Myasthenia gravis and Lambert-Eaton myasthenic syndrome

• Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction in which antibodies against acetylcholine receptors or related proteins produce fluctuating skeletal muscle weakness that worsens with use and improves with rest.
• In MG, weakness characteristically begins in the eyelids and eye movement muscles, so ptosis and diplopia are common early features; bulbar, axial, and limb muscles can follow.
• Lambert-Eaton myasthenic syndrome (LEMS) is a different autoimmune neuromuscular junction disease in which antibodies against presynaptic voltage-gated calcium channels reduce acetylcholine release, producing proximal limb weakness that often improves briefly with activity, areflexia, and autonomic symptoms.
• About half of patients with LEMS have an underlying small cell lung cancer; LEMS can be the first clue to that cancer.
• Modern management separates symptomatic treatment from immunotherapy: anticholinesterase drugs such as pyridostigmine for many patients with MG, and amifampridine for LEMS, plus corticosteroids, steroid-sparing agents, thymectomy for selected patients with MG, immune modulation in severe disease, and prompt treatment of myasthenic crisis.

By the end of this page you should be able to:

1. Define myasthenia gravis and LEMS as autoimmune disorders at opposite sides of the neuromuscular junction, and name the main antibodies in each.
2. Explain why weakness in MG worsens with effort while weakness in LEMS often improves briefly with effort.
3. Plan the bedside, serological, and electrophysiological evaluation of a patient with suspected MG or LEMS, including cut-offs for repetitive nerve stimulation.
4. Use the Myasthenia Gravis Foundation of America (MGFA) clinical classes and explain when thymectomy is considered.
5. Outline the stepped treatment of MG following the 2020 international consensus and the treatment of LEMS, including amifampridine dosing and cancer screening.
6. Recognise a myasthenic crisis, unsafe drugs, LEMS as a paraneoplastic syndrome, and special situations such as pregnancy, children, and older adults.

Myasthenia gravis is the most common disorder of the skeletal muscle neuromuscular junction ^[2]. It is a true autoimmune disease rather than a degenerative one, so the weakness is variable, with good days and bad days, and often resolves partly or completely with treatment. It has two clinical forms, ocular and generalized. In ocular MG, weakness is limited to the muscles that move the eyes and close the eyelids. Generalized MG involves limb, axial, facial, chewing, swallowing, or speech muscles as well, and may include the respiratory muscles.

LEMS is a model presynaptic disease: the problem is not the receiving muscle membrane but the nerve terminal's ability to send a signal. In roughly half of patients it is a paraneoplastic syndrome caused by a small cell lung cancer; the other half is autoimmune without an identifiable tumour ^[3]. It belongs with MG in any teaching of neuromuscular junction disease, but the clinical details are quite different.

The clinical behaviour, treatment, and prognosis of MG depend on which antibody is present ^[2].

• Anti-acetylcholine receptor (AChR) antibody MG is the classic form. Antibodies are of the IgG1 and IgG3 subtype. They bind the acetylcholine receptor on the postsynaptic membrane, activate complement, and form the membrane attack complex, degrading receptors; they may also block acetylcholine from binding and accelerate receptor endocytosis.
• Muscle-specific kinase (MuSK) antibody MG is an IgG4-mediated form. The Agrin-lipoprotein-related protein 4-MuSK complex at the junction maintains receptor clustering. Antibodies against MuSK disrupt that maintenance and leave fewer receptors. MuSK MG is more common in females, often spares the extraocular muscles, frequently involves facial, bulbar, and neck muscles, and carries a high frequency of myasthenic crisis ^[2].
• Lipoprotein-related protein 4 (LRP4) antibodies occur in some patients who are seronegative for both AChR and MuSK antibodies.
• Seronegative MG means that neither AChR nor MuSK antibodies are detectable. Thymic pathology may still be present in some patients.
• Thymoma-associated MG occurs in about 10% of patients with MG ^[2], and is usually AChR-antibody positive.
• LEMS is characterised by antibodies against the P/Q-type voltage-gated calcium channel (Cav2.1) on the presynaptic motor nerve terminal. These are present in about 85% of patients with LEMS ^[3]. The antibodies reduce the number of functioning calcium channels, so calcium influx falls, acetylcholine release falls, and muscle contraction weakens.
• SOX (sry-like high-mobility group box) antibodies are a serological marker of small cell lung cancer; they are found in about 67% of patients with paraneoplastic LEMS, compared with about 36% of patients with small cell lung cancer without LEMS ^[3].

A common trap is to think of LEMS as a kind of MG. It is not. The antibody site, electrophysiology, reflex changes, autonomic features, and cancer association differ, and treatment differs too.

The Myasthenia Gravis Foundation of America (MGFA) clinical classification divides MG into 5 main classes according to muscle groups involved and severity. This is a teaching and outcome measure, not a diagnosis by itself ^[2].

MG has a prevalence of about 20 per 100,000 population in the United States, with female predominance in people under 40 years of age and male predominance in people over 50 ^[2]. Childhood MG is uncommon in Western populations but is prevalent in Asian countries, where around half of patients are under 15 years of age at onset and often present with extraocular muscle weakness ^[2].

LEMS is rare. A study from South Holland found a prevalence of about 2.3 per million and an annual incidence of about 0.5 per million. In that cohort, 60% of patients were male and the mean age at onset was 58 years, with two peaks, one around 40 years and one at an older age ^[3]. LEMS affects males and females about equally in many reports but small cell lung cancer-associated LEMS shows a male predominance, reflecting smoking. LEMS occurs in 0.5% to 3% of patients with small cell lung cancer ^[3]. Non-tumour LEMS patients have a lower age at onset than those with associated cancer ^[3]. ^[5]

The contrast matters for practice: in any older smoker who presents with weakness, LEMS is a reason to look for small cell lung cancer immediately, even before the neurological syndrome is fully worked out.

There is no single known preventable cause of MG, and no consistent modifiable risk factor for sporadic disease. The main determinants are autoimmune susceptibility and the state of the thymus.

• Thymic hyperplasia is characteristic of early-onset MG in patients whose disease begins before 50 years of age. Thymic atrophy is more characteristic of late-onset disease after 50 ^[2].
• Thymoma is present in about 10% of patients with MG ^[2], and it can produce autoantibodies. Any patient with MG and a thymoma should be evaluated for thymectomy as part of treatment.
• Other autoimmune conditions commonly coexist (thyroid disease, rheumatoid disease, and others). Testing for antinuclear antibodies, rheumatoid factor, and baseline thyroid function is commonly recommended ^[2].
• Genetic susceptibility is likely polygenic. Non-tumour LEMS is significantly associated with HLA-B8, HLA-DR3, and HLA-DQ2, the same haplotypes seen in many other autoimmune diseases, and autoimmune overlap is common ^[3]. There is no such HLA association in paraneoplastic LEMS or in thymoma-associated MG, which supports the view that these are driven by tumour neoantigens rather than by genetic autoimmunity.
• Small cell lung cancer is the initiating event in paraneoplastic LEMS. Voltage-gated calcium channels are expressed on the surface of small cell lung cancer cells, the immune response to tumour neoantigens cross-reacts with presynaptic calcium channels, and LEMS often appears before the cancer is diagnosed ^[3].
• Precipitating factors in MG include infection, immunization, surgery, heat, emotional stress, pregnancy, and drugs, particularly aminoglycosides, fluoroquinolones, beta-blockers, and neuromuscular blocking agents ^[2].

LEMS without cancer does not have a known initiating event; as in other autoimmune disorders, an environmental trigger has been proposed but not proved.

At the normal junction, a motor nerve action potential opens presynaptic voltage-gated calcium channels; calcium enters the terminal, synaptic vesicles fuse, and acetylcholine is released into the synaptic cleft. Acetylcholine binds postsynaptic receptors on the muscle membrane, producing an end-plate potential large enough to fire a muscle action potential. Small changes in any step can abolish transmission, which is why this synapse is so sensitive to antibodies, toxins, and drugs. The distinction between presynaptic and postsynaptic failure is the key to distinguishing MG from LEMS ^[4].

In anti-AChR MG, the antibodies are IgG1 and IgG3. Complement activation damages the postsynaptic membrane and reduces the number of functioning receptors. Acetylcholine release is normal, but fewer receptors remain to detect it, so the end-plate potential is small. Repeated use depletes acetylcholine stores further in relative terms, which is why weakness is worse after sustained effort and better after rest. MuSK and LRP4 antibodies damage the receptor-clustering machinery rather than the receptor itself, but the final result is the same: too few acetylcholine receptors and too small an end-plate potential ^[2].

LEMS antibodies bind the presynaptic P/Q-type calcium channel, chiefly its alpha-1 subunit. This cross-links and down-regulates channels, reduces calcium influx, and lowers the quantal release of acetylcholine ^[3]. Transmission improves briefly with repeated activation because accumulating calcium in the terminal partially overcomes the block, which explains the classic clinical picture of strength that briefly rises with exercise. The same antibodies act on autonomic nerve terminals, where they reduce transmitter release from parasympathetic and sympathetic neurons; this explains dry mouth, constipation, reduced sweating, and erectile dysfunction ^[3].

The simplest bedside model is: MG is a problem of receiving the message, so repeated contraction worsens weakness; LEMS is a problem of sending it, so brief repeated contraction can improve it. That model is not perfect, but it directs the examination and helps avoid diagnostic delay.

Incomplete or fixed weakness would not be MG. The defining story is weakness that changes through the day, worse after sustained use and better after rest. Patients may not complain of "weakness"; they report vision changing, food getting stuck, or handwriting deteriorating.

• Extraocular muscle weakness occurs in about 85% of patients at the start, often as diplopia or ptosis, and secondary generalization occurs in about half within 2 years ^[2].
• Bulbar weakness is the first feature in about 15% of patients, causing dysphagia, chewing fatigue, dysarthria, hoarseness, nasal speech, and choking ^[2].
• Limb weakness tends to involve proximal more than distal muscles, with arms often affected more than legs, producing dropped arms on hair washing, difficulty climbing stairs, head drop, and facial weakness with an expressionless face ^[2].
• Respiratory weakness is the dangerous end of the spectrum and can produce a myasthenic crisis.
• Fatigability is often noticed late in the day or at the end of a work shift; patients may cough after swallowing or take longer over meals.
• There are no autonomic bowel or bladder symptoms, unlike LEMS, because MG targets nicotinic receptors at skeletal muscle rather than autonomic terminals ^[2].

MuSK MG deserves separate mention: it is more common in females, relatively spares the extraocular muscles, often presents with bulbar, facial, or neck weakness, and has a high frequency of myasthenic crisis ^[2]. Juvenile MG tends to progress more slowly and has a higher rate of remission than adult disease ^[2].

LEMS presents with a different triad: proximal muscle weakness, loss of tendon reflexes, and autonomic dysfunction ^[3].

• Weakness begins nearly always in proximal muscles, especially the legs. About 80% of patients have proximal weakness in both arms and legs ^[3]. Facial weakness, ocular symptoms, bulbar weakness, and distal weakness can occur but are not dominant.
• Areflexia is common. Tendon reflexes may briefly return after sustained contraction.
• Autonomic dysfunction affects a large majority of patients but is milder than the weakness: dry mouth, dry eyes, constipation, reduced sweating, and erectile dysfunction ^[3].
• Paraneoplastic disease is more severe and progresses more rapidly, so a patient with rapid worsening should be assessed for small cell lung cancer urgently ^[3].

In MG the resting examination may be normal because weakness is fluctuating. Sustained or repeated muscle contraction can bring it out, and a period of rest or application of an ice pack can improve weakness. The pupils, deep tendon reflexes, and sensory examination are normal. Ptosis and diplopia that worsen with sustained upgaze are common. Bulbar clues include a nasal or hoarse voice and weak cough.

In LEMS, examination shows proximal weakness, reduced or absent tendon reflexes, and evidence of autonomic failure. Bulbar and ocular signs are less prominent than in MG, and many patients report that strength improves briefly after exercise.

Red-flag symptoms are breathlessness at rest, weak cough, inability to clear secretions, a falling vital capacity, and any change in neck flexor strength after infection, anaesthesia, or new medication. These mark progression towards myasthenic crisis and should be treated as an emergency ^[2].

MG has many mimics; LEMS has fewer. The table compares the conditions most likely to be confused at the bedside.

A common examination trap is to accept unexplained "mitochondrial" or "functional" ptosis. When a ptosis changes during the day, think MG.

Multiple sclerosis deserves its own note for study: it is a central nervous system demyelinating disease, not a neuromuscular junction disease, and can mimic the visual or bulbar problems of MG, but it does not cause fatigable junctional weakness and usually shows upper motor neuron signs.

Serology is the most useful confirmatory step when the clinical picture fits.

Two antibodies do not necessarily exclude each other in practice, and a proportion of patients are seronegative. Serology is therefore supportive, not a substitute, for the clinical picture.

Repetitive nerve stimulation and single-fibre electromyography assess neuromuscular junction transmission. Routine nerve conduction studies are usually performed first to check nerve and muscle integrity.

• In repetitive nerve stimulation, stimulating at 2 to 3 Hz depletes acetylcholine in the synapse and produces a low excitatory postsynaptic potential. A 10% or more decrease in the amplitude between the first and fifth stimulus is diagnostic of MG ^[2].
• Single-fibre electromyography records action potentials from individual muscle fibres supplied by one motor neuron and measures "jitter", the variation in time between two muscle fibre action potentials. Jitter increases when transmission is reduced. It is the most sensitive diagnostic test for MG, though less specific than serology ^[2].
• In LEMS, electrophysiology shows low baseline compound muscle action potential amplitudes with facilitation after brief exercise, rather than the decremental pattern typical of MG. Serology and cancer screening then secure the diagnosis.

• Edrophonium (tensilon) test. Edrophonium is a short-acting acetylcholinesterase inhibitor given intravenously. Improvement in ptosis or diplopia within seconds supports MG. It is particularly useful in ocular MG when electrophysiology is not feasible. Its sensitivity is reported as 71% to 95% ^[2].
• Ice-pack test. When edrophonium is contraindicated, an ice pack is placed over the eye for 2 to 5 minutes and any improvement in ptosis assessed. This test cannot be used to assess extraocular muscle movements ^[2].
• Edrophonium can provoke bronchospasm and bradycardia, so resuscitation drugs and atropine should be available.

Every patient diagnosed with MG should undergo chest CT or MRI to look for a thymoma ^[2]. In pure ocular MG, MRI of the orbits and brain is used to exclude a localized orbital or intracranial lesion. In LEMS, the imaging question is cancer rather than thymus: chest imaging looking for small cell lung cancer, with further staging if the clinical picture or SOX antibodies point that way.

The association between LEMS and small cell lung cancer changes the whole approach to investigation and follow-up. Once LEMS is suspected or confirmed, the search for cancer should include imaging of the chest and, depending on local practice, PET-CT. If the initial screen is negative, screening should be repeated after 3 months, then every 6 months for up to 2 years after the onset of LEMS, following European Federation of Neurological Societies guidance cited in the review literature ^[3].

A clinical score derived in large Dutch and English cohorts uses independent predictors of small cell lung cancer in LEMS: older age at onset, smoking, weight loss, poor general well-being, bulbar involvement, male sexual impotence, and SOX antibody positivity ^[3]. It is not a screening test by itself, but it helps communicate risk and urgency.

There is no single laboratory result that makes the diagnosis on its own. MG is diagnosed clinically, then supported by antibody testing, electrophysiology, and imaging. The essential reasoning is: does the weakness have the right pattern (fluctuating, fatigable, usually ocular or bulbar first), do the findings fit the bedside tests, and does the patient lack features of an upper motor neuron or myopathic disease?

LEMS is diagnosed on the triad of proximal weakness, areflexia, and autonomic features, with supportive pharmacological testing (improvement after 3,4-diaminopyridine or pyridostigmine), abnormal neuromuscular electrophysiology, and P/Q-type VGCC antibodies, followed by a search for small cell lung cancer.

Severity scores serve different purposes in the two diseases. In MG, MGFA classes, the Quantitative Myasthenia Gravis (QMG) score, and the MG Activities of Daily Living (MG-ADL) scale are used as outcome measures in trials. The international consensus cites trial outcomes such as reduction in QMG score and prednisone dose to show benefit of thymectomy added to prednisone, but the key clinical message is not the exact number; it is that benefit is sustained to 60 months ^[1]. In LEMS, QMG is also used as a trial endpoint in amifampridine studies.

Management of MG follows current international consensus guidance published in 2021, updating the 2016 guidance of the Myasthenia Gravis Foundation of America task force ^[1], together with an American Academy of Neurology practice advisory on thymectomy (referenced within that consensus) and StatPearls summaries. Management of LEMS follows the European Federation of Neurological Societies treatment guidelines, which are discussed in the LEMS review literature, and product information for symptomatic drugs ^[3][5].

Four principles recur:

1. Symptomatic treatment first, usually with an anticholinesterase, because it works within minutes.
2. Immunosuppression for sustained control.
3. Thymectomy for a defined subgroup.
4. Fast treatment for crisis or severe exacerbation, then a plan to reduce long-term drug exposure.

Acetylcholinesterase inhibitors increase the amount of acetylcholine at the neuromuscular junction by preventing its breakdown.

• Pyridostigmine bromide is preferred to neostigmine because of its longer duration of action. For patients who cannot tolerate the bromide salt because of gastrointestinal effects, ambenonium chloride can be used ^[2].
• Patients with MuSK MG respond poorly to anticholinesterase drugs and may require higher doses ^[2].
• Pyridostigmine treats symptoms; it does not alter the autoimmune process, and the patient's need for it often falls once immunotherapy takes effect.

Corticosteroids and azathioprine are the first-line immunosuppressive agents for MG ^[2]. The consensus position on when and how to use them rests on their benefits and on the side-effect burden of long-term steroid use.

• Corticosteroids (prednisone, prednisolone, methylprednisolone) are effective. In ocular MG, a small randomised trial supports low-dose prednisone rather than the high doses traditionally used; the median prednisone dose to achieve sustained minimal manifestation status was 15 mg per day, compared with none in the placebo group ^[1].
• Steroid-sparing agents such as azathioprine, mycophenolate, cyclosporine, tacrolimus, cyclophosphamide, methotrexate, and others are added when corticosteroids are inadequate, poorly tolerated, or contraindicated.
• Methotrexate has weak evidence in MG. In a double-blind trial of methotrexate 20 mg per week versus placebo in patients on prednisone, there was no meaningful difference in steroid dose or clinical scores ^[1]; the international consensus therefore permits its consideration only when agents with stronger randomised evidence have failed or are not tolerated ^[1].
• Rituximab is particularly recommended as an early therapeutic option in MuSK-antibody-positive MG that has responded poorly to initial immunotherapy. In AChR-antibody-positive MG its efficacy is uncertain; it may be used if patients fail or cannot tolerate other agents ^[1].
• Eculizumab, a C5 complement inhibitor that prevents formation of the membrane attack complex, is considered for severe, refractory, AChR-antibody-positive generalized MG. In a phase II crossover trial, 6 of 7 treated patients (86%) achieved a 2-point improvement in QMG score, compared with 57% with placebo ^[1]. In the phase III REGAIN trial of 125 patients with refractory non-thymomatous AChR MG, the primary MG-ADL endpoint did not quite reach significance, but secondary and sensitivity analyses favoured treatment, and a long-term open-label extension showed a 75% reduction in exacerbations and 56% of patients reaching minimal manifestation status or pharmacological remission at a median follow-up of 22.7 months ^[1].
• Vaccination before eculizumab is mandatory: meningococcal conjugate (MenACWY) and serogroup B (MenB) vaccines must be given at least 2 weeks before starting treatment, with antibiotic cover if treatment cannot be delayed. Penicillin VK 250 to 500 mg every 12 hours is usually first-line chemoprophylaxis; macrolide or fluoroquinolone alternatives exist for patients allergic to penicillin, but these can worsen MG ^[1].
• Intravenous immunoglobulin and plasmapheresis are used when a rapid response is required, such as in myasthenic crisis or peri-operatively. They are not usually long-term maintenance for most patients; European guidelines cite a short-term benefit in LEMS too ^[3].

Steroids can transiently worsen MG when first started, so inpatient monitoring is sensible when they are commenced in a patient with significant weakness.

Thymectomy is a mainstay for a defined subgroup of MG. Evidence from the randomised MGTX trial showed that extended transsternal thymectomy plus alternate-day prednisone gave lower time-weighted QMG scores and lower prednisone requirements than prednisone alone, with fewer patients needing azathioprine or hospitalisation for exacerbation over 3 years, and benefit is still present at 60 months ^[1].

The international consensus and the AAN practice advisory it cites guide practice ^[1]:

• In non-thymomatous generalized MG with AChR antibodies in patients aged 18 to 50 years, thymectomy should be considered early, to improve clinical outcomes and reduce immunotherapy and hospitalisation requirements. ^[1]
• Thymectomy should be strongly considered if the patient fails an adequate trial of immunotherapy or has intolerable adverse effects from it.
• It is an elective procedure and should be done when the patient is stable, because postoperative pain and mechanical factors can limit respiratory function.
• Endoscopic and robotic approaches have a good safety record in experienced centres and appear to yield results similar to transsternal thymectomy, although data from direct randomised comparisons are not available.
• Thymectomy may also be considered in generalized MG without detectable AChR antibodies if the patient does not respond adequately to immunosuppressive therapy.
• There is no current evidence of benefit in MuSK, LRP4, or agrin antibody disease, or in non-thymomatous ocular MG without secondary generalization.
• Thymectomy is indicated in all patients with thymoma, irrespective of antibody status, and it is commonly performed 1 to 2 years from disease onset in non-thymomatous AChR MG in patients aged 15 to 50 years ^[2].
• An American Academy of Neurology practice advisory recommends that clinicians should discuss thymectomy with patients who have AChR-antibody-positive generalized MG and who are 18 to 65 years old ^[1]. The two age ranges differ because the consensus reflects the MGTX inclusion criteria, while the advisory applies the trial to routine practice; explain that difference to patients when counselling.

Thymectomy in children, in MuSK disease, or purely for ocular MG should be discussed with the neuromuscular and thoracic surgical team rather than applied routinely.

LEMS treatment follows European EFNS guidelines as summarised in the review literature ^[3]:

• Symptomatic treatment: acetylcholinesterase inhibitors such as pyridostigmine can help but are less predictably effective than in MG and are not the first line of symptomatic therapy for many patients. The better documented symptomatic drug is 3,4-diaminopyridine, which blocks presynaptic voltage-gated potassium channels, prolongs the presynaptic action potential, increases acetylcholine release, and has a well-documented clinical benefit ^[3]. Its phosphate salt (amifampridine) is the marketed formulation.
• Amifampridine dosing (Firdapse prescribing information) ^[5]:
  • Adults and children weighing 45 kg or more: 15 to 30 mg by mouth each day in 3 to 5 divided doses, with increases of 5 mg every 3 or 4 days as needed, to a maximum single dose of 20 mg and a maximum total daily dose of 100 mg. ^[5]
  • Children weighing less than 45 kg: 5 to 15 mg per day in 3 to 5 divided doses, with increases of 2.5 mg every 3 or 4 days, to a maximum single dose of 10 mg and a maximum total daily dose of 50 mg. ^[5]
  • In renal impairment, hepatic impairment, or known NAT2 poor metaboliser status, start at the lowest recommended initial dose and titrate carefully; no dose recommendation exists for end-stage renal disease.
  • Contraindications are a history of seizures or hypersensitivity to amifampridine or another aminopyridine; seizures occur in about 2% of treated patients at recommended doses. Firdapse is indicated from 6 years of age; it is given with or without food, and doses are spaced 3 to 5 times daily. ^[5]
• Immunotherapy: if symptomatic treatment is insufficient, immunosuppression is added. Prednisone or prednisolone with azathioprine is the best documented combination. Mycophenolate and cyclosporine are commonly considered; rituximab has shown benefit in a small number of patients. Intravenous immunoglobulin may improve symptoms in the short term, and plasmapheresis is useful for acute worsening but not usually for maintenance ^[3].
• Cancer treatment is central when there is associated small cell lung cancer. Treating the tumour often improves the LEMS, and survival in small cell lung cancer with LEMS is slightly better than in small cell lung cancer without LEMS ^[3].
• Supportive care: physical training is safe in mild or moderate LEMS, obesity should be avoided, and infections or other complications should be treated promptly. Drugs that worsen neuromuscular transmission should be avoided. Standard vaccinations are appropriate. In pregnancy, intravenous immunoglobulin should be considered because of the risk of fetal arthrogryposis; transient neonatal LEMS from transplacental antibody transfer has been described ^[3].

Amifampridine should not be combined casually with cholinesterase inhibitors: the combination can increase cholinergic effects and adverse reactions ^[5]. Amifampridine interacts importantly with drugs that lower seizure threshold.

A myasthenic crisis is acute respiratory paralysis due to involvement of the intercostal muscles and diaphragm; it is a medical emergency requiring ventilatory support, intensive care, and close airway monitoring ^[2]. Precipitants are the same as for exacerbation: infection, surgery, drugs, heat, emotional stress, and medication changes.

When rapid improvement is required (crisis, severe exacerbation before surgery, peri-operative stabilisation):

• Intravenous immunoglobulin or plasmapheresis is the treatment of choice because of its rapid onset of action.
• High-dose corticosteroids may be used; their effect starts over days rather than minutes.
• Mechanical ventilation is needed when vital capacity or bulbar strength is inadequate.
• In immune checkpoint inhibitor-related MG, early aggressive treatment with high-dose steroids, plasma exchange, or intravenous immunoglobulin may be required ^[1].

Where possible, elective intubation and timing of immunotherapy before thymectomy reduce crisis risk in patients with borderline respiratory muscle function.

Some medicines worsen neuromuscular transmission or provoke MG. This list should be kept close to hand when treating patients with MG or LEMS.

• Drugs commonly implicated in MG worsening include aminoglycosides, fluoroquinolones, beta-blockers, and neuromuscular blocking agents ^[2].
• Macrolides and fluoroquinolones can worsen MG and complicate meningococcal prophylaxis before eculizumab ^[1].
• Immune checkpoint inhibitors (PD-1, PD-L1, or CTLA-4 inhibitors used in cancer therapy) can cause de novo severe MG or flare pre-existing MG. Estimated frequency among PD-1 treated patients is 0.12% to 0.2%. Onset is usually early, with a median of 4 weeks (range 6 days to 16 weeks), and myasthenic crisis occurs in about 45% of affected patients. Concurrent myositis occurs in about 37% and myocarditis in about 8% ^[1]. Pre-existing MG is not an absolute contraindication to checkpoint therapy if disease is well controlled, but monitoring and avoiding combined regimens is advised ^[1].
• Drugs with cholinergic effects should be used carefully with amifampridine because cholinergic effects may add up ^[5].
• Seizure-threshold-lowering drugs are especially risky with amifampridine ^[5].
• Penicillamine, chloroquine, and some antimalarials and antibiotics are recognised precipitants in clinical references even if not detailed in the sources used here; local formularies and neuromuscular advice should be followed.
• Magnesium tends to worsen transmission and is avoided or used very cautiously.

MG complications include:

• Myasthenic crisis with respiratory failure, once a major cause of death but now uncommon with modern immunotherapy: crisis mortality was estimated at 50% to 80% 50 years ago and is now about 4.47% ^[2]. ^[1]
• Aspiration pneumonia from bulbar weakness.
• Thymoma-related disease (local effects and paraneoplastic MG) in patients with thymoma.
• Adverse effects of long-term immunosuppression, including opportunistic infections and lymphoproliferative malignancies after prolonged drug treatment.
• Ophthalmoparesis-related disability and chronic fatigue.

LEMS complications include:

• Progressive proximal weakness and functional dependence, occasionally including respiratory muscle involvement.
• Autonomic failure (dry mouth, constipation, syncope from blood pressure change).
• Cerebellar ataxia in some patients (particularly with VGCC antibodies and brain involvement).
• Paraneoplastic disease association: LEMS may be a marker of small cell lung cancer that is otherwise asymptomatic ^[3].
• Fetal arthrogryposis or transient neonatal LEMS in pregnancy ^[3].

LEMS itself does not produce the same crisis pattern as MG, but severe weakness can still require ventilatory support, and drug treatment must be chosen with seizure risk in mind.

Most patients with MG have a near-normal lifespan with current treatment modalities, and morbidity comes mainly from intermittent weakness (including aspiration) and from adverse drug effects ^[2]. Factors predicting risk of secondary generalization include older age at onset, high anti-AChR antibody titres, and the presence of a thymoma; conversely, early immunosuppression with corticosteroids or azathioprine and the presence of only one of ptosis or diplopia are associated with lower risk ^[2]. Risk of relapse is lower in patients whose disease begins before 40 years, in those who have early thymectomy, and in those given prednisolone, whereas it is higher in those with anti-Kv1.4 antibodies and coexisting autoimmune disease ^[2].

In LEMS, non-tumour patients have near-normal survival. Patients with small cell lung cancer have a serious prognosis from the cancer, although the presence of LEMS is associated with slightly better survival than in small cell lung cancer without LEMS ^[3]. Early cancer treatment improves both cancer outcomes and weakness.

Primary prevention of MG or LEMS is not possible, but secondary prevention matters.

• Screen new-onset MG for thymoma with chest CT or MRI ^[2].
• Screen all patients with LEMS for small cell lung cancer repeatedly for 2 years if the first screen is negative ^[3].
• Screen for coexisting autoimmune thyroid, connective tissue, and haematological disease in MG.
• Medication safety: give patients a card listing drugs to avoid or use only with specialist advice; every prescriber and pharmacist should be told about MG before any new drug is started.
• Avoid dangerous anaesthesia practices: drugs that worsen neuromuscular transmission and neuromuscular blocking agents should be avoided whenever possible, and if anaesthesia is required the team should be warned in advance.
• Vaccination: standard vaccination is appropriate in LEMS. Before eculizumab, meningococcal vaccination (and appropriate antibiotic cover) is mandatory.
• Post-surgical risk: patients should know that worsening weakness after surgery is possible but often treatable, and that they should report promptly rather than wait.

Both MG and LEMS can worsen, improve, or stay stable during pregnancy, and the neonate can be affected. In LEMS, intravenous immunoglobulin should be considered during pregnancy because of the risk of fetal arthrogryposis; transient neonatal LEMS due to transplacental transfer of IgG antibodies has been described ^[3]. In MG, treatment decisions should be made by a combined obstetric, neurology, and neonatal team; pyridostigmine is continued and most immunosuppressants are chosen for fetal safety, but exact regimens should follow local maternity and neuromuscular guidance. The main teaching point is to plan delivery and neonatal observation in advance rather than to improvise.

In the West, childhood MG is uncommon; in Asia it is common and often presents with ocular symptoms. Juvenile MG progresses more slowly and remits more often than adult MG ^[2]. Congenital myasthenic syndromes are not autoimmune; they are genetic junction defects and should not be treated with immunotherapy. Thymectomy is generally not used in very young children unless the course is severe. Anticholinesterase drugs and steroids are used carefully in paediatric patients. In LEMS, amifampridine is licensed from 6 years of age ^[5].

Late-onset MG is commoner in males and is often associated with thymic atrophy rather than hyperplasia ^[2]. Drug side effects matter more in older patients, and comorbidities are more frequent. Thymectomy may still be appropriate but should be discussed individually; the AAN advisory range extends thymectomy discussion to 65 years, while the consensus specifies 18 to 50 years for routine early consideration ^[1]. In LEMS, about 19 of 63 patients in the main amifampridine studies were 65 or older, and dosing should start cautiously in the presence of decreased organ function ^[5].

Patients receiving immune checkpoint inhibitors for cancer can develop severe new-onset MG, or worsening of pre-existing MG, usually early in treatment and often with myositis or myocarditis. Pre-existing well-controlled MG is not an absolute contraindication, but close monitoring (especially of bulbar and respiratory function), avoidance of combined checkpoint regimens, and continuation of MG treatment are recommended. If overt MG develops, high-dose steroids with plasma exchange or intravenous immunoglobulin may be needed, and the decision to stop cancer immunotherapy depends on the oncological situation ^[1].

• A focused neurological examination, looking for fatigable weakness and (in LEMS) areflexia, is available everywhere and is more important than expensive technology.
• One ice-pack test and an edrophonium response, used carefully, can secure a clinical diagnosis when antibodies and electrophysiology are unavailable.
• A plain CT of the chest may be feasible when MRI is not; its main job is to look for a thymoma in MG or small cell lung cancer in older smokers with LEMS.
• Pyridostigmine and prednisone are inexpensive and widely available; their use, with screening for worsening and infection, is the backbone of management where biologics are unavailable.
• Amifampridine may not be available or affordable; symptomatic treatment and immunosuppression then carry the whole management in LEMS, with attention to tumour treatment.
• Respiratory support and intensive care are the limiting resource in crisis. Early recognition, avoidance of precipitating drugs, and early referral to a centre with ventilatory support prevent many deaths.

A point worth remembering for examinations: the same weakness can look similar in MG and LEMS. Keeping the junction model in mind (sending versus receiving) is faster and more reliable than rote lists.

• MG and LEMS are both autoimmune neuromuscular junction diseases, but antibodies bind opposite sides of the synapse and produce different patterns of weakness.
• MG weakness worsens with use and improves with rest; ocular or bulbar symptoms are common at onset, and reflexes are normal.
• LEMS produces proximal lower-limb weakness, areflexia, and autonomic symptoms; strength may briefly improve with repeated contraction; about half of patients have small cell lung cancer.
• Diagnosis is clinical, supported by antibodies (AChR, MuSK, LRP4, VGCC), repetitive nerve stimulation (a 10% or more decrement in MG), single-fibre EMG, ice-pack and edrophonium testing, and imaging.
• Modern MG treatment starts with pyridostigmine, adds corticosteroids and steroid-sparing agents, uses thymectomy in a defined subgroup of AChR-antibody-positive generalized MG, and reserves intravenous immunoglobulin, plasma exchange, eculizumab, and rituximab for selected or severe cases.
• LEMS treatment uses 3,4-diaminopyridine (amifampridine) as the best documented symptomatic therapy, immunosuppression (prednisone or prednisolone with azathioprine) if needed, and essential treatment of any associated cancer.
• Amifampridine dosing in adults is 15 to 30 mg per day by mouth in 3 to 5 divided doses, titrated by 5 mg every 3 to 4 days up to a maximum single dose of 20 mg and a maximum total daily dose of 100 mg. It is contraindicated in patients with a history of seizures.
• Myasthenic crisis is a respiratory emergency with modern mortality around 4.47%, compared with 50% to 80% historically.
• Drugs that can worsen transmission (aminoglycosides, fluoroquinolones, macrolides, beta-blockers, magnesium, neuromuscular blockers) must be used cautiously in these patients.
• Screening for thymoma in MG and for lung cancer in LEMS should not be forgotten.
• Pregnancy, childhood, older age, and cancer immunotherapy each modify management and need individual planning.

Multiple sclerosis. Small cell lung cancer and paraneoplastic syndromes. Thymic tumours. Neuromuscular junction physiology. Respiratory failure and airway management. Congenital myasthenic syndromes.