The enigmatic figure of Leon Pierce Clark and his contribution to epilepsy.

Leon Pierce Clark (1870-1933) was a prominent American neurologist and psychiatrist and an enigmatic figure. He made enduring contributions to status epilepticus and to epilepsy. In the 1910s and 1920s, his chief focus was on the psychological mechanisms of epilepsy and on the personality of those with idiopathic epilepsy which he interpreted from a psychoanalytical perspective. He also described the epileptic voice sign, wrote psychobiographies of among others Abraham Lincoln and Napoleon Bonaparte, and published a book of poetry. He held many important positions in American professional societies and yet was embroiled in controversy.

Change in Mortality of Generalized Convulsive Status Epilepticus in High-Income Countries Over Time: A Systematic Review and Meta-analysis.

IMPORTANCE: Status epilepticus (SE) is associated with significant morbidity and mortality. Since the late 1990s, a more aggressive management of prolonged convulsive seizures lasting longer than 5 minutes has been advocated. OBJECTIVE: To determine if convulsive SE mortality has decreased during a time of increasing advocacy for out-of-hospital treatment and escalating and earlier treatment protocols for prolonged seizures and SE. DATA SOURCE: This systemic review and meta-analysis on studies focused on the mortality of convulsive status epilepticus was conducted by searching MEDLINE, Embase, PsychINFO, CINAHL Plus, and the Cochrane Database of Systematic Reviews between January 1, 1990, and June 30, 2017. STUDY SELECTION: Studies were excluded if they had fewer than 30 participants (<20 for refractory SE), were limited to SE of single specific etiology or an evaluation of a single treatment modality, or were studies of nonconvulsive SE. DATA EXTRACTION AND SYNTHESIS: Data were abstracted and their quality was assessed via a modified Newcastle-Ottawa scale independently by 2 reviewers (A.N. and T.D.G.) using the Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines. Data were pooled using a random-effects model. MAIN OUTCOMES AND MEASURES: The main outcome measure was in-hospital mortality or 30-day case fatality expressed as proportional mortality. RESULTS: Sixty-one studies were included in the analysis. The pooled mortality ratios were 15.9% (95% CI, 12.7-19.2) for adult studies, 13.0% (95% CI, 7.2-19.0) for all-age population studies, 3.6% (95% CI, 2.0%-5.2%) for pediatric studies, and 17.3% (95% CI, 9.8-24.7) for refractory SE studies, with very high between-study heterogeneity. We found no evidence of a change in prognosis over time nor by the definition of SE used. CONCLUSIONS AND RELEVANCE: The mortality of convulsive SE is higher in adults than in children and there was no evidence for improved survival over time. Although there are many explanations for these findings, they can be explained by aetiology of SE being the major determinant of mortality. However, there are potential confounders, including differences in case ascertainment and study heterogeneity. This meta-analysis highlights the need for strict international guidelines for the study of this condition.

Antiepileptic drug treatment of generalized tonic-clonic seizures: An evaluation of regulatory data and five criteria for drug selection.

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.

Outcome of seizures in the general population after 25†years: a prospective follow-up, observational cohort study.

OBJECTIVES: We investigated long-term (to 25 years) seizure prognosis and survival in people with newly diagnosed epilepsy in the community. We explored whether prognosis is different in those with epilepsy (>2 unprovoked seizures) and those with a single seizure at presentation. METHODS: This is a prospective observational cohort study of people with newly diagnosed seizures. We investigated seizure outcome and survival in people presenting with a single seizure and in those presenting with >2 seizures (epilepsy). RESULTS: 695 people (median follow-up 23.6 years) had unprovoked epileptic seizures. For seizure analysis we excluded 38 people with missing data leaving 657 (309 male, and 249 aged <18 years). Seizures recurred in 67%. The 354 people with epilepsy were only slightly more likely to have further seizure recurrence than the 302 people with a single seizure at presentation (HR 1.32, 95% CI 1.09 to 1.59). In 327 people with complete follow-up, 268 (82%, 95% CI 77% to 86%) were in terminal remission; (80%, (95% CI 73% to 85%) in those with epilepsy at presentation). Premature mortality was increased in people with epilepsy (standardised mortality ratio 1.67; 95% CI 1.40 to 1.99) and those with a single seizure at presentation (standardised mortality ratio 2.65; 95% CI 2.23 to 3.15). It is also high in those with early remission. CONCLUSIONS: People with epilepsy and with single seizures at presentation in the community generally have good prognosis for seizure control with prolonged follow-up. The risk of premature mortality is significantly increased in both groups.

The beliefs among patients with epilepsy in Saudi Arabia about the causes and treatment of epilepsy and other aspects.

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.

The use of the NDDI-E in Arabic to identify symptoms of depression of moderate or greater severity in people with epilepsy.

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.

The relative effectiveness of five antiepileptic drugs in treatment of benzodiazepine-resistant convulsive status epilepticus: a meta-analysis of published studies.

PURPOSE: Systematic evaluation of published evidence-base of the efficacy of five antiepileptic drugs - lacosamide, levetiracetam, valproate, phenytoin and phenobarbital - in convulsive benzodiazepine-resistant status epilepticus. METHODS: Data sources included electronic databases, personal communication, and back tracing of references in pertinent studies. These were prospective and retrospective human studies presenting original data for participants with convulsive benzodiazepine-resistant status epilepticus. Interventions were intravenous lacosamide, levetiracetam, phenobarbital, phenytoin and valproate. Outcome measured is clinically detectable cessation of seizure activity. Level-of-evidence was assessed according to Oxford Centre of Evidence-Based Medicine and The Cochrane Collaboration's Tool for Assessment of Risk. Twenty seven studies (798 cases of convulsive status epilepticus) were identified and 22 included in a meta-analysis. Random-effects analysis of dichotomous outcome of a single group estimate (proportion), with inverse variance weighting, was implemented. Several sources of clinical and methodological heterogeneity were identified. RESULTS: Efficacy of levetiracetam was 68.5% (95% CI: 56.2-78.7%), phenobarbital 73.6% (95% CI: 58.3-84.8%), phenytoin 50.2% (95% CI: 34.2-66.1%) and valproate 75.7% (95% CI: 63.7-84.8%). Lacosamide studies were excluded from the meta-analysis due to insufficient data. CONCLUSION: Valproate, levetiracetam and phenobarbital can all be used as first line therapy in benzodiazepine-resistant status epilepticus. The evidence does not support the first-line use of phenytoin. There is not enough evidence to support the routine use of lacosamide. Randomized controlled trials are urgently needed.

The contribution of British general practice to our knowledge of epilepsy and its effects on people.

INTRODUCTION: British general practice is a good base for epidemiological research which is evidenced by the study of epilepsy. SOURCES OF DATA: A comprehensive search of PubMed using various keywords for articles on epilepsy research performed in British general practice. AREAS OF AGREEMENT: Studies in the setting of general practice have contributed significantly to knowledge in the field of epilepsy, especially in relation to epidemiology, studies of prognosis and treatment patterns and psychosocial aspects. AREAS OF CONTROVERSY: The extent to which epilepsy can be managed in general practice. GROWING POINTS: The importance of primary care research and the importance of collaborative studies between general practice, hospital and university departments. AREAS TIMELY FOR DEVELOPING RESEARCH: The effects of interventions at general practice level on seizure control, morbidity and mortality.

Longitudinal cohort studies of the prognosis of epilepsy: contribution of the National General Practice Study of Epilepsy and other studies.

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.

How phenobarbital revolutionized epilepsy therapy: the story of phenobarbital therapy in epilepsy in the last 100 years.

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.

Treatment changes in a cohort of people with apparently drug-resistant epilepsy: an extended follow-up.

BACKGROUND: The 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. METHODS: The 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. RESULTS: During 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). DISCUSSION: This 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.

Heredity in epilepsy: neurodevelopment, comorbidity, and the neurological trait.

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.

How refractory is refractory epilepsy? Patterns of relapse and remission in people with refractory epilepsy.

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.

The etiologic classification of epilepsy.

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.

The causes of epilepsy: changing concepts of etiology of epilepsy over the past 150 years.

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.

The long-term risk of premature mortality in people with epilepsy.

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.