Medicine chapters
Myasthenia gravis and Lambert-Eaton myasthenic syndrome
The two main autoimmune diseases of the neuromuscular junction: myasthenia gravis, with fatiguable ocular, bulbar and limb weakness from acetylcholine receptor antibodies, and Lambert-Eaton syndrome, a paraneoplastic calcium channel disorder linked to small-cell lung cancer.
- Myasthenia gravis is an autoimmune (type II) disease with antibodies against postsynaptic acetylcholine receptors, giving fatiguable weakness of eye, bulbar and proximal limb muscles with normal reflexes; check for thymoma.
- Diagnose with AChR (or MuSK) antibodies and decrement on repetitive nerve stimulation; treat with pyridostigmine, steroids and immunosuppressants, thymectomy, and IVIG or plasma exchange for crisis.
- Lambert–Eaton is a presynaptic calcium channel disorder, usually with small-cell lung cancer: proximal leg weakness that improves with exercise, absent reflexes that return, autonomic features, and an increment on fast repetitive stimulation.
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Overview
At the neuromuscular junction (NMJ) a nerve impulse opens voltage-gated calcium channels in the nerve terminal. Calcium entry releases acetylcholine (ACh), which crosses the cleft and binds nicotinic ACh receptors on the muscle end-plate. Acetylcholinesterase then breaks ACh down.
- Myasthenia gravis (MG): the problem is postsynaptic; antibodies destroy the ACh receptors.
- Lambert–Eaton myasthenic syndrome (LEMS): the problem is presynaptic; antibodies block calcium channels, so less ACh is released.
The hallmark of NMJ disease is fatiguable weakness: muscles weaken with repeated use and recover with rest. Sensation is always normal.
Myasthenia gravis
Epidemiology
- Prevalence about 4 per 100 000.
- Twice as common in women; a peak around age 30 (mostly women) and a smaller peak in older men.
Pathogenesis
- IgG antibodies against the nicotinic acetylcholine receptor (anti-AChR) bind the end-plate, activate complement and destroy receptors. The end-plate folds become simplified.
- This is a type II (antibody-mediated) hypersensitivity reaction.
- With fewer receptors, each nerve impulse produces a smaller end-plate potential. With repeated firing, ACh release naturally falls, and transmission fails in more and more fibres, giving fatigue.
- Anti-MuSK (muscle-specific tyrosine kinase) antibodies are found in some AChR-negative patients.
The thymus
- Thymic hyperplasia (lymphoid follicles with germinal centres) in about 70% of patients under 40.
- Thymoma in about 10%, more common with age. Antibodies to striated muscle suggest a thymoma.
Associations
- Other autoimmune diseases: thyroid disease (Graves, Hashimoto), rheumatoid arthritis, pernicious anaemia, SLE, type 1 diabetes.
- D-penicillamine can cause a transient, drug-induced MG.
Clinical features
- Fatiguable weakness, worse at the end of the day and after exercise, better after rest.
- Ocular (often first, may stay the only feature: ocular myasthenia):
- Ptosis, often asymmetric and fluctuating; worsens on sustained upgaze.
- Diplopia from weak extraocular muscles; complex patterns that do not fit one nerve.
- Pupils are always normal.
- Bulbar: difficulty chewing (jaw tires during a meal), dysphagia, nasal speech, nasal regurgitation, "myasthenic snarl" (weak smile).
- Limbs: proximal weakness, neck flexor weakness, arms tire when held out.
- Respiratory: weakness of breathing muscles can cause myasthenic crisis.
- Reflexes are normal (may fatigue with repeated testing); no wasting early; no sensory loss.
A patient with fluctuating ptosis and diplopia, normal pupils and normal sensation and reflexes has myasthenia until proven otherwise. A IIIrd nerve palsy in contrast usually involves the pupil or is fixed.
Investigations
| Test | Finding |
|---|---|
| Anti-AChR antibodies | Positive in 80–90% of generalised MG but less than 30% of purely ocular MG; highly specific |
| Anti-MuSK antibodies | In a subgroup of AChR-negative patients; mainly bulbar, facial and neck weakness |
| Repetitive nerve stimulation | Decrement: the muscle action potential gets smaller with each of the first few stimuli at low rates |
| Single-fibre EMG (often of orbicularis oculi) | Increased jitter and blocking; the most sensitive test |
| CT or MRI of the mediastinum | Done in all patients to look for thymoma |
| Edrophonium (Tensilon) test | Short-acting anticholinesterase; weakness improves within seconds for a few minutes. Now rarely used; can cause bradycardia and bronchospasm, so atropine and resuscitation must be at hand |
| Thyroid function | Associated thyroid disease |
| Vital capacity | Monitors respiratory weakness |
Myasthenia Minus (decrement, Down); Lambert–Eaton Lifts (increment, up).
Edrophonium is used for diagnosis because it acts for only a few minutes; pyridostigmine is used for treatment because it lasts 3–4 hours.
Management
1. Symptomatic: anticholinesterases
Pyridostigmine is the first drug for symptoms; steroids and azathioprine treat the immune disease; IVIG or plasma exchange act fastest in a crisis.
- Pyridostigmine (oral) blocks acetylcholinesterase, so ACh stays longer in the cleft. Each dose lasts about 3–4 hours; the daily dose is titrated to response.
- Side effects are muscarinic: abdominal colic, diarrhoea, salivation, sweating, bradycardia. An antimuscarinic such as propantheline or glycopyrrolate can be added.
- It improves strength but does not change the course of the disease.
2. Immunosuppression
- Corticosteroids (prednisolone) for patients not controlled by pyridostigmine. About 70% improve. Start low and increase slowly, because high starting doses can cause a temporary worsening in the first weeks.
- Steroid-sparing drugs: azathioprine (first choice), mycophenolate, methotrexate, ciclosporin, tacrolimus; rituximab for resistant (especially MuSK) disease.
3. Thymectomy
- Recommended for patients with AChR-positive generalised MG and thymic hyperplasia, especially younger adults; benefit appears over months to years.
- All thymomas are removed because of the risk of local invasion, even though the myasthenia may not improve.
4. Rapid-acting treatments
- Plasma exchange or intravenous immunoglobulin (IVIG): rapid but short-lived improvement; used for crisis, severe exacerbations and before thymectomy or other surgery.
Myasthenic crisis versus cholinergic crisis
| Feature | Myasthenic crisis | Cholinergic crisis |
|---|---|---|
| Cause | Disease flare: infection, surgery, stopping drugs, aggravating drugs, pregnancy | Too much anticholinesterase |
| Weakness | Severe, including breathing and swallowing | Severe; fasciculations may be seen |
| Muscarinic signs | Absent | Miosis (small pupils), salivation, sweating, lacrimation, diarrhoea, bradycardia, bronchial secretions |
| Response to edrophonium | Improves | Worsens |
| Treatment | Ventilatory support, IVIG or plasma exchange, treat trigger, steroids | Stop anticholinesterase, ventilatory support, atropine for muscarinic effects |
In both crises the immediate priority is the airway and breathing: monitor vital capacity and ventilate early (around 10 mL/kg or less). Pulse oximetry falls late.
Drugs that can worsen myasthenia
- Aminoglycosides (gentamicin, streptomycin): block neuromuscular transmission. Also polymyxins.
- Fluoroquinolones, macrolides (erythromycin, azithromycin), telithromycin.
- Magnesium sulphate (avoid for eclampsia prophylaxis; use another anticonvulsant).
- Beta-blockers, calcium channel blockers, quinine, quinidine, procainamide.
- Lithium, phenytoin, chloroquine.
- Neuromuscular blocking agents: patients are very sensitive to non-depolarising blockers (rocuronium, vecuronium) and relatively resistant to suxamethonium.
- D-penicillamine (can induce MG) and checkpoint inhibitors (immunotherapy).
Myasthenia and pregnancy
- The course is unpredictable; flares are common after delivery (about 30% in Kumar and Clark).
- Pyridostigmine, steroids and azathioprine are usually continued.
- Transient neonatal myasthenia affects up to 1 in 10 babies of myasthenic mothers: maternal IgG anti-AChR crosses the placenta, causing a floppy baby with weak cry and poor feeding for a few weeks; full recovery as the antibodies clear.
- Magnesium sulphate is avoided for pre-eclampsia.
Lambert–Eaton myasthenic syndrome (LEMS)
Cause
- IgG antibodies against presynaptic P/Q-type voltage-gated calcium channels (VGCC), found in about 90% of cases. Less calcium enters the nerve terminal, so less ACh is released.
- Mostly paraneoplastic, almost always with small-cell lung carcinoma (smokers). A smaller group is purely autoimmune with no tumour.
- LEMS may appear before the cancer is found, so repeated screening (CT chest, PET) is needed.
Clinical features
- Proximal weakness, especially of the legs (difficulty climbing stairs, rising from a chair); a waddling gait.
- Strength improves for a short time after repeated or sustained effort (post-tetanic facilitation), the opposite of MG.
- Reflexes are reduced or absent at rest, but may return after brief exercise: a key sign.
- Autonomic features: dry mouth, constipation, erectile dysfunction, blurred vision.
- Eye and bulbar muscles are less affected than in MG; ptosis may be mild.
Investigations
- Anti-VGCC antibodies.
- Repetitive nerve stimulation: low resting muscle action potential that increases (increment) after brief maximal exercise or high-frequency (fast) stimulation.
- CT chest / PET to look for small-cell lung cancer.
Treatment
- Treat the underlying tumour: weakness often improves.
- 3,4-Diaminopyridine (amifampridine): blocks potassium channels, prolonging the nerve action potential so more calcium enters and more ACh is released. Reasonably safe and effective.
- Pyridostigmine has a small added effect.
- Steroids, azathioprine, IVIG or plasma exchange for non-cancer cases or severe disease.
Myasthenia gravis versus Lambert–Eaton
| Feature | Myasthenia gravis | Lambert–Eaton |
|---|---|---|
| Site of lesion | Postsynaptic ACh receptor | Presynaptic calcium channel |
| Antibody | Anti-AChR (or anti-MuSK) | Anti-VGCC |
| Associated tumour | Thymoma | Small-cell lung cancer |
| Muscles | Ocular and bulbar first, then proximal limbs | Proximal legs first; eyes less involved |
| Effect of exercise | Worse (fatigue) | Better briefly (facilitation) |
| Reflexes | Normal | Reduced or absent, return after exercise |
| Autonomic features | None | Dry mouth, constipation, impotence |
| Repetitive nerve stimulation | Decrement | Increment at high rates or after exercise |
| Response to edrophonium | Marked | Poor |
| Specific drug | Pyridostigmine | 3,4-Diaminopyridine |
An older smoker with proximal leg weakness that improves after a few contractions, absent knee jerks and a dry mouth has LEMS, not myasthenia. Look for a small-cell lung cancer.
Other myasthenic syndromes
- Congenital myasthenic syndromes: genetic defects of NMJ proteins; not autoimmune, so no antibodies; no response to immunosuppression.
- Botulism: toxin blocks presynaptic ACh release; descending paralysis with dilated pupils.
- Drug-induced (penicillamine) and neonatal myasthenia, described above.
Expect: the postsynaptic acetylcholine receptor as the target in myasthenia and type II hypersensitivity; fluctuating ptosis and diplopia with normal pupils and reflexes; antibody sensitivity in generalised versus ocular disease and anti-MuSK; decrement on repetitive stimulation and single-fibre EMG as the most sensitive test; CT chest for thymoma; edrophonium versus pyridostigmine; myasthenic versus cholinergic crisis; drugs that worsen myasthenia (aminoglycosides, magnesium, beta-blockers, quinine) and sensitivity to non-depolarising blockers; thymectomy; neonatal myasthenia; and the contrasts with Lambert–Eaton (presynaptic calcium channel, small-cell lung cancer, improvement with exercise, absent reflexes, autonomic signs, increment, 3,4-diaminopyridine).
Quick revision
- MG: anti-AChR (postsynaptic, type II); anti-MuSK in some seronegative cases.
- Fatiguable ptosis, diplopia, bulbar and proximal weakness, worse in evening; pupils, reflexes and sensation normal.
- Thymic hyperplasia in most young patients; thymoma in about 10%; image the mediastinum in all.
- Decrement on repetitive stimulation; single-fibre EMG jitter most sensitive.
- Pyridostigmine (symptomatic), steroids (start low), azathioprine, thymectomy, IVIG or plasma exchange for crisis.
- Cholinergic crisis: weakness plus miosis, sweating, salivation, diarrhoea.
- Avoid aminoglycosides, magnesium, quinine, beta-blockers; very sensitive to non-depolarising relaxants.
- LEMS: anti-VGCC (presynaptic), small-cell lung cancer, proximal leg weakness better with effort, absent reflexes, dry mouth, increment, 3,4-DAP.
Written by The House Job from standard references (Kumar and Clark's Clinical Medicine).
FAQ
Why are the pupils normal in myasthenia gravis?
The pupil muscles are smooth muscle controlled by the autonomic system through muscarinic receptors, which are not attacked by antibodies to the nicotinic receptors of skeletal muscle.
What is the most sensitive test for myasthenia gravis?
Single-fibre electromyography, which shows increased jitter and blocking, although antibody testing is usually done first because it is simple and specific.
Why does strength improve with exercise in Lambert–Eaton syndrome?
Repeated firing lets calcium build up inside the nerve terminal, which partly overcomes the blocked channels and releases more acetylcholine.
Should all myasthenic patients have a thymectomy?
No; it is advised for those with a thymoma and for many younger patients with acetylcholine receptor positive generalised disease, but not usually for purely ocular disease.