Clobazam-treated patients with Lennox-Gastaut syndrome experienced fewer seizure-related injuries than placebo patients during trial OV-1012
Drop seizures are especially problematic in patients with Lennox-Gastaut syndrome (LGS) because of their potential for serious injury. In this post hoc analysis of phase 3 OV-1012 data, a medical review was conducted of seizure-related injuries based on Medical Dictionary for Regulatory Activities (MedDRA) preferred terms from all adverse event (AE) listings. Patients receiving clobazam experienced fewer seizure-related injuries than those receiving placebo (8.9% all clobazam dosages vs. 27.1% placebo, p ≤ 0.05). Significant differences in the rates of seizure-related injuries were observed for the medium- and high-dosage clobazam treatment groups (4.8% and 10.2%, respectively, p ≤ 0.05). A total of 50 of 53 AEs considered seizure-related were mild or moderate in intensity; 3 severe AEs occurred in the placebo group (fall, contusion, and jaw fracture). A single serious AE (jaw fracture, which required hospitalization and surgery) occurred in a placebo-treated patient. Most injuries resolved by the end of the study. This analysis indicates that the reduction in drop-seizure frequency achieved with clobazam provides a clinically meaningful benefit, a reduced likelihood of experiencing seizure-related injuries.
This longitudinal prospective study updated a previous report on premature mortality and focused on the risk factors among patients with convulsive epilepsy in resource-poor settings. The present cohort size (7,231) and follow-up (mean 33.4 months) were expanded. The basic epidemiologic aspects of this cohort were similar to the original report (case fatality: 3.26% vs. 2.97%, respectively; injury contributed more than half of the deaths). Cox regression analysis suggested that male patients, late ages of onset (>45 years old), short duration of epilepsy (<10 years), and high convulsive seizure frequency (>2 per month) were independent risk factors for overall premature death. Male patients with late ages of onset and high seizure frequency had a higher risk of injury-specific death. This study emphasizes the preventable nature of injuries that are leading putative causes of death among people with convulsive epilepsy in rural West China. Education on specific populations and efficient seizure control are of paramount importance in reducing the risk of premature mortality.
Effects of valproic acid on the placental barrier in the pregnant mouse: Optical imaging and transporter expression studies
Our aim was to evaluate the effects of valproic acid (VPA) on the function of the placental barrier in vivo, in pregnant mice. Studies were conducted on gestational days 12.5 (mid-gestation) or 17.5 (late gestation), following intraperitoneal treatment with 200 mg/kg VPA or the vehicle. Indocyanine green (ICG; 0.167 mg, i.v.) was used as a marker for the placental barrier permeability. Transporter expression was evaluated by quantitative -PCR. VPA treatment was associated with a 40% increase (p < 0.05) in accumulation of ICG in maternal liver in mid-pregnancy and a decrease by one fifth (p < 0.05) in late pregnancy. Ex vivo, VPA treatment led to a 20% increase (p < 0.05) in fetal ICG emission in mid-pregnancy. Also in mid-pregnancy, the placental expression of the L-type amino acid transporter, the organic anion–transporting polypeptide (Oatp)4a1 (thyroid hormone transporter), and the reduced folate carrier was lower in VPA-treated mice (p < 0.05). In late pregnancy, hepatic Oatp4a1 levels were 40% less than in controls (p > 0.05). The observed changes in placental transporter expression and function support further research into the potential role of the placenta in the adverse pregnancy outcomes of VPA. Near-infrared imaging provides a noninvasive, nonradioactive tool for future studies on the effects of epilepsy and antiepileptic drugs on tissue transport functions.
More than 1,200 mutations in neuronal voltage-gated sodium channel (VGSC) genes have been identified in patients with several epilepsy syndromes. A common feature of genetic epilepsies is variable expressivity among individuals with the same mutation. The Scn2aQ54 transgenic mouse model has a mutation in Scn2a that results in spontaneous epilepsy. Scn2aQ54 phenotype severity varies depending on the genetic strain background, making it a useful model for identifying and characterizing epilepsy modifier genes. Scn2aQ54 mice on the [C57BL/6JxSJL/J]F1 background exhibit earlier seizure onset, elevated spontaneous seizure frequency, and decreased survival compared to Scn2aQ54 mice congenic on the C57BL/6J strain. Genetic mapping and RNA-Seq analysis identified Cacna1g as a candidate modifier gene at the Moe1 locus, which influences Scn2aQ54 phenotype severity. In this study, we evaluated the modifier potential of Cacna1g, encoding the Cav3.1 voltage-gated calcium channel, by testing whether transgenic alteration of Cacna1g expression modifies severity of the Scn2aQ54 seizure phenotype. Scn2aQ54 mice exhibited increased spontaneous seizure frequency with elevated Cacna1g expression and decreased seizure frequency with decreased Cacna1g expression. These results provide support for Cacna1g as an epilepsy modifier gene and suggest that modulation of Cav3.1 may be an effective therapeutic strategy.
Rapid eye movement (REM) sleep has a suppressing effect on epileptic activity. This effect might be directly related to neuronal desynchronization mediated by cholinergic neurotransmission. We investigated whether interictal epileptiform discharges (IEDs) and high frequency oscillations—a biomarker of the epileptogenic zone—are evenly distributed across phasic and tonic REM sleep. We hypothesized that IEDs are more suppressed during phasic REM sleep because of additional cholinergic drive.Methods
Twelve patients underwent polysomnography during long-term combined scalp-intracerebral electroencephalography (EEG) recording. After sleep staging in the scalp EEG, we identified segments of REM sleep with rapid eye movements (phasic REM) and segments of REM sleep without rapid eye movements (tonic REM). In the intracerebral EEG, we computed the power in frequencies <30 Hz and from 30 to 500 Hz, and marked IEDs, ripples (>80 Hz) and fast ripples (>250 Hz). We grouped the intracerebral channels into channels in the seizure-onset zone (SOZ), the exclusively irritative zone (EIZ), and the normal zone (NoZ).Results
Power in frequencies <30 Hz was lower during phasic than tonic REM sleep (p < 0.001), most likely reflecting increased desynchronization. IEDs, ripples and fast ripples, were less frequent during phasic than tonic REM sleep (phasic REM sleep: 39% of spikes, 35% of ripples, 18% of fast ripples, tonic REM sleep: 61% of spikes, 65% of ripples, 82% of fast ripples; p < 0.001). In contrast to ripples in the epileptogenic zone, physiologic ripples were more abundant during phasic REM sleep (phasic REM sleep: 73% in NoZ, 30% in EIZ, 28% in SOZ, tonic REM sleep: 27% in NoZ, 70% in EIZ, 72% in SOZ; p < 0.001).Significance
Phasic REM sleep has an enhanced suppressive effect on IEDs, corroborating the role of EEG desynchronization in the suppression of interictal epileptic activity. In contrast, physiologic ripples were increased during phasic REM sleep, possibly reflecting REM-related memory consolidation and dreaming.
Anti–tumor necrosis factor alpha therapy (adalimumab) in Rasmussen's encephalitis: An open pilot study
Rasmussen's encephalitis (RE) is a severe chronic inflammatory brain disease affecting one cerebral hemisphere and leading to drug-resistant epilepsy, progressive neurologic deficit, and unilateral brain atrophy. Hemispherotomy remains the gold standard treatment but causes permanent functional impairment. No standardized medical treatment protocol currently exists for patients prior to indication of hemispherotomy, although some immunotherapies have shown partial efficacy with functional preservation but poor antiseizure effect. Some studies suggest a role for tumor necrosis factor alpha (TNF-α) in RE pathophysiology.Methods
We report an open-label study evaluating the efficacy and the safety of anti-TNF-α therapy (adalimumab) in 11 patients with RE. The primary outcome criterion was the decrease of seizure frequency. The secondary outcome criteria were neurologic and cognitive outcomes and existence of side effects.Results
Adalimumab was introduced with a median delay of 31 months after seizure onset (range 1 month to 16 years), and follow-up was for a median period of 18 months (range 9–54 months). There was a significant seizure frequency decrease after adalimumab administration (from a median of 360 to a median of 32 seizures per quarter, p ≤ 0.01). Statistical analysis showed that adalimumab had a significant intrinsic effect (p < 0.005) independent from disease fluctuations. Five patients (45%) were found to have sustained improvement over consecutive quarters in seizure frequency (decrease of 50%) on adalimumab. Three of these five patients also had no further neurocognitive deterioration. Adalimumab was well tolerated.Significance
Our study reports efficacy of adalimumab in terms of seizure frequency control. In addition, stabilization of functional decline occurred in three patients. This efficacy might be particularly relevant for atypical slowly progressive forms of RE, in which hemispherotomy is not clearly indicated. Due to our study limitations, further studies are mandatory to confirm these preliminary results.
Novartis drug Afinitor significantly reduces seizures in Phase III study of patients with tuberous sclerosis complex
VANCOUVER – Once-daily eslicarbazepine may offer a more convenient option for controlling newly diagnosed partial-onset seizures, suggest findings of a phase III trial reported at the annual meeting...
Extrastriate visual cortex in idiopathic occipital epilepsies: The contribution of retinotopic areas to spike generation
To provide insight into the pathophysiology of idiopathic childhood occipital epilepsies (ICOEs), by mapping the contribution of retinotopic visual areas to the generation and sustainment of epileptic activity.Methods
Thirteen patients affected by ICOEs (mean age = 10.9 years) underwent a video electroencephalography–functional magnetic resonance imaging (EEG-fMRI) study. A flexible-related fMRI analysis was applied to estimate the shape of the blood oxygen level–dependent (BOLD) response in each patient. Second-level analysis was performed using the interictal EEG discharge (IED)–specific response shape for the ICOE group. The resulting fMRI t-maps were warped to the Population-Average, Landmark- and Surface-based (PALS)-B12 atlas in Caret. For localization purposes, functional results were plotted and compared against 19 retinotopic areas for each hemisphere. A correlation analysis was performed between the hemodynamic maps and electroclinical variables.Results
The shape of the group-averaged hemodynamic response in ICOE patients showed an earlier time-to-peak and a more pronounced undershoot than the canonical hemodynamic response function (HRF). The random-effect analysis showed positive hemodynamic changes in the bilateral temporooccipital network. With regard to the retinotopic subdivision of the visual cortex, the primary visual area was consistently spared. Conversely, an extensive involvement of the occipitotemporal cortex, including the fusiform gyrus, and the occipitoparietal areas was observed. Moreover, a linear relationship was detected between the occipital spike-density and BOLD increases at the postcentral gyrus and temporooccipital cortex.Significance
Our data indicate that both the ventral and dorsal visual pathways are involved in spike generation in ICOEs, to extents that vary between patients, and reinforce the concept of benign childhood seizure susceptibility syndrome as a substrate for ICOEs. Finally, these results underscore the need for appropriate neuropsychological testing in these children, aimed at revealing selective impairments in functions subserved by both visual pathways.