Showing papers in "Epilepsia in 2011"

The clinicopathologic spectrum of focal cortical dysplasias: A consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission

Abstract: Purpose Focal cortical dysplasias (FCD) are localized regions of malformed cerebral cortex and are very frequently associated with epilepsy in both children and adults. A broad spectrum of histopathology has been included in the diagnosis of FCD. An ILAE task force proposes an international consensus classification system to better characterize specific clinicopathological FCD entities. Methods Thirty-two Task Force members have reevaluated available data on electroclinical presentation, imaging, neuropathological examination of surgical specimens as well as postsurgical outcome. Key findings The ILAE Task Force proposes a three-tiered classification system. FCD Type I refers to isolated lesions, which present either as radial (FCD Type Ia) or tangential (FCD Type Ib) dyslamination of the neocortex, microscopically identified in one or multiple lobes. FCD Type II is an isolated lesion characterized by cortical dyslamination and dysmorphic neurons without (Type IIa) or with balloon cells (Type IIb). Hence, the major change since a prior classification represents the introduction of FCD Type III, which occurs in combination with hippocampal sclerosis (FCD Type IIIa), or with epilepsy-associated tumors (FCD Type IIIb). FCD Type IIIc is found adjacent to vascular malformations, whereas FCD Type IIId can be diagnosed in association with epileptogenic lesions acquired in early life (i.e., traumatic injury, ischemic injury or encephalitis). Significance This three-tiered classification system will be an important basis to evaluate imaging, electroclinical features, and postsurgical seizure control as well as to explore underlying molecular pathomechanisms in FCD.

Standards for epidemiologic studies and surveillance of epilepsy

Abstract: Worldwide, about 65 million people are estimated to have epilepsy. Epidemiologic studies are necessary to define the full public health burden of epilepsy; to set public health and health care priorities; to provide information needed for prevention, early detection, and treatment; to identify education and service needs; and to promote effective health care and support programs for people with epilepsy. However, different definitions and epidemiologic methods complicate the tasks of these studies and their interpretations and comparisons. The purpose of this document is to promote consistency in definitions and methods in an effort to enhance future population-based epidemiologic studies, facilitate comparison between populations, and encourage the collection of data useful for the promotion of public health. We discuss: (1) conceptual and operational definitions of epilepsy, (2) data resources and recommended data elements, and (3) methods and analyses appropriate for epidemiologic studies or the surveillance of epilepsy. Variations in these are considered, taking into account differing resource availability and needs among countries and differing purposes among studies.

Modern antiepileptic drug development has failed to deliver: ways out of the current dilemma.

Abstract: Despite the development of various new antiepileptic drugs (AEDs) since the early 1990s, the available evidence indicates that the efficacy and tolerability of drug treatment of epilepsy has not substantially improved. What are the reasons for this apparent failure of modern AED development to discover drugs with higher efficacy? One reason is certainly the fact that, with few exceptions, all AEDs have been discovered by the same conventional animal models, particularly the maximal electroshock seizure test (MES) in rodents, which served as a critical gatekeeper. These tests have led to useful new AEDs, but obviously did not help developing AEDs with higher efficacy in as yet AED-resistant patients. This concern is not new but, surprisingly, has largely been unappreciated for several decades. A second-admittedly speculative-reason is that progress in pharmacologic treatment of drug-resistant epilepsy will not be made unless and until we develop drugs that specifically target the underlying disease. Although better preclinical approaches will not be able to circumvent regulatory requirements, more efficacious drugs may allow us to abandon clinically questionable trials with intentionally less efficacious controls and noninferiority designs, and require evidence for comparative effectiveness. The failure of AED development has led to increasing disappointment among clinicians, basic scientists, and industry and may halt any further improvement in the treatment of epilepsy unless we find ways out of this dilemma. Therefore, we need new concepts and fresh thinking about how to radically change and improve AED discovery and development. In this respect, the authors of this critical review will discuss several new ideas that may hopefully lead to more efficacious drug treatment of epilepsy in the future.

The core Dravet syndrome phenotype

Abstract: Dravet syndrome was described in 1978 by Dravet (1978) under the name of severe myoclonic epilepsy in infancy (SMEI). The characteristics of the syndrome were confirmed and further delineated by other authors over the years. According to the semiologic features, two forms have been individualized: (1) the typical, core, SMEI; and (2) the borderline form, SMEIB, in which the myoclonic component is absent or subtle. Clinical manifestations at the onset, at the steady state, and during the course of the disease are analyzed in detail for the typical Dravet syndrome, and the differential diagnosis is discussed. Onset in the first year of life by febrile or afebrile clonic and tonic-clonic, generalized, and unilateral seizures, often prolonged, in an apparently normal infant is the first symptom, suggesting the diagnosis. Later on, multiple seizure types, mainly myoclonic, atypical absences, and focal seizures appear, as well as a slowing of developmental and cognitive skills, and the appearance of behavioral disorders. Mutation screening for the SCN1A gene confirms the diagnosis in 70-80% of patients. All seizure types are pharmacoresistent, but a trend toward less severe epilepsy and cognitive impairment is usually observed after the age of 5 years.

Neuropsychological outcomes after epilepsy surgery: systematic review and pooled estimates.

Abstract: Summary Purpose: Epilepsy surgery is a safe surgical procedure, but it may be associated with cognitive changes. Estimates of the risk of decline in specific neuropsychological domains after epilepsy surgery would assist surgical decision making in clinical practice. The goal of this study was to conduct a systematic review to derive pooled estimates of the rate of losses and gains in neuropsychological functions after epilepsy surgery, using empirically based methods for quantifying cognitive change. Methods: An extensive literature search using PubMed, EmBase, and the Cochrane database was conducted, yielding 5,061 articles on epilepsy surgery, with 193 on neuropsychological outcomes (IQ, memory, language, executive functioning, attention, and subjective cognitive changes). Key Findings: Of these, 23 met final eligibility criteria, with 22 studies involving temporal surgery only. Key aspects of inclusion criteria were N ≥ 20 and use of reliable change index or standardized regression-based change estimates. In addition to the proportion of patients experiencing losses and gains in each individual test, a single pooled estimate of gains and losses for each cognitive domain was derived using a random effects model. Weighted estimates indicated a risk to verbal memory with left-sided temporal surgery of 44%, twice as high as the rate for right-sided surgery (20%). Naming was reduced in 34% of left-sided temporal patients, with almost no patients with gains (4%). Pooled data on IQ, executive functioning, and attention indicated few patients show declines post surgery, but a substantial rate of improvement in verbal fluency with left-sided temporal surgery (27%) was found. Self-reported cognitive declines after epilepsy surgery were uncommon, and gains were reported in some domains where losses were found on objective tests (i.e., verbal memory and language). Variations in surgical techniques did not appear to have a large effect on cognitive outcomes, except for naming outcomes, which appeared better with more conservative resections. Sensitivity to postoperative changes differed across visual memory tests, but not verbal memory tests. Few conclusions could be made regarding cognitive risks and benefits of extratemporal epilepsy surgery, or of epilepsy surgery in children. Significance: In sum, epilepsy surgery is associated with specific cognitive changes, but may also improve cognition in some patients. The results provide base rate estimates of expected cognitive gains and losses associated with epilepsy surgery that may prove useful in clinical settings.

Combined analysis of risk factors for SUDEP.

Abstract: Summary Purpose: To pool data from four published case–control studies of sudden unexpected death in epilepsy (SUDEP) with live controls, to increase the power to determine risk factors. Methods: Case–control studies from the United States, Sweden, Scotland, and England were combined. SUDEP was defined as (1) a history of epilepsy (>1 epileptic seizure during a period of <5 years); (2) death occurring suddenly; (3) death unexpected (i.e., no life-threatening illness); and (4) death remained unexplained after all investigative efforts, including autopsy. Definite SUDEP required all criteria. Logistic regression analyses adjusted for study. Further analysis simultaneously adjusted for study, age at death, gender, and duration of epilepsy. Key Findings: Of the risk factors that could be analyzed across some or all studies, those that were statistically significant were increased frequency of generalized tonic–clonic seizures (GTCS), use of polytherapy, duration of epilepsy, young age at onset, gender, symptomatic etiology, and lamotrigine therapy. Results persisted when epilepsy onset was younger than 16 years and when it was 16 years or older. In univariate analysis, lamotrigine therapy was associated with significantly increased risk for SUDEP among individuals with idiopathic generalized epilepsy. Significance: This analysis refines the identification of people with epilepsy that are at particular risk of SUDEP. The emerging profile indicates that people with early onset refractory symptomatic epilepsy with frequent GTCS and antiepileptic drug (AED) polytherapy are at higher risk. The results suggest that reduction of the number of GTCS is a priority, of more importance than reducing the number of AEDs. The role of AEDs and other treatment should be analyzed further in future studies.

Seizure prediction with spectral power of EEG using cost-sensitive support vector machines

Abstract: Summary Purpose: We propose a patient-specific algorithm for seizure prediction using multiple features of spectral power from electroencephalogram (EEG) and support vector machine (SVM) classification. Methods: The proposed patient-specific algorithm consists of preprocessing, feature extraction, SVM classification, and postprocessing. Preprocessing removes artifacts of intracranial EEG recordings and they are further preprocessed in bipolar and/or time-differential methods. Features of spectral power of raw, or bipolar and/or time-differential intracranial EEG (iEEG) recordings in nine bands are extracted from a sliding 20-s–long and half-overlapped window. Nine bands are selected based on standard EEG frequency bands, but the wide gamma bands are split into four. Cost-sensitive SVMs are used for classification of preictal and interictal samples, and double cross-validation is used to achieve in-sample optimization and out-of-sample testing. We postprocess SVM classification outputs using the Kalman Filter and it removes sporadic and isolated false alarms. The algorithm has been tested on iEEG of 18 patients of 20 available in the Freiburg EEG database who had three or more seizure events. To investigate the discriminability of the features between preictal and interictal, we use the Kernel Fisher Discriminant analysis. Key findings: The proposed patient-specific algorithm for seizure prediction has achieved high sensitivity of 97.5% with total 80 seizure events and a low false alarm rate of 0.27 per hour and total false prediction times of 13.0% over a total of 433.2 interictal hours by bipolar preprocessing (92.5% sensitivity, a false positive rate of 0.20 per hour, and false prediction times of 9.5% by time-differential preprocessing). This high prediction rate demonstrates that seizures can be predicted by the patient-specific approach using linear features of spectral power and nonlinear classifiers. Bipolar and/or time-differential preprocessing significantly improves sensitivity and specificity. Spectral powers in high gamma bands are the most discriminating features between preictal and interictal. Significance: High sensitivity and specificity are achieved by nonlinear classification of linear features of spectral power. Power changes in certain frequency bands already demonstrated their possibilities for seizure prediction indicators, but we have demonstrated that combining those spectral power features and classifying them in a multivariate approach led to much higher prediction rates. Employing only linear features is advantageous, especially when it comes to an implantable device, because they can be computed rapidly with low power consumption.

Perampanel: a novel, orally active, noncompetitive AMPA-receptor antagonist that reduces seizure activity in rodent models of epilepsy.

Abstract: Summary Purpose: To assess the pharmacology of perampanel and its antiseizure activity in preclinical models. Perampanel [2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl) benzonitrile] is a novel, orally active, prospective antiepileptic agent currently in development for refractory partial-onset seizures. Methods: Perampanel pharmacology was assessed by examining changes in intracellular free Ca2+ ion concentration ([Ca2+]i) in primary rat cortical neurones, and [3H]perampanel binding to rat forebrain membranes. Antiseizure activity of orally administered perampanel was examined in amygdala-kindled rats and in mice exhibiting audiogenic, maximal electroshock (MES)–induced, pentylenetetrazole (PTZ) –induced, or 6 Hz-induced seizures. Key Findings: In cultured rat cortical neurones, perampanel inhibited α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)–induced increases in [Ca2+]i (IC50 93 nm vs. 2 μm AMPA). Perampanel had a minimal effect on N-methyl-d-aspartate (NMDA)–induced increases in [Ca2+]i, and only at a high concentration (30 μm). [3H]Perampanel binding to rat forebrain membranes was not significantly displaced by glutamate or AMPA but was displaced by the noncompetitive AMPA receptor antagonists CP465022 (Ki 11.2 ± 0.8 nm) and GYKI52466 (Ki 12.4 ± 1 μm). In mice, perampanel showed protective effects against audiogenic, MES-induced, and PTZ-induced seizures (ED50s 0.47, 1.6, and 0.94 mg/kg, respectively). Perampanel also inhibited 6 Hz electroshock-induced seizures when administered alone or in combination with other antiepileptic drugs (AEDs). In amygdala-kindled rats, perampanel significantly increased afterdischarge threshold (p < 0.05 vs. vehicle), and significantly reduced motor seizure duration, afterdischarge duration, and seizure severity recorded at 50% higher intensity than afterdischarge threshold current (p < 0.05 for all measures vs. vehicle). Perampanel caused dose-dependent motor impairment in both mice (TD50 1.8 mg/kg) and rats (TD50 9.14 mg/kg), as determined by rotarod tests. In mice, the protective index (TD50 in rotarod test/ED50 in seizure test) was 1.1, 3.8, and 1.9 for MES-induced, audiogenic, and PTZ-induced seizures, respectively. In rat, dog, and monkey, perampanel had a half-life of 1.67, 5.34, and 7.55 h and bioavailability of 46.1%, 53.5%, and 74.5%, respectively. Significance: These data suggest that perampanel is an orally active, noncompetitive, selective AMPA receptor antagonist with potential as a broad spectrum antiepileptic agent.

International consensus clinical practice statements for the treatment of neuropsychiatric conditions associated with epilepsy.

Abstract: In order to address the major impact on quality of life and epilepsy management caused by associated neuropsychiatric conditions, an international consensus group of epileptologists met with the aim of developing clear evidence-based and practice-based statements to provide guidance on the management of these conditions. Using a Delphi process, this group prioritized a list of key management areas. These included: depression, anxiety, psychotic disorders, nonepileptic seizures, cognitive dysfunction, antiepileptic drug (AED)-related neurobehavioral disorders, suicidality, disorders in children and adolescents, disorders in children with intellectual disability, and epilepsy surgery. Clinical practice statements were developed for each area and consensus reached among members of the group. The assessment and management of these conditions needs to combine knowledge of psychiatric disorders, knowledge of the impact of epilepsy and its treatment on psychopathology, and an ability to deliver care within epilepsy services. The aim of these statements is to provide guidance on quality care for people with epilepsy that have a range of neuropsychiatric disorders.

Graph analysis of epileptogenic networks in human partial epilepsy

Abstract: Historically, the epileptogenic zone in human partial epilepsy has been conceptually thought to consist of one or more discrete focal sources (Luders & Comair, 2001). Recently, alternative views of epileptic brain and ictogenesis (seizure generation) have been proposed, in that the ictal activity is thought to arise from the activity of epileptogenic cortical networks (Franaszczuk et al., 1994; Franaszczuk & Bergey, 1998; Baccala et al., 2004; Worrell et al., 2004; Jirsch et al., 2006; Kramer et al., 2008; Worrell et al., 2008). It is hypothesized that the activity of these networks, rather than a single focal “pacemaker,” is responsible for the initiation and propagation of the ictal activity. As a result, this has opened the door for potential novel therapies for medically intractable epilepsy through the disruption or inhibition of these epileptogenic networks. Techniques by which to identify and characterize these networks would, therefore, have a significant impact upon the medical treatment of these patients. The application of network topology measures has revolutionized the study of brain function in both physiologic and pathologic states (Stam & Reijneveld, 2007; Bullmore & Sporns, 2009). Through this work, a clearer picture has emerged regarding the basic properties underlying these brain networks, which are highly conserved among a variety of scales (Bullmore & Sporns, 2009). Disruptions of these networks have further been shown to exist in a range of neurologic disorders (Montoya et al., 2006; Stoffers et al., 2008; Hashimoto et al., 2009; Magnee, et al. 2009). In the study of epilepsy, graph theory techniques have been applied to the identification and characterization of the cortical networks giving rise to the ictal activity (Franaszczuk et al., 1994; Franaszczuk & Bergey, 1998; Baccala et al., 2004). Analysis of network connectivity in patients with epilepsy has been performed using functional data garnered from ECoG (Ortega et al., 2008a,b; Van Dellen et al., 2009), electroencephalography (EEG) (Ponten et al., 2009; Horstmann et al., 2010), magnetoencephalography (MEG) (Chavez et al., 2010), and functional magnetic resonance imaging (fMRI) (Zhang et al., 2009) measurements. These studies have demonstrated the existence of highly interconnected “hubs,” which may play a role in the initiation and propagation of the ictal activity by the epileptogenic networks (Morgan & Soltesz, 2008). Selective modulation of these hubs could, theoretically, prevent or abolish seizure activity without the need for removal of the entire network, which in turn could lead to better preoperative planning and more focused interventions. In this study, graph theoretic measures were applied to evaluate the local and global connectivity within the network. Examination of the network properties was performed during resting interictal periods as well as during interictal spikes, in order to determine whether the network properties observed during the ictal periods could also be observed during the interictal intervals. It was observed that the functional changes in the connectivity were correlated with the seizure onset zone (SOZ) and the activity of the cortical networks affiliated with these regions was also enhanced during interictal periods as well.

Predictors of health-related quality of life and costs in adults with epilepsy: a systematic review.

Abstract: Summary Purpose: Given the high burden of epilepsy on both health-related quality of life (HRQoL) and costs, identification of factors that are predictive of either reduced HRQoL or increased expenditure is central to the better future targeting and optimization of existing and emerging interventions and management strategies for epilepsy. Methods: Searches of Medline, Embase, and Cochrane Library (up to July 2010) to identify studies examining the association between demographic, psychosocial, and condition-related factors and HRQoL, resource utilization or costs in adults with epilepsy. For each study, predictor factor associations were summarized on the basis of statistical significance and direction; the results were then combined across studies. Key Findings: Ninety-three HRQoL and 16 resource utilization/cost studies were included. Increases in seizure frequency, seizure severity, level of depression, and level of anxiety and presence of comorbidity were strongly associated with reduced HRQoL. The majority of studies were cross-sectional in design and had an overall methodologic quality that was judged to be “moderate” for HRQoL studies and “poor” for health care resource or costs studies. In the 53 multivariate studies, age, gender, marital status, type of seizure, age at diagnosis, and duration of epilepsy did not appear to be associated with HRQoL, whereas the predictive influence of educational and employment status, number of antiepileptic drugs (AEDs) and AED side effects was unclear. The association between predictive factors and HRQoL appeared to be consistent across individuals whether refractory or seizures controlled or managed by AEDs. There were insufficient multivariate studies (five) to reliably comment on the predictors of resource utilization or cost in epilepsy. Significance: In addition to seizure control, effective epilepsy management requires the early detection of those most at risk of psychological dysfunction and comorbidity, and the targeting of appropriate interventions. There is need for more rigorous studies with appropriate multivariate statistical methods that prospectively investigate the predictors of HRQoL, resource utilization, and costs in epilepsy.

New concepts in classification of the epilepsies: Entering the 21st century

Abstract: SUMMARY Concepts and terminology for classifying seizures and epilepsies have, until recently, rested on ideas developed nearly a century ago. In order for clinical epilepsy and practice to benefit fully from the major technological and scientific advances of the last several years, advances that are revolutionizing our understanding and treatment of the epilepsies, it is necessary to break with the older vocabulary and approaches to classifying epilepsies and seizures. The Commission on Classification and Terminology made specific recommendations to move this process along and ensure that classification will reflect the best knowledge, will not be arbitrary, and will ultimately serve the purpose of improving clinical practice as well as research on many levels. The recommendations include new terms and concepts for etiology and seizure types as well as abandoning the 1989 classification structure and replacing it instead with a flexible multidimensional approach in which the most relevant features for a specific purpose can be emphasized. This is not a finished product and will take yet more time to achieve. Waiting any longer, however, would be a disservice to patient care and will continue the longstanding frustrations with the earlier system which, at this point in time, can be viewed as both antiquated and arbitrary.

The etiologic classification of epilepsy.

Abstract: The etiology of epilepsy is a major determinant of clinical course and prognosis, yet the current classifications of epilepsy do not list etiology in any detail. In this article, a classification (database) of the etiologies of epilepsy is proposed. In this scheme, the etiology of epilepsy is divided into four categories: idiopathic, symptomatic, provoked, and cryptogenic. These are defined and subcategories are proposed. A commentary addressing the following points is included: problems associated with assigning causation, symptomatic versus idiopathic epilepsy, focal versus generalized epilepsy, acquired epilepsy, acute symptomatic epilepsy, risk factor analysis, provoked epilepsy genetic and developmental epilepsy, and epilepsy as a disease not a symptom.

Inflammation in epilepsy: Clinical observations

Abstract: Over the past decade, an increasing number of observations indicate that activation of inflammatory processes occurs in variety of focal epilepsies. Understanding the feature and consequences of neuroinflammation, including the contribution to development and perpetuation of seizures, as well as to mood or cognitive dysfunction, is a major requisite for delineating its role in epilepsy. The present article discusses the most recent observations supporting the involvement of the inflammatory response in human focal epilepsy. It also evaluates emerging evidence concerning the possibility to identify epilepsy-associated inflammatory biomarkers in cerebrospinal fluid and serum, as well as the potential application of neuroimaging approaches to study the inflammatory reactions in chronic epilepsy patients in vivo, aiming to improve the recognition of appropriate patient populations who might benefit from antiinflammatory or immunomodulatory therapies.

Focal resection of fast ripples on extraoperative intracranial EEG improves seizure outcome in pediatric epilepsy

Abstract: Summary Purpose: High-frequency oscillations (HFOs), termed ripples at 80–200 Hz and fast ripples (FRs) at >200/250 Hz, recorded by intracranial electroencephalography (EEG), may be a valuable surrogate marker for the localization of the epileptogenic zone. We evaluated the relationship of the resection of focal brain regions containing high-rate interictal HFOs and the seizure-onset zone (SOZ) determined by visual EEG analysis with the postsurgical seizure outcome, using extraoperative intracranial EEG monitoring in pediatric patients and automated HFO detection. Methods: We retrospectively analyzed 28 pediatric epilepsy patients who underwent extraoperative intracranial video-EEG monitoring prior to focal resection. Utilizing the automated analysis, we identified interictal HFOs during 20 min of sleep EEG and determined the brain regions containing high-rate HFOs. We investigated spatial relationships between regions with high-rate HFOs and SOZs. We compared the size of these regions, the surgical resection, and the amount of the regions with high-rate HFOs/SOZs within the resection area with seizure outcome. Key Findings: Ten patients were completely seizure-free and 18 were not at 2 years after surgery. The brain regions with high-rate ripples were larger than those with high-rate FRs (p = 0.0011) with partial overlap. More complete resection of the regions with high-rate FRs significantly correlated with a better seizure outcome (p = 0.046). More complete resection of the regions with high-rate ripples tended to improve seizure outcome (p = 0.091); however, the resection of SOZ did not influence seizure outcome (p = 0.18). The size of surgical resection was not associated with seizure outcome (p = 0.22–0.39). Significance: The interictal high-rate FRs are a possible surrogate marker of the epileptogenic zone. Interictal ripples are not as specific a marker of the epileptogenic zone as interictal FRs. Resection of the brain regions with high-rate interictal FRs in addition to the SOZ may achieve a better seizure outcome.

Dravet syndrome: The long-term outcome

Abstract: Few studies focused on the long-term outcome of Dravet syndrome in adulthood are available in the literature, but all are concordant In this article, we consider the outcomes of 24 patients followed at the Centre Saint-Paul, Marseille, up to the age of 50, and compare them to the patients reported in the literature Five patients (208%) died, at a mean age of 248 years, one by status epilepticus, three by sudden unexpected death in epilepsy (SUDEP), and one of unknown cause Epileptic seizures tend to become less frequent and less severe after childhood Fever sensitivity (temperature variations) persists throughout the clinical course of DS, but its impact on seizure frequency and severity is milder than in infancy Generalized convulsive seizures, mostly reported as generalized tonic-clonic seizures (GTCS), were the only seizure type observed in almost all of the patients, often with a focal onset They are less frequent than in childhood and mostly nocturnal Some of these major convulsive seizures have less typical aspects, for example, bilateral or asymmetric tonic posturing, followed in some cases by a tonic vibratory state or clonic movements (Oguni et al, Brain Dev 2001;23:736-748; Akiyama et al, Epilepsia 2010;51:1043-1052) Other seizures like myoclonic seizures, atypical absences, and complex partial seizures (CPS) are less common in adulthood: Among our 24 patients, only 6 had atypical absences, and one myoclonic and one complex focal seizures Electroencephalography (EEG) also changes with age but is still multiple and heterogenous, interictally and ictally Photosensitivity and pattern sensitivity also showed a tendency to disappear before the age of 20 Motor abnormalities are common Cerebellar features, including ataxia, dysarthria, intention tremor, and eye movement disorder, become more prominent Walking is markedly impaired, often due to orthopedic signs such as kyphosis, kyphoscoliosis, flat feet, or claw feet This symptomatology was minor during childhood and worsened during and after adolescence, despite physiotherapy Mental retardation ranged from moderate to severe, with predominance of language impairment, and some patients had a major personality disorder, labeled autistic or psychotic Dependency in adulthood is nearly constant: Only 3 of our 24 adult patients lived independently

Determinants of health-related quality of life in pharmacoresistant epilepsy: results from a large multicenter study of consecutively enrolled patients using validated quantitative assessments.

Abstract: Summary Purpose: To evaluate the relative contribution of demographic and epilepsy-related variables, depressive symptoms, and adverse effects (AEs) of antiepileptic drugs (AEDs) to health-related quality of life (HRQOL) in adults with pharmacoresistant epilepsy. Methods: Individuals with epilepsy whose seizures failed to respond to at least one AED were enrolled consecutively at 11 tertiary referral centers. HRQOL was assessed by the Quality of Life in Epilepsy Inventory-31 (QOLIE-31), AEs by the Adverse Event Profile (AEP), and depressive symptoms by the Beck Depression Inventory-II (BDI-II). Multivariate linear regression models were used to identify variables associated with QOLIE-31 total score and subscale scores. Key Findings: Of 933 enrolled individuals aged 16 years or older, 809 (87%) were able to complete the self-assessment instruments and were included in the analysis. Overall, 61% of the variance in QOLIE-31 scores was explained by the final model. The strongest predictors of HRQOL were AEP total scores (β = −0.451, p < 0.001) and BDI-II scores (β = −0.398, p < 0.001). These factors were also the strongest predictors of scores in each of the seven QOLIE-31 subscales. Other predictors of HRQOL were age (β = −0.060, p = 0.008), lack of a driving license (β = −0.053, p = 0.018), pharmacoresistance grade, with higher HRQOL in individuals who had failed only one AED (β = 0.066, p = 0.004), and location of the enrolling center. Epilepsy-related variables (seizure frequency, occurrence of tonic–clonic seizures, age of epilepsy onset, disease duration) and number of AEDs had no significant predictive value on HRQOL. The AEP total score was the strongest negative predictor of HRQOL in the subgroup of 362 patients without depressive symptoms (BDI-II score <10), but even in this subgroup the BDI-II score was retained as a significant predictor. Significance: In individuals with pharmacoresistant epilepsy, AEs of medication and depressive symptoms are far more important determinants of HRQOL than seizures themselves. When seizure freedom cannot be achieved, addressing depressive comorbidity and reducing the burden of AED toxicity is likely to be far more beneficial than interventions aimed at reducing the frequency of seizures.

Febrile infection-related epilepsy syndrome (FIRES): pathogenesis, treatment, and outcome: a multicenter study on 77 children.

Abstract: SUMMARY Purpose: To explore the correlations between treatment modalities and selected disease parameters with outcome in febrile infection–related epilepsy syndrome (FIRES), a catastrophic epileptic encephalopathy with a yet undefined etiology. Methods: We conducted a retrospective multicenter study on children who had been included in eight studies published between November 2001 and July 2010. Additional data were retrieved from six of the eight participating centers. Key Findings: The 77 enrolled patients presented with prolonged refractory status epilepticus. A preceding febrile infection had been reported in 96% of them. Treatment modalities included antiepileptic drugs (a median of six), intravenous immunoglobulin (IVIG, 30 patients), steroids (29 patients), burst-suppression coma (BSC, 46 patients), and other less conventional agents. There was no evidence of efficacy for those treatment modalities except for IVIG (two patients), a ketogenic diet (one patient), and a prolonged cycle of barbiturate anesthesia coma (one patient). Nine patients (11.7%) died during the acute phase of FIRES. Only 12 of the 68 surviving patients (18%) retained normal cognitive level, but most of them had learning disabilities. Sixty-three patients (93%) had refractory epilepsy at follow-up. Cognitive levels at follow-up were significantly associated with duration of BSC (p = 0.005) and younger age at FIRES onset (p = 0.02). Significance: The outcome of FIRES is poor. No therapeutic agent was efficacious in shortening the acute phase, with the possible exception of a ketogenic diet. Treatment by inducing a prolonged BSC was associated with a worse cognitive outcome.

The genetics of Dravet syndrome

Abstract: Dravet syndrome (DS), otherwise known as severe myoclonic epilepsy of infancy (SMEI), is an epileptic encephalopathy presenting in the first year of life. DS has a genetic etiology: between 70% and 80% of patients carry sodium channel α1 subunit gene (SCN1A) abnormalities, and truncating mutations account for about 40% and have a significant correlation with an earlier age of seizures onset. The remaining SCN1A mutations comprise splice-site and missense mutations, most of which fall into the pore-forming region of the sodium channel. Mutations are randomly distributed across the SCN1A protein. Most mutations are de novo, but familial SCN1A mutations also occur. Somatic mosaic mutations have also been reported in some patients and might explain the phenotypical variability seen in some familial cases. SCN1A exons deletions or chromosomal rearrangements involving SCN1A and contiguous genes are also detectable in about 2-3% of patients. A small percentage of female patients with a DS-like phenotype might carry PCDH19 mutations. Rare mutations have been identified in the GABARG2 and SCN1B genes. The etiology of about 20% of DS patients remains unknown, and additional genes are likely to be implicated.

A perfect storm: Converging paths of epilepsy and Alzheimer's dementia intersect in the hippocampal formation.

Abstract: Seizures in the human temporal lobe transiently impair cognition and steadily damage hippocampal circuitry, leading to progressive memory loss. Similarly, the toxic accumulation of Aβ peptides underlying Alzheimer's disease (AD) triggers synaptic degeneration, circuit remodeling, and abnormal synchronization within the same networks. Because neuronal hyperexcitability amplifies the synaptic release of Aβ, seizures create a vicious spiral that accelerates cell death and cognitive decline in the AD brain. The confluence of hyperexcitability and excitotoxicity, combined with the challenge of seizure detection in the human hippocampus, make epilepsy in these individuals extremely important to correctly diagnose and treat. Emerging clinical evidence reveals an elevated comorbidity of epilepsy in AD, particularly when linked to mutations in the APP/Aβ gene pathway. Experimental models in genetically engineered mice confirm and extend these findings, highlighting the presence of subclinical seizures and overlapping pathophysiologic cascades. There is an urgent need for more clinical and basic investigation to improve the early recognition of hippocampal seizures arising during the course of dementing disorders, and to validate molecular blockers of Aβ-induced aberrant excitability that can slow and potentially reverse the progression of cognitive decline.

The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway

Abstract: The ketogenic diet (KD) is an effective treatment for epilepsy, but its mechanisms of action are poorly understood. We investigated the hypothesis that the KD inhibits mammalian target of rapamycin (mTOR) pathway signaling. The expression of pS6 and pAkt, markers of mTOR pathway activation, was reduced in hippocampus and liver of rats fed KD. In the kainate model of epilepsy, KD blocked the hippocampal pS6 elevation that occurs after status epilepticus. Because mTOR signaling has been implicated in epileptogenesis, these results suggest that the KD may have anticonvulsant or antiepileptogenic actions via mTOR pathway inhibition.

Comorbidities of epilepsy: results from the Epilepsy Comorbidities and Health (EPIC) survey.

Abstract: Summary Purpose: To estimate the prevalence of neuropsychiatric and pain disorders in adults with epilepsy in the United States. Methods: In 2008, an 11-item survey including validated questions to screen for a lifetime history of epilepsy was mailed to 340,000 households from two national panels selected to be generally representative of the noninstitutionalized U.S. population. Information on epilepsy and other disorders was collected from 172,959 respondents aged 18 or older. Propensity scoring was used to match respondents with and without epilepsy on baseline characteristics and risk factors for epilepsy. Prevalence ratios (PRs) of comorbidities in respondents with epilepsy were calculated using log-binomial generalized linear models. Comorbidities were categorized as neuropsychiatric (anxiety, depression, bipolar disorder, attention-deficit/hyperactivity disorder, sleep disorder/apnea, and movement disorder/tremor), pain (migraine headache, chronic pain, fibromyalgia, neuropathic pain), and other (asthma, diabetes, and high blood pressure). Key Findings: Two percent (3,488) of respondents reported ever having been told they had epilepsy or a seizure disorder. Respondents with self-reported epilepsy were more likely (p < 0.001) than those without epilepsy to report all six neuropsychiatric disorders (PR from 1.27–2.39), all four pain disorders (PR 1.36–1.96), and asthma (PR 1.25). Significance: Neuropsychiatric conditions and pain disorder comorbidities were reported more often in individuals with self-reported epilepsy than in those without epilepsy. Identification of these conditions is an important consideration in the clinical management of epilepsy.

The effect of lead time to treatment and of age of onset on developmental outcome at 4 years in infantile spasms: Evidence from the United Kingdom Infantile Spasms Study

Abstract: Summary Purpose: Infantile spasms is a severe infantile seizure disorder. Several factors affect developmental outcome, especially the underlying etiology of the spasms. Treatment also affects outcome. Both age at onset of spasms and lead time to treatment (the time from onset of spasms to start of treatment) may be important. We investigated these factors. Methods: Developmental assessment using Vineland Adaptive Behaviour Scales (VABS) at 4 years of age in infants enrolled in the United Kingdom Infantile Spasms Study. Date of or age at onset of spasms was obtained prospectively. Lead time to treatment was then categorized into five categories. The effects of lead time to treatment, age of onset of spasms, etiology, and treatment on developmental outcome were investigated using multiple linear regression. Key Findings: Age of onset ranged (77 infants) from 2 months in 21 and not known in 6. Each month of reduction in age at onset of spasms was associated with a 3.1 [95% confidence interval (CI) 0.64–5.5, p = 0.03] decrease, and each increase in category of lead time duration associated with a 3.9 (95% CI 7.3–0.4, p = 0.014) decrease in VABS, respectively. There was a significant interaction between treatment allocation and etiology with the benefit in VABS in those allocated steroid therapy being in children with no identified etiology (coefficient 29.9, p = 0.004). Significance: Both prompt diagnosis and prompt treatment of infantile spasms may help prevent subsequent developmental delay. Younger infants may be more at risk from the epileptic encephalopathy than older infants.

The serotonin axis: Shared mechanisms in seizures, depression and SUDEP

Abstract: There is a growing appreciation that patients with seizures are also affected by a number of comorbid conditions, including an increase in prevalence of depression (Kanner, 2009), sleep apnea (Chihorek et al., 2007), and sudden death (Ryvlin et al., 2006; Tomson et al., 2008). The mechanisms responsible for these associations are unclear. Herein we discuss the possibility that underlying pathology in the serotonin (5-HT) system of patients with epilepsy lowers the threshold for seizures, while also increasing the risk of depression and sudden death. We propose that postictal dysfunction of 5-HT neurons causes depression of breathing and arousal in some epilepsy patients, and this can lead to sudden unexpected death in epilepsy (SUDEP). We further draw parallels between SUDEP and sudden infant death syndrome (SIDS), which may share pathophysiologic mechanisms, and which have both been linked to defects in the 5-HT system.

Depression and epilepsy: A bidirectional relation?

Abstract: A bidirectional relation between depressive disorders and epilepsy has been suggested by several population-based studies and is supported by experimental studies. This article reviews the potential pathogenic mechanisms operant in both disorders that may explain such a relation. These mechanisms include a hyperactive hypothalamic-pituitary-adrenal (HPA) axis and its neuroanatomic and neuropathologic complications, as well as disturbances in serotonergic, noradrenergic, γ-aminobutyric acid (GABA)ergic and glutamatergic neurotransmitter systems, all of which may be interrelated.

Definition and natural history of Lennox-Gastaut syndrome.

Abstract: Lennox-Gastaut syndrome (LGS) is a rare epileptic encephalopathy with a peak age of onset of 3-5 years of age. Reported prevalence rates for LGS vary widely from 1-10% of all childhood epilepsies. Incidence rates are much lower. LGS is characterized by intractable, multiple, generalized seizure types and an interictal electroencephalogram showing bursts of slow spike-and-wave, paroxysmal bursts of generalized polyspikes, and a slow background. All patients have tonic seizures during sleep that may be subtle, and nearly all have treatment-resistant, lifelong epilepsy. Cognitive stagnation and behavioral problems are seen in almost all patients and lead to a life of dependency. The differential diagnosis includes other symptomatic generalized epilepsies and pseudo-Lennox syndrome. Misdiagnosis is common. Children and adults with LGS have an enormous impact on their families, and efforts to improve the quality of life for these patients are complex.

The adverse event profile of pregabalin: A systematic review and meta‐analysis of randomized controlled trials

Abstract: Summary Purpose: Despite the widespread use of antiepileptic drugs (AEDs) across different neurologic and psychiatric disorders, no study has systematically reviewed all available randomized controlled trials (RCTs) of a given AED to fully uncover its tolerability profile. We aimed at identifying treatment emergent adverse events (AEs) associated with pregabalin through a systematic review and meta-analysis of all available RCTs. We also assessed the association between serious AEs and pregabalin, and investigated whether pregabalin AEs display a dose–response relationship. Methods: We searched MEDLINE, EMBASE, and Cochrane CENTRAL to February 2010 for RCTs. Additional studies were identified from reference lists of retrieved papers and from online clinical databases. We selected placebo-controlled, double-blind RCTs investigating the therapeutic effects of pregabalin in adults with any condition. Studies had to include at least 20 subjects per arm and have a duration of at least 4 weeks. AEs were assessed for their association with pregabalin after identification/exclusion of synonyms, rare AEs, and nonassessable AEs due to methodologic limitations. We used relative risks (RRs) to assess the association of any [99% confidence intervals (CIs)] or serious AEs (95% CIs) with pregabalin, and risk differences (RDs, 95% CIs) to investigate dose–response relationships of pregabalin AEs. Key findings: Thirty-eight RCTs were included in our study. Of 39 AEs, 20 (51%) were significantly associated with pregabalin (dizziness, vertigo, incoordination, balance disorder, ataxia, diplopia, blurred vision, amblyopia, tremor, somnolence, confusional state, disturbance in attention, thinking abnormal, euphoria, asthenia, fatigue, edema, peripheral edema, dry mouth, constipation). The highest RRs were found for cognition/coordination AEs. There was no significant association between serious AEs and pregabalin. There was a selective dose–response pattern in the onset of pregabalin AEs, with certain AEs appearing at lower doses than others. Significance: Individuals starting treatment with pregabalin are at increased risk for several AEs, particularly those affecting cognition/coordination. Pregabalin AEs appear according to a selective dose–response pattern, possibly reflecting the severity of dysfunction of distinct anatomic structures. These findings may aid clinicians in providing better patient management, and support the value of including in meta-analyses of AED tolerability profiles RCTs performed in different conditions.

Second‐line status epilepticus treatment: Comparison of phenytoin, valproate, and levetiracetam

Abstract: Purpose Phenytoin (PHT), valproic acid (VPA), or levetiracetam (LEV) are commonly used as second-line treatment of status epilepticus (SE), but comparative studies are not available. Methods Among 279 adult SE episodes identified prospectively in our tertiary care hospital over 4 years, we retrospectively identified 187 episodes in which PHT, VPA, or LEV were given after benzodiazepines. Patients with postanoxic SE were not included. Demographics, clinical SE features, failure of second-line treatment to control SE, new handicap, and mortality at hospital discharge were assessed. Uni- and multivariable statistical analyses were applied to compare the three agents. Key findings Each compound was used in about one third of SE episodes. VPA failed to control SE in 25.4%, PHT in 41.4%, and LEV in 48.3% of episodes in which these were prescribed. A deadly etiology was more frequent in the VPA group, whereas SE episodes tended to be more severe in the PHT group. After adjustment for these known SE outcome predictors, LEV failed more often than VPA [odds ratio (OR) 2.69; 95% confidence interval (CI) 1.19-6.08]; 16.8% (95% CI: 6.0-31.4%) of second-line treatment failures could be attributed to LEV. PHT was not statistically different from the other two compounds. Second-line treatment did not seem to influence new handicap and mortality, whereas etiology and the SE Severity Score (STESS) were robust independent predictors. Significance Even without significant differences on outcome at discharge, LEV seems less efficient than VPA to control SE after benzodiazepines. A prospective comparative trial is needed to address this potentially concerning finding.

Epilepsy, cognition, and behavior: The clinical picture.

Abstract: Although epilepsy is defined by the occurrence of spontaneous epileptic seizures, a large body of evidence indicates that epilepsy is linked to a spectrum of behavioral, psychiatric, and cognitive disorders as well as to sudden death. Explanations for these associations include the following: (1) The effects of structural lesions that may impair the functions subserved by the regions of the brain involved in the lesion. (2) The effects of seizure activity that may begin well before a clinical seizure occurs and may persist long after it is over, raising questions about what truly constitutes "interictal." In addition, encephalopathic effects of epilepsy in infancy during critical periods in development may be particularly severe and potentially irreversible. (3) Shared mechanisms underlying seizures as well as these other disorders in the absence of structural lesions or separate diseases of the central nervous system (CNS). Epidemiologic and clinical studies demonstrate the elevated risk of cognitive, psychiatric, and behavioral disorders not just during but also prior to the onset of epilepsy (seizures) itself. These may outlast the active phase of epilepsy as well. The mounting evidence argues strongly for the recognition of epilepsy as part of a spectrum of disorders and against the notion that even uncomplicated epilepsy can a priori be considered benign.

Molecular cascades that mediate the influence of inflammation on epilepsy.

Abstract: Experimental evidence strongly indicates a significant role for inflammatory and immune mediators in initiation of seizures and epileptogenesis. Here we will summarize data supporting the involvement of IL-1β, TNF-α and toll-like receptor 4 in seizure generation and the process of epileptogenesis. The physiological homeostasis and control over brain immune response depends on the integrity of the blood-brain barrier, transforming growth factor (TGF)-β signaling and leukocyte migration. To what extent targeting the immune system is successful in preventing epileptogenesis, and which signaling pathway should be beleaguered is still under intensive research.