Myasthenia gravis

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

MG is an autoimmune postsynaptic neuromuscular-junction disorder, most often due to antibodies against the acetylcholine receptor, muscle-specific kinase or related proteins. Weakness is variable and fatigable: ptosis increases during sustained upgaze, diplopia changes direction, speech becomes nasal after counting, chewing fails near the end of a meal and proximal limb power declines with repetition. Reflexes, sensation and pupils are preserved. Ocular disease remains confined to eyelids and extraocular muscles in some people; generalisation commonly occurs in the first years. MuSK-associated disease often has prominent bulbar, neck and respiratory weakness with less ocular dominance and can respond poorly to pyridostigmine. Fixed ophthalmoplegia, sensory symptoms, autonomic pupils, facilitation and reduced reflexes suggest other junction, nerve, mitochondrial or brainstem disease.

Diagnosis combines phenotype, antibodies and neurophysiology. AChR antibodies are highly specific but less sensitive in ocular disease. If negative, test MuSK and consider specialist cell-based assays; seronegativity does not exclude MG. Repetitive stimulation shows a decrement, while single-fibre EMG is highly sensitive but not specific and requires expert muscle selection. An ice-pack test can support ptosis at the bedside; edrophonium is not routine because of cardiac and cholinergic risk. CT or MRI mediastinum assesses thymoma regardless of antibody titre. Screen thyroid and other autoimmune disease. Respiratory assessment uses serial forced vital capacity, single-breath count and inspiratory or expiratory pressures with bulbar and secretion evaluation; spirometry can be unreliable with facial weakness, so clinical trajectory governs escalation.

Pyridostigmine improves transmission and is titrated around waking and meals, but does not modify autoimmunity. Generalised function-limiting disease usually needs prednisolone and a steroid-sparing agent such as azathioprine; initial steroid dose and setting are specialist decisions because weakness can worsen early. Check TPMT or NUDT15 and blood and liver monitoring before and during azathioprine under local policy. Thymectomy is indicated for thymoma and is considered in selected AChR-positive generalised patients, commonly younger adults, after disease stabilisation. Myasthenic crisis is respiratory or bulbar failure requiring high-acuity care, trigger treatment and IVIg or plasma exchange. Cholinergic excess causes muscarinic symptoms plus weakness but is much less common than undertreated disease; do not withhold ventilation while trying to distinguish them. Maintain a current caution list for medicines and coordinate pregnancy, surgery and vaccination with the specialist team.

Key points

Myasthenia gravis causes fluctuating, fatigable skeletal-muscle weakness that worsens with use and later in the day and improves with rest, while sensation and pupils remain normal.
Ptosis and diplopia are common first features; variability between eyes and during sustained upgaze supports ocular fatigability but does not replace antibody and neurophysiology assessment.
Bulbar disease causes nasal or slurred speech, chewing fatigue, nasal regurgitation, choking and weak cough and can progress to respiratory crisis without dramatic limb weakness.
Test acetylcholine-receptor antibodies first in generalised or ocular disease, then MuSK and selected LRP4 or cell-based assays through specialist practice if seronegative.
Repetitive nerve stimulation or single-fibre EMG demonstrates impaired neuromuscular transmission; routine nerve conduction and sensation are otherwise generally preserved.
Image the mediastinum for thymoma in confirmed MG; thymectomy is required for thymoma and benefits selected non-thymomatous AChR-positive generalised disease.
Pyridostigmine provides symptomatic improvement but can cause abdominal cramps, diarrhoea, sweating, salivation and, in excess, cholinergic weakness.
Corticosteroids and steroid-sparing immunosuppression control generalised disease, but starting steroids can transiently worsen weakness and requires specialist timing and monitoring.
In crisis secure ventilation and treat triggers, using IV immunoglobulin or plasma exchange for rapid immune effect; review antibiotics, magnesium, beta blockers and anaesthetic drugs that can worsen transmission.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Acetylcholine-receptor autoimmunity

Most generalised autoimmune MG involves antibodies against postsynaptic acetylcholine receptors, often with thymic hyperplasia or other immune susceptibility.

MuSK and related antibodies

MuSK, LRP4 and less common targets disrupt organisation of the neuromuscular junction and can produce prominent bulbar or respiratory phenotypes.

Thymoma-associated disease

A thymic epithelial tumour can break immune tolerance and generate MG, making mediastinal assessment important after diagnosis.

Seronegative autoimmune MG

A compatible fatigable syndrome and neurophysiology may persist despite standard antibody negativity, requiring specialist assays and careful mimic exclusion.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Postsynaptic antibody injury
Antibodies block, internalise or disrupt clustering of acetylcholine receptors and may activate complement at the motor endplate.
2
Reduced transmission safety margin
Each nerve impulse produces a smaller endplate response, leaving less reserve to trigger reliable muscle action potentials.
3
Use-dependent failure
Repeated activity temporarily depletes available transmitter and exposes the reduced safety margin, causing fatigable weakness that improves with rest.
4
Bulbar and respiratory involvement
Failure in swallowing, cough and ventilatory muscles can progress rapidly despite preserved sensation and relatively mild limb weakness.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Ocular fatigability

Variable asymmetric ptosis or diplopia that increases with sustained gaze and improves after rest or cooling strongly suggests impaired neuromuscular transmission.

Bulbar fatigabilityRed flag

Speech fading or becoming nasal, chewing failure late in meals, nasal regurgitation and choking indicate pharyngeal and facial weakness and aspiration risk.

Myasthenic crisisRed flag

Rapidly worsening cough, secretion handling, swallowing, neck flexion or breathing represents respiratory failure risk regardless of current oxygen saturation.

MuSK phenotypeRed flag

Prominent facial, neck, bulbar and respiratory weakness with relative limb sparing and limited pyridostigmine response raises MuSK-associated MG.

Cholinergic excessRed flag

Worsening weakness accompanied by diarrhoea, abdominal cramps, salivation, sweating, bronchial secretions, bradycardia or miosis suggests excessive acetylcholinesterase inhibition.

Lambert-Eaton mismatch

Proximal leg weakness that transiently improves with exercise, autonomic dry mouth and reduced reflexes suggests presynaptic Lambert-Eaton syndrome rather than MG.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
AChR, MuSK and specialist antibody testingFirst step
Why
Confirm autoimmune MG subtype and guide thymectomy, prognosis and treatment discussions.
Interpretation and limitations
AChR positivity is specific; test MuSK after negative AChR and use specialist assays when clinical and neurophysiological evidence remains strong.
02
Repetitive nerve stimulation and single-fibre EMG
Why
Demonstrate a decrement or increased jitter consistent with impaired neuromuscular transmission.
Interpretation and limitations
Select a clinically involved muscle and account for treatment and temperature; sensitive jitter is not unique to MG and needs phenotype concordance.
03
CT or MRI mediastinum
Why
Detect thymoma or define thymic anatomy after MG is confirmed.
Interpretation and limitations
Thymoma requires thoracic and neurology coordination; non-thymomatous thymectomy eligibility depends on antibody, generalisation, age and specialist assessment.
04
Serial respiratory mechanics
Why
Detect falling vital capacity and inspiratory or expiratory strength during exacerbation or crisis.
Interpretation and limitations
Trend with bulbar function and secretion clearance; facial weakness can impair the seal and a normal saturation does not exclude hypoventilation.
05
Swallow and speech assessment
Why
Identify aspiration, fatigable chewing and communication risk and guide texture, timing and enteral support.
Interpretation and limitations
Assessment should consider deterioration through a meal; a safe first swallow does not guarantee endurance for full oral intake.
06
Autoimmune and treatment baseline
Why
Check thyroid disease and establish blood, liver, renal, infection and thiopurine-safety measures before immunosuppression.
Interpretation and limitations
TPMT or NUDT15 does not replace blood monitoring, and infection screening is tailored to the intended agent and local protocol.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Lambert–Eaton syndrome

Leg-predominant weakness, autonomic symptoms and reflex facilitation favour presynaptic LEMS; ocular-bulbar fluctuation with preserved reflexes favours MG.

Botulism

Acute descending paralysis with fixed pupils, constipation and a food or wound exposure supports toxin-mediated presynaptic failure.

Brainstem or motor neurone disease

Focal central signs, sensory pathways or progressive wasting and fasciculation indicate structural brainstem or motor-neuron pathology rather than fatigable transmission.

Myopathy or thyroid eye disease

Persistent proximal weakness or mechanically restricted eye movement with proptosis lacks the characteristic variable, use-dependent junctional pattern.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01DiagnosisDemonstrate fatigable transmission failureFirst stepVariable ocular, bulbar or proximal weakness occurs without sensory loss.

1Examine ptosis, eye movements, speech, neck flexion and proximal power before and after safe sustained activity, documenting normal sensation, pupils and reflexes.
2Send AChR then MuSK or specialist antibodies and arrange repetitive stimulation or single-fibre EMG when required.
3Assess swallowing and respiratory symptoms immediately, admitting for progression rather than waiting for antibody results.
4After confirmation image the mediastinum, screen associated autoimmunity and refer to a neuromuscular service for subtype-specific treatment.

02CrisisSecure airway and reverse acute immune failureBulbar, cough or respiratory weakness is progressing or measurements are falling.

1Move to monitored high-acuity care, involve anaesthesia and neurology early, trend respiratory mechanics and assess secretion and aspiration continuously.
2Identify infection, aspiration, surgery, pregnancy, missed treatment and transmission-worsening medicines, treating the precipitant without unsafe antibiotics.
3Intubate electively when airway or ventilation is failing and use anaesthetic expertise because responses to neuromuscular blocking drugs are altered.
4Deliver plasma exchange or IVIg under the specialist protocol, adjust pyridostigmine around ventilation and nutrition, and begin rehabilitation after stabilisation.

03Long-term controlBalance strength with treatment toxicityGeneralised or persistent ocular disease requires ongoing symptomatic or immune management.

1EscalationTime pyridostigmine to symptoms and meals, recording benefit and muscarinic adverse effects rather than escalating every episode of fatigue.
2Introduce prednisolone cautiously and a steroid-sparing agent when indicated, with infection, bone, metabolic, blood and liver safeguards.
3Discuss thymectomy for thymoma and eligible AChR-positive generalised disease after adequate perioperative stabilisation.
4Provide a medicine-alert list, emergency plan and tailored surgery, pregnancy, vaccine, occupation and driving advice at regular specialist review.

Key medicines and prescribing safety4 treatments · regimens, roles and cautions

Provides short-acting symptomatic improvement in ocular, bulbar and limb strength by inhibiting acetylcholinesterase at the neuromuscular junction.

Pyridostigmine bromide

Often start 30 mg four times daily and titrate timing and dose, commonly to 60 mg four times daily, within specialist and BNF limits.

Abdominal cramps, diarrhoea, sweating, salivation, bradycardia and excess secretions can limit use; renal impairment reduces clearance and overdose can worsen weakness.

Suppresses pathogenic autoimmunity and improves generalised MG, often while a slower steroid-sparing medicine becomes effective.

Prednisolone

Use a neuromuscular-specialist low-start or inpatient regimen with gradual titration and taper chosen according to bulbar, respiratory and disease severity.

Initial worsening can precipitate crisis; monitor infection, glucose, blood pressure, mood, eyes, bone and adrenal suppression and never stop prolonged therapy abruptly.

A steroid-sparing immunosuppressant for longer-term control, with benefit developing over many months rather than during crisis.

Azathioprine

Begin and titrate under specialist care towards the weight-based maintenance regimen after TPMT or NUDT15 assessment and baseline blood and liver tests.

Myelosuppression, liver injury, infection, pancreatitis, malignancy risk and allopurinol interaction require scheduled monitoring, sun protection and urgent review for fever or bruising.

Provides relatively rapid immune modulation during crisis, severe bulbar disease or perioperative stabilisation when plasma exchange is not selected.

Intravenous human immunoglobulin

Under current NHS England criteria, life-threatening disease with intensive-care respiratory or bulbar failure receives a total 2 g/kg over 2–5 days. A hospitalised acute exacerbation without life-threatening disease receives 1 g/kg initially, with a further 1 g/kg only for deterioration or no response; use the commissioned weight protocol.

Assess thrombosis, renal function, haemolysis, aseptic meningitis, fluid and reaction risk; it does not replace airway management and routine repeated use needs governance.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Myasthenic crisis

Bulbar and respiratory weakness can cause aspiration, hypoventilation and ventilatory failure before oxygen saturation becomes abnormal.

Thymoma morbidity

An unrecognised thymic tumour can progress locally or metastasise and may require oncological surgery independent of weakness control.

Medicine-triggered deterioration

Infection, magnesium, selected antibiotics, beta blockers, anaesthesia and abrupt immune-treatment changes can reduce transmission reserve and precipitate severe weakness.

Immunotherapy harm

Corticosteroids and steroid-sparing treatment increase infection, metabolic, bone, reproductive and monitoring burdens, while initiation can transiently worsen weakness.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Track ocular, speech, chewing, swallowing, neck, limb and respiratory endurance at comparable times relative to pyridostigmine, not only a resting power grade.
During exacerbation trend FVC, inspiratory strength, cough, secretions and bulbar function frequently and escalate trajectory before saturation or gases fail.
Monitor pyridostigmine benefit, dose timing, diarrhoea, cramps, sweating, secretions and bradycardia and review renal function when clearance may change.
For corticosteroid and azathioprine therapy follow local blood count, liver, metabolic, infection, bone and eye schedules and assess cumulative toxicity.
Review thymus status, antibody subtype, relapse frequency, admissions, quality of life and need for advanced targeted therapy in the specialist clinic.
At every transition reconcile antibiotics, cardiovascular, psychiatric, magnesium and anaesthetic medicines against a current MG caution list.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Meals are endurance tests

A patient may swallow safely at the first mouthful and aspirate when chewing and pharyngeal muscles fatigue later, so assessment must reflect a full meal.

Pupils help localisation

MG weakens skeletal muscle but not pupillary autonomic function; abnormal pupils suggest botulism, third-nerve disease or another diagnosis.

Steroids can worsen before helping

Early transient weakness is why initiation strategy depends on bulbar and respiratory reserve and sometimes requires monitored inpatient care.

Seronegative is not symptom-free

Standard antibodies can be absent, especially in ocular disease; expert neurophysiology and newer cell-based assays may still establish autoimmune transmission failure.

Crisis is a clinical trajectory

No single vital-capacity number captures facial seal, bulbar protection and speed of decline, so early anaesthetic judgement matters.

11Common pitfallsFrequent interpretation and management errors.

01
Reassuring from normal sensation, pupils and oxygen saturation while bulbar function, cough and vital capacity progressively deteriorate.
02
Interpreting a negative AChR antibody as exclusion of MG without MuSK, specialist assay and neurophysiology assessment.
03
Escalating pyridostigmine for every weakness episode without checking cholinergic gastrointestinal, secretory and bradycardic features.
04
Starting high-dose corticosteroids in severe bulbar disease without anticipating transient worsening and respiratory support.
05
Failing to image the thymus after diagnosis or omitting thymectomy discussion for thymoma and selected AChR-positive generalised disease.
06
Prescribing aminoglycoside, fluoroquinolone, macrolide, intravenous magnesium or neuromuscular blocker without assessing MG-specific risk and alternatives.