RESUMEN
BACKGROUND: Routinely recorded data held in electronic health records can be used to inform the conduct of randomised controlled trials (RCTs). However, limitations with access and accuracy have been identified. OBJECTIVE: Using epilepsy as an exemplar condition, we assessed the attributes and agreement of routinely recorded data compared to data collected using case report forms in a UK RCT assessing antiepileptic drug treatments for individuals newly diagnosed with epilepsy. METHODS: The case study RCT is the Standard and New Antiepileptic Drugs II (SANAD II) trial, a pragmatic, UK multicentre RCT assessing the clinical and cost-effectiveness of antiepileptic drugs as treatments for epilepsy. Ninety-eight of 470 eligible participants provided consent for access to routinely recorded secondary care data that were retrieved from NHS Digital Hospital Episode Statistics (N=71) and primary and secondary care data from The Secure Anonymised Information Linkage Databank (N=27). We assessed data items relevant to the identification of individuals eligible for inclusion in SANAD II, baseline and follow-up visits. The attributes of routinely recorded data were assessed including the degree of missing data. The agreement between routinely recorded data and data collected on case report forms in SANAD II was assessed using calculation of Cohen's kappa for categorical data and construction of Bland-Altman plots for continuous data. RESULTS: There was a significant degree of missing data in the routine record for 15 of the 20 variables assessed, including all clinical variables. Agreement was poor for the majority of comparisons, including the assessments of seizure occurrence and adverse events. For example, only 23/62 (37%) participants had a date of first-ever seizure identified in routine datasets. Agreement was satisfactory for the date of prescription of antiepileptic drugs and episodes of healthcare resource use. CONCLUSIONS: There are currently significant limitations preventing the use of routinely recorded data for participant identification and assessment of clinical outcomes in epilepsy, and potentially other chronic conditions. Further research is urgently required to assess the attributes, agreement, additional benefits, cost-effectiveness and 'optimal mix' of routinely recorded data compared to data collected using standard methods such as case report forms at clinic visits for people with epilepsy. TRIAL REGISTRATION: Standard and New Antiepileptic Drugs II (SANAD II (EudraCT No: 2012-001884-64, registered 05/09/2012; ISRCTN Number: ISRCTN30294119 , registered 03/07/2012)).
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Anticonvulsivantes , Epilepsia , Anticonvulsivantes/efectos adversos , Registros Electrónicos de Salud , Epilepsia/diagnóstico , Epilepsia/tratamiento farmacológico , Humanos , Convulsiones/diagnóstico , Convulsiones/tratamiento farmacológico , Reino UnidoRESUMEN
BACKGROUND AND PURPOSE: Patients with chronic focal epilepsy may have atrophy of brain structures important for the generation and maintenance of seizures. However, little research has been conducted in patients with newly diagnosed focal epilepsy (NDfE), despite it being a crucial point in time for understanding the underlying biology of the disorder. We aimed to determine whether patients with NDfE show evidence of volumetric abnormalities of subcortical structures. METHODS: Eighty-two patients with NDfE and 40 healthy controls underwent magnetic resonance imaging scanning using a standard clinical protocol. Volume estimation of the left and right hippocampus, thalamus, caudate nucleus, putamen and cerebral hemisphere was performed for all participants and normalised to whole brain volume. Volumes lower than two standard deviations below the control mean were considered abnormal. Volumes were analysed with respect to patient clinical characteristics, including treatment outcome 12 months after diagnosis. RESULTS: Volume of the left hippocampus (p(FDR-corr) = 0.04) and left (p(FDR-corr) = 0.002) and right (p(FDR-corr) = 0.04) thalamus was significantly smaller in patients relative to controls. Relative to the normal volume limits in controls, 11% patients had left hippocampal atrophy, 17% had left thalamic atrophy and 9% had right thalamic atrophy. We did not find evidence of a relationship between volumes and future seizure control or with other clinical characteristics of epilepsy. CONCLUSIONS: Volumetric abnormalities of structures known to be important for the generation and maintenance of focal seizures are established at the time of epilepsy diagnosis and are not necessarily a result of the chronicity of the disorder.
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Epilepsias Parciales , Epilepsia del Lóbulo Temporal , Atrofia/patología , Encéfalo/patología , Epilepsias Parciales/complicaciones , Epilepsias Parciales/diagnóstico por imagen , Epilepsia del Lóbulo Temporal/patología , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Humanos , Imagen por Resonancia Magnética , Tálamo/diagnóstico por imagen , Tálamo/patologíaRESUMEN
AIM: To evaluate whether a dedicated epilepsy research protocol with expert image re-evaluation can increase identification of patients with lesions and to attempt to ascertain the potential reasons why lesions were not identified previously on earlier clinical magnetic resonance imaging (MRI). MATERIALS AND METHODS: Forty-three patients (26 female) with focal refractory epilepsy who had failed at least two trials of anti-epileptic drug treatments were studied. Patients were recruited prospectively into the study if previous clinical MRI was deemed to be "non-lesional" by the clinicians involved in the initial assessment. Three-dimensional (3D) T1-weighted (T1W), T2-weighted (T2W), T2 fluid-attenuated inversion recovery (T2-FLAIR) sequences, and two-dimensional (2D) coronal T1-/T2W FLAIR were assessed by a neuroradiologist, including the previous clinical MRI of individual patients. RESULTS: Twenty-nine or 43 (67%) patients remained MRI-negative after scanning with the epilepsy-dedicated protocol and image reappraisal by expert consultant neuroradiologists; however, 14/43 (33%) patients were found to have potentially epileptogenic brain lesions. The lesion that most frequently escaped the attention of clinicians was hippocampal sclerosis (nine cases, of which two had an additional focal cortical dysplasia, FCD), followed by single FCDs (two cases), and others including gliosis, encephalocoele, and amygdala enlargement (one case each). Eleven of the 14 (79%) previously "non-lesional" patients had electroencephalogram (EEG) imaging-concordant localisation features, rendering them potential candidates for resective surgery. CONCLUSIONS: The primary factors explaining the newly identified lesions were the choice of MRI sequences, imaging parameters, data quality, lesion not reported (human factor), and loss of information through incomplete documentation. It is important for all clinicians to proceed meticulously in the detailed assessment of epilepsy-dedicated in-vivo MRI and discuss difficult patient cases in multidisciplinary team meetings.
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Encéfalo/diagnóstico por imagen , Epilepsia Refractaria/diagnóstico por imagen , Epilepsias Parciales/diagnóstico por imagen , Neuroimagen , Adolescente , Adulto , Amígdala del Cerebelo/diagnóstico por imagen , Amígdala del Cerebelo/patología , Encéfalo/patología , Protocolos Clínicos , Epilepsia Refractaria/patología , Electroencefalografía , Epilepsias Parciales/patología , Femenino , Gliosis/diagnóstico por imagen , Gliosis/patología , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis/diagnóstico por imagen , Esclerosis/patología , Adulto JovenRESUMEN
BACKGROUND: In the UK, routinely recorded data may benefit prospective studies including randomised controlled trials (RCTs). In an on-going study, we aim to assess the feasibility of access and agreement of routinely recorded clinical and non-clinical data compared to data collected during a RCT using standard prospective methods. This paper will summarise available UK routinely recorded data sources and discuss our experience with the feasibility of accessing routinely recorded data for participants of a RCT before finally proposing recommendations for improving the access and implementation of routinely recorded data in RCTs. METHODS: Setting: the case study RCT is the Standard and New Antiepileptic Drugs II (SANAD II) trial, a pragmatic, UK, multicentre, phase IV RCT assessing the clinical and cost-effectiveness of antiepileptic drug treatments for newly diagnosed epilepsy. PARTICIPANTS: 98 participants have provided written consent to permit the request of routinely recorded data. Study procedures: routinely recorded clinical and non-clinical data were identified and data requested through formal applications from available data holders for the duration that participants have been recruited into SANAD II. The feasibility of accessing routinely recorded data during a RCT is assessed and recommendations for improving access proposed. RESULTS: Secondary-care clinical and socioeconomic data is recorded on a national basis and can be accessed, although there are limitations in the application process. Primary-care data are recorded by a number of organisations on a de-identified basis but access for specific individuals has not been feasible. Access to data recorded by non-clinical sources, including The Department for Work and Pensions and The Driving and Vehicle Licensing Agency, was not successful. CONCLUSIONS: Recommendations discussed include further research to assess the attributes of routinely recorded data, an assessment of public perceptions and the development of strategies to collaboratively improve access to routinely recorded data for research. TRIAL REGISTRATION: International Standard Randomised Controlled Trials, ISRCTN30294119 . Registered on 3 July 2012. EudraCT No: 2012-001884-64. Registered on 9 May 2012.
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Acceso a la Información , Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Proyectos de Investigación , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/economía , Ensayos Clínicos Fase IV como Asunto/métodos , Análisis Costo-Beneficio , Minería de Datos , Bases de Datos Factuales , Costos de los Medicamentos , Registros Electrónicos de Salud , Determinación de Punto Final , Epilepsia/diagnóstico , Epilepsia/economía , Estudios de Factibilidad , Humanos , Estudios Multicéntricos como Asunto/métodos , Ensayos Clínicos Pragmáticos como Asunto/métodos , Resultado del Tratamiento , Reino UnidoRESUMEN
OBJECTIVES: A breakthrough seizure is one occurring after at least 12 months seizure freedom while on treatment. The Driver and Vehicle Licensing Agency (DVLA) allows an individual to return to driving once they have been seizure free for 12 months following a breakthrough seizure. This is based on the assumption that the risk of a further seizure in the next 12 months has dropped <20%. This analysis considers whether the prescribed 1 year off driving following a breakthrough seizure is sufficient for this and stratifies risk according to clinical characteristics. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS AND MAIN OUTCOME MEASURES: The multicentre UK-based Standard versus New Antiepileptic Drugs (SANAD) study was a randomised controlled trial assessing standard and new antiepileptic drugs for patients with newly diagnosed epilepsy. For participants aged at least 16 with a breakthrough seizure, data have been analysed to estimate the annual seizure recurrence risk following a period of 6, 9 and 12 months seizure freedom. Regression modelling was used to investigate how antiepileptic drug treatment and a number of clinical factors influence the risk of seizure recurrence. RESULTS: At 12 months following a breakthrough seizure, the overall unadjusted risk of a recurrence over the next 12 months is lower than 20%, risk 17% (95% CI 15% to 19%). However, some patient subgroups have been identified which have an annual recurrence risk significantly greater than 20% after an initial 12-month seizure-free period following a breakthrough seizure. CONCLUSIONS: This reanalysis of SANAD provides estimates of seizure recurrence risks following a breakthrough seizure that will inform policy and guidance about regaining an ordinary driving licence. Further guidance is needed as to how such data should be used. TRIAL REGISTRATION NUMBER: SANAD is registered with the International Standard Randomised Controlled Trial Number Register ISRCTN38354748.
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Anticonvulsivantes/uso terapéutico , Conducción de Automóvil , Epilepsia/complicaciones , Epilepsia/tratamiento farmacológico , Convulsiones/epidemiología , Adulto , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Recurrencia , Inducción de Remisión , Medición de Riesgo , Factores de Tiempo , Reino Unido , Adulto JovenRESUMEN
Between 2009 and 2012 there were 26 epilepsy-related deaths in the UK of women who were pregnant or in the first post-partum year. The number of pregnancy-related deaths in women with epilepsy (WWE) has been increasing. Expert assessment suggests that most epilepsy-related deaths in pregnancy were preventable and attributable to poor seizure control. While prevention of seizures during pregnancy is important, a balance must be struck between seizure control and the teratogenic potential of antiepileptic drugs (AEDs). A range of professional guidance on the management of epilepsy in pregnancy has previously been issued, but little attention has been paid to how optimal care can be delivered to WWE by a range of healthcare professionals. We summarise the findings of a multidisciplinary meeting with representation from a wide group of professional bodies. This focussed on the implementation of optimal pregnancy epilepsy care aiming to reduce mortality of epilepsy in mothers and reduce morbidity in babies exposed to AEDs in utero. We identify in particular -What stage to intervene - Golden Moments of opportunities for improving outcomes -Which Key Groups have a role in making change -When - 2020 vision of what these improvements aim to achieve. -How to monitor the success in this field We believe that the service improvement ideas developed for the UK may provide a template for similar initiatives in other countries.
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Epilepsia/complicaciones , Complicaciones del Embarazo/terapia , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Epilepsia/mortalidad , Femenino , Humanos , Embarazo , Complicaciones del Embarazo/tratamiento farmacológico , Complicaciones del Embarazo/mortalidad , Mejoramiento de la Calidad , Reino UnidoRESUMEN
PURPOSE: Epilepsy is the third most common diagnosis in older people, however management in this group remains variable. National Audit of Seizure management in Hospitals (NASH) set out to assess care provided to patients attending hospitals in England following a seizure. METHOD: 154 Emergency Departments (EDs) across the UK took part. 1256 patients aged 60 years or over were included for analysis (median age 74 years, 54% men). 51% were known to have epilepsy, 17% had history of previous seizure or blackout and 32% presented with a suspected first seizure. RESULTS: 14% of older patients with epilepsy were not on treatment, 59% were on monotherapy. Sodium valproate was the most commonly used antiepileptic, 28%. 35% of patients with epilepsy, aged 60 and over, had a CT during admission compared to only 17% of those under 60. 80% of patients aged 60 and over presenting with a likely first seizure were admitted to hospital, compared to 65% of those under 60. 34% of those with suspected first seizure were referred to a neurologist on discharge compared to 68% of patients under the age of 60. 52% of 60-69year olds with a suspected first seizure were referred to neurology compared to 25% of patients aged 80-89. CONCLUSIONS: Older patients presenting with seizures are more likely to be admitted to hospital and have imaging. They are less likely to be referred to specialist services on discharge. There appears to be significant disparity in patient age and rate of referral.
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Epilepsia/terapia , Convulsiones/terapia , Factores de Edad , Anciano , Anciano de 80 o más Años , Anticonvulsivantes/uso terapéutico , Servicio de Urgencia en Hospital/estadística & datos numéricos , Inglaterra , Epilepsia/diagnóstico por imagen , Epilepsia/tratamiento farmacológico , Femenino , Disparidades en Atención de Salud , Hospitalización/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Neuroimagen/estadística & datos numéricos , Convulsiones/diagnóstico por imagen , Convulsiones/tratamiento farmacológicoRESUMEN
The International League Against Epilepsy (ILAE) is an important source of guidance for health professionals when it comes to epilepsy. Their latest recommendation that epilepsy should no longer be called a "disorder," but a "disease" has though caused controversy. The ILAE contends the change will improve epilepsy's image. Some clinicians and other organizations fear the change may not though be accepted by patients as in common parlance "disease" can be associated with "contagiousness"/"infection." To allow practicing clinicians to make informed judgements about what language they use, we completed the first study to assess the preferences of those with epilepsy and significant others and explore if any of their characteristics were associated with preference. Via epilepsy interest groups and associations in England, Wales, Scotland and the Republic of Ireland, 971 patients and significant others were surveyed. Participants identified which of four labels for epilepsy ("disorder," "illness," "disease," "condition") they favoured and rated each using a Likert-scale. Patients' median age was 39; 69% had experienced seizures in the prior year. "Condition" was favoured by most patients (74.3%) and significant others (71.2%). Only 2.2% of patients and 1.2% of significant others chose "disease"; it received a median Likert-rating indicating "strongly dislike." Multinomial logistic regression found it was not possible to reliably distinguish between participants favouring the different terms on the basis of demographics. The ILAE's position is at odds with what most patients and carers want and we discuss the implications of this.
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Actitud , Epilepsia/psicología , Terminología como Asunto , Adulto , Anciano , Anciano de 80 o más Años , Epilepsia/clasificación , Epilepsia/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Encuestas y Cuestionarios , Reino UnidoRESUMEN
OBJECTIVES: Meningiomas are common intracranial tumors, and despite surgery or therapy with anti-epileptic drugs (AEDs), many patients suffer from seizures. Epilepsy has a significant impact on quality of life (QoL) in non-tumor populations, but the impact of epilepsy on QoL in patients with meningioma is unknown. Our aim was to evaluate the impact of epilepsy on QoL in patients that have undergone resection of a benign meningioma. MATERIALS AND METHODS: We recruited meningioma patients without epilepsy (n=109), meningioma patients with epilepsy (n=56), and epilepsy patients without meningioma (n=64). QoL was measured with the Short Form 36 version 2 (SF-36), the Functional Assessment of Cancer Therapy (FACT-BR), and the Liverpool Adverse Events Profile (LAEP). Regression analyses identified significant determinants of QoL. RESULTS: Patients with meningioma and epilepsy had poorer QoL scores than meningioma patients without epilepsy in all measures. In FACT-BR, this difference was significant. Multiple regression analyses demonstrated that current AED use had a greater impact on QoL scores than recent seizures. Other variables associated with impaired QoL included depression, unemployment, and meningioma attributed symptoms. CONCLUSIONS: Epilepsy has a negative impact on quality of life in patients with benign meningioma. AED use is correlated with impaired QoL and raised LAEP scores, suggesting that AEDs and adverse effects may have led to impaired QoL in our meningioma patients with epilepsy. The severity of epilepsy in our meningioma population was comparatively mild; therefore, a more conservative approach to AED therapy may be indicated in an attempt to minimize adverse effects.
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Epilepsia/epidemiología , Neoplasias Meníngeas/cirugía , Meningioma/cirugía , Procedimientos Neuroquirúrgicos/efectos adversos , Complicaciones Posoperatorias/epidemiología , Calidad de Vida , Adulto , Depresión/epidemiología , Depresión/etiología , Epilepsia/complicaciones , Epilepsia/etiología , Femenino , Humanos , Masculino , Neoplasias Meníngeas/complicaciones , Meningioma/complicaciones , Persona de Mediana EdadRESUMEN
Feelings of stigma are one of the main burdens reported by people with epilepsy (PWE). Adults with temporal or frontal lobe epilepsy and children with idiopathic generalised epilepsy are at risk of Theory of Mind (ToM) deficits. ToM refers to social cognitive skills, including the ability to understand the thoughts, intentions, beliefs, and emotions of others. It has been proffered that ToM deficits may contribute to the feelings of stigma experienced by PWE. In this study we tested this for the first time. We also determined the association between clinical and demographic factors and ToM performance. Five hundred and three PWE were recruited via epilepsy organisations and completed measures online. Feelings of stigma were measured using Jacoby's Stigma Scale, whilst the Reading the Mind in the Eyes Test and the Faux Pas Test measured ToM. The median age of participants was 37 years, their median years living with epilepsy were 15, and 70% had experienced seizures in the prior 12 months. Feelings of stigma held a negligible, negative, and nonsignificant association with ToM performance (r s -0.02 and -0.05). Our results indicate that the ToM model for understanding epilepsy stigma has limited utility and alternative approaches to understanding and addressing epilepsy-related stigma are required.
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Epilepsia/psicología , Estereotipo , Adulto , Anciano , Cognición/fisiología , Comprensión , Emociones , Epilepsia/terapia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Proyectos Piloto , Teoría de la MenteRESUMEN
OBJECTIVE: So that informed treatment decisions can be made, clinical trials need to evaluate treatments against domains that are important to people with epilepsy (PWE), their carers, and clinicians. Health professionals have identified domains of importance to them via the International League Against Epilepsy's Commission on Outcome Measurement (COME). However, patients and carers have not been systematically asked. METHODS: Via the membership of the British Epilepsy Association, we recruited and surveyed 352 PWE and 263 of their informal carers. They were presented with 10 outcome domains (including the 5 identified by COME) and asked to rate their importance using a 9-point Likert scale. They were also asked to identify any additional domains of importance. RESULTS: The patients' mean age was 49years, the median number of years since diagnosis was 20, and 65% had experienced seizures in the prior 12months. Most carers were the spouse or parent. Patients' and carers' mean ratings indicated that their outcome priorities were similar, as were those of patients who had and had not experienced recent seizures. There was consensus among patients that 6 domains were of critical importance. These included the 5 identified by COME (namely, and in order of importance, the effects of the treatment on "Seizure severity", "Seizure frequency", "Quality of life", "Cognitive function", and "Adverse events"), as well as one additional domain ("Independence/need for support"). There was consensus among carers that the 5 COME domains were also critically important. They, however, identified 3 further domains as critically important. These were the effects of the treatment on patient "Depression", "Anxiety", and "Independence/need for support". CONCLUSIONS: Our study found some overlap between the priorities of PWE, carers, and health professionals. They, however, highlight additional areas of importance to patients and carers. Our results could inform a core outcome set for epilepsy that represents the domains that should be reported as a minimum by all trials. This could promote trials which produce meaningful results and consistency in measurement and reporting.
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Cuidadores/psicología , Ensayos Clínicos como Asunto/métodos , Epilepsia/psicología , Evaluación de Resultado en la Atención de Salud/métodos , Encuestas y Cuestionarios , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Epilepsia/diagnóstico , Epilepsia/terapia , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Calidad de Vida/psicología , Adulto JovenRESUMEN
INTRODUCTION: People with chronic epilepsy (PWE) often make costly but clinically unnecessary emergency department (ED) visits. Offering them and their carers a self-management intervention that improves confidence and ability to manage seizures may lead to fewer visits. As no such intervention currently exists, we describe a project to develop and pilot one. METHODS AND ANALYSIS: To develop the intervention, an existing group-based seizure management course that has been offered by the Epilepsy Society within the voluntary sector to a broader audience will be adapted. Feedback from PWE, carers and representatives from the main groups caring for PWE will help refine the course so that it addresses the needs of ED attendees. Its behaviour change potential will also be optimised. A pilot randomised controlled trial will then be completed. 80 PWE aged ≥16 who have visited the ED in the prior 12â months on ≥2 occasions, along with one of their family members or friends, will be recruited from three NHS EDs. Dyads will be randomised to receive the intervention or treatment as usual alone. The proposed primary outcome is ED use in the 12â months following randomisation. For the pilot, this will be measured using routine hospital data. Secondary outcomes will be measured by patients and carers completing questionnaires 3, 6 and 12â months postrandomisation. Rates of recruitment, retention and unblinding will be calculated, along with the ED event rate in the control group and an estimate of the intervention's effect on the outcome measures. ETHICS AND DISSEMINATION: Ethical approval: NRES Committee North West-Liverpool East (Reference number 15/NW/0225). The project's findings will provide robust evidence on the acceptability of seizure management training and on the optimal design of a future definitive trial. The findings will be published in peer-reviewed journals and presented at conferences. TRIAL REGISTRATION NUMBER: ISRCTN13â 871â 327.
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Servicio de Urgencia en Hospital/estadística & datos numéricos , Primeros Auxilios , Educación del Paciente como Asunto , Convulsiones/terapia , Autocuidado , Epilepsia/complicaciones , Conocimientos, Actitudes y Práctica en Salud , Humanos , Proyectos Piloto , Proyectos de Investigación , Convulsiones/etiología , Autoeficacia , Método Simple Ciego , Encuestas y CuestionariosRESUMEN
Epilepsy affects 50 million persons worldwide, a third of whom continue to experience debilitating seizures despite optimum anti-epileptic drug (AED) treatment. Twelve-month remission from seizures is less likely in female patients, individuals aged 11-36 years and those with neurological insults and shorter time between first seizure and starting treatment. It has been found that the presence of multiple seizures prior to diagnosis is a risk factor for pharmacoresistance and is correlated with epilepsy type as well as intrinsic severity. The key role of neuroinflammation in the pathophysiology of resistant epilepsy is becoming clear. Our work in this area suggests that high-mobility group box 1 isoforms may be candidate biomarkers for treatment stratification and novel drug targets in epilepsy. Furthermore, transporter polymorphisms contributing to the intrinsic severity of epilepsy are providing robust neurobiological evidence on an emerging theory of drug resistance, which may also provide new insights into disease stratification. Some of the rare genetic epilepsies enable treatment stratification through testing for the causal mutation, for example SCN1A mutations in patients with Dravet's syndrome. Up to 50% of patients develop adverse reactions to AEDs which in turn affects tolerability and compliance. Immune-mediated hypersensitivity reactions to AED therapy, such as toxic epidermal necrolysis, are the most serious adverse reactions and have been associated with polymorphisms in the human leucocyte antigen (HLA) complex. Pharmacogenetic screening for HLA-B*15:02 in Asian populations can prevent carbamazepine-induced Stevens-Johnson syndrome. We have identified HLA-A*31:01 as a potential risk marker for all phenotypes of carbamazepine-induced hypersensitivity with applicability in European and other populations. In this review, we explore the currently available key stratification approaches to address the therapeutic challenges in epilepsy.
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Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Mutación , Canal de Sodio Activado por Voltaje NAV1.1/genética , Polimorfismo Genético , Medicina de Precisión , Algoritmos , Resistencia a Medicamentos/genética , Epilepsia/epidemiología , Marcadores Genéticos/genética , Salud Global , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Humanos , Fenotipo , Factores de Riesgo , Síndrome de Stevens-Johnson/prevención & control , Resultado del TratamientoRESUMEN
At the blood-brain barrier, overexpression of the drug efflux transporter ABCC2 (also known as MRP2) has been proposed as a mechanism for impaired carbamazepine (CBZ) treatment response in epilepsy. However, investigation of the impact of ABCC2 polymorphisms on CBZ treatment efficacy has produced conflicting and inconclusive results. A series of in vitro cell efflux and plasma membrane vesicle uptake assays were undertaken to investigate whether CBZ was an ABCC2 substrate. In addition, the effect of three common ABCC2 polymorphisms, -24C>T, c.1249G>A and c.3972C>T, on the efficacy of CBZ in epilepsy (assessed using the clinical end points time to first seizure and time to 12-month remission from the SANAD (Standard and New Antiepileptic Drugs) trial) was determined. CBZ was found not to be a substrate for human ABCC2 in vitro. Clinically, no significant association was observed for the ABCC2 genetic variants and CBZ treatment outcomes. This comprehensive analysis does not support a role for ABCC2 in CBZ treatment efficacy.
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Carbamazepina/uso terapéutico , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Adulto , Femenino , Humanos , Masculino , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Polimorfismo Genético/genética , Células Tumorales CultivadasRESUMEN
Carbamazepine (CBZ) therapy is associated with cutaneous adverse reactions in up to 10% of patients. Predisposition to these hypersensitivity reactions has been linked to the human leukocyte antigen (HLA) genotype. This systematic review determines the strength of these associations and accuracy of proposed genetic screening. We determined that carriage of HLA-B*1502 in Asian patients was associated with a pooled odds ratio (OR) of 113.4 (95% confidence interval (CI) = 51.2-251.0, P < 1 × 10(-5)) for CBZ-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). A total of 461 patients would need to be screened for HLA-B*1502 to prevent one episode of SJS/TEN. HLA-A*3101 is significantly associated with all phenotypes of CBZ hypersensitivity in multiple ethnicities with a pooled OR of 9.5 (95% CI = 6.4-13.9, P < 1 × 10(-5)). Between 47 and 67 patients would need to be tested for HLA-A*3101 to prevent one episode of hypersensitivity. Our findings suggest that HLA testing before carbamazepine therapy would be effective at identifying individuals at risk of hypersensitivity and applicable to multiple populations providing hope for prevention in the future.
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Anticonvulsivantes/efectos adversos , Carbamazepina/efectos adversos , Erupciones por Medicamentos/genética , Antígenos HLA/genética , Alelos , Pueblo Asiatico , Estudios de Casos y Controles , Intervalos de Confianza , Hipersensibilidad a las Drogas/genética , Genotipo , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Humanos , Oportunidad Relativa , Valor Predictivo de las PruebasRESUMEN
OBJECTIVE: Adverse effects (AEs) are a major concern when starting antiepileptic drug (AED) treatment. This study quantified the extent to which AE reporting in people with new-onset seizures started on AEDs is attributable to the medication per se, and investigated variables contributing to AE reporting. METHODS: We pooled data from 2 large prospective studies, the Multicenter Study of Early Epilepsy and Single Seizures and the Northern Manhattan Study of incident unprovoked seizures, and compared adverse event profile (AEP) total and factor scores between adult cases prescribed AEDs for new-onset seizures and untreated controls, adjusting for several demographic and clinical variables. Differences in AEP scores were also tested across different AED monotherapies and controls, and between cases and controls grouped by number of seizures. RESULTS: A total of 212 cases and 206 controls were identified. Most cases (94.2%) were taking low AED doses. AEP scores did not differ significantly between the 2 groups. Depression, female gender, symptomatic etiology, younger seizure onset age, ≥2 seizures, and history of febrile seizures were associated with higher AEP scores. There were no significant differences in AEP scores across different monotherapies and controls. AEP scores increased in both cases and controls with increasing number of seizures, the increment being more pronounced in cases. CONCLUSIONS: When AED treatment is started at low doses following new-onset seizures, AE reporting does not differ from untreated individuals. Targeting specific factors affecting AE reporting could lead to improved tolerability of epilepsy treatment.
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Anticonvulsivantes/efectos adversos , Convulsiones/inducido químicamente , Convulsiones/fisiopatología , Adolescente , Adulto , Análisis de Varianza , Anticonvulsivantes/administración & dosificación , Estudios de Casos y Controles , Cognición/efectos de los fármacos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Destreza Motora/efectos de los fármacos , Estudios Multicéntricos como Asunto , Estudios Prospectivos , Convulsiones/tratamiento farmacológico , Sueño/efectos de los fármacos , Adulto JovenRESUMEN
OBJECTIVE: To determine for how long after a first unprovoked seizure a driver must be seizure-free before the risk of recurrence in the next 12 months falls below 20%, enabling them to regain their driving licence. DESIGN: Randomised controlled trial: Multicentre study of early Epilepsy and Single Seizures (MESS). SETTING: UK hospital outpatient clinics from 1 January 1993 to 31 December 2000. PARTICIPANTS: People entered MESS if they had had one or more unprovoked seizures and both the participant and the clinician were uncertain about the need to start antiepileptic drug treatment. The subset of people used for this analysis comprised participants aged at least 16 years with a single unprovoked seizure. MAIN OUTCOME MEASURE: Risk of seizure recurrence in the 12 months after a seizure-free period of 6, 12, 18, or 24 months from the date of the first (index) seizure. Regression modelling was used to investigate how antiepileptic treatment and several clinical factors influence the risk of seizure recurrence. RESULTS: At six months after the index seizure the risk of recurrence in the next 12 months for those who start antiepileptic drugs was significantly below 20% (unadjusted risk 14%, 95% confidence interval 10% to 18%). For patients who did not start treatment the risk estimate was less than 20% but the upper limit of the confidence interval was greater than 20% (18%, 13% to 23%). Multivariable analyses identified subgroups with a significantly greater than 20% risk of seizure recurrence in the 12 months after a six month seizure-free period, such as those with a remote symptomatic seizure with abnormal electroencephalogram results. CONCLUSION: After a single unprovoked seizure this reanalysis of MESS provides estimates of seizure recurrence risks that will inform policy and guidance about regaining an ordinary driving licence. Further guidance is needed as to how such data should be utilised; in particular, whether a population approach should be taken with a focus on the unadjusted results or whether attempts should be made to individualise risk. Guidance is also required as to whether the focus should be on risk estimates only or on the confidence interval as well. If the focus is on the estimate only our unadjusted estimates suggest that treated and untreated patients are eligible to drive after being seizure-free for six months. If the focus is also on confidence intervals, direction is needed as to whether a conservative or liberal approach should be taken. TRIAL REGISTRATION: Current Controlled Trials ISRCTN98767960.
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Anticonvulsivantes/uso terapéutico , Conducción de Automóvil/legislación & jurisprudencia , Convulsiones/tratamiento farmacológico , Adulto , Humanos , Concesión de Licencias , Persona de Mediana Edad , Análisis Multivariante , Recurrencia , Factores de Riesgo , Convulsiones/epidemiología , Factores de Tiempo , Reino Unido/epidemiología , Adulto JovenRESUMEN
We present a model for meta-regression in the presence of missing information on some of the study level covariates, obtaining inferences using Bayesian methods. In practice, when confronted with missing covariate data in a meta-regression, it is common to carry out a complete case or available case analysis. We propose to use the full observed data, modelling the joint density as a factorization of a meta-regression model and a conditional factorization of the density for the covariates. With the inclusion of several covariates, inter-relations between these covariates are modelled. Under this joint likelihood-based approach, it is shown that the lesser assumption of the covariates being Missing At Random is imposed, instead of the more usual Missing Completely At Random (MCAR) assumption. The model is easily programmable in WinBUGS, and we examine, through the analysis of two real data sets, sensitivity and robustness of results to the MCAR assumption.
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Metaanálisis como Asunto , Modelos Estadísticos , Análisis de Regresión , Anticonvulsivantes/farmacología , Teorema de Bayes , Bioestadística , Ensayos Clínicos como Asunto/estadística & datos numéricos , Humanos , Funciones de Verosimilitud , Análisis Multivariante , Vigabatrin/farmacologíaRESUMEN
BACKGROUND: Epilepsy has a pervasive impact on the lives of people with intellectual disability and their carers. The delivery of high-quality care is impacted on by the complexity and diversity of epilepsy in this population. This article presents the results of a consensus clinical guideline process. RESULTS: A Delphi process identified a list of priority areas for the development of evidence-based guidelines. All guidelines were graded and consensus on scoring was achieved across the guideline group. CONCLUSION: There is a dearth of high-quality evidence from well-constructed studies on which to base guidance. However, the development of internationally derived consensus guidelines may further support the management of epilepsy in adults with an intellectual disability.
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Anticonvulsivantes/uso terapéutico , Consenso , Epilepsia/epidemiología , Epilepsia/terapia , Guías como Asunto , Discapacidad Intelectual/epidemiología , Adulto , Anticonvulsivantes/efectos adversos , Cuidadores , Comorbilidad , Técnica Delphi , Diagnóstico Diferencial , Interacciones Farmacológicas , Quimioterapia Combinada , Epilepsia/diagnóstico , Estado de Salud , Humanos , Trastornos Mentales/epidemiologíaRESUMEN
PURPOSE OF REVIEW: This review discusses the interpretation of regulatory randomized controlled trials of antiepileptic drugs. An ever increasing number of drugs have been licensed, more so for add-on treatment than for monotherapy. Regulatory trials constitute the main body of evidence to inform clinical decisions about their use. Designs of regulatory trials for monotherapy are the most controversial as regulators take different views as to the type of designs that are required, which has implications for interpretation and for the risks to which patients are exposed. FINDINGS: From the perspective of the regulator, the interpretation of placebo controlled add-on trials is straightforward as they have the capacity to show efficacy compared with placebo. These designs do not, however, inform clinical decisions where a choice among drugs is required. For monotherapy the European Medicines Agency will accept head-to-head trials designed to show noninferiority for licensing. The Food and Drug Administration in the USA will not, and requires trials that show superiority. The resulting 'pseudoplacebo' trials expose patients allocated to pseudoplacebo to risks that may be unacceptable. SUMMARY: Regulatory trials continue to have major limitations for informing clinical decisions and this should be addressed.