ABSTRACT
A. Anatomy (Fig. 23-1) 1. Motor unit: consists of a motor neuron, its axon and
nerve terminals, and muscle fibers the axon innervates 2. Presynaptic nerve terminal: synthesis, storage, and
release of acetylcholine (ACh) a. Nerve terminal does not have myelin sheath b. ACh is synthesized from choline and acetyl coenzyme A
by action of choline acetyltransferase (ChAT) c. ACh is stored in synaptic vesicles d. One synaptic vesicle contains about 6,000 to 10,000
ACh molecules, termed a quantum of ACh e. Synaptic vesicles are stored in the immediate or second-
ary storage areas of nerve terminal
f. P/Q-type calcium channels: located on presynaptic membranes of nerve terminals
3. Synaptic space: space between nerve terminal and postsynaptic muscle membrane, about 50 nm wide
4. Postsynaptic muscle membrane, also called an end plate a. Has several clefts and folds, thus increasing surface area b. ACh receptors (AChRs): located on postsynaptic folds c. Acetylcholinesterase (AChE): attached to collagen fibrils
of basement membrane within synaptic cleft; it breaks down ACh to choline and acetate
5. AChR: transmembrane protein of postsynaptic (muscle) membrane a. It consists of two α and one β, δ, and ε subunits b. AChRs: concentrated at end plate, directly across from
nerve terminal c. Argin, rapsyn, and muscle-specific tyrosine kinase
(MuSK): proteins important in clustering of AChRs at postsynaptic terminal
d. Two molecules of ACh needed to bind to each α unit (at a site different from the immunogenic region) to open AChR channel, allowing sodium (Na+) influx
B. Physiology of Neuromuscular Transmission 1.Release of single quantum occurs during resting state,
produces postsynaptic depolarization, and is responsible for miniature end plate potential (MEPP)
2.MEPP amplitude: determined by amount of ACh released by each quantum
3.MEPP duration: determined by amount of time the AChR that receives the quantum is open
4.Action potential a. Generated by motor neuron b. Travels down axon and depolarizes nerve terminal
5.Depolarization of nerve terminal opens voltage-gated calcium (Ca+) channel, allowing influx of Ca+ into presynaptic nerve terminal, which triggers release of multiple quanta of ACh by exocytosis
6.Depolarization of nerve terminal allows docking and fusion of synaptic vesicles
7.Synaptic vesicles fuse with the nerve terminal (presynaptic) membrane, releasing ACh into synaptic space
8.ACh diffuses across synaptic space and binds to AChR (α subunits)
9.Binding of ACh to AChR allows influx of cations (Na+
>> Ca+), which depolarizes end plate, generating end plate potentials (EPPs)
10. When EPP reaches threshold voltage for activating voltage-gated sodium channels, muscle fiber action potential is produced
a. EPP: result of action potential and release of many synaptic vesicles
b. Number of synaptic vesicles (quanta) released by action potential is called quantal content, which indicates the amount of ACh released
c. Quantal content: m=n × p (m = amount of released quanta, n = number of quanta immediately available at nerve terminal, and p = probability of quantal release)
d. At rest: low p and high n→ low m value → small number of ACh quanta released → EPP does not reach threshold to generate muscle action potential (muscle fiber action potential is all-or-none)
e. Generation of muscle action potential in normal subject: high p and n→ high m→ large number of ACh quanta released → EPP reaches threshold, generating muscle action potential
f. Safety margin of neuromuscular transmission: defined
by actual EPP amplitude produced by depolarization of nerve terminal and its difference with EPP amplitude required to trigger muscle fiber action potential (threshold)
g. Safety margin: determined by quantal content (amount of ACh in each quantum), mechanism of quantal release, efficiency of AChE and AChRs
h. Normal subjects: high safety margin (i.e., much higher EPP than threshold required for neuromuscular transmission)
i. Repetitive nerve stimulation in normal subject 1) p is high 2) n decreases after several stimulations 3) m gradually decreases 4) Despite fewer molecules of ACh released, EPP is
maintained above threshold to generate muscle action potential: this is due to high safety margin of neuromuscular transmission
j. Patients with disorders of neuromuscular transmission: lower safety margin
k. Repetitive stimulation in patient with myasthenia gravis (MG): EPP is not maintained above threshold to generate muscle action potential because of low safety margin
11. ACh is hydrolyzed by AChE a. 20% of released ACh hydrolyzed before binding and
80% after dissociation from AChR b. ACh is boken down rapidly into choline and acetate
12. Choline: taken up by presynaptic nerve terminal through sodium-dependent active transport mechanism
13. Muscle fiber action potential causes Ca+ release from sarcoplasmic reticulum, leading to muscle contraction
A. Epidemiology 1. Incidence: 2 to 4/million annually 2. Prevalence: 50 to 400/million 3. Female:male = 3:2 4. Onset (bimodal mean age at onset) in generalized,
seropositive MG a. Early onset
1) Second to third decade 2) Female predominance 3) Associated with HLA antigens B8 and DR3
b. Late onset 1) Sixth to eighth decade 2) Male predominance 3) Associated with HLA antigens A3, B7, and DR2
5. Diseases associated with MG: connective tissue disorder, thyroid disease, insulin-dependent diabetes, Lambert-Eaton myasthenic syndrome (LEMS), pernicious anemia, multiple sclerosis, neuromyotonia, cramp-fasciculation syndrome, rippling muscle disease
B. Clinical Presentation 1. Fluctuating, intermittent symptoms sometimes with
periods of spontaneous improvement, often appearing with repetitive activity and worsening as day progresses
2. Early onset a. Present usually after adolescence (before age 40-50 years) b. Female predominance c. Majority of patients
1) Positive for AChR antibodies 2) Have hyperplastic thymus glands
3. Late onset a. Present after age 40-50 years b. Slight male predominance c. Thymus gland usually not hyperplastic
4. Cranial symptoms a. Typically asymmetric, fluctuate over seconds to days b. Ocular
1) More common in elderly men 2) Evidence of subclinical generalized disease (electro-
physiologic or pathologic) often present 3) Anti-AChR antibodies present in 50% to 60% of
patients (in the other patients, antibodies may be present at undetectable levels or there may be other antibodies not tested)
4) Ocular symptoms: presenting features in about 50% of patients with MG, eventually occur in up to 90% of patients with MG
5) 15% of patients with ocular symptoms continue to have ocular symptoms without involvement of other muscles (ocular myasthenia)
6) Little more than 50% of patients with ocular myasthenia have generalized symptoms within the first 6 months (75% within the first year, 6% within 3 years)
7) Pure ocular myasthenia a) Tends to have relatively benign course after 2 years b) Is only rarely associated with thymoma c) Is not likely to respond to thymectomy
c. Ptosis 1) Most common symptom 2) Often exacerbated by fatigue, exposure to bright lights
and heat 3) Unilateral or bilateral (often asymmetric when
bilateral) 4) May or may not be associated with hyperretraction of
normal eyelid; normal eyelid may then droop when examiner lifts the affected eyelid (seesaw effect)
5) When gaze is directed upward, there may be a transient correction of the ptosis and possibly excessive elevation of the eyelid, termed Cogan’s eye twitch
6) Ptosis may improve after application of ice pack to the ptotic eyelid (ice pack test): sensitive (89%) and specific (100%) sign for diagnosis of MG
d. Diplopia 1) Constant or intermittent and fluctuating 2) Worse when reading, watching television, or driving,
especially in bright sunlight 3) Extraocular muscle weakness best quantified with
Lancaster red-green test e. Pupillary function: always spared f. Facial weakness: myasthenic “snarl” due to weakness of
obicularis oris muscle g. Dysphagia: pooling in oropharynx, aspiration, nasal
regurgitation (due to palatal weakness) h. Difficulty chewing: especially worse with prolonged
chewing of solids like meat, hard candy (from weakness of muscles of mastication)
i. Fatigable flaccid dysarthria: nasal speech due to palatal muscle weakness, may become more prominent with prolonged reading, counting, and so forth
j. Dysphonia (rare) 5. Weakness
a. Axial muscle weakness: neck flexors often weaker than neck extensors (may present with “dropped head” syndrome)
b. Proximal upper and lower limbs c. Distal upper and lower limbs (less frequently and less
severely affected than proximal involvement), more prominent in wrist and finger extensors and ankle dorsiflexors than other distal muscles
6. Respiratory involvement a. May be assessed by observing abdominal excursion and
use of accessory respiratory muscles b. Measured by respiratory function tests (vital capacity and
maximal inspiratory and expiratory pressures): accurate measurements rely on good effort and adequate seal of the lips around spirometer tube, which may be lacking for patients with facial weakness
c. Symptoms of obstructive sleep apnea with bulbar involvement
d. Initial manifestation may be exclusively respiratory muscle weakness and/or upper airway obstruction
7. Clinical course variable but progressive 8. Normal reflexes and sensory examination 9. Immune-mediated MG may be exacerbated by drugs:
aminoglycoside antibiotics, prednisone, chloroquine, quinidine, procainamide, magnesium, calcium channel blockers, and iodinated intravenous contrast agents
10. New immune-mediated MG may be drug induced (e.g., penicillamine)
11. Thymoma-associated MG: onset at any age after adolescence (peak: fourth-sixth decades)
12. Antibody-negative MG: more common with ocular MG or childhood MG
13. MuSK-antibody-associated MG a. More likely to have bulbar than limb weakness b. Majority are female (those without MuSK antibodies are
more evenly distributed) c. Atrophy of bulbar muscles d. Poor response to conventional treatments, including cor-
ticosteroids and azathioprine
C. Pathophysiology 1. Increased degradation of AChRs and decreased number
of functional AChRs a. Antibodies bind to extracellular portion of theα1 sub-
unit of AChR (optimal binding to ε subunit in ocular MG)
b. Cross-linking of bound antibodies facilitates endocytosis c. Degradation of internalized AChRs d. Complement-mediated destruction of AChRs on post-
synaptic membranes 2. Damaged postsynaptic folds
a. Complement activation and formation of membrane attack complex (MAC) on the membrane
b. Reduced postsynaptic folds: postsynaptic membranes appear distorted and simplified
3. “Seronegative” MG a. Likely also an autoimmune mechanism b. Improvement observed with plasma exchange c. Antibodies may be present but not yet identified
D. Myasthenia Gravis Foundation of America Classification
1. Class I: ocular MG 2. Class II: mild generalized MG (with or without ocular
muscle weakness of any severity) a. Class IIa: predominately affecting limb or axial muscles
(or both), may have lesser involvement of oropharyngeal muscles
b. Class IIb: predominately affecting oropharyngeal or respiratory muscles (or both), may have lesser involvement of limb or axial muscles (or both)
3. Class III: moderate generalized MG (with or without
ocular muscle weakness of any severity) a. Class IIIa: predominately affecting limb or axial muscles
(or both), may have lesser involvement of oropharyngeal muscles
b. Class IIIb: predominately affecting oropharyngeal or respiratory muscles (or both), may have lesser involvement of limb or axial muscles (or both)
4. Class IV: severe generalized MG (with or without ocular muscle weakness of any severity) a. Class IVa: predominately affecting limb or axial muscles
(or both), may have lesser involvement of oropharyngeal muscles
b. Class IVb: predominately affecting oropharyngeal or respiratory muscles (or both), may have lesser involvement of limb or axial muscles (or both), including patients requiring use of a feeding tube without intubation
5. Class V: intubation
E. Acutely Deteriorating Patient 1. Myasthenic crisis: respiratory distress, bulbar symp-
toms (dysphagia, flaccid dysarthria, poor cough, reduced ability to handle oral secretions and sialorrhea), weakness, diaphoresis, improvement with edrophonium
2. Cholinergic crisis: diarrhea; fasciculations; weakness (including respiratory muscle weakness); miosis; abdominal cramps; nausea and vomiting; excessive secretions causing lacrimation, sialorrhea, and diaphoresis; worsening with edrophonium; tachycardia (immediate use of atropine and withdrawal of cholinesterase inhibitors recommended)
F. Drugs With Adverse Effects in Myasthenia Gravis and Lambert-Eaton Myasthenic Syndrome
1. Aminoglycoside antibodies (block presynaptic calcium channels): streptomycin, neomycin, gentamicin, kanamycin, others
2. Penicillamine, botulinum toxin, and interferon α are absolutely contraindicated
3. Neuromuscular-blocking agents such as succinylcholine or tubocurarine, vecuronium
4. Quinidine, procainamide, procaine, magnesium salts, chloroquine, prednisone
5. β-Blockers and calcium channel blockers 6. Drugs with anectodal reports of exacerbation
a. Erythromycin, clindamycin, ampicillin, chlorpromazine, quinine, morphine, lithium, gabapentin
b. Contrast agents: gadolinium diethylenetriamine pentaacetic acid contrast agent used for magnetic resonance imaging (MRI) and iodine-based contrast agents
G. Drug-induced Myasthenia Gravis 1. Immune-mediated disease: associated with increased
serum levels of AChR antibodies 2. Slow, insidious onset: weeks to months after initiation
of offending drug 3. Penicillamine-induced myasthenia: usually mild, often
restricted to ocular muscles 4. Recovery: slow and incomplete 5. Associated with penicillamine, procainamide, quinidine,
chloroquine
H. Diagnostic Evaluation 1. Serologic testing
a. Antibodies present in 80% to 85% of patients with generalized MG and 50% to 60% of those with pure ocular MG
b. Titers vary among patients c. Titers may be elevated in patients with thymoma with-
out MG or in asymptomatic family members d. Striational antibodies
1) Present in 2/3 of patients before age 45 with thymoma (high predictive value for this group)
2) Heterogeneous group of antibodies against various muscle proteins, including titin, actin, myosin, αactinin, ryanodine receptor
3) Titin antibodies associated with late-onset, severe MG and in association with thymoma (found in 90% of patients with MG and thymoma)
4) Not specific for MG: may also be present in patients with LEMS, lung cancer, autoimmune liver disease, thymoma without myasthenia, drug-induced MG (e.g., penicillamine), and in bone marrow allograft recipients with graft-vs-host disease
e. Anti-AChR-binding antibodies 1) Highly sensitive for MG: most sensitive test, often
used for screening 2) Moderate correlation with disease severity: patients
with mild or early disease are often seronegative 3) False-positive results observed with LEMS, autoim-
mune liver disease, thymoma without myasthenia, and healthy relatives of patients with MG
f. Anti-AChR-modulating antibodies 1) Increased degradation of AChR 2) Highly sensitive and specific for MG 3) Performed when binding antibodies are negative
(higher sensitivity when used in combination) with binding antibodies
g. Anti-AChR-blocking antibodies 1) Inhibits ACh and AChR binding 2) Low sensitivity; test often does not help make diagno-
sis of MG
3) When present, often correlates with disease severity 4) False-positive results observed with LEMS
h. Anti-MuSK antibodies 1) Detected in up to 70% of patients with “seronegative”
MG 2) Not detected in patients with anti-AChR antibody-
positive MG 3) MuSK
a) Receptor tyrosine kinase b) Muscle-specific and localized to neuromuscular
junction c) Important in development of neuromuscular
junctions 2. Chest computed tomography (CT): exclude thymoma
(all patients) 3. Edrophonium test
a. Concept 1) Cholinesterase inhibitor: increases availability of ACh
at neuromuscular junction 2) Relatively low sensitivity (60%) compared with other
tests 3) False-positive results described in amyotrophic lateral
sclerosis (ALS), LEMS, and brainstem lesions 4) Most useful in patients with clinical weakness 5) Most accurate in presence of ptosis or extraocular
muscle weakness (examination of limb muscles is often limited to patient’s maximal effort)
6) Use in ocular MG: edrophonium may improve one of the several affected extraocular muscles, and the rest could become weaker
7) Positive response does not predict response to other longer-acting cholinesterase inhibitors
b. Pharmacology 1) Mechanism: AChE inhibitor 2) Onset of action: in 30 to 60 seconds 3) Duration: 2 to 5 minutes 4) Side effects (cholinergic): nausea, salivation, tearing,
sweating, flushing, perioral fasciculations, bradycardia, asystole (rare), hypotension (atropine should be administered immediately)
c. Procedure 1) Initial test dose: 1 to 2 mg intravenously (IV);
response monitored for 60 seconds 2) If no response after 60 seconds: administer another 3
mg 3) If no response after 60 seconds: administer additional
5 mg (for total of 10 mg IV) 4) If clinical improvement: no further increments necessary 5) Assessment: clinically, electrophysiologically, or
Lancaster red-green test
6) If no clear response, may give 0.8 mg IV 7) Assess again for clinical change 8) Vital signs should be monitored throughout test
d. Disadvantage 1) Lack of objective measurement of strength (best done
for ptosis or extraocular muscle weakness) 2) Short duration of action 3) Low sensitivity (about 60%) 4) False-positive results: may be seen in other conditions
(e.g., LEMS, ALS) 4. Routine nerve conduction studies (NCSs)
a. Motor: usually normal compound muscle action potential (CMAP), conduction velocity, and distal latency, but low CMAP may be found in severe MG
b. Sensory: normal 5. Repetitive nerve stimulation (RNS) (see Chapter 5)
a. Concept 1) MG patients have low safety factor: EPPs fail to reach
threshold levels at neuromuscular junction 2) RNS: depleting the immediately available ACh pro-
duces decrement in repetitive trains of CMAPs 3) RNS at low rates (2-5 Hz)
a) Decrement of CMAP in weak muscles at baseline b) Repair of the decrement immediately after exer-
cise, followed by worsening of the decrement for 2 to 5 minutes after exercise (postexercise exhaustion)
4) Decrement is greatest between the first and second responses, with a smooth, continuous pattern
5) Anticholinesterase medicines: if possible, withhold for 12 hours before test
b. Disadvantage 1) Abnormal RNS results may be obtained only in weak
muscles 2) May be normal in very mild disease and in ocular
MG 3) Decrement is more likely seen in proximal limb or
cranial muscles 4) RNS is technically challenging: unacceptable false-
positive rate with poor technique and poor patient relaxation and discomfort
6. Concentric needle electromyography (EMG) a. Usually normal, may observe varying motor unit poten-
tials (MUPs) b. Short-duration MUPs can be seen in severe cases
7. Single fiber EMG (SFEMG) a. Concept (see Chapter 5)
1) Records two muscle fibers of same motor neuron 2) Jitter: abnormal (increased) interpotential variability;
indicative of slowed neuromuscular junction trans-
mission (may be observed in seemingly unaffected muscles with normal strength)
3) Blocking: complete failure of transmission; usually observed in weak muscles (significant blocking is not expected to be observed in seemingly unaffected muscle with normal strength)
4) May be obtained when RNS and standard needle examinations are normal and MG is suspected clinically (e.g., mild generalized or ocular MG)
5) Normal SFEMG findings in a clinically weak muscle excludes the diagnosis of MG
b. Advantage 1) Detection of mild generalized MG or ocular MG 2) Most sensitive test (>95%) for detecting MG
c. Disadvantage 1) Not specific for MG, abnormal findings are found in
certain neuropathic (e.g., ALS) or myopathic disorders with neuromuscular junction instability or other neuromuscular junction disorders
2) Patient’s tolerance and cooperation are required 3) Time-consuming test
I. Treatment: needs to be individualized 1. Cholinesterase inhibitors
a. Adverse dose-dependent effects: nausea, vomiting, muscle cramps, diarrhea, excessive salivation, and lacrimation; cholinergic crisis with overdose
b. Pyridostigmine bromide (Mestinon) 1) Oral formulation: 60-mg regular tablets; a syrup
containing 12 mg of the medicine per milliliter 2) IV, intramuscular, or subcutaneous formulations: 2
mg 3) Onset of action: 10 to 45 minutes 4) Usual duration of action: 3 to 6 hours 5) Indication: first line of treatment 6) Dosage: 30 mg every 6 hours to 90 mg every 3 hours
(total daily dose not to exceed 600 mg) 7) Risk of cholinergic crisis with doses larger than 120
mg every 2 hours c. Slow-release pyridostigmine bromide (Mestinon,
Timespan) 1) Oral formulation: 90 to 180-mg slow-release tablets 2) No IV formulation 3) Onset of action: 1 hour 4) Usual duration of action: 6 to 10 hours 5) Should be limited to nighttime dose for treatment of
morning symptoms, because absorption is erratic d. Neostigmine methylsulfate (Prostigmin)
1) Oral formulation: 15-mg tablets 2) Onset of action: 30 minutes
3) Usual duration of action: 2 to 3 hours (shorter than for pyridostigmine bromide)
4) Dosage (adults): 7.5 to 30 mg every 3 to 4 hours 5) More cholinergic adverse affects than with pyridostig-
mine bromide e. Ambenonium chloride (Mytelase)
1) Oral formulation: 10-mg tablets 2) Duration of action: about 6 to 8 hours, greater ten-
dency to accumulate than other cholinesterase inhibitors
2. Prednisone a. Indication: disabling MG not responding adequately to
cholinesterase inhibitors b. Alternate-day therapy is relatively safe and effective c. Onset: usually days to weeks, but peak is 4 to 8 weeks
after initiation of therapy or change in dose d. Adverse effect: about 10% of patients become worse ini-
tially (occurs in patients taking prednisone for first time); cushingoid features, weight gain, hypertension, myopathy, osteoporosis, aseptic necrosis of femoral head, glaucoma, cataracts, infection, diabetes mellitus, increased skin fragility, acne, sleep disturbance, psychosis, pseudotumor cerebri, adrenal suppression, peptic ulcer disease
e. Low-dose prednisone used for mild generalized MG or disabling ocular MG not responsive to cholinesterase inhibitors 1) Starting dose: generally 30 mg every other day (for 2
months) 2) Slow taper to lowest effective dose
f. High-dose prednisone used for moderate to severe generalized MG 1) Starting dose: generally 60 to 80 mg daily (usually for
1 to 2 months) 2) Slow taper over several months
g. Monitor patients carefully for exacerbation of MG while tapering prednisone
h. Blood tests (complete blood count and metabolic panel) and chest radiograph must be obtained at baseline and periodically thereafter
i. Preventive measures for complications of high-dose prednisone should be considered 1) Routine screening for osteoporosis, cataracts, glauco-
ma, hypertension, diabetes mellitus, hypokalemia 2) Avoidance of extra dietary salt 3) Antacids for all patients: treatment of concurrent
peptic ulcer disease 4) Supplemental calcium and vitamin D 5) Prophylactic antituberculosis antibiotics for tuber-
culin-positive patients 6) Pneumocystis jiroveci (formerly carinii) pneumonia
prophylaxis with trimethoprim-sulfamethoxazole (Bactrim)
3. Azathioprine (Imuran) a. Mechanism of action: decreased purine synthesis; inter-
feres with DNA and RNA synthesis; inhibits proliferation of lymphocytes and, thus, interferes with antibody and cytokine production
b. Metabolism 1) Metabolized by oxidation or methylation in erythro-
cytes and liver; excreted by kidney 2) Metabolite: 6-mercaptopurine (6MP) (nonenzymat-
ic break down), which is purine analogue acting to disrupt de novo purine synthesis
3) 6MP: eventually converted into active metabolites, 6-thioguanine nucleotides (TGNs)
4) TGNs: eventually incorporated into DNA, interfering with DNA synthesis
5) Through a different metabolic pathway, 6MP is metabolized to mercaptopurines by thiopurine methyltransferase (TPMT) a) TPMT levels: may be used to predict and moni-
tor efficacy and toxicity b) Variability in TPMT levels (and metabolism of the
drug): due to genetic polymorphism of TPMT; homozygous defect may lead to fatal bone marrow toxicity
6) Main pathway for detoxification of azathioprine: conversion to inactive 6-thiouric acid by xanthine oxidase (inhibited by concurrent use of allopurinol, in which case azathioprine dose has to be reduced)
c. Dose: initial dose 2.5 to 3 mg/kg; maintain dose at 1.5 to 2.5 mg/kg daily
d. Dose may be adjusted to achieve mild leukopenia and macrocytosis
e. Onset of action: slow (over 4-12 months), may be delayed further if initial dose is subtherapeutic
f. Indicated for patients with poor response to corticosteroids or limited by corticosteroid-induced side effects
g. Considered first line for patients with moderate to severe MG at high risk for corticosteroid-induced side effects (e.g., postmenopausal women and diabetics)
h. Advantage: steroid-sparing i. Disadvantage: slow onset, expensive j. Adverse effects: elevation in liver enzymes (reversible),
dose-dependent, reversible bone marrow suppression (leukopenia, pure red cell aplasia), macrocytosis, pancreatitis, infection, possible risk of later development of malignancy (debated), infertility, teratogenic
k. Dosage should be reduced for leukocyte count <4×109/L; held for leukocyte count <3×109/L
4. Cyclophosphamide (Cytoxan) a. Interferes with DNA synthesis: alkylates and crosslinks
DNA b. Often prescribed for disease refractory to prednisone
and/or azathioprine c. Usual dosage: 1.0 to 1.5 mg/kg daily d. Adverse effects: severe bone marrow depression and
cytopenias, increased risk of infection and malignancy, hemorrhagic cystitis, increased risk of bladder neoplasm, cardiomyopathy, congestive heart failure, hair loss, sterility (azoospermia, anovulation)
5. Cyclosporine a. Interferes with lymphocytic proliferation by reducing
expression of cytokine genes required for T cell activation and proliferation
b. Limited use because of toxicity 6. Mycophenolate mofetil (CellCept)
a. Mechanism of action 1) Inhibitor of de novo pathway of purine nucleotide
synthesis, impairing proliferation of B and T lymphocytes
2) Induces apoptosis of activated T cells 3) Reduces lymphocyte attachment and mobilization by
reducing synthesis of E and P selectins by endothelial cells and inhibiting interaction of lymphocytic ligands with endothelial selectin receptors (thus interfering with adhesion of lymphocytes) and by reducing glycosylation of intracellular adhesion molecules
b. Dosage: 1 to 1.5 g every 12 hours c. Improvement is expected to begin 2 weeks to 2 months
after initiation of treatment, but peak effect may be delayed up to 9 to 12 months
d. Advantage: steroid-sparing, potency similar to azathioprine and cyclosporine but with lower toxicity
e. Disadvantage: expensive f. Adverse effects: gastrointestinal discomfort with or with-
out diarrhea, dose-dependent leukopenia (need to monitor blood counts, as with azathioprine)
7. Plasmapheresis a. Effective in all patients b. Proposed mechanism of action: transient removal of
causative antibodies and immune mediators responsible for destruction of AChRs
c. Three to five treatments often required for satisfactory response in setting of exacerbation 1) Daily treatment tolerated by young patients with no
other comorbidities 2) Alternate-day treatments preferred for older patients
and young patients with other comorbidities or unstable disease course
d. May be used in myasthenic crisis and to optimize muscle function before a surgical procedure, including thymectomy
e. Rarely used as long-term therapy (as adjunct to longterm immunosuppressive therapy)
f. When treatment is stopped: antibody titers increase, symptoms recur, use of immunosuppressant is often needed
g. Disadvantages: complicated (often requires placement of central venous catheter), costly, limited availability
h. Risks and adverse effects: risks of central venous catheter (infection, pneumothorax, thrombosis), hypotension, and hypocalcemia and citrate toxicity (due to use of citrate salts)
8. Intravenous immunoglobulin (IVIg) a. Mechanism: unclear b. Used in myasthenic crisis, may be used as adjunct to
long-term immunosuppressive therapy (as with plasmapheresis)
c. Dosage: 400 mg/kg daily, usually for 5 consecutive days d. Advantage: easier to administer than plasmapheresis e. Disadvantage: costly f. Adverse effects
1) Low-grade fevers, headaches, with or without aseptic meningitis
2) Serum hyperviscosity and hyperosmolarity, sometimes inducing renal insufficiency, deep venous thrombosis, cerebral infarctions
3) Anaphylactic reactions, especially in patients with selective IgA deficiency, agammaglobulinemia, or severe hypogammaglobulinemia
9. Thymectomy a. Retrospective data suggest eventual improvement in nat-
ural history of MG in up to 80% and complete remission in up to 40% of patients; improvement is often gradual (within 5-15 years)
b. May be transient symptomatic improvement immediately postoperatively, lasting up to 2 to 3 weeks
c. Recommended for most patients younger than 60 years d. Not recommended for patients older than 60 years: usu-
ally higher surgical morbidity and patients may not have adequate time to realize benefit
e. Usually not recommended for pure ocular MG (although may prevent generalization of disease in ocular myasthenia and is sometimes recommended for young patients with relatively recent onset of symptoms)
f. Thymoma is an absolute indication (done to cure or debulk the tumor)
g. Thymectomy does not benefit myasthenic symptoms in patients with thymoma
h. Most effective in females with shorter duration of disease, hyperplastic glands, and high antibody titers (results equalize after 10 years, continue to be effective despite presence or absence of these factors)
i. More effective in patients who have thymectomy within 2 years after onset of symptoms
j. Preferred approach: transsternal thymectomy (ectopic thymic tissue can be missed with the transcervical approach), but data directly comparing the two surgical techniques are lacking
10. Other adjunctive measures a. Vaccination against influenza b. Immunization against pneumococcus before prednisone
or other immunosuppressants are given c. Avoidance of drugs that can exacerbate MG: aminogly-
cosides, erythromycin or related antibiotics, quininerelated drugs
11. Treatment strategies a. Transient neonatal MG
1) Transient disorder of infants born to mothers with MG: general weakness (floppy infants), difficulty feeding, respiratory insufficiency when severe
2) Syndrome resolves after several weeks 3) Anticholinesterase agents (parenteral if poor feeding) 4) Plasma exchange or IVIg considered for severely
affected infants 5) Risk of development of neonatal MG is independent
of clinical status or antibody levels of the mother b. MG during pregnancy
1) MG may become worse during pregnancy or post partum
2) Pyridostigmine and corticosteroids are relatively safe, but azathioprine and cyclosporine need to be avoided because of teratogenic effects and need to be discontinued several months before pregnancy is contemplated
3) Dose of cholinesterase inhibitors needs to be adjusted because of altered intestinal absorption and renal excretion
4) Changes in maternal blood volume and renal clearance affect pharmacokinetics of first-line agents
5) One-third of infants born to mothers with MG have transient neonatal myasthenia
c. Juvenile MG 1) Similar approach to that for adults, with special
considerations 2) Higher rates of spontaneous remission with prepuber-
tal onset: thymectomy is often delayed 3) Corticosteroids inhibit growth of long bones and pre-
dispose to early osteoporosis and are best avoided
d. Ocular MG 1) Ptosis crutches for ptosis 2) Alternating eye patch for diplopia 3) Treatment with cholinesterase inhibitors attempted
first 4) Treatment with alternate-day prednisone (10-30 mg
every other day) may be given for disabling diplopia or ptosis not responsive to cholinesterase inhibitors (can prevent generalization because majority of patients with ocular MG eventually develop generalized disease)
e. Mild generalized MG 1) All patients receive pyridostigmine 2) Alternate-day prednisone is added for those without
adequate response to cholinesterase inhibitors 3) Azathioprine is often added for patients without ade-
quate response to pyridostigmine and low doses of alternate-day prednisone
4) Onset before age 60: thymectomy (preoperative treatment with plasmapheresis and/or high-dose prednisone to minimize risks of surgery)
f. Moderate to severe MG 1) Alternate-day prednisone with pyridostigmine 2) Azathioprine, myocophenolate mofetil, or
cyclosporine 3) Onset before age 60: thymectomy, as above 4) Onset after age 60: treatment with cholinesterase
inhibitors and prednisone (temporary), and immunosuppressive (steroid-sparing) agent such as azathioprine always initiated with intention to taper and discontinue prednisone
g. MG crisis or fulminant MG 1) Usually treated initially with IVIg or plasmapheresis 2) High-dose IV corticosteroids (methylprednisolone),
followed by oral prednisone 3) Prednisone eventually tapered off to alternate-day
regimen 4) Immunosuppressive agents may be needed as steroid-
sparing agents if prednisone cannot be discontinued because of recurrence of symptoms while dose is tapered
A. Epidemiology 1. Incidence: 4/1 million 2. Male > female 3. Middle age or older patients
4. About 50% of cases of LEMS are associated with malignancy (majority, small cell lung cancer [SCLC]): neoplastic-related LEMS uncommon in patients younger than 40 years
5. About 3% of cases of SCLC are associated with LEMS
B. Symptoms and Signs 1. Insidious onset 2. Fluctuating proximal muscle weakness (lower limbs >
upper limbs), e.g., difficulty rising from a low chair, climbing stairs
3. Weakness elicited on examination is often less impressive than severity of symptoms reported by patient
4. Improvement in strength with repeated examinations and exercise (in contrast to MG)
5. Reflexes: markedly reduced or absent initially, but increase after a brief exercise (in contrast to MG)
6. Ocular and pharyngeal muscle weakness possible; if present, much less severe than MG
7. Sensory: may be involved, e.g., distal paresthesias 8. Metallic taste 9. Dysautonomia: dry mouth, dry eyes, impotence, con-
stipation, blurred vision, postural hypotension 10. Lambert’s sign: patient grasping the examiner’s hand
with maximal force has a weak grip that improves over several seconds with continued exertion
C. Pathophysiology 1. Antibodies to prejunctional P/Q-type voltage-gated cal-
cium channel at presynaptic motor nerve terminal 2. Reduced calcium influx into presynaptic nerve terminal
and reduced quantal release 3. Reduced ACh release; hence, decreased number of ACh
molecules binding to AChRs 4. Reduced EPPs and activation of muscle fiber action
potentials, producing clinically weak muscle contraction
D. Diagnostic Tools 1. Minimal response to edrophonium chloride (in contrast
to MG) 2. Serum
a. Antibodies to P/Q-type voltage-gated calcium channel b. More than 90% of patients are positive
3. Search for an underlying malignancy: CT of chest, bronchoscopy (with or without biopsy), positron emission tomography (PET) considered for chronic smokers
4. If no tumor found, a search for occult malignancy should be repeated periodically
5. NCSs
a. Motor: low CMAP amplitude, but normal conduction velocities and distal latencies
b. Sensory: normal 6. RNS
a. LEMS has low safety factor b. Low-amplitude resting CMAP because of decreased
release of ACh c. Decrement with repetitive stimulation at 2 Hz because
of depletion of immediately available ACh d. Marked increment (more than 100%) and facilitation
(more than 200%) noted immediately after rapid rates of stimulation or brief (10 seconds) exercise 1) Due to increased calcium concentrations in presynap-
tic nerve terminal, allowing more ACh release, which leads to increased EPPs, increased muscle fiber activation, and improved strength on clinical examination
2) Facilitation is noted immediately after exercise 3) CMAP amplitudes return to baseline about 60 to 120
seconds after exercise 4) Decrement returns about 3 to 4 minutes after exercise
7. Needle EMG: usually normal insertional activity, but motor unit potentials may be varying and/or of short duration and amplitude (“myopathic”)
8. SFEMG: highly sensitive in disorders of neuromuscular transmission (not specific); abnormal jitter and blocking, less prominent when high-frequency stimulation is used
E. Treatment 1. Treatment of underlying malignancy, if present 2. Pyridostigmine bromide 3. Neostigmine methylsulfate 4. 3,4-Diaminopyridine (DAP)
a. Mechanism of action (in sequence) 1) Blocks voltage-gated potassium channels responsible
for repolarization of action potentials, increases action potential duration and opening of P/Q-type voltagegated calcium channels
2) Increased duration of voltage-gated calcium channels
3) Increased calcium influx into presynaptic nerve terminal
4) Increased release of acetylcholine 5) Result: improved strength
b. Improvement seen in about 80% of patients c. Effective for both autonomic and neuromuscular
manifestations d. Dose
1) Initial: 5 to 25 mg three or four times daily 2) Titration: gradual, by 5 mg per day
e. Effect of DAP is enhanced by concomitant use of pyridostigmine
f. Adverse effects 1) Perioral or digital paresthesias (transient, usually with
high doses) 2) Other potential side effects (especially when given
with pyridostigmine): cramps, diarrhea, nausea, and vomiting
5. Immunosuppressants considered when DAP or cholinesterase inhibitors are not effective in face of disabling symptoms, including prednisone or azathioprine
6. Plasmapheresis and IVIg: short-term improvement, less effective than with MG
A. General Characteristics 1. Onset: often in infancy or childhood, but may occur
in adolescence or adulthood with mild phenotype, most commonly with slow-channel syndrome and familial limb-girdle myasthenia
2. Family history of similarly affected family members: autosomal dominant inheritance in slow-channel syndrome, autosomal recessive inheritance in remaining congenital myasthenic syndromes
3. Decremental response on repetitive stimulation (see below)
4. Repetitive CMAPs: AChE deficiency and slow-channel syndrome
5. Increasing weakness on sustained exertion 6. Selectively severe involvement of truncal muscles: end
plate AChE deficiency 7. Selectively severe involvement of finger and wrist exten-
sors and cervical axial muscles: end plate AChE deficiency and slow-channel syndrome
8. Mild ocular involvement: end plate AChE deficiency and slow-channel syndrome
9. Apnea episodes: ChAT deficiency (also called “congenital myasthenic syndrome with episodic apnea”)
10. Negative AChR antibodies in all cases 11. Tensilon test
a. Often positive, although a negative test does not exclude the diagnosis of a congenital myasthenic syndrome
b. May be negative in asymptomatic patients during the time between episodes of exacerbation
c. Always negative in patients with end plate AChE deficiency
d. Inconsistent results in patients with slow-channel syndrome
B. Presynaptic Congenital Myasthenic Syndromes 1. End-plate ChAT deficiency
a. Autosomal recessive; due to mutation of gene on chromosome 10q11.2 encoding ChAT protein
b. Clinical course 1) Marked by episodic, rapid exacerbations of bulbar
and respiratory weakness 2) Episodes of sudden, unexpected apnea, spontaneous
or precipitated by concurrent infection, excitement, or exertion
c. Recovery after each episode may be partial or complete d. Gradual improvement with age: reduced frequency of
attacks e. Patients may be symptomatic at birth or in neonatal
period, with poor feeding, hypotonia, bulbar and respiratory weakness (gradually improves but may be followed by attacks of apnea and bulbar weakness later in life)
f. Patients may be normal at birth and in neonatal period, but develop ptosis, fatigable weakness, and apneic episodes during infancy or childhood; children may complain of fatigability with exertion
g. Rare: sudden death h. Electrophysiologic testing
1) Decremental response with 2-Hz repetitive stimulation; SFEMG abnormalities noted in weak muscles
2) Decrement often not present in muscles with normal strength, especially between attacks
i. Treatment: prophylaxis with anticholinesterase medications for patients with symptomatic weakness or frequent apneic episodes
j. Patients with febrile illness should be hospitalized for close observation
2. Congenital myasthenic syndrome resembling LEMS 3. Congenital paucity of synaptic vesicles and reduced
quantal release
C. Synaptic Congenital Myasthenic Syndrome 1. Congenital end-plate AChE deficiency
a. Autosomal recessive inheritance b. Pathophysiology and microscopic morphologic features
1) Absence of AChE 2) Small presynaptic nerve terminals 3) Extension of the Schwann cell processes to synaptic
cleft and encasement of small nerve terminals 4) Reduced quantal release from abnormal nerve
terminals 5) Despite restricted ACh release, there is cholinergic
overloading of the synapse and prolonged exposure and desensitization of AChRs at physiologic states
6) Cholinergic overloading is responsible for depolariza-
tion block at physiologic rates of stimulation 7) Degradation of junctional folds, with reduced num-
ber of AChRs 8) End-plate myopathy: type II muscle fiber atrophy
and type I muscle fiber preponderance c. Often presents in neonatal period with weakness d. Lifelong history of weakness: delayed motor milestones,
diffuse weakness (including facial, extraocular, proximal limb, respiratory)
e. Sluggish pupillary response f. Slow progression g. Spine deformities often develop h. Electrodiagnostic evaluation: repetitive CMAP response
1) Subsides quickly with repetitive stimulation (faster than initial CMAP) in a patient not exposed to AChE inhibitors
2) Similar to slow-channel syndrome 3) Repetitive CMAP response may be absent in infancy
i. Tensilon test is always negative, may worsen clinical weakness
j. Need to avoid AChE inhibitors
D. Postsynaptic Congenital Myasthenic Syndromes 1. Slow-channel syndromes: increased response to ACh
a. Most often autosomal dominant inheritance (gain-offunction mutations) 1) Mutation of gene on chromosome 2q24-q32 encod-
ing AChR α subunit: autosomal dominant inheritance
2) Mutation of gene on chromosome 17p13.1 encoding AChR β subunit: autosomal dominant inheritance
3) Mutation of gene on chromosome 2q33-q34 encoding AChR δ subunit: autosomal dominant inheritance
4) Mutation of gene on chromosome 17p13-p12 encoding AChR ε subunit: autosomal dominant or recessive inheritance
b. Variable clinical presentation 1) May present in early life and cause severe disability by
end of first decade 2) May present later in life with little progression and
disability (as late as sixth decade) c. Selective, severe involvement of cervical axial muscula-
ture and digit and wrist extensors d. Cranial musculature tends to be relatively spared e. May be atrophy of severely affected muscles f. Tensilon test: variable results g. Electrodiagnostic evaluation
1) Decremental response with repetitive stimulation 2) Repetitive CMAP response, which subsides with
repetitive stimulation (Fig. 23-2) h. Pathophysiology
1) Mutations often involve proteins near extracellular ACh binding sites
2) Mutations cause increased affinity of AChRs for ACh (causing channel reopening) or act to prolong open
state (mutant AChR can stay open even in absence of ACh)
3) End result: continuous cation leak into postsynaptic area is responsible for prolonged decay phase of MEPPs and EPPs
4) Focal calcium excess may produce local excitotoxic damage and degeneration of junctional folds and reduced number of AChRs: responsible for smallamplitude MEPPs
i. Pathology 1) End-plate myopathy with type I fiber predominance,
vacuoles in end plates, increased variation in muscle fiber size
2) Degeneration of junctional folds j. Treatment
1) Anticholinesterase inhibitors: little or no benefit 2) Quinidine sulfate 3) Fluoxetine: effective at relatively high doses (80
mg/day in adults) 2. Fast-channel syndromes: reduced response to ACh
a. Autosomal recessive inheritance (loss-of-function mutations) 1) Mutation of gene on chromosome 2q24-q32 encod-
ing AChR α subunit 2) Mutation of gene on chromosome 2q33-q34 encod-
ing AChR δ subunit 3) Mutation of gene on chromosome 17p13-p12 encod-
ing AChR ε subunit b. Pathophysiology related to mutations of AChR
1) May be decreased rates of channel opening and increased rates of channel closing
2) Reduced gate efficiency (mild phenotype) 3) Unstable channel kinetics (moderate phenotype) 4) Reduced affinity of receptors for ACh (severe
phenotype) c. Onset at birth d. Extraocular movement paralysis and ptosis, dysarthria,
dysphagia, difficulty chewing, generalized limb weakness and fatigability, respiratory distress
e. Definite diagnosis requires patch-clamp studies and in vitro microelectrode studies of neuromuscular junction
f. Treatment 1) Pyridostigmine 2) 3,4-DAP (synergistic effect with pyridostigmine)
A. Epidemiology 1. Caused by toxin produced by anaerobic pathogen
Clostridium botulinum 2. Pathogen produces spores (heat-resistant up to 120°C)
and toxin (heat-sensitive) 3. At least eight immunologically distinct types of botu-
linum toxin (BTX): A, B, C1, C2, D, E, F, and G 4. BTX A: most commonly involved 5. Several clinical forms of botulism; most common are
the following: a. Food-borne (classic) botulism b. Infant botulism c. Wound botulism (most common form of botulism in
United States, usually occurs in injection drug users)
B. Pathophysiology 1. Inhibits ACh release (presynaptic blockade) from neu-
romuscular junction and parasympathetic and sympathetic ganglia, resulting in autonomic dysfunction and muscle weakness
2. Transfer of botulinum into cytosol: BTX binds to receptors on unmyelinated presynaptic membrane, is transferred via endocytosis into endosomes in nerve terminals, and transported to cytosol
3. In normal condition, collaboration of synaptosomalassociated protein (SNAP)-25, synaptobrevin, and syntaxin is necessary for neuroexocytosis (ACh release from presynaptic nerve terminal)
4. In botulism, BTX enters presynaptic nerve terminal and cleaves protein components of neuroexocytosis apparatus a. Botulinum A and E cleave SNAP-25 b. Botulinum B, D, F, and G cleave synaptobrevin (vesicle-
associated membrane protein) c. Botulinum C cleaves SNAP-25 and syntaxin
5. This results in impaired docking and fusion of synaptic vesicles with terminal membrane
6. This leads to impaired neuroexocytosis and fewer quanta of ACh released (number of released quanta is below threshold, but size of each quantum of ACh is normal)
C. Classic (adult) Botulism 1. Due to ingestion of preformed toxin in contaminated
food 2. Initial symptoms of food-borne botulism often include
nausea and vomiting, followed by neuromuscular symptoms, often after 12 to 38 hours
3. Some patients who ingest contaminated food do not become symptomatic
4. Descending weakness: involvement progressing from cranial to upper limbs to lower limbs
5. Cranial involvement: dysphagia, ptosis, diplopia,
blurred vision, dysarthria 6. Respiratory muscle weakness 7. Reduced deep tendon reflexes 8. Limb weakness: proximal more than distal 9. Normal sensory function 10. Pupillary paralysis: dilated pupils in many patients 11. Autonomic disturbance: dry mouth, urinary retention 12. Gastrointestinal autonomic involvement
a. Nausea, vomiting b. Abdominal cramping c. Diarrhea, constipation d. Ileus
D. Infantile Botulism 1. Due to ingestion of pathogenic spores, with subsequent
germination of spores and growth of pathogen in gastrointestinal tract and slow and steady production of small quantities of toxin
2. Sometimes due to ingestion of honey (tends to harbor type B organisms)
3. Constipation is first sign: may predispose to production of toxins
4. Listless, lethargic floppy infants (hypotonia), with reduced spontaneous movements
5. Poor sucking, drooling, and weak cry 6. Poorly reactive pupils 7. Respiratory distress
E. Diagnostic Methods 1. Tensilon test: positive in one-third of patients 2. NCSs
a. Normal to mildly reduced CMAP with normal conduction velocity and distal latency
b. Sensory NCS: normal 3. RNS
a. Botulinum has low safety factor b. Decrement responses at rest may be seen due to reduced
number of ACh quanta released because of impaired neuroexocytosis
c. Facilitation occurs after exercise because of mobilization of stored ACh due to accumulation of calcium
d. Facilitation is less impressive than in LEMS 4. Needle EMG
a. Short duration, small-amplitude, varying motor unit potentials
b. Possibly fibrillation potentials
F. Treatment 1. Mainstay: medical supportive care (including mechani-
cal ventilation if required) 2. Botulism immune globulin 3. Antitoxin if patient presents early (must be given as
early as possible, while toxin is still in bloodstream) 4. Surgical treatment of wound in wound botulism 5. Guanidine has been attempted (mixed results)
some time before the presentation. What is the most likely diagnosis? a. Subdural hematoma due to shaken baby syndrome b.Central core myopathy c. Infantile botulism d.Tick paralysis
3. A 35-year-old woman presents with a 10-year history of asymmetric ptosis and fatigable limb weakness. Physical examination also reveals digit and wrist extensor weakness. The tensilon test was reportedly positive. Nerve conduction studies showed a repetitive compound muscle action potential, which displayed a quick decrement with repetitive stimulation. This patient most likley has: a. Slow-channel syndrome b.Fast-channel syndrome c. Autoimmune myasthenia gravis d.Congenital end-plate acetylcholinesterase
deficiency
1. Which of the following is true about myasthenia gravis (MG) in pregnancy? a. Pregnant mothers with MG usually do not experi-
ence exacerbation of MG during pregnancy or the postpartum period
b.Use of prednisone is contraindicated in pregnancy c. Uterine contractions during delivery are affected by
the underlying disorder of neuromuscular transmission
d.Changes in maternal blood volume and renal clearance affect the pharmacokinetic properties of some treatments used for MG
2. A 3-month-old infant is brought to the emergency department by her grandmother because of poor feeding and increasing lethargy. Physical examination shows a listless, hypotonic “floppy” baby with poorly reactive pupils, a weak cry, and drooling. The grandmother states that she has not hit or shaken the baby but says she mixed honey with the infant formula
1. Answer: d. Changes in maternal blood volume and renal clearance affect the pharmacokinetic properties of first-line treatments, including pyridostigmine. Patients often experience an exacerbation of MG during pregnancy or the postpartum period. Prednisone and cholinesterase inhibitors are relatively safe in pregnancy. Uterine smooth muscle is not affected by MG.
