Ohtahara Syndrome

Ohtahara syndrome (early infantile developmental and epileptic encephalopathy) is a severe epileptic encephalopathy beginning in the first 3 months, usually the first 10 days, with tonic spasms and a burst suppression EEG. It is rare, and the outcome is poor, with high mortality in the first years and severe developmental impairment. Many evolve to West syndrome and later Lennox-Gastaut syndrome.

Causes. Structural brain malformations (hemimegalencephaly, cortical dysplasia, Aicardi syndrome), genetic variants (STXBP1, KCNQ2, SCN2A, CDKL5, ARX, SLC25A22) and metabolic disease (non-ketotic hyperglycinaemia, mitochondrial disease, pyridoxine dependent epilepsy).

Pathophysiology. Disruption of neuronal development and synaptic function in the neonatal brain leads to an epileptic burst suppression pattern.

Frequent tonic spasms (single or clusters), seen in sleep and wakefulness, sometimes with focal seizures or myoclonus, with severe developmental delay, hypotonia, feeding difficulty and microcephaly. Examination may show dysmorphism or neurological deficit.

Red flags.

• Neonatal seizures with burst suppression EEG.
• Treatable metabolic cause suspected (seizures in a baby with lethargy and hiccups).

EEG shows burst suppression pattern in both waking and sleep. MRI brain for structure and myelination. Metabolic workup: glucose, lactate, ammonia, amino acids, organic acids, CSF glycine ratio and glucose, and a pyridoxine challenge. Genetic testing with an epilepsy gene panel or exome sequencing. Echocardiography and ophthalmology as required.

Differential diagnosis.

• Early myoclonic encephalopathy, and other neonatal epileptic encephalopathies.
• West syndrome and Dravet syndrome.
• Neonatal seizures of hypoxic, infective or metabolic origin.

Treat reversible causes first. Pyridoxine 100 mg IV under EEG and cardiorespiratory monitoring (then 15 to 30 mg/kg daily orally), pyridoxal 5-phosphate 30 mg/kg daily, folinic acid 3 to 5 mg/kg daily, biotin, and glucose for hypoglycaemia. Treat infection.

Antiseizure drugs. Phenobarbital 20 mg/kg IV loading, then 3 to 5 mg/kg daily, levetiracetam 20 to 60 mg/kg daily, vigabatrin 50 to 150 mg/kg daily, topiramate, sodium channel blockers (carbamazepine, phenytoin or lacosamide) for KCNQ2 and SCN2A disease. Seizure control is often poor.

Other treatments. Adrenocorticotropic hormone or prednisolone for spasms, and the ketogenic diet.

Surgery. Resection or hemispherectomy for focal structural lesions (for example hemimegalencephaly) in selected infants.

Supportive. Feeding support (gastrostomy), respiratory care, physiotherapy, developmental and palliative care, and family support.

Monitoring. Seizure burden, development, EEG and drug adverse effects.

Referral and escalation. Refer urgently to a tertiary paediatric neurology centre, and genetics.