Validation of the Seizure-Related Impact Assessment Scale (SERIAS): a study protocol.

INTRODUCTION: This study aims to validate the Seizure-Related Impact Assessment Scale (SERIAS). This novel patient-reported outcome measure (PROM) compares the 'trade-off' between seizures and treatment-related adverse effects, and measures epilepsy disability qualitatively and quantitively. It fills an important gap in PROMs for epilepsy clinical trials and practice. METHODS AND ANALYSIS: Adults with epileptologist-confirmed epilepsy from two Australian Epilepsy Centres are being recruited. People with functional seizures, or who are unable to self-complete English-language validated instruments are excluded. Participants providing informed consent are invited to complete questionnaires at baseline, 3 and 6 months later. SERIAS includes five questions that ask about the number of days per month that seizures or treatment-related adverse effects partially or fully impact work/home/school and family/social/non-work activities, as well as a visual analogue scale regarding epilepsy-related disability. SERIAS is completed alongside seven internationally validated instruments measuring treatment-related adverse effects, mood disorders and quality of life. Target recruitment is n=100, ensuring>50 people complete all questionnaires at all timepoints. Comprehensive psychometric analysis will be performed. Convergent validity will be investigated using bivariate correlations with relevant measures. Reliability will be investigated using Cronbach's alpha, McDonald's omega and test-retest correlation coefficients. SERIAS will be a novel PROM for epilepsy clinical trials and practice. ETHICS AND DISSEMINATION: Multisite ethics approval was granted by the Alfred Health Ethics Committee (HREC 17/23). Results of this study will be disseminated through publication in peer-reviewed journals and presentations at scientific conferences. TRIAL REGISTRATION NUMBER: ACTRN12623000599673.

The Australian Traumatic Brain Injury Initiative: Systematic Review and Consensus Process to Determine the Predictive Value of Pre-existing Health Conditions for People with Moderate-Severe Traumatic Brain Injury.

The first aim of the Australian Traumatic Brain Injury Initiative (AUS-TBI) encompasses development of a set of measures that comprehensively predict outcomes for people with moderate-severe TBI across Australia. This process engaged diverse stakeholders and information sources across six areas: social, health, and clinical factors; biological markers; treatments; and longer-term outcomes. Here, we report the systematic review of pre-existing health conditions as predictors of outcome for people with moderate-severe TBI. Standardized searches were implemented across databases until March 31, 2022. English-language reports of studies evaluating association between pre-existing health conditions and clinical outcome in at least 10 patients with moderate-severe TBI were included. A predefined algorithm was used to assign a judgement of predictive value to each observed association. The list of identified pre-existing health conditions was then discussed with key stakeholders during a consensus meeting to determine the feasibility of incorporating them into standard care. The searches retrieved 22,217 records, of which 47 articles were included. The process led to identification of 88 unique health predictors (homologized to 21 predictor categories) of 55 outcomes (homologized to 19 outcome categories). Only pre-existing health conditions with high and moderate predictive values were discussed during the consensus meeting. Following the consensus meeting, 5 out of 11 were included (migraine, mental health conditions, ≥4 pre-existing health conditions, osteoporosis, and body mass index [BMI]) as common data elements in the AUS-TBI data dictionary. Upon further discussion, 3 additional pre-existing health conditions were included. These are pre-existing heart disease, frailty score, and previous incidence of TBI.

Monash-Alfred protocol for assessment of atypical parkinsonian syndromes (MAP-APS).

Introduction: Atypical parkinsonian syndromes (APS) are rare neurodegenerative syndromes for which parkinsonism is one significant feature. APS includes progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and corticobasal syndrome (CBS). The diagnosis of APS remains reliant on clinical features with no available diagnostic or prognostic biomarker. Clinical scales remain the gold standard assessment measures in clinical trials and research. The lack of standardised approach for research cohorts has contributed to shortcomings in disease understanding and limits collaboration between researchers. The primary objectives of this study are to (1) establish an assessment protocol for parkinsonian syndromes and (2) to implement it at a single site to establish the viability and utility of populating a clinical and biological databank of patients with APS. Methods: The Monash Alfred Protocol for Assessment of APS was devised by expert consensus within a broad multidisciplinary team. Eligible patients are diagnosed as possible or probable PSP, MSA or CBS by a consultant neurologist with expertise in movement disorders. Participants will be assessed at recruitment and then annually for up to 3 years; individuals within 5 years of index symptom onset will also undergo a once-off 6-month assessment. Ethics and dissemination: Each participant or their legally authorised representative will provide informed written consent prior to commencement of the study. Data will be stored on a locally hosted Research Electronic Data Capture database. Trial registration number: Australian New Zealand Clinical Trials Registry (ANZCTN 12622000923763).

The Australian Traumatic Brain Injury Initiative: Systematic Review and Consensus Process to Determine the Predictive Value of Demographic, Injury Event, and Social Characteristics on Outcomes for People With Moderate-Severe Traumatic Brain Injury.

The objective of the Australian Traumatic Brain Injury (AUS-TBI) Initiative is to develop a data dictionary to inform data collection and facilitate prediction of outcomes of people who experience moderate-severe TBI in Australia. The aim of this systematic review was to summarize the evidence of the association between demographic, injury event, and social characteristics with outcomes, in people with moderate-severe TBI, to identify potentially predictive indicators. Standardized searches were implemented across bibliographic databases to March 31, 2022. English-language reports, excluding case series, which evaluated the association between demographic, injury event, and social characteristics, and any clinical outcome in at least 10 patients with moderate-severe TBI were included. Abstracts and full text records were independently screened by at least two reviewers in Covidence. A pre-defined algorithm was used to assign a judgement of predictive value to each observed association. The review findings were discussed with an expert panel to determine the feasibility of incorporation of routine measurement into standard care. The search strategy retrieved 16,685 records; 867 full-length records were screened, and 111 studies included. Twenty-two predictors of 32 different outcomes were identified; 7 were classified as high-level (age, sex, ethnicity, employment, insurance, education, and living situation at the time of injury). After discussion with an expert consensus group, 15 were recommended for inclusion in the data dictionary. This review identified numerous predictors capable of enabling early identification of those at risk for poor outcomes and improved personalization of care through inclusion in routine data collection.

A Multidimensional Assessment of Activities of Daily Living, Mental Status, Communication, and Social Abilities Among Older Adults in Shenzhen, China: Cross-Sectional Study.

BACKGROUND: China is facing a rapidly expanding aging population. Insights into the health status of older adults are of great significance for health resource allocation and health care provision to this population. OBJECTIVE: With the goal of providing a comprehensive understanding of the health status of older adults and to inform potential interventions, we investigated the level of disability and identified risk factors associated with disability among the older population (aged ≥60 years) living in China. METHODS: A total of 8467 older adults living in the Chinese city of Shenzhen were enrolled in this cross-sectional study. We used a multidimensional ability assessment survey, which assessed their activities of daily living (ADL; including eating, bathing, grooming, dressing, defecation control, urination control, using a toilet unaided, transfer, flat-ground walking, stair activity), mental status (including cognitive function, aggressive behavior, depression symptoms), sensory and communication (including consciousness level, vision, hearing, communication), and social participation (including living, working, time/space orientation, distinguish persons, social communication) abilities. The impact of demographic risk factors on ability levels was analyzed using ordinal logistic regression. The correlations between the four dimensions of ability mentioned above were analyzed using Spearman correlation analysis. RESULTS: A total of 7766 participants were effectively assessed. The participants' average age was 70.64 (SD 8.46) years comprising 56.53% females. The overall ability level was classified as mildly, moderately, and severely impaired for 27.57% (n=2141), 2.83% (n=220), and 4.28% (n=332) of the 7766 participants, respectively. With increasing age, the proportion of impaired participants increased from 17.62% (365/2071) in the age group 60-64 years to 91.3% (253/277) in the age group above 90 years (P<.001), corresponding to an approximate 10% rise for every 5-year age increment. The odds of having more severe overall ability impairment in females was 1.15 times that in males (odds ratio [OR] 1.15, 95% CI 1.04-1.28). Participants who were divorced or widowed had a higher risk of more severe overall ability impairment than those currently married (OR 1.98, 95% CI 1.68-2.33). Participants living with nonrelatives had an increased risk of more severe overall ability impairment than those living alone (OR 2.38, 95% CI 1.46-3.91). Higher education level was a protective factor of overall ability impairment (college degree or above: OR 0.32, 95% CI 0.24-0.42). The four dimensions of ability assessed were significantly correlated; a low score for ADL was significantly correlated with poorer mental status, sensory and communication, and social participation (all P<.001). CONCLUSIONS: The proportion of disability among Chinese older adults increases with age, being female, having lower education levels, being divorced or widowed, and living with nonrelatives. Impairment in ADL ability is significantly correlated with poor mental status, social participation, and sensory and communication abilities. A holistic approach to improving the health of the older population is recommended in China.

Systematic Review of Cost-Effectiveness Analysis for Surgical and Neurostimulation Treatments for Drug-Resistant Epilepsy in Adults.

BACKGROUND AND OBJECTIVES: Surgical and neurostimulator treatments are effective for reducing seizure burden in selected individuals living with drug-resistant epilepsy (DRE). We aimed to determine the presence and key model determinants for cost-effectiveness of these interventions, compared with medical management alone, to assist with decisions about resource allocation. METHODS: A systematic literature search was conducted on June 1, 2022, using MEDLINE, EMBASE, the NHS Economic Evaluation Database, and the Cost-Effectiveness Analysis database. Included studies were economic evaluations in adult DRE cohorts, comparing surgical and neurostimulator treatments (vagus nerve stimulation [VNS], responsive neurostimulation [RNS], and deep brain stimulation [DBS]) vs medical management alone and reporting cost-benefit analysis, cost-utility, or cost-effectiveness. Exclusion criteria were studies with pediatric cohorts and those published in a language other than English. Three independent reviewers screened, extracted, and assessed data against the Consolidated Health Economic Evaluation Reporting Standards checklist, and a fourth reviewer adjudicated discrepancies. RESULTS: Ten studies met inclusion criteria. Seven studies evaluated epilepsy surgery, and 3 evaluated neurostimulation treatments. All relevant studies established that epilepsy surgery is a cost-effective intervention compared with medical management alone, for quality-adjusted life-years and seizure freedom at 2 and 5 years. All relevant studies found neurostimulator treatments to be potentially cost-effective. The incremental cost-effectiveness ratio (ICER), with lower ICER indicating greater cost-effectiveness, was reported for 9 studies and varied between GBP £3,013 and US $61,333. Cost adaptation revealed ICERs from US $170 to US $121,726. Key model determinants included, but were not limited to, improved surgical outcomes and quality of life, reduced surgical and presurgical evaluation costs, higher rates of surgical eligibility after referral and evaluation, epilepsy subtype, less expensive neurostimulator devices with improved longevity, and cost analysis strategy used in the analysis. DISCUSSION: There is consistent evidence that epilepsy surgery is a cost-effective treatment of eligible candidates with DRE. Limited evidence suggests that VNS, RNS, and DBS may be cost-effective therapies for DRE, although more health economic evaluations alongside prospective clinical trials are needed to validate these findings. STUDY REGISTRATION INFORMATION: PROSPERO CRD42021278436.

Assessment of Safety of a Fully Implanted Endovascular Brain-Computer Interface for Severe Paralysis in 4 Patients: The Stentrode With Thought-Controlled Digital Switch (SWITCH) Study.

Importance: Brain-computer interface (BCI) implants have previously required craniotomy to deliver penetrating or surface electrodes to the brain. Whether a minimally invasive endovascular technique to deliver recording electrodes through the jugular vein to superior sagittal sinus is safe and feasible is unknown. Objective: To assess the safety of an endovascular BCI and feasibility of using the system to control a computer by thought. Design, Setting, and Participants: The Stentrode With Thought-Controlled Digital Switch (SWITCH) study, a single-center, prospective, first in-human study, evaluated 5 patients with severe bilateral upper-limb paralysis, with a follow-up of 12 months. From a referred sample, 4 patients with amyotrophic lateral sclerosis and 1 with primary lateral sclerosis met inclusion criteria and were enrolled in the study. Surgical procedures and follow-up visits were performed at the Royal Melbourne Hospital, Parkville, Australia. Training sessions were performed at patients' homes and at a university clinic. The study start date was May 27, 2019, and final follow-up was completed January 9, 2022. Interventions: Recording devices were delivered via catheter and connected to subcutaneous electronic units. Devices communicated wirelessly to an external device for personal computer control. Main Outcomes and Measures: The primary safety end point was device-related serious adverse events resulting in death or permanent increased disability. Secondary end points were blood vessel occlusion and device migration. Exploratory end points were signal fidelity and stability over 12 months, number of distinct commands created by neuronal activity, and use of system for digital device control. Results: Of 4 patients included in analyses, all were male, and the mean (SD) age was 61 (17) years. Patients with preserved motor cortex activity and suitable venous anatomy were implanted. Each completed 12-month follow-up with no serious adverse events and no vessel occlusion or device migration. Mean (SD) signal bandwidth was 233 (16) Hz and was stable throughout study in all 4 patients (SD range across all sessions, 7-32 Hz). At least 5 attempted movement types were decoded offline, and each patient successfully controlled a computer with the BCI. Conclusions and Relevance: Endovascular access to the sensorimotor cortex is an alternative to placing BCI electrodes in or on the dura by open-brain surgery. These final safety and feasibility data from the first in-human SWITCH study indicate that it is possible to record neural signals from a blood vessel. The favorable safety profile could promote wider and more rapid translation of BCI to people with paralysis. Trial Registration: ClinicalTrials.gov Identifier: NCT03834857.

Economic Evaluation of the Community Benefit of the Australian Pregnancy Register of Antiseizure Medications.

BACKGROUND AND OBJECTIVE: The Raoul Wallenberg Australian Pregnancy Register (APR) was established to collect, analyze, and publish data on the risks to babies exposed to antiseizure medications (ASMs) and to facilitate quality improvements in management care over time. It is one of the seveal prospective observational pregnancy registers of ASMs that has been established around the world. Although the APR and other registries have contributed to knowledge gain that has been applied to decrease adverse pregnancy outcomes, their cost-effectiveness remains unknown. Here, we aimed to evaluate the economic impacts of the APR from both societal and health care system perspectives. METHODS: Using decision analytic modeling, we estimated the effectiveness (prevention of adverse pregnancy outcomes) and costs (costs of adverse pregnancy outcomes and the register itself) of the APR over a 20-year time horizon (2000-2019). The comparator was set as the adverse pregnancy outcomes collected by the APR between 1998 and 2002 (i.e., no APR derived improvements in care). In the scenario analysis, we conservatively assumed a 2.5% and 5% contribution of the APR to the savings in health care and societal costs. Adverse pregnancy outcomes included stillbirth, birth defects, and induced abortion. All cost data were derived from published sources. Health and economic outcomes were extrapolated to the total target Australian epilepsy population. The primary outcomes of interest were the return of investment (ROI) for the APR and incremental cost-effectiveness ratio (ICER) for cost per adverse outcome avoided. RESULTS: Over the 20-year time horizon, the ROI from the APR from a societal perspective was Australian dollars (AUD) 2,250 (i.e., every dollar spent on the program resulted in a return of AUD2,250). Over this time, it was estimated that 9,609 adverse pregnancy outcomes were avoided, and health care and societal costs were reduced by AUD 191 million and AUD 9.0 billion, respectively. Hence, from a health economic point of view, the APR was dominant, providing cost saving ICERs from both perspectives. DISCUSSION: Following its inception 20+ years ago, the APR has represented excellent value for investment for Australia, being also health-saving and cost saving from a societal and a health care perspective. With the growing number of marketed ASMs, the APR is expected to continue to have a major impact in the foreseeable future.

Comorbidities in newly diagnosed epilepsy: Pre-existing health conditions are common and complex across age groups.

OBJECTIVES: People with epilepsy have a higher prevalence of medical and psychiatric comorbidities compared to the general population. Comorbidities are associated with poor epilepsy outcomes, and there have been recommendations for screening and early identification to improve clinical management. Data from 'First Seizure Clinics' (FSCs) with expert epileptological review can inform about disorders already present at the point of diagnosis of epilepsy or unprovoked seizures. Here, we aimed to describe pre-existing conditions with a focus on psychiatric, substance use, cardiac, neurological, and cancer health domains. METHODS: We included 1383 adults who received a new diagnosis of epilepsy or unprovoked seizures at Austin Hospital (AH) or Royal Melbourne Hospital (RMH) (Australia) FSCs from 2000 to 2010. Data were audited from FSC records, primarily detailed interviews undertaken by epileptologists. Logistic regression examined age distribution and other risk factors. RESULTS: The median age at FSC presentation was 37 years (IQR 26-53, range 18-94). Pre-existing conditions were reported by 40 %; from 32 % in the youngest group (18-30 years) to 53 % in the oldest (65+ years). Psychiatric (18 %) and substance use (16 %) disorders were most common, with higher prevalence among patients 18 to 65 years of age compared to those older than 65 years (p < 0.001). Cardiac, neurological, or cancer conditions were reported by 3-6 %, most often amongst those older than 65 years (p < 0.01). Eight percent (n = 112) reported disorders in >1 health domain. The commonest combination was a psychiatric condition with substance use disorder. Of the sixty-two patients reporting this combination, 61 were ≤65 years of age. CONCLUSIONS: Pre-existing health conditions are present in a substantial proportion of patients diagnosed with epilepsy or unprovoked seizures. Disorders are highest amongst elders, but one-third of younger adults also reported positive histories. These are predominantly psychiatric and/or substance use disorders, conditions strongly associated with poor outcomes in the general population. These findings inform post-diagnosis planning and management, as well as research examining post-diagnostic outcomes and associations between comorbidities and epilepsy.

Interictal EEG and ECG for SUDEP Risk Assessment: A Retrospective Multicenter Cohort Study.

Objective: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality. Although lots of effort has been made in identifying clinical risk factors for SUDEP in the literature, there are few validated methods to predict individual SUDEP risk. Prolonged postictal EEG suppression (PGES) is a potential SUDEP biomarker, but its occurrence is infrequent and requires epilepsy monitoring unit admission. We use machine learning methods to examine SUDEP risk using interictal EEG and ECG recordings from SUDEP cases and matched living epilepsy controls. Methods: This multicenter, retrospective, cohort study examined interictal EEG and ECG recordings from 30 SUDEP cases and 58 age-matched living epilepsy patient controls. We trained machine learning models with interictal EEG and ECG features to predict the retrospective SUDEP risk for each patient. We assessed cross-validated classification accuracy and the area under the receiver operating characteristic (AUC) curve. Results: The logistic regression (LR) classifier produced the overall best performance, outperforming the support vector machine (SVM), random forest (RF), and convolutional neural network (CNN). Among the 30 patients with SUDEP [14 females; mean age (SD), 31 (8.47) years] and 58 living epilepsy controls [26 females (43%); mean age (SD) 31 (8.5) years], the LR model achieved the median AUC of 0.77 [interquartile range (IQR), 0.73-0.80] in five-fold cross-validation using interictal alpha and low gamma power ratio of the EEG and heart rate variability (HRV) features extracted from the ECG. The LR model achieved the mean AUC of 0.79 in leave-one-center-out prediction. Conclusions: Our results support that machine learning-driven models may quantify SUDEP risk for epilepsy patients, future refinements in our model may help predict individualized SUDEP risk and help clinicians correlate predictive scores with the clinical data. Low-cost and noninvasive interictal biomarkers of SUDEP risk may help clinicians to identify high-risk patients and initiate preventive strategies.

Clinical predictors of discordance between screening tests and psychiatric assessment for depressive and anxiety disorders among patients being evaluated for seizure disorders.

OBJECTIVE: This study was undertaken to identify factors that predict discordance between the screening instruments Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) and Generalized Anxiety Disorder scale (GAD-7), and diagnoses made by qualified psychiatrists among patients with seizure disorders. Importantly, this is not a validation study; rather, it investigates clinicodemographic predictors of discordance between screening tests and psychiatric assessment. METHODS: Adult patients admitted for inpatient video-electroencephalographic monitoring completed eight psychometric instruments, including the NDDI-E and GAD-7, and psychiatric assessment. Patients were grouped according to agreement between the screening instrument and psychiatrists' diagnoses. Screening was "discordant" if the outcome differed from the psychiatrist's diagnosis, including both false positive and false negative results. Bayesian statistical analyses were used to identify factors associated with discordance. RESULTS: A total of 411 patients met inclusion criteria; mean age was 39.6 years, and 55.5% (n = 228) were female. Depression screening was discordant in 33% of cases (n = 136/411), driven by false positives (n = 76/136, 56%) rather than false negatives (n = 60/136, 44%). Likewise, anxiety screening was discordant in one third of cases (n = 121/411, 29%) due to false positives (n = 60/121, 50%) and false negatives (n = 61/121, 50%). Seven clinical factors were predictive of discordant screening for both depression and anxiety: greater dissociative symptoms, greater patient-reported adverse events, subjective cognitive impairment, negative affect, detachment, disinhibition, and psychoticism. When the analyses were restricted to only patients with psychogenic nonepileptic seizures (PNES) or epilepsy, the rate of discordant depression screening was higher in the PNES group (n = 29, 47%) compared to the epilepsy group (n = 70, 30%, Bayes factor for the alternative hypothesis = 4.65). SIGNIFICANCE: Patients with seizure disorders who self-report a variety of psychiatric and other symptoms should be evaluated more thoroughly for depression and anxiety, regardless of screening test results, especially if they have PNES and not epilepsy. Clinical assessment by a qualified psychiatrist remains essential in diagnosing depressive and anxiety disorders among such patients.

Assessment of the DTI-ALPS Parameter Along the Perivascular Space in Older Adults at Risk of Dementia.

BACKGROUND AND PURPOSE: Recently, there has been growing interest in the glymphatic system (the functional waste clearance pathway for the central nervous system and its role in flushing solutes (such as amyloid ß and tau), metabolic, and other cellular waste products in the brain. Herein, we investigate a recent potential biomarker for glymphatic activity (the diffusion tensor imaging along the perivascular space [DTI-ALPS] parameter) using diffusion MRI imaging in an elderly cohort comprising 10 cognitively normal, 10 mild cognitive impairment (MCI), and 16 Alzheimer's disease (AD). METHODS: All 36 participants imaged on a Siemens 3.0T Tim Trio. Single-SE diffusion weighted Echo-planar imaging scans were acquired as well as T1 magnetization prepared rapid gradient echo, T2 axial, and susceptibility weighted imaging. Three millimeter regions of interest were drawn in the projection and association fibers adjacent to the medullary veins at the level of the lateral ventricle. The DTI-ALPS parameter was calculated in these regions and correlated with cognitive status, Mini-Mental State Examination (MMSE), and ADASCog11 measures. RESULTS: Significant correlations were found between DTI-ALPS and MMSE and ADASCog11 in the right hemisphere adjusting for age, sex, and APoE ε4 status. Significant differences were also found in the right DTI-ALPS indices between cognitively normal and AD groups (P < .026) and MCI groups (P < .025) in a univariate general linear model corrected for age, sex, and APoE ε4. Significant differences in apparent diffusion coefficient between cognitively normal and AD groups were found in the right projection fibers (P = .028). CONCLUSION: Further work is needed to determine the utility of DTI-ALPS index in larger elderly cohorts and whether it measures glymphatic activity.

Cognitive profiles in patients with epileptic and nonepileptic seizures evaluated using a brief cognitive assessment tool.

BACKGROUND: There is a need for the development of brief tools to screen for cognitive impairments in epilepsy patients in order to prioritize and direct formal comprehensive cognitive testing. Yet, shorter cognitive screening tools are limited in their breadth of cognitive domains or have not been intensively studied on an epilepsy population. This study used a brief cognitive screening tool in order to compare cognitive profiles between patients with epilepsy and those with nonepileptic seizures. METHODS: Patients admitted to the Royal Melbourne Hospital video-EEG monitoring unit between 2005 and 2017 were included. Patients were categorized according to seizure etiology (epileptic, psychogenic or other nonepileptic seizures), epilepsy syndrome (focal or generalized; temporal lobe (TLE) or extra-temporal lobe epilepsy (ETLE)), seizure frequency, and anti-seizure medications (ASMs). Attention, visuoconstructional, memory, executive, and language functioning were assessed with the Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG). General linear mixed models were computed to investigate cognitive profiles according to diagnostic group and other clinicodemographic variables. RESULTS: 800 patients were included in the analysis (61% female and 39 % male, median age 36 years). Patients with both epileptic seizures and psychogenic seizures (n = 25) had the lowest total scores on NUCOG, followed by patients with epileptic seizures (n = 411), psychogenic seizures (n = 185), and nonepileptic seizures (n = 179, p = 0.002). Specifically, patients with epileptic seizures performed worse than those with nonepileptic seizures in the executive, language, and memory domain, and had lower language domain scores than those with psychogenic seizures. Patients with bilateral TLE had poorer performance than those with unilateral TLE, particularly for memory function. Specific ASMs and polypharmacy but not seizure frequency had a negative effect on cognition (p < 0.001). NUCOG scores did not differ between focal and generalized epilepsies, or between TLE and ETLE. CONCLUSION: The NUCOG differentiated cognitive profiles in patients with uncontrolled seizures due to different etiologies. Bilateral TLE and medication adversely affected cognitive performance, and overall patients with epilepsy performed worse than those with nonepileptic seizures. These results provide further evidence for sensitivity of the NUCOG for detecting cognitive impairment in patients with seizure disorders.

The costs of epilepsy in Australia: A productivity-based analysis.

OBJECTIVE: To determine the health economic burden of epilepsy for Australians of working age by using life table modeling and to model whether improved seizure control may result in substantial health economic benefits. METHODS: Life table modeling was used for working age Australians aged 15-69 years with epilepsy and the cohort was followed until age 70 years. Published 2017 population and epilepsy-related data regarding epilepsy prevalence, mortality, and productivity were used. This model was then re-simulated, assuming the cohort no longer had epilepsy. Differences in outcomes between these cohorts were attributed to epilepsy. Scenarios were also simulated in which the proportion of seizure-free patients increased from baseline 70% up to 75% and 80%. RESULTS: In 2017, Australians of working age with epilepsy followed until age 70 years were predicted to experience over 14,000 excess deaths, more than 78,000 years of life lost, and over 146,000 productivity-adjusted life years lost due to epilepsy. This resulted in lost gross domestic product (GDP) of US $22.1 billion. Increasing seizure freedom by 5% and 10% would reduce health care costs, save years of life, and translate to US $2.6 billion and US $5.3 billion GDP retained for seizure freedom rates of 75% and 80%, respectively. CONCLUSIONS: Our study highlights the considerable societal and economic burden of epilepsy. Relatively modest improvements in overall seizure control could bring substantial economic benefits.

Mortality in patients with psychogenic nonepileptic seizures.

OBJECTIVE: To investigate the hypothesis that patients diagnosed with psychogenic nonepileptic seizures (PNES) on video-EEG monitoring (VEM) have increased mortality by comparison to the general population. METHODS: This retrospective cohort study included patients evaluated in VEM units of 3 tertiary hospitals in Melbourne, Australia, between January 1, 1995, and December 31, 2015. Diagnosis was based on consensus opinion of experienced epileptologists and neuropsychiatrists at each hospital. Mortality was determined in patients diagnosed with PNES, epilepsy, or both conditions by linkage to the Australian National Death Index. Lifetime history of psychiatric disorders in PNES was determined from formal neuropsychiatric reports. RESULTS: A total of 5,508 patients underwent VEM. A total of 674 (12.2%) were diagnosed with PNES, 3064 (55.6%) with epilepsy, 175 (3.2%) with both conditions, and 1,595 (29.0%) received other diagnoses or had no diagnosis made. The standardized mortality ratio (SMR) of patients diagnosed with PNES was 2.5 (95% confidence interval [CI] 2.0-3.3). Those younger than 30 had an 8-fold higher risk of death (95% CI 3.4-19.8). Direct comparison revealed no significant difference in mortality rate between diagnostic groups. Among deaths in patients diagnosed with PNES (n = 55), external causes contributed 18%, with 20% of deaths in those younger than 50 years attributed to suicide, and "epilepsy" was recorded as the cause of death in 24%. CONCLUSIONS: Patients diagnosed with PNES have a SMR 2.5 times above the general population, dying at a rate comparable to those with drug-resistant epilepsy. This emphasizes the importance of prompt diagnosis, identification of risk factors, and implementation of appropriate strategies to prevent potential avoidable deaths.

Comparisons of direct and indirect utilities in adult epilepsy populations: A systematic review.

OBJECTIVE: Epilepsy is common and carries substantial morbidity, and therefore identifying cost-effective health interventions is essential. Cost-utility analysis is a widely used method for such analyses. For this, health conditions are rated in terms of utilities, which provide a standardized score to reflect quality of life. Utilities are obtained either indirectly using quality of life questionnaires, or directly from patients or the general population. We sought to describe instruments used to estimate utilities in epilepsy populations, and how results differ according to methods used. METHODS: We undertook a systematic review of studies comparing at least two instruments for obtaining utilities in epilepsy populations. MEDLINE, Embase, ScienceDirect, Cochrane Library, Google Scholar, and gray literature were searched from inception to June 2019. Mean utilities were recorded and compared for each method. RESULTS: Of the 38 unique records initially identified, eight studies met inclusion criteria. Utilities were highest for direct "tradeoff" methods, obtained via instruments including standard gamble (0.93) and time tradeoff (0.92), compared to indirect methods, obtained via instruments including EuroQoL five-dimensional form (range = 0.72-0.86) and Health Utilities Index Mark 3 (range = 0.52-0.71). Visual analog scale (VAS), a direct "nontradeoff" instrument, provided equal or lower utilities (range = 68.0-79.8) compared to indirect instruments. SIGNIFICANCE: Direct methods, with the important exception of VAS, may provide higher utilities than indirect methods. More studies are needed to identify the most appropriate utility instruments for epilepsy populations, and to investigate whether there is variation between utilities for different types of epilepsy and other patient- and disease-specific factors.

Abbreviated assessment of psychopathology in patients with suspected seizure disorders.

PURPOSE: Psychopathology is common in patients undergoing investigation for seizure-related disorders. Psychometric examination using self-report instruments, such as the Symptom Checklist 90 - Revised (SCL-90-R), can assist diagnosis. The SCL-90-R, however, is a lengthy instrument and might not be tolerated by all patients. We assessed several abbreviated forms of the SCL-90-R in patients undergoing video encephalographic monitoring (VEM). METHOD: Six hundred eighty-seven patients completed the SCL-90-R, and scores were computed for the full SCL-90-R and five abbreviated forms. Correlations and mean differences were computed between different forms. Classification accuracy was assessed via receiver operating characteristic (ROC) curves, and measurements models were examined using confirmatory factor analysis (CFA). RESULTS: All abbreviated forms were strongly correlated with the SCL-90-R for general psychopathology (r = 0.93-0.99), depression (r = 0.89-0.95), anxiety (r = 0.97-0.98), psychosis (r = 0.95-0.99), and obsessive-compulsive symptoms (r = 0.97). Classification performance was similar across forms for depression and anxiety, with high negative predictive values (0.90-0.94) and lower positive predictive values (0.34-0.38). Classification performance for psychotic and obsessive-compulsive disorders was poor. Differences were observed between the full SCL-90-R and its abbreviated forms across most domains (d = 0.00-0.65). The published measurement model was most strongly validated for the SCL-27, SCL-14, and the SCL-K-9. CONCLUSIONS: These five SCL-90-R abbreviated forms show high convergent validity with the full version. In patients undergoing investigation for seizure-related disorders, the Brief Symptom Inventory full form (BSI) or short form (BSI-18) is most appropriate where screening for both depression and anxiety is required. The SCL-K-9 is appropriate when only a single measure of global psychological distress is required. None of the instruments were able to detect psychotic or obsessive-compulsive symptoms with great accuracy. Caution should be exercised when making direct comparisons across the different forms.

Prospective assessment of autism traits in children exposed to antiepileptic drugs during pregnancy.

PURPOSE: The association between autism spectrum disorders (ASDs) and prenatal anticonvulsant exposure is increasingly investigated, but comprehensive, blinded assessment using a validated instrument for autism within a well-characterized prospective cohort has not been conducted. Thus, existing studies may represent an underestimate of the true risk. Herein we present a prospective cohort study in children exposed to anticonvulsants during pregnancy, with all assessments conducted by examiners who were blinded to drug-exposure status. METHODS: Participants were 105 Australian children aged 6-8 years who were recruited via the Australian Pregnancy Register for Women on Antiepileptic Medication. Maternal epilepsy, pregnancy, and medical history data were obtained prospectively. Autism traits were assessed using the Childhood Autism Rating Scale (CARS). RESULTS: Eleven children (10.5%) had elevated CARS scores. Two were exposed to valproate monotherapy (2/26; 7.7%), two to carbamazepine monotherapy (2/34; 5.9%), and seven to valproate in polytherapy (7/15; 46.7%). Linear regression analysis showed that the mean valproate dose during pregnancy was a significant predictor of CARS scores after controlling for polytherapy, mean carbamazepine dose, folic acid use, seizures during pregnancy, tobacco and marijuana use, maternal intelligence quotient (IQ), and socioeconomic status. First trimester folic acid supplementation and marijuana use were also significant predictors of CARS scores. SIGNIFICANCE: Using direct assessment of children in our prospective study, we found an elevated rate of autism traits across the sample. The most important determinant of association with autistic traits was higher doses of sodium valproate exposure. The use of valproate in women who may become pregnant is now generally avoided; however, there are insufficient data regarding the risk of ASD with low-dose valproate. If this risk is no greater than with other antiepileptic drugs (AED)s, it may enable women with genetic generalized epilepsy to retain optimal seizure control as well as minimize harm to their unborn child.

Proposal for a "phase II" multicenter trial model for preclinical new antiepilepsy therapy development.

There is a pressing need to address the current major gaps in epilepsy treatment, in particular drug-resistant epilepsy, antiepileptogenic therapies, and comorbidities. A major concern in the development of new therapies is that current preclinical testing is not sufficiently predictive for clinical efficacy. Methodologic limitations of current preclinical paradigms may partly account for this discrepancy. Here we propose and discuss a strategy for implementing a "phase II" multicenter preclinical drug trial model based on clinical phase II/III studies designed to generate more rigorous preclinical data for efficacy. The goal is to improve the evidence resulting from preclinical studies for investigational new drugs that have shown strong promise in initial preclinical "phase I" studies. This should reduce the risk for expensive clinical studies in epilepsy and therefore increase the appeal for funders (industry and government) to invest in their clinical development.