Ohtahara syndrome

Overview

Ohtahara syndrome, also known as early infantile epileptic encephalopathy with burst-suppression (EIEE), is a rare and severe form of epilepsy that begins in the first few weeks or months of life. First described by Japanese neurologist Shunsuke Ohtahara in 1976, the syndrome is characterized by frequent, treatment-resistant seizures and a profoundly abnormal electroencephalogram (EEG) pattern known as "burst-suppression." It is one of the earliest and most malignant forms of childhood epileptic encephalopathies.

Ohtahara syndrome often progresses to other severe epileptic conditions such as West syndrome or Lennox–Gastaut syndrome as the child ages. Affected infants typically show marked developmental delay, poor motor control, and limited responsiveness. Early diagnosis and management are essential, though outcomes remain generally poor due to the underlying neurological damage.

Causes

Ohtahara syndrome can result from a wide variety of structural, genetic, or metabolic abnormalities. In many cases, the condition is associated with congenital brain malformations or mutations in key genes involved in brain development and electrical signaling.

Structural Causes

• Cortical dysplasia

• Hemimegalencephaly

• Aicardi syndrome

• Porencephaly or encephalomalacia

Genetic Causes

• ARX gene mutations – associated with X-linked forms of the disorder

• STXBP1 mutations – one of the most commonly identified gene defects in non-structural cases

• CDKL5, SCN2A, KCNQ2, and SLC25A22 mutations – also reported in several cases

Metabolic and Other Causes

• Mitochondrial disorders

• Perinatal hypoxic-ischemic injury

• Inborn errors of metabolism

Despite extensive testing, the exact cause remains unknown in some cases.

Symptoms

Symptoms of Ohtahara syndrome typically appear within the first few days to weeks of life. The condition is marked by multiple types of seizures and severe neurodevelopmental impairment.

Seizures

• Tonic spasms: Sudden stiffening of muscles, often occurring in clusters and during both wakefulness and sleep.

• Focal seizures: Involving one part of the body, such as an arm or leg.

• Myoclonic jerks: Sudden, brief muscle twitches.

• Seizure frequency: Seizures are often very frequent and resistant to medication.

Neurological and Developmental Signs

• Global developmental delay: Severe delays in motor, cognitive, and social milestones.

• Hypotonia: Poor muscle tone and reduced spontaneous movement.

• Lack of visual tracking or eye contact

• Poor feeding and failure to thrive

Progression

• Many infants with Ohtahara syndrome evolve into other epileptic encephalopathies such as:

  • West syndrome (infantile spasms and hypsarrhythmia) in early infancy

  • Lennox–Gastaut syndrome (multiple seizure types and cognitive impairment) later in childhood

Diagnosis

Diagnosis of Ohtahara syndrome involves a combination of clinical observation, EEG findings, neuroimaging, and genetic testing.

Electroencephalogram (EEG)

• Burst-suppression pattern: Hallmark feature of the syndrome, characterized by high-voltage electrical bursts alternating with flat periods of suppression.

• EEG abnormalities are typically present both during wakefulness and sleep.

Neuroimaging

• MRI of the brain: Helps detect structural abnormalities such as cortical dysplasia, brain atrophy, or malformations.

Genetic and Metabolic Testing

• Whole exome sequencing or targeted gene panels: May identify causative mutations (e.g., STXBP1, ARX).

• Metabolic screening: May reveal underlying inborn errors of metabolism.

Clinical Evaluation

• Comprehensive neurological assessment

• Developmental screening and physical examination

Treatment

Treatment of Ohtahara syndrome is challenging due to its resistance to conventional antiepileptic drugs. Management focuses on seizure control and supportive care to improve quality of life.

Antiepileptic Medications

• Phenobarbital, valproate, levetiracetam, or topiramate: Common first-line agents, though often with limited effectiveness.

• Vigabatrin: Sometimes used, especially if infantile spasms develop.

• Ketogenic diet: High-fat, low-carbohydrate diet that may reduce seizures in some patients.

Other Therapies

• Steroids or ACTH: May be considered if the condition evolves into West syndrome.

• Resective surgery: In rare cases where seizures are focal and a structural lesion is resectable.

Supportive and Palliative Care

• Feeding support (e.g., gastrostomy tube)

• Physical, occupational, and speech therapy

• Seizure precautions and monitoring

• Multidisciplinary palliative care for comfort and family support

Prognosis

The prognosis for infants with Ohtahara syndrome is very poor. Most children experience:

• Severe intellectual and motor disability

• Intractable epilepsy despite medication

• Dependence on caregivers for daily needs

Many children with Ohtahara syndrome die in infancy or early childhood due to complications such as recurrent infections, uncontrolled seizures, or respiratory failure. Long-term survival is rare and usually associated with profound disabilities. Continued research is essential to better understand the condition and develop more effective therapies.