Myasthenia Gravis Viva

Long Case Viva Defence

Candidate's opening statement (model answer)

"Mr Tan is a 41-year-old engineer with a 14-month history of acetylcholine-receptor-antibody-positive generalized myasthenia gravis. He presents for review two weeks after a myasthenic crisis requiring three days of intensive care and plasma exchange, triggered by a respiratory infection. His CT thorax at diagnosis demonstrated a 3-centimetre anterior mediastinal mass reported as a thymoma. He is currently on pyridostigmine 90 milligrams five times daily and prednisolone 40 milligrams daily, and over the past year he has developed steroid-induced osteoporosis with a vertebral wedge fracture. [1]

His main problems are:

1. AChR-positive generalized MG, recently in crisis — disease control inadequate on current therapy
2. Thymoma on CT thorax — 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 driving implications — he has been off work for three months" [1]

Examiner probing questions and model answers

Q1: "What is the MGFA clinical classification, and where does this patient sit?" [1]

"The MGFA clinical classification, established in 2000, stratifies myasthenia gravis severity from Class I to Class V [1]. Class I is any ocular weakness only. Class II is mild weakness affecting other than ocular muscles, subdivided into IIa limb-predominant and IIb bulbar or respiratory predominant. Class III is moderate weakness, again IIIa limb and IIIb bulbar or respiratory. Class IV is severe weakness, IVa limb and IVb bulbar or respiratory. Class V is defined by the need for intubation, with or without mechanical ventilation — the operational definition of myasthenic crisis. This patient, who required intubation during his recent crisis, was at Class V at that point; he is now recovering and probably sits at Class III to IV. The classification is the common language of MG trials and clinic letters and guides the intensity of treatment."

Q2: "Why is this patient a candidate for thymectomy, and what is the evidence?" [1]

"He has two indications. First, the thymoma is an absolute indication for thymectomy — it may be malignant and must be resected en bloc with the surrounding thymic tissue for diagnosis, staging and therapy [3]. About 10 to 15 per cent of MG patients have a thymoma, and all of them undergo thymectomy. Second, even setting the thymoma aside, he is young — 41 — with AChR-positive generalized MG that is poorly controlled and recently culminated in crisis. The MGTX trial, published in the New England Journal of Medicine in 2016, randomised 126 patients with non-thymomatous AChR-positive generalized MG to extended transsternal thymectomy plus prednisone versus prednisone alone, and showed that the thymectomy group had a lower time-weighted average Quantitative Myasthenia Gravis score, required a lower average prednisone dose, and needed fewer azathioprine courses and hospitalisations over three years [2]. So thymectomy in this patient is both mandatory (thymoma) and beneficial (disease control and steroid reduction). I would refer him to a thoracic surgeon for an extended transsternal thymectomy once his MG is stabilised. Critically, this does not apply to MuSK-positive MG, where thymectomy is not beneficial — the thymus is not part of the pathology in MuSK disease."

Q3: "How would you optimise his immunosuppression to reduce the chance of another crisis?" [1]

"His disease is inadequately controlled — he has had a crisis on pyridostigmine and prednisolone alone. My plan is to add a steroid-sparing immunosuppressant so that I can taper the prednisolone and reduce both his risk of recurrence and his steroid toxicity. I would check TPMT activity and start azathioprine, titrating to 1 to 3 milligrams per kilogram per day, accepting that it takes 6 to 12 months to reach full effect. Mycophenolate mofetil is an alternative with a slightly faster onset. If he remains refractory or has another crisis despite azathioprine, I would escalate to a biological therapy. Rituximab — anti-CD20 B-cell depletion — is effective in both AChR-positive and MuSK-positive MG, with a particularly strong response in MuSK disease. Eculizumab, a monoclonal antibody against complement C5, is approved for refractory AChR-positive MG on the basis of the REGAIN trial [4], and its open-label extension showed that 57 per cent of patients achieved minimal-manifestation status by 130 weeks. Before eculizumab, he must be vaccinated against meningococcus at least two weeks in advance. The newer FcRn inhibitors such as efgartigimod deplete IgG including pathogenic antibodies and offer a rapid-onset option. The aim throughout is MGFA minimal-manifestations status on the lowest possible drug burden."

Q4: "He fractured a vertebra on prednisolone. How will you manage his bone health?" [1]

"Steroid-induced osteoporosis is a predictable and preventable complication. He already has a fragility fracture, which puts him in a high-risk category. My plan is: first, reduce the steroid exposure as fast as disease control allows, by adding the steroid-sparing agent and tapering prednisolone. Second, initiate bone-protective therapy — a bisphosphonate such as alendronate 70 milligrams weekly with calcium and vitamin D supplementation, having checked his bone densitometry, renal function, calcium and 25-hydroxyvitamin D level. A denosumab or zoledronate is an alternative if oral bisphosphonate is not tolerated. Third, screen for and manage other steroid complications — monitor fasting glucose and blood pressure, consider gastric protection, and counsel on weight, diet and smoking. I would involve a bone-health or endocrine service for the fragility fracture. The principle is that the complications of treatment are themselves a reason to minimise steroids — every effort to achieve disease control on steroid-sparing therapy protects his bones as well as his myasthenia." [1]

Q5: "What advice would you give him about future crises?" [1]

"I would give him a written action plan and a medical alert. The key messages are: recognise the early warning signs of a crisis — increasing breathlessness, a weak cough, slurred or fading speech, difficulty clearing secretions, and difficulty chewing — and seek emergency care early rather than waiting. He should carry a list of drugs to avoid: aminoglycosides such as gentamicin, fluoroquinolones, macrolides, beta-blockers, calcium channel blockers, magnesium, and immune checkpoint inhibitors. He should be up to date with influenza, pneumococcal and COVID-19 vaccination to reduce infectious precipitants. He should not stop his myasthenia medications abruptly. And he should tell any doctor, dentist or anaesthetist that he has myasthenia gravis before any procedure or prescription. I would document this conversation and give him a written summary." [1]

Short Case Discussion

Scenario: "Examine this patient's neurological system. She has noticed drooping of her eyelids and double vision."

Candidate presentation (model): [1]

"I examined Mrs Khan's neurological system. She is a 47-year-old woman who is alert and cooperative. [1]

On general inspection, there is asymmetric ptosis, more marked on the left, and the patient holds her head slightly tilted, consistent with compensation for diplopia. There are no cutaneous or surgical stigmata of note. [1]

Cranial nerve examination of the eyes reveals ptosis that is variable. On asking her to sustain upgaze at the ceiling for one minute, the ptosis worsens on both sides, markedly on the left — fatigability of the levator palpebrae superioris. I performed an ice pack test: after two minutes of ice applied to the left upper eyelid, the left ptosis improved visibly. Extraocular movements reveal a fatigable, asymmetric ophthalmoplegia, worse on sustained lateral gaze. The pupils are equal and reactive — there is no pupillary involvement. Bulbar assessment shows that her speech is initially clear but becomes nasal and fades after counting to fifty, consistent with fatigable bulbar weakness. [1]

Motor examination reveals normal tone. Power at rest is 5 out of 5 in all four limbs, but on holding the arms outstretched for one minute the left arm drifts down and the grip fatigues. 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 together with the fatigability 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]

Examiner: "Why are the spared pupils and preserved reflexes important?" [1]

"They are the key discriminators that distinguish myasthenia gravis from its closest differential, Lambert-Eaton myasthenic syndrome, and from a cranial nerve palsy. The acetylcholine receptors at the neuromuscular junction of skeletal muscle are nicotinic, while the pupillary sphincter and the autonomic ganglia use different receptors — so MG, which targets the muscle-type nicotinic AChR, spares the pupils. Pupillary involvement immediately argues against MG and points to a third nerve palsy or an autonomic disorder. Similarly, the reflexes are preserved in MG because the problem is at the effector muscle end plate, not the sensory-motor reflex arc. In LEMS, the presynaptic voltage-gated calcium channel antibody reduces ACh release everywhere, including at the autonomic ganglia, so reflexes are depressed or absent and autonomic features such as a dry mouth and erectile dysfunction are prominent — and, critically, the weakness and the reflexes improve with brief exercise (facilitation), the opposite of MG. So the spared pupils and preserved reflexes in this patient both confirm MG and exclude LEMS." [1]

Examiner: "How would you confirm the diagnosis?" [1]

"My investigation plan is, first, serology — anti-acetylcholine receptor antibodies, positive in about 85 per cent of generalized MG and about 50 per cent of ocular MG; if negative in a compatible picture, I would send anti-MuSK antibodies. Second, electrophysiology — repetitive nerve stimulation at 3 hertz, looking for a decremental response of greater than 10 per cent, which confirms impaired neuromuscular transmission; single-fibre EMG, measuring jitter and blocking, is the most sensitive test but is non-specific. Third, a CT thorax in every patient to screen for thymoma — about 10 to 15 per cent of MG patients have a thymoma, and its detection changes management toward thymectomy. I would also check thyroid function, because autoimmune thyroid disease coexists in up to 15 per cent. The clinical picture plus a positive antibody is usually sufficient for diagnosis." [1]

Examiner: "This patient is 47 and found to have an AChR-positive generalized MG. If no thymoma is seen on CT, would you recommend thymectomy?" [1]

"I would discuss it with her. The MGTX trial established that in non-thymomatous AChR-positive generalized MG, extended transsternal thymectomy plus prednisone was superior to prednisone alone over three years — lower QMG score, lower prednisone dose, fewer hospitalisations [2]. So in a young patient under 50 with AChR-positive generalized MG, thymectomy is a reasonable recommendation to improve long-term outcome and reduce drug burden. It is not a cure, and the benefit accrues over years. I would present it as a shared decision, weighing the surgical risk against the expected benefit, and involving a thoracic surgeon. I would not recommend thymectomy if she were MuSK-positive — there the thymus is not part of the pathology and thymectomy has been shown not to help."

Examiner: "She is started on prednisolone. How do you initiate it, and why?" [1]

"I start prednisolone low — 10 to 20 milligrams daily — and titrate up gradually over two to four weeks toward 0.75 to 1 milligram per kilogram per day. The reason for the cautious start is that high-dose corticosteroids can precipitate a marked early worsening of myasthenic weakness in the first one to two weeks — a recognised steroid-induced exacerbation that can tip a patient into crisis. Once I have a response at the target dose, I introduce a steroid-sparing agent such as azathioprine — after confirming TPMT activity — so that I can taper the prednisolone to the lowest effective dose. Throughout, I monitor for steroid toxicity — bone densitometry and bisphosphonate cover, glucose, blood pressure — because the complications of long-term steroids are themselves a reason to minimise the dose. Pyridostigmine provides symptomatic relief while the immunosuppression takes effect." [1]