Quality-of-life results in adults with epilepsy using diazepam nasal spray for seizure clusters from a long-term, open-label safety study.

BACKGROUND: The impact of seizure clusters and the use of intermittent rescue therapy for clusters on the quality of life (QoL) of patients with epilepsy has not been widely studied. The present analysis assessed QoL as a secondary endpoint among adult patients with seizure clusters enrolled in a long-term, phase 3, open-label safety study (NCT02721069) of diazepam nasal spray (Valtoco®). The QoL aspect of patients in this study has not been previously published. METHODS: The 12-month safety study of diazepam nasal spray enrolled patients aged 6-65 years with seizure clusters. Adults aged ≥18 years completed the Quality of Life in Epilepsy (QOLIE)-31-P at baseline (day 0) and days 30, 150, 270, and 365. This instrument includes questions about patient health and daily activities with numeric values (1-100) assigned to responses; higher scores indicate better QoL. The QOLIE-31-P includes 7 subscales: Seizure Worry, Overall QoL, Emotional Well-Being, Energy/Fatigue, Cognitive Functioning, Medication Effects, and Social Functioning; an Overall Score is calculated as a weighted composite of the 7 subscales. Comparisons were made between subgroups of patients who had frequent (≥2) and infrequent (<2) monthly dosing of diazepam nasal spray and those whose doses were administered by the patient or a care partner. This safety study was not powered to assess efficacy endpoints; descriptive statistics were calculated across time points. In addition, safety measures, including treatment-emergent adverse events, are reported. RESULTS: Seventy-two adults who responded to the QOLIE-31-P were included in the analyses. Mean QOLIE-31-P scores were stable or increased across time points. The mean total scores increased from day 0 to day 365 by 5.2 among patients providing data for ≥1 time point (follow-up group) and 2.2 among patients providing data at all time points (QOLIE all-assessments subgroup). Subscale means for Seizure Worry and Social Functioning showed the greatest numeric increase from baseline. Mean QOLIE-31-P scores were similar in all subgroups. The safety profile in the follow-up group was similar to that seen in all study adults. CONCLUSIONS: Adults with refractory epilepsy who were treated with diazepam nasal spray for seizure clusters maintained or improved QOLIE subscale scores across the 12-month study period. Seizure Worry and Social Functioning subscale scores increased over time, suggesting improvement in these domains for this population with intractable epilepsy. Changes among subscale results suggest differences in sensitivity to the use of an intermittent treatment. The potential to improve patient function with treatment for seizure clusters warrants further study.

Minimum clinically important difference (MCID) of the personal impact of epilepsy scale (PIES).

INTRODUCTION: The Personal Impact of Epilepsy Scale (PIES) assesses patient functional status in subscales of (1) seizure impact, (2) medication effects, (3) mood & social status, and (4) overall quality of life. This study was designed to determine the Minimal Clinically Important Change (MCID) in PIES subscale and total scores that demonstrate improvement. METHODS: To ascertain the correspondence of PIES score change and clinical status change (improved, same, worse) in each PIES subscale and total score, we used two distinct retrospective anchor-based assessments of clinical status (patient self-assessment and trained rater assessment) across two clinic visits. Mean PIES scores were compared between clinical status groups, controlling for days between visits and initial clinical status. Personal Impact of Epilepsy Scale score change was quantified for each group to determine MCID. A small prospective proof-of-concept study was conducted in a separate subject group. RESULTS: Patient self-report anchor analysis demonstrated lower (better) PIES scores in the "improved" group vs the "worse" group on the mood & social subscale (p < .001) and total score (p = .002), with a similar trend on the seizure subscale (p = 0.056). Clinical rater anchor analysis demonstrated lower PIES scores in the "improved" vs "worse" group in the mood & social subscale (p = .029) and a trend in total score (p = .082). For the "improved" group, the reduction in PIES scores between visits averaged across both anchor analyses was 8.14% for subscales and 8.67% for total score. DISCUSSION/CONCLUSION: Reduction of 8% on a PIES subscale or total score indicates meaningful improvement in patient clinical status, and is designated the MCID for this instrument. Personal Impact of Epilepsy Scale can be useful in day-to-day clinical care and as an outcome metric in clinical research.

Identification of seizure clusters using free text notes in an electronic seizure diary.

SIGNIFICANCE: Online seizure diaries offer a wealth of information regarding real world experience of patients living with epilepsy. Free text notes (FTN) written by patients reflect concerns and priorities of patients and provide supplemental information to structured diary data. OBJECTIVE: This project evaluated feasibility using an automated lexical analysis to identify FTN relevant to seizure clusters (SCs). METHODS: Data were extracted from EpiDiary™, a free electronic epilepsy diary with 42,799 unique users, generating 1,096,168 entries and 247,232 FTN. Both structured data as well as FTN were analyzed for presence of SC. A pilot study was conducted to validate an automated lexical analysis algorithm to identify SC in FTN in a sample of 98 diaries. The lexical analysis was then applied to the entire dataset. Outcomes included cluster prevalence and frequency, as well as the types of triggers commonly reported. RESULTS: At least one FTN was found among 13,987 (32.68%) individual diaries. An automated lexical analysis algorithm identified 5797 of FTN as SC. There were 2423 unique patients with SC that were not identified by structured data alone and were identified using lexical analysis of FTN only. Seizure clusters were identified in n = 10,331 (24.1%) of diary users through both structured data and FTN. The median number of SCs days per year was 13.7, (interquartile rank (IQR): 3.2-54.7). The median number of seizures in a cluster day was 3 (IQR 2-4). The most common missed medication linked to patients with SC was levetiracetam (n = 576, 29%) followed by lamotrigine (n = 495, 24%), topiramate (n = 208, 10.5%), carbamazepine (n = 190, 9.6%), and lacosamide (n = 170, 8.6%). These percentages generally reflected prevalence of medication use in this population. The use of rescue medications was documented in 3306 of structured entries and 4305 in FTN. CONCLUSION: This exploratory study demonstrates a novel approach applying lexical analysis to previously untapped FTN in a large electronic seizure diary database. Free text notes captured information about SC not available from the structured diary data. Diary FTN contain information of high importance to people with epilepsy, written in their own words.

Associations between seizure severity change and patient characteristics, changes in seizure frequency, and health-related quality of life in patients with focal seizures treated with adjunctive eslicarbazepine acetate: Post hoc analyses of clinical trial results.

The relationships between seizure severity change and patient characteristics, changes in seizure frequency, and health-related quality of life (HRQoL) may be important for determining the overall impact of medication therapy on patients with epilepsy. The objectives of these post hoc analyses of the global Phase III 093-0304 trial (NCT00988429, Study 304) of adjunctive eslicarbazepine acetate (ESL) in patients with refractory focal (partial-onset) seizures (FS) were to evaluate associations between seizure severity change, measured by the Seizure Severity Questionnaire (SSQ), and 1) patient characteristics, 2) seizure frequency change, standardized as the seizure frequency (SSF) per 28-day period, and 3) change in HRQoL, evaluated by the Quality of Life in Epilepsy Inventory-31 (QOLIE-31) and the Montgomery-Åsberg Depression Rating Scale (MADRS). The analyses were conducted on the per-protocol population (PPP) of patients who were randomized to a placebo arm (n = 188) or an ESL-active group that included treatment with adjunctive ESL 800 mg once daily (QD; n = 184) or adjunctive ESL 1200 mg QD (n = 175). General linear models (GLM) were used to measure the association between SSQ change and patient baseline characteristics or percentage change in the SSF from baseline. Associations between changes in the SSQ and changes in the QOLIE-31 and MADRS were examined using GLM with patient baseline characteristics as covariates. Subgroup analyses were performed for patients in the ESL-active group and those treated with ESL 800 mg or ESL 1200 mg. Minimal clinically important difference (MCIDs) thresholds were used to assess improvements in SSQ scores. The analyses included 547 per-protocol patients. Patients using 1 antiepileptic drug (AED) at baseline had greater improvements in the SSQ compared with those receiving 2 AEDs (P = 0.0606). Treatment with ESL 1200 mg was significantly associated with clinically meaningful improvements in the SSQ (P = 0.0005). The SSQ improvements were significantly associated with an SSF reduction of ≥75%, compared with no reduction (P < 0.0001). In the PPP and the ESL-active group, SSQ improvements were significantly associated with improvements in QOLIE-31 Total Score (TS; P < 0.0001) and the Seizure Worry (SW; P < 0.0001) and Social Functioning (SF; P = 0.0030) subscales. In the ESL 1200 mg subgroup, SSQ improvements were significantly associated with improvements in QOLIE-31 TS (P < 0.0001) and the SW (P < 0.0001) and Energy/Fatigue (EF; P = 0.0007) subscales. In the ESL 800 mg subgroup, improvements in the SSQ were significantly associated with improvements in QOLIE-31 TS (P = 0.0362) and the SW (P = 0.0241) subscale. There was no significant association between changes in the SSQ and changes in the MADRS in patients treated with ESL. These findings demonstrated that in this clinical trial population, adding ESL to baseline AED therapy had utility for decreasing seizure severity and improving HRQoL. There were no significant associations between changes in seizure severity and changes in depressive symptoms in patients with FS.

Living safely with epilepsy: a key learning review.

This review focusses on counselling to reduce the risks of seizures in epilepsy patients. Risk reduction, whilst maximising the independence of persons with epilepsy, is a core element of epilepsy practice. The importance of the issue is reflected by the inclusion of risk assessment and reduction in the recent International League Against Epilepsy Curriculum for epileptology. This article addresses the key elements of epilepsy risk and provides practical guidance for counselling and risk reduction. A review of key publications was performed focusing on: (1) the risk of injury associated with seizures; (2) safety issues related to seizures and lifestyle; (3) SUDEP risk and avoidance; and (4) assessing individual risks. Risk is common in epilepsy and is multifactorial. Clinicians should be aware of the risk factors associated with different epilepsy features, such as seizure type, as well as those related to lifestyle and common indoor and outdoor activities. In addition, transcultural differences should be considered in risk assessment and counselling, e.g. regarding SUDEP or even driving, for which regulations vary across nations. Assessment of individual risk is evolving through a better understanding of risk factors and methodologies which can improve communication and empower patients to help identify and manage their individual risks.

Assessing the personal impact of epilepsy in a population-based cohort of Veterans.

PURPOSE: Epilepsy impacts patient lives in multidimensional ways. Although previous work has investigated epilepsy impact on health status, little is known about the overall quantified impact of epilepsy in Veterans. Our goal was to describe the impact of epilepsy on Veterans' lives using the Personal Impact of Epilepsy Scale (PIES) and determine the patient and clinical characteristics most strongly correlated with epilepsy impact. We described cohort characteristics and developed regression models to determine which characteristics were most strongly associated with PIES subscale (seizure, medication, comorbidity) scores and quality of life (QOL). RESULTS: Approximately 36% of those who were invited responded to the survey. Of the 438 respondents included in the analyses, roughly 50% were aged 45-64 years (35% >65; 14% 18-44); 19% were women. Almost 90% had previously received care by an epilepsy specialist, 37% of which was in Veterans Health Administration (VHA) and 38% in both VHA and community. The PIES scores were moderately low (mean: 88.68, [standard deviation (SD) = 63.24]; 300 total). The PIES overall and subscale scores were significantly lower for older Veterans with epilepsy (VWE) (>65) compared with younger (18-44 years) and middle-aged (45-64 years) VWE [p < 0.001], indicating that older Veterans had a lower epilepsy impact overall, and for seizures, medication, and comorbidity. The younger and middle-aged VWE had a significantly higher proportion with psychiatric diagnosis compared with older VWE [p < 0.001]. There was a trend for significance for the overall PIES scores by gender, with women having total higher (worse) scores (mean = 93.10, SD = 69.68) than men (mean = 74.39, SD = 59.97), which was driven by a statistically higher score on the seizure subscale for women (mean = 27.66, SD = 27.97) compared with men (mean = 19.29, SD 25.35; p = 0.04). Regression models revealed that frequent seizures (>1/month, >2/month) and diagnoses of dementia significantly predicted higher (more negative) Seizure Severity PIES score [all p < 0.05]. Frequent seizures (>1/month), number of antiepileptic drugs (AEDs), and diagnosis of dementia predicted negative impact, and older age predicted positive impact for medication subscale. Frequent seizures (>1/month) and diagnoses of depression and dementia predicted negative mood and social impact [all p < 0.05]. Seizure frequency (>2/month) was the only variable that significantly predicted lack of excellent QOL [p < 0.05]. Effects for gender were not significant after controlling for other variables. CONCLUSIONS: Findings were similar to a prior study of generic health outcomes in younger and older VWE using the 36-Item Short Form Survey (SF-36). Seizure frequency was consistently associated with negative impact of epilepsy in all age groups. While dementia and other diagnosed health conditions also contributed to epilepsy impact, older VWE had significantly lower PIES scores even after controlling for physical conditions and dementia. Lower (better) scores for comorbidity and medication scales in older VWE may be due to fewer diagnosed psychiatric comorbidities and psychiatric medication that have similar cognitive impact as AEDs, and which may also interact with AEDs. Implementation of patient self-management programs to improve seizure control may reduce epilepsy impact for Veterans and reduce Veterans Affairs (VA) healthcare utilization. The PIES may also be useful to measure outcomes of self-management interventions.

Risk of hospitalization among patients with epilepsy using long versus short half-life adjunctive antiepileptic drugs.

INTRODUCTION: While antiepileptic drugs (AEDs) remain the primary treatment for epilepsy, many patients continue to have seizures. Uncontrolled seizures may be related to AED half-life, since short half-life (SHL) AEDs require more frequent dosing compared with the simplified regimens of long half-life (LHL) AEDs. Long half-life AEDs may also improve seizure control by extending missed dose forgiveness periods. The value of LHL AEDs may be assessed as reduced healthcare utilization. The study's objective was to examine the impact of adding an LHL versus SHL adjunctive AED on the risk of hospitalizations in patients with uncontrolled epilepsy. METHODS: This was a retrospective, longitudinal cohort study using the Symphony Health Solution Patient Integrated Dataverse. Patients ≥12 years old with uncontrolled epilepsy (≥2 medical claims ≥30 days apart) were identified during a study period (8/1/2012-7/31/2017). Patients were selected if they were subsequently initiated an adjunctive AED (excluding modified release formulations), and the prescription date served as the index. Patients were stratified into two mutually exclusive cohorts based on the index AED half-life (≤20 versus >20 h). Poisson regressions with robust error variances were performed for the relative risks (RRs) of all-cause, epilepsy-related, and injury-related hospitalizations. RESULTS: A total of 4984 patients were identified (2705 in the LHL and 2279 in the SHL cohort). Compared with those in the SHL cohort, patients in the LHL cohort were significantly younger [mean (SD, years): 43.9 (18.5) versus 49.2 (17.2), p < 0.001] and were less comorbid [mean (SD) of Charlson comorbidity index: 1.2 (1.8) versus 1.8 (2.2), p < 0.001]. In the one-year postindex date, adjusting for group differences, the risks of both all-cause and epilepsy-related hospitalizations were significantly lower in the LHL cohort than in the SHL cohort [all-cause: 0.84 (95% CI: 0.76-0.93), p = 0.0006; epilepsy-related: 0.83 (0.73-0.94), p = 0.0046].Injury-related hospitalizations did not differ between LHL and SHL cohorts. CONCLUSION: In patients with uncontrolled epilepsy who were initiated on an adjunctive AED, the choice of an LHL versus SHL was associated with significantly lower risks of all-cause and epilepsy-related hospitalizations.

Health-related quality of life in patients treated with eslicarbazepine acetate monotherapy: Pooled analysis from two registered clinical trials.

PURPOSE: While antiepileptic drug (AED) treatment effectiveness is traditionally assessed based on seizure frequency reduction (SFR), the overall value of AEDs in managing epilepsy and associated sequelae may be best assessed by how patients feel and function in terms of overall health-related quality of life (HRQoL). We conducted a pooled analysis of the Quality of Life in Epilepsy-31 (QOLIE-31) questionnaire from two phase 3 trials to explore the effect of response to conversion to eslicarbazepine acetate (ESL) monotherapy on HRQoL. METHODS: Data were pooled from two multicenter, randomized, double-blind, historical control phase 3 trials examining conversion to ESL monotherapy in adults with inadequately controlled partial-onset seizures (POS). The relationship between HRQoL and ESL treatment response was examined through the analysis of week 18 QOLIE-31 scores between patients who met the SFR ≥50% threshold (responders) and patients with SFR <50% (nonresponders). The analysis was conducted in the efficacy population (intent-to-treat (ITT) patients who entered the AED taper/conversion period) and completer population (efficacy patients who completed the ESL monotherapy period) and was repeated using an SFR ≥75% threshold. RESULTS: In the efficacy population, week 18 QOLIE-31 total score least squares mean (LSM) was significantly higher for responders with ≥50% SFR (LSM difference: 3.0; 95% confidence interval (CI): 0.2-5.8; p = 0.037) and with ≥75% SFR (LSM difference: 7.0; 95% CI: 3.6-10.3; p < 0.001) than nonresponders. In the completer population, overall quality of life (QoL) (LSM difference: 5.1; 95% CI: 1.5-8.6; p = 0.006) and social functioning (LSM difference: 5.4; 95% CI: 0.1-10.7; p = 0.046) were significantly higher for responders with ≥50% SFR than nonresponders, and all domain LSMs were higher for responders with ≥75% SFR (all p < 0.05) than nonresponders. CONCLUSIONS: This analysis of data from the phase 3 trials demonstrated significantly higher HRQoL among ESL responders with SFR of ≥75% and also at the lower SFR threshold of ≥50% compared with nonresponders.

Impact of seizure frequency reduction on health-related quality of life among clinical trial subjects with refractory partial-onset seizures: A pooled analysis of phase III clinical trials of eslicarbazepine acetate.

BACKGROUND: Subjects who received eslicarbazepine acetate (ESL) as adjunctive therapy experienced significantly greater seizure frequency reduction (SFR) than placebo in three phase III, randomized, double-blind trials. This analysis compared changes in health-related quality of life (HRQOL) between treatment responders and non-responders across the pooled, per-protocol population (N=842) using the validated Quality of Life in Epilepsy Inventory-31 (QOLIE-31). METHODS: QOLIE-31 scores were calculated for Total Score (TS) and seven subscales; higher scores indicate better HRQOL. Mean changes from baseline were calculated. Analysis of covariance examined least square mean (LSM) differences in final scores between responders (≥50% and ≥75% SFR) and non-responders. Clinical significance was based on established minimal clinically important differences (MCIDs). RESULTS: Mean changes were greater among responders for TS (5.2 versus 1.4 for ≥50% SFR; 7.5 versus 1.9 for ≥75% SFR) and all subscales. Additionally, the percentage of subjects with changes meeting or exceeding MCIDs was higher among responders for TS (48.4% versus 33.9% for ≥50% SFR; 56.9% versus 35.8% for ≥75% SFR) and all subscales. Responders had significantly higher final scores for TS (LSM difference=4.0 for ≥50% SFR; LSM difference=5.7 for ≥75% SFR) and all subscales except emotional well-being at ≥50% SFR. LSM differences exceeded MCIDs at ≥75% SFR for TS and five of seven subscales, and two subscales at ≥50% SFR. In a subgroup analysis with placebo removed, LSM differences were larger overall. SIGNIFICANCE: In clinical trials of adjunctive ESL, higher levels of SFR were associated with greater improvements in HRQOL.

Treatment issues for children with epilepsy transitioning to adult care.

This is the third of three papers that summarize the second symposium on Transition in Epilepsies held in Paris in June 2016. This paper focuses on treatment issues that arise during the course of childhood epilepsy and make the process of transition to adult care more complicated. Some AEDs used during childhood, such as stiripentol, vigabatrin, and cannabidiol, are unfamiliar to adult epilepsy specialists. In addition, new drugs are being developed for treatment of specific childhood onset epilepsy syndromes and have no indication yet for adults. The ketogenic diet may be effective during childhood but is difficult to continue in adult care. Regional adult epilepsy diet clinics could be helpful. Polytherapy is common for patients transitioning to adult care. Although these complex AED regimes are difficult, they are often possible to simplify. AEDs used in childhood may need to be reconsidered in adulthood. Rescue medications to stop prolonged seizures and clusters of seizures are in wide home use in children and can be continued in adulthood. Adherence/compliance is notoriously difficult for adolescents, but there are simple clinical approaches that should be helpful. Mental health issues including depression and anxiety are not always diagnosed and treated in children and young adults even though effective treatments are available. Attention deficit hyperactivity disorder and aggressive behavior disorders may interfere with transition and successful adulthood but these can be treated. For the majority, the adult social outcome of children with epilepsy is unsatisfactory with few proven interventions. The interface between pediatric and adult care for children with epilepsy is becoming increasingly complicated with a need for more comprehensive transition programs and adult epileptologists who are knowledgeable about special treatments that benefit this group of patients.

Sleep disturbance in chronic military-related PTSD: clinical impact and response to adjunctive risperidone in the Veterans Affairs cooperative study #504.

OBJECTIVE: Sleep disturbances are common among veterans with chronic military-related posttraumatic stress disorder (PTSD). This article reports the results of a multicenter clinical trial that explored the clinical correlates of reported sleep impairment in these veterans and tested the impact of the second-generation antipsychotic risperidone upon these symptoms. METHOD: This article reports secondary analyses of a 24-week multicenter randomized placebo-controlled trial of adjunctive risperidone in patients with chronic military-related PTSD symptoms (n = 267, 97% male) who were symptomatic despite treatment with antidepressants and other medications. The study was conducted between February 2007 and February 2010. DSM-IV PTSD diagnoses were made by using the Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Nonpatient Edition. Sleep disturbances were assessed principally by using the Pittsburgh Sleep Quality Index (PSQI) (primary outcome measure). Analyses were conducted using bivariate correlations and longitudinal mixed model regressions. RESULTS: Eighty-eight percent of the patients in this study had clinically significantly impaired sleep on the PSQI. Severity of sleep disturbances correlated with PTSD symptom severity as measured by the Clinician-Administered PTSD Scale (CAPS) and reductions in multiple measures of quality of life (Veterans RAND 36-item Health Survey [SF-36 V] subscales, Boston Life Satisfaction Index). Risperidone produced small but statistically significant effects on total PSQI scores (main effect of drug: F1,228 = 4.57, P = .034; drug-by-time interaction: F2,421 = 4.32, P = .014) and severity of nightmares as assessed by the CAPS (main effect of drug: F1,248 = 4.60, P = .033). The improvements in sleep quality produced by risperidone correlated with reductions in PTSD symptom severity and improvement in the mental health subscale of the SF-36 V. CONCLUSIONS: This study highlighted the near universality and significant negative impact of severe disturbances in sleep quality in veterans with chronic military-related PTSD who were partial responders to standard pharmacotherapies. The modest improvements in sleep quality produced by adjunctive risperidone were correlated with limited reductions in PTSD severity and improvements in quality of life. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00099983.

Severity and burden of partial-onset seizures in a phase III trial of eslicarbazepine acetate.

OBJECTIVE: The objective of this study was to compare posttreatment seizure severity in a phase III clinical trial of eslicarbazepine acetate (ESL) as adjunctive treatment of refractory partial-onset seizures. METHODS: The Seizure Severity Questionnaire (SSQ) was administered at baseline and posttreatment. The SSQ total score (TS) and component scores (frequency and helpfulness of warning signs before seizures [BS]; severity and bothersomeness of ictal movement and altered consciousness during seizures [DS]; cognitive, emotional, and physical aspects of postictal recovery after seizures [AS]; and overall severity and bothersomeness [SB]) were calculated for the per-protocol population. Analysis of covariance, adjusted for baseline scores, estimated differences in posttreatment least square means between treatment arms. RESULTS: Out of 547 per-protocol patients, 441 had valid SSQ TS both at baseline and posttreatment. Mean posttreatment TS for ESL 1200 mg/day was significantly lower than that for placebo (2.68 vs 3.20, p<0.001), exceeding the minimal clinically important difference (MCID: 0.48). Mean DS, AS, and SB were also significantly lower with ESL 1200 mg/day; differences in AS and SB exceeded the MCIDs. The TS, DS, AS, and SB were lower for ESL 800 mg/day than for placebo; only SB was significant (p=0.013). For both ESL arms combined versus placebo, mean scores differed significantly for TS (p=0.006), DS (p=0.031), and SB (p=0.001). CONCLUSIONS: Therapeutic ESL doses led to clinically meaningful, dose-dependent reductions in seizure severity, as measured by SSQ scores. CLASSIFICATION OF EVIDENCE: This study presents Class I evidence that adjunctive ESL (800 and 1200 mg/day) led to clinically meaningful, dose-dependent seizure severity reductions, measured by the SSQ.

Is a separate monotherapy indication warranted for antiepileptic drugs?

Antiepileptic drugs (AEDs) are the only neurotherapeutics for which regulatory approval is consistently separated into monotherapy or adjunctive-therapy indications. Because head-to-head comparisons of AEDs (used in the European Union to approve drugs for monotherapy) have not shown substantial differences in efficacy between drugs, FDA approval for use of an AED as monotherapy has typically been based on trials with novel designs that have been criticised for reasons of ethics and clinical relevance. Many new-generation AEDs have not been approved for monotherapy, causing drug labelling and real-world use to be increasingly inconsistent, with negative consequences for patients. The regulatory requirement for separate monotherapy and adjunctive-therapy indications in epilepsy is unnecessarily restrictive. We recommend that regulatory agencies approve AEDs for the treatment of specific seizure types or epilepsy syndromes, irrespective of concomitant drug use.

Use of an online epilepsy diary to characterize repetitive seizures.

SIGNIFICANCE: Little is known about patterns of seizures that occur multiple times a day, sometimes called clusters or serial seizures. OBJECTIVE: The online diary, My Epilepsy Diary (MED), provided self-reported data from community-based patients to describe the characteristics of clusters. METHODS: We used MED data to define a population of 5098 community outpatients, including 1177 who specified time of multiple seizures in a 24-hour period. Outcomes included cluster prevalence and frequency, distribution of interseizure time intervals, as well as the types of triggers commonly reported. RESULTS: One-fourth of days with any seizures included clusters for these patients. Most days with clusters included 2 seizures, with >5 events occurring in only 10% of days. One-third of seizures occurred within 3h of the initial event and two-thirds within 6h. When more than 2 seizures occurred, the time to the next seizure decreased from an average of over 2h (to the 3rd event) to a quarter-hour (from the 4th to the 5th event). CONCLUSION: My Epilepsy Diary data have provided the first overview of cluster seizures in a large community-based population. Treatments with less than 3-hour duration of action would be bioavailable at the time of only one-third of subsequent seizures. Although limited by the self-reported and observational nature of the diary data, some general patterns emerge and can help to focus questions for future studies.

Attention-deficit/hyperactivity disorder symptoms in adults with self-reported epilepsy: Results from a national epidemiologic survey of epilepsy.

OBJECTIVE: To assess symptoms of attention-deficit/hyperactivity disorder (ADHD) and their impact among adults with epilepsy from a large community-based survey. METHODS: Adults who self-reported epilepsy were sent a postal survey including the Adult ADHD Self-Report Scale version 6 (ASRS-6), Physicians Health Questionnaire (PHQ-9), Generalized Anxiety Disorder Assessment 7 (GAD-7), and questions about seizure frequency and number of antiepileptic drugs (AEDs) during the preceding 3 months. Individuals with ASRS-6 scores >14 were classified as ASRS+, and those with lower scores as ASRS-. Outcome measures included the Quality of Life in Epilepsy Inventory 10 (QOLIE-10), Quality of Life and Enjoyment and Satisfaction Questionnaire (Q-LES-Q), and the Sheehan Disability Scale (SDS). The relationship of ADHD symptoms to quality of life outcomes was modeled hierarchically, with linear regression controlling for sociodemographic covariates, comorbid depression and anxiety, seizure frequency, and number of AEDs. RESULTS: Among 1,361 of respondents with active epilepsy, 18.4% (n = 251) were classified as ASRS+ and at risk for ADHD. Compared to ASRS- cases, ASRS+ individuals were more likely to have elevated depression and anxiety scores as well as greater seizure frequency and more AED use (p < 0.05 for all). Modeling results comparing ASRS+ and ASRS- cases, controlling for all covariates, indicated that ASRS+ cases had lower quality of life (Beta [ß] = -3.07, 95% confidence interval [CI] -4.19 to -1.96) and worse physical (ß = -0.048 95% CI -0.076 to -0.020) and social functioning (ß = -0.058, 95% CI -0.081 to -0.035) on the Q-LES-Q, and increases in family (ß = 1.57, 95% CI 1.09-2.05), social (ß = 1.68, 95% CI 1.20-2.16), and work-related disability (ß-1.86, 95% CI 1.27-2.46). SIGNIFICANCE: ADHD symptoms occur in nearly one of five adults with epilepsy, and are associated with increased psychosocial morbidity and lowered QOL. Future studies should clarify the nature and causes of ADHD symptoms in adults with epilepsy.

Health-care costs and utilization related to long- or short-acting antiepileptic monotherapy use.

PURPOSE: This study aimed to compare health-care utilization and costs in patients treated with long-acting (LA) vs. short-acting (SA) antiepileptic drug (AED) monotherapy. METHODS: We conducted a cross-sectional study of claims from the OptumInsight™ database. Our analysis was restricted to adults diagnosed with epilepsy and who used AED monotherapy. Patients were excluded if they used >1 type of AED, had <9months of treatment, or had a treatment gap of >60days. Antiepileptic drugs were classified as LA or SA based on published data and expert opinion. Medical and pharmacy claims were used to estimate health-care utilization and costs, and baseline group differences were adjusted using multivariate analyses. RESULTS: There were 4058 (49.6%) LA AED users and 4122 (50.4%) SA AED users. Medication possession ratios (MPRs) were not significantly different between LA AED users and SA AED users (P=0.125). Long-acting AED users had lower mean overall health-care costs ($9757 vs. $12,689), lower epilepsy-related costs ($3539 vs. $5279), and lower rate of overall (8.8% vs. 10.9%) and epilepsy-related hospitalizations (5.7% vs. 7.6%) compared with SA AED users (all P<0.01). After adjusting for demographics and clinical characteristics, mean overall costs were lower by $686 and the mean epilepsy-related costs were lower by $894 in LA AED users. CONCLUSION: Although MPRs were similar in LA AED and SA AED groups, patients treated with LA monotherapy had a lower economic burden compared with those treated with SA monotherapy, indicating that using AEDs with extended duration of action is associated with decreased health-care use and lower health-care costs.

The Personal Impact of Epilepsy Scale (PIES).

OBJECTIVE: The impact of epilepsy is manifest by effects related to seizures and side effects of therapy and comorbidities such as depression. This report describes the development of a brief patient-reported outcome (PRO) instrument, the Personal Impact of Epilepsy Scale (PIES), to measure the influence of epilepsy overall and in each of these domains. METHODS: Instrument development followed standard procedures and an FDA Guidance. People with epilepsy were surveyed with open-ended questions to derive major themes of their concerns, resulting in 4 key areas: seizures, side effects, comorbidities, and overall quality of life (QOL). A preliminary set of 152 questions was based on these themes and completed by 50 patients, age 42.7 (range: 21-71) years, concurrent with comparator instruments, including the NH Seizure Severity Scale (NHSSS), the Liverpool Adverse Events Profile (LAEP), the Quality of Life in Epilepsy (QOLIE-31) scale, the Beck Depression Inventory, and the Epilepsy Foundation Depression: A Checklist. A multiple regression model indicated which PIES measures were associated with scores from the comparator instruments. Questions in each of the domains were selected for correlations and nonduplication. Test-retest consistency at a 3-day interval was completed by 38 subjects and a final set of questions constructed. RESULTS: The final question set comprised 25 items: 9 about characteristics of seizures, 7 about medication side effects, 8 about comorbidities, and 1 about overall quality of life. All items had 5 response choices (0-4), with higher scores reflecting more negative status. A total of 46 subjects completed the 25 questions. Cronbach's alpha was 0.87, indicating good internal consistency. Each of the three domains correlated well with the overall QOL item. The questions pertaining to seizures correlated with the NHSSS, the side effect questions with the LAEP, and the comorbidity questions with the QOLIE-31. CONCLUSION: The PIES provides a simple, brief PRO measure as a profile of overall impact of seizures, medication side effects, comorbidities, and overall QOL for people with epilepsy. Further study will explore sensitivity to change quantification of the minimal clinically significant change.

Elucidating the transdiagnostic dimensional structure of trauma-related psychopathology: Findings from VA cooperative study 504 - risperidone treatment for military service related chronic post traumatic stress disorder.

BACKGROUND: Three of the most common trauma-related mental disorders-posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and generalized anxiety disorder (GAD)-are highly comorbid and share common transdiagnostic symptom dimensions of threat (i.e., fear) and loss (i.e., dysphoria) symptomatology. However, empirical evaluation of the dimensional structure of component aspects of these disorders is lacking. METHODS: Using structured clinical interview data from U.S. military veterans with chronic military-related PTSD, we evaluated the transdiagnostic dimensional structure of PTSD, MDD, and GAD symptoms. We then examined the relationship between the best-fitting transdiagnostic model of these symptoms, and measures of physical and mental functioning, and life satisfaction and well-being. RESULTS: Exploratory factor analysis revealed that a 3-factor transdiagnostic model comprised of loss (i.e., dysphoria), threat (i.e., anxious arousal, re-experiencing, and avoidance symptoms), and somatic anxiety (i.e., physiological manifestations of anxiety) symptoms provided the best representation of trauma-related PTSD, MDD, and GAD symptoms. Somatic anxiety symptoms were independently associated with physical functioning, while loss symptoms were independently associated with mental functioning and life satisfaction and well-being. LIMITATIONS: Evaluation of study aims in a relatively homogeneous sample of veterans with chronic, military-related PTSD. CONCLUSIONS: Results of this study suggest that a 3-factor transdiagnostic model best characterizes the dimensional structure of PTSD, MDD, and GAD symptoms in military veterans with chronic military-related PTSD. This model evidenced external validity in demonstrating differential associations with measures of physical and mental functioning, and life satisfaction and well-being. Results provide support for emerging contemporary models of psychopathology, which emphasize transdiagnostic and dimensional conceptualizations of mental disorders. Such models may have utility in understanding the functional status of trauma survivors.