Medicine (RMH) - Research Publications

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    Rare Genetic Variation and Outcome of Surgery for Mesial Temporal Lobe Epilepsy
    Perucca, P ; Stanley, K ; Harris, N ; McIntosh, AM ; Asadi-Pooya, AA ; Mikati, MA ; Andrade, DM ; Dugan, P ; Depondt, C ; Choi, H ; Heinzen, EL ; Cavalleri, GL ; Buono, RJ ; Devinsky, O ; Sperling, MR ; Berkovic, SF ; Delanty, N ; Goldstein, DB ; O'Brien, TJ (WILEY, 2023-04)
    OBJECTIVE: Genetic factors have long been debated as a cause of failure of surgery for mesial temporal lobe epilepsy (MTLE). We investigated whether rare genetic variation influences seizure outcomes of MTLE surgery. METHODS: We performed an international, multicenter, whole exome sequencing study of patients who underwent surgery for drug-resistant, unilateral MTLE with normal magnetic resonance imaging (MRI) or MRI evidence of hippocampal sclerosis and ≥2-year postsurgical follow-up. Patients with either sustained seizure freedom (favorable outcome) or ongoing uncontrolled seizures since surgery (unfavorable outcome) were included. Exomes of controls without epilepsy were also included. Gene set burden analyses were carried out to identify genes with significant enrichment of rare deleterious variants in patients compared to controls. RESULTS: Nine centers from 3 continents contributed 206 patients operated for drug-resistant unilateral MTLE, of whom 196 (149 with favorable outcome and 47 with unfavorable outcome) were included after stringent quality control. Compared to 8,718 controls, MTLE cases carried a higher burden of ultrarare missense variants in constrained genes that are intolerant to loss-of-function (LoF) variants (odds ratio [OR] = 2.6, 95% confidence interval [CI] = 1.9-3.5, p = 1.3E-09) and in genes encoding voltage-gated cation channels (OR = 2.4, 95% CI = 1.4-3.8, p = 2.7E-04). Proportions of subjects with such variants were comparable between patients with favorable outcome and those with unfavorable outcome, with no significant between-group differences. INTERPRETATION: Rare variation contributes to the genetic architecture of MTLE, but does not appear to have a major role in failure of MTLE surgery. These findings can be incorporated into presurgical decision-making and counseling. ANN NEUROL 2022.
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    Familial Mesial Temporal Lobe Epilepsy: Clinical Spectrum and Genetic Evidence for a Polygenic Architecture
    Harris, RV ; Oliver, KL ; Perucca, P ; Striano, P ; Labate, A ; Riva, A ; Grinton, BE ; Reid, J ; Hutton, J ; Todaro, M ; O'Brien, TJ ; Kwan, P ; Sadleir, LG ; Mullen, SA ; Dazzo, E ; Crompton, DE ; Scheffer, IE ; Bahlo, M ; Nobile, C ; Gambardella, A ; Berkovic, SF (WILEY, 2023-11)
    OBJECTIVE: Familial mesial temporal lobe epilepsy (FMTLE) is an important focal epilepsy syndrome; its molecular genetic basis is unknown. Clinical descriptions of FMTLE vary between a mild syndrome with prominent déjà vu to a more severe phenotype with febrile seizures and hippocampal sclerosis. We aimed to refine the phenotype of FMTLE by analyzing a large cohort of patients and asked whether common risk variants for focal epilepsy and/or febrile seizures, measured by polygenic risk scores (PRS), are enriched in individuals with FMTLE. METHODS: We studied 134 families with ≥ 2 first or second-degree relatives with temporal lobe epilepsy, with clear mesial ictal semiology required in at least one individual. PRS were calculated for 227 FMTLE cases, 124 unaffected relatives, and 16,077 population controls. RESULTS: The age of patients with FMTLE onset ranged from 2.5 to 70 years (median = 18, interquartile range = 13-28 years). The most common focal seizure symptom was déjà vu (62% of cases), followed by epigastric rising sensation (34%), and fear or anxiety (22%). The clinical spectrum included rare cases with drug-resistance and/or hippocampal sclerosis. FMTLE cases had a higher mean focal epilepsy PRS than population controls (odds ratio = 1.24, 95% confidence interval = 1.06, 1.46, p = 0.007); in contrast, no enrichment for the febrile seizure PRS was observed. INTERPRETATION: FMTLE is a generally mild drug-responsive syndrome with déjà vu being the commonest symptom. In contrast to dominant monogenic focal epilepsy syndromes, our molecular data support a polygenic basis for FMTLE. Furthermore, the PRS data suggest that sub-genome-wide significant focal epilepsy genome-wide association study single nucleotide polymorphisms are important risk variants for FMTLE. ANN NEUROL 2023;94:825-835.
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    Diagnostic delay in focal epilepsy: Association with brain pathology and age
    Yang, M ; Tan, KM ; Carney, P ; Kwan, P ; O'Brien, TJ ; Berkovic, SF ; Perucca, P ; McIntosh, AM (W B SAUNDERS CO LTD, 2022-03)
    PURPOSE: Between 16-77% of patients with newly diagnosed epilepsy report seizures before diagnosis but little is known about the risk factors for diagnostic delay. Here, we examined the association between prior seizures and neuroimaging findings in newly diagnosed focal epilepsy. METHODS: Adults diagnosed with focal epilepsy at First Seizure Clinics (FSC) at the Royal Melbourne Hospital or Austin Health, Melbourne, Australia, between 2000 and 2010 were included. Medical records were audited for seizure history accrued from the detailed FSC interview. Potentially epileptogenic brain abnormality type, location and extent was determined from neuroimaging. Statistical analysis comprised multivariate logistic regression. RESULTS: Of 735 patients, 44% reported seizure/s before the index seizure. Among the 260 individuals with a potentially epileptogenic brain imaging abnormality, 34% reported prior seizures. Of 475 individuals with no abnormality, 50% reported prior seizures (p < 0.001). Patients with post-stroke changes had lower odds of prior seizures (n = 24/95, OR 0.5, p = 0.005) compared to patients without abnormalities, as did patients with high-grade tumors (n = 1/10, OR 0.1, p = 0.04). Abnormality location or extent was not associated with seizures. Prior seizures were inversely associated with age, patients aged >50 years had lower odds compared to those 18-30 years (OR 0.5, p = 0.01). CONCLUSIONS: A history of prior seizures is less common in patients with newly diagnosed focal epilepsy associated with antecedent stroke or high-grade tumor than in those without a lesion, and is also less common in older individuals. These findings may be related to age, biological mechanisms or aspects of diagnosis and assessment of these events.
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    A founder event causing a dominant childhood epilepsy survives 800 years through weak selective pressure
    Grinton, BE ; Robertson, E ; Fearnley, LG ; Scheffer, IE ; Marson, AG ; O'Brien, TJ ; Pickrell, WO ; Rees, M ; Sisodiya, SM ; Balding, DJ ; Bennett, MF ; Bahlo, M ; Berkovic, SF ; Oliver, KL (CELL PRESS, 2022-11-03)
    Genetic epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant familial epilepsy syndrome characterized by distinctive phenotypic heterogeneity within families. The SCN1B c.363C>G (p.Cys121Trp) variant has been identified in independent, multi-generational families with GEFS+. Although the variant is present in population databases (at very low frequency), there is strong clinical, genetic, and functional evidence to support pathogenicity. Recurrent variants may be due to a founder event in which the variant has been inherited from a common ancestor. Here, we report evidence of a single founder event giving rise to the SCN1B c.363C>G variant in 14 independent families with epilepsy. A common haplotype was observed in all families, and the age of the most recent common ancestor was estimated to be approximately 800 years ago. Analysis of UK Biobank whole-exome-sequencing data identified 74 individuals with the same variant. All individuals carried haplotypes matching the epilepsy-affected families, suggesting all instances of the variant derive from a single mutational event. This unusual finding of a variant causing an autosomal dominant, early-onset disease in an outbred population that has persisted over many generations can be attributed to the relatively mild phenotype in most carriers and incomplete penetrance. Founder events are well established in autosomal recessive and late-onset disorders but are rarely observed in early-onset, autosomal dominant diseases. These findings suggest variants present in the population at low frequencies should be considered potentially pathogenic in mild phenotypes with incomplete penetrance and may be more important contributors to the genetic landscape than previously thought.
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    Risk of sudden unexpected death in epilepsy (SUDEP) with lamotrigine and other sodium channel-modulating antiseizure medications
    Nightscales, R ; Barnard, S ; Laze, J ; Chen, Z ; Tao, G ; Auvrez, C ; Sivathamboo, S ; Cook, MJ ; Kwan, P ; Friedman, D ; Berkovic, SF ; D'Souza, W ; Perucca, P ; Devinsky, O ; O'Brien, TJ (WILEY, 2023-06)
    OBJECTIVE: In vitro data prompted U.S Food and Drug Administration warnings that lamotrigine, a common sodium channel modulating anti-seizure medication (NaM-ASM), could increase the risk of sudden death in patients with structural or ischaemic cardiac disease, however, its implications for Sudden Unexpected Death in Epilepsy (SUDEP) are unclear. METHODS: This retrospective, nested case-control study identified 101 sudden unexpected death in epilepsy (SUDEP) cases and 199 living epilepsy controls from Epilepsy Monitoring Units (EMUs) in Australia and the USA. Differences in proportions of lamotrigine and NaM-ASM use were compared between cases and controls at the time of admission, and survival analyses from the time of admission up to 16 years were conducted. Multivariable logistic regression and survival analyses compared each ASM subgroup adjusting for SUDEP risk factors. RESULTS: Proportions of cases and controls prescribed lamotrigine (P = 0.166), one NaM-ASM (P = 0.80), or ≥2NaM-ASMs (P = 0.447) at EMU admission were not significantly different. Patients taking lamotrigine (adjusted hazard ratio [aHR] = 0.56; P = 0.054), one NaM-ASM (aHR = 0.8; P = 0.588) or ≥2 NaM-ASMs (aHR = 0.49; P = 0.139) at EMU admission were not at increased SUDEP risk up to 16 years following admission. Active tonic-clonic seizures at EMU admission associated with >2-fold SUDEP risk, irrespective of lamotrigine (aHR = 2.24; P = 0.031) or NaM-ASM use (aHR = 2.25; P = 0.029). Sensitivity analyses accounting for incomplete ASM data at follow-up suggest undetected changes to ASM use are unlikely to alter our results. SIGNIFICANCE: This study provides additional evidence that lamotrigine and other NaM-ASMs are unlikely to be associated with an increased long-term risk of SUDEP, up to 16 years post-EMU admission.
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    Cerebrospinal fluid neurofilament light chain differentiates primary psychiatric disorders from rapidly progressive, Alzheimer's disease and frontotemporal disorders in clinical settings
    Eratne, D ; Loi, SM ; Qiao-Xin, L ; Stehmann, C ; Malpas, CB ; Santillo, A ; Janelidze, S ; Cadwallader, C ; Walia, N ; Ney, B ; Lewis, V ; Senesi, M ; Fowler, C ; McGlade, A ; Varghese, S ; Ravanfar, P ; Kelso, W ; Farrand, S ; Keem, M ; Kang, M ; Goh, AMY ; Dhiman, K ; Gupta, V ; Watson, R ; Yassi, N ; Kaylor-Hughes, C ; Kanaan, R ; Perucca, P ; Dobson, H ; Vivash, L ; Ali, R ; O'Brien, TJ ; Hansson, O ; Zetterberg, H ; Blennow, K ; Walterfang, M ; Masters, CL ; Berkovic, SF ; Collins, S ; Velakoulis, D (WILEY, 2022-11)
    INTRODUCTION: Many patients with cognitive and neuropsychiatric symptoms face diagnostic delay and misdiagnosis. We investigated whether cerebrospinal fluid (CSF) neurofilament light (NfL) and total-tau (t-tau) could assist in the clinical scenario of differentiating neurodegenerative (ND) from psychiatric disorders (PSY), and rapidly progressive disorders. METHODS: Biomarkers were examined in patients from specialist services (ND and PSY) and a national Creutzfeldt-Jakob registry (Creutzfeldt-Jakob disease [CJD] and rapidly progressive dementias/atypically rapid variants of common ND, RapidND). RESULTS: A total of 498 participants were included: 197 ND, 67 PSY, 161 CJD, 48 RapidND, and 20 controls. NfL was elevated in ND compared to PSY and controls, with highest levels in CJD and RapidND. NfL distinguished ND from PSY with 95%/78% positive/negative predictive value, 92%/87% sensitivity/specificity, 91% accuracy. NfL outperformed t-tau in most real-life clinical diagnostic dilemma scenarios, except distinguishing CJD from RapidND. DISCUSSION: We demonstrated strong generalizable evidence for the diagnostic utility of CSF NfL in differentiating ND from psychiatric disorders, with high accuracy.
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    Adjunctive Transdermal Cannabidiol for Adults With Focal Epilepsy A Randomized Clinical Trial
    O'Brien, TJ ; Berkovic, SF ; French, JA ; Messenheimer, JA ; Sebree, TB ; Bonn-Miller, MO ; Gutterman, DL (AMER MEDICAL ASSOC, 2022-07-08)
    IMPORTANCE: Cannabidiol has shown efficacy in randomized clinical trials for drug-resistant epilepsy in specific syndromes that predominantly affect children. However, high-level evidence for the efficacy and safety of cannabidiol in the most common form of drug-resistant epilepsy in adults, focal epilepsy, is lacking. OBJECTIVE: To investigate the efficacy, safety, and tolerability of transdermally administered cannabidiol in adults with drug-resistant focal epilepsy. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled, multicenter clinical trial at 14 epilepsy trial centers in Australia and New Zealand. Participants were adults with drug-resistant focal epilepsy receiving a stable regimen of up to 3 antiseizure medications. Data were analyzed from July 2017 to November 2018. INTERVENTIONS: Eligible participants were randomized (1:1:1) to 195-mg or 390-mg transdermal cannabidiol or placebo twice daily for 12 weeks, after which they could enroll in an open-label extension study for up to 2 years. MAIN OUTCOMES AND MEASURES: Seizure frequency was self-reported using a daily diary. The primary efficacy end point was the least squares mean difference in the log-transformed total seizure frequency per 28-day period, adjusted to a common baseline log seizure rate, during the 12-week treatment period. RESULTS: A total of 188 patients (45% male [85 patients] and 54.8% female [103 patients]) with a mean (SD) age of 39.2 (12.78) years were randomized, treated, and analyzed (195-mg cannabidiol, 63 participants; 390-mg cannabidiol, 62 participants; placebo, 63 participants). At week 12 of the double-blind period, there was no difference in seizure frequency between placebo (mean [SD] 2.49 [1.31] seizures per 28 days) and 195-mg cannabidiol (mean [SD] 2.51 [1.15] seizures per 28 days; least squares mean difference, 0.014; 95% CI, -0.175 to 0.203; P = .89) or 390-mg cannabidiol (mean [SD] 2.59 [1.12] seizures per 28 days; least squares mean difference, 0.096; 95% CI, -0.093 to 0.285; P = .32). By month 6 of the open-label extension, 115 patients (60.8%) achieved a seizure reduction of at least 50%. Treatment-emergent adverse events occurred in 50.4% (63 of 125 participants) of the cannabidiol group vs 41.3% (26 of 63 participants) in the placebo group, with a treatment difference of 9.1% (95% CI, -6.0% to 23.6%), and occurred at similar rates in the cannabidiol groups. Few participants discontinued (7% [14 of 188 participants]), and most (98% [171 of 174 participants]) continued into the open-label extension. CONCLUSIONS AND RELEVANCE: Both doses of transdermal cannabidiol were well tolerated and safe. No significant difference in efficacy was observed between cannabidiol and placebo during the double-blind treatment period. The open-label extension demonstrated the long-term safety, tolerability, and acceptability of transdermal cannabidiol delivery. TRIAL REGISTRATION: ACTRN12616000510448 (double-blind); ACTRN12616001455459 (open-label).
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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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    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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    Machine learning approaches for imaging-based prognostication of the outcome of surgery for mesial temporal lobe epilepsy
    Sinclair, B ; Cahill, V ; Seah, J ; Kitchen, A ; Vivash, LE ; Chen, Z ; Malpas, CB ; O'Shea, MF ; Desmond, PM ; Hicks, RJ ; Morokoff, AP ; King, JA ; Fabinyi, GC ; Kaye, AH ; Kwan, P ; Berkovic, SF ; Law, M ; O'Brien, TJ (WILEY, 2022-05)
    OBJECTIVES: Around 30% of patients undergoing surgical resection for drug-resistant mesial temporal lobe epilepsy (MTLE) do not obtain seizure freedom. Success of anterior temporal lobe resection (ATLR) critically depends on the careful selection of surgical candidates, aiming at optimizing seizure freedom while minimizing postoperative morbidity. Structural MRI and FDG-PET neuroimaging are routinely used in presurgical assessment and guide the decision to proceed to surgery. In this study, we evaluate the potential of machine learning techniques applied to standard presurgical MRI and PET imaging features to provide enhanced prognostic value relative to current practice. METHODS: Eighty two patients with drug resistant MTLE were scanned with FDG-PET pre-surgery and T1-weighted MRI pre- and postsurgery. From these images the following features of interest were derived: volume of temporal lobe (TL) hypometabolism, % of extratemporal hypometabolism, presence of contralateral TL hypometabolism, presence of hippocampal sclerosis, laterality of seizure onset volume of tissue resected and % of temporal lobe hypometabolism resected. These measures were used as predictor variables in logistic regression, support vector machines, random forests and artificial neural networks. RESULTS: In the study cohort, 24 of 82 (28.3%) who underwent an ATLR for drug-resistant MTLE did not achieve Engel Class I (i.e., free of disabling seizures) outcome at a minimum of 2 years of postoperative follow-up. We found that machine learning approaches were able to predict up to 73% of the 24 ATLR surgical patients who did not achieve a Class I outcome, at the expense of incorrect prediction for up to 31% of patients who did achieve a Class I outcome. Overall accuracies ranged from 70% to 80%, with an area under the receiver operating characteristic curve (AUC) of .75-.81. We additionally found that information regarding overall extent of both total and significantly hypometabolic tissue resected was crucial to predictive performance, with AUC dropping to .59-.62 using presurgical information alone. Incorporating the laterality of seizure onset and the choice of machine learning algorithm did not significantly change predictive performance. SIGNIFICANCE: Collectively, these results indicate that "acceptable" to "good" patient-specific prognostication for drug-resistant MTLE surgery is feasible with machine learning approaches utilizing commonly collected imaging modalities, but that information on the surgical resection region is critical for optimal prognostication.