ORCID Profile
0000-0002-8948-4763
Current Organisations
Wolfson College, University of Oxford
,
University of Oxford
,
University of Oxford Corpus Christi College
,
National Institute for Health and Care Excellence
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Publications
Whole-genome sequencing of patients with rare diseases in a national health system
Publisher: Springer Science and Business Media LLC
Date: 24-06-2020
Development of EpiRisk: An online clinical tool for estimating the risk of major congenital malformations in pregnant women treated for epilepsy
Publisher: Wiley
Date: 22-03-2018
DOI: 10.1002/EPI4.12109
Predictive models for starting antiseizure medication withdrawal following epilepsy surgery in adults
Publisher: Cold Spring Harbor Laboratory
Date: 24-07-2022
DOI: 10.1101/2022.07.22.22277802
Abstract: More than half of adults with epilepsy undergoing resective epilepsy surgery achieve long-term seizure freedom and might consider withdrawing antiseizure medications (ASMs). We aimed to identify predictors of seizure recurrence after starting postoperative ASM withdrawal and develop and validate predictive models. We performed an international multicentre observational cohort study in nine tertiary epilepsy referral centres. We included 850 adults who started ASM withdrawal following resective epilepsy surgery and were free of seizures other than focal non-motor aware seizures (auras) before starting ASM withdrawal. We developed a model predicting recurrent seizures, other than auras, using Cox proportional hazards regression in a derivation cohort (n=231). Independent predictors of seizure recurrence, other than auras, following the start of ASM withdrawal were focal-aware seizures after surgery and before withdrawal (adjusted hazards ratio [aHR] 5.5, 95% confidence interval [CI] 2.7-11.1), history of focal to bilateral tonic-clonic seizures before surgery (aHR 1.6, 95% CI 0.9-2.8), time from surgery to the start of ASM withdrawal (aHR 0.9, 95% CI 0.8-0.9), and number of ASMs at time of surgery (aHR 1.2, 95% CI 0.9-1.6). Model discrimination showed a concordance statistic of 0.67 (95% CI 0.63-0.71) in the external validation cohorts (n=500). A secondary model predicting recurrence of any seizures (including auras) was developed and validated in a subgroup that did not have auras before withdrawal (n=639), showing a concordance statistic of 0.68 (95% CI 0.64-0.72). Calibration plots indicated high agreement of predicted and observed outcomes for both models. We show that simple algorithms, available as graphical nomograms and online tools ( predictepilepsy.github.io ), can provide probabilities of seizure outcomes after starting postoperative ASMs withdrawal. These multicentre-validated models may assist clinicians when discussing ASM withdrawal after surgery with their patients.
Genomic analysis of “microphenotypes” in epilepsy
Publisher: Wiley
Date: 27-09-2021
DOI: 10.1002/AJMG.A.62505
Abstract: Large international consortia examining the genomic architecture of the epilepsies focus on large diagnostic subgroupings such as “all focal epilepsy” and “all genetic generalized epilepsy”. In addition, phenotypic data are generally entered into these large discovery databases in a unidirectional manner at one point in time only. However, there are many smaller phenotypic subgroupings in epilepsy, many of which may have unique genomic risk factors. Such a subgrouping or “microphenotype” may be defined as an uncommon or rare phenotype that is well recognized by epileptologists and the epilepsy community, and which may or may not be formally recognized within the International League Against Epilepsy classification system. Here we examine the genetic structure of a number of such microphenotypes and report in particular on two interesting clinical phenotypes, Jeavons syndrome and pediatric status epilepticus. Although no single gene reached exome‐wide statistical significance to be associated with any of the diagnostic categories, we observe enrichment of rare damaging variants in established epilepsy genes among Landau–Kleffner patients ( GRIN2A ) and pediatric status epilepticus patients ( MECP2, SCN1A, SCN2A, SCN8A ).
Impact of the COVID-19 pandemic on people with epilepsy: Findings from the Brazilian arm of the COV-E study
Publisher: Elsevier BV
Date: 10-2021
Very late-onset mitochondrial cytopathy featuring epilepsia partialis continua and bilateral deafness: A case report
Publisher: Elsevier BV
Date: 03-2020
Predictive models for starting antiseizure medication withdrawal following epilepsy surgery in adults
Publisher: Oxford University Press (OUP)
Date: 23-11-2022
Abstract: More than half of adults with epilepsy undergoing resective epilepsy surgery achieve long-term seizure freedom and might consider withdrawing antiseizure medications. We aimed to identify predictors of seizure recurrence after starting postoperative antiseizure medication withdrawal and develop and validate predictive models. We performed an international multicentre observational cohort study in nine tertiary epilepsy referral centres. We included 850 adults who started antiseizure medication withdrawal following resective epilepsy surgery and were free of seizures other than focal non-motor aware seizures before starting antiseizure medication withdrawal. We developed a model predicting recurrent seizures, other than focal non-motor aware seizures, using Cox proportional hazards regression in a derivation cohort (n = 231). Independent predictors of seizure recurrence, other than focal non-motor aware seizures, following the start of antiseizure medication withdrawal were focal non-motor aware seizures after surgery and before withdrawal [adjusted hazard ratio (aHR) 5.5, 95% confidence interval (CI) 2.7–11.1], history of focal to bilateral tonic-clonic seizures before surgery (aHR 1.6, 95% CI 0.9–2.8), time from surgery to the start of antiseizure medication withdrawal (aHR 0.9, 95% CI 0.8–0.9) and number of antiseizure medications at time of surgery (aHR 1.2, 95% CI 0.9–1.6). Model discrimination showed a concordance statistic of 0.67 (95% CI 0.63–0.71) in the external validation cohorts (n = 500). A secondary model predicting recurrence of any seizures (including focal non-motor aware seizures) was developed and validated in a subgroup that did not have focal non-motor aware seizures before withdrawal (n = 639), showing a concordance statistic of 0.68 (95% CI 0.64–0.72). Calibration plots indicated high agreement of predicted and observed outcomes for both models. We show that simple algorithms, available as graphical nomograms and online tools (predictepilepsy.github.io), can provide probabilities of seizure outcomes after starting postoperative antiseizure medication withdrawal. These multicentre-validated models may assist clinicians when discussing antiseizure medication withdrawal after surgery with their patients.
Evaluating risk to people with epilepsy during the COVID-19 pandemic: Preliminary findings from the COV-E study
Publisher: Elsevier BV
Date: 02-2021
YouTube as a potential learning tool to help distinguish tonic-clonic seizures from nonepileptic attacks.
Publisher: Elsevier BV
Date: 08-2014
DOI: 10.1016/J.YEBEH.2014.06.003
Abstract: Medical students are increasingly turning to the website YouTube as a learning resource. This study set out to determine whether the videos on YouTube accurately depict the type of seizures that a medical student may search for. Two consultant epileptologists independently assessed the top YouTube videos returned following searches for eight terms relating to different categories of seizures. The videos were rated for their technical quality, concordance of diagnosis with an epileptologist-assigned diagnosis, and efficacy as a learning tool for medical education. Of the 200 videos assessed, 106 (63%) met the inclusion criteria for further analysis. Technical quality was generally good and only interfered with the diagnostic process in 8.5% of the videos. Of the included videos, 40.6-46.2% were judged to depict the purported diagnosis with moderate agreement between raters (75% agreement, κ=0.50). Of the videos returned after searching "tonic-clonic seizure", 28.6-35.7% were judged to show nonepileptic seizures with almost perfect interrater agreement (92.9% agreement, κ=0.84). Of the videos returned following the search "pseudoseizure", 77.8-88.9% of videos were judged to show nonepileptic seizures with substantial agreement (88.9% agreement, κ=0.61). Across all search terms, 19.8-33% of videos were judged as potentially useful as a learning resource, with fair agreement between raters (75.5% agreement, κ=0.38). These findings suggest that the majority of videos on YouTube claiming to show specific seizure subtypes are inaccurate, and YouTube should not be recommended as a learning tool for students. However, a small group of videos provides excellent demonstrations of tonic-clonic and nonepileptic seizures, which could be used by an expert teacher to demonstrate the difference between epileptic and nonepileptic seizures.
Vagus nerve stimulation therapy in people with drug-resistant epilepsy (CORE-VNS): rationale and design of a real-world post-market comprehensive outcomes registry
Publisher: BMJ
Date: 12-2021
DOI: 10.1136/BMJNO-2021-000218
Abstract: The Vagus Nerve Stimulation Therapy System (VNS Therapy) is an adjunctive neuromodulatory therapy that can be efficacious in reducing the frequency and severity of seizures in people with drug-resistant epilepsy (DRE). CORE-VNS aims to examine the long-term safety and clinical outcomes of VNS in people with DRE. The CORE-VNS study is an international, multicentre, prospective, observational, all-comers, post-market registry. People with DRE receiving VNS Therapy for the first time as well as people being reimplanted with VNS Therapy are eligible. Participants have a baseline visit (prior to device implant). They will be followed for a minimum of 36 months and a maximum of 60 months after implant. Analysis endpoints include seizure frequency (average number of events per month), seizure severity (in idual-rated categorical outcome including very mild, mild, moderate, severe or very severe) as well as non-seizure outcomes such as adverse events, use of antiseizure medications, use of other non-pharmacological therapies, quality of life, validated measures of quality of sleep (Pittsburgh Sleep Quality Index or Children’s Sleep Habit Questionnaire) and healthcare resource utilisation. While the CORE-VNS registry was not expressly designed to test hypotheses, subgroup analyses and exploratory analysis that require hypothesis testing will be conducted across propensity score matched treatment groups, where possible based on s ling. The CORE-VNS registry has already enrolled 823 participants from 61 centres across 15 countries. Once complete, CORE-VNS will represent one of the largest real-world clinical data sets to allow a more comprehensive understanding of the management of DRE with adjunctive VNS. Manuscripts derived from this database will shed important new light on the characteristics of people receiving VNS Therapy the practical use of VNS across different countries, and factors influencing long-term response. NCT03529045 .
Apathy in small vessel cerebrovascular disease is associated with deficits in effort-based decision making
Publisher: Oxford University Press (OUP)
Date: 18-03-2021
Abstract: Patients with small vessel cerebrovascular disease frequently suffer from apathy, a debilitating neuropsychiatric syndrome, the underlying mechanisms of which remain to be established. Here we investigated the hypothesis that apathy is associated with disrupted decision making in effort-based decision making, and that these alterations are associated with abnormalities in the white matter network connecting brain regions that underpin such decisions. Eighty-two patients with MRI evidence of small vessel disease were assessed using a behavioural paradigm as well as diffusion weighted MRI. The decision-making task involved accepting or rejecting monetary rewards in return for performing different levels of physical effort (hand grip force). Choice data and reaction times were integrated into a drift diffusion model that framed decisions to accept or reject offers as stochastic processes approaching a decision boundary with a particular drift rate. Tract-based spatial statistics were used to assess the relationship between white matter tract integrity and apathy, while accounting for depression. Overall, patients with apathy accepted significantly fewer offers on this decision-making task. Notably, while apathetic patients were less responsive to low rewards, they were also significantly averse to investing in high effort. Significant reductions in white matter integrity were observed to be specifically related to apathy, but not to depression. These included pathways connecting brain regions previously implicated in effort-based decision making in healthy people. The drift rate to decision parameter was significantly associated with both apathy and altered white matter tracts, suggesting that both brain and behavioural changes in apathy are associated with this single parameter. On the other hand, depression was associated with an increase in the decision boundary, consistent with an increase in the amount of evidence required prior to making a decision. These findings demonstrate altered effort-based decision making for reward in apathy, and also highlight dissociable mechanisms underlying apathy and depression in small vessel disease. They provide clear potential brain and behavioural targets for future therapeutic interventions, as well as modelling parameters that can be used to measure the effects of treatment at the behavioural level.
Hippocampal MRS and subfield volumetry at 7T detects dysfunction not specific to seizure focus.
Publisher: Springer Science and Business Media LLC
Date: 23-11-2017
DOI: 10.1038/S41598-017-16046-5
Abstract: Ultra high-field 7T MRI offers sensitivity to localize hippoc al pathology in temporal lobe epilepsy (TLE), but has rarely been evaluated in patients with normal-appearing clinical MRI. We applied multimodal 7T MRI to assess if focal subfield atrophy and deviations in brain metabolites characterize epileptic hippoc i. Twelve pre-surgical TLE patients (7 MRI-negative) and age-matched healthy volunteers were scanned at 7T. Hippoc al subfields were manually segmented from 600μm isotropic resolution susceptibility-weighted images. Hippoc al metabolite spectra were acquired to determine absolute concentrations of glutamate, glutamine, myo-inositol, NAA, creatine and choline. We performed case-controls analyses, using permutation testing, to identify abnormalities in hippoc al imaging measures in in idual patients, for evaluation against clinical evidence of seizure lateralisation and neuropsychological memory test scores. Volume analyses identified hippoc al subfield atrophy in 9/12 patients (75%), commonly affecting CA3. 7/8 patients had altered metabolite concentrations, most showing reduced glutamine levels (62.5%). However, neither volume nor metabolite deviations consistently lateralized the epileptogenic hippoc us. Rather, lower subiculum volumes and glutamine concentrations correlated with impaired verbal memory performance. Hippoc al subfield and metabolic abnormalities detected at 7T appear to reflect pathophysiological processes beyond epileptogenesis. Despite limited diagnostic contributions, these markers show promise to help elucidate mnemonic processing in TLE.
The phenotype of bilateral hippocampal sclerosis and its management in real life clinical settings.
Publisher: Wiley
Date: 14-06-2018
DOI: 10.1111/EPI.14436
Abstract: There is little detailed phenotypic characterization of bilateral hippoc al sclerosis (HS). We therefore conducted a multicenter review of people with pharmacoresistant epilepsy and bilateral HS to better determine their clinical characteristics. Databases from 11 EPIGEN centers were searched. For identified cases, clinicians reviewed the medical notes, imaging, and electroencephalographic (EEG), video-EEG, and neuropsychometric data. Data were irretrievably anonymized, and a single database was populated to capture all phenotypic information. These data were compared with phenotyped cases of unilateral HS from the same centers. In total, 96 patients with pharmacoresistant epilepsy and bilateral HS were identified (43 female, 53 male age range = 8-80 years). Twenty-five percent had experienced febrile convulsions, and 27% of patients had experienced status epilepticus. The mean number of previously tried antiepileptic drugs was 5.32, and the average number of currently prescribed medications was 2.99 44.8% of patients had cognitive difficulties, and 47.9% had psychiatric comorbidity 35.4% (34/96) of patients continued with long-term medical therapy alone, another 4 being seizure-free on medication. Sixteen patients proceeded to, or were awaiting, neurostimulation, and 11 underwent surgical resection. One patient was rendered seizure-free postresection, with an improvement in seizures for 3 other cases. By comparison, of 201 patients with unilateral HS, a significantly higher number (44.3%) had febrile convulsions and only 11.4% had experienced status epilepticus. Importantly, 41.8% (84/201) of patients with unilateral HS had focal aware seizures, whereas such seizures were less frequently observed in people with bilateral HS, and were never observed exclusively (P = .002 Fisher's exact test). The current work describes the phenotypic spectrum of people with pharmacoresistant epilepsy and bilateral HS, highlights salient clinical differences from patients with unilateral HS, and provides a large platform from which to develop further studies, both epidemiological and genomic, to better understand etiopathogenesis and optimal treatment regimes in this condition.
Binding deficits in visual short-term memory in patients with temporal lobe lobectomy
Publisher: Wiley
Date: 19-11-2018
DOI: 10.1002/HIPO.22998
Rare Genetic Variation and Outcome of Surgery for Mesial Temporal Lobe Epilepsy
Publisher: Wiley
Date: 02-01-2023
DOI: 10.1002/ANA.26581
Abstract: Genetic factors have long been debated as a cause of failure of surgery for mesial temporal lobe epilepsy (MTLE). We investigated whether rare genetic variation influences seizure outcomes of MTLE surgery. We performed an international, multicenter, whole exome sequencing study of patients who underwent surgery for drug‐resistant, unilateral MTLE with normal magnetic resonance imaging (MRI) or MRI evidence of hippoc al sclerosis and ≥2‐year postsurgical follow‐up. Patients with either sustained seizure freedom (favorable outcome) or ongoing uncontrolled seizures since surgery (unfavorable outcome) were included. Exomes of controls without epilepsy were also included. Gene set burden analyses were carried out to identify genes with significant enrichment of rare deleterious variants in patients compared to controls. Nine centers from 3 continents contributed 206 patients operated for drug‐resistant unilateral MTLE, of whom 196 (149 with favorable outcome and 47 with unfavorable outcome) were included after stringent quality control. Compared to 8,718 controls, MTLE cases carried a higher burden of ultrarare missense variants in constrained genes that are intolerant to loss‐of‐function (LoF) variants (odds ratio [OR] = 2.6, 95% confidence interval [CI] = 1.9–3.5, p = 1.3E‐09) and in genes encoding voltage‐gated cation channels (OR = 2.4, 95% CI = 1.4–3.8, p = 2.7E‐04). Proportions of subjects with such variants were comparable between patients with favorable outcome and those with unfavorable outcome, with no significant between‐group differences. Rare variation contributes to the genetic architecture of MTLE, but does not appear to have a major role in failure of MTLE surgery. These findings can be incorporated into presurgical decision‐making and counseling. ANN NEUROL 2023 :752–761
Development and validation of a predictive model of drug-resistant genetic generalized epilepsy
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-08-2020
DOI: 10.1212/WNL.0000000000010597
Abstract: To develop and validate a clinical prediction model for antiepileptic drug (AED)–resistant genetic generalized epilepsy (GGE). We performed a case-control study of patients with and without drug-resistant GGE, nested within ongoing longitudinal observational studies of AED response at 2 tertiary epilepsy centers. Using a validation dataset, we tested the predictive performance of 3 candidate models, developed from a training dataset. We then tested the candidate models' predictive ability on an external testing dataset. Of 5,189 patients in the ongoing longitudinal study, 121 met criteria for AED-resistant GGE and 468 met criteria for AED-responsive GGE. There were 66 patients with GGE in the external dataset, of whom 17 were cases. Catamenial epilepsy, history of a psychiatric condition, and seizure types were strongly related with drug-resistant GGE case status. Compared to women without catamenial epilepsy, women with catamenial epilepsy had about a fourfold increased risk for AED resistance. The calibration of 3 models, assessing the agreement between observed outcomes and predictions, was adequate. Discriminative ability, as measured with area under the receiver operating characteristic curve (AUC), ranged from 0.58 to 0.65. Catamenial epilepsy, history of a psychiatric condition, and the seizure type combination of generalized tonic clonic, myoclonic, and absence seizures are negative prognostic factors of drug-resistant GGE. The AUC of 0.6 is not consistent with truly effective separation of the groups, suggesting other unmeasured variables may need to be considered in future studies to improve predictability.
Related Organisations
Wolfson College, University Of Oxford
Location: United Kingdom of Great Britain and Northern Ireland
University Of Oxford
Location: United Kingdom of Great Britain and Northern Ireland
University Of Oxford Corpus Christi College
Location: United Kingdom of Great Britain and Northern Ireland
National Institute For Health And Care Excellence
Location: United Kingdom of Great Britain and Northern Ireland
Oxford University Hospitals NHS Foundation Trust
Location: United Kingdom of Great Britain and Northern Ireland
Related Funding Activities
No related grants have been discovered for Arjune Sen.