In 2001, ILAE Commission on Classification and Terminology proposed a diagnostic scheme of epilepsy that included a new concept of epileptic encephalopathy in which epileptic abnormalities contribute to a progressive disturbance in cerebral function.¹ Also called catastrophic epilepsy, the earliest form of epileptic encephalopathies are Ohtahara syndrome (OS) and early myoclonic encephalopathy (EME).^2,3,4 This chapter outlines OS and EME, referring to their treatment and prognoses.

PRINCIPLES OF DIAGNOSIS

EEG

The suppression–burst pattern (SB) is a unique EEG pattern in which bursts of high voltage paroxysmal activity and near-flat suppression appear alternately, and likely represents disconnection of the cortex from subcortical structures.^2,3 Clinically, SB is also observed in (1) neonatal hypoxic–ischemic encephalopathy, in which it is usually called burst–suppression pattern, (2) deep anesthesia/sedation, and (3) neonatal epileptic encephalopathy such as OS and EME. SB in these latter disorders differs from the former two conditions; SB in the epileptic encephalopathy includes active epileptic discharges in bursts and has a shorter suppression phase than the former two transient nonepileptic conditions. To separate from other conditions with transient SB, Aicardi and Ohtahara³ considered that SB in the severe neonatal epilepsies must be stable or “invariant” for more than two weeks. As OS and EME share similar features besides SB such as very early onset, frequent and intractable seizures and severe prognoses, they are sometimes inclusively described such as early infantile epileptic syndromes with suppression–burst⁵ or severe neonatal epilepsies with suppression–burst pattern.³

DIFFERENTIAL DIAGNOSIS

Differential Diagnosis of Ohtahara and West Syndromes

The age at onset of the two syndromes is different: OS appears from the neonatal period to early infancy and West syndrome (WS) in middle infancy (Table 12–1).

The main seizure type is tonic spasms in both syndromes, but tonic spasms in OS appear not only while awake but also during sleep, and not always in clusters. Focal seizures also occur in some cases of both syndromes, but are much less frequent in WS.

OS usually has more severe cortical pathology, often displaying asymmetric lesions in neuroimaging, and some asymmetry or focal features in EEG, that is, SB, subsequent hypsarrythmia or focal spikes.

The EEG helps discriminate SB in OS from hypsarrhythmia in WS. SB in OS differs from the periodic type of hypsarrhythmia, in which periodicity becomes remarkable only during sleep.

Seizures are more intractable in OS, and adrenocorticotrophic hormone (ACTH) is usually much less effective. Furthermore, OS has a poorer developmental prognosis than WS.

Differential Diagnosis Between EME and OS

As EME and OS share some clinicoelectrical characteristics, such as very early onset and SB on EEG, differentiation may be challenging in atypical cases (Table 12–1). The cardinal seizure type in OS is tonic spasms whereas myoclonias are rare. However, myoclonias, especially erratic myoclonias, and frequent partial seizures are the main seizure types in EME.^3,4,6,7,8

SB differs considerably in both syndromes in the age of its appearance and its relation to the circadian cycle. SB in OS appears at the onset of the disorder, with the onset of tonic spasms, and is consistently observed during both the awake and sleep states. In contrast, SB in EME becomes distinct at age 1–5 months in some cases and is enhanced by sleep and often not apparent in waking records.^2,4,6,8,9

The age-related EEG evolution also differs considerably between OS and EME.^4,8 In OS the transition from SB to hypsarrhythmia occurs within 6 months of life in many cases and may progress to diffuse slow spike-waves or multiple independent spike foci (MISF) in some cases.^{2,4,10,11,12,13} In EME, however, SB persists for a longer time, at least in sleep although atypical hypsarrhythmia may appear transiently in some cases.^4,8

OS is the earliest age-dependent epileptic encephalopathy and may sequentially evolve to WS and Lennox–Gastaut syndrome (LGS) in accordance with EEG transition, while EME shows no age-specific evolution.

Etiologically, OS usually occurs on the basis of gross organic brain lesions including brain malformations and cerebral dysgenesis, while EME may associate with some verified or undetermined inborn errors of metabolism.^2,3,4

Differential Diagnosis of EME from Malignant Migrating Partial Seizures in Infancy (MMPSI)

MMPSI is a recently recognized epileptic syndrome that begins in the first 6 months of life in which frequent partial seizures involve multiple independent areas of both hemispheres with arrest of psychomotor development.¹⁴ EME and MMPSI share some characteristics such as onset in early infancy, no evidence of organic brain lesion, various types of partial seizures with ictal EEG features migrating from one cortical area to the other. Decisive difference is absence of myoclonias or tonic spasms and SB in MMPI.

EPIDEMIOLOGY

OS is a rare syndrome compared with WS and LGS. An epidemiologic study on childhood epilepsy carried out in Okayama Prefecture, Japan, detected one case of OS (0.04%), 4 cases of EME (0.17%), and 40 cases (1.68%) of WS among 2378 epileptic children younger than 10 years of age in 1980.¹⁵ Compared to WS, the prevalence of OS is 1/40. A similar study in 1999 observed two cases of EME (0.09%), no cases of OS, and 59 cases of WS (2.7%) among 2222 epileptic children younger than 13 years of age.¹⁶ Similarly, Kramer et al¹⁷ described one case of OS (0.2%) and 40 cases of WS (9.1%) in a cohort of 440 consecutive children with epilepsy under 15 years of age in Tel Aviv. The incidence rates of OS and WS were estimated as 0.1 and 4.2/10,000 live births, respectively, in Miyagi Prefecture, Japan. Thus, the relative incidence of OS and EME to WS is nearly 1/40 or less and 1/10–30, respectively. There are no obvious sex differences.

ETIOLOGY

Among the heterogeneous causes of OS, static structural brain lesions including brain malformations and cerebral dysgenesis are often found; it may be reasonably called an organic encephalopathy.^2,12 Documented etiologies are porencephaly, Aicardi syndrome, olivary–dentate dysplasia,¹⁸ olivary–dentate dysplasia with agenesis of the mamillary bodies,¹⁹ hemimegalencephaly,^{5,20,21,22,23} lissencephaly, linear sebaceous nevus syndrome.^2,3,10,12 Pathologic analysis has sometimes disclosed significant abnormalities not demonstrated on neuroimagings.^18,19,24 Metabolic disorders have not been reported except mitochondrial respiratory chain complex IV²⁵ and I^26,27 deficiency or Leigh encephalopathy, in which OS may be caused by secondary neuronal migration disorders or extensive brain damage rather than the metabolic disorder itself.³

No etiology has been identified in nearly one-third of cases.^12,28 However, these cryptogenic cases may have undetectable microdysgenesis or migration disorders that cause the progressive atrophy during the follow-up.

Recently, mutations have been identified in the aristaless-related homeobox gene (ARX) at Xp22.13, involving in the development of GABAergic interneurons,²⁹ STXBP1 (MUNC18–1) gene at 9q34.1, relating synapse vesicle release,³⁰ and SLC25A22 gene at 11p15.5 encoding a mitochondrial glutamate carrier,^31,32 mainly in cryptogenic OS. ARX gene mutations are also reported in familiar cases of OS^33,34 and each one boy with OS and WS are found in a family.³⁵ STXBP1 gene mutations were identified in as many as 14 of 43 cryptogenic OS cases by Saitsu et al,³⁶ one of 10 cases (10%) by Otsuka et al,³⁷ but none of 9 cases by Deprez et al.³⁸ One mutation of SLC25A22 gene had been reported in a family with 4 children with “EME”,³⁹ but later it was regarded to be responsible for OS as well as another mutation of this gene.^31,32 A precise and accurate acquisition or diagnosis of clinicoelectrical features will be fundamentally important for the proper interpretation of the results of molecular genetic studies.

As the expression of these genes is essential for early brain development such as neuronal progenitor cells proliferation and migration, and neurotransmitter regulation, their dysfunction could cause migration disorders or microdysgenesis, and neuronal miscommunication or hyperexcitability.³² Further investigation of these gene functions is expected to elucidate the manifestation mechanism of OS and WS.

CLINICAL PRESENTATION

OS is an intractable and severe epileptic syndrome that begins within the first few months of life that is characterized by frequent tonic spasms/epileptic spasms, either in clusters or sporadic, with SB in the EEG, in both the awake and sleep states

EIEE was initially described by Ohtahara et al in 1976 and was designated as the earliest form of the age-dependent epileptic encephalopathy that was proposed as the inclusive concept of OS, WS, and LGS.^2,4,10 Each of these syndromes is an independent clinicoelectrical entity with unique features; OS is characterized by clustering and/or single tonic spasms and SB in early infancy, while WS evidences tonic spasms in cluster and hypsarrhtymia in middle infancy, while LGS is distinguished by multiple types of generalized minor seizures and a diffuse slow spike-wave pattern in late infancy or childhood.

The three syndromes share several common features: (1) age dependency, (2) frequent minor generalized seizures, (3) severe and continuous epileptic EEG abnormalities, (4) etiological heterogeneity, often causing gross organic brain damage and developmental/mental deficit, and (5) seizure intractability and severe psychomotor prognoses.^2,4,10 Mutual transition is often observed among three syndromes; many patients with OS evolve into WS and more than half of WS to LGS.^11,12 The shared characteristics and transition with age support the concept of age-dependent epileptic encephalopathy for these syndromes. “Epileptic encephalopathy” was applied to the group of disorders according to (1) the presence of a serious underlying disorder, (2) extremely frequent clinical seizures, (3) continuous and widespread epileptic EEG abnormalities and (4) catastrophic features of cognitive stagnation or deterioration associated with seizure persistence.^2,4,10 These features are compatible with the concept of epileptic encephalopathy formulated by the ILAE.¹