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Objective: To detect determinants for photoparoxysmal EEG response (PPR) in SCN1A -related Dravet syndrome (DS). Methods: Data were studied from nationwide medical histories and EEGs of DS-patients ( n =53; 31 males, age 2–19years). Detailed questionnaires on visual stimuli were completed by parents ( n =49). Results: PPR was found in 22 patients (42%; median age 1.25yr), and repeatedly in 17%. PPR (17% of 249 intermittent photic stimulation (IPS)-EEGs) occurred more often with optimal IPS protocols (OR 2.11 [95%CI 1.09–4.13]) and in EEGs showing spontaneous epileptiform abnormalities (OR 5.08 [95%CI 2.05–12.55]). PPR-positive patients tended to be younger at first ( p =0.072) and second seizure ( p =0.049), showed severe intellectual disability ( p =0.042), and had more often spontaneous occipital epileptiform abnormalities ( p Clinical sensitivity was reported in medical files in 22% of patients and by parents in 43% (self-induction 24%). Clinical or EEG proven visual sensitivity was detected in 65% of cases. Conclusions: Sensitivity to visual stimuli is very common in DS and more often noticed by parents than confirmed by EEG. Detection of PPR improves with repetitive tests using accurate IPS protocols. Significance: Photosensitivity is an important feature in DS and seems to be a marker of the severity of the disorder. Therefore repeated standardized IPS should be encouraged.

Stress is among the most frequently self-reported factors provoking epileptic seizures in children and adults. It is still unclear, however, why some people display stress-sensitive seizures and others do not. Recently, we showed that young epilepsy patients with stress-sensitive seizures exhibit a dysregulated hypothalamic-pituitary-adrenal (HPA)-axis. Most likely, this dysregulation gradually develops, and is triggered by stressors occurring early in life (early-life stress [ELS]). ELS may be particularly impactful when overlapping with the period of epileptogenesis. To examine this in a controlled and prospective manner, the present study investigated the effect of repetitive variable stressors or control treatment between postnatal day (PND) 12 and 24 in male mice exposed on PND10 to hyperthermia (HT)-induced prolonged seizures (control: normothermia). A number of peripheral and central indices of HPA-axis activity were evaluated at pre-adolescent and young adult age (ie, at PND25 and 90, respectively). At PND25 but not at PND90, body weight gain and absolute as well as relative (to body weight) thymus weight were reduced by ELS (vs control), whereas relative adrenal weight was enhanced, confirming the effectiveness of the stress treatment. Basal and stress-induced corticosterone levels were unaffected, though, by ELS at both ages. HT by itself did not affect any of these peripheral markers of HPA-axis activity, nor did it interact with ELS. However, centrally we did observe age-specific interaction effects of HT and ELS with regard to hippocampal glucocorticoid receptor mRNA expression, neurogenesis with the immature neurone marker doublecortin and the number of hilar (ectopic) granule cells using Prox1 staining. This lends some support to the notion that exposure to repetitive stress after HT-induced seizures may dysregulate central components of the stress system in an age-dependent manner. Such dysregulation could be one of the mechanisms conferring higher vulnerability of individuals with epilepsy to develop seizures in the face of stress.

People with epilepsy often report seizures precipitated by stress. This is believed to be due to effects of stress hormones, such as cortisol, on neuronal excitability. Cortisol, regardless of stress, is released in hourly pulses, whose effect on epileptic activity is unknown. We tested the relation between cortisol levels and the incidence of epileptiform abnormalities in the electroencephalogram of people with focal epilepsy. Morning cortisol levels were measured in saliva samples obtained every 15 min. Interictal epileptiform discharges were determined in the same time periods. We investigated the relationship between cortisol levels and the epileptiform discharges distinguishing persons with from those without stress-precipitated seizures (linear mixed model), and analysed the contribution of individual, epilepsy and recording characteristics with multivariable analysis. Twenty-nine recordings were performed in 21 individuals. Cortisol was positively related to incidence of epileptiform discharges (β = 0.26, P = 0.002) in people reporting stress-sensitive seizures, but not those who did not report stress sensitivity (β = -0.07, P = 0.64). The relationship between cortisol and epileptiform discharges was positively associated only with stress sensitivity of seizures (β = 0.31, P = 0.005). The relationship between cortisol levels and incidence of interictal epileptiform discharges in people with stress-sensitive seizures suggests that stress hormones influence disease activity in epilepsy, also under basal conditions.

Stress can influence epilepsy in multiple ways. A relation between stress and seizures is often experienced by patients with epilepsy. Numerous questionnaire and diary studies have shown that stress is the most often reported seizure-precipitating factor in epilepsy. Acute stress can provoke epileptic seizures, and chronic stress increases seizure frequency. In addition to its effects on seizure susceptibility in patients with epilepsy, stress might also increase the risk of epilepsy development, especially when the stressors are severe, prolonged, or experienced early in life. Although the latter has not been fully resolved in humans, various preclinical epilepsy models have shown increased seizure susceptibility in naïve rodents after prenatal and early postnatal stress exposure. In the current review, we first provide an overview of the effects of stress on the brain. Thereafter, we discuss human as well as preclinical studies evaluating the relation between stress, epileptic seizures, and epileptogenesis, focusing on the epileptogenic effects of early life stress. Increased knowledge on the interaction between early life stress, seizures, and epileptogenesis could improve patient care and provide a basis for new treatment strategies for epilepsy.

Purpose Accurate classification of epileptic seizures, epilepsies, and epilepsy syndromes is mandatory in both clinical practice and epilepsy research. In 2010, the International League Against Epilepsy (ILAE) proposed a new classification scheme. The aim of this study is to determine whether application of this new classification for epileptic seizures and epilepsies has improved interobserver agreement compared to the classification schemes used previously. Methods Three pediatric neurologists working in different university hospitals retrospectively classified seizures and epilepsies of 80 children (165 seizures) referred to the University Center Utrecht, based on anonymized data, according to the newly proposed (2010) as well as the old (1981/1989) ILAE classification schemes. We determined interobserver agreement of the application of both ILAE classifications with kappa statistics. Key Findings Interobserver agreement of the new classification for seizures and epilepsies is comparable to that of previous classifications. There is substantial agreement on the newly introduced etiologic axis. Significance Introduction of the new epilepsy classification has not substantially improved interobserver agreement. This study shows which items cause considerable interobserver disagreement and therefore need specification.

Summary Objective To test whether specific classes of antiepileptic drugs increase the risk for behavioral disinhibition, a frequent complication of treatment of childhood epilepsy. Methods In a sample of children with active epilepsy and antiepileptic drug (AED) treatment (n = 146, age 4–17 years), we performed a retrospective chart analysis of the occurrence of symptoms indicating reduced behavioral disinhibition following AED treatment. We used a risk‐set approach to analyze whether the presence or recent addition of AED categories defined by their mechanism of action were associated with enhanced risk for behavioral disinhibition symptoms. Results Mean duration of follow‐up was 2,343 days (range 218–6,292, standard deviation [SD] 1,437). Episodes of behavioral disinhibition were reported in 51 (34.9%) children, with variable latencies between latest change and occurrence of behavioral disinhibition symptoms (mean 67 days, range 2–367). Current use of AEDs targeting gamma‐aminobutyric acid (GABA) (odds ratio [OR] 1.8, 95% confidence interval [CI] 1.02–3.29, p = 0.04) and SV2A‐mediated neurotransmitter release (SV2A)‐mediated (2.0, 1.13–3.60, p = 0.02) neurotransmitter release was associated with increased risk for behavioral disinhibition. Restricting the analysis to the 90 days before behavioral disinhibition episode occurrence revealed that only addition of GABAergic AEDs (OR = 26.88, 95% CI = 6.71–107.76, p < 0.001) was associated with behavioral disinhibition. In contrast to our expectations, seizure control was reported to have improved parallel to most behavioral disinhibition episodes. Significance This exploration of behavioral disinhibition in relation to antiepileptic drug treatment indicates that GABA potentiating drugs are specifically associated with behavioral problems during treatment of childhood epilepsy. Behavioral disinhibition episodes often occurred while seizure control improved, which may have reduced alertness for the consequences of AEDs on interictal symptoms. Our findings may be related to the increasing evidence for a role for excitatory actions of GABA in childhood epilepsy.

Summary Purpose: To evaluate the effect of stress on seizure frequency in childhood epilepsy, and to assess possible differences between children in whom seizures are precipitated by stress and those in whom they are not. Methods: Parents or caregivers of children with active epilepsy (aged 2–16 years) were sent questionnaires on developmental and epilepsy characteristics, life-time stress exposure, and the effect of stressful periods and moments of acute stress on seizure frequency in their child. Further information was extracted from patient files. Key Findings: Parents or caregivers of 153 children with a median age of 8.8 years responded to the questionnaires. Thirty-nine percent reported an increase in seizure frequency during periods of stress, with a median increase of 2.5 times the frequency compared to nonstressful periods. Thirty-seven percent reported that seizures were precipitated by acute stress, with stress being a precipitating factor in 33% (median value) of the seizures. Overall, 51% of the patients reported stress sensitivity of seizures. A higher number of negative life events experienced in total life was related to an increase in seizure frequency in stressful periods (odds ratio [OR] 1.3, p = 0.01) as well as to the precipitation of seizures by acute stress (OR 1.3, p = 0.02). Significance: Stress sensitivity is reported in half of the children with epilepsy. Results of this study suggest a relation between experienced negative life events and stress sensitivity of childhood epilepsy. One possible explanation could be that experiencing negative life events may cause a larger response to daily stressors, thereby increasing the likelihood to induce epileptic activity.

BACKGROUND: Altered sensory sensitivity is generally linked to seizure-susceptibility in childhood epilepsy but may also be associated to the highly prevalent problems in behavioral adaptation. This association is further suggested by the frequent overlap of childhood epilepsy with autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), conditions in which altered behavioral responses to sensory stimuli have been firmly established. A continuum of sensory processing defects due to imbalanced neuronal inhibition and excitation across these disorders has been hypothesizedthat may lead to common symptoms of inadequate modulation of behavioral responses to sensory stimuli. Here, we investigated the prevalence of sensory modulation disorders among children with epilepsy and their relation with symptomatology of neurodevelopmental disorders. METHODS: We used the Sensory Profile questionnaire to assess behavioral responses to sensory stimuli and categorize sensory modulation disorders in children with active epilepsy (aged 4-17 years). We related these outcomes to epilepsy characteristics and tested their association with comorbid symptoms of ASD (Social Responsiveness Scale) and ADHD (Strengths and Difficulties Questionnaire). RESULTS: Sensory modulation disorders were reported in 49 % of the 158 children. Children with epilepsy reported increased behavioral responses associated with sensory "sensitivity," "sensory avoidance," and "poor registration" but not "sensory seeking." Comorbidity of ASD and ADHD was associated with more severe sensory modulation problems, although 27 % of typically developing children with epilepsy also reported a sensory modulation disorder. CONCLUSIONS: Sensory modulation disorders are an under-recognized problem in children with epilepsy. The extent of the modulation difficulties indicates a substantial burden on daily functioning and may explain an important part of the behavioral distress associated with childhood epilepsy.

Purpose Stress is the seizure precipitant most often reported by patients with epilepsy or their caregivers. The relation between stress and seizures is presumably mediated by stress hormones such as cortisol, affecting neuronal excitability. Endogenous cortisol is released in a circadian pattern. To gain insight into the relation between the circadian rhythm of cortisol and seizure occurrence, we systematically reviewed studies on the diurnal distribution of epileptic seizures in children and adults and linked the results to the circadian rhythm of cortisol. Methods A structured literature search was conducted to identify relevant articles, combining the terms ‘epilepsy’ and ‘circadian seizure distribution’, plus synonyms. Articles were screened using predefined selection criteria. Data on 24-hour seizure occurrence were extracted, combined, and related to a standard circadian rhythm of cortisol. Results Fifteen relevant articles were identified of which twelve could be used for data aggregation. Overall, seizure occurrence showed a sharp rise in the early morning, followed by a gradual decline, similar to cortisol rhythmicity. The occurrence of generalized seizures and focal seizures originating from the parietal lobe in particular followed the circadian rhythm of cortisol. Conclusions The diurnal occurrence of epileptic seizures shows similarities to the circadian rhythm of cortisol. These results support the hypothesis that circadian fluctuations in stress hormone level influence the occurrence of epileptic seizures.

Stress is the most often reported seizure-precipitant in epilepsy. As most evidence for the relation between stress and epilepsy is derived from human self-reports, observational studies including a larger part of the population could provide additional proof. A stressor often reported to increase seizure frequency in children with epilepsy in the Netherlands is the national celebration of Saint Nicholas' eve (December 5) and the weeks before; this is the main period of festivities for children in this country. To study the relation between stress and epilepsy, we analyzed epilepsy information-seeking behavior on the Internet, an indirect measure of seizure frequency, around this national children's celebration.Google Trends was used to extract relative search percentages for 'epilepsy' on Google in the Netherlands, the United States, and the United Kingdom between 2004 and 2013. Relative search percentages during the Saint Nicholas period were compared with baseline.Epilepsy searches increased by 14% in the Saint Nicholas period compared with baseline (p0.001). This effect was not found for searches performed in the same period in the United States or the United Kingdom, countries where this holiday is not celebrated.The increase in epilepsy information-seeking behavior in the Saint Nicholas period is possibly caused by an increased occurrence of epileptic seizures. This underscores the potential of health information-seeking behavior on the Internet to answer clinically relevant research questions and provides circumstantial evidence for a relation between stress and the occurrence of epileptic seizures.

To evaluate the effect of stress on seizure frequency in childhood epilepsy, and to assess possible differences between children in whom seizures are precipitated by stress and those in whom they are not.Parents or caregivers of children with active epilepsy (aged 2-16 years) were sent questionnaires on developmental and epilepsy characteristics, life-time stress exposure, and the effect of stressful periods and moments of acute stress on seizure frequency in their child. Further information was extracted from patient files.Parents or caregivers of 153 children with a median age of 8.8 years responded to the questionnaires. Thirty-nine percent reported an increase in seizure frequency during periods of stress, with a median increase of 2.5 times the frequency compared to nonstressful periods. Thirty-seven percent reported that seizures were precipitated by acute stress, with stress being a precipitating factor in 33% (median value) of the seizures. Overall, 51% of the patients reported stress sensitivity of seizures. A higher number of negative life events experienced in total life was related to an increase in seizure frequency in stressful periods (odds ratio [OR] 1.3, p = 0.01) as well as to the precipitation of seizures by acute stress (OR 1.3, p = 0.02).Stress sensitivity is reported in half of the children with epilepsy. Results of this study suggest a relation between experienced negative life events and stress sensitivity of childhood epilepsy. One possible explanation could be that experiencing negative life events may cause a larger response to daily stressors, thereby increasing the likelihood to induce epileptic activity.

The majority of patients with epilepsy report that seizures are sometimes triggered or provoked. Stress is the most frequently self-reported seizure-precipitant. The mechanisms underlying stress-sensitivity of seizures are currently unresolved. We hypothesized that stress-sensitivity of seizures relates to alteration of the stress response, which could affect neuronal excitability and hence trigger seizures. To study this, children with epilepsy between 6 and 17 years of age and healthy controls, with similar age, sex and intelligence, were exposed to a standardized acute psychosocial stressor (the Trier Social Stress Test for Children), during which salivary cortisol and sympathetic parameters were measured. Beforehand, the relation between stress and seizures in children with epilepsy was assessed by (i) a retrospective questionnaire; and (ii) a prospective 6-week diary on stress and seizure occurrence. Sixty-four children with epilepsy and 40 control subjects were included in the study. Of all children with epilepsy, 49% reported that seizures were precipitated by acute stress. Diary analysis showed a positive association between acute stress and seizures in 62% of children who experienced at least one seizure during the diary period. The acute social stress test was completed by 56 children with epilepsy and 37 control subjects. Children with sensitivity of seizures for acute stress, either determined by the questionnaire or by the prospective diary, showed a blunted cortisol response to stress compared with patients without acute stress-precipitated seizures and healthy controls (questionnaire-based F = 2.74, P = 0.018; diary-based F = 4.40, P = 0.007). No baseline differences in cortisol were observed, nor differences in sympathetic stress response. The relation between acute stress-sensitivity of seizures and the cortisol response to stress remained significant in multivariable analysis (β = -0.30, P = 0.03). Other variables associated with the acute stress response were the number of anti-epileptic drugs (β = -0.27, P = 0.05) and sleep quality (β = 0.30, P = 0.03). In conclusion, we show that children with acute stress-sensitive seizures have a decreased cortisol response to stress. These results support our hypothesis that stress-sensitivity of seizures is associated with alterations of the stress response, thereby providing a first step in unravelling the mechanisms behind the seizure-precipitating effects of stress. Increased knowledge of the relation between stress and seizures in childhood epilepsy might benefit our understanding of the fundamental processes underlying epilepsy and ictogenesis in general, and provide valuable clues to direct the development of new therapeutic strategies for epilepsy.