Sleep and seizure risk in epilepsy: bed and wake times are more important than sleep duration.

Sleep duration, sleep deprivation and the sleep-wake cycle are thought to play an important role in the generation of epileptic activity and may also influence seizure risk. Hence, people diagnosed with epilepsy are commonly asked to maintain consistent sleep routines. However, emerging evidence paints a more nuanced picture of the relationship between seizures and sleep, with bidirectional effects between changes in sleep and seizure risk in addition to modulation by sleep stages and transitions between stages. We conducted a longitudinal study investigating sleep parameters and self-reported seizure occurrence in an ambulatory at-home setting using mobile and wearable monitoring. Sixty subjects wore a Fitbit smartwatch for at least 28 days while reporting their seizure activity in a mobile app. Multiple sleep features were investigated, including duration, oversleep and undersleep, and sleep onset and offset times. Sleep features in participants with epilepsy were compared to a large (n = 37 921) representative population of Fitbit users, each with 28 days of data. For participants with at least 10 seizure days (n = 34), sleep features were analysed for significant changes prior to seizure days. A total of 4956 reported seizures (mean = 83, standard deviation = 130) and 30 485 recorded sleep nights (mean = 508, standard deviation = 445) were included in the study. There was a trend for participants with epilepsy to sleep longer than the general population, although this difference was not significant. Just 5 of 34 participants showed a significant difference in sleep duration the night before seizure days compared to seizure-free days. However, 14 of 34 subjects showed significant differences between their sleep onset (bed) and/or offset (wake) times before seizure occurrence. In contrast to previous studies, the current study found undersleeping was associated with a marginal 2% decrease in seizure risk in the following 48 h (P < 0.01). Nocturnal seizures were associated with both significantly longer sleep durations and increased risk of a seizure occurring in the following 48 h. Overall, the presented results demonstrated that day-to-day changes in sleep duration had a minimal effect on reported seizures, while patient-specific changes in bed and wake times were more important for identifying seizure risk the following day. Nocturnal seizures were the only factor that significantly increased the risk of seizures in the following 48 h on a group level. Wearables can be used to identify these sleep-seizure relationships and guide clinical recommendations or improve seizure forecasting algorithms.

User experience of a seizure risk forecasting app: A mixed methods investigation.

OBJECTIVE: Over recent years, there has been a growing interest in exploring the utility of seizure risk forecasting, particularly how it could improve quality of life for people living with epilepsy. This study reports on user experiences and perspectives of a seizure risk forecaster app, as well as the potential impact on mood and adjustment to epilepsy. METHODS: Active app users were asked to complete a survey (baseline and 3-month follow-up) to assess perspectives on the forecast feature as well as mood and adjustment. Post-hoc, nine neutral forecast users (neither agreed nor disagreed it was useful) completed semi-structured interviews, to gain further insight into their perspectives of epilepsy management and seizure forecasting. Non-parametric statistical tests and inductive thematic analyses were used to analyse the quantitative and qualitative data, respectively. RESULTS: Surveys were completed by 111 users. Responders consisted of "app users" (n = 58), and "app and forecast users" (n = 53). Of the "app and forecast users", 40 % believed the forecast was accurate enough to be useful in monitoring for seizure risk, and 60 % adopted it for purposes like scheduling activities and helping mental state. Feeling more in control was the most common response to both high and low risk forecasted states. In-depth interviews revealed five broad themes, of which 'frustrations with lack of direction' (regarding their current epilepsy management approach), 'benefits of increased self-knowledge' and 'current and anticipated usefulness of forecasting' were the most common. SIGNIFICANCE: Preliminary results suggest that seizure risk forecasting can be a useful tool for people with epilepsy to make lifestyle changes, such as scheduling daily events, and experience greater feelings of control. These improvements may be attributed, at least partly, to the improvements in self-knowledge experienced through forecast use.

Influence of comorbidity on mortality in patients with epilepsy and psychogenic nonepileptic seizures.

OBJECTIVE: This study aims to determine the contribution of comorbidities to excess psychogenic nonepileptic seizures (PNES) mortality. METHODS: A retrospective cohort study was conducted of tertiary epilepsy outpatients from St. Vincent's Hospital Melbourne, Australia with an 8:1 comparison cohort, matched by age, sex, and socioeconomic status (SES) to national administrative databases between 2007 and 2017. Privacy-preserving data linkage was undertaken with the national prescription, National Death Index, and National Coronial Information System. Forty-five comorbid disease classes were derived by applying the Australian validated RxRisk-V to all dispensed prescriptions. We fitted Cox proportional hazard models controlling for age, sex, SES, comorbidity, disease duration, and number of concomitant antiseizure medications, as a marker of disease severity. We also performed a parallel forward-selection change in estimate strategy to explore which specific comorbidities contributed to the largest changes in the hazard ratio. RESULTS: A total of 13 488 participants were followed for a median 3.2 years (interquartile range = 2.4-4.0 years), including 1628 tertiary epilepsy outpatients, 1384 patients with epilepsy, 176 with PNES, and 59 with both. Eighty-two percent of epileptic seizures and 92% of typical PNES events were captured in an epilepsy monitoring unit. The age-/sex-/SES-adjusted hazard ratio was elevated for epilepsy (4.74, 95% confidence interval [CI] = 3.36-6.68) and PNES (3.46, 95% CI = 1.38-8.68) and remained elevated for epilepsy (3.21, 95% CI = 2.22-4.63) but not PNES (2.15, 95% CI = .77-6.04) after comorbidity adjustment. PNES had more pre-existing comorbidities (p = .0007), with a three times greater median weighted Rx-RiskV score. Psychotic illness, opioid analgesia, malignancies, and nonopioid analgesia had the greatest influence on PNES comorbid risk. SIGNIFICANCE: Higher comorbidity appears to explain the excess PNES mortality and may represent either a wider underrecognized somatoform disorder or a psychological response to physical illness. Better understanding and management of the bidirectional relationship of these wider somatic treatments in PNES could potentially reduce the risk of death.

Adherence patterns in antiseizure medications influencing risk of sudden unexplained death in epilepsy: A data linkage study using dispensed prescriptions.

OBJECTIVE: Medication adherence is considered an important risk factor for sudden unexpected death in epilepsy (SUDEP), although measurement accuracy is difficult. Using prescription dispensations, this study aims to estimate antiseizure medication (ASM) adherence and identify adherence patterns that influence epilepsy mortality. METHODS: This is a retrospective cohort study of tertiary epilepsy outpatients seen at St Vincent's Hospital Melbourne, Victoria, Australia, from January 1, 2012 until December 31, 2017. Privacy-preserving data linkage with the Australian national prescription, death, and coroner's databases was performed. We fitted a four-cluster longitudinal group-based trajectory model for ASM adherence from recurring 90-day windows of prescription dispensations during a 3-year "landmark period" from January 1, 2012 to December 31, 2014, using the AdhereR package. We estimated the risk of SUDEP and all-cause death for each adherence pattern during an "observation period" from January 1, 2015 to December 31, 2017. The Cox proportional hazards and logistic regression models were adjusted for age, sex, socioeconomic status, epilepsy duration, comorbidity, drug resistance, and inadequate seizure control. RESULTS: One thousand one hundred eighty-seven participants were observed for a median of 3.2 years (interquartile range = 2.4-4.0 years). We observed 66 deaths with 10 SUDEP cases during the observation period. We identified four patterns of ASM adherence: good, 51%; declining, 24%; poor, 16%; and very poor, 9%. Declining adherence was associated with an increased risk for SUDEP, with hazard ratio (HR) = 8.43 (95% confidence interval [CI] = 1.10-64.45) at 1 year and HR = 9.17 (95% CI = 1.16-72.21) at 3 years. Compared to no ASM therapeutic change, the addition of a second to fourth ASM offered increased protection against SUDEP in patients with continuing drug-resistant epilepsy. SIGNIFICANCE: ASM nonadherence was observed in half of outpatients with epilepsy. A declining pattern of adherence, observed in a quarter of patients, was associated with more than eight times increased risk of SUDEP. Any ongoing medication interventions must include strategies to maintain and improve ASM adherence if we are to reduce the risk of SUDEP.

A cross-sectional investigation of cognition and epileptiform discharges in juvenile absence epilepsy.

OBJECTIVES: Despite the prevalence of cognitive symptoms in the idiopathic generalized epilepsies (IGEs), cognitive dysfunction in juvenile absence epilepsy (JAE), a common yet understudied IGE subtype, remains poorly understood. This descriptive study provides a novel, comprehensive characterization of cognitive functioning in a JAE sample and examines the relationship between cognition and 24-h epileptiform discharge load. METHOD: Forty-four individuals diagnosed with JAE underwent cognitive assessment using Woodcock Johnson III Test of Cognitive Abilities with concurrent 24-h ambulatory EEG monitoring. Generalized epileptiform discharges of any length, and prolonged generalized discharges ≥3 s were quantified across wakefulness and sleep. The relationship between standardized cognitive scores and epileptiform discharges was assessed through regression models. RESULTS: Cognitive performances in overall intellectual ability, acquired comprehension-knowledge, processing speed, long-term memory storage and retrieval, and executive processes were 0.63-1.07 standard deviation (SD) units lower in the JAE group compared to the population reference mean, adjusted for educational attainment. Prolonged discharges (≥3 s) were recorded in 20 patients (47.6%) from 42 available electroencephalography (EEG) studies and were largely unreported. Duration and number of prolonged discharges were associated with reduced processing speed and long-term memory storage and retrieval. SIGNIFICANCE: Cognitive dysfunction is seen in patients with JAE across various cognitive abilities, including those representing more stable processes like general intellect. During 24-h EEG, prolonged epileptiform discharges are common yet underreported in JAE despite treatment, and they show moderate effects on cognitive abilities. If epileptiform burden is a modifiable predictor of cognitive dysfunction, therapeutic interventions should consider quantitative 24-h EEG with routine neuropsychological screening. The growing recognition of the spectrum of neuropsychological comorbidities of IGE highlights the value of multidisciplinary approaches to explore the causes and consequences of cognitive deficits in epilepsy.

Exploring the Semantic Structure of WMS-IV Verbal Paired Associates using the Hub-and-Spoke Model.

OBJECTIVES: This study aimed to identify a well-fitting and theoretically justified item-level latent factor structure for the Wechsler Memory Scales (WMS)-IV verbal paired associates (VerbalPA) subtest to facilitate the ease and accuracy of score interpretations for patients with lateralized temporal lobe epilepsy (TLE). METHODS: Archival data were used from 250 heterogeneous neurosciences patients who were administered the WMS-IV as part of a standard neuropsychological assessment. Three theoretically motivated models for the latent structure of VerbalPA were tested using confirmatory factor analysis. The first model, based on cognitive principles of semantic processing from hub-and-spoke theory, tested whether performance is related to specific semantic features of target words. The second, motivated by the Cattell-Horn-Carroll (CHC) model of cognitive abilities, investigated whether the associative properties of items influence performance. A third, Hybrid model tested whether performance is related to both semantic and associative properties of items. The best-fitting model was tested for diagnostic group effects contrasting the heterogeneous neuroscience patients with subsets of left and right TLE (n = 51, n = 26, respectively) patients. RESULTS: The Hybrid model was found to have the best fit. Patients with left TLE scored significantly less well than the heterogeneous neurosciences sample on selected semantic factor scores, although the effect size was small. CONCLUSIONS: Future editions of the WMS may consider implementing a semantic scoring structure for the VerbalPA to facilitate test score interpretation. Additionally, these results suggest that principles of hub-and-spoke theory may be integrated into CHC cognitive ability taxonomy.

Resting-state functional connectivity in the idiopathic generalized epilepsies: A systematic review and meta-analysis of EEG and MEG studies.

For idiopathic generalized epilepsies (IGE), brain network analysis is emerging as a biomarker for potential use in clinical care. To determine whether people with IGE show alterations in resting-state brain connectivity compared to healthy controls, and to quantify these differences, we conducted a systematic review and meta-analysis of EEG and magnetoencephalography (MEG) functional connectivity and network studies. The review was conducted according to PRISMA guidelines. Twenty-two studies were eligible for inclusion. Outcomes from individual studies supported hypotheses for interictal, resting-state brain connectivity alterations in IGE patients compared to healthy controls. In contrast, meta-analysis from six studies of common network metrics clustering coefficient, path length, mean degree and nodal strength showed no significant differences between IGE and control groups (effect sizes ranged from -0.151 -1.78). The null findings of the meta-analysis and the heterogeneity of the included studies highlights the importance of developing standardized, validated methodologies for future research. Network neuroscience has significant potential as both a diagnostic and prognostic biomarker in epilepsy, though individual variability in network dynamics needs to be better understood and accounted for.

Quality of life and its association with comorbidities and adverse events from antiepileptic medications: Online survey of patients with epilepsy in Australia.

OBJECTIVE: This study aimed to explore the quality of life (QoL) of adult patients with epilepsy (PwE) in Australia and its relationship with comorbidities and adverse events (AEs) from antiepileptic drugs (AEDs). METHODS: Cross-sectional surveys were completed by PwE, or carer proxies, recruited via the online pharmacy application MedAdvisor and Australian PwE Facebook groups from May to August 2018. Data were collected on demographics, epilepsy severity and management, AEs, comorbidities, and QoL (using the Patient-Weighted Quality of Life in Epilepsy Inventory [QOLIE-10-P] total score). Two linear regression models were constructed to explore associations between AEs or comorbidities and QOLIE-10-P score, with possible confounders determined using stepwise selection. RESULTS: Nine hundred and seventy-eight of 1267 responses were eligible (mean age of respondents: 44.5 years, 64% female, 52% employed). Recent AED use was reported by 97%; 47% were on AED monotherapy, 35% had ≤2 lifetime AEDs, and 55% were seizure-free for >1 year. After stepwise selection, control variables included in both models were time since diagnosis, employment status, seizure frequency, number of currently prescribed AEDs, and number of general practitioner (GP) visits per year. In the model for comorbidities, "psychiatric disorders" was associated with the largest QOLIE-10-P score decrease (-23.14, p < 0.001). In the model for AEs, which additionally controlled for depression and anxiety disorder, self-reported "memory problems" was associated with the largest decrease in QOLIE-10-P score (-14.27, p < 0.001). CONCLUSIONS: In this survey of Australian PwE, many of whom had relatively well-controlled epilepsy, psychiatric and self-reported memory problems were common and associated with the greatest detrimental impact on QoL. Further research is needed to better understand the underlying causes of impaired QoL and thereby improve its management.

Bilateral volume reduction in posterior hippocampus in psychosis of epilepsy.

OBJECTIVE: Psychosis of epilepsy (POE) occurs more frequently in temporal lobe epilepsy, raising the question as to whether abnormalities of the hippocampus are aetiologically important. Despite decades of investigation, it is unclear whether hippocampal volume is reduced in POE, perhaps due to small sample sizes and methodological limitations of past research. METHODS: In this study, we examined the volume of the total hippocampus, and the hippocampal head, body and tail, in a large cohort of patients with POE and patients with epilepsy without psychosis (EC). One hundred adults participated: 50 with POE and 50 EC. Total and subregional hippocampal volumes were manually traced and compared between (1) POE and EC; (2) POE with temporal lobe epilepsy, extratemporal lobe epilepsy and generalised epilepsy; and (3) patients with POE with postictal psychosis (PIP) and interictal psychosis (IP). RESULTS: Compared with EC the POE group had smaller total left hippocampus volume (13.5% decrease, p<0.001), and smaller left hippocampal body (13.3% decrease, p=0.002), and left (41.5% decrease, p<0.001) and right (36.4% decrease, p<0.001) hippocampal tail volumes. Hippocampal head volumes did not differ between groups. CONCLUSION: Posterior hippocampal volumes are bilaterally reduced in POE. Volume loss was observed on a posteroanterior gradient, with severe decreases in the tail and moderate volume decreases in the body, with no difference in the hippocampal head. Posterior hippocampal atrophy is evident to a similar degree in PIP and IP. Our findings converge with those reported for the paradigmatic psychotic disorder, schizophrenia, and suggest that posterior hippocampal atrophy may serve as a biomarker of the risk for psychosis, including in patients with epilepsy.

Risk factors for injury in a community-treated cohort of patients with epilepsy in Australia.

OBJECTIVE: There remains a paucity of knowledge regarding specific epilepsy-related risk factors for accidents and injuries in people with epilepsy. Injury studies in people with epilepsy are overrepresented, with tertiary based populations that are prone to bias from severe disease. This study aims to assess the contribution of epilepsy-related risk factors to injuries in a community-based cohort. METHODS: We performed a retrospective nested case-control study on patients recruited into the Tasmanian Epilepsy Register (TER) from July 1, 2001 to June 30, 2002. The TER is a community-based cohort of patients with epilepsy in Tasmania, Australia, recruited from the national prescription database and interviewed for epilepsy diagnosis, injuries, and risk factors using validated questionnaires with diagnosis made by an epilepsy specialist. The primary outcome measures were lifetime and recent 12-month injury. Multivariate logistic regression with multiple imputation modeling responder nondisclosure was performed, adjusting for age, gender, region, socioeconomic status, seizure frequency, and epilepsy duration. RESULTS: A total of 819 patients with epilepsy were included in this study. Ten percent of patients experienced an injury in the preceding year. Before adjusting for seizure frequency, any seizure over the past 12 months was associated with recent injury (adjusted odds ratio [OR] = 7.90, 95% confidence interval [CI] = 4.17-14.96). Impaired awareness, cluster seizures, sleep-only seizures, and convulsive seizure were characteristics found to significantly influence injuries irrespective of seizure frequency. Although a warning appeared initially protective for recent injuries (OR = 0.39, 95% CI = 0.22-0.69), this was entirely explained by seizure frequency, with the effect becoming nonsignificant. SIGNIFICANCE: Likely due to their unpredictable nature, seizures expose patients with epilepsy to a high risk of life-threatening injury. These findings emphasize the importance of seizure freedom for maximizing the safety of patients with epilepsy.

Preictal autonomic dynamics in psychogenic nonepileptic seizures.

OBJECTIVES: Psychogenic nonepileptic seizures (PNES) resemble seizures but are psychological in origin. The etiology of PNES remains poorly understood, yet several theories argue for the importance of autonomic dysregulation in its pathophysiology. We therefore conducted a retrospective study to investigate autonomic dynamics leading up to a seizure to inform their mechanistic relevance. METHODS: One hundred one patients with PNES and 45 patients with epileptic seizure (ES) were analyzed for preictal heart rate (HR) and respiratory rate (RR) at baseline and at minute intervals from 5 min to onset. RESULTS: Patients with PNES showed rising HR (p < 0.001, repeated-measures analysis of variance (ANOVA)) and rising RR (p = 0.012, repeated-measures ANOVA) from baseline to the onset of their seizures. Patients with ES did not exhibit significant preictal HR or RR increase. Patients with PNES had nonsignificantly higher preictal HR and RR than patients with ES. SIGNIFICANCE: Patients with PNES exhibit increasing autonomic arousal prior to seizure events unlike patients with epilepsy. This may reflect increasing levels of preictal anxiety, and future studies could study patients' subjective experiences of the preictal period, and more definitive measures of ventilation to see if this supported a model of PNES as "panic without panic".

Self and informant report ratings of psychopathology in genetic generalized epilepsy.

The psychological sequelae of genetic generalized epilepsies (GGE) is of growing research interest, with up to a third of all adults with GGE experiencing significant psychiatric comorbidity according to a recent systematic review. A number of unexplored questions remain. Firstly, there is insufficient evidence to determine relative prevalence of psychopathology between GGE syndromes. Secondly, the degree to which self-report and informant-report questionnaires accord in adults with epilepsy is unknown. Finally, while epilepsy severity is one likely predictor of worse psychopathology in GGE, evidence regarding other possible contributing factors such as epilepsy duration and antiepileptic drugs (AEDs) has been equivocal. The potential impact of subclinical epileptiform discharges remains unexplored. Self-report psychopathology symptoms across six DSM-Oriented Subscales were prospectively measured in 60 adults with GGE, with informant-report provided for a subset of 47. We assessed the burden of symptoms from both self- and informant-report, and the relationship between clinical epilepsy variables and self-reported symptoms. Results showed elevated symptoms in almost half of the sample overall. Depression and anxiety were the most commonly reported types of symptoms. There was a trend towards greater symptoms endorsement by self-report, and relatively modest interrater agreement. Symptoms of ADHD were significantly positively associated with number of AEDs currently prescribed. Other psychopathology symptoms were not significantly predicted by epilepsy duration, seizure-free duration or total duration of epileptiform discharges over a 24-hour period. The high prevalence of psychological needs suggests that routine screening of psychopathology and provision of psychoeducation may be essential to improving patient care and outcomes. Further investigation is required to better understand predictive and causal factors for psychopathology in GGE.

What factors contribute to the risk of depression in epilepsy?--Tasmanian Epilepsy Register Mood Study (TERMS).

OBJECTIVE: To model the factors associated with depression in a community sample of people with epilepsy. The factors investigated were derived from proposed risk factors for depression from patients with epilepsy, other chronic illness, and the general population. METHODS: Multivariate analysis using general linear regression models of factors associated with depression in the Tasmanian Epilepsy Register Mood Study (TERMS), a cross-sectional community sample of 440 patients with epilepsy. RESULTS: A model with acceptable fit was created that explained 66% of the variance of depression. Associated factors included in this model were neuroticism, physical functioning, social support, past history of depression, and stressful life events. SIGNIFICANCE: In this cross-sectional study designed specifically to investigate depression in epilepsy, we showed that general risk factors for depression in other illness and in the general population are also important in patients with epilepsy, with little support for disease-related risk factors.

Isolated amygdala enlargement in temporal lobe epilepsy: A systematic review.

OBJECTIVE: The objective of this study was to compare the seizure characteristics and treatment outcomes in patient groups with temporal lobe epilepsy (TLE) identified with isolated amygdala enlargement (AE) on magnetic resonance imaging studies. METHODS: PubMed, Embase, and the Cochrane Library were searched for relevant studies using the keywords 'amygdala enlargement', 'epilepsy', and 'seizures' in April 2015. Human studies, written in English, that investigated cohorts of patients with TLE and AE were included. RESULTS: Of 204 abstracts initially identified using the search strategy, 14 studies met the inclusion criteria (11 epilepsy studies and 3 psychiatry studies). Ultimately, 8 full studies on AE and TLE involving 107 unique patients were analyzed. Gender distribution consisted of 50 males and 57 females. Right amygdala enlargement was seen in 39 patients, left enlargement in 58 patients, and bilateral enlargement in 7 patients. Surgical resection was performed in 28 patients, with the most common finding being dysplasia/hamartoma or focal cortical dysplasia. Most studies involved small samples of less than 12 patients. There was a wide discrepancy in the methods used to measure amygdala volume, in both patients and controls, hindering comparisons. Most TLE with AE studies observed a later age of seizure onset (mean: 32.2years) compared with studies involving TLE with HS (mean of mid- to late childhood). A higher frequency of complex partial seizures compared with that of convulsive seizures is seen in patients with AE (67-100% vs. 26-47%), and they have an excellent response to antiepileptic drugs (81.8%-100% of seizure-free patients). All studies that included controls also found a significant difference in frequency of seizure types between their cases and controls. CONCLUSIONS: Reliable assessment of amygdala volume remains a critical issue hindering better understanding of the clinical management and research of this focal epilepsy syndrome. Within these limitations, the literature suggests characteristics of an older age of epilepsy onset, a greater tendency to nonconvulsive seizures, and a good response to antiepileptic drugs in this interesting group of epilepsies.

Epilepsy beyond seizures: Predicting enduring cognitive dysfunction in genetic generalized epilepsies.

Reduced cognitive functioning has been documented in the genetic generalized epilepsies (GGE). Among a number of hypothesized causal mechanisms, some evidence from other epilepsy syndromes suggests the impact of epileptiform discharges. This study investigates the relationship between cognitive function in GGE and burden of epileptiform discharges within a 24-hour EEG recording, controlling for variables relevant to cognitive function in epilepsy. As part of a larger prospective cohort study, 69 patients with EEG-confirmed GGE (11-58years) underwent 24-hour EEG and detailed neuropsychological assessment using the Woodcock Johnson III Tests. Ten-second pages of the EEG were marked manually page-by-page on longitudinal bipolar montage with 0.5 to 70Hz bandwidth by an experienced EEG reader. Multiple regression analyses were conducted. Epileptiform discharges were detected in 90% of patients. Less than 0.01% of electrophysiological events of two or more seconds were recognized by patients. Regression analysis demonstrated that the cumulative duration of epileptiform discharges over a 24-hour period predicted overall cognitive ability and memory function, accounting for 9.6% and 11.8% of adjusted variance, respectively. None of the epilepsy covariates included in multiple regression analysis added significantly to the model. Duration of epileptiform discharges negatively predicts overall cognitive ability and memory function, even after accounting for other known determinants of cognition. Prolonged epileptiform discharges are common and remain unreported by patients, raising important questions regarding the management of GGE syndromes and their associated comorbidities. Further research is required to investigate causal mechanisms if we are to improve cognitive outcomes in this common group of epilepsies.

Risk factors for depression in community-treated epilepsy: systematic review.

OBJECTIVE: Depression is one of the most common psychiatric comorbidities in epilepsy; however, the factors contributing to this association remain unclear. There is a growing consensus that methodological limitations, particularly selection bias, affect many of the original studies. A systematic review focussed on community-based studies offers an alternative approach for the identification of the risk factors for depression. METHODS: Searches were performed in MEDLINE (Ovid), 2000 to 31 December 2013, EMBASE, and Google Scholar to identify studies examining risk factors for depression in epilepsy. Community-based studies of adults with epilepsy that reported at least one risk factor for depression were included. RESULTS: The search identified 17 studies that met selection criteria, representing a combined total of 12,212 people with epilepsy with a mean sample size of 718. The most consistent risk factors for depression were sociodemographic factors, despite the fact that most studies focus on epilepsy-related factors. SIGNIFICANCE: Most studies lacked a systematic conceptual approach to investigating depression, and few risk factors were consistently well studied. Future community-based studies require a detailed systematic approach to improve the ability to detect risk factors for depression in epilepsy. Psychological factors were rarely studied in community-based samples with epilepsy, although the consistent association with depression in the few studies that did suggests this warrants further examination.

Development and validation of an epidemiologic case definition of epilepsy for use with routinely collected Australian health data.

OBJECTIVES: We report the diagnostic validity of a selection algorithm for identifying epilepsy cases. STUDY DESIGN AND SETTING: Retrospective validation study of International Classification of Diseases 10th Revision Australian Modification (ICD-10AM)-coded hospital records and pharmaceutical data sampled from 300 consecutive potential epilepsy-coded cases and 300 randomly chosen cases without epilepsy from 3/7/2012 to 10/7/2013. Two epilepsy specialists independently validated the diagnosis of epilepsy. A multivariable logistic regression model was fitted to identify the optimum coding algorithm for epilepsy and was internally validated. RESULTS: One hundred fifty-eight out of three hundred (52.6%) epilepsy-coded records and 0/300 (0%) nonepilepsy records were confirmed to have epilepsy. The kappa for interrater agreement was 0.89 (95% CI=0.81-0.97). The model utilizing epilepsy (G40), status epilepticus (G41) and ≥1 antiepileptic drug (AED) conferred the highest positive predictive value of 81.4% (95% CI=73.1-87.9) and a specificity of 99.9% (95% CI=99.9-100.0). The area under the receiver operating curve was 0.90 (95% CI=0.88-0.93). CONCLUSION: When combined with pharmaceutical data, the precision of case identification for epilepsy data linkage design was considerably improved and could provide considerable potential for efficient and reasonably accurate case ascertainment in epidemiological studies.

Serotonin transporter gene × environment and risk of depression in community-treated epilepsy.

OBJECTIVES: This study aimed to test whether a specific serotonin transporter (5HTT) gene polymorphism interacting with life stress increased the risk of depression in patients with epilepsy. METHODS: The Tasmanian Epilepsy Register Mood Study (TERMS) used a cross-sectional study design of a community sample of patients with epilepsy previously recruited into the Tasmanian Epilepsy Register. It employed a mailed self-complete questionnaire and saliva DNA collection. Depression was assessed using the Center for Epidemiologic Studies Depression Scale. Environmental measures were selected to cover recent stressful events, epilepsy-related stress, current social support, and early life stress. RESULTS: Of 820 eligible participants, 553 (67%) participants completed the study. Experience of at least one stressful life event was very common, with a significant association between depression and the stressful life events (F=26.2, df=3, p<0.001). There was no association between serotonin transporter genotype and level of depressive symptoms reported (F=0.421, df=2, p=0.7). There was no evidence of any adverse life experiences interacting with serotonin transporter genotype to moderate the risk of depression. SIGNIFICANCE: The failure to demonstrate a main effect of genotype on depression or a gene × environment interaction differs from several studies of patients with other chronic diseases. However, it is consistent with larger general population studies.

Australia's seizure divide - indigenous versus non-indigenous seizure hospitalization.

Indigenous Australians suffer the highest mortality and morbidity rates of any ethnic minority in the developed world. To determine if the health outcome gulf between indigenous and non-indigenous Australians also applied to seizures, we conducted a retrospective analysis of seizure hospitalization (1998-2004) based on ethnicity (indigenous (I) and non-indigenous (NI)) for four Australian jurisdictions - Northern Territory (NT), Queensland (Qld), South Australia (SA), and Western Australia (WA). Total admissions were converted to age-standardized rates (ASR) and I/NI ASR ratios (I/NIRR) and compared across multiple variables. The summed admission (combined jurisdictions over six years) was 71,185 (I=11,593 and NI=59,592). Seizure hospitalization rate was always higher in the indigenous population (six-year I/NIRR - NT=5.6, Qld=4.0, SA=6.4, and WA=10.9; combined jurisdictions=5.6). Disparity was greatest for ages 40-64years (13.8) and 15-39years (7.0) and for indigenous males (7.4). As socioeconomic status rose, non-indigenous admission rates fell (ASR=1.7 to 1.1), yet indigenous admission rates rose (ASR=7.9 to 14.0). Indigenous emergency to elective admission ratios were higher (I=27 and NI=8), as were readmissions (1.5-2 fold), self-discharge separations (I=9.4% and NI=1.4%), bed days (I/NIRR=5.1), and admissions with an additional diagnosis (I/NIRR=3.3) or procedure (I/NIRR=3.4). Indigenous Australians maintained disproportionately high rates of emergency seizure hospitalization; from 1998 to 2004, the combined jurisdiction rate was more than five times the mean non-indigenous rate. Indigenous males aged 15-64years were overrepresented. Indigenous patients had lengthier admissions but higher self-discharge and readmission rates. The socioeconomic data raise the concern that social disadvantage restricts access to hospital-based seizure care for indigenous patients.

Risk factors for psychological distress in community-treated epilepsy.

The study aimed to determine risk factors for psychological distress in a community-treated sample of patients with epilepsy. This study investigated the Tasmanian Epilepsy Register participants. Participants included were as follows: aged 13 years and over, able to complete the individual computer-assisted participant interview, and diagnosed with epilepsy following an epilepsy specialist review of the diagnostic epilepsy interview, which was interpreted using standardized diagnostic guidelines. Psychological distress was assessed with the Kessler-10 questionnaire. Risk factors were grouped into four domains: sociodemographic factors, disease-related factors, psychological factors, and treatment-related factors. High or very high levels of psychological distress were reported by 22% of the participants, with 7.8% having very high distress. The regression model showed that psychological distress was significantly associated with female gender (F=18.1, p<0.001), diabetes mellitus (F=8.7, p=0.003), intellectual disability (F=7.1, p=0.06), and not receiving phenytoin (F=5.1, p=0.02). While the model was significant (F=5.78, p<0.001), only 11% of the variance of the K-10 score was explained by these factors (adjusted R-squared=0.11). This study identifies female gender and comorbid medical conditions as risk factors for psychological distress and the use of phenytoin as a protective factor. The few factors identified and the limited variance explained suggest that a focus on epilepsy-related variables is unlikely to explain key influences underlying psychiatric comorbidity in patients with epilepsy.