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.
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 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.
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 • 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.
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.
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.
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.
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.
Summary The Tenth Eilat Conference on New Antiepileptic Drugs (AEDs)-EILAT X, took place in Eilat, Israel from the 25th to 29th of April 2010. About 200 basic scientists, clinical pharmacologists and neurologists from 25 countries attended the conference, whose main themes included learning from the past: Lessons learnt after 18 years of Eilat Conferences and Detecting assessing and preventing adverse effects of AEDs. 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 previous EILAT (EILAT IX) manuscript, the current (EILAT X) manuscript focuses only on the preclinical and clinical pharmacology of AEDs that are currently in development. These include brivaracetam, carisbamate, 2-deoxy-glucose, ganaxolone, huperizine A, ICA-105665, NAX-5055, retigabine, perampanel, T-2007, valnoctamide and YK3089. Since the previous Eilat Conference (EILAT IX-2008) two new AEDs; eslicarbazepine acetate and lacosamide have been marketed and three new AEDs in development not included in the EILAT IX manuscript were added: ICA-105665, perampanel and valnoctamide. The CNS efficacy of these compounds in anticonvulsant animal models as well as other disease model systems are presented in Tables 1 and 2 and their proposed mechanism of action at summarized in Table 3.
Summary Outcome data were analysed from 780 patients newly diagnosed with epilepsy and followed up at a single centre over a 20-year period to investigate which clinical factors predicted pharmacoresistance. Patients were divided at the time of analysis into those whose seizures had been controlled for at least the last 12 months of follow up ( n = 462) and those whose epilepsy remained refractory ( n = 318). Numbers of pre-treatment seizures were greater in uncontrolled patients. Those reporting more than 10 seizures prior to initiation of therapy were more than twice as likely to develop refractory epilepsy. Univariate and multivariate logistic regression analyses demonstrated that pharmacoresistance was also associated with family history of epilepsy, previous febrile seizures, traumatic brain injury as the cause of the epilepsy, intermittent recreational drug use, and prior or current psychiatric comorbidity, particularly depression. Factors not predicting poorer outcome included gender, neurological deficit and mental retardation. The most interesting new finding was the correlation between psychiatric comorbidity and lack of response to antiepileptic drug therapy. The deleterious neurobiological processes that underpin depression, anxiety and psychosis may interact with those producing seizures to increase the extent of brain dysfunction and thereby the likelihood of developing pharmacoresistant epilepsy.
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 • 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.
Summary Objective To investigate the efficacy and safety of once-daily eslicarbazepine acetate (ESL) when used as add-on treatment in adults with ≥4 partial-onset seizures per 4-week despite treatment with 1 to 3 antiepileptic drugs (AEDs). Methods This double-blind, parallel-group, multicenter study consisted of an 8-week observational baseline period, after which patients were randomized to placebo ( n = 100) or once-daily ESL 400 mg ( n = 96), 800 mg ( n = 101), or 1200 mg ( n = 98). Patients then entered a 14-week double-blind treatment phase. All patients started on their full maintenance dose except for those in the ESL 1200 mg group who received once-daily ESL 800 mg for 2 weeks before reaching their full maintenance dose. Results Seizure frequency per 4-week (primary endpoint) over the 14-week double-blind treatment period was significantly lower than placebo in the ESL 800 mg and 1200 mg ( p 5%) AEs in any group were dizziness, somnolence, headache, nausea, diplopia, abnormal coordination, vomiting, blurred vision, and fatigue. The majority of AEs were of mild or moderate severity. Conclusions Treatment with once-daily eslicarbazepine acetate 800 mg and 1200 mg was more effective than placebo and generally well tolerated in patients with partial-onset seizures refractory to treatment with 1 to 3 concomitant AEDs.
Summary Treatment of epileptic patients with valproic acid (VPA) may be associated with substantial weight changes that may increase morbidity and impair adherence to the treatment regimen. VPA-induced weight gain seems to be associated with many metabolic disturbances; the most frequent are hyperinsulinemia and insulin resistance, hyperleptinemia and leptin resistance. Patients who gain weight during VPA therapy can develop dyslipidemia and metabolic syndrome that are associated with long-term vascular complications such as hypertension and atherosclerosis. Moreover, an elevation in the levels of uric acid and homocysteine, together with oxidative stress, may contribute to atherosclerotic risk in patients under long-term therapy with VPA. The aim of this review is to discuss the metabolic and endocrine effects of VPA chronic treatment in patients with epilepsy.
This review discusses the updated classifications of seizures and the epilepsies, which were recently published by the International League Against Epilepsy (ILAE). While it is always a challenge to learn a new classification system, particularly one that has remained essentially unchanged for over three decades, these new classifications allow for the inclusion of some previously unclassifiable seizure types and utilize more intuitive terminology. In this review, we specifically discuss the use of these new classifications for patients, clinicians, and researchers.
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 • Second functional characterization of SCN8A mutation in epileptic encephalopathy. • Channel functioning was investigated in neuronal cells. • Protein stability was investigated after correction for transcript abundance. • Functional effects of this mutation only partially overlapping with previously described mutation. • Raises discussion about functional mechanism of sodium channels in epileptic encephalopathy.