Commentary: It's time to talk about SUDEP

Sudden unexpected death in epilepsy (SUDEP) is the most tragic potential outcome of epilepsy. Despite recommendations from epilepsy organizations in the United Kingdom and the United States, many neurologists choose not to discuss the risk of SUDEP with their patients with epilepsy. Yet, the literature clearly demonstrates that people with epilepsy and their caregivers want to know more about SUDEP. When health care providers do not provide information, people with epilepsy turn to other sources, risking misinformation and potentially increasing anxiety and distress. Sharing accurate information about SUDEP can optimize epilepsy self‐management and engage the person with epilepsy as a partner in their own care. Information about SUDEP must be part of the comprehensive education given to all people with epilepsy.     

SUDEP and epilepsy‐related mortality in pregnancy

Although data are limited, research in 2004 estimated a 10‐fold increase in mortality in pregnancy in the United Kingdom in women with epilepsy (WWE) compared to women without epilepsy. We highlight epilepsy mortality in pregnancy based on the 2011 report of the United Kingdom Confidential Enquiries into Maternal Deaths, relating its findings to previous reports and epilepsy‐rates in pregnancy. Among 2,291,493 maternities (2006–2008), we estimated 0.6% or 13,978 were in WWE. Fourteen deaths were epilepsy‐related, of which 11 (79%) were sudden and unexpected (SUDEP). Nine occurred during pregnancy and five were postpartum. Nine (64%) were in women taking lamotrigine, seven as monotherapy. We estimated that 1:1,000 women died from epilepsy (mostly SUDEP) during or shortly after pregnancy. Epilepsy‐related mortality is a significant risk in pregnancy. Antiepileptic drug–related factors may be relevant. The high proportion of women taking lamotrigine may reflect United Kingdom prescribing practice. Recent observations from the European and International Registry of Antiepileptic Drugs and Pregnancy (EURAP), whereby women on lamotrigine, the levels of which significantly decrease in pregnancy, had more difficulties with epilepsy control, argue against this being the sole explanation. Given the potential risks, every attempt should be made to prevent seizures, particularly convulsive, during pregnancy and postpartum. This, we believe, includes being proactive in maintaining lamotrigine levels during pregnancy. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .     

Guidelines for the use of EEG methodology in the diagnosis of epilepsy. International League Against Epilepsy: commission report. Commission on European Affairs: Subcommission on European Guidelines

The Commission of European Affairs of the International League Against Epilepsy published 'Appropriate Standards for Epilepsy Care Across Europe' which contained recommendations for the use of electroencephalography (EEG) in the diagnosis of epilepsy (Brodie et al. Epilepsia 1997; 38:1245). The need for a more specific basic document of EEG methodology was recognized and the Subcommission on European Affairs was asked to produce more detailed guidelines to be used across Europe recognizing the range of practices in EEG laboratories. There are many general guidelines published on EEG methodology but this document focuses on the diagnosis of epilepsy. Details from previously published guidelines are included in references and in an appendix. These guidelines are not meant to be used as minimal standards but recommendations that can be applied to all EEG laboratories despite variations in equipment.     

Proposed criteria for referral and evaluation of children for epilepsy surgery: recommendations of the Subcommission for Pediatric Epilepsy Surgery

The Commission on Neurosurgery of the International League Against Epilepsy (ILAE) formed the Pediatric Epilepsy Surgery Subcommission in 1998 and charged it with formulating guidelines and recommendations for epilepsy surgery in childhood. Also endorsed by the Commission on Paediatrics, the following document is the consensus agreement after a meeting of 32 individuals from 12 countries in 2003. The panel agreed that insufficient class 1 evidence exists to recommend practice guidelines at this time. Instead, the panel generated criteria concerning the unique features of pediatric epilepsy patients to justify dedicated resources for specialty pediatric surgical centers, suggested guidelines for physicians for when to refer children with refractory epilepsy, and recommendations on presurgical evaluation and postoperative assessments. The panel also outlined areas of agreement and disagreement on which future research and consensus meetings should focus attention to generate practice guidelines and criteria for pediatric epilepsy surgery centers.     

ILAE Official Report: A practical clinical definition of epilepsy

Epilepsy was defined conceptually in 2005 as a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. This definition is usually practically applied as having two unprovoked seizures >24 h apart. The International League Against Epilepsy (ILAE) accepted recommendations of a task force altering the practical definition for special circumstances that do not meet the two unprovoked seizures criteria. The task force proposed that epilepsy be considered to be a disease of the brain defined by any of the following conditions: (1) At least two unprovoked (or reflex) seizures occurring >24 h apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome. Epilepsy is considered to be resolved for individuals who either had an age‐dependent epilepsy syndrome but are now past the applicable age or who have remained seizure‐free for the last 10 years and off antiseizure medicines for at least the last 5 years. “Resolved” is not necessarily identical to the conventional view of “remission or “cure.” Different practical definitions may be formed and used for various specific purposes. This revised definition of epilepsy brings the term in concordance with common use. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .     

Review: The past,present and future challenges in epilepsy‐related and sudden deaths and biobanking

Awareness and research on epilepsy‐related deaths (ERD), in particular Sudden Unexpected Death in Epilepsy (SUDEP), have exponentially increased over the last two decades. Most publications have focused on guidelines that inform clinicians dealing with these deaths, educating patients, potential risk factors and mechanisms. There is a relative paucity of information available for pathologists who conduct these autopsies regarding appropriate post mortem practice and investigations. As we move from recognizing SUDEP as the most common form of ERD toward in‐depth investigations into its causes and prevention, health professionals involved with these autopsies and post mortem procedure must remain fully informed. Systematizing a more comprehensive and consistent practice of examining these cases will facilitate (i) more precise determination of cause of death, (ii) identification of SUDEP for improved epidemiological surveillance (the first step for an intervention study), and (iii) biobanking and cell‐based research. This article reviews how pathologists and healthcare professionals have approached ERD, current practices, logistical problems and areas to improve and harmonize. The main neuropathology, cardiac and genetic findings in SUDEP are outlined, providing a framework for best practices, integration of clinical, pathological and molecular genetic investigations in SUDEP, and ultimately prevention.     

Extrapolating evidence of antiepileptic drug efficacy in adults to children ≥2 years of age with focal seizures: The case for disease similarity

Expediting pediatric access to new antiseizure drugs is particularly compelling, because epileptic seizures are the most common serious neurological symptom in children. Analysis of antiepileptic drug (AED) efficacy outcomes of randomized controlled trials, conducted during the past 20 years in different populations and a broad range of study sites and countries, has shown considerable consistency for each drug between adult and pediatric populations. Historically, the majority of regulatory approvals for AEDs have been for seizure types and not for specific epilepsy syndromes. Available data, both anatomical and neurophysiological, support a similar pathophysiology of focal seizures in adults and young children, and suggest that by age 2 years the structural and physiological milieu upon which seizures develop is similar. Although the distribution of specific etiologies and epilepsy syndromes is different in children from in adults, this should not impact approvals of efficacy based on seizure type, because the pathophysiology of focal seizures and the drug responsiveness of these seizure types are quite similar. Safety and pharmacokinetics cannot be extrapolated from adults to children. The scientific rationale, clinical consensus, and published data support a future approach accepting efficacy data from adult trials and focusing exclusively on prospective pharmacokinetic, tolerability, and safety studies and long‐term follow‐up in children. Whereas tolerability studies can be compared easily in children and adults, safety studies require large numbers of patients followed for many years.     

Adults with learning disabilities and epilepsy: knowledge about epilepsy before and after an educational package.

The understanding individuals have about their epilepsy may influence the success with which that individual copes with his/her epilepsy. This paper presents the first evaluation of a video-assisted brief educational package for adults with mild learning disabilities and epilepsy ("Epilepsy and You"; Paul, 1996 21). Utilizing a deferred entry to treatment design to evaluate intervention effects eighteen subjects participated in the study. Their knowledge about epilepsy before and after training was assessed using a checklist of knowledge and the Epilepsy Knowledge Questionnaire-Revised for use with people with learning disabilities. Results demonstrated significant gains in knowledge which were durable over a short follow-up period (1 month). "Epilepsy and You" was found to be suitable for use with a wide range of individuals and subjects' opinions demonstrated they enjoyed taking part. This study is a preliminary investigation from which other research can develop. Therefore, criticisms and suggestions for further research have been made.     

Indications and expectations for neuropsychological assessment in routine epilepsy care: Report of the ILAE Neuropsychology Task Force,Diagnostic Methods Commission, 2013–2017

The International League Against Epilepsy (ILAE) Diagnostic Methods Commission charged the Neuropsychology Task Force with the job of developing a set of recommendations to address the following questions: (1) What is the role of a neuropsychological assessment? (2) Who should do a neuropsychological assessment? (3) When should people with epilepsy be referred for a neuropsychological assessment? and (4) What should be expected from a neuropsychological assessment? The recommendations have been broadly written for health care clinicians in established epilepsy settings as well as those setting up new services. They are based on a detailed survey of neuropsychological assessment practices across international epilepsy centers, and formal ranking of specific recommendations for advancing clinical epilepsy care generated by specialist epilepsy neuropsychologists from around the world. They also incorporate the latest research findings to establish minimum standards for training and practice, reflecting the many roles of neuropsychological assessment in the routine care of children and adults with epilepsy. The recommendations endorse routine screening of cognition, mood, and behavior in new‐onset epilepsy, and describe the range of situations when more detailed, formal neuropsychological assessment is indicated. They identify a core set of cognitive and psychological domains that should be assessed to provide an objective account of an individual's cognitive, emotional, and psychosocial functioning, including factors likely contributing to deficits identified on qualitative and quantitative examination. The recommendations also endorse routine provision of feedback to patients, families, and clinicians about the implications of the assessment results, including specific clinical recommendations of what can be done to improve a patient's cognitive or psychosocial functioning and alleviate the distress of any difficulties identified. By canvassing the breadth and depth of scope of neuropsychological assessment, this report demonstrates the pivotal role played by this noninvasive and minimally resource intensive investigation in the care of people with epilepsy.     

Present status of surgical intervention for children with intractable seizures

We present a discussion of recent relevant publications in pediatric epilepsy surgery. In 1998, the Commission on Neurosurgery of the International League Against Epilepsy formed the Subcommission for Pediatric Epilepsy Surgery. Their proposed recommendations are included here. We also discuss updates on identification and selection of children with severe refractory epilepsy. Functional imaging has advanced in recent years as an important adjunct in identifying the epileptogenic zone during the preoperative evaluation. The newer imaging modalities are summarized. Routine positron emission tomography, positron emission tomography with special tracers, and single photon emission computed tomography have proven to be beneficial. Other newer investigative techniques await validation. A number of studies on postoperative outcomes over the past few years have demonstrated the benefits of early surgical treatment for selected children.     

Implementation of psychological clinical trials in epilepsy: Review and guide

The International League Against Epilepsy (ILAE) Neuropsychiatry commission and United States Institute of Medicine report both identified cognitive and psychological comorbidities as a significant issue for individuals with epilepsy, with rates as high as 60%. However, there is a paucity of evidence-based treatments for many psychological conditions (e.g., learning disorders, cognitive disorders, behavioral disorders). Because of inherent challenges in the implementation of psychological therapy trials and specific considerations for the population with epilepsy, the focus of the current review was to provide guidance and recommendations to conduct psychological trials for individuals with epilepsy. Several key areas will be discussed, including selection of patients, trial design, psychological intervention considerations, outcomes and evaluation of results, publication of trial results, and special issues related to pediatric clinical trials. Rigorously designed psychological therapy trials will set the stage for evidence-based practice in the care of individuals with epilepsy, with the goal of improving seizures, side effects, and HRQOL.     

ICD coding for epilepsy: Past,present, and future—A report by the International League Against Epilepsy Task Force on ICD codes in epilepsy

The World Health Organization (WHO) International Classification of Diseases (ICD) has been used to classify causes of morbidity and mortality such as epilepsy for more than 50 years. The aims of this critical commentary are to do the following: (1) Introduce the ICD classification, summarize the ICD‐9 and ICD‐10 codes for epilepsy and seizures, and discuss the challenges of mapping epilepsy codes between these two versions; (2) discuss how the ICD‐9 and ICD‐10 relate to the revised International League Against Epilepsy (ILAE) terminology and concepts for classification of seizures and epilepsies; (3) discuss how ICD‐coded data have been used for epilepsy care and research and briefly examine the potential impact of the international ICD‐10 clinical modifications on research; (4) discuss the upcoming ICD‐11 codes and the role of the epilepsy community in their development; and (5) discuss how the ICD‐11 will conform more closely to the current ILAE terminology and classification of the epilepsies and seizures and its potential impact on clinical care, surveillance, and public health and research.     

Analogy between psychosis antedating epilepsy and epilepsy antedating psychosis

Purpose: Patients with recurrent epileptic seizures after the development of psychosis (Psychosis‐Epilepsy) have been regarded as belonging to a different clinical entity from those with epilepsy antedating the development of psychosis (Epilepsy‐Psychosis). However, clinical characteristics of patients with Psychosis‐Epilepsy have not been well described, except for early German studies. We aimed to estimate the reliability of distinction between Psychosis‐Epilepsy and Epilepsy‐Psychosis by comparing their clinical characteristics. Methods: Among 312 patients with epilepsy and psychosis enrolled in this multicenter study, 23 patients had Psychosis‐Epilepsy and 289 patients had Epilepsy‐Psychosis (i.e., interictal psychosis). Demographic (i.e., sex, age at time of evaluation, and intellectual functioning), psychiatric (i.e., age at onset of psychosis, subtype of psychosis, duration of psychotic episode, and a family history of psychosis), and epileptic (i.e., age at onset of epilepsy, subtype of epilepsy, seizure type, and a family history of epilepsy) characteristics of both groups were compared. Key Findings: Clinical characteristics, either in their psychoses or epilepsies, except for age‐related variables, were equivalent between patients with Psychosis‐Epilepsy and those with Epilepsy‐Psychosis. Time intervals between onset of psychosis and that of epilepsy in the two groups showed a normal distribution curve. Significance: The presence of many common features and the linear distribution of the time intervals did not fully support that Psychosis‐Epilepsy and Epilepsy‐Psychosis were two distinctly different entities. Among certain patients who have genetic vulnerabilities to both psychoses and seizures, psychosis may develop either antedating or postdating the development of epilepsy. These findings may suggest a necessary reconceptualization of psychoses in epilepsy.     

Empirical evidence of underutilization of referrals for epilepsy surgery evaluation

Background: Epilepsy surgery is a treatment that can cure patients with intractable epilepsy. This study investigates whether referrals for epilepsy surgery evaluation are underutilized. Methods: Patients with epilepsy aged 18–60 years were identified in a computerized registry held by public health care providers in a Swedish county using ICD codes. Clinical data and data on referral status for epilepsy surgery were obtained from the patients’ medical records. Potential candidates for epilepsy surgery evaluation were identified using pre‐specified criteria. Obstacles for referral were analysed by comparing clinical data in patients who were considered for referral and those who were not. Appropriateness of non‐referral was evaluated against recommendations from the Swedish Council on Technology in Health Care (SBU). Results: Of 378 patients with epilepsy in the registry, 251 agreed to participate. Of 251, 40 were already referred patients and 48 patients were identified as potential candidates for epilepsy surgery evaluation by study criteria. Referral had been considered but not performed in 15 of the potential candidates. Potential candidates not considered for referral were less likely to have seen a neurologist, to have had an EEG, CT and MRI, and more likely to have cognitive disturbances. Following the recommendations by the SBU, 28 of 48 potential candidates were identified as inappropriately not referred patients. Conclusion: The number of missed referrals for epilepsy surgery evaluation was estimated to be 60 per 100 000 inhabitants. Several important obstacles were found for not referring patients for epilepsy surgery evaluation.     

Autosomal dominant cortical tremor,myoclonus, and epilepsy (ADCME) in a unique south Indian community

Autosomal dominant cortical tremor, myoclonus, and epilepsy (ADCME)/familial adult onset myoclonic epilepsy (FAME) is a nonprogressive disorder characterized by (1) distal tremors that are usually precipitated by posture and action; (2) stimulus‐sensitive myoclonus that is predominantly seen in the upper limb and is precipitated by photic stimuli, fatigue, emotional stress, and sleep deprivation; (3) seizures that were predominantly of the generalized tonic–clonic type that showed significant response to antiepileptic drugs (AEDs). ADCME has been reported worldwide with different genetic loci in Japanese families (8q23.3‐q24.1), Italian families (2p11.1‐q12.2), a French family (5p15.3.1‐p15.1), and a Thai family (3q26.32‐q28). ADCME has not been reported in South India and is still not recognized as an independent entity under the International League Against Epilepsy (ILAE). We report 241 patients with ADCME identified belonging to 48 families. The 48 families are domiciled in two southern districts of Tamilnadu in India, belonging to a community called “Nadar” whose nativity is confined to these southern districts, with reported unique genetic characteristics. This study is reported for the presentation of this rare disease in a unique ethnic group, and is the largest single report on ADCME worldwide.     

Guidelines for epilepsy management in India classification of seizures and epilepsy syndromes

This article is part of the Guidelines for Epilepsy management in India. This article reviews the classification systems used for epileptic seizures and epilepsy and present the recommendations based on current evidence. At present, epilepsy is classified according to seizure type and epilepsy syndrome using the universally accepted International League Against Epilepsy (ILAE) classification of epileptic seizures and epilepsy syndromes. A multi-axial classification system incorporating ictal phenomenology, seizure type, epilepsy syndrome, etiology and impairments is being developed by the ILAE task force. The need to consider age-related epilepsy syndromes is particularly important in children with epilepsy. The correct classification of seizure type and epilepsy syndrome helps the individual with epilepsy to receive appropriate investigations, treatment, and information about the likely prognosis.     

PCDH19‐related epilepsy in two mosaic male patients

PCDH19 gene mutations have been recently associated with an epileptic syndrome characterized by focal and generalized seizures. The PCDH19 gene (Xq22.1) has an unusual X‐linked inheritance with a selective involvement for female subjects. A cellular interference mechanism has been hypothesized and male patients can manifest epilepsy only in the case of a mosaicism. So far about 100 female patients, and only one symptomatic male have been described. Using targeted next generation sequencing (NGS) approach we found a PCDH19 point mutation in two male patients with a clinical picture suggestive of PCDH19‐related epilepsy. The system allowed us to verify that the two c.1352 C>T; p.(Pro451Leu) and c.918C>G; p.(Tyr306*) variants occurred in mosaic status. Mutations were confirmed by Sanger sequencing and quantified by real‐time polymerase chain reaction (PCR). Up to now, the traditional molecular screening for PCDH19‐related epilepsy has been targeted to all females with early onset epilepsy with or without cognitive impairment. Male patients were generally excluded. We describe for the first time two mosaic PCDH19 point mutations in two male patients with a clinical picture suggestive of PCDH19‐related epilepsy. This finding opens new opportunities for the molecular diagnoses in patients with a peculiar type of epilepsy that remains undiagnosed in male patients.     

Activation of mTOR signaling pathway is secondary to neuronal excitability in a mouse model of mesio‐temporal lobe epilepsy

Recent studies in animal models have suggested that the mammalian target of rapamycin (mTOR) signaling pathway is involved in several features of mesio‐temporal lobe epilepsy (MTLE), and that its inhibition could have therapeutic interests. However, it remains controversial whether mTOR activation is the cause or the consequence of MTLE. We previously showed in a mouse model of MTLE associated with hippocampal sclerosis that increased neuronal excitability and brain‐derived neurotrophic factor (BDNF) overexpression contribute to the development of morphological features of this form of epilepsy. Here, we addressed whether mTOR activation promotes MTLE epileptogenesis via increasing neuronal excitability and/or BDNF expression or rather mediates neuroplasticity associated with hippocampal sclerosis. In mice injected intrahippocampally with kainate (1 nmol), we showed a biphasic increase of phospho‐S6 (p‐S6) ribosomal protein expression, the downstream product of the mTOR signaling pathway, in the dispersed granule cell layer (GCL) of the dentate gyrus with a second phase lasting up to 6 months. Chronic treatment with rapamycin suppressed p‐S6 expression, granule cell dispersion and mossy fiber sprouting, but did not reduce cell loss, BDNF overexpression, glutamic acid decarboxylase (GAD)67 expression or the development of hippocampal paroxysmal discharges. Neuronal inhibition by midazolam (2 × 10 mg/kg, i.p.) abolished the increased expression of p‐S6 in the dispersed GCL. Our data suggest that activation of the mTOR signaling pathway results from the increased neuronal excitation that develops in the GCL and may contribute to MTLE morphological changes. However, these data do not support the role of this pathway in the development of MTLE or its inhibition as a therapy for this form of epilepsy.     

Medical and Surgical Strategies for Epilepsy Care in Developing Countries

Summary: Epilepsy is a major health problem, and there is hope that current international initiatives—epitomized in the "Epilepsy: Out of the Shadows" campaign—will increase the commitment of the general public and health officials to the care of patients. Particularly in developing countries, there is great need for alleviation of the extremely difficult situation of people with epilepsy and their families. Doctors can play their part by adhering to specific medical and surgical strategies aimed at the improvement of epilepsy care in these countries. Included in the former are joining efforts to guarantee a regular distribution of conventional antiepileptic drugs (AEDs), make optimal use of the more easily available AEDs, and improve communication with patients and families at all levels. It is also important to support the creation of local and regional specialized epilepsy centers with the capability to perform presurgical evaluation and epilepsy surgery in many patients with medically refractory seizures. The establishment of such centers in developing countries will face several challenges, including a critical view of technological advances and the need to support well-trained, creative people who can evaluate and operate on patients with relatively limited resources. This article proposes that the success of such an approach depends on the progressive build-up of a "critical mass" of specialized people who are trained locally to select or reject epilepsy patients for surgery using the available resources. A stepwise approach to the increasing levels of complexity involved in the evaluation and surgical treatment is proposed, with the expectation that each center will find its level and adhere to its capability.     

National Association of Medical Examiners position paper: Recommendations for the investigation and certification of deaths in people with epilepsy

Sudden unexpected death of an individual with epilepsy can pose a challenge to death investigators, as most deaths are unwitnessed, and the individual is commonly found dead in bed. Anatomic findings (eg, tongue/lip bite) are commonly absent and of varying specificity, thereby limiting the evidence to implicate epilepsy as a cause of or contributor to death. Thus it is likely that death certificates significantly underrepresent the true number of deaths in which epilepsy was a factor. To address this, members of the National Association of Medical Examiners, North American SUDEP Registry, Epilepsy Foundation SUDEP Institute, American Epilepsy Society, and the Centers for Disease Control and Prevention constituted an expert panel to generate evidence‐based recommendations for the practice of death investigation and autopsy, toxicological analysis, interpretation of autopsy and toxicology findings, and death certification to improve the precision of death certificate data available for public health surveillance of epilepsy‐related deaths. The recommendations provided in this paper are intended to assist medical examiners, coroners, and death investigators when a sudden unexpected death in a person with epilepsy is encountered.