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Disorders of the neuromuscular junction 

Disorders of the neuromuscular junction

Chapter:
Disorders of the neuromuscular junction
Author(s):

David Hilton-Jones

and Jacqueline Palace

DOI:
10.1093/med/9780199204854.003.2423_update_002

July 30, 2015: This chapter has been re-evaluated and remains up-to-date. No changes have been necessary.

Update:

Identification of low-affinity antibodies in acquired myasthenia gravis aids diagnosis.

Possibility of newly identified antibody targets in myasthenia.

Move towards keyhole surgery for thymectomy rather than conventional sternal-splitting surgery.

Advice with respect to drug therapy in pregnancy.

Update on congenital myasthenic syndromes.

Further reading added.

Updated on 28 Nov 2012. The previous version of this content can be found here.
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date: 27 March 2017

Two fundamentally different pathological processes are associated with disease at the neuromuscular junction: (1) acquired disorders in which autoantibodies are directed against nerve or muscle receptor or ion channels; (2) rare inherited conditions in which the defect may be pre- or postsynaptic.

Myasthenia gravis

Aetiology and epidemiology—the fundamental disorder is loss of functional acetylcholine receptors most frequently as a result of binding of anti-acetylcholine receptor (anti-AChR) antibodies. Incidence is about 10 per million population and prevalence about 8 per 100 000, with a marked female bias in cases aged under 40 years and male preponderance in those over 50 years. Thymomas occur in about 10% of cases.

Clinical features and diagnosis—the most characteristic feature is fatiguability, meaning demonstrable weakness (without muscle pain) precipitated by repeated or sustained muscular activity. In more than 50% cases this first manifests as diplopia and ptosis. For practical purposes, a positive anti-AChR or anti-MuSK antibody test is confirmatory and no further diagnostic investigations are required; electromyography and the intravenous edrophonium test are helpful in seronegative patients. The presence of a thymoma can only be assessed by CT or MRI of the thorax.

Treatment and prognosis—thymomas require excision, but this in itself will not improve myasthenia. Anticholinesterase drugs (e.g. pyridostigmine) give symptomatic improvement in most patients, and may be sufficient in those with very mild disease. Other management is determined by the type of disease: (1) ocular myasthenia—alternate-day prednisolone with/without steroid sparing agents (e.g. azathioprine); (2) early-onset seropositive disease—some patients benefit from thymectomy, with prednisolone and azathioprine indicated for those who do not, and other immunosuppressants in those who are refractory; (3) late onset, anti-MuSK, and seronegative diseases—most respond to immunosuppression; (4) myasthenic crisis—supportive care with intubation and assisted ventilation may be required; plasma exchange and intravenous immunoglobulin may both lead to rapid improvement. Overall prognosis is good, with over 90% achieving near-normal functional recovery.

Lambert–Eaton myasthenic syndrome

A presynaptic disorder, associated with small-cell lung cancer in ~60% of cases, caused by the presence of antibodies that reduce the number of functional presynaptic P/Q-type voltage-gated calcium channels (VGKC). The condition is characterized by limb-girdle weakness and symptoms of autonomic dysfunction. Pyridostigmine may offer some symptomatic benefit, but 3,4-diaminopyridine is more effective and the drug of choice. For those with inadequate symptomatic benefit, immunosuppression, as for myasthenia gravis, is indicated. In cancer-associated disease, removal of the tumour often leads to improvement; immunosuppression can be effective when an associated cancer is unlikely.

Other conditions

These include (1) congenital myasthenic syndromes—usually autosomal recessive; various forms include presynaptic, endplate acetylcholinesterase deficiency, and postsynaptic; (2) neuromyotonia—may be idiopathic, but recognized associations include tumour and acquired demyelinating polyneuropathies; the main clinical features are muscle stiffness, cramps, and twitching; electromyography shows highly characteristic features; most patients gain symptomatic relief from carbamazepine, phenytoin or lamotrigine.

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