Write a short note on epilepsy, including phenytoin toxicity.

Definitions

A seizure is a transient occurrence of signs or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. Epilepsy is a disease of the brain defined by any of:

• Two or more unprovoked seizures more than 24 hours apart, or
• One unprovoked seizure with a probability of further seizures of at least 60% (for example, with a structural lesion or epileptiform EEG), or
• Diagnosis of an epilepsy syndrome.

A provoked (acute symptomatic) seizure — due to hypoglycaemia, hyponatraemia, alcohol withdrawal, drugs, fever or acute brain injury — is not epilepsy, and treatment is directed at the cause.

Classification (ilae)

Aetiology BY Age

• Children and young adults: idiopathic and genetic epilepsies, birth injury, congenital malformation, febrile seizures, neurocysticercosis (a leading cause of new-onset seizures in India).
• Adults: head trauma, neurocysticercosis and tuberculoma, alcohol, tumour, cerebrovascular disease.
• Elderly: cerebrovascular disease (commonest), tumour, degenerative disease, metabolic.

Investigations

• The diagnosis is clinical and rests on the history — especially an eyewitness account, which is more valuable than any test.
• EEG — supports the diagnosis and classifies the syndrome; a normal EEG does not exclude epilepsy, and epileptiform discharges occur in some people without seizures. Sleep-deprived and prolonged recordings improve yield.
• MRI brain — the imaging of choice for all except clear-cut idiopathic generalised epilepsy; identifies hippocampal sclerosis, cortical malformation, tumour, and neurocysticercosis (CT is better for the calcified scolex).
• Bloods: glucose, sodium, calcium, magnesium, renal and liver function, CBC; prolactin rises transiently after a generalised seizure but is unreliable.
• ECG — to exclude cardiac syncope and long QT syndrome masquerading as seizure.
• Consider lumbar puncture if infection is suspected.

Management

General principles: treatment is usually started after a second unprovoked seizure, or after a first with high recurrence risk. Aim for monotherapy at the lowest effective dose, titrated slowly, choosing the drug by seizure type, comorbidity, age, sex and cost.

Counselling — as important as the prescription:

• Adherence — non-adherence is the commonest cause of breakthrough seizures and status epilepticus.
• Driving restrictions as per regulation; avoid swimming alone, working at heights, and operating dangerous machinery; take showers rather than baths.
• Sleep, alcohol and trigger avoidance; recognition of prodrome; first-aid instruction for family.
• Women: valproate must be avoided in women of childbearing potential because of major teratogenicity and neurodevelopmental harm; discuss contraception (enzyme-inducing drugs reduce oral contraceptive efficacy), pre-conception folic acid, and planned pregnancy with the lowest effective dose of the safest agent.
• Withdrawal may be considered after 2–5 years seizure-free, with slow tapering and discussion of recurrence risk.

Drug-resistant epilepsy (failure of two appropriate, tolerated drugs): refer for evaluation for epilepsy surgery (temporal lobectomy for hippocampal sclerosis is highly effective), vagal nerve stimulation, or ketogenic diet.

Phenytoin Toxicity

Phenytoin has zero-order (saturable) kinetics — once the metabolic pathway is saturated, a small dose increase produces a disproportionate, sometimes dramatic rise in serum level. This is the pharmacological basis of its narrow therapeutic index and the reason toxicity is common.

Features, which appear in a characteristic sequence as the level rises:

• Nystagmus (earliest)
• Ataxia and dysarthria
• Drowsiness, confusion
• Coma, and paradoxically increased seizures at very high levels
• Acute intravenous toxicity: hypotension, bradycardia and arrhythmia from rapid infusion (largely due to the propylene glycol diluent) — hence the requirement for slow administration with cardiac monitoring.

Chronic adverse effects (important for counselling): gingival hyperplasia, hirsutism and coarsening of facial features, acne, megaloblastic anaemia (folate antagonism), osteomalacia (vitamin D catabolism), peripheral neuropathy, cerebellar atrophy, DRESS and SJS/TEN, hepatotoxicity, and teratogenicity (fetal hydantoin syndrome).

Interactions: phenytoin is a potent enzyme inducer — reducing levels of oral contraceptives, warfarin, corticosteroids and antiretrovirals; and its own level is raised by isoniazid, cimetidine, fluconazole and sodium valproate (which also displaces it from protein binding).

Management of toxicity: stop the drug, supportive care with cardiac monitoring, activated charcoal in acute overdose (with repeated doses for enhanced elimination), and correction of hypotension. There is no antidote; dialysis is ineffective because of high protein binding. Measure the free (unbound) level in hypoalbuminaemia and renal failure, where the total level underestimates toxicity.