Isaacs Syndrome

Isaacs syndrome is peripheral nerve hyperexcitability with continuous muscle fibre activity, causing muscle stiffness, cramps, myokymia and delayed muscle relaxation. It is a form of acquired neuromyotonia. It is often autoimmune, with antibodies to contactin associated protein like 2 (CASPR2) or leucine rich glioma inactivated protein 1 (LGI1), which are part of the voltage gated potassium channel complex. Thymoma is found in some.

Pathophysiology. Potassium channel dysfunction in the distal motor nerve leads to spontaneous repetitive firing.

Muscle twitching (myokymia), stiffness, cramps, pseudomyotonia (delayed relaxation after contraction), hyperhidrosis, pain and paraesthesia, worsening with exertion. Autonomic features and sleep disturbance occur. Insomnia and encephalopathy suggest Morvan syndrome.

Electromyography shows spontaneous doublet, triplet and multiplet discharges (neuromyotonic discharges), myokymic discharges and fasciculations, persisting after nerve block or sleep. Test serum for CASPR2 and LGI1 antibodies (cell based assay). Check thyroid function, electrolytes, creatine kinase, and screen for thymoma and cancer with CT chest.

Differential diagnosis.

• Cramp fasciculation syndrome and stiff person syndrome.
• Myotonic disorders, hypocalcaemia and hypothyroidism.
• Hereditary neuropathy with pressure palsies and motor neuron disease.

Symptomatic therapy (sodium channel blockers).

• Carbamazepine 100 mg twice daily, increased to 200 to 400 mg twice daily (maximum 1200 mg daily), with checks of sodium, full blood count and liver tests.
• Or phenytoin 300 mg daily with level monitoring, or lamotrigine or mexiletine 150 mg twice daily, increased to 200 mg three times daily (avoid in cardiac disease).
• Gabapentin 300 mg three times daily, increased as tolerated (adjust to eGFR).

Immunotherapy. For antibody positive or severe disease.

• Plasma exchange (5 exchanges) or intravenous immunoglobulin 0.4 g/kg daily for 5 days.
• Prednisolone 1 mg/kg daily, with azathioprine 2 to 3 mg/kg daily or rituximab as sparing agents.

Tumour. Remove thymoma and treat cancer.

Monitoring. Symptoms, sodium, liver tests, and antibody status where used.

Referral and escalation. Refer to neurology.

Special groups. Avoid carbamazepine and phenytoin in pregnancy unless needed, with folic acid 5 mg daily.