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There is a large body of evidence suggesting that parasites could be a major preventable risk factor for epilepsy in low- and middle-income countries. We review potentially important substrates for epileptogenesis in parasitic diseases. Taenia solium is the most widely known parasite associated with epilepsy, and the risk seems determined mainly by the extent of cortical involvement and the evolution of the primary cortical lesion to gliosis or to a calcified granuloma. For most parasites, however, epileptogenesis is more complex, and other favorable host genetic factors and parasite-specific characteristics may be critical. In situations where cortical involvement by the parasite is either absent or minimal, parasite-induced epileptogenesis through an autoimmune process seems plausible. Further research to identify important markers of epileptogenesis in parasitic diseases will have huge implications for the development of trials to halt or delay onset of epilepsy.

This population-based cross-sectional survey with a follow-up case-control study assessed the prevalence, incidence, and risk factors for epilepsy in a rural health district in the North-West Region of Cameroon. Community-based epilepsy screening targeted all inhabitants, six years and older, in all 16 health areas in the Batibo Health District. During door-to-door visits, trained fieldworkers used a validated questionnaire to interview consenting household heads to screen for epilepsy in eligible residents. Trained physicians subsequently assessed people with suspected seizures. After clinical assessment, they confirmed or refuted the diagnosis and estimated the date of epilepsy onset. A trained nurse interviewed people with epilepsy and randomly selected healthy individuals, obtaining relevant demographic details and information on exposure to risk factors for epilepsy. Out of 36,282 residents screened, 524 had active epilepsy. The age-standardized prevalence of active epilepsy was 33.9/1,000 (95% CI: 31.0-37.1/1,000). We estimated the one-year age-standardized epilepsy incidence at 171/100,000 (95%CI: 114.0-254.6). Active epilepsy prevalence varied widely between health areas, ranging between 12 and 75 per 1,000. The peak age-specific prevalence was in the 25-34 age group. In adults, multivariate analysis showed that having a relative with epilepsy was positively associated with epilepsy. Epilepsy characteristics in this population, geographical heterogeneity, and the age-specific prevalence pattern suggest that endemic neurocysticercosis and onchocerciasis may be implicated. Further investigations are warranted to establish the full range of risk factors for epilepsy in this population.

Introduction Epilepsy is a common yet misunderstood condition in Cameroon, including in the Batibo Health district. Methods This cross-sectional study describes epilepsy clinical characteristics, the treatment gap, and associated factors in a rural district in Cameroon. After screening for epilepsy using a door-to-door survey, physicians confirmed suspected cases of epilepsy. Detailed information on the medical, seizure, and treatment history was collected from everyone with epilepsy, followed by a general and neurological examination. Results We diagnosed 546 people with active epilepsy (at least one seizure in the previous 12 months). The mean age of people with active epilepsy was 25.2 years (SD: 11.1). The mean age at first seizure was 12.5 years (SD: 8.2). Convulsive seizures (uncertain whether generalized or focal) were the most common seizure types (60%), while 41% had focal-onset seizures. About 60% of people had seizures at least monthly. One-quarter of participants had had at least one episode of status epilepticus. Anti-seizure medication (ASM) was taken by 85%, but most were receiving inappropriate treatment or were non-adherent, hence the high treatment gap (80%). Almost a third had had seizure-related injuries. Epilepsy was responsible for low school attendance; 74% of school dropouts were because of epilepsy. Conclusion The high proportion of focal-onset seizures suggests acquired causes (such as neurocysticercosis and onchocerciasis, both endemic in this area). The high epilepsy treatment gap and the high rates of status epilepticus and epilepsy-related injuries underscore the high burden of epilepsy in this rural Cameroonian health district.

Epilepsy surgery is an effective treatment for refractory focal epilepsy. Risks of surgery need to be considered when advising individuals of treatment options. We describe the frequency and nature of physical adverse events associated with epilepsy surgery in a single center.We reviewed the prospectively maintained records of adults who underwent epilepsy surgery at our center between 1990 and 2014 to identify peri/postsurgical adverse events. These were categorized into neurological deficits and those related to surgery (e.g. wound infections). Neurological deficits were categorized as expected or unexpected and into transient (≤3 months) or persistent (3 months), RESULTS: There were 911 procedures with no peri-operative deaths. Persistent neurological adverse events were seen following 157 (17.2%) procedures. The most common persistent expected complication was quadrantanopia after temporal lobe resections (72/764, 9.4%). Unexpected persistent neurological complications occurred in 20 procedures (2.2%) and included: quadrantanopia (6, 0.7%); hemianopia (2, 0.2%); hemi/mono-paresis/sensory loss (9, 1%); dysphasia (10, 1%); frontalis muscle weakness (2, 0.2%); and oculomotor weakness (1, 0.1%). 106 surgery related adverse events occurred in 83 procedures, with severe infections requiring bone-flap removal in 24 (2.6%) procedures and intracranial infections in 8 (0.9%). The risk of post-resective severe infection increased by 4 fold (OR 4.32, 95% CI 2.1-8.9, p0.001) with use of subdural EEG monitoring prior to resection. In consequence, in August 2011 we introduced antibiotic coverage in all individuals undergoing intracranial monitoring. Also, after August 2011 there was greater use of Stereo-EEG (SEEG) than subdural (OR 9.0 CI 0.36-224.2, p=0.18ns). One complicated by severe infection. Other surgical complications included haematoma (0.3%), hydrocephalus (0.3%) and CSF leak (1.2%). None had permanent complications.Adverse event rates are similar to other series. Epilepsy surgery carries well defined surgical and neurological risks. The risks of somatic adverse events, in addition to neuropsychiatric and neuropsychological complications need to be made clear to individuals considering this treatment option.

Introduction Bilateral interictal epileptiform discharges (IED) and ictal patterns are common in temporal lobe epilepsy (TLE) and have been associated with decreased chances of seizure freedom after epilepsy surgery. It is unclear whether secondary epileptogenesis, although demonstrated in experimental models, exists in humans and may account for progression of epilepsy. Material and methods We reviewed consecutive video-EEG recordings from 1992 to 2014 repeated at least two years apart (mean interval 6.14 years) in 100 people diagnosed with TLE. Results Ictal EEG patterns and IED remained restricted to one hemisphere in 36 people (group 1), 46 exhibited bilateral abnormalities from the first recording (group 2), 18 progressed from unilateral to bilateral EEG pathology over time (group 3). No significant differences between the three groups were seen with respect to age at epilepsy onset, duration, or underlying pathology. Extra-temporal IED during the first EEG recording were associated with an increased risk of developing bilateral epileptiform changes over time (hazard ratio 3.67; 95% CI 1.4, 9.4). Conclusion Our findings provide some support of progression in TLE and raise the possibility of secondary epileptogenesis in humans. The development of an independent contra-lateral epileptogenic focus is known to be associated with a less favorable surgical outcome. We defined reliable EEG markers for an increased risk of progression to more widespread or independent bitemporal epileptogenicity at an early stage, thus allowing for individualized pre-surgical counselling.

We investigated long-term (to 25 years) seizure prognosis and survival in people with newly diagnosed epilepsy in the community. We explored whether prognosis is different in those with epilepsy (>2 unprovoked seizures) and those with a single seizure at presentation. This is a prospective observational cohort study of people with newly diagnosed seizures. We investigated seizure outcome and survival in people presenting with a single seizure and in those presenting with >2 seizures (epilepsy). 695 people (median follow-up 23.6 years) had unprovoked epileptic seizures. For seizure analysis we excluded 38 people with missing data leaving 657 (309 male, and 249 aged

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.

IMPORTANCE: Surgical treatment can bring seizure remission in people with focal epilepsy but requires careful selection of candidates.OBJECTIVES: To determine which preoperative factors are associated with postoperative seizure outcome.DESIGN: We audited seizure outcome of 693 adults who had resective epilepsy surgery between 1990 and 2010 and used survival analysis to detect preoperatively identifiable risk factors of poor seizure outcome.RESULTS: Seven factors were significantly associated with increased probability of recurrence of seizures with impaired awareness postsurgery: MRI findings (eg, HR adjusted for other variables in the model 2.5; 95% CI 1.6 to 3.8 for normal MRI compared with hippocampal sclerosis), a history of secondarily generalised convulsive seizures (2.3; 95% CI 1.7 to 3.0 for these seizures in the previous year vs never), psychiatric history (1.3; 95% CI 1.1 to 1.7), learning disability (1.8; 95% CI 1.2 to 2.6) and extratemporal (vs temporal) surgery (1.4; 95% CI 1.02, 2.04). People with an older onset of epilepsy had a higher probability of seizure recurrence (1.01; 95% CI 1.00, 1.02) as did those who had used more antiepileptic drugs (1.05; 95% CI 1.01 to 1.09). Combinations of variables associated with seizure recurrence gave overall low probabilities of 5-year seizure freedom (eg, a normal MRI and convulsive seizures in the previous year has a probability of seizure freedom at 5 years of approximately 0.19).CONCLUSIONS AND RELEVANCE: Readily identified clinical features and investigations are associated with reduced probability of good outcome and need consideration when planning presurgical evaluation.

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: 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.

Background Phenobarbital is an effective treatment for epilepsy but concerns remain over its potential neurocognitive toxicity. This prospective study evaluated the effects of phenobarbital treatment on cognition and mood in people with epilepsy in rural China. Methods We recruited 144 adults with convulsive seizures and 144 healthy controls from six sites in rural China. People with epilepsy were treated with phenobarbital monotherapy for 12 months. At baseline, and at 3, 6 and 12 months, cases and controls were evaluated with a battery of neuropsychological tests: the Mini-Mental State Examination, the Hamilton Depression Rating Scale, a digit span test, a verbal fluency test, an auditory verbal learning test and a digit cancellation test. Efficacy of phenobarbital treatment was evaluated at the end of follow-up for those with epilepsy. Results Cognitive test scores and mood ratings were available for 136 (94%) people with epilepsy and 137 (95%) controls at the 12 month follow-up. Both groups showed slightly improved performance on a number of neuropsychological measures. The people with epilepsy showed greater performance gains (p=0.012) in verbal fluency. Nine people with epilepsy complained of memory problems during the treatment period. Conclusion In this study, phenobarbital was not found to have a major negative impact on cognitive function of people with convulsive seizures and some cognitive gains were observed, possibly due to improved seizure control.

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.

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.

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.

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.

The standardised mortality ratio in people with epilepsy is raised to between 2 and 3 compared with the general population. Some biomarker levels, including higher C-reactive protein (CRP), higher glycosylated haemoglobin (HbA1c) and lower estimated glomerular filtration rate (eGFR), are associated with an increase risk of premature mortality. These biomarkers were measured in 125 people with refractory epilepsy to estimate the potential effect of antiepileptic drug (AED) use on these markers. Multiple regression analysis showed that valproate (N=50) use was associated with 55% lower mean CRP concentrations and higher mean eGFR values; and phenytoin (N=32) use with 4% lower mean HbA1c values. These potentially represent health markers improved by AEDs. On the other hand, lamotrigine use (N=48) was associated with 13% lower mean eGFR and this may represent a negative effect on a health marker. These preliminary observations clearly require further controlled studies ideally in people on AED monotherapy.

Summary Purpose: It is now generally accepted that people with epilepsy are at increased risk of premature death compared with peers in the general population. It has, however, not been clearly established how this risk changes over time, nor whether mortality rates have been changing over time. Methods: We carried out a systematic review: (1) To determine the pattern of change of mortality risk relative to the general population in people with epilepsy in the course of their condition as measured by standardized mortality ratios (SMRs), by reviewing longitudinal prospective cohort studies. (2) To establish whether there have been any changes in reported mortality rates for epilepsy in general populations over time. This was complemented by comparison of SMRs in people with epilepsy in the same types of source populations (population-based, hospital-based, and institutional studies) in different time periods to ascertain any changes in reported mortality rates. Results: The SMR is highest in the initial years after diagnosis and subsequently decreases. There is a suggestion that there may be an increase after 10 years from diagnosis despite the fact that the majority of people in these cohorts are in long-term remission. There is no evidence that either the overall SMR or the mortality rate of people with epilepsy has changed significantly over time. Discussion: Further population and cohort studies are needed to confirm these findings.

Suicide is an important cause of premature death, and people with epilepsy are thought to be at increased risk for suicide. Antiepileptic drugs (AEDs) continue to be the mainstay of epilepsy treatment, but the benefits of seizure control must be balanced with their psychotropic potential. In recent years, suicidality has been recognized as a complication of several groups of drugs and, most recently, AEDs were implicated in an alert by the US Food and Drug Administration. The risk of suicidal ideation and behavior as side effects of AED treatment is low, and in people with epilepsy, such a risk must be balanced against the risk of not treating the seizures.

In old and modern times and across cultures, recurrent seizures have been attributed to the lunar phase. It is unclear whether this relationship should be classified as a myth or whether a true connection exists between moon phases and seizures. We analyzed the worldwide aggregated search queries related to epilepsy health-seeking behavior between 2005 and 2012. Epilepsy-related Internet searches increased in periods with a high moon illumination. The overall association was weak (r=0.11, 95% confidence interval: 0.07 to 0.14) but seems to be higher than most control search queries not related to epilepsy. Increased sleep deprivation during periods of full moon might explain this positive association and warrants further study into epilepsy-related health-seeking behavior on the Internet, the lunar phase, and its contribution to nocturnal luminance.

Pregabalin (PGB) is a new antiepileptic drug (AED) which is a structural, non-functional analogue of gamma-aminobutyric acid. It acts at presynaptic calcium channels to modulate neurotransmitter release in the CNS. While the efficacy and tolerability of PGB have been demonstrated in several randomised controlled trials, few studies have addressed long-term outcome in large groups of patients. A cohort of patients attending a tertiary referral centre for epilepsy was identified as having started taking PGB. Patients' data were obtained through medical records. Of 402 patients included, 42% of patients were still taking PGB at last follow-up. The estimated 2.5-year retention rate was 32%. Males appeared more likely to continue on PGB therapy than females. The common adverse experiences (AEs) leading to withdrawal were CNS-related, psychiatric AEs and weight gain. Published retention rates for levetiracetam appear to be higher, and those for gabapentin lower, than the rates estimated for PGB.

P>Purpose:We attempted to establish whether month and season, or lunar phase, are risk factors for sudden unexpected death in epilepsy (SUDEP), as these have all been suggested as potential risk factors.Methods:We used the dataset of the National Sentinel Clinical Audit of Epilepsy-Related Death; all death certificates of people who died in England and Wales between September 1999 and August 2000 and in which epilepsy was mentioned were reviewed. We identified people who probably died of SUDEP during that time. We compared the number of observed SUDEP cases with those expected according to month of death, season of death, minimum external temperature, mean external temperature, and lunar phase.Results:Of 2,412 deaths, we identified 409 probable SUDEPs. We found no evidence for an association between either mean temperature group or minimum temperature group and SUDEP, although there appeared to be a slight excess of sudden deaths in the coldest (mean temperature) groups. We also found no association between SUDEP and month, season, or lunar phase.Discussion:Some causes of death appear to be related to temperature, but we found no convincing evidence to support a link between temperatures or seasons and sudden unexpected death in epilepsy. It is important to identify risk factors for SUDEP, but it is also important that evidence is established before hypotheses are accepted.

Purpose: Suicide is more common in populations with epilepsy, but estimates vary concerning the magnitude of the risk. We aimed to estimate the risk using meta-analysis. Methods: A literature search identified 74 articles (76 cohorts of people with epilepsy) in whom the number of deaths by suicide in people with epilepsy and the number of person-years at risk could be estimated. Standardized mortality ratios (SMRs) with 95% confidence intervals (CIs) were calculated for each cohort, for groups of cohorts, and for the total population. Results: The overall SMR was 3.3 (95% CI 2.8-3.7) based on 190 observed deaths by suicide compared with 58.4 expected. The SMR was significantly increased in people with incident or newly diagnosed epilepsy in the community (SMR 2.1), in populations with mixed prevalence and incidence cases (SMR 3.6), in those with prevalent epilepsy (SMR 4.8), in people in institutions (SMR 4.6), in people seen in tertiary care clinics (SMR 2.28), in people with temporal lobe epilepsy (SMR 6.6), in those following temporal lobe excision (SMR 13.9), and following other forms of epilepsy surgery (SMR 6.4). The SMR was significantly low overall in two community-based studies of people with epilepsy and developmental disability. Discussion: We confirm that the risk of suicide is increased in most populations of people with epilepsy. Psychiatric comorbidity has been demonstrated to be a risk factor for suicide in the general population and in people with epilepsy, and such comorbidity should thus be identified and treated. Language: en

Purpose of review For many years, it has been accepted that suicide may be more common in people with epilepsy. Recent studies have investigated risk factors. Recent findings Studies have shown that a history of psychiatric disease increases the risk of suicide in a person with epilepsy but have also shown that the risk of suicide in people with epilepsy is increased in the absence of a psychiatric history. People with epilepsy may have undiagnosed and untreated psychiatric illness, and depression (both reactive and endogenous) may occur. Studies have suggested that the relationship between seizures and depression or suicidal behaviour may be bidirectional, and both major depression and attempted suicide increase the risk of developing seizures. Forced normalization and postictal psychosis may also contribute to suicidal behaviour. Antiepileptic drugs have been implicated in causing psychiatric adverse effects and suicidal behaviour. Summary It is important to take an holistic approach when evaluating and monitoring people with epilepsy. Clinicians should screen for depression and treat appropriately. The choice of which antiepileptic drug to use may also be influenced by the presence of depression or suicidal ideation.

Suicide is an important cause of premature death. In the general population, most people who commit suicide have a psychiatric problem at the time. People with epilepsy are thought to be at increased risk from suicide and suicidality (suicidal ideation or behaviour). Standardized mortality ratios estimated for suicide in people with epilepsy are usually between 3 and 5. Risk factors for suicide in people with epilepsy have been suggested, including early age of onset of seizures, temporal lobe epilepsy, severe seizures and recent control of seizures. Psychiatric co-morbidity also seems to be an important factor in people with epilepsy who commit suicide. In recent years, suicidality has been recognized as a complication of several groups of drugs and, most recently, antiepileptic drugs (AEDs) have been implicated. The US FDA performed a meta-analysis of 199 placebo-controlled studies of 11 AEDs used for seizure control, psychiatric or 'other' indications. There were four completed suicides in those taking AEDs and none in those taking placebo. The odds ratio for suicidal behaviour or ideation was 1.8 (95% CI 1.24, 2.66), suggesting that people taking AEDs are more at risk than those taking placebo. The odds ratio was significantly raised for people taking AEDs for epilepsy, but not for the other indications. AEDs may affect mood by means of several mechanisms. In people with epilepsy, however, the concept of forced normalization (or alternative psychosis) may also play a part. In this situation, control of seizures (by AEDs or epilepsy surgery) may alternate with psychotic features or, less commonly, depression, although this is not fully understood. The risk of suicidal ideation and behaviour as adverse effects of AED treatment, although increased, seems low. As a result of the FDA's alert clinicians are supposed to inform patients and their families of this increased risk but it is important to place it in a proper perspective. Some people with epilepsy are more likely to develop psychiatric adverse effects with any AEDs, and these people should be followed closely whenever a new AED is introduced. Nonetheless, in people with epilepsy the risk of suicidality associated with AEDs needs to be balanced against the risk of not treating the seizures. In fact, the risk of stopping AEDs or refusing to start AEDs for the control of a seizure disorder may be significantly worse and may result in serious harm, including death of the patient.

OBJECTIVE: The Global Campaign Against Epilepsy demonstration project in rural China aimed: to reduce the treatment gap and morbidity of people with epilepsy by using community-level interventions; to train and educate health professionals; to dispel stigma; to identify potential for prevention and to develop models of integration of epilepsy control into the local health systems. We report the overall results of the demonstration project, focusing on the prevalence and the change in the treatment gap of epilepsy after an intervention. METHODS: Door-to-door epidemiological surveys were carried out before, and 6 months after the end of, an intervention project for epilepsy in rural settings in five provinces of China. The intervention consisted of a treatment programme available to patients without prior appropriate treatment and a public health educational programme about epilepsy. The sampled population in the second survey was 51 644 people. FINDINGS: In the second survey, epilepsy was confirmed in 320 people, yielding a lifetime prevalence of 6.2/1000 and a prevalence of active epilepsy of 4.5/1000. The lifetime prevalence and prevalence of active epilepsy in the first survey were 7.0/1000 and 4.6/1000, respectively. The treatment gap of active epilepsy in the second survey was 49.8%, 12.8 percentage points lower than that of the first survey (62.6%). CONCLUSION: The results of this study suggest that the intervention measures used were possibly effective and evidently feasible in rural China, contributing to a decrease in the treatment gap of epilepsy.

Background: People with epilepsy are known to be at increased risk of death by drowning but there are few data available regarding the size of the risk. We aimed to quantify the risk using meta-analysis. Methods: A literature search identified 51 cohorts of people with epilepsy in whom the number of deaths by drowning in people with epilepsy and the number of person-years at risk could be estimated. Population data were taken from the WHO Statistical Information Service or from the UK Office for National Statistics where available. Standardized mortality ratios (SMRs) with 95% CIs were calculated for each cohort, for groups of cohorts, and for the total population. Additionally, an SMR for drowning in people with epilepsy in England and Wales (1999–2000) was calculated using National Registries. Results: Eighty-eight drowning deaths were observed compared with 4.70 expected, giving an SMR of 18.7 (95% CI 15.0 to 23.1). Compared with community-based incident studies (SMR 5.4), the SMR was significantly raised in prevalent epilepsy (SMR 18.0), in people with epilepsy and learning disability (SMR 25.7), in those in institutional care (SMR 96.9), and in those who had a temporal lobe excision (SMR 41.1). The SMR for people with epilepsy in England and Wales was 15.3. Conclusion: The risk of drowning in people with epilepsy is raised 15- to 19-fold compared with people in the general population. It is important that people with epilepsy and their carers be informed of these risks so that deaths can be prevented.

Fatty acids (FAs) determine membrane properties and may affect cardiac and neuronal function. In this study, FA profiles were determined in 56 patients with epilepsy who participated in a 12-week double-blind randomized trial of omega-3 FA supplementation (1 g eicosapentaenoic acid and 0.7 g docosahexaenoic acid daily). At baseline, subjects on carbamazepine (CBZ) had lower docosahexaenoic acid levels, lower levels of long-chain omega-3 FAs, and a lower Omega-3 Index (a risk factor for coronary heart disease mortality), whereas those on oxcarbazepine had higher total polyunsaturated FAs and a higher Omega-3 Index. Following omega-3 FA supplementation, the Omega-3 Index, eicosapentaenoic acid, and docosahexaenoic acid concentrations significantly increased. Patients on CBZ exhibited a less favorable FA profile, associated with a greater risk of coronary heart disease mortality. As arrhythmias are thought to be an important mechanism in coronary heart disease mortality and sudden unexplained death in epilepsy (SUDEP), the effect of CBZ effect in reducing omega-3 FAs might potentially explain some cases of SUDEP among patients prescribed CBZ.

The decision to treat or not treat individuals who have suffered a single epileptic seizure is based on clinical factors, which are considered within the individual's social, cultural, and emotional environment. Even if optimally communicated, individuals and their carers will make different decisions about first seizures and their treatment, as they will judge the risks and benefits of treatment (or its deferment) in this wider context. There is a significant body of literature that describes the impact of established epilepsy on aspects of an individual's overall quality of life (QoL), and more recently evidence is emerging about the factors that may be important in 2 years after a single seizure on and off treatment. Little research, however, has considered the importance of nonclinical factors in individual's choices at the time of a first seizure, and in particular in an individual's decision to use or not use treatment. Understanding these issues may improve communication of risks and benefits to individuals, and may offer insight into the mechanisms by which social and socioeconomic disadvantage occur in epilepsy.

Recreational scuba diving is a popular sport, and people with epilepsy often ask physicians whether they may engage in diving. Scuba diving is not, however, without risk for anyone; apart from the risk of drowning, the main physiological problems, caused by exposure to gases at depth, are decompression illness, oxygen toxicity, and nitrogen narcosis. In the United Kingdom, the Sport Diving Medical Committee advises that, to dive, someone with epilepsy must be seizure free and off medication for at least 5 years. The reasons for this are largely theoretical. We review the available evidence in the medical literature and diving websites. The risk of seizures recurring decreases with increasing time in remission, but the risk is never completely abolished. We suggest that people with epilepsy who wish to engage in diving, and the physicians who certify fitness to dive, should be provided with all the available evidence. Those who have been entirely seizure-free on stable antiepileptic drug therapy for at least 4 years, who are not taking sedative antiepileptic drugs and who are able to understand the risks, should then be able to consider diving to shallow depths, provided both they and their diving buddy have fully understood the risks.

People with epilepsy (PWE), particularly those with more severe seizures, are at risk of premature death. The contribution of deaths unrelated to epilepsy to this risk is likely to be significant. Recent studies indicate that comorbid conditions are similarly increased in PWE. The reason for these increases in unrelated deaths and comorbid conditions is unclear. In this article, we argue that having seizures is psychologically stressful, and that this stress can lead to a whole range of pathophysiological changes that may trigger various physical illnesses. Hence, psychological stress may be a significant factor contributing to the increase in mortality and comorbidity rates in PWE. This speculation is unlikely to be proven at this stage because of the complexity of the trials required. In PWE who continue to have seizures, more needs to be done to help them cope with the stress. Additionally, attention needs to be paid to improve nutritional status and physical fitness. These steps are likely to enhance the overall health of PWE and may reduce premature mortality and comorbidity rates.

Summary Mortality risk-adjustment comorbidity indices are an efficient means of controlling for the important confounding effect of somatic and psychiatric comorbidities in observational mortality studies. We carried out an external validation study and compared the performance of the Charlson, Elixhauser and Epilepsy-specific (ES) indices using the National General Practice Study of Epilepsy, a community-based prospective cohort of 558 people with incident epilepsy followed for 23.3 years (median). The minimum and maximum crude mortality rates were similar between the three indices, but mid-range Elixhauser scores predicted lower rates relative to the two other indices. Two of the stratified Charlson Kaplan-Meier survival probability curves crossed, and a low Elixhauser score was associated with a counterintuitive increase in mortality. Each comorbidity index was a significant predictor of mortality in the Cox proportional hazards models, although there was evidence that the unadjusted Charlson regression model violated the proportionality assumption. Harrell's c-statistics were >0.87 in all adjusted models. All three indices performed well, but there is evidence that the ES index may be more discriminating and have a better model fit than the Charlson or Elixhauser indices in a community-based clinical cohort of people with epilepsy.

To the Editor , We read with interest the recent paper by Bardai et al ,1 which reports that epilepsy and antiepileptic drugs (AEDs) were independently associated with sudden cardiac death (SCD). We are unconvinced that such a clear distinction between disease and drug effects can be made in this study as all people with epilepsy were by definition taking AEDs. We believe this is why SCD risk in those with epilepsy (table 2) and in AED users with epilepsy (table …

Summary Background Many people with epilepsy need not experience further seizures if the diagnosis and treatment are correct. Most epilepsy patients have convulsions, which are usually fairly easy to diagnose. This study tested a model for treatment of people with convulsive forms of epilepsy at primary health-care level in rural areas of China. Methods Patients with convulsive epilepsy were identified at primary care level and provided with phenobarbital monotherapy. Local physicians, who were provided with special training, carried out screening, treatment, and follow-up. A local neurologist confirmed the diagnoses. Efficacy was assessed from the percentage reduction in seizure frequency from baseline and the retention of patients on treatment. Findings The study enrolled 2455 patients. In 68% of patients who completed 12 months' treatment, seizure frequency was decreased by at least 50%, and a third of patients were seizure free. 72% of patients who completed 24 months' treatment had reduction of seizure frequency of at least 50% and a quarter of patients remained seizure free. Probability of retention was 0·84 at 1 year, and 0·76 at 2 years. Medication was well tolerated and reported adverse events were mild; only 32 patients (1%) discontinued medication because of side-effects. Interpretation This pragmatic study confirmed that this simple protocol was suitable for the treatment of convulsive forms of epilepsy in rural areas of China. Physicians with basic training could treat epilepsy patients with phenobarbital, with beneficial effects for most patients with convulsive seizures. Few cognitive or behavioural adverse events were noted, but formal psychometric testing was not done.

Animal studies and a preliminary clinical observation suggest that nutritional supplementation with long chain omega-3 fatty acids (omega-3 FAs) may be useful in the nonpharmacological treatment of patients with epilepsy. Omega-3 FAs increase seizure thresholds, and lower inflammatory mediators, which are increased in patients with epilepsy. In this first randomized, placebo-controlled parallel group trial of omega-3 FA supplementation with 1 g eicosapentaenoic acid (EPA) and 0.7 g docosahexaenoic acid (DHA) daily, 57 patients completed a 12-week double-blind phase. Seizure frequency was reduced over the first 6 weeks of treatment in the supplement group, but this effect was not sustained. The supplementation produced a significant increase in EPA and DHA concentrations and a reciprocal fall in arachidonic and linoleic acid concentrations. No change in serum AED concentrations was detected. Further studies are required to examine different omega-3 FA preparations, different doses, longer treatment duration, and larger sample sizes.

Objectives : To describe the clinical characteristics of epilepsy in a representative sample of the UK population, including seizure frequency and severity; overall severity of epilepsy; patterns of anti-epileptic drug (AED) use; and the impact of epilepsy on patients' lives. Secondly, to determine if these characteristics differ according to age. Method : A large, geographically comprehensive survey of people with epilepsy by means of a postal questionnaire distributed by general practitioners to 3455 unselected patients receiving AEDs for epilepsy, regardless of age or type of epilepsy and including all regions of the UK. Data were collected on age and gender; age of onset of seizures; seizure frequency and severity; AED use and adverse effect levels; and impact on life of epilepsy. Sub-analyses were performed with stratification by epilepsy severity and age-group. Results : There were 1652 completed replies. The mean age was 44.2 years; there were 47.2% males, 48.5% females (4.4% not recorded). The mean age at first seizure, 25.1 years, and the mean duration of epilepsy, 19.7 years, were comparable with previous studies. In the preceding one year, 51.7% of patients had no seizures; 7.9% one seizure, 17.2% 2–9 seizures and 23.2% 10 or more. Sixty-four percent of patients had epilepsy classified as mild and 32% severe. There was a marked and significant decrement of seizure frequency with increasing age. The most commonly used AEDs were carbamazepine (37.4%), valproate (35.7%), phenytoin (29.4%), phenobarbitone or primidone (14.2%) and lamotrigine (10.3%). Monotherapy was used in 68% of patients. Patients taking multiple AEDs reported significantly higher levels of adverse effects and worse seizure control. The major impacts of epilepsy on life were work and school difficulties, driving prohibition, psychological and social life. The impacts listed varied with the epilepsy severity and age. Conclusions : Seizures remain uncontrolled in up to half of all people with epilepsy in the UK with significant impact on work, family and social life. Previously, there has been a deficiency of data on the characteristics of epilepsy in older people, although it is recognized that the condition is of increasing epidemiological importance in this age group. We have found clear differences in the clinical characteristics of epilepsy in older people, particularly that seizure frequency appears to decline with increasing age.

Serial quantitative magnetic resonance imaging (MRI) allows the detection of subtle volumetric changes in brain volume. We used serial volumetry and voxel-based difference image analysis to quantify and characterize longitudinal changes in the hippocampus, cerebellum, and neocortex in younger and middle-age individuals. Paired volumetric MRI brain scans 3.5 years apart were performed on 90 healthy subjects 14 to 77 years old. Quantitative assessment of registered images included hippocampal volumetry, cerebellar volumetry, and automatically determined regional brain volumes. Longitudinal volume changes in three age epochs (35, 35-54,54 years) were compared and neocortical changes beyond regions of interest were visualized using filtered difference images. Cross-sectional analysis revealed a significant association between age and reduction in all brain volumes except hippocampal volume. Changes in normalized hippocampal and white matter volume were significantly different among the three groups. Individual analysis revealed 5 subjects with significant longitudinal volume changes lying outside the normative range. Difference image analysis showed global involutional changes in the54 age group. Our findings suggest that cross-sectional observations in intracranial volume, cerebellar volume, and gray matter volume are likely to reflect uniform rates of volume loss or secular changes. Accelerated brain atrophy was seen from the age of 35-54 and increased rates of hippocampal atrophy from the age of 54. Our findings emphasize the importance of controlling for age effects when studying pathological brain changes over a wide age range.

Women with epilepsy have different needs from men, particularly associated with childbearing. Despite clinical guidelines, the care of women with epilepsy remains suboptimal. The aim of this study was to establish whether women with epilepsy recall being given information on topics relating to childbearing. Design of study and methods included a postal questionnaire study of 795 women with epilepsy and of childbearing age. The respondents were identified through both general practices and hospital clinics as part of the Clinical Standards Advisory Group study into Epilepsy Services. Of those women who considered the questions personally relevant, 38-48% recalled receiving information about contraception, pre-pregnancy planning, folic acid and teratogenicity, with lower overall proportions among adolescent women. The proportions that recalled receiving information about vitamin K, safety in child-care and breast-feeding were lower at 12, 24 and 24%, respectively. While it is recognised that information provided may not be recalled, our results suggest that further measures are required to improve the effectiveness of information provision in the UK in relation to women of childbearing age with epilepsy.

The reported incidence (rate of new cases in a population) of epilepsy is consistently lower in high-income than in lower-income economies, whereas opinions vary regarding comparative prevalence rates (proportion of the population with epilepsy). For any condition that does not influence mortality, lifetime prevalence should approximate to the cumulative incidence. We suspected that epilepsy prevalence might be uniform throughout the world, whereas incidence is higher in resource-poor countries. To test whether our suspicion was reasonable, we conducted a Medline search to estimate the prevalence of active and lifetime epilepsy in different economic areas throughout the world. We found that the range of estimated prevalence of epilepsy may be broadly similar throughout the world, but comparison is limited by lack of door-to-door studies in high-income economies and by variations in the definitions of active epilepsy. We contend that any inconsistencies between incidence and prevalence are due largely to the excess premature death rate in people with epilepsy in lower-income economies. Much of the variability in epidemiologic indices arises from differences in study methodology, definitions, and risk factors. The epidemiology of epilepsy, and particularly its mortality, needs thorough investigation using uniform definitions that do not include antiepileptic drug use; causes of death should be identified and actions, including treatment and education, should be taken to avoid preventable deaths.

Network meta-analysis (NMA) is a new technique that allows multiple treatment comparisons and provides estimates of effect sizes for all possible pair-wise comparisons. Several NMAs of antiepileptic drug (AED) efficacy and tolerability in individuals with refractory focal epilepsy, however, came to non-specific and, in some cases, divergent conclusions. We review some clinical factors that may be responsible for these inconsistent findings.A major issue is the small number of individuals included in the meta-analyses with consequent wide confidence intervals and lack of ability to achieve significant results. Further issues are lack of robustness of the measured efficacy outcome-the responder ratio (the percentage of individuals with a50 % improvement in seizure frequency); the selection of randomized studies (RCTs) included, i.e., the inclusion of studies with heterogeneous populations (children and adults); and inclusion of people treated with different doses of the experimental drug. Some methods of analysing data from RCTs, such as the last observation carried forward (LOCF) analysis, the choice of different phases of the study to compare to baseline, and the year in which the trial was conducted, selectively affect measurement of efficacy outcomes. Titration speed and other methodological aspects selectively affect tolerability.Several factors restrict the analysis of clinically useful estimates of the comparative efficacy of AEDs, while analysis of tolerability may be easier to accomplish.

Experimental and human data suggest that progressive cerebral damage may result from the cumulative effect of brief recurrent seizures. Longitudinal studies addressing this fundamental question, however, are lacking. We have addressed this need with a large prospective community-based observational study, which aims to rescan 154 patients with chronic active epilepsy and 90 patients with newly diagnosed seizures, after an interval of 3.5 years. Here, we describe the quantitative magnetic resonance methods used to identify subtle volume changes in hippocampal, cerebellar, and neocortical structures over time and report preliminary findings. Using this methodology, we have previously shown that we can reliably detect individual hippocampal volume (HV) and cerebellar volume (CBV) changes greater than 3.1 and 3.0%, respectively (Lemieux et al, 2000). Analysis of the first 53 subjects (24 patients with chronic active epilepsy, 9 patients with newly diagnosed seizures, and 20 controls) has demonstrated significant HV losses in 4 individuals. Automated and semiautomated calculation has detected significant reductions in CBV, total brain volume, and gray matter volume in 2, 3, and 1 subject, respectively. There were no significant white matter volume losses detected. Data collected from rescanning the entire cohorts will help to provide further information on the relationship between recurrent seizures and secondary brain damage.

The prevalence of epilepsy is generally taken as between 5 and 10 cases per 1000 persons, and the overall incidence as about 50 cases per 100 000 persons. The rates are dependent on case ascertainment and on definitions used. The prognosis depends on many factors, including the number of seizures at presentation, the seizure type and the use of anti-epileptic drugs. Epilepsy carries an excess mortality; the cause of death can be unrelated to epilepsy, related to the underlying disease causing epilepsy, or related to epilepsy itself.

Background: Epilepsy carries an increased risk of premature death. For some people with intractable focal epilepsy, surgery offers hope for a seizure-free life. The authors aimed to see whether epilepsy surgery influenced mortality in people with intractable epilepsy. Methods: The authors audited survival status in two cohorts (those who had surgery and those who had presurgical assessment but did not have surgery). Results: There were 40 known deaths in the non-surgical group (3365 person years of follow-up) and 19 in the surgical group (3905 person-years of follow-up). Non-operated patients were 2.4 times (95% CI 1.4 to 4.2) as likely to die as those who had surgery. They were 4.5 times (95% CI 1.9 to 10.9) as likely to die a probable epilepsy-related death. In the surgical group, those with ongoing seizures 1 year after surgery were 4.0 (95% CI 1.2 to 13.7) times as likely to die as those who were seizure-free or who had only simple partial seizures. Time-dependent Cox analysis showed that the yearly outcome group did not significantly affect mortality (HR 1.3, 95% CI 0.9 to 1.8). Conclusion: Successful epilepsy surgery was associated with a reduced risk of premature mortality, compared with those with refractory focal epilepsy who did not have surgical treatment. To some extent, the reduced mortality is likely to be conferred by inducing freedom from seizures. It is not certain whether better survival is attributable only to surgery, as treatment decisions were not randomised, and there may be inherent differences between the groups.