Burst Suppression and Impairment of Neocortical Ontogenesis: Electroclinical and Neuropathologic Findings in Two Infants with Early Myoclonic Encephalopathy

Spreafico, Roberto; Angelini, Lucia; Binelli, S.; Granata, Tiziana; Rumi, V.; Rosti, D.; Runza, L.; Bugiani, Orso

doi:10.1111/j.1528-1157.1993.tb02093.x

Cited by 35 publications

(17 citation statements)

References 29 publications

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“…This may be the explanation for the Ohtahara syndrome and the psychomotor delay in the proband (Kuroiwa & Celesia, 1980). The suppression‐burst EEG in Ohtahara syndrome has been noted in conditions disconnecting the cerebral cortex from deep gray structures (Ohtahara et al., 1976; Spreafico, 1993). Impaired thalamocortical connections observed in the Arx knockout mice, in addition to impairments in interneuron development and migration, might be associated with of the suppression‐burst EEG pattern in patients with ARX mutations (Kitamura et al., 2002; Collombat et al., 2003, 2005).…”

Section: Discussionmentioning

confidence: 99%

A novel mutation in the aristaless domain of the ARX gene leads to Ohtahara syndrome, global developmental delay, and ambiguous genitalia in males and neuropsychiatric disorders in females

2011

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SUMMARYPurpose: ARX, the aristaless-related homeobox gene, is implicated in cerebral, testicular, and pancreatic development. ARX mutations are associated with various forms of epilepsy, developmental delay, and ambiguous genitalia in humans. A mouse model that recapitulates X-linked lissencephaly with ambiguous genitalia (XLAG) is far from elucidating the substrate for phenotypes that different ARX mutations cause. Moreover, despite phenotypic pleomorphism associated with X-linked dominant ARX mutations, heterozygous female carriers have not been thoroughly studied. Reviewing records of patients with ARX mutations, infantile epilepsies, and psychomotor retardation, we analyzed a family harboring a novel ARX mutation with different phenotypes in males and females, including Ohtahara syndrome. Methods: Children's Hospital Boston patient records were retrospectively screened for patients with infantile epileptic encephalopathies who underwent ARX sequencing based on clinical suspicion. Identified families were analyzed for genetic and neuropsychiatric phenomena.Key Findings: The proband was a male with Ohtahara syndrome, ambiguous genitalia, psychomotor delay, and central nervous system dysgenesis due to a novel ARX mutation in exon 5, causing a frameshift in the aristaless domain. Heterozygous females demonstrated neurocognitive/psychiatric phenomena including learning difficulties, anxiety, depression, and schizophrenia. Significance: This is the first reported case of Ohtahara syndrome with abnormal genital and psychomotor development in the setting of this novel ARX mutation in exon 5. Based on the unique phenotype of the proband and on the presence of heterozygous females with neurocognitive/psychiatric ailments, this study describes the potential roles for ARX mutations in epilepsy and neuropsychiatric disease, underscoring the importance of ARX in interneuron development, cerebral electrical activity, cognition, and behavior.

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Section: Discussionmentioning

confidence: 99%

A novel mutation in the aristaless domain of the ARX gene leads to Ohtahara syndrome, global developmental delay, and ambiguous genitalia in males and neuropsychiatric disorders in females

2011

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“…30 have suggested as a possible pathophysiologic mechanism for BS pattern GA, gestational age in weeks; CA, conceptional age in weeks and days; MIBI, mean interburst duration; MAXIIBI, maximum interburst duration; SharpIB, presence of sharp waves among IBI; Burst amp, amplitude of burst microvolts; Burst Spike, number of spikes in each burst; M Burst, mean burst duration; EEG Sz, electrographic seizure).…”

Section: Discussionmentioning

confidence: 99%

Prognostic value of non-reactive burst suppression EEG pattern associated to early neonatal seizures

Nunes

Giraldes

Pinho

et al. 2005

Arq. Neuro-Psiquiatr.

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-Seizures are the most frequent neurological event in newborns and clinical data suggest that etiology is the dominant factor in long term outcome. However, there are consistent background EEG abnormalities associated to neonatal seizures that are usually related to unfavorable outcome as the burst -suppression pattern. Objective: The objective of this study was to correlate clinical and EEG features associated to long -term outcome of newborns with non -reactive burst -suppression (BS) EEG. Method: Newborns included in the study were selected from our database and had conceptional age (at the time of first EEG) >37 weeks, EEG recordings with non -reactive BS available for review and clinical follow up. Results: 12 newborns met inclusion criteria, 50% had seizures in the first day of life. Seizures became refractory to treatment in all of them. In 50% the etiology of seizures was considered cryptogenic, 33% had inborn errors of metabolism and 17% had clinical history and neuroimage suggestive of hypoxic-ischemic encephalopathy. The follow-up showed that 7/12 infants deceased, 3 during the first year of life, and one in the neonatal period. All the survivors had severe developmental delay and multifocal neurological impairment. 92% developed refractory epilepsy, 58% were latter diagnosed with West syndrome. Conclusion: The non-reactive BS pattern may appear related to many neonatal neurological disorders and is associated with early and refractory neonatal seizures. It is clearly associated with elevated morbidity and mortality and to the development of post-neonatal epilepsy.KEY WORDS: neonatal EEG, neonatal seizures, burst-suppression pattern, neonatal epileptic syndromes.Valor prognóstico do EEG com padrão de surto-supressão não reativo associado a convulsões neonatais precoces RESUMO -Convulsões representam o evento neurológico mais freqüente no período neonatal e a etiologia das crises parece ser o aspecto clínico mais associado ao prognóstico a longo prazo. Entretanto, existem padrões anormais de EEG, que de forma consistente relacionam-se a prognóstico, entre eles o padrão de surto -supressão. Objetivo: Este estudo teve como objetivo correlacionar aspectos clínicos e eletroencefalográficos associados a prognóstico em longo prazo de recém -nascidos (RN) com padrão de surto -supressão não reativo no EEG. Método: Foram selecionados para este estudo RN com EEG neonatal realizado no Laboratório de Neurofisiologia Clínica do Hospital São Lucas da PUCRS e acompanhados na mesma instituição, com idade concepcional superior a 37 semanas (na data do EEG), cujos registros estivessem disponíveis para revisão. Resultados: Foram incluídos 12 RN, 50% apresentaram crises convulsivas a partir do primeiro dia de vida. Em todos as convulsões eram refratárias ao tratamento medicamentoso. Em 50% a etiologia foi considerada criptogênica, 33% apresentavam erros inatos do metabolismo e 17% tinham história clíni-ca e achados de neuroimagem sugestivos de encefalopatia hipóxico -isquêmica. O seguimento clínico demonstrou que...

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“…Supporting this hypothesis are studies in the juvenile monkey and in the adult rat which indicate that homologous surviving subplate neurons may be modulated by dopamine (Descarries et al, 1987;Berger et al, 1990;Ouimet, 1991), a catecholamine implicated in some characteristic symptoms of schizophrenia. Abnormal interstitial neuronal arrangement at the human cortex and white matter border has also been implicated in aberrant human electrophysiological responses (Spreafico et al, 1993), Alzheimer's disease (Ferrer et al, 1990), and Rett Syndrome (Kaufmann et al, 1995).…”

Section: Subgriseal Neurons In the Mature Mammalian Cortexmentioning

confidence: 98%

Widespread projections from subgriseal neurons (layer VII) to layer I in adult rat cortex

Clancy

Cauller

1999

J. Comp. Neurol.

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Burst Suppression and Impairment of Neocortical Ontogenesis: Electroclinical and Neuropathologic Findings in Two Infants with Early Myoclonic Encephalopathy

Cited by 35 publications

References 29 publications

A novel mutation in the aristaless domain of the ARX gene leads to Ohtahara syndrome, global developmental delay, and ambiguous genitalia in males and neuropsychiatric disorders in females

A novel mutation in the aristaless domain of the ARX gene leads to Ohtahara syndrome, global developmental delay, and ambiguous genitalia in males and neuropsychiatric disorders in females

Prognostic value of non-reactive burst suppression EEG pattern associated to early neonatal seizures

Widespread projections from subgriseal neurons (layer VII) to layer I in adult rat cortex

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