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Introduction
Stratified medicine research in epilepsy
Additional affiliations
September 2009 - February 2015
Publications
Publications (193)
Introduction
The prevalence of mental health symptoms in people with epilepsy (PWE) is elevated compared with that of the general population. These symptoms can negatively impact epilepsy management and patient outcomes but can be treated once recognised. It is, therefore, important to screen for these symptoms to identify needs and put in place ap...
Introduction
Children and young people (CYP) with epilepsy consult clinicians for management of their seizures but may require advice and support with a range of broader topics, including sleep. However, understanding of clinicians’ perspectives of providing this support is limited. This study aimed to identify, from clinicians, the extent to which...
Elevated impulsivity is a key component of attention-deficit hyperactivity disorder (ADHD), bipolar disorder and juvenile myoclonic epilepsy (JME). We performed a genome-wide association, colocalization, polygenic risk score, and pathway analysis of impulsivity in JME ( n = 381). Results were followed up with functional characterisation using a dro...
Purpose:
Electroencephalography (EEG) can be considered the gold standard diagnostic technique for selflimited epilepsy with centrotemporal spikes (SeLECTS). Recent studies built functional brain networks from EEG recordings to understand patterns of connectivity between brain areas of interest. In this study, we applied graph theory metrics to fu...
Genetic variants in the SLC6A1 gene can cause a broad phenotypic disease spectrum by altering the protein function. Thus, systematically curated clinically relevant genotype-phenotype associations are needed to understand the disease mechanism and improve therapeutic decision-making.
We aggregated genetic and clinical data from 172 individuals with...
Objective:
Self-limiting Rolandic epilepsy (RE) is the most common epilepsy in school-age children. Seizures are generally infrequent, but cognitive, language, and motor coordination problems can significantly impact the child's life. To better understand brain structure and function changes in RE, we longitudinally assessed neurocognition, cortic...
Reliable definitions, classifications and prognostic models are the cornerstones of stratified medicine, but none of the current classifications systems in epilepsy address prognostic or outcome issues. Although heterogeneity is widely acknowledged within epilepsy syndromes, the significance of variation in electroclinical features, comorbidities a...
Introduction
Sleep and epilepsy have an established bidirectional relationship yet only one randomised controlled clinical trial has assessed the effectiveness of behavioural sleep interventions for children with epilepsy. The intervention was successful, but was delivered via face-to-face educational sessions with parents, which are costly and non...
Background
In paediatric epilepsy, the evidence of effectiveness of antiseizure treatment is inconclusive for some types of epilepsy. As with other paediatric clinical trials, researchers undertaking paediatric epilepsy clinical trials face a range of challenges that may compromise external validity
Main body
In this paper, we critically reflect u...
Introduction
Sleep problems in children with epilepsy (CWE) are common. However, little is known about parental experiences and feelings about managing sleep in their CWE. To provide the most appropriate services' provision, it is essential that the lived experience of parents of this patient group and the issues and problems that they face in mana...
Objectives/Aims
Children with epilepsy (cwE) are at a higher risk of mental health disorders such as depression, anxiety, and attention deficit hyperactivity disorder (ADHD) compared to the general population. Psychiatric comorbidities can negatively impact cwE as they can be associated with reduced response to treatment, reduced quality of life, a...
Purpose:
Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported.
Methods:
Genotype and phenotype data were collated and analyzed for 61 biallelic PIGN...
Quinidine has been proposed as a repurposed licensed drug for the treatment of seizures in KCNT1 gain-of-function associated Epilepsy of infancy with Migrating Focal Seizures (EIMFS). Sparse evidence from case reports suggests limited effectiveness and tolerability. Here we report the adaptation of a n-of-1 trial protocol and results of adjunctive...
Objective: Impulsivity is a multidimensional construct that can predispose to psychopathology. Meta-analysis demonstrates an association between response impulsivity and Juvenile Myoclonic Epilepsy (JME), a common genetic generalized epilepsy. Here, we test the hypotheses that trait impulsivity is (i) elevated in JME compared to controls; (ii) mode...
Abnormal EEG features are a hallmark of epilepsy, and abnormal frequency and network features are apparent in EEGs from people with idiopathic generalised epilepsy in both ictal and interictal states. Here, we characterise differences in the resting-state EEG of individuals with juvenile myoclonic epilepsy and assess factors influencing the heterog...
Introduction
Sleep and epilepsy have an established bi-directional relationship yet only one randomised controlled clinical trial has assessed the effectiveness of behavioural sleep interventions for children with epilepsy. The intervention was successful, but delivered via face-to-face educational sessions with parents, which are costly and non-sc...
Introductory Paragraph
Elevated impulsivity is a key component of attention-deficit hyperactivity disorder (ADHD), bipolar disorder and epilepsy ¹⁻⁵ . We performed a genome-wide association, colocalization and pathway analysis of impulsivity in juvenile myoclonic epilepsy (JME). We identify genome-wide associated SNPs at 8q13.3 (p=7.5 × 10 ⁻⁹ ) and...
Abnormal EEG features are a hallmark of epilepsy, and abnormal frequency and network features are apparent in EEGs from people with idiopathic generalised epilepsy in both ictal and interictal states. Here, we characterise differences in the resting-state EEG of individuals with juvenile myoclonic epilepsy (JME) and assess factors influencing the h...
In the last two decades new noninvasive mobile electroencephalography (EEG) solutions have been developed to overcome limitations of conventional clinical EEG and to improve monitoring of patients with long‐term conditions. Despite the availability of mobile innovations, their adoption is still very limited. The aim of this study is to review the c...
Juvenile myoclonic epilepsy (JME) is a common idiopathic generalised epilepsy with variable seizure prognosis and sex differences in disease presentation. Here, we investigate the combined epidemiology of sex, seizure types and precipitants, and their influence on prognosis in JME, through cross-sectional data collected by The Biology of Juvenile M...
TUBA1A tubulinopathy is a rare neurodevelopmental disorder associated with brain malformations as well as early-onset and intractable epilepsy. As pathomechanisms and genotype-phenotype correlations are not completely understood, we aimed to provide further insights into the phenotypic and genetic spectrum. We here present a multicenter case series...
Variants of the SCN1A gene encoding the neuronal voltage-gated sodium channel NaV1.1 cause over 85% of all cases of Dravet syndrome, a severe and often pharmacoresistent epileptic encephalopathy with mostly infantile onset. But with the increased availability of genetic testing for patients with epilepsy, variants in SCN1A have now also been descri...
FZR1, which encodes the Cdh1 subunit of the Anaphase Promoting Complex, plays an important role in neurodevelopment by regulating the cell cycle and by its multiple post-mitotic functions in neurons. In this study, evaluation of 250 unrelated patients with developmental and epileptic encephalopathies and a connection on GeneMatcher led to the ident...
Purpose: Evaluate the acceptability and feasibility of a procedure (EEG@HOME) that allows patients with epilepsy to independently, remotely, and continuously acquire non-invasive variables at home.
Method: Adults with pharmaco-resistant epilepsy were recruited at King’s College Hospital, London. Participants were trained for one week to self-apply...
Many of the same sleep problems seen in typically developing (TD) children are frequently experienced by children with epilepsy (CWE). Behavioural sleep interventions (BSIs) are commonly and successfully used to treat these sleep problems in TD children and in some neurodevelopmental disorder populations. Therefore, BSIs should be effective in CWE,...
ZMYND11 is the critical gene in chromosome 10p15.3 microdeletion syndrome, a syndromic cause of intellectual disability. The phenotype of ZMYND11 variants has recently been extended to autism and seizures. We expand on the epilepsy phenotype of 20 individuals with pathogenic variants in ZMYND11. We obtained clinical descriptions of 16 new and nine...
Introduction: Many of the sleep problems experienced by children with epilepsy (CWE) have the same behavioural basis as common sleep problems seen in typically developing (TD) children. Behavioural sleep interventions (BSIs) are widely used to treat these sleep problems in TD children and are hypothesised to be effective for CWE. However, specific...
Epilepsy has been historically defined as the recurrence of two or more seizures, together with typical electroencephalogram (EEG) changes, and significant comorbidities, including cardiac and autonomic changes, injuries, intellectual disability, permanent brain damage, and higher mortality risk. Epilepsy may be the consequence of several causes, i...
Epilepsies due to SCN2A mutations can present with a broad range of phenotypes that are still not fully understood. Clinical characteristics of SNC2A-related epilepsy may vary from neonatal benign epilepsy to early-onset epileptic encephalopathy, including Ohtahara syndrome and West syndrome, and epileptic encephalopathies occurring at later ages (...
Objective
Recent neuroimaging studies have revealed differences in cortical and white matter brain structure in children with self‐limiting rolandic epilepsy (RE). Despite this, reproducibility of the findings has been difficult, and there is no consensus about where and when structural differences are most apparent. We performed a systematic revie...
Objective
Impulsivity is a multidimensional construct that can predispose to psychopathology. Meta‐analysis demonstrates an association between response impulsivity and Juvenile Myoclonic Epilepsy (JME), a common genetic generalized epilepsy. Here, we test the hypotheses that trait impulsivity is (i) elevated in JME compared to controls; (ii) mode...
Background
Juvenile myoclonic epilepsy (JME) is a common subtype of genetic generalized epilepsy (GGE) arising in adolescence and is often associated with executive function (EF) deficits. Some EF components like response inhibition have been extensively evaluated in JME, but few studies have focused upon trait impulsivity or compared between GGE s...
BACKGROUND
Epileptic seizures are spontaneous events that severely affect the lives of patients due to their recurrence and unpredictability. The integration of new wearable and mobile technology to collect EEG and extra-cerebral signals into a portable system might be the solution to prospectively identify times of seizure occurrence or propensity...
Background
Epileptic seizures are spontaneous events that severely affect the lives of patients due to their recurrence and unpredictability. The integration of new wearable and mobile technologies to collect electroencephalographic (EEG) and extracerebral signals in a portable system might be the solution to prospectively identify times of seizure...
Objective:
The objectives of the study were to (1) map questions in epilepsy-specific patient-reported outcome measures (PROMs) of children's health-related quality of life (HRQoL) to a proposed core outcome set (COS) for childhood epilepsy research and (2) gain insight into the acceptability of two leading candidate PROMs.
Method:
We identified...
Objective
We aimed to describe the extent of neurodevelopmental impairments and identify the genetic etiologies in a large cohort of patients with epilepsy with myoclonic atonic seizures (MAE).
Methods
We deeply phenotyped MAE patients for epilepsy features, intellectual disability, autism spectrum disorder, and attention‐deficit/hyperactivity dis...
Background
Patients with juvenile myoclonic epilepsy (JME) show evidence of cognitive impulsivity that may be linked to later adverse psychosocial outcomes. Here, we quantify the strength of association and estimate effect size (ES) of response inhibition by pooling available evidence in a meta-analysis.
Methods
We conducted a systematic review of...
Objective
To identify and appraise published evidence of the measurement properties for epilepsy‐specific patient‐reported outcome measures (PROMs) of children's health‐related quality of life (HRQoL).
Methods
We searched multiple databases for studies evaluating the measurement properties of English‐language epilepsy‐specific PROMs of children's...
Rolandic epilepsy (RE) is one of the most common epilepsies of childhood. The seizures of RE are easily managed, but cognitive problems frequently co-occur. Cognitive problems include dyslexia, speech and language problems, ADHD and developmental coordination disorder. These problems may persist into seizure remission.
In previous longitudinal, m...
Severe early onset epilepsies are often caused by de novo pathogenic variants. Few studies have reported the frequency of somatic mosaicism in parents of children with severe epileptic encephalopathies. Here we aim to investigate the frequency of mosaicism in the parents of children with epilepsy caused by alleged de novo variants. We tested parent...
The developmental and epileptic encephalopathies (DEEs) are heterogeneous disorders with a strong genetic contribution, but the underlying genetic etiology remains unknown in a significant proportion of individuals. To explore whether statistical support for genetic etiologies can be generated on the basis of phenotypic features, we analyzed whole-...
OBJECTIVE: Pathogenic variants in SCN8A have been associated with a wide spectrum of epilepsy phenotypes, ranging from benign familial infantile seizures (BFIS) to epileptic encephalopathies with variable severity. Furthermore, a few patients with intellectual disability (ID) or movement disorders without epilepsy have been reported. The vast major...
Objective
Establishing a core set of outcomes to be evaluated and reported in intervention trials aims to improve the usefulness of health research. There is no established core outcome set (COS) for childhood epilepsies. The aim of this study was to select a COS to be used in evaluative research of interventions for children with rolandic epilepsy...
Purpose:
To provide a detailed electroclinical description and expand the phenotype of PIGT-CDG, to perform genotype-phenotype correlation, and to investigate the onset and severity of the epilepsy associated with the different genetic subtypes of this rare disorder. Furthermore, to use computer-assisted facial gestalt analysis in PIGT-CDG and to...
Objective
Pathogenic variants in SCN8A have been associated with a wide spectrum of epilepsy phenotypes, ranging from benign familial infantile seizures (BFIS) to epileptic encephalopathies with variable severity. Furthermore, a few patients with intellectual disability (ID) or movement disorders without epilepsy have been reported. The vast majori...
OBJECTIVE: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and establish genotype-phenotype correlations by identifying further disease-related variants. METHODS: We used next-generation sequencing in the framework of research projects and diagnostic testing. Cli...
We evaluated a new epilepsy genetic diagnostic and counseling service covering a UK population of 3.5 million. We calculated diagnostic yield, estimated clinical impact, and surveyed referring clinicians and families. We costed alternative investigational pathways for neonatal onset epilepsy. Patients with epilepsy of unknown aetiology onset < 2 ye...
This pilot study investigated the change in cortical thickness within the left hemisphere of four adolescents with rolandic epilepsy (RE) in seizure remission and four healthy controls. We found evidence of a delay in the cortical thinning process in adolescents with RE in seizure remission compared to healthy controls. A t-test of average symmetri...
Background
Rolandic epilepsy (RE) is the most common genetic childhood epilepsy, consisting of focal, nocturnal seizures and frequent neurodevelopmental impairments in speech, language, literacy and attention. A complex genetic aetiology is presumed in most, with monogenic mutations in GRIN2A accounting for >5% of cases.
Objective
To identify rare...
Graphic illustration (a cartoon) by @ScienceofCookie explanaining this research protocol in an engaging and accessible way
Background: Consolidation of learning occurs during sleep but when it is disturbed there may be an adverse impact upon these functions. While research has focused upon how sleep affects cognition in adulthood, the effects of disrupted sleep are likely to impact more heavily on learning among children and adolescents. We aimed to investigate whether...
Objective:
Pathogenic SLC6A1 variants were recently described in patients with myoclonic atonic epilepsy (MAE) and intellectual disability (ID). We set out to define the phenotypic spectrum in a larger cohort of SCL6A1-mutated patients.
Methods:
We collected 24 SLC6A1 probands and 6 affected family members. Four previously published cases were i...
Following on from a poster presented at the ICE2017 in Barcelona 2017, this poster investigates an expanded cohort of children with rolandic epilepsy (n= 40 ), siblings (n=32) and controls (n=21) using the DCDQ’07. We found that the indication for developmental coordination disorder (DCD) in children with RE was greater than siblings and healthy co...
The treatise of Indian and tropical soils ends with a chapter ‘Summary and Concluding Remarks’, which projects a concise but a precious synthesis of unique research results obtained by the soil and earth scientists on major soil types of tropical Indian environments. In the past, much valuable work has been done throughout the tropics, but it has b...
Background
There is increasing recognition that establishing a core set of outcomes to be evaluated and reported in trials of interventions for particular conditions will improve the usefulness of health research. There is no established core outcome set for childhood epilepsy. The aim of this work is to select a core outcome set to be used in eval...
Introduction The predominant cognitive problems in Rolandic epilepsy (RE) involve speech, language and literacy (Vega et al., 2015, Smith et al., 2015, Pal et al., 2010). These problems may represent an endophenotype as they are prevalent within families of children with RE (Smith et al., 2012). While recent evidence suggests additional problems wi...
The classic epileptic encephalopathies, including infantile spasms (IS) and Lennox–Gastaut syndrome (LGS), are severe seizure disorders that usually arise sporadically. De novo variants in genes mainly encoding ion channel and synaptic proteins have been found to account for over 15% of patients with IS or LGS. The contribution of autosomal recessi...
Previous research shows that children with Rolandic Epilepsy have deficits of auditory processing. We wanted to confirm the nature of this deficit and whether it aggregates in families. We compared 40 children with Rolandic Epilepsy and 32 unaffected siblings with 99 typically developing children and 71 parents of RE children with 31 healthy adults...
Figure S1. Mean adjacency matrices (left panel) and graphs (middle and right panels) for participants with BECTS (top), siblings (middle). and healthy controls (bottom).
Figure S2. Global efficiency (E) versus connection density, for the BECTS, siblings, and control groups.
Figure S3. Mean local efficiency (Eloc) versus connection density, for th...
Appendix S1. Comparison of graph metrics between groups.
Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those,...
Mutations in the N-methyl-D-aspartate receptor (NMDAR) gene GRIN2A cause epilepsy-aphasia
syndrome (EAS), a spectrum of epileptic, cognitive and language disorders. Using bioinformatic
and patient data we shortlisted 10 diverse missense mutations for characterisation. We used highthroughput
calcium-flux assays and patch clamp recordings of transien...
Objective
Benign epilepsy with centrotemporal spikes (BECTS, also known as Rolandic epilepsy) is a common epilepsy syndrome that is associated with literacy and language impairments. The neural mechanisms of the syndrome are not known. The primary objective of this study was to test the hypothesis that functional connectivity within the language ne...
Objective:
To delineate the genetic, neurodevelopmental and epileptic spectrum associated with GRIN2A alterations with emphasis on epilepsy treatment.
Methods:
Retrospective study of 19 patients (7 females; age: 1-38 years; mean 10.1 years) with epilepsy and GRIN2A alteration. Genetic variants were classified according to the guidelines and reco...
© 2017(The American Journal of Human Genetics 95, 360–370; October 2, 2014) In the list of consortium members for the Epilepsy Phenome/Genome Project, member Dina Amrom's name was misspelled as Amron. The authors regret the error.
We report a de novo SMARCA2 missense mutation discovered on exome sequencing in a patient with myoclonic astatic epilepsy, leading to reassessment and identification of Nicolaides–Baraitser syndrome. This de novo SMARCA2 missense mutation c.3721C>G, p.Gln1241Glu is the only reported mutation on exon 26 outside the ATPase domain of SMARCA2 to be ass...