Search

Summary When developing a new medicine for children, the potential to extrapolate from adult efficacy data is well recognized. However, significant assumptions about the similarity of adults and children are needed for extrapolations to be biologically plausible. One such assumption is that of similar exposure–response (E–R-) relationships. Motivated by applications to antiepileptic drug development, we consider how data that are available from existing trials of adults and adolescents can be used to quantify prior uncertainty about whether E–R-relationships are similar in adults and younger children. A Bayesian multivariate meta-analytic model is fitted to existing E–R-data and adjusted for external biases that arise because these data are not perfectly relevant to the comparison of interest. We propose a strategy for eliciting expert prior opinion on external biases. From the bias-adjusted meta-analysis, we derive prior distributions quantifying our uncertainty about the degree of similarity between E–R-relationships for adults and younger children. Using these we calculate the prior probability that average pharmacodynamic responses in adults and younger children, both on placebo and at an effective concentration, are sufficiently similar to justify a complete extrapolation of efficacy data. A simulation study is performed to evaluate the operating characteristics of the approach proposed.

Gene identification in epilepsy has mainly been limited to large families segregating genes of major effect and de novo mutations in epileptic encephalopathies. Many families that present with common non-acquired focal epilepsies and genetic generalized epilepsies remain unexplained. We assembled a cohort of 'genetically enriched' common epilepsies by collecting and phenotyping families containing multiple individuals with unprovoked seizures. We aimed to determine if specific clinical epilepsy features aggregate within families, and whether this segregation of phenotypes may constitute distinct 'familial syndromes' that could inform genomic analyses. Families with three or more individuals with unprovoked seizures were studied across multiple international centres. Affected individuals were phenotyped and classified according to specific electroclinical syndromes. Families were categorized based on syndromic groupings of affected family members, examined for pedigree structure and phenotypic patterns and, where possible, assigned specific familial epilepsy syndromes. A total of 303 families were assembled and analysed, comprising 1120 affected phenotyped individuals. Of the 303 families, 117 exclusively segregated generalized epilepsy, 62 focal epilepsy, and 22 were classified as genetic epilepsy with febrile seizures plus. Over one-third (102 families) were observed to have mixed epilepsy phenotypes: 78 had both generalized and focal epilepsy features within the same individual (n = 39), or within first or second degree relatives (n = 39). Among the genetic generalized epilepsy families, absence epilepsies were found to cluster within families independently of juvenile myoclonic epilepsy, and significantly more females were affected than males. Of the 62 familial focal epilepsy families, two previously undescribed familial focal syndrome patterns were evident: 15 families had posterior quadrant epilepsies, including seven with occipito-temporal localization and seven with temporo-parietal foci, and four families displayed familial focal epilepsy of childhood with multiple affected siblings that was suggestive of recessive inheritance. The findings suggest (i) specific patterns of syndromic familial aggregation occur, including newly recognized forms of familial focal epilepsy; (ii) although syndrome-specificity usually occurs in multiplex families, the one-third of families with features of both focal and generalized epilepsy is suggestive of shared genetic determinants; and (iii) patterns of features observed across families including pedigree structure, sex, and age of onset may hold clues for future gene identification. Such detailed phenotypic information will be invaluable in the conditioning and interpretation of forthcoming sequencing data to understand the genetic architecture and inter-relationships of the common epilepsy syndromes.

We present the analysis of a prospective multicentre study to investigate genetic effects on the prognosis of newly treated epilepsy. Patients with a new clinical diagnosis of epilepsy requiring medication were recruited and followed up prospectively. The clinical outcome was defined as freedom from seizures for a minimum of 12 months in accordance with the consensus statement from the International League Against Epilepsy (ILAE). Genetic effects on remission of seizures after starting treatment were analysed with and without adjustment for significant clinical prognostic factors, and the results from each cohort were combined using a fixed-effects meta-analysis. After quality control (QC), we analysed 889 newly treated epilepsy patients using 472 450 genotyped and 6.9 × 10(6) imputed single-nucleotide polymorphisms. Suggestive evidence for association (defined as Pmeta5.0 × 10(-7)) with remission of seizures after starting treatment was observed at three loci: 6p12.2 (rs492146, Pmeta = 2.1 × 10(-7), OR[G] = 0.57), 9p23 (rs72700966, Pmeta = 3.1 × 10(-7), OR[C] = 2.70) and 15q13.2 (rs143536437, Pmeta = 3.2 × 10(-7), OR[C] = 1.92). Genes of biological interest at these loci include PTPRD and ARHGAP11B (encoding functions implicated in neuronal development) and GSTA4 (a phase II biotransformation enzyme). Pathway analysis using two independent methods implicated a number of pathways in the prognosis of epilepsy, including KEGG categories 'calcium signaling pathway' and 'phosphatidylinositol signaling pathway'. Through a series of power curves, we conclude that it is unlikely any single common variant explains4.4% of the variation in the outcome of newly treated epilepsy.

Some patients with pharmacoresistant epilepsy undergo therapeutic resection of the epileptic focus. At least 12 large-scale microarray studies on brain tissue from epilepsy surgery have been published over the last 10 years, but they have failed to make a significant impact upon our understanding of pharmacoresistance, because (1) doubts have been raised about their reproducibility, (2) only a small number of the gene expression changes found in each microarray study have been independently validated and (3) the results of different studies have not been integrated to give a coherent picture of the genetic changes involved in epilepsy pharmacoresistance. To overcome these limitations, we (1) assessed the reproducibility of the microarray studies by calculating the overlap between lists of differentially regulated genes from pairs of microarray studies and determining if this was greater than would be expected by chance alone, (2) used an inter-study cross-validation technique to simultaneously verify the expression changes of large numbers of genes and (3) used the combined results of the different microarray studies to perform an integrative analysis based on enriched gene ontology terms, networks and pathways. Using this approach, we respectively (1) demonstrate that there are statistically significant overlaps between the gene expression changes in different publications, (2) verify the differential expression of 233 genes and (3) identify the biological processes, networks and genes likely to be most important in the development of pharmacoresistant epilepsy. Our analysis provides novel biologically plausible candidate genes and pathways which warrant further investigation to assess their causal relevance.

BACKGROUND: There is increasing interest in the use of ketogenic diets (KD) as adjuvant therapy for glioblastoma (GBM). This trial aimed to: (i) investigate protocol feasibility, (ii) measure patient/carer acceptability and (iii) inform phase III trial design. METHODS: A prospective, randomised, feasibility study, with an embedded qualitative design. Twelve newly diagnosed GBM patients were randomised to the modified ketogenic diet (MKD) or the medium chain triglyceride ketogenic diet (MCTKD). Primary outcome was retention; secondary outcomes included recruitment rate, side effects, extent of ketosis and dietary acceptability, assessed at 12 weeks and 12 months. Semi-structured interviews were conducted with a representative sample of patients and relatives (n=15). RESULTS: Recruitment was achieved within the defined timeframe of 12 months; 42 patients were eligible, of which 12 were recruited (29% recruitment rate). Retention was poor; of the 12 patients randomised, 4 completed the 12-week dietary trial (3 on MCTKD; 1 on MKD). Median duration on diet was 36.5 days (range 0–49) for those who discontinued prior to 12 weeks (n=8). Those who completed the 12-week intervention (n=4) achieved ketosis (1.65mmol/L 1.3mmol/L). No dietary related serious adverse events occurred. Qualitative interviews revealed patients who completed the 12-week diet consented without hesitation. Those who declined participation pre-empted the issues experienced by those who withdrew prior to 12-weeks; namely high levels relative/carer burden and social exclusion. Retainers had a positive experience and reported the diet became the new normal. Patients stated that the 3-month diet duration was too long, but 6 weeks would be more attainable. CONCLUSION: Recruitment to a GBM ketogenic trial is feasible. Retention at 3 months was poor due to the diet negatively impacting patient lifestyle and causing burden for relatives. To assess efficacy in a phase III trial, a 6-week dietary intervention would be advantageous.

BACKGROUND: There is increasing interest in the use of ketogenic diets (KD) as adjuvant therapy for glioblastoma (GBM). This trial aimed to: (i) investigate protocol feasibility, (ii) measure patient and carer tolerability and (iii) inform the design of future phase III clinical trials. MATERIAL AND METHODS: A prospective, non-blinded, randomised, feasibility study with an embedded qualitative design assessing recruitment and retention challenges and experiences. Twelve newly diagnosed GBM patients were randomised to the modified ketogenic diet (MKD) or the medium chain triglyceride ketogenic diet (MCT KD). Primary outcome was retention at 12 weeks. Secondary outcomes assessed at 12 weeks and 12 months included recruitment rate, side effects, anthropometric changes, dietary acceptability and long term retention. Semi-structured interviews were conducted with a purposive sample of patients and relatives (n=15), including those who declined, withdrew and retained up until 12 weeks. RESULTS: Recruitment was achieved within the desired timeframe of 12 months. Fifty-seven patients were screened, 42 were eligible to participate and 12 were recruited (29% recruitment rate). Retention was poor; of the 12 patients randomised, 4 completed the 12 week dietary trial, of which 3 followed MCT KD. Median duration on diet was 36.5 days (range 0–49 days) for those who discontinued prior to 12 weeks (n=8). No dietary related serious adverse events occurred. Mean weight loss was 8.51kg (S.D 9.66kg) over 12 weeks (n=4), however this was intentional as all patients were overweight or obese at baseline. Gastrointestinal intolerances occurred at dietary initiation (n=3), resolving by week 6. Those who participated in the study reported their decision to be a ‘gut reaction’, whilst those who declined to participate appeared more considered in their decision, reporting the diet to be too restrictive and too time consuming for the relative to prepare. Whilst relatives did not influence the patient’s decision to participate in the study, all patients sought their relative’s opinion. Participants reported high levels of relative burden and support required when implementing KD. Some underestimated this, resulting in withdrawal. Those who withdrew reported KD to negatively impact their lifestyle. Retainers had a positive experience and reported that the diet became ‘the new normal’. Ketone monitoring was seen as a motivation for retainers, and a burden for withdrawers. Patients reported that the 3-month diet duration was too long but 5–6 weeks to be more attainable. CONCLUSION: Recruitment to a GBM ketogenic trial is possible. Retention at 3 months was poor due to the diet negatively impacting patients’ lifestyle and causing burden for relatives. To assess efficacy in a stage III trial, a 6 week dietary intervention would be advantageous.

INTRODUCTION: Epilepsy is known to impair quality of life (QoL) but the impact of epilepsy on QoL in meningioma population is not certain. The aim of this cross-sectional postal study was to investigate the effects of benign meningioma and epilepsy on QoL. METHOD: Three patient groups were recruited: (1) meningioma without epilepsy; (2) meningioma with epilepsy; and (3) epilepsy without meningioma. Three QoL questionnaires were used: (a) Sf-36; (b) Fact-Br; and (c) the Liverpool Adverse Events Profile (LAEP). Mean scores of each scale were compared between meningioma patients with and without epilepsy, and between epilepsy patients with and without meningioma. Regression models identified factors that correlated with poor QoL. RESULTS: There were 229 participants (mean age 59.9 ± 12.2 years); 109 meningioma, 56 meningioma and epilepsy, and 64 epilepsy without meningioma. QoL was impaired in the meningioma with epilepsy group compared to the meningioma without epilepsy group in all questionnaires; but only the Fact-Br was significantly impaired (t-test; p = 0.012). Antiepileptic drugs (AEDs) significantly impaired QoL in the regression analyses, while seizures were less influential. QoL was impaired in the epilepsy without meningioma group compared to the meningioma and epilepsy group, but this difference was not significant (t-test; p = 0.44). Increased seizure frequency and AEDs (particularly Levetiracetam) significantly impaired QoL in the regression analyses. CONCLUSION: In meningioma, epilepsy has a minor impact on QoL; but AEDs significantly impair QoL and this has potential implications for seizure management. Meningioma patients with epilepsy have comparable QoL to epilepsy patients without meningioma.