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.     

Mortality in children with severe epilepsy: 10 years of follow-up

Epilepsy is the main neurological condition in children and adolescents. Unfortunately patients with medical refractory epilepsy are more susceptible for clinical complications and death. We report a prospectively evaluated cohort of children followed for approximately 10 years. Fifty-three of 1012 patients died. Forty-two patients died due to epilepsy or its clinical complications and the main causes of death were pneumonia (in 16 cases), sepsis (in 9 patients), status epilepticus (in 8 patients). In 11 patients cause of death was sudden unexpected death in epilepsy (SUDEP). Mental retardation was significantly more frequent in patients who did not die from SUDEP. SUDEP may be a significant condition associated with mortality in children and adolescents with epilepsy.     

Valproic acid for children below 2 years of age with epilepsy

Objectives:To evaluate the efficacy of valproic acid (VPA) in a cohort of children below 2 years of age. We also aim to review the characteristics of such patients and the role and safety of VPA for this age group.Methods:A retrospective chart review conducted at King Abdulaziz University Hospital, Jeddah, Kingdome of Saudi Arabia, for children below 2 years of age diagnosed with epilepsy and treated with valproic acid from January 2016 to January 2020.Results:The cohort for this study includes 50 children below the age of 2 years (25 males, 25 females). Aged 3 months to 23 months at commencing valproic acid. The mean age of seizure onset was 9 months and the mean age of starting valproic acid was 16 months. Thirty-two patients (64%) had more than 50% seizure improvement after valproic acid. Eleven patients (22%) were seizure-free. No statistical significance abnormalities in blood count indices and ammonia were seen during the treatment period. Two patients had dose-related lethargy that improved after decreasing their dosage. Asymptomatic mild elevation in glutamate dehydrogenase was noticed in 18% of patients.Conclusion:Using valproic acid in infants and children below the age of 2 years can be considered as a safe and effective treatment option for epilepsy in this age group.

Epilepsy is a major neurological disorder that occurs across different age groups. Children below the age of 2 years are an important subcategory. They are more prone to have seizures compared to older children.¹ Moreover, uncontrolled seizures in early life can result in poor outcomes on cognition, motor and language development.² Seizure-freedom in children below 2 years ranges between 49–57% compared to >60% in older children.^3,4 A myriad group of etiologies can result in seizures in this vulnerable age group including: electrolytes disturbances, asphyxia, inborn errors of metabolism, structural brain etiologies, infection and genetic etiologies. Brain ion channels, neurotransmitters and cellular maturation is unique in this age group making them at higher risk for seizures. Response to antiseizure medications (ASMs) also is different in this category of patients.⁵ Safety and options of ASMs is also another challenge.Multiple electroclinical epilepsy syndromes occur in this category like West syndrome, Dravet syndrome and myoclonic epilepsy which can be challenging to treat. Most available ASMs has not been studied in this age group. Valproic acid (VPA) has been available as a treatment for more than 50 years. It is classified as broad spectrum ASM. It is one of old generation ASM with few side effects reported.⁶ Its use below the age of 2 years is limited by its potential hepatotoxicity especially when used as polytherapy or in high dosage. Other factors like POLG mutation and mitochondrial disease could increase the chance for hepatic insult.⁷The incidence of hepatotoxicity in children in general is higher than adults, 1:5000 compared to 1:40000, respectively. Multiple proposed mechanisms have been implicated like reduction of intracellular CoA, defects of oxidative phosphorylation and inhibition of gluconeogenesis.^8,9The aim of this study is to evaluate the efficacy and safety of valproic acid (VPA) in this age group and to review the clinical characteristics of this cohort. Few studies in literature evaluated VPA usage below the age of 2 years.^7,9     

Cognitive functioning over 3 years in community dwelling older adults with chronic partial epilepsy

Little is known about cognitive functioning of older adults with chronic partial epilepsy. We examined cognitive performance of this epilepsy patient group over 2-3 years. Seventeen older adults with epilepsy and 17 healthy older adults were administered measures of overall cognition and verbal memory at baseline and 2-3 years later. At baseline, older adults with epilepsy performed below controls on overall cognition and verbal memory (p's<0.001). These deficits generally remained stable at follow-up, although executive control appeared to decline (p<0.05). Older adults with epilepsy showed a failure to benefit from practice on a verbal memory measure (p=0.017). Older adults with epilepsy demonstrated cognitive deficits that generally are not progressive. A failure to benefit from repeat exposure to a Delayed Recall task could indicate learning deficits. These patients may also progressively lose executive control, possibly as a result of accelerated aging.     

Stability of adaptive behaviors in middle-school children with autism spectrum disorders

This 5-year follow-up study examined the stability of adaptive functioning in two cognitive ability groups of children with an autism spectrum disorder (ASD). Nonverbal intelligence (NVIQ) was assessed at the time of this study and no participant changed cognitive group membership from the previous study (High NVIQ ≥ 97; Low NVIQ ≤ 56). In each group, adaptive skills, as measured by the Vineland Adaptive Behavior Scales (VABS) composite standard score, were significantly below NVIQ. Both groups exhibited a significant decrease in the VABS composite standard scores over time, but analysis of VABS total raw scores showed a significant increase in adaptive functioning over time in the High NVIQ group with no change in the Low NVIQ group. Examining the profile of VABS age equivalent scores in each NVIQ group revealed potential suggestions for interventionists. Caregivers of the Low NVIQ group endorsed having significantly higher stress levels related to their child's level of adaptive functioning. Groups did not differ significantly in the quantity of treatment received within the 9 months preceding this study or caregiver satisfaction with intervention services. Caregivers from both groups identified a variety of school-based service needs to address their child's adaptive skill deficits.     

Family function in cognitively normal children with epilepsy: impact on competence and problem behaviors

A cross-sectional cohort of 82 cognitively normal children with epilepsy attending the pediatric neurology clinic, who were aged 6-17 years and who had a similarly aged sibling without seizures or cognitive delay, were identified. The parent was asked to complete the Family Assessment Measure III (FAM-III) as well as the Child Behavior Checklist (CBCL) for both the child with epilepsy and his or her sibling. The Overall Rating Score on FAM-III did not differ significantly from the normative mean, although families scored significantly better on the Involvement subscale and significantly worse on the Role Performance subscale. Moderate correlations were found between competence and behavior problems and family function in both children with epilepsy and their siblings. In families functioning at the highest level, both cohorts did well. In those at the lowest level, approximately half of the children in either cohort had problems. For average functioning families, behavior and competence issues were more frequent in children with epilepsy than their siblings.     

Postoperative improvement of executive function and adaptive behavior in children with intractable epilepsy

IntroductionAn alteration in postoperative cognitive function varies according to the patients’ background characteristics, such as etiology, focus, and seizure duration. Accurate prediction and assessment of postoperative cognitive function is difficult in each patient. Adaptive behavior could describe the typical performance of daily activities and represents the ability to translate cognitive potential into real-world skills. We examined the relationship between alterations of executive function (EF) and adaptive behavior in school children undergoing surgery for intractable epilepsy.MethodologyWe enrolled 31 children with focal resection or corpus callosotomy for intractable epilepsy [mean age at surgery, 12.5 years; 16 boys; mean intellectual quotient, 73.3]. We surveyed answered questionnaires on attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and adaptive behavior using the Vineland Adaptive Behavior Scale, 2nd edition (VABS-II), and performed continuous performance tests (CPTs) on children pre- and postoperatively.ResultADHD and ASD symptoms improved after epilepsy surgery. The omission error (OE) in the CPT variable improved after epilepsy surgery, especially in children with a shorter preoperative period. Improved ASD symptoms led to an increased score of the coping skills subdomain. The reduced OE observed after surgery also increased the score of the community skills subdomain.ConclusionImprovement in EF and ASD symptoms resulted in better adaptive behavior postoperatively. These results were important for the pre- and postoperative evaluation and re-evaluation of children with epilepsy requiring special education and related services.     

Examining perceived stigma of children with newly-diagnosed epilepsy and their caregivers over a two-year period

The purpose of this study was to examine the following: 1) the course of perceived epilepsy-related stigma among children newly diagnosed with epilepsy (n = 39) and their caregivers (n = 97) over a two-year period, 2) the influence of seizure absence/presence on children and caregivers' perception of epilepsy-related stigma, and 3) the congruence of child and caregiver perception of child epilepsy-related stigma. Participants completed a measure of perceived epilepsy-related stigma at three time points, and seizure status was collected at the final time point. Results indicated that both caregivers (t_1,76 = − 2.57, p < .01) and children with epilepsy (t_1,29 = − 3.37, p < .01) reported decreasing epilepsy-related stigma from diagnosis to two years postdiagnosis. No significant differences were found in caregiver and child reports of perceived stigma for children experiencing seizures compared with children who have been seizure-free for the past year. Results revealed poor caregiver–child agreement of perceived epilepsy-related stigma at all three time points. These data suggest that while children with epilepsy initially perceive epilepsy-related stigma at diagnosis, their perception of stigma decreases over time. Having a better understanding of the course of epilepsy-related stigma provides clinicians with information regarding critical times to support families with stigma reduction interventions.     

Hemispheric surgery in children with refractory epilepsy: seizure outcome, complications, and adaptive function

PURPOSE: To describe seizure control, complications, adaptive function and language skills following hemispheric surgery for epilepsy. METHODS: Retrospective chart review of patients who underwent hemispheric surgery from July 1993 to June 2004 with a minimum follow-up of 12 months. RESULTS: The study population comprised 24 children, median age at seizure onset six months and median age at surgery 41 months. Etiology included malformations of cortical development (7), infarction (7), Sturge-Weber Syndrome (6), and Rasmussen's encephalitis (4). The most frequent complication was intraoperative bleeding (17 transfused). Age <2 yr, weight <11 kg, and hemidecortication were risk factors for transfusion. Postoperative complications included aseptic meningitis (6), and hydrocephalus (3). At median follow-up of 7 yr, 79% of patients are seizure free. Children with malformations of cortical development and Rasmussen's encephalitis were more likely to have ongoing seizures. Overall adaptive function scores were low, but relative strengths in verbal abilities were observed. Shorter duration of epilepsy prior to surgery was related significantly to better adaptive functioning. CONCLUSIONS: Hemispheric surgery is an effective therapy for refractory epilepsy in children. The most common complication was bleeding. Duration of epilepsy prior to surgery is an important factor in determining adaptive outcome.     

Reliable change indices and standardized regression-based change score norms for evaluating neuropsychological change in children with epilepsy

Reliable change indices (RCIs) and standardized regression-based (SRB) change score norms permit evaluation of meaningful changes in test scores following treatment interventions, like epilepsy surgery, while accounting for test–retest reliability, practice effects, score fluctuations due to error, and relevant clinical and demographic factors. Although these methods are frequently used to assess cognitive change after epilepsy surgery in adults, they have not been widely applied to examine cognitive change in children with epilepsy. The goal of the current study was to develop RCIs and SRB change score norms for use in children with epilepsy. Sixty-three children with epilepsy (age range: 6–16; M = 10.19, SD = 2.58) underwent comprehensive neuropsychological evaluations at two time points an average of 12 months apart. Practice effect-adjusted RCIs and SRB change score norms were calculated for all cognitive measures in the battery. Practice effects were quite variable across the neuropsychological measures, with the greatest differences observed among older children, particularly on the Children's Memory Scale and Wisconsin Card Sorting Test. There was also notable variability in test–retest reliabilities across measures in the battery, with coefficients ranging from 0.14 to 0.92. Reliable change indices and SRB change score norms for use in assessing meaningful cognitive change in children following epilepsy surgery are provided for measures with reliability coefficients above 0.50. This is the first study to provide RCIs and SRB change score norms for a comprehensive neuropsychological battery based on a large sample of children with epilepsy. Tables to aid in evaluating cognitive changes in children who have undergone epilepsy surgery are provided for clinical use. An Excel sheet to perform all relevant calculations is also available to interested clinicians or researchers.     

The challenge of evaluating rehabilitative activity holidays for burn-injured children: qualitative and quantitative outcome data from a Burns Camp over a five-year period

Specialized holidays for burn-injured children are currently considered an important part of their rehabilitation. These holidays, or Camps, aim to help children face the challenges of their burn injury and treatment in a fun and supportive environment. Manchester Children's Burns Camps have been run by professionals from the Burns Unit at Booth Hall Children's Hospital together with volunteers since 1983. Formal evaluation has been a crucial component of these Camps since 1999. The purpose of this study was to summarize the findings of the evaluation process over the last 5 years, and to discuss any issues raised by the results. Standardized measures were administered to 97 children and their parents over this time period. These measures, designed to assess self-esteem, social relationships and general emotional and behavioural well-being, were completed before and after the children attended the Camp. The quantitative data showed little consistent evidence of change on these measures over the 5 years. However, the qualitative data shows consistent themes of increased confidence and improved coping with the burn injury, amongst others. The discrepancy between the quantitative and qualitative results is discussed, and implications and challenges for further evaluation of Burns Camps are raised.     

Efficacy of levetiracetam in children with epilepsy younger than 2 years of age

Despite the high incidence of epilepsy in very young children, the availability of approved antiepileptic drugs for this population is limited. This study assessed the efficacy and tolerability of levetiracetam in children younger than 2 years of age with various types of epilepsy. A single-center, retrospective chart review of 28 patients ranging in age from 2 weeks to 22 months treated with levetiracetam over a 2.5-year period was conducted. The mean dosage of levetiracetam was 39 mg/kg per day, and the mean duration of treatment was 6.3 months. The majority of patients (54%) were also taking 1 or 2 other antiepileptic drugs. A reduction in seizure frequency was found in 54%, with 14% achieving seizure freedom. Eight patients showed no response to levetiracetam treatment. Efficacy was highest among patients with generalized epilepsy. Adverse effects occurred in 2 patients and were behavioral in nature. Levetiracetam treatment was safe and effective in this group of very young patients with various types of epilepsy.     

Cost-effectiveness analysis of epilepsy surgery in children and adolescents with drug resistant focal epilepsy at three years in a tertiary care epilepsy center in Thailand

Epilepsy surgery is proven as a cost-effective treatment in developed countries, especially in adults with drug resistant epilepsy (DRE). This study is aimed to demonstrate the cost-effectiveness of epilepsy surgery in children and adolescents with DRE at three years compared with those who were eligible for surgery but received medical treatment. This study was conducted from January 2014 to December 2018. Clinical data were obtained from a retrospective chart review. Direct medical costs, including epilepsy surgery, inpatient and outpatient treatment were retrieved from the finance department. Direct non-medical costs were collected from the family interview. The effectiveness was determined by percent seizure reduction and quality of life assessed by EQ-5D scores. Decision tree analysis using TreeAge Pro® 2018 was deployed to determine the cost-effectiveness. Seventeen patients had epilepsy surgery and 19 were in the medical group. Seizure freedom was noted in 52% and 16% in the surgical and medical groups, respectively. Incremental cost-effectiveness ratio (ICER) was 743,040 THB (22,793 USD) per 1 QALY and 3302 THB (101 USD) per 1% seizure reduction. The study did not demonstrate cost-effectiveness of epilepsy surgery in the short term compared with Thailand’s threshold (160,000 THB (4908 USD) per 1 QALY). Epilepsy surgery may be cost-effective if evaluated beyond three years.     

Helping parents and children with epilepsy cope successfully: The outcome of a group programme for parents

This paper describes a study to determine the effectiveness of a group programme for parents designed to reduce the psychosocial morbidity among children with epilepsy and their families. The participants were the parents children attending the seizure clinic at a children's hospital. The first part of the project had shown that half of the children and their families had considerable morbidity. Despite the high rate of psychosocial morbidity among these children and thier families, only 35% of the parents expressed an interest in participation in the intervention programme, with only 12% attending any meetings. The latter were mainly the small number of parents whose children had severe intractable epilepsy as well as educational and family problems. Many parents did, however, request more information about epilepsy and for the provision of a counselling service. The latter is likely to be most beneficial in the months following diagnosis.     

Social support for self-management behaviors among people with epilepsy: a content analysis of the WebEase program

Social support is an important component in managing epilepsy; however little is known about support provided to people with epilepsy. This study examined whom people with epilepsy identify as supportive, and how those individuals support people with epilepsy's self-management efforts. Data come from the WebEase project, an effective online epilepsy self-management program. People with epilepsy who participated in the pilot (n=35) and efficacy trials (n=118) were included. A content analysis was conducted on responses to open-ended questions related to support. The majority of participants provided information about their supporters. The number of support providers ranged from 0 to 6, with about 12% indicating no support. Parents and significant others were most commonly listed as supporters. Support providers mainly offer emotional and instrumental support, reminders and aid for taking medication, and support for self-management strategies. These results could be useful for interventions aimed at bolstering support in order to improve self-management.     

famoses: a modular educational program for children with epilepsy and their parents

BackgroundIt is known that most adult patients with epilepsy often have poor knowledge of their disorder, treatment options, and social and vocational consequences, despite the huge amount of information available. Being pressed for time, health care professionals often are not able to provide the repetitive counseling and instruction necessary to address epilepsy care adequately. Therefore educational programs are considered extremely important in filling the gap.MethodFor German-speaking countries, two educational programs called famoses, modulares Schulungsprogramm Epilepsie fűr Familien [modular service package epilepsy for families], were developed by a multidisciplinary group of neuropediatricians, psychologists, social workers, and educators. The aims of the famoses programs are to improve children’s and parents’ knowledge about epilepsy and to help patients of childhood age and their parents achieve a better understanding of their disease, gain more self-confidence, and reduce specific fears regarding epilepsy. famoses comprises two different educational programs: famoses for kids with epilepsy within the developmental period of ages 7 to 13, and famoses for parents or caretakers. The programs are designed for interactive small-group education.ResultsThe child-centered educational program is based on a fictional story: The children are sailors on a virtual cruise, sailing from island to island, accompanied by educated trainers. On each island there is something new to discover about epilepsy. The parent (and caretaker)-centered educational program covers different topics—overview and content of the program, basic knowledge, diagnostics, therapy, prognosis and development, and living with epilepsy—within six modules. The program was implemented in Germany and Switzerland in the spring of 2005 and is now operating in different epilepsy centers.ConclusionWithin comprehensive therapeutic management of epilepsy, educational programs for patients, and for parents (caretakers) of children with epilepsy, are considered to be extremely important. Such educational programs have two main goals: to increase knowledge about the disorder, and to strengthen the patients’ responsibility for themselves, with the consequence of living with as few limitations as possible. famoses is an effective component of this comprehensive care. The program has been operating successfully in different epilepsy centers in Germany and Switzerland since the spring of 2005.