Myasthenia Gravis: Consultant-Level Review

1. Definition and Epidemiology

• US prevalence ~20/100,000 (~60,000 patients); increasing over the past 50 years due to better ascertainment, older populations, and reduced mortality
• Bimodal distribution: early onset peak in 2nd-3rd decades (female predominance, ~3:1 F:M below age 40); late onset peak in 6th-8th decades (male predominance)
• The majority of US MG patients are now over age 50, with men now outnumbering women overall

2. Pathophysiology

2a. AChR-Antibody MG (85% of generalized MG)

2b. MuSK-Antibody MG (~10% of generalized MG; up to 50% of seronegative GMG)

• More commonly affects bulbar, facial, and neck muscles - respiratory crisis is more frequent and severe
• Patients may worsen with cholinesterase inhibitors (ChEIs) - unlike AChR-MG
• Responds well to plasma exchange and rituximab
• Thymic pathology is less common

2c. LRP4-Antibody MG (minority of double-seronegative patients)

2d. Seronegative MG

3. Thymic Pathology

• Thymic hyperplasia (germinal centre formation): 60-70% of cases - predominantly in younger, AChR-antibody positive women
• Thymoma (neoplasm of thymic epithelium): 10-15% of cases - nearly all thymomatous MG patients have elevated AChR-abs; "modulating" antibodies predominate
• Thymoma is a paraneoplastic cause of MG; initial evaluation requires CT thorax with contrast

4. Clinical Presentation

Ocular (earliest and most common features)

• Ptosis and diplopia are the initial symptom in ~two-thirds of patients
• Nearly all develop both within 2 years of onset
• Ptosis worsens with sustained upgaze (fatigable - see image below); typically worst in the evening
• Ice bag test: improvement in ptosis ≥2 mm after 2 min of ice application has pooled sensitivity 0.94, specificity 0.97

Fatigable ptosis and ophthalmoparesis in MG - note asymmetric brow furrowing as a compensatory manoeuvre (Bradley & Daroff's Neurology)

Bulbar

• Dysarthria (nasal, slurred voice worsening over conversation), dysphagia, and difficulty chewing are initial symptoms in ~1 in 6 patients
• "Dropped head" syndrome from neck extensor weakness

Limb/Generalised

• Proximal limb weakness (difficulty combing hair, rising from chair)
• Weakness least in morning, worsens through the day and with exercise

Respiratory

• Rarely the presenting symptom but may develop in bulbar-prominent MG
• Forced vital capacity (FVC) and negative inspiratory force (NIF) are the key bedside monitors

Two clinical forms:

1. Ocular MG (OMG): weakness confined to ocular muscles; ~50% of OMG patients will generalise within 2 years; seropositivity is ~50%
2. Generalised MG (GMG): ocular plus bulbar/limb/respiratory involvement

5. Diagnosis

Serological Testing (first-line)

• False positives occur in: autoimmune liver disease, SLE, inflammatory neuropathies, ALS, penicillamine-treated RA, thymoma without MG
• AChR-ab level does not reliably correlate with disease severity and should not be used to monitor clinical response alone
• Repeat testing is appropriate if initial testing within 6-12 months of symptom onset was negative

Electrodiagnostic Studies

• Decrement in compound muscle action potential (CMAP) amplitude >10-15% at 2-3 Hz stimulation
• Sensitivity ~50-75% for GMG; lower for OMG
• Proximal muscles (trapezius, facial) have higher yield

• Most sensitive test for NMJ dysfunction
• Increased jitter (variability in inter-potential interval) and blocking
• Sensitivity >95% for GMG if proximal muscles tested
• Not specific for MG (abnormal in any NMJ disorder and some myopathies)

Ice Bag Test

• Bedside test for ptosis: improvement ≥2 mm after 2-min ice application = positive
• Sensitivity 0.94, specificity 0.97 - excellent for ocular MG at the bedside
• Now preferred over edrophonium due to better safety profile and availability

Edrophonium (Tensilon) Test

• Short-acting ChEI; positive in 60-95% of OMG and 72-95% GMG
• Largely fallen out of favour due to: widespread antibody testing, drug availability issues, and risk of bradycardia/bronchospasm; atropine must be available

Imaging

• CT thorax with contrast: mandatory in all newly diagnosed MG to screen for thymoma/mediastinal mass

Diagnostic Criteria Summary

1. Typical clinical pattern (fatigable weakness of characteristic distribution)
2. Plus: elevated AChR or MuSK antibodies OR unequivocal response to ChEIs OR abnormal RNS/SFEMG

6. Classification

7. Treatment

7a. Symptomatic: Cholinesterase Inhibitors

• First-line symptomatic treatment
• Inhibits acetylcholinesterase → increases ACh at synapse → improved NMT
• Starting dose: 30-60 mg every 4-6 hours (up to 120 mg per dose in severe cases)
• Maximum total daily dose generally 600 mg/day
• Side effects: muscarinic effects (diarrhoea, cramps, increased secretions, bradycardia); excess doses can paradoxically worsen weakness (cholinergic crisis - now rare)
• Caution: MuSK-MG patients may worsen with pyridostigmine

7b. Immunosuppression: Long-term Disease Modification

Corticosteroids

• Most rapid-onset immunosuppressant (weeks)
• Prednisolone 1-1.5 mg/kg/day (alternate-day dosing reduces side effects)
• Important pitfall: up to 50% of patients experience transient early worsening in the first 2-3 weeks of steroid initiation - start inpatient or with slow dose escalation in moderate-severe disease
• Long-term steroid-sparing agents are almost always needed

Azathioprine (AZA)

• First-line steroid-sparing agent; RCT evidence of efficacy
• Standard dose: 2-3 mg/kg/day
• Onset of benefit: 6-18 months - the key clinical limitation
• Check thiopurine methyltransferase (TPMT) status before initiating
• Monitor: full blood count, LFTs
• Side effects: myelosuppression, hepatotoxicity, increased lymphoma risk (long-term)

Mycophenolate Mofetil (MMF)

• Widely used despite lack of definitive RCT evidence (two RCTs failed to show benefit vs prednisolone alone)
• Dose: 1000-1500 mg twice daily
• Better tolerated than AZA
• Contraindicated in pregnancy (teratogenic - category D); two reliable contraceptive methods required; stop ≥4 months before planned conception
• Side effects: GI (diarrhoea, nausea), rare PML

Tacrolimus

• Calcineurin inhibitor; RCT evidence in MG; approved for MG in Japan
• Useful as steroid-sparing agent in AZA/MMF-intolerant patients or for rapid response
• Monitor: renal function, blood glucose (inhibits insulin), potassium, drug levels
• Drug interactions including grapefruit

Cyclosporine

• RCT evidence; reserved for refractory cases due to nephrotoxicity, hypertension, drug interactions

Cyclophosphamide

• For severe, refractory GMG after failure of standard therapy
• Pulsed IV (500 mg/m²) or high-dose (50 mg/kg × 4 days) regimens
• Significant toxicity: myelosuppression, haemorrhagic cystitis, infertility, malignancy

7c. Short-term Immunomodulation

Plasma Exchange (PLEX / Plasmapheresis)

• Removes circulating autoantibodies rapidly
• Effective in up to 95% of patients in acute myasthenic crisis
• Typically 5 exchanges over 1-2 weeks
• Onset of benefit: days
• Indications: myasthenic crisis, pre-operative preparation, bridge to IS therapy, or chronic treatment in refractory patients
• Limitations: IV access, cardiovascular stress, coagulopathy, need for anticoagulation

Intravenous Immunoglobulin (IVIg)

• Comparable efficacy to PLEX in acute exacerbations; practical alternative
• Dose: 1-2 g/kg over 2-5 days
• Onset: days to weeks
• Mainstay of ED crisis management alongside PLEX
• Side effects: headache, aseptic meningitis, thrombosis, haemolysis; contraindicated in IgA deficiency

7d. Targeted Biologics (Newer Therapies)

Rituximab (anti-CD20)

• Depletes B cells; especially effective in MuSK-MG (often dramatic response)
• Also used in refractory AChR-MG
• Cochrane review 2025 [PMID: 40607605]: systematic review of evidence
• Avoid in pregnancy (crosses placenta; haematological abnormalities in neonates)

Eculizumab (anti-C5 complement inhibitor)

• FDA/EMA approved for refractory generalised AChR-antibody positive MG
• Blocks terminal complement activation → prevents NMJ destruction
• Requires meningococcal vaccination ≥2 weeks before initiating
• Maintenance every 2 weeks IV; expensive

Ravulizumab

• Long-acting anti-C5; every-8-week dosing; FDA approved

FcRn Inhibitors (efgartigimod, rozanolixizumab, nipocalimab)

• Block the neonatal Fc receptor → increased IgG catabolism → rapid reduction in all IgG antibodies including AChR-abs
• Efgartigimod (Vyvgart): FDA approved 2021 for generalised AChR-positive MG
• Meta-analysis 2025 [PMID: 40288289]: confirmed efficacy and safety; rapid onset (1-2 weeks)
• Network meta-analysis 2025 [PMID: 40346603]: FcRn inhibitors and complement inhibitors showed superior efficacy vs standard immunosuppression in refractory GMG

7e. Thymectomy

• Mandatory for thymoma (regardless of MG severity)
• Recommended for non-thymomatous AChR-positive GMG in patients aged 18-65 years - the MGTX RCT (2016) demonstrated improved outcomes (less immunosuppression, better QMG scores) at 3 years after transsternal thymectomy vs medical therapy alone
• Less clear benefit in: MuSK-MG, OMG, elderly, seronegative MG
• Benefit is delayed (months to years post-surgery)
• Video-assisted thoracoscopic (VATS) or robotic approaches are standard

8. Myasthenic Crisis

Definition

Precipitants (Box - drugs that worsen MG)

Management

1. Airway first: Respiratory failure is from muscle weakness, not hypoxaemia - supplemental O₂ alone is insufficient
   • Monitor with capnometry (detects CO₂ retention early, before oximetry desaturation)
   • BiPAP if airway can be protected; endotracheal intubation if not
   • Indicators for intubation: FVC <15-20 mL/kg, NIF weaker than -20 to -25 cmH₂O
2. PLEX or IVIg: mainstays of acute crisis management (comparable efficacy)
3. Hold or reduce pyridostigmine during crisis (increased secretions worsen respiratory mechanics and risk aspiration)
4. Identify and treat precipitant (infection, medication, aspiration)
5. Immunosuppression: bridge to or intensify long-term IS

Cholinergic Crisis vs Myasthenic Crisis

9. Special Populations

Pregnancy

• Fertility unaffected; OCP does not worsen MG
• ~2/3 of patients report some worsening at some point during pregnancy or puerperium
• Greatest risk: first trimester and puerperium
• Safe drugs: pyridostigmine, prednisolone, azathioprine (with caution)
• Avoid: mycophenolate (teratogenic - category D), cyclophosphamide, rituximab
• Neonatal MG: transient in neonates from placental transfer of maternal antibodies; resolves over weeks
• Uterine smooth muscle is not affected (normal labour)
• Magnesium sulphate for pre-eclampsia is contraindicated (blocks NMJ)

Ocular MG

• 50% generalise within 2 years
• Pyridostigmine first-line; early immunotherapy with low-dose steroids may prevent generalisation
• Patients without generalisation by 2 years are unlikely to do so

Elderly

• Increasing demographic; often present late/atypically
• Higher rates of thymoma
• Greater vulnerability to steroid and immunosuppressant side effects
• Drug interactions more likely (renal/hepatic function)

Lambert-Eaton Myasthenic Syndrome (LEMS) - key differential

10. Outcome and Prognosis

• Most patients have normal life expectancy with modern treatment
• ~10% remain treatment-refractory
• Minimal manifestation status (MMS) or pharmacological remission is achievable in the majority
• Spontaneous remission occurs in ~10-20% (higher in prepubertal juvenile MG)
• Thymectomy in non-thymomatous GMG approximately doubles the rate of MMS at 3 years

Recent Evidence Updates (2024-2026)

• FcRn inhibitors (efgartigimod, rozanolixizumab, nipocalimab) have an established role in refractory GMG with rapid onset of action - network meta-analysis confirmed superiority over standard IST [PMID: 40346603]
• Rituximab Cochrane review (2025) confirms evidence for use, particularly in MuSK-MG [PMID: 40607605]
• FcRn inhibitor meta-analysis (2025) confirms class efficacy and safety [PMID: 40288289]