Disorders of
neuromuscular
junction:
Prepared by:
Dr. Sarwer Jamal Bajalan
M.B.Ch.B, F.I.B.M.S(Neurology)
Myasthenia Gravis
Epidemiology
• Occurs in 50–125/1,000,000.
• Bimodal distribution, often affecting females in their second
and third decades, and males in their sixth and seventh
decades.
Pathophysiology
• Autoimmune disease with antibodies against acetylcholine receptor,
results in decrease of the nicotinic AChR at NMJ.
• End-plate potentials (EPPs) have decreased amplitude and do not trigger
a muscle action potential.
• With repeated contractions, more fibers fail to contract, leading to
fatigue.
• Thymus is abnormal in 75% of cases (15% thymoma, 85% thymic
hyperplasia).
• May be associated with other autoimmune diseases: thyroiditis, Graves
disease, RA, SLE, pernicious anemia, Addison disease & vitiligo.
Clinical manifestations
• Fatigable weakness
• Diplopia and ptosis are the most common presenting features.
• In 15%–20%, the disease never progresses beyond ocular muscles
(Ocular MG).
• Bulbar weakness, limb weakness, and respiratory weakness may
occur.
• Weakness may get worse as the day goes on ( diurnal variation).
• In patients with longstanding disease, weakness may be fixed.
• No pain, sensory loss, or reflex abnormalities.
Symptoms of MG exacerbated by
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Superimposed infection
Surgery
Hyperthyroidism (found in 3%)
Drugs that affect neuromuscular transmission
Anesthetics that cause neuromuscular blockade
Antibiotics (aminoglycosides, quinolones, some macrolides, possibly
penicillins)
• Antihypertensives (beta blockers, verapamil)
• Anti-arrhythmic drugs (quinine, procainamide)
• Other: magnesium, phenothiazines, chloroquine, lithium, some
antiepileptics, iodinated contrast agents
• Penicillamine can cause a drug-induced myasthenic syndrome in
people without autoantibodies
Investigations
Laboratory
• Acetylcholine receptor antibodies (AChR Ab) present in 85% of
patients with generalized MG and 50% of patients with ocular MG.
• A subgroup of AChR Ab -negative patients will have antibodies to
musclespecific kinase (MUSK Ab) instead.
• Striated muscle antibody occurs in 90% of patients with MG and
thymoma, compared to 30% in all MG patients.
• Consider screening for associated autoimmune diseases with:
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Thyroid function studies,
Thyroid antibodies,
Vitamin B12, and
Intrinsic and gastric parietal cell antibodies.
Electrodiagnostic testing
• Repetitive stimulation of CMAP shows decrement at rest.
After brief exercise, the decrement repairs, and then gradually
worsens over 3 minutes. Sensitivity 50%–60%, better with
proximal muscles.
• Single-fi ber EMG shows increased jitter and blocking (90%
sensitive, but specificity is not as high).
CT of the thorax with contrast is essential to look for thymic
enlargement suspicious for thymoma.
Pharmacologic Test
Edrophonium (Tensilon) test
Edrophonium is a short-acting cholinesterase inhibitor.
• An easily testable muscle must be selected , often the deltoid, finger
extensors, or levator palpebrae.
The latter is especially useful in a neuro-ophthalmology offi ce, where degree of
ptosis can be quantified.
• Prepare two syringes. One has 1 mL of saline, and one has 10 mg of
edrophonium in a 1 mL solution.
• Inject the saline first and observe for 1 minute, looking for
improvement in strength.
• Inject 2 mg of the edrophonium. If no improvement after 1 minute,
inject the remaining 8 mg. If no improvement after 1 minute, the test is
negative.
• Atropine (0.4 mg, repeat every 3–10 minutes as needed) can be
used to counteract side effects, including asystole, bradycardia,
nausea, excessive salivation and lacrimation, increasing weakness and
fasciculations.
Differential diagnosis
Generalized MG
• Lambert–Eaton syndrome
• Botulism
• Drug-induced myasthenia (penicillamine)
• Congenital myasthenic syndromes (defects in neuromuscular
transmission that are not caused by autoimmune disease)
• Inflammatory myopathies
• Motor neuron disease (especially bulbar onset)
Ocular MG
• Thyroid ophthalmopathy
• Mitochondrial disease (progressive external ophthalmoplegia)
• Intracranial lesion (cavernous sinus)
• Wernicke encephalopathy
• Oculopharyngeal muscular dystrophy
Management
Pyridostigmine
• Good first-line agent
• A cholinesterase inhibitor
• Acts within 1 hour with duration about 4 hours
• Starting dose 30–60 mg bid-tid. Titrate to effect (often up to 60 mg five
times a day). Higher doses can be used but side effects may be limiting.
• Side effects:
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GI upset,
diarrhea,
excessive salivation,
Fasciculations
Overdose can cause cholinergic crisis, with increased bulbar and respiratory
weakness.
• Side effects can be treated with decreasing the dose, or adding
glycopyrrolate 1 mg qd to bid.
Prednisone
• Good second-line agent if pyridostigmine is inadequate.
• Note that about half of patients will initially worsen 7–21 days
after steroids are started.
• Start with 10 mg on a ternate days, increased every 2 or 3 days to
1–1.5 mg/kg on alternate days.
• Improvement begins after 2–4 weeks with maximal benefit at 6 to 12
months.
• After 3 months or when remission is evident, the dose is slowly
tapered to the minimum dose required. Often a small dose is required
to prevent relapse.
• All patients should be treated for osteoporosis with calcium, vitamin
D, and a bisphosphonate.
Flowchart for the management of MG
Other Immunosuppressants
• Used when steroids are insufficient or contraindicated, or when
steroid side effects are dose limiting.
• Response may take 3–12 months.
• Follow CBC and LFT every week for 2 months and then every 3
months after that.
Azathioprine
• Thiopurine methyltransferase (TPMT) level may predict risk of
hematologic side effects.
• Dose: 50 mg/day for 1 week increasing by 50 mg/week to a goal
dose of 2.5 mg/kg/day
• Side effects:
 Hypersensitivity reaction,
 bone marrow suppression,
 hepatotoxicity
Cyclosporine
• Dosages of 2–5 mg/kg/day in two divided doses
• Side effects: nephrotoxicity, hypertension
• Monitor trough drug levels
Cyclophosphamide
• Reserved for severe cases
• Oral or intravenous
Etanercept,
Rituximab,
Tacrolimus,
Mycophenolate mofetil at 1000 mg bid is commonly used
Plasma exchange
Indications:
• Myasthenic crisis with bulbar weakness and respiratory
compromise
• Perioperative morbidity from thymectomy
• Rarely, as maintenance therapy when other modalities have failed.
• Five to six exchanges over 2 weeks, 2–4 L per exchange.
• Improvement usually noted within days, lasting 1–12 weeks.
Side effects
• Bleeding from removal of circulating clotting factors
• Hypotension and bradycardia
• Transient electrolyte disturbances
• Side effects related to need for vascular access (line infections, local
thrombosis, vascular perforation)
IV immunoglobulin
• Indications and time course for benefit similar to plasma
exchange
• Dose: 400 mg/kg/day for 5 days (total: 2 g/kg)
• If used for maintenance, 1 g/kg q2–4 weeks.
• Side effects
• Common: headaches, nausea, flu-like symptoms
• Serious: Renal failure, anaphylaxis, risk of hypercoagulability
Thymectomy
Indications
• Thymoma
Therapeutic benefit
— No good trials, but consensus is that it is helpful in patients
under 45 with AChR antibodies
— More effective in generalized MG than ocular MG
— Benefits may not be evident for months or years after surgery.
— Can be curative in a fraction of patients
• Mortality is low in the hands of experienced surgeons
• Consider pre-operative plasma exchange to reduce the risk of
MG exacerbation immediately following surgery.
Women and MG
MG and pregnancy
Therapy
• Pyridostigmine and plasma exchange are probably safest.
• There is a low risk of fetal malformations with prednisone.
• Azathioprine and mycophenolate are teratogenic.
• In patients with eclampsia, magnesium sulfate should be avoided if
possible.
• Exacerbations during and after pregnancy are common.
Neonatal MG
• 14% of babies born to mothers with MG develop neonatal MG due to
placental transfer of maternal antibodies.
• Weakness may be apparent days after birth and last for days or
months.
• Treat supportively.
Lambert-Eaton Myasthenic Syndrome (LEMS)
Pathophysiology
• 60% are paraneoplastic, usually associated with small cell lung
cancer. Usually, the discovery of LEMS predates the discovery of cancer.
• 40% are autoimmune (usually in younger, female patients).
• Both have voltage-gated calcium channel antibody.
Clinical manifestations
• Proximal > distal weakness, often worse in the lower extremities
• Weakness may improve with sustained exercise.
• Reflexes are diffusely low or absent, but may appear after exercise.
• Cranial nerve involvement in about 30% (diplopia, ptosis, dysarthria,
dysphagia)
• Autonomic dysfunction (dry mouth, blurred vision, constipation,
erectile dysfunction)
Investigations of LEMS
NCS & EMG
• Reduced CMAP amplitudes that facilitate >200% with rapid
repetitive stimulation (>30 Hz) or after brief intense exercise.
•Decrement on slow (2 Hz) repetitive stimulation.
• Single-fiber EMG may show increased jitter.
Laboratory
 P/Q voltage-gated calcium channel Abs
 SOX1 Ab (50% sensitivity in patients with paraneoplastic LEMS)
Chest CT or MRI
 To look for occult tumor. If negative,
 Repeat at regular intervals for 5 years or until tumor is discovered.
Management of LEMS
• Treat underlying tumor, if present.
• Pyridostigmine
 Same doses as for MG
 Usually only partially effective
• Diaminopyridine
• Guanidine
• Plasma exchange
• IV Immunoglobulin
Botulism
Pathophysiology
• Botulism is poisoning by a toxin produced by clostridium botulinum.
• Most commonly comes from inadequately sterilized canned or
prepared foods.
• Adult botulism is caused by ingestion of toxin; infantile botulism is
caused by ingestion of live bacteria (i.e., in honey).
Clinical manifestations
• Occur 6–48 hours after ingestion
• Diffilculty with convergence, ptosis, paralysis of extraocular muscles
• Dilated, poorly reactive pupils, other autonomic dysfunction
• Jaw weakness, dysarthria, dysphagia
• Spreads to trunk and imbs
• Rare cardiac or respiratory involvement
Investigations
• NCS show incremental response with rapid
repetitive stimulation, mimicking LEMS
• Laboratory: Serum analysis for toxin by bioassay in mice.
Management
• Monitor respiration closely, mechanical ventilation if indicated
• Equine serum trivalent botulism antitoxin.
• Do not wait for positive toxin assay if clinical suspicion is high.
• Side effects: anaphylaxis (3%), serum sickness (20%)