Martina Bebin

Epilepsy surgery outcome Comprehensive assessment in children

The effect of extratemporal and temporal lobe cortical resection on children with intractable epilepsy is not well understood. We evaluated a comprehensive array of outcome variables in 33 consecutive children who received epilepsy surgery at 12 years of age or younger. Twenty-two (67%) children were seizure-free, three (9%) had a greater than 90% reduction in seizures, and four had no improvement. Antiepileptic drugs (AEDs) were not required in 10 (30%) children and were reduced in number in another 10. Six (29%) of 21 tested children had an improvement of greater than 10 points in Verbal or Performance IQ after surgery, while one (4%) had a decrease greater than 10 points in Verbal IQ. One mild hemiparesis and one inferior quadrantanopsia occurred; both were anticipated. We used the Child Health Questionnaire (CHQ), a valid and reliable instrument for children, to assess health-related quality of life (HRQOL). Six of 12 subscale scores of the CHQ were significantly lower in the surgical group compared with 410 age-matched control subjects. Parents were satisfied with surgical results in 28 (85%) cases. Pathologic tissue diagnosis and site of resection were not associated significantly with any outcome measure. We conclude that surgery eliminates seizures and reduces AED requirements in most children with intractable epilepsy selected by currently available methods. Further investigation is needed to establish the nature and significance of inferior scores in the surgical group in the HRQOL domains of physical function, general health, and self-esteem.

Magnetic resonance imaging abnormalities associated with vigabatrin in patients with epilepsy

Purpose:  Vigabatrin used to treat infantile spasms (IS) has been associated with transient magnetic resonance imaging (MRI) abnormalities. We carried out a retrospective review to better characterize the frequency of those abnormalities in IS and in children and adults treated with vigabatrin for refractory complex partial seizures (CPS).

Cortical reorganization in malformations of cortical development A magnetoencephalographic study

Background: The evaluation for epilepsy surgery of patients with malformations of cortical development (MCDs) in areas of clinically important cerebral function is a challenge because of the unpredictable localization of critical sensory, motor, and cognitive function. Magnetoencephalography (MEG) source localization of evoked fields can address whether functional reorganization of primary sensory modalities exists in MCDs. Methods: Consecutive patients with MRI-demonstrated rolandic and calcarine cortex MCDs were identified who had a 148-channel whole-head MEG study to identify the localization of primary somatosensory and visual cortices. Reorganization was considered when localization contrasted that expected upon general anatomic or homuncular rules and was defined against controls. Results: Twelve patients (n = 12) were studied. Six had focal cortical dysplasia, two had polymicrogyria and schizencephaly, and four had isolated polymicrogyria. In the patients with cortical dysplasias, the somatosensory cortices were identified outside the rolandic area. In the two patients with polymicrogyria and schizencephaly, the somatosensory cortices remained in the rolandic areas as long as the anatomy was not distorted by the presence of the schizencephalic cleft. In the patients with isolated polymicrogyria, the somatosensory cortex was mapped without evidence of reorganization. Conclusion: In patients with epileptic MCDs involving rolandic and calcarine regions, cortical function may be reorganized if the MCDs are due to an abnormal neuronal or glial proliferation (i.e., cortical dysplasia) but may not be in MCDs caused by abnormal cortical organization (i.e., polymicrogyria).

Pharmacokinetics of Levetiracetam in Infants and Young Children with Epilepsy

Summary:  Purpose: To assess the single‐dose pharmacokinetics of levetiracetam and its major metabolite ucb L057 in infants and young children with epilepsy.

Congenital porencephaly and hippocampal sclerosis: Clinical features and epileptic spectrum

We studied clinical features and seizure localization in 14 patients with porencephaly and intractable seizures. Perinatal complications were present in nine patients, childhood febrile convulsions in two, congenital hemiparesis in 12, and intellectual impairment in seven. Ten patients had psychoparetic complex partial seizures (CPS), three had sensorimotor simple partial seizures, and one had generalized tonic-clonic seizures. Surface EEG showed temporal onset in nine patients (one bitemporal) and extratemporal onset in four. MRI showed porencephaly in the distribution of the middle cerebral artery in eight patients, posterior cerebral in three, internal carotid in one, and multiple vessels in two. MR-based volumetry revealed hippocampal formation atrophy in 13 patients (eight unilateral and five bilateral) and amygdalar atrophy in 10 patients (nine unilateral and one bilateral). Hippocampal formation atrophy was concordant with CPS semiology in 10 patients (71%) and with EEG temporal localization in nine patients. Two patients had pathologic confirmation of mesial temporal sclerosis and were seizure free after temporal lobectomy. We conclude that mesial temporal sclerosis often coexists with porencephaly and is the likely seizure focus in the presence of concordant electro-clinical data. This recognition implies that effective surgical intervention can be offered to certain patients with porencephaly-related seizure disorders. The dual pathology and association with perinatal cerebral vascular occlusion suggest a common ischemic pathogenesis.

Electroclinical and magnetoencephalographic studies in epilepsy patients with polymicrogyria

RATIONALE Malformations of cortical development (MCDs) are increasingly recognized as important causes of developmental delay, epilepsy, and other neurological disorders. Polymicrogyria, a type of MCD, is characterized by many small microgyria separated by shallow sulci, a slightly thick cortex, neuronal heterotopia and often enlarged ventricles. The present descriptive study analysis the electroclinical and magnetoencephalographic findings of patients with epilepsy and polymicrogyria without schizencephaly. METHODS We studied six patients; mean age was 27 years, who had evidence of polymicrogyria in neuroimaging studies. A single equivalent-current dipole (ECD) model was used to estimate the location of epileptiform spike dipole sources. Analysis was performed on selected data segments containing MEG spikes. MEG results were combined with MRI to create magnetic source images (MSI). RESULTS In all cases we present results of MRI, MEG, Video-EEG monitoring, and other functional neuroimaging studies if performed. CONCLUSIONS MSI can be used to accurately localize sources of epileptiform discharges. As such MSI can play a role of directly determining the functional epileptogenic significance of abnormalities depicted in imaging.

UBQLN2 mutation causing heterogeneous X-linked dominant neurodegeneration.

We report a 5‐generation family with phenotypically diverse neurodegenerative disease including relentlessly progressive choreoathetoid movements, dysarthria, dysphagia, spastic paralysis, and behavioral dementia in descendants of a 67‐year‐old woman with amyotrophic lateral sclerosis. Disease onset varied with gender, occurring in male children and adult women. Exome sequence analyses revealed a novel mutation (c.1490C>T, p.P497L) in the ubiquilin‐2 gene (UBQLN2) with X‐linked inheritance in all studied affected individuals. As ubiquilin‐2–positive inclusions were identified in brain, we suggest that mutant peptide predisposes to protein misfolding and accumulation. Our findings expand the spectrum of neurodegenerative phenotypes caused by UBQLN2 mutations. ANN NEUROL 2014;75:793–798

Monosomy1p36.3 and Trisomy 19p13.3 in a Child With Periventricular Nodular Heterotopia

Monosomy 1p36 is a clinically recognizable syndrome that is considered to be the most common terminal deletion syndrome. It has characteristic clinical features that include craniofacial dysmorphism, congenital anomalies, hearing deficits, developmental delay, mental retardation, hypotonia, seizures, and brain anomalies. Brain anomalies in patients with 1p36 deletion are frequent but inconsistent. To date, 2 cases with monosomy 1p36 associated with periventricular nodular heterotopia (PNH) have been reported. We report a 2-month-old boy with multiple congenital anomalies; brain magnetic resonance imaging revealed PNH. The first 2 described cases were pure terminal deletions, whereas our patient carried unbalanced translocation due to an adjacent 1 segregation of a balanced maternal translocation, resulting in monosomy 1p36.3 and trisomy 19p13.3 identified by whole-genome array comparative genomic hybridization analysis. Our patient, with a smaller deletion that the 2 previously reported cases, can help narrow the critical region for PNH in association with the 1p36 deletion. Several potential candidate genes are discussed.

Core elements of epilepsy diagnosis and management: expert consensus from the Leadership in Epilepsy, Advocacy, and Development (LEAD) faculty

ABSTRACT Background: Although epilepsy is relatively common, only a limited number of specialized epilepsy centers exist in the United States. Therefore, epilepsy diagnosis and management frequently occur in the community setting. This can complicate patient management and suboptimal care is a potential concern. Delayed recognition and inadequate treatment increase the risk of subsequent seizures, brain damage, disability, and death from seizure-related injuries. To identify core elements of epilepsy management that should be offered to all patients, the Leadership in Epilepsy, Advocacy, and Development (LEAD) faculty assessed current practical issues and identified practices to improve patient care and outcomes. Scope: This paper presents a consensus opinion formed from a survey of 26 current LEAD faculty members, who answered 105 questions about epilepsy diagnosis and patient evaluation, treatment decisions, lifelong monitoring, and the management of special patient subgroups. Consensus agreement was concluded when ≥50% of the faculty provided the same answer. The results were compiled and areas of consensus are included in this report. The recommendations provided in this commentary are limited by the scope of the survey. Findings: Consensus was reached on several minimum standard patient management practices. Primary among these minimum standards of care is the need for diagnosis including a detailed medical history, neurological examination, discussions with caregivers, and diagnostic tests including electroencephalograms and magnetic resonance imaging. As the overall goals of therapy include seizure freedom, minimizing side effects, and improving quality of life and long-term safety, therapy decisions should consider parameters that affect these goals, including potential adverse effects of therapy. Antiepileptic drug selection should consider coexisting conditions for possible exacerbation of disease and potential drug–drug interactions. Conclusions: The core elements of epilepsy management identified here suggest minimum standards that can be used across all settings to improve consistency and quality of epilepsy diagnosis and care.

MYT1L mutations cause intellectual disability and variable obesity by dysregulating gene expression and development of the neuroendocrine hypothalamus.

Deletions at chromosome 2p25.3 are associated with a syndrome consisting of intellectual disability and obesity. The smallest region of overlap for deletions at 2p25.3 contains PXDN and MYT1L. MYT1L is expressed only within the brain in humans. We hypothesized that single nucleotide variants (SNVs) in MYT1L would cause a phenotype resembling deletion at 2p25.3. To examine this we sought MYT1L SNVs in exome sequencing data from 4, 296 parent-child trios. Further variants were identified through a genematcher-facilitated collaboration. We report 9 patients with MYT1L SNVs (4 loss of function and 5 missense). The phenotype of SNV carriers overlapped with that of 2p25.3 deletion carriers. To identify the transcriptomic consequences of MYT1L loss of function we used CRISPR-Cas9 to create a knockout cell line. Gene Ontology analysis in knockout cells demonstrated altered expression of genes that regulate gene expression and that are localized to the nucleus. These differentially expressed genes were enriched for OMIM disease ontology terms “mental retardation”. To study the developmental effects of MYT1L loss of function we created a zebrafish knockdown using morpholinos. Knockdown zebrafish manifested loss of oxytocin expression in the preoptic neuroendocrine area. This study demonstrates that MYT1L variants are associated with syndromic obesity in humans. The mechanism is related to dysregulated expression of neurodevelopmental genes and altered development of the neuroendocrine hypothalamus.