Myasthenia Gravis (MG) - Comprehensive Overview

Definition

• Bradley and Daroff's Neurology in Clinical Practice, p. 2769

Epidemiology

• US prevalence: approximately 20 per 100,000 (~60,000 patients total)
• Prevalence has been increasing over the past 50 years, largely due to better ascertainment, reduced mortality, and an aging population
• Sex and age patterns:
  • Women are affected ~3 times more often than men before age 40
  • Men have higher incidence after age 50
  • Roughly equal incidence during puberty
  • Mean age of onset: women 28-35 years; men 42-49 years
  • Today, the majority of US MG patients are over age 50
• Bradley and Daroff's Neurology, p. 2769

Pathophysiology

The Neuromuscular Junction

Autoantibody Mechanisms

1. Direct blockade - Antibodies block ACh binding sites, preventing ion channel opening
2. Cross-linking and internalization - Divalent antibodies cross-link AChRs, accelerating their internalization and degradation (antigenic modulation)
3. Complement-mediated lysis - Complement activation destroys the postjunctional membrane and reduces AChR number

Target Antigens

Role of the Thymus

• In early-onset MG: thymic hyperplasia with germinal centers suggests immune tolerance breakdown is initiated in the thymus; autoreactive B cells persist even after thymectomy
• In thymoma-associated MG: deficiency of the autoimmune regulatory protein AIRE leads to deficient regulatory T cells and increased autoreactivity; local expression of muscle antigens (including AChRs) within the thymoma activates autoreactive T cells
• Goldman Cecil Medicine, p. 4111

Clinical Presentation

Initial Symptoms (frequency)

• Ocular symptoms (ptosis, diplopia): initial symptom in ~66% of patients; virtually all develop both within 2 years
• Bulbar symptoms (dysphagia, dysarthria): initial symptom in ~16% of patients
• Limb weakness: initial symptom in ~10% of patients
• Respiratory failure as the initial symptom is rare

Ocular Manifestations

• Ptosis can be unilateral or bilateral, variable throughout the day
• Diplopia results from asymmetric weakness of extraocular muscles
• Gaze can be restricted in any direction; the pattern mimics various third-nerve palsies or gaze palsies but does not conform to a single nerve pattern
• The enhanced ptosis sign: when the ptotic lid is manually elevated, the contralateral lid droops more (Cogan's lid twitch is also classic)

Bulbar Manifestations

• Dysphagia, dysarthria, fatigable chewing
• Pharyngeal phase involvement in virtually all patients with dysphagia (100% in one study)
• Silent aspiration occurs in ≥35% of MG patients with dysphagia
• Bulbar symptoms are a major precipitant of myasthenic crisis in 56% of cases

Respiratory Involvement

• Diaphragmatic and intercostal weakness can develop
• Most feared complication: myasthenic crisis (see below)

Classification / Subtypes

1. Ocular MG (OMG)

• Weakness confined to extraocular muscles and eyelids
• 10%-15% of MG in Caucasians; up to 58% in Asian populations
• If ocular weakness persists exclusively beyond 2 years - 90% probability it will not generalize
• Often seronegative; SFEMG required for confirmation

2. Generalized MG (GMG)

3. Thymomatous MG

• ~10%-15% of MG patients have a thymoma
• Equal sex distribution; peak onset age 50
• Often have striated muscle antibodies (anti-titin, anti-ryanodine receptor)
• Removal of thymoma does not cure MG

4. MuSK-Antibody MG

• Found in up to 50% of AChR-negative GMG patients
• Predominantly affects females
• Clinically distinctive: prominent facial, bulbar, and neck weakness with muscle atrophy; less ocular involvement
• Geographic variation: higher incidence closer to the equator
• Responds poorly to acetylcholinesterase inhibitors; more responsive to rituximab

5. LRP4-Antibody MG

• Minority of seronegative patients
• Milder phenotype generally

6. Seronegative MG

• No detectable antibodies by standard assays
• May have low-affinity antibodies detectable by cell-based assays

Diagnostic Procedures

1. Antibody Testing

• AChR binding antibody assay (most widely used): sensitivity ~85% GMG, ~50% OMG; essentially confirms diagnosis when positive in compatible clinical setting
• AChR blocking antibody: lower sensitivity; <1% of patients test positive without also having binding antibodies
• AChR modulating antibody: ~10% of binding-antibody-negative patients are positive
• Anti-MuSK antibody: essential in AChR-negative patients with GMG
• Anti-LRP4 antibody: tested in seronegative patients after negative AChR and MuSK
• AChR-ab levels do not reliably predict disease severity or guide therapy

2. Electrodiagnostic Studies

• Repetitive nerve stimulation (RNS): Low-frequency (2-3 Hz) stimulation shows >10% decremental response in compound muscle action potential (CMAP) amplitude - a hallmark of postsynaptic NMJ disorder; sensitivity higher for proximal/bulbar muscles
• Single-fiber electromyography (SFEMG): Most sensitive test for NMJ dysfunction (>90% sensitivity); measures jitter (variability in interpotential interval between muscle fiber pairs); increased jitter and blocking are characteristic; essential for OMG and seronegative cases

3. Edrophonium (Tensilon) Test

• Edrophonium is a rapid, short-acting acetylcholinesterase inhibitor
• Positive in 60%-95% of OMG and 72%-95% of GMG patients
• Increasingly difficult to obtain; losing favor with widespread autoantibody availability

4. Imaging

• CT of the chest (with/without contrast) in all newly diagnosed MG: mandatory to evaluate for thymoma
• MRI of orbits/brain: to exclude orbital or brainstem lesions mimicking ocular MG

5. Pulmonary Function Tests

• Forced vital capacity (FVC) and negative inspiratory force (NIF) for monitoring respiratory compromise and guiding intubation decisions

Treatment

Pillar 1: Symptomatic Treatment - Acetylcholinesterase Inhibitors

• First-line symptomatic agent
• Initial dose: 30-60 mg TID; titrate to 60-120 mg TID to 5x/day based on symptoms
• Maximum dose typically not exceeding 480 mg/day
• Onset: 15-30 minutes
• Side effects: cholinergic - GI cramps, nausea, diarrhea, sweating, increased secretions, muscle fasciculations
• Does not alter the underlying disease course; does not induce remission
• Less effective in MuSK-MG

Pillar 2: Long-Term Immunosuppression

Pillar 3: Short-Term (Rapid-Onset) Immune Therapies

• Reduces circulating antibodies; improvement within days
• Typical course: 5-6 exchanges every other day (2-3 liters per exchange)
• Duration of benefit: typically begins wearing off at 4 weeks, may last up to 3 months
• Indications: myasthenic crisis, pre-thymectomy optimization, to prevent corticosteroid-induced exacerbations
• Side effects: hypocalcemia (citrate), hypotension, arrhythmias, access-related complications
• Effective in up to 95% of patients in myasthenic crisis

• Mechanism: modulates immune response (Fc receptor blockade, anti-idiotype antibodies, complement inhibition)
• Dose: 1-2 g/kg over 2-5 days
• Onset: days; duration similar to PLEX
• Side effects: headache, aseptic meningitis, renal failure, thromboembolism, hemolysis
• Mainstay of myasthenic crisis management alongside PLEX

Pillar 4: Thymectomy

• Indicated in all patients with thymoma regardless of disease severity
• Recommended in non-thymomatous generalized MG patients aged 18-50 years with anti-AChR antibodies (MGTX trial showed benefit even in patients not meeting thymectomy criteria previously)
• Role less clear in MuSK-MG, seronegative MG, ocular MG, and patients >50 years
• Effect on MG is delayed: benefit typically seen 6-12 months post-operatively
• Complete stable remission may occur years later

Newer Targeted Therapies

Myasthenic Crisis

• Affects approximately 20% of MG patients at some point
• Precipitants: infections (most common), recent surgery, aspiration/dysphagia, interruption of immunosuppressants, many drugs (aminoglycosides, fluoroquinolones, magnesium, beta-blockers, neuromuscular blocking agents, some anesthetics), and stress

1. Secure the airway - intubate if FVC <15 mL/kg or NIF <-20 cmH2O
2. BiPAP may temporize and prevent intubation in select patients
3. PLEX or IVIG are the mainstays of therapy
4. Hold or reduce pyridostigmine (may increase secretions and worsen respiratory function)
5. Treat precipitating cause
6. Escalate immunosuppression once stabilized

MG in Special Populations

Pregnancy

• Fertility is unaffected by MG
• Course during pregnancy is unpredictable; ~2/3 of patients report some worsening during pregnancy or puerperium
• Greatest risk: first trimester and puerperium
• Safe drugs: pyridostigmine, prednisone (low dose), PLEX (relatively safe), IVIG
• Avoid: azathioprine, mycophenolate (teratogenic), cyclosporine if possible; rituximab not recommended for non-life-threatening MG in pregnancy
• MG does not affect uterine smooth muscle (labor strength unaffected)
• Regional anesthesia preferred over general for delivery; neuromuscular blocking agents should be avoided
• Neonatal MG: Transient, affecting 10%-20% of neonates born to MG mothers due to transplacental IgG transfer; resolves within weeks

Elderly Patients

• Late-onset MG is now the most common subgroup in Western countries
• Higher risk of thymoma (especially men)
• Drug tolerability is reduced; corticosteroid side effects (osteoporosis, diabetes) are more common

Prognosis

• With modern treatment, most patients achieve minimal manifestation status or pharmacological remission
• Spontaneous remission occurs in ~10%-15% of patients (more common in early disease)
• Thymectomy can eventually lead to complete stable remission in a significant proportion
• Historically, MG had a mortality of ~30%; current mortality is <5% with optimal management
• Myasthenic crisis still carries a mortality of ~5%

Drugs That Worsen MG (to Avoid or Use Cautiously)

• Aminoglycoside antibiotics (gentamicin, tobramycin, neomycin)
• Fluoroquinolones
• Beta-blockers
• Calcium channel blockers (some)
• Magnesium salts
• Neuromuscular blocking agents (both depolarizing and non-depolarizing)
• Chloroquine/hydroxychloroquine
• Penicillamine
• Statins (rarely)
• Checkpoint inhibitors (can unmask or exacerbate MG)

Summary Table: MG at a Glance