Summary Purpose Carisbamate, a novel neuromodulatory agent with antiepileptic properties, was evaluated in patients with photoparoxysmal responses to intermittent photic stimulation (IPS) in this ...multicenter, non-randomized, single-blind, placebo-controlled, proof-of-concept study. Methods Eighteen Caucasian patients (14 females, 4 males) with a mean age of 30 years (range: 16–51 years) underwent standardized IPS under three eye conditions (during eye closure, eyes closed and eyes open) at hourly intervals for up to 8 h after receiving placebo (Day 1), carisbamate (Day 2) and placebo (Day 3). Carisbamate was given at single doses of 250–1000 mg. All patients received one or two concomitant antiepileptic drugs, most commonly valproate. Results Carisbamate produced a dose-dependent reduction in photosensitivity in the 13 evaluable patients, with abolishment of photoparoxysmal responses in 3 patients and clinically significant suppression of such responses in 7 additional patients. Photosensitivity was abolished or reduced in all five patients in the 1000-mg dose group. The onset of carisbamate occurred rapidly, with clinically significant suppression achieved before or near the time peak plasma drug levels were reached. The duration of action was dose-related and long-lasting, with clinically significant reductions of photosensitivity observed for up to 32 h after doses of 750 or 1000 mg. Carisbamate was generally well tolerated, with dizziness and nausea reported more frequently after active drug than placebo. Conclusion This study shows that carisbamate exhibits dose-related antiepileptic effects in the photosensitivity model. Randomized, controlled studies of carisbamate in epilepsy patients inadequately controlled by their existing AED therapy are warranted.
Summary
Intermittent photic stimulation (IPS) is a common procedure performed in the electroencephalography (EEG) laboratory in children and adults to detect abnormal epileptogenic sensitivity to ...flickering light (i.e., photosensitivity). In practice, substantial variability in outcome is anecdotally found due to the many different methods used per laboratory and country. We believe that standardization of procedure, based on scientific and clinical data, should permit reproducible identification and quantification of photosensitivity. We hope that the use of our new algorithm will help in standardizing the IPS procedure, which in turn may more clearly identify and assist monitoring of patients with epilepsy and photosensitivity. Our algorithm goes far beyond that published in 1999 (Epilepsia, 1999a, 40, 75; Neurophysiol Clin, 1999b, 29, 318): it has substantially increased content, detailing technical and logistical aspects of IPS testing and the rationale for many of the steps in the IPS procedure. Furthermore, our latest algorithm incorporates the consensus of repeated scientific meetings of European experts in this field over a period of 6 years with feedback from general neurologists and epileptologists to improve its validity and utility. Accordingly, our European group has provided herein updated algorithms for two different levels of methodology: (1) requirements for defining photosensitivity in patients and in family members of known photosensitive patients and (2) requirements for tailored studies in patients with a clear history of visually induced seizures or complaints, and in those already known to be photosensitive.
Abstract Objectives This study aimed to describe seizure precipitants in Dravet syndrome (DS) compared with other epilepsies. Methods Seizure precipitants as reported in a Dutch cohort of patients ...with DS with pathogenic SCN1A mutations (n = 71) were compared with those of a cohort with childhood epilepsy (n = 149) and of a community-based cohort with epilepsy (n = 248); for all three Dutch cohorts, the same type of questionnaire was used. Seizure precipitants were categorized as ‘fever’, ‘visual stimuli’, ‘sleep deprivation’, ‘stress, including physical exercise’, ‘auditory stimuli’, and ‘other’. Results For 70 (99%) of 71 patients with DS, at least one seizure precipitant was recalled by parents. Seizure precipitants that were reported in more than half of the cohort with DS were as follows: having a fever (97%), having a cold (68%), taking a bath (61%), having acute moments of stress (58%), and engaging in physical exercise (56%). Seizure precipitants freely recalled by parents were often related to ambient warmth or cold–warmth shifts (41%) and to various visual stimuli (18%). Patients with DS had more positive seizure precipitant categories (median 4) compared with the cohort with childhood epilepsy (median 2) and the community-based cohort with epilepsy (median 0) (p < 0.001) and showed the highest percentage in each category (all p < 0.001). Within the category ‘stress, including physical exercise’, physical exercise was more often reported to provoke seizures in stress-sensitive patients in the cohort with DS than in the cohort with childhood epilepsy (78% vs. 35%, p < 0.001). In the cohort with childhood epilepsy, physical exercise was more often reported in fever-sensitive children than in other children (25% vs. 12%, p = 0.042). Conclusions Our study shows a high prevalence of a range of seizure precipitants in DS. Our results underscore elevated body temperature as an important seizure precipitant, whether caused by fever, warm bath, ambient warmth, or physical exercise. Knowledge of these seizure precipitants may improve preventive strategies in the otherwise difficult treatment of DS.
To evaluate the effect of cenobamate in patients with photoparoxysmal-EEG response (PPR) to intermittent photic stimulation (IPS) as proof of principle of efficacy in patients with epilepsy.
In this ...multicenter, single-blind study, adults with photosensitive epilepsy, with/without concomitant antiepileptic drug therapy, underwent IPS under 3 eye conditions after a single dose of placebo (day -1, day 2) or cenobamate (day 1; 100, 250, or 400 mg). Complete suppression was a standardized photosensitivity range reduction to 0 over ≥1 time points for all eye conditions. Partial suppression was a ≥3-point reduction over ≥3 testing times vs the same time points on day -1 in ≥1 eye condition. Pharmacokinetics and safety were assessed.
Of 6 evaluable patients, 5 reentered to receive higher doses. Cenobamate 100 mg produced partial suppression in 1 of 3 patients; 250 mg produced complete suppression in 1 of 4 and partial suppression in 4 of 4 patients; and 400 mg produced complete suppression in 1 of 4 and partial suppression in 2 of 4 patients. PPR was consistently reduced on days 1 and 2 (>24 hours after cenobamate) vs day -1 (placebo) with the 250- and 400-mg doses. Area under the plasma concentration-time curve (before dose to last measurable concentration) values between 201 and 400 μg/h/mL resulted in partial suppression in 4 of 6 (66%) patients. Most common adverse events were dizziness and somnolence.
This proof-of-principle study demonstrated that cenobamate is a potentially effective product for epilepsy.
NCT00616148.
This study provides Class III evidence that, for patients with photosensitive epilepsy, cenobamate suppresses IPS-induced PPR.
Purpose: Cognitive deficits are one of the major limiting factors in the everyday life functioning of patients with focal seizures. Although cognitive rehabilitation methods have been successfully ...applied to patients with other central nervous system (CNS) lesions, these methods have not yet been evaluated in cognitively impaired patients with epilepsy. The present study evaluated the effectiveness of two commonly used methods for attention deficits: (a) the Retraining Method, aimed at retraining impaired cognitive functions; and (b) the Compensation Method, aimed at teaching compensatory strategies while taking neuronal loss for granted.
Methods: Fifty adult outpatients with focal seizures and attention impairments receiving carbamazepine (CBZ) monotherapy were randomly assigned to the Retraining Method, the Compensation Method, or to a waiting‐list control group. Established and self‐reported neuropsychological outcomes and self‐reported quality of life of these groups were evaluated at pretraining, posttraining, and at a 6‐month follow‐up measurement point and were completed by 44 patients.
Results: Neuropsychological outcomes related to training, self‐reported neuropsychological outcomes, and quality of life at the 6‐month follow‐up measurement point improved both in the Retraining Method group (n = 19) and the Compensation Method group (n = 17) relative to the waiting‐list control group (n = 8). The Compensation Method was more effective in improving self‐reported neuropsychological outcomes and quality of life, especially for patients with less education. The patients with active epilepsy benefited more from both methods than did the seizure‐free patients.
Conclusions: These data show that cognitive rehabilitation programs are effective for patients with focal seizures and attention deficits and should, therefore, be incorporated into comprehensive care programs.
Although many observations in patients with this intriguing type of epilepsy have been described and detailed studies have been performed, only a few meet the current criteria of class 1 or 2 ...evidence-based studies. In general, the selection bias is due to studying a referral population instead of the general population, and to different age and sex distributions of the subjects under study. Comparing the various studies is often difficult, because of differences in the populations studied (single seizures, epilepsy centre population, etc.), but also because of different methods (photic stimulator, flash frequencies, eye conditions, etc.) and the terminology used.
Finally, and most crucial, in many studies there is often no information on how the data were actually obtained (EEG or clinical data or both?). The popular term “photosensitive” is used widely and applied to patients with a history of visually induced seizures, with and without a photoparoxysmal response (PPR), and to those with only a PPR. An overview of the “hard” data is given with future needs for a better understanding of this type of epilepsy and for improving the endophenotype for genetic research.
It is important to standardise the studies as much as possible and describe in detail the methodology of the study, taking at least the above variables into account.
Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs ...remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, P(meta) = 2.5 × 10(-9), ORT = 0.81) and 17q21.32 (rs72823592, P(meta) = 9.3 × 10(-9), ORA = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, P(meta) = 9.1 × 10(-9), ORT = 0.68) and at 1q43 for JME (rs12059546, P(meta) = 4.1 × 10(-8), ORG = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, P(meta) = 4.0 × 10(-6)) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes.
Behavioral aspects of epilepsy Schachter, Steven C; Holmes, Gregory L; Kasteleijn-Nolst Trenite, Dorothée G. A
2008., 2007, 20071015, 2007-10-15
eBook
Covers the mechanisms underlying epilepsy and behavior, neurophysiologic function, neuropsychiatric and behavioral disorders in patients with epilepsy, the effects of treatments and surgery on ...behavior, pediatric and adolescent epilepsy, disorders associated with epilepsy that impact behavior, and more.
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