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Early infantile epileptic encephalopathy

Orpha number ORPHA1934
Synonym(s) EIEE
Early infantile epileptic encephalopathy with suppression-bursts
Ohtahara syndrome
Prevalence Unknown
Inheritance
  • Sporadic
  • Autosomal dominant
  • Autosomal recessive
  • X-linked recessive
Age of onset Neonatal/infancy
ICD-10
  • G40.3
OMIM
UMLS
  • C0393706
MeSH -
MedDRA
  • 10071545
SNOMED CT
  • 230429005

Summary

Early infantile epileptic encephalopathy (EIEE), or Ohtahara syndrome, is one of the most severe forms of age-related epileptic encephalopathies, characterized by the onset of tonic spasms within the first 3 months of life that can be generalized or lateralized, independent of the sleep cycle and that can occur hundreds of times per day, leading to psychomotor impairment and death.

Incidence has been estimated at 1/100 000 births in Japan and 1/50,000 births in the U.K.

Onset of EIEE occurs within the first 3 months of life but some present within the first few weeks after birth. Neonates have poor suckling reflexes, hypotonia and manifest with generalized and symmetrical tonic spasms that can appear in clusters or singly and can last for up to 10 seconds. The pattern of these spasms remains unchanged during wakefulness and sleep and they can occur hundreds of times per day. Other seizure types, including generalized tonic-clonic seizures, focal motor seizures and hemiconvulsions, are seen in 1/3 of cases. Those who live past the age of 2 years manifest with severe psychomotor deficits. In some, EIEE can transition into West syndrome (between 2-6 months of age) and later into Lennox-Gastaut syndrome (see these terms). Certain genetic variants manifest with additional signs such as dyskinetic movements and an atypical Rett-syndrome phenotype (see this term). Death is often due to pneumonia or other complications of a complex disability.

EIEE may be the result of different etiologies. Many cases have been associated with structural brain abnormalities. Some cases are due to metabolic disorders (cytochrome C oxidase deficiency, carnitine palmitoyl transferase II deficiency; see these terms) or brain malformations (such as porencephaly, hemimegalencephaly; see these terms) that may or not be genetic in origin. Genetic variants of EIEE have been associated with mutations in certain genes such as ARX (Xp22.13) , CDKL5 (Xp22) , SL25A22 (11p15.5) and STXBP1 (9q34.1), among others. The genetic abnormalities are thought to lead to EIEE as they are related to neuronal dysfunction or brain dysgenesis.

Diagnosis is based on clinical and electroencephalographic findings. The characteristic electroencephalogram (EEG) displays a suppression burst pattern (which appears with the onset of spasms) that is comprised of bursts of high amplitude spikes and polyspikes that alternate with periods of low voltage basic rhythm (suppression). This EEG pattern is continuous and remains unchanged during both waking and sleeping states. Structural abnormalities can often be seen on cranial MRI.

Differential diagnoses include other epileptic encephalopathies such as early myoclonic encephalopathy, West syndrome (see these terms) and other early onset epileptic encephalopathies.

Prenatal diagnosis is possible in families with a known genetic etiology.

Autosomal recessive inheritance has been reported, but most cases of EIEE are sporadic (de novo mutations). Genetic counseling is therefore very valuable to inform parents that their risk of having further children with EIEE is low.

There is no cure for EIEE and patients require constant supervision and care. Antiepileptic drugs such as benzodiazepines, valproate, levetiracetam, zonisamide and phenobarbital have shown limited success in controlling seizures as has pyridoxine. A ketogenic diet has been reported to show some success in seizure control. In those with associated metabolic disorders, once these conditions have been treated there can be an improvement in the course of EIEE. Similarly, EIEE patients with certain structural abnormalities have benefited from surgical intervention, if unilateral.

Prognosis is poor with death usually occurring in infancy (50% before age of 2). Survivors have severe psychomotor impairments with continuing seizures.

Expert reviewer(s)

  • Pr Helen CROSS

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