Epileptic or chronic seizures occurring during the neonatal and early infantile periods are rarely observed compared with those occurring during other stages of childhood, because of the morphologic and biochemical immaturity of the central nervous system. Only a few epileptic syndromes begin in these periods, most of them refractory and catastrophic epilepsies.^3,7,21 Of these, this chapter describes the Ohtahara syndrome (OS): Early infantile epileptic encephalopathy with suppression-burst.

This syndrome, which has not only characteristic clinical and electroencephalographic (EEG) features, but also a distinct age dependence and evolution of epileptic syndromes with age, is considered the youngest form of the age-dependent epileptic encephalopathy.

In 1976, Ohtahara et al.²⁷ first described OS as an independent epileptic syndrome. It is the earliest form of the age-dependent epileptic encephalopathies, which include OS, West syndrome, and Lennox-Gastaut syndrome. Although each of these is an independent clinicoelectrical entity with individual clinical and EEG features, they have the following characteristics in common: (a) predominance in a certain age group (age dependence); (b) a peculiar type of frequent, minor, generalized seizure; (c) a severe and continuous epileptic EEG abnormality; (d) heterogeneous etiology; (e) frequent association with a mental defect; and (f) poor response to treatment and grave prognosis.^25,26,29 Furthermore, these syndromes often evolve with age. During their clinical course, a considerable number of cases of OS evolve into West syndrome and then from West syndrome into Lennox-Gastaut syndrome.^25,28,49 Because of their common characteristics and their transitions with age, Ohtahara applied the inclusive term age-dependent epileptic encephalopathy to this group of three syndromes.^25,26,29

We adopt the term “epileptic encephalopathy” instead of “epilepsy” based on the following characteristics: (a) the presence of serious underlying disorders, (b) extremely frequent seizures, (c) continuously appearing marked epileptic EEG abnormality, and (d) mental stagnation or deterioration often manifesting with the persistence of seizures.

Although the etiologies of these syndromes are heterogeneous, each syndrome occurs predominantly within a certain age range and is associated with specific clinical and EEG traits. Because the clinical and electrical characteristics of each syndrome are based on a diverse group of etiologies, age should be considered the common factor underlying the manifestation of specific features. Thus, these syndromes may represent an age-specific epileptic reaction to various nonspecific exogenous insults to the brain occurring at an age-specific developmental stage.

Ohtahara syndrome is characterized by very early onset, within a few months of birth, frequent tonic spasms, and a suppression-burst pattern in the EEG.^27,29,31,32 This periodic EEG pattern is consistently observed in both awake and sleep states. The main seizure pattern is tonic spasms but not myoclonic seizures. Tonic spasms appear often in clusters but sometimes sporadically. Partial motor seizures may occur. Although the etiologies are heterogeneous, neuroimaging usually discloses gross structural abnormalities due to mainly prenatal cerebral dysgenesis. The prognosis is serious: For example, early death or marked psychomotor retardation and intractable seizures with frequent evolution to West syndrome and still further to Lennox-Gastaut syndrome in some cases^28,29,49 or to severe epilepsy with multiple independent spike foci.⁵¹ The Commission on Classification and Terminology of the International League Against Epilepsy (ILAE)⁷ placed this syndrome among “symptomatic generalized epilepsies and syndromes with nonspecific etiology,” and the proposed diagnostic scheme of the ILAE¹⁰ categorized it as “epileptic encephalopathy.”

Several dozen cases of OS have been reported, but occurrence has been rare in comparison with West syndrome (WS) and Lennox-Gastaut syndrome. An epidemiologic study of childhood epilepsy carried out in Okayama Prefecture, Japan, detected 1 case of OS (0.04%) among 2,378 epileptic children <10 years of age.³⁶ The prevalence of this syndrome was much lower than that of West syndrome (40 cases, or 1.68%). Similarly, Kramer et al.¹⁸ described 1 case of OS (0.2%) and 40 cases of WS (9.1%) in a cohort of 440 consecutive children <15 years of age with epilepsy in Tel Aviv, Israel. Thus, the relative prevalence of OS to WS may be 1:40 or less. On the other hand, in a study of 75 infants with epilepsy of neonatal onset who were monitored intensively, Watanabe et al. observed 8 cases (10.7%) of OS and no case of WS.⁴⁶

No obvious racial differences have been observed in the respective incidences. No significant gender difference was confirmed, but male slightly exceeded female cases by 9:7 in our series.⁵⁰

Although the etiologies of OS are heterogeneous, the majority are static gross brain pathologies such as cerebral dysgenesis, although some are cryptogenic. Development of neuroimaging techniques, particularly magnetic resonance imaging (MRI), has disclosed that various types of cerebral dysgenesis are the greatest underlying pathologies of this syndrome.^40,50 It is also important that asymmetry is often
observed in structural abnormalities of the brain. Porencephaly, Aicardi syndrome,^34,50 cerebral dysgenesis, olivary-dentate dysplasia,^13,39,44 hemimegalencephaly,^12,33,50 linear sebaceous nevus,¹⁵ Leigh encephalopathy,⁴² and subacute diffuse encephalopathy²⁹ have been reported.

Of 16 cases in our series, 5 (31.3%) were cryptogenic.⁵⁰ With regard to genetic factors, no sibling case was reported except for Leigh encephalopathy.

With regard to metabolic disorders, although they are very rare, Williams et al.^14,48 first reported a case with cytochrome oxidase deficiency. This case, however, had only transient reversible deficiency that may have caused impaired neuronal migration or demyelination due to energy depletion during a critical period. Miller et al.²⁰ reported the absence of γ-aminobutyric acid (GABA) in cerebrospinal fluid (CSF) in a case with diffuse cerebral migration disorder. Fusco et al.¹¹ described one case each with pyridoxine dependency and carnitine palmitoyltransferase deficiency.

Fundamentally, the age factor should be emphasized, on the basis of polyetiology.

The pathophysiologic mechanisms underlying suppression-bursts are not fully elucidated. Aso et al.⁴ found that the suppression-burst pattern correlated with multifocal severe brain damage, although no one structure was consistently affected. Any of these anomalies can prevent the establishment of normal neuronal connectivity necessary for the EEG ontogeny. This hypothesis is corroborated by the observation that a normal EEG pattern at any age can revert to a suppression-burst pattern after catastrophic events that cause laminal necrosis of the cortex, as in severe hypoxic-ischemic encephalopathy.⁴⁷ Similar but less readily identifiable cortical and subcortical abnormalities must be invoked to explain cryptogenic cases of OS and those with olivary-dentate dysplasia. Spreafico et al.⁴¹ suggested that in OS and early myoclonic encephalopathy (EME) the suppression-burst (SB) pattern primarily reflects a diffuse structural or junctional disturbance of gray matter connectivity.