Myasthenia Gravis and Other Diseases of the Neuromuscular Junction¶

Chapter 459 | Part 13: Neurologic Disorders · Part 13 – Neurologic Disorders · Chapter 459

Key Clinical Points¶

Myasthenia gravis (MG) is an autoimmune neuromuscular junction (NMJ) disorder characterized by muscle weakness and fatigability due to a decrease in available acetylcholine receptors (AChRs).
Anti-AChR antibodies are present in ~85% of generalized MG and ~50% of ocular MG; a positive result is virtually diagnostic.
Anti-MuSK antibodies are associated with bulbar, neck, and ventilatory weakness and do not respond to complement inhibition (IgG4 subtype).
The Ice-Pack Test is a highly sensitive bedside test: application of ice over a ptotic eye for 2 min often results in improvement (lid rise ≥ 2 mm).
Repetitive nerve stimulation (RNS) shows a decrement of >10% at 3 Hz in MG; single-fiber electromyography (SFEMG) is confirmatory but not specific.
Thymoma occurs in 10–15% of MG patients; chest imaging (CT or MRI) is mandatory at diagnosis to evaluate for thymoma or thymic hyperplasia.
Pyridostigmine is the first-line anticholinesterase medication (30–60 mg three to four times daily); maximum useful dose rarely exceeds 480 mg daily.
Thymectomy in AChR-positive generalized MG improves strength, reduces steroid requirements, and decreases exacerbations.
Lambert-Eaton myasthenic syndrome (LEMS) is a presynaptic disorder with anti-P/Q-type calcium channel antibodies, characterized by high-frequency increments (20–50 Hz).
Congenital myasthenic syndromes (CMS) are genetic disorders of the NMJ; treatment varies by subtype (e.g., some worsen with AChE inhibitors).

DEFINITION & OVERVIEW¶

• Definition (Harrison's 22e): Myasthenia gravis (MG) is a neuromuscular junction (NMJ) disorder characterized by weakness and fatigability of skeletal muscles. The underlying defect is a decrease in the number of available acetylcholine receptors (AChRs) at NMJs due to an antibody-mediated autoimmune attack. • Pathophysiology: ◦ At the NMJ, acetylcholine (ACh) is synthesized in the motor nerve terminal and stored in vesicles (quanta). ◦ Action potential triggers release of ACh from 150 to 200 vesicles. ◦ ACh combines with AChRs (composed of five subunits: 2α, 1β, 1δ, 1γ, or ε) at the postsynaptic membrane. ◦ Normal transmission is terminated by hydrolysis by acetylcholinesterase (AChE) and diffusion. ◦ Defect in MG: Reduced number of available AChRs leads to smaller end-plate potentials that may fail to trigger muscle action potentials. ◦ Fatigue Mechanism: Presynaptic rundown combined with reduced receptor efficiency results in fewer fibers activated by successive impulses, causing myasthenic fatigue. ◦ AChR Antibody Mechanisms: (1) Accelerated turnover of AChRs via cross-linking and endocytosis; (2) Damage to postsynaptic membrane through complement activation; (3) Blockade of the active site of the AChR. ◦ MuSK/LRP4 Pathway: Agrin released from presynaptic terminal binds LRP4, activating MuSK. This recruits proteins like DOK7 and rapsyn to cluster AChRs. ◦ Anti-MuSK Antibodies: IgG4 subtype; do not activate complement; no response to complement inhibition. ◦ LRP4 Antibodies: IgG1 subclass; cause complement-mediated destruction. • Congenital Myasthenic Syndromes (CMS): ◦ Non-autoimmune, heterogeneous group caused by mutations in >30 genes. ◦ Includes defects in presynaptic terminals, AChR subunits, AChE, or clustering proteins (rapsyn, COLQ, DOK7, agrin, GFPT).

EPIDEMIOLOGY¶

• Incidence: 6.3 to 29 per million. • Prevalence: 100% to 361 per million. • Demographics: ◦ Affects all ages; peak incidence in women (20s-30s) and men (50s-60s). ◦ Ratio of women to men: ≈ 3:2. • CMS Prevalence: ≈ 3.8 per 100,000.

ETIOLOGY & PATHOPHYSIOLOGY¶

• Autoimmune Mechanisms: ◦ Anti-AChR Antibodies: (Present in ≈ 85% generalized; ≈ 50% ocular) → Mechanism: Accelerated turnover, complement activation, and active site blockade. ◦ Anti-MuSK Antibodies: (Present in ≈ 40% of AChR-negative generalized MG) → Associated with bulbar, neck, and ventilatory weakness; IgG4 subtype (no complement activation). ◦ LRP4 Antibodies: (IgG1 subclass) → cause complement-mediated destruction. • Thymic Involvement: ◦ Thymic abnormalities in ≈ 75% of AChR-positive patients. ◦ Thymoma: Present in 10–15% of MG patients; mandatory chest imaging (CT/MRI) at diagnosis. ◦ Note: Enlarged thymus in patients >40 years is highly suspicious for thymoma. • Associated Conditions: ◦ Hyperthyroidism (3–8%) → may aggravate weakness. ◦ Other autoimmune: SLE, Rheumatoid Arthritis, Neuromyelitis Optica, MS, Morvan's syndrome, rippling muscle disease, GMD/M, CIDP. ◦ Infection Screening: Mandatory search for chronic/latent infections (e.g., TB, Hepatitis) before starting steroids. • Congenital Myasthenic Syndromes (CMS): ◦ Not autoimmune; mutations in >30 genes. ◦ Most common: \epsilon subunit of AChR (≈ 50%); others include rapsyn, COLQ, DOK7, agrin, and GFPT (≈ 40%).

CLINICAL FEATURES¶

• General Characteristics: ◦ Weakness and fatigability → worse with use/late in day, better with rest. ◦ Course: Variable; exacerbations/remissions common in first 1–3 years. • Distribution of Weakness: ◦ Ocular: Ptosis and diplopia (common initial symptoms). If restricted to ocular muscles for 3 years, termed 'ocular MG'. ◦ Facial: 'Snarling' appearance. ◦ Bulbar: → Weakness in chewing (noted after prolonged effort/hard foods). → Speech: Nasal timbre or 'mushy' quality. → Swallowing: Dysphagia, nasal regurgitation, aspiration. ◦ Neck: Weakness in extensors → head drop. ◦ Limb: Often proximal and asymmetric; occasionally distal (foot/wrist drop). ◦ MuSK-specific: Bulbar, neck, and ventilatory weakness are more prominent. • Physical Exam Findings: ◦ Deep tendon reflexes: Typically preserved. ◦ Sensory symptoms: Absent. • Myasthenic Crisis: → Defined by ventilatory weakness requiring intubation or noninvasive ventilation. → All other worsening is termed 'exacerbation'. • Congenital Myasthenic Syndromes (CMS) Features: → Share many features with MG; some have additional features like afterdischarges on nerve stimulation.

DIFFERENTIAL DIAGNOSIS¶

• Lambert-Eaton Myasthenic Syndrome (LEMS): → Presynaptic disorder; anti-P/Q-type calcium channel antibodies. → Clinical: Proximal lower limb weakness, depressed/absent reflexes, autonomic symptoms (dry mouth, orthostasis). → Electrophysiology: Initial low-amplitude CMAP → decrement at 2–3 Hz; increment at 20–50 Hz or after exercise. • Botulism: → Blocked ACh release; clinical includes bulbar weakness and dilated pupils. • Drug-Induced / ICI-Related: → Immune Checkpoint Inhibitors (ICIs) can cause MG, myositis, or myocarditis. → Other drugs: Penicillamine, Aminoglycosides, Quinolones, Macrolides, Procainamide, and high-dose Magnesium may exacerbate weakness. • Other Conditions: → Hyperthyroidism (Graves' disease). → Intracranial mass lesions (e.g., sphenoid ridge meningioma). → Mitochondrial disorders (Progressive external ophthalmoplegia).

DIAGNOSTIC APPROACH¶

Clinical Assessment:
Identify hallmark features: Ptosis, diplopia, fatigable weakness in proximal muscles/neck.
Rule out other causes (e.g., hyperthyroidism, intracranial lesions via CT/MRI).
Bedside Testing:
Ice-Pack Test: Apply ice to ptotic eye for 2 min → lid rise of ≥ 2 mm = positive.
Electrodiagnostic Testing:
Repetitive Nerve Stimulation (RNS): Measure at 3 Hz; decrement of >10\% in amplitude is highly probable for MG.
Single-fiber EMG (SFEMG): Confirmatory but not specific; shows blocking and jitter.
Laboratory Testing:
Anti-AChR antibodies: ≈ 85% positive in generalized MG; ≈ 50% in ocular MG. (Positive = definitive diagnosis).
Anti-MuSK antibodies: Check if AChR-negative and presenting with bulbar/neck weakness.
LRP4 antibodies: Check if both AChR and MuSK are negative.
Edrophonium chloride (Enlon): 2 mg + 8 mg IV; highly probable diagnosis if unequivocally positive.
Other tests: Thyroid function, Pulmonary Function Tests (PFTs), and imaging for thymoma.

MANAGEMENT & TREATMENT¶

Initial Pharmacotherapy:
Anticholinesterase: Pyridostigmine is first-line.
Dose: 30–60 mg three to four times daily.
Max useful dose: ≤ 480 mg/day.
Surgical Intervention:
Thymectomy: Indicated for patients with AChR antibodies and thymoma or generalized MG with anti-AChR antibody.
Benefit: Improves strength, reduces steroid requirements, decreases exacerbations.
Acute Management & Crisis:
Crisis: Requires intensive care (IV steroids, antibiotics, fluids).
Rapid Treatment: Plasmapheresis or intravenous Ig for severe/life-threatening symptoms or if initial therapy is insufficient.
Immunomodulation:
Complement Inhibitors:
Eculizumab: Loading: 900 mg IV weekly imes 4; Maintenance: 1200 mg IV on week 5 then q2 weeks.
Ravulizumab: Weight-based (40–60 kg: 3000 mg; 60–100 kg: 3300 mg; ≥100 kg: 3600 mg) every 8 weeks.
Zilucoplan: 0.3 mg/kg SC daily.
FcRn Inhibitors: Used in patients with AChR or MuSK Ab + gMG.
Specialized Treatment for CMS:
Slow channel syndrome: Fluoxetine, quinidine; avoid AChE inhibitors.
AChE deficiency/DOK7/Rapsyn/Agrin: Albuterol, ephedrine, 3,4-diaminopyridine (3,4-DAP).
Monitoring & Precautions:
Drug Avoidance: Avoid aminoglycosides, quinolones, macrolides, beta-blockers (Propranolol, atenolol, metoprolol), and botulinum toxin.
Pre-treatment Screening: Screen for infections (TB, Hepatitis), hypertension, diabetes, renal disease, and glaucoma before starting long-term immunosuppression.

PROGNOSIS & COMPLICATIONS¶

• Exacerbation vs. Crisis: → Exacerbation: Any worsening of symptoms. → Crisis: Respiratory failure requiring intubation or noninvasive ventilation. • Complications of Treatment: → Steroid-related issues (infection, diabetes, etc.). → Risk of myocarditis in patients treated with ICIs.

SPECIAL POPULATIONS¶

• Congenital Myasthenic Syndromes (CMS): - Diagnosis: Suspected if symptoms begin in infancy/childhood; absence of AChR/MuSK antibodies; presence of afterdischarges on nerve stimulation. - Management: Tailored to specific mutation (e.g., Albuterol for certain mutations, avoid AChE inhibitors in slow channel syndrome).

KEY PEARLS & HIGH-YIELD POINTS¶

• Ice-Pack Test: High sensitivity; lid rise ≥ 2 mm is a positive finding. • MuSK vs. AChR: MuSK antibodies are IgG4 (no complement) and favor bulbar/neck involvement. • Thymoma: Always check chest CT/MRI in patients with MG. • LEMS Distinction: Look for high-frequency increment, absent reflexes, and autonomic symptoms; often associated with malignancy. • Drug Safety: Avoid aminoglycosides, quinolones, macrolides, and beta-blockers (Propranolol, atenolol, metoprolor) in MG patients.

FLOWCHARTS¶

Management of Myasthenia Gravis¶

Initial Presentation:
Ocular only → MRI of brain (if positive, reassess) → Anticholinesterase (pyridostigmine).
Generalized → Anticholinesterase (pyridostigmine) → Evaluate for thymectomy (indications: thymoma or generalized MG with anti-AChR antibody).
Crisis → Intensive care (IV steroids, antibiotics, fluids) → [Merge with general management pathway].
Decision Point: FVC Assessment:
If Good risk (good FVC) → Proceed to Thymectomy.
If Poor risk (low FVC) → Proceed to Plasmapheresis or intravenous Ig.
Final Step:
Evaluate clinical status → if indicated, go to immunosuppression → See text for specific treatment types.

TABLES & FIGURES¶

• Table 459-1 (Diagnosis of MG): Summarizes history (ptosis, diplopia, fatigue), physical exam (muscle strength, ptosis measurement), and labs (AChR ≈ 85% pos, RNS decrement >10\%, Ice-pack test). • Table 459-2 (CMS Subtypes): Lists specific mutations (e.g., CHRNA1, DOK7, MuSK) and their unique features; e.g., Slow channel syndrome worsens with AChE inhibitors while others improve. • Table 459-3 (Associated Disorders): Lists conditions to screen for: Thymoma/hyperplasia, thyroid disease, infections (TB), and comorbidities like diabetes or renal disease. • Table 459-4 (Complement & FcRn Inhibitors): Compares Eculizumab, Ravulizumab, Zilucoplan (complement inhibitors) and FcRn Inhibitors; notes specific dosing for different weight brackets. • Table 459-5 (Drugs to Avoid): Lists high-risk drugs: Aminoglycosides, Quinolones, Macrolides, Nondepolarizing muscle relaxants, Beta-blockers (Propranolol, atenolol, metoprolol), and Botulinum toxin.

Reference Tables¶

TABLE 459-1 Diagnosis of Myasthenia Gravis (MG) History¶

Harrison's 22e, p.3627

History
Diplopia, ptosis, dysarthria, dysphagia, dyspnea
Weakness in characteristic distribution: proximal limbs, neck extensors,
generalized
Fluctuation and fatigue: worse with repeated activity, improved by rest
Effects of previous treatments
Physical examination
Evaluation for ptosis at rest and following 1 min of exercise, extraocular
muscles and subjective diplopia, orbicularis oculi and oris strength, jaw
opening and closure
Assessment of muscle strength in neck and extremities
Weakness following repeated shoulder abduction
Vital capacity measurement
Absence of other neurologic signs
Laboratory testing
Anti-AChR radioimmunoassay: ~85% positive in generalized MG; 50% in ocular
MG; definite diagnosis if positive; negative result does not exclude MG; ~40%
of AChR antibody–negative patients with generalized MG have anti-MuSK
antibodies and ~2% have LRP4 antibodies
Repetitive nerve stimulation: decrement of >10% at 3 Hz: highly probable
Single-fiber electromyography: blocking and jitter, with normal fiber density;
confirmatory, but not specific
Edrophonium chloride (Enlon) 2 mg + 8 mg IV; highly probable diagnosis if
unequivocally positive
Ice-pack test looking for improvement in ptosis is very sensitive
For ocular or cranial MG: exclude intracranial lesions by CT or MRI

TABLE 459-2 Congenital Myasthenic Syndromes¶

Harrison's 22e, p.3629

CMS SUBTYPE	GENE	CLINICAL FEATURES	ELECTROPHYSIOLOGIC FEATURES	RESPONSE TO ACHE INHIBITORS	TREATMENT
Presynaptic Disorders
CMS with paucity of ACh release	CHAT; CHT	AR; early onset, respiratory failure at birth, episodic apnea, improvement with age	Decremental response to RNS	Improve	AChE inhibitors; 3,4-DAP
Synaptic Disorders
COLQ	AR; early onset; variable severity; axial weakness with scoliosis; apnea; +/– EOM involvement, slow or absent pupillary responses	After discharges on nerve stimulation and decrement on RNS	Worsen
Postsynaptic Disorders Involving AChR Deficiency or Kinetics
Primary AChR deficiency	AChR subunit genes	AR; early onset; variable severity; fatigue; typical MG features	Decremental response to RNS	Improve	AChE inhibitors; 3,4-DAP
AChR kinetic disorder: slow channel syndrome	AChR subunit genes	AD; onset childhood to early adult; weak forearm extensors and neck; respiratory weakness; variable severity	After discharges on nerve stimulation and decrement on RNS	Worsen	Fluoxetine and quinidine; avoid AChE inhibitors
AChR kinetic disorder: fast channel syndrome	AChR subunit genes	AR; early onset; mild to severe; ptosis, EOM involvement; weakness and fatigue	Decremental response to RNS	Improve	AChE inhibitors; caution with 3,4-DAP
Postsynaptic Disorders Involving Abnormal Clustering/Function of AChR
DOK 7	AR; limb girdle weakness with ptosis but no EOM involvement	Decremental response to RNS	Variable
Rapsyn	AR; early onset with hypotonia, respiratory failure, and arthrogryposis at birth to early adult onset resembling MG	Decremental response to RNS	Variable
Agrin	AR; limb girdle or distal weakness, apnea	Decremental response to RNS	Variable
MuSK	AR; congenital or childhood onset of ptosis, EOM and progressive limb girdle weakness	Decremental response to RNS	Variable
LRP4	AR; congenital onset with hypotonia; ventilatory failure, mild ptosis, and EOM weakness	Decremental response to RNS	Worsen
Other Postsynaptic Disorders
Limb-girdle CMS with tubular aggregates	GFPT1; DPAGT1; ALG2; ALG14; DPAGT1	AR; limb-girdle weakness usually without ptosis or EOM weakness; onset in infancy or early adult	Decremental response to RNS	Variable	Albuterol; ephedrine; variable response to AChE inhibitors and 3,4- DAP; albuterol
Congenital muscular dystrophy with myasthenia	Plectin	AR; infantile or childhood onset of generalized weakness including ptosis and EOM; epidermolysis bullosa simplex; elevated CK	Decremental response to RNS	Variable	No response to AChE and 3,4-DAP

TABLE 459-3 Disorders Associated with Myasthenia Gravis and Recommended Laboratory Tests Associated disorders¶

Harrison's 22e, p.3630

Associated disorders
Disorders of the thymus: thymoma, hyperplasia
Other autoimmune neurologic disorders: chronic inflammatory demyelinating
polyneuropathy, neuromyelitis optica
Other autoimmune disorders: Hashimoto’s thyroiditis, Graves’ disease,
rheumatoid arthritis, systemic lupus erythematosus, skin disorders, family
history of autoimmune disorder
Disorders or circumstances that may exacerbate myasthenia gravis:
hyperthyroidism or hypothyroidism, occult infection, medical treatment for
other conditions (see Table 459-5)
Disorders that may interfere with therapy: tuberculosis, diabetes, peptic ulcer,
gastrointestinal bleeding, renal disease, hypertension, asthma, osteoporosis,
obesity
Recommended laboratory tests or procedures
CT or MRI of chest
Tests for antinuclear antibodies, rheumatoid factor
Thyroid function tests
Testing for tuberculosis
Fasting blood glucose, hemoglobin A
1c
Pulmonary function tests
Bone densitometry

TABLE 459-4 Comparison of New Complement Inhibitors and FcRn Inhibitors for Generalized Myasthenia DRUG/MECHANISM…¶

Harrison's 22e, p.3632

DRUG/MECHANISM	TRIAL(S)	FDA APPROVED DOSING	CLINICAL TRIAL POPULATION	NOTES
Approved Complement Inhibitors
Eculizumab (humanized monoclonal Ab anti-C5, inhibits terminal complement/MAC activation)	Phase 2 REGAIN : 26 weeks REGAIN open-label extension: 22.7 months (median), up to 3 years	Loading: 900 mg IV weekly × 4 Maintenance: 1200 mg IV on week 5 then q2 weeks	AChR ab + gMG (class II–IV) Refractory (at least 2 NSISTs or at least 1 NSIST and PLEX/IVIg) MGADL score ≥6	Did not reach statistical significance for primary MGADL endpoint Reached significance for multiple secondary endpoints Requires meningococcal vaccination
Ravulizumab (humanized monoclonal Ab anti-C5, inhibits terminal complement/MAC activation)	Phase 2 CHAMPION MG: 26 weeks CHAMPION MG open-label extension	Actual body weight–based dosing Loading: 40 to <60 kg: 2400 mg IV; 60 to <100 kg: 2700 mg IV; ≥100 kg: 3000 mg IV Maintenance (14 days after loading and then q8 weeks): 40 to <60 kg: 3000 mg IV; 60 to <100 kg: 3300 mg IV; ≥100 kg: 3600 mg IV	Adults with AChR ab + gMG (class II–IV) MGADL score ≥6	Requires meningococcal vaccination
Zilucoplan (synthetic macrocyclic peptide targeting C5/C5b, inhibits terminal complement/MAC activation)	Phase 2 RAISE: 12 weeks RAISE-XT open-label extension	Phase 3 dosing 0.3 mg/kg SC daily Label dosing (prefilled syringes): Actual body weight–based daily SC injections <56 kg: 16.6 mg daily; 56 kg to <77 kg: 23 mg; ≥77 kg: 32.4 mg	Adults with AChR ab + gMG (class II–IV) MGADL score ≥6 QMG ≥12	Requires meningococcal vaccination Self-administered SC
Approved FcRn Inhibitors
Phase 2 ADAPT: 26 weeks ADAPT open-label extension: up to 3 years ADAPT-SC noninferiority study, open-label parallel-group: 12 weeks with open-label extension	Weight-based IV: 10 mg/kg IV (up to 1200 mg) weekly × 4 = 1 cycle Fixed dose SC: 1,008 mg SC weekly × 4 = 1 cycle	Adults with gMG regardless of Ab status, MGADL at least 5 with 50% nonocular
Phase 2 MycarinG: 18 weeks Open-label extension: completed	Phase 3 included 7 and 10 mg/ kg given as SC infusion weekly for 6 weeks followed by 8 weeks off. Patients averaged 4 treatment cycles per year (range 1–7) Clinical dosing: <50 kg: 420 mg; 50 to <100 kg: 560 mg; ≥100 kg: 840 mg given as a weekly health care provider–administered SC infusion for 6 weeks (1 cycle)	Adults with AChR or MuSK Ab + gMG (11% of participants) MGADL score ≥3 QMG score ≥11

TABLE 459-5 Drugs with Interactions in Myasthenia Gravis (MG) Drugs That May Exacerbate Weakness in Patients with MG…¶

Harrison's 22e, p.3633

Drugs That May Exacerbate Weakness in Patients with MG
Antibiotics
Aminoglycosides: e.g., streptomycin, tobramycin, kanamycin
Quinolones: e.g., ciprofloxacin, levofloxacin, ofloxacin, gatifloxacin
Macrolides: e.g., erythromycin, azithromycin
Nondepolarizing muscle relaxants for surgery
d-Tubocurarine (curare), pancuronium, vecuronium, atracurium
Beta-blocking agents
Propranolol, atenolol, metoprolol
Local anesthetics and related agents
Procaine, Xylocaine in large amounts
Procainamide (for arrhythmias)
Botulinum toxin
Botox exacerbates weakness
Quinine derivatives
Quinine, quinidine, chloroquine, mefloquine (Lariam)
Magnesium
Decreases acetylcholine release
Penicillamine
May cause MG
Checkpoint inhibitors
May cause MG and other autoimmune neuromuscular disorders (e.g., myositis,
inflammatory neuropathy)
Drugs with Important Interactions in MG
Cyclosporine and tacrolimus
Broad range of drug interactions, which may raise or lower levels
Azathioprine
Avoid allopurinol—combination may result in myelosuppression