,
Wernicke encephalopathy)
Peripheral
nervous system
Nerve Microvascular/diabetic cranial Amyotrophic lateral sclerosis,
neuropathies, Horner syndrome, Guillain-Barre syndrome,
Miller Fisher syndrome, focal neuropathies affecting
isolated/combined III, IV, and craniobulbar function
VI cranial neuropathies
Neuromuscular Lambert-Eaton myasthenic Lambert-Eaton myasthenic
junction syndrome,a botulism, congenital syndrome, botulism, congenital
myasthenic syndrome myasthenic syndrome,
organophosphate toxicity
Muscle Chronic progressive Chronic progressive external
external ophthalmoplegia, ophthalmoplegia, other
oculopharyngeal muscular mitochondrial myopathies,
dystrophy, myotonic dystrophy oculopharyngeal muscular
dystrophy, myotonic dystrophy
Other Idiopathic, convergence spasm Systemic disease, thyroid disease,
idiopathic , chronic fatigue,
functional/conversion disorder
a
Ocular manifestations are rare at onset of Lambert-Eaton myasthenic syndrome.

KEY POINTS
being considered. Microvascular neurop- history and examination. Functional weak- h A congenital myasthenic
athies, including diabetic or hypertensive ness is also commonly in the differential. syndrome should be
microvascular cranial neuropathies, af- considered in patients
fecting the III, IV, or VI cranial nerves Management who are seronegative and
should be considered, especially with The crucial first steps in managing MG who have onset at birth,
periorbital pain or headache at the onset are to ensure that the diagnosis is cor- early in life, and even in
adulthood.
of diplopia. Symmetric restriction in rect and that the symptoms being treated
extraocular muscles and progressive sym- are those of MG. Causes of refractory MG h Causes of refractory
include an incorrect diagnosis or symp- myasthenia gravis include
metric ptosis, even with a history of minor
an incorrect diagnosis or
fluctuations, suggests chronic progressive toms that are not due to MG. When
symptoms that are not
external ophthalmoplegia. Thyroid eye patients do not improve as expected, it due to myasthenia gravis.
disease may mimic or coexist with ocular is useful to reconsider the diagnosis, When patients do not
MG. In about 25% of patients who have a especially if the patient is seronegative. improve as expected, it is
combination of ptosis and diplopia, no If a patient is seropositive, it is important useful to reconsider the
diagnosis is determined.48 to establish that the symptoms are con- diagnosis, especially if the
Generalized. In a typical case of gen- sistent with MG. A patient with MG who patient is seronegative.
eralized MG, the differential is limited improves with treatment but then reports
(Table 11-1), and the sensitivity of diag- increasing weakness may be describing
nostic tests is higher.27 A congenital fatigue, exhaustion, or daytime somno-
myasthenic syndrome should be consid- lence, which may be symptoms of ob-
ered in patients who are seronegative structive sleep apnea.24 In addition to a
and who have onset at birth, early in life, clinical assessment, repeat electrophysio-
and even in adulthood. Some congenital logic studies (ie, repetitive nerve stimula-
myasthenic syndromes can present in tion) may help determine whether the
adolescence or even adulthood caused weakness is secondary to MG. Other rea-
by mutations in the genes RAPSN, DOK7, sons for worsening symptoms include
or COLQ. When ocular symptoms are adverse effects from medications (pred-
absent and hyporeflexia or areflexia and nisone in particular), mood disorders,
autonomic dysfunction occur, consider and social circumstances.
LEMS. Other conditions to be consid- Education of patients and primary care
ered when the deep tendon reflexes are physicians is crucial. Expectations of the
reduced include Guillain-Barre syn- treating physician or patient about when
drome and its Miller Fisher variant and treatments should start being effective
rare cases of multifocal neuropathy with are sometimes unreasonable.49 Under-
conduction block with cranial nerve mus- dosing (or occasionally overdosing) or
cle involvement. In oculopharyngeal mus- abandoning a treatment too early can
cular dystrophy, ptosis and generalized both result in treatment failure. A
weakness can occur, but extraocular discussion about each medication, pos-
muscle involvement is usually absent. sible adverse effects and strategies to
Mitochondrial myopathies can be difficult manage them, expected time course of
to distinguish clinically from MG, and benefits (hours to days for pyridostig-
single fiber EMG can be abnormal in mine, weeks to many months for predni-
many myopathic disorders including sone, and many months to a year or more
oculopharyngeal muscular dystrophy for azathioprine) is crucial. For some med-
and mitochondrial myopathies.34 Central ications, monitoring for adverse effects is
nervous system disorders such as Parkinson essential, and a discussion of the impor-
disease, progressive supranuclear palsy, tance of this increases compliance. For
or brainstem lesions are usually not diffi- physicians managing many patients with
cult to distinguish from MG after a careful MG, having this educational information

KEY POINTS
h A complete lack of in print form in addition to a verbal Rarely, patients need lower initial doses
response to treatment is discussion saves time and reinforces the or a slower rate of escalation. Having
unusual in patients with message. Sending a list of the medica- already discussed the next options with
myasthenia gravis and tions that should be avoided in patients the patient at the time of medication
should prompt physicians with MG to the primary care physician initiation, the author has the patient call
to reconsider the diagnosis is useful, although this is not infre- to provide an update on his or her re-
of myasthenia gravis in
quently ignored. Finally, a discussion sponse 2 weeks after starting the medica-
patients who are
seronegative or reconsider
of which symptoms might be secondary tion. Even when a complete response
whether myasthenia to MG (weakness) and which almost never occurs, occasionally symptoms will break
gravis is the cause of the occur (eg, pain, memory loss, sensory through over the next several months. If a
symptoms in patients who symptoms, systemic disorders) maximizes partial response occurs, further increases
are seropositive. efficiency of the neurologists time. of 30 mg to 60 mg at each dose can be
h Many treatments of Management of ocular myasthenia made at intervals of 1 to 2 weeks up to
myasthenia gravis take gravis. Although not life-threatening, ocu- a maximum of 480 mg/d, depending on
time to reach maximal lar MG can be disabling. The first decision tolerance. Higher doses are unlikely to
efficacy, and another is whether symptoms require treatment. produce additional benefit. Diarrhea,
cause for nonresponse to
When symptoms are mild and infrequent, one of the more common side effects,
treatment is unreasonable
expectations about how
it may be best to defer treatment until is often self-limited, but loperamide helps
long it should take before they become troublesome. A trial of in most cases. If no response occurs, the
improvement begins. pyridostigmine may be warranted, but author moves on to immunosuppression,
the medication is often ineffective or usually adding to pyridostigmine, although
minimally effective, especially for diplo- if it is clear that no response has oc-
pia. The risk to benefit ratio of prednisone curred, the medication could be stopped.
may not be worth accepting. Retrospective Prednisone is very useful in patients
evidence suggests that prednisone may with ocular MG, although patience is re-
reduce the risk of generalization.50 How- quired. The evidence in adults that pred-
ever, it may be better to avoid predni- nisone given on alternate days is less
sone when not required, knowing that it likely to cause adverse effects is prac-
is just as likely to be effective if and when tically nonexistent, but starting low doses
MG becomes generalized. (eg, 25 mg every other day) of prednisone
MG is treated symptomatically with will help most patients in about 3 to 4
pyridostigmine, which inhibits acetyl- months.51 Occasionally, patients fluctu-
cholinesterase at the neuromuscular ate and are worse on the off day, and
junction and increases available acetylcho- glycemic control using the alternate-day
line but does not treat the underlying approach is difficult in diabetics, so
immunopathogenesis. Pyridostigmine is sometimes starting or reverting to an
the usual first step in treating ocular MG. equivalent daily dose is required. If at
It has few serious side effects and, if ef- 3 to 4 months the symptoms are not
fective, works quickly. Starting at 30 mg improving (they may not be completely
every 4 hours during the waking day, with gone), doubling the dose to either 25 mg/d
the first tablet taken within an hour of or 50 mg on alternate days helps most of
arising, is a reasonable strategy. Unless the remaining patients. Physicians should
nocturnal symptoms occur, a bedtime be familiar with common side effects of
tablet is wasted. If required, the dose prednisone and discuss these with the
can be increased to 60 mg every 4 hours patient.3 Anticipating worsening in hy-
in 3 to 7 days. The regular 60 mg pyri- pertension and glycemic control and
dostigmine pills have a more consistent enlisting the help of the primary care
bioavailability, and the author rarely physician in managing these is helpful.
uses the sustained-release formulation. Individuals older than age 50 taking more

KEY POINT
than 7.5 mg/d for more than 3 months author avoids combining more than two h With patience, most
should be on osteoporosis prophylaxis at (prednisone and one other) immuno- patients with myasthenia
the outset.52 suppressants because of the increased gravis will respond to
With patience, prednisone doses risk of infections. lower doses of prednisone,
higher than 25 mg/d to 30 mg/d are Management of generalized myas- although this may take
rarely required in patients with ocular thenia gravis. The treatment of MG is several months.
MG. About 2 to 3 months after the highly individualized, and only general
symptoms have resolved, it may be guidelines are discussed. The options
appropriate to start tapering the dose. chosen depend on serostatus (AChR ver-
With doses of more than 20 mg/d, taper sus other), age, comorbidities, and dis-
by 10 mg a month, and with doses of less ease severity. For most choices, no trial
than 20 mg/d, taper by 5 mg a month evidence exists to establish effective-
(10 mg on the alternate day). It is often ness.53 However, the collective experi-
useful to taper by 2.5 mg or even 1 mg ence supports the most commonly used
reductions every 1 to 2 months with medications and treatments. The choice
doses of less than 5 mg/d to 10 mg/d. often comes down to physician experi-
Symptoms often recur at doses of less ence and familiarity as well as patient
than 5 mg/d to 10 mg/d, and many pa- tolerance. For all treatment options, a
tients require long-term low-dose pred- discussion of expected benefits, includ-
nisone. Tapering too quickly or while ing the time frame that is involved, as
the patient is still symptomatic will almost well as common adverse effects and
always result in a relapse, often several monitoring required, is useful.
months after a reduction. Symptomatic. As is the case for ocular
The databases used by most pharma- MG, in mild to moderate generalized
cies in North America sometimes flag the MG, pyridostigmine may be the only
combination of prednisone and pyridos- treatment at first. The same strategy and
tigmine as a potentially harmful interac- advice about pyridostigmine previously
tion. The vast majority of patients with discussed for ocular MG also applies to
MG will be on this combination at some the treatment of generalized MG. A cho-
point. The literature supporting this linergic crisis, in which weakness is
warning is decades old and likely relates worsened by increased doses of pyri-
to the early worsening that can be seen dostigmine, rarely occurs. Almost always,
with the use of high-dose prednisone and a careful history will reveal worsening in
not to an interaction between the two. MG symptoms prior to increases in the
To avoid future telephone calls and con- dose of pyridostigmine. In mild to mod-
fusion on the part of the patient, the erate generalized MG, the concomitant
author often sends a form letter with the use of prednisone and sometimes another
prescription politely suggesting that immunosuppressant is often required.
the pharmacist ignore this warning. In more severe MG, immunosuppres-
Azathioprine can be used in ocular sion and sometimes immunomodula-
MG, either alone (if the patient is willing tion should be started at the same time
to wait) or along with prednisone in pa- as pyridostigmine.
tients where long-term/high-dose predni- Immunosuppression. For mild gen-
sone is best avoided. Azathioprine can eralized MG, when pyridostigmine alone
also be added later if no response to is not helpful, low-dose alternate-day
prednisone occurs by 6 to 9 months or prednisone is useful. For moderate gen-
if the patient worsens when tapering. eralized MG, higher doses may be re-
Other immunosuppressants can also be quired. For severe MG, especially if bulbar
used in patients with ocular MG. The or respiratory weakness occurs, higher

KEY POINT
h Caution is advised when doses are effective more rapidly. How- effects. In the authors experience, about
starting patients with ever, if high doses (the author considers 1% to 2% of patients, higher in others
myasthenia gravis who doses higher than 30 mg/d as the cutoff experience, will experience a flulike re-
have any bulbar or for concerns about this phenomenon ) action within the first 2 weeks that almost
respiratory weakness on are used initially, about 40% of patients always requires discontinuation. Monitor
high doses of prednisone with MG may worsen initially before they hepatic transaminases (alanine amino-
as patients may
start to improve, and 10% overall worsen transferase [ALT], aspartate amino-
worsen initially.
significantly.54 This usually starts 4 to 5 transferase [AST], and most importantly
days after beginning prednisone and ,-glutamyltransferase [GGT]) and a com-
lasts about 4 to 7 days before improve- plete blood count and differential weekly
ment then occurs. Strategies to avoid for the first 8 weeks and monthly there-
this initial worsening of symptoms in- after. Hepatotoxicity, usually mild and
clude starting at low doses (eg, 10 mg/d) reversible, occurs in 15% and mye-
with increases every 3 to 5 days in 10 mg losuppression in 10% at a median of
steps until the desired dose is reached.55 about 6 weeks after starting.58 Both will
The use of IVIg or plasma exchange when resolve after a dose reduction, although
prednisone is started may also prevent if these adverse effects are rapid or
initial worsening. Prednisone doses of significant, discontinuation may be re-
more than 1 mg/kg/d are rarely required, quired. Neutropenia is the main concern,
and the author usually uses a maximum whereas lymphopenia and macrocytosis
dose of 0.5 mg/kg/d to 0.75 mg/kg/d. are common and benign findings that are
Recent trial evidence suggests that, with seen when monitoring blood work with
patience, most patients respond to rela- long-term azathioprine use. After 6 to
tively low doses of prednisone.56 Predni- 12 months on azathioprine, if no im-
sone takes months (usually 3 to 6 months provement occurs at 150 mg/d, in most
and sometimes longer) before maximum patients not at maximal doses based on
benefit occurs. Higher doses might accel- weight (ie, the patient weighs more than
erate this slightly but definitely increase 50 kg [110 lb]), the dose can be increased
the risk of adverse effects. With bulbar or in 50 mg to 100 mg steps every 3 to 6
respiratory weakness, when a more rapid months to a maximum of 2.5 mg/kg/d to
response is required, immunomodulatory 3.0 mg/kg/d based on actual body weight.
treatments should be used (see the fol- Long-term azathioprine use may increase
lowing section on immunomodulation). the risk of malignancies, particularly der-
In mild generalized MG, if predni- matologic, although the absolute risk of
sone is best avoided, azathioprine can this is low.59 Strategies to reduce this are
be used alone provided the patient can prudent.60 If a risk of or previous
wait the 12 to 18 months (or more) that it history of skin cancers already exists,
may take before optimal benefit is seen.57 using mycophenolate might pose a
Starting prednisone and azathioprine at lower risk.61
the same time takes advantage of the In patients who do not respond to or
earlier benefits from prednisone as tolerate azathioprine, other immuno-
well as the eventual steroid-sparing suppressants can be used. Mycophenolate
effects of azathioprine. Tapering regi- (either mofetil or sodium) is a common
mens are similar to ocular MG (larger next step. Although two trials failed to
reductions at doses of more than 30 mg/d show an additional benefit compared
and smaller below this). Starting aza- to prednisone alone over 36 weeks,
thioprine at 25 mg/d with increases this may reflect the efficacy of predni-
every 2 weeks to 50 mg/d, 100 mg/d, sone in relatively mild MG within the
and 150 mg/d lessens some adverse first 9 months rather than a failure of

KEY POINT
mycophenolate. 56 Mycophenolate is medications, which can interfere with h In a myasthenic crisis,
widely used in MG and likely takes at neuromuscular transmission.64 In al- pyridostigmine is often
least 6 months and perhaps longer to pro- most one-third of cases, a cause is not sufficient, and
duce significant benefit. Mycophenolate not identified. immunosuppressive
is generally well tolerated and may be For patients who have an acute exac- options, although
more suitable in patients with skin erbation of MG, pyridostigmine is often effective, can take months
to produce benefit.
cancer. Other immunosuppressants used insufficient, and its adverse effects of
Immunomodulation, with
frequently in MG include cyclosporine, increased oral and tracheobronchial either IV immunoglobulin
tacrolimus, methotrexate, and cyclophos- secretions may worsen the situation. or plasma exchange,
phamide. Some retrospective and limited Immunosuppressants may take months; produces earlier
trial evidence supports the efficacy of therefore, in addition to treating the un- improvement in most
each of these. Most of these agents have derlying precipitant, immunomodulatory patients and bridges the
greater toxicity than azathioprine and treatments are useful for a crisis or severe gap while waiting for
immunosuppression
mycophenolate and require more in- exacerbation and include IVIg and plasma
to work.
tense monitoring. exchange.65,66 Both treatments are simi-
Patients with MuSK antibodies larly effective, although plasma exchange
may be less likely to respond to (and may be slightly faster and more effective
may even worsen) and have more in a myasthenic crisis and more useful in
adverse effects from pyridostigmine.42,62 patients with MuSK MG.42,67 Either IVIg
MuSK MG may also be less likely to or plasma exchange is also used pre-
respond to IVIg and perhaps immuno- operatively, before thymectomy or other
suppressants in general, but azathio- urgent surgery, in a patient with MG who
prine in particular.42,63 is significantly symptomatic. Neither is re-
Immunomodulation. In a myasthen- quired routinely, and their use should be
ic crisis, respiratory weakness requires restricted to those patients with signifi-
intubation. Historically, a myasthenic crisis cant preoperative respiratory or bulbar
occurred in 15% to 30% of patients with weakness. IVIg or plasma exchange have
MG but is less common now with effective no effect on the long-term course of MG
management options. A myasthenic crisis and, with few exceptions, are not indi-
usually occurs within the first few years cated for the chronic management of
after disease onset and is sometimes MG.68 Rarely, a patient will require on-
the presenting incident. Along with going treatment with IVIg or plasma
severe bulbar weakness producing as- exchange for refractory MG.
piration, a myasthenic crisis was the Immunomodulatory treatments target-
cause of mortality rates of 50% or more ing B lymphocytes have shown significant
prior to effective treatment. With the promise in patients with MuSK or AChR
current options and improved intensive MG. Rituximab, which targets CD20 on the
care, mortality from a myasthenic crisis B lymphocyte cell surface, works in many
is less than 5%. Severe MG with dyspnea patients with MG with severe disease
managed with noninvasive ventilation and who are refractory to the usual
or severe dysphagia should be managed treatments. It has been suggested that
similarly to a crisis. Common precipi- MuSK MG is more likely to respond to
tants for a myasthenic crisis include rituximab.21,42 However, a meta-analysis
underlying infection (often pneumo- showed efficacy of rituximab in more than
nia), aspiration, surgery including thy- 80% of patients with MG regardless of
mectomy, hormonal changes during or which antibody was positive.69 The onset
after pregnancy, tapering or dis- of action is probably slower than IVIg or
continuation of MG medications, and plasma exchange but the duration of
high doses of prednisone or other improvement is often 6 to 12 months or

KEY POINTS
h Although the specifics of more.70 Rituximab may offer significant Other surgical approaches are used
each indication are still benefits in severe or refractory MG, in some centers. Most consider a cervical
somewhat controversial, especially in those being treated with thymectomy suboptimal because of the
the most accepted long-term IVIg or plasma exchange. risk that thymic tissue will be left behind.
indications for a IgG3 and, to a lesser extent, IgG1 The role for minimally invasive approaches
trans-sternal thymectomy and IgG2 AChR antibodies, which fix (robotic or video-assisted thoracoscopy)
include patients with
complement, can destroy the muscle remains to be proven, although these
generalized early-onset
myasthenia gravis who are
endplate. Therapies targeting comple- approaches are increasingly used in
acetylcholine receptor ment including eculizumab have been many centers. Despite occasional reports
antibody positive and assessed in MG and its experimental of efficacy of thymectomy in MuSK MG,
within 5 years of model and appear promising.70 given the lack of thymic pathology in
disease onset. Thymectomy. Indications for a thy- MuSK MG this remains a controversial
h Many commonly used mectomy in patients with MG include indication.21 Thymectomy in seronega-
medications to treat removal of a thymoma and to increase tive MG, where thymic hyperplasia is
myasthenia gravis, the chance of a sustained drug-free remis- less prominent, is also less proven and a
including pyridostigmine, sion, but these two indications are not chance always exists that a patient who is
prednisone, and
synonymous. Removing a thymoma prob- seronegative does not have MG.
azathioprine, are safe for
use during pregnancy.
ably does not improve the course of MG Pregnancy. For the most part MG is
but is almost always indicated to reduce managed during pregnancy as usual. Plan-
the chance of local growth, invasion, ning any changes in management in ad-
and metastases.71 If removed at an early vance, including before conception when
stage, the long-term survival is good. possible, is important. When MG is well
Once local invasion or metastases occur, controlled, the risks to mother and child
adjuvant therapy with radiation or che- are minimal. Vaginal deliveries are en-
motherapy is usually indicated. couraged, and indications for a cesarean
Given its role in the production of delivery are no different than in a mother
AChR antibodies, removal of a hyper- without MG.75 Although neonatal MG is
plastic thymus has long been considered rare in the authors experience, mothers
a management option for generalized with MG should be managed as a high-
MG. The evidence supporting this is risk pregnancy in a center capable of
mostly retrospective, and evidence-based caring for both neonate and mother.
reviews concluded that thymectomy Most medications used in MG, including
may be a management option in some pyridostigmine, prednisone, and azathio-
patients with MG.72,73 A recently con- prine, appear to be safe in pregnancy.21,76,77
cluded randomized trial supports the Methotrexate and mycophenolate must
role for thymectomy under specific con- be avoided as they are teratogenic. IVIg
ditions in MG.74 Although the specifics and plasma exchange are also relatively
of each indication are still somewhat safe in pregnancy. The severity of the
controversial, the most accepted indica- weakness in MG may improve or worsen,
tions for a trans-sternal thymectomy the latter especially in the puerperium,
include patients with generalized early- during pregnancy.
onset MG who are AChR antibody pos- Other medications and myasthenia
itive and within 5 years of disease onset. gravis. There are many lists of drugs to
The role for thymectomy outside these avoid in MG as they might worsen the
indications is less certain. Improvement weakness in a patient with MG. The
may take 1 to 2 years after thymectomy. evidence supporting inclusion of some
Patients with MG should be medically of these is often weak. Many patients
well controlled and ideally on lower doses with MG, especially the elderly, will be
of prednisone prior to thymectomy. on one or more of these (beta-blockers

KEY POINT
and calcium channel blockers in parti- Pathophysiology h Although some
cular) with no worsening in their MG.78 The antigenic target in LEMS is the P/Q medications might
Some antibiotics (aminoglycosides, type voltage-gated calcium channel produce worsening in
macrolides, and fluoroquinolones, for (VGCC) on the presynaptic nerve termi- patients with myasthenia
instance) are probably best avoided if nal.79 VGCC antibodies reduce calcium gravis, few medications
possible but even then, many patients are absolutely
influx into the nerve terminal and, there-
contraindicated, and
with MG have been on one or more of fore, reduce the amount of acetylcholine the potential benefits
these without ill effect. Most should released into the synaptic cleft. At the of a medication should
be considered a relative contraindica- neuromuscular junction of skeletal mus- be weighed against
tion, and patients and physicians should cle, this can result in neuromuscular the evidence that it
weigh the benefits of that specific medi- transmission failure. Involvement of the might produce
cation versus the risk that the MG may same VGCC at autonomic synapses pro- worsening weakness.
be worsened while on the medication. If duces autonomic dysfunction. VGCC
worsening does occur, it is sometimes antibodies can be found in other para-
difficult to exclude worsening because neoplastic disorders including subacute
of an underlying infection, which is a cerebellar degeneration.
common reason for exacerbation in MG. LEMS is divided into paraneoplastic
Patients with MG undergoing a general and primary autoimmune groups. In
anesthetic may be more sensitive to paraneoplastic LEMS, an underlying
nondepolarizing neuromuscular blocking small cell lung cancer is almost always
agents and less sensitive to depolarizing present. In children with LEMS, lym-
neuromuscular blocking agents. Spinal phoproliferative disorders may be asso-
or local anesthetics are generally safer ciated instead.
options. Any patient with MG who has
significant weakness, especially if bulbar Epidemiology
or respiratory, and who is started on one LEMS is rare, with an estimated incidence
of the potentially offending medications of 0.5 out of 1 million and a prevalence
should be monitored carefully. of 2.3 out of 1 million. Relative to MG,
the prevalence of LEMS is reduced
Trends compared to its incidence.80 This reflects
Recent advances in identifying new anti- the poor survival in paraneoplastic
genic targets and improved assays for LEMS. Approximately 40% to 50% of
existing antibodies promise to further patients with LEMS have a primary
reduce the cases of generalized MG that autoimmune disorder, and in 50% to
are difficult to diagnose. Therapies that 60%, LEMS occurs as a paraneoplastic
are directed to specific components of disorder, almost always with an under-
the aberrant immune response, includ- lying small cell lung cancer.81 Studies
ing complement and CTLA4, may prove suggest that LEMS occurs in 2% to 3%
interesting. Trials that demonstrate ef- of small cell lung cancer cases and is
ficacy of current off-label options will likely underrecognized.81,82
expand the list of available treatments
for many patients with MG. Clinical Features
The clinical triad characteristic for LEMS
LAMBERT-EATON is best remembered by the three As:
MYASTHENIC SYNDROME apraxia, areflexia, and autonomic involve-
Although much less common than MG, it ment.83,84 Although not true apraxia,
is important for neurologists to recognize this is a useful way of remembering that
the clinical features of LEMS and be leg weakness producing difficulties
familiar with its management. with gait is the most prominent clinical

KEY POINT
h Patients with feature and that, frequently, patients Clinical. The biggest delay to a diag-
Lambert-Eaton with LEMS have more functional diffi- nosis of LEMS is not suspecting the
myasthenic syndrome culties than predicted by the strength condition. Abnormalities on the neuro-
often present with of individual muscles. logic examination will usually be most
difficulty walking and The clinical features of LEMS usually prominent in the extremities, especially
with leg weakness, with precede the diagnosis of underlying small the legs. Reduced deep tendon reflexes
areflexia and autonomic
cell lung cancer, which is more often at a in a patient where MG is being consid-
involvement comprising
the other two key features.
limited stage or occult when compared ered suggests LEMS instead. Prominent
to small cell lung cancer without LEMS. ocular findings at onset is against a diag-
Weakness almost always begins in the nosis of LEMS.25 Characteristic in LEMS
proximal legs and causes difficulties is the paradox between significant func-
walking.83,85 Arm weakness is also com- tional impairment with walking but only
mon. The onset is often subacute, and mild weakness on examination.
fluctuation is less prominent than in MG. The author has not found clinical
However, ocular and bulbar weakness facilitation in strength, in which the
may be absent or, if present, occur as a second contraction of a muscle group
late manifestation. The presence of ocu- has increased power relative to the first,
lar and perhaps bulbar involvement at to be a reliable sign when elicited by an
onset is strongly against a diagnosis of unbiased examiner. However, in up to
LEMS and suggests MG.25 Thus, LEMS 40% of patients with LEMS, a previously
starts in the legs and ascends while MG absent or significantly reduced deep
often starts with craniobulbar involve- tendon reflex will return to normal after
ment and descends. Respiratory involve- 10 seconds of maximal voluntary con-
ment is uncommon. traction.84 Autonomic involvement is
Deep tendon reflexes are almost al- best established by a careful history.
ways reduced or absent, especially in Many patients will not volunteer symp-
the legs. Involvement of sympathetic toms suggesting autonomic involvement
and perhaps more frequently parasympa- unless asked.
thetic systems occurs eventually in 80% Weakness in a patient with small cell
to 90% of patients with LEMS and can lung cancer is often blamed on cachexia,
produce almost any autonomic manifes- malnutrition, or chemotherapy, and para-
tation. A dry mouth, constipation, and neoplastic LEMS is often not suspected.
erectile dysfunction in men are par- LEMS should be considered when a
ticularly common but loss of sweating, patient with an underlying small cell lung
orthostatic hypotension, and pupillary cancer develops prominent leg weakness
abnormalities are also seen.84 and the deep tendon reflexes are reduced
Sensory loss or cerebellar features are or autonomic involvement occurs.
not features of LEMS but might suggest The prediction of an underlying
an overlapping paraneoplastic disorder small cell lung cancer in patients with
associated with an underlying small cell LEMS may be increased when the pa-
lung cancer. tient has a higher Dutch-English LEMS
Tumor Association Prediction (DELTA-P)
Diagnosis score. This uses clinical features such as
Once suspected, the diagnosis of bulbar weakness (dysarthria, dysphagia,
LEMS can often be made based on chewing weakness, and neck weakness),
characteristic electrophysiologic abnor- autonomic involvement (erectile dys-
malities, which distinguish it from MG. function), weight loss, tobacco use, age
Serologic confirmation of the diagnosis of older than 50 years, and a Karnofsky
is important. Performance Status Scale score of less

KEY POINT
than 70, with 1 point allocated for each. often less than 50% of the h Although a decrement
A total score of 3 or more predicted a laboratorys lower limits of normal. on repetitive nerve
greater than 90% chance of an underly- & Decrement with low-frequency stimulation can be seen in
ing small cell lung cancer.86 stimulation; as opposed to MG, where either myasthenia gravis
the decrement is usually maximal at or Lambert-Eaton
Electrophysiologic studies. As for MG, the fourth or fifth stimulation in the myasthenic syndrome, a
routine nerve conduction studies and reduction in baseline
train, in LEMS the maximal decrement
needle EMG should be done first. The motor amplitudes and
may occur later in the train.87
triad of electrophysiologic abnormali- increment after either
& Increment with high-frequency maximal voluntary
ties in LEMS consists of the following: stimulation or facilitation after contraction or
& Diffusely reduced motor amplitudes 10 seconds of maximal voluntary high-frequency
on motor nerve conduction studies, contraction (Figure 11-2); stimulation are
characteristic of
Lambert-Eaton
FIGURE 11-2 PreY and postYmaximal voluntary contraction

ulnar motor nerve conduction study in a
patient with Lambert-Eaton myasthenic
syndrome. A 32-year-old woman presented with a 1-year
history of fatigable weakness of her legs. She also described a
dry mouth. She was a lifetime nonsmoker. On examination, in
addition to mild weakness of hip flexors, she was areflexic. PreY
and postYmaximal voluntary contraction motor nerve conduc-
tion studies of the ulnar nerve with stimulation at the wrist and
recording over abductor digiti minimi are shown, demonstrat-
ing an over 500% increment in motor amplitude after maximal
voluntary contraction.
MVC = maximal voluntary contraction.

KEY POINT
h Whereas pyridostigmine postYmaximal voluntary contraction clinical features of LEMS are often
may not produce studies are as sensitive and better attributed to the effects of cachexia and
significant benefit, tolerated than high-frequency malnutrition. Electrolyte and metabolic
3,4-diaminopyridine is a stimulation.88 Increments of more abnormalities affecting calcium or mag-
very effective than 100% are very suggestive for nesium, as well as hypothyroidism are
symptomatic treatment LEMS but not specific for LEMS
of Lambert-Eaton
also in the differential.
and occur in some cases of
botulism and MG. Management
The abnormalities may be subtle The most effective symptomatic treat-
early in the disease course. Although ment in LEMS is 3,4-diaminopyridine
leg weakness is most predominant in (3,4-DAP).92 Through blocking voltage-
LEMS, electrodiagnostic studies of the gated potassium channels, 3,4-DAP
ulnar or median nerves have the highest prolongs nerve terminal depolarization
sensitivities.89 Single fiber EMG abnor- and increases acetylcholine release.79,92,93
malities usually do not distinguish LEMS In small trials, 3,4-DAP has been shown
from MG. to produce clinical and electrophysio-
Serologic studies. VGCC antibodies logic benefit in patients with LEMS.92,94
are more than 90% sensitive in primary Improvement after each dose is usually
autoimmune LEMS and approach 100% in seen within 30 minutes and is maximal
paraneoplastic LEMS.84 VGCC antibodies at 90 minutes. 92 Starting doses are
are not specific and are found in small usually 5 mg to 10 mg three to four
cell lung cancer without LEMS as well as times a day, with gradual increases up
other paraneoplastic disorders.83,90 to 80 mg/d, divided into four to six
Ancillary investigations. Given its doses. Many patients respond to 40 mg/d
association with LEMS, patients should to 60 mg/d. Common adverse effects
be investigated for an underlying small include perioral and acral paresthesia,
cell lung cancer, especially in elderly maximal about an hour after each dose,
smokers with weight loss. If an initial CT nausea, abdominal pain, tachycardia, and
chest is negative, a bronchoscopy or palpitations.92,95 Insomnia is minimized
positron emission tomography (PET) by avoiding the last dose at bedtime.
scan may be indicated in high-risk Doses of more than 100 mg/d may
patients. When initial investigations are increase the risk of seizures, although
negative in a high-risk patient, repeating this is likely a rare adverse effect.92,95
the CT chest every 3 to 6 months for at Seizures are more likely with other pre-
least the first 2 years is suggested, after dispositions, so caution is advised with
which the chance of a small cell lung brain metastases or the use of other
cancer being found is less.91 medications that might lower the thresh-
old for seizures.
Differential Diagnosis In theory, pyridostigmine should be
MG is the disorder most commonly in the synergistic with 3,4-DAP but many pa-
differential for LEMS. A myopathy, espe- tients with LEMS have no benefit from
cially dermatomyositis, might present like pyridostigmine either on its own or in
LEMS in the setting of an underlying small combination with 3,4-DAP.96,97
cell lung cancer. Guillain-Barre syndrome, Given its immunopathogenesis, im-
chronic inflammatory demyelinating poly- munosuppression may also be useful to
radiculoneuropathy (CIDP), and other treat LEMS.97 The choice of immunosup-
motor predominant subacute neuropa- pressant drugs in LEMS is similar to
thies occasionally mimic LEMS. In the MG. However, avoiding immunosup-
context of small cell lung cancer, the pression in paraneoplastic LEMS may

be advisable because of concerns about with pyridostigmine helps many patients
reduced immunosurveillance and tumor with MG, although it is less effective for
progression. Immunosuppressants can patients with ocular MG. Many options
be useful in primary autoimmune LEMS exist for immunosuppression, the choice
if 3,4-DAP alone is insufficient. IVIg, of which often depends on practitioner
plasma exchange, and rituximab might familiarity. The goal should be to balance
also be useful, although the evidence benefits with potential adverse effects;
for their efficacy in treating LEMS is with patience, most patients will respond
weaker.94,97 Treatment of the underlying to lower doses than are commonly used.
small cell lung cancer may improve An underlying small cell lung cancer will
paraneoplastic LEMS, although it is diffi- be found in more than one-half of
cult to distinguish an effect of this from patients with LEMS. 3,4-DAP is the most
immunosuppression.97,98 effective symptomatic treatment in LEMS,
and immunosuppression is best reserved
Prognosis for nonparaneoplastic LEMS that does
Primary autoimmune LEMS has an ex- not respond to 3,4-DAP.
cellent prognosis, and most patients re-
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INTRODUCTION treatments in MG and LEMS. 1 The

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is to look for a thymoma, although it can plasia is a pathologic diagnosis made at

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TABLE 11-1 Differential for Myasthenia Gravis

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FIGURE 11-2 PreY and postYmaximal voluntary contraction

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