Abstract Controversy has surrounded the reported association of the single nucleotide polymorphism (SNP) C3435T of the ATP-binding cassette subfamily B member 1 ( ABCB1 , MDR1) gene, with refractory ...epilepsy. Here we examine this question by: (1) attempting to replicate the original association, (2) assessing the association of other variants in high linkage disequilibrium (LD) with C3435T, and (3) evaluating and comparing our findings with other published studies. We defined drug-responsiveness as seizure freedom or a 50% or more reduction in seizure frequency in the preceding year. Drug resistance was defined as a less than 50% reduction in seizure frequency in the preceding year. We used a combination of map-based (tagging SNPs) and direct sequence-based methods allowing a comprehensive assessment of variation across the associated interval. Genotypic data on 8 SNPs was collected on 440 patients, of whom 242 were drug-responsive and 198 were drug-resistant. We were unable to observe the original association of drug-resistant epilepsy with C3435T, nor any association with other functional variants at SNP or haplotype level in the ABCB1 gene. Evaluation of other attempted replication studies suggest that if the original C3435T association is indeed real, it would appear highly sensitive to the phenotype used. Alternatively, the discrepant results of this and other association attempts may be indicative of the original report of the CC genotype at C3435T in ABCB1 being a false positive finding. Variability in phenotypic descriptions in genetic association studies may partly explain the inconsistency of attempted replications.
Summary
Purpose: To investigate cerebral cortical surface morphology in a magnetic resonance (MRI)–negative temporal lobe epilepsy (TLE) cohort, and to differentiate between the effects on cortical ...morphology of cerebral volume loss associated with TLE, and abnormalities suggestive of malformations of cortical development (MCDs).
Methods: MRI data was gathered for 29 MRI‐negative patients and 40 neurologically normal controls. Automated methods of surface reconstruction were applied to all MRI data for the purposes of localized analysis of cortical curvature. As an adjunct to this analysis, measures of whole‐brain gray and white matter volumes, as well as cortical thickness, were also generated to determine the degree of whole‐brain volume loss in TLE, and its impact on cortical morphology.
Results: Automated analysis of the average cortical surface of the patient group revealed an area of abnormal cortical curvature in the basal left temporal lobe. The presence of whole‐brain volume loss in TLE was confirmed and found not to contribute to the cortical curvature abnormality in the temporal lobe. These results support the hypothesis that cortical curvature abnormalities in TLE may be indicative of a subtle MCD.
Discussion: Subtle MCDs such as abnormal indices of curvature may be associated with partial epilepsy. Analysis of these parameters may increase the diagnostic yield from MRI.
Abstract Seizures in some 30% to 40% of patients with epilepsy fail to respond to antiepileptic drugs or other treatments. While much has been made of the risks of new drug therapies, not enough ...attention has been given to the risks of uncontrolled and progressive epilepsy. This critical review summarizes known risks associated with refractory epilepsy, provides practical clinical recommendations, and indicates areas for future research. Eight international epilepsy experts from Europe, the United States, and South America met on May 4, 2013, to present, review, and discuss relevant concepts, data, and literature on the consequences of refractory epilepsy. While patients with refractory epilepsy represent the minority of the population with epilepsy, they require the overwhelming majority of time, effort, and focus from treating physicians. They also represent the greatest economic and psychosocial burdens. Diagnostic procedures and medical/surgical treatments are not without risks. Overlooked, however, is that these risks are usually smaller than the risks of long-term, uncontrolled seizures. Refractory epilepsy may be progressive, carrying risks of structural damage to the brain and nervous system, comorbidities (osteoporosis, fractures), and increased mortality (from suicide, accidents, sudden unexpected death in epilepsy, pneumonia, vascular disease), as well as psychological (depression, anxiety), educational, social (stigma, driving), and vocational consequences. Adding to this burden is neuropsychiatric impairment caused by underlying epileptogenic processes (“essential comorbidities”), which appears to be independent of the effects of ongoing seizures themselves. Tolerating persistent seizures or chronic medicinal adverse effects has risks and consequences that often outweigh risks of seemingly “more aggressive” treatments. Future research should focus not only on controlling seizures but also on preventing these consequences.
Recent clinical trials and meta-analyses of beta-hydroxy-beta-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have demonstrated a reduction in ischemic stroke in patients with a ...history of coronary artery disease both with and without elevations of serum cholesterol. This review summarizes clinical trials of these compounds and their recent impact on stroke and explores the underlying vascular mechanisms of their actions.
Use of statins in patients with vascular disease has been shown to lower the incidence of stroke by approximately 30%. Statins exhibit a number of antiatherosclerotic and antithrombotic properties that likely underlie the recently observed reductions in cerebrovascular disease. Statins reduce inflammatory, proliferative, and thrombogenic processes in plaque, making it less likely to rupture. Additionally, they reverse the endothelial dysfunction and platelet activation accompanying hypercholesterolemia and may reduce the tendency to thrombosis.
Hypercholesterolemia has reemerged as a risk factor for ischemic stroke. Statins protect against thromboembolic stroke through multiple beneficial effects within the vascular milieu. Further data are awaited to support the growing importance of cholesterol as a risk factor for ischemic stroke and the benefits of statin therapy in patients with cerebrovascular disease.
Purpose: To evaluate prospectively patient's aims for epilepsy surgery as previously outlined theoretically by Taylor et al. (Epilepsia 1997;3:625–30).
Methods: Ninety‐three consecutive patients were ...interviewed by a psychiatrist as part of their evaluation for epilepsy surgery. Open‐ended questions about the patient were asked, and carers' aims or ambitions for change as a result of putative relief of seizures were elicited. The interviewer aimed to obtain a maximum of five aims for later follow‐up purposes. These questions were part of an extensive psychiatric interview that is described.
Results: The aims of 69 patients or carers were analyzed. The 204 statements of aims were grouped into 59 categories initially. The five most frequently cited constituted 50% of all the aims listed. These aims were desire for work, driving of motor vehicles, independence, socializing, and freedom from drugs. The patients rarely identified a desire for improvement in cognitive functioning as an aim for epilepsy surgery. A final analysis into six categories showed that changes in social process predominated, even over changes in personal behavior.
Conclusions: The social and personal aims to accompany relief of epilepsy identified by patients are consistent with the literature on psychosocial adjustment to epilepsy.
Purpose: Although complex idiopathic generalized epilepsies (IGEs) are recognized to have a significant genetic component, as yet there are no known common susceptibility variants. It has recently ...been suggested that variation in the BRD2 gene confers increased risk of juvenile myoclonic epilepsy (JME), which accounts for around a quarter of all IGE. Here we examine the association between the candidate causal SNP (the promoter variant rs3918149) and JME in five independent cohorts comprising in total 531 JME cases and 1,390 healthy controls.
Methods: The strongest candidate causal variant from the original report (rs3918149) was genotyped across all five cohorts. In an effort to identify novel candidate causal polymorphisms, previously unscreened regions of UTR were resequenced.
Results: We observed a significant effect in a small sample recruited in Britain (genotype p = 0.001, allele p = 0.001), a borderline significant effect in a sample recruited in Ireland and no association in larger samples of German, Australian, and Indian populations. There was no association with other common forms of epilepsy or any other clear candidate casual variants in or near the BRD2 region.
Conclusions: The replication of an effect in the British cohort and suggestive evidence from that recruited in Ireland but lack of replication from the larger German, Australian, and Indian cohorts is surprising and difficult to explain. Further replication in carefully matched populations is required. Results presented here do not, however, support a strong effect for susceptibility to JME across populations of European descent.
Traditional antiepileptic drug development approaches have yielded many important clinically valuable anti-epileptic drugs. However, the screening of promising compounds has been naturally agnostic ...to epilepsy etiology in individual human patients. Now, genomic medicine is changing the way we view human disease. International collaborations are unraveling the many molecular genetic causes of the epilepsies, including the early onset epileptic encephalopathies, and some of the familial focal epilepsies. Further advances in precision diagnostics will be facilitated by ongoing large collaborations and the wider availability of whole exome and whole genome sequencing in clinical practice. Securing a precise molecular diagnosis in some individual patients will pave the way for the advent of precision therapeutics of new and re-purposed compounds in the treatment of the epilepsies. This new approach is already beginning, e.g., with the use of everolimus in patients with tuberous sclerosis complex (and perhaps other mTORopathies), the use of quinidine in some children with KCNT1 mutations, and the use of the ketogenic diet in individuals with GLUT-1 deficiency. This article explores the promise of genomics guided drug development as an approach to complement the more traditional model.
Epilepsy surgery should be considered in all patients with drug-resistant focal epilepsy. The diagnostic presurgical evaluation aims to delineate the epileptogenic zone and its relationship to ...eloquent brain regions. Genetic testing is not yet routine in presurgical evaluations, despite many monogenic causes of severe epilepsies, including some focal epilepsies. This review highlights genomic data that may inform decisions regarding epilepsy surgery candidacy and strategy. Focal epilepsies due to pathogenic variants in mechanistic target of rapamycin pathway genes are amenable to surgery if clinical, electroencephalography and imaging data are concordant. Epilepsy surgery outcomes are less favourable in patients with pathogenic variants in ion channel genes such as SCN1A. However, genomic data should not be used in isolation to contraindicate epilepsy surgery and should be considered alongside other diagnostic modalities. The additional role of somatic mosaicism in the pathogenesis of focal epilepsies may have implications for surgical planning and prognostication. Here, we advocate for including genomic data in the presurgical evaluation and multidisciplinary discussion for many epilepsy surgery candidates. We encourage neurologists to perform genetic testing in patients with focal non-lesional epilepsy, epilepsy in the setting of intellectual disability and epilepsy due to specific malformations of cortical development. The integration of genomics into the presurgical evaluation assists selection of patients for resective surgery and fosters a personalised medicine approach, where precision or targeted therapies are considered alongside surgical procedures.
•A monogenic cause can be identified in many people with severe epilepsy.•Genomic data may inform predictions about epilepsy surgery candidacy and strategy.•Somatic mosaicism is an important cause of epilepsy, with implications for surgery.•Precision therapies should be considered alongside epilepsy surgery procedures.•Epilepsy genomic data should be discussed at the epilepsy surgery review meeting.
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