Stiripentol in Dravet syndrome: results of a retrospective U.S. study.

PURPOSE: To review the efficacy and tolerability of stiripentol in the treatment of U.S. children with Dravet syndrome. METHODS: U.S. clinicians who had prescribed stiripentol for two or more children with Dravet syndrome between March 2005 and 2012 were contacted to request participation in this retrospective study. Data collected included overall seizure frequency, frequency of prolonged seizures, and use of rescue medications and emergency room (ER)/hospital visits in the year preceding stiripentol initiation, and with stiripentol therapy. We separately assessed efficacy in the following treatment groups: group A, stiripentol without clobazam or valproate; group B, stiripentol with clobazam but without valproate; group C, stiripentol with valproate but without clobazam; and group D, stiripentol with clobazam and valproate. In addition, adverse effects were recorded. KEY FINDINGS: Thirteen of 16 clinicians contacted for study participated and provided data on 82 children. Stiripentol was initiated a median of 6.0 years after seizure onset and 1.2 years after diagnosis of Dravet syndrome. Compared to baseline, overall seizure frequency was reduced in 2/6 in group A, 28/35 in group B, 8/14 in group C, and 30/48 in group D. All children with prolonged seizure frequency greater than quarterly during the baseline period experienced a reduction in this frequency on the various treatment arms with stiripentol. Similarly, 2/4 patients in group A, 25/25 in group B, 5/10 in group C, and 26/33 in group D experienced reduction in frequency of rescue medication use and 1/1 in group A, 12/12 in group B, 3/5 in group C, and 18/19 in group D had reduction in frequency of ER/hospital visits. Adverse effects were reported in 38, most commonly sedation and reduced appetite. Four patients (5%) discontinued stiripentol for adverse effects and two (2%) for lack of efficacy. SIGNIFICANCE: Stiripentol is an effective and well-tolerated therapy that markedly reduced frequency of prolonged seizures in Dravet syndrome.

Social outcomes after temporal or extratemporal epilepsy surgery: a systematic review.

PURPOSE: The objective of this study was to systematically review the literature to assess social outcomes after epilepsy surgery. METHODS: A systematic literature search was conducted as part of a larger project on the development of an appropriateness and necessity rating tool to identify patients with focal epilepsy that may benefit from an epilepsy surgery evaluation. Studies were included if they reported postsurgical data on social outcomes (employment, driving, social relationships, marriage, education, financial status, behavior, and social interactions) and had a follow-up period of at least 24 months. Our search strategy yielded 5,061 studies. Sixty-five of these studies addressed social outcomes, but only 19 met all eligibility criteria. KEY FINDINGS: In adults, a significant improvement in full-time employment postsurgery was documented. The ability to drive was significantly increased after surgery and was dependent on seizure freedom. Patients generally perceived improved relationships, independence, and overall lifestyle postsurgery. Marital status generally remained unchanged when compared to controls, education improved modestly, and income/financial status changes depended on how it was assessed (e.g., income level vs. receipt of disability pension). In children, a study examining behavior showed improved social interactions in those who underwent surgery compared to controls. The results for other social outcome categories were more variable. SIGNIFICANCE: Overall, the majority of studies reported improvement in social outcomes after surgery. However, prospective controlled observational studies using objective social outcome measures are necessary prior to making specific conclusions about the influence of surgery on social outcomes other than employment or driving status in all age groups, but particularly in children and the elderly.

Child psychiatry.

This paper first summarizes the main findings of clinical studies conducted over the past two and a half decades on psychopathology (i.e., psychiatric diagnoses, behavior and emotional problems) in children with new onset and chronic epilepsy both with and without intellectual disability who are treated medically and surgically. Although impaired social relationships are core features of the psychiatric disorders found in pediatric epilepsy, few studies have examined social competence (i.e., social behavior, social adjustment, and social cognition) in these children. There also is a dearth of treatment studies on the frequent psychiatric comorbidities of pediatric epilepsy, attention deficit hyperactivity disorder, anxiety disorders, and depression. Drs. Hamiwka and Jones then describe their current and planned studies on social competence and cognitive behavioral treatment of anxiety disorders, respectively, in these children and how they might mitigate the poor long-term psychiatric and social outcome of pediatric epilepsy.

Social skills in children with epilepsy: how do they compare to healthy and chronic disease controls?

Studies have shown poor long-term social outcomes in adults with childhood-onset epilepsy. Our goal was to compare social skills in children with epilepsy with those of healthy and chronic disease controls. Children (8-16 years) with epilepsy (n=59) were compared with age- and gender-matched children with chronic kidney disease (n=40) and healthy controls (n=41). Parents completed the Social Skills Rating System (SSRS) questionnaire. Children with epilepsy had significantly poorer SSRS total scores when compared with healthy controls (P=0.002); however, their scores did not differ from those of children with chronic kidney disease (P=0.52). Children with epilepsy were less cooperative (P=0.02), less assertive (P=0.004), and less responsible (P=0.05) and displayed poorer self-control (P=0.005) than healthy controls. Our results suggest that having a chronic disease plays a role in the social functioning of children with epilepsy. The impact of epilepsy itself on social functioning should be further elucidated through detailed prospective assessments over time.

Current dipole orientation and distribution of epileptiform activity correlates with cortical thinning in left mesiotemporal epilepsy.

To evaluate cortical architecture in mesial temporal lobe epilepsy (MTLE) with respect to electrophysiology, we analyze both magnetic resonance imaging (MRI) and magnetoencephalography (MEG) in 19 patients with left MTLE. We divide the patients into two groups: 9 patients (Group A) have vertically oriented antero-medial equivalent current dipoles (ECDs). 10 patients (Group B) have ECDs that are diversely oriented and widely distributed. Group analysis of MRI data shows widespread cortical thinning in Group B compared with Group A, in the left hemisphere involving the cingulate, supramarginal, occipitotemporal and parahippocampal gyri, precuneus and parietal lobule, and in the right hemisphere involving the fronto-medial, -central and -basal gyri and the precuneus. These results suggest that regardless of the presence of hippocampal sclerosis, in a subgroup of patients with MTLE a large cortical network is affected. This finding may, in part, explain the unfavorable outcome in some MTLE patients after epilepsy surgery.

The incidence of injuries in persons with and without epilepsy--a population-based study.

PURPOSE: To compare the 1-year population-based incidence and types of injuries in persons with and without epilepsy. METHODS: Three administrative databases (inpatient visits, physician claims, and emergency room visits) were linked from fiscal years 1996-2003 using a provincial insurance plan registry, which captures 99% of a population of 1.4 million in a large Canadian health region. Epilepsy cases (all age groups) from fiscal year 1996-2002 were identified. Three people without epilepsy were matched to one person with epilepsy for age (±1 year) and sex. Injuries were defined as any of 16 types of injuries for which medical attention was sought that occurred within fiscal year 2003. RESULTS: Eight thousand eight hundred ninety subjects with epilepsy were identified and matched to 26,670 controls for age and sex. The mean age was 37.4 years (range 0.01-96.4 years), and 51.3% of subjects were male. The 1-year incidence of one or more injuries was 20.6% among persons with epilepsy and 16.1% among those without epilepsy (p < 0.001). Of the 16 types of injuries studied, 11 were higher in persons with epilepsy compared to those without epilepsy, and included fractures, crushing injuries, intracranial injuries, other types of head injuries, and multiple injuries. The difference was still significant after adjusting for age, gender, and comorbidities. DISCUSSION: The 1-year incidence of injuries in this study was greater in persons with epilepsy compared to those without epilepsy, for nearly all injury types. Injury prevention should be discussed during routine visits in persons with epilepsy.

Are children with epilepsy at greater risk for bullying than their peers?

The primary goal of this study was to determine the prevalence of bullying in children with epilepsy compared with their healthy peers and peers with chronic disease. Children with epilepsy were compared with healthy children and a cohort of children with chronic kidney disease (CKD). The following self-report questionnaires were completed: Revised Olweus Bully/Victim, Piers-Harris Self-Concept Scale, Revised Child Manifest Anxiety Scale, Child Depression Index, and Social Skills Rating System. Children with epilepsy were more frequently victims of bullying (42%) than were healthy controls (21%) or children with CKD (18%) (P = 0.01). Epilepsy factors such as early age at seizure onset, seizure type, and refractory epilepsy were not found to be predictors of victim status. Surprisingly, poor social skills, increased problem behaviors, poor self-concept, depression, and anxiety did not correlate with bully victim status. The relatively high prevalence of bullying behaviors in these children is concerning and, from a clinical standpoint, requires greater research specifically addressing peer relationships and consideration of the implementation of anti-bullying measures and coping strategies for children with epilepsy.

Perceived health in children presenting with a "first seizure".

The goal of this study was to determine health perceptions of children and parents after a "first seizure." Children 5-17 years of age referred with a first recognized seizure (FRS) were included in the study. Children and primary caregivers completed the Child Health Questionnaire. Sixty-seven of 70 (96%) participated (mean age=11.2, SD=3.4; 48 seizure, 19 nonseizure). Parents of children with a first recognized epileptic seizure (FRS-e) had significantly lower scores on Psychosocial Summary scores (P<0.001) and on 6 of 12 subscales. Children who had had their first recognized nonepileptic seizure (FRS-ne) tended to have poorer Parental Time-Emotional scores (P=0.05). Although children did not receive lower scores, they did report a change in perceived health (P=0.017). While parents of children presenting with a FRS report increased emotional impact, those with a FRS-e report more significant difficulties in several domains of perceived health. It is important for physicians and health care providers to be aware of these concerns as they might impact further interventions.

Parenting stress in mothers of children with intractable epilepsy.

OBJECTIVE: The goal of the work described here was to determine the prevalence and characteristics of maternal stress in families of children with intractable epilepsy. METHODS: Mothers of children aged 2-18 with intractable epilepsy were asked to complete the Parenting Stress Index, Scales of Independent Behavior-Revised, and Child Behavior Checklist, and were queried regarding family type, maternal education, and family income. Neurology clinic charts were reviewed for seizure variables including age at onset, number of failed therapies, and seizure frequency. The Parenting Stress Index measures stress in two broad domains [stress related to characteristics of the child (Child Domain) and stress related to characteristics of the parent (Parent Domain)] as well as a Total Stress score. RESULTS: Fifty-two of 80 (65%) eligible mothers returned completed questionnaires. Sixty-three percent scored in the clinical range for Total Stress, 75% for the Child Domain, but only 29% for the Parent Domain. Mothers scored more adversely on the Isolation, Health, Role Restriction, and Spouse subscales of the Parent Domain, but more favorably on the Attachment subscale. A moderate to high correlation was noted between behavior problems in the child and higher Total Stress scores, but no significant correlations were found between other seizure or demographic variables. CONCLUSION: Intractable childhood epilepsy is associated with markedly increased maternal parenting stress. Increased stress is due predominantly to child factors. Mothers would strongly benefit from added support to alleviate the constant caregiving demands.

Depression, anxiety, and quality of life in siblings of children with intractable epilepsy.

Thirty-seven siblings (aged 6-18) of children with intractable epilepsy were surveyed regarding their anxiety, depression, and quality of life, by both self-report (Revised Children's Manifest Anxiety Scale, RCMAS; Children's Depression Inventory, CDI; and Peds QL) and parental report (Child Behavior Checklist, CBCL). Completed forms were returned by 37 of 58 (64%) eligible families. No sibling had a score in the clinical range on the CDI, and only 2 of 37 (6%) scored in the clinical range on the RCMAS, a proportion similar to the normative population. In contrast, 25% were rated by their parents to have elevated Internalizing Behaviors scores on the CBCL. There was a trend for PedsQL scores to be lower than the normative mean. Comorbid behavior and attention problems in the child with epilepsy and sibling CDI and RCMAS scores correlated significantly with self-reported quality of life. However, other epilepsy, child, and family variables (income, parental education, family function, maternal depression) did not correlate. We conclude that siblings of children with intractable epilepsy are functioning well overall and have a good quality of life.

Health behavior in teens with epilepsy: how do they compare with controls?

The goal of the study was to determine if adolescents with epilepsy have poorer health behavior than healthy controls. Health behavior was compared in two cohorts: cognitively normal teens aged 11-16 with epilepsy and similarly aged controls. Teens completed the Health Behaviour in School-Aged Children (HBSC) and Piers-Harris II, and the primary caregiver completed the Family Assessment Measure III. Forty-four teens with epilepsy and 119 orthopedic controls returned questionnaires. Adolescents with epilepsy had poorer health behavior than controls (P<0.003). They felt significantly less positive about their health (P<0.01) and were less physically active (P<0.02). Poorer family function (P<0.05) and lower self-esteem (P<0.001) were predictors of poorer health behavior. Given the increased prevalence of comorbid diseases in adults with epilepsy, clinicians should routinely query teens with epilepsy regarding health behavior and provide anticipatory guidance and appropriate interventions for poor health behavior choices.

Seizures in children after kidney transplantation: has the risk changed and can we predict who is at greatest risk?

Children undergoing kidney transplantation are at increased risk for symptomatic seizures with a previously reported incidence of approximately 20%. Little data exist to help predict which children may be at risk. We retrospectively reviewed all children who underwent kidney transplantation evaluation at our center between October 1993 and August 2007 and identified 41 children who had an EEG prior to transplant. Demographic data as well as the following were collected: immunosuppressive medications, developmental status, history of seizures, family history of seizures, post-transplant seizures and EEG results. EEGs were classified as normal or abnormal. Prior to transplantation, one child had a history of febrile seizures and six experienced afebrile seizures. Nine (22%) children identified had an abnormal EEG prior to transplant. In eight cases the EEG was non-epileptiform and in one case was epileptiform. Abnormal EEGs did not correlate with a family history of seizures. Delayed development was noted in seven children and was not associated with an epileptiform EEG. Following kidney transplantation, no child experienced a seizure. Our single center study suggests that current rates of seizures following kidney transplantation are lower than previously reported and that routine EEG as part of the pretransplant evaluation in these children is of limited use to predict those at risk.

Deterioration in cognitive function in children with benign epilepsy of childhood with central temporal spikes treated with sulthiame.

The purpose of this study was to determine if reduction in spike frequency in children with benign epilepsy of childhood with centrotemporal spikes treated with sulthiame correlates with improved neuropsychologic function. Six untreated children (5 boys, 1 girl) with a mean (standard deviation) age of 9.1 years (1.5 years) underwent overnight ambulatory electroencephalograph recording and neuropsychologic evaluation at baseline and after 6 months of sulthiame monotherapy. The Reliable Change Index was used to determine whether a statistically reliable change in neuropsychologic function occurred. All children continued receiving sulthiame monotherapy (dose range, 8.0-9.3 mg/kg per day) for the study period without further seizures. Although spike frequency was reduced in all 6 children (3 showing a decrease to less than 10% of baseline), they all demonstrated significant deterioration in their reading ability, 5 had significant declines in general memory, and more than half had reduction in attention skills and mathematics ability. Although sulthiame was effective at seizure control and significantly reduced spike frequency in children, it was also associated with deterioration in cognitive function.

Ambulatory electroencephalography (EEG) in children: diagnostic yield and tolerability.

Sixty-four children, aged 0-17 years, undergoing ambulatory electroencephalography (EEG) were prospectively recruited during a 12-month period. The diagnostic yield of ambulatory electroencephalography was determined for each of the following groups: group 1: differentiation of seizures from nonepileptic events; group 2: determination of seizure/interictal discharge frequency; and group 3: classification of seizure type or localization. The ambulatory electroencephalography answered the clinical question in 61% of group 1 (27/44) and 100% of groups 2 (16/16) and 3 (4/4). Of 44 cases in Group 1, clinical events were recorded in 61%; the ambulatory electroencephalography result changed the diagnosis from epileptic to nonepileptic or vice versa in 27%. When clinicians suspected that events were epileptic, ambulatory electroencephalography changed the clinical impression in 50%, whereas when events were suspected to be nonepileptic, ambulatory electroencephalography confirmed that impression in 83%.

Peri-ictal headache in children: prevalence and character.

Structured interviews regarding peri-ictal headaches and personal or family histories of interictal headaches were conducted on 101 children (aged 5-18 years), with generalized tonic-clonic or partial seizures. Epilepsy-specific details were collected by interviews and reviews of neurology clinic charts. Peri-ictal headaches were reported by 41% (29%, postictal only; 5%, preictal only; 7%, both). Clear migrainous features were present in 50% of preictal and 58% of postictal headaches. Most children described bilateral headaches. No demographic or epilepsy-specific correlates were identified that predicted peri-ictal headaches. Interictal headaches occurred in 24%, with 14% of children meeting criteria for migraines. However, neither interictal migraines nor a positive family history of migraines was significantly predictive of either peri-ictal headaches or migrainous peri-ictal headaches. Postictal headaches occurred reliably after most seizures in predisposed children, and interrupted activities in the majority. Whereas only half of children received abortive medications for these headaches, simple analgesics were effective in most cases. We conclude that peri-ictal headaches are common, affecting 41% of children with epilepsy. Their presence should be routinely queried, and if documented, treatment with simple analgesics appears beneficial and should be considered.

Anxiety and depressive symptoms in children presenting with a first seizure.

We investigated whether children presenting with a first seizure experienced anxiety and depressive signs. Children (aged 7-17 years) with a first unprovoked afebrile seizure participated. These patients (mean age, 12 +/- 2.7 years S.D.; 14 female/8 male) completed the Revised Child Manifest Anxiety Scale (n = 22) and Children's Depression Inventory (n = 20). Scores were compared with: (1) published norms, and (2) control patients with new medical signs. Compared with the published norms, children reported greater total anxiety (P < 0.02), worry/oversensitivity (P < 0.008), and social concerns/concentration (P < 0.005). However, compared with the control patients, no difference was seen between groups. Total Children's Depression Inventory scores were higher than for published norms (P = 0.05) and control patients (P = 0.04). Children with a first seizure reported greater interpersonal problems (P < 0.01), ineffectiveness (P < 0.03), and negative self-esteem (P < 0.05) than published norms, and increased negative mood (P = 0.04), ineffectiveness (P = 0.04), anhedonia (P = 0.05), and negative self-esteem (P = 0.05) than control patients. Our results suggest that anxiety may be related to an illness or to the hospital experience itself, whereas depressive signs may be a comorbidity present at time of presentation of the first seizure. If a larger cohort substantiates these results, early screening for these signs would be of clinical importance.

Self-concept in adolescents with epilepsy: biological and social correlates.

The purposes of this study were to (1) compare self-esteem in teens with epilepsy to the normative mean, and (2) identify which neurologic/epilepsy and social/familial variables are associated with self-esteem. Thirty-seven adolescents (aged 12-18 years) attending a pediatric neurology clinic completed the Piers-Harris 2 Self-Concept Scale, Family Assessment Measure III, Child Attitude to Illness Scale, and a brief questionnaire about current seizure status (frequency, severity, and number of antiepileptic drugs). Neurology clinic charts were reviewed for seizure types, etiology, age at diagnosis, and number of failed therapies. While Total Piers-Harris t score and most subscales did not differ significantly from the normative mean, teens with epilepsy had higher scores on Behavioral Adjustment (P < 0.04) and Physical Appearance and Attributes (P < 0.03). On univariate analysis, number of current antiepileptic drugs (P < 0.05) and Attitude to Illness and Family Function scores (P < 0.02 for both) were significantly associated with self-esteem. On linear regression analysis, only the Family Function score (P < 0.02) and number of antiepileptic drugs (P < 0.05) were associated with total self-concept. We conclude that self-concept in teens with epilepsy is most strongly associated with Family Function. With the exception of current number of antiepileptic drugs used, epilepsy-specific factors are of minimal importance.

Maternal depression: the cost of caring for a child with intractable epilepsy.

The aims of this study were to: (1) determine the prevalence of depression and sleep disruption in mothers of children with intractable epilepsy, and (2) assess which family factors and neurologic/behavioral characteristics of a child with epilepsy correlate with maternal depression. Mothers of children aged 2-18 years with intractable epilepsy completed a Beck Depression Inventory and Pittsburgh Sleep Questionnaire for themselves, and a Child Behavior Checklist, Attention Deficit Hyperactivity Disorder Rating Scale, and Scale of Independent Behavior-Revised for their child. Charts were reviewed for age at seizure onset, seizure frequency and type, number of failed treatments, and presence of autism. Mothers were queried regarding family type, educational level, income, and number of children in the home. Fifty-two of 80 (65%) eligible mothers returned completed questionnaires. Forty-five percent demonstrated elevated scores on the depression questionnaire, with 25% in the moderate/severely depressed range. Sleep disruption was reported in 67%. Maternal depression correlated with high attention deficit and problem behaviors in children, but not with most epilepsy-related variables, autism, adaptive delay, or family income.

Provider Practices of Phenobarbital Discontinuation in Neonatal Seizures.

Neonatal seizures are treated with phenobarbital and prolonged treatment does not prevent postneonatal epilepsy. The authors documented factors influencing phenobarbital use and determined whether published data changed practice. A total of 83 neonates with symptomatic seizures, clinical or electrographic, were evaluated for treatment, incidence of postneonatal epilepsy, and associated factors. Median phenobarbital treatment was 81 days. Nineteen children (23%) developed postneonatal epilepsy. Longer duration of seizures and an infectious etiology were associated with postneonatal epilepsy suggesting no impact on duration of phenobarbital treatment. Treatment duration was associated with duration of seizures and use of a second antiseizure medication. This study supports early discontinuation of phenobarbital and suggests providers utilize factors such as use of a second antiseizure medication and time to seizure control to determine phenobarbital duration, despite prior studies suggesting no impact of treatment length.

Hemispherectomy in early infantile epileptic encephalopathy.

The authors report the successful surgical treatment of early infantile epileptic encephalopathy and suppression burst in 2 children with hemispheric dysplasia. At surgical evaluation, focal epileptic patterns were recorded from the abnormal hemisphere, and ictal single-photon emission computed tomography demonstrated ipsilateral regional hyperperfusion. Functional hemispherectomy was performed after electrocorticography revealed near-continuous spike and slow-wave discharges over the affected hemisphere. Histopathology revealed Taylor-type cortical dysplasia. Postoperatively, both patients are seizure free on antiepileptic drug monotherapy and have shown improved developmental status. Their favorable outcome demonstrates that children with early infantile epileptic encephalopathy due to unilateral malformations of cortical development may benefit from early surgical intervention.