Medicine (Austin & Northern Health) - Research Publications

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    Plasma neurofilament light chain and phosphorylated tau 181 in neurodegenerative and psychiatric disorders: moving closer towards a simple diagnostic test like a 'C‐reactive protein' for the brain?
    Eratne, D ; Santillo, A ; Li, Q ; Kang, M ; Keem, M ; Lewis, C ; Loi, SM ; Walterfang, M ; Hansson, O ; Janelidze, S ; Yassi, N ; Watson, R ; Berkovic, SF ; Masters, CL ; Collins, S ; Velakoulis, D (Wiley, 2021-12)
    Abstract Background Accurate, timely diagnosis of neurodegenerative disorders, in particular distinguishing primary psychiatric from neurological disorders and in younger people, can be challenging. There is a need for biomarkers to reduce the diagnostic odyssey and improve outcomes. Neurofilament light (NfL) has shown promise as a diagnostic biomarker in a wide range of disorders. Our Markers in Neuropsychiatric Disorders (MiND) Study builds on our pilot (Eratne et al, ANZJP, 2020), to explore the diagnostic and broader utility of plasma and cerebrospinal fluid (CSF) NfL and other novel markers such as phosphorylated tau 181 (p‐tau181), in a broad range of psychiatric and neurodegenerative/neurological disorders, with a view of translation into routine clinical practice. Methods We assessed plasma and/or CSF NfL and p‐tau181 concentrations in broad cohorts, including: patients assessed for neurocognitive/psychiatric symptoms at Neuropsychiatry and Melbourne Young‐Onset Dementia services and other services, in a wide range of disorders including Alzheimer disease, frontotemporal dementia, schizophrenia, bipolar disorder, depression, Niemann‐Pick Type C, epilepsy, functional neurological disorders. The most recent primary consensus diagnosis informed by established diagnostic criteria was categorised: primary psychiatric disorder (PPD), neurodegenerative/neurological disorder (ND), or healthy controls (HC). Results Findings from over 500 patients/participants will be presented, which indicate that CSF and plasma NfL levels are significantly elevated in a broad range of ND compared to a broad range of PPD, and HC, and bvFTD progressors from phenocopy syndromes, differentiating with areas under the curve of >0.90, sensitivity and specificity >90%. Plasma P‐tau181 levels distinguished Alzheimer disease (mainly younger sporadic), compared to other neurodegenerative disorders, with AUC 0.90, 90% sensitivity and specificity. As recruitment, sample analysis, data collection is ongoing, the most up to date results will be presented. Conclusions NfL shows great promise as a diagnostic test to assist with the common, challenging diagnostic dilemma of distinguishing neurodegenerative from non‐neurodegenerative and primary psychiatric disorders. Plasma p‐tau181 shows strong diagnostic utility in younger‐onset Alzheimer disease. A significantly elevated NfL in someone with a psychiatric diagnosis should prompt consideration of neurodegenerative differentials. Plasma NfL could dramatically alter clinical care of patients with neuropsychiatric and neurological symptoms, improving outcomes for patients, their families, the healthcare system, and clinical trials.
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    Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals
    Motelow, JE ; Povysil, G ; Dhindsa, RS ; Stanley, KE ; Allen, AS ; Feng, Y-CA ; Howrigan, DP ; Abbott, LE ; Tashman, K ; Cerrato, F ; Cusick, C ; Singh, T ; Heyne, H ; Byrnes, AE ; Churchhouse, C ; Watts, N ; Solomonson, M ; Lal, D ; Gupta, N ; Neale, BM ; Cavalleri, GL ; Cossette, P ; Cotsapas, C ; De Jonghe, P ; Dixon-Salazar, T ; Guerrini, R ; Hakonarson, H ; Heinzen, EL ; Helbig, I ; Kwan, P ; Marson, AG ; Petrovski, S ; Kamalakaran, S ; Sisodiya, SM ; Stewart, R ; Weckhuysen, S ; Depondt, C ; Dlugos, DJ ; Scheffer, IE ; Striano, P ; Freyer, C ; Krause, R ; May, P ; McKenna, K ; Regan, BM ; Bennett, CA ; Leu, C ; Leech, SL ; O'Brien, TJ ; Todaro, M ; Stamberger, H ; Andrade, DM ; Ali, QZ ; Sadoway, TR ; Krestel, H ; Schaller, A ; Papacostas, SS ; Kousiappa, I ; Tanteles, GA ; Christou, Y ; Sterbova, K ; Vlckova, M ; Sedlackova, L ; Lassuthova, P ; Klein, KM ; Rosenow, F ; Reif, PS ; Knake, S ; Neubauer, BA ; Zimprich, F ; Feucht, M ; Reinthaler, EM ; Kunz, WS ; Zsurka, G ; Surges, R ; Baumgartner, T ; von Wrede, R ; Pendziwiat, M ; Muhle, H ; Rademacher, A ; van Baalen, A ; von Spiczak, S ; Stephani, U ; Afawi, Z ; Korczyn, AD ; Kanaan, M ; Canavati, C ; Kurlemann, G ; Muller-Schluter, K ; Kluger, G ; Haeusler, M ; Blatt, I ; Lemke, JR ; Krey, I ; Weber, YG ; Wolking, S ; Becker, F ; Lauxmann, S ; Bosselmann, C ; Kegele, J ; Hengsbach, C ; Rau, S ; Steinhoff, BJ ; Schulze-Bonhage, A ; Borggraefe, I ; Schankin, CJ ; Schubert-Bast, S ; Schreiber, H ; Mayer, T ; Korinthenberg, R ; Brockmann, K ; Wolff, M ; Dennig, D ; Madeleyn, R ; Kalviainen, R ; Saarela, A ; Timonen, O ; Linnankivi, T ; Lehesjoki, A-E ; Rheims, S ; Lesca, G ; Ryvlin, P ; Maillard, L ; Valton, L ; Derambure, P ; Bartolomei, F ; Hirsch, E ; Michel, V ; Chassoux, F ; Rees, M ; Chung, S-K ; Pickrell, WO ; Powell, R ; Baker, MD ; Fonferko-Shadrach, B ; Lawthom, C ; Anderson, J ; Schneider, N ; Balestrini, S ; Zagaglia, S ; Braatz, V ; Johnson, MR ; Auce, P ; Sills, GJ ; Baum, LW ; Sham, PC ; Cherny, SS ; Lui, CHT ; Delanty, N ; Doherty, CP ; Shukralla, A ; El-Naggar, H ; Widdess-Walsh, P ; Barisi, N ; Canafoglia, L ; Franceschetti, S ; Castellotti, B ; Granata, T ; Ragona, F ; Zara, F ; Iacomino, M ; Riva, A ; Madia, F ; Vari, MS ; Salpietro, V ; Scala, M ; Mancardi, MM ; Nobili, L ; Amadori, E ; Giacomini, T ; Bisulli, F ; Pippucci, T ; Licchetta, L ; Minardi, R ; Tinuper, P ; Muccioli, L ; Mostacci, B ; Gambardella, A ; Labate, A ; Annesi, G ; Manna, L ; Gagliardi, M ; Parrini, E ; Mei, D ; Vetro, A ; Bianchini, C ; Montomoli, M ; Doccini, V ; Barba, C ; Hirose, S ; Ishii, A ; Suzuki, T ; Inoue, Y ; Yamakawa, K ; Beydoun, A ; Nasreddine, W ; Zgheib, NK ; Tumiene, B ; Utkus, A ; Sadleir, LG ; King, C ; Caglayan, SH ; Arslan, M ; Yapici, Z ; Topaloglu, P ; Kara, B ; Yis, U ; Turkdogan, D ; Gundogdu-Eken, A ; Bebek, N ; Tsai, M-H ; Ho, C-J ; Lin, C-H ; Lin, K-L ; Chou, I-J ; Poduri, A ; Shiedley, BR ; Shain, C ; Noebels, JL ; Goldman, A ; Busch, RM ; Jehi, L ; Najm, IM ; Ferguson, L ; Khoury, J ; Glauser, TA ; Clark, PO ; Buono, RJ ; Ferraro, TN ; Sperling, MR ; Lo, W ; Privitera, M ; French, JA ; Schachter, S ; Kuzniecky, R ; Devinsky, O ; Hegde, M ; Greenberg, DA ; Ellis, CA ; Goldberg, E ; Helbig, KL ; Cosico, M ; Vaidiswaran, P ; Fitch, E ; Berkovic, SF ; Lerche, H ; Lowenstein, DH ; Goldstein, DB (CELL PRESS, 2021-06-03)
    Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.
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    Cutting edge approaches to detecting brain mosaicism associated with common focal epilepsies: implications for diagnosis and potential therapies
    Ye, Z ; Bennett, MF ; Bahlo, M ; Scheffer, IE ; Berkovic, SF ; Perucca, P ; Hildebrand, MS (TAYLOR & FRANCIS LTD, 2021-11-02)
    INTRODUCTION: Mosaic variants arising in brain tissue are increasingly being recognized as a hidden cause of focal epilepsy. This knowledge gain has been driven by new, highly sensitive genetic technologies and genome-wide analysis of brain tissue from surgical resection or autopsy in a small proportion of patients with focal epilepsy. Recently reported novel strategies to detect mosaic variants limited to brain have exploited trace brain DNA obtained from cerebrospinal fluid liquid biopsies or stereo-electroencephalography electrodes. AREAS COVERED: The authors review the data on these innovative approaches published in PubMed before 12 June 2021, discuss the challenges associated with their application, and describe how they are likely to improve detection of mosaic variants to provide new molecular diagnoses and therapeutic targets for focal epilepsy, with potential utility in other nonmalignant neurological disorders. EXPERT OPINION: These cutting-edge approaches may reveal the hidden genetic etiology of focal epilepsies and provide guidance for precision medicine.
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    Climate change and epilepsy: Insights from clinical and basic science studies
    Gulcebi, M ; Bartolini, E ; Lee, O ; Lisgaras, CP ; Onat, F ; Mifsud, J ; Striano, P ; Vezzani, A ; Hildebrand, MS ; Jimenez-Jimenez, D ; Junck, L ; Lewis-Smith, D ; Scheffer, IE ; Thijs, RD ; Zuberi, SM ; Blenkinsop, S ; Fowler, HJ ; Foley, A ; Sisodiya, SM ; Balestrini, S ; Berkovic, S ; Cavalleri, G ; Correa, DJ ; Custodio, HM ; Galovic, M ; Guerrini, R ; Henshall, D ; Howard, O ; Hughes, K ; Katsarou, A ; Koeleman, BPC ; Krause, R ; Lowenstein, D ; Mandelenaki, D ; Marini, C ; O'Brien, TJ ; Pace, A ; De Palma, L ; Perucca, P ; Pitkanen, A ; Quinn, F ; Selmer, KK ; Steward, CA ; Swanborough, N ; Thijs, R ; Tittensor, P ; Trivisano, M ; Weckhuysen, S ; Zara, F (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2021-03)
    Climate change is with us. As professionals who place value on evidence-based practice, climate change is something we cannot ignore. The current pandemic of the novel coronavirus, SARS-CoV-2, has demonstrated how global crises can arise suddenly and have a significant impact on public health. Global warming, a chronic process punctuated by acute episodes of extreme weather events, is an insidious global health crisis needing at least as much attention. Many neurological diseases are complex chronic conditions influenced at many levels by changes in the environment. This review aimed to collate and evaluate reports from clinical and basic science about the relationship between climate change and epilepsy. The keywords climate change, seasonal variation, temperature, humidity, thermoregulation, biorhythm, gene, circadian rhythm, heat, and weather were used to search the published evidence. A number of climatic variables are associated with increased seizure frequency in people with epilepsy. Climate change-induced increase in seizure precipitants such as fevers, stress, and sleep deprivation (e.g. as a result of more frequent extreme weather events) or vector-borne infections may trigger or exacerbate seizures, lead to deterioration of seizure control, and affect neurological, cerebrovascular, or cardiovascular comorbidities and risk of sudden unexpected death in epilepsy. Risks are likely to be modified by many factors, ranging from individual genetic variation and temperature-dependent channel function, to housing quality and global supply chains. According to the results of the limited number of experimental studies with animal models of seizures or epilepsy, different seizure types appear to have distinct susceptibility to seasonal influences. Increased body temperature, whether in the context of fever or not, has a critical role in seizure threshold and seizure-related brain damage. Links between climate change and epilepsy are likely to be multifactorial, complex, and often indirect, which makes predictions difficult. We need more data on possible climate-driven altered risks for seizures, epilepsy, and epileptogenesis, to identify underlying mechanisms at systems, cellular, and molecular levels for better understanding of the impact of climate change on epilepsy. Further focussed data would help us to develop evidence for mitigation methods to do more to protect people with epilepsy from the effects of climate change.
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    Variants in ATP6V0A1 cause progressive myoclonus epilepsy and developmental and epileptic encephalopathy
    Bott, LC ; Forouhan, M ; Lieto, M ; Sala, AJ ; Ellerington, R ; Johnson, JO ; Speciale, AA ; Criscuolo, C ; Filla, A ; Chitayat, D ; Alkhunaizi, E ; Shannon, P ; Nemeth, AH ; Angelucci, F ; Lim, WF ; Striano, P ; Zara, F ; Helbig, I ; Muona, M ; Courage, C ; Lehesjoki, A-E ; Berkovic, SF ; Fischbeck, KH ; Brancati, F ; Morimoto, RI ; Wood, MJA ; Rinaldi, C (OXFORD UNIV PRESS, 2021-10-01)
    The vacuolar H+-ATPase is a large multi-subunit proton pump, composed of an integral membrane V0 domain, involved in proton translocation, and a peripheral V1 domain, catalysing ATP hydrolysis. This complex is widely distributed on the membrane of various subcellular organelles, such as endosomes and lysosomes, and plays a critical role in cellular processes ranging from autophagy to protein trafficking and endocytosis. Variants in ATP6V0A1, the brain-enriched isoform in the V0 domain, have been recently associated with developmental delay and epilepsy in four individuals. Here, we identified 17 individuals from 14 unrelated families with both with new and previously characterized variants in this gene, representing the largest cohort to date. Five affected subjects with biallelic variants in this gene presented with a phenotype of early-onset progressive myoclonus epilepsy with ataxia, while 12 individuals carried de novo missense variants and showed severe developmental and epileptic encephalopathy. The R740Q mutation, which alone accounts for almost 50% of the mutations identified among our cases, leads to failure of lysosomal hydrolysis by directly impairing acidification of the endolysosomal compartment, causing autophagic dysfunction and severe developmental defect in Caenorhabditis elegans. Altogether, our findings further expand the neurological phenotype associated with variants in this gene and provide a direct link with endolysosomal acidification in the pathophysiology of ATP6V0A1-related conditions.
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    Identification of a recurrent mosaic KRAS variant in brain tissue from an individual with nevus sebaceous syndrome
    Green, TE ; MacGregor, D ; Carden, SM ; Harris, RV ; Hewitt, CA ; Berkovic, SF ; Penington, AJ ; Scheffer, IE ; Hildebrand, MS (COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT, 2021-12)
    Nevus sebaceous syndrome (NSS) is a rare, multisystem neurocutaneous disorder, characterized by a congenital nevus, and may include brain malformations such as hemimegalencephaly or focal cortical dysplasia, ocular, and skeletal features. It has been associated with several eponyms including Schimmelpenning and Jadassohn. The isolated skin lesion, nevus sebaceous, is associated with postzygotic variants in HRAS or KRAS in all individuals studied. The RAS proteins encode a family of GTPases that form part of the RAS/MAPK signaling pathway, which is critical for cell cycle regulation and differentiation during development. We studied an individual with nevus sebaceous syndrome with an extensive nevus sebaceous, epilepsy, intellectual disability, and hippocampal sclerosis without pathological evidence of a brain malformation. We used high-depth gene panel sequencing and droplet digital polymerase chain reaction (PCR) to detect and quantify RAS/MAPK gene variants in nevus sebaceous and temporal lobe tissue collected during plastic and epilepsy surgery, respectively. A mosaic KRAS c.34G > T; p.(Gly12Cys) variant, also known as G12C, was detected in nevus sebaceous tissue at 25% variant allele fraction (VAF), at the residue most commonly substituted in KRAS Targeted droplet digital PCR validated the variant and quantified the mosaicism in other tissues. The variant was detected at 33% in temporal lobe tissue but was absent from blood and healthy skin. We provide molecular confirmation of the clinical diagnosis of NSS. Our data extends the histopathological spectrum of KRAS G12C mosaicism beyond nevus sebaceous to involve brain tissue and, more specifically, hippocampal sclerosis.
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    Hypothalamic Hamartomas Evolving Understanding and Management
    Cohen, NT ; Cross, JH ; Arzimanoglou, A ; Berkovic, SF ; Kerrigan, JF ; Miller, IP ; Webster, E ; Soeby, L ; Cukiert, A ; Hesdorffer, DK ; Kroner, BL ; Saper, CB ; Schulze-Bonhage, A ; Gaillard, WD (LIPPINCOTT WILLIAMS & WILKINS, 2021-11-02)
    Hypothalamic hamartomas (HH) are rare, basilar developmental lesions with widespread comorbidities often associated with refractory epilepsy and encephalopathy. Imaging advances allow for early, even prenatal, detection. Genetic studies suggest mutations in GLI3 and other patterning genes are involved in HH pathogenesis. About 50%-80% of children with HH have severe rage and aggression and a majority of patients exhibit externalizing disorders. Behavioral disruption and intellectual disability may predate epilepsy. Neuropsychological, sleep, and endocrine disorders are typical. The purpose of this article is to provide a summary of the current understanding of HH and to highlight opportunities for future research.
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    Progressive Myoclonus Epilepsies Diagnostic Yield With Next-Generation Sequencing in Previously Unsolved Cases
    Canafoglia, L ; Franceschetti, S ; Gambardella, A ; Striano, P ; Giallonardo, AT ; Tinuper, P ; Di Bonaventura, C ; Michelucci, R ; Ferlazzo, E ; Granata, T ; Magaudda, A ; Licchetta, L ; Filla, A ; La Neve, A ; Riguzzi, P ; Cantisani, TA ; Fanella, M ; Castellotti, B ; Gellera, C ; Bahlo, M ; Zara, F ; Courage, C ; Lehesjoki, A-E ; Oliver, KL ; Berkovic, SF (LIPPINCOTT WILLIAMS & WILKINS, 2021-12)
    BACKGROUND AND OBJECTIVES: To assess the current diagnostic yield of genetic testing for the progressive myoclonus epilepsies (PMEs) of an Italian series described in 2014 where Unverricht-Lundborg and Lafora diseases accounted for ∼50% of the cohort. METHODS: Of 47/165 unrelated patients with PME of indeterminate genetic origin, 38 underwent new molecular evaluations. Various next-generation sequencing (NGS) techniques were applied including gene panel analysis (n = 7) and/or whole-exome sequencing (WES) (WES singleton n = 29, WES trio n = 7, and WES sibling n = 4). In 1 family, homozygosity mapping was followed by targeted NGS. Clinically, the patients were grouped in 4 phenotypic categories: "Unverricht-Lundborg disease-like PME," "late-onset PME," "PME plus developmental delay," and "PME plus dementia." RESULTS: Sixteen of 38 (42%) unrelated patients reached a positive diagnosis, increasing the overall proportion of solved families in the total series from 72% to 82%. Likely pathogenic variants were identified in NEU1 (2 families), CERS1 (1 family), and in 13 nonfamilial patients in KCNC1 (3), DHDDS (3), SACS, CACNA2D2, STUB1, AFG3L2, CLN6, NAXE, and CHD2. Across the different phenotypic categories, the diagnostic rate was similar, and the same gene could be found in different phenotypic categories. DISCUSSION: The application of NGS technology to unsolved patients with PME has revealed a collection of very rare genetic causes. Pathogenic variants were detected in both established PME genes and in genes not previously associated with PME, but with progressive ataxia or with developmental encephalopathies. With a diagnostic yield >80%, PME is one of the best genetically defined epilepsy syndromes.
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    Postictal Psychosis in Epilepsy: A Clinicogenetic Study
    Braatz, V ; Custodio, HM ; Leu, C ; Agro, L ; Wang, B ; Calafato, S ; Rayner, G ; Doyle, MG ; Hengsbach, C ; Bisulli, F ; Weber, YG ; Gambardella, A ; Delanty, N ; Cavalleri, G ; Foong, J ; Scheffer, IE ; Berkovic, SF ; Bramon, E ; Balestrini, S ; Sisodiya, SM (WILEY, 2021-09)
    OBJECTIVE: Psychoses affecting people with epilepsy increase disease burden and diminish quality of life. We characterized postictal psychosis, which comprises about one quarter of epilepsy-related psychoses, and has unknown causation. METHODS: We conducted a case-control cohort study including patients diagnosed with postictal psychosis, confirmed by psychiatric assessment, with available data regarding epilepsy, treatment, psychiatric history, psychosis profile, and outcomes. After screening 3,288 epilepsy patients, we identified 83 with psychosis; 49 had postictal psychosis. Controls were 98 adults, matched by age and epilepsy type, with no history of psychosis. Logistic regression was used to investigate clinical factors associated with postictal psychosis; univariate associations with a p value < 0.20 were used to build a multivariate model. Polygenic risk scores for schizophrenia were calculated. RESULTS: Cases were more likely to have seizure clustering (odds ratio [OR] = 7.59, p < 0.001), seizures with a recollected aura (OR = 2.49, p = 0.013), and a family history of psychiatric disease (OR = 5.17, p = 0.022). Cases showed predominance of right temporal epileptiform discharges (OR = 4.87, p = 0.007). There was no difference in epilepsy duration, neuroimaging findings, or antiseizure treatment between cases and controls. Polygenic risk scores for schizophrenia in an extended cohort of postictal psychosis cases (n = 58) were significantly higher than in 1,366 epilepsy controls (R2  = 3%, p = 6 × 10-3 ), but not significantly different from 945 independent patients with schizophrenia (R2  = 0.1%, p = 0.775). INTERPRETATION: Postictal psychosis occurs under particular circumstances in people with epilepsy with a heightened genetic predisposition to schizophrenia, illustrating how disease biology (seizures) and trait susceptibility (schizophrenia) may interact to produce particular outcomes (postictal psychosis) in a common disease. ANN NEUROL 2021;90:464-476.
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    Association Between Psychiatric Comorbidities and Mortality in Epilepsy
    Tao, G ; Auvrez, C ; Nightscales, R ; Barnard, S ; McCartney, L ; Malpas, CB ; Perucca, P ; Chen, Z ; Adams, S ; McIntosh, A ; Ignatiadis, S ; O'Brien, P ; Cook, MJ ; Kwan, P ; Berkovic, SF ; D'Souza, W ; Velakoulis, D ; O'Brien, TJ (LIPPINCOTT WILLIAMS & WILKINS, 2021-10)
    OBJECTIVE: To explore the impact of psychiatric comorbidities on all-cause mortality in adults with epilepsy from a cohort of patients admitted for video-EEG monitoring (VEM) over 2 decades. METHODS: A retrospective medical record audit was conducted on 2,709 adults admitted for VEM and diagnosed with epilepsy at 3 Victorian comprehensive epilepsy programs from 1995 to 2015. A total of 1,805 patients were identified in whom the record of a clinical evaluation by a neuropsychiatrist was available, excluding 27 patients who died of a malignant brain tumor known at the time of VEM admission. Epilepsy and lifetime psychiatric diagnoses were determined from consensus opinion of epileptologists and neuropsychiatrists involved in the care of each patient. Mortality and cause of death were determined by linkage to the Australian National Death Index and National Coronial Information System. RESULTS: Compared with the general population, mortality was higher in people with epilepsy (PWE) with a psychiatric illness (standardized mortality ratio [SMR] 3.6) and without a psychiatric illness (SMR 2.5). PWE with a psychiatric illness had greater mortality compared with PWE without (hazard ratio 1.41, 95% confidence interval 1.02-1.97) after adjusting for age and sex. No single psychiatric disorder by itself conferred increased mortality in PWE. The distribution of causes of death remained similar between PWE with psychiatric comorbidities and those without. CONCLUSION: The presence of comorbid psychiatric disorders in adults with epilepsy is associated with increased mortality, highlighting the importance of identifying and treating psychiatric comorbidities in these patients.