Amre Shahwan

Vagus nerve stimulation for refractory epilepsy in children: More to VNS than seizure frequency reduction

Purpose:  Vagus nerve stimulation (VNS) is used increasingly as adjunctive therapy for refractory epilepsy. Studies of VNS in children report mainly seizure frequency reduction as a measure of efficacy and clinical details are often scanty. We report our experience with VNS in children with refractory epilepsy and emphasize the positive effects of VNS in terms of seizure severity.

The prevalence of seizures in comatose children in the pediatric intensive care unit: A prospective video-EEG study

Purpose:  Studies in adult and neonatal intensive care units (ICUs) report a high prevalence of epileptic seizures in comatose patients. The prevalence of seizures in pediatric ICUs is variably reported in a few retrospective studies using different electroencephalography (EEG) methods. We aimed to determine prospectively the prevalence of epileptic seizures (clinical and subclinical) in comatose children in the pediatric ICU using continuous video‐EEG (v‐EEG) monitoring.

Unexplained early onset epileptic encephalopathy: Exome screening and phenotype expansion

Early onset epileptic encephalopathies (EOEEs) represent a significant diagnostic challenge. Newer genomic approaches have begun to elucidate an increasing number of responsible single genes as well as emerging diagnostic strategies. In this single‐center study, we aimed to investigate a cohort of children with unexplained EOEE. We performed whole‐exome sequencing (WES), targeting a list of 137 epilepsy‐associated genes on 50 children with unexplained EOEE. We characterized all phenotypes in detail and classified children according to known electroclinical syndromes where possible. Infants with previous genetic diagnoses, causative brain malformations, or inborn errors of metabolism were excluded. We identified disease‐causing variants in 11 children (22%) in the following genes: STXBP1 (n = 3), KCNB1 (n = 2), KCNT1, SCN1A, SCN2A, GRIN2A, DNM1, and KCNA2. We also identified two further variants (in GRIA3 and CPA6) in two children requiring further investigation. Eleven variants were de novo, and in one paternal testing was not possible. Phenotypes were broadened for some variants identified. This study demonstrates that WES is a clinically useful screening tool for previously investigated unexplained EOEE and allows for reanalysis of data as new genes are being discovered. Detailed phenotyping allows for expansion of specific gene disorders leading to epileptic encephalopathy and emerging sub‐phenotypes.

The variable phenotypes of KCNQ-related epilepsy

Mutations in KCNQ2 and KCNQ3 were originally described in infants with benign familial neonatal seizures (BFNS). Recently, KCNQ2 mutations have also been shown to cause epileptic encephalopathy. This report describes three infants carrying abnormalities of KCNQ2 and one infant with a KCNQ3 mutation. The different KCNQ2 abnormalities led to different phenotypes and included a novel intragenic duplication, c.419_430dup, in an infant with BFNS, a 0.761Mb 20q13.3 contiguous gene deletion in an infant with seizures at 3 months, and a recurrent de novo missense mutation c.881C>T in a neonate with “KCNQ2‐encephalopathy.” The mutation in KCNQ3, c.989G>A, was novel and occurred in an infant with BFNS. KCNQ‐related seizures often present with tonic/clonic manifestations, cyanosis, or apnea. Certain genotype–phenotype correlations help predict outcome. Similarly affected family members suggests benign familial “KCNQ‐related” epilepsy, whereas neonatal seizures with unexplained multifocal epileptiform discharges or burst suppression on electroencephalography, and acute abnormalities of the basal ganglia/thalami are suggestive of KCNQ2‐encephalopathy, which is often sporadic. 20q13.33 contiguous gene deletion encompassing KCNQ2 may harbor atypical features depending on deletion size. Although the phenotype often guides direct targeted gene testing in these conditions, array CGH should also be considered in suspected sporadic or atypical familial cases to diagnose 20q13.33 deletion.

To tell or not to tell: A systematic review of the disclosure practices of children living with epilepsy and their parents

Disclosing an epilepsy diagnosis to others is complex due to the conditions largely invisible nature and associated stigma. Despite this, little has been documented in terms of what this process involves for children living with epilepsy (CWE) and their parents. A systematic review was conducted to examine and synthesize evidence pertaining to: (i) the disclosure practices of CWE and their parents, (ii) enablers and barriers for disclosure, (iii) the impact of disclosure practices, and (iv) the relationship between disclosure management and other variables. The electronic databases PsycINFO, PubMed, MEDLINE, CINAHL, Scopus, and Web of Science were searched systematically. Any empirical, peer-reviewed journal articles with findings reported regarding the self- or proxy-reported disclosure practices of children aged 0-18years with any type of epilepsy and/or their parents were deemed eligible for inclusion. Two review authors completed all stages of screening, data extraction, and quality assessment independently with two additional review authors resolving any discrepancies. A total of 32 articles were included in the review. Only one dated study examined disclosure as a primary focus; in the remaining studies, disclosure was a subfocus of larger studies or pertinent qualitative themes/subthemes incidentally emerged. The limited evidence suggests that: 1) CWE and parents adopt varying disclosure management strategies - from concealment to voluntary disclosure; 2) disclosure decisions are challenging for CWE and parents; 3) many barriers to disclosure exist (e.g., fear of stigmatization and rejection); 4) only a limited number of factors that enable disclosure are known (e.g., openness by others to engage with and learn about epilepsy); 5) disclosure management is significantly related to a number of variables (e.g., child/maternal perceived stigma and seizure control); and 6) there are varying outcomes for CWE and/or their parents in accordance with the adoption of specific disclosure management strategies (e.g., disclosure resulting in greater acceptance and the receipt of support or evoking anxiety/fear in others; and concealment resulting in misunderstandings, embarrassment, and stigma-coaching), but the evidence remains inconclusive in terms of which disclosure management strategy is optimal. While some preliminary work has been conducted, disclosure of epilepsy is a topic that has been largely neglected to date. This is despite the fact that disclosure is a significant source of concern for CWE and parent populations. Future studies should focus on elucidating the unique contextual factors that inform disclosure decisions in order to develop a theoretical framework that can explain the epilepsy disclosure decision-making process.

NAPB - a novel SNARE-associated protein for early-onset epileptic encephalopathy.

Next‐generation sequencing has accelerated the identification of disease genes in many rare genetic disorders including early‐onset epileptic encephalopathies (EOEEs). While many of these disorders are caused by neuronal channelopathies, the role of synaptic and related neuronal proteins are increasingly being described. Here, we report a 6‐year‐old girl with unexplained EOEE characterized by multifocal seizures and profound global developmental delay. Recessive inheritance was considered due to parental consanguinity and Irish Traveller descent. Exome sequencing was performed. Variant prioritization identified a homozygous nonsense variant in the N‐ethylmaleimide‐sensitive factor attachment protein, beta (NAPB) gene resulting in a premature stop codon and 46% loss of the protein. NAPB plays a role in soluble N‐ethylmaleimide‐sensitive fusion attachment protein receptor (SNARE)‐complex dissociation and recycling (synaptic vesicle docking). Knockout mouse models of the murine ortholog Napb have been previously reported. These mice develop recurrent post‐natal epileptic seizures in the absence of structural brain changes. The identification of a disease‐causing variant in NAPB further recognizes the importance of the SNARE complex in the development of epilepsy and suggests that this gene should be considered in patients with unexplained EOEE.

Malignant Refractory Epilepsy in Identical Twins Mosaic for a Supernumerary Ring Chromosome 19

Summary:  We report identical twins with supernumerary ring chromosome 19 mosaicism, who had severe refractory epilepsy at an early age. The epilepsy was dominated largely by severe life‐threatening tonic seizures. Both twins died, likely as a consequence of their severe epilepsy. They displayed no dysmorphic features. Eight cases of ring chromosome 19 have been reported in the literature, all to our knowledge without epilepsy. The clinical picture of these twins emphasizes the importance of carrying out a karyotype study on patients with early‐onset epilepsy even in the absence of dysmorphic features.

Atypical presentation of ataxia‐oculomotor apraxia type 1

A subgroup of autosomal recessive cerebellar ataxias (ARCAs) associated with oculomotor apraxia (OMA) and other variable features has been reported. Ataxia-oculomotor apraxia types 1 and 2 (AOA1 and AOA2) belong to this subgroup and have been described in adults with early onset cerebellar ataxia. AOA1 is associated with oculomotor apraxia, severe sensorimotor neuropathy, choreiform movements, cognitive impairment, and cerebellar atrophy at an early age. We describe a male child with AOA1 who is homozygous for the G837A (W279X) mutation in the APTX gene. He presented at the age of 3 years 6 months with some atypical features including absence of OMA, chorea, and cerebellar atrophy. These manifestations, in addition to peripheral neuropathy, appeared at 8 years of age. We highlight the importance of considering the diagnosis of AOA1 in children with early-onset cerebellar ataxia, once other well-known disorders such as Friedreichs ataxia and ataxia-telangiectasia have been excluded.

Talking about epilepsy: Challenges parents face when communicating with their child about epilepsy and epilepsy-related issues.

The aim of this qualitative study was to explore the challenges that parents of children with epilepsy experienced when engaging in dialog with their child about epilepsy and epilepsy-related issues. Using a qualitative exploratory approach, interviews were conducted with 34 parents of children with epilepsy (aged 6-16 years), consisting of 27 mothers and 7 fathers. Data were transcribed verbatim and thematically analyzed. Findings revealed five main themes: normalizing epilepsy, the invisibility of epilepsy, information concealment, fear of misinforming the child, and difficulty in discussing particular epilepsy-related issues. Many of the communicative challenges experienced by parents impacted on their ability to engage openly in parent-child dialog about epilepsy in the home. Parents face specific challenges when choosing to communicate with their child about epilepsy, relating to creating a sense of normality, reducing fear of causing their child worry, and having a lack of epilepsy-related knowledge. Healthcare professionals who work closely with families living with epilepsy should remain mindful of the importance of discussing family communication surrounding epilepsy and the challenges parents of children with epilepsy face when talking about epilepsy within the home.

Chromosomal microarray in unexplained severe early onset epilepsy – A single centre cohort

BACKGROUND Severe early onset epilepsy may lead to impaired cognitive and motor development, and consists of a group of specific and overlapping electro-clinical phenotypes which may be the result of an inborn error of metabolism, congenital or acquired structural brain lesion, known chromosomal or mono-genetic disorder. A significant proportion of cases however remain unexplained, representing a major diagnostic and management challenge. METHODS In this study we describe a cohort of children with severe early onset epilepsy and examine the clinical utility of chromosomal microarray (array-comparative genomic hybridisation, CGH) in this group of epilepsies. RESULTS In 51 children with unexplained severe early onset epilepsy, all of whom had chromosomal array tested, copy number variants were detected in 17.6% and pathogenic variants in 5.9% of infants. CONCLUSIONS Chromosomal microarray is a useful investigation in early onset refractory epilepsy and epileptic encephalopathy. Detailed review of the precise array abnormality and phenotypes associated are important for determining significance.