Makindo Medical Notes

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Acetylcholine receptor (AChR) antibodies are autoantibodies that disrupt neuromuscular transmission by targeting AChRs at the postsynaptic membrane. They are a hallmark of Myasthenia Gravis (MG), an autoimmune disorder causing fluctuating skeletal muscle weakness and fatigability. 💡 The key feature: weakness worsens with exertion and improves with rest.

🧬 Pathophysiology of MG and Antibodies

• Blocking: AChR antibodies prevent acetylcholine from binding to its receptor.
• Modulating/Internalisation: Antibody binding → receptor internalisation and degradation → ↓ receptor density.
• Complement-mediated damage: Antibody binding activates complement, damaging the postsynaptic folds and reducing efficiency of neuromuscular transmission.
• Result: ↓ endplate potentials, many fail to reach threshold for action potential → fatigable weakness.

📌 Clinical Features

• Ocular: Ptosis, diplopia (often asymmetric, worsens in evening).
• Bulbar: Dysphagia, dysarthria, nasal speech, jaw fatigue.
• Generalised: Limb weakness (proximal > distal), neck flexor weakness.
• Respiratory: Myasthenic crisis → life-threatening respiratory failure, precipitated by infection, surgery, drugs.

🔎 Types of AChR Antibodies

• Binding antibodies: Present in ~85% of generalised MG, ~50% ocular MG.
• Blocking antibodies: Prevent acetylcholine binding, usually tested alongside binding antibodies.
• Modulating antibodies: Promote receptor internalisation and degradation.

⚠️ ~10–15% of MG patients are "seronegative" for AChR antibodies. Some of these have MuSK antibodies or LRP4 antibodies.

🧪 Investigations

• Serology: AChR, MuSK, and LRP4 antibodies.
• Neurophysiology: Repetitive nerve stimulation → decremental response; single-fibre EMG most sensitive.
• Imaging: Chest CT/MRI for thymoma or thymic hyperplasia.
• Clinical bedside tests: Ice-pack test (ptosis improves with cooling), edrophonium test (historical, rarely used now).

💊 Management

• Symptomatic: Pyridostigmine (anticholinesterase) improves transmission.
• Immunosuppression: Corticosteroids (prednisolone) ± steroid-sparing agents (azathioprine, mycophenolate, ciclosporin).
• Rapid rescue: IVIG or plasmapheresis in myasthenic crisis or pre-op stabilisation.
• Thymectomy: Recommended if thymoma present; considered in younger patients with generalised MG even without thymoma (per RCT evidence: MGTX trial).

🚨 Myasthenic Crisis

• Defined as life-threatening weakness requiring intubation or ventilation.
• Common triggers: infection, surgery, pregnancy, drugs (aminoglycosides, quinolones, beta-blockers).
• Management: ICU admission, airway support, IVIG or plasma exchange, corticosteroid optimisation.

🧪 Sample Requirements (for antibody testing)

• Adult: 5 ml blood in Gold-top SST tube (serum) or 3.5 ml rust-top gel tube.
• Send to reference immunology lab; some centres batch test.

💡 Exam Tip: Differentiate MG from Lambert-Eaton Myasthenic Syndrome (LEMS) — in LEMS, weakness improves with repeated activity, reflexes are reduced, and it often associates with small cell lung carcinoma.

📚 References

• BNF: Myasthenia Gravis treatment protocols
• NICE CG186: Neurological conditions
• MGTX trial: Thymectomy in non-thymomatous MG (NEJM 2016)
• Association of British Neurologists (ABN) MG guidelines