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Epilepsy: HELP
Articles by Sophia M. Varadkar
Based on 16 articles published since 2010
(Why 16 articles?)
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Between 2010 and 2020, Sophia Varadkar wrote the following 16 articles about Epilepsy.
 
+ Citations + Abstracts
1 Review Optimising Evidence-Based Psychological Treatment for the Mental Health Needs of Children with Epilepsy: Principles and Methods. 2020

Shafran, Roz / Bennett, Sophie / Coughtrey, Anna / Welch, Alice / Walji, Fahreen / Cross, J Helen / Heyman, Isobel / Sibelli, Alice / Smith, Jessica / Ross, Jamie / Dalrymple, Emma / Varadkar, Sophia / Anonymous5341122 / Moss-Morris, Rona. ·Population, Policy and Practice Research and Teaching Department, University College London Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK. r.shafran@ucl.ac.uk. · Great Ormond Street Hospital NHS Foundation Trust, Great Ormond Street, London, WC1N 3JH, UK. r.shafran@ucl.ac.uk. · Population, Policy and Practice Research and Teaching Department, University College London Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK. · Great Ormond Street Hospital NHS Foundation Trust, Great Ormond Street, London, WC1N 3JH, UK. · Health Psychology, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, SE1 9RT, UK. · King's College London, Strand, London, WC2R 2LS, UK. · Department of Primary Care and Population Health, UCL Medical School (Royal Free Campus), University College London, Rowland Hill Street, London, NW3 2PF, UK. ·Clin Child Fam Psychol Rev · Pubmed #31965422.

ABSTRACT: There are potent evidence-based psychological treatments for youth with mental health needs, yet they are rarely implemented in clinical practice, especially for youth with mental health disorders in the context of chronic physical illness such as epilepsy. Implementation science, the study of the translation of research into practice, can promote the uptake of existing effective interventions in routine clinical practice and aid the sustainable integration of psychological treatments with routine health care. The aim of this report was to use four implementation science methods to develop a version of an existing effective psychological treatment for mental health disorders [the Modular Approach to Treatment of Children with Anxiety, Depression or Conduct Problems (MATCH-ADTC)] for use within paediatric epilepsy services: (a) literature search; (b) iterative focus groups underpinned by normalisation process theory; (c) Plan-Do-Study-Act methods; and (d) qualitative patient interviews. Findings: Three modifications were deemed necessary to facilitate implementation in children with both mental health disorders and epilepsy. These were (a) a universal brief psychoeducational component addressing the relationship between epilepsy and mental health; (b) supplementary, conditionally activated interventions addressing stigma, parental mental health and the transition to adulthood; and (c) additional training and supervision. The intervention needed relatively little alteration for implementation in paediatric epilepsy services. The modified treatment reflected the scientific literature and the views of clinicians and service users. The multi-method approach used in this report can serve as a model for implementation of evidence-based psychological treatments for children with mental health needs in the context of other chronic illnesses.

2 Review Rasmussen Syndrome and Other Inflammatory Epilepsies. 2015

Varadkar, Sophia / Cross, J Helen. ·Epilepsy Unit, Great Ormond Street Hospital for Children NHS Foundation Trust and UCL Institute of Child Health, London, United Kingdom. · Department of Clinical Neurosciences, UCL-Institute of Child Health, Great Ormond Street for Children NHS Foundation Trust, London and Young Epilepsy, Lingfield, United Kingdom. ·Semin Neurol · Pubmed #26060905.

ABSTRACT: An underlying immune basis is emerging in an increasing number of epileptic and encephalopathic syndromes. The immunopathological mechanisms may be categorized into antibody-mediated, T-cell cytotoxicity, and microglia-induced degeneration. The immune basis in Rasmussen syndrome is thought to be T-cell mediated. Antibodies to extracellular and intracellular epitopes are implicated in limbic and other encephalitides, characterized by seizures, movement disorder, sleep disorder, obtundation, psychosis, mutism, and other psychiatric symptoms. Extracellular antibodies are directed at cell-surface-expressed neuronal or glial proteins: glutamate receptors (N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazol-propionic acid), voltage-gated potassium channel complex (contactin-associated-protein 2 [CASPR2], contactin-2 and leucin-rich, glioma-inactivated 1 [LGI1]), and γ-aminobutyric acid (GABA) receptors (GABABR and GABAAR). Antibodies to intracellular antigens are less commonly seen (for example, glutamic acid decarboxylase). Diseases caused by antibodies to cell-surface-expressed antigens are better expected to respond to immune treatments than to those where the presumed mechanism is T-cell driven. Antibodies to the folate receptor FR1 are a cause of primary cerebral folate deficiency. Febrile infection-related epilepsy syndrome (FIRES) may also have an immune basis, although this is yet to be proven. For all these epilepsies, the best treatment and the long-term outcomes are not yet clear.

3 Review Inborn errors of metabolism causing epilepsy. 2013

Rahman, Shamima / Footitt, Emma J / Varadkar, Sophia / Clayton, Peter T. ·Clinical and Molecular Genetics and Neurosciences Units, University College London Institute of Child Health, London and Metabolic and Neurosciences Units, Great Ormond Street Hospital for Children NHS Trust, London, UK. shamima.rahman@ucl.ac.uk ·Dev Med Child Neurol · Pubmed #22998469.

ABSTRACT: Seizures may be the first and the major presenting feature of an inborn error of metabolism (IEM), for example in a neonate with pyridoxine-dependent epilepsy. In other IEMs, seizures may be preceded by other major symptoms: by a reduced level of consciousness in a child with an organic acidaemia or urea cycle defect; or by loss of skills, progressive weakness, ataxia, and upper motor signs in a child with a lysosomal storage disorder or peroxisomal leukodystrophy. This review concentrates on those IEMs for which specific treatment is available. The common metabolic causes of seizures vary according to the age at presentation. Features from the history, examination, imaging, and first line biochemical investigations can all provide clues to an inborn error. This review attempts to delineate these and to provide a guide to the specific tests that can be used to make the diagnosis of disorders with specific treatment.

4 Clinical Trial Guided self-help for mental health disorders in children and young people with chronic neurological conditions: A qualitative evaluation. 2018

Bennett, Sophie D / Coughtrey, Anna E / Heyman, Isobel / Greally, Suzanna / Clarkson, Harriet / Bhattacharyya, Tuhina / Lewis, Corah / Varadkar, Sophia / Shafran, Roz. ·UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, United Kingdom. Electronic address: sophie.bennett.10@ucl.ac.uk. · UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, United Kingdom; Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, London, WC1N 3JH, United Kingdom. · UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, United Kingdom. ·Eur J Paediatr Neurol · Pubmed #29631920.

ABSTRACT: OBJECTIVE: Children with neurological conditions such as epilepsy are at high risk of developing mental health disorders. Guided self-help can be used to increase access to psychological therapies. When developing and evaluating interventions, it is important to obtain the views of service-users about their acceptability. A telephone-guided self-help intervention was used to treat common mental health difficulties in children and young people with neurological conditions. The intervention was not adapted in content to account for chronic illness. This study therefore reports on qualitative interviews with participants to determine the acceptability of the intervention. METHODS: Semi-structured interviews were conducted with 27 participants (25 parents and 2 young people) who had undertaken a telephone-delivered guided self-help intervention for common mental health difficulties in the context of a paediatric neurological condition. Transcripts were analysed thematically using the framework approach. RESULTS: Thirteen themes were extracted, organised into three main domains, which covered: the practicalities of telephone guided self-help treatment; the outcomes of the intervention; and the extent to which adaptation was needed for chronic illness. Most families found the intervention helpful in working towards their specific goals and noticed changes for the child and/or parents and family. CONCLUSIONS: Participants had a positive experience of the intervention and the majority of parents found the standard intervention with individualised goals sufficient to meet the young person's mental health needs.

5 Article Neuropsychiatric profile of paediatric hypothalamic hamartoma: systematic review and case series. 2019

Corbet Burcher, Georgina / Liang, Holan / Lancaster, Rebecca / Cross, J Helen / Tisdall, Martin / Varadkar, Sophia / Spoudeas, Helen A / Caredda, Elisabetta / Bennett, Sophie / Heyman, Isobel. ·Department of Child and Adolescent Psychiatry, Centre for Psychiatry, Imperial College London, London, UK. · Department of Psychological Medicine, Great Ormond Street Hospital for Children, London, UK. · UCL Great Ormond Street Institute of Child Health, London, UK. · Department of Neurology, Great Ormond Street Hospital for Children, London, UK. · Department of Neurosurgery, Great Ormond Street Hospital for Children, London, UK. · Department of Paediatric Neuroendocrinology, Great Ormond Street Hospital for Children and University College Hospital, London, UK. · Evelina London Children's Hospital, Guy's and St Thomas' Hospital NHS Foundation Trust, London, UK. ·Dev Med Child Neurol · Pubmed #30977116.

ABSTRACT: AIM: To evaluate neuropsychiatric comorbidities in children and adolescents with hypothalamic hamartoma. METHOD: We retrospectively analysed case notes for all individuals with hypothalamic hamartoma referred to Great Ormond Street Hospital, London, between 2000 and 2016. In addition, a systematic review aiming to identify all previous paediatric case series was performed. Psychiatric symptoms, demographics, physical comorbidities, and cognitive functioning were recorded for all cases where possible. Analyses were performed to determine which factors were associated with psychopathology and potential mechanisms investigated. RESULTS: Forty-six cases were included in the case series (28 males, 18 females; mean age at assessment 11y 8mo [1y 11mo-16y 11mo, SD 4y 0mo]). Twenty-nine papers representing data from 264 cases met inclusion criteria for the systematic review. Overall, at least 50% of cases presented with psychopathology. Epilepsy, intellectual disability, and male sex were associated with externalizing disorders (attention-deficit/hyperactivity disorder, conduct and oppositional defiance disorders, and rage attacks). Intellectual disability mediated the effects of epilepsy on externalizing psychopathology. No factors were associated with internalizing disorders (anxiety and depressive disorders), although these were not well reported. INTERPRETATION: Psychiatric comorbidities are highly prevalent in the presentation of paediatric hypothalamic hamartoma. The aetiology of psychopathology comprises a range of interacting biological and psychosocial factors with particular influence from epilepsy. Further research is required to achieve an evidence base for treatment. WHAT THIS PAPER ADDS: Over half of children with hypothalamic hamartoma present with psychiatric comorbidity. Externalizing and internalizing disorders are present in approximately 60% and 30% of children with hypothalamic hamartomas respectively. Epilepsy and male sex are associated with externalizing psychopathology. Intellectual disability mediates the association between epilepsy and externalizing symptoms. No clear associations are evident for internalizing disorders or precocious puberty.

6 Article Neurologic phenotypes associated with 2018

Zagaglia, Sara / Selch, Christina / Nisevic, Jelena Radic / Mei, Davide / Michalak, Zuzanna / Hernandez-Hernandez, Laura / Krithika, S / Vezyroglou, Katharina / Varadkar, Sophia M / Pepler, Alexander / Biskup, Saskia / Leão, Miguel / Gärtner, Jutta / Merkenschlager, Andreas / Jaksch, Michaela / Møller, Rikke S / Gardella, Elena / Kristiansen, Britta Schlott / Hansen, Lars Kjærsgaard / Vari, Maria Stella / Helbig, Katherine L / Desai, Sonal / Smith-Hicks, Constance L / Hino-Fukuyo, Naomi / Talvik, Tiina / Laugesaar, Rael / Ilves, Pilvi / Õunap, Katrin / Körber, Ingrid / Hartlieb, Till / Kudernatsch, Manfred / Winkler, Peter / Schimmel, Mareike / Hasse, Anette / Knuf, Markus / Heinemeyer, Jan / Makowski, Christine / Ghedia, Sondhya / Subramanian, Gopinath M / Striano, Pasquale / Thomas, Rhys H / Micallef, Caroline / Thom, Maria / Werring, David J / Kluger, Gerhard Josef / Cross, J Helen / Guerrini, Renzo / Balestrini, Simona / Sisodiya, Sanjay M. ·From the Department of Clinical and Experimental Epilepsy (S.Z., Z.M., L.H.-H., S.K., S. Balestrini, S.M.S.) and Division of Neuropathology (Z.M., M.T.), UCL Institute of Neurology, London, UK · Clinic of Neurology (S.Z.), Department of Experimental and Clinical Medicine, Marche Polytechnic University, Ancona, Italy · Department of Pediatric Neurology and Neurological Rehabilitation (C.S., T.H., P.W., G.J.K.) and Neurosurgery Clinic and Clinic for Epilepsy Surgery (M.K.), Schön Klinik Vogtareuth · Department of Pediatrics (C.S., M.S.), Children's Hospital Augsburg, Germany · UCL Great Ormond Street Institute of Child Health (J.R.N., K.V., S.M.V., J.H.C.), London, UK · Paediatric Neurology and Neurogenetics Unit and Laboratories (D.M., R.G.), A. Meyer Children's Hospital, University of Florence, Italy · Chalfont Centre for Epilepsy (Z.M., L.H.-H., S.K., S. Balestrini, S.M.S.), Chalfont-St-Peter, Buckinghamshire, UK · CeGaT-Center for Genomics and Transcriptomics (A.P., S. Biskup), Tübingen, Germany · Neurogenetics Unit (M.L.), Department of Medical Genetics, Hospital de São João, Porto, Portugal · Department of Pediatrics and Adolescent Medicine (J.G.), University Medical Center Göttingen · Hospital for Children and Adolescents (A.M.), University Clinic Leipzig, Germany · Freiburg Medical Laboratory (M.J.), Dubai · The Danish Epilepsy Centre (R.S.M., E.G.), Dianalund · Institute for Regional Health Services (R.S.M., E.G.), University of Southern Denmark, Odense · Department of Clinical Genetics (B.S.K.), Odense University Hospital · Hans Christian Andersen Children's Hospital (L.K.H.), Odense, Denmark · Pediatric Neurology and Muscular Diseases Unit (M.S.V., P.S.), Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health, University of Genoa "G. Gaslini" Institute, Italy · Division of Neurology (K.L.H.), Children's Hospital of Philadelphia, PA · Department of Neurology (S.D., C.L.S.-H.), Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD · Center for Genomic Medicine (N.H.-F.), Tohoku University · Department of Pediatrics (N.H.-F.), Tohoku University School of Medicine, Sendai, Japan · Department of Pediatrics (T.T., R.L.) and Institute of Clinical Medicine (K.O.), University of Tartu · Children's Clinic (T.T., R.L.), Department of Radiology (P.I.), and Department of Clinical Genetics, United Laboratories (K.O.), Tartu University Hospital, Estonia · Ludwig-Maximilians-University Munich (I.K.) · Department of Pediatric Neurology (A.H.), Clinic Traunstein · Children's Hospital (M.K.), Dr. Horst Schmidt Klinik, Wiesbaden · Altona Children's Hospital (J.H.), Hamburg · Department of Pediatrics (C. Makowski), Technische Universität München, Germany · Department of Clinical Genetics (S.G.), Royal North Shore Hospital, St Leonards · John Hunter Children's Hospital (G.M.S.), New Lambton Heights, New South Wales, Australia · Department of Neurology (R.T.), University Hospital of Wales · Institute of Psychological Medicine and Clinical Neurosciences (R.H.T.), Cardiff University · Division of Neuroradiology (C. Micallef), National Hospital for Neurology and Neurosurgery, London · Department of Brain Repair & Rehabilitation (D.J.W.), Stroke Research Centre, UCL Institute of Neurology, London, UK · Paracelsus Medical University (G.J.K.), Salzburg, Austria · and IRCCS Stella Maris Foundation (R.G.), Pisa, Italy. ·Neurology · Pubmed #30413629.

ABSTRACT: OBJECTIVE: To characterize the neurologic phenotypes associated with METHODS: We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with RESULTS: Childhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform discharges in the context of other abnormalities, including generalized sharp waves or slowing. In 46.4% of new patients with focal seizures, porencephalic cysts on brain MRI colocalized with the area of the focal epileptiform discharges. In patients with porencephalic cysts, brain MRI frequently also showed extensive white matter abnormalities, consistent with the finding of diffuse cerebral disturbance on EEG. Notably, we also identified a subgroup of patients with epilepsy as their main clinical feature, in which brain MRI showed nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry. Analysis of 15 pedigrees suggested a worsening of the severity of clinical phenotype in succeeding generations, particularly when maternally inherited. Mutations associated with epilepsy were spread across

7 Article Pre- and postsurgical cognitive trajectories and quantitative MRI changes in Rasmussen syndrome. 2018

Rudebeck, Sarah R / Shavel-Jessop, Sara / Varadkar, Sophia / Owen, Tamsin / Cross, J Helen / Vargha-Khadem, Faraneh / Baldeweg, Torsten. ·Developmental Neurosciences Programme, UCL Great Ormond Street Institute of Child Health, London, UK. · Great Ormond Street Hospital NHS Trust, London, UK. · Evelina London Children's Hospital, St Thomas' Hospital, London, UK. ·Epilepsia · Pubmed #29750339.

ABSTRACT: OBJECTIVE: To quantify the longitudinal cognitive trajectory, before and after surgery, of Rasmussen syndrome (RS), a rare disease characterized by focal epilepsy and progressive atrophy of one cerebral hemisphere. METHOD: Thirty-two patients (mean age = 6.7 years; 17 male, 16 left hemispheres affected) were identified from hospital records. The changes in intelligence scores during 2 important phases in the patients' journey to treatment were investigated: (1) during the preoperative period (n = 28, mean follow-up 3.4 years) and (2) from before to after surgery (n = 21 patients, mean time to follow-up 1.5 years). A volumetric magnetic resonance imaging (MRI) analysis of longitudinal changes in gray matter volume was conducted in a subsample of 18 patients. RESULTS: (1) IQ during the preoperative period: At baseline assessment (on average 2.4 years after seizure onset), the left RS group had lower verbal than nonverbal intellectual abilities, whereas the right group exhibited more difficulties in nonverbal than verbal intellect. Verbal and nonverbal scores declined during the follow-up in both groups, irrespective of the affected side. Hemispheric gray matter volumes declined over time in both groups in affected as well as unaffected hemispheres. (2) Postoperative IQ change: The left surgery group declined further in verbal and nonverbal intellect. The right group's nonverbal intellect declined after surgery, whereas verbal abilities did not. Patients with higher abilities preoperatively experienced large declines, whereas those with poorer abilities showed little change. Postoperative seizures negatively impacted on cognitive abilities. SIGNIFICANCE: During the chronic phase of the disease, parallel decline of verbal and nonverbal abilities suggest progressive bilateral hemispheric involvement, supported by evidence from MRI morphometry. Postsurgical cognitive losses are predicted by greater presurgical ability and continuing seizures. A shorter duration from seizure onset to surgery could reduce the postoperative cognitive burden by minimizing the decline in functions supported by the unaffected hemisphere.

8 Article Cannabidiol for drop seizures in Lennox-Gastaut syndrome. 2018

Varadkar, Sophia. ·Neuroscience Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK. Electronic address: sophia.varadkar@gosh.nhs.uk. ·Lancet · Pubmed #29395274.

ABSTRACT: -- No abstract --

9 Article Continuous spike-wave during sleep: treating an epilepsy without seizures. 2018

Varadkar, Sophia. ·Neurosciences Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. ·Dev Med Child Neurol · Pubmed #29283182.

ABSTRACT: -- No abstract --

10 Article Seizure and cognitive outcomes after resection of glioneuronal tumors in children. 2018

Faramand, Andrew M / Barnes, Nicola / Harrison, Sue / Gunny, Roxanna / Jacques, Tom / Tahir, M Zubair / Varadkar, Sophia M / Cross, Helen J / Harkness, William / Tisdall, Martin M. ·University College London, London, United Kingdom. · Great Ormond Street Hospital, London, United Kingdom. · UCL Great Ormond Street Institute of Child Health, London, United Kingdom. · National Centre for Young People with Epilepsy, Lingfield, United Kingdom. ·Epilepsia · Pubmed #29178251.

ABSTRACT: OBJECTIVE: Glioneuronal tumors (GNTs) are well-recognized causes of chronic drug-resistant focal epilepsy in children. Our practice involves an initial period of radiological surveillance and antiepileptic medications, with surgery being reserved for those with radiological progression or refractory seizures. We planned to analyze the group of patients with low-grade GNTs, aiming to identify factors affecting seizure and cognitive outcomes. METHODS: We retrospectively reviewed the medical records of 150 children presenting to Great Ormond Street Hospital with seizures secondary to GNTs. Analysis of clinical, neuroimaging, neuropsychological, and surgical factors was performed to determine predictors of outcome. Seizure outcome at final follow-up was classified as either seizure-free (group A) or not seizure-free (group B) for patients with at least 12-months follow-up postsurgery. Full-scale intelligence quotient (FSIQ) was used as a measure of cognitive outcome. RESULTS: Eighty-six males and 64 females were identified. Median presurgical FSIQ was 81. One hundred twenty-one patients (80.5%) underwent surgery. Median follow-up after surgery was 2 years, with 92 patients (76%) having at least 12 months of follow-up after surgery. Seventy-four patients (80%) were seizure-free, and 18 (20%) continued to have seizures. Radiologically demonstrated complete tumor resection was associated with higher rates of seizure freedom (P = .026). Higher presurgical FSIQ was related to shorter epilepsy duration until surgery (P = .012) and to older age at seizure onset (P = .043). SIGNIFICANCE: A high proportion of children who present with epilepsy and GNTs go on to have surgical tumor resection with excellent postoperative seizure control. Complete resection is associated with a higher chance of seizure freedom. Higher presurgical cognitive functioning is associated with shorter duration of epilepsy prior to surgery and with older age at seizure onset. Given the high rate of eventual surgery, early surgical intervention should be considered in children with continuing seizures associated with GNTs.

11 Article The biochemical basis of genetic epilepsies and the genetic basis of inherited metabolic disease. 2016

Varadkar, Sophia. ·Neurosciences Unit, Great Ormond Street Hospital, London, UK. ·Dev Med Child Neurol · Pubmed #27302035.

ABSTRACT: -- No abstract --

12 Article Vagus nerve stimulation for drug-resistant epilepsy: a European long-term study up to 24 months in 347 children. 2014

Orosz, Iren / McCormick, David / Zamponi, Nelia / Varadkar, Sophia / Feucht, Martha / Parain, Dominique / Griens, Roger / Vallée, Louis / Boon, Paul / Rittey, Christopher / Jayewardene, Amara K / Bunker, Mark / Arzimanoglou, Alexis / Lagae, Lieven. ·Department of Neuropediatrics, Children's Hospital, University of Leubeck, Leubeck, Germany. ·Epilepsia · Pubmed #25231724.

ABSTRACT: OBJECTIVE: To gain insight into the long-term impact of vagus nerve stimulation (with VNS Therapy) in children with drug-resistant epilepsy, we conducted the largest retrospective multicenter study to date over an extended follow-up period of up to 24 months. METHODS: The primary objective was to assess change in seizure frequency of the predominant seizure type (defined as the most disabling seizure) following VNS device implantation. Treating physicians collected data from patient records from baseline to 6, 12, and 24 months of follow-up. RESULTS: The analysis population included 347 children (aged 6 months to 17.9 years at the time of implant). At 6, 12, and 24 months after implantation, 32.5%, 37.6%, and 43.8%, respectively, of patients had ≥ 50% reduction in baseline seizure frequency of the predominant seizure type. The responder rate was higher in a subgroup of patients who had no change in antiepileptic drugs (AEDs) during the study. Favorable results were also evident for all secondary outcome measures including changes in seizure duration, ictal severity, postictal severity, quality of life, clinical global impression of improvement, and safety. Post hoc analyses demonstrated a statistically significant correlation between VNS total charge delivered per day and an increase in response rate. VNS Therapy is indicated as adjunctive therapy in children with focal, structural epilepsies, who for any reason are not good candidates for surgical treatment following the trial of two or more AEDs. Children with predominantly generalized seizures from genetic, structural epilepsies, like Dravet syndrome or Lennox-Gastaut syndrome, could also benefit from VNS Therapy. SIGNIFICANCE: The results demonstrate that adjunctive VNS Therapy in children with drug-resistant epilepsy reduces seizure frequency and is well tolerated over a 2-year follow-up period. No new safety issues were identified. A post hoc analysis revealed a dose-response correlation for VNS in patients with epilepsy.

13 Article COL4A1 mutations should not be a contraindication for epilepsy surgery. 2014

Papandreou, Apostolos / Tisdall, Martin M / Chong, W K / Cross, J Helen / Harkness, William F / Varadkar, Sophia M. ·Paediatric Neurology Department, Great Ormond Street Hospital, Great Ormond Street, London, WC1N 3JH, UK, apostolos.papandreou@gosh.nhs.uk. ·Childs Nerv Syst · Pubmed #24864020.

ABSTRACT: PURPOSE: We describe the first case in the literature of complication-free epilepsy surgery in a paediatric patient with collagen type IV alpha 1 (COL4A1) mutation. METHODS: This is a case report. RESULTS: COL4A1 mutations disrupt the integrity of vascular basement membranes, so predisposing to a broad spectrum of disorders including periventricular leucomalacia, haemorrhagic stroke, aneurysm formation, epilepsy and developmental delay. Intracranial haemorrhage is reported and may be recurrent or associated with trauma and anticoagulant therapy. Children have an increased risk of stroke with general anaesthesia. A 6-year-old girl, COL4A1 mutation positive, had drug-resistant epilepsy, cerebral palsy and developmental delay. Following presurgical evaluation, she was a candidate for corpus callosotomy. Previous general anaesthesia had been uncomplicated. Preoperative full blood count and coagulation studies were normal. Perioperatively, normotension was maintained, and anticoagulation was avoided. A complete corpus callosotomy was performed with no intracranial haemorrhage or other perioperative complications. CONCLUSION: Although there is an increased risk of intracranial haemorrhages in COL4A1 patients, this is not clearly quantifiable. There are minimal data in the literature on the subject. COL4A1 mutations should not be a contraindication for presurgical evaluation. Each patient should be individually evaluated and assessed, risks and benefits were carefully weighed, and informed decisions were reached after thorough discussions with patients and families.

14 Article Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome. 2014

Mills, Philippa B / Camuzeaux, Stephane S M / Footitt, Emma J / Mills, Kevin A / Gissen, Paul / Fisher, Laura / Das, Krishna B / Varadkar, Sophia M / Zuberi, Sameer / McWilliam, Robert / Stödberg, Tommy / Plecko, Barbara / Baumgartner, Matthias R / Maier, Oliver / Calvert, Sophie / Riney, Kate / Wolf, Nicole I / Livingston, John H / Bala, Pronab / Morel, Chantal F / Feillet, François / Raimondi, Francesco / Del Giudice, Ennio / Chong, W Kling / Pitt, Matthew / Clayton, Peter T. ·1 Clinical and Molecular Genetics Unit, UCL Institute of Child Health, 30 Guilford St, London WC1N 1EH, UK. ·Brain · Pubmed #24645144.

ABSTRACT: The first described patients with pyridox(am)ine 5'-phosphate oxidase deficiency all had neonatal onset seizures that did not respond to treatment with pyridoxine but responded to treatment with pyridoxal 5'-phosphate. Our data suggest, however, that the clinical spectrum of pyridox(am)ine 5'-phosphate oxidase deficiency is much broader than has been reported in the literature. Sequencing of the PNPO gene was undertaken for a cohort of 82 individuals who had shown a reduction in frequency and severity of seizures in response to pyridoxine or pyridoxal 5'-phosphate. Novel sequence changes were studied using a new cell-free expression system and a mass spectrometry-based assay for pyridoxamine phosphate oxidase. Three groups of patients with PNPO mutations that had reduced enzyme activity were identified: (i) patients with neonatal onset seizures responding to pyridoxal 5'-phosphate (n = 6); (ii) a patient with infantile spasms (onset 5 months) responsive to pyridoxal 5'-phosphate (n = 1); and (iii) patients with seizures starting under 3 months of age responding to pyridoxine (n = 8). Data suggest that certain genotypes (R225H/C and D33V) are more likely to result in seizures that to respond to treatment with pyridoxine. Other mutations seem to be associated with infertility, miscarriage and prematurity. However, the situation is clearly complex with the same combination of mutations being seen in patients who responded and did not respond to pyridoxine. It is possible that pyridoxine responsiveness in PNPO deficiency is affected by prematurity and age at the time of the therapeutic trial. Other additional factors that are likely to influence treatment response and outcome include riboflavin status and how well the foetus has been supplied with vitamin B6 by the mother. For some patients there was a worsening of symptoms on changing from pyridoxine to pyridoxal 5'-phosphate. Many of the mutations in PNPO affected residues involved in binding flavin mononucleotide or pyridoxal 5'-phosphate and many of them showed residual enzyme activity. One sequence change (R116Q), predicted to affect flavin mononucleotide binding and binding of the two PNPO dimers, and with high residual activity was found in Groups (ii) and (iii). This sequence change has been reported in the 1000 Genomes project suggesting it could be a polymorphism but alternatively it could be a common mutation, perhaps responsible for the susceptibility locus for genetic generalized epilepsy on 17q21.32 (close to rs72823592). We believe the reduction in PNPO activity and B6-responsive epilepsy in the patients reported here indicates that it contributes to the pathogenesis of epilepsy.

15 Article Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency). 2010

Mills, Philippa B / Footitt, Emma J / Mills, Kevin A / Tuschl, Karin / Aylett, Sarah / Varadkar, Sophia / Hemingway, Cheryl / Marlow, Neil / Rennie, Janet / Baxter, Peter / Dulac, Olivier / Nabbout, Rima / Craigen, William J / Schmitt, Bernhard / Feillet, François / Christensen, Ernst / De Lonlay, Pascale / Pike, Mike G / Hughes, M Imelda / Struys, Eduard A / Jakobs, Cornelis / Zuberi, Sameer M / Clayton, Peter T. ·Institute of Child Health, University College London with Great Ormond Street Hospital for Children, National Health Service Trust, London, UK. ·Brain · Pubmed #20554659.

ABSTRACT: Pyridoxine-dependent epilepsy was recently shown to be due to mutations in the ALDH7A1 gene, which encodes antiquitin, an enzyme that catalyses the nicotinamide adenine dinucleotide-dependent dehydrogenation of l-alpha-aminoadipic semialdehyde/L-Delta1-piperideine 6-carboxylate. However, whilst this is a highly treatable disorder, there is general uncertainty about when to consider this diagnosis and how to test for it. This study aimed to evaluate the use of measurement of urine L-alpha-aminoadipic semialdehyde/creatinine ratio and mutation analysis of ALDH7A1 (antiquitin) in investigation of patients with suspected or clinically proven pyridoxine-dependent epilepsy and to characterize further the phenotypic spectrum of antiquitin deficiency. Urinary L-alpha-aminoadipic semialdehyde concentration was determined by liquid chromatography tandem mass spectrometry. When this was above the normal range, DNA sequencing of the ALDH7A1 gene was performed. Clinicians were asked to complete questionnaires on clinical, biochemical, magnetic resonance imaging and electroencephalography features of patients. The clinical spectrum of antiquitin deficiency extended from ventriculomegaly detected on foetal ultrasound, through abnormal foetal movements and a multisystem neonatal disorder, to the onset of seizures and autistic features after the first year of life. Our relatively large series suggested that clinical diagnosis of pyridoxine dependent epilepsy can be challenging because: (i) there may be some response to antiepileptic drugs; (ii) in infants with multisystem pathology, the response to pyridoxine may not be instant and obvious; and (iii) structural brain abnormalities may co-exist and be considered sufficient cause of epilepsy, whereas the fits may be a consequence of antiquitin deficiency and are then responsive to pyridoxine. These findings support the use of biochemical and DNA tests for antiquitin deficiency and a clinical trial of pyridoxine in infants and children with epilepsy across a broad range of clinical scenarios.

16 Minor Misleading data in Shastin et al.'s paper. 2015

Verity, Christopher / Philip, Sunny / Martland, Timothy / Carter, Michael / Varadkar, Sophia / Harkness, William / Cross, Helen / Walsh, Richard. ·Addenbrooke's Hospital, Cambridge, UK, christopher.verity@addenbrookes.nhs.uk. ·Childs Nerv Syst · Pubmed #26058502.

ABSTRACT: -- No abstract --