Myasthenia Gravis and the Eye

Myasthenia gravis is an antibody mediated disorder of the neuromuscular junction, with antibodies against the acetylcholine receptor (about 85 percent of generalised disease), muscle specific kinase, or lipoprotein receptor related protein 4. Weakness is fatigable and varies through the day.

• The eye is involved at presentation in about 50 to 60 percent and in over 90 percent, because the extraocular muscles and levator have small motor units, high firing rates and fewer safety factors. About 50 to 80 percent of patients with purely ocular symptoms develop generalised disease within 2 years, and the risk falls sharply after that.
• Pupillary reflexes are normal, because smooth muscle is not affected. Any isolated ptosis or diplopia with a normal pupil must be considered myasthenia until excluded.
• Thymic hyperplasia (about 65 percent) and thymoma (10 to 15 percent) are associated, and autoimmune thyroid disease occurs in about 10 percent.

• Ptosis: variable, asymmetric, worsens with sustained upgaze (more than 30 to 60 seconds) and at the end of the day, and improves after rest or an ice pack. Contralateral lid retraction when the ptotic lid is lifted manually (enhanced ptosis).
• Cogan lid twitch: the lid overshoots upward briefly on looking up from downgaze.
• Diplopia: variable, any pattern, mimicking cranial nerve palsy, internuclear ophthalmoplegia, gaze palsies or restrictive disease. Fatiguable ocular movements with quiver or slowing of saccades.
• Orbicularis oculi weakness (lid closure weak, with the eyelashes buried less than normal when closing), snarl smile, and facial weakness.
• Generalised features: bulbar symptoms (dysphagia, dysarthria, nasal speech), neck and limb weakness, and respiratory weakness, worsening towards the evening.
• Myasthenic crisis: respiratory failure with severe weakness, triggered by infection, surgery, pregnancy or drugs.

• Bedside: ice pack test (a bag of ice on the closed ptotic lid for 2 minutes, improvement of ptosis by 2 mm or more, with sensitivity about 80 percent in ptosis), rest test (2 minutes of eye closure), sustained upgaze for 60 seconds, and review of variability in a clinic video.
• Serology: acetylcholine receptor antibody (positive in about 50 percent of purely ocular myasthenia), muscle specific kinase antibody when negative, and lipoprotein receptor related protein 4 antibody if still negative.
• Neurophysiology: repetitive nerve stimulation (decrement over 10 percent at 3 Hz, less sensitive in ocular disease) and single fibre electromyography of the frontalis or orbicularis (increased jitter, over 90 percent sensitive in ocular disease).
• Edrophonium or neostigmine test is used less now, because of cardiac side effects: neostigmine 1.5 mg intramuscular with atropine 0.6 mg, observed over 30 to 60 minutes.
• CT or MRI chest for thymoma in all patients, thyroid function tests and thyroid antibodies, ANA, glucose and vitamin B12 where indicated, and orbital or brain imaging when the picture is atypical, for instance with a pupil abnormality.
• Exclusion of mimics: thyroid eye disease, chronic progressive external ophthalmoplegia (mitochondrial), Lambert-Eaton syndrome, botulism, brainstem lesions and aneurysm.

• Symptomatic: pyridostigmine 30 to 60 mg three to four times daily orally (maximum about 360 mg/day, 120 mg per dose), with side effects of cramps, diarrhoea, hypersalivation and bradycardia (glycopyrronium 1 mg when needed). Helps ptosis more than diplopia.
• Ocular myasthenia not controlled by pyridostigmine: oral prednisolone starting 10 to 20 mg daily on alternate days, increasing by 5 mg every 3 to 5 days to 0.75 mg/kg on alternate days, hold until remission then taper slowly over 6 to 12 months, with bone protection, glucose and blood pressure monitoring. Steroids reduce progression to generalised disease. Warn the patient about transient worsening in the first 2 weeks.
• Steroid sparing therapy: azathioprine 2 to 3 mg/kg/day (after thiopurine methyltransferase testing, onset of benefit 6 to 12 months), mycophenolate mofetil 1 g twice daily, or methotrexate 10 to 17.5 mg weekly. Rituximab 375 mg/m2 weekly for 4 weeks, or 1000 mg twice 2 weeks apart, particularly in muscle specific kinase disease. Efgartigimod, eculizumab, ravulizumab and rozanolixizumab in refractory antibody positive generalised disease under neurology.
• Thymectomy: indicated for thymoma, and considered in acetylcholine receptor positive generalised disease under 65 years. Not indicated in purely ocular disease without thymoma.
• Myasthenic crisis or rapid worsening: admission, respiratory monitoring (forced vital capacity under 20 mL/kg or negative inspiratory force worse than minus 30 cmH2O indicates intubation), intravenous immunoglobulin 2 g/kg divided over 2 to 5 days, or plasma exchange 5 exchanges over 10 days, followed by steroids and a steroid sparing agent.
• Ptosis and diplopia: eyelid crutches on spectacles, prisms for small stable angles, occlusion or fogged lens for diplopia, and strabismus surgery (recession and resection) or ptosis surgery only once the angle has been stable for at least 6 months on treatment.
• Drugs to avoid or use with care in myasthenia: fluoroquinolones, aminoglycosides, macrolides, telithromycin, beta blockers including timolol eye drops, calcium channel blockers, magnesium, neuromuscular blocking agents, procainamide, statins, penicillamine, botulinum toxin, and checkpoint inhibitors. Preservatives in some drops and local anaesthetics are generally safe.
• Patients are counselled about crisis triggers (infection, drugs, surgery) and given an alert card. When the thyroid is also involved, orbital imaging (CT or MRI) and thyroid antibodies are needed to separate thyroid orbitopathy (restrictive myopathy, lid retraction, proptosis) from myasthenic weakness, since both cause diplopia and ptosis and can coexist.