A comparison of the responsiveness of EQ-5D-5L and the QOLIE-31P and mapping of QOLIE-31P to EQ-5D-5L in epilepsy

Objective: To investigate the responsiveness of and correlation between the EQ-5D-5L and the QOLIE-31P in patients with epilepsy, and develop a mapping function to predict EQ-5D-5L values based on the QOLIE-31P for use in economic evaluations. Methods: The dataset was derived from two clinical trials, the ZMILE study in the Netherlands and the SMILE study in the UK. In both studies, patients’ quality of life using the EQ-5D-5L and QOLIE-31P was measured at baseline and 12 months follow-up. Spearman’s correlations, effect sizes (EF) and standardized response means (SRM) were calculated for both the EQ-5D-5L and QOLIE-31P domains and sub scores. Mapping functions were derived using ordinary least square (OLS) and censored least absolute deviations models. Results: A total of 509 patients were included in this study. Low to moderately strong significant correlations were found between both instruments. The EQ-5D-5L showed high ceiling effects and small EFs and SRMs, whereas the QOLIE-31P did not show ceiling effects and also showed small to moderate EFs and SRMs. Results of the different mapping functions indicate that the highest adjusted R2 we were able to regress was 0.265 using an OLS model with squared terms, leading to a mean absolute error of 0.103. Conclusions: Results presented in this study emphasize the shortcomings of the EQ-5D-5L in epilepsy and the importance of the development of condition-specific preference-based instruments which can be used within the QALY framework. In addition, the usefulness of the constructed mapping function in economic evaluations is questionable

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

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 (R) taVNS 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

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.</p