Myasthenia Gravis — SAQ

Stem

A 28-year-old woman presents to the neurology outpatient department with a four-month history of fluctuating double vision and drooping of both eyelids, worse towards the end of the day and after using her phone for an hour. Over the past three weeks she has noticed that her voice fades after a few minutes of conversation, that food sticks in her throat and she occasionally regurgitates fluids through her nose, and that her arms feel heavy after carrying groceries. She has no sensory symptoms and no bowel or bladder disturbance. Her aunt has autoimmune hypothyroidism. [1]

On examination: pulse 84/min, blood pressure 118/74 mmHg, respiratory rate 16/min. After one minute of sustained upgaze she develops asymmetric bilateral ptosis, worse on the right (the curtain sign is positive — the right lid flicks upward on shifting gaze to primary position). Extraocular movements reveal fatigable diplopia on sustained lateral gaze. Her voice fades after counting aloud to forty. Power is Medical Research Council grade 5 at rest but fatigues to grade 4 plus in the proximal arms after 60 seconds of outstretched elevation. Reflexes, sensation and plantar responses are normal. A two-minute ice pack over the right eyelid improves the ptosis by 4 millimetres. [1]

Questions

a) What is the most likely diagnosis, and which three features of the examination support it? (2 marks) [1]

The most likely diagnosis is myasthenia gravis — an autoimmune disorder of the postsynaptic neuromuscular junction in which antibodies against the acetylcholine receptor (or related proteins such as MuSK or LRP4) reduce receptor density, producing fluctuating, fatigable weakness that worsens with sustained activity and improves with rest. The three most diagnostic features are: (1) the fatigable ocular weakness with a positive Simpson test (asymmetric bilateral ptosis provoked by sustained upgaze for one minute, with the curtain sign of a brief upward lid twitch on shifting gaze to primary position — the signature of a partially-recovered acetylcholine release at the start of contraction); (2) the fatigable bulbar and proximal limb weakness (voice fading with counting, nasal regurgitation from palatal weakness, and proximal arm weakness appearing only with sustained elevation); and (3) the preserved reflexes, sensation and plantar responses — confirming this is a purely motor disorder of voluntary muscle and excluding a neuropathy (LEMS or Guillain-Barre), myelopathy, or motor neuron disease.[1][2]

b) Outline the diagnostic investigations you would arrange, including the antibody tests, electrophysiology, and the imaging required. (3 marks) [1]

The diagnostic sequence is serology first, electrophysiology second, imaging third, with routine bloods to exclude mimics and to detect co-existing autoimmunity. [1]

• Anti-acetylcholine receptor (anti-AChR) antibody is the primary serological test and is positive in about 85 percent of generalised MG and 50 percent of ocular-only MG, with a specificity of over 99 percent. Three assays exist — binding (most sensitive), blocking, and modulating.
• Anti-MuSK antibody is ordered in every AChR-negative case; positive in 5 to 8 percent of all MG and in 30 to 40 percent of AChR-seronegative generalised MG; predicts a phenotype with prominent bulbar and respiratory weakness, less response to pyridostigmine, and excellent response to rituximab.
• Anti-LRP4 antibody in AChR and MuSK double-negative cases; positive in 2 to 5 percent overall.
• Repetitive nerve stimulation (RNS) at 3 Hz before and after one minute of ischaemic or voluntary exercise; a decremental response of greater than 10 percent in compound muscle action potential amplitude between the first and the fourth or fifth stimulus is diagnostic. Sensitivity is about 75 percent in generalised MG.
• Single-fibre electromyography (SFEMG) — the gold standard with sensitivity over 95 percent in specialist hands, demonstrating increased jitter and impulse blocking in a voluntarily activated muscle (test the frontalis in ocular MG); it is operator-dependent and not specific (any NMJ disorder raises jitter).
• Contrast-enhanced CT or MRI chest in every newly diagnosed MG patient to identify thymoma (10 to 15 percent) and to characterise thymic hyperplasia (about 65 percent of early-onset AChR-positive MG).
• Routine bloods: thyroid function (TSH and free T4 — autoimmune thyroid disease coexists in 5 to 10 percent), antinuclear antibody, creatine kinase (to exclude myopathy), full blood count, electrolytes, liver and renal function, vitamin B12. CSF is not indicated — it is normal in MG.[1][2]

c) State the Myasthenia Gravis Foundation of America clinical classification and assign this patient a class. (1 mark) [1]

The MGFA clinical classification (Jaretzki 2000) is the international standard for grading severity: Class I — ocular muscle weakness only; Class II — mild generalised weakness (IIa predominantly limb/axial; IIb predominantly bulbar or respiratory); Class III — moderate generalised weakness (IIIa predominantly limb/axial; IIIb predominantly bulbar or respiratory); Class IV — severe generalised weakness (IVa predominantly limb/axial; IVb predominantly bulbar or respiratory, often requiring a feeding tube); Class V — intubation required for myasthenic crisis (excluding elective post-operative intubation). This patient has ptosis, diplopia, fatigable bulbar weakness (nasal regurgitation, voice fading), and fatigable proximal limb weakness with normal power at rest and no respiratory involvement — she is Class IIIb (moderate generalised, predominantly bulbar).[5]

d) Outline your stepwise management with named drugs, doses, routes, and the indication for thymectomy. (2 marks) [1]

Management is layered — most patients end up on several agents simultaneously. [1]

• Step 1 — symptomatic: oral pyridostigmine 30 to 60 mg four times daily, titrated to response over days to weeks (maximum single dose 120 mg, maximum total daily 1200 mg). It inhibits acetylcholinesterase, raises synaptic acetylcholine, and partially corrects the safety factor — but it is symptomatic only and is rarely sufficient for generalised MG.
• Step 2 — corticosteroid plus a steroid-sparing agent: prednisolone 1 to 1.5 mg/kg on alternate days, started at a low dose of 10 to 20 mg on alternate days and titrated up by 5 mg every 2 to 3 days to avoid the steroid-induced worsening of the first 1 to 2 weeks (give as inpatient if bulbar or respiratory compromise, or co-administer IVIg or plasma exchange). Once minimal-manifestation status is stable for 4 to 8 weeks, taper by 5 to 10 percent every 2 to 4 weeks and add azathioprine 1 to 3 mg/kg per day orally (50 to 150 mg per day) after baseline TPMT activity, which is the first-line steroid-sparing agent and takes 6 to 12 months for full effect. Alternatives if azathioprine is not tolerated or fails include mycophenolate mofetil 1 to 2 g per day orally, methotrexate 7.5 to 15 mg orally once weekly plus folic acid 5 mg weekly, and tacrolimus 3 to 5 mg at night.
• Step 3 — thymectomy: this patient is a textbook candidate for thymectomy, by extended transsternal approach, because she is AChR-antibody-positive (presumed), generalised MGFA Class II to IV, aged 18 to 65 years, with disease duration under 5 years — the population in whom the MGTX trial (Wolfe 2016, NEJM, 5-year extension 2019) demonstrated sustained benefit of thymectomy plus prednisone over prednisone alone. Thymectomy is contraindicated in anti-MuSK MG and is not first-line in purely ocular MG.
• Step 4 — acute therapy: IVIg 0.4 g/kg per day for 5 days (total 2 g/kg) or plasma exchange 5 sessions of one plasma volume (about 50 mL/kg) on alternate days over 1 to 2 weeks for crisis or major exacerbation. The two are equally effective and are not combined.[6][3][11]

e) If her FVC at presentation were 1.4 L and falling, what would you do immediately? Name the drug regimens and the precipitants you would exclude. (2 marks) [1]

A forced vital capacity of 1.4 L (under 20 mL/kg) and falling in a patient with bulbar weakness is myasthenic crisis — a neurological emergency. The immediate management is: [1]

1. ABCDE — secure the airway: this patient meets the intubation criteria (FVC under 20 mL/kg or under 1.5 L, falling, with bulbar weakness). Intubate electively in a controlled manner, avoiding suxamethonium (unpredictable response; risk of prolonged blockade or hyperkalaemia) and using a reduced dose of a non-depolarising agent such as rocuronium 0.6 mg/kg or less, titrated to a peripheral-nerve stimulator.
2. Acute disease-modifying therapy: IVIg 0.4 g/kg per day for 5 days (total 2 g/kg) OR plasma exchange 5 sessions of one plasma volume (about 50 mL/kg) on alternate days over 1 to 2 weeks — equally effective, never combined. Plasma exchange works faster (effect within days) and is preferred when volume overload is a concern; IVIg is simpler and has fewer access-related complications.
3. Identify and treat the precipitant: search for infection (chest X-ray, urinalysis, blood cultures if febrile) — the commonest precipitant; review the drug chart for precipitants (aminoglycosides, fluoroquinolones, macrolides, beta-blockers, magnesium, iodinated contrast, neuromuscular blockers, telithromycin, D-penicillamine) and stop them; check thyroid function (hyperthyroidism or hypothyroidism worsens MG); consider perioperative state, pregnancy or puerperium, and emotional or physical stress.
4. Supportive bundle: mechanical ventilation (or non-invasive ventilation once weaning), nasogastric feeding, DVT prophylaxis with enoxaparin 40 mg subcutaneously daily, pressure-area care, careful secretion management (suction, mucolytics), and continued pyridostigmine via nasogastric tube once intubated (with the dose reviewed daily to avoid cholinergic excess).
5. Myasthenic vs cholinergic crisis: distinguish clinically — myasthenic shows mydriasis, dry, constipation, tachycardia; cholinergic shows miosis, sweating, salivation, diarrhoea, fasciculations, bradycardia. Do not perform the edrophonium (Tensilon) test to differentiate — it can precipitate fatal bronchospasm or asystole. [1]

If this patient's anti-AChR antibody later returns positive and her crisis is managed successfully, she would proceed to thymectomy once stable, on the basis of the MGTX trial evidence in early-onset AChR-positive generalised MG.[6][3][11]

References

1. [1]Gilhus NE, Verschuuren JJ. Myasthenia gravis: subgroup classification and therapeutic strategies. Lancet Neurology, 2015.PMID 26376969
2. [2]Ciafaloni E. Myasthenia Gravis and Congenital Myasthenic Syndromes. Continuum (Minneapolis, Minn.), 2019.PMID 31794470
3. [3]Wolfe GI, Kaminski HJ, Aban IB, et al. Randomized Trial of Thymectomy in Myasthenia Gravis. New England Journal of Medicine, 2016.PMID 27509100
4. [5]Jaretzki A 3rd, Barohn RJ, Ernstoff RM, Kaminski HJ, Keesey JC, Penn AS, Sanders DB. Myasthenia gravis: recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Annals of Thoracic Surgery, 2000.PMID 10921745
5. [6]Sanders DB, Wolfe GI, Benatar M, et al. International consensus guidance for management of myasthenia gravis: Executive summary. Neurology, 2016.PMID 27358333
6. [7]Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A, Vincent A. Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nature Medicine, 2001.PMID 11231638
7. [11]Gajdos P, Chevret S, Toyka KV. Intravenous immunoglobulin for myasthenia gravis. Cochrane Database of Systematic Reviews, 2012.PMID 23235588