Myasthenia gravis

Recognition

Recognised classically by ptosis, nasal speech and fatiguability. Myasthenia confined to the eyes can sometimes be quite difficult to diagnose.

Differential diagnosis:

• Motor neurone disease (amyotrophic lateral sclerosis)
• Depression
• Drug-induced myasthenia (penicillamine, nitrofurantoin, aminoglycosides)
• Eaton-Lambert syndrome (malignancy associated – do a CXR!)

Diagnosis

The diagnosis is primarily clinical initially, and the presence of weakness that worsens with exertion is strongly suggestive of the diagnosis – e.g. a ptosis worse in the afternoon than the morning, a voice that changes character with use.

Test for fatiguability by grading muscle strength before and after exercise, e.g. test arm abduction before and after the patient moves a muscle group with suspected weakness for a minute (e.g. abducts shoulder)

Edrophonium is still mentioned next in most books as if it is the gold standard but is not available. Neostigmine side-effects (especially the nausea) make testing difficult to interpret. Oral pyridostigmine seems a logical alternative, although it is poorly validated. One option is to give 30 or 60 mg orally and assess response after 60 to 90 minutes, another is to give pyridostigmine 30 mg 4 hourly for 2 or 3 days and asses response. There is little evidence to back either strategy.

The ice test¹ comes and goes in popularity amongst ophthalmologists – place ice in a rubber glove over the ptotic eye for 2 minutes; an increase in width of the palpebral fissure of more than 2 mm is regarded as positive. This gets complicated by the rest test (glove for two minutes, but filled with cotton wool instead of ice), which is also an option with similar 2 mm cut point. Doing both² may be worth considering. Diagnostic performance of the ice test is all over the show based on quite small series (sensitivity 28% to 96%, and specificity 31 to 100%, 4 small studies)³

Acetylcholine receptor antibodies were present in about 85% of patients with generalised myasthenia and 55% of those with ocular disease in an earlier review⁴ but in the Yoganathan et al. review the range was 50% to 97%. If negative, consider doing ant-MUSK antibodies.

Always do a TSH as well, as in 5% of patients there is concurrent hyperthyroidism.

Prognosis in myasthenia

Overall about 50% of patients with an initial presentation of ocular disease progress to generalised disease, however ocular myasthenia that had remained confined to the eyes for more than a year is likely to remain so.

Management

Pyridostigmine 30-120 mg 3-4 hourly. Start at the lowest dose and work up as GIT autonomic effects are common. Regular use of an anti-diarrhoeal such as loperamide is necessary on rare occasions.

Prednisone – start at 5 mg per day and work up slowly (weekly increments) – too high a dose too early can lead to rapid worsening. Aim for a final dose of 30-40 mg per day (don’t forget about steroid induced myopathy, which very occasionally may complicate things – is the worsening due to disease or therapy?)

Thymectomy. Although evidence of benefit is still limited, a recent trial⁵ suggests that it may confer benefit even in the absence of a thymoma (improvement in Quantitative Myasthenia Gravis score, fewer hospitalisations, fewer life threatening events over 3 years). In that trial however, patients certainly didn’t become medicine-free (mean alternate day prednisone dose 60 mg vs 44 mg in the surgery group.)

Azathioprine in doses ranging from 50 to 200 mg per day, with some evidence (historical controls)⁶ suggesting that higher doses may work better. (Keep the WCC above 3.0.) Consult before starting.

In myasthenic crisis possibly requiring ventilation repeated measure of vital capacity may be unreliable in predicting the need for ventilation.⁷ Peak flow measurement is of even less value. Regular personal review is helpful. In patients requiring ventilation, prednisone does not need to be ‘tailed up’ – it is probably reasonable to start at 0.5 mg/kg/day, although there is no empiric evidence for this. Disconcertingly, a 2019 systematic review found absolutely no evidence on how to wean patients with neuromuscular disease off ventilation⁸

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1. Golnik KC, Pena R, Lee AG, et al. An ice test for the diagnosis of myasthenia gravis. Ophthalmology. 1999;106:1282-6 ↩

2. Kubis KC, Danesh-Meyer DV, Savino PJ, Sergott RC. The ice test versus the rest test in myasthenia gravis. Ophthalmology. (2000) 107:1995–8. doi: 10.1016/s0161-6420(00)00458-9 ↩

3. Yoganathan, K., Stevenson, A., Tahir, A. et al. Bedside and laboratory diagnostic testing in myasthenia. J Neurol 269, 3372–3384 (2022). https://doi.org/10.1007/s00415-022-10986-3 ↩

4. Palace J, Vincent A, Beeson D. Myasthenia gravis: diagnostic and management dilemmas. Curr Opin Neurol. 2001;14:583-9 ↩

5. Wolfe GI, Kaminski HJ, Aban IB et al. Randomised trial of thymectomy in myasthenia gravis. New Engl J Med. 2016;375:511-522. DOI: 10.1056/NEJMoa1602489 ↩

6. Heckmann JM, LeePan EB, Eastman RW. High-dose immunosuppressive therapy in generalised myasthenia gravis – a 2-year follow-up study. S Afr Med J. 2001;91:765-70 ↩

7. [1] Rieder P, Luois M, Jolliet P, et al. The repeated measure of vital capacity is a poor predictor of the need for mechanical ventilation in myasthenia gravis. Intensive Care Med. 1995;21:663-8 ↩

8. Bernardes Neto SCG, Torres-Castro R, Lima Í, et al Weaning from mechanical ventilation in people with neuromuscular disease: a systematic review BMJ Open 2021;11:e047449.  doi: 10.1136/bmjopen-2020-047449 ↩

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