Summary Epilepsy is a chronic disease experienced by millions and a cause of substantial morbidity and mortality. This review summarizes prevalence and incidence studies of epilepsy that provided a clear definition of epilepsy and could be age-adjusted: requirements if comparisons across studies are to be made. Although few exceptions, age-adjusted prevalence estimates from record-based studies (2.7–17.6 per 1000), are lower than those from door-to-door surveys (2.2–41.0 per 1000). Age-adjusted incidence ranged from 16 to 51 per 100,000, with one exception in Chile, where incidence was 111 per 100,000. Variation in reported prevalence and incidence may be related to factors such as access to health care, regional environmental exposures, or socioeconomic status. A higher proportion of epilepsy characterized by generalized seizures was reported in most prevalence studies. Epilepsy characterized by partial seizures accounted for 20–66% of incident epilepsies. Virtually all prevalence and incidence studies report a preponderance of seizures of unknown cause. Additional prevalence studies are needed in regions where data does not exist, and additional incidence studies in all regions. Interpretation of differences in prevalence and incidence will require understanding of the role of cultural, social and economic factors influencing epilepsy and its care.
Summary Purposes To provide evidence-based quantitative summary estimates of seizure outcomes in patients with non-lesional and lesional epilepsy treated with surgery, and to assess the consistency of results among published studies. Methods An exhaustive literature search identified articles published since 1995, describing outcomes according to lesional status in patients of any age who underwent resective epilepsy surgery. Two reviewers independently assessed study eligibility and extracted the data. Disagreements were resolved through discussion. Random effects meta-analyses were used after assessing the dataset for heterogeneity. Results Forty articles fulfilled eligibility criteria and described outcomes in 697 patients with non-lesional epilepsy and 2860 patients with lesional epilepsy. Overall, the odds of being seizure-free after surgery were 2.5 times higher in patients with lesions on MRI or histopathology (OR 2.5, 95%CI 2.1, 3.0, p < 0.001). In patients with temporal lobe epilepsy surgery the odds were 2.7 times higher in those with lesions (OR 2.7, 95%CI 2.1, 3.5, p < 0.001). In patients with extratemporal epilepsy surgery the odds were 2.9 higher in those with lesions (OR 2.9, 95%CI 1.6, 5.1, p < 0.001). Outcomes were similar in children, adults, and studies that used MRI or histopathology to identify lesions. Discussion Overall, the odds of seizure freedom after surgery are two to three times higher in the presence of a lesion on histopathology or MRI. The results are clinically and statistically significant, consistent across various subgroups, and quite homogeneous across studies.
Highlights • The Twelfth Eilat Conference on New Antiepileptic Drugs (AEDs)-EILAT XII. • Antiepileptic drugs in development. • Preclinical evaluation and clinical trials. • Development strategies of new AEDs.
Summary The Eleventh Eilat Conference on New Antiepileptic Drugs (AEDs)-EILAT XI, took place in Eilat, Israel from the 6th to 10th of May 2012. About 100 basic scientists, clinical pharmacologists and neurologists from 20 countries attended the conference, whose main themes included “Indications overlapping with epilepsy” and “Securing the successful development of an investigational antiepileptic drug in the current environment”. Consistent with previous formats of this conference, a large part of the program was devoted to a review of AEDs in development, as well as updates on AEDs introduced since 1994. Like the EILAT X report, the current manuscript focuses only on the preclinical and clinical pharmacology of AEDs that are currently in development. These include brivaracetam, 2-deoxy-glucose, ganaxolone, ICA-105665, imepitoin, NAX 801-2, perampanel and other AMPA receptor antagonists, tonabersat, valnoctamide and its homologue sec -propylbutylacetamide (SPD), VX-765 and YK3089. Since the previous Eilat conference, retigabine (ezogabine) has been marketed and four newer AEDs in development (NAX 810-2, SPD, tonabersat and VX-765) are included in this manuscript.
Summary Background Although the US FDA recommends screening for HLA-B*1502 allele in most of Asian ancestry before initiating carbamazepine therapy, the HLA associations with carbamazepine hypersensitivity in non-Chinese Asian populations remain unclear. This study investigated the association between the HLA class I genotype and carbamazepine-induced severe cutaneous adverse reaction (SCAR) in Koreans. Methods Twenty-four patients who had developed carbamazepine-induced SCAR (7 Stevens–Johnson syndrome (SJS), 17 drug hypersensitivity syndrome (HSS)), 50 carbamazepine-tolerant controls from the Korean Pharmacogenetic Adverse Drug Reaction Research Network and data of 485 Korean general population from a previously published study were recruited. HLA-A, -B, and -C genotyping was performed by direct DNA sequence analysis. Results Only one of the seven SJS patients was positive for the B*1502 allele, but the frequency of B*1511 was much higher in the patients with CBZ-SJS than in the CBZ-tolerant control patients ( P = 0.011, Pc = not significant; OR = 18.0(2.3–141.2)). The frequencies of A*3101 in carbamazepine-induced HSS and SCAR were significantly higher than those in carbamazepine-tolerant controls ( Pc = 0.011, OR = 8.8(2.5–30.7) and Pc = 0.013, OR = 7.3(2.3–22.5), respectively). The frequencies of B*1511 in carbamazepine-SJS and A*3101 in carbamazepine-HSS/SCAR were significantly higher than those in the general population. Conclusions HLA-B*1502 does not seem to be an effective predictive marker for carbamazepine-induced SCAR, while HLA-B*1511 and A*3101 was associated with carbamazepine-induced SJS and HSS/SCAR respectively in the Korean population.
Summary The automatic detection and classification of epileptic EEG are significant in the evaluation of patients with epilepsy. This paper presents a new EEG classification approach based on the extreme learning machine (ELM) and nonlinear dynamical features. The theory of nonlinear dynamics has been a powerful tool for understanding brain electrical activities. Nonlinear features extracted from EEG signals such as approximate entropy (ApEn), Hurst exponent and scaling exponent obtained with detrended fluctuation analysis (DFA) are employed to characterize interictal and ictal EEGs. The statistics indicate that the differences of those nonlinear features between interictal and ictal EEGs are statistically significant. The ELM algorithm is employed to train a single hidden layer feedforward neural network (SLFN) with EEG nonlinear features. The experiments demonstrate that compared with the backpropagation (BP) algorithm and support vector machine (SVM), the performance of the ELM is better in terms of training time and classification accuracy which achieves a satisfying recognition accuracy of 96.5% for interictal and ictal EEG signals.
Highlights • Lacosamide was identified by virtue of activity in the maximal electroshock test. • The profile of lacosamide in animal seizure models is similar to that of sodium channel blocking antiepileptic drugs. • The biophysical characteristics of lacosamide block of voltage-gated sodium channels is distinct from that of other sodium channel blocking antiepileptic drugs, conferring unique properties.
Summary Mitochondrial oxidative stress and dysfunction are contributing factors to various neurological disorders. Recently, there has been increasing evidence supporting the association between mitochondrial oxidative stress and epilepsy. Although certain inherited epilepsies are associated with mitochondrial dysfunction, little is known about its role in acquired epilepsies such as temporal lobe epilepsy (TLE). Mitochondrial oxidative stress and dysfunction are emerging as key factors that not only result from seizures, but may also contribute to epileptogenesis. The occurrence of epilepsy increases with age, and mitochondrial oxidative stress is a leading mechanism of aging and age-related degenerative disease, suggesting a further involvement of mitochondrial dysfunction in seizure generation. Mitochondria have critical cellular functions that influence neuronal excitability including production of adenosine triphosphate (ATP), fatty acid oxidation, control of apoptosis and necrosis, regulation of amino acid cycling, neurotransmitter biosynthesis, and regulation of cytosolic Ca2+ homeostasis. Mitochondria are the primary site of reactive oxygen species (ROS) production making them uniquely vulnerable to oxidative stress and damage which can further affect cellular macromolecule function, the ability of the electron transport chain to produce ATP, antioxidant defenses, mitochondrial DNA stability, and synaptic glutamate homeostasis. Oxidative damage to one or more of these cellular targets may affect neuronal excitability and increase seizure susceptibility. The specific targeting of mitochondrial oxidative stress, dysfunction, and bioenergetics with pharmacological and non-pharmacological treatments may be a novel avenue for attenuating epileptogenesis.
Highlights • Periventricular nodular heterotopias (PVNH) causing medically refractory epilepsy. • Surgical resection of PVNH is limited by their deep location. • Stereotactic MR guided laser interstitial thermal therapy (MRgLITT) done for PVNH. • Accomplished focal ablation of PVNH with lower risk of neurological deficits.
Highlights • Dravet-specific mortality rate is 15.84/1000-person-years (CI 9.01–27.85). • Dravet-specific SUDEP rate is 9.32/1000-person-years (CI 4.46–19.45). • Dravet-specific SUDEP rate is the only documented syndrome specific SUDEP rate.
Highlights • Validated and predictive animal models are essential for discovery of novel therapies. • For models of seizures or epilepsy, principles of translational medicine are useful. • The focus is on the fit for purpose paradigm that is key for success in drug discovery. • Suitable animal models and areas where such models are missing are discussed. • In several areas, further development is needed to develop models that are fit for purpose.
Summary Purpose To conduct a systematic review and meta-analysis to quantify the incidence of congenital malformations (CMs) and other pregnancy outcomes as a function of in utero anti-epileptic drug (AED) exposure. Methods We performed a systematic literature review to identify all published registries and cohort studies of births from pregnant women with epilepsy (WWE) that reported incidence of CMs. Overall incidences were calculated using a random effects model. Results The review included 59 studies that met inclusion/exclusion criteria, involving 65,533 pregnancies in WWE and 1,817,024 in healthy women. The calculated incidence of births with CM in WWE [7.08%; 95% CIs 5.62, 8.54] was higher than healthy women [2.28%; CIs 1.46, 3.10]. Incidence was highest for AED polytherapy [16.78%; CIs 0.51, 33.05]. The AED with the highest CM incidence was valproate, which was 10.73% [CIs 8.16, 13.29] for valproate monotherapy. Conclusions Results of this systematic literature review suggest that the overall incidence of CMs in children born of WWE is approximately threefold that of healthy women. The risk is elevated for all AED monotherapy and further elevated for AED polytherapy compared to women without epilepsy. The risk was significantly higher for children exposed to valproate monotherapy and to polytherapy of 2 or more drugs when the polytherapy combination included phenobarital, phenytoin, or valproate. Further research is needed to delineate the specific risk for each individual AED and to determine underlying mechanisms including genetic risk factors.
Summary Pregabalin (Lyrica™) is a new antiepileptic drug that is active in animal seizure models. Pregabalin is approved in US and Europe for adjunctive therapy of partial seizures in adults, and also has been approved for the treatment of pain from diabetic neuropathy or post-herpetic neuralgia in adults. Recently, it has been approved for treatment of anxiety disorders in Europe. Pregabalin is structurally related to the antiepileptic drug gabapentin and the site of action of both drugs is similar, the alpha2 –delta (α2 –δ) protein, an auxiliary subunit of voltage-gated calcium channels. Pregabalin subtly reduces the synaptic release of several neurotransmitters, apparently by binding to α2 –δ subunits, and possibly accounting for its actions in vivo to reduce neuronal excitability and seizures. Several studies indicate that the pharmacology of pregabalin requires binding to α2 –δ subunits, including structure-activity analyses of compounds binding to α2 –δ subunits and pharmacology in mice deficient in binding at the α2 –δ Type 1 protein. The preclinical findings to date are consistent with a mechanism that may entail reduction of abnormal neuronal excitability through reduced neurotransmitter release. This review addresses the preclinical pharmacology of pregabalin, and also the biology of the high affinity binding site, and presumed site of action.
Summary Inflammation is an important factor in the pathophysiology of seizure generation and epileptogenesis. While the role of CNS inflammation is well acknowledged as an important factor in seizure pathophysiology, less is known about the role of peripheral inflammation. Systemic inflammation induces a mirror inflammatory response in the brain that might have transient or long-term effects on seizure susceptibility. The focus of our laboratory research is the study of the interaction of systemic inflammatory events with neuronal excitability and seizure susceptibility. In this paper we provide a review of our findings and discuss possible mechanisms.
Summary Epileptogenesis is common following brain insults such as trauma, ischemia and infection. However, the mechanisms underlying injury-related epileptogenesis remain unknown. Recent studies demonstrated impaired integrity of the blood–brain barrier (BBB) during epileptogenesis. Here we review accumulating experimental evidence supporting the potential involvement of primary BBB lesion in epileptogenesis. Data from animal experiments demonstrate that primary breakdown of the BBB prone animals to develop focal neocortical epilepsy that is followed by neuronal loss and impaired functions. The extravasation of albumin from the circulation into the brain neuropil was found to be sufficient for the induction of epileptogenesis. Albumin binds to transforming growth factor β receptor 2 (TGFβR2) in astrocytes and induces rapid transcriptional modifications, astrocytic transformation and dysfunction. We highlight a novel cascade of events which is initiated by increased BBB permeability, eventually leading to neuronal dysfunction, epilepsy and cell loss. We review potential mechanisms and existing experimental evidence for the important role of astrocytes and the TGFβ pathway in epileptogenesis. Finally, we review evidence from human clinical data supporting the involvement of BBB lesion in epilepsy. We propose that primary vascular injury, and specifically BBB breakdown and repair, are key elements in altered interactions within the neurovascular unit and thus may serve as new therapeutic targets.
Pregabalin (Lyrica (TM)) is a new antiepileptic drug that is active in animal seizure models. Pregabalin is approved in US and Europe for adjunctive therapy of partial seizures in adults, and also has been approved for the treatment of pain from diabetic neuropathy or post-herpetic neuralgia in adults. Recently, it has been approved for treatment of anxiety disorders in Europe. Pregabalin is structurally related to the antiepileptic drug gabapentin and the site of action of both drugs is similar, the alpha(2)-delta (alpha(2)-delta) protein, an auxiliary subunit of voltage-gated calcium channels. Pregabalin subtly reduces the synaptic release of several neurotransmitters, apparently by binding to alpha(2)-delta subunits, and possibly accounting for its actions in vivo to reduce neuronal excitability and seizures. Several studies indicate that the pharmacology of pregabalin requires binding to alpha(2)-delta subunits, including structure-activity analyses of compounds binding to alpha(2)-delta subunits and pharmacology in mice deficient in binding at the alpha(2)-delta Type 1 protein. The preclinical findings to date are consistent with a mechanism that may entail reduction of abnormal neuronal excitability through reduced neurotransmitter release. This review addresses the preclinical pharmacology of pregabalin, and also the biology of the high affinity binding site, and presumed site of action. (c) 2006 Published by Elsevier B.V.
Highlights • We report real-world data from 464 patients treated with perampanel over 1 year. • Efficacy and tolerability of perampanel were comparable with clinical trial data. • Patients ≥65 years, vascular aetiology or fewer prior AEDs had a superior response. • Patients with psychiatric comorbidities (hyperactivity and personality disorder) were more likely to experience psychiatric AEs. • Patients with slower titration schedules were less likely to experience an AE.
Highlights • Absolute risk increase of comorbidity was 18.5% higher in epilepsy than in migraine. • Neurodevelopmental comorbidities showed the strongest association with epilepsy. • The absolute risk increase of death was 233.3% higher in epilepsy than in migraine. • Of somatic comorbidities, stroke showed the strongest association with epilepsy. • Depression and anxiety were the most prevalent psychiatric comorbidities in epilepsy.
Highlights • Collection of practical clinical experience with adjunctive perampanel in 281 patients according to a multicenter survey. • It is shown that adjunctive perampanel may be effective in this group of difficult-to-treat patients some of which even acquire seizure freedom at least for a certain period of time. • Adverse events were similar to those reported in the randomized controlled trials.
Highlights • Malformations of cortical development are a common cause of refractory epilepsy. • They are often invisible on structural imaging and only detected following surgery. • We assess a novel diffusion imaging technique (NODDI) in patients with dysplasia. • This shows more conspicuous changes than other clinical or diffusion scans. • This technique may assist the identification of FCD in patients with epilepsy.