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.

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).

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.

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.

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.

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.

Risk factors predisposing to psychotic symptoms during levetiracetam therapy: A retrospective study.

PURPOSE: While levetiracetam (LEV) usage is a known risk factor for psychosis in epilepsy, the modulating effect of certain patient and treatment characteristics on the risk of psychosis has yet to be fully elucidated. METHODS: In our tertiary epilepsy center, 84 patients with psychotic symptoms during LEV usage and 100 controls without psychotic symptoms during LEV usage were selected. Patient records were reviewed including demographics, medical history, antiepileptic drug use, and cognitive abilities. Univariate comparisons were performed, and variables with p < 0.1 were selected for binary logistic regression analysis. RESULTS: The total incidence of psychosis during LEV therapy in our population was 3.7%. The timing of psychotic symptoms was classified as postictal in 20 (19.8%), interictal in 14 (15.4%), postepilepsy surgery in 1 (1.1%), and unknown in 18 cases (19.8%). In 31 cases (34.1%), psychotic symptoms were classified as an antiepileptic drug-induced psychotic disorder (AIPD) as a result of LEV. In 7 cases (7.7%), AIPD occurred as a result of a different antiepileptic drug. A significant association was found between the experience of psychotic symptoms and status epilepticus (p = 0.002), a history of psychotic symptoms (p < 0.000), a history of psychiatric illness other than psychosis (p = 0.010), and concomitant phenytoin (PHT) usage (p = 0.044). Cotherapy with lamotrigine (LTG) was protective (p = 0.042). A separate analysis of controls and exclusively the 31 cases with LEV-induced AIPD yielded comparable results; a significant association was confirmed with status epilepticus (p = 0.021) and history of psychotic symptoms (p = 0.018), as well as with female gender (p = 0.047) and intellectual disability (p = 0.043). CONCLUSION: Our retrospective study found that psychotic symptoms during LEV therapy were significantly associated with status epilepticus, a history of psychotic symptoms, a history of psychiatric illness other than psychosis, and concomitant PHT usage, whereas concomitant LTG usage was protective. Psychotic symptoms specifically as an adverse drug reaction to LEV were significantly associated with female gender, intellectual disability, status epilepticus, and a history of psychotic symptoms.

Effectiveness of a multicomponent self-management intervention for adults with epilepsy (ZMILE study): A randomized controlled trial.

BACKGROUND: The objective of the ZMILE study was to compare the effectiveness of a multicomponent self-management intervention (MCI) with care as usual (CAU) in adult patients with epilepsy (PWE) over a six-month period. METHODS: Participants (PWE & relative) were randomized into intervention or CAU groups. Self-report questionnaires were used to measure disease-specific self-efficacy as the primary outcome measure and general self-efficacy, adherence, seizure severity, emotional functioning, quality of life, proactive coping, and side-effects of antiepileptic drugs (AED) as secondary outcome measures. Instruments used at baseline and during a six-month follow-up period were the following: disease-specific self-efficacy (Epilepsy Self-Efficacy Scale [ESES], General Self-Efficacy Scale [GSES]); adherence (Medication Adherence Scale [MARS] and Medication Event Monitoring System [MEMS]); seizure severity (National Hospital Seizure Severity Scale [NHS3]); emotional well-being (Hospital Anxiety and Depression Scale [HADS]); quality of life (Quality of Life in Epilepsy [QOLIE-31P]); proactive coping (Utrecht Proactive Coping Competence [UPCC]); and side-effects of antiepileptic drugs [SIDAED]. Multilevel analyses were performed, and baseline differences were corrected by inclusion of covariates in the analyses. RESULTS: In total, 102 PWE were included in the study, 52 of whom were in the intervention group. On the SIDAED and on three of the quality of life subscales QOLIE-31P, a significant difference was found (p<0.05) in the intervention group. Self-efficacy, however, showed no significant differences between the MCI and the CAU groups. None of the other outcome measures showed any significant difference between the two groups. SIGNIFICANCE: Although we found no statistically significant difference in the primary outcome measure, disease-specific self-efficacy, this MCI could prove promising, since we found improvement in some domains of quality of life in epilepsy scale and a decrease in AED side-effects in the MCI group compared with the CAU group.

Anti-GAD antibodies in a cohort of neuropsychiatric patients.

OBJECTIVE: Antiglutamate decarboxylase (anti-GAD) antibodies are associated with several neurological manifestations, like epilepsy and movement disorders. However, in daily neurological practice, it remains hard to define when to test for anti-GAD antibodies in patients with neurologic and/or psychiatric symptoms. Therefore, here, we report the patient characteristics of a large retrospective cohort of patients tested for anti-GAD antibodies in clinical practice and compare the characteristics of anti-GAD positive and anti-GAD negative patients. METHODS: We blindly assessed relevant clinical symptoms and comorbidities and functional outcome with the modified Rankin Scale (mRS) in a retrospective observational cohort of all patients in which the decision to assess anti-GAD levels had been made based solely on the presence of possible associated neurological and/or psychiatric symptoms (N=119). RESULTS: Out of 119 patients, 17 (14.3%) were anti-GAD positive. The anti-GAD positive patients had a median age of 30years (range: 3-64; 2 children). They all had epilepsy, with 8 (47%) patients reporting cognitive complaints. Psychiatric symptoms were less prevalent in anti-GAD positive patients, only 1 anti-GAD positive patient (6%) versus 34 anti-GAD negative patients (33%) reported psychiatric symptoms (p=0.021). The most frequent comorbidity of anti-GAD positive patients was diabetes mellitus type 1 (n=8). Twelve (71%) and 13 (78%) of the anti-GAD positive patients were functionally independent at the time of diagnosis and after one year, respectively (mRS score: 0 to 2). There was no significant difference in functional status at any time during follow-up compared with the anti-GAD negative group. CONCLUSION: Antiglutamate decarboxylase (anti-GAD) antibodies relate to epilepsy with or without cognitive complaints. However, psychiatric symptoms were almost absent in anti-GAD positive patients, and the presence of anti-GAD antibodies contributed little to the prognosis in our cohort.

An economic evaluation of a multicomponent self-management intervention for adults with epilepsy (ZMILE study).

OBJECTIVE: The objective of this (trial-based) economic evaluation was, from a societal perspective, to compare the cost-effectiveness of a multicomponent self-management intervention (MCI) with care as usual (CAU) in adult patients with epilepsy over a 12-month period. METHODS: In a randomized-controlled trial, participants were randomized into intervention or CAU group. Adherence, self-efficacy (Epilepsy Self-Efficacy Scale [ESES]), quality-adjusted life years (QALYs), healthcare costs, production losses, and patient and family costs were assessed at baseline and during the 12-month study period. Incremental cost-effectiveness ratios (ICERs) (i.e., cost per increased adherence, self-efficacy, or QALY), and cost-effectiveness acceptability curves were calculated. RESULTS: In total, 102 patients were included in the study, of whom 52 were in the intervention group. Adherence rates over 6 months were 63.7% for the CAU group and 75.9% for the intervention group. Adherence, ESES, and quality of life did not differ significantly between groups. An ICER of €54 per point increase in ESES score at 6 months and €1,105 per point increase at 12-month follow-up was found. The intervention resulted in an ICER of €88 per percentage of adherence increase at 6 months. ICERs of €8,272 and €15,144 per QALY gained were found at 6- and 12-month follow-up, respectively. SIGNIFICANCE: Although no statistically significant difference was found after baseline adjustments, cost-effectiveness estimates for MCI appear promising. As rules of inference are arbitrary, it has been argued that decisions should be based only on the net benefits, irrespective of whether differences are statistically significant. Hence, the MCI may be a cost-effective addition to the current standard care for adults with epilepsy.

A systematic review of economic evaluations of treatments for patients with epilepsy.

The increasing number of treatment options and the high costs associated with epilepsy have fostered the development of economic evaluations in epilepsy. It is important to examine the availability and quality of these economic evaluations and to identify potential research gaps. As well as looking at both pharmacologic (antiepileptic drugs [AEDs]) and nonpharmacologic (e.g., epilepsy surgery, ketogenic diet, vagus nerve stimulation) therapies, this review examines the methodologic quality of the full economic evaluations included. Literature search was performed in MEDLINE, EMBASE, NHS Economic Evaluation Database (NHS EED), Econlit, Web of Science, and CEA Registry. In addition, Cochrane Reviews, Cochrane DARE and Cochrane Health Technology Assessment Databases were used. To identify relevant studies, predefined clinical search strategies were combined with a search filter designed to identify health economic studies. Specific search strategies were devised for the following topics: (1) AEDs, (2) patients with cognitive deficits, (3) elderly patients, (4) epilepsy surgery, (5) ketogenic diet, (6) vagus nerve stimulation, and (7) treatment of (non)convulsive status epilepticus. A total of 40 publications were included in this review, 29 (73%) of which were articles about pharmacologic interventions. Mean quality score of all articles on the Consensus Health Economic Criteria (CHEC)-extended was 81.8%, the lowest quality score being 21.05%, whereas five studies had a score of 100%. Looking at the Consolidated Health Economic Evaluation Reporting Standards (CHEERS), the average quality score was 77.0%, the lowest being 22.7%, and four studies rated as 100%. There was a substantial difference in methodology in all included articles, which hampered the attempt to combine information meaningfully. Overall, the methodologic quality was acceptable; however, some studies performed significantly worse than others. The heterogeneity between the studies stresses the need to define a reference case (e.g., how should an economic evaluation within epilepsy be performed) and to derive consensus on what constitutes "standard optimal care."

Evaluation of perampanel in patients with intellectual disability and epilepsy.

INTRODUCTION: Initial registration studies of perampanel (PMP), an AMPA receptor antagonist, have now been followed up by 'clinical' studies that confirmed its efficacy and safety in patients with refractory epilepsy. Publications on the use of PMP among patients with intellectual disability (ID) are still limited. This study extends our knowledge with respect to the relevance of PMP for patients with both ID and epilepsy, and furthermore specifies the behavioral side effects of PMP in this specific population. METHODS: Retrospective evaluation of medical records at 3, 6 and 12months of follow-up after the initial start of PMP. RESULTS: 62 patients were included. 21 patients (33.9%) were female. All patients had complete data of 6months follow-up and we were able to review 42 patients with a 1-year follow-up. Level of ID varied from borderline to profound, and mild ID was most common (43.5%). The mean maximum daily dosage of PMP was 5.6mg (range 1-12mg). Retention rates for PMP were 87.1% and 67.7% after three and six months. A trend indicated a longer mean retention time in patients with a more severe ID (borderline-mild-moderate ID: 205days, severe-profound ID: 275days). Seizure reduction was achieved in 53.2%. 36 patients (58.1%) experienced adverse effects, 80.6% of those within 3months. 45.2% of the patients experienced somatic adverse effects. Most common were fatigue & sleep problems, motor problems & unsteadiness, and gastrointestinal problems. Behavioral adverse effects were present in 40.3%. Most common were aggression, agitated behavior, disruptive behavior, and mood symptoms. Reasons for discontinuation of PMP were lack of efficacy in 14.8%, intolerable adverse effects in 44.4%, and a combination of both in 40.7%. Altogether, 24.2% (15/62) of the patients achieved seizure reduction without experiencing adverse effects, though none reached seizure freedom. CONCLUSIONS: The use of PMP might lead to an effective seizure reduction without adverse effects in a minority of patients with both epilepsy and ID. Pre-existing behavioral problems or polypharmacy do not predict the occurrence of additional behavioral adverse effects, implying that these patients need not be excluded from the introduction of PMP when clinically indicated. Patients should, ideally, be monitored at a multidisciplinary clinic.

Process evaluation of a multi-component self-management intervention for adults with epilepsy (ZMILE study).

BACKGROUND: People with epilepsy need to monitor and manage their symptoms. They, as well as their relatives, have to deal with the psychological burden, reflected in a reduced quality of life. Support in self-management can be of importance. We have developed a multi-component self-management intervention for patients and their relatives (MCI). This eight-week group intervention is conducted by nurse practitioners and consists of six two-hour sessions. The main components are: 1) providing self-management education, 2) stimulating proactive coping and goal-setting and 3) facilitating peer and social support. This study is a process evaluation to establish the feasibility, fidelity and acceptability of the intervention by assessing performance according to protocol, attendance and adherence, and the opinion of patients, relatives and facilitators about the intervention. METHOD: Study population consists of 52 patients with epilepsy living in the community (e.g. at home), 37 relatives and six facilitators. In this prospective mixed methods study, data were gathered using questionnaires for patients and relatives, registration forms for facilitators and by carrying out semi-structured group interviews with patients, relatives and facilitators. RESULTS: Patients and relatives attended a mean of 5.2 sessions. Forty-seven (90%) patients and 32 (86.5%) relatives attended at least five sessions. The mean group size was 8.1 (SD=1.3; range 6-10). All elements of the intervention were offered to participants, except for one e-Health tool which was only available at the start of the study. Overall, the sessions were considered useful by patients, their relatives and facilitators. The participation of a relative (social support) and sharing ideas and feelings about having epilepsy with peers (peer support) were rated as important aspects. CONCLUSION: This process evaluation revealed that the MCI was largely performed according to protocol, attendance rate was high, and participants and facilitators had, on the whole, a favourable opinion about the MCI, and would recommend it to others with epilepsy and their relatives. Overall, the adherence of patients and relatives was high. The MCI is considered feasible according to patients, relatives and facilitators. Implementation is recommended if the intervention proves to be effective.

An economic evaluation of the ketogenic diet versus care as usual in children and adolescents with intractable epilepsy: An interim analysis.

OBJECTIVES: To gain insight into the cost-effectiveness of the ketogenic (KD) diet compared with care as usual (CAU) in children and adolescents with intractable epilepsy, we conducted an economic evaluation from a societal perspective, alongside a randomized controlled trial. METHODS: Participants from a tertiary epilepsy center were randomized into KD (intervention) group or CAU (control) group. Seizure frequency, quality adjusted life years (QALYs), health care costs, production losses of parents and patient, and family costs were assessed at baseline and during a 4-month study period and compared between the intervention and control groups. The incremental cost-effectiveness ratios (ICERs) (i.e., cost per QALY and cost per responder), and cost-effectiveness acceptability curves (CEACs) were calculated and presented. RESULTS: In total, 48 children were included in the analyses of this study (26 KD group). At 4 months, 50% of the participants in the KD group had a seizure reduction ≥50% from baseline, compared with 18.2 of the participants in the CAU group. The mean costs per patient in the CAU group were €15,245 compared to €20,986 per patient in the KD group, resulting in an ICER of €18,044 per responder. We failed, however, to measure any benefits in terms of QALYs and therefore, the cost per QALY rise high above any acceptable ceiling ratio. It might be that the quality of life instruments used in this study were not sufficiently sensitive to detect changes, or it might be that being a clinical responder is not sufficient to improve a patient's quality of life. Univariate and multivariate sensitivity analyses and nonparametric bootstrapping were performed and demonstrated the robustness of our results. SIGNIFICANCE: The results show that the KD reduces seizure frequency. The study did not find any improvements in quality of life and, therefore, unfavorable cost per QALY ratio's resulted.

Are people with epilepsy using eHealth-tools?

INTRODUCTION: Self-management for people with epilepsy (PWE) should lead to shared decision-making and thus to adherence to the treatment plan. eHealth is an important way of supporting PWE in their self-management. METHOD: In this survey, we used a mixed method to explore the following: 1) which factors were monitored by PWE and how (using pen and paper or eHealth-tools), 2) how many PWE own a computer or smartphone, and 3) how do they perceive the use of eHealth. A consecutive series of 1000 PWE attending the outpatient clinic of a tertiary epilepsy center were asked to fill in a questionnaire. RESULTS: In comparison with the general population, fewer PWE owned a computer or smartphone. They were, however, more likely to self-monitor their health than other patients suffering from a chronic condition. Although PWE did not use eHealth-tools often, they perceived it as a user-friendly tool, promoting health behavior as well as adherence. On the other hand, problems with privacy and the perception that not everyone is able to use eHealth were considered as disadvantages by PWE. Promoting self-care was perceived as both an advantage and a disadvantage. It was seen as an advantage when PWE mentioned the option of eHealth-tools in order to gain insight into one's epilepsy. At the same time, it was seen as a disadvantage because it confronts PWE with their disease, which causes emotional stress. CONCLUSION: The high level of self-monitoring combined with a low usage of eHealth-tools seems to indicate that there is a need for a more tailored approach to stimulate the use of eHealth-tools by PWE. Further research should focus on this aspect, e.g., what PWE need in order to make more use of eHealth-tools in their self-care.

Cognitive and behavioral impact of the ketogenic diet in children and adolescents with refractory epilepsy: A randomized controlled trial.

PURPOSE: The ketogenic diet (KD) is increasingly used for the treatment of refractory epilepsy in childhood because of the beneficial effect on seizure reduction. The aim of the current study was to objectively assess cognition and aspects of behavior during the first 4months of a randomized controlled study in children and adolescents. METHODS: Participants from a tertiary epilepsy center were randomized to a KD group (intervention) or a care-as-usual (CAU) group (control). Follow-up assessments on cognition and behavior were performed approximately 4months after initiation of the KD with a combination of parent report questionnaires and individually administered psychological tests for the children. RESULTS: A total of 50 patients were enrolled in this study, 28 patients from the KD group and 22 patients from the CAU group. The KD group showed lower levels of anxious and mood-disturbed behavior and was rated as more productive. Cognitive test results showed an improvement of activation in the KD group. CONCLUSIONS: This study showed a positive impact of the KD on behavioral and cognitive functioning in children and adolescents with refractory epilepsy. More specifically, an activated mood and cognitive activation were observed in patients treated with the KD.

The MCT-ketogenic diet as a treatment option in refractory childhood epilepsy: A prospective study with 2-year follow-up.

The present study assessed the long-term (i.e., 24months) efficacy of the ketogenic diet (KD) as an add-on therapy in children with refractory epilepsy, with focus on seizure frequency, seizure severity, and tolerability. Most patients were treated with the MCT-diet. At one and two years, 33% and 23%, respectively, of the 48 included patients were still on the KD. After three months, one year, and two years of treatment, 16.7% of the patients were responders. The highest responder rate (i.e., 22.9%) was seen at six and nine months of treatment. Of the fifteen patients with seizure clusters during baseline, 60% were responders after three months when looking at cluster reduction and most of them were not responders for the total seizure frequency. From three months of treatment onwards, most of the patients had a relevant decrease in seizure severity which was mainly related to the most severe seizure type. Gastrointestinal dysfunction was often reported, especially in the first six weeks of treatment. Growth deceleration was present in 30% of the patients, and weight reduction in 15%. Improved arousal was mentioned in 30% of patients. No patients developed ECG abnormalities or kidney stones. Increase in lipid profile was rare. The KD is an effective therapy for children with therapy-resistant epilepsy. Effectiveness is reflected in the reduction of seizure frequency as well as in the reduction of seizure severity. After 6months of treatment, it is obvious which patients are responders and tolerate the treatment well. Most of these patients will continue to benefit from the KD for a longer time. Long-term use of the diet was well tolerated.

Vagus nerve stimulation lead removal or replacement: surgical technique, institutional experience, and literature overview.

BACKGROUND: With the growing use of vagus nerve stimulation (VNS) as a treatment for refractory epilepsy, there is a growing demand for complete removal or replacement of the VNS system. We evaluate the safety and efficacy of complete removal or replacement of the VNS system and provide an extensive description of our surgical technique. METHODS: We retrospectively reviewed our patient registry for all VNS surgeries performed between January 2007 (the year of our first complete removal) and May 2014. In order to assess patient satisfaction, a written questionnaire was sent to patients or their caregivers. Additionally, we reviewed all literature on this topic. RESULTS: The VNS system was completely removed in 22 patients and completely replaced in 13 patients. There were no incomplete removals. Revision surgery was complicated by a small laceration of the jugular vein in two patients and by vocal cord paralysis in one patient. Seizure frequency was unaltered or improved after revision surgery. Electrode-related side effects all improved after revision surgery. Twenty-one studies reported a total of 131 patients in whom the VNS system was completely removed. In 95 patients, the system was subsequently replaced. The most frequently reported side effect was vocal cord paresis, which occurred in four patients. CONCLUSIONS: Complete removal or replacement of the VNS system including lead and coils is feasible and safe. Although initial results seem promising, further research and longer follow-up are needed to assess whether lead replacement may affect VNS effectiveness.

(Cost)-effectiveness of a multi-component intervention for adults with epilepsy: study protocol of a Dutch randomized controlled trial (ZMILE study).

BACKGROUND: In patients with epilepsy, poor adherence to anti-epileptic drugs has been shown to be the most important cause of poorly controlled epilepsy. Furthermore, it has been noted that the quality of life among patients with epilepsy can be improved by counseling and treatments aimed at increasing their self-efficacy and concordance, thus stimulating self-management skills. However, there is a need for evidence on the effectiveness of such programs, especially within epilepsy care. Therefore, we have developed a multi-component intervention (MCI) which combines a self-management/education program with e-Health interventions. Accordingly, the overall objective of this study is to assess the (cost)-effectiveness and feasibility of the MCI, aiming to improve self-efficacy and concordance in patients with epilepsy. METHODS: A RCT in two parallel groups will be conducted to compare the MCI with a control condition in epilepsy patients. One hundred eligible epilepsy patients will be recruited and allocated to either the intervention or control group. The intervention group will receive the MCI consisting of a self-management/education program of six meetings, including e-Health interventions, and will be followed for 12 months. The control group will receive care as usual and will be followed for 6 months, after which patients will be offered the possibility of participating in the MCI. The study will consist of three parts: 1) a clinical effectiveness study, 2) a cost-effectiveness study, and 3) process evaluation. The primary outcome will be self-efficacy. Secondary outcomes include adherence, side effects, change in seizure severity & frequency, improved quality of life, proactive coping, and societal costs. Outcome assessments will be done using questionnaires at baseline and after 3, 6, 9, and 12 months (last two applicable only for intervention group). DISCUSSION: In times of budget constraints, MCI could be a valuable addition to the current healthcare provision for epilepsy, as it is expected that higher concordance and self-efficacy will result in reduced use of healthcare resources and an increased QOL. Accordingly, this study is aimed helping patients to be their own provider of health care, shifting epilepsy management from professionals to self-care by patients equipped with appropriate skills and tools. TRIAL REGISTRATION NUMBER: NTR4484 .