Episodic Ataxia

Episodic ataxia is a group of rare autosomal dominant channelopathies causing recurrent attacks of cerebellar incoordination between normal periods. Two types account for most cases: type 1 (KCNA1) and type 2 (CACNA1A).

Prevalence is under 1 in 100,000. Type 2 is the commonest. Onset is usually in childhood or adolescence.

Classification. Type 1 has brief attacks of seconds to minutes with interictal myokymia. Type 2 has attacks of hours to days with interictal nystagmus and often migraine. Types 3 to 8 are rare and have varied genes and features.

Pathophysiology. KCNA1 variants impair a voltage gated potassium channel and raise cerebellar and peripheral nerve excitability. CACNA1A variants reduce P/Q-type calcium channel function in Purkinje cells, which disturbs their regular pacemaking firing.

Attacks bring gait and limb ataxia, dysarthria, vertigo, nausea and nystagmus. Triggers are emotional stress, exertion, caffeine, alcohol, fever and sudden movement. In type 1 there is facial or hand twitching (myokymia) between attacks and sometimes neuromyotonia. In type 2 there is downbeat or gaze evoked nystagmus between attacks, and over time progressive cerebellar atrophy. Hemiplegic migraine and seizures can coexist.

Diagnosis rests on the history of recurrent attacks with normal function between them, a family history and confirmation by genetic testing (KCNA1 and CACNA1A sequencing with deletion and duplication analysis, or an ataxia gene panel). MRI is normal early, and may show vermian atrophy in type 2. Check calcium, magnesium, glucose, thyroid function, lactate and electrolytes.

Differential diagnosis.

• Multiple sclerosis and brainstem demyelination.
• Vertebrobasilar transient ischaemic attack and vestibular migraine.
• Seizures, paroxysmal dyskinesia and metabolic ataxias (pyruvate dehydrogenase deficiency, urea cycle disorders, maple syrup urine disease).
• Drug and alcohol effects.

Avoid known triggers (excess caffeine, alcohol, stress, strenuous exertion, sleep loss).

Acetazolamide. First line in type 2 and often helpful in type 1: 125 mg orally twice daily, increased every 1 to 2 weeks as needed to a usual maximum of 1000 mg daily in divided doses.

Children: 4 to 8 mg/kg daily in divided doses, increasing to a maximum of 20 mg/kg daily (up to 750 mg).

Monitor for paraesthesia, taste change, fatigue, kidney stones and metabolic acidosis (check bicarbonate). Avoid in sulphonamide allergy and severe renal or hepatic impairment, and reduce the dose when eGFR is 10 to 50 mL/min.

Dichlorphenamide 50 mg orally twice daily is an alternative.

4-aminopyridine. For type 2 not controlled by acetazolamide: 5 mg orally three times daily, increased to 10 mg three times daily. It carries seizure risk, so avoid in epilepsy and renal impairment (eGFR under 50 mL/min), and do not combine with other potassium channel blockers.

Type 1. Carbamazepine 100 mg twice daily, increased to 200 to 400 mg twice daily (maximum 1200 mg daily), is an alternative when acetazolamide fails. Monitor sodium, full blood count and liver tests, and check HLA-B*1502 in people of Asian ancestry before starting.

Supportive care. Physiotherapy, balance training, falls prevention, and treatment of migraine (avoid triptans in hemiplegic migraine).

Monitoring. Attack frequency and severity, bicarbonate and renal function on acetazolamide, and annual neurological review.

Referral and escalation. Refer to neurology and clinical genetics. Refer urgently for new persistent deficits or progressive ataxia.

Special groups. In pregnancy, acetazolamide and carbamazepine carry foetal risk, so decide treatment with neurology and obstetrics, and give folic acid 5 mg daily. Genetic counselling applies to all.