Myasthenia Gravis — Symptoms, Causes & Treatment | MyMedicPlus

Myasthenia gravis (MG) is an acquired autoimmune disorder of the neuromuscular junction (NMJ) in which pathogenic autoantibodies impair neuromuscular transmission, causing the characteristic hallmark feature of fatigable skeletal muscle weakness — weakness that worsens with sustained or repetitive muscle activity (due to progressive depletion of available acetylcholine receptors) and improves with rest. Three antibody subtypes define MG: anti-acetylcholine receptor (AChR) antibodies — present in 85% of generalised MG; anti-muscle-specific kinase (MuSK) antibodies — in 6% of AChR-seronegative patients; and anti-low-density lipoprotein receptor-related protein 4 (LRP4) antibodies — a smaller proportion. Seronegative MG (no detectable antibodies with current assays) occurs in approximately 5–10%. Prevalence is 20–30 per 100,000, with increasing incidence due to improved recognition and an ageing population. A bimodal age distribution is characteristic: early-onset MG in women aged 20–40 (thymic hyperplasia associated); and late-onset MG in men over 60 (thymoma less common, thymic atrophy more typical). MG is a treatable condition — with appropriate immunotherapy, most patients achieve minimal manifestation status or complete remission, though relapses and medication dependency are common.

Autoantibodies against AChR disrupt neuromuscular transmission through three mechanisms: complement-mediated AChR destruction at the NMJ; accelerated AChR internalisation (receptor endocytosis); and direct blockade of the acetylcholine binding site — the net result is a severely reduced number of functional acetylcholine receptors at the postsynaptic membrane, impairing the depolarisation required for muscle contraction. Anti-MuSK antibodies (IgG4 class — non-complement fixing) disrupt clustering of AChRs and the rapsyn scaffold at the NMJ. Thymic abnormalities are central to MG pathogenesis: thymic hyperplasia (germinal centre formation — abnormal B cell activation) is present in 65% of early-onset AChR-positive MG; thymoma (encapsulated thymic epithelial neoplasm — may be benign or malignant) is found in 10–15% of generalised MG, predominantly AChR-antibody positive. The thymus is the site of autoreactive T cell priming and B cell activation in most cases — explaining the therapeutic benefit of thymectomy. Genetic susceptibility: HLA-DR3 and HLA-B8 associations in early-onset female AGA-positive MG; HLA-DR7 in late-onset male MG. Triggers for myasthenic crisis or exacerbation: infections (most common trigger — particularly respiratory infections); surgical procedures (anaesthetic agents, neuromuscular blocking drugs); medications that impair NMJ function (aminoglycoside and fluoroquinolone antibiotics, beta-blockers, lithium carbonate, magnesium salts, and iodinated contrast agents); abrupt immunosuppression reduction; hypokalaemia; thyroid dysfunction; and psychological stress.

Ptosis (unilateral or bilateral drooping of the upper eyelid) and diplopia (double vision from extra-ocular muscle weakness) are the most common presenting symptoms — ocular MG (affecting only the eyes) accounts for 50% of initial presentations. In 50–80% of ocular MG patients, the disease generalises to involve other muscle groups within 2 years. Fatigability is characteristic — symptoms worsen progressively with sustained or repetitive activity throughout the day, typically worst in the afternoon or evening, and improve with rest. Specific clinical patterns: ptosis varies and may be enhanced by upward gaze or sustained eye opening — the Cogan's lid twitch test (brief upward twitch of the ptotic lid) is characteristic; diplopia varies in direction (different muscles affected at different times). Bulbar involvement: facial muscle weakness (reduced facial expression — 'MG face'); dysphagia (difficulty swallowing, regurgitation, choking — risk of aspiration); dysarthria (nasal, slurred, or breathy speech — worsening through a meal); jaw fatigue (difficulty chewing — typically worsens through a meal; the 'ice pack test' — cooling the ptotic eyelid with ice for 2 minutes causes temporary improvement of ptosis by improving NMJ function at lower temperature). Limb weakness: proximal more than distal; neck weakness (difficulty holding head up); respiratory muscle involvement — can be subtle until precipitated into crisis. Myasthenic crisis: acute severe weakness of respiratory muscles causing respiratory failure — respiratory rate above 25/min, low peak flow, use of accessory muscles, paradoxical abdominal breathing, and inability to count to 20 in one breath indicate impending crisis.

Anti-AChR antibody testing (serum): positive in 85% of generalised MG and 50% of ocular MG — a positive result is diagnostic of MG (high specificity). Anti-MuSK antibodies: tested in AChR-seronegative patients — present in approximately 40% of AChR-negative generalised MG; characterised by prominent facial, bulbar, and neck weakness, with relative sparing of the eyes. Anti-LRP4 antibodies: a third serological marker tested in double-seronegative patients. Ice pack test: a simple, safe bedside test — application of an ice pack to a ptotic eyelid for 2 minutes causes temporary improvement in ptosis due to cold-induced improvement of NMJ function; sensitivity approximately 80% for ocular MG. Repetitive nerve stimulation (RNS): demonstrates a characteristic decremental compound muscle action potential (CMAP) of more than 10% on 3 Hz stimulation — sensitivity 50–70% in generalised MG. Single-fiber electromyography (SFEMG): the most sensitive test for MG (sensitivity 95% in generalised MG) — measures NMJ transmission jitter (variability in neuromuscular transmission latency); the gold standard electrophysiological test. CT chest (or MRI chest): essential in all newly diagnosed MG to identify thymoma — present in 10–15% of MG patients; requires thoracic surgery referral if present. Edrophonium (Tensilon) test: short-acting acetylcholinesterase inhibitor administered IV with objective assessment of ptosis or diplopia — historically diagnostic but now rarely performed due to cardiac risk (bradycardia, bronchospasm) and the availability of antibody tests.

Symptomatic treatment: pyridostigmine (Mestinon — acetylcholinesterase inhibitor — inhibits breakdown of acetylcholine at the NMJ, increasing acetylcholine availability; 30–120 mg every 4–6 hours; provides rapid symptomatic relief for ptosis, diplopia, swallowing, and limb weakness; does not modify disease — does not reduce antibody levels; side effects include diarrhoea, increased salivation, and abdominal cramps — manage with loperamide or propantheline). Immunosuppression (disease-modifying): oral prednisolone — first-line immunosuppressant; started at low doses and titrated up slowly to avoid initial paradoxical worsening (steroid-induced exacerbation risk in first 2–3 weeks on high-dose steroids — typically initiated as inpatient in those with bulbar involvement); maintenance typically 10–30 mg/day or alternate days. Azathioprine (2.5 mg/kg/day) as steroid-sparing agent — effective but slow onset (3–6 months); mycophenolate mofetil (1–1.5 g twice daily) as alternative; ciclosporin or tacrolimus for refractory cases. Thymectomy: extended transsternal thymectomy is recommended for all AChR-antibody positive generalised MG patients aged 18–65, even without thymoma (MGTX trial demonstrated significantly better clinical outcomes and reduced prednisone requirements at 3 years); mandatory for all thymoma regardless of MG severity. Acute exacerbations and pre-crisis treatment: intravenous immunoglobulin (IVIG 2 g/kg over 5 days — effective, safe, fast onset over days to weeks); plasmapheresis/plasma exchange (rapid removal of circulating pathogenic antibodies — most rapid effect, particularly useful pre-operatively or in crisis). Novel therapies: efgartigimod (Vyvgart — FcRn receptor blocker that reduces IgG antibody levels including pathogenic AChR antibodies — ADAPT trial; IV infusions every 2 weeks; approved FDA 2021 and MHRA 2022); rozanolixizumab (subcutaneous FcRn inhibitor); ravulizumab and eculizumab (C5 complement inhibitors — approved for AChR-positive generalised MG; prevents complement-mediated AChR destruction).

Myasthenic crisis is the most dangerous acute complication — respiratory muscle failure requiring intubation and mechanical ventilation occurs in approximately 15–20% of MG patients at some point in their disease course. Common precipitants include respiratory infections (most frequent), surgical procedures, aspiration pneumonia, abrupt immunosuppression withdrawal, and NMJ-impairing medications. ICU mortality has decreased substantially with improved respiratory monitoring, but crisis remains a serious event with a prolonged recovery phase. Cholinergic crisis (from excessive pyridostigmine dosing) mimics myasthenic crisis with weakness but additionally causes cholinergic features (SLUDGE: Salivation, Lacrimation, Urination, Defaecation, GI upset, Emesis) and miosis — differentiated from myasthenic crisis by these muscarinic signs. Thymoma-associated MG requires oncological management — thymoma can be locally invasive (WHO classification B2/B3 or thymic carcinoma) and requires resection, adjuvant radiotherapy, or chemotherapy; these patients also have elevated risk of paraneoplastic syndromes (Lambert-Eaton syndrome, pure red cell aplasia, myocarditis). Long-term corticosteroid use causes osteoporosis (bisphosphonate prophylaxis required), weight gain, metabolic syndrome, cataracts, and adrenal suppression. Dysphagia in MG carries aspiration risk — aspiration pneumonia is a major cause of morbidity and mortality. Psychological complications — anxiety, depression, and fear of crisis — are common and require active mental health support.

Avoid medications known to exacerbate MG or precipitate crisis — this is critical for all patients to know: aminoglycoside antibiotics (gentamicin, tobramycin — impair acetylcholine release presynaptically); fluoroquinolone antibiotics (ciprofloxacin, levofloxacin — block NMJ transmission); beta-blockers (propranolol, atenolol — reduce acetylcholine at NMJ); lithium carbonate; magnesium sulfate and magnesium-containing antacids and laxatives; telithromycin (ketek); and depolarising and non-depolarising neuromuscular blocking agents (suxamethonium, rocuronium — always inform anaesthetists). Treat infections promptly with appropriate antibiotics (selecting non-NMJ-impairing antibiotics — amoxicillin, cefalexin are safe) to prevent infection-triggered crisis — infections are the leading precipitant of myasthenic crisis. Carry a Myasthenia Gravis Association (MGFA) medical alert card listing medications to avoid; wear a medical alert bracelet. Educate all surgeons, anaesthetists, and dentists about MG before any procedure — pre-surgical specialist review is essential; anaesthesia without a neurologist's input is unsafe in MG. Do not stop pyridostigmine or immunosuppressants without medical advice. Regular neurological follow-up every 3–6 months for medication dose adjustment and monitoring of treatment response using validated scores (Quantitative Myasthenia Gravis score — QMG; MG-ADL scale). Annual LFTs and FBC for azathioprine monitoring; DEXA scan for bone density if on long-term steroids.

Seek emergency care for myasthenic crisis: severe, rapidly progressive weakness of breathing muscles (dyspnoea, inability to take deep breaths, paradoxical breathing), difficulty swallowing, and bulbar weakness — these indicate impending respiratory failure requiring intensive care admission and ventilatory support. If a patient with known MG develops these features, call emergency services immediately. Also seek urgent care for cholinergic crisis (excessive anticholinesterase — increased secretions, bradycardia, miosis, diarrhoea with worsening weakness — requires dose reduction). See a neurologist promptly for: new onset ptosis (drooping eyelid), diplopia (double vision), or unexplained muscle weakness that worsens with exertion and improves with rest — these are hallmark features of MG. Early diagnosis allows effective treatment and prevents crisis.