Shunsuke Ohtahara

The Early-Infantile Epileptic Encephalopathy with Suppression-Burst: Developmental Aspects

A clinico-electroencephalographic study on 14 cases of the early-infantile epileptic encephalopathy with suppression-burst (EIEE) including long-term follow-up studies for one year 8 months to 12 years 2 months disclosed the specificity of EIEE in its developmental aspects. With age, clinical evolution from EIEE to the West syndrome was observed in as many as 10 cases, among which two cases showed further transition to the Lennox-Gastaut syndrome. Electroencephalographically, suppression-burst pattern gradually began to disappear from age of 3 months and disappeared by 6 months in all the cases, transforming to hypsarhythmia in 10 cases from 2 to 6 months of age, showing further transition to diffuse slow spike-and-waves in 2 cases at one year and one month and at 3 years and one month of age, respectively. Changing pattern of EEG were classifiable into two types which strongly related to the prognosis. These findings indicated EIEE to be an independent epileptic syndrome as the earliest form of the age-dependent epileptic encephalopathy.

Epileptic encephalopathies in early infancy with suppression-burst.

Early infantile epileptic encephalopathy with suppression-burst, or Ohtahara syndrome (OS), and early myoclonic encephalopathy (EME) are epileptic encephalopathies with onset of frequent seizures in the neonatal and early infancy period and with a characteristic EEG pattern, namely, suppression-burst, in which higher-voltage bursts of slow waves mixed with multifocal spikes alternate with isoelectric suppression phase. Their nosologic independence is now widely accepted, although some controversy initially occurred because of their common characteristics such as age of onset, EEG features, seizure intractability, and poor prognosis. Major differences between the two syndromes include (1) tonic spasms in OS versus partial seizures and erratic myoclonias in EME, (2) continuous suppression-burst pattern in both waking and sleeping states in OS versus this EEG pattern almost limited to sleep in EME, and (3) static structural brain damage in OS versus genetic or metabolic disorders in EME. The most important differentiating point is their evolutional pattern with age, which may reflect their pathophysiologic difference. Ohtahara syndrome evolves to West syndrome and further to Lennox-Gastaut syndrome with age, but EME demonstrates no unique evolution; namely, it continues as such for a long time or changes into partial epilepsy or severe epilepsy with multiple independent spike foci.

Early-infantile epileptic encephalopathy with suppression-bursts, Ohtahara syndrome; its overview referring to our 16 cases

Ohtahara syndrome (OS) is characterized by frequent tonic spasms, with or without clustering, of early onset within a few months of life, and a suppression-burst (S-B) pattern in electroencephalography (EEG). Tonic spasms occur in not only waking but also sleeping state in most cases. Partial seizures are observed in about one-third of cases. Brain imagings reveal structural abnormalities including malformations, notably asymmetric lesions in most cases.S-B pattern is persistently observed regardless of circadian cycle. Bursts of 1-3s duration alternate with nearly flat suppression phase of 2-5s at an approximately regular rate; 5-10s of burst-burst interval. Some asymmetry in S-B is noted in about two-thirds of cases. Ictal EEG of tonic spasms shows principally desynchronization with or without initial rapid activity. Tonic spasms appear concomitant with bursts. Characteristic age-dependent evolution from OS to West syndrome (WS) in many cases, and further from WS to Lennox-Gastaut syndrome (LGS) in some, proceed concomitantly with EEG transition from S-B to hypsarrhythmia at around age 3-6 months, and further from hypsarrhythmia to diffuse slow spike-waves at around age 1. Under the inclusive concept of the age-dependent epileptic encephalopathy, OS, WS, and LGS have common characteristics such as age preference, frequent minor generalized seizures, and continuous massive epileptic EEG abnormality. Mutual transition suggests the same pathophysiology among three syndromes and the age factor should be considered as the common denominator responsible for the manifestation of each of their own specific clinico-electrical features. Namely, these syndromes may be the age-specific epileptic reaction to various non-specific exogenous brain insults, acting at the specific developmental stages.

Ohtahara syndrome: With special reference to its developmental aspects for differentiating from early myoclonic encephalopathy

UNLABELLED Ohtahara syndrome (OS) is well known as a peculiar early onset epileptic syndrome with serious prognosis. The outline of OS, mainly in relation to the evolution with age, and differentiation from related conditions, particularly early myoclonic encephalopathy (EME) were mentioned. RESULTS Etiologically, structural brain lesions are most probable in OS, and non-structural/metabolic disorders in EME. Clinically, tonic spasms are the main seizures in OS, while myoclonia and frequent partial motor seizures in EME. Another difference is noted in EEG findings: suppression-bursts (SB) are consistently observed in both waking and sleeping states in OS, but suppression-bursts become more apparent in sleep in EME. The course observation clarifies differences between both syndromes; SBs evolve to hypsarrhythmia around 3-4 months of age, and sometimes further to diffuse slow spike-waves in OS. In contrast, in EME suppression-bursts may persist up to late childhood after a transient evolution to hypsarryhtmia in the middle to late infancy. Transition between syndromes is also specific; OS evolves to West syndrome, and further to Lennox-Gastaut syndrome with age, but EME persists long without such evolution excepting a transient phase of West syndrome. CONCLUSION These clinicoelectrical characteristics and differential points strongly indicate the efficiency of the developmental study to delineate both syndromes.

Epilepsy with Electrical Status Epilepticus During Slow Sleep and Secondary Bilateral Synchrony

Summary: In 3 children with “epilepsy with electrical status epilepticus during slow sleep” (ESES), we estimated interhemispheric small time differences (TDs) during spike‐wave activity in EEG by coherence and phase analysis by the two‐dimensional autoregressive model to differentiate their continuous diffuse spike‐waves during slow‐wave sleep (CSWS) between primary bilateral synchrony and secondary bilateral synchrony (SBS). Maximal TDs at onset of apparently bilateral synchronous spike‐wave bursts (BSSWs) during slow‐wave sleep were 12·0–26·5 ms (mean 20·3 ms) with consistent leading hemispheres in eight bursts of the 3 patients, indicating SBS as pathophysiology of their CSWS. This suggestion was supported by their clinico‐EEG findings, including the effect of a single oral dose of clobazam (CLB) on EEG. Three ictal BSSWs of atypical absence seizures in 2 patients were also analyzed to obtain maximal TDs of 17·9–41·7 ms (mean 26·3 ms) at onset, with the same leading sides as in sleep, also indicating SBS. Examination of intraburst TD variations showed no consistent disappearance of TDs during the latter part of the bursts, in either sleep or the ictal EEGs of atypical absences, and a role of the corpus callosum was suggested in the generation of SBS in ESES.

The effects of age on the N200 component of the auditory event-related potentials

This study was undertaken to determine the effects of development and aging on N200 of event-related potentials from childhood to adulthood. Event-related potentials were recorded from 164 normal subjects ranging in age from 4 to 77 years. A total of 127 of the 164 subjects demonstrated N200 peaks. N200 showed marked developmental changes. During childhood, the N200 latency decreased rapidly with age to the minimum (217 +/- 17.3 ms) at 16 years of age, while it was prolonged gradually with age during adulthood. The latency/age slope in the subjects from 5 to 15 years of age was -9.03 ms/year, while +0.97 ms/year in those from 16 to 77. The N200-P300 interpeak latency remained constant in all age groups and showed no age-related changes. The N200 amplitude decreased as age increased. Nineteen young cases showed N200 peaks to the frequent stimuli. Their ages ranged from 5 to 17 years. Our study suggests that N200 is valuable in evaluating the developmental and aging processes in the central nervous system. The results of this study could be used as normative data in clinical practices.

Primary and secondary bilateral synchrony in epilepsy: differentiation by estimation of interhemispheric small time differences during short spike-wave activity ☆

Estimation of interhemispheric small time differences (TDs) during spike-wave bursts in the EEG by coherence and phase analysis is useful for differentiation between primary bilateral synchrony (PBS) and secondary bilateral synchrony (SBS) in epilepsy. Because the previous method via Fast Fourier Transform needed long bursts for reliable analysis, a method using a 2-dimensional autoregressive model was newly developed to enable estimation of TDs even in 1.2 sec bursts, and applied to 19 epileptic patients with apparently bilaterally synchronous spike-wave bursts. At the onsets of bursts, estimated maximal TDs were 5.8 msec or less and inconsistent in leading hemispheres in 10 patients with a clinical diagnosis of idiopathic, cryptogenic or symptomatic generalized epilepsy indicating PBS, while the maximal TDs were 9.3-41.5 msec and consistent in leading in 7 patients with clinically symptomatic partial epilepsy and also in two with idiopathic and symptomatic generalized epilepsy suggesting SBS. Among 8 patients with bursts which suggested SBS and long enough for evaluation of intra-burst TD variation, TDs tended to disappear in the middle to end parts of the bursts in 5 cases, but not in the other 3, suggesting 2 different pathophysiological mechanisms in SBS.

Neuroepidemiological Study of Childhood Epilepsy by Application of International Classification of Epilepsies and Epileptic Syndromes (ILAE, 1989)

Summary: A population‐based survey of childhood epilepsy was made in 1975 on the total population of children aged >10 years living in Okayama Prefecture (n = 2,378 patients). Using the data obtained, we attempted to re‐classify the various types of epilepsy according to the international classification (ILAE, 1989). Reclassification was possible in 1,872 (78.7%) of the 2,378 cases. The 1,872 cases consisted of 1,045 (55.8%) with localization‐related epilepsies, 824 (44.0%) with generalized epilepsies, and 3 (0.2%) with epilepsies undetermined whether focal or generalized. Classification of the epilepsies in a population‐based survey using the international classification involves difficulties, because both clinical and EEG findings are essential. However, if an appropriate area is selected, classification of epilepsies and epileptic syndromes in a population‐based survey is possible by referring to all medical records stored at every hospital and practitioners clinic that administers treatment to patients with epilepsy in the area.

Treatment of the west syndrome with high-dose pyridoxal phosphate

Fifteen (12.7%) among 118 cases of the West syndrome were effectively treated by high-dose pyridoxal phosphate (PAL-P). 1) Clinical seizures were completely suppressed in 12 cases with PAL-P alone, and in 3 cases by an addition of PAL-P to the previously poorly-effective regimen. At the follow-up, 12 cases have continued to be free from seizures, while two cases relapsed into the Lennox-Gastaut syndrome, and one died. 2) Electroencephalographically hypsarhythmia disappeared by PAL-P in all 15 effective cases. 3) Effective daily dose of PAL-P was 30 to 400 mg. 4) Notably, PAL-P was effective even in the cases with obvious organic brain pathology, such as tuberous sclerosis, porencephaly, holoprosencephaly, postmeningitis, besides 5 idiopathic cases. 5) Efficacy of PAL-P was significantly higher in idiopathic cases than symptomatic cases; 35.7% vs 9.6%. 6) Response to PAL-P was not predictable by any laboratory data nor clinical features. 7) Prognosis of PAL-P responsive cases was favorable; as many as 6 cases developed normally among 14 cases followed-up. Treatment with a high-dose PAL-P should be tried in all cases of the West syndrome at first.

Treatment of Intractable Childhood Epilepsy with High-Dose Valproate

Summary: Forty‐six children with refractory epilepsy (12 with symptomatic generalized epilepsy, 14 with symptomatic partial epilepsy, and 20 with undetermined epilepsy) were treated by high‐dose (serum level above 100 μg/ml) valproate (VPA) therapy. Monotherapy was used with 34 patients and two drugs with 12. Serum VPA concentrations ranged from 105.1 to 198.4 μg/ml. Assessment of initial response to treatment, after the serum level had reached the appropriate level, showed seizures to be completely controlled in 15 (32.6%) of 46 patients and improved in 12 (26.1%) (50% or more). Follow‐up of more than 6 months after the time of initial response showed control of seizures in 14 (30.4%) and improvement in 11 (23.9%). The initial effect on EEG was the disappearance of epileptic discharges in 3 (6.5%) of 46 patients and marked improvement in 15 (32.6%). Follow‐up revealed the disappearance of epileptic discharges in 7 (15.2%) and marked improvement in 9 patients (19.6%). High‐dose VPA therapy was especially effective for West syndrome and for epilepsy with continuous spike‐waves during slow‐wave sleep. Control of atypical absences and myoclonic seizures was relatively good. Hypofibrinogenemia and thrombocytopenia were sometimes encountered but these side effects were reversible with reduction of dosage.