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Background A generalized tonic–clonic seizure (GTCS) is the most severe form of common epileptic seizure and carries the greatest risk of harm. The aim of this review is to provide an evidence-based guide for the selection of antiepileptic drugs (AEDs) for patients with GTCSs. Eight AEDs are approved in Europe and the USA for the treatment of both primarily GTCSs (PGTCSs) and secondarily GTCSs (SGTCSs) and are considered in this paper. Methods Each AED is evaluated using five criteria: (1) efficacy, by seizure type (a: PGTCSs and b: SGTCSs); (2) adverse effects; (3) interactions; (4) adherence and dosing; and (5) mechanism of action (MOA). To ensure the inclusions of robust data, only efficacy data accepted by regulatory authorities were considered, and data related to adverse effects, interactions, adherence, and MOA were all extracted from UK Summaries of Product Characteristics (SPCs). Results (1a) There is class 1 evidence of the efficacy of only four AEDs in controlling PGTCSs (lamotrigine, levetiracetam, perampanel, and topiramate). (1b) There is no class 1 evidence of the efficacy of any AED in SGTCSs although some evidence from pooled/subgroup analyses or meta-analyses supports the use of the four AEDs (levetiracetam, perampanel, topiramate, and with less robust data for lamotrigine). (2) AEDs are associated with different, but to some extent overlapping, common adverse effect profiles but have differing idiosyncratic adverse effects. (3) Pharmacokinetic interactions are seen with most, but not all, AEDs and are most common with carbamazepine and phenytoin. (4) Good adherence is important for seizure control and is influenced by frequency of dosing, among other factors. (5) Mechanism of action is also a consideration in rationalising AED selection when switching or combining AEDs. Conclusion Ultimately, the choice of AED depends on all these factors but particularly on efficacy and adverse effects. Different patients will weigh the various factors differently, and the role of the treating physician is to provide accurate information to allow patients to make informed choices. [ABSTRACT FROM AUTHOR]

Longitudinal cohort studies of prognosis in epilepsy have been carried out since the late 1970s and these have transformed our understanding of prognosis in epilepsy. This paper reviews the contribution of such studies and focuses particularly on the National General Practice Study of Epilepsy, a prospective population-based cohort study of 1195 patients that was initiated in 1983. The National General Practice Study of Epilepsy and other studies have shown that: (i) epilepsy has an often good prognosis with 65–85% of cases eventually entering long-term remission, and an even higher proportion of cases entering a short-term remission; (ii) the likelihood of long-term remission of seizures is much better in newly diagnosed cases than in patients with chronic epilepsy; (iii) the early response to treatment is a good guide to longer term prognosis (although not inevitably so, as in a minority of cases seizure remission can develop after prolonged activity); (iv) the longer is the remission (and follow-up), the less likely is subsequent recurrence; (v) the longer an epilepsy is active, the poorer is the longer term outlook; (vi) that delaying treatment, even for many years, does not worsen long-term prognosis; (vii) the ‘continuous’ and ‘burst’ patterns are more common than the ‘intermittent’ seizure pattern; (viii) epilepsy has a mortality that is highest in the early years after diagnosis, and in the early years is largely due to the underlying cause, however, higher mortality rates than expected are observed throughout the course of an epilepsy; (ix) the prognosis of febrile seizures is generally good, with ∼6–7% developing later epilepsy; and (x) clinical factors associated with outcome have been well studied, and those consistently found to predict a worse outcome include: the presence of neurodeficit, high frequency of seizures before therapy (seizure density), poor response to initial therapy, some epilepsy syndromes. [ABSTRACT FROM PUBLISHER]

Abstract: The genetic bases of common, nonmendelian epilepsy have been difficult to elucidate. In this article, we argue for a new approach to genetic inquiry in epilepsy. In the latter part of the 19th century, epilepsy was universally acknowledged to be part of a wider “neurological trait” that included other neuropsychiatric conditions. In recent years, studies of comorbidity have shown clear links between epilepsy and various neuropsychiatric disorders including psychosis and depression, and genetic studies of copy number variants (CNVs) have shown that in some cases, the same CNV underpins neuropsychiatric illness and epilepsy. Functional annotation analysis of the sets of genes impacted by epilepsy CNVs shows enrichment for genes involved with neural development, with gene ontological (GO) categories including “neurological system process” (P =0.006), “synaptic transmission” (P =0.009), and “learning or memory” (P =0.01). These data support the view that epilepsy and some neuropsychiatric conditions share pathogenic neurodevelopmental pathways, and that epilepsy should be included in the spectrum of neurodevelopmental disorders. Yet, most current genetic research in epilepsy has restricted samples to specific types of epilepsy categorized according to the clinical classification schemes on the basis of seizure type, anatomical location, or epilepsy syndrome. These schemes are, to an extent, arbitrary and do not necessarily align with biological reality. We propose an alternative approach that makes no phenotypic assumptions beyond including epilepsy in the neurodevelopmental spectrum. A “‘value-free” strategy of reverse phenotyping may be worth exploring, starting with genetic association and looking backward at the phenotype. Finally, it should be noted that there are societal implications to associating epilepsy with other neuropsychiatric disorders, and it is vital to ensure research in this area does not result in increased stigma for patients with epilepsy. [Copyright &y& Elsevier]

The etiology of epilepsy is a major determinant of clinical course and prognosis, yet the current classifications of epilepsy do not list etiology in any detail. In this article, a classification (database) of the etiologies of epilepsy is proposed. In this scheme, the etiology of epilepsy is divided into four categories: idiopathic, symptomatic, provoked, and cryptogenic. These are defined and subcategories are proposed. A commentary addressing the following points is included: problems associated with assigning causation, symptomatic versus idiopathic epilepsy, focal versus generalized epilepsy, acquired epilepsy, acute symptomatic epilepsy, risk factor analysis, provoked epilepsy genetic and developmental epilepsy, and epilepsy as a disease not a symptom. [ABSTRACT FROM AUTHOR]

This paper provides a survey of the changing concepts of the etiology of epilepsy from 1860 to 2010, focusing on the first two 50-year periods and outlining more briefly major developments in the past 50 years. Among the concepts reviewed in the first 100 years are: the division between predisposing and exciting causes, idiopathic and genuine epilepsy, organic epilepsy, the concept of 'cause' being equivalent to 'causal mechanism,' Russell Reynolds etiological classification, the neurological taint and theories of degeneration, the self-perpetuating nature of seizures, reflex theories of etiology, autointoxication, heredity and eugenics, epilepsy due to brain disorders, the role of EEG and of hippocampal sclerosis, psychological theories of causation, and the multifactorial view of epilepsy etiology. In the past 50 years, the major advances in studying causation in epilepsy have been: clinical biochemistry, neuroimaging, molecular genetics, studies of mechanisms of epilepsy, better statistical methodologies and classification. A number of general observations can be made: the identification of 'cause' is not as simple as it might at first appear; progress in the study of causation has been often erratic and travelled up many cul-de-sacs; theories of causation are heavily influenced by societal influences and fashion, and is also heavily dependent on applied methodologies; the recently explored possibility that the underlying inherited mechanisms of epilepsy are shared with other neuropsychiatric conditions is in effect a reinvention of the concept of the neurological trait, and this has ethical and social implications. Considering and classifying cause in terms of causal mechanism, as was suggested by Hughlings Jackson, is an ultimate goal. [ABSTRACT FROM AUTHOR]

Summary: Stroke is an important cause of symptomatic epilepsy especially in the elderly. Seizures in the setting of stroke will furthermore worsen the prognosis of stroke. Studies show that the frequency of seizures in stroke ranges between 2.3% and 14%. Typically early seizures are defined as those that occur within 14 days of the stroke, and later seizures those that occur after this period. A number of risk factors have been identified like cortical involvement, size of the infarct and stroke severity. Status epilepticus can be a presenting symptom of acute stroke and can lead to increased mortality. Early seizures are risks for recurrent seizures though not for the development of epilepsy but late seizures do carry a higher risk. There are no clear cut guidelines for the treatment of seizures in stroke and hence treatment needs to be initiated in the context of the patient. The presence of co morbid conditions and the use of other drugs also complicate antiepileptic therapy, and the risk of drug interactions is a particular hazard in elderly patients on multiple co medication. Although hemorrhagic and ischaemic stroke can both result in epilepsy, this review focuses primarily the association of epilepsy and ischaemic stroke. [Copyright &y& Elsevier]

The drug therapy of epilepsy evolved enormously in this 50 year period. Advances in therapeutics included the incorporation of pharmacokinetics into clinical practice, enormous advances in neurochemistry, a trend to antiepileptic drug monotherapy, better drug assessment, better understanding of therapeutic outcomes, and the recognition of the large epilepsy treatment gap in many countries. An unprecedented range of new drugs was introduced in this period. Before 1989, these included carbamazepine, valproate, ethosuximide, and the benzodiazepines. Since 1989, 13 more new drugs have been licensed and marketed and there are others in the pipeline. The International League Against Epilepsy and its leading figures have played an important role in these developments. In this period, too, there has been a rapid expansion in research and development within the pharmaceutical industry and a rise in the value of the antiepileptic drug market. In parallel, governmental regulation of pharmaceuticals has greatly increased. To what extent the overall prognosis of epilepsy has improved as a result of these activities is an interesting and perplexing question. [ABSTRACT FROM AUTHOR]

Profound advances in the field of clinical imaging in epilepsy occurred between 1909 and 2009, the century of the International League Against Epilepsy, and these are reviewed briefly in this paper. Initially imaging was carried out with plain x-ray, air encephalography, and angiography, and these techniques had a relatively minor role in epilepsy. Computerized tomographic (CT) scanning was introduced in 1971, and magnetic resonance imaging (MRI) a decade or so later, and both these technologies had an immediate and far-reaching impact on epilepsy. MRI techniques continued to evolve during the 1990s and profoundly influenced many aspects of epilepsy clinical practice. These structural imaging techniques revealed pathological lesions in large numbers of patients with hitherto cryptogenic epilepsy, widened the indications for surgical therapy, and improved our understanding of the pathogenesis and etiology of epilepsy. In recent years, the research focus has turned to fMRI but its impact on epilepsy currently is relatively small. Magnetic resonance spectroscopy (MRS), positron emission tomography (PET) and single photon emission computed tomography (SPECT) also have had a limited impact on clinical practice in epilepsy. [ABSTRACT FROM AUTHOR]

Despite the fact that status epilepticus was been recognized since antiquity, its existence was largely ignored until the mid-nineteenth century. In this review we cover the medical literature of status epilepticus from the late nineteenth century until the early 1970s when the modern era of status epilepticus began. We pay particular attention to the impact of the ILAE and its principal members on the understanding and awareness of status epilepticus. We also cover the evolution of treatment regimens advocated for status epilepticus from the late nineteenth century to the early 1970s when the benzodiazepines were established as first line treatments. [ABSTRACT FROM AUTHOR]

This paper provides a review of the drug treatment of epilepsy from 1909, the year of the foundation of the International League Against Epilepsy (ILAE), to 1958. It was during this period that modern approaches to the medicinal therapy of epilepsy were formulated and many new drugs were introduced. Of these, both phenytoin and phenobarbital continue to be widely used today. This was the period when scientific screening was also introduced into drug discovery. The leading figures in the ILAE played an important role in guiding the evolution of the treatment of epilepsy during this period. [ABSTRACT FROM AUTHOR]

The recent discovery of archival material has shed interesting light on the origins of Epilepsia and also the International League Against Epilepsy (ILAE). The idea of an international journal devoted to epilepsy seems first to have arisen from talks between Dr. L. J. J. Muskens and Dr. W. Aldren Turner in 1905. A protracted series of subsequent letters between Muskens and a Haarlem publisher show how the idea slowly took shape. The committee of patronage, editorial board, and editorial assistants was probably first approached at the First International Congress of Psychiatry, Neurology, Psychology, and Nursing of the Insane, held in Amsterdam in 1907. At this meeting, the concept of an international organization to fight epilepsy (to become the ILAE) was also first proposed in public, again by Muskens. The concept of the ILAE was clearly modeled on another international organization—the International Commission for the Study of the Causes of Mental Diseases and Their Prophylaxis. This Commission had been first publicly proposed in 1906 by Ludwig Frank, at the Second International Congress for the Care and Treatment of the Insane. The proposed Commission and ILAE shared many features, aims, and personnel. Despite an auspicious start, the International Commission was prevented by personal and political differences from ever actually coming into being. However, the first issue of Epilepsia appeared in March 1909 and the ILAE was inaugurated in August 1909; and both have flourished and celebrate their centenaries this year. [ABSTRACT FROM AUTHOR]

Since extratemporal clinical features in patients with unilateral hippocampal sclerosis (HS) are likely to indicate aberrant ictal spread or a more extensive epileptogenic zone, we asked whether such features are associated with more severe HS and a worse outcome following temporal lobectomy. We reviewed all patients (174) who had undergone temporal lobectomy for histologically proven unilateral HS related temporal lobe epilepsy between 1997–2005 at the National Hospital for Neurology and Neurosurgery. We divided patients into those with severe HS (side-to-side ratio < 0.6) and those with mild HS (side-to-side ratio > 0.75). We examined all seizures recorded on electroencephalography (EEG) video telemetry in these patients for clinical features of temporal lobe epilepsy. The postsurgical outcome was classified using the Engel classification at the time of follow up (median 4.7 years, range 1–9 years). Patients (28 out 39) with severe HS had atypical features compared to 7 out of 27 in the mild HS [Chi square (χ 2 ) test, p = 0.0013]. The mean number of atypical clinical features was 2.2 in the severe HS group and 0.62 in the mild HS group (Mann Whitney U Test, p < 0.001). The percentage of postsurgery seizure freedom (class 1 Engel classification) was 87%, and there was no significant effect of the presence of atypical clinical features. This study shows that atypical (extratemporal) clinical features tend to occur more frequently in patients with severe HS and do not correlate with worse surgical outcome. [ABSTRACT FROM AUTHOR]

Summary: Saccadic eye movements can be used to evaluate different aspects of brain function, and in this article we are concerned with possible applications in relation to anti-epileptic drug treatment. Recent improvements in the technology of measurement have improved the sensitivity and objectivity of the measures. Here we review the neurophysiology of saccades, their classification, their anatomical basis and cortical control, and then published research articles concerned with the influence of anti-epileptic drugs on saccades and their parameters. It seems likely that certain anti-epileptic drugs (especially those acting on ion channels) exert their effect on saccades through ion channels, and this may have relevance to clinical and pharmacogenetic studies. [Copyright &y& Elsevier]

Objective It has long been known that the response to treatment in newly diagnosed epilepsy is better than in chronic epilepsy. However, in the past 15 years, 8 major new antiepileptic drugs have been licensed, and the effect of this wider range of treatment options on prognosis has not been fully assessed. The aim of this study was to quantify the effect of adding a previously unused antiepileptic drug to the treatment regimen in adults with uncontrolled chronic epilepsy that had been resistant to previous antiepileptic drug treatment. Methods A total of 265 drug additions were studied in 155 adult patients with chronic epilepsy (defined as epilepsy active at least 5 years after and initiation of therapy). Results About 16% of all drug introductions resulted in seizure freedom (defined as seizure freedom at last follow-up for 12 months or longer), and a 50 to 99% seizure reduction occurred in a further 21%. Of the 155 patients, 28% were rendered seizure free by a drug introduction. Clinical factors associated with a better effect were fewer previously used antiepileptic drugs, shorter duration epilepsy, and idiopathic epilepsy. Interpretation This study provides a quantitative estimate of the value of changing drug therapy in patients in whom seizures were previously uncontrolled by previous therapy. The application of a systematic protocol to the treatment of chronic epilepsy will improve seizure control in a substantial proportion of cases. The rather nihilistic view that intractability is inevitable if seizure control is not obtained within a few years of the onset of therapy is incorrect. Ann Neurol 2007 [ABSTRACT FROM AUTHOR]

Summary: Despite the introduction of newer antiepileptic drugs (AEDs), nonresponsiveness to AEDs remains a common problem in epilepsy clinics. There may be important genetic determinants for responsiveness, and this discussion focused on some potential areas: drug transporters; drug-metabolizing enzymes, and ion channels. We review the literature and speculate the contribution of each of these factors in management of patients with epilepsy in the future. [ABSTRACT FROM AUTHOR]

The article introduces the November 3, 2007 issue of the journal "Epilepsia."

The article presents updates of the journal "Epilepsia," in the November 2007 issue. The author offers information about the new guidelines for manuscript preparation and submission. They have also discussed the position of the journal on issues related to ethical publication practices. Information about the online archive of the back issues of the journal is also presented.

People who the author would like to thank for their assistance in the creation of the periodical Epilepsia are mentioned including associate editors Albert Becker, Ettore Beghi and Anne Berg.

The article offers the authors' insight concerning the continued support of readers and authors on "Epilepsia." The authors mention that the support is essential against the background pressures of declining sponsorship from commercial sources, increasing selectivity by institutions in their journal subscription choices, and new online journals. The authors add that the changes and initiatives in the journal include homepage enhancements.

The author reflects on the poor management of epilepsy during pregnancy by physicians worldwide. The authors state the lack of knowledge of some physicians regarding the association between exposure to valproate in utero and a higher risk of teratogenicity. In addition, they suggest the importance of providing patients with guidelines or advice to avoid epilepsy in children.

The article offers an overview on the centenary publication of the issue "Epilepsia." The author cites the topics which will mark the centennial publication of the issue particularly containing personal commentaries from previous International League Against Epilepsy (ILAE) presidents and editors-in-chiefs, and supplemental topics on the developments in the epilepsy during the last 100 years. Furthermore, a retrospect on how the publication started and its improvements through years is provided.

The author discusses the downsides of creating new terminologies that refer to the concept of consciousness being proposed for seizure classification. He believes that new terms are confusing to the wider community and can lessen the credibility and authority of any classification scheme. He mentions the advantages of the traditional terminologies of the International League Against Epilepsy (ILAE).

The article announces that Mark R. Bower will receive the 2012 Morris-Coole Epilepsia Prize from the association International League Against Epilepsy (ILAE) and Morris-Coole Trust.

Phenobarbital (phenobarbitone) was first used as an antiepileptic drug 100 years ago, in 1912. This article tells the story of the discovery of its antiepileptic action, its early development, and the subsequent course of its clinical use over the 100-year period. The side effects, pharmacokinetics, and misuse of barbiturates are considered, along with the more recent clinical trials and the drug's current clinical utilization. The introduction of controlled drug regulations, the comparative cost of phenobarbital, and its inclusion on the World Health Organization (WHO) essential drug list are discussed. It is one of the few drugs on the formulary in 1912 that is still listed today, and remarkably its efficacy in epilepsy has not been significantly bettered. The current recommendation by the WHO is that phenobarbital should be offered as the first option for therapy for convulsive epilepsy in adults and children if availability can be ensured. This is rated as a strong recommendation because of the proven efficacy and low cost of phenobarbital, and despite its perceived side-effect profile and the practical problems of access. Whether this recommendation puts 'a hierarchy on the brain,' as has been suggested, is arguable. Much still needs to be learned about the drug's effects, and the issues raised by phenobarbital have lessons for all antiepileptic drug therapy. [ABSTRACT FROM AUTHOR]

The article announces the 2011 Morris-Coole Epilepsia award winner Sebastian Schuchmann for his article ''Respiratory alkalosis in children with febrile seizures'' published in a previous issue of the journal.

People who the author would like to thank for their assistance in the creation of the journal "Epilepsia," are mentioned.

The article discusses the changes in the current issue of the journal "Epilepsia" including changes in the publication policies.

People who the editors would like to thank for their contribution to the publication of the journal are mentioned including members of the editorial board and reviewers.

The article presents the changes and developments in the publication "Epilepsia."

A message from the editors-in-chief is presented thanking individuals who dedicate themselves to the operation of the journal and the members of the Editorial Board for their time and expertise in reviewing manuscripts.

The article announces that Nicola Marchi has been awarded the 2007 Morris-Coole prize from "Epilepsia" journal and the International League Against Epilepsy.

The article offers information on the mandatory Public Access Policies introduced by the U.S. National Institutes of Health (NIH) and the British agency Wellcome Trust for all research papers. The NIH policy requires all investigators funded by the National Library of Medicine's PubMed Central (PMC) to submit an electronic version of their final manuscripts. The Wellcome Trust policy mandates electronic copies of any research papers accepted for publication to be made available through PMC.

Purpose The current survey sought to identify the religious and cultural beliefs about the causes and treatment of epilepsy in people with epilepsy from Saudi Arabia and a number of other aspects relating to the possibility of cure, coping with the condition, and public awareness. Methods Study instruments were developed on the basis of the literature, a focus group of people with epilepsy, and feedback from people in the field with local knowledge. These were then piloted. A survey was then carried out among a total of 110 adults with epilepsy. Participants were asked to complete questionnaires inquiring into their beliefs about the causes and range of treatments used for epilepsy. Each participant was allowed to choose more than one cause and more than one treatment method. The questionnaires were administered face to face by a clinical psychologist (HAA) to improve the quality of the responses. Results We found that most adults with epilepsy in Saudi Arabia believe that epilepsy is a condition with multifactorial causation and for which more than one treatment method should be applied. A test from God was the most commonly ascribed cause (83% as well as 40% who believed that some cases of the illness were a punishment from God). The belief in the concept of God's will helped many in the cohort to accept their illness as part of their destiny. Ninety-six percent of the patients believed that there were also medical causes (such as an illness, brain insult, inflammation, heredity, contagion), and a similar proportion believed that there were also religious causes. Smaller proportions believed epilepsy could be due to cultural (78%) or psychosocial causes (64%). Thirty-four percent of people believed that there could be sometimes no cause, but only 2% thought that epilepsy never had any identifiable cause. Most patients did not believe that one treatment alone would help. Ninety-three percent of patients believed in medical treatment, 93% in religious treatment, and 64% in traditional treatments, and 7% believed in changing lifestyle (eating balanced food and positive thinking). Seventy-eight percent of the sample believed that their epilepsy was a curable illness. Ninety-six percent believed that faith and practicing religious rituals helped in coping with epilepsy, and 92% believed that family support helped in coping with epilepsy. Nine percent of patients had stopped their medication for religious reasons or because of a sense of shame, and 7% had at one time been forced by their family to stop their medication. Ninety-two percent of the sample reported having enough family support. Ninety-five percent believed that Saudi society needs more awareness to understand epilepsy. Conclusion In Saudi Arabia, religious and cultural beliefs about the causes and treatment of epilepsy exist alongside medical beliefs. The holding of religious beliefs, the practicing of religious rituals, and the presence of family support were found to be of great importance in coping with epilepsy, and their role needs to be fully appreciated in the medical management of the condition. [ABSTRACT FROM AUTHOR]

Abstract: Aim: The aims of the current study were to translate and to validate the NDDI-E to the Arabic language to be used as a screening instrument to identify moderately severe symptoms of depression in people with epilepsy. Methods: The English version of the NDDI-E was translated to Arabic and back translated to English by two independent translators. A total of 51 patients, aged 18–56years old, with a diagnosis of epilepsy, completed the Arabic versions of the Beck Depression Inventory (BDI-II) and the NDDI-E. Patients with BDI scores >20 were considered to be suffering from moderately severe depressive symptoms. Cutoff scores, sensitivity, specificity, and positive and negative predictive values of the NDDI-E to identify symptomatic patients on the BDI were calculated. Results: A sensitivity of 93.33% and a specificity of 94.44% were found with NDDI-E total scores >15. The positive predictive value was 87.5%, and the negative predictive value was 97.14%. Spearman's rank correlation between the BDI and the NDDI-E was high (r=.78, p=0.000, N=51). Internal consistency was at 0.926 (Cronbach's alpha). Conclusion: The Arabic version of the NDDI-E appears to be a reliable and sensitive instrument in the identification of moderately severe or severe depressive symptoms in people with epilepsy, and it can be used with all Arabic-speaking patients. [Copyright &y& Elsevier]

It is now generally accepted that people with epilepsy are at increased risk of premature death compared with peers in the general population. It has, however, not been clearly established how this risk changes over time, nor whether mortality rates have been changing over time. We carried out a systematic review: (1) To determine the pattern of change of mortality risk relative to the general population in people with epilepsy in the course of their condition as measured by standardized mortality ratios (SMRs), by reviewing longitudinal prospective cohort studies. (2) To establish whether there have been any changes in reported mortality rates for epilepsy in general populations over time. This was complemented by comparison of SMRs in people with epilepsy in the same types of source populations (population-based, hospital-based, and institutional studies) in different time periods to ascertain any changes in reported mortality rates. The SMR is highest in the initial years after diagnosis and subsequently decreases. There is a suggestion that there may be an increase after 10 years from diagnosis despite the fact that the majority of people in these cohorts are in long-term remission. There is no evidence that either the overall SMR or the mortality rate of people with epilepsy has changed significantly over time. Further population and cohort studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

BackgroundThe seizure response to the addition of a previously unused antiepileptic drug in a cohort of 155 people with refractory epilepsy was previously reported after a median of 18 months follow-up.MethodsThe authors followed 139 (90%) of the original cohort for a median follow-up of 6.9 years to determine the longer term outcome in people with refractory epilepsy.ResultsDuring the 6.9 year follow-up period, a total of 448 medication changes were made. Eight per cent of these resulted in 12 months or more of seizure freedom and a further 17% of changes resulted in at least 50% improvement in seizure frequency. At the last follow-up, 26 (19%) of individuals had been seizure-free for 12 months or more, and 41 (29%) had 50%–99% improvement in seizure frequency. Terminal seizure freedom was correlated with having no seizures at the time of the previous report (p=0.03), a lower number of previous antiepileptic drugs taken (p=0.052) and a lower number of concomitant antiepileptic drugs (p=0.03). In those who entered remission the probability of remaining seizure-free 5 years later was 0.48 (95% CI 0.32 to 0.63).DiscussionThis suggests that about half of people with apparent drug-resistant epilepsy can have significant improvements in seizure control with further drug changes. Some will subsequently relapse, but long periods of seizure freedom or significantly improved seizure control in the absence of complete seizure control can occur. Such valuable improvements suggest that the recently proposed International League against Epilepsy definition of refractory epilepsy may be too restrictive. [ABSTRACT FROM AUTHOR]

Summary: Background: Outcome studies in people with epilepsy have largely focused on the prognosis in the early stages and factors predictive of early remission. Few studies have examined prognosis in chronic refractory epilepsy. Methods: We determined the pattern of remission and relapse of epilepsy in a cohort of people with refractory epilepsy (seizures in the past two years, at least five years after onset and who have been treated with at least 2 appropriate antiepileptic drugs during that time) to investigate whether any clinical or demographic features are predictive of seizure patterns. Seizure patterns were defined as intermittent (at least one previous period of remission of two or more years with a subsequent relapse) or continuous (no periods of remission of two years or more since seizure onset). We correlated clinical variables with these patterns. We devised a prognostic model summarising patterns of remission and relapse over time in epilepsy. Results: 290 people were recruited, of whom 70% had a continuous pattern of seizures with the remaining 30% having an intermittent pattern. The only clinical variables which significantly differed between the two groups were a higher total number of antiepileptic drugs taken by those in the continuous group (P =0.01) and fewer seizures in the previous year in the intermittent group (P <0.001). A prognostic model of epilepsy is proposed. Conclusion: There is considerable heterogeneity in long-term seizure patterns in people who do not enter long-term remission in the early years after diagnosis. [Copyright &y& Elsevier]

People with epilepsy have an increased risk of premature death. The risk is highest soon after onset of seizures. We report the findings of a long-term follow-up population-based study of people with epilepsy with regards to premature mortality. The National General Practice Study of Epilepsy is a prospective study flagged at the National Health Service Information Centre in the UK. Over 1000 people with new onset seizures were followed from the mid 1980s until April 2009. Of these, 564 people were classified at 6 months as having definite epileptic seizures, 228 as having possible epileptic seizures and 220 as having febrile seizures. The remainder were excluded (n = 104 because of an unknown prior diagnosis of epilepsy or neonatal seizures) or classified as not having epilepsy (n = 79). At median follow-up of 22.8 years there had been 301 deaths in the cohort; 300 of these were in people with definite or possible seizures. Death certificates were obtained for all but three of those who died. The overall standardized mortality ratio for those with definite or possible epilepsy was 2.2 (95% confidence interval 1.97–2.47), and was higher in those with definite seizures (2.6). In those who were alive at 20 years follow-up, the standardized mortality ratio in the subsequent years remained significantly elevated (2.2, 95% confidence interval 1.6–3.2). Pneumonia (standardized mortality ratio 6.6, 95% confidence incidence 5.1, 8.4) was a common cause of death with a consistently elevated standardized mortality ratio throughout follow-up. The standardized mortality ratio for ischaemic heart disease was significantly elevated for the first time in the last 5 years of follow-up (3.3, 95% confidence interval 1.6–7.0). Few people died from epilepsy-related causes. The risk of premature death remains significantly elevated at 20–25 years after the index seizure despite most of the cohort being in terminal remission (defined as 5 years or more seizure-free, on or off anti-epileptic medication) at the last follow-up. Further studies are needed to explore the reasons for this long-term increase in premature mortality. [ABSTRACT FROM AUTHOR]

Purpose: Whether cerebral damage results from epileptic seizures remains a contentious issue. We report on the first longitudinal community-based quantitative magnetic resonance imaging (MRI) study to investigate the effect of seizures on the hippocampus, cerebellum, and neocortex. Methods: One hundred seventy-nine patients with epilepsy (66 temporal lobe epilepsy, 51 extratemporal partial epilepsy, and 62 generalized epilepsy) and 90 control subjects underwent two MRI brain scans 3.5 years apart. Automated and manual measurement techniques identified changes in global and regional brain volumes and hippocampal T2 relaxation times. Results: Baseline hippocampal volumes were significantly reduced in patients with temporal lobe epilepsy and could be attributed to an antecedent neurologic insult. Rates of hippocampal, cerebral, and cerebellar atrophy were not syndrome specific and were similar in control and patient groups. Global and regional brain atrophy was determined primarily by age. A prior neurologic insult was associated with reduced hippocampal and cerebellar volumes and an increased rate of cerebellar atrophy. Significant atrophy of the hippocampus, neocortex, or cerebellum occurred in 17% of patients compared with 6.7% of control subjects. Patients with and without significant volume reduction were comparable in terms of seizure frequency, antiepileptic drug (AED) use, and epilepsy duration, with no identifiable risk factors for the development of atrophy. Conclusions: Overt structural cerebral damage is not an inevitable consequence of epileptic seizures. In general, brain volume reduction in epilepsy is the cumulative effect of an initial precipitating injury and age-related cerebral atrophy. Significant atrophy developed in individual patients, particularly those with temporal lobe and generalized epilepsy. Longer periods of observation may detect more subtle effects of seizures. [ABSTRACT FROM AUTHOR]

Phenytoin and carbamazepine are effective and inexpensive anti- epileptic drugs (AEDs). As with many AEDs, a broad range of doses is used, with the final "maintenance" dose normally determined by trial and error. Although many genes could influence response to these medicines, there are obvious candidates. Both drugs target the a-subunit of the sodium channel, encoded by the SCN family of genes. Phenytoin is principally metabolized by CYP2C9, and both are probable substrates of the drug transporter P-glycoprotein. We therefore assessed whether variation in these genes associates with the clinical use of carbamazepine and phenytoin in cohorts of 425 and 281 patients, respectively. We report that a known functional polymorphism in CYP2C9 is highly associated with the maximum dose of phenytoin (P = 0.0056). We also show that an intronic polymorphism in the SCNIA gene shows significant association with maximum doses in regular usage of both carbamazepine and phenytoin (P = 0.0051 and P = 0.014, respectively). This polymorphism disrupts the consensus sequence of the 5' splice donor site of a highly conserved alternative exon (SN), and it significantly affects the proportions of the alternative transcripts in individuals with a history of epilepsy. These results provide evidence of a drug target polymorphism associated with the clinical use of AEDs and set the stage for a prospective evaluation of how pharmacogenetic diagnostics can be used to improve dosing decisions in the use of phenytoin and carbamazepine. Although the case made here is compelling, our results cannot be considered definitive or ready for clinical application until they are confirmed by independent replication. [ABSTRACT FROM AUTHOR]

Association studies are widely seen as the most promising approach for finding polymorphisms that influence genetically complex traits, such as common diseases and responses to their treatment. Considerable interest has therefore recently focused on the development of methods that efficiently screen genomic regions or whole genomes for gene variants associated with complex phenotypes. One key element in this search is the use of linkage disequilibrium to gain maximal information from typing a selected subset of highly informative single-nucleotide polymorphism (SNP) markers, now often called 'tagging SNPs' (tSNPs). Probably the most common approach to linkage-disequilibrium gene mapping involves a three-step program: (1) characterization of the haplotype structure in candidate genes or genomic regions of interest, (2) identification of tSNPs sufficient to represent the most common haplotypes, and (3) typing of tSNPs in clinical material. Early definitions of tSNPs focused on the amount of haplotype diversity that they explained. To select tSNPs that would have maximal power in a genetic association study, however, we have developed optimization criteria based on the measure of association and have compared these with other criteria based on the haplotype diversity. To evaluate the full program and to assess how well the selected tags are likely to perform, we have determined the haplotype structure and have assessed tSNPs in the SCN1A gene, an important candidate gene for sporadic epilepsy. We find that as few as four tSNPs are predicted to maintain a consistently high value with all other common SNPs in the gene, indicating that the tags could be used in an association study with only a modest reduction in power relative to direct assays of all common SNPs. This implies that very large case-control studies can be screened for variation in hundreds of candidate genes with manageable experimental effort, once tSNPs are identified. However, our results also show that tSNPs identified in one population may not necessarily perform well in another, indicating that the preliminary study to identify tSNPs and the later case-control study should be performed in the same population. Our results also indicate that tSNPs will not easily identify discrepant SNPs, which lie on importantly discriminating but apparently short genealogical branches. This could significantly complicate tagging approaches for phenotypes influenced by variants that have experienced positive selection. [ABSTRACT FROM AUTHOR]

Summary: Purpose: Of the 30,000 persons in whom epilepsy develops annually in the United Kingdom, in ∼6000 (20%), intractability develops. Some of these patients will be appropriate for epilepsy surgery. We aimed to estimate the number of patients who should be considered surgical candidates, by extrapolation from a population-based study of prognosis and the number who are receiving epilepsy surgery, by a survey of U.K. neurosurgeons. Methods: We identified the number of patients who may eventually require surgery from a prospective cohort of patients with newly diagnosed epilepsy. We identified all U.K. neurosurgeons who had performed any epilepsy surgery in the past year. Each identified surgeon prospectively recorded the number and types of operations carried out for 6 months. Results: Of newly diagnosed patients each year, 450 (1.5%) may eventually require surgery. Thirty-two respondents (22% of all U.K. neurosurgeons) reported that they performed epilepsy surgery. The 211 operations were carried out in the 6 months surveyed (422 operations annually or 13 per surgeon per year). Temporal lobe resection (77%) was the most common procedure. Conclusions: Based on a prevalence of 5/1,000 persons with epilepsy, ≤4,500 patients in the U.K. require epilepsy surgery. Every year, 450 patients with newly diagnosed epilepsy who may eventually require surgery are added to this “surgical pool.” At the current annual rate of operations, a large number of refractory patients remain untreated. This is probably partly because many patients are not referred for specialist care and therefore remain underinvestigated. [ABSTRACT FROM AUTHOR]

Status epilepticus (SE) in humans and animal models results in significant cerebral damage and an increased risk of subsequent seizures, associated with a characteristic pattern of neuronal loss particularly affecting the hippocampus. Seizure related cell death is considered to be excitotoxic, but studies have been limited, concentrating on terminal events rather than initial mechanisms. We have studied the biochemical events in the first few days following SE. Self-sustaining limbic SE was induced in adult rats using perforant path stimulation, and animals were allowed to recover. Biochemical studies were performed at 16, 44 h and 8 days following SE, using spectrophotometric enzyme assays and HPLC on regional brain homogenates compared with those from sham-operated controls. Haematoxylin and eosin histology was also undertaken at each time point. Brain aconitase and α-ketoglutarate dehydrogenase (αKDH) activity were both significantly (P<0.05) reduced by approximately 20% in the first 16–44 h following status, but had returned to normal by 8 days. These enzymes are part of the tri-carboxylic acid (Krebbs) cycle in the mitochondrial matrix, and are known to be sensitive to free radical, especially peroxynitrite damage. There was a similar decrease in reduced glutathione levels. Histological studies confirmed evidence of acute neuronal damage up to 44 h, and neuronal loss by 8 days. This is the first in vivo demonstration of this pattern of mitochondrial dysfunction and loss of brain glutathione following SE. The pattern of abnormalities is consistent with reversible mechanisms being involved in excitotoxic cell damage. This, together with the timing of changes, suggests new avenues for therapeutic intervention. [Copyright &y& Elsevier]

We report a 12-year follow-up study of children with febrile convulsions (FCs). The National General Practice Study of Epilepsy (NGPSE) is a large prospective community-based cohort study of 1,195 patients of all ages from first presentation with an identified seizure. Two hundred and twenty children with a first febrile convulsion were identified from the above study between 1984 and 1987. Children were prospectively followed up to ascertain subsequent seizures, neurological problems and treatment. Two hundred and seven patients were followed for a minimum of 8.4 years (median 11.2 years). In the FC cohort, 6% of the children developed subsequent epilepsy, which compares with a population risk of about 1.4%. Ten percent had neurological sequelae. Eleven percent of the children had received medication to prevent recurrence of FC, and in one third of these cases, this was for simple FCs. Using a time-dependent covariate Cox proportional hazards model, the number of FCs was associated with an increased risk of epilepsy (hazard ratio 2.48; 95% confidence limits, CL 1.68, 3.65) up to a limit of 4. A statistically significant association between occurrence of complex FC and subsequent epilepsy was not found, but a review of other studies quantified the odds ratio for epilepsy after a complex first FC as 3.4 (95% CL 2.1, 5.4). Epilepsy is a significant if infrequent sequel to FCs. Factors associated with subsequent epilepsy are the number of FCs or a complex first FC. Overtreatment of this condition continues. [ABSTRACT FROM AUTHOR]

PAX6 is widely expressed in the central nervous system. Heterozygous PAX6 mutations in human aniridia cause defects that would seem to be confined to the eye. Magnetic resonance imaging (MRI) and smell testing reveal the absence or hypoplasia of the anterior commissure and reduced olfaction in a large proportion of aniridia cases, which shows that PAX6 haploinsuffiency causes more widespread human neuro developmental anomalies. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to article regarding meta-analysis and the comparison of efficacy and tolerability of anti-epileptic drugs for treating refractory focal epilepsy.