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Current thumbnail: Ohtahara syndrome, also called early infantile epileptic encephalopathy with suppression bursts, is the earliest developing form of epileptic encephalopathy. The syndrome is characterized by tonic spasms, partial seizures, a peculiar pattern of suppression bursts in EEG, and poor prognosis. In this clinical summary, Federico Vigevano, MD, Head of the Neurology Division at Bambino Gesu Children’s Hospital in Rome, Italy, reviews the clinical and neurophysiological data and the different etiologic factors related to Ohtahara syndrome. At present, this disorder is considered to be a result, primarily, of static structural brain damage.

Historical note and nomenclature

Early infantile epileptic encephalopathy with suppression bursts was first described by Ohtahara and colleagues in 1976 (Ohtahara et al 1976) and subsequently was presented as the earliest form of epileptic encephalopathy (Ohtahara 1978). The 1985 Classification of Epilepsies and Epileptic Syndromes by the International League Against Epilepsy did not give the disorder status as a separate entity. The 1989 revised classification, however, placed it under "symptomatic generalized epilepsies and syndromes with nonspecific etiology" (Commission on Classification and Terminology of the International League Against Epilepsy 1985; 1989).
In 2001, the ILAE Task Force on Classification and Terminology proposed to include this entity in the list of epileptic encephalopathies (Engel 2001), precisely those conditions in which not only epileptic activity but also the epileptiform EEG abnormalities themselves are believed to contribute to the progressive disturbance in cerebral function. Moreover, in this group we also find early myoclonic encephalopathy, West syndrome, and Lennox-Gastaut syndrome.

Therefore, Ohtahara’s theory that considers this entity the earliest of the age-dependent epileptic encephalopathies has been accepted, based also on the notion that 75% of the cases subsequently evolve to West syndrome, and later a much smaller number progress to Lennox-Gastaut syndrome.

Clinical manifestations

In 2002, Aicardi and Ohtahara summarized the characteristics of the syndrome (Aicardi and Ohtahara 2002):

(1) Onset in early infancy, within the first 3 months, mainly within the first 10 days of life

(2) Main seizure pattern: tonic spasms

(3) Other seizures: partial seizures, rare myoclonic seizures

(4) Suppression-bursts in EEG, during both waking and sleeping states

(5) Poor prognosis: severe psychomotor retardation and frequent death during infancy

(6) Intractable seizures and frequent progression to West syndrome

(7) Polyetiology, but majority of cases are associated with structural brain damage

The seizures in Ohtahara syndrome develop within the first 10 days of life in the majority of reported cases and may occur as early as the first hour after delivery (Ohtahara 1984; Clarke et al 1987). Onset is acute in a previously normal infant. Du Plessis and colleagues extend the earliest age of onset into the prenatal period with intrauterine seizures (du Plessis et al 1993). The disorder takes a progressively deteriorating course with increasing frequency of seizures and with severe retardation of psychomotor development. The infants are usually left profoundly handicapped. Boys are affected more often than girls in the reported cases (Clarke et al 1987).

The seizure types in Ohtahara syndrome are variable. The most frequently observed type is tonic spasms, which may be either generalized and symmetrical or lateralized. The tonic spasms may occur in clusters or singly, both while awake and during sleep. The duration of spasms is up to 10 seconds, and interval between spasms within cluster ranges from 9 to 15 seconds. In one third of cases, other seizure types include partial motor seizures or hemiconvulsions (Yamatogi and Ohtahara 2002). Massive or segmentary myoclonic jerks are rarely present; erratic myoclonus is not a feature of this syndrome. Later in the course, there may be generalized tonic-clonic seizures.
The most characteristic EEG feature peculiar to the syndrome is suppression-burst pattern: discharges of wide amplitude spikes and polyspikes that alternate with suppression of electric activity. The bursts last 2 to 6 seconds, whereas the suppression phase lasts usually 3 to 8 seconds. Suppression-burst pattern can be widespread, synchronous, or asynchronous on both hemispheres or prevail clearly on one side, as observed in hemimegalencephaly.

Suppression-burst pattern occurs while awake and during sleep.
In a study of the video-EEG aspects of the syndrome, Fusco and colleagues demonstrated the coincidence between tonic spasms and burst EEG (Fusco et al 2001).

Soon after the onset of seizures, the infants become inactive and hypotonic. Their psychomotor development is arrested, and they usually develop severe neurologic abnormalities such as spastic diplegia, hemiplegia, tetraplegia, ataxia, or dystonia.
Between 2 and 6 months of age, the cases may evolve into West syndrome. This occurred in 12 out of the 16 cases (75%) in one series (Yamatogi and Ohtahara 2002). The clinical manifestations were spasms and a hypsarrhythmic pattern on EEG. Two of the 12 West syndrome cases later developed Lennox-Gastaut syndrome, with its characteristic slow spike-waves on EEG and minor motor seizures.

Clinical vignette

The female patient was born from an uneventful pregnancy by cesarean section at 38 weeks of gestation. Apgar scores were 8 at 1 minute and 9 at 5 minutes. During the first day of the patient’s life, seizures began with bilateral clonic movements and oral automatism. MRI showed left hemimegalencephaly, with homolateral cerebellar and basal ganglia enlargement. At 16 days of life, she came to our department and underwent her first video/EEG recording. The EEG showed a pattern of suppression-burst continuously through wakefulness and sleep; only during wakefulness was it associated with a bilateral brief tonic contraction, simultaneous with the burst. Although at times a right deltoid contraction was evident without the burst, no other ictal discharges were recognizable on the EEG. This child presented with a mild right hemiparesis and visual inattention, but she had no dysmorphic features. She showed an alternation between a state of wakefulness with eyes opened and with some response to environmental stimulation and a state of apparent sleep poor response to external stimuli. The EEG did not change during the 2 separate states; the only difference was a less obvious ictal clinical involvement simultaneous with the burst during sleep than when awake. She was taking anti-epileptic drugs (phenobarbital and vigabatrin). At 1 month old, she underwent adrenocorticotropic hormone therapy without success. During the video/EEG examination recorded at 53 days of life, it was clear that even during sleep there was a subtle sign of an ictal burst discharge, consisting of a brief arrest of respiration. Tonic spasms were also present continuously on awakening and during the whole wakefulness. At the age of 2 months and 17 days, the patient’s seizures worsened, and tonic spasms were associated with more complex partial seizures. She developed breathing difficulty and high fever. She was hospitalized, and after 10 days, she died of septic shock.

Etiology

In Ohtahara's original series of 10 cases, 2 infants had porencephaly, 1 had Aicardi syndrome, and 1 had "subacute diffuse encephalopathy" (Ohtahara 1984). In the remaining 6 cases, no cause could be identified.

In another series of 11 cases, 1 case was associated with asphyxia at birth, 1 with agenesis of the corpus callosum, and 1 with nonketotic hyperglycinemia; no cause for seizures could be identified in 8 cases (Clarke et al 1987). Only 1 of the latter 8 idiopathic cases had a family history of epilepsy.

In the series of Schlumberger and colleagues, all 8 infants had identified brain malformations, including 6 cases of hemimegalencephaly, 1 of Aicardi syndrome, and 1 of dentato-olivary dysplasia (Schlumberger et al 1992). Hemimegalencephaly was also the cause in the cases of Martin and colleagues, Ohtsuka and colleagues, and in 2 of the 8 cases of Fusco and colleagues (Martin et al 1981; Ohtsuka et al 1999; Fusco et al 2001).

In a review of the malignant epilepsies of childhood, cerebral malformations were cited as a common etiology for Ohtahara syndrome (Renier 1995). Murakami and colleagues explored the same territory (Murakami et al 1993). Several studies discuss the role of cortical dysgenesis in relation to the early infantile encephalopathies (du Plessis et al 1993; Ogihara et al 1993; Spreafico et al 1993; Tominaga et al 1993).

Robain and Dulac also reported a case associated with olivary dentate nuclei dysplasia (Robain and Dulac 1992). Miller and coworkers reported a case with diffuse cerebral migrational disorder associated with absence of gamma-aminobutyric acid in the cerebrospinal fluid (Miller et al 1998).

Metabolic disorders were rarely observed. In addition to the above mentioned case of nonketotic hyperglycinemia (Clarke et al 1987), Tatsuno and colleagues reported a case of Leigh encephalopathy (Tatsuno et al 1984), Williams and coworkers reported a case associated with cytochrome c oxidase deficiency (Williams et al 1998), and Fusco and coworkers reported a case with pyridoxine dependency and a case with carnitine palmitoyltransferase deficiency (Fusco et al 2001).

Despite the presence of different neuropathologic pictures, the syndrome is now believed to be mainly secondary to a cerebral malformative disorder.

Pathogenesis and pathophysiology

Because of the close relationship of Ohtahara syndrome, West syndrome, and Lennox-Gastaut syndrome, it is suggested that they all represent age-specific reactions of the brain at various developmental stages to heterogeneous, nonspecific exogenous factors (Ohtahara 1984). This form of epilepsy also occurs in patients with hemispheric or focal malformative lesions causing catastrophic partial epilepsies that sometimes precede, but more often follow, the syndrome (Schlumberger et al 1992).

Epidemiology

The incidence and prevalence of Ohtahara syndrome are unknown.

Prevention

No information is available.

Differential diagnosis

Early myoclonic encephalopathy is associated with onset in early infancy, a suppression-burst pattern in EEG, a variety of seizure types, and poor psychomotor outcome. It is similar to Ohtahara syndrome, which was not regarded as a separate entity until the 1989 Revised Classification of Epilepsies and Epileptic Syndromes of the International League Against Epilepsy (Commission on Classification and Terminology of the International League Against Epilepsy 1989). The 2 entities are now classified in the group of epileptic encephalopathies (Engel 2001).

The prominent erratic myoclonia in early myoclonic encephalopathy is not present in Ohtahara syndrome: spasms and tonic seizures predominate in the latter. Etiology is also different: metabolic pathologies dominate in early myoclonic encephalopathy and malformative pathologies in Ohtahara syndrome. Recently, the major differences between the 2 syndromes have been confirmed: (1) tonic spasms in Ohtahara syndrome versus partial seizures and erratic myoclonias in early myoclonic encephalopathy, (2) continuous suppression-burst pattern in both waking and sleeping states in Ohtahara syndrome versus this EEG pattern almost limited to sleep in early myoclonic encephalopathy, (3) static structural brain damage in Ohtahara syndrome versus genetic or metabolic disorders in early myoclonic encephalopathy, (4) different evolutional pattern with age. Ohtahara syndrome evolves often to West syndrome and further to Lennox-Gastaut syndrome with age, but early myoclonic encephalopathy 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.

With respect to West syndrome, differential diagnosis is based on age at onset, which is earlier in Ohtahara syndrome; on interictal EEG because hypsarrhythmia is not present in Ohtahara syndrome; and on seizure type, as the EEG pattern of spasms in West syndrome is completely different from that of tonic spasms (Fusco and Vigevano 1993).

Donat provided an overview of the age-dependent epileptic encephalopathies of infancy and sought to define the place of Ohtahara syndrome or early infantile epileptic encephalopathy in the scheme of things vis-à-vis early myoclonic encephalopathy, West syndrome, and Lennox-Gastaut syndrome—all of which display a certain degree of overlap, which is not surprising considering the limited capability of the infantile brain (Donat 1992).

Diagnostic workup

In the initial stage of Ohtahara syndrome, interictal EEG shows a pattern of suppression-burst with high-voltage paroxysmal discharges separated by prolonged periods of nearly flat tracing that last for up to 18 seconds (Clarke et al 1987). The suppression-burst pattern may be predominant or asynchronous in one hemisphere and increase during sleep. Ictal EEG shows the coincidence of the burst and tonic spasms (Fusco et al 2001).

Between 3 and 6 months of age, the suppression-burst pattern may gradually be replaced by hypsarrhythmia, characteristic for West syndrome. Transition to the slow spike-waves that are characteristic for Lennox-Gastaut syndrome may occur in early childhood (Ohtahara et al 1987). In other cases, the Ohtahara syndrome is replaced by severe partial epilepsy, and the epileptiform abnormalities tend to focalize in a limited area or in an entire hemisphere. Considering that the most frequent etiology is structural brain damage, it is evident that the most important diagnostic evaluation is by neuroimaging. CT and MRI may reveal specific findings compatible with the malformative etiologies described previously. Metabolic investigations are indicated in cases with normal or nonspecific imaging abnormalities. However, it is important to remember that some metabolic disorders, such as glutaric aciduria and mitochondrial disorders and others, can also produce cerebral malformation (Tharp 2002).

Prognosis

The seizures in Ohtahara syndrome are often intractable and resistant to antiepileptic therapy. Severe psychomotor retardation is the rule. With time, the disorder may evolve into West syndrome or partial epilepsy. Psychomotor development may be slightly better if the infants do not develop West or Lennox-Gastaut syndrome (Clarke et al 1987). Half the cases reported die in infancy or childhood.

Management

Phenobarbital may help to reduce seizure frequency, but the anticonvulsant helps little in controlling the seizures and halting the deterioration of psychomotor development. None of the reported cases responded to adrenocorticotropic hormone therapy (Clarke et al 1987). Ohno and colleagues reported a case that responded to zonisamide (Ohno et al 2000), whereas Fusco and coworkers reported a case that responded to vitamin B6 (Fusco et al 2001). Cases with hemimegalencephaly or cortical dysplasia can benefit from neurosurgical treatment with hemispherectomy (Pedespan et al 1995) or focal resection (Komaki et al 1999).

Pregnancy

Not applicable.

Anesthesia

No information is available.

References cited

Aicardi J, Ohtahara S. Severe neonatal epilepsies with suppression-burst pattern. In: Roger J, Bureau M, Dravet CH, Genton P, Tassinari CA, Wolf P, editors. Epileptic Syndromes in Infancy, Childhood and Adolescence. 3rd ed. London: John Libbey & Company Ltd, 2002:33-44.

Clarke M, Gill J, Noronha M, McKinlay I. Early infantile epileptic encephalopathy with suppression burst: Ohtahara syndrome. Dev Med Child Neurol 1987;29:520-8.

Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for classification of epilepsies and epileptic syndromes. Epilepsia 1985;26:268-78.

Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389-99.

Donat JF. The age-dependent epileptic encephalopathies. J Child Neurol 1992;7:7-21.

du Plessis AJ, Kaufmann WE, Kupsky WJ. Intra-uterine onset myoclonic encephalopathy associated with cerebral cortical dysgenesis. J Child Neurol 1993;8:164-70.

Engel J. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: Report of the ILAE Task Force on classification and terminology. Epilepsia 2001;42:796-803.

Fusco L, Pachatz C, Di Capua M, Vigevano F. Video-EEG aspects of early-infantile epileptic encephalopathy with suppression-bursts (Ohtahara syndrome). Brain Dev 2001;23:708-14.

Fusco L, Vigevano F. Ictal clinical electroencephalographic findings of spasms in West syndrome. Epilepsia 1993;34(4):671-8.

Komaki H, Sugai K, Sasaki K, et al. Surgical treatment of a case of early infantile epileptic encephalopathy with suppression-bursts associated with focal cortical dysplasia. Epilepsia 1999;40:365-9.

Martin HJ, Deroubaix-Tella P, Thelliez PH. Encéphalopathie épileptique néonatale à bouffées périodiques. Rev EEG Neurophysiol 1981;11:397-403.

Miller SP, Dilenge ME, Meagher-Villemure K, O'Gorman AM, Shevell MI. Infantile epileptic encephalopathy (Ohtahara syndrome) and migrational disorder. Pediatr Neurol 1998;19(1):50-4.

Murakami N, Ohtsuka Y, Ohtahara S. Early infantile epileptic syndromes with suppression-bursts: early myoclonic encephalopathy vs. Ohtahara syndrome. Jpn J Psychiatry Neurol 1993;47:197-200.

Ogihara M, Kinoue K, Takamiya H, et al. A case of early infantile epileptic encephalopathy (EIEE) with anatomical cerebral asymmetry and myoclonus. Brain Dev 1993;15:133-9.

Ohno M, Shimotsuji Y, Abe J, Shimada M, Tamiya H. Zonisamide treatment of early infantile epileptic encephalopathy. Pediatr Neurol 2000;23:341-4.

Ohtahara S. Clinico-electrical delineation of epileptic encephalopathies in childhood. Asian Med J 1978;21:499-509.

Ohtahara S. Seizure disorders in infancy and childhood. Brain Dev 1984;6:509-19.

Ohtahara S, Ishida T, Oka E, Yamatogy Y, Inoue H. On the specific age-dependent epileptic syndromes: the early-infantile epileptic encephalopathy with suppression-burst. No To Hattatsu 1976;8:270-80.

Ohtahara S, Ohtsuka Y, Yamatogi Y, Oka E. The early-infantile epileptic encephalopathy with suppression-burst: developmental aspects. Brain Dev 1987;9:371-6.

Ohtsuka Y, Ohno S, Oka E. Electroclinical characteristics of hemimegalencephaly. Pediatr Neurol 1999;20:390-3.

Ohtahara S, Yamatogi Y. Epileptic encephalopathies in early infancy with suppression-burst. J Clin Neuro 2003;20(6):398-407.

Pedespan JM, Loiseau H, Vital A, et al. Surgical treatment of an early epileptic encephalopathy with suppression-bursts and focal cortical dysplasia. Epilepsia 1995;36:37-40.

Renier WO. The malignant epilepsies of childhood and adolescence. In: Aldenkamp AP, Dreifuss FE, Reiner WO, Suumeijer PBM, editors. Epilepsy in children and adolescence. Boca Raton: CRC Press, 1995.

Robain O, Dulac O. Early epileptic encephalopathy with suppression bursts and olivary-dentate dysplasia. Neuropediatrics 1992;23(3):162-4.

Schlumberger E, Dulac O, Plouin P. Early-infantile epileptic syndrome(s) with suppression-burst: nosological considerations. In: Roger J, Bureau M, Dravet CH, Dreifuss FE, Perret A, Wolf P, editors. Epileptic syndromes in infancy, childhood, and adolescence. London: John Libbey & Company Ltd; 1992:35-42.

Spreafico R, Angelini L, Binelli S, et al. Burst suppression and impairment of neocortical ontogenesis: electro-clinical and neuropathologic findings in two infants with early myoclonic encephalopathy. Epilepsia 1993;34:800-8.

Tatsuno M, Hayashi M, Iwamoto H, et al. [Autopsy case of Leigh's encephalopathy with wide lesions in central nervous system and early infantile epileptic encephalopathy with burst suppression] [Japanese]. No To Hattatsu 1984;16:68-75.

Tharp BR. Neonatal seizures and syndromes. Epilepsia 2002;43:2-10.

Tominaga I, Kaihou M, Kimura T, et al. Early infantile epileptic encephalopathy (Ohtahara syndrome) with poly-microgyria. Rev Neurol (Paris) 1993;149(10):532-5.

Williams AN, Gray RG, Poulton K, et al. A case of Ohtahara syndrome with cytochrome oxidase deficiency. Dev Med Child Neurol 1998;40:568-70.

Yamatogi Y, Ohtahara S. Early-infantile epileptic encephalopathy with suppression-bursts, Ohtahara syndrome; its overview referring to our 16 cases. Brain Dev 2002;24:13-23.

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Abbreviations

CT:computed tomography

EEG:electroencephalogram

Synonyms

Early infantile epileptic encephalopathy with suppression-burst

Ohtahara’s syndrome

Ohtaharas syndrome

Associated disorders

Lennox-Gastaut syndrome

West syndrome

Catastrophic partial epilepsy

Major keyword descriptors

ataxia

brain malformation

cortical dysgenesis

dystonia

generalized tonic-clonic seizures

hemiplegia

hemimegalencephaly

hypsarrhythmia

infantile spasms

metabolic errors

motor partial seizures

myoclonus

phenobarbital

psychomotor retardation

quadriplegia

slow spike-and-wave

spastic diplegia

tonic spasms

Minor keyword descriptors

clonic seizures

epilepsy

infancy

mental retardation

Age of presentation

0-03 months

Age of typical presentation

0-01 month

Population group(s) preferentially affected

none selectively affected

Occupation group(s) preferentially affected

none selectively affected

Sex

male>female, >1:1

Family history

none

Heredity

none

Glossary

Ohtahara syndrome

Epileptic syndrome characterized by onset in early infancy, mental deterioration, and multiple seizure types.

Permuted topic, synonyms, and subtopics

Ohtahara syndrome

infantile epileptic encephalopathy with suppression-burst, Early

epileptic encephalopathy with suppression-burst, Early infantile

encephalopathy with suppression-burst, Early infantile epileptic

suppression-burst, Early infantile epileptic encephalopathy with

Related topics

Aicardi syndrome

Focal cortical dysplasia

Hemimegalencephaly

Differential diagnosis

early myoclonic encephalopathy

West syndrome

Lennox-Gastaut syndrome

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