Medicine (RMH) - Research Publications

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    Psychometric deficits in autoimmune encephalitis: A retrospective study from the Australian Autoimmune Encephalitis Consortium
    Griffith, S ; Wesselingh, R ; Broadley, J ; O'Shea, M ; Kyndt, C ; Meade, C ; Long, B ; Seneviratne, U ; Reidy, N ; Bourke, R ; Buzzard, K ; D'Souza, W ; Macdonell, R ; Brodtmann, A ; Butzkueven, H ; O'Brien, TJ ; Alpitsis, R ; Malpas, CB ; Monif, M (WILEY, 2022-08)
    BACKGROUND AND PURPOSE: Despite the rapid increase in research examining outcomes in autoimmune encephalitis (AE) patients, there are few cohort studies examining cognitive outcomes in this population. The current study aimed to characterise psychometric outcomes in this population, and explore variables that may predict psychometric outcomes. METHODS: This retrospective observational study collected psychometric data from 59 patients across six secondary and tertiary referral centres in metropolitan hospitals in Victoria, Australia between January 2008 and July 2019. Frequency and pattern analysis were employed to define and characterize psychometric outcomes. Univariable logistic regression was performed to examine predictors of intact and pathological psychometric outcomes. RESULTS: Deficits in psychometric markers of executive dysfunction were the most common finding in this cohort, followed by deficits on tasks sensitive to memory. A total of 54.2% of patients were classified as having psychometric impairments across at least two cognitive domains. Twenty-nine patterns were observed, suggesting outcomes in AE are complex. None of the demographic data, clinical features or auxiliary examination variables were predictors of psychometric outcome. CONCLUSIONS: Cognitive outcomes in AE are complex. Further detailed and standardized cognitive testing, in combination with magnetic resonance imaging volumetrics and serum/cerebrospinal fluid biomarkers, is required to provide rigorous assessments of disease outcomes.
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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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    Long-term open-label perampanel: Generalized tonic-clonic seizures in idiopathic generalized epilepsy
    French, JA ; Wechsler, RT ; Trinka, E ; Brandt, C ; O'Brien, TJ ; Patten, A ; Salah, A ; Malhotra, M (WILEY, 2022-09)
    OBJECTIVE: Assess the longer-term efficacy and safety of adjunctive perampanel (up to 12 mg/day) in patients aged ≥12 years with generalized tonic-clonic (GTC) seizures from the Open-label Extension (OLEx) Phase of Study 332 to determine whether responses obtained during the Core Study are maintained during long-term treatment. METHODS: Patients with GTC seizures previously enrolled in a randomized placebo-controlled trial of perampanel could enter an OLEx Phase comprising 6-week blinded conversion (during which patients previously randomized to placebo-switched to perampanel) and up to 136-week maintenance periods (maximum perampanel dose of 12 mg/day). A 4-week follow-up period was completed by all patients after the last on-treatment visit during the OLEx. We assessed seizure frequency outcomes from preperampanel baseline and the Core Study Pre-randomization Phase, retention rates, doses selected, and treatment-emergent adverse events (TEAEs). RESULTS: Overall, 138 patients entered the OLEx. Median percent reductions in GTC seizures per 28 days from preperampanel were 77% (Weeks 1-13) and 90% (Weeks 40-52). Retention rates were 88% (6 months) and 75% (12 months). Seizure-freedom rates were maintained for at least 2 years regardless of prior treatment received during the Core Study. Most common modal daily dose was >4-8 mg/day (n = 93). Across the Core and OLEx Phases, 120 (87%) patients experienced TEAEs; the most common was dizziness. SIGNIFICANCE: Perampanel was generally well-tolerated, and the TEAEs reported here are consistent with the known safety profile of perampanel. Perampanel offers a long-term treatment option for patients (aged ≥12 years) with GTC seizures.
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    Perivascular spaces as a potential biomarker of Alzheimer's disease
    Lynch, M ; Pham, W ; Sinclair, B ; O'Brien, TJ ; Law, M ; Vivash, L (FRONTIERS MEDIA SA, 2022-10-18)
    Alzheimer's disease (AD) is a highly damaging disease that affects one's cognition and memory and presents an increasing societal and economic burden globally. Considerable research has gone into understanding AD; however, there is still a lack of effective biomarkers that aid in early diagnosis and intervention. The recent discovery of the glymphatic system and associated Perivascular Spaces (PVS) has led to the theory that enlarged PVS (ePVS) may be an indicator of AD progression and act as an early diagnostic marker. Visible on Magnetic Resonance Imaging (MRI), PVS appear to enlarge when known biomarkers of AD, amyloid-β and tau, accumulate. The central goal of ePVS and AD research is to determine when ePVS occurs in AD progression and if ePVS are causal or epiphenomena. Furthermore, if ePVS are indeed causative, interventions promoting glymphatic clearance are an attractive target for research. However, it is necessary first to ascertain where on the pathological progression of AD ePVS occurs. This review aims to examine the knowledge gap that exists in understanding the contribution of ePVS to AD. It is essential to understand whether ePVS in the brain correlate with increased regional tau distribution and global or regional Amyloid-β distribution and to determine if these spaces increase proportionally over time as individuals experience neurodegeneration. This review demonstrates that ePVS are associated with reduced glymphatic clearance and that this reduced clearance is associated with an increase in amyloid-β. However, it is not yet understood if ePVS are the outcome or driver of protein accumulation. Further, it is not yet clear if ePVS volume and number change longitudinally. Ultimately, it is vital to determine early diagnostic criteria and early interventions for AD to ease the burden it presents to the world; ePVS may be able to fulfill this role and therefore merit further research.
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    Perivascular spaces as a marker of disease severity and neurodegeneration in patients with behavioral variant frontotemporal dementia
    Moses, J ; Sinclair, B ; Schwartz, DLL ; Silbert, LCC ; O'Brien, TJJ ; Law, M ; Vivash, L (FRONTIERS MEDIA SA, 2022-10-20)
    BACKGROUND: Behavioural Variant Frontotemporal Dementia (bvFTD) is a rapidly progressing neurodegenerative proteinopathy. Perivascular spaces (PVS) form a part of the brain's glymphatic clearance system. When enlarged due to poor glymphatic clearance of toxic proteins, PVS become larger and more conspicuous on MRI. Therefore, enlarged PVS may be a useful biomarker of disease severity and progression in neurodegenerative proteinopathies such as bvFTD. This study aimed to determine the utility of PVS as a biomarker of disease progression in patients with bvFTD. MATERIALS AND METHODS: Serial baseline and week 52 MRIs acquired from ten patients with bvFTD prospectively recruited and followed in a Phase 1b open label trial of sodium selenate for bvFTD were used in this study. An automated algorithm quantified PVS on MRI, which was visually inspected and validated by a member of the study team. The number and volume of PVS were extracted and mixed models used to assess the relationship between PVS burden and other measures of disease (cognition, carer burden scale, protein biomarkers). Additional exploratory analysis investigated PVS burden in patients who appeared to not progress over the 12 months of selenate treatment (i.e., "non-progressors"). RESULTS: Overall, PVS cluster number (ß = -3.27, CI [-7.80 - 1.27], p = 0.267) and PVS volume (ß = -36.8, CI [-84.9 - 11.3], p = 0.171) did not change over the paired MRI scans 12 months apart. There was association between cognition total composite scores and the PVS burden (PVS cluster ß = -0.802e-3, CI [9.45e - 3 - -6.60e - 3, p ≤ 0.001; PVS volume ß = -1.30e - 3, CI [-1.55e - 3 - -1.05e - 3], p ≤ 0.001), as well as between the change in the cognition total composite score and the change in PVS volume (ß = 4.36e - 3, CI [1.33e - 3 - 7.40e - 3], p = 0.046) over the trial period. There was a significant association between CSF t-tau and the number of PVS clusters (ß = 2.845, CI [0.630 - 5.06], p = 0.036). Additionally, there was a significant relationship between the change in CSF t-tau and the change in the number of PVS (ß = 1.54, CI [0.918 - 2.16], p < 0.001) and PVS volume (ß = 13.8, CI [6.37 - 21.1], p = 0.003) over the trial period. An association was found between the change in NfL and the change in PVS volume (ß = 1.40, CI [0.272 - 2.52], p = 0.045) over time. Within the "non-progressor" group (n = 7), there was a significant relationship between the change in the CSF total-tau (t-tau) levels and the change in the PVS burden (PVS cluster (ß = 1.46, CI [0.577 - 2.34], p = 0.014; PVS volume ß = 14.6, CI [3.86 - 25.4], p = 0.032) over the trial period. Additionally, there was evidence of a significant relationship between the change in NfL levels and the change in the PVS burden over time (PVS cluster ß = 0.296, CI [0.229 - 0.361], p ≤ 0.001; PVS volume ß = 3.67, CI [2.42 - 4.92], p = 0.002). CONCLUSION: Analysis of serial MRI scans 12 months apart in patients with bvFTD demonstrated a relationship between PVS burden and disease severity as measured by the total cognitive composite score and CSF t-tau. Further studies are needed to confirm PVS as a robust marker of neurodegeneration in proteinopathies.
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    18F-FDG-PET hypometabolism as a predictor of favourable outcome in epilepsy surgery: protocol for a systematic review and meta-analysis
    Courtney, MR ; Antonic-Baker, A ; Sinclair, B ; Nicolo, J-P ; Neal, A ; Law, M ; Kwan, P ; O'Brien, TJ ; Vivash, L (BMJ PUBLISHING GROUP, 2022-10)
    INTRODUCTION: A substantial proportion of patients who undergo surgery for drug resistant focal epilepsy do not become seizure free. While some factors, such as the detection of hippocampal sclerosis or a resectable lesion on MRI and electroencephalogram-MRI concordance, can predict favourable outcomes in epilepsy surgery, the prognostic value of the detection of focal hypometabolism with 18F-fluorodeoxyglucose positive emission tomography (18F-FDG-PET) hypometabolism is uncertain. We propose a protocol for a systematic review and meta-analysis to examine whether localisation with 18F-FDG-PET hypometabolism predicts favourable outcomes in epilepsy surgery. METHODS AND ANALYSIS: A systematic literature search of Medline, Embase and Web of Science will be undertaken. Publications which include evaluation with 18F-FDG-PET prior to surgery for drug resistant focal epilepsy, and which report ≥12 months of postoperative surgical outcome data will be included. Non-human, non-English language publications, publications with fewer than 10 participants and unpublished data will be excluded. Screening and full-text review of publications for inclusion will be undertaken by two independent investigators, with discrepancies resolved by consensus or a third investigator. Data will be extracted and pooled using random effects meta-analysis, with heterogeneity quantified using the I2 analysis. ETHICS AND DISSEMINATION: Ethics approval is not required. Once complete, the systematic review will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42022324823.
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    A critical guide to the automated quantification of perivascular spaces in magnetic resonance imaging
    Pham, W ; Lynch, M ; Spitz, G ; O'Brien, T ; Vivash, L ; Sinclair, B ; Law, M (FRONTIERS MEDIA SA, 2022-12-14)
    The glymphatic system is responsible for waste clearance in the brain. It is comprised of perivascular spaces (PVS) that surround penetrating blood vessels. These spaces are filled with cerebrospinal fluid and interstitial fluid, and can be seen with magnetic resonance imaging. Various algorithms have been developed to automatically label these spaces in MRI. This has enabled volumetric and morphological analyses of PVS in healthy and disease cohorts. However, there remain inconsistencies between PVS measures reported by different methods of automated segmentation. The present review emphasizes that importance of voxel-wise evaluation of model performance, mainly with the Sørensen Dice similarity coefficient. Conventional count correlations for model validation are inadequate if the goal is to assess volumetric or morphological measures of PVS. The downside of voxel-wise evaluation is that it requires manual segmentations that require large amounts of time to produce. One possible solution is to derive these semi-automatically. Additionally, recommendations are made to facilitate rigorous development and validation of automated PVS segmentation models. In the application of automated PVS segmentation tools, publication of image quality metrics, such as the contrast-to-noise ratio, alongside descriptive statistics of PVS volumes and counts will facilitate comparability between studies. Lastly, a head-to-head comparison between two algorithms, applied to two cohorts of astronauts reveals how results can differ substantially between techniques.
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    Protocol for the development of an international Core Outcome Set for treatment trials in adults with epilepsy: the Epilepsy outcome Set for Effectiveness Trials Project (EPSET)
    Mitchell, JW ; Noble, A ; Baker, G ; Batchelor, R ; Brigo, F ; Christensen, J ; French, J ; Gil-Nagel, A ; Guekht, A ; Jette, N ; Kalviainen, R ; Leach, JP ; Maguire, M ; O'Brien, T ; Rosenow, F ; Ryvlin, P ; Tittensor, P ; Tripathi, M ; Trinka, E ; Wiebe, S ; Williamson, PR ; Marson, T (BMC, 2022-11-17)
    BACKGROUND: A Core Outcome Set (COS) is a standardised list of outcomes that should be reported as a minimum in all clinical trials. In epilepsy, the choice of outcomes varies widely among existing studies, particularly in clinical trials. This diminishes opportunities for informed decision-making, contributes to research waste and is a barrier to integrating findings in systematic reviews and meta-analyses. Furthermore, the outcomes currently being measured may not reflect what is important to people with epilepsy. Therefore, we aim to develop a COS specific to clinical effectiveness research for adults with epilepsy using Delphi consensus methodology. METHODS: The EPSET Study will comprise of three phases and follow the core methodological principles as outlined by the Core Outcome Measures in Effectiveness Trials (COMET) Initiative. Phase 1 will include two focused literature reviews to identify candidate outcomes from the qualitative literature and current outcome measurement practice in phase III and phase IV clinical trials. Phase 2 aims to achieve international consensus to define which outcomes should be measured as a minimum in future trials, using a Delphi process including an online consensus meeting involving key stakeholders. Phase 3 will involve dissemination of the ratified COS to facilitate uptake in future trials and the planning of further research to identify the most appropriate measurement instruments to use to capture the COS in research practice. DISCUSSION: Harmonising outcome measurement across future clinical trials should ensure that the outcomes measured are relevant to patients and health services, and allow for more meaningful results to be obtained. CORE OUTCOME SET REGISTRATION: COMET Initiative as study 118 .
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    Correction of Radiometry Data for Temperature Effect on Dark Current, with Application to Radiometers on Profiling Floats
    O'Brien, T ; Boss, E (MDPI, 2022-09)
    Measurements of daytime radiometry in the ocean are necessary to constrain processes such as photosynthesis, photo-chemistry and radiative heating. Profiles of downwelling irradiance provide a means to compute the concentration of a variety of in-water constituents. However, radiometers record a non-negligible signal when no light is available, and this signal is temperature dependent (called the dark current). Here, we devise and evaluate two consistent methods for correction of BGC-Argo radiometry measurements for dark current: one based on measurements during the day, the other based on night measurements. A daytime data correction is needed because some floats never measure at night. The corrections are based on modeling the temperature of the radiometer and show an average bias in the measured value of nearly 0.01 W m-2 nm-1, 3 orders of magnitude larger than the reported uncertainty of 2.5×10-5 W m-2 nm-1 for the sensors deployed on BGC-Argo floats (SeaBird scientific OCR504 radiometers). The methods are designed to be simple and robust, requiring pressure, temperature and irradiance data. The correction based on nighttime profiles is recommended as the primary method as it captures dark measurements with the largest dynamic range of temperature. Surprisingly, more than 28% of daytime profiles (130,674 in total) were found to record significant downwelling irradiance at 240-250 dbar. The correction is shown to be small relative to near-surface radiance and thus most useful for studies investigating light fields in the twilight zone and the impacts of radiance on deep organisms. Based on these findings, we recommend that BGC-Argo floats profile occasionally at night and to depths greater than 250 dbar. We provide codes to perform the dark corrections.
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    The effect of epilepsy surgery on productivity: A systematic review and meta-analysis
    Siriratnam, P ; Foster, E ; Shakhatreh, L ; Neal, A ; Carney, PW ; Jackson, GD ; O'Brien, TJ ; Kwan, P ; Chen, Z ; Ademi, Z (WILEY, 2022-04)
    OBJECTIVES: An important but understudied benefit of resective epilepsy surgery is improvement in productivity; that is, people's ability to contribute to society through participation in the workforce and in unpaid roles such as carer duties. Here, we aimed to evaluate productivity in adults with drug-resistant epilepsy (DRE) pre- and post-resective epilepsy surgery, and to explore the factors that positively influence productivity outcomes. METHODS: We conducted a systematic review and meta-analysis using four electronic databases: Medline (Ovid), EMBASE (Ovid), EBM Reviews - Cochrane Central Register of Controlled Trials (CENTRAL), and Cochrane Library. All studies over the past 30 years reporting on pre- and post-resective epilepsy surgical outcomes in adults with DRE were eligible for inclusion. Meta-analysis was performed to assess the post-surgery change in employment outcomes. RESULTS: A total of 1005 titles and abstracts were reviewed. Seventeen studies, comprising 2056 unique patients, were suitable for the final quantitative synthesis and meta-analysis. Resective epilepsy surgery resulted in a 22% improvement in overall productivity (95% confidence interval [CI]: 1.07-1.40). The factors associated with increased post-surgery employment risk ratios were lower pre-surgical employment in the workforce (relative risk ratio [RRR] =0.34; 95% CI: 0.15-0.74), shorter follow-up duration (RRR = 0.95; 95% CI: 0.90-0.99), and lower mean age at time of surgery (RRR= 0.97; 95% CI: 0.94-0.99). The risk of bias of the included studies was assessed using Risk Of Bias In Non-randomised Studies - of Interventions and was low for most variables except "measurement of exposure." SIGNIFICANCE: There is clear evidence that resective surgery in eligible surgical DRE patients results in improved productivity. Future work may include implementing a standardized method for collecting and reporting productivity in epilepsy cohorts and focusing on ways to reprioritize health care resource allocation to allow suitable candidates to access surgery earlier. This will ultimately benefit individuals with DRE, their families, our communities, and the wider health care system.