Medicine (Austin & Northern Health) - Research Publications
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ItemPsychometric deficits in autoimmune encephalitis: A retrospective study from the Australian Autoimmune Encephalitis Consortium(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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ItemNo Preview AvailableOcular motility as a measure of cerebral dysfunction in adults with focal epilepsy(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2023-04)OBJECTIVE: Using objective oculomotor measures, we aimed to: (1) compare oculomotor performance in patients with drug-resistant focal epilepsy to healthy controls, and (2) investigate the differential impact of epileptogenic focus laterality and location on oculomotor performance. METHODS: We recruited 51 adults with drug-resistant focal epilepsy from the Comprehensive Epilepsy Programs of two tertiary hospitals and 31 healthy controls to perform prosaccade and antisaccade tasks. Oculomotor variables of interest were latency, visuospatial accuracy, and antisaccade error rate. Linear mixed models were performed to compare interactions between groups (epilepsy, control) and oculomotor tasks, and between epilepsy subgroups and oculomotor tasks for each oculomotor variable. RESULTS: Compared to healthy controls, patients with drug-resistant focal epilepsy exhibited longer antisaccade latencies (mean difference = 42.8 ms, P = 0.001), poorer spatial accuracy for both prosaccade (mean difference = 0.4°, P = 0.002), and antisaccade tasks (mean difference = 2.1°, P < 0.001), and more antisaccade errors (mean difference = 12.6%, P < 0.001). In the epilepsy subgroup analysis, left-hemispheric epilepsy patients exhibited longer antisaccade latencies compared to controls (mean difference = 52.2 ms, P = 0.003), while right-hemispheric epilepsy was the most spatially inaccurate compared to controls (mean difference = 2.5°, P = 0.003). The temporal lobe epilepsy subgroup displayed longer antisaccade latencies compared to controls (mean difference = 47.6 ms, P = 0.005). SIGNIFICANCE: Patients with drug-resistant focal epilepsy exhibit poor inhibitory control as evidenced by a high percentage of antisaccade errors, slower cognitive processing speed, and impaired visuospatial accuracy on oculomotor tasks. Patients with left-hemispheric epilepsy and temporal lobe epilepsy have markedly impaired processing speed. Overall, oculomotor tasks can be a useful tool to objectively quantify cerebral dysfunction in drug-resistant focal epilepsy.
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ItemCerebrospinal fluid neurofilament light chain differentiates primary psychiatric disorders from rapidly progressive, Alzheimer's disease and frontotemporal disorders in clinical settings(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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ItemMachine learning approaches for imaging-based prognostication of the outcome of surgery for mesial temporal lobe epilepsy(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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ItemA phase 1b open-label study of sodium selenate as a disease-modifying treatment for possible behavioral variant frontotemporal dementia(WILEY, 2022)INTRODUCTION: Sodium selenate increases tau dephosphorylation through protein phosphatase 2 activation. Here we report an open-label Phase 1b study of sodium selenate as a disease-modifying treatment for behavioral variant frontotemporal dementia (bvFTD). METHODS: Twelve participants with bvFTD received sodium selenate (15 mg, three times a day) for 52 weeks. Safety assessments were carried out throughout the trial. Primary outcomes were frequency of adverse events (AEs), serious adverse events (SAEs), and discontinuations. Secondary outcomes of potential efficacy included cognitive and behavioral assessments, magnetic resonance imaging (MRI) whole brain volume, and cerebrospinal fluid (CSF) and blood total tau (t-tau), phosphorylated tau (p-tau), and neurofilament light (NfL) levels, which were measured at baseline and at week 52. RESULTS: Sodium selenate was safe and well tolerated. All participants completed the study, and the majority (64.7%) of reported AEs were mild. One SAE occurred, which was not treatment related. Small declines in MRI and cognitive and behavioral measures were observed over the treatment period. There was no evidence for change in CSF protein levels (t-tau, p-tau, or NfL). Further analysis showed two distinct groups when measuring disease progression markers over the course of the study-one (n = 4) with substantial brain atrophy (2.5% to 6.5% reduction) and cognitive and behavioral decline over the 12-month treatment period, and the second group (n = 7) with no detectable change in cognitive and behavioral measures and less brain atrophy (0.3% to 1.7% reduction). CONCLUSION: Sodium selenate is safe and well tolerated in patients with bvFTD. Randomized-controlled trials are warranted to investigate potential efficacy.
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ItemSodium selenate as a disease-modifying treatment for mild-moderate Alzheimer's disease: an open-label extension study(BMJ PUBLISHING GROUP, 2021-12)INTRODUCTION: Sodium selenate is a potential disease-modifying treatment for Alzheimer's disease (AD) which reduces hyperphosphorylated tau through activation of the protein phosphatase 2A enzyme. We have shown sodium selenate to be safe and well tolerated in a 24-week, phase 2a double-blind placebo-controlled randomised controlled trial (RCT), also reporting sodium selenate reduced neurodegeneration on diffusion-weighted MRI. This study assessed the safety and tolerability of chronic sodium selenate treatment (up to 23 months) in patients with AD who had been enrolled in the RCT. Cognitive measures served as secondary outcomes of potential disease-modification. METHODS: An open-label extension study of sodium selenate (10 mg three times a day) in patients with AD who had completed the previous RCT. Twenty-eight patients were enrolled. Patients were regularly monitored for safety, adverse events (AEs) and protocol compliance. Cognitive tests were administered for measures of disease progression. RESULTS: Sixteen patients were discontinued by the sponsor, and 12 discontinued for other reasons. Treatment duration ranged from 6 to 23 months. The majority of AEs were mild (83%), and 33% were treatment-related. Common treatment-related AEs were alopecia (21%) and nail disorder (32%), which both resolved either prior to or following cessation of treatment. Two serious AEs occurred, which were not treatment-related. Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 score increased 1.8 points over 12 months. DISCUSSION: Chronic sodium selenate treatment is safe and well tolerated in patients with AD. Cognitive measures suggest a slowing of disease progression though this could not be confirmed as the study was not controlled. Further research into sodium selenate as a treatment for AD is warranted.
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ItemPrenatal valproate exposure and adverse neurodevelopmental outcomes: Does sex matter?(WILEY, 2021-03)OBJECTIVE: Prenatal exposure to the antiepileptic drug (AED) valproic acid (VPA) is associated with an increased risk of impaired postnatal neurodevelopment, including autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). We aimed to evaluate the influence of sex and drug dosage on the association between prenatal VPA exposure and postnatal behavioral outcomes. METHODS: The Australian Pregnancy Register of AEDs was interrogated to identify children aged 4-11 years prenatally exposed to AEDs. Parents reported on their child's behavior using the Autism Spectrum Quotient-Children's Version and the National Institute for Children's Health Quality Vanderbilt Assessment Scale for ADHD. General linear mixed-effects models were used to investigate the relationship between clinicodemographic variables and psychometric scores. RESULTS: A total of 121 children were studied: 54 prenatally exposed to VPA (28 males, 26 females; mean dose ± SD: 644 ± 310 mg/day) and 67 exposed to other AEDs. There was a main effect of sex showing higher ASD scores in males compared to females (p = .006). An interaction between sex and VPA exposure revealed that males had higher ASD symptoms among children exposed to AEDs other than VPA (p = .01); however, this typical sex dynamic was not evident in VPA-exposed children. There was no evidence of any dose-response relationship between VPA exposure and ASD symptoms. Males had higher ADHD scores compared to females, but there was no evidence for a link between ADHD symptoms and VPA exposure. SIGNIFICANCE: Prenatal VPA exposure seems to negate the usual male sex-related predominance in the incidence of ASD. These initial findings deepen the concept of VPA as a "behavioral teratogen" by indicating that its effect might be influenced by sex, with females appearing particularly sensitive to the effects of VPA. No association between VPA doses and adverse postnatal behavioral outcomes was detected, possibly related to the low VPA doses used in this study.
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ItemAssociation Between Psychiatric Comorbidities and Mortality in Epilepsy(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.
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ItemA study protocol for a phase II randomised, double-blind, placebo-controlled trial of sodium selenate as a disease-modifying treatment for behavioural variant frontotemporal dementia(BMJ PUBLISHING GROUP, 2020)INTRODUCTION: Behavioural variant frontotemporal dementia (bvFTD) is a neurodegenerative disorder often neuropathologically associated with the accumulation of abnormally hyperphosphorylated tau, for which there is currently no disease-modifying treatment. Previous work by our group has shown sodium selenate upregulates the activity of protein phosphatase 2 in the brain, increasing the rate of tau dephosphorylation. The objective of this study is to evaluate the efficacy and safety of sodium selenate as a disease-modifying treatment for bvFTD. METHODS AND ANALYSIS: This will be a multisite, phase IIb, double-blind placebo-controlled trial of sodium selenate. One hundred and twenty participants will be enrolled across 4 Australian academic hospitals. Following screening eligible participants will be randomised (1:1) to sodium selenate (15 mg three times a day) or placebo for 52 weeks. Participants will have regular safety and efficacy visits throughout the study period. The primary study outcome will be percentage brain volume change (PBVC) as measured on MRI over 52 weeks of treatment. This will be analysed with a general linear model (analysis of covariance (ANCOVA)) with the PBVC as an output, the treatment as an input and the baseline brain volume as covariate for adjustment purposes. Secondary outcomes include safety and tolerability measures, and efficacy measures; change in cerebrospinal fluid total-tau, Addenbrooke's Cognitive Examination-III and Cambridge Behavioural Inventory-Revised scores over the 52 weeks of treatment. These will also be analysed with ANCOVA where the corresponding baseline measure will be incorporated in the model. Additional exploratory outcomes will include other imaging, cognitive and biospecimen analyses. ETHICS AND DISSEMINATION: The study was approved by the Human Research and Ethics Committee of the lead site as part of the Australian Multisite Ethics approval system. The results of the study will be presented at national and international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12620000236998 .