Evaluation of carisbamate, a novel antiepileptic drug, in photosensitive patients: an exploratory, placebo-controlled study.

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 8h 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.

Heterogeneity at the JME 6p11-12 locus: absence of mutations in the EFHC1 gene in linked Dutch families.

PURPOSE: The EFHC1 gene, encoding a protein with a Ca(2+)-sensing EF-hand motif, is localized at 6p12 and was recently reported as mutated in six Mexican juvenile myoclonic epilepsy (JME) families linked to this region. We had previously confirmed linkage between JME and 6p11-12 in 18 Dutch families, and shown exclusionary lod scores at 6p21.3. We therefore evaluated the relevance of EFHC1 in our set of 6p11-12-linked families. METHODS: We screened all coding and regulatory regions of EFHC1 by direct sequencing, and the detected variants were tested in a case-control association study. RESULTS: We found none of the five mutations previously reported in the Mexican families, but identified nine variants, three of which are novel: 5' upstream region (c.-146_147delGC), nonsynonymous (R159W, R182H, M448T, I619L), intronic (IVS3 + 10A>G, IVS8 + 175_176delTT, IVS10 + 59C>T), and 3' UTR (c.+121C>A). These variants did not cosegregate with JME and did not account for the observed linkage at the 6p11-12 locus. Furthermore, no significant association was detected between JME and these variants in 112 unrelated patients and 180 controls. Finally, none of the mutations reported in Mexican families was found in 100 unrelated patients. CONCLUSIONS: We found no evidence that EFHC1 is a major genetic risk factor for JME susceptibility in Dutch patients. The EFHC1 variants reported in Mexican families may be mendelian variants specific for those families, suggesting that for Dutch patients and possibly many other populations, the main disease variant at the 6p11-12 is yet to be identified.

Photosensitivity, visually sensitive seizures and epilepsies.

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.

Oligogenic inheritance in photosensitive juvenile myoclonic epilepsy?

The interplay of multiple genetic factors, as opposed to monogenic inheritance, is suspected to play a role in many idiopathic generalized epilepsies. This leads to a digenic or oligogenic inheritance model, which although rather simplified, may explain at least some of the clinical observations. Here we describe a family in which the clinical phenotype in the offspring can be explained by a combination of photosensitivity and epilepsy traits that segregated independently of each other. This case history demonstrates the need to evaluate family histories in more detail in order to uncover potential clinical markers for genetic factors in complex epilepsies.

Genome-wide linkage scan of epilepsy-related photoparoxysmal electroencephalographic response: evidence for linkage on chromosomes 7q32 and 16p13.

Photoparoxysmal response (PPR) is an abnormal visual sensitivity of the brain in reaction to intermittent photic stimulation. It is an epilepsy-related electroencephalographic trait with high prevalence in idiopathic epilepsies, especially in common idiopathic generalized epilepsies (IGEs), such as childhood absence epilepsy and juvenile myoclonic epilepsy. This degree of co-morbidity suggests that PPR may be involved in the predisposition to IGE. The identification of genes for PPR would, therefore, aid the dissection of the genetic basis of IGE. Sixteen PPR-multiplex families were collected to conduct a genome-wide linkage scan using broad (all PPR types) and narrow (exclusion of PPR types I and II and the occipital epilepsy cases) models of affectedness for PPR. We found an empirical genome-wide significance for parametric (HLOD) and non-parametric (NPL) linkage (Pgw(HLOD)=0.004 and Pgw(NPL)=0.01) for two respective chromosomal regions, 7q32 at D7S1804 (HLOD=3.47 with alpha=1, P(NPL)=3.39x10(-5)) and 16p13 at D16S3395 (HLOD=2.44 with alpha=1, P(NPL)=7.91x10(-5)). These two genomic regions contain genes that are important for the neuromodulation of cortical dynamics and may represent good targets for candidate-gene studies. Our study identified two susceptibility loci for PPR, which may be related to the underlying myoclonic epilepsy phenotype present in the families studied.

Localization of slow wave activity in patients with tumor-associated epilepsy.

OBJECTIVE: Brain tumors are frequently accompanied by abnormal low frequency magnetic activity (ALFMA). The prevalence and clinical meaning of ALFMA are not well known, although a relation with epileptic brain tissue has been suggested. We studied the prevalence, characteristics and clinical correlates of ALFMA in 20 patients with brain tumors. METHODS: In 20 patients with clinical seizures due to a supratentorial tumor, MEG was performed, followed by MR imaging. MEG signals were band pass-filtered (1-4 Hz); the sources of this activity were localized and projected onto the MRI of the patient. RESULTS: Peritumoral ALFMA could be detected in 13 of 20 patients. A pattern of ALFMA distribution around the tumor could be recognized. In eight cases ALFMA also appeared to be localized within the tumor. In three cases ALFMA was also detected in peritumoral white matter. CONCLUSIONS: Automatic detection of abnormal delta-activity in patients with a brain tumor and seizures can be performed in a clinical setting. When detected, ALFMA is mostly present in circumscribed regions around the tumor. Presence of ALFMA within the tumor might be an important warning signal for the neurosurgeon that the tumor area comprises functional brain tissue.

The effectiveness of cognitive rehabilitation for attention deficits in focal seizures: a randomized controlled study.

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.