What is Othahara syndrome?

Ohtahara Syndrome

Ohtahara syndrome is an early infantile epileptic encephalopathy characterized by tonic spasms beginning within the first 10 days of life (often within hours of delivery), suppression-burst pattern on EEG, and severe psychomotor retardation with a high mortality rate in infancy. 1, 2

Clinical Features

Seizure Characteristics

• Tonic spasms are the hallmark seizure type, occurring either as generalized symmetrical events or lateralized presentations 2
• Spasms last up to 10 seconds with intervals of 9-15 seconds between events within clusters 2
• Seizures occur both during wakefulness and sleep, distinguishing this from some other epileptic encephalopathies 2
• Approximately one-third of patients also experience partial motor seizures or hemiconvulsions 2

Electroencephalographic Pattern

• The pathognomonic EEG finding is a suppression-burst pattern consisting of high-voltage paroxysmal discharges separated by prolonged periods (up to 18 seconds) of nearly flat tracing 2
• This pattern is present both ictally and interictally in the initial stage 2

Neuroimaging Findings

• Brain malformations are frequently detected on MRI, particularly cortical dysplasias including pachygyria and polymicrogyria 3, 4
• Neuronal migration disorders are commonly associated, with excessive folding of small, fused gyri and bilateral perisylvian polymicrogyria reported 4

Genetic Etiology

At least four genes have been identified as causative, with mutations affecting neuronal and interneuronal functions including mitochondrial respiratory chains 1:

• ARX gene at Xp22.13 (EIEE-1 variant) 1
• CDKL5 gene at Xp22 (EIEE-2 variant) 1
• SLC25A22 gene at 11p15.5 (EIEE-3 variant) 1
• STXBP1 gene at 9q34-1 (EIEE-4 variant) 1
• SCN2A gene mutations have been identified in patients with neuronal migration disorders and Ohtahara syndrome, expanding the phenotypic spectrum 4
• Mitochondrial respiratory chain complex I deficiency has been documented as a metabolic cause 5

Prognosis and Natural History

• Approximately 50% of affected children die in infancy, often from complications related to intractable seizures 2
• Severe psychomotor retardation is universal in survivors 2
• The syndrome frequently evolves into West syndrome and subsequently may progress to Lennox-Gastaut syndrome 2
• Psychomotor development may be slightly better in patients who do not progress through this evolution to West and Lennox-Gastaut syndromes 2

Treatment Approach

Standard Anticonvulsant Therapy

• Conventional anticonvulsants (phenobarbital, vigabatrin, valproate) provide minimal seizure control and do not halt psychomotor deterioration 3

ACTH Therapy

• A therapeutic trial of ACTH is indicated given the possibility of seizure control, though response is variable 3
• In reported cases, ACTH achieved complete seizure freedom with EEG improvement in some patients, while others showed no response 3

Metabolic-Targeted Therapy

• For cases associated with mitochondrial respiratory chain defects, ketogenic diet combined with mitochondrial cocktail therapy (vitamins, coenzymes, and antioxidants) may achieve complete seizure control and resolution of suppression-burst patterns 5
• This intensive metabolic approach should be considered when mitochondrial dysfunction is suspected or confirmed 5

Treatment Algorithm

1. Initiate standard anticonvulsants (phenobarbital or valproate) while pursuing diagnostic workup 3
2. Obtain MRI to identify structural brain malformations 3
3. Consider genetic testing for ARX, CDKL5, SLC25A22, STXBP1, and SCN2A genes 1, 4
4. Evaluate for mitochondrial respiratory chain defects if clinical suspicion exists 5
5. If standard anticonvulsants fail (which is typical), proceed with ACTH trial 3
6. For confirmed or suspected mitochondrial dysfunction, implement ketogenic diet with mitochondrial cocktail therapy 5

Critical Pitfalls

• Do not delay ACTH trial while waiting for complete genetic workup, as early intervention may improve outcomes 3
• Do not assume all cases are structural—metabolic causes like mitochondrial defects require specific targeted therapy 5
• Do not confuse with early myoclonic encephalopathy (EME), which has different etiologic mechanisms and may involve ErbB4 mutations 1