ORCID Profile
0000-0002-9834-4498
Current Organisations
Monash Health
,
Monash University
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Publisher: BMJ
Date: 20-05-2020
DOI: 10.1136/PRACTNEUROL-2020-002530
Abstract: Genetic and acquired disorders of white matter comprise a erse group of conditions, with often overlapping clinical and radiological findings. Patients present with a variable combination of cognitive impairment, ataxia, spasticity or movement disorders, among others. There are many genetic causes, and the route to diagnosis involves comprehensive clinical assessment, radiological expertise, metabolic investigations and finally genetic studies. It is essential not to miss the treatable acquired causes. In this review, we present a practical approach to investigating patients with acquired and genetic disorders of white matter, based on the experience of a large international referral centre. We present a guide for clinicians, including pitfalls of testing, clinical pearls and where to seek advice.
Publisher: American Society of Neuroradiology (ASNR)
Date: 05-11-2020
DOI: 10.3174/AJNR.A6809
Publisher: Elsevier BV
Date: 03-2020
Publisher: Elsevier BV
Date: 06-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-03-2022
DOI: 10.1212/WNL.0000000000200144
Abstract: To explore the relationship between slowly expanding lesions (SELs) on MRI and disability in secondary progressive multiple sclerosis (SPMS). We retrospectively studied 345 patients with SPMS enrolled in the MS-SMART trial. They underwent brain MRI at baseline and at 24 and 96 weeks. Definite SELs were defined as concentrically expanding T2 lesions, as assessed by nonlinear deformation of volumetric T1-weighted images. Associations of SEL volumes with other MRI metrics and disability were assessed through Pearson correlations and regression analyses. Averaged across patients, 29% of T2 lesions were classified as being definite SELs. A greater volume of definite SELs correlated with a higher total baseline T2 lesion volume ( r = 0.55, p 0.001) and percentage brain volume reduction ( r = −0.26, p 0.001), a higher number of new persisting T1 black holes ( r = 0.19, p 0.001), and, in a subset of 106 patients, with a greater reduction in magnetization transfer ratio (adjusted difference 0.52, p 0.001). In regression analyses, a higher definite SEL volume was associated with increasing disability, as assessed by the Expanded Disability Status Scale (β = 0.23, p = 0.020), z scores of the Multiple Sclerosis Functional Composite (β = −0.47, p = 0.048), Timed 25-Foot Walk Test (β = −2.10, p = 0.001), and Paced Auditory Serial Addition Task (β = −0.27, p = 0.006), and increased risk of disability progression (odds ratio 1.92, p = 0.025). Definite SELs represent almost one-third of T2 lesions in SPMS. They are associated with neurodegenerative MRI markers and related to clinical worsening, suggesting that they may contribute to disease progression and be a new target for therapeutic interventions.
Publisher: Cold Spring Harbor Laboratory
Date: 23-08-2022
DOI: 10.1101/2022.08.22.22279090
Abstract: There is growing interest in the topography of brain regions associated with disorders of consciousness. This has caused increased research output, yielding many publications investigating the topic with varying methodologies. The objective of this study was to ascertain the topographical regions of the brain most frequently associated with disorders of consciousness. We performed a cross-sectional text mining analysis of disorders of consciousness studies. A text mining algorithm built in the Python programming language searched documents for anatomical brain terminology. We reviewed PubMed studies up to 9 th July 2021 for the search query “Disorders of Consciousness.” The frequency of brain regions mentioned in these articles was recorded, ranked, then built into a graphical network. Subgroup analysis was performed by evaluating the impact on our results if analyses were based on abstracts, full-texts, or topic modelled groups (non-negative matric factorization was used to create subgroups of each collection based on their key topics). Brain terms were ranked by their frequency and concordance was measured between subgroups. Graphical analysis was performed to explore relationships between anatomical regions mentioned. The PageRank algorithm (used by Google to list search results in order of relevance) was used to determine global importance of the regions. The PubMed search yielded 14,945 abstracts and 2178 full-texts. The topic-modelled subgroups contained 2440 abstracts and 367 full-texts. Text Mining across all document groups concordantly ranked the thalamus the highest (Savage score = 14.191). Graphical analysis had 4 clusters: cluster 1 had 20 members with the insular cortex [PageRank =0.167] as the most important member cluster 2 had 29 members with the amygdala [PageRank =0.0199] being most important cluster 3 had 10 members with the thalamus [PageRank = 0. 0205] being most important cluster 4 had 19 members with the cingulate cortex [PageRank = 0. 0.020] being the most important. The cingulate cortex and thalamus are strongly associated with disorders of consciousness, likely due to the roles they play in maintaining awareness and involvement in the Default Mode Network respectively. Other areas of the brain like the cuneus, amygdala and hippoc us should be further investigated.
Publisher: BMJ
Date: 27-11-2018
DOI: 10.1136/BMJ.K4674
Publisher: BMJ
Date: 11-05-2019
Publisher: Mark Allen Group
Date: 02-02-2019
DOI: 10.12968/BJNN.2019.15.1.20
Abstract: Multiple sclerosis (MS) can result in multi-level uro-neurological dysfunction that significantly increases the risk of urinary tract infections (UTIs). UTIs in patients with MS can lead to significant patient morbidity and cost to the National Health Service (NHS). Data collected from the NHS clinical commissioning groups in 2012/2013, and again in 2016/2017, revealed that UTI remains the most common cause of non-elective hospital admission in patients with MS, and that the overall cost of such admissions continued to rise across this period. In order to address this burgeoning problem, we used the evidence-based co-design methodology to collaborate with patients, their families and clinical staff to create a novel and innovative, patient-centred model called NeuroResponse®. We present the multi-faceted NeuroResponse® model and the results of the pilot study in the London Borough of Camden.
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.JNS.2019.116456
Abstract: To evaluate an updated algorithm in the detection of urinary tract infection (UTI) prior to high-dose corticosteroid treatment in acute relapses in multiple sclerosis (MS). This updated algorithm aimed to decrease the unnecessary use of antibiotics, whilst maintaining accuracy and safety. Prospective cohort study of 471 consecutive patients with MS relapses in a hospital-based outpatient acute relapse clinic. 172 patients met exclusion criteria, leaving 299 patients for analysis. Patients underwent urine dipstick and were treated for UTI if 2 or more of: nitrites, leukocyte esterase and cloudy urine were positive. Patients with confirmed acute MS relapse were treated with high dose intravenous or oral methylprednisolone. Significant bacteriuria (>10 With an improved specificity, this updated algorithm addresses previous issues concerning the unnecessary prescription of antibiotics, whilst improving accuracy and maintaining safety.
Publisher: BMJ
Date: 22-11-2018
Abstract: Adult-onset leukodystrophies and genetic leukoencephalopathies comprise a erse group of neurodegenerative disorders of white matter with a wide age of onset and phenotypic spectrum. Patients with white matter abnormalities detected on MRI often present a diagnostic challenge to both general and specialist neurologists. Patients typically present with a progressive syndrome including various combinations of cognitive impairment, movement disorders, ataxia and upper motor neuron signs. There are a number of important and treatable acquired causes for this imaging and clinical presentation. There are also a very large number of genetic causes which due to their relative rarity and sometimes variable and overlapping presentations can be difficult to diagnose. In this review, we provide a structured approach to the diagnosis of inherited disorders of white matter in adults. We describe clinical and radiological clues to aid diagnosis, and we present an overview of both common and rare genetic white matter disorders. We provide advice on testing for acquired causes, on excluding small vessel disease mimics, and detailed advice on metabolic and genetic testing available to the practising neurologist. Common genetic leukoencephalopathies discussed in detail include CSF1R , AARS2 , cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and mitochondrial and metabolic disorders.
Publisher: Wiley
Date: 03-10-2023
DOI: 10.1002/JMRI.29017
Publisher: BMJ
Date: 08-2018
DOI: 10.1136/BMJOPEN-2018-021944
Abstract: The major unmet need in multiple sclerosis (MS) is for neuroprotective therapies that can slow (or ideally stop) the rate of disease progression. The UK MS Society Clinical Trials Network (CTN) was initiated in 2007 with the purpose of developing a national, efficient, multiarm trial of repurposed drugs. Key underpinning work was commissioned by the CTN to inform the design, outcome selection and drug choice including animal models and a systematic review. This identified seven leading oral agents for repurposing as neuroprotective therapies in secondary progressive MS (SPMS). The purpose of the Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART) will be to evaluate the neuroprotective efficacy of three of these drugs, selected with distinct mechanistic actions and previous evidence of likely efficacy, against a common placebo arm. The interventions chosen were: amiloride (acid-sensing ion channel antagonist) fluoxetine (selective serotonin reuptake inhibitor) and riluzole (glutamate antagonist). Patients with progressing SPMS will be randomised 1:1:1:1 to amiloride, fluoxetine, riluzole or matched placebo and followed for 96 weeks. The primary outcome will be the percentage brain volume change (PBVC) between baseline and 96 weeks, derived from structural MR brain imaging data using the Structural Image Evaluation, using Normalisation, of Atrophy method. With a s le size of 90 per arm, this will give 90% power to detect a 40% reduction in PBVC in any active arm compared with placebo and 80% power to detect a 35% reduction (analysing by analysis of covariance and with adjustment for multiple comparisons of three 1.67% two-sided tests), giving a 5% overall two-sided significance level. MS-SMART is not powered to detect differences between the three active treatment arms. Allowing for a 20% dropout rate, 110 patients per arm will be randomised. The study will take place at Neuroscience centres in England and Scotland. MS-SMART was approved by the Scotland A Research Ethics Committee on 13 January 2013 (REC reference: 13/SS/0007). Results of the study will be submitted for publication in a peer-reviewed journal. NCT01910259 2012-005394-31 ISRCTN28440672 .
Publisher: National Institute for Health and Care Research
Date: 05-2020
DOI: 10.3310/EME07030
Abstract: Neuroprotective drugs are needed to slow or prevent neurodegeneration and disability accrual in secondary progressive multiple sclerosis. Amiloride, fluoxetine and riluzole are repurposed drugs with potential neuroprotective effects. To assess whether or not amiloride, fluoxetine and riluzole can reduce the rate of brain volume loss in people with secondary progressive multiple sclerosis over 96 weeks. The secondary objectives that were assessed were feasibility of a multiarm trial design approach, evaluation of anti-inflammatory effects, clinician- and patient-reported efficacy and three mechanistic substudies. A multicentre, multiarm, randomised, double-blind, placebo-controlled, parallel-group Phase IIb trial with follow-up at 4, 8, 12, 24, 36, 48, 72 and 96 weeks. Patients, investigators (including magnetic resonance imaging analysts), and treating and independent assessing neurologists were blinded to the treatment allocation. The target s le size was 440 patients. Thirteen UK clinical neuroscience centres. Participants were aged 25–65 years, had secondary progressive multiple sclerosis with evidence of disease progression independent of relapses in the previous 2 years, and had an Expanded Disability Status Scale score of 4.0–6.5. Patients were ineligible if they could not have a magnetic resonance imaging scan had a relapse or steroids in the previous 3 months or had epilepsy, depression, bipolar disorder, glaucoma, bleeding disorders or significant organ comorbidities. Exclusion criteria were concurrent disease-modified treatments, immunosuppressants or selective serotonin reuptake inhibitors. Participants received amiloride (5 mg), fluoxetine (20 mg), riluzole (50 mg) or placebo (randomised 1 : 1 : 1 : 1) twice daily. The primary end point was magnetic resonance imaging-derived percentage brain volume change at 96 weeks. Secondary end points were new/enlarging T2 lesions, pseudoatrophy, and clinician- and patient-reported measures (including the Expanded Disability Status Scale, Multiple Sclerosis Functional Composite, Symbol Digit Modalities Test, low-contrast letter visual acuity, Multiple Sclerosis Impact Scale 29 items, version 2, Multiple Sclerosis Walking Scale, version 2, and questionnaires addressing pain and fatigue). The exploratory end points included measures of persistent new T1 hypointensities and grey matter volume changes. The substudies were advanced magnetic resonance imaging, optical coherence tomography and cerebrospinal fluid analyses. Between December 2014 and June 2016, 445 patients were randomised (analysed) to amiloride [ n = 111 (99)], fluoxetine [ n = 111 (96)], riluzole [ n = 111 (99)] or placebo [ n = 112 (99)]. A total of 206 randomised patients consented to the advanced magnetic resonance imaging substudy, 260 consented to the optical coherence tomography substudy and 70 consented to the cerebrospinal fluid substudy. No significant difference was seen between the active drugs and placebo in percentage brain volume change at week 96 as follows (where negative values mean more atrophy than placebo): amiloride minus placebo 0.0% (Dunnett-adjusted 95% confidence interval –0.4% to 0.5%), fluoxetine minus placebo –0.1% (Dunnett-adjusted 95% confidence interval –0.5% to 0.3%) riluzole minus placebo –0.1% (Dunnett-adjusted 95% confidence interval –0.6% to 0.3%). There was good adherence to study drugs. The proportion of patients experiencing adverse events was similar in the treatment and placebo groups. There were no emergent safety issues. There was a lower than expected uptake in the cerebrospinal fluid substudy. A multiarm Phase II paradigm is efficient in determining which neuroprotective agents to take through to Phase III trials. Amiloride, fluoxetine and riluzole were not effective in reducing the brain atrophy rate in people with secondary progressive multiple sclerosis. Mechanistic pathobiological insight was gained. To use the information gained from the Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART) to inform future trial design as new candidate agents are identified. Current Controlled Trials ISRCTN28440672, NCT01910259 and EudraCT 2012-005394-31. This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation Vol. 7, No. 3. See the NIHR Journals Library website for further project information. This trial also received funding from the UK MS Society and the US National Multiple Sclerosis Society.
Publisher: Springer Science and Business Media LLC
Date: 26-08-2012
DOI: 10.1007/S00234-012-1084-Y
Abstract: Intra-arterial mechanical thrombectomy (IAMT) is an endovascular technique that allows for the acute retrieval of intravascular thrombi and is increasingly being used for the treatment of acute ischaemic stroke (AIS). There are currently two anaesthetic options during IAMT: general anaesthesia (GA) and conscious sedation (CS). The decision to use GA versus CS is the source of controversy, as it requires careful balance between patient pain, movement and airway protection whilst minimising time delay and haemodynamic fluctuations. This review examines and summarises the evidence for the use of GA versus CS in the treatment of AIS by IAMT. Studies were identified using systematic bibliographic searches. The five applicable studies were analysed with reference to overall outcomes and the key parameters that govern the decision to use GA or CS. The key parameters included the impact of GA and CS on pain, complication rates, time delays, airway protection and haemodynamic stability. Several retrospective analyses have shown that the use of GA is associated with adverse outcomes. Intra-arterial mechanical thrombectomy under general anaesthesia is associated with poor outcomes in observational studies. It is reasonable to offer conscious sedation as the preferred option where adverse patient factors such as agitation are lacking.
No related grants have been discovered for Nevin Alex John.