Clinical outcomes among initial survivors of cryptogenic new-onset refractory status epilepsy (NORSE).

OBJECTIVE: New-onset refractory status epilepticus (NORSE) is a rare but severe clinical syndrome. Despite rigorous evaluation, the underlying cause is unknown in 30%-50% of patients and treatment strategies are largely empirical. The aim of this study was to describe clinical outcomes in a cohort of well-phenotyped, thoroughly investigated patients who survived the initial phase of cryptogenic NORSE managed in specialist centers. METHODS: Well-characterized cases of cryptogenic NORSE were identified through the EPIGEN and Critical Care EEG Monitoring Research Consortia (CCEMRC) during the period 2005-2019. Treating epileptologists reported on post-NORSE survival rates and sequelae in patients after discharge from hospital. Among survivors >6 months post-discharge, we report the rates and severity of active epilepsy, global disability, vocational, and global cognitive and mental health outcomes. We attempt to identify determinants of outcome. RESULTS: Among 48 patients who survived the acute phase of NORSE to the point of discharge from hospital, 9 had died at last follow-up, of whom 7 died within 6 months of discharge from the tertiary care center. The remaining 39 patients had high rates of active epilepsy as well as vocational, cognitive, and psychiatric comorbidities. The epilepsy was usually multifocal and typically drug resistant. Only a minority of patients had a good functional outcome. Therapeutic interventions were heterogenous during the acute phase of the illness. There was no clear relationship between the nature of treatment and clinical outcomes. SIGNIFICANCE: Among survivors of cryptogenic NORSE, longer-term outcomes in most patients were life altering and often catastrophic. Treatment remains empirical and variable. There is a pressing need to understand the etiology of cryptogenic NORSE and to develop tailored treatment strategies.

Somatic variants as a cause of drug-resistant epilepsy including mesial temporal lobe epilepsy with hippocampal sclerosis.

OBJECTIVE: The contribution of somatic variants to epilepsy has recently been demonstrated, particularly in the etiology of malformations of cortical development. The aim of this study was to determine the diagnostic yield of somatic variants in genes that have been previously associated with a somatic or germline epilepsy model, ascertained from resected brain tissue from patients with multidrug-resistant focal epilepsy. METHODS: Forty-two patients were recruited across three categories: (1) malformations of cortical development, (2) mesial temporal lobe epilepsy with hippocampal sclerosis, and (3) nonlesional focal epilepsy. Participants were subdivided based on histopathology of the resected brain. Paired blood- and brain-derived DNA samples were sequenced using high-coverage targeted next generation sequencing to high depth (585× and 1360×, respectively). Variants were identified using Genome Analysis ToolKit (GATK4) MuTect-2 and confirmed using high-coverage Amplicon-EZ sequencing. RESULTS: Sequence data on 41 patients passed quality control. Four somatic variants were validated following amplicon sequencing: within CBL, ALG13, MTOR, and FLNA. The diagnostic yield across 41 patients was 10%, 9% in mesial temporal lobe epilepsy with hippocampal sclerosis and 20% in malformations of cortical development. SIGNIFICANCE: This study provides novel insights into the etiology of mesial temporal lobe epilepsy with hippocampal sclerosis, highlighting a potential pathogenic role of somatic variants in CBL and ALG13. We also report candidate diagnostic somatic variants in FLNA in focal cortical dysplasia, while providing further insight into the importance of MTOR and related genes in focal cortical dysplasia. This work demonstrates the potential molecular diagnostic value of variants in both germline and somatic epilepsy genes.

Blood, Sweat, and Tears: Implications for Hydration Testing in Combat Sports-Investigating Body Mass Loss and Biomarker Changes.

Combat sports athletes often undergo rapid body mass loss (BML), which presents health risks. Hydration testing has been proposed as a possible solution to reduce or eliminate rapid BML. However, combat sports athletes may exhibit distinct physiological characteristics due to repeated exposure to BML. Thus, traditional and emerging hydration biomarkers should be investigated to determine their potential suitability for field use in this cohort. This study examined whether BML can explain changes in serum and urine osmolality (SosmΔ, UosmΔ), tear osmolarity (TosmΔ), hematocrit (HctΔ), and urine-specific gravity (USGΔ) after mild-moderate passive dehydration. Biomarker reliability was also assessed across two trials. Fifteen male and female combat sports athletes (age: 26.3 ± 5.3 years, body mass: 67.7 ± 9.9 kg) underwent a sauna protocol twice (5-28 days apart) aiming for 4% BML. The average BML in Trials 1 and 2 was 3.0 ± 0.7%. Regression analysis revealed that BML explained HctΔ (R2 = 0.22, p = 0.009) but not SosmΔ (R2 = 0.11, p = 0.079) or other biomarkers. Intraclass correlation coefficients (ICCs) were significant for all biomarkers except TosmΔ (ICC = 0.06, p = 0.37) and post-Tosm (ICC = 0.04, p = 0.42); post-Hct performed best (ICC = 0.82, p < 0.001). Contingency tables with post-Sosm (295 mOsm/kg) and post-USG (1.020) cutoffs revealed an 80% true negative rate (TNR) and a 62% true positive rate (TPR). Increasing the Sosm cutoff to 301 mOsm/kg decreased the TNR to 52% but increased the TPR to 83%. Although blood parameters were most sensitive to BML, they could only explain 11%-22% of biomarker variation. The typical USG cutoff misclassified 42% of athletes postdehydration, and reliability was generally poor-moderate. Alternative strategies should be pursued to manage rapid BML in combat sports.

Sex Differences in Hydration Biomarkers and Test-Retest Reliability Following Passive Dehydration.

This study investigated (a) differences between males and females for changes in serum, tear, and urine osmolality, hematocrit, and urine specific gravity following acute passive dehydration and (b) assessed the reliability of these biomarkers separately for each sex. Fifteen males (age: 26.3 ± 3.5 years, body mass: 76 ± 7 kg) and 15 females (age: 28.8 ± 6.4 years, body mass: 63 ± 7 kg) completed a sauna protocol twice (5-28 days apart), aiming for 4% body mass loss (BML). Urine, blood, and tear markers were collected pre- and postdehydration, and change scores were calculated. Male BML was significantly greater than that of females in Trial 1 (3.53% ± 0.55% vs. 2.53% ± 0.43%, p < .001) and Trial 2 (3.36% ± 0.66% vs. 2.53% ± 0.44%, p = .01). Despite significant differences in BML, change in hematocrit was the only change marker that displayed a significant difference in Trial 1 (males: 3% ± 1%, females: 2% ± 1%, p = .004) and Trial 2 (males: 3% ± 1%, females: 1% ± 1%, p = .008). Regression analysis showed a significant effect for sex (male) predicting change in hematocrit (ß = 0.8, p = .032) and change in serum osmolality (ß = -3.3, p = .005) when controlling for BML but not for urinary or tear measures. The intraclass correlation coefficients for females (ICC 2, 1) were highest for change in urine specific gravity (ICC = .62, p = .006) and lowest for change in tear osmolarity (ICC = -.14, p = .689), whereas for males, it was posthematocrit (ICC = .65, p = .003) and post tear osmolarity (ICC = .18, p = .256). Generally, biomarkers showed lower test-retest reliability in males compared with females but, overall, were classified as poor-moderate in both sexes. These findings suggest that the response and reliability of hydration biomarkers are sex specific and highlight the importance of accounting for BML differences.

Futureproofing Medical Education Through Scenario Analysis: Instrumental Case Study.

Developments in technology and climate change, as well as other "megatrends" are having lasting impacts in society and healthcare. A scenario analysis was conducted to explore the impact of megatrends on medical education. Three scenarios were developed for the year 2035, showing varying levels of technological integration and environmental focus. Implications for an updated curricula focus on health inequalities, digital health, and globalization effects.

Cocreating an Automated mHealth Apps Systematic Review Process With Generative AI: Design Science Research Approach.

BACKGROUND: The use of mobile devices for delivering health-related services (mobile health [mHealth]) has rapidly increased, leading to a demand for summarizing the state of the art and practice through systematic reviews. However, the systematic review process is a resource-intensive and time-consuming process. Generative artificial intelligence (AI) has emerged as a potential solution to automate tedious tasks. OBJECTIVE: This study aimed to explore the feasibility of using generative AI tools to automate time-consuming and resource-intensive tasks in a systematic review process and assess the scope and limitations of using such tools. METHODS: We used the design science research methodology. The solution proposed is to use cocreation with a generative AI, such as ChatGPT, to produce software code that automates the process of conducting systematic reviews. RESULTS: A triggering prompt was generated, and assistance from the generative AI was used to guide the steps toward developing, executing, and debugging a Python script. Errors in code were solved through conversational exchange with ChatGPT, and a tentative script was created. The code pulled the mHealth solutions from the Google Play Store and searched their descriptions for keywords that hinted toward evidence base. The results were exported to a CSV file, which was compared to the initial outputs of other similar systematic review processes. CONCLUSIONS: This study demonstrates the potential of using generative AI to automate the time-consuming process of conducting systematic reviews of mHealth apps. This approach could be particularly useful for researchers with limited coding skills. However, the study has limitations related to the design science research methodology, subjectivity bias, and the quality of the search results used to train the language model.

Prevalence of disordered eating and its relationship with rapid weight loss amongst male and female combat sport competitors: A prospective study.

OBJECTIVES: To compare prevalence and change scores of disordered eating (DE) in combat sport athletes by sex and explore the potential relationship between rapid weight loss (RWL) and DE scores. DESIGN: Prospective study based on 24 events (September 2022-2023). METHODS: A body mass (BM) questionnaire was completed at ~1 day post-competition providing pre-competition BM data for -7 days, -24 h, and weigh-in. The Athletic Disordered Eating (ADE) online questionnaire was completed at ~7 and ~28 days post-competition, providing overall DE and four subscale scores (food and energy control, bingeing, body control, and body discontent). RESULTS: There were 122, 132, and 89 respondents for the BM (77 % male), and ADE questionnaires at 7 (79 % male), and 28 days (74 % male). A large proportion of males' (83 %) and females' (89 %) DE scores were moderate to very high; minimal (17 % vs. 11 %), moderate (36 % vs. 32 %), high (37 % vs. 36 %), and very high (11 % vs. 21 %). Comparing DE change scores in males and females indicated deterioration (5 % vs. 0 %), improvement (3 % vs. 25 %, p = 0.013), and no difference (92 % vs. 75 %). Body discontent change score showed a significant sex difference (p = 0.014), with females improving (42 % vs. 17 %, p = 0.035) and males deteriorating (35 % vs. 4 %, p = 0.008). Correlation analyses were significant for RWL -7 days and males' food control score (R = 0.22, p = 0.031). CONCLUSIONS: Moderate to very high DE indications were identified in 4 of every 5 combat sport competitors. A sex-specific change in body discontent is evident, and most competitors struggle with their food-body relationship post-competition, irrespective of RWL magnitude.

Attitudes and perceptions of Irish health care professionals regarding functional neurological disorder: A national survey.

BACKGROUND: Functional neurological disorder (FND) is a common and often disabling condition. Limited access to services for FND poses challenges both for patients and their health care providers. This survey explored the attitudes, experiences, support needs and training needs of health care professionals (HCPs) who provide care to individuals with FND in Ireland. METHODS: A broad range of HCPs working with patients with FND in Ireland partook in an anonymous online 12-item survey. Participants were recruited via professional bodies and snowball convenience sampling utilising social media and email invitation. Descriptive and inferential statistics were employed to analyze data. RESULTS: A total of 314 HCPs working in Ireland completed the survey. 80% were female and over half worked in their current role for more than 10 years.   75% of the sample encountered three or less individuals with FND per month. Identified service-related challenges to effective patient care included insufficient clinic time, lack of confidence explaining the diagnosis, and the need for greater access to specialist support.  Data revealed persisting negative attitudes toward FND patients among a proportion of respondents. The majority of respondents did not feel they received adequate education on FND, with the exception of neurologists, of whom 65% felt adequately trained.  The majority of respondents (85%) also felt that people with FND did not have access to appropriate FND services in Ireland. CONCLUSION: This study indicates that there is a significant need to improve FND education among HCPs in Ireland, in addition to developing appropriately resourced, integrated, multidisciplinary care pathways for the FND patient group.

Multimodal Analysis of the Retinal Manifestations of Tuberous Sclerosis Complex: A Case Series.

BACKGROUND AND OBJECTIVE: We used a multi-modal imaging approach including fundus fluorescein angiography (FFA) to assess the retinal lesions in tuberous sclerosis complex (TSC) and evaluate their correlation with intracranial tuber burden on magnetic resonance imaging (MRI). PATIENTS AND METHODS: Participants with TSC underwent bilateral fundus photography, optical coherence tomography (OCT), infrared (IR) imaging, and FFA. Participants' most recent MRI brain scans were analyzed to determine intracranial tuber load. RESULTS: Nine participants were included. OCT identified all retinal astrocytic hamartoma (RAH) lesions, IR identified 75%, fundus photography identified 63%, and FFA detected just 57%. On FFA, 20% of flat-type hamartomas and all multi-nodular and transitional types were hyperfluorescent. There were significant positive correlations between the quantities of intracranial tubers and all TSC-retinal lesions (r = 0.8, P < 0.01) and all RAH lesions (r = 0.8, P = 0.01). CONCLUSIONS: A multimodal imaging-based approach with fundal photography, IR imaging, and OCT should be used to assess the retina in TSC as it may indicate the intracranial tuber burden. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Blood-brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment.

Vascular disruption has been implicated in coronavirus disease 2019 (COVID-19) pathogenesis and may predispose to the neurological sequelae associated with long COVID, yet it is unclear how blood-brain barrier (BBB) function is affected in these conditions. Here we show that BBB disruption is evident during acute infection and in patients with long COVID with cognitive impairment, commonly referred to as brain fog. Using dynamic contrast-enhanced magnetic resonance imaging, we show BBB disruption in patients with long COVID-associated brain fog. Transcriptomic analysis of peripheral blood mononuclear cells revealed dysregulation of the coagulation system and a dampened adaptive immune response in individuals with brain fog. Accordingly, peripheral blood mononuclear cells showed increased adhesion to human brain endothelial cells in vitro, while exposure of brain endothelial cells to serum from patients with long COVID induced expression of inflammatory markers. Together, our data suggest that sustained systemic inflammation and persistent localized BBB dysfunction is a key feature of long COVID-associated brain fog.

A WORLDWIDE ENIGMA STUDY ON EPILEPSY-RELATED GRAY AND WHITE MATTER COMPROMISE ACROSS THE ADULT LIFESPAN.

Objectives: Temporal lobe epilepsy (TLE) is commonly associated with mesiotemporal pathology and widespread alterations of grey and white matter structures. Evidence supports a progressive condition although the temporal evolution of TLE is poorly defined. This ENIGMA-Epilepsy study utilized multimodal magnetic resonance imaging (MRI) data to investigate structural alterations in TLE patients across the adult lifespan. We charted both grey and white matter changes and explored the covariance of age-related alterations in both compartments. Methods: We studied 769 TLE patients and 885 healthy controls across an age range of 17-73 years, from multiple international sites. To assess potentially non-linear lifespan changes in TLE, we harmonized data and combined median split assessments with cross-sectional sliding window analyses of grey and white matter age-related changes. Covariance analyses examined the coupling of grey and white matter lifespan curves. Results: In TLE, age was associated with a robust grey matter thickness/volume decline across a broad cortico-subcortical territory, extending beyond the mesiotemporal disease epicentre. White matter changes were also widespread across multiple tracts with peak effects in temporo-limbic fibers. While changes spanned the adult time window, changes accelerated in cortical thickness, subcortical volume, and fractional anisotropy (all decreased), and mean diffusivity (increased) after age 55 years. Covariance analyses revealed strong limbic associations between white matter tracts and subcortical structures with cortical regions. Conclusions: This study highlights the profound impact of TLE on lifespan changes in grey and white matter structures, with an acceleration of aging-related processes in later decades of life. Our findings motivate future longitudinal studies across the lifespan and emphasize the importance of prompt diagnosis as well as intervention in patients.