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Myasthenia Gravis (MG) - Comprehensive Exam Notes

Note: A "Sullivan" textbook was not found in the library. These notes are compiled from the most authoritative neurology and pathology references available - Bradley and Daroff's Neurology (the primary neurology reference for MG) plus Robbins Pathology.

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1. DEFINITION

• Fatigable skeletal muscle weakness that worsens with activity and improves with rest
• Caused by autoantibodies directed against postsynaptic NMJ proteins, most commonly the acetylcholine receptor (AChR)

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2. EPIDEMIOLOGY

• Bimodal distribution: Early onset (2nd-3rd decade, female predominance) and late onset (6th-8th decade, male predominance)

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3. PATHOPHYSIOLOGY

The Neuromuscular Junction in MG

Antibody Types and Mechanisms

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4. THYMIC ABNORMALITIES

• Thymic hyperplasia (reactive B-cell follicles): 60-70% of cases - perturb tolerance to self-antigens → generate anti-AChR antibodies
• Thymoma (neoplasm of thymic epithelium): 10-15% of cases
  • 1/3 of thymoma patients develop MG
  • Nearly always associated with AChR antibodies (not MuSK or LRP4)
  • Often have additional antibodies against titin and ryanodine receptor
• Thymic carcinoma: rare association

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5. CLINICAL FEATURES

Cardinal Features

• Fatigable weakness - worsens with repetitive use, improves with rest
• Fluctuating - usually worst in the evening, least in the morning
• Tendon reflexes and sensation are NORMAL (key exam point)

Ocular Symptoms (initial in ~2/3 of patients)

• Ptosis (drooping eyelids) - often asymmetric, worsens with sustained gaze
• Diplopia (double vision) - from extraocular muscle weakness
• Progressive right lid ptosis during sustained forward gaze (fatigable)

Bulbar Symptoms

• Dysphagia (difficulty swallowing) - oral, pharyngeal, and esophageal phases affected; silent aspiration in >35%
• Dysarthria (nasal or slurred speech)
• Jaw weakness - worsens with prolonged chewing (tough/fibrous foods)
• Dysphagia is a major precipitant of myasthenic crisis (56% of cases)

Distribution of Initial Symptoms

Disease Forms

1. Ocular MG - confined to eyelids and extraocular muscles (10-15% of patients; up to 58% in Asian/pediatric populations)
2. Generalized MG (GMG) - involves facial, oropharyngeal, limb, and/or respiratory muscles

Disease Course (Historical, Pre-immunosuppression)

• 1/3 improved spontaneously
• 1/3 became worse
• 1/3 died of the disease

• Active stage: Fluctuating, then progressively more severe
• Inactive stage: Fluctuations still occur but attributable to identifiable triggers
• Burnt-out stage: Fixed weakness, muscle atrophy (rare today)

Factors That Worsen MG

• Emotional upset
• Systemic illness (especially viral respiratory infections)
• Thyroid dysfunction (hypo- or hyperthyroidism)
• Pregnancy and menstrual cycle
• Surgery, fever
• Drugs affecting NMT (see below)

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6. MuSK-ANTIBODY MG (Special Features)

• Predominantly female, childhood through middle age
• Prominent cranial and bulbar muscle weakness with atrophy (often marked tongue wasting)
• Neck, shoulder, and respiratory weakness with little/no ocular involvement in some
• Electrodiagnostic abnormalities may be restricted (examine different muscles)
• Often does NOT improve with cholinesterase inhibitors - some worsen; fasciculations common
• Responds well to plasmapheresis and corticosteroids
• Rituximab strongly supported by retrospective studies
• Thymic changes absent or minimal; role of thymectomy unclear

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7. DIAGNOSIS

Diagnostic Criteria

1. Serology (Antibody Testing)

2. Pharmacological Tests

• Edrophonium (Tensilon) test - IV short-acting ChEI; dramatic improvement in MG (no longer available at bedside in some settings)
• Neostigmine test - IM alternative

3. Electrodiagnostic Testing

• Repetitive nerve stimulation (RNS): Characteristic decremental response (decrease in amplitude of successive responses) - the hallmark finding
• Single-fiber EMG (SFEMG): Most sensitive; increased jitter (variability in firing of adjacent muscle fibers); may show blocking
• MuSK MG may have restricted EMG abnormalities - test different muscles

4. Imaging

• CT or MRI of the chest - to detect thymoma (present in 10% of MG patients)

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8. CLASSIFICATION (MGFA - Myasthenia Gravis Foundation of America)

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9. MYASTHENIC CRISIS

• Severe exacerbation requiring mechanical ventilation due to respiratory failure
• Precipitants: infections (especially respiratory), surgery, medications, dysphagia, pregnancy
• Emergency treatment: Intubation + mechanical ventilation + plasma exchange (PLEX) or IVIG

Cholinergic Crisis (vs. Myasthenic Crisis)

• From overdose of cholinesterase inhibitors
• Features: SLUDGE/DUMBELS (muscarinic excess) + weakness (nicotinic excess)
• Key: muscarinic side effects (diarrhea, bradycardia, miosis, hypersalivation, bronchospasm) point to cholinergic crisis

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10. TREATMENT

A. Symptomatic Treatment - Cholinesterase Inhibitors (ChEIs)

B. Short-Term (Rapid-Onset) Immune Therapies

• PLEX regimen: 5-6 exchanges every other day; 2-3 L plasma per exchange
• PLEX side effects: Paresthesias (citrate-induced hypocalcemia), hypotension, cardiac arrhythmias, nausea, edema

C. Long-Term Immunosuppression

D. Surgical Treatment - Thymectomy

• Indications: Thymoma (mandatory); generalized AChR-positive MG (beneficial)
• Timing: Effect is delayed; advise pregnancy planning ~1 year after surgery
• Role in MuSK MG: Unclear (thymic changes absent/minimal)
• Benefits are most evident in younger patients with thymic hyperplasia

E. Amifampridine (3,4-DAP)

• Potassium channel blocker (increases action potential duration at presynaptic membrane)
• Preliminary evidence for benefit in some MG patients, especially MuSK MG

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11. MEDICATIONS TO AVOID IN MG

• Aminoglycosides (gentamicin, neomycin, streptomycin)
• Fluoroquinolones (ciprofloxacin)
• Macrolides (azithromycin)
• Beta-blockers
• Calcium channel blockers
• Neuromuscular blocking agents (curare-type)
• Magnesium (in high doses)
• D-penicillamine (can actually induce MG)
• Chloroquine / hydroxychloroquine
• Lithium

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12. MG IN SPECIAL POPULATIONS

Pregnancy

• Fertility not affected by MG; oral contraceptives do not worsen symptoms
• ~2/3 of patients report some worsening during pregnancy/puerperium
• Highest risk: First trimester and puerperium
• MG does not affect uterine smooth muscle contractions, postpartum hemorrhage, or toxemia
• Safe drugs: Anticholinesterases (edrophonium, neostigmine), PLEX
• Drugs to avoid: Azathioprine, cyclosporine; mycophenolate (teratogenic); rituximab (crosses placenta)
• Neonatal MG: Transplacental transfer of AChR antibodies from affected mother → transient neonatal MG in ~10-15% of neonates; resolves within weeks

Pediatric Forms

1. Neonatal MG (transient) - from maternal antibody transfer
2. Congenital myasthenic syndromes - genetic, not autoimmune
3. Juvenile MG - similar to adult form; more common in females, early school age

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13. PROGNOSIS

• Significantly improved with modern treatment; most patients have a normal lifespan
• ~10% of cases are treatment refractory
• Some patients still die from respiratory failure
• MuSK MG patients often require more immunosuppression but long-term outcome is generally good

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14. COMPARISON: MG vs. LAMBERT-EATON SYNDROME

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15. KEY EXAM MNEMONICS & HIGH-YIELD POINTS

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