Myasthenia Gravis — Clinical Case

DCE Long Case

Patient brief (provided to trainee)

Patient: Mr Daniel Okonkwo, 43 years old, project manager. [1]

Presenting complaint: Review in the neurology clinic two weeks after discharge from intensive care following a myasthenic crisis. He wants to understand why it happened and how to prevent another. [1]

History of presenting complaint: Diagnosed with acetylcholine-receptor-antibody-positive generalized myasthenia gravis 14 months ago, presenting with fatigable diplopia and slurred speech that progressed to difficulty climbing stairs and lifting his arms overhead. Initially controlled on pyridostigmine, but over the past three months his bulbar and limb weakness worsened and his prednisolone was increased from 25 mg to 40 mg daily. Two weeks ago he developed a chest infection and over 36 hours became increasingly breathless and unable to clear his secretions; he was admitted, found to have a forced vital capacity of 13 mL/kg, intubated, and received five sessions of plasma exchange and IV antibiotics for right basal pneumonia. He was extubated after three days. [1]

Past history:

• A 4-centimetre anterior mediastinal mass (thymoma) on CT thorax at MG diagnosis, not yet resected
• Steroid-induced osteoporosis with a T12 wedge fracture six months ago
• Hypertension [1]

Current medications:

• Pyridostigmine 90 mg five times daily
• Prednisolone 40 mg daily
• Alendronate 70 mg weekly, calcium-vitamin D
• Perindopril 5 mg daily [1]

Examination findings (trainee elicits):

• Alert, hypophonic speech that fatigues
• Asymmetric fatigable ptosis (worse left), positive sustained-upgaze test at 45 seconds, positive ice-pack test
• Mild fatigable ophthalmoplegia, pupils spared and reactive
• Bulbar weakness with nasal regurgitation history
• Proximal limb power 4+ out of 5 at rest, fatiguing to 4 out of 5 on sustained arm elevation
• Reflexes present and symmetrical, flexor plantar responses
• FVC 32 mL/kg at rest (improved from crisis) [1]

Candidate's structured presentation (model)

Opening statement: [1]

"Mr Okonkwo is a 43-year-old project manager with a 14-month history of acetylcholine-receptor-antibody-positive generalized myasthenia gravis. He presents for review two weeks after a myasthenic crisis requiring intubation and plasma exchange, triggered by a chest infection. He has an unresected 4-centimetre thymoma on CT thorax and steroid-induced osteoporosis with a vertebral wedge fracture. He is currently on pyridostigmine 90 milligrams five times daily and prednisolone 40 milligrams daily. [1]

His main problems are:

1. AChR-positive generalized MG, recently in crisis (MGFA Class V at that point, now recovering to Class III) — disease control inadequate
2. Unresected thymoma — requires thymectomy
3. Steroid-induced osteoporosis with a vertebral wedge fracture — on prednisolone 40 milligrams daily
4. Risk of recurrent myasthenic crisis — precipitant (infection) and exacerbating drugs to address
5. Occupational and psychosocial impact — off work for two months, anxious about recurrence and driving" [1]

Management plan: [1]

1. Add a steroid-sparing agent and optimise immunosuppression. His crisis occurred despite prednisolone 40 milligrams daily, so add azathioprine (after confirming TPMT activity) 1 to 3 milligrams per kilogram per day, accepting a 6 to 12 month lag to full effect, with the aim of tapering prednisolone. Consider mycophenolate if azathioprine is not tolerated. If he remains refractory or has another crisis, escalate to rituximab or eculizumab.
2. Thymectomy. The thymoma is an absolute indication. Refer to thoracic surgery for an extended transsternal thymectomy once his MG is stabilised — possibly with a short pre-operative course of IVIG or plasma exchange to reduce peri-operative respiratory risk.
3. Crisis prevention. Vaccinate against influenza, pneumococcus and COVID-19; provide a written action plan and a medical-alert card listing drugs to avoid (aminoglycosides, fluoroquinolones, magnesium, beta-blockers, calcium channel blockers, immune checkpoint inhibitors); educate on early warning signs.
4. Bone protection. Continue alendronate and calcium-vitamin D; repeat bone densitometry; reduce prednisolone as disease control allows; consider an endocrine referral for the fragility fracture.
5. Shared decision-making. Discuss the timing of thymectomy relative to his recovery and work, driving restrictions, and the realistic goal of minimal manifestations rather than cure. Address his anxiety and arrange neurology nurse and psychology support. [1]

Examiner discussion questions

Q: "Why did he have a crisis despite being on prednisolone 40 milligrams daily?" [1]

"Prednisolone controls the autoimmune attack but takes weeks to reach full effect, and his disease was still active — his bulbar and limb weakness had been worsening for three months before the crisis. A crisis is usually triggered by an identifiable precipitant, and here it was the chest infection, compounded by the natural history of inadequately controlled disease. The lesson is that a patient whose MG is worsening despite current therapy needs escalation of immunosuppression before a crisis occurs, not after. His prednisolone dose was increased but he was not given a steroid-sparing agent, and without one the options for further escalation are limited and the steroid toxicity accrues. The crisis tells me his disease is refractory to his current regimen and he needs a steroid-sparing agent and, given the recent crisis, early consideration of a biological therapy such as rituximab or eculizumab." [1]

Q: "What is the role of thymectomy in this patient, and would it have prevented the crisis?" [1]

"Thymectomy has two roles here. The thymoma makes it mandatory — it may be malignant and must be resected en bloc with surrounding thymic tissue for diagnosis, staging and therapy [3]. Beyond the thymoma, in a young patient under 50 with AChR-positive generalized MG, thymectomy improves long-term outcome and reduces drug burden — the MGTX trial showed superiority of extended transsternal thymectomy plus prednisone over prednisone alone over three years [2]. Whether earlier thymectomy would have prevented this specific crisis is uncertain — thymectomy is not a rescue therapy and its benefit accrues over years — but over the longer term it reduces disease severity and the need for immunosuppression, which would lower his future crisis risk. Thymectomy is not indicated in MuSK-positive MG, but this patient is AChR-positive. I would refer him to thoracic surgery once his MG is stabilised."

Q: "How would you choose between IVIG and plasma exchange for a future crisis?" [1]

"Both are effective and neither has been shown clearly superior in head-to-head trials. Plasma exchange works faster — improvement within days — and is preferred in severe crisis and in MuSK-MG, where IVIG is less effective. It requires central venous access and carries risks of hypotension, line infection and bleeding. IVIG is easier to administer and has fewer line complications, with a slightly slower onset of one to two weeks; its adverse effects include headache, aseptic meningitis, thromboembolism and volume overload. For this patient, who has a history of response to plasma exchange and who is AChR-positive, either would be reasonable; I would lean toward plasma exchange for the fastest response in a severe crisis and reserve IVIG for a moderate deterioration or when vascular access is problematic." [1]

Q: "What are the common precipitants of a myasthenic crisis, and how do you address them?" [1]

"The common precipitants are infection — respiratory most often, as here — aspiration, medication non-adherence or abrupt withdrawal, a steroid taper, surgery, pregnancy and the postpartum period, and drugs that worsen neuromuscular transmission such as aminoglycosides, fluoroquinolones, magnesium and immune checkpoint inhibitors. The approach is to find and treat the precipitant in every crisis — in his case the chest infection, treated with beta-lactam antibiotics that do not worsen MG — while giving rapid immunotherapy and ventilatory support. For prevention, I vaccinate, provide an action plan and a drugs-to-avoid list, ensure medication adherence, and avoid unnecessary steroid tapers. Patient education is central: he needs to recognise early warning signs and present early." [1]

DCE Short Case — Neurological Examination for Fatigable Weakness

Instruction

"Examine this patient's neurological system. She has noticed drooping of her eyelids and double vision. You have 7 minutes for examination and 8 minutes for discussion." [1]

Key signs the patient demonstrates

• Fatigable ptosis — asymmetric, worse on the left; develops or worsens on sustained upgaze
• Positive sustained-upgaze test — ptosis appears at 45 to 60 seconds of upgaze
• Positive ice-pack test — ptosis improves after two minutes of ice over the eyelid
• Fatigable ophthalmoplegia — asymmetric, worsens on sustained lateral gaze
• Pupils spared and reactive — the key discriminator
• Fatigable nasal speech — voice fades after counting
• Fatigable proximal limb weakness — arms drift and grip fatigues on sustained elevation
• Preserved deep tendon reflexes — the other key discriminator (depressed reflexes would point to Lambert-Eaton) [1]

Systematic examination routine

1. Observe from the end of the bed: posture (head tilt to compensate for diplopia), ptosis, facial weakness (myasthenic snarl), a sternotomy scar (previous thymectomy), Cushingoid features (chronic steroids), a medical-alert bracelet.
2. Cranial nerves — eyes first: inspect for ptosis; assess lid position and levator function; perform sustained upgaze for one minute; perform the ice-pack test; test extraocular movements (watch for fatigability on sustained gaze); check pupils (spared in MG); look for a Cogan lid twitch.
3. Bulbar: ask the patient to count to 100 (voice fades and becomes nasal); test palatal movement and fatigability.
4. Motor: test power, then fatigability — arms outstretched for one minute, repeated sit-to-stand, neck flexion and extension against resistance. Power may be normal at rest and decline with use. Test reflexes (preserved in MG).
5. Respiratory: measure FVC at the bedside if available; assess cough strength. [1]

Presentation template

"I examined Mrs Lee's neurological system. She is a 52-year-old woman who is alert and cooperative. [1]

On inspection, there is asymmetric ptosis, more marked on the left. There are no surgical scars or stigmata of chronic steroid use. [1]

Cranial nerve examination of the eyes reveals variable ptosis. On sustained upgaze for one minute, the ptosis worsens on both sides, markedly on the left. The ice-pack test — two minutes of ice over the left eyelid — improved the left ptosis. Extraocular movements show a fatigable, asymmetric ophthalmoplegia. The pupils are equal and reactive. [1]

Bulbar assessment: her speech is initially clear but becomes nasal and fades after counting to sixty. [1]

Motor examination reveals normal tone. Power is 5 out of 5 at rest but fatigues on sustained arm elevation, with the left arm drifting down after one minute. Deep tendon reflexes are present and symmetrical. Sensation is intact. Coordination is intact. [1]

In summary, this patient has fatigable weakness of the ocular, bulbar and limb muscles with a positive sustained-upgaze test and a positive ice-pack test. The pupils are spared and the reflexes are preserved, which localises the problem to the postsynaptic neuromuscular junction — myasthenia gravis. I would confirm with anti-acetylcholine receptor antibodies and a CT thorax to screen for thymoma." [1]

Discussion questions

Q: "How do you distinguish myasthenia gravis from Lambert-Eaton myasthenic syndrome at the bedside?" [1]

"The two conditions are mirror images. Myasthenia gravis is postsynaptic, caused by antibodies against the acetylcholine receptor, and the weakness worsens with sustained activity — it fatigues. The reflexes are preserved and the pupils are spared, because the autonomic ganglia and the pupillary muscles use different receptors from the skeletal-muscle nicotinic receptor. Lambert-Eaton is presynaptic, caused by antibodies against the P/Q-type voltage-gated calcium channel on the motor nerve terminal, which reduces acetylcholine release. In LEMS the weakness improves with brief exercise — facilitation — the reflexes are depressed or absent and may reappear after exercise, and autonomic features such as a dry mouth, constipation and erectile dysfunction are prominent because the calcium channel antibody also affects the autonomic nervous system. LEMS is paraneoplastic in about half of cases, classically with small cell lung cancer, so a smoker with proximal weakness, areflexia and a dry mouth needs a CT chest and an anti-P/Q-type voltage-gated calcium channel antibody. In this patient the fatigability, the preserved reflexes and the spared pupils all point to MG, not LEMS." [1]

Q: "What is the role of the ice-pack test and the sustained-upgaze test?" [1]

"Both are bedside tests that demonstrate fatigability, the hallmark of myasthenia gravis, and distinguish it from fixed causes of ptosis such as a third nerve palsy or chronic progressive external ophthalmoplegia. The sustained-upgaze test asks the patient to hold upward gaze for a minute; in MG the levator palpebrae fatigues and ptosis develops or worsens, because sustained firing depletes the available acetylcholine against a reduced receptor reserve. The ice-pack test exploits the fact that cold locally inhibits acetylcholinesterase and improves neuromuscular transmission; applying ice to the ptotic eyelid for two minutes improves the ptosis in MG with a sensitivity of over 90 per cent for ocular MG. Both are simple, safe and bedside. The edrophonium, or Tensilon, test — a short-acting intravenous acetylcholinesterase inhibitor — is now rarely used because of the risk of bradycardia and bronchospasm and because these simpler tests and serology are usually sufficient." [1]

Q: "If her anti-acetylcholine receptor antibodies are negative, what would you do next?" [1]

"A negative anti-acetylcholine receptor antibody does not exclude myasthenia gravis — it is positive in only about 50 per cent of ocular MG and about 85 per cent of generalized MG. In an AChR-negative patient with a compatible phenotype I would send anti-MuSK antibodies, which account for 5 to 8 per cent of all MG and up to 30 to 40 per cent of AChR-negative generalized MG. Identifying MuSK-MG matters because it is a different disease — prominent bulbar and respiratory weakness, a female predominance, a poor response to pyridostigmine that can even worsen symptoms, no benefit from thymectomy, and a particularly good response to rituximab [4]. If both AChR and MuSK are negative, I would test anti-LRP4 in selected cases, and pursue electrophysiology — repetitive nerve stimulation for a decrement and single-fibre EMG for increased jitter — which can confirm impaired neuromuscular transmission even when antibodies are negative."

Q: "What is the most appropriate symptomatic treatment, and what is its limitation?" [1]

"Pyridostigmine, an acetylcholinesterase inhibitor, is the symptomatic mainstay — typically 30 to 60 milligrams four to six times daily, titrated to a maximum of about 600 to 1200 milligrams a day. It prolongs the action of acetylcholine at the junction and improves most patients with AChR-positive MG. Its key limitation is that it is purely symptomatic — it does not modify the underlying autoimmune attack on the receptor, so it does not control the disease or prevent progression or crisis. Patients with generalized MG therefore need immunosuppression, typically prednisolone introduced cautiously with an early steroid-sparing agent. A second limitation is that pyridostigmine is often ineffective or worsens MuSK-MG, where immunosuppression rather than symptomatic therapy drives management." [1]