Optimizing antiseizure medication treatment in glioma patients with epilepsy

The aim of this thesis was to assess the efficacy (part 1) and tolerability (part 2) of antiseizure medications (ASMs) in glioma patients with epilepsy. In addition, we aimed to get insight into the ASM prescription behavior and treatment policy in brain tumor-related epilepsy (part 3).First-line levetiracetam seems to be the most efficacious ASM in glioma patients, with favourable tolerability. This is demonstrated in multicenter retrospective observational cohort studies, a systematic review, and is the opinion among the vast majority of European neuro-oncology professionals. Enzyme-inducing AMSs should be avoided in glioma patients due to the high risk of adverse effects. ASM use was not independently associated with neuropsychiatric symptoms in glioma patients, but alternative factors seem to pose a greater risk for developing neuropsychiatric symptoms. If patients experience uncontrolled seizures on ASM monotherapy, levetiracetam combined with valproic acid has better efficacy than other ASM combinations in glioma patients, while toxicity is similar. Subsequently, potential add-on ASMs in glioma patients experiencing uncontrolled seizures on ASM dual therapy include clobazam, lamotrigine, and lacosamide. UCB Pharma; Eisai Co., Ltd.; Stichting Neuro-Oncologie; St. JacobusstichtingLUMC / Geneeskund

Effect of antiepileptic drugs in glioma patients on self-reported depression, anxiety, and cognitive complaints

Introduction AEDs have been associated with depression, anxiety, and cognitive impairment, all frequent complications of glioma and its subsequent treatment, with considerable morbidity and an adverse effect on health-related quality of life. This study aimed to determine the independent association between AED use and self-reported depression, anxiety, and subjective cognitive impairment in glioma patients. Methods In this multicenter cross-sectional study, depression and anxiety were assessed with the HADS and subjective cognitive impairment was assessed with the MOS-CFS. Univariable logistic regression analyses were performed on all potential confounding predictor variables. Potential confounders were included in the multivariable analyses if p-value < 0.1, to evaluate whether use of AEDs was independently related to depression, anxiety, and/or subjective cognitive impairment. Results A total of 272 patients were included. Prevalence of depression differed significantly between patients not using (10%) and using AEDs (21%, unadjusted Odds Ratio [uOR] = 2.29 [95%CI 1.05-4.97], p = 0.037), but after correction for confounders the statistical significant difference was no longer apparent (adjusted Odds Ratio [aOR] = 1.94 [95%CI 0.83-4.50], p = 0.125). Prevalences of anxiety (aOR = 1.17 [95%CI 0.59-2.29], p = 0.659) and subjective cognitive impairment (aOR = 0.83 [95%CI 0.34-2.04], p = 0.684) did not differ significantly before or after adjustment of confounders between patients not using (19% and 16%, respectively) and using AEDs (26% and 21%, respectively). Conclusions Our results indicate AED use was not independently associated with concurrent depression, anxiety, or subjective cognitive impairment in glioma patients. Alternative factors seem to have a greater contribution to the risk of developing neuropsychiatric symptoms in glioma patients.Neurolog

Efficacy of antiepileptic drugs in glioma patients with epilepsy: a systematic review

Background: Comprehensive data on the efficacy and tolerability of antiepileptic drugs (AED) treatment in glioma patients with epilepsy are currently lacking. In this systematic review, we specifically assessed the efficacy of AEDs in patients with a grade II-IV glioma.Methods: Electronic databases PubMed/MEDLINE, EMBASE, Web of Science, and Cochrane Library were searched up to June 2020. Three different outcomes for both mono- and polytherapy were extracted from all eligible articles: (i) seizure freedom; (ii) >= 50% reduction in seizure frequency; and (iii) treatment failure. Weighted averages (WA) were calculated for outcomes at 6 and 12 months.Results: A total of 66 studies were included. Regarding the individual outcomes on the efficacy of monotherapy, the highest seizure freedom rate at 6 months was with phenytoin (WA = 72%) while at 12-month pregabalin (WA = 75%) and levetiracetam (WA = 74%) showed highest efficacy. Concerning >= 50% seizure reduction rates, levetiracetam showed highest efficacy at 6 and 12 months (WAs of 82% and 97%, respectively). However, treatment failure rates at 12 months were highest for phenytoin (WA = 34%) and pregabalin (41%). When comparing the described polytherapy combinations with follow-up of >= 6 months, levetiracetam combined with phenytoin was most effective followed by levetiracetam combined with valproic acid.Conclusion: Given the heterogeneous patient populations and the low scientific quality across the different studies, seizure rates need to be interpreted with caution. Based on the current limited evidence, with the ranking of AEDs being confined to the AEDs studied, levetiracetam, phenytoin, and pregabalin seem to be most effective as AED monotherapy in glioma patients with epilepsy, with levetiracetam showing the lowest treatment failure rate, compared to the other AEDs studied.Neurolog

Determinants and predictors for the long-term disease burden of intracranial meningioma patients

Introduction Meningioma is a heterogeneous disease and patients may suffer from long-term tumor- and treatment-related sequelae. To help identify patients at risk for these late effects, we first assessed variables associated with impaired long-term health-related quality of life (HRQoL) and impaired neurocognitive function on group level (i.e. determinants). Next, prediction models were developed to predict the risk for long-term neurocognitive or HRQoL impairment on individual patient-level. Methods Secondary data analysis of a cross-sectional multicenter study with intracranial WHO grade I/II meningioma patients, in which HRQoL (Short-Form 36) and neurocognitive functioning (standardized test battery) were assessed. Multivariable regression models were used to assess determinants for these outcomes corrected for confounders, and to build prediction models, evaluated with C-statistics. Results Data from 190 patients were analyzed (median 9 years after intervention). Main determinants for poor HRQoL or impaired neurocognitive function were patients' sociodemographic characteristics, surgical complications, reoperation, radiotherapy, presence of edema, and a larger tumor diameter on last MRI. Prediction models with a moderate/good ability to discriminate between individual patients with and without impaired HRQoL (C-statistic 0.73, 95% CI 0.65 to 0.81) and neurocognitive function (C-statistic 0.78, 95%CI 0.70 to 0.85) were built. Not all predictors (e.g. tumor location) within these models were also determinants. Conclusions The identified determinants help clinicians to better understand long-term meningioma disease burden. Prediction models can help early identification of individual patients at risk for long-term neurocognitive or HRQoL impairment, facilitating tailored provision of information and allocation of scarce supportive care services to those most likely to benefit.Neurolog

First-line antiepileptic drug treatment in glioma patients with epilepsy: levetiracetam vs valproic acid

Objective This study aimed at estimating the cumulative incidence of antiepileptic drug (AED) treatment failure of first-line monotherapy levetiracetam vs valproic acid in glioma patients with epilepsy.Methods In this retrospective observational study, a competing risks model was used to estimate the cumulative incidence of treatment failure, from AED treatment initiation, for the two AEDs with death as a competing event. Patients were matched on baseline covariates potentially related to treatment assignment and outcomes of interest according to the nearest neighbor propensity score matching technique. Maximum duration of follow-up was 36 months.Results In total, 776 patients using levetiracetam and 659 using valproic acid were identified. Matching resulted in two equal groups of 429 patients, with similar covariate distribution. The cumulative incidence of treatment failure for any reason was significantly lower for levetiracetam compared to valproic acid (12 months: 33% [95% confidence interval (CI) 29%-38%] vs 50% [95% CI 45%-55%]; P < .001). When looking at specific reasons of treatment failure, treatment failure due to uncontrolled seizures was significantly lower for levetiracetam compared to valproic acid (12 months: 16% [95% CI 12%-19%] vs 28% [95% CI 23%-32%]; P < 0.001), but no differences were found for treatment failure due to adverse effects (12 months: 14% [95% CI 11%-18%] vs 15% [95% CI 11%-18%]; P = .636).Significance Our results suggest that levetiracetam may have favorable efficacy compared to valproic acid, whereas level of toxicity seems similar. Therefore, levetiracetam seems to be the preferred choice for first-line AED treatment in patients with glioma.Neurolog

Effectiveness of antiseizure medication triple therapy in patients with glioma with refractory epilepsy: an observational cohort study

Background and ObjectivesApproximately 10% of patients with glioma with epilepsy need antiseizure medication (ASM) triple therapy due to refractory epilepsy. The aim of this study was to evaluate whether levetiracetam combined with valproic acid and clobazam (LEV + VPA + CLB), a frequently prescribed triple therapy, has favorable effectiveness compared with other triple therapy combinations in patients with glioma.MethodsThis was a multicenter retrospective observational cohort study. The primary outcome was the cumulative incidence of time to treatment failure for any reason, from the start of ASM triple therapy treatment. The secondary outcomes included cumulative incidences of the following: (1) time to treatment failure due to uncontrolled seizures; (2) time to treatment failure due to adverse effects; and (3) time to recurrent seizures. Patients were followed up for a maximum duration of 36 months.ResultsOf 1,435 patients in the original cohort, 90 patients received ASM triple therapy after second-line ASM treatment failure due to uncontrolled seizures. LEV + VPA + CLB was prescribed to 48% (43/90) and other ASM triple therapy to 52% (47/90) of patients. The cumulative incidence of treatment failure for any reason of LEV + VPA + CLB did not statistically significantly differ from that of other ASM triple therapy combinations (12 months: 47% [95% CI 31%–62%] vs 42% [95% CI 27%–56%], p = 0.892). No statistically significant differences for treatment failure due to uncontrolled seizures (12 months: 12% [95% CI 4%–25%] vs 18% [95% CI 8%–30%], p = 0.445), adverse effects (12 months: 22% [95% CI 11%–36%] vs 15% [95% CI 7%–27%], p = 0.446), or recurrent seizures (1 month: 65% [95% CI 48%–78%] vs 63% [95% CI 47%–75%], p = 0.911) were found.Development and application of statistical models for medical scientific researc

The effectiveness of antiepileptic drug treatment in glioma patients: lamotrigine versus lacosamide

Purpose Optimal treatment with antiepileptic drugs (AEDs) is an important part of care for brain tumor patients with epileptic seizures. Lamotrigine and lacosamide are both examples of frequently used non-enzyme inducing AEDs with limited to no drug-drug interactions, reducing the risk of unfavorable side effects. This study aimed to compare the effectiveness of lamotrigine versus lacosamide. Methods In this multicenter study we retrospectively analyzed data of patients with diffuse grade 2-4 glioma with epileptic seizures. All patients received either lamotrigine or lacosamide during the course of their disease after treatment failure of first-line monotherapy with levetiracetam or valproic acid. Primary outcome was the cumulative incidence of treatment failure, from initiation of lamotrigine or lacosamide, with death as competing event, for which a competing risk model was used. Secondary outcomes were uncontrolled seizures after AED initiation and level of toxicity. Results We included a total of 139 patients of whom 61 (44%) used lamotrigine and 78 (56%) used lacosamide. At 12 months, there was no statistically significant difference in the cumulative incidence of treatment failure for any reason between lamotrigine and lacosamide: 38% (95%CI 26-51%) versus 30% (95%CI 20-41%), respectively. The adjusted hazard ratio for treatment failure of lacosamide compared to lamotrigine was 0.84 (95%CI 0.46-1.56). The cumulative incidences of treatment failure due to uncontrolled seizures (18% versus 11%) and due to adverse events (17% versus 19%) did not differ significantly between lamotrigine and lacosamide. Conclusion Lamotrigine and lacosamide show similar effectiveness in diffuse glioma patients with epilepsy.Neurolog

Long-term disease burden and survivorship issues after surgery and radiotherapy of intracranial meningioma patients

BACKGROUND: Many intracranial meningioma patients have an impaired health-related quality of life (HRQoL) and neurocognitive functioning up to 4 yr after intervention.OBJECTIVE: To assess the long-term (>= 5 yr) disease burden of meningioma patients.METHODS: In this multicenter cross-sectional study, patients >= 5 yr after intervention (including active magnetic resonance imaging (MRI) surveillance) were included and assessed for HRQoL (Short-Form Health Survey 36), neurocognitive functioning (neuropsychological assessment), anxiety and depression (Hospital Anxiety and Depression Scale), and work productivity (Short Form-Health and Labour Questionnaire). Multivariable and propensity score regression analyses were used to compare patients and controls, and different treatment strategies corrected for possible confounders. Clinically relevant differences were reported.RESULTS: At amedian of 9 yr follow-up after intervention, meningioma patients (n = 190) reported more limitations due to physical (difference 12.5 points, P = .008) and emotional (13.3 points, P = .002) health problems compared with controls. Patients also had an increased risk to suffer from anxiety (odds ratio [OR]: 2.6, 95% CI: 1.2-5.7) and depression (OR: 3.7, 95% CI: 1.3-10.5). Neurocognitive deficits were found in 43% of patients. Although postoperative complications, radiotherapy, and reresection were associated with worse verbal memory, attention, and executive functioning when compared to patients resected once, the only clinically relevant association was between reresection and worse attention (-2.11, 95% CI: -3.52 to -0.07). Patients of working age less often had a paid job (48%) compared with the working-age Dutch population (72%) and reported more obstacles at work compared with controls.CONCLUSION: In the long term, a large proportion of meningioma patients have impaired HRQoL, neurocognitive deficits, and high levels of anxiety or depression. Patients treated with 1 resection have the best neurocognitive functioning.Neurolog

Impact of sex-specific target dose in chronic heart failure patients with reduced ejection fraction

Aims: A recent study suggested that women with heart failure and heart failure reduced ejection fraction might hypothetically need lower doses of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (= renin-angiotensin-system inhibitors) and β-blockers than men to achieve the best outcome. We assessed the current medical treatment of heart failure reduced ejection fraction in men and women in a large contemporary cohort and address the hypothetical impact of changing treatment levels in women. Methods: This analysis is part of a large contemporary quality of heart failure care project which includes 5320 (64%) men and 3003 (36%) women with heart failure reduced ejection fraction. Detailed information on heart failure therapy prescription and dosage were collected. Results: Women less often received renin-angiotensin-system inhibitors (79% vs 83%, p 100% of the new hypothetical target dose would be 24% for β-blockers and 52% for renin-angiotensin-system inhibitors, which can be considered as relatively overdosed. Conclusion: In this large contemporary heart failure registry, there were significant but relatively small differences in drug dose between men and women with heart failure reduced ejection fraction. Implementation of the hypothetical sex-specific target dosing schedule would lead to considerably more women adequately treated. In contrast, we identified a group of women who might have been relatively overdosed with increased risk of side-effects and intolerance