Isaacs syndrome: the frontier of neurology, psychiatry, immu
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Isaacs used the term ‘syndrome of continuous muscle-fibre activity’ or the more descriptive ‘armadillo disease’ for the condition which now has become known as Isaacs syndrome or acquired autoimmune neuromyotonia. In his landmark series, Isaacs described a phenotype of progressive muscle stiffness, with widespread fasciculation leading to weakness. A key finding was continuous muscle activity on electromyography, occurring at rest and unaffected by local nerve blockade. The original report also detailed a number of unsuccessful treatment approaches, as well as an astonishing improvement produced by sodium diphenyl hydantoinate (phenytoin) treatment.

A critical factor in understanding the Isaacs jigsaw puzzle came with the identification of the autoimmune basis for the disorder. Presently, autoantibodies are identified in a significant proportion (45–50%) of Isaacs syndrome patients. The molecular identification of these antibodies has revealed a spectrum of overlapping disorders from Isaacs syndrome, through to Morvan’s syndrome and limbic encephalitis.

In addition to the classical muscle symptoms of Isaacs syndrome, there is a spectrum of autonomic and central nervous system involvement that link Isaacs syndrome to other autoimmune disorders.

Sensory symptoms including paraesthesia and pain and autonomic disturbance including excessive sweating, tachycardia or diarrhoea are reported by almost half of patients. CNS symptoms are also prominently reported including insomnia, personality and mood changes, anxiety and depression. There is no specific association of autoantibody type with clinical symptoms—while LGI1 antibodies are primarily associated with limbic encephalitis and CNS involvement, 31% of patients display peripheral involvement including hyperexcitability or neuropathic pain in less than 20%. Similarly, CASPR2 antibodies are associated with both CNS and peripheral-predominant clinical presentations, and associated with neuromyotonia in less than 40% of cases.

Underlying the immune basis of Isaacs syndrome there is a prominent association with cancer, with 21–25% of Isaacs syndrome patients diagnosed with recent tumours, highlighting the need to screen carefully for malignancy. In particular, CASPR2 antibodies are associated with thymoma in 20% of cases.

In terms of understanding the clinical hallmark of Isaacs syndrome, namely continuous muscle activity, the site of origin for this spontaneous activity remains to be determined. The typical patterns of ectopic activity do not seem to be caused by a generalised disturbance of motor axon membrane excitability. Most likely, the activity is generated focally, perhaps at the motor nerve terminal which is relatively unprotected by the blood–nerve barrier, making it vulnerable to autoantibody attack.

Source: https://jnnp.bmj.com/content/91/12/1243
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