Myasthenia Gravis — Causes, Symptoms & Treatment Guide — Symptoms, Causes & Treatment | MyMedicPlus

Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction characterised by fatigable weakness of skeletal muscles — weakness that worsens with sustained or repeated activity and improves with rest. The term derives from Greek and Latin meaning grave muscle weakness, though modern treatment has transformed prognosis dramatically. MG has a prevalence of approximately 20 per 100,000, affecting an estimated 200,000 people globally. It displays a bimodal age distribution: a first peak in young women (20–30 years — most commonly antibody-positive) and a second peak in older men (60–70 years — thymoma association more common). Pathologically, autoantibodies (most commonly against nicotinic acetylcholine receptors — AChR — in 85% of cases) disrupt neuromuscular transmission by blocking acetylcholine binding, cross-linking receptors causing endocytosis, and activating complement-mediated destruction of the postsynaptic membrane. Myasthenic crisis — respiratory failure from diaphragmatic and intercostal muscle weakness — is the most feared complication and requires ICU admission and ventilation.

MG is an autoimmune disease — the immune system erroneously produces autoantibodies against neuromuscular junction proteins. In 85% of MG patients, antibodies target the nicotinic acetylcholine receptor (AChR) — particularly the alpha-subunit. In 6–8% of patients (seronegative for AChR antibodies), antibodies target muscle-specific kinase (MuSK) — a receptor tyrosine kinase critical for AChR clustering at the neuromuscular junction. MuSK-MG has distinct features: more bulbar and respiratory involvement, less response to pyridostigmine, good response to rituximab. 1–2% have antibodies against low-density lipoprotein receptor-related protein 4 (LRP4). The thymus is implicated in MG pathogenesis: thymic hyperplasia (65% of AChR-positive MG — particularly younger patients), thymoma (15% of MG — a thymic tumour that triggers immune dysregulation). Risk factors: female sex in young patients, HLA-DR3 (associated with MuSK-MG and early-onset MG), first-degree family history (3% familial), D-penicillamine or checkpoint inhibitor immunotherapy (drug-induced MG). Drugs that can worsen MG: aminoglycosides, fluoroquinolones, macrolides, beta-blockers, magnesium, chloroquine, neuromuscular blocking agents.

MG hallmark: fatigable weakness — symptoms worsen throughout the day and with sustained activity, improving after rest. Ocular manifestations (initial presentation in 85% of MG cases): ptosis (drooping of one or both upper eyelids — typically asymmetric) and diplopia (double vision — from extraocular muscle weakness — fluctuates with gaze direction). Purely ocular MG accounts for 20% of cases — in 50–60%, this progresses to generalised MG within 2 years. Bulbar weakness: dysarthria (slurred, nasal speech — worse after talking for extended periods), dysphagia (difficulty swallowing — liquid regurgitation through the nose), jaw fatigue (difficulty chewing — jaw drops open with sustained chewing). Limb and trunk weakness: proximal upper limb weakness (arm fatigue with sustained abduction), lower limb weakness, neck flexor weakness (head drop — inability to hold head upright). Respiratory involvement: diaphragm and intercostal muscle weakness causing dyspnoea, initially on exertion then at rest — risk of myasthenic crisis. Myasthenic crisis: acute respiratory failure requiring mechanical ventilation, often triggered by infection, surgery, medications, or rapid tapering of immunosuppression — ICU emergency.

Serological testing: anti-acetylcholine receptor (AChR) antibodies — positive in 85% of generalised MG and 50% of ocular MG; highly specific (above 99%). Anti-MuSK antibodies — positive in 40% of AChR-seronegative MG. Anti-LRP4 antibodies — positive in some double-seronegative patients. Ice pack test: applying ice to the closed eyelid for 2 minutes in ptosis — cooling reverses acetylcholinesterase inhibition, transiently improving ptosis in MG (sensitivity 80%). Edrophonium (Tensilon) test: short-acting acetylcholinesterase inhibitor — transient dramatic improvement in ptosis or diplopia within 30 seconds (test now rarely used due to cardiac risks, largely replaced by serology and EMG). Repetitive nerve stimulation (RNS): stimulating a nerve at 3 Hz and recording compound muscle action potential (CMAP) — decremental response above 10% is positive in 75% of generalised MG. Single-fibre EMG (SFEMG): gold standard electrophysiological test — increased jitter (variability in neuromuscular transmission) in 95%+ of MG; can diagnose seropositive MG. CT chest: mandatory in all MG — thymic hyperplasia or thymoma detection. Pulmonary function tests (PFTs): forced vital capacity (FVC) monitored in all MG patients for respiratory involvement — FVC below 1 L indicates impending respiratory failure requiring intubation.

Symptomatic therapy: pyridostigmine (Mestinon) 30–60 mg every 3–4 hours — acetylcholinesterase inhibitor; increases acetylcholine availability at the neuromuscular junction; improves strength within 30–60 minutes of each dose. Starting dose 30 mg TDS, titrating to maximum 60 mg 5–6 times daily. Muscarinic side effects: nausea, diarrhoea, cramps, increased secretions — manageable with dose adjustment. Less effective in MuSK-MG. Immunosuppressive therapy: prednisolone starting at low dose (10–15 mg/day) with gradual increase to 1 mg/kg/day (maximum 60–80 mg/day) — initial paradoxical worsening in first 2–4 weeks possible; improvement over weeks to months. Azathioprine 2–3 mg/kg/day (maximum 150–200 mg/day) — steroid-sparing agent; takes 12–18 months for full benefit; monitor FBC and liver function; check TPMT enzyme status before starting. Mycophenolate mofetil (alternative steroid-sparer); tacrolimus (particularly effective in MuSK-MG). Thymectomy: robotic or video-assisted thoracoscopic thymectomy (VATS) — mandatory for thymoma; significantly improves long-term outcomes in non-thymoma AChR-positive generalised MG aged 18–65 (MGTX trial — greater remission rates vs. prednisone alone). Plasma exchange (plasmapheresis — PLEX): removes circulating AChR antibodies; rapid but short-lived effect (3–4 weeks); used for myasthenic crisis and pre-surgical optimisation. Intravenous immunoglobulin (IVIg — 2 g/kg over 2–5 days): equivalent efficacy to PLEX for crisis; slower onset but easier to administer. Novel therapies: efgartigimod alfa (anti-FcRn — reduces IgG antibody levels including AChR antibodies — ADAPT trial — approved FDA 2021); eculizumab (anti-C5 complement inhibitor — approved for refractory AChR-positive MG — REGAIN trial); rozanolixizumab (anti-FcRn, SC injection). Rituximab: effective in MuSK-MG and refractory AChR-positive MG.

Myasthenia gravis causes potentially life-threatening and functionally impairing complications. Myasthenic crisis: the most dangerous complication — acute severe worsening of bulbar and respiratory muscle weakness causing respiratory failure requiring ICU admission and mechanical ventilation; triggers include infection, surgery, certain medications (aminoglycosides, fluoroquinolones, beta-blockers), and rapid reduction of immunosuppression; occurs in approximately 15–20% of MG patients at some point. Aspiration pneumonia: bulbar weakness impairs swallowing, causing aspiration of food and saliva into the airways — a major cause of MG-related morbidity and mortality. Thymoma: found in 10–15% of MG patients at diagnosis — thymoma requires resection and may require radiotherapy or chemotherapy; thymoma-associated MG tends to be more severe and refractory to treatment; malignant thymoma occurs in 30–40% of thymoma cases. Treatment complications: long-term corticosteroid use causes Cushingoid features, osteoporosis, avascular necrosis of the femoral head, cataracts, hypertension, and diabetes; azathioprine causes bone marrow suppression and is a rare lymphoma risk; IVIg carries thrombosis and haemolytic anaemia risks. Generalisation: 50% of patients with purely ocular MG develop generalised disease within 2 years of onset. Neonatal MG: 10–20% of babies born to mothers with MG have transient neonatal MG (passive antibody transfer) — requires neonatal unit monitoring and pyridostigmine until maternal antibodies clear, usually within 2–8 weeks. Pregnancy can precipitate exacerbations, particularly in the postpartum period.

There is no known way to prevent MG onset as it is an autoimmune condition with complex genetic and environmental triggers. Prevention of exacerbations and crises is achievable: avoid medications known to worsen MG (aminoglycosides — gentamicin, tobramycin; fluoroquinolones; macrolides; beta-blockers; magnesium; high-dose chloroquine; checkpoint inhibitors — always inform all prescribers of MG diagnosis before new medications). Vaccinations: annual influenza vaccination recommended (infection is a major exacerbation trigger); avoid live vaccines during heavy immunosuppression. Stress management — psychological stress and physical overexertion trigger weakness. Adequate sleep — fatigue worsens MG. Heat avoidance — hot weather, hot baths, and fever worsen neuromuscular transmission. Inform employers of the condition as symptoms fluctuate and accommodations may be needed. Carry a MG medical alert card listing medications to avoid. Regular monitoring: FVC measurements to detect respiratory decline early; annual thymoma surveillance CT if thymoma history.

Call emergency services immediately and go to hospital for: increasing difficulty breathing or shortness of breath at rest (myasthenic crisis — may need mechanical ventilation within hours), severe difficulty swallowing with risk of aspiration, inability to hold the head upright (neck muscle weakness), or acute worsening of all MG symptoms in the context of a new infection or recent medication change. Seek urgent neurologist or emergency review within 24 hours for: rapid deterioration in swallowing or speech, FVC dropping below 2 litres if self-monitoring at home, or significant bulbar symptoms (choking on liquids). See your neurologist within 1–2 weeks for: new or worsening ptosis, new diplopia, or gradual increase in weakness. If you have ocular MG, attend regular follow-up — 50% of ocular MG progresses to generalised disease within 2 years, often while symptoms still appear mild.