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    Interpretable surface-based detection of focal cortical dysplasias: a Multi-centre Epilepsy Lesion Detection study
    Spitzer, H ; Ripart, M ; Whitaker, K ; D'Arco, F ; Mankad, K ; Chen, AA ; Napolitano, A ; De Palma, L ; De Benedictis, A ; Foldes, S ; Humphreys, Z ; Zhang, K ; Hu, W ; Mo, J ; Likeman, M ; Davies, S ; Guttler, C ; Lenge, M ; Cohen, NT ; Tang, Y ; Wang, S ; Chari, A ; Tisdall, M ; Bargallo, N ; Conde-Blanco, E ; Pariente, JC ; Pascual-Diaz, S ; Delgado-Martinez, I ; Perez-Enriquez, C ; Lagorio, I ; Abela, E ; Mullatti, N ; O'Muircheartaigh, J ; Vecchiato, K ; Liu, Y ; Caligiuri, ME ; Sinclair, B ; Vivash, L ; Willard, A ; Kandasamy, J ; McLellan, A ; Sokol, D ; Semmelroch, M ; Kloster, AG ; Opheim, G ; Ribeiro, L ; Yasuda, C ; Rossi-Espagnet, C ; Hamandi, K ; Tietze, A ; Barba, C ; Guerrini, R ; Gaillard, WD ; You, X ; Wang, I ; Gonzalez-Ortiz, S ; Severino, M ; Striano, P ; Tortora, D ; Kalviainen, R ; Gambardella, A ; Labate, A ; Desmond, P ; Lui, E ; O'Brien, T ; Shetty, J ; Jackson, G ; Duncan, JS ; Winston, GP ; Pinborg, LH ; Cendes, F ; Theis, FJ ; Shinohara, RT ; Cross, JH ; Baldeweg, T ; Adler, S ; Wagstyl, K (OXFORD UNIV PRESS, 2022-11-21)
    One outstanding challenge for machine learning in diagnostic biomedical imaging is algorithm interpretability. A key application is the identification of subtle epileptogenic focal cortical dysplasias (FCDs) from structural MRI. FCDs are difficult to visualize on structural MRI but are often amenable to surgical resection. We aimed to develop an open-source, interpretable, surface-based machine-learning algorithm to automatically identify FCDs on heterogeneous structural MRI data from epilepsy surgery centres worldwide. The Multi-centre Epilepsy Lesion Detection (MELD) Project collated and harmonized a retrospective MRI cohort of 1015 participants, 618 patients with focal FCD-related epilepsy and 397 controls, from 22 epilepsy centres worldwide. We created a neural network for FCD detection based on 33 surface-based features. The network was trained and cross-validated on 50% of the total cohort and tested on the remaining 50% as well as on 2 independent test sites. Multidimensional feature analysis and integrated gradient saliencies were used to interrogate network performance. Our pipeline outputs individual patient reports, which identify the location of predicted lesions, alongside their imaging features and relative saliency to the classifier. On a restricted 'gold-standard' subcohort of seizure-free patients with FCD type IIB who had T1 and fluid-attenuated inversion recovery MRI data, the MELD FCD surface-based algorithm had a sensitivity of 85%. Across the entire withheld test cohort the sensitivity was 59% and specificity was 54%. After including a border zone around lesions, to account for uncertainty around the borders of manually delineated lesion masks, the sensitivity was 67%. This multicentre, multinational study with open access protocols and code has developed a robust and interpretable machine-learning algorithm for automated detection of focal cortical dysplasias, giving physicians greater confidence in the identification of subtle MRI lesions in individuals with epilepsy.
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    Structural network alterations in focal and generalized epilepsy assessed in a worldwide ENIGMA study follow axes of epilepsy risk gene expression
    Lariviere, S ; Royer, J ; Rodriguez-Cruces, R ; Paquola, C ; Caligiuri, ME ; Gambardella, A ; Concha, L ; Keller, SS ; Cendes, F ; Yasuda, CL ; Bonilha, L ; Gleichgerrcht, E ; Focke, NK ; Domin, M ; von Podewills, F ; Langner, S ; Rummel, C ; Wiest, R ; Martin, P ; Kotikalapudi, R ; O'Brien, TJ ; Sinclair, B ; Vivash, L ; Desmond, PM ; Lui, E ; Vaudano, AE ; Meletti, S ; Tondelli, M ; Alhusaini, S ; Doherty, CP ; Cavalleri, GL ; Delanty, N ; Kalviainen, R ; Jackson, GD ; Kowalczyk, M ; Mascalchi, M ; Semmelroch, M ; Thomas, RH ; Soltanian-Zadeh, H ; Davoodi-Bojd, E ; Zhang, J ; Winston, GP ; Griffin, A ; Singh, A ; Tiwari, VK ; Kreilkamp, BAK ; Lenge, M ; Guerrini, R ; Hamandi, K ; Foley, S ; Ruber, T ; Weber, B ; Depondt, C ; Absil, J ; Carr, SJA ; Abela, E ; Richardson, MP ; Devinsky, O ; Severino, M ; Striano, P ; Tortora, D ; Kaestner, E ; Hatton, SN ; Vos, SB ; Caciagli, L ; Duncan, JS ; Whelan, CD ; Thompson, PM ; Sisodiya, SM ; Bernasconi, A ; Labate, A ; McDonald, CR ; Bernasconi, N ; Bernhardt, BC (NATURE PORTFOLIO, 2022-07-27)
    Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but associations between neurobiological mechanisms and macroscale connectomics remain unclear. This multisite ENIGMA-Epilepsy study examined whole-brain structural covariance networks in patients with epilepsy and related findings to postmortem epilepsy risk gene expression patterns. Brain network analysis included 578 adults with temporal lobe epilepsy (TLE), 288 adults with idiopathic generalized epilepsy (IGE), and 1328 healthy controls from 18 centres worldwide. Graph theoretical analysis of structural covariance networks revealed increased clustering and path length in orbitofrontal and temporal regions in TLE, suggesting a shift towards network regularization. Conversely, people with IGE showed decreased clustering and path length in fronto-temporo-parietal cortices, indicating a random network configuration. Syndrome-specific topological alterations reflected expression patterns of risk genes for hippocampal sclerosis in TLE and for generalized epilepsy in IGE. These imaging-transcriptomic signatures could potentially guide diagnosis or tailor therapeutic approaches to specific epilepsy syndromes.
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    Topographic divergence of atypical cortical asymmetry and atrophy patterns in temporal lobe epilepsy
    Park, B-Y ; Lariviere, S ; Rodriguez-Cruces, R ; Royer, J ; Tavakol, S ; Wang, Y ; Caciagli, L ; Caligiuri, ME ; Gambardella, A ; Concha, L ; Keller, SS ; Cendes, F ; Alvim, MKM ; Yasuda, C ; Bonilha, L ; Gleichgerrcht, E ; Focke, NK ; Kreilkamp, BAK ; Domin, M ; von Podewils, F ; Langner, S ; Rummel, C ; Rebsamen, M ; Wiest, R ; Martin, P ; Kotikalapudi, R ; Bender, B ; O'Brien, TJ ; Law, M ; Sinclair, B ; Vivash, L ; Kwan, P ; Desmond, PM ; Malpas, CB ; Lui, E ; Alhusaini, S ; Doherty, CP ; Cavalleri, GL ; Delanty, N ; Kalviainen, R ; Jackson, GD ; Kowalczyk, M ; Mascalchi, M ; Semmelroch, M ; Thomas, RH ; Soltanian-Zadeh, H ; Davoodi-Bojd, E ; Zhang, J ; Lenge, M ; Guerrini, R ; Bartolini, E ; Hamandi, K ; Foley, S ; Weber, B ; Depondt, C ; Absil, J ; Carr, SJA ; Abela, E ; Richardson, MP ; Devinsky, O ; Severino, M ; Striano, P ; Parodi, C ; Tortora, D ; Hatton, SN ; Vos, SB ; Duncan, JS ; Galovic, M ; Whelan, CD ; Bargallo, N ; Pariente, J ; Conde-Blanco, E ; Vaudano, AE ; Tondelli, M ; Meletti, S ; Kong, X-Z ; Francks, C ; Fisher, SE ; Caldairou, B ; Ryten, M ; Labate, A ; Sisodiya, SM ; Thompson, PM ; McDonald, CR ; Bernasconi, A ; Bernasconi, N ; Bernhardt, BC (OXFORD UNIV PRESS, 2022-03-25)
    Temporal lobe epilepsy, a common drug-resistant epilepsy in adults, is primarily a limbic network disorder associated with predominant unilateral hippocampal pathology. Structural MRI has provided an in vivo window into whole-brain grey matter structural alterations in temporal lobe epilepsy relative to controls, by either mapping (i) atypical inter-hemispheric asymmetry; or (ii) regional atrophy. However, similarities and differences of both atypical asymmetry and regional atrophy measures have not been systematically investigated. Here, we addressed this gap using the multisite ENIGMA-Epilepsy dataset comprising MRI brain morphological measures in 732 temporal lobe epilepsy patients and 1418 healthy controls. We compared spatial distributions of grey matter asymmetry and atrophy in temporal lobe epilepsy, contextualized their topographies relative to spatial gradients in cortical microstructure and functional connectivity calculated using 207 healthy controls obtained from Human Connectome Project and an independent dataset containing 23 temporal lobe epilepsy patients and 53 healthy controls and examined clinical associations using machine learning. We identified a marked divergence in the spatial distribution of atypical inter-hemispheric asymmetry and regional atrophy mapping. The former revealed a temporo-limbic disease signature while the latter showed diffuse and bilateral patterns. Our findings were robust across individual sites and patients. Cortical atrophy was significantly correlated with disease duration and age at seizure onset, while degrees of asymmetry did not show a significant relationship to these clinical variables. Our findings highlight that the mapping of atypical inter-hemispheric asymmetry and regional atrophy tap into two complementary aspects of temporal lobe epilepsy-related pathology, with the former revealing primary substrates in ipsilateral limbic circuits and the latter capturing bilateral disease effects. These findings refine our notion of the neuropathology of temporal lobe epilepsy and may inform future discovery and validation of complementary MRI biomarkers in temporal lobe epilepsy.
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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.
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    Atlas of lesion locations and postsurgical seizure freedom in focal cortical dysplasia: A MELD study
    Wagstyl, K ; Whitaker, K ; Raznahan, A ; Seidlitz, J ; Vertes, PE ; Foldes, S ; Humphreys, Z ; Hu, W ; Mo, J ; Likeman, M ; Davies, S ; Lenge, M ; Cohen, NT ; Tang, Y ; Wang, S ; Ripart, M ; Chari, A ; Tisdall, M ; Bargallo, N ; Conde-Blanco, E ; Carlos Pariente, J ; Pascual-Diaz, S ; Delgado-Martinez, I ; Perez-Enriquez, C ; Lagorio, I ; Abela, E ; Mullatti, N ; O'Muircheartaigh, J ; Vecchiato, K ; Liu, Y ; Caligiuri, M ; Sinclair, B ; Vivash, L ; Willard, A ; Kandasamy, J ; McLellan, A ; Sokol, D ; Semmelroch, M ; Kloster, A ; Opheim, G ; Yasuda, C ; Zhang, K ; Hamandi, K ; Barba, C ; Guerrini, R ; Gaillard, WD ; You, X ; Wang, I ; Gonzalez-Ortiz, S ; Severino, M ; Striano, P ; Tortora, D ; Kalviainen, R ; Gambardella, A ; Labate, A ; Desmond, P ; Lui, E ; O'Brien, T ; Shetty, J ; Jackson, G ; Duncan, JS ; Winston, GP ; Pinborg, L ; Cendes, F ; Cross, JH ; Baldeweg, T ; Adler, S (WILEY, 2022-01)
    OBJECTIVE: Drug-resistant focal epilepsy is often caused by focal cortical dysplasias (FCDs). The distribution of these lesions across the cerebral cortex and the impact of lesion location on clinical presentation and surgical outcome are largely unknown. We created a neuroimaging cohort of patients with individually mapped FCDs to determine factors associated with lesion location and predictors of postsurgical outcome. METHODS: The MELD (Multi-centre Epilepsy Lesion Detection) project collated a retrospective cohort of 580 patients with epilepsy attributed to FCD from 20 epilepsy centers worldwide. Magnetic resonance imaging-based maps of individual FCDs with accompanying demographic, clinical, and surgical information were collected. We mapped the distribution of FCDs, examined for associations between clinical factors and lesion location, and developed a predictive model of postsurgical seizure freedom. RESULTS: FCDs were nonuniformly distributed, concentrating in the superior frontal sulcus, frontal pole, and temporal pole. Epilepsy onset was typically before the age of 10 years. Earlier epilepsy onset was associated with lesions in primary sensory areas, whereas later epilepsy onset was associated with lesions in association cortices. Lesions in temporal and occipital lobes tended to be larger than frontal lobe lesions. Seizure freedom rates varied with FCD location, from around 30% in visual, motor, and premotor areas to 75% in superior temporal and frontal gyri. The predictive model of postsurgical seizure freedom had a positive predictive value of 70% and negative predictive value of 61%. SIGNIFICANCE: FCD location is an important determinant of its size, the age at epilepsy onset, and the likelihood of seizure freedom postsurgery. Our atlas of lesion locations can be used to guide the radiological search for subtle lesions in individual patients. Our atlas of regional seizure freedom rates and associated predictive model can be used to estimate individual likelihoods of postsurgical seizure freedom. Data-driven atlases and predictive models are essential for evidence-based, precision medicine and risk counseling in epilepsy.
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    Assessment of the DTI-ALPS Parameter Along the Perivascular Space in Older Adults at Risk of Dementia
    Steward, CE ; Venkatraman, VK ; Lui, E ; Malpas, CB ; Ellis, KA ; Cyarto, EV ; Vivash, L ; O'Brien, TJ ; Velakoulis, D ; Ames, D ; Masters, CL ; Lautenschlager, NT ; Bammer, R ; Desmond, PM (WILEY, 2021-05)
    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.
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    Sodium selenate as a disease-modifying treatment for progressive supranuclear palsy: protocol for a phase 2, randomised, double-blind, placebo-controlled trial
    Vivash, L ; Bertram, KL ; Malpas, CB ; Marotta, C ; Harding, IH ; Kolbe, S ; Fielding, J ; Clough, M ; Lewis, SJG ; Tisch, S ; Evans, AH ; O'Sullivan, JD ; Kimber, T ; Darby, D ; Churilov, L ; Law, M ; Hovens, CM ; Velakoulis, D ; O'Brien, TJ (BMJ PUBLISHING GROUP, 2021-12)
    INTRODUCTION: Progressive supranuclear palsy (PSP) is a neurodegenerative disorder for which there are currently no disease-modifying therapies. The neuropathology of PSP is associated with the accumulation of hyperphosphorylated tau in the brain. We have previously shown that protein phosphatase 2 activity in the brain is upregulated by sodium selenate, which enhances dephosphorylation. Therefore, the objective of this study is to evaluate the efficacy and safety of sodium selenate as a disease-modifying therapy for PSP. METHODS AND ANALYSIS: This will be a multi-site, phase 2b, double-blind, placebo-controlled trial of sodium selenate. 70 patients will be recruited at six Australian academic hospitals and research institutes. Following the confirmation of eligibility at screening, participants will be randomised (1:1) to receive 52 weeks of active treatment (sodium selenate; 15 mg three times a day) or matching placebo. Regular safety and efficacy visits will be completed throughout the study period. The primary study outcome is change in an MRI volume composite (frontal lobe+midbrain-3rd ventricle) over the treatment period. Analysis will be with a general linear model (GLM) with the MRI composite at 52 weeks as the dependent variable, treatment group as an independent variable and baseline MRI composite as a covariate. Secondary outcomes are change in PSP rating scale, clinical global impression of change (clinician) and change in midbrain mean diffusivity. These outcomes will also be analysed with a GLM as above, with the corresponding baseline measure entered as a covariate. Secondary safety and tolerability outcomes are frequency of serious adverse events, frequency of down-titration occurrences and frequency of study discontinuation. Additional, as yet unplanned, exploratory outcomes will include analyses of other imaging, cognitive and biospecimen measures. ETHICS AND DISSEMINATION: The study was approved by the Alfred Health Ethics Committee (594/20). Each participant or their legally authorised representative and their study partner will provide written informed consent at trial commencement. The results of the study will be presented at national and international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12620001254987).
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    Artificial intelligence for classification of temporal lobe epilepsy with ROI-level MRI data: A worldwide ENIGMA-Epilepsy study
    Gleichgerrcht, E ; Munsell, BC ; Alhusaini, S ; Alvim, MKM ; Bargallo, N ; Bender, B ; Bernasconi, A ; Bernasconi, N ; Bernhardt, B ; Blackmon, K ; Caligiuri, ME ; Cendes, F ; Concha, L ; Desmond, PM ; Devinsky, O ; Doherty, CP ; Domin, M ; Duncan, JS ; Focke, NK ; Gambardella, A ; Gong, B ; Guerrini, R ; Hatton, SN ; Kalviainen, R ; Keller, SS ; Kochunov, P ; Kotikalapudi, R ; Kreilkamp, BAK ; Labate, A ; Langner, S ; Lariviere, S ; Lenge, M ; Lui, E ; Martin, P ; Mascalchi, M ; Meletti, S ; O'Brien, TJ ; Pardoe, HR ; Pariente, JC ; Rao, JX ; Richardson, MP ; Rodriguez-Cruces, R ; Ruber, T ; Sinclair, B ; Soltanian-Zadeh, H ; Stein, DJ ; Striano, P ; Taylor, PN ; Thomas, RH ; Vaudano, AE ; Vivash, L ; von Podewills, F ; Vos, SB ; Weber, B ; Yao, Y ; Yasuda, CL ; Zhang, J ; Thompson, PM ; Sisodiya, SM ; McDonald, CR ; Bonilha, L (ELSEVIER SCI LTD, 2021)
    Artificial intelligence has recently gained popularity across different medical fields to aid in the detection of diseases based on pathology samples or medical imaging findings. Brain magnetic resonance imaging (MRI) is a key assessment tool for patients with temporal lobe epilepsy (TLE). The role of machine learning and artificial intelligence to increase detection of brain abnormalities in TLE remains inconclusive. We used support vector machine (SV) and deep learning (DL) models based on region of interest (ROI-based) structural (n = 336) and diffusion (n = 863) brain MRI data from patients with TLE with ("lesional") and without ("non-lesional") radiographic features suggestive of underlying hippocampal sclerosis from the multinational (multi-center) ENIGMA-Epilepsy consortium. Our data showed that models to identify TLE performed better or similar (68-75%) compared to models to lateralize the side of TLE (56-73%, except structural-based) based on diffusion data with the opposite pattern seen for structural data (67-75% to diagnose vs. 83% to lateralize). In other aspects, structural and diffusion-based models showed similar classification accuracies. Our classification models for patients with hippocampal sclerosis were more accurate (68-76%) than models that stratified non-lesional patients (53-62%). Overall, SV and DL models performed similarly with several instances in which SV mildly outperformed DL. We discuss the relative performance of these models with ROI-level data and the implications for future applications of machine learning and artificial intelligence in epilepsy care.
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    7T Magnetic Resonance Imaging Quantification of Brain Glutamate in Acute Ischaemic Stroke
    Nicolo, J-P ; Moffat, B ; Wright, DK ; Sinclair, B ; Neal, A ; Lui, E ; Desmond, P ; Glarin, R ; Davis, KA ; Reddy, R ; Yan, B ; O'Brien, TJ ; Kwan, P (Korean Stroke Society, 2021-05-01)
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    Study protocol for a phase II randomised, double-blind, placebo-controlled trial of perampanel as an antiepileptogenic treatment following acute stroke
    Nicolo, J-P ; Chen, Z ; Moffat, B ; Wright, DK ; Sinclair, B ; Glarin, R ; Neal, A ; Thijs, V ; Seneviratne, U ; Yan, B ; Cloud, G ; O'Brien, TJ ; Kwan, P (BMJ PUBLISHING GROUP, 2021-05)
    INTRODUCTION: Stroke is a common cause of epilepsy that may be mediated via glutamate dysregulation. There is currently no evidence to support the use of antiseizure medications as primary prevention against poststroke epilepsy. Perampanel has a unique antiglutamatergic mechanism of action and may have antiepileptogenic properties. This study aims to evaluate the efficacy and safety of perampanel as an antiepileptogenic treatment in patients at high risk of poststroke epilepsy. METHODS AND ANALYSIS: Up to 328 patients with cortical ischaemic stroke or lobar haemorrhage will be enrolled, and receive their first treatment within 7 days of stroke onset. Patients will be randomised (1:1) to receive perampanel (titrated to 6 mg daily over 4 weeks) or matching placebo, stratified by stroke subtype (ischaemic or haemorrhagic). Treatment will be continued for 12 weeks after titration. 7T MRI will be performed at baseline for quantification of cerebral glutamate by magnetic resonance spectroscopy and glutamate chemical exchange saturation transfer imaging. Blood will be collected for measurement of plasma glutamate levels. Participants will be followed up for 52 weeks after randomisation.The primary study outcome will be the proportion of participants in each group free of late (more than 7 days after stroke onset) poststroke seizures by the end of the 12-month study period, analysed by Fisher's exact test. Secondary outcomes will include time to first seizure, time to treatment withdrawal and 3-month modified Rankin Scale score. Quality of life, cognitive function, mood and adverse events will be assessed by standardised questionnaires. Exploratory outcomes will include correlation between cerebral and plasma glutamate concentration and stroke and seizure outcomes. ETHICS AND DISSEMINATION: This study was approved by the Alfred Health Human Research Ethics Committee (HREC No 44366, Reference 287/18). TRIAL REGISTRATION NUMBER: ACTRN12618001984280; Pre-results.