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BackgroundPeople with epilepsy have more concomitant medical conditions than the general population; these comorbidities play an important role in premature mortality. We sought to generate explanatory hypotheses about the co-occurrence of somatic comorbidities and epilepsy, avoiding causal and treatment-resultant biases.MethodsWe collected clinical, demographic and somatic comorbidity data for 2016 consecutive adults with epilepsy undergoing assessment at a tertiary centre and in 1278 people with epilepsy in the community. Underlying causes of epilepsy were not classed as comorbidities.ResultsSomatic comorbidities were more frequent in the referral centre (49%) where people more frequently had active epilepsy than in the community (36%). Consistent risk factors for comorbidities were found in both cohorts. Using multivariable ordinal regression adjusted for age, longer epilepsy duration and an underlying brain lesion were independently associated with a smaller burden of somatic conditions. The treatment burden, measured by the number of drugs to which people were exposed, was not an independent predictor. Shorter epilepsy duration was a predictor for conditions that conceivably harbour significant mortality risks.ConclusionsSomatic comorbidities do not occur randomly in relation to epilepsy; having more severe epilepsy seems to be a risk factor. Independently from age, the early period after epilepsy onset appears to be at particular risk, although it is not clear whether this relates to an early mortality or to a later decrease in the burden of comorbidities. These results suggest that, for some people, epilepsy should be considered a systemic condition not limited to the CNS.

It is not fully understood how seizures terminate and why some seizures are followed by a period of complete brain activity suppression, postictal generalized EEG suppression. This is clinically relevant as there is a potential association between postictal generalized EEG suppression, cardiorespiratory arrest and sudden death following a seizure. We combined human encephalographic seizure data with data of a computational model of seizures to elucidate the neuronal network dynamics underlying seizure termination and the postictal generalized EEG suppression state. A multi-unit computational neural mass model of epileptic seizure termination and postictal recovery was developed. The model provided three predictions that were validated in EEG recordings of 48 convulsive seizures from 48 subjects with refractory focal epilepsy (20 females, age range 15-61 years). The duration of ictal and postictal generalized EEG suppression periods in human EEG followed a gamma probability distribution indicative of a deterministic process (shape parameter 2.6 and 1.5, respectively) as predicted by the model. In the model and in humans, the time between two clonic bursts increased exponentially from the start of the clonic phase of the seizure. The terminal interclonic interval, calculated using the projected terminal value of the log-linear fit of the clonic frequency decrease was correlated with the presence and duration of postictal suppression. The projected terminal interclonic interval explained 41% of the variation in postictal generalized EEG suppression duration (P < 0.02). Conversely, postictal generalized EEG suppression duration explained 34% of the variation in the last interclonic interval duration. Our findings suggest that postictal generalized EEG suppression is a separate brain state and that seizure termination is a plastic and autonomous process, reflected in increased duration of interclonic intervals that determine the duration of postictal generalized EEG suppression.

Summary Objectives The epilepsy treatment gap is large in low‐ and middle‐income countries, but the reasons behind nonadherence to treatment with antiepileptic drugs (AEDs) across African countries remain unclear. We investigated the extent to which AEDs are not taken and associated factors in people with active convulsive epilepsy (ACE) identified in cross‐sectional studies conducted in five African countries. Methods We approached 2,192 people with a confirmed diagnosis of ACE for consent to give blood voluntarily. Participants were asked if they were taking AEDs, and plasma drug concentrations were measured using a fluorescence polarization immunoassay analyzer. Information about possible risk factors was collected using questionnaire‐based clinical interviews. We determined factors associated with nonadherence to AED treatment in children and adults, as measured by detectable and optimal levels, using multilevel logistic regression. Results In 1,303 samples assayed (43.7% were children), AEDs were detected in 482, but only 287 had optimal levels. Of the 1,303 samples, 532 (40.8%) were from people who had reported they were on AEDs. The overall prevalence of nonadherence to treatment was 63.1% (95% confidence interval [CI] 60.5–65.6%) as measured by detectable AED levels and 79.1% (95% CI 73.3–84.3%) as measured by optimal AED levels; self‐reported nonadherence was 65.1% (95% CI 45.0–79.5%). Nonadherence was significantly (p

Diets that increase production of ketone bodies to provide alternative fuel for the brain are evolving from the classic ketogenic diet for epilepsy devised nearly a century ago. The classic ketogenic diet and its more recent variants all appear to have similar efficacy with approximately 50% of users showing a greater than 50% seizure reduction. They all require significant medical and dietetic support, and there are tolerability issues. A review suggests that low-grade chronic metabolic acidosis associated with ketosis is likely to be an important contributor to the short term and long term adverse effects of ketogenic diets. Recent studies, particularly with the characterization of the acid sensing ion channels, suggest that chronic metabolic acidosis may increase the propensity for seizures. It is also known that low-grade chronic metabolic acidosis has a broad range of negative health effects and an increased risk of early mortality in the general population. The modified ketogenic dietary treatment we propose is formulated to limit acidosis by measures that include monitoring protein intake and maximizing consumption of alkaline mineral-rich, low carbohydrate green vegetables. We hypothesize that this acidosis-sparing ketogenic diet is expected to be associated with less adverse effects and improved efficacy. A case history of life-long intractable epilepsy shows this diet to be a successful long-term strategy but, clearly, clinical studies are needed.

Background Epilepsy is a public health issue in sub-Saharan Africa (SSA) where many people with the condition receive no treatment. Health-care services for epilepsy in this region have not been comprehensively assessed. We examined key features of epilepsy health services provided in SSA. Methodology This was a scoping review conducted using pre-specified protocols. We implemented an electronic search strategy to identify relevant citations using PUBMED, EMBASE, Web of Science, Scopus, Cumulative Index to Nursing and Allied Health Literature (CINAHL), African Index Medicus (AIM), Open Grey, Cochrane database, and Google Scholar. Articles eligible for full-text review were screened and data of interest were reported. Result The search identified 81 eligible articles, forty-nine from East Africa, 19 from West Africa, 8 from South Africa, and 5 from Central Africa. A variety of care services were identified, with reporting of rural epilepsy care in 75% of retrieved articles mainly from East and South African countries. The majority of the rural epilepsy clinics were health worker- or nurse-led, reporting good seizure control in about two-thirds of patients using phenobarbital as the most commonly prescribed antiepileptic drug. Funding for rural epilepsy care came mainly from external donor agencies. Conclusion We attempted to provide a ‘snapshot’ of epilepsy care services in SSA. The successes achieved in some of the centers are due to the use of existing primary health-care systems and employing non-physician health-care personnel. The true picture of epilepsy care coverage is not apparent due to the lack of data and proper health system structure in most parts of SSA. As more individuals begin to receive care, the long-term funding for epilepsy care in African countries will depend on the commitment of their respective governments. Watila, Musa M., et al. "Health service provision for people with epilepsy in sub-Saharan Africa: A situational review." Epilepsy & Behavior 70 (2017): 24-32. © 2017. This manuscript version is made available under the CC-BY-NC-ND 4.0 license.

Cardiovascular (CV) comorbidities are common in people with epilepsy. Several mechanisms explain why these conditions tend to co-exist including causal associations, shared risk factors and those resulting from epilepsy or its treatment. Various arrhythmias occurring during and after seizures have been described. Ictal asystole is the most common cause. The converse phenomenon, arrhythmias causing seizures, appears extremely rare and has only been reported in children following cardioinihibitory syncope. Arrhythmias in epilepsy may not only result from seizure activity but also from a shared genetic susceptibility. Various cardiac and epilepsy genes could be implicated but firm evidence is still lacking. Several antiepileptic drugs (AEDs) triggering conduction abnormalities can also explain the co-existence of arrhythmias in epilepsy. Epidemiological studies have consistently shown that people with epilepsy have a higher prevalence of structural cardiac disease and a poorer CV risk profile than those without epilepsy. Shared CV risk factors, genetics and etiological factors can account for a significant part of the relationship between epilepsy and structural cardiac disease. Seizure activity may cause transient myocardial ischaemia and the Takotsubo syndrome. Additionally, certain AEDs may themselves negatively affect CV risk profile in epilepsy. Here we discuss the fascinating borderland of epilepsy and cardiovascular conditions. The review focuses on epidemiology, clinical presentations and possible mechanisms for shared pathophysiology. It concludes with a discussion of future developments and a call for validated screening instruments and guidelines aiding the early identification and treatment of CV comorbidity in epilepsy.

Rationale Observational data on antiepileptic drugs (AEDs) inform about their use in clinical practice. We describe our clinical experience with perampanel (PER) in a large UK tertiary epilepsy center. Methods Adults initiated on PER between October 2012 and March 2015 were followed until they discontinued PER or 10 September 2016. Data on epilepsy syndrome, duration, seizure types, concomitant and previous AED use, PER dosing, efficacy and side effects were recorded. Efficacy was categorized as temporary or ongoing (at last follow-up) seizure freedom, ≥ 50% seizure reduction, or other benefit (e.g. No convulsions or daytime seizures). These categories were mutually exclusive except for people with temporary seizure freedom. Results 391 received a PER prescription, five of whom never took it. No follow-up data were available for ten. 83% had focal epilepsy. People were prescribed PER in addition to 1–7 (Interquartile range [IQR] 2, 2, 3) AEDs and had previously used up to 18 (IQR 5, 7, 10) AEDs. Total exposure was 639 patient/years. Retention rates were 60.4% at one year, 48.3% at two years, and 42.7% at three years. 19 (5%) people reported seizure free periods lasting at least six months. A ≥ 50% reduction in seizures lasting at least six months was reported by 76 people (20%), and marked improvement for ≥ 6 months was seen in 52 (14%). Five (1%) were taken off other AEDs and continued on PER monotherapy for 4–27 months. Seizures were aggravated in 57 (15%). Somatic side effects were reported by 197 (52%), mostly CNS. Mood changes, irritability or challenging behavior were reported by 137 (36%). PER was discontinued by 211 (56%) due to adverse effects (39%), inefficacy (26%), or both (35%). No idiosyncratic adverse events were seen. Conclusion PER resulted in some benefit in 40% of those exposed. Adverse effects on mental health and on balance were common and should be discussed with people before initiating PER.

Objective:To determine the incidence rates of sudden unexpected death in epilepsy (SUDEP) in different epilepsy populations and address the question of whether risk factors for SUDEP have been identified.Methods:Systematic review of evidence; modified Grading Recommendations Assessment, Development, and Evaluation process for developing conclusions; recommendations developed by consensus.Results:Findings for incidence rates based on 12 Class I studies include the following: SUDEP risk in children with epilepsy (aged 0–17 years) is 0.22/1,000 patient-years (95% confidence interval [CI] 0.16–0.31) (moderate confidence in evidence). SUDEP risk increases in adults to 1.2/1,000 patient-years (95% CI 0.64–2.32) (low confidence in evidence). The major risk factor for SUDEP is the occurrence of generalized tonic-clonic seizures (GTCS); the SUDEP risk increases in association with increasing frequency of GTCS occurrence (high confidence in evidence).Recommendations:Level B: Clinicians caring for young children with epilepsy should inform parents/guardians that in 1 year, SUDEP typically affects 1 in 4,500 children; therefore, 4,499 of 4,500 children will not be affected. Clinicians should inform adult patients with epilepsy that SUDEP typically affects 1 in 1,000 adults with epilepsy per year; therefore, annually 999 of 1,000 adults will not be affected. For persons with epilepsy who continue to experience GTCS, clinicians should continue to actively manage epilepsy therapies to reduce seizures and SUDEP risk while incorporating patient preferences and weighing the risks and benefits of any new approach. Clinicians should inform persons with epilepsy that seizure freedom, particularly freedom from GTCS, is strongly associated with decreased SUDEP risk.

OBJECTIVE Lacosamide (LCM), a new antiepileptic drug (AED) approved as adjunctive therapy for the treatment of patients with partial-onset seizures, has limited pharmacokinetic and drug interaction data. The main objectives of the present study were to investigate the effects of dose, age, gender, and hepatic enzyme-inducing AEDs on the pharmacokinetics of LCM as assessed by steady state serum LCM values. METHODS An LCM AED therapeutic drug monitoring database was analyzed with regard to LCM serum concentrations and other relevant patient and AED drug information. One hundred twenty eight sera were identified. These were collected from 68 women and 61 men aged 19-66 years, who were prescribed a median LCM dose of 300 mg (range 50-600 mg). RESULTS Serum LCM concentrations were observed in the following main groupings: LCM monotherapy (n = 5), LCM with nonenzyme-inducing AEDs (n = 50), LCM with enzyme-inducing AEDs (n = 49), LCM with valproic acid (n = 20), and LCM with enzyme-inducing AEDs plus valproic acid (n = 4). Analysis of variance showed a correlation of dose with LCM concentrations (r = 0.53, P < 0.001), and women had statistically higher mean LCM concentration than did men, 37.2 ± 23.6 versus 26.8 ± 12.9 μmol/L (P = 0.001). Serum LCM concentrations were significantly lower (P = 0.002) in the enzyme-inducing AED group (carbamazepine and phenytoin) compared with the LCM monotherapy group and the nonenzyme-inducing group, 23.5 ± 11.0, 34.5 ± 7.7, and 32.7 ± 17.9 μmol/L, respectively. CONCLUSIONS Serum LCM concentrations increased dose dependently, were age independent, and were higher in women compared with men. Carbamazepine and phenytoin can significantly decrease serum LCM concentrations, probably via induction of LCM metabolism.

Purpose We aimed to assess and compare the psychometric properties of the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E), Hospital Anxiety and Depression Scale Depression Subscale (HADS-D), and Beck Depression Inventory (BDI) as screening instruments for depression and suicidality in people with epilepsy. Methods One hundred twenty-six people (54% women) diagnosed with epilepsy were recruited and evaluated on their sociodemographic and clinical features. Depression and suicide risk were assessed with a structured psychiatric interview, the Mini International Neuropsychiatric Interview (MINI-Plus), and the performance of NDDI-E, HADS-D, and BDI was evaluated. Results The sensitivity and specificity of BDI for the diagnosis of depression was around 90%; HADS-D and NDDI-E have sensitivity higher than 80%, and specificity was greater than 75%. For identifying suicide risk, the NDDI-E sensitivity was 92.9%, and HADS-D sensitivity was 85.7%, and a reasonable specificity (68%) was observed for both instruments. All instruments showed a negative predictive value of over 90%. Comparisons of the areas under the ROC curve for these instruments were not significantly different regarding depression or moderate/severe risk of suicide. Conclusion All three instruments evaluated have clinical utility in the screening of depression in people with epilepsy. Both NDDI-E and HADS-D are brief efficient screening instruments to identify depression in people with epilepsy. The BDI is a more robust instrument, but it takes longer to apply, which hampers its use by busy clinicians and by people with cognitive impairment.

Little published information exists about the management of dental treatment procedures for people with epilepsy who, despite their medication, continue to have seizures. This paper draws on relevant literature in neurology and anaesthetics to provide a multi-speciality consensus on methods of assessment and adjunctive treatment options in order to manage the risk of a clinically significant seizure occurring during a procedure. It aims to enhance current guidelines and practice in the provision of specialist care for this diverse group.

Mortality in people with epilepsy has not previously been estimated in Georgia. We identified a prevalent cohort of people with epilepsy from a tertiary referral centre in Tbilisi, Georgia and attempted to establish survivorship status for all. One-way sensitivity analysis estimating mortality rates in those lost to follow-up was also used. Of 1952 people, 1250 (64%) were located; 93 (7%) had died over a median of 11 years follow up. The main cause specific Proportional Mortality Ratios were: underlying diseases (39%) and accidental death (9%). One SUDEP was confirmed with a further 4 possible, but the cause of death was unknown in 47%. The overall SMR was 1.4, with much higher SMRs (up to 12) in young people. The sensitivity analysis suggested an SMR of 3.0.

Background There have been inconsistent reports on the potential association between diabetes mellitus and epilepsy. Methods We examined a consecutive cohort of 2016 people with pharmacoresistant epilepsy admitted to a tertiary medical centre. Results We identified 20 individuals with type 1 diabetes mellitus (T1DM); a point prevalence of 9.9 (95% CI: 6.4, 15.3) cases per 1000 individuals. This represents a more than two-fold increase relative to published prevalence estimates of T1DM in the general population. The onset of T1DM preceded that of epilepsy in 80% of individuals, by a median of 1.5 years. Individuals with T1DM were significantly more likely to have cryptogenic/unknown epilepsy relative to those with type 2 diabetes mellitus or without diabetes (85% versus 35% and 49%, p =0.045). All individuals with T1DM had focal epilepsy, the majority of which were temporal lobe in origin, although there was no evidence that this proportion was any different from those without T1DM ( p >0.999). Conclusions The prevalence of T1DM appears to be increased in people with pharmacoresistant epilepsy and is associated with cryptogenic/unknown epilepsy. These findings may have pathophysiological implications, especially in the context of anti-glutamic acid decarboxylase antibodies.

Age as well as estrogen levels may have an impact on the pharmacokinetics of lamotrigine (LTG) and monohydroxycarbazepine (MHD), the active metabolite of oxcarbazepine (OXC). To assess the effects of age and menopause, we evaluated retrospectively a therapeutic drug-monitoring database. Samples from 507 women and 302 men taking LTG and 464 women and 319 men taking OXC were used to develop a population pharmacokinetic model. Data were analyzed using NONMEM software and were compared with a population pharmacokinetic model based on samples of 1705 women and 1771 men taking carbamazepine (CBZ). Age was a significant factor contributing to pharmacokinetic variability in individuals using LTG, OXC, and CBZ with increasing clearance as a function of bioavailability (Cl/F) over age 18, a maximum Cl/F at 33 years (CBZ) and 36 years (LTG and OXC), and a gradual decrease of Cl/F towards older age. We found no effect of perimenopausal age range on LTG and MHD clearance.

Ketogenic Dietary Therapies (KDT) are an effective treatment option for some people with drug-resistant epilepsy. They are, however, resource-intensive and can cause adverse side effects. Predictors of response would improve the selection process and perhaps further our understanding of the mechanisms behind dietary treatments for epilepsy. We conducted a literature review to identify factors that may influence response to KDT. We found no strong evidence that there are any specific factors that affect response. Gender and intellectual status do not seem to affect response; evidence is inconsistent for all other factors. Experimental studies may point us in the right direction for future work.

Summary Purpose Vigabatrin-associated visual field loss (VAVFL) occurs in around 45% of exposed people. It is generally accepted that, once established, VAVFL is stable and does not progress with continued VGB use. Most studies have, however, only followed people for short periods. We assessed the evolution of VAVFL over a ten-year period of continued VGB use. Methods From a group of 201 vigabatrin-exposed individuals with epilepsy, fourteen individuals were identified who were currently taking vigabatrin. All individuals had at least ten years exposure to vigabatrin. Individuals underwent several visual field examinations using Goldmann perimetry between Test 1 (first recorded examination) and Test 2 (most recent examination). All visual field results were analysed and quantified retrospectively by one investigator. Results 174 visual fields from the fourteen participants were available. The average follow-up period was 128 months. The prevalence of VAVFL increased from 64% at Test 1 to 93% at Test 2. The visual field size was significantly smaller at Test 2 compared to Test 1. All subjects showed a trend for decreasing visual field size with increasing cumulative vigabatrin exposure, when all fields for an individual were taken into account. There was a high degree of variability in visual field size between successive test sessions. Conclusions VAVFL progresses with continued vigabatrin exposure over a ten-year period. Progression may be slow and difficult to detect because of the high degree of variability in visual field size between successive test sessions. New techniques are needed to monitor the effects of vigabatrin retinotoxicity in people who continue vigabatrin therapy.

Background: The prevalence of epilepsy in sub-Saharan Africa seems to be higher than in other parts of the world, but estimates vary substantially for unknown reasons. We assessed the prevalence and risk factors of active convulsive epilepsy across five centres in this region. Methods: We did large population-based cross-sectional and case-control studies in five Health and Demographic Surveillance System centres: Kilifi, Kenya (Dec 3, 2007-July 31, 2008); Agincourt, South Africa (Aug 4, 2008-Feb 27, 2009); Iganga-Mayuge, Uganda (Feb 2, 2009-Oct 30, 2009); Ifakara, Tanzania (May 4, 2009-Dec 31, 2009); and Kintampo, Ghana (Aug 2, 2010-April 29, 2011). We used a three-stage screening process to identify people with active convulsive epilepsy. Prevalence was estimated as the ratio of confirmed cases to the population screened and was adjusted for sensitivity and attrition between stages. For each case, an age-matched control individual was randomly selected from the relevant centre's census database. Fieldworkers masked to the status of the person they were interviewing administered questionnaires to individuals with active convulsive epilepsy and control individuals to assess sociodemographic variables and historical risk factors (perinatal events, head injuries, and diet). Blood samples were taken from a randomly selected subgroup of 300 participants with epilepsy and 300 control individuals from each centre and were screened for antibodies to Toxocara canis, Toxoplasma gondii, Onchocerca volvulus, Plasmodium falciparum, Taenia solium, and HIV. We estimated odds ratios (ORs) with logistic regression, adjusted for age, sex, education, employment, and marital status. Results: 586 607 residents in the study areas were screened in stage one, of whom 1711 were diagnosed as having active convulsive epilepsy. Prevalence adjusted for attrition and sensitivity varied between sites: 7·8 per 1000 people (95% CI 7·5-8·2) in Kilifi, 7·0 (6·2-7·4) in Agincourt, 10·3 (9·5-11·1) in Iganga-Mayuge, 14·8 (13·8-15·4) in Ifakara, and 10·1 (9·5-10·7) in Kintampo. The 1711 individuals with the disorder and 2032 control individuals were given questionnaires. In children (aged

Objective: The effectiveness of anthelminthic and corticosteroid drug therapy in parenchymal neurocysticercosis is well established. The treatment of parenchymal solitary cysticercus granuloma (SCG), however, remains controversial. We attempted to obtain a consistent estimate of the efficacy of anthelminthic and corticosteroid drug treatment in SCG. Methods: Randomized-controlled trials (RCTs) comparing rates of seizure freedom, granuloma resolution, and residual calcification in individuals with SCG treated with anthelminthic or corticosteroid drugs with those treated with antiepileptic drugs (AEDs) alone were systematically reviewed and quantified using fixed- or random-effects meta-analysis. Results: Fifteen RCTs were identified for inclusion. Ten RCTs assigned 765 people with SCG to AED treatment with or without anthelminthic drug (albendazole) treatment. A further 5 RCTs assigned 457 people with SCG to AED treatment with or without corticosteroid drugs. Anthelminthic treatment was associated with significantly increased rates of seizure freedom (nonevent odds ratio: 2.45; 95% confidence interval: 1.49–4.03; p = 0.0004) and significantly higher rates of granuloma resolution (odds ratio: 2.09; 95% confidence interval: 1.41–3.00; p = 0.0003), but did not alter the risk of residual calcification. Corticosteroid treatment was not significantly associated with any outcome. Conclusions: Anthelminthic treatment with albendazole provides improved rates of seizure freedom and hastens resolution of the granuloma. The role of corticosteroid treatment remains uncertain. The benefits (or lack thereof in the case of corticosteroids) are consistent when measured across different time points after treatment.

Purpose: Detailed data on the mortality of epilepsy are still lacking from resource-poor settings. We conducted a long-term follow-up survey in a cohort of people with convulsive epilepsy in rural areas of China. In this longitudinal prospective study we investigated the causes of death and premature mortality risk among people with epilepsy. Methods: We attempted to trace all 2,455 people who had previously participated in a pragmatic assessment of epilepsy management at the primary health level. Putative causes of death were recorded for those who died, according to the International Classification of Diseases. We estimated proportional mortality ratios (PMRs) for each cause, and standardized mortality ratios (SMRs) for each age-group and cause. Survival analysis was used to detect risk factors associated with increased mortality. Key Findings: During 6.1 years of follow-up there were 206 reported deaths among the 1,986 people with epilepsy who were located. The highest PMRs were for cerebrovascular disease (15%), drowning (14%), self-inflicted injury (13%), and status epilepticus (6%), with probable sudden unexpected death in epilepsy (SUDEP) in 1%. The risk of premature death was 2.9 times greater in people with epilepsy than in the general population. A much higher risk (SMRs 28-37) was found in young people. Duration of epilepsy and living in a waterside area were independent predictors for drowning. Significance: Drowning and status epilepticus were important, possibly preventable, causes of death. Predictors of increasing mortality suggest interventions with efficient treatment and education to prevent premature mortality among people with epilepsy in resource-poor settings. Language: en

Objective: Dravet syndrome is a rare neurodevelopmental disorder characterized by seizures and other neurologic problems. SCN1A mutations account for ∼80% of cases. Animal studies have implicated mutation-related dysregulated cortical inhibitory networks in its pathophysiology. We investigated such networks in people with the condition. Methods: Transcranial magnetic stimulation using single and paired pulse paradigms was applied to people with Dravet syndrome and to 2 control groups to study motor cortex excitability. Results: Short interval intracortical inhibition (SICI), which measures GABAergic inhibitory network behavior, was undetectable in Dravet syndrome, but detectable in all controls. Other paradigms, including those testing excitatory networks, showed no difference between Dravet and control groups. Conclusions: There were marked differences in inhibitory networks, detected using SICI paradigms, while other inhibitory and excitatory paradigms yielded normal results. These human data showing reduced GABAergic inhibition in vivo in people with Dravet syndrome support established animal models.

Introduction Premature mortality is a major issue in Dravet syndrome (DS). To improve understanding of DS premature mortality, we conducted a comprehensive literature search with a particular emphasis on SUDEP. Methods We searched PubMed, Embase, Web of Science, Cochrane, CENTRAL, CINAHL, PsycINFO, Academic Search Premier, and ScienceDirect on the following terms: “Dravet syndrome”, “severe myoclonic epilepsy”, “SMEI”, “mortality”, “survivors”, “prognosis”, and “death”. DS cases or cohorts studies reporting mortality were included. Results The search yielded 676 articles and 86 meeting abstracts. After removing duplicates and screening titles and abstracts, full text of 73 articles was reviewed. Only 28 articles and six meeting abstracts met inclusion criteria. Five articles and four meeting abstracts were excluded, as the case(s) were also described elsewhere. After checking the references, five additional studies were included. The 30 items reported 177 unique cases. Sudden unexpected death in epilepsy was the likely cause in nearly half of the cases (n = 87, 49%), followed by status epilepticus (n = 56, 32%). Drowning or accidental death was reported in 14 cases (8%), infections in 9 (5%), other causes in six (3%), and unknown in five (3%). Age at death was reported for 142 of the 177 cases (80%), with a mean age of 8.7 ± 9.8 years (SD); 73% died before the age of 10 years. Discussion Dravet syndrome is characterized by high epilepsy-related premature mortality and a marked young age at death. Sudden unexpected death in epilepsy is the leading reported cause of death in DS, accounting for nearly half of all deaths. The cause of this excess mortality remains elusive but may be explained by epilepsy severity, as well as genetic susceptibility to SUDEP.

Epilepsy commonly presents in childhood as part of a syndrome, and some such children may reach adult services without an underlying syndromic diagnosis. For adult neurologists taking over their care, it is often unclear how hard to search for an underlying diagnosis. The diagnostic yield may be small and such a diagnosis may not change management. Young adults with learning difficulties are also challenging to investigate, as they may not tolerate standard epilepsy tests.We present such a case in which simple tests identified a unifying diagnosis. With the new diagnosis came a new treatment that had a significant impact on seizures and quality of life.

Objective Up to 30% of people with juvenile myoclonic epilepsy (JME) have photoparoxysmal responses (PPR). Recent studies report on structural and pathophysiological differences between people with JME with (JME+PPR) and without PPR (JME−PPR). We investigated whether electrophysiological features outside photic stimulation differ between these subtypes. Methods We analysed EEG recordings of people with JME at a tertiary epilepsy centre and an academic hospital. Photosensitivity was assessed in a drug-naïve condition. We compared the occurrence and involvement of posterior electrodes for focal abnormalities and generalised spike-wave activity in the EEG outside photic stimulation between JME+PPR and JME−PPR. Results We included EEG recordings of 18 people with JME+PPR and 21 with JME−PPR. People with JME−PPR had less focal abnormalities in the posterior brain regions than people with JME+PPR (19% vs 55%, p

Background Most victims of sudden unexpected death in epilepsy (SUDEP) are found prone with signs suggestive of an unwitnessed convulsive seizure (CS). Prone sleeping has been proposed as a risk factor for SUDEP. Little is known, however, about the change of body position during the course of CSs. Methods We retrospectively reviewed video-EEG data and assessed body positions during the course of CSs, until there was a physical interaction by nursing staff with the subject. Results We identified 180 CSs in 90 individuals. In 16 of the 180 CSs (9%), the subject started in or turned to the prone position. Of the seven CSs that started in the prone position, three turned to a lateral position during the CS. In 13 CSs, the subject was in prone position at time of nursing intervention; nine (69%) of these started in a nonprone position. Discussion Our data suggest that the prone position occurs infrequently in closely supervised nonfatal CSs, a notable contrast to the number of victims of SUDEP found prone. Whether prone sleeping prior to CSs increases SUDEP risk, however, remains speculative, as body position during the course of a CS appeared to be dynamic.

Findings from randomised controlled trials, along with more than 100 case series and observational studies, support the efficacy and safety of resective surgery and, more recently, non-resective surgical interventions for the treatment of drug-resistant epilepsy in appropriately selected individuals. There is an argument that epilepsy surgery remains underused, but the evidence to support this assertion is at times unclear. Results from longitudinal studies show a stagnant or declining rate of epilepsy surgery over time, despite the evidence and guidelines supporting its use. Some suggest that this stagnation is due to a decreasing pool of eligible surgical candidates, whereas others emphasise the numerous barriers to epilepsy surgery. Strategies exist to increase access to surgery and to improve communication about the effectiveness of this potentially life-changing procedure. Further investigation into the nature and causes of the presumed underuse of epilepsy surgery and the elaboration of strategies to address this treatment gap are necessary and pressing.

International audience; Epilepsy is the tendency to have unprovoked epileptic seizures. Anything causing structural or functional derangement of brain physiology may lead to seizures, and different conditions may express themselves solely by recurrent seizures and thus be labelled "epilepsy." Worldwide, epilepsy is the most common serious neurological condition. The range of risk factors for the development of epilepsy varies with age and geographic location. Congenital, developmental and genetic conditions are mostly associated with the development of epilepsy in childhood, adolescence and early adulthood. Head trauma, infections of the central nervous system (CNS) and tumours may occur at any age and may lead to the development of epilepsy. Infections of the CNS are a major risk factor for epilepsy. The reported risk of unprovoked seizures in population-based cohorts of survivors of CNS infections from developed countries is between 6.8 and 8.3 %, and is much higher in resource-poor countries. In this review, the various viral, bacterial, fungal and parasitic infectious diseases of the CNS which result in seizures and epilepsy are discussed. The pathogenesis of epilepsy due to brain infections, as well as the role of experimental models to study mechanisms of epileptogenesis induced by infectious agents, is reviewed. The sterile (non-infectious) inflammatory response that occurs following brain insults is also discussed, as well as its overlap with inflammation due to infections, and the potential role in epileptogenesis. Furthermore, autoimmune encephalitis as a cause of seizures is reviewed. Potential strategies to prevent epilepsy resulting from brain infections and non-infectious inflammation are also considered.

Background: Comorbidities are rarely taken into account in studies of neurological conditions although they may be a confounder of the outcome and treatment. The

Objective: The risk of premature mortality is increased in people with epilepsy. The reasons for this and how it may relate to epilepsy etiology remain unclear. Methods: The National General Practice Study of Epilepsy is a prospective, community-based cohort that includes 558 people with recurrent unprovoked seizures of whom 34% died during almost 25 years of follow-up. We assessed the underlying and immediate causes of death and their relationship to epilepsy etiology. Psychiatric and somatic comorbidities of epilepsy as predictors of mortality were scrutinized using adjusted Cox proportional hazards models. Results: The 3 most common underlying causes of death were noncerebral neoplasm, cardiovascular, and cerebrovascular disease, accounting for 59% (111/189) of deaths, while epilepsy-related causes (e.g., sudden unexplained death in epilepsy) accounted for 3% (6/189) of deaths. In 23% (43/189) of individuals, the underlying cause of death was directly related to the epilepsy etiology; this was significantly more likely if death occurred within 2 years of the index seizure (percent ratio 4.28 [95% confidence interval 2.63–6.97]). Specific comorbidities independently associated with increased risk of mortality were neoplasms (primary cerebral and noncerebral neoplasm), certain neurologic diseases, and substance abuse. Conclusions: Comorbid diseases are important causes of death, as well as predictors of premature mortality in epilepsy. There is an especially strong relationship between cause of death and epilepsy etiology in the first 2 years after the index seizure. Addressing these issues may help stem the tide of premature mortality in epilepsy.

Summary Purpose: To evaluate the long-term outcome of phenobarbital treatment for convulsive epilepsy in rural China, and to explore factors associated with overall seizure outcomes. Methods: We carried out follow-up assessments of people who took part in an epilepsy community management program conducted in rural counties of six provinces in China. People with convulsive epilepsy who were previously untreated (or on irregular treatment) were commenced on regular treatment with phenobarbital. Information was collected using a standardized questionnaire by face-to-face interviews of the individuals (and their families where necessary). Information collected included treatment status, medication change, seizure frequency, and mortality. Key Findings: Among the 2,455 people who participated in the original program, outcomes were successfully ascertained during the follow-up assessment in 1986. Among them, 206 had died. Information on treatment response was obtained in 1,780 (56% male; mean age 33.9 years, range 3-84; mean duration of follow-up 6.4 years). Among them, 939 (53%) were still taking phenobarbital. The most common reasons for stopping phenobarbital were seizure freedom or substantial seizure reduction, socioeconomic reasons, and personal preference. Four hundred fifty-three individuals (25%) became seizure-free for at least 1 year while taking phenobarbital, 88% of whom did so at daily doses of 120 mg or below. Four hundred six (23%) reported adverse events, which led to withdrawal of phenobarbital in

Summary Purpose: Postictal generalized EEG suppression (PGES) seems to be a pathophysiologic hallmark in ictal recordings of sudden unexpected death in epilepsy (SUDEP). It has recently been suggested that presence and duration of PGES might be a predictor of SUDEP risk. Little is known about the etiology of PGES. Methods: We conducted a retrospective case-control study in 50 people with convulsive seizures (CS) recorded on digital video-electroencephalography (EEG). One CS per individual was reviewed for presence and duration of PGES by two independent observers: Preictal and postictal heart rate (HR) (1 min before seizure onset and 1, 3, 5, 15, and 30 min after seizure end) and frequency domain measures of heart rate variability (HRV), including the ratio of low frequency (LF) versus high frequency (HF) power, were analyzed. The relationship between PGES and periictal autonomic changes was evaluated, as well as its association with several clinical variables. Key Findings: Thirty-seven individuals (74%) exhibited PGES and 13 (26%) did not. CS resulted in a significant increase of periictal HR and the LF/HF ratio. PGES was associated with neither periictal HR (mean HR difference between PGES+ and PGES- seizures: -2 beats per minute [bpm], 95% confidence interval [CI] -10 to +6 bpm) nor HRV change. There was no association between the duration of PGES and periictal HR change. People with PGES were more likely to be asleep before seizure onset (odds ratio [OR] 4.7, 95% CI 1.2-18.3) and had a higher age of onset of epilepsy (median age 15 vs. 4 years). Significance: PGES was not associated with substantial changes in measures of cardiac autonomic instability but was more prevalent in CS arising from sleep. © Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

SUMMARY Purpose: To assess the association between epilepsy and exposure to the parasites, Toxocara canis and Taenia solium in a slum-community in India. Methods: A door-to-door survey to determine the prevalence of epilepsy was carried out by trained field workers. For every case, one age- and gender-matched control was selected from the same community. Serologic evaluation was carried out to detect antibodies against T. canis and T. solium. Key Findings: The crude prevalence of active epilepsy was 7.2 per 1,000. We enrolled 114 people with active epilepsy and 114 controls. The prevalence of antibodies to T. canis was similar in people with active epilepsy (4.7%; 5 of 106 people) and in controls (5.7%; 6 of 106 people). The prevalence of antibodies to T. solium was 25.5% (27 of 106) in people with active epilepsy, significantly higher than in controls (12.3%; 13 of 106 cases; p = 0.02). Adjusted conditional (fixed-effects) logistic regression estimated an odds ratio of 2.8 (95% confidence interval 1.2–6.8) for detection of T. solium antibodies. Nineteen people with active epilepsy demonstrated evidence of neurocysticercosis (NCC) on magnetic resonance imaging (MRI), including 7 (36.5%) with solitary cysticercus granuloma. Significance: Our findings do not support an association between epilepsy and exposure to T. canis in the community studied. A significant association between T. solium exposure and epilepsy was observed. Of those with active epilepsy and evidence of NCC on MRI, a large proportion demonstrated solitary cysticercus granuloma.

Background The seizure response to the addition of a previously unused antiepileptic drug in a cohort of 155 people with refractory epilepsy was previously reported after a median of 18 months follow-up. Methods The authors followed 139 (90%) of the original cohort for a median follow-up of 6.9 years to determine the longer term outcome in people with refractory epilepsy. Results During the 6.9 year follow-up period, a total of 448 medication changes were made. Eight per cent of these resulted in 12 months or more of seizure freedom and a further 17% of changes resulted in at least 50% improvement in seizure frequency. At the last follow-up, 26 (19%) of individuals had been seizure-free for 12 months or more, and 41 (29%) had 50%–99% improvement in seizure frequency. Terminal seizure freedom was correlated with having no seizures at the time of the previous report (p=0.03), a lower number of previous antiepileptic drugs taken (p=0.052) and a lower number of concomitant antiepileptic drugs (p=0.03). In those who entered remission the probability of remaining seizure-free 5 years later was 0.48 (95% CI 0.32 to 0.63). Discussion This suggests that about half of people with apparent drug-resistant epilepsy can have significant improvements in seizure control with further drug changes. Some will subsequently relapse, but long periods of seizure freedom or significantly improved seizure control in the absence of complete seizure control can occur. Such valuable improvements suggest that the recently proposed International League against Epilepsy definition of refractory epilepsy may be too restrictive.

A range of medical and neurologic disorders occurs more frequently in people with epilepsy than in the general population and constitutes its somatic comorbidity. Common examples include cardiac, gastrointestinal, and respiratory disorders; stroke; dementia; and migraine. Alzheimer's disease and migraine are not only more common in epilepsy but are also risk factors for the development of seizures, suggesting a bidirectional association and shared disease mechanisms. Less well-appreciated associations with epilepsy include Parkinson's disease and obstructive sleep apnea. The association between epilepsy and other conditions can be due to a variety of interacting genetic, biologic, and environmental factors. We propose an etiologic classification of comorbidity into uncertain (coincidence or unknown), causal (cause), shared risk factors (common disease mechanisms or shared predisposing risk factors), and resultant (consequence). Co-occurrence of other conditions in a person with epilepsy can complicate diagnosis or have adverse prognostic implications. Management of these conditions may facilitate the treatment of epilepsy, as in the case of obstructive sleep apnea. The presence of somatic disorders in epilepsy is associated with increased health care needs, poorer health-related quality of life, and premature mortality. Prevention, identification, and adequate treatment of comorbid disorders in epilepsy should be an important part of epilepsy management at all levels of care.

Objective: We report the prospective follow-up of a cohort of people from the onset of febrile seizures for a median of 24 years to estimate the long-term risk of developing epilepsy. Methods: The National General Practice Study of Epilepsy is a large prospective community study of 1,195 people with a first suspected seizure followed from the 1980s, of whom 220 (18%) had febrile seizures. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) for subsequent epilepsy were calculated in 5-year age bands. Results: Follow-up information was obtained for 181 (83%) people with a mean follow-up for the whole cohort of 21.6 (SD 6.0) years. Of these, 175 (97%) were seizure-free in the preceding 5 years, whereas 171 (94%) were seizure-free and off antiepileptic drugs. Six percent developed epilepsy, but the risk of developing epilepsy in the cohort over the whole follow-up period was almost 10 times that of the general population (SIR 9.7, 95% CI 5.7–16.4). The SIR was significantly elevated in the 0- to 14-year age groups but not in the 15- to 19-year age group (SIR 4.5, 95% CI 0.6–32.1). Conclusion: The risk of developing epilepsy in people who had febrile seizures seems to decrease with time. Further long-term studies are needed to confirm this.

Summary Purpose: Diffusion tensor imaging (DTI) is used increasingly to study white matter integrity in people with temporal lobe epilepsy (TLE). Most studies report fractional anisotropy (FA) decrease and mean diffusivity (MD) increase in multiple white matter regions. The disturbance of white matter integrity varies across studies and between regions. We aimed to obtain a more consistent estimate of white matter diffusion characteristics and relate these to the distance from the seizure focus. Methods: Studies comparing diffusion characteristics of people with epilepsy with those of healthy controls were systematically reviewed and quantified using random and mixed effects meta analysis. In addition to the overall meta-analysis, pooled FA and MD differences were determined per hemisphere and white matter category separately. Key Findings: We included 13 cross-sectional studies. The pooled FA difference for all white matter was −0.026 (95% confidence interval [CI] −0.033 to −0.019) and MD difference was 0.028 × 10−3 mm2/s (95% CI 0.015–0.04). FA was reduced significantly in people with TLE compared with healthy controls in both ipsilateral (mean difference −0.03) and contralateral white matter (−0.02). MD was significantly increased ipsilaterally and contralaterally. MD differed significantly between white matter connected to the affected temporal lobe and remote white matter. Significance: The meta-analysis provides a better estimation of the true diffusion characteristics. White matter structural integrity in TLE is disturbed more severely in the ipsilateral than in the contralateral hemisphere, and tracts closely connected with the affected temporal lobe are most disturbed. The exact underlying mechanisms remain to be elucidated.

Summary Purpose: Most people with epilepsy who die suddenly and whose death is attributed to sudden unexpected death in epilepsy (SUDEP) are found in or by the bed for unknown reasons. We assessed whether those with sleep-related SUDEP were more likely to have nocturnal seizures, and whether seizure patterns (diurnal vs. nocturnal) differed from people dying suddenly and living controls with epilepsy. Methods: Seizure patterns in a cohort of 154 people with epilepsy who died suddenly and after autopsy conformed to the definition of SUDEP and 616 controls living with epilepsy were classified as having “exclusively diurnal” or “nocturnal seizures.” Comparisons were made between the groups. SUDEP was classified as sleep-related or non–sleep-related based on eyewitness accounts and the circumstances surrounding death. Key Findings: SUDEP was primarily a sleep-related (58%) and unwitnessed (86%) event. If sleep-related, SUDEP was more likely to be unwitnessed [odds ratio (OR) 4.4, 95% confidence interval (CI) 1.6–12]. Those with sleep-related SUDEP were more likely to have a history of nocturnal seizures than those who had non–sleep-related SUDEP (OR 3.6, 95% CI 1.4–9.4). Those who died were more likely to have a history of nocturnal seizures than living controls (OR 3.9, 95% CI 2.5–6.0). After correction for previously established SUDEP risk factors (Langan et al., 2005), the presence of nocturnal seizures remained significant (OR 2.6, 95% CI 1.3–5.0). Significance: Nocturnal seizures seem to be an independent risk factor for SUDEP. These findings underscore the importance of preventive measures, which may include night supervision.

Summary Purpose: In an analysis of four case–control studies of sudden unexpected death in epilepsy (SUDEP), we found that yearly frequency of generalized tonic–clonic seizures (GTCS) and antiepileptic drug (AED) polytherapy were associated with an increased risk for SUDEP. The prior analysis, however, did not evaluate AEDs and GTCS frequency concurrently. Methods: We combined data from the three case–control studies with information on the frequency of GTCS and AED therapy, that is, carbamazepine, phenytoin, valproic acid, and other AED therapy. Number of AEDs was also considered. Lamotrigine and GTCS frequency were considered separately in two of the case–control studies. Logistic regression analysis was used to evaluate GTCS frequency, each of the AEDs, and number of AEDs. Adjusted analysis of the different AEDs accounted for study, age at death, gender, and GTCS frequency. Key Findings: In crude analysis, GTCS frequency, AED polytherapy, and number of AEDs were associated with an increased risk for SUDEP. Analysis of individual AEDs and of number of AEDs, adjusting for GTCS frequency, revealed no increased risk associated with AEDs as monotherapy, polytherapy, or total number. GTCS frequency remained strongly associated with an increased risk for SUDEP. Significance: Our findings—that none of the AEDs considered were associated with increased SUDEP risk as monotherapy or as polytherapy when GTCS frequency was taken into account—provide a consistent message that number of GTCS increases SUDEP risk and not AEDs. These results suggest that prevention of SUDEP must involve increased efforts to decrease GTCS frequency in order to avert the occurrence of this devastating epilepsy outcome.

Singh G, Bell GS, Hernaiz-Driever P, Sander JW. Cancer risk in people with epilepsy using valproate-sodium. Acta Neurol Scand: 2012: 125: 234–240. © 2011 John Wiley & Sons A/S. Objectives – Based on reports of antitumour properties of sodium-valproate, we hypothesised that valproate has a cancer-protective effect in people with epilepsy. We aimed to determine cancer risk in people with epilepsy using sodium-valproate. Materials and methods – Continuous data for 2997 people with epilepsy who had been prescribed valproate for at least two years, and for 11,988 unexposed people were provided by the UK General Practice Research Database. Hazard ratios (HRs) for all cancers and individual cancers between the exposed and unexposed groups, with smoking and alcohol consumption and age as covariates, were calculated using the Cox proportional hazards method. Results – Exposure to valproate had no influence on the incidence of the composite of all cancers [HR: 1.19, 95% CI: 0.97–1.47, P = 0.10]; there was, however, a significant excess of colon cancers [HR: 3.95, 95% CI: 1.97–7.92, P = 0.001] and a trend towards an excess of prostate neoplasms [HR: 2.15, 95% CI: 0.92–5.02, P = 0.08] and in addition, a trend towards reduced incidence of breast cancer [HR: 0.40, 95% CI: 0.14–1.30, P = 0.08] in the exposed group. Conclusions – The lack of an inverse association between valproate use and hazard ratios for all cancers and several individual cancer sites does not lend support for a cancer-protective role for valproate.

Complex partial seizures (CPS) are a form of localization-related seizures associated with serious comorbidities and risks. CPS can be difficult to treat and may remain refractory to treatment with antiepileptic drugs (AEDs). Refractory CPS (rCPS) can be hazardous because of the potential for severe dysfunction and bodily harm, sometimes with fatal consequences. Control of seizure activity is critical to the clinical management of CPS. Vigabatrin is a unique AED approved in both Europe and the United States as adjunctive therapy for adult patients with rCPS who have responded inadequately to several alternative treatments. This review focuses on appropriately controlled studies of vigabatrin conducted in Europe. Several double-blind studies randomized those with rCPS to treatment with vigabatrin vs placebo, and two evaluated durability of response to long-term, open-label vigabatrin. Endpoints included seizure frequency, treatment satisfaction, and adverse events (AEs). Efficacy outcomes demonstrated that vigabatrin add-on therapy significantly reduced the frequency of seizures. Long-term studies indicated durability of response and tolerability of vigabatrin therapy for up to several years. Treatment satisfaction data indicated a preference for vigabatrin vs placebo for both physicians and study participants. Vigabatrin was well-tolerated with generally mild AEs considered common to AEDs. Vision effects were not formally monitored in these studies. In European trials, vigabatrin was efficacious as adjunctive therapy for rCPS.

We report a clinical and genetic follow-up study of a large consanguineous family from an endogamous Roma/Gypsy sub-isolate, where previous analyses have been inconclusive. Detailed clinical information was collected through extensive field work, repeat interviews and electrophysiological and neuroimaging investigations on 18 affected subjects. The phenotype is compatible with GEFS+, with some unusual features, e.g. GTCS persisting into late adult life and high frequency of focal epilepsy. Updated genealogical information, a dense SNP genome scan and linkage analysis identified a novel GEFS+ locus on 12p13.33, where 13 affected individuals from two branches of the kindred shared an identical haplotype. This haplotype was not found in the 3rd branch or in the remaining 21 Roma epilepsy families in our collection. Genetic heterogeneity and evidence of bilineality were found despite the inbreeding and endogamous nature of the family and population of origin. These data add to the growing evidence of lack of founder effect and significant genetic heterogeneity in epilepsy in the Roma/Gypsy population. Sequencing of the coding regions of three genes linked to neurotransmitter transport and release, SLC6A12, SLC6A13 and ERC1, on 12p did not identify a causative mutation.

The ketogenic diet (KD) has been used to treat children with epilepsy who are resistant to antiepileptic drugs (AEDs) since the 1920s, and has undergone a resurgence in popularity over the last 15 years Its use in adolescents and adults has been more restrained. During the past few decades, more liberal regimens have emerged that may seem more attractive to older people while still proving effective, often independent of ketone levels. The KD and its variants may lead to similar reductions in seizure frequency in adolescents and adults as seen in children, although studies are limited and of poor quality. A total of only 122 adults and 82 adolescents have been included in open-label studies on the KD, and only 56 adults and 10 adolescents on the Modified Atkins Diet. Side effects appear similar to those encountered in children. Noncompliance may be higher in adolescents and adults than in children, but the main reason for discontinuation is lack of efficacy. A better understanding of the mechanisms underlying the effects of the KD might allow the same treatment effects to be achieved using novel, better-tolerated, nondietary approaches.

Summary Zonisamide (ZNS) is an antiepileptic drug (AED) with multiple putative mechanisms of action. It is chemically unrelated to other AEDs. It has been available in Japan since 1989 but was only licensed in Europe in 2005. Its efficacy and tolerability have been shown in several randomised controlled trials, but large studies on long-term performance in Western clinical practice are scarce. We assessed a large cohort of consecutive people who started ZNS at a tertiary epilepsy referral centre, from June 2005 to July 2009. Forty-six percent of the 417 people included were still taking ZNS at last follow-up, with an estimated retention rate at three years of 30%. Almost one third of the population reported a period of improvement in terms of seizure reduction of at least six months duration whilst on ZNS. Sixteen people became seizure free for at least six months and seven of these were seizure free for one year or more. Adverse events occurred in 58%, frequently CNS-related. People on three or more AEDs and people starting zonisamide at 25 mg daily rather than 50 mg or more, were more likely to discontinue ZNS. Retention rates for ZNS were similar to those previously reported, and comparable to lamotrigine, topiramate, pregabalin, higher than gabapentin, and lower than levetiracetam.

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.

Background: Epilepsy is a serious health problem associated with an increased risk of premature mortality. Few studies have investigated risk factors for this. Understanding these risks may enable the implementation of preventative measures to reduce premature mortality. Methods: A management program for convulsive forms of epilepsy has been in place at the primary health care level in rural West China since May 2005. Demographic data and putative causes of death of attendees of the program since inception to the end of December 2009 have been recorded. Case fatality (CF), the proportional mortality ratios (PMRs) for each cause, and standardized mortality ratios (SMRs) for each age and cause were estimated based on the 2007 Chinese rural population. Results: There were 106 reported deaths (70 male) among 3,568 people. CF was 2.97% during a median of 28 months9 follow-up. The highest PMRs were for accidental death (59%) including drowning (45.1%); probable sudden unexpected death in epilepsy (SUDEP) (14.7%); status epilepticus (6.9%), and neoplasm (6.9%). The overall SMR was 4.92 (95% confidence interval 4.0–6.1); the risks were high in young people. The risk of drowning was 82-fold higher in the cohort than the general population. Conclusion: In rural West China, the risk of premature death is nearly 5 times higher in people with convulsive epilepsy than in the general Chinese population and especially high among young people. Accidental death, including drowning, and probable SUDEP are the leading putative causes of death in people with convulsive epilepsy in rural West China.

Postictal generalized electroencephalographic suppression (PGES) may be involved in sudden unexpected death in epilepsy (SUDEP). We examined whether the occurrence of PGES depends on seizure type and whether PGES occurs more frequently in people with epilepsy who died suddenly. EEG recordings of people with pharmacoresistant focal epilepsies who died from SUDEP after presurgical video/EEG telemetry were compared with recordings of living controls. To test if PGES depends on seizure type, EEG recordings of people with temporal lobe epilepsy who had complex partial seizures (CPS) and secondarily generalized tonic-clonic seizures (GTCS) were reviewed. A total of 122 seizures in 57 individuals have been included. PGES was observed in 15% of all seizures in 26% of all individuals. Secondarily GTCS were significantly associated with PGES. Neither presence nor duration of PGES differed between the SUDEP and control groups. In conclusion, PGES is facilitated by secondarily GTCS, but does not seem to be an independent risk factor for SUDEP.