Surgical complications of vagus nerve stimulation surgery: A 14-years single-center experience.

Introduction: Vagus nerve stimulation (VNS) is the most frequently used neuromodulation treatment for Drug-Resistant Epilepsy (DRE) patients. Complications of VNS surgery include surgical site infection and unilateral vocal cord paresis. Complication rates vary across studies. Research question: What is the safety profile of VNS related surgeries? Materials and methods: Retrospective cohort study using patient files of DRE-patients who had undergone primary implantation of a VNS-system, replacement of the VNS pulse generator, replacement of the lead, replacement of both pulse generator and lead, or VNS removal surgery in the Maastricht UMC+. Multiple Imputation was used for missing data. Univariable and multivariable logistic regression analysis were performed to analyze possible risk factors, in case of a small sample size, an independent-samples t-test and Fisher's exact test or Pearson's X2-test were used. The complication rate was calculated as percentage. Results: This study included a total of 606 VNS surgical procedures, leading to 67 complications of which 3 permanent complications. Complication rate after primary implantation was 13.4%; 2,5% for pulse generator replacement; 21.4% for lead revision and 27.3% for complete VNS removal. No statistically significant results were found when analyzing the results of adults and children <18 years separately. Discussion and conclusion: Complication rates of VNS-related surgeries in our own institutional series are low and comparable to previously reported series. VNS surgery is a relatively safe procedure. The complication rate differs per type of surgery and mean surgery duration was longer for patients with complications after lead revision surgery compared to patients without complications.

What Do You See? Signature Pedagogy in Continuous Electroencephalography Teaching.

PURPOSE: Electroencephalography (EEG) is commonly used in neurology, but there is variability in how neurologists interpret EEGs, potentially from variability in EEG teaching. Little is known about how EEG teaching is done to prepare neurologists for professional practice. METHODS: We interviewed a group of EEG experts to characterize their teaching practices around continuous EEG (cEEG). We used signature pedagogy as a framework to analyze and interpret the data. RESULTS: We identified pervasive and characteristic forms of cEEG teaching. Teaching is based on apprenticeship, relying on "learning by doing" in the context of real-life clinical practice. There are habitual steps that learners take to anchor teaching, which typically occurs during rounds. There is a common language and core knowledge that trainees need to master early in their training. CONCLUSIONS: There are pervasive characteristic forms of cEEG teaching. These findings can help facilitate instructional design and implementation of complementary or enhanced cEEG teaching practices.

Economic evaluations of nonpharmacological treatments for drug-resistant epilepsy: A systematic review.

This study was undertaken to systematically identify and critically appraise all published full economic evaluations assessing the cost-effectiveness of nonpharmacological interventions for patients with drug-resistant epilepsy. The Population, Intervention, Comparison, Outcome, Study criteria was used to design search strategies for the identification and selection of relevant studies. Literature search was performed using the MEDLINE (via PubMed), Embase, International Health Technology Assessment, National Institute for Health Research Economic Evaluation Database, and Cost-Effectiveness Analysis Registry databases to identify articles published between January 2000 and May 2023. Web of Science was additionally used to perform forward and backward referencing. Title, abstract, and full-text screening was performed by two independent researchers. The Consensus Health Economic Criteria (CHEC) checklist and Consolidated Health Economic Evaluation Reporting Standards (CHEERS) 2022 were applied for quality assessment. A total of 4470 studies were identified, of which 18 met our inclusion criteria. Twelve of the studies conducted model-based economic evaluation, and others were trial-based. Three studies showed that epilepsy surgery was cost-effective in adults, whereas this remained inconclusive for children (two positive, three negative). Three studies showed negative economic outcome for ketogenic diet in children. One of four studies showed positive results for self-management. For vagus nerve stimulation, one study showed positive results in adults and another one negative results in children. One recent study showed cost-effectiveness of responsive neurostimulation (RNS) in adults. Finally, one study showed promising but inconclusive results for deep brain stimulation (DBS). The mean scores for risk of bias assessment (based on CHEC) and for reporting quality (CHEERS 2022) were 95.8% and 80.5%, respectively. This review identified studies that assessed the cost-effectiveness of nonpharmacological treatments in both adults and children with drug-resistant epilepsy, suggesting that in adults, epilepsy surgery, vagus nerve stimulation, and RNS are cost-effective, and that DBS and self-management appear to be promising. In children, the cost-effectiveness of epilepsy surgery remains inconclusive. Finally, the use of ketogenic diet was shown not to be cost-effective. However, limited long-term data were available for newer interventions (i.e., ketogenic diet, DBS, and RNS).

Resective Epilepsy Surgery, QUality of life and Economic evaluation (RESQUE): the change in quality of life after resective epilepsy surgery-protocol for a multicentre, prospective cohort study.

INTRODUCTION: Resective epilepsy surgery is often seen as a last resort when treating drug-resistant epilepsy. Positive results on quality of life (QoL) and economic benefits after surgery argue for a less restrictive attitude towards epilepsy surgery for drug-resistant epilepsy. QoL and economic benefits are country-dependent. The objective of the Resective Epilepsy Surgery, QUality of life and Economic evaluation (RESQUE) trial is to evaluate the change in QoL before and after epilepsy surgery in Dutch people with drug-resistant epilepsy. The results will form part of an economic evaluation of epilepsy surgery in people with epilepsy (PWE) in The Netherlands. METHODS AND ANALYSIS: A longitudinal prospective multicentre cohort study involving 100 PWE undergoing epilepsy surgery between 2019 and 2025 is being performed in three Dutch academic hospitals. Excluded are PWE who have a lower level of intelligence (TIQ<70) or who do not master the Dutch language. Before surgery and 3, 6, 12 and 24 months after surgery, PWE receive validated online questionnaires (QOLIE-31, EQ-5D, iMCQ and iPCQ) on QoL, cost of care, expectations and satisfaction. Primary outcome is the change in QoL. Secondary outcomes are change in generic QoL, seizure reduction (International League Against Epilepsy Outcome Classification), medical consumption, productivity, the correlation between QoL and seizure reduction and expectation of and satisfaction with the surgery. ETHICS AND DISSEMINATION: The study design has been approved by the Medical Ethics Review Committee (METC) of Maastricht UMC+ (2019-1134) and the Amsterdam UMC (vu). At the time of writing, UMC Utrecht is in the process of considering approval. The study will be conducted according to the Dutch Medical Research Involving Human Subjects Act and the Declaration of Helsinki. The results will be publicly disclosed and submitted for publication in international peer-reviewed scientific journals. There is no veto on publication by the involved parties. TRIAL REGISTRATION: NL8278; Pre-results.

SCN1A-deficient excitatory neuronal networks display mutation-specific phenotypes.

Dravet syndrome is a severe epileptic encephalopathy, characterized by (febrile) seizures, behavioural problems and developmental delay. Eighty per cent of patients with Dravet syndrome have a mutation in SCN1A, encoding Nav1.1. Milder clinical phenotypes, such as GEFS+ (generalized epilepsy with febrile seizures plus), can also arise from SCN1A mutations. Predicting the clinical phenotypic outcome based on the type of mutation remains challenging, even when the same mutation is inherited within one family. This clinical and genetic heterogeneity adds to the difficulties of predicting disease progression and tailoring the prescription of anti-seizure medication. Understanding the neuropathology of different SCN1A mutations may help to predict the expected clinical phenotypes and inform the selection of best-fit treatments. Initially, the loss of Na+-current in inhibitory neurons was recognized specifically to result in disinhibition and consequently seizure generation. However, the extent to which excitatory neurons contribute to the pathophysiology is currently debated and might depend on the patient clinical phenotype or the specific SCN1A mutation. To examine the genotype-phenotype correlations of SCN1A mutations in relation to excitatory neurons, we investigated a panel of patient-derived excitatory neuronal networks differentiated on multi-electrode arrays. We included patients with different clinical phenotypes, harbouring various SCN1A mutations, along with a family in which the same mutation led to febrile seizures, GEFS+ or Dravet syndrome. We hitherto describe a previously unidentified functional excitatory neuronal network phenotype in the context of epilepsy, which corresponds to seizurogenic network prediction patterns elicited by proconvulsive compounds. We found that excitatory neuronal networks were affected differently, depending on the type of SCN1A mutation, but did not segregate according to clinical severity. Specifically, loss-of-function mutations could be distinguished from missense mutations, and mutations in the pore domain could be distinguished from mutations in the voltage sensing domain. Furthermore, all patients showed aggravated neuronal network responses at febrile temperatures compared with controls. Finally, retrospective drug screening revealed that anti-seizure medication affected GEFS+ patient- but not Dravet patient-derived neuronal networks in a patient-specific and clinically relevant manner. In conclusion, our results indicate a mutation-specific excitatory neuronal network phenotype, which recapitulates the foremost clinically relevant features, providing future opportunities for precision therapies.

A model of healthy aging based on smartphone interactions reveals advanced behavioral age in neurological disease.

Smartphones offer unique opportunities to trace the convoluted behavioral patterns accompanying healthy aging. Here we captured smartphone touchscreen interactions from a healthy population (N = 684, ∼309 million interactions) spanning 16 to 86 years of age and trained a decision tree regression model to estimate chronological age based on the interactions. The interactions were clustered according to their next interval dynamics to quantify diverse smartphone behaviors. The regression model well-estimated the chronological age in health (mean absolute error = 6 years, R2 = 0.8). We next deployed this model on a population of stroke survivors (N = 41) to find larger prediction errors such that the estimated age was advanced by 6 years. A similar pattern was observed in people with epilepsy (N = 51), with prediction errors advanced by 10 years. The smartphone behavioral model trained in health can be used to study altered aging in neurological diseases.

Brivaracetam for the treatment of refractory epilepsy in patients with prior exposure to levetiracetam: A retrospective outcome analysis.

PURPOSE: To determine whether brivaracetam (BRV) provides an evident improvement in treatment efficacy and a reduction in treatment-emergent adverse events (TEAEs) in patients with refractory epilepsy, who previously failed treatment with levetiracetam (LEV). DESIGN: Retrospective analysis of data extracted from electronic patient files at Epilepsy Centre Kempenhaeghe (Heeze, the Netherlands) from the year 2000 until October 2020. METHODS: The inclusion criteria were met by 407 patients >18 years of age. During data collection, 26 patients were excluded due to too little follow-up information on the use of either LEV or BRV, and two more due to poor medication compliance, leaving a total of 379 patients for further analyses. All had used LEV before they started treatment with BRV. For every patient, data were collected including demographic information, efficacy (positive responder or non-responder) of LEV and BRV, and TEAEs occurring during LEV and BRV treatment. RESULTS: A total of 121 (29.8%) patients had discontinued BRV treatment before the end of data collection. At time of data collection the mean time since first seizure was 25.4 years. Of the 379 patients, 82.8% were diagnosed with focal epilepsy and 9.8% with generalized epilepsy. The median duration of treatment was 39 months for LEV and 20 months for BRV, the mean maximum dose was 1749.9 mg/day for LEV and 144.2 mg/day for BRV, and the mean number of concomitant AEDs was 1.4 at the start of LEV treatment and 2.0 at the start of BRV treatment. LEV was switched directly to BRV in 208 (54.9%) patients; 171 (45.1%) patients had an interval between discontinuation of LEV and the start of BRV. The mean duration of interval was 77.7 months. Of the patients who discontinued BRV, 30 (24.8%) switched back to LEV. Discontinuation of initial LEV treatment was due to TEAEs in 63.6% of patients, including 55.1% because of behavioural TEAEs. Discontinuation of BRV was due to inadequate efficacy in 24.0% of patients, to TEAEs in 47.1% and to both inadequate efficacy and TEAEs in 22.3%. Concerning efficacy, the analysis showed no significant difference between the positive responder rate of LEV and BRV (72.0% vs 69.1%, p>0.05). Of the patients who were positive responders to LEV treatment, 78.0% also had a positive response to BRV treatment. Of the non-responders to LEV treatment, 46.2% did have a positive response to BRV treatment. In comparison to LEV, patients reported significantly fewer TEAEs during BRV treatment (86.5% vs 61.7%, p<0.05). The most substantial difference was seen in the category 'behaviour' (55.1% vs 22.4%, p<0.05). Newly found behavioural TEAEs after switching from LEV to BRV were found in 7.1% of patients. CONCLUSION: Overall BRV was better tolerated than LEV, especially regarding the behavioural TEAEs. Efficacy analyses showed that patients are likely to have a positive response to BRV when they had a positive response to LEV. However, this is not always guaranteed. Lack of response to LEV does not preclude a positive response to BRV. All in all, BRV seems to be an interesting treatment option in patients previously treated with LEV.

Assessment of Quality of Life 8-Dimension (AQoL-8D): translation, validation, and application in two Dutch trials in patients with epilepsy and schizophrenia.

BACKGROUND: To translate and linguistically validate the Assessment of Quality of Life 8-dimensions (AQoL-8D) for use in the Netherlands and to compare the psychometric properties of AQoL-8D with the EuroQol 5-dimensions 5-levels (EQ-5D-5L) in two patient samples. METHODS: AQoL-8D was translated from English into Dutch. The translated AQoL-8D was then administered alongside the EQ-5D-5L at baseline and follow-up of two Dutch randomized controlled trials among patients with epilepsy and schizophrenia. These data were subjected to a post-hoc analysis assessing the psychometric properties of AQol-8D vis-à-vis EQ-5D-5L in terms of known-groups construct validity, responsiveness, and floor/ceiling effects. RESULTS: In total, 103 epilepsy patients and 99 schizophrenia patients were included in this study. In both datasets, the two instruments discriminated between known-groups, but in schizophrenia, AQoL-8D showed higher responsiveness than EQ-5D-5L, while both instruments showed equal responsiveness in epilepsy. Ceiling effects were only found for EQ-5D-5L in both epilepsy (26.6%) and schizophrenia (6.1%). CONCLUSION: Our results have shown that, among other things, AQoL-8D presents better ability to discriminate between known-groups and shows no ceiling effect. Based on our results, we would recommend the use of AQoL-8D in addition to EQ-5D-5L in trials assessing patient's quality of life in patients with epilepsy or schizophrenia.

Economic evaluation of deep brain stimulation compared with vagus nerve stimulation and usual care for patients with refractory epilepsy: A lifetime decision analytic model.

OBJECTIVES: This study was undertaken to estimate the cost-effectiveness of deep brain stimulation (DBS) compared with vagus nerve stimulation (VNS) and care as usual (CAU) for adult patients with refractory epilepsy from a health care perspective using a lifetime decision analytic model. METHODS: A Markov decision analytic model was constructed to estimate the lifetime cost-effectiveness of DBS compared with VNS and CAU. Transition probabilities were estimated from a randomized controlled trial, and assumptions were made in consensus with an expert panel. Primary outcomes were expressed as incremental costs per quality-adjusted life-year (QALY) and per responder. Univariate and probabilistic sensitivity analyses were conducted to characterize parameter uncertainty. RESULTS: In DBS, 28.4% of the patients were responders, with an average of 21.38 QALYs per patient and expected lifetime health care costs of €187 791. VNS had fewer responders (22.3%), fewer QALYs (20.70), and lower lifetime costs (€156 871). CAU had the fewest responders (6.2%), fewest QALYs (18.74), and lowest total health care costs (€64 670). When comparing with CAU, incremental cost-effectiveness ratios (ICERs) showed that costs per QALY gained were slightly lower for DBS (€46 640) than for VNS (€47 155). When comparing DBS with VNS, an incremental cost per additional QALY gained of €45 170 was found for DBS. Sensitivity analyses showed that ICERs were heavily dependent on assumptions regarding loss to follow-up in the respective clinical trial. SIGNIFICANCE: This study suggests that, given current limited evidence, VNS and DBS are potentially cost-effective treatment strategies compared to CAU for patients with refractory epilepsy. However, results for DBS were heavily impacted by assumptions made to extrapolate nonresponse from the original trial. More stringent assumptions regarding nonresponse resulted in an ICER just above an acceptable willingness to pay threshold. Given the uncertainty surrounding the effectiveness of DBS and the large impact of assumptions related to nonresponse, further empirical research is needed to reduce uncertainty.

Feasibility of transcutaneous auricular vagus nerve stimulation in treatment of drug resistant epilepsy: A multicenter prospective study.

BACKGROUND: Transcutaneous auricular vagus nerve stimulation (ta-VNS) is a new non-invasive technique developed as treatment option for drug resistant epilepsy. A few studies have been carried out showing that the efficacy and tolerability of ta-VNS is comparable with traditional implanted VNS but the feasibility of the therapy has been poorly described. This study aimed to explore potential clinical benefits of ta-VNS and to evaluate adaptation, compliance, as well as the usability of the device from a service design perspective. METHODS: A prospective, multicenter, clinical, investigator-initiated trial was conducted using the NEMOS® ta-VNS device. After eight weeks baseline, all subjects started ta-VNS with individually adjusted currents for four hours per day for six-months (first endpoint) followed by optional 12 months follow-up (second endpoint). The primary outcome was six months retention rate of ta-VNS therapy. Secondary outcomes included the user retention rate at 12 months follow-up, compliance, changes in scores of psychometric measures. For the study of feasibility, a service design questionnaire on medical devices used in the home was developed. RESULTS: In total 37 subjects had been included in the study after 45 months where the study was prematurely terminated due to recruitment problems and due to a high drop-out rate. Twenty-two subjects (59 %) completed the first six months of the study and in total six subjects (16 %) completed the following 12 months follow-up. The reasons for discontinuation were a mixture of medical and practical issues of which the majority were related to a combination of both. Those, who managed to continue to use ta-VNS throughout the study, gave generally higher scores for the device usability and compatibility with lifestyle. The study turned out to be inadequately powered to reach any conclusion in terms of the clinical benefits of ta-VNS but present an example of difficulties that are encountered in conducting high-quality studies with digital devices. CONCLUSION: The feasibility of ta-VNS therapy showed to be relatively modest which is most likely due to practical usability issues and lifestyle fits. The results of this study stress the importance of generating data based on patients experiences at an early stage during the development phase and when designing clinical trials on medical devices that depend on patient's active participation and motivation.

Evaluation of two anti-seizure medication strategies in refractory epilepsy patients from a tertiary center with complementary insights from data visualization.

OBJECTIVE: To evaluate the healthcare resources in a tertiary center related to exclusive use of non-enzyme inducing anti-seizure medications relative to concomitant use of enzyme-inducing anti-seizure medications in patients with refractory epilepsy. METHODS: In this retrospective case-time-control study, we compared the effects of two anti-seizure medication strategies: exclusively non-inducing anti-seizure medications (NIND) or a combination of NIND and inducing anti-seizure medications (IND+). The primary outcome parameter was the number of consultations with relevant healthcare professionals in our tertiary center, assessed with a negative binomial regression model, adjusting for several covariates like blood drug level and time interval (TI). Results from statistical models were visualized to explore the contribution of all covariates on the outcome in the total population and in subgroups. RESULTS: From the 21538 patients with refractory epilepsy referred to our center 1648 patients met the inclusion criteria. The regression model showed that the IND + strategy was significantly associated with fewer consultations compared to the NIND strategy (p < 0.001), reflected in an incidence risk ratio (IRR) of 0.844 (0.799-0.890). Visualization of subgroups, defined by anti-seizure medications strategy, revealed patterns in contribution of blood drug level measurements on the outcome. Although sex was not included as a covariate in the regression model, as it was eliminated by the backward-elimination approach, visualization of this subgroup showed differences in effects of blood drug level and TI. CONCLUSION: For patients with refractory epilepsy in our tertiary center, treatment following the IND + strategy is associated with fewer consultations with healthcare professionals compared to the NIND strategy. Comprehensive visualization of the results facilitated the exploration of effects of covariates across subgroups.

Antibodies Contributing to Focal Epilepsy Signs and Symptoms Score.

OBJECTIVE: Diagnosing autoimmune encephalitis (AIE) is difficult in patients with less fulminant diseases such as epilepsy. However, recognition is important, as patients require immunotherapy. This study aims to identify antibodies in patients with focal epilepsy of unknown etiology, and to create a score to preselect patients requiring testing. METHODS: In this prospective, multicenter cohort study, adults with focal epilepsy of unknown etiology, without recognized AIE, were included, between December 2014 and December 2017, and followed for 1 year. Serum, and if available cerebrospinal fluid, were analyzed using different laboratory techniques. The ACES score was created using factors favoring an autoimmune etiology of seizures (AES), as determined by multivariate logistic regression. The model was externally validated and evaluated using the Concordance (C) statistic. RESULTS: We included 582 patients, with median epilepsy duration of 8 years (interquartile range = 2-18). Twenty patients (3.4%) had AES, of whom 3 had anti-leucine-rich glioma inactivated 1, 3 had anti-contactin-associated protein-like 2, 1 had anti-N-methyl-D-aspartate receptor, and 13 had anti-glutamic acid decarboxylase 65 (enzyme-linked immunosorbent assay concentrations >10,000IU/ml). Risk factors for AES were temporal magnetic resonance imaging hyperintensities (odds ratio [OR] = 255.3, 95% confidence interval [CI] = 19.6-3332.2, p < 0.0001), autoimmune diseases (OR = 13.31, 95% CI = 3.1-56.6, p = 0.0005), behavioral changes (OR 12.3, 95% CI = 3.2-49.9, p = 0.0003), autonomic symptoms (OR = 13.3, 95% CI = 3.1-56.6, p = 0.0005), cognitive symptoms (OR = 30.6, 95% CI = 2.4-382.7, p = 0.009), and speech problems (OR = 9.6, 95% CI = 2.0-46.7, p = 0.005). The internally validated C statistic was 0.95, and 0.92 in the validation cohort (n = 128). Assigning each factor 1 point, an antibodies contributing to focal epilepsy signs and symptoms (ACES) score ≥ 2 had a sensitivity of 100% to detect AES, and a specificity of 84.9%. INTERPRETATION: Specific signs point toward AES in focal epilepsy of unknown etiology. The ACES score (cutoff ≥ 2) is useful to select patients requiring antibody testing. ANN NEUROL 2021;89:698-710.

Efficacy and tolerability of brivaracetam in patients with intellectual disability and epilepsy.

Patients with intellectual disability (ID) are often excluded from clinical trials, and little is known about the best approach to treat their epilepsy. Brivaracetam (BRV) is a new antiepileptic drug (AED) for adjunctive treatment in patients with focal-onset seizures with or without secondary generalization. We analyzed the efficacy and tolerability of BRV in patients with ID and epilepsy who either had or had not previously received treatment with levetiracetam (LEV). Data on efficacy and tolerability were retrospectively collected. After the initial start of BRV in our tertiary epilepsy center, we analyzed medical records at 0, 3, 6 and 12 months of follow-up. 116 patients were included (mean age = 34.9 years, 44% female). All had complete data of 3-month follow-up, 76 of 6-month follow-up, and 39 patients of 1-year follow-up. Median starting dose of BRV was 50.0 mg/day and the mean number of concomitant AEDs was 2.6. Seizure reduction and no side effects were reported in more than half of all patients. The most reported side effects were somnolence, dizziness and aggression. Retention rates for BRV were 84.4%, 75.5% and 58.1% after 3, 6 and 12 months, respectively. Seizure reduction and side effects did not differ significantly between the groups with or without previous LEV treatment. We demonstrate that BRV is effective and well tolerated in patients with epilepsy and ID, even in those where previous LEV treatment failed.

ZMILE, a multicomponent self-management intervention for adults with epilepsy: Rationale and description of the intervention.

OBJECTIVE: In this paper, we aim to provide a comprehensive description of the multicomponent self-management intervention for adults with epilepsy, ZMILE. RATIONALE OR THEORY: Acquiring self-management skills has been shown to play a vital role in enabling patients with epilepsy overcoming (health-related) struggles in daily life and coping with limitations their condition poses on them. ZMILE is a course consisting of education (to increase concordance to treatment), goal-setting (proactive coping), and self-monitoring. RESOURCES NEEDED: The course is guided by two nurse practitioners and each patient is allowed to bring one family member or friend. Self-monitoring plays an important role and can be done through e-Health tools or written diaries. PROCESSES INVOLVED: During and after the course, patients are required to work toward a personally defined goal using a five-step approach by means of pro-active coping. Moreover, patients are expected to use self-monitoring tools to reflect on their own behavior and identify ways to optimize medication intake when required. QUANTIFICATION: ZMILE is provided in an outpatient setting over five weekly group sessions and one booster session. From the start, patients are encouraged to set individual goals. Each group session will have a different theme but part of every session is reflecting on personal goals and to learn from eachother. CONCLUSIONS: The ZMILE-intervention has been evaluated and may be a promising intervention in terms of effectiveness and feasibility for adults with epilepsy, relatives, and professionals. We present the adapted version which can be implemented in clinical practice.

Padsevonil randomized Phase IIa trial in treatment-resistant focal epilepsy: a translational approach.

Therapeutic options for patients with treatment-resistant epilepsy represent an important unmet need. Addressing this unmet need was the main factor driving the drug discovery program that led to the synthesis of padsevonil, a first-in-class antiepileptic drug candidate that interacts with two therapeutic targets: synaptic vesicle protein 2 and GABAA receptors. Two PET imaging studies were conducted in healthy volunteers to identify optimal padsevonil target occupancy corresponding to levels associated with effective antiseizure activity in rodent models. Optimal padsevonil occupancy associated with non-clinical efficacy was translatable to humans for both molecular targets: high (>90%), sustained synaptic vesicle protein 2A occupancy and 10-15% transient GABAA receptor occupancy. Rational dose selection enabled clinical evaluation of padsevonil in a Phase IIa proof-of-concept trial (NCT02495844), with a single-dose arm (400 mg bid). Adults with highly treatment-resistant epilepsy, who were experiencing ≥4 focal seizures/week, and had failed to respond to ≥4 antiepileptic drugs, were randomized to receive placebo or padsevonil as add-on to their stable regimen. After a 3-week inpatient double-blind period, all patients received padsevonil during an 8-week outpatient open-label period. The primary endpoint was ≥75% reduction in seizure frequency. Of 55 patients randomized, 50 completed the trial (placebo n = 26; padsevonil n = 24). Their median age was 36 years (range 18-60), and they had been living with epilepsy for an average of 25 years. They were experiencing a median of 10 seizures/week and 75% had failed ≥8 antiepileptic drugs. At the end of the inpatient period, 30.8% of patients on padsevonil and 11.1% on placebo were ≥75% responders (odds ratio 4.14; P = 0.067). Reduction in median weekly seizure frequency was 53.7% and 12.5% with padsevonil and placebo, respectively (unadjusted P = 0.026). At the end of the outpatient period, 31.4% were ≥75% responders and reduction in median seizure frequency was 55.2% (all patients). During the inpatient period, 63.0% of patients on placebo and 85.7% on padsevonil reported treatment-emergent adverse events. Overall, 50 (90.9%) patients who received padsevonil reported treatment-emergent adverse events, most frequently somnolence (45.5%), dizziness (43.6%) and headache (25.5%); only one patient discontinued due to a treatment-emergent adverse event. Padsevonil was associated with a favourable safety profile and displayed clinically meaningful efficacy in patients with treatment-resistant epilepsy. The novel translational approach and the innovative proof-of-concept trial design maximized signal detection in a small patient population in a short duration, expediting antiepileptic drug development for the population with the greatest unmet need in epilepsy.

Prevalence and incidence of vertebral fractures: a 7-year follow-up study in institutionalized adults with refractory epilepsy and intellectual disability.

OBJECTIVE: The main objective of this cohort study is to determine the prevalence and incidence of morphometric vertebral fractures (VFs) over 7 years follow-up, in institutionalized adults with refractory epilepsy and intellectual disability (ID). METHODS: Dual-energy X-ray Absorptiometry (DXA) and Vertebral Fracture Assessment (VFA) were performed in 2009 and 2016. Vertebrae T4-L4 were assessed using quantitative morphometry. Severity of VFs was graded as 1 (mild; 20-25% reduction in height), 2 (moderate; 25-40% reduction) or 3 (severe; >40% reduction) according to the method described by Genant. Prevalent VFs were analyzed at baseline. VFs (grade 1, 2 or 3) present at follow-up, but not at baseline, were considered new VFs. Worsening VFs were defined as VFs with at least one grade deterioration at follow-up, compared to baseline (grade 1 to 2 or 3, or grade 2 to 3). Patients were treated with anti-osteoporosis treatment according to the Dutch guideline. RESULTS: Baseline and follow-up DXA and VFA could be obtained in 141 patients (87 male) aged between 18-79 years old (mean 44.8 ± 15.7). At baseline, 56 patients had at least one prevalent VF. Patients with a prevalent VF were significantly older than patients without (49.2 ± 13.7 vs 41.9 ± 16.4, p < .01). After 7 years follow-up, 38 new VFs occurred in 27 patients and 15 patients had a worsening VF, leading to an overall cumulative incidence of 27.0%. VF incidence was significantly higher in patients with at least one prevalent VF at baseline (48.2% vs 12.9%, respectively, p < .01) compared to no VF. SIGNIFICANCE: In adults with refractory epilepsy VFA is challenging, due to physical and behavioral aspects, resulting in a substantial proportion of unevaluable vertebrae and scans. Nevertheless, 40% of the patients had a VF at baseline and after 7 years follow-up, 27% had at least one new and/or worsening VF despite adequate anti-osteoporosis treatment.

Effectiveness and tolerability of adjunctive brivaracetam in patients with focal seizures: Second interim analysis of 6-month data from a prospective observational study in Europe.

Brivaracetam (BRV) is indicated for adjunctive treatment of focal (partial-onset) seizures with or without secondary generalisation in patients 4 years of age and older in the European Union (EU). An ongoing 12-month, prospective, non-interventional post-marketing study (EP0077; NCT02687711) is collecting real-world information on patients receiving treatment with adjunctive BRV in Europe. In this study, BRV is prescribed according to routine clinical practice and the EU Summary of Product Characteristics. This second interim analysis assessed effectiveness, tolerability and health-related quality of life outcomes for up to 6 months of treatment. At the cut-off date (13 April 2018), 266 patients from five countries had attended Visit 1, 24.1 % (64/266) had completed the study, 37.6 % (100/266) were ongoing, and 38.3 % (102/266) had discontinued. In total, 261 patients had at least one dose of BRV and were included in the analyses. Patients had a mean time since epilepsy diagnosis of 23.2 years, a mean of eight lifetime AEDs (sum of AEDs discontinued prior to study entry and concomitant at study entry), and a median of five focal seizures per 28 days during the 3-month retrospective Baseline. 66.3 % of patients initiated BRV at a dose within the recommended starting range (50-100 mg/day) and 87.1 % of patients received BRV modal doses within the recommended dose range (50-200 mg/day) during the study. Retention rates were 79.1 % (N = 239) at 3 months and 62.1 % (N = 211) at 6 months. The 50 % responder rates for focal seizures were 46.8 % (N = 139) at 3 months and 53.6 % (N = 97) at 6 months. The proportions of patients who were seizure-free were 10.7 % (21/196) and 7.5 % (15/199) at 3 and 6 months of treatment, respectively. Median percent reductions in focal seizure frequency per 28 days from Baseline to 3 and 6 months were 34.6 % (N = 139) and 53.3 % (N = 97), respectively. Overall, 44.2 % of patients had an improvement and 15.4 % had a worsening in Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 total score from Baseline to 6 months (N = 52). At least one treatment-emergent adverse event (TEAE) was reported in 51.0 % (133/261) of patients, and 34.5 % (90/261) of patients had drug-related TEAEs. The most common drug-related TEAEs (≥5% of patients) were drug ineffective (7.7 %), seizure (6.5 %), and fatigue (6.1 %). In this 6-month interim analysis, BRV showed effectiveness when used in clinical practice in five European countries. BRV was well tolerated, and no new safety signals were observed.

European perspective of perampanel response in people with Intellectual Disability.

BACKGROUND: Epilepsy prevalence is over 20% for those with ID. It is difficult to diagnose and treat and more likely to be treatment resistant. The evidence informing prescribing is sparse, particularly for new drugs such as perampanel (PMP). AIMS OF THE STUDY: This study seeks to strengthen the research evidence regarding PMP for people with ID by pooling information from two isolated and separately conducted studies: the UK-based Epilepsy Database Register (Ep-ID) and the data from the Kempenhaeghe clinic in the Netherlands. METHODS: A single data set of comparable data was created and analysed under agreement and supervision of a UK statistician. RESULTS: Seizure reduction within twelve months was evident in 62% of Dutch and 47% of UK patients. Retention rates were higher for those in the UK (P = .01) and for patients with moderate to profound ID, whilst side effects were more prominent in the Dutch cohort. CONCLUSIONS: Comparable rates of seizure reduction are in line with estimates for non-ID patients, adding to the evidence suggesting that PMP has a similar impact on those with ID. Taking a European perspective and sharing data across centres can help strengthen the evidence for prescribing antiepileptic drugs in the ID population.

Ketogenic diet for the treatment of pediatric epilepsy: review and meta-analysis.

The ketogenic diet (KD), containing high levels of fat and low levels of carbohydrates, has been used to treat refractory epilepsy since the 1920s. In the past few decades, there has been more interest in less restrictive KDs such as the modified Atkins diet (MAD). PURPOSE: Our aim was to review all evidence regarding the efficacy and tolerability of the KD and MAD from randomized controlled trials (RCTs) in children and adolescents with refractory epilepsy. METHODS: We reviewed the current literature using Cochrane, EMBASE, and MEDLINE (using PubMed). We implemented predefined criteria regarding dataextraction and study quality. RESULTS: We identified five RCTs that generated seven publications and recruited 472 children and adolescents with refractory epilepsy (≤ 18 years). The primary outcome (seizure frequency reduction (SFR) ≥ 50%) was attained in 35-56.1% of the participants in the intervention group, compared with 6-18.2% in the control group. Our meta-analysis underlined the significant efficacy of the KD compared with the control group: RR = 5.1 (95% CI 3.18-8.21, p < 0.001). Additionally, only two studies mentioned possible biomarkers to objectively evaluate the efficacy. Secondary outcomes, such as seizure severity and quality of life, were studied in three trials, leading to indecisive generalization of these findings. Gastro-intestinal adverse effects were the most prevalent, and no severe adverse effects were reported. CONCLUSION: Despite the heterogeneity between all studies, the beneficial results underline that dietary interventions should be considered for children and adolescents with refractory epilepsy who are not eligible for epilepsy surgery. Future studies should be multi-center and long-term, and evaluate potential biomarkers and adverse effects.

Short-term discontinuation of vagal nerve stimulation alters 18F-FDG blood pool activity: an exploratory interventional study in epilepsy patients.

BACKGROUND: Vagus nerve activation impacts inflammation. Therefore, we hypothesized that vagal nerve stimulation (VNS) influenced arterial wall inflammation as measured by 18F-FDG uptake. RESULTS: Ten patients with left-sided VNS for refractory epilepsy were studied during stimulation (VNS-on) and in the hours after stimulation was switched off (VNS-off). In nine patients, 18F-FDG uptake was measured in the right carotid artery, aorta, bone marrow, spleen, and adipose tissue. Target-to-background ratios (TBRs) were calculated to normalize the respective standardized uptake values (SUVs) for venous blood pool activity. Median values are shown with interquartile range and compared using the Wilcoxon signed-rank test. Arterial SUVs tended to be higher during VNS-off than VNS-on [SUVmax all vessels 1.8 (1.5-2.2) vs. 1.7 (1.2-2.0), p = 0.051]. However, a larger difference was found for the venous blood pool at this time point, reaching statistical significance in the vena cava superior [meanSUVmean 1.3 (1.1-1.4) vs. 1.0 (0.8-1.1); p = 0.011], resulting in non-significant lower arterial TBRs during VNS-off than VNS-on. Differences in the remaining tissues were not significant. Insulin levels increased after VNS was switched off [55.0 pmol/L (45.9-96.8) vs. 48.1 pmol/L (36.9-61.8); p = 0.047]. The concurrent increase in glucose levels was not statistically significant [4.8 mmol/L (4.7-5.3) vs. 4.6 mmol/L (4.5-5.2); p = 0.075]. CONCLUSIONS: Short-term discontinuation of VNS did not show a consistent change in arterial wall 18F-FDG-uptake. However, VNS did alter insulin and 18F-FDG blood levels, possibly as a result of sympathetic activation.