Benign Familial Neonatal Epilepsy

Benign familial neonatal epilepsy is an autosomal dominant epilepsy syndrome in which healthy term infants have brief seizures in the first week of life, with spontaneous remission within weeks to months and usually normal development. It is caused by variants in the potassium channel genes KCNQ2 and, less often, KCNQ3.

It is rare, with an incidence of about 1 in 100 000 live births. Onset is typically between day 2 and day 8, and most infants stop having seizures by 6 months of age. A minority (about 10 to 15%) develop epilepsy later in life.

Penetrance is high, so a family history of neonatal seizures that stopped in infancy is usually present. The same genes also cause a severe early developmental and epileptic encephalopathy, which must be distinguished.

Pathophysiology.

KCNQ2 and KCNQ3 encode subunits of the voltage gated potassium channel that generates the M-current, which stabilises neuronal membrane potential. Loss of function by about 25% in heterozygous carriers lowers the seizure threshold.

The channel matures over the first months of life, which explains the limited time window of susceptibility and spontaneous resolution.

• Brief seizures (under 2 minutes), often several a day, with tonic posturing, apnoea, cyanosis and autonomic features, followed by focal clonic or generalised movements.
• Infants are well between seizures, feed normally and have a normal examination.
• Seizures often cluster on days 3 to 5 and then settle.

Red flags.

• Onset in the first 24 to 48 hours, or seizures with encephalopathy or poor tone between events.
• Burst suppression or multifocal activity on EEG.
• Seizures that persist beyond 4 to 6 weeks despite treatment, or developmental delay: consider a KCNQ2 encephalopathy.

• Clinical diagnosis from the family history and the typical course. A normal examination and normal development support it.
• Interictal EEG is normal or shows mild discontinuity. Ictal EEG shows initial attenuation then focal or generalised discharges.
• Exclude other causes: glucose, calcium, magnesium, sodium, blood gas, ammonia, culture and lumbar puncture when infection is suspected, and cranial ultrasound or MRI for haemorrhage and stroke.
• Genetic testing of KCNQ2 and KCNQ3, including deletion analysis, confirms the diagnosis and distinguishes benign from encephalopathic variants.

Differential diagnosis. Hypoxic ischaemic encephalopathy, neonatal stroke, intracranial haemorrhage, infection, hypoglycaemia, hypocalcaemia and hypomagnesaemia, inborn errors of metabolism, KCNQ2 developmental and epileptic encephalopathy, other early onset epilepsy genes and benign neonatal sleep myoclonus.

• Treat acute seizures with phenobarbital 20 mg/kg IV over 20 minutes, repeated at 10 mg/kg once or twice if needed, to a maximum of 40 mg/kg.
• Sodium channel blockers are effective in KCNQ2 disease. Carbamazepine 5 mg/kg/day orally in 2 divided doses, increased every 3 to 5 days to a usual range of 10 to 20 mg/kg/day. Phenytoin 20 mg/kg IV is an alternative for acute control.
• Check HLA-B*1502 in people of Asian ancestry before carbamazepine. Monitor sodium, liver function and blood count.
• Stop treatment once seizure free, usually between 6 and 12 months of age, by weaning over 2 to 4 weeks. Long term prophylaxis is not usually needed.

Monitoring. Seizure diary, development, growth, drug levels, sodium and liver function. Review at each visit for later epilepsy.

Referral and escalation. Refer to paediatric neurology for all neonatal seizures. Genetic counselling for the family, as each child of an affected parent has a 50% risk.

Special groups. Infants with KCNQ2 encephalopathy have early onset, abnormal EEG background and developmental delay, and need early sodium channel blocker treatment and specialist epilepsy care.