MED 7721 CLINICAL NEUROLOGY

• Learning Objectives
• Neuromuscular Transmission
• Myasthenia Gravis
• General Considerations
• Pathogenesis
• Clinical Findings
• Differential Diagnosis
• Treatment
• Prognosis
• Congenital Myasthenia Syndromes
• Lambert-Eaton Myasthenic Syndrome
• General Considerations
• Clinical Findings

CONTENTS • Differential Diagnosis

• Treatment
• Prognosis
• Botulism
• General Considerations
• Clinical Findings
• Differential Diagnosis
• Treatment
• Prognosis
• Tick Paralysis
• YouTube Video Link
• Clinical Case
• Main Reference
• Related Readings
 • To review the process of neuromuscular
transmission
LEARNING • To learn the different neuromuscular junction
disorders, including their pathogenesis, clinical
OBJECTIVES features, differential diagnoses, diagnostic
investigations and management
NEUROMUSCULAR
TRANSMISSION
The neuromuscular junction is the synaptic connection formed between a motor neuron
axon and the muscle fiber it innervates. The transmitter used at the neuromuscular
junction, acetylcholine, is stored in the presynaptic motor nerve terminals. The
postsynaptic muscle membrane has many folds in which receptors for acetylcholine are
located. When a motor nerve action potential reaches the presynaptic nerve terminal,
there is a resultant increase in calcium conductance through voltage-gated calcium
channels. This increase in intracellular calcium leads to the fusion of acetylcholine-filled
presynaptic vesicles with the plasma membrane of the motor nerve terminal.
Acetylcholine is subsequently released into the synaptic cleft by exocytosis.

The acetylcholine diffuses across the synapse and binds to the acetylcholine receptors on
the postsynaptic muscle membrane. The binding of acetylcholine to these receptors
facilitates increased conduction of sodium and potassium. This leads to transient
depolarization of the postjunctional muscle membrane known as an end-plate potential.
This depolarization allows for the generation and propagation of action potentials in the
postsynaptic muscle cell. These processes initiate a chain of events in the muscle cell that
culminates in muscle contraction. Disorders of the neuromuscular junction result from a
disruption of this series of events.
MYASTHENIAGRAVIS
(AUTOIMMUNE
MYASTHENIA)
General Considerations

Myasthenia gravis (MG), the most common of the neuromuscular junction disorders,
is an acquired, predominantly antibody-mediated autoimmune disease. In this
disorder, antibodies are often targeted against the nicotinic acetylcholine receptor
(AChR) at the neuromuscular junction, resulting in an overall reduction in the number
of AChRs and damage to the postsynaptic membrane. However, other associated
antibodies have also been identified, as discussed below.

The prevalence of autoimmune MG is estimated at 1 case in 10,000–20,000 people.

Women are affected more often in the second and third decades of life, and men
more often in the fifth and sixth decades. Associated autoimmune diseases are
present in approximately 5% of patients, and comorbid thyroid disease occurs in more
than 10%.

Pathogenesis

The AChR, located on the postsynaptic membrane, is a ligand-gated ion channel

composed of five subunits, including α2βγδ in the developing fetus and α2βεδ in the
adult receptor. AChR autoantibodies most often target the α subunit, and these tend
to be more pathogenic than those targeting other subunits. In generalized MG, AChR
antibodies are detected in up to 90% of patients, whereas in purely ocular MG, only
about 50% of patients are antibody positive. Furthermore, they can be found in
individuals with early and late onset disease. Three subtypes of AChR antibodies have
been identified: binding, blocking, and modulating. All of these lead to AChR loss on
the postsynaptic membrane via accelerated receptor degradation or receptor
blockade. AChR modulation is caused by antibodies that cross-link AChRs and facilitate
endocytosis, resulting in receptor loss on the postsynaptic membrane. In addition,
complement-mediated damage to the postsynaptic membrane results in fewer
membrane folds and widened synaptic clefts.
Antibodies to epitopes other than the AChR have been identified in patients with MG.
These include antibodies to another postsynaptic neuromuscular junction protein,
muscle-specific kinase (MuSK), found in about 40% of MG patients who do not have
AChR antibodies. Anti-MuSK antibodies are seen with higher prevalence in females; in
individuals of Mediterranean descent; and although age can vary, tend to occur in
patients who are younger at time of disease onset. MuSK antibodies have been shown to
disrupt neuromuscular junction function by adversely affecting the maintenance of AChR
clustering at the muscle endplate, thus leading to reduced numbers of functional AChRs.

Although MuSK antibody-positive patients can present similarly to those with AChR
antibody-positive myasthenia, they can also have atypical features such as selective
weakness of the face, bulbar or respiratory muscles, as well as marked muscle atrophy
with relative ocular sparing. This presentation can also be associated with paraspinal and
esophageal muscle weakness, which is uncommonly seen in more classic MG
presentations. In addition, MuSK-associated MG can have variable responses to
anticholinesterase drugs, such as hypersensitivity and nonresponsiveness, and clinical
worsening has been documented.

Lipoprotein-related protein 4 (LRP4) is another well-documented antibody in myasthenia,

seen in approximately 7% of patients that have neither AChR nor MuSK antibodies; it is
so-called seronegative MG. Antibodies against agrin, a protein that contributes to the
development of the neuromuscular junction and stabilization of the AChR, have also
been identified, both in patients with and without AChR and MuSK antibodies. However,
it remains unclear whether agrin antibodies contribute to muscle weakness.
Antibodies to striated muscle proteins, such as titin and the ryanodine receptor (RyR),
have also been found in myasthenia patients, although they can be associated with
other autoimmune diseases. In the setting of MG, these antibodies are rarely seen in the
absence of AChR antibodies and therefore may not be diagnostically helpful in isolation.
Antititan antibodies are commonly seen in MG associated with thymoma, as well as late
onset, AChR-positive MG. RyR positivity is also associated with the presence of
thymoma and prominent bulbar and respiratory weakness. Both of these antibodies
have been found to correlate with disease severity and may help clinicians identify
which patients are more likely to be refractory to therapy.

Additional antibodies, such as voltage-gated potassium channel (VGKC) antibodies, have

also been reported in MG, specifically in the Japanese population, where they are
estimated to be seen in 12–28% of patients. One study also found an association
between VGKC positivity and thymoma as well as bulbar symptoms.

Antibody production is a T cell–mediated process thought to be associated with thymic

dysfunction. Thymic lymphofollicular hyperplasia occurs in 70% of MG patients.
Thymoma, an epithelial tumor of the thymus, occurs in 10% of patients with MG. In the
subpopulation of patients with a thymoma and the presence of thymoma-associated
antibodies, the disease can be thought of as a paraneoplastic disorder.
Clinical Findings

A. Symptoms and Signs

MG is clinically characterized by fluctuating, fatigable weakness of commonly

used muscles. Hallmark features include ptosis, diplopia, dysarthria, dysphagia,
and respiratory and limb muscle weakness. About half of patients present with
ocular findings. The ocular muscle weakness is usually bilateral and asymmetric
and results in diplopia, ptosis, or both. Notably, the pupil is spared. Eventually,
almost all patients with MG develop ocular symptoms, and in some the disease is
limited to the extraocular muscles.

Within the first year of disease onset, up to 75% of patients develop generalized
symptoms. Bulbar symptoms are common and include dysarthria, dysphagia,
facial weakness, and weakness of mastication. Because of palatal weakness,
patients often have nasal speech and can regurgitate liquids through the nose.
Bulbar manifestations are often the most disabling symptoms. Limb and trunk
weakness is common in a proximal greater than distal distribution. Frequently, the
arms are more affected than the legs. The quadriceps, triceps, and neck extensor
muscles appear to be preferentially involved.

A hallmark of myasthenic weakness is its fluctuating and fatigable nature. It may

increase throughout the day, worsen with sustained activity, and improve with
rest. The most serious symptom is respiratory compromise caused by weakness of
diaphragmatic and intercostal muscles. This respiratory symptom, in conjunction
with severe bulbar symptoms, can culminate in so-called myasthenic crisis,
defined as respiratory failure requiring mechanical ventilation. This complication
occurs in about 15–20% of patients with MG and may be precipitated by infection
or aspiration.
In roughly one third of pregnant women, MG is exacerbated by the pregnancy, with
the greatest risk during the first trimester. In some patients, symptoms and signs
improve during the second and third trimesters coincident with the relative
immunosuppression that occurs during this phase of pregnancy. A high risk then
returns during the postpartum period.

In addition to the effects on the mother, infants and children of mothers with
myasthenia can develop transient or, rarely, permanent weakness. Approximately
one third of infants of mothers with autoimmune MG have transitory neonatal
myasthenia, with weakness appearing within the first 4 days of life and usually
lasting for approximately 3 weeks. Infants with neonatal myasthenia often are poor
feeders and have a weak cry. Weakness is the result of placental transfer of
maternal antibodies to the fetal blood circulation, most commonly involving AChR
antibodies, which can bind both the fetal and adult forms of the receptor. This
condition also has a high recurrence risk for future pregnancies. The fetal form of
the receptor, which differs from the adult form by a single subunit, persists until 30–
33 weeks’ gestation, after which it is replaced by the adult receptor. There is no
clear association between neonatal weakness and maternal clinical status or
antibody levels.

In contrast to neonatal myasthenia, which is transient, permanent deficits can occur

in a rare condition, known as fetal AChR inactivation syndrome. This condition is
characterized by facial weakness, high-arched palate, soft palate and pharyngeal
weakness, conductive hearing loss, and cryptorchidism, and in the most severe
cases marked arthrogryposis and respiratory impairment. It is caused by the
presence of maternal antibodies that preferentially target the fetal subunit, resulting
in inactivation of the fetal AChR subunit during a critical period of muscle
development.
B. Diagnostic Studies

1. History & physical examination—Eliciting a detailed history and

performing a comprehensive examination looking for signs and symptoms is
the mainstay of diagnosing MG. For example, multiple maneuvers can be
used to assess for muscle fatigability. For example, sustained upgaze looking
for 30–60 seconds can elicit ocular muscle weakness and ptosis. Sustained
abduction of the arms for 120 seconds and repeat rising from a chair without
use of arms, done up to 20 times, can be used to elicit fatigability in proximal
limb muscles.

2. Laboratory studies—Serologic testing should be performed in several

steps. The first screening antibody should be the AChR-binding antibody,
because it is the most sensitive. If it is negative, then an AChR-modulating
antibody test increases the diagnostic yield. Testing for AChR-blocking
antibodies does not increase sensitivity. In patients who are seronegative for
these antibodies, antibodies against MuSK may be present. In double-
seronegative individuals, LRP4 antibodies can be sent. Additional antibody
testing for the striated muscle proteins ryanodine and titin, as described
above, may be necessary.
3. Electrodiagnostic studies—Routine nerve conduction studies and electromyography
usually do not identify dysfunction of the neuromuscular junction. Slow repetitive nerve
stimulation is the most commonly used test to evaluate for MG. In this test, a nerve is
stimulated 6–10 times at a rate of 2 or 3 Hz, and the compound muscle action potential
(CMAP) is measured over the corresponding muscle. In normal individuals, no change occurs
in the CMAP over time. In patients with MG, however, there is a decrease of more than 10%
in CMAP with the first four to five stimuli. Immediately following 10 seconds of maximal
voluntary exercise, the decrement typically repairs toward normal. This is followed by post-
exercise exhaustion, with progressively greater decrement when stimulating at 1-minute
intervals after maximal voluntary exercise. Low-frequency repetitive stimulation has low
sensitivity; only 75% of patients with generalized MG and even fewer with only ocular or
distal limb weakness have a positive test. In addition, repetitive nerve stimulation is not
entirely specific for MG and can be positive in Lambert-Eaton myasthenic syndrome, and to a
lesser degree in myositis or lower motor neuron disease. Abnormalities noted on repetitive
nerve stimulation do not correlate well with the severity of weakness.

Single-fiber electromyography has a sensitivity of approximately 95% in MG. This test

measures the variability in synaptic transmission time, otherwise known as “jitter,” between
two fibers innervated by the same axon. In MG, there is an increased variability of latencies
among muscle fibers in a single motor unit. In addition, muscle fiber potential may be
blocked if transmission at its neuromuscular junction fails completely. As with slow repetitive
nerve stimulation, abnormalities seen on single-fiber electromyography are not specific to
MG.
4. Ice pack test—When significant ptosis is present, myasthenic weakness can
sometimes be evaluated by placing an ice pack over the closed ptotic eyelid for 2
minutes. The test is considered supportive of myasthenic weakness if the ptosis visibly
improves. Cold is thought to decrease cholinesterase activity and promote the
efficiency of acetylcholine at eliciting depolarizations at the end plate. Similarly, one
can evaluate for improved ptosis after 30 minutes of sleep.

5. Tensilon (edrophonium) test—Tensilon, which has been used since the 1950s,
evaluates the response to a short-acting cholinesterase inhibitor. When performed, the
examiner must choose a clinical feature to observe, most commonly ptosis. One
milligram of edrophonium is given intravenously as a test dose, followed by 3-mg dose
if no adverse event is seen. A clinical response should be seen within 30–60 seconds. If
no response is seen, an additional 3 mg of edrophonium can be given and the patient
examined again. If there is still no improvement, a final 3-mg dose can be given, for a
total of 10 mg. If there is no clinical improvement after 2 minutes, the test is negative.
Studies suggest a sensitivity of 70–95% for this test. Specificity is not as high; positive
tests have been reported in a variety of conditions, including Lambert-Eaton
myasthenic syndrome, botulism, snake envenomation, motor neuron disease, and
multiple sclerosis. Of note, this test has fallen out of favor over the years due to
potential, serious cholinergic side effects, including increased oropharyngeal
secretions and respiratory decompensation as well as bradycardia or asystole. It should
be performed under cardiac monitoring with atropine readily available.

6. Imaging and other studies—Because of the association between MG and

thymoma, all patients should be screened for this tumor using either a computed
tomographic or magnetic resonance imaging scan of the chest. In addition, patients
should be screened for common comorbid diseases such as thyroid disease or
autoimmune diseases (eg, systemic lupus erythematosus, rheumatoid arthritis).
Differential Diagnosis

For generalized MG, the differential diagnosis includes Lambert-Eaton

myasthenic syndrome, botulism, and myopathy. For ocular myasthenia,
alternative diagnoses include progressive external ophthalmoplegia, thyroid
disease, and oculopharyngeal muscular dystrophy. Motor neuron disease,
brainstem stroke, diphtheria, and botulism must be considered in the differential
for patients with bulbar-predominant MG.

Treatment

A. Symptomatic Treatment

The mainstays of symptomatic treatment are the cholinesterase inhibitors, which

increase the concentration of acetylcholine at the AChR. Acetylcholinesterase
inhibitors are most effective early in the disease when there are still adequate
numbers of receptors present. In patients with mild disease and minimal bulbar
symptoms, these agents may be used alone without immunosuppressive therapy.
As the disease progresses, increasing doses may be required to achieve the same
therapeutic effect. Pyridostigmine is the most effective of these agents, usually
given at least three to four times daily, but dose intervals need to be adjusted
according to symptoms. A long-acting formulation is available and may be useful
with overnight symptom control. In MuSK myasthenia, these agents may have a
less favorable response.
The main side effects of the cholinesterase inhibitors are related to excess levels of
acetylcholine at nicotinic and muscarinic synapses. Common muscarinic side effects
including nausea, diarrhea, abdominal pain and cramping, increased flatulence,
salivation, and urinary urgency. Additional risks include bradycardia and excessive
oral secretions, increasing the risk of respiratory compromise. Nicotinic side effects
include muscle fasciculations, muscle cramps, and rarely, increased blockade of
neuromuscular transmission leading to cholinergic crisis. Central nervous system side
effects include dizziness, drowsiness, and seizures, especially in patients with
underlying epilepsy. These are seen less frequently with neostigmine, which has
decreased penetrance through the blood brain barrier.

B. Immunosuppressive Treatment

1. Thymectomy—For patients with a neoplastic thymoma, surgical removal of the

tumor is necessary to prevent tumor spread. For patients without thymoma,
thymectomy has been shown to increases the likelihood of remission. One recent
randomized, multicenter trial compared thymectomy and prednisone with
prednisone alone in a group of generalized, non-thymomatous, AChR antibody–
positive MG patients within 5 years of disease onset. This study found that those who
underwent thymectomy experienced greater reduction in symptoms, as well as fewer
exacerbations and hospitalizations over a 3-year period. In addition, thymectomy
patients required less immunosuppressive therapy, including a lower likelihood of
being treated with azathioprine and lower prednisone dose. Clinical improvement
was seen in patients with disease onset before and after age 40, suggesting that in
the absence of contraindications, thymectomy should potentially be considered for
patients of any age with AChR antibody–positive, generalized MG, with onset in the
past 5 years and symptoms not fully controlled with anticholinesterase drugs.
Furthermore, in most experienced centers, perioperative morbidity and mortality
were very low and were outweighed by the chances for improvement in most cases.
Partnering with an experienced surgeon is important. Medical treatment of
MG prior to surgery decreases the perioperative morbidity. Preoperative
intravenous immunoglobulin (IVIG) or plasmapheresis is often used to
stabilize patients with generalized MG. Nonetheless, thymectomy remains an
invasive procedure with some level of risk, and therefore should be carefully
considered on an individual basis in collaboration with the treating
neurologist and surgeon.

When the decision is made to undergo thymectomy, removal of all thymic

tissue is recommended for maximum benefit. However, there is debate about
the best surgical procedure. Protocols have included open, trans-sternal
approaches, as well as newer endoscopic and robot-assisted techniques.

Currently, there is no clear evidence supporting the use of thymectomy in

MuSK or LRP4 antibody MG. In addition, there is insufficient evidence
regarding the use of thymectomy in ocular myasthenia.
2. Medical therapy—For most patients, treatment includes inducing remission with
the use of an immunosuppressant. Once remission is achieved, the immunosuppressant
can be gradually tapered, but most patients need to continue at least a small dose of
medication.

a. Corticosteroids—These agents are the first-line immunosuppressive therapy for MG.

Many patients have transient worsening of symptoms within the first 2 weeks of
initiating such treatment. Corticosteroid therapy may therefore have to be initiated
following stabilization with a course of plasmapheresis or IVIG. Patients should be closely
monitored when corticosteroid therapy is initiated, and hospitalization may be
warranted.

Corticosteroids induce remission in up to 50% of patients, and up to 80% of all patients

benefit from the therapy. Steroids can also help prevent generalization of ocular
myasthenia. Most patients improve within the first few weeks of treatment. Once
remission is obtained, the corticosteroids are slowly tapered to the lowest dose possible
that does not result in a flare-up of disease.

Complications of corticosteroids include impaired glucose tolerance, hypertension,

cataracts, gastrointestinal ulcers, myopathy, avascular necrosis of the hip, osteoporosis,
infection, and psychosis. Some of the risks can be reduced by implementation of a low-
sodium, low-sugar diet, along with calcium supplementation and exercise. Fasting blood
glucose should be checked periodically. Annual ophthalmologic evaluations should be
arranged to screen for glaucoma or cataracts. The osteoporosis risk can be reduced by
prophylactic treatment (eg, alendronate sodium, 5 mg/day orally).
b. Nonsteroidal immunosuppression—Because of side effects from corticosteroids,
clinicians often use so-called steroid-sparing medications, such as azathioprine. At least
50% of patients appear to benefit from this medication. Most studies describe its use in
conjunction with corticosteroids, not as monotherapy. Side effects are generally mild but
can include bone marrow and hepatic toxicity; for this reason, blood counts and liver
function need to be monitored. Azathioprine acts much more slowly than corticosteroids.
Improvement may begin only after several months of treatment, and maximal
improvement may require 1–2 years. Up to 20% of patients develop an idiosyncratic
reaction to azathioprine during the first weeks of treatment, consisting of fever, chills, rash,
and gastrointestinal symptoms. In these intolerant patients, azathioprine must be
discontinued immediately.

Mycophenolate mofetil has been suggested as an adjunctive or corticosteroid-sparing

therapy and perhaps as monotherapy. Side effects include gastrointestinal symptoms,
hypertension, and peripheral edema. Patients should be advised to avoid ultraviolet-light
exposure while taking this medication. The medication can also cause bone marrow
suppression, and monitoring of blood counts is therefore indicated. The concurrent use of
azathioprine and mycophenolate mofetil is not recommended. The efficacy of
mycophenolate has been controversial. Two, short-duration (<36 weeks), randomized
controlled trials failed to show a benefit of mycophenolate mofetil over prednisone.
However, one retrospective study looking at the long-term use of mycophenolate (>2
years) found a significant benefit after 6 months of use both with prednisone and as
monotherapy.

Cyclophosphamide is an alkylating agent that has been used in patients with refractory
disease. Side effects include severe bone marrow suppression, bladder toxicity, and risk of
neoplasm.
Cyclosporine is used for patients with severe MG who cannot be managed with less toxic
forms of therapy. Major side effects include renal toxicity, hypertension, neurotoxicity.
Tacrolimus, another macrolide with greater potency than cyclosporine, has also been
recently recommended as a potential second-line agent in cases of MG that do not respond
to traditional immunosuppressive agents. Although evidence for its efficacy is limited, one
meta-analysis looking at five trials found clinical improvement and a trend toward a steroid-
sparing effect at 6 months of therapy. Major side effects include hypertension, hyperkalemia,
neurotoxicity, and nephrotoxicity. Treatment with cyclophosphamide, cyclosporine, and
tacrolimus should be managed by a physician who is familiar with their adverse effects and
monitoring requirements.

Rituximab, a monoclonal antibody targeting CD20, a B-lymphocyte antigen, has been

increasingly used for the treatment of MG and other antibody-mediated autoimmune
disease. Evidence for its use has been limited. One meta-analysis recommends its use in
medically refractory patients (insufficient response to prednisone and azathioprine),
although there has not been consensus on the recommended dose. There are also safety
concerns with its use, including precipitation of other autoimmune diseases and progressive
multifocal leukoencephalopathy.

Autologous hematopoietic stem cell transplant, although not readily performed at this point,
has been shown to be effective in the treatment of seven severe, refractory cases of MG.

For all of these corticosteroid-sparing immunosuppressive drugs, there is a risk of infection

and potentially lymphoma or other malignancies.
c. Short-term treatments—Plasmapheresis and IVIG each induce rapid clinical
improvement but have only short-term effects. Although plasmapheresis is more
often used for this indication, both are often used in the special situation of
myasthenic crisis. In addition, either treatment can be used to stabilize patients
prior to thymectomy or to treat exacerbations that occur during infection, surgery,
or the tapering of a corticosteroid regimen.

Plasmapheresis usually produces clinical improvement within the first week, and
benefits usually last for 1–2 months. Complications are uncommon but include
hypotension, bradycardia, electrolyte imbalance, and infection. IVIG has similar
efficacy to plasmapheresis. Side effects include malaise, hypersensitivity, aseptic
meningitis, and, rarely, renal insufficiency, stroke, and myocardial infarction. In
addition, patients with immunoglobulin A deficiency can develop anaphylaxis. In
most patients, however, IVIG is well tolerated. There has been debate as to whether
plasma exchange or IVIG is the preferred short-term immunotherapy for MG. In
practice, the choice of therapy for acute disease is often dependent on feasibility
and on resources available in a given situation.
C. Treatment of Myasthenic Crisis

Myasthenic crisis is defined as an exacerbation of weakness that leads to respiratory

failure requiring mechanical ventilation. For patients with myasthenic exacerbation
involving respiratory and bulbar symptoms, hospitalization should be considered to
closely monitor clinical status and pulmonary function. Once a patient is intubated,
anticholinesterase medications should be discontinued because they can promote
excessive secretions. Corticosteroids can actually prolong the duration of a crisis by
exacerbating weakness or predisposing to infection. The mainstay of therapy for
myasthenic crisis is therefore short-term immunotherapy, either plasmapheresis or IVIG.

D. Drugs That May Worsen Symptoms of Myasthenia Gravis

Several classes of drugs are associated with clinical worsening of existing MG, and a
smaller group of drugs actually causes MG in occasional patients. D-Penicillamine,
interferon alpha, and bone marrow transplantation have all been implicated in causing
MG. The mechanism is unclear, but there is evidence of an autoimmune basis for both
penicillamine and interferon alpha. In most cases, the symptoms resolve with
discontinuation of the medication. Many other drugs are associated with myasthenic
worsening.

Because any drug can potentially worsen symptoms, patients with MG should be warned
about possible exacerbation with the use of prescription and over-the-counter
medications.
Prognosis

Eighty percent of patients with more focal disease eventually develop generalized MG.
Progression to maximum severity typically occurs within the first 2 years of onset.
Spontaneous, long-lasting remissions are uncommon, but have been reported in 10–20%
of patients. For patients with disease limited to the ocular muscles, cholinesterase
inhibitors, low-dose corticosteroids, or nonmedicinal therapy (eg, eyelid crutches) may be
sufficient to control symptoms.

Most patients with generalized MG enjoy a normal and productive life when adequately
treated. However, quality of life may be compromised as a result of both the limited
efficacy and the side effects of available drugs. Patients with an underlying thymoma often
have a more aggressive disease course.
CONGENITAL
MYASTHENIA
SYNDROMES
There are multiple congenital myasthenic syndromes, which are the
result of genetic defects in presynaptic, synaptic, and postsynaptic
proteins. Symptoms are present at birth or appear in early childhood.
Typical symptoms are similar to those seen in autoimmune MG, with
fluctuating and fatigable muscle weakness resulting in ptosis,
ophthalmoparesis, neck and limb, as well as respiratory muscle,
weakness. Weakness typically affects cranial muscles, and there is often
an associated high-arched palate. Similarly affected relatives can often be
identified. Cholinesterase inhibitors are helpful in the treatment of some
of these syndromes only.

CMS should be considered in the differential diagnosis in seronegative

myasthenia especially when there is a positive family history or the onset
of symptoms is in infancy or at a young age. There may be a history of
decreased fetal movement in utero, and arthrogryposis is seen in some
newborn infants. CMS may be classified according to the site of defect.
LAMBERT-EATON
MYASTHENIC
SYNDROME
General Considerations

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune or

paraneoplastic disease caused by a presynaptic abnormality of acetylcholine
release. It is characterized by chronic fluctuating weakness of the proximal limb
muscles, especially the legs. Approximately 60% of patients with LEMS have an
associated small cell carcinoma of the lung or, less often, another type of
malignancy. The diagnosis of LEMS often precedes clinical detection of the
malignancy. In those who do not have an underlying malignancy, a concurrent
autoimmune disease is common. The onset of the disease is often midlife or
later, but it has also been reported in childhood. Younger patients are more
likely to have underlying autoimmune disease as opposed to malignancy.

LEMS is caused by antibodies directed at P/Q-type voltage-gated calcium

channels (VGCCs) and reduced neurotransmitter release at the neuromuscular
junction and autonomic nerve terminals.
Clinical Findings

A. Symptoms and Signs

The onset of symptoms is usually insidious. Generalized fatigable weakness is the

major symptom. Patients often complain of myalgia, muscle tenderness, and
stiffness. There may be improvement in strength with exercise. Oculobulbar and
respiratory symptoms are much less common than with MG, but patients with
LEMS can present with respiratory compromise. Unlike patients with MG, those
with LEMS may complain of a metallic taste, and often have autonomic
dysfunction causing dry mouth, orthostasis, constipation, and impotence. On
examination, the elicited weakness is often mild compared with the patient’s
complaints. Deep tendon reflexes are often hypoactive or absent but may be
potentiated by brief contraction. Pupils may be dilated and weakly responsive to
light secondary to autonomic dysfunction.

B. Laboratory and Electrodiagnostic Findings

Antibodies against P/Q-type VGCCs can be detected in more than 90% of patients
with LEMS. In addition, antibodies to N-type VGCCs can be found in up to 50% of
patients; this percentage is higher in malignancy-associated LEMS. Organ-specific
autoantibodies (to thyroid, gastric parietal cells, or skeletal muscle) and non–
organ-specific autoantibodies (antinuclear, antimitochondrial) are also found in
patients with LEMS.
Electrodiagnostic studies help confirm the diagnosis and monitor disease
progression. The CMAP is low in most muscles tested and CMAP amplitude at
rest is the best marker of disease severity. As in MG, most patients have a
decrementing response to slow rates of repetitive stimulation; however, the
decrement progresses during the course of the stimulation. Following exercise
or repetitive stimulation at 20–50 Hz, there is usually a marked facilitation, with
doubling of the CMAP amplitude. Of note, electrodiagnostic study findings in
LEMS differ markedly from MG and are useful in distinguishing these
neuromuscular junction disorders.

Conventional needle electromyography demonstrates unstable motor unit

action potentials that change configuration from impulse to impulse due to
blocking of individual muscle fibers. When many muscle fibers are blocked, the
motor units can be small, polyphasic, and of short duration. As with MG,
increased jitter and impulse blocking are seen on single-fiber
electromyography.

Differential Diagnosis

The main alternative diagnosis to consider is MG. LEMS can often be

distinguished from MG by its mild oculobulbar symptoms and often prominent
autonomic symptoms and signs. In addition, electrodiagnostic abnormalities
are often more prominent in LEMS than in MG despite the often more severe
weakness in MG. LEMS is often misdiagnosed as a myopathy because of the
predominantly proximal weakness.
Treatment

The first step in management should be an evaluation for malignancy, especially in older
patients or those with a history of smoking. If LEMS is associated with a malignancy,
symptoms often improve dramatically with tumor removal. If no malignancy is found at
initial presentation, patients should undergo regular surveillance, because the
presentation of LEMS can predate the detection of neoplasm by years. For those with no
underlying neoplasm, or insufficient symptom control with tumor removal,
pharmacotherapy is used.

3,4-Diaminopyridine (3,4-DAP) improves muscle strength and autonomic symptoms in

approximately 80% of patients with LEMS. By blocking VGKCs, the drug prolongs action
potentials at motor nerve terminals. Perioral paresthesias are the most common side
effect, but seizures can occur at high doses. 3,4-DAP is not approved by the Food and
Drug Administration (FDA) in the United States but can be obtained for compassionate
use. Guanidine hydrochloride inhibits mitochondrial calcium uptake, facilitating the
release of acetylcholine at the motor nerve terminal. Guanidine effectively increases
strength in patients with LEMS, but its use is limited by side effects that include bone
marrow suppression.

Unlike MG, LEMS is not very responsive to anticholinesterase drugs, which, however, do
potentiate the effects of 3,4-DAP and guanidine, allowing the use of lower doses. If the
preceding symptomatic therapy is insufficient, immunosuppressive therapy can be
attempted, but it is less effective in LEMS than in MG. If weakness is severe,
plasmapheresis or high-dose IVIG often provides rapid, although usually transitory,
improvement.

Prognosis

Prognosis in patients with underlying malignancy is determined by the prognosis of that

malignancy. Because LEMS is less responsive to immunosuppressive therapy than MG,
most patients with LEMS have residual weakness even with optimal immunosuppression.
BOTULISM
General Considerations

Botulism is caused by ingesting the neurotoxin of the bacterium Clostridium

botulinum, an obligate anaerobic, robust, spore-forming bacillus commonly found
in soil. After absorption into the bloodstream, botulinum toxin binds irreversibly to
the presynaptic nerve endings of the peripheral nervous system and cranial nerves.
Once internalized, the toxin inhibits the release of acetylcholine through the
cleavage of polypeptides essential for the docking of synaptic vesicles to the
presynaptic membrane of the nerve terminal.

Food-borne botulism is caused by the ingestion of preformed toxin. The most

frequent source is home-canned or home-processed low-acid foods. In the infant
form of botulism, C botulinum spores enter and colonize the immature
gastrointestinal tract and produce toxin. This is most often associated with the
ingestion of honey. In wound botulism, the toxin is produced from C botulinum
infection of a wound. Recently, a number of cases of wound botulism in
intravenous drug users have been traced to contaminated drugs, suggesting a
particular risk of botulism in this demographic. Inadvertent botulism has also been
reported in patients treated with intramuscular injections of botulinum toxin.
Clinical Findings

A. Symptoms and Signs

The initial symptoms of food-borne botulism (but not the wound-acquired form)
may be gastrointestinal—nausea, vomiting, and diarrhea—and generally appear
within 2–36 hours of ingestion. Constipation is more common once neurologic
symptoms are present. The earliest neurologic symptoms are oculobulbar and
include dry mouth, blurred vision, diplopia, dysarthria, dysphagia, and dysphonia. In
contrast to most cases of Guillain-Barré syndrome, botulism is characterized by a
descending paralysis. Weakness begins in the cranial nerves, followed by the upper
extremities, respiratory muscles, and finally lower extremities. The weakness
progresses from proximal to distal muscles. Respiratory weakness can be severe and
require prolonged intubation. Botulism also affects autonomic synaptic
transmission, resulting in constipation, postural hypotension, and urinary retention.
On examination, pupils are unreactive and tendon reflexes are absent.

Most infantile cases occur before the age of 6 months, and the first signs may be
constipation, weak cry, and poor feeding. Weakness then progresses over days,
causing poor suck and head control, hypotonia, and deceased movement.
Autonomic signs and symptoms include hypotension, tachycardia, and dry mouth.

The symptoms of wound botulism are similar to those of food-borne botulism

except that gastrointestinal manifestations are usually absent, the incubation period
is longer, and symptoms are gradual in onset.
B. Laboratory and Electrodiagnostic Findings

Both blood and stool can be sent for detection of the botulinum toxin. C botulinum
itself can be detected in stool. If possible, a food sample should also be sent for
identification of the toxin.

Electrodiagnostic studies can support the diagnosis of botulism and help rule out other
possible diagnoses such as Guillain-Barré syndrome. The most consistent finding is a
small CMAP in response to a supramaximal stimulus. As with LEMS, repetitive
stimulation testing may show a decrement of the CMAP to low rates of stimulation and
post-exercise facilitation of the CMAP amplitude.

Differential Diagnosis

Botulism must be distinguished from MG, LEMS, Guillain- Barré syndrome (particularly
the Miller Fisher variant), tick paralysis, diphtheritic neuropathy, and intoxication
(including paralytic shellfish poisoning and organophosphates).
Treatment

The major treatment is intensive supportive care. Patients should be closely

monitored for respiratory decompensation. If the ingestion is recent, removal of
unabsorbed gut toxin can be considered. The Centers for Disease Control and
Prevention can provide a trivalent botulinum antitoxin, which, however, must be
given early while toxin is still in the blood. The antitoxin can decrease the severity
of disease and overall mortality, but side effects include anaphylaxis. Human
botulism immune globulin is an FDA-approved treatment of infant botulism, which
was shown in a randomized clinical trial to reduce length of hospital stay in treated
infants. This intravenous treatment neutralizes all circulating botulinum toxin and
remains present in neutralizing amounts for several months.

Prognosis

Although significantly reduced, mortality from botulism remains high at 5–10%.

Type A toxin is associated with a more severe course and higher mortality than
other toxins. Clinical recovery is often prolonged over months, because it requires
the formation of new presynaptic end plates and neuromuscular junctions.
Recovery of autonomic function may take longer than recovery of muscle strength.
For those who survive, the recovery is generally complete.
TICK PARALYSIS
Tick paralysis is a rare disease that usually affects children, with a higher
prevalence among young girls, although older men exposed to ticks may
also be affected. This disease has been associated with 43 different tick
species globally. Most reported cases have been from Australia and North
America, in particular the Rocky Mountain states, the Pacific Northwest,
and the Southeast. In Australia the Ixodes species dominates, especially I
holocyclus and I cornuatus. In North America members of the Dermacentor
species, D andersoni and D variabilis, are most commonly involved.

Often a prodrome of gait instability is followed by ascending paralysis and

hyporeflexia or areflexia. Bulbar structures are eventually affected, leading
to dysphagia, dysarthria, facial paralysis, and ocular weakness. If the tick is
not removed, fatal respiratory failure can develop. The engorged tick
attached to the patient produces a neurotoxin that acts on the
neuromuscular junction. Removal of the tick is usually followed by rapid
improvement. This disease is most often confused with Guillain-Barré
syndrome.
 YouTube Neuromuscular Junction Disorders

VIDEO LINK • https://www.youtube.com/watch?v=6fLv2ejq0vM

 A 30-year-old female plastic surgery resident presents with a 1-month history of
intermittent ptosis (droopiness of the eyelids) and fatigue. She has been on call every
third night over the past 2 months and has been attributing her fatigue to her hectic call
schedule. However she became concerned when she acutely developed ptosis last
month after being on call. She went home and went to sleep, and by morning her ptosis
had resolved. Her 6-year-old triplets have pointed out to her that she can’t keep up with
them when they’re riding their bicycles. She has experienced three more episodes of
ptosis over the past month. They all have occurred while she has been post-call and have
improved by the morning. Today for the first-time she developed ptosis while performing

CLINICAL a complicated facial lift. Her attending asked her to stop assisting in surgery and to
immediately seek medical evaluation. She has not experienced diplopia, dysarthria,
dysphagia, difficulty walking up stairs, difficulty blow drying her hair, or shortness of

CASE breath. She had always been healthy until now.

Her neurologic examination is notable for normal mental status and speech. Her cranial
nerve examination reveals bilateral ptosis on primary gaze, which worsens with sustained
upward gaze for 90 seconds. Extraocular muscles are intact as is her facial strength. Her
motor strength is normal with the exception of 4+/5 in the deltoid muscles bilaterally. On
repetitive testing of the right iliopsoas muscle fatigability is elicited, which improves after
2 minutes of rest. Her sensory examination and deep tendon reflexes are normal.

QUESTIONS

1. What is the most likely diagnosis? What are the other possibilities?
2. What diagnostic workup will you order?
3. How will you manage this patient?
 MAIN • Current Diagnosis & Treatment Neurology, 3rd ed,
John C.M. Brust, Chapter 22, pp 363-374
REFERENCE

The contents of this slide presentation are largely lifted from the above reference book, with some minor
alterations in wordings, sentence construction and sequence of sentences or paragraphs to suit the needs of
the students of AMA School of Medicine. Materials in the presentation that are not found in the above
reference are taken from the references listed under Related Readings or from various internet sources.
 • Hankey’s Clinical Neurology, 2ed, Philip B. Gorelick
RELATED et al, Chapter 22, pp 855-870

READINGS • Netter’s Neurology, 2ed, H. Royden Jones, Jr., MD

et al, Section XIX, pp 682-696