Neuroimaging in the definition and organization of the epilepsies: we're not there yet

Neuroimaging significantly affects the diagnosis and treatment of patients with patients. Despite its importance, magnetic resonance imaging (MRI) has been marginally incorporated into concepts used to define epilepsy etiologies by the International League Against Epilepsy (ILAE) Classification Commission. We propose that Structural etiology be defined as positive neuroimaging abnormalities likely causing the seizures. This would contrast with Genetic and Unknown etiologies, where imaging shows no overt structural abnormality that explains the seizures. It is further recommended that Structural and Metabolic be separated into individual categories, as the outcomes and therapies are different. It is advocated that Structural etiology be subdivided into subgroups based on MRI and surgical syndromes. With this approach, the ILAE should acknowledge that both MRI and electroencephalography (EEG) are necessary diagnostic tools in the classification of epilepsy syndromes and etiologies in the modern era. Promoting the use of neuroimaging into concepts that determine terminology will promote the notion that epilepsy classification should consider structural etiology of the seizures, along with the frequency of the most common epilepsy syndromes, and prognosis for spontaneous and treated remission and cure.     

Development and psychometric properties of the Thinking about Epilepsy questionnaire assessing children's knowledge and attitudes about epilepsy

OBJECTIVE: Epilepsy is the most common neurological disorder in the world, yet it is still widely misunderstood. A lack of knowledge and negative attitudes about epilepsy are largely blamed for the stigma felt by people with epilepsy and their families. Recent calls for research into stigma have been made by the World Health Organization and international epilepsy organizations. Our objective is to describe the development, structure, and psychometric properties of the Thinking about Epilepsy questionnaire. METHODS: A 36-item questionnaire was designed to assess Grade 5 (ages 9-11) students' knowledge of and attitudes about epilepsy and to evaluate changes in knowledge and attitudes following an epilepsy education program. The questionnaire contains 18 knowledge, 10 attitude, and 8 demographic questions. RESULTS: Psychometric properties of the Thinking about Epilepsy questionnaire were ascertained using data from 783 Grade 5 students. Three items (one knowledge item and two attitude items) were removed prior to the factor analysis due to their low extraction communalities. Factor analysis revealed a bidimensional structure (knowledge and attitudes) with five knowledge factors and two attitude factors. The questionnaire was found to have good internal consistency reliability (Cronbach's alpha=0.74 for knowledge and 0.82 for attitudes). Both the knowledge and attitude measures were deemed to have acceptable face, content, and construct validity. CONCLUSION: The final 33-item Thinking about Epilepsy questionnaire demonstrates adequate reliability for the knowledge measure, good reliability for the attitude measure, and excellent validity for both measures. The Thinking about Epilepsy questionnaire offers a viable option for assessing elementary school students' knowledge and attitudes regarding epilepsy in general or in conjunction with its affiliated Thinking about Epilepsy education program.     

Neuroimaging in epilepsy in tropics

Epilepsy is a major public health problem in many tropical countries. Also, some of the tropical diseases are major contributors to the higher prevalence of epilepsy in these countries. The etiologic factors responsible for epilepsy in these countries are quite different from those in the developed world. This article discusses the etiologic factors and neuroimaging of epilepsy in light of the conditions in these tropical countries.     

Relations of genetic and environmental factors in the etiology of epilepsy

We assessed the relations of genetic and environmental factors in the etiology of epilepsy. The study population comprised 9,705 first-degree relatives of 1,951 adults with epilepsy ascertained from voluntary organizations. We calculated standardized morbidity ratios for specific etiologies of epilepsy in the relatives of probands with the same etiologies, using population incidence rates from Rochester, MN, as the reference. Relatives of probands with idiopathic/cryptogenic epilepsy had increased risk for idiopathic/cryptogenic epilepsy and for epilepsy associated with neurological deficit presumed present at birth (cerebral palsy or mental retardation) but not for symptomatic epilepsy associated with postnatal central nervous system insults. Relatives of probands with neurodeficits had increased risks for idiopathic/ cryptogenic epilepsy. Risk for epilepsy was not increased among relatives of probands with postnatal symptomatic epilepsy. The degree of increased risk of idiopathic/cryptogenic epilepsy in relatives of probands with idiopathiclcryptogenic epilepsy diminished with increasing age of the relatives; risk was not increased at age 35 or older. These findings support the possibility of a shared genetic susceptibility to epilepsy and cerebral palsy, and suggest that the genetic contributions to postnatal symptomatic epilepsy are minimal.     

Genetic predisposition to severe myoclonic epilepsy in infancy

PURPOSE: To address genetic predisposition to febrile convulsions (FCs) and epilepsy as an etiologic background of severe myoclonic epilepsy in infancy (SMEI). METHODS: Familial antecedents of epilepsy and FCs were analyzed in four groups of patients with SMEI (65 cases), FCs (57 cases), childhood absences (67 cases), and a control group of patients with no neurologic problems (64 cases). RESULTS: Patients with SMEI and those with FCs had significantly increased incidence of FCs in their relatives compared with those with absence epilepsy and with the control group. The incidence of epilepsy in relatives of patients with SMEI and absence epilepsy was increased compared with that in the control group and reached statistical significance. Epilepsy in relatives with SMEI had the characteristics of idiopathic generalized epilepsy. CONCLUSIONS: A genetic predisposition could determine three types of epileptic syndromes: FCs, idiopathic generalized epilepsy, and SMEI.     

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.     

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.     

Depression and suicide in epileptic victims: a population-based study of suicide victims during the years 1988-2002 in northern Finland

Patients with epilepsy are known to have comorbid affective disorders and a higher risk for suicide compared with the general population. Epilepsy, depression, and suicidal behavior have been shown to have common pathogenic mechanisms in their etiology. We evaluated the association between epilepsy, suicidal behavior, and depression by using the comprehensive database of all suicides (n=1877) committed in northern Finland during the years 1988-2002 with information on all hospital-treated somatic and psychiatric disorders. Hospital-treated epilepsy occurred in 1.3% of the victims. Compared with other suicide victims, those with epilepsy were more often female, were older, and had significantly more often suffered from depression. Epilepsy was first diagnosed 8.8 (3.9-11.6) years before suicide, and depression, about 1 year after epilepsy diagnosis. Interictal depression among patients with chronic epilepsy is often classified as atypical or chronic depression, or it can mimic a dysthymic disorder. Therefore, diagnosis and treatment of depression among patients with epilepsy constitute a great challenge in clinical practice.     

Knowledge, attitudes, behaviors, and practices regarding epilepsy among Zambian clerics

BACKGROUND: Epilepsy carries a high burden of social morbidity. An understanding of who propagates stigma and the determinants of stigmatizing attitudes is needed to develop effective interventions. Clerics represent an especially influential social group in Africa. Therefore, we conducted a survey of the knowledge, attitudes, behavior, and practices of Zambian clerics with respect to epilepsy. METHODS: We studied clerics in one large rural region as well as in the capital city. The rural survey was conducted door-to-door. In the urban areas, central administration for multiple denominations assisted in survey delivery. The survey, adapted from previously published instruments, included cleric-specific questions and demographic data. Composite scores for knowledge and tolerance were developed. Determinants of higher knowledge and tolerance were assessed. RESULTS: Almost all Zambian clerics know someone with epilepsy and have witnessed a seizure. More than 40% report having a family member with epilepsy. Unfortunately, this familiarity is not associated with more knowledge or tolerance for the condition. Younger clerics, urban dwellers, those with fewer children, and those with more years of formal education were significantly more tolerant. More knowledgeable clerics are more likely to recommend that a person with epilepsy seek care from a physician rather than a traditional healer. Formal education was the most important factor in determining tolerance toward epilepsy. CONCLUSIONS: Zambian clerics are very familiar with epilepsy, yet have relatively little knowledge of the etiology. Many view traditional healers as the appropriate care provider for epilepsy. To decrease stigma and improve the quality of advice offered by clerics to their congregations, educational programs focusing on the biomedical nature of the disorder are needed, particularly in rural regions.     

Racial/ethnic disparities in the treatment of epilepsy: what do we know? What do we need to know?

We examine current understanding of the minority disadvantage in the clinical management of epilepsy. We performed an online literature search using several keywords (race, ethnicity, epilepsy, treatment, and quality of life) and identified additional literature through cross-referencing/manual search. The search produced 58 items published between 1977 and 2005. Of 49 original research studies, 38 were quantitative, 7 were qualitative, and 4 used mixed methods. Three or more articles were published in Epilepsia, Epilepsy &Behavior, Epilepsy Research, Neurology, and Seizure. Research concerning racial/ethnic differences in epilepsy treatment is scarce and limited by methodology, but suggests underutilization of state-of-the-art therapies by minorities. Racial/ethnic minorities also appear to have limited knowledge about epilepsy and its treatment, experience barriers to care, lack social support, and seek alternative therapies for epilepsy. We propose a framework to identify the array of disparities, points of intervention, and interventions.     

Information on Sudden Deaths from Epilepsy

Summary: Epilepsy Bereaved? is a charity representing those who have experienced the sudden death of a loved one due to epilepsy. Many individuals with epilepsy, as well as their partners, relatives, and friends, are unaware of the risk for sudden unexpected death in epilepsy (SUDEP). Much of the literature available does not include information on SUDEP. When information is given, the risk for SUDEP may be underestimated. Epilepsy Bereaved? believes that people with epilepsy and their partners, families, and friends have the same right to be informed as any others dealing with a chronic condition, unless they express a wish to the contrary. Information should include the risk for SUDEP. Bereaved families agree that they would rather have been informed of the risks than left ignorant. Increased awareness and understanding of this condition may help improve treatment compliance and enable individuals to take measures to reduce the risk for sudden death.     

Stress,seizures, and hypothalamic–pituitary–adrenal axis targets for the treatment of epilepsy

Epilepsy is a heterogeneous condition with varying etiologies including genetics, infection, trauma, vascular, neoplasms, and toxic exposures. The overlap of psychiatric comorbidity adds to the challenge of optimal treatment for people with epilepsy. Seizure episodes themselves may have varying triggers; however, for decades, stress has been commonly and consistently suspected to be a trigger for seizure events. This paper explores the relationship between stress and seizures and reviews clinical data as well as animal studies that increasingly corroborate the impact of stress hormones on neuronal excitability and seizure susceptibility. The basis for enthusiasm for targeting glucocorticoid receptors for the treatment of epilepsy and the mixed results of such treatment efforts are reviewed. In addition, this paper will highlight recent findings identifying a regulatory pathway controlling the body's physiological response to stress which represents a novel therapeutic target for modulation of the hypothalamic–pituitary–adrenal (HPA) axis. Thus, the HPA axis may have important clinical implications for seizure control and imply use of anticonvulsants that influence this neuronal pathway.This article is part of a Special Issue entitled “The Future of Translational Epilepsy Research”.     

Functional MRI and structural MRI as tools for understanding comorbid conditions in children with epilepsy

Children with epilepsy are at risk for behavioral and cognitive comorbidities. Potential etiologies can be assessed in part by neuroimaging. Functional magnetic resonance imaging (MRI) has a major role in presurgical evaluation and prediction of postoperative outcome by mapping of language and memory. Structural MRI and functional MRI have shown changes in children and adolescents with attention deficit hyperactivity disorder and disruptive behavior, common comorbidities in children with epilepsy. Neuroimaging has the potential for significantly increasing understanding of the basis of cognitive and behavioral problems in children with epilepsy.This article is part of a Special Issue entitled “The Future of Translational Epilepsy Research”.     

Diagnostic difficulty in infants and children

Making an accurate diagnosis is the first and most critical step in the treatment of pediatric epilepsy, but it can be a daunting challenge for clinicians. Seizure types and syndromes in infants and very young children do not present with the same clarity and consistency as in adults. Work is currently being done to revise traditional International League Against Epilepsy classifications to make it easier for physicians to accurately diagnose and effectively treat epilepsy in infants and young children. A simplified approach can be formed by combining some of the International League Against Epilepsy recommendations with new findings on the clinical manifestations of pediatric seizures. Refinements in the new system will occur as knowledge of the pathophysiology of epilepsy and genetic susceptibilities expands, but even in its early stages the new classification system has much to offer, resulting in improved patient care and more effective management of the disease.     

Evaluation of HCN2 abnormalities as a cause of juvenile audiogenic seizures in Black Swiss mice

Epilepsy is an often-debilitating disease with many etiologies. Genetic predisposition is common for many of the generalized epilepsy syndromes, and mutations in genes encoding neuronal ion channels are causative in many cases. We previously identified a locus for juvenile audiogenic monogenic seizures (jams1) in the Black Swiss mouse strain, delimited by the gene basigin (Bsg) and the marker D10Mit140. This region includes Hcn2, the gene encoding the hyperpolarization-activated cyclic nucleotide-gated channel subunit 2 (HCN2), an ion channel implicated in epilepsy. By sequencing genomic DNA, we found that Black Swiss mice have a single polymorphism in exon 2 within the Hcn2 gene. This single G/C to A/T base change alters the third position of a codon specifying alanine residue 293, without changing the predicted amino acid sequence. Furthermore, we found no detectable differences in HCN2 protein expression in the brains of Black Swiss mice, compared to control mice. We therefore reason that juvenile audiogenic seizures in Black Swiss mice are unlikely to be due to abnormalities of HCN2 channel function.     

Linkage analysis and exome sequencing identify a novel mutation in KCTD7 in patients with progressive myoclonus epilepsy with ataxia

Epilepsy affects approximately 1% of the world's population. Genetic factors and acquired etiologies, as well as a range of environmental triggers, together contribute to epileptogenesis. We have identified a family with three daughters affected with progressive myoclonus epilepsy with ataxia. Clinical details of the onset and progression of the neurologic presentation, epileptic seizures, and the natural history of progression over a 10‐year period are described. Using autozygosity genetic mapping, we identified a high likelihood homozygous region on chromosome 7p12.1‐7q11.22. We subsequently applied whole‐exome sequencing and employed a rare variant prioritization analysis within the homozygous region. We identified p.Tyr276Cys in the potassium channel tetramerization domain–containing seven gene, KCTD7, which is expressed predominantly in the brain. Mutations in this gene have been implicated previously in epileptic phenotypes due to disturbances in potassium channel conductance. Pathogenicity of the mutation was supported by bioinformatic predictive analyses and variant cosegregation within the family. Further biologic validation is necessary to fully characterize the pathogenic mechanisms that explain the phenotypic causes of epilepsy with ataxia in these patients.     

Education of a child neurologist: epilepsy and electroencephalography

Epilepsy is one of the most common disorders encountered in pediatric neurology. A well-trained child neurologist should have an understanding of the neurobiological causes of seizures, classification of seizures and epilepsy, etiologic evaluation, and treatment of both seizures and associated comorbid conditions. Electroencephalography (EEG) is an important diagnostic test in epilepsy, and child neurologists should be knowledgeable in the physiological basis of EEG and how to identify normal and abnormal patterns in neonates and children.     

Efficacy of the ketogenic diet: Which epilepsies respond?

We report the efficacy of the ketogenic diet in refractory epilepsies focusing on outcomes with regard to epilepsy syndromes and etiology in children and adults with refractory epilepsy. Sixty-four consecutive children and four adults were prospectively enrolled from 2002 to 2009; seven were excluded from analysis. The classical ketogenic diet was initiated on an inpatient basis with dietary ratios ranging from 2:1 to 4:1 fat to carbohydrate and protein. Patients were classified according to syndrome and etiology using the 1989 and more recent 2010 International League Against Epilepsy (ILAE) classification systems. Responders were defined as >50% reduction in seizure frequency compared to baseline. Syndromes included symptomatic generalized (52), genetic (idiopathic) generalized (7), and focal epilepsies (2) and etiologies included structural (24), genetic (18), and unknown (19). Twenty-nine (48%) of 61 patients were responders at 3 months. Two children became seizure-free: one with focal epilepsy of unknown etiology and another with refractory childhood absence epilepsy. Responsive syndromes included migrating partial epilepsy of infancy, childhood absence epilepsy, focal epilepsy, epilepsy with myoclonic-atonic seizures, and Dravet syndrome. Children with lissencephaly and hypoxic ischemic encephalopathy had surprisingly good responses. The ketogenic diet is an effective treatment for children and adults with refractory epilepsy. The response is predicted by type of epilepsy syndrome. Accurate characterization of the electroclinical syndrome is an important factor in decisions about timing of initiation of the ketogenic diet.     

Neurostimulation for the Treatment of Epilepsy: A Review of Current Surgical Interventions

Objectives: Epilepsy continues to provide challenges to clinicians, as a significant proportion of patients continue to suffer from seizures despite medical and surgical treatments. Neurostimulation has emerged as a new treatment modality that has the potential to improve quality of life and occasionally be curative for patients with medically refractory epilepsy who are not surgical candidates. In order to continue to advance the frontier of this field, it is imperative to have a firm grasp of the current body of knowledge. Methods: We performed a thorough review of the current literature regarding the three main modalities of vagus nerve stimulation, deep brain stimulation, and closed‐loop stimulation (responsive neurostimulator [RNS]) for the treatment of refractory epilepsy. For each of these forms of treatment, we discuss the current understanding of the underlying mechanism of action, patient selection, outcomes to date, and associated side effects or adverse reactions. We also provide an overview of related ongoing clinical trials. Results: A total of 189 sources from 1938 to 2012 pertaining to neuromodulation for the treatment of epilepsy were reviewed. Sources included review articles, clinical trials, case reports, conference proceedings, animal studies, and government data bases. Conclusions: This review shows us how neurostimulation provides us with yet another tool with which to treat the complex disease of medically refractory epilepsy.