Myasthenia Gravis — Presentation, Laboratory Evaluation and Treatment

Myasthenia Gravis — Presentation, Laboratory Evaluation and Treatment Fifteen–Twenty High-Yield Points Definition and epidemiology

Myasthenia gravis (MG) is an antibody-mediated disorder of neuromuscular transmission. The commonest target antigen is the postsynaptic muscle nicotinic acetylcholine receptor (AChR); these structures are vulnerable because they lie outside the blood-nerve barrier.

Overall incidence is 2–10 per 100,000. It affects all races and can begin at any age after the first year of life. Incidence rises with age but MG is underdiagnosed in the elderly.

Late-onset MG (LOMG) is increasingly recognised; reports of rising incidence may reflect improved diagnosis rather than a true biological change.

The hallmark is fatigable weakness — weakness that worsens with sustained or repeated activity and improves with rest, with characteristic diurnal variation (worse in the evening).

Ocular presentation is commonest: ptosis and diplopia, often asymmetrical, with Cogan's lid twitch. MG can mimic blepharospasm.

Bulbar features: dysarthria (nasal speech that fatigues), dysphagia, nasal regurgitation, jaw fatigue on chewing, and facial weakness with a "myasthenic snarl".

Generalised disease: proximal limb weakness, dropped head syndrome, and respiratory muscle weakness. Unusual presentations include distal MG and the "myasthenic hand".

In older patients, MG may present with recurrent falls — a presentation of major importance in geriatric practice and easily attributed to other causes.

Cardiac involvement and cognitive impairment have both been described in MG, and determinants of cognitive impairment in elderly myasthenic patients have been specifically studied.

MG is a treatable disease — more than 90% of patients return to normal function — so the diagnosis must be considered in anyone presenting with ptosis, diplopia, dysphagia, or limb or respiratory muscle weakness.

Serology: anti-AChR antibodies are the primary test and are positive in the majority; late-onset MG is characteristically anti-AChR seropositive. Anti-MuSK (muscle-specific tyrosine kinase) antibodies define a subgroup with predominant facial and bulbar involvement; anti-LRP4 accounts for a smaller fraction.

Neurophysiology: repetitive nerve stimulation showing a decremental response, and single-fibre EMG demonstrating increased jitter, which is the most sensitive test.

Bedside tests: the ice pack test for ptosis (cooling improves neuromuscular transmission) and the sleep/rest test — a safe alternative to the edrophonium (Tensilon) test, which is now rarely used because of cardiac risk in older patients.

CT of the thorax is mandatory in every new diagnosis to look for thymoma or thymic hyperplasia. Paraneoplastic MG is recognised, including with carcinoid tumour.

Additional baseline work: thyroid function and screening for associated autoimmune disease; forced vital capacity as the objective measure of respiratory reserve; and review of drugs that unmask or worsen MG (aminoglycosides, fluoroquinolones, macrolides, beta-blockers, magnesium, penicillamine).

Anticholinesterase inhibitors remain first-line for all patients, acting by inhibiting acetylcholine breakdown at the NMJ. Pyridostigmine is started at 30 mg two to four times daily and titrated. It acts in 10–30 minutes, peaks at two hours, and lasts about four hours. Muscarinic side effects (abdominal cramps, diarrhoea, sweating, bronchial and oral secretions) can be treated with propantheline, which may however mask overdose; nicotinic effects are fasciculation and cramps. Chronic high doses may increase weakness by downregulating AChRs.

Steroids are short-term immunosuppressives used while other agents take effect. A "steroid dip" — temporary worsening 4–10 days after starting high-dose steroids — is avoided by starting low and going slow, or by alternate-day treatment. In elderly patients, steroids and immunosuppressives carry greater risk, notably steroid-induced osteoporosis, so prophylaxis is required.

Steroid-sparing agents: azathioprine, mycophenolate mofetil, methotrexate, ciclosporin and tacrolimus. Rituximab (B-cell depletion) is particularly effective in MuSK-associated MG.

Rapid therapies: plasma exchange (PE) and intravenous immunoglobulin (IVIG). IVIG is given as 0.4 g/kg/day for five days, improves most patients within four to five days, and lasts weeks to months. Adverse effects of IVIG (fever, headache, nausea, allergic reaction; anaphylaxis in IgA deficiency; volume overload; renal failure; thrombosis and stroke with high infusion rates) are less severe than those of PE, whose complications relate mainly to vascular access, fluid shifts, and citrate-induced hypocalcaemia.

Thymectomy is the treatment of choice for thymoma (radiotherapy if unfit). In non-thymoma patients it is usually performed in generalised, AChR-positive MG under the age of 50–60. The randomised trial of transsternal thymectomy plus alternate-day steroids versus steroids alone showed improved clinical outcomes over three years. Benefit may take 6–12 months to appear; predictors of good response are female sex, limb-predominant weakness and AChR antibody positivity.

Crises: myasthenic crisis (weakness requiring ventilation) is precipitated by infection, intercurrent illness, surgery or too-rapid reduction of immunotherapy; cholinergic crisis results from excessive anticholinesterase. If the two cannot be distinguished, it is safe to stop anticholinesterases once the patient is ventilated. Treat infection aggressively and give IVIG or PE. For anaesthesia, prefer local or spinal; if general anaesthesia is needed, insert a nasotracheal tube, keep it for one to two days, avoid anticholinesterases on the morning of surgery and for 24 hours afterwards, and continue immunosuppressants.