Myasthenia Gravis

• Autoantibody-mediated AChR destruction: In approximately 85% of generalized MG and 50% of purely ocular MG, IgG autoantibodies bind to the extracellular domain of the α-subunit of the nicotinic AChR. This binding triggers three pathogenic mechanisms: (1) complement-mediated lysis via activation of the classical complement cascade (C1q binding → membrane attack complex formation → postsynaptic membrane destruction), (2) antibody-dependent cellular cytotoxicity (ADCC) mediated by Fc-receptor bearing immune cells including macrophages and NK cells, and (3) functional blockade of acetylcholine binding and ion channel opening. The result is progressive loss of postsynaptic AChRs (up to 70-80% reduction compared to normal), widening of the synaptic cleft, and simplified postsynaptic folds, reducing the safety margin for neuromuscular transmission. Even small fluctuations in acetylcholine release become clinically significant when receptor density falls below critical threshold.

• Muscle-specific kinase (MuSK) antibodies and alternative pathology: In seronegative MG patients lacking AChR antibodies, approximately 40% possess anti-MuSK antibodies (found in only 1% of AChR-positive patients). MuSK, a receptor tyrosine kinase localized at the neuromuscular junction, is essential for clustering and stabilization of AChRs. Anti-MuSK antibodies disrupt MuSK signaling and impair AChR clustering, resulting in a distinct pathophysiology from classical AChR-MG: these patients typically present with purely seronegative disease, more ocular and facial weakness, less thymoma association, worse response to some immunosuppressants, and occasional exacerbation with acetylcholinesterase inhibitors. MuSK-antibody mediated disease may involve complement-independent mechanisms, explaining differential responsiveness to therapies.

• Thymic pathology and T cell mediated immunity: The thymus plays a central role in MG pathogenesis through multiple mechanisms. In 30-50% of MG patients, thymic hyperplasia with germinal center formation occurs, creating an ectopic immune compartment where autoreactive B cells and T cells are generated and activated. Thymic epithelial cells (myoid cells) express AChR and may serve as antigen-presenting targets. In 10-15% of patients, thymoma (usually WHO grade B or AB) develops, and 30-50% of thymoma patients develop MG. Thymomas promote MG through direct autoimmunization against AChR (thymoma cells express AChR), loss of immune tolerance, and generation of autoreactive T helper cells. Even in thymoma-negative patients, thymic T cells show abnormal responses to AChR epitopes with reduced regulatory T cell (Treg) function, allowing Th17-mediated B cell help and antibody production. The thymus-derived autoimmunity extends beyond simple AChR targeting to include antibodies against other neuromuscular junction proteins (LRP4, agrin).

• Quantum hypothesis and safety margin reduction: Normal neuromuscular transmission operates with significant safety margin—a single action potential triggers release of 200-300 quanta (packets) of acetylcholine, while only 1.5-2 quanta are necessary to achieve threshold depolarization. In MG, the combination of reduced AChR numbers (from complement-mediated lysis), impaired clustering, and altered postsynaptic geometry reduces this safety margin. With each successive muscle contraction, acetylcholine mobilization from the readily-releasable pool becomes depleted (a normal phenomenon), causing progressive decline in quantum release. In healthy individuals, this modest decline remains above threshold; in MG patients operating with reduced baseline safety margin, successive contractions fall below threshold, manifesting clinically as fatigability—the hallmark symptom that worsens with repeated muscle use and improves with rest.

• Seronegative MG pathophysiology: In 10-15% of patients with clinical MG but absent both AChR and MuSK antibodies, alternative mechanisms are postulated: (1) low-affinity AChR antibodies not detected by standard immunoassays, (2) conformational antibodies against native AChR structure, (3) antibodies to other neuromuscular junction proteins (LRP4, agrin, rapsyn, MUSK isoforms), or (4) T cell mediated immunity without significant humoral autoimmunity. These seronegative cases often present with milder, predominantly ocular disease and may represent a spectrum of related neuromuscular junction disorders rather than a single pathophysiological entity.

• Genetic predisposition and HLA associations: Strong familial clustering occurs in certain populations, particularly with rare congenital myasthenic syndromes caused by monogenic mutations in neuromuscular junction genes (CHRNE, CHAT, RAPSN, MUSK, AGRN, LRP4). Acquired autoimmune MG shows HLA associations including HLA-B8, HLA-DR3, and HLA-DR2, particularly in early-onset disease. Polymorphisms in immune regulatory genes (PTPN22, CTLA4) modify disease susceptibility. However, genetic factors alone are insufficient—discordance in identical twins indicates critical environmental triggers. The incomplete genetic penetrance and variable phenotype even among carriers of pathogenic mutations underscore the importance of acquired environmental factors.

• Thymoma and thymic hyperplasia: Thymoma represents the single most important associated condition, present in 10-15% of MG patients at diagnosis and developing in additional patients during disease course. Conversely, 30-50% of thymoma patients develop MG. Thymoma-associated MG typically presents with more aggressive, generalized disease requiring intensive immunosuppression. Thymic hyperplasia (follicular hyperplasia with germinal centers) occurs in 40-70% of non-thymomatous MG and may represent either a secondary response to aberrant immune activation or a primary pathogenic lesion. Both thymoma and hyperplasia warrant thymectomy consideration for potential disease modification.

• Other autoimmune and systemic conditions: MG frequently coexists with other autoimmune disorders, suggesting shared pathogenic mechanisms and common genetic/environmental risk factors. Associated conditions include systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), thyroiditis, Graves' disease (3-10% of MG patients), myositis, and pemphigus. Thyroid dysfunction appears in 5-10% of MG patients even without overt thyroiditis, potentially reflecting shared HLA-mediated autoimmunity. These associations necessitate screening for thyroid disease and other autoimmune conditions at baseline and during disease monitoring.

• Age and sex: Women develop MG more frequently than men, with female:male ratio of 1.5-2:1 overall. Early-onset MG (age <40 years) shows female predominance (2-3:1) and strong HLA-B8/DR3 associations with frequent thymoma and antibody positivity. Late-onset MG (age >50 years) shows male predominance and is associated with HLA-DR2, less frequent thymoma, and lower seropositive rates. These demographic patterns suggest distinct immunological and genetic backgrounds for early versus late-onset disease, with implications for prognosis and treatment response.

• Infection and environmental triggers: Viral infections, particularly respiratory tract infections and herpes simplex virus, may precipitate MG onset or exacerbation through molecular mimicry or bystander activation of autoreactive T cells. Bacterial infections (Campylobacter jejuni cross-reactivity, Helicobacter pylori) have been implicated in case reports. Medication triggers including β-blockers, quinolones, aminoglycosides, and interferon-α can worsen MG or unmask latent disease. Environmental exposures and lifestyle factors may contribute but remain incompletely characterized.

• Seronegative versus seropositive MG: The distinction between AChR-antibody positive, MuSK-antibody positive, and double-seronegative MG reflects different etiological pathways. MuSK-MG shows distinct features including younger age at onset, predominantly ocular/bulbar symptoms, female predominance, less thymoma association, and potential worsening with acetylcholinesterase inhibitors. Seronegative MG may encompass multiple etiologies including low-affinity antibodies, alternative antibody targets, and potentially non-antibody mediated dysfunction, warranting expanded diagnostic testing when suspicion remains high despite negative standard antibody panels.

• Ocular symptoms (initial presentation in 50%, ever present in 90%): Ptosis (drooping of one or both eyelids) and diplopia (binocular double vision) represent the most frequent initial manifestations. Ptosis results from weakness of the levator palpebrae superioris muscle, classically worsening toward evening and improving after sleep. Importantly, ice pack test (applying ice to the ptotic eyelid for 2 minutes) causes temporary mechanical improvement not due to temperature but rather reproducibility of the weakened state. Diplopia reflects extraocular muscle weakness, often with a vertical or diagonal pattern depending on which muscles are predominantly affected. Ocular symptoms show female predominance, older age at onset in purely ocular disease, and variable progression—approximately 80% of patients with initial ocular-only disease eventually develop generalized symptoms within 3 years, while 20% remain limited to ocular manifestations. Pure ocular MG is more common in men and older patients.

• Bulbar symptoms and oropharyngeal weakness: Weakness of muscles controlling speech and swallowing manifests as dysarthria (nasal speech quality when nasal muscles weaken, slurred speech with lip and tongue weakness), dysphagia (difficulty swallowing, risk of aspiration), and facial weakness (difficulty smiling, pursing lips). Patients report worsening speech as they continue talking, characteristic of fatigability. Nasal regurgitation of liquids indicates palatal weakness. Ptosis of the palate, weakness of masseter muscles (assessed by jaw closure resistance), and asymmetric smile may be noted on examination. Bulbar involvement carries significance as it may progress to respiratory compromise and increases risk of aspiration pneumonia.

• Limb weakness: Proximal limb weakness (shoulders, hips) predominates over distal weakness, distinguishing MG from many peripheral neuropathies and myopathies. Patients report difficulty with overhead activities (combing hair, reaching shelves), climbing stairs, or rising from chairs. Notably, fatigability is more apparent than fixed weakness—strength testing shows variable results depending on prior muscle use, with strength declining progressively through repeated contraction (characteristic of MG vs. pyramidal weakness pattern). Neck flexors and extensors may weaken, causing head drop. Respiratory muscles (diaphragm, intercostals) can be involved in severe disease.

• Respiratory symptoms and respiratory muscle weakness: In generalized MG affecting approximately 15-20% of patients overall, and up to 25-30% of those hospitalized, respiratory compromise ranges from subtle dyspnea on exertion to acute respiratory failure. Weakness of diaphragm and intercostal muscles reduces vital capacity, which may be normal at rest but falls markedly with activity. Patients may report dyspnea when lying flat (orthopnea) due to loss of accessory muscle contribution. Rapid progression of weakness, particularly bulbar weakness combined with proximal limb weakness, raises concern for myasthenic crisis—life-threatening acute respiratory failure requiring mechanical ventilation.

• Myasthenic crisis: Acute, severe exacerbation of MG resulting in respiratory failure requiring mechanical ventilation occurs in 15-20% of MG patients during disease course, with peak incidence in first years after diagnosis. Crisis may be precipitated by infection, medication changes, stress, pregnancy, or anesthesia. Initial presentation as MG may occasionally manifest as acute respiratory failure (ocular-onset progressive cases typically do not, but acute-onset generalized cases may). The distinction between myasthenic and cholinergic crisis (excess acetylcholinesterase inhibitor) has become less clinically relevant with modern management, as both require mechanical ventilation and cautious medication adjustment.

• Cholinergic crisis: Paradoxical worsening of weakness from excessive acetylcholinesterase inhibitor administration, accompanied by muscarinic effects (bradycardia, bronchospasm, salivation, lacrimation). Modern management using minimal pyridostigmine dosing and preferring immunosuppression reduces cholinergic crisis incidence compared to historical frequency.

• Physical examination findings beyond obvious weakness: Eaton-Lambert sign (brief improvement of strength with brief high-intensity muscle contraction), distinct from the poor sustained strength seen in MG, is not characteristic of MG despite frequent student confusion. However, decremental response on repetitive nerve stimulation (see Diagnosis section) manifests clinically as progressive weakness during repeated examination. Cogan's lid twitch sign (brief twitching of the eyelid lid when returning from downgaze to primary position) shows high specificity for ocular MG. Sensory examination is normal, distinguishing MG from sensory neuronopathies.

• Negative symptoms important for diagnosis: Notably absent are hyperreflexia, spasticity, sensory loss, atrophy (unless severe/chronic), fasciculations, and upper motor neuron signs. Preserved sensation and normal cognitive function help exclude central nervous system causes. These negative findings in a patient with acquired weakness pattern should prompt consideration of neuromuscular disorders including MG.

• Severity spectrum classification: The Osserman classification traditionally grades MG from Class I (ocular only) through Class IIa (mild generalized), IIb (moderate generalized), III (acute severe onset), to IV (late severe, progressive disease). More contemporary Quantitative Myasthenia Gravis Score (QMG) measures 13 items (eyelid ptosis, ocular motility, facial strength, mastication, swallowing, speech, respiratory, neck flexion, shoulder abduction, hip flexion, hand grip, foot dorsiflexion) to quantify severity and track treatment response.

• Ice pack test (ice water immersion test): Simple, bedside diagnostic test with sensitivity 60-95% in generalized MG, 80-90% in ocular MG. Procedure involves applying ice (or ice water-soaked gauze) to closed eyelid for 2 minutes, with positive test demonstrating objective improvement in ptosis (widening of palpebral fissure by ≥2mm or complete resolution of ptosis). The mechanism is mechanical—cold reduces ice-water-induced artifact, though some suggest brief inhibition of antibody-complement complex formation. Importantly, ice pack test does not demonstrate causation but rather provides high-specificity evidence of neuromuscular junction dysfunction. Negative test does not exclude MG, particularly in purely bulbar or generalized MG. Ice pack test is often the first diagnostic maneuver, particularly for ocular disease, providing rapid supportive evidence before serological and electrophysiological testing.

• Anti-acetylcholine receptor (AChR) antibodies: Radioimmunoassay or enzyme-linked immunosorbent assay (ELISA) detects IgG antibodies against the α-

Immediate stabilisation (myasthenic crisis)

• Airway and ventilatory monitoring: serial forced vital capacity and negative inspiratory force at the bedside; intubate pre-emptively for declining FVC/NIF, weak cough, or bulbar failure. Hypercapnia on ABG is a late finding — do not wait for it.
• Rapid immunotherapy: plasma exchange or IVIG. Per MGFA International Consensus Guidance, both are effective; PLEX generally works faster and is favoured in crisis and severe bulbar weakness, while IVIG is easier to deliver and preferred with unstable haemodynamics or poor venous access.
• Supportive measures: treat the precipitant (usually infection or an offending drug); pyridostigmine is often held in the intubated patient to reduce secretions and diagnostic ambiguity with cholinergic excess.

Chronic symptomatic therapy

• Acetylcholinesterase inhibitors (pyridostigmine): prolongs ACh dwell time in the cleft, raising the safety margin. Symptomatic only — it does not alter the autoimmune process. MuSK-antibody patients often respond poorly or worsen.

Immunotherapy (MGFA consensus framework)

• Corticosteroids (prednisone): first-line disease-modifying therapy. Start low and titrate up in outpatients, since high-dose initiation can cause transient steroid-induced worsening in the first one to two weeks; initiate in hospital when bulbar or respiratory muscles are involved.
• Steroid-sparing immunosuppressants: azathioprine, mycophenolate mofetil, tacrolimus, cyclosporine, or methotrexate; all have a delayed onset measured in months.
• Refractory disease: anti-CD20 therapy (rituximab), particularly effective in MuSK-MG; terminal complement C5 inhibitors (eculizumab, ravulizumab) for AChR-antibody-positive refractory generalised MG, which require meningococcal vaccination beforehand; neonatal Fc receptor blockers (efgartigimod) to accelerate IgG catabolism.

Surgical management

• Thymectomy: indicated in all patients with thymoma regardless of symptoms. In non-thymomatous AChR-positive generalised MG, the randomised MGTX trial supported thymectomy in younger adults, reducing steroid requirement and disease burden.

Avoid

• Neuromuscular-blocking drugs (aminoglycosides, fluoroquinolones, macrolides; telithromycin is contraindicated), IV magnesium, beta blockers, procainamide/quinidine, iodinated contrast in susceptible patients, and penicillamine or immune checkpoint inhibitors, which can induce MG. Patients are sensitive to non-depolarising agents and relatively resistant to succinylcholine.

Disease-related

• Myasthenic crisis (emergency): respiratory muscle and bulbar failure from loss of safety margin at the junction. Signalled by falling vital capacity, staccato speech, inability to count to 20 on one breath, paradoxical abdominal movement, and orthopnea. Hypercapnia appears late — act on bedside pulmonary mechanics, not the blood gas.
• Aspiration pneumonia (emergency when hypoxaemic): palatal and pharyngeal weakness with nasal regurgitation and wet voice; often the precipitant of crisis rather than its consequence.
• Thymoma-related disease: local mediastinal invasion, and the paraneoplastic associations of pure red cell aplasia and hypogammaglobulinaemia (Good syndrome) presenting as recurrent sinopulmonary infection.
• Transient neonatal myasthenia: transplacental maternal IgG causes a hypotonic, poorly feeding newborn with weak cry, resolving over weeks as maternal antibody clears; unrelated to maternal disease severity.

Treatment-related

• Cholinergic crisis: excess acetylcholinesterase inhibition causes depolarising blockade plus muscarinic overflow — miosis, salivation, lacrimation, bradycardia, cramps, diarrhoea. Weakness with small pupils and copious secretions rather than the dry, tachycardic patient of true myasthenic crisis. Rare with modern dosing.
• Steroid-induced early worsening (potential emergency in bulbar disease): paradoxical deterioration within the first days to two weeks of high-dose prednisone, the reason for inpatient initiation in severe disease. Long-term: hyperglycaemia, osteoporosis, cataracts, infection.
• Azathioprine: myelosuppression and hepatotoxicity, exaggerated in TPMT or NUDT15 deficiency — check before starting and monitor counts.
• Mycophenolate: teratogenic; requires contraception counselling.
• Rituximab: hepatitis B reactivation, hypogammaglobulinaemia, rare progressive multifocal leukoencephalopathy.
• Eculizumab/ravulizumab (emergency if febrile): terminal complement blockade removes membrane attack complex defence against encapsulated organisms — Neisseria meningitidis sepsis; vaccinate before therapy and treat fever urgently.
• IVIG: thrombosis, aseptic meningitis, renal injury; contraindicated in IgA deficiency with anti-IgA antibodies. Plasma exchange: citrate-induced hypocalcaemia, hypotension, catheter complications.

• Fatigability is the buzzword: ptosis and diplopia that are absent in the morning and worst in the evening, worsening with sustained upgaze and improving after rest or ice. Pupils are always spared — a blown pupil points to a posterior communicating artery aneurysm or CN III palsy, not MG.
• The single best next step after a positive antibody test is a CT of the chest to look for thymoma. Examiners test this reflex relentlessly; thymoma mandates thymectomy irrespective of symptom severity.
• The one association to know: MG with thymoma or thymic hyperplasia, and the wider autoimmune cluster (autoimmune thyroid disease in particular). Screen thyroid function at diagnosis.
• In suspected crisis, order bedside vital capacity and negative inspiratory force — not an ABG. A normal or low-normal PaCO2 provides false reassurance because hypercapnia is terminal. Then give plasma exchange or IVIG and treat the trigger.
• The classic distractor is Lambert–Eaton myasthenic syndrome: presynaptic anti-P/Q-type voltage-gated calcium channel antibodies, associated with small cell lung cancer, with autonomic features (dry mouth, impotence), depressed reflexes, and strength that improves with brief exercise — an incremental response at high-rate repetitive stimulation, opposite the decremental response of MG.
• MuSK-positive MG behaves differently: prominent bulbar/facial and neck weakness, little thymoma association, poor or paradoxical response to pyridostigmine, and notably good response to rituximab.
• Drug-precipitated crisis is a favourite stem: a myasthenic given a fluoroquinolone, an aminoglycoside, IV magnesium for pre-eclampsia, or a beta blocker who then decompensates. Penicillamine and immune checkpoint inhibitors can cause MG outright.
• Do not treat a steroid-induced early worsening as treatment failure — high-dose prednisone transiently worsens weakness before it helps, which is why severe bulbar patients start steroids in hospital.