Brivaracetam (BRV) decreases seizure activity in a number of epilepsy models and binds to the synaptic vesicle glycoprotein 2A (SV2A) with a higher affinity than the antiepileptic drug levetiracetam (LEV). Experiments were performed to determine if BRV acted similarly to LEV to induce or augment short-term depression (STD) under high-frequency neuronal stimulation and slow synaptic vesicle recycling.Methods
Electrophysiologic field excitatory postsynaptic potential (fEPSP) recordings were made from CA1 synapses in rat hippocampal slices loaded with BRV or LEV during intrinsic activity or with BRV actively loaded during hypertonic stimulation. STD was examined in response to 5 or 40 Hz stimulus trains. Presynaptic release of FM1-43 was visualized using two-photon microscopy to assess drug effects upon synaptic vesicle mobilization.Results
When hippocampal slices were incubated in 0.1–30 μm BRV or 30 μm–1 mm LEV for 3 h, the relative CA1 field EPSPs decreased over the course of a high-frequency train of stimuli more than for control slices. This STD was frequency- and concentration-dependent, with BRV being 100-fold more potent than LEV. The extent of STD depended on the length of the incubation time for both drugs. Pretreatment with LEV occluded the effects of BRV. Repeated hypertonic sucrose treatments and train stimulation successfully unloaded BRV from recycling vesicles and reversed BRVs effects on STD, as previously reported for LEV. At their maximal concentrations, BRV slowed FM1-43 release to a greater extent than in slices loaded with LEV during prolonged stimulation.Significance
BRV, similar to LEV, entered into recycling synaptic vesicles and produced a frequency-dependent decrement of synaptic transmission at 100-fold lower concentrations than LEV. In addition, BRV slowed synaptic vesicle mobilization more effectively than LEV, suggesting that these drugs may modify multiple functions of the synaptic vesicle protein SV2A to curb synaptic transmission and limit epileptic activity.
Evolution of temporal and spectral dynamics of pathologic high-frequency oscillations (pHFOs) during epileptogenesis
In temporal lobe epilepsy (TLE), pathologic high frequency oscillations (pHFOs, 200–600 Hz) are present in the hippocampus, especially the dentate gyrus (DG). The pHFOs emerge during a latent period prior to the onset of spontaneous generalized seizures. We used a unilateral suprahippocampal injection of kainic acid (KA) mouse model of TLE to characterize the properties of hippocampal pHFOs during epileptogenesis.Methods
In awake head-fixed mice, 4–14 days after KA-induced status epilepticus (SE), we recorded local field potentials (LFPs) with 64-channel silicon probes spanning from CA1 alveus to the DG hilus, or with glass pipettes in the DC mode in the CA1 str radiatum.Results
The pHFOs, are observed simultaneously in the CA1 and the DG, or in the DG alone, as early as 4 days post-SE. The pHFOs ride on top of DC deflections, occur during motionless periods, persist through the onset of TLE, and are generated in bursts. Burst parameters remain remarkably constant during epileptogenesis, with a random number of pHFOs generated per burst. In contrast, pHFO duration and spectral dynamics evolve from short events at 4 days post-SE to prolonged discharges with complex spectral characteristics by 14 days post-SE. Simultaneous dural EEG recordings were exceedingly unreliable for detecting hippocampal pHFOs; therefore, such recordings may deceptively indicate a “silent” period even when massive hippocampal activity is present.Significance
Our results demonstrate that hippocampal pHFOs exhibit a dynamic evolution during the epileptogenic period following SE, consistent with their role in transitioning to the chronic stage of TLE.
Developing clinical practice guidelines for epilepsy: A report from the ILAE Epilepsy Guidelines Working Group
Clinical practice guidelines (CPGs) contain evidence-based recommendations to guide clinical care, policy development, and quality of care improvement. A recent systematic review of epilepsy guidelines identified considerable variability in the quality of available guidelines. Although excellent frameworks for CPG development exist, processes are not followed uniformly internationally, and resources to develop CPGs may be limited in certain settings. An International League Against Epilepsy (ILAE) working group was charged with proposing methodology to guide the development of future epilepsy-specific CPGs. A comprehensive literature search (1985–2014) identified articles related to CPG development and handbooks. Guideline handbooks were included if they were publicly available, and if their methodology had been used to develop CPGs. The working group's expertise also informed the creation of methodologies and processes to develop future CPGs for the ILAE. Five handbooks from North America (American Academy of Neurology), Europe (Scottish Intercollegiate Guidelines Network & National Institute for Health and Care Excellence), Australia (National Health and Medical Research Council), World Health Organization (WHO), and additional references were identified to produce evidence-based, consensus-driven methodology for development of epilepsy-specific CPGs. Key components of CPG development include the following: identifying the topic and defining the scope; establishing a working group; identifying and evaluating the evidence; formulating recommendations and determining strength of recommendations; obtaining peer reviews; dissemination, implementation, and auditing; and updating and retiring the CPG. A practical handbook and toolkit was developed. The resulting CPG development toolkit should facilitate the development of high-quality ILAE CPGs to improve the care of persons with epilepsy.
Mutations in the syntaxin binding protein 1 gene (STXBP1) have been associated mostly with early onset epileptic encephalopathies (EOEEs) and Ohtahara syndrome, with a mutation detection rate of approximately 10%, depending on the criteria of selection of patients. The aim of this study was to retrospectively describe clinical and electroencephalography (EEG) features associated with STXBP1-related epilepsies to orient molecular screening.Methods
We screened STXBP1 in a cohort of 284 patients with epilepsy associated with a developmental delay/intellectual disability and brain magnetic resonance imaging (MRI) without any obvious structural abnormality. We reported on patients with a mutation and a microdeletion involving STXBP1 found using array comparative genomic hybridization (CGH).Results
We found a mutation of STXBP1 in 22 patients and included 2 additional patients with a deletion including STXBP1. In 22 of them, epilepsy onset was before 3 months of age. EEG at onset was abnormal in all patients, suppression-burst and multifocal abnormalities being the most common patterns. The rate of patients carrying a mutation ranged from 25% in Ohtahara syndrome to <5% in patients with an epilepsy beginning after 3 months of age. Epilepsy improved over time for most patients, with an evolution to West syndrome in half. Patients had moderate to severe developmental delay with normal head growth. Cerebellar syndrome with ataxic gait and/or tremor was present in 60%.Significance
Our data confirm that STXBP1 mutations are associated with neonatal-infantile epileptic encephalopathies. The initial key features highlighted in the cohort of early epileptic patients are motor seizures either focal or generalized, abnormal initial interictal EEG, and normal head growth. In addition, we constantly found an ongoing moderate to severe developmental delay with normal head growth. Patients often had ongoing ataxic gait with trembling gestures. Altogether these features should help the clinician to consider STXBP1 molecular screening.
To investigate cross-sectional and longitudinal differences in static and dynamic standing balance measures and lower limb muscle strength in patients who are treated chronically with antiepileptic drugs (AEDs).Methods
Twenty-six AED exposure–discordant same-gender twin and sibling pairs were studied. Clinical and laboratory balance examinations were conducted twice, separated by at least 1 year. The mean within-pair differences in balance measures were calculated cross-sectionally at baseline and follow-up, and longitudinally.Results
No significant mean within-pair difference was found at baseline in age (44 years), weight, and height (p > 0.05). Between study assessments, the median (interquartile range [IQR]) interval was 3.0 (2.1–4.3) years in users and 2.9 (2.0–4.4) years in nonusers. The median duration of AED therapy was 19 (11–21) years.
At baseline and follow-up, cross-sectional sway measures from posturography (Chattecx Balance System) and clinical static balance tests showed poorer performance in users compared to nonusers on several test conditions (p = 0.002–0.032). At follow-up, the users took longer than nonusers to complete the Four-Square-Step Test (p = 0.005) and Five-Times-Sit-to-Stand Test (p = 0.018).
A greater annual rate of deterioration in sway was found in users compared to nonusers using posturography on the anteroposterior tilting platform task with distraction (p = 0.032). In both groups, higher baseline sway predicted greater annual deterioration in sway in all platform conditions (β = 0.3–0.5, p < 0.001–0.013). The annual change in measures did not differ between groups in the clinical balance and lower limb strength assessments.Significance
In this longitudinal twin and sibling study, chronic AED users had poorer standing balance compared to nonusers. Users showed greater deterioration in postural sway with one dynamic platform condition. AEDs may progressively impair balance mechanisms, although this requires further investigations. Repeated dynamic posturography could provide a basis for preventive trials for maintaining or improving balance.
How to reduce the treatment gap for people with epilepsy in resource-limited settings by innovative galenic formulations: A review of the current situation, overview of potential techniques, interests and limits
Advances in epilepsy genetics have been rapid, and it is challenging for clinicians on the ground to keep pace with these advances. The International League Against Epilepsy (ILAE) Genetics Commission has thus crafted a new Genetic Literacy series targeted at busy clinicians. Our goal is to help provide a concise, accessible resource on epilepsy genetics for the busy, on-the-ground clinician so that he/she can apply that knowledge at point-of-care to help patients. This new series is grounded in educational theories and evidence to ensure that learning is effective and efficient. We hope that by promoting and encouraging continuing medical education in epilepsy genetics, this eventually translates to better patient management and therefore better patient health outcomes.
Premature death among individuals with epilepsy is higher than in the general population, and sudden unexpected death is the most common cause of this mortality. A new multisite collaborative research consortium, the Center for sudden unexpected death in epilepsy (SUDEP) Research (CSR), has received major funding from the National Institutes of Health (NIH) to examine the possible biologic mechanisms underlying this potentially preventable comorbidity and develop predictive biomarkers for interventions that could lower SUDEP incidence. This inaugural report describes the structure of the CSR, its priorities for human and experimental research, and the strategic collaborations and advanced tools under development to reduce this catastrophic outcome of epilepsy. The CSR Partners Program will work closely with committed volunteer agencies, industry, and academic institutions to accelerate and communicate these advances to the professional and lay community.
Global assessment of the severity of epilepsy (GASE) Scale in children: Validity, reliability, responsiveness
The Global Assessment of Severity of Epilepsy (GASE) Scale is a single-item, 7-point global rating scale designed for neurologist-report of overall severity of epilepsy in children. Building on previous preliminary evidence of its validity and reliability for research and clinical use, this study evaluated the GASE Scale's construct validity, reliability, and responsiveness to changes in severity of epilepsy.Methods
Data used for the study arose from the Health-Related Quality of Life in Children with Epilepsy Study (HERQULES), a 2-year multicenter prospective cohort study (n = 374) with observations taken at baseline, and 6, 12, and 24 months after diagnosis. Construct validity and reliability were quantified using Spearman's correlation and intraclass correlation coefficient (ICC). Responsiveness was assessed using both distribution-based and anchor-based indices.Results
The GASE Scale was at least moderately correlated (r ≥ 0.30) with several key clinical aspects and most strongly correlated with frequency and intensity of seizures and interference of epilepsy or drugs with daily activities (r > 0.30). Total variation in GASE Scale scores explained by seven core clinical aspects of epilepsy increased over time (R2 = 28% at baseline to R2 = 70% at 24 months). The GASE Scale had modest test–retest reliability (ICC range: 0.52–0.64) and was responsive to changes in clinical criteria (standardized response mean range: 0.49–0.68; probability of change range: 0.69–0.75; Guyatt's responsiveness statistic range: 0.56–0.84). The GASE Scale showed potential to discriminate “stable” and “changed” patients according to select criteria and to a composite score (area under the receiver operating characteristic [ROC] curve range: 0.50–0.67).Significance
Results offer additional evidence in support of the GASE Scale's validity, reliability, as well as responsiveness to changes in severity of epilepsy in children. We conclude that the GASE Scale is a potentially useful tool for assessing the severity of epilepsy in both clinical and research settings.