Neurology

Oxcarbazepine (OXC) has been licensed as monotherapy and add-on treatment in epilepsy patients with partial seizures with or without secondarily generalized seizures (PS) and generalized tonic-clonic seizures without partial onset (GTCS). Its use as monotherapy in adults with ...

To assess the activity of brivaracetam, a novel SV2A ligand, in the photosensitivity model as a proof-of-principle of efficacy in patients with epilepsy. A subject-blind placebo-controlled study in patients with photosensitive epilepsy was performed to investigate the effect of single-dose brivaracetam (10, 20, 40, or 80 mg) on photosensitive responses. Each patient was exposed to intermittent photic stimulation that evoked a generalized photoparoxysmal EEG response. Individual standard photosensitivity ranges (SPRs) were recorded post-placebo (day -1) and post-brivaracetam until return to baseline (day 1 to 3). Plasma concentrations of brivaracetam and any concomitant antiepileptic drugs were determined. Of the 18 evaluable patients, none achieved SPR abolishment post-placebo, whereas 14 (78%) achieved complete abolishment post-brivaracetam. Decrease in SPR was seen in 8 patients (44%) post-placebo compared to 17 (94%) post-brivaracetam. Duration of response was twice as long post-brivaracetam 80 mg (59.5 hours) compared with lower doses, although the overall effect was not dose-dependent. Time to maximal photosensitive response was dose-related with the shortest time interval observed at the highest dose (0.5 hours post-brivaracetam 80 mg). The area under the effect curve (SPR change from pre-dose vs time) appeared linearly correlated with the area under the plasma concentration curve. Brivaracetam was well tolerated. The most common adverse events were dizziness and somnolence. Our findings show that brivaracetam clearly suppresses generalized photoparoxysmal EEG response. As such, investigations of the antiepileptic properties and tolerability of brivaracetam are warranted in further clinical studies of patients with epilepsy.

The reliability of frontal and temporal fMRI activations for the determination of hemisphere language dominance was evaluated in comparison with intracarotid amytal testing (IAT). Twenty-two patients were studied by IAT (bilateral in 13, unilateral in 9 patients) and fMRI using a paradigm requiring semantic decisions. Global and regional (frontal and temporoparietal) lateralisation indices (LI) were calculated from the number of activated (r>0.4) voxels in both hemispheres. Frontolateral activations associated with the language task were seen in all patients, temporoparietal activations in 20 of 22. Regional LI corresponded better with IAT results than global LI. Frontolateral LI were consistent with IAT in all patients with bilateral IAT (including three patients with right dominant and one patient with bilateral language representation) and were not conflicting in any of the patients with unilateral IAT. Temporoparietal LI were discordant with IAT in two patients with atypical language representation. In the determination of hemisphere dominance for language, regional analysis of fMRI activation is superior to global analysis. In cases with clear-cut fMRI lateralisation, i.e. consistent lateralised activation of frontal and temporoparietal language zones, IAT may be unnecessary. FMRI should be performed prior to IAT in all patients going to be operated in brain regions potentially involved in language.

Epilepsies are amongst the most frequent chronic neurological conditions. Patients suffer from spontaneously recurring seizures because of sudden extensive electrical gray matter discharges. Although the current drug therapy allows many patients at least some degree of a satisfying course of the disease, a substantial number of patients remain without adequate seizure control. Reasons are either refractoriness to anticonvulsant drugs or intolerable drug-related side effects. Epilepsy surgery should be considered in these cases as possible treatment option. Nevertheless, a considerable rate of patients will not be suitable candidates or continue to have seizures despite surgery. Therefore there is a substantial need for better antiepileptic drugs. The aim of this review is to highlight currently emerging different treatment approaches which may ameliorate the perspectives of patients with difficult-to-treat epilepsies.

7 Zusammenfassung Lacosa-mid (LCM, R-2-Acetamido-N-ben-zyl-3-methoxypropionamid) ge-hört zu der Gruppe der funktionali-sierten Aminosäuren. In tierexperi-mentellen Studien erwies sich LCM als ein wirksames Medikament ge-gen fokale Anfälle und beeinflusst ...

Deletions at 16p13.11 are associated with schizophrenia, mental retardation, and most recently idiopathic generalized epilepsy. To evaluate the role of 16p13.11 deletions, as well as other structural variation, in epilepsy disorders, we used genome-wide screens to identify copy number variation in 3812 patients with a diverse spectrum of epilepsy syndromes and in 1299 neurologically-normal controls. Large deletions (> 100 kb) at 16p13.11 were observed in 23 patients, whereas no control had a deletion greater than 16 kb. Patients, even those with identically sized 16p13.11 deletions, presented with highly variable epilepsy phenotypes. For a subset of patients with a 16p13.11 deletion, we show a consistent reduction of expression for included genes, suggesting that haploinsufficiency might contribute to pathogenicity. We also investigated another possible mechanism of pathogenicity by using hybridization-based capture and next-generation sequencing of the homologous chromosome for ten 16p13.11-deletion patients to look for unmasked recessive mutations. Follow-up genotyping of suggestive polymorphisms failed to identify any convincing recessive-acting mutations in the homologous interval corresponding to the deletion. The observation that two of the 16p13.11 deletions were larger than 2 Mb in size led us to screen for other large deletions. We found 12 additional genomic regions harboring deletions > 2 Mb in epilepsy patients, and none in controls. Additional evaluation is needed to characterize the role of these exceedingly large, non-locus-specific deletions in epilepsy. Collectively, these data implicate 16p13.11 and possibly other large deletions as risk factors for a wide range of epilepsy disorders, and they appear to point toward haploinsufficiency as a contributor to the pathogenicity of deletions.