Myasthenia Gravis

1. Clinical pattern and boundaries

The defining pattern is variable weakness within a day and from day to day, with fatigability on repeated or sustained use. Evening worsening is common but not obligatory. Ocular weakness causes asymmetric ptosis or variable diplopia; bulbar weakness causes a fading or nasal voice, fatigable chewing, dysphagia, nasal regurgitation and weak cough; limb weakness is usually proximal; neck flexor or extensor and respiratory muscles may be involved. Fixed weakness can develop in severe or longstanding disease, so a normal brief examination does not exclude MG.[2][3]

[1] [7] [8]

The MGFA clinical classification (Jaretzki 2000, the international standard) grades severity from symptoms at presentation without treatment modifications, and it is examined verbatim:[5]

MG is a motor disorder: sensation and pupils are preserved, and reflexes are usually normal. Reduced reflexes plus dry mouth or other autonomic symptoms favour Lambert–Eaton myasthenic syndrome (LEMS); fixed sensory loss, sphincter dysfunction, a sensory level, encephalopathy or an internuclear/long-tract pattern requires another diagnosis. Reflex preservation is a useful clue, not an absolute rule.[3][19]

2. Classification: overlapping axes

The figure separates dimensions that must not be collapsed into one exclusive taxonomy. “Ocular MG” means weakness restricted to ocular muscles at the time of assessment; it does not require two years of symptoms. “Generalised MG” means any non-ocular weakness. Age at onset and thymic pathology modify phenotype and management but are not MGFA classes.[2][4][20]

MGFA clinical classification

MGFA class records current clinical severity; it is not a treatment-response scale. Outcomes should be documented separately using MGFA post-intervention status—complete stable remission, pharmacologic remission, minimal manifestations—or change categories such as improved, unchanged, worse, exacerbation or death. Serial MG-ADL adds the patient's functional view; QMG is a clinician-administered examination measure. Neither replaces airway and bulbar assessment in an acute deterioration.[1][4]

3. Antibody phenotypes and mechanism

AChR antibodies are usually complement-fixing IgG1/IgG3 and reduce functional receptor density through receptor blockade, antigenic modulation and complement-mediated junctional injury. About 80–85% of generalised MG, but only about half of ocular MG, is AChR-antibody positive; these denominators must not be applied to all MG.[3][20]

• AChR MG: the commonest autoimmune subtype. Thymic hyperplasia is associated particularly with younger-onset AChR-positive disease; thymoma can occur at any adult age.[20]
• MuSK MG: IgG4 antibodies disrupt the agrin–LRP4–MuSK clustering pathway. Facial, bulbar, tongue, neck and respiratory weakness may be prominent; ocular involvement is common, but purely ocular MuSK MG is uncommon. Pyridostigmine may be poorly tolerated, and early rituximab is a specialist option when initial immunotherapy is unsatisfactory.[1][17]
• LRP4 MG: frequency varies widely with assay and cohort. Interpret a positive result only in a compatible syndrome and objective neuromuscular-junction context.[3][18]
• Seronegative MG: conventional AChR and MuSK assays are negative; specialist cell-based AChR, MuSK or LRP4 testing may identify additional cases. Before immunotherapy, demonstrate a compatible transmission defect and reconsider LEMS, botulism, congenital myasthenic syndrome (CMS), motor neuron, muscle, brainstem and orbital disease. A serum antibody titre does not reliably track current clinical severity.[2][3][19]

4. Bedside assessment and differential diagnosis

Examine strength before and after standardized sustained activity: prolonged upgaze for ptosis, repeated gaze for diplopia, counting for voice fade, repeated shoulder abduction or chair rise for limb fatigue, and repeated neck flexion where safe. The ice-pack test can support ocular MG when ptosis objectively improves after cooling, but protocol and accuracy vary; it neither excludes MG when negative nor replaces serology/electrophysiology. Do not ask a dysphagic patient to drink merely to demonstrate aspiration.[3]

[5]

Other mimics include mitochondrial or oculopharyngeal myopathy, inflammatory myopathy, cranial neuropathy and functional neurological disorder. Diagnose functional symptoms by positive features, not merely because MG tests are negative.[3][19]

5. Diagnostic sequence and limitations

1. Confirm the clinical phenotype and current safety. Document ocular, bulbar, limb, axial and respiratory involvement; review medicines and mimics. Urgent airway/ventilatory assessment takes priority over outpatient testing when bulbar or respiratory weakness is worsening.[2][3]
2. Serology. Test AChR antibodies first; if negative in a compatible generalised syndrome, test MuSK. Specialist LRP4 and cell-based assays are useful in selected double-seronegative cases. A negative panel does not exclude MG, and a low-specificity result without the phenotype does not establish it.[3]
3. Electrophysiology. Repetitive nerve stimulation (RNS) seeks a reproducible decrement—commonly more than 10% between the first and fourth/fifth compound muscle action potentials—using clinically affected muscles. Sensitivity is lower in ocular disease. Single-fibre EMG or concentric-needle jitter is highly sensitive but not specific; a normal study in a properly selected symptomatic muscle argues against a transmission disorder, whereas increased jitter also occurs in other nerve and muscle disease.[3]
4. Bedside ocular support. Use an ice-pack test only when ptosis can be measured before and after cooling. It is supportive, not a universal diagnostic standard.[3]
5. Image the mediastinum once. In newly confirmed autoimmune MG—including seronegative MG—perform chest CT (or MRI if CT is unsuitable) to exclude thymoma. Contrast use is individualized; it is a caution with monitoring, not a universal prohibition. Do not repeat thymic imaging routinely without an oncologic or clinical reason.[1][2]
6. Pattern-directed tests for mimics and coexisting disease. Thyroid testing is often appropriate; CK, brain/orbital imaging, malignancy evaluation, genetics or other tests depend on the phenotype. CSF is not a routine MG test.[2][3]

6. Stable disease: layered treatment

Pyridostigmine is first-line symptomatic treatment for most patients. A common adult starting regimen is 30–60 mg orally every 4–6 waking hours, then individualized to function, adverse effects and renal function; there is no single safe examination “maximum” for every patient. Diarrhoea, cramping, sweating, salivation, bronchial secretions, bradycardia and fasciculation indicate cholinergic adverse effects. MuSK MG may respond poorly or develop troublesome cholinergic effects at low doses.[1][2]

Corticosteroid is used when symptoms are functionally important or pyridostigmine is inadequate. Dose and escalation strategy depend on severity and setting. Initial worsening can occur, especially with bulbar or respiratory disease: start and escalate under specialist monitoring, and consider rescue therapy before or during steroid initiation when deterioration would threaten airway or ventilation. Once control is sustained, taper slowly; abrupt withdrawal can exacerbate MG.[1][2]

Steroid-sparing treatment includes azathioprine, mycophenolate mofetil, ciclosporin or tacrolimus according to phenotype, comorbidity, pregnancy potential, monitoring burden, access and local authorization. Effects take months. Check agent-specific baseline and follow-up blood counts, liver/renal function, infection risk, interactions and vaccination; do not apply one laboratory schedule to every drug. Methotrexate has limited evidence and is generally considered only when better-supported agents are unsuitable. Rituximab is off-label for MG in many jurisdictions; the 2020 consensus supports early consideration in MuSK-positive MG with an unsatisfactory response to initial immunotherapy, while benefit in refractory AChR-positive MG remains uncertain.[1][2]

7. Thymoma and non-thymomatous thymectomy

A suspected thymoma needs thoracic-surgery/oncology assessment. Resect a resectable thymoma for oncologic control, irrespective of MG severity; surgery may not itself normalize MG, so optimize bulbar and respiratory status and continue neurological treatment.[1][2]

MGTX randomized 126 patients with non-thymomatous, AChR-antibody-positive generalised MG, age 18–65 years, disease duration under 5 years and MGFA II–IV to extended transsternal thymectomy plus alternate-day prednisone or prednisone alone. Thymectomy improved time-weighted QMG and reduced prednisone exposure over three years; benefit persisted in the five-year extension. Do not extrapolate this randomized evidence to ocular-only, MuSK, LRP4, seronegative, thymomatous, older-than-65 or long-duration disease.[5][6]

Current consensus advises discussing thymectomy early in AChR-positive generalised MG age 18–50 years and strongly considering it when an adequate immunotherapy response is not achieved or adverse effects are unacceptable. The AAN advises counselling that minimally invasive approaches may be safer perioperatively but randomized evidence has not established the same long-term benefit as the MGTX transsternal procedure. Thymectomy is not recommended for MuSK MG without thymoma; selected AChR-positive ocular cases refractory to appropriate therapy require individualized specialist discussion rather than a routine rule.[1][7]

8. Current targeted biologics and jurisdiction

These are label- and antibody-specific, costly treatments selected by an MG specialist; trial eligibility and authorization differ from country to country. The following is a US-label snapshot checked 27 July 2026. Other jurisdictions must use their current regulator/product information.[1][2]

Reader-visible official labels: SOLIRIS, ULTOMIRIS, ZILBRYSQ, VYVGART, RYSTIGGO, IMAAVY and UPLIZNA. Pivotal trial populations support eculizumab, ravulizumab, zilucoplan, efgartigimod, rozanolixizumab, nipocalimab and inebilizumab, but labels—not trial shorthand—define current regional use.[10][11][12][13][14][15][16]

9. Exacerbation and myasthenic crisis

Myasthenic crisis is respiratory failure from MG that requires non-invasive or invasive ventilatory support. Infection is common, but aspiration, surgery, pregnancy/puerperium, medication change, steroid initiation/escalation, undertreatment and other physiological stressors can contribute. Cholinergic crisis is now rare; do not diagnose crisis from a simplistic wet/dry pupil table.[2][8]

Immediate bundle

1. Airway, breathing, monitoring: ICU/neurocritical-care review; frequent bulbar examination, cough and secretion assessment, respiratory rate/work, serial bedside respiratory measurements and blood gas when hypoventilation is suspected. Do not delay airway protection for a threshold.[2][8]
2. Ventilation: NIV is only for carefully selected, cooperative patients who can protect the airway and clear secretions, without severe bulbar failure or rapidly worsening gas exchange. Prepare controlled intubation if selection or response is poor. MG patients are sensitive to non-depolarising neuromuscular blockers; if one is essential, use a reduced, titrated dose with quantitative monitoring and an expert reversal/extubation plan. Succinylcholine response is unpredictable; MG is not a denervation disorder.[2][8]
3. Rapid immunomodulation: use IV immunoglobulin, total 2 g/kg divided over 2–5 days, or therapeutic plasma exchange, commonly 4–6 exchanges over about 1–2 weeks, individualized to renal/cardiac status, thrombosis risk, vascular access, haemodynamics, sepsis and local expertise. Both are accepted; the randomized comparison concerns moderate-to-severe worsening rather than a definitive crisis head-to-head trial. PLEX is often selected when a faster response is clinically important or in MuSK crisis, but access and haemodynamic complications matter. Do not combine routinely.[1][2][9]
4. Treat the trigger: culture and image as clinically indicated, give appropriate antimicrobials, correct electrolyte/endocrine disturbance, and review recent medicines without delaying treatment of infection. Thymoma imaging is part of the diagnostic pathway, not a routine first-hour repeat scan in known MG.[2][8]
5. Medication handling: when intubated or when secretions are marked, temporarily hold pyridostigmine and restart during objective improvement/weaning. Plan corticosteroid initiation or escalation with the early-worsening risk in mind; rescue therapy and monitoring may be needed first.[1][2]
6. Support and recovery: aspiration-safe nutrition, individualized VTE prophylaxis, pressure care, glucose/electrolyte monitoring, physiotherapy and secretion management. Extubation requires improving MG, adequate cough/secretions, safe bulbar function and a successful spontaneous-breathing assessment—not a spirometric number alone.[2][8]

10. Medicines that may worsen MG

The MGFA cautionary-drugs resource explicitly warns that a caution list does not make every listed medicine absolutely contraindicated; untreated infection or cardiovascular disease may be more dangerous. Record the MG phenotype, choose an alternative when sensible, and monitor after starting a necessary higher-risk drug.[1][2]

• Highest concern / avoid: telithromycin, botulinum toxin and D-penicillamine should be avoided; D-penicillamine is strongly associated with causing MG. Fluoroquinolones carry an FDA boxed warning for MG worsening. Aminoglycosides and macrolides can impair transmission, particularly in a patient who is already weak.[1][2]
• Use only after explicit risk-benefit review and monitoring: intravenous magnesium, beta-blockers (including eye drops), procainamide, quinine and some neuromuscular blockers. Modern iodinated contrast is a caution, not a blanket prohibition.[1][2]
• Other context-dependent signals: statins and immune-checkpoint inhibitors can induce or worsen MG; coordinate with the prescribing specialist. Never stop essential treatment abruptly without a safe alternative.[1][2]

11. Pregnancy, neonate and anaesthesia

MG may improve, remain stable or worsen during pregnancy; exacerbation risk is important in the puerperium. Plan pregnancy jointly with neurology, maternal-fetal medicine, anaesthesia and neonatology. Pyridostigmine and corticosteroids are generally usable. Azathioprine decisions are jurisdiction- and guideline-dependent; mycophenolate and methotrexate are teratogenic/contraindicated and require preconception specialist washout planning. IVIg or PLEX can be used for severe exacerbation. Magnesium sulfate impairs neuromuscular transmission and should be avoided if possible in pre-eclampsia/eclampsia through an individualized obstetric-neurology-anaesthesia plan; do not substitute another MG-worsening anticonvulsant casually.[1][2][19]

Vaginal delivery is usual unless an obstetric indication dictates otherwise. Regional analgesia/anaesthesia is often preferable, but bulbar and respiratory status determine the plan. For any operation, continue an individualized MG medication plan, assess respiratory/bulbar reserve, minimize sedatives, use quantitative neuromuscular monitoring, reduce/titrate non-depolarising blocker if essential and plan postoperative observation and reversal with an experienced anaesthetist.[1][2]

Observe the newborn because transient neonatal MG occurs in roughly 10–15% (reported ranges extend to 20%) of infants born to mothers with MG. It may occur despite good maternal control; maternal AChR titre does not reliably predict it. Weak cry/suck, hypotonia, ptosis or respiratory weakness typically begins within hours to days and resolves over days to weeks as maternal antibody clears. Counsel about rare fetal AChR-antibody disease/arthrogryposis and recurrent pregnancy risk.[1][19]

12. MDT, rehabilitation and follow-up

The core team is neurology/MG specialist and primary care, with respiratory or ICU clinicians for ventilatory disease; speech-language pathology for swallow/communication; dietetics for safe nutrition; physiotherapy and occupational therapy for graded activity, energy conservation, falls/work adaptations and deconditioning; pharmacy for interaction and vaccination review; thoracic surgery/oncology for thymoma; and obstetric, neonatal and anaesthesia teams when relevant.[1][2]

At follow-up, document distribution and trajectory, MG-ADL and (when useful) QMG/MGFA class; medication adherence and adverse effects; agent-specific blood monitoring; infection/vaccination status; bone, metabolic and cardiovascular health with corticosteroid exposure; swallowing, weight, cough and respiratory symptoms; mood, participation, work and driving. Give a written crisis plan and MG alert card. The patient should know to seek urgent care for new breathlessness, orthopnoea, weak cough, choking, pooling secretions or rapidly worsening weakness.[1][2]

13. Exam application

Ward-round test — three stems, thirty seconds each

Stem 1 — the woman from the top of the topic (answer)

The 28-year-old with evening ptosis, diplopia on reading, a voice that fades to a nasal whisper by 30 when counting, and ptosis provoked by one minute of upgaze. Reflexes and sensation are normal. What is the diagnosis, the diagnostic sequence, and the first treatment? Model: This is anti-AChR myasthenia gravis — fatigable weakness worse with activity and better with rest, ocular and bulbar, with preserved reflexes and sensation (the three features that are NOT in MG are absent). The diagnostic sequence is anti-AChR antibody first (85 percent positive, specificity over 99 percent), then anti-MuSK if negative, then repetitive nerve stimulation (decrement over 10 percent), then single-fibre EMG if needed (gold-standard sensitivity over 95 percent), and a contrast CT chest for thymoma (10 to 15 percent). The two-minute ice pack test will improve her ptosis by at least 2 mm at the bedside while antibodies are pending. Start pyridostigmine 30 to 60 mg four times daily; if that is insufficient for generalised symptoms, add low-dose prednisolone titrated up with a steroid-sparing agent. Do not request CSF — it is normal in MG.[1][2]

Stem 2 — weaker after the dose was increased (answer)

A 60-year-old with known MG on pyridostigmine is admitted with worsening weakness. The registrar increases the pyridostigmine and she deteriorates further — now with sweating, salivation, abdominal cramps, a heart rate of 44 and constricted pupils. What happened, and what is the error? Model: This is cholinergic crisis — excess pyridostigmine causing nicotinic and muscarinic over-stimulation — and the error was increasing the dose without reading the autonomic signature. The mirror-image signs tell the two crises apart: myasthenic is mydriasis, dry, tachy; cholinergic is miosis, wet, brady. This patient has the cholinergic pattern. Stop the pyridostigmine, give supportive care (airway and ventilation as needed), and give atropine for severe bradycardia. Do not use the edrophonium (Tensilon) test to differentiate — it can precipitate fatal bronchospasm or asystole, and the diagnosis is clear from the autonomic signature. Restart pyridostigmine at a lower dose once the crisis resolves, and consider IVIg or plasma exchange if the underlying myasthenic weakness is the driver.[2][6]

Stem 3 — the patient who fails pyridostigmine (answer)

A 35-year-old woman of South Asian ancestry presents with severe dysphagia, nasal voice, tongue weakness and respiratory compromise, but almost no ocular symptoms. Pyridostigmine makes her worse. Her CT chest shows a normal thymus. What is the likely antibody, and how does management differ from classic AChR MG? Model: This is anti-MuSK myasthenia gravis — IgG4 antibodies that disrupt agrin-LRP4-MuSK signalling and AChR clustering, producing prominent bulbar, facial, tongue and respiratory weakness with less ocular disease. Three management deltas follow: pyridostigmine is often ineffective or counterproductive (so reduce and stop it here, do not increase); the thymus is normal and thymectomy is not indicated (so do not refer for surgery); and rituximab is highly effective in refractory disease (375 mg per metre squared weekly for 4 doses, or 1 g on days 1 and 15). For the acute crisis, intubate early (FVC under 20 mL/kg) and give IVIg 0.4 g/kg/day for 5 days or plasma exchange, then prednisolone plus an early steroid-sparing agent (mycophenolate or tacrolimus). Anti-MuSK MG is commoner in women of South Asian or Mediterranean ancestry — a demographic cue worth holding.[7]

References

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