Epilepsy surgery in the first months of life: a large type IIb focal cortical dysplasia causing neonatal drug-resistant epilepsy.

Focal cortical dysplasia is a common cause of medically refractory epilepsy in infancy and childhood. We report a neonate with seizures occurring within the first day of life. Continuous video-EEG monitoring led to detection of left motor seizures and a right frontal EEG seizure pattern. Brain MRI revealed a lesion within the right frontal lobe without contrast enhancement. The patient was referred for epilepsy surgery due to drug resistance to vitamin B6 and four antiepileptic drugs. Lesionectomy was performed at the age of two and a half months, and histopathological evaluation confirmed the diagnosis of focal cortical dysplasia type IIb (FCD IIb). The patient is free of unprovoked seizures without medication (Engel Class I) and is normally developed at 36 months after surgery. The case study demonstrates that FCD IIb may cause seizures within the first day of life and that epilepsy surgery can be successfully performed in medically intractable patients with a clearly identifiable seizure onset zone within the first three months of life. Although radical surgery such as hemispherectomy and multi-lobar resections are over-represented in early infancy, this case also illustrates a favourable outcome with a more limited resection in this age group.

Somatic Mutations in the MTOR gene cause focal cortical dysplasia type IIb.

OBJECTIVE: Focal cortical dysplasia (FCD) type IIb is a cortical malformation characterized by cortical architectural abnormalities, dysmorphic neurons, and balloon cells. It has been suggested that FCDs are caused by somatic mutations in cells in the developing brain. Here, we explore the possible involvement of somatic mutations in FCD type IIb. METHODS: We collected a total of 24 blood-brain paired samples with FCD, including 13 individuals with FCD type IIb, 5 with type IIa, and 6 with type I. We performed whole-exome sequencing using paired samples from 9 of the FCD type IIb subjects. Somatic MTOR mutations were identified and further investigated using all 24 paired samples by deep sequencing of the entire gene's coding region. Somatic MTOR mutations were confirmed by droplet digital polymerase chain reaction. The effect of MTOR mutations on mammalian target of rapamycin (mTOR) kinase signaling was evaluated by immunohistochemistry and Western blotting analyses of brain samples and by in vitro transfection experiments. RESULTS: We identified four lesion-specific somatic MTOR mutations in 6 of 13 (46%) individuals with FCD type IIb showing mutant allele rates of 1.11% to 9.31%. Functional analyses showed that phosphorylation of ribosomal protein S6 in FCD type IIb brain tissues with MTOR mutations was clearly elevated, compared to control samples. Transfection of any of the four MTOR mutants into HEK293T cells led to elevated phosphorylation of 4EBP, the direct target of mTOR kinase. INTERPRETATION: We found low-prevalence somatic mutations in MTOR in FCD type IIb, indicating that activating somatic mutations in MTOR cause FCD type IIb.

Dynamic changes of interictal post-spike slow waves toward seizure onset in focal cortical dysplasia type II.

OBJECTIVE: A post-spike slow wave (PSS) as part of a spike and slow wave is presumably related to inhibition of epileptic activity. In this study, we evaluated dynamic changes of PSS power toward seizure onset in patients with focal cortical dysplasia (FCD) type II. METHODS: We collected data from 10 pediatric patients with FCD type II, who underwent invasive monitoring with subdural grids. The PSS were averaged based on spike-triggering in 30s epochs during both interictal and preictal periods. We quantitatively measured and compared PSS power and distribution between interictal and preictal periods, both within and outside the seizure onset zone (SOZ). RESULTS: PSS power was significantly higher in all areas during preictal period compared with interictal period. During preictal period, PSS power within SOZ was significantly higher than outside SOZ. From interictal to preictal period, the number of electrodes with high power PSS significantly increased within SOZ and decreased outside SOZ. CONCLUSIONS: Toward seizure onset, PSS power increased in all areas, predominantly within SOZ, and became confined into SOZ in a subset of FCD type II patients. SIGNIFICANCE: Preictal PSS power increase and confinement into SOZ accompany transition to seizures.

Expanding the spectrum of TUBA1A-related cortical dysgenesis to Polymicrogyria.

De novo mutations in the TUBA1A gene are responsible for a wide spectrum of neuronal migration disorders, ranging from lissencephaly to perisylvian pachygyria. Recently, one family with polymicrogyria (PMG) and mutation in TUBA1A was reported. Hence, the purpose of our study was to determine the frequency of TUBA1A mutations in patients with PMG and better define clinical and imaging characteristics for TUBA1A-related PMG. We collected 95 sporadic patients with non-syndromic bilateral PMG, including 54 with perisylvian PMG and 30 PMG with additional brain abnormalities. Mutation analysis of the TUBA1A gene was performed by sequencing of PCR fragments corresponding to TUBA1A-coding sequences. Three de novo missense TUBA1A mutations were identified in three unrelated patients with PMG representing 3.1% of PMG and 10% of PMGs with complex cerebral malformations. These patients had bilateral perisylvian asymmetrical PMG with dysmorphic basal ganglia cerebellar vermian dysplasia and pontine hypoplasia. These mutations (p.Tyr161His; p.Val235Leu; p.Arg390Cys) appear distributed throughout the primary structure of the alpha-tubulin polypeptide, but their localization within the tertiary structure suggests that PMG-related mutations are likely to impact microtubule dynamics, stability and/or local interactions with partner proteins. These findings broaden the phenotypic spectrum associated with TUBA1A mutations to PMG and further emphasize that additional brain abnormalities, that is, dysmorphic basal ganglia, hypoplastic pons and cerebellar dysplasia are key features for the diagnosis of TUBA1A-related PMG.

[Developmental malformations of the cerebral cortex]. / Heterotopie, Polymikrogyrie, Lissenzephalie und Co - Malformationen der kortikalen Hirnentwicklung.

Migration disorders (MD) are increasingly recognized as an important cause of epilepsy and developmental delay. Up to 25 % of children with refractory epilepsy have a cortical malformation. MD encompass a wide spectrum with underlying genetic etiologies and clinical manifestations. Research regarding the delineation of the genetic and molecular basis of these disorders has provided greater insight into the pathogenesis of not only the malformation but also the process involved in normal cortical development. Diagnosis of MD is important since patients who fail three antiepileptic medications are less likely to have their seizures controlled with additional trials of medications and therefore epilepsy surgery should be considered. Recent improvements in neuroimaging have resulted in a significant increase in the recognition of MD. Findings can be subdivided in disorders due to abnormal neurogenesis, neuronal migration, neuronal migration arrest and neuronal organization resulting in different malformations like microcephaly, lissencephaly, schizencephaly and heterotopia. The examination protocol should include T 1-w and T 2-w sequences in adequate slice orientation. T 1-w turbo-inversion recovery sequences (TIR) can be helpful to diagnose heterotopia. Contrast agent is needed only to exclude other differential diagnoses.

Neuropsychological functioning in a young adult case of schizencephaly.

Schizencephaly is a rare neuromigrational/organizational disorder characterized by the development of cerebral clefts, which are typically associated with neurological sequelae including seizures, motor disturbances, and cognitive dysfunction. Although there are multiple case reports of schizencephaly and associated neurological sequelae, primarily in children, the literature regarding neuropsychological manifestations of schizencephaly is limited. This article reviews the case of a woman diagnosed with bilateral schizencephaly at age 29. Neuropsychological testing revealed intact intelligence and memory functioning. However, impairments were noted in attention, executive functioning, expressive language skills, visual-spatial abilities, and bilateral manual motor skills, all of which were adversely impacting her functional abilities (e.g., ability to be gainfully employed). Given the potential variability in deficits associated with schizencephaly, this case demonstrates the utility of neuropsychological evaluation for understanding cognitive and functional consequences of bilateral schizencephaly.

Neuronal migration disorders: clinical, neuroradiologic and genetics aspects.

UNLABELLED: Disorders of neuronal migration are a heterogeneous group of disorders of nervous system development. One of the most frequent disorders is lissencephaly, characterized by a paucity of normal gyri and sulci resulting in a 'smooth brain'. There are two pathologic subtypes: classical and cobblestone. Six different genes could be responsible for this entity (LIS1, DCX, TUBA1A, VLDLR, ARX, RELN), although co-delection of YWHAE gene with LIS1 could result in Miller-Dieker Syndrome. Heterotopia is defined as a cluster of normal neurons in abnormal locations, and divided into three main groups: periventricular nodular heterotopia, subcortical heterotopia and marginal glioneural heterotopia. Genetically, heterotopia is related to Filamin A (FLNA) or ADP-ribosylation factor guanine exchange factor 2 (ARFGEF2) genes mutations. Polymicrogyria is described as an augmentation of small circonvolutions separated by shallow enlarged sulci; bilateral frontoparietal form is characterized by bilateral, symmetric polymicrogyria in the frontoparietal regions. Bilateral perisylvian polymicrogyria results in a clinical syndrome manifested by mild mental retardation, epilepsy and pseudobulbar palsy. Gene mutations linked to this disorder are SRPX2, PAX6, TBR2, KIAA1279, RAB3GAP1 and COL18A1. Schizencephaly, consisting in a cleft of cerebral hemisphere connecting extra-axial subaracnoid spaces and ventricles, is another important disorder of neuronal migration whose clinical characteristics are extremely variable. EMX2 gene could be implicated in its genesis. Focal cortical dysplasia is characterized by three different types of altered cortical laminations, and represents one of most severe cause of epilepsy in children. TSC1 gene could play a role in its etiology. CONCLUSION: This review reports the main clinical, genetical and neuroradiological aspects of these disorders. It is hoped that accumulating data of the development mechanisms underlying the expanded network formation in the brain will lead to the development of therapeutic options for neuronal migration disorders.