Publications by authors named "Michael H Barnett"

94 Publications

Eculizumab in Asian patients with anti-aquaporin-IgG-positive neuromyelitis optica spectrum disorder: A subgroup analysis from the randomized phase 3 PREVENT trial and its open-label extension.

Authors:
Ho Jin Kim Ichiro Nakashima Shanthi Viswanathan Kai-Chen Wang Shulian Shang Larisa Miller Marcus Yountz Dean M Wingerchuk Sean J Pittock Michael Levy Achim Berthele Natalia Totolyan Jacqueline Palace Michael H Barnett Kazuo Fujihara

Mult Scler Relat Disord 2021 Feb 20;50:102849. Epub 2021 Feb 20.

Department of Neurology, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, Miyagi 980-8574, Japan; Department of Multiple Sclerosis Therapeutics, Fukushima Medical University School of Medicine, 1 Hikariga-oka, Fukushima City, Fukushima 960-1295, Japan; Multiple Sclerosis and Neuromyelitis Optica Center, Southern TOHOKU Research Institute for Neuroscience (STRINS), Koriyama, 7-115, Yatsuyamada, Koriyama, Fukushima 963-8563, Japan. Electronic address:

Background Eculizumab, a terminal complement inhibitor, significantly reduced the risk of relapse compared with placebo in patients with anti-aquaporin-4 immunoglobulin G-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD) in the PREVENT trial. We report efficacy and safety analyses in Asian patients in PREVENT and its open-label extension (OLE). Methods PREVENT was a double-blind, randomized, phase 3 trial. Patients with AQP4+ NMOSD were randomly assigned (2:1) to receive intravenous eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo. Patients who completed PREVENT could receive eculizumab in an OLE. Analyses were performed in a prespecified subgroup of Asian patients. Results Of 143 patients enrolled, 52 (36.4%) were included in the Asian subgroup (eculizumab, n = 37; placebo, n = 15); 45 Asian patients received eculizumab in the OLE. Most Asian patients (86.5%) received concomitant immunosuppressive therapy. During PREVENT, one adjudicated relapse occurred in patients receiving eculizumab and six occurred in patients receiving placebo in the Asian subgroup (hazard ratio, 0.05; 95% confidence interval: 0.01-0.35; p = 0.0002). An estimated 95.2% of Asian patients remained relapse-free after 144 weeks of eculizumab treatment. Upper respiratory tract infections, headache, and nasopharyngitis were the most common adverse events with eculizumab in the Asian subgroup. Conclusion Eculizumab reduces the risk of relapse in Asian patients with AQP4+ NMOSD, with a benefit-risk profile similar to the overall PREVENT population. The benefits of eculizumab were maintained during long-term therapy. Clinical trial registration ClinicalTrials.gov identifiers: NCT01892345 (PREVENT); NCT02003144 (open-label extension).
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http://dx.doi.org/10.1016/j.msard.2021.102849DOI Listing
February 2021

Development of a Web-Based Mindfulness Program for People With Multiple Sclerosis: Qualitative Co-Design Study.

Authors:
Amy-Lee Sesel Louise Sharpe Heidi N Beadnall Michael H Barnett Marianna Szabo Sharon L Naismith

J Med Internet Res 2021 Mar 2;23(3):e19309. Epub 2021 Mar 2.

School of Psychology, University of Sydney, Sydney, Australia.

Background: Mindfulness-based stress reduction is an efficacious treatment for people with chronic health problems; however, it is highly intensive and time-consuming, which is a barrier for service provision.

Objective: This study aims to develop an internet-delivered adapted version of mindfulness-based stress reduction for people with multiple sclerosis to make the intervention more accessible.

Methods: We co-designed a web-based mindfulness program with end users, that is, people with multiple sclerosis (N=19). Iterative feedback was also collected from a subsample of the initial group of end users (n=11), and the program was reviewed by experts (n=8).

Results: We identified three main themes common to people with multiple sclerosis: dealing with uncertainty and fears for the future, grief and loss, and social isolation. These themes were incorporated into narratives throughout the program. People with multiple sclerosis who reviewed the program gave feedback that the program was relatable, feasible, and acceptable. Experts agreed that the program appropriately represented the main tenets of mindfulness. Iterative feedback was used to further refine the program.

Conclusions: The web-based mindfulness program that we developed was viewed positively by both experts and end users. The program reflects common concerns for people with multiple sclerosis and has the potential to meet important unmet psychological needs. A randomized controlled trial was planned to determine the efficacy of the program.
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http://dx.doi.org/10.2196/19309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967236PMC
March 2021

Nerve biopsy: Current indications and decision tools.

Authors:
Dev Nathani Judith Spies Michael H Barnett John Pollard Min-Xia Wang Claudia Sommer Matthew C Kiernan

Muscle Nerve 2021 Feb 25. Epub 2021 Feb 25.

Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia.

After initial investigation of patients presenting with symptoms suggestive of neuropathy, a clinical decision is made for a minority of patients to undergo further assessment with nerve biopsy. Many nerve biopsies do not demonstrate a definitive pathological diagnosis and there is considerable cost and morbidity associated with the procedure. This highlights the need for appropriate selection of patients, nerves and neuropathology techniques. Additionally, concomitant muscle and skin biopsies may improve the diagnostic yield in some cases. Several advances have been made in diagnostics in recent years, particularly in genomics. The indications for nerve biopsy have consequently changed over time. This review explores the current indications for nerve biopsies and some of the issues surrounding its use. Also included are comments on alternative diagnostic modalities that may help to supplant or reduce the use of nerve biopsy as a diagnostic test. These primarily include extraneural biopsy and neuroimaging techniques such as magnetic resonance neurography and nerve ultrasound. Finally, we propose an algorithm to assist in deciding when to perform nerve biopsies.
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http://dx.doi.org/10.1002/mus.27201DOI Listing
February 2021

Interferon-β Is Less Effective Than Other Drugs in Controlling the Rate of Retinal Ganglion Cell Loss in MS.

Authors:
Yuyi You Michael H Barnett Con Yiannikas John D E Parratt Jim G Matthews Stuart L Graham Alexander Klistorner

Neurol Neuroimmunol Neuroinflamm 2021 05 17;8(3). Epub 2021 Feb 17.

From the Department of Clinical Medicine (Y.Y., S.L.G., A.K.), Macquarie University, NSW, Australia; Save Sight Institute (Y.Y., A.K.), The University of Sydney, NSW, Australia; Brain and Mind Centre (M.H.B.), The University of Sydney, NSW, Australia; Sydney Neuroimaging Analysis Centre (M.H.B.), NSW, Australia; Department of Neurology (C.Y., J.D.E.P.), Royal North Shore Hospital, NSW, Australia; and Sydney Informatics and Data Science Hub (J.G.M.), The University of Sydney, NSW, Australia.

Objective: To investigate the association between disease-modifying therapies (DMTs) and the rate of progressive retinal ganglion cell (RGC) and nerve fiber loss in MS.

Methods: One hundred five relapsing-remitting patients with MS were followed annually for a median of 4.0 years using optical coherence tomography. Twenty-five healthy subjects were also included as normal controls. The rates of global peripapillary retinal nerve fiber layer (pRNFL), temporal RNFL (tRNFL), and ganglion cell inner plexiform layer (GCIPL) thinning were analyzed according to DMT type using a linear mixed-effects model. Optic radiation lesion volume was measured on brain MRI and included as a covariate to minimize the effects of retrograde transsynaptic degeneration.

Results: The annual rates of RNFL and GCIPL thinning were higher in patients treated with "platform" therapies (interferon-β and glatiramer acetate) compared with DMTs of higher clinical efficacy (including fingolimod, dimethyl fumarate, natalizumab, alemtuzumab, rituximab, and ocrelizumab) (difference = -0.22 μm/y, = 0.02 for pRNFL; difference = -0.34 μm/y, = 0.009 for tRNFL; and difference = -0.16 μm/y, = 0.005 for GCIPL). Based on an analysis of individual treatments (interferon-β, glatiramer acetate, fingolimod, and natalizumab), interferon-β was associated with inferior RGC preservation, relative to the other drugs. No effect difference was found between glatiramer acetate, fingolimod, and natalizumab.

Conclusions: Progressive loss of RGCs in patients with MS is more pronounced in patients treated with interferon-β than other DMTs. This finding may have implications for DMT selection in MS.

Classification Of Evidence: This study provides Class IV evidence that for patients with MS, treatment with interferon-β compared with other DMTs leads to a more pronounced rate of retinal ganglion cell loss.
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http://dx.doi.org/10.1212/NXI.0000000000000971DOI Listing
May 2021

Differentiating axonal loss and demyelination in chronic MS lesions: A novel approach using single streamline diffusivity analysis.

Authors:
Samuel Klistorner Michael H Barnett Jakob Wasserthal Con Yiannikas Joshua Barton John Parratt Yuyi You Stuart L Graham Alexander Klistorner

PLoS One 2021 6;16(1):e0244766. Epub 2021 Jan 6.

Save Sight Institute, Sydney Medical School, University of Sydney, Sydney, Australia.

We describe a new single-streamline based approach to analyse diffusivity within chronic MS lesions. We used the proposed method to examine diffusivity profiles in 30 patients with relapsing multiple sclerosis and observed a significant increase of both RD and AD within the lesion core (0.38+/-0.09 μm2/ms and 0.30+/-0.12 μm2/ms respectively, p<0.0001 for both) that gradually and symmetrically diminished away from the lesion. T1-hypointensity derived axonal loss correlated highly with ΔAD (r = 0.82, p<0.0001), but moderately with ΔRD (r = 0.60, p<0.0001). Furthermore, the trendline of the ΔAD vs axonal loss intersected both axes at zero indicating close agreement between two measures in assessing the degree of axonal loss. Conversely, the trendline of the ΔRD function demonstrated a high positive value at the zero level of axonal loss, suggesting that even lesions with preserved axonal content exhibit a significant increase of RD. There was also a significant negative correlation between the level of preferential RD increase (ΔRD-ΔAD) in the lesion core and the degree of axonal damage (r = -0.62, p<0.001), indicating that ΔRD dominates in cases with milder axonal loss. Modelling diffusivity changes in the core of chronic MS lesions based on the direct proportionality of ΔAD with axonal loss and the proposed dual nature of ΔRD yielded results that were strikingly similar to the experimental data. Evaluation of lesions in a sizable cohort of MS patients using the proposed method supports the use of ΔAD as a marker of axonal loss; and the notion that demyelination and axonal loss independently contribute to the increase of RD in chronic MS lesions. The work highlights the importance of selecting appropriate patient cohorts for clinical trials of pro-remyelinating and neuroprotective therapeutics.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244766PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787472PMC
January 2021

Overlapping central and peripheral nervous system syndromes in MOG antibody-associated disorders.

Authors:
Simon Rinaldi Alexander Davies Janev Fehmi Heidi N Beadnall Justine Wang Todd A Hardy Michael H Barnett Simon A Broadley Patrick Waters Stephen W Reddel Sarosh R Irani Fabienne Brilot Russell C Dale Sudarshini Ramanathan

Neurol Neuroimmunol Neuroinflamm 2021 01 3;8(1). Epub 2020 Dec 3.

From the Inflammatory Neuropathy Group (S. Rinaldi, A.D., J.F.), Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital; University of Oxford; Department of Neurology (S. Rinaldi, S.R.I.), Oxford University Hospitals NHS Foundation Trust, UK; Department of Neurology (H.N.B., M.H.B.), Royal Prince Alfred Hospital, Sydney; Brain and Mind Centre (H.N.B., T.A.H., M.H.B., S.W.R., F.B., R.C.D.), University of Sydney; Department of Neurology (J.W.), St George Hospital, Sydney; Department of Neurology (T.A.H., S.W.R., S. Ramanathan), Concord Repatriation General Hospital, Sydney; Menzies Institute of Health Queensland (S.A.B.), Griffith University; Department of Neurology (S.A.B.), Gold Coast University Hospital, Australia; Autoimmune Neurology Group (P.W., S.R.I., S. Ramanathan), Nuffield Department of Clinical Neuroscience, John Radcliffe Hospital; University of Oxford, UK; Brain Autoimmunity and Clinical Neuroimmunology Groups (F.B., R.C.D., S. Ramanathan), Kids Neuroscience Centre, Kids Research at the Children's Hospital at Westmead, Sydney; Faculty of Medicine and Health (F.B., R.C.D., S. Ramanathan), University of Sydney; School of Medical Sciences (F.B.), Discipline of Applied Medical Science, Faculty of Medicine and Health, University of Sydney, Australia; and TY Nelson Department of Paediatric Neurology (R.C.D.), Children's Hospital at Westmead, Sydney, Australia.

Objective: Antibodies to myelin oligodendrocyte glycoprotein (MOG) are associated with CNS demyelination inclusive of optic neuritis (ON) and transverse myelitis (TM). To examine whether peripheral nervous system (PNS) involvement is associated with MOG antibody-associated disorders (MOGAD), we performed detailed characterization of an Australasian MOGAD cohort.

Methods: Using a live cell-based assay, we diagnosed 271 adults with MOGAD (2013-2018) and performed detailed clinical and immunologic characterization on those with likely PNS involvement.

Results: We identified 19 adults with MOGAD and PNS involvement without prior TM. All patients had CNS involvement including ON (bilateral [n = 3], unilateral [n = 3], and recurrent [n = 7]), a cortical lesion (n = 1), meningoencephalitis (n = 1), and subsequent TM (n = 4). Clinical phenotyping and neurophysiology were consistent with acute inflammatory demyelinating polyneuropathy (n = 1), myeloradiculitis (n = 3), multifocal motor neuropathy (n = 1), brachial neuritis (n = 2), migrant sensory neuritis (n = 3), and paresthesia and/or radicular limb pain (n = 10). Onset MRI spine was consistent with myeloradiculitis with nerve root enhancement in 3/19 and normal in 16/19. Immunotherapy resulted in partial/complete PNS symptom resolution in 12/15 (80%) (steroids and/or IV immunoglobulin n = 9, rituximab n = 2, and plasmapheresis n = 1). We identified serum antibodies targeting neurofascin 155, contactin-associated protein 2, or GM1 in 4/16 patients with MOGAD PNS compared with 0/30 controls ( = 0.01). There was no binding to novel cell surface antigens using an in vitro myelinating sensory neuronal coculture model.

Conclusions: Myeloradiculitis, combined central and peripheral demyelination syndromes, and inflammatory neuropathies may be associated with MOGAD and may be immunotherapy responsive. We identified a subgroup who may have pathology mediated by coexistent autoantibodies.
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http://dx.doi.org/10.1212/NXI.0000000000000924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803332PMC
January 2021

Latency of Multifocal Visual Evoked Potential in Multiple Sclerosis: A Visual Pathway Biomarker for Clinical Trials of Remyelinating Therapies.

Authors:
Alexander Klistorner James D Triplett Michael H Barnett Con Yiannikas Joshua Barton John Parratt Yuyi You Stuart L Graham

J Clin Neurophysiol 2020 Nov 20. Epub 2020 Nov 20.

Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia.

Purpose: Acute focal demyelination is the characteristic feature of multiple sclerosis, with the majority of damaged axons undergoing limited remyelination and forming chronic lesions. Potential remyelinating agents are currently under development and there is therefore an urgent need for reliable in vivo biomarkers of remyelination. This study aimed to investigate potential changes in multifocal visual evoked potentials' (mfVEPs) latency in a cohort of relapsing-remitting multiple sclerosis (RRMS) patients. The potential sample size required for a remyelination-based clinical trial using different treatment effect sizes and the mfVEP latency as an outcome measure was also estimated.

Methods: A total of 50 RRMS consecutive patients with no previous history of optic neuritis in at least one eye and 15 normal controls of similar age and gender composition were prospectively enrolled. Fifteen patients had a history of unilateral ON more than 12 months earlier, whereas 41 patients demonstrated optic radiations lesions on MRI at baseline. Most patients were on disease modifying therapy. A mfVEP was recorded at baseline and 12 months later.

Results: At baseline, the mfVEP latency in RRMS patients was delayed compared with normal controls in both optic neuritis and nonoptic neuritis eyes. Latency delay was significantly correlated to optic radiation lesion volume (R = 0.38, P < 0.001). There was no significant latency change in multiple sclerosis patients' eyes or optic neuritis and nonoptic neuritis eyes over the follow-up period with latency remaining remarkably constant. This was despite the fact that 46 of 50 patients were on disease-modifying therapies, implying current treatments do not affect myelination in chronic RRMS cases. Sample size calculations to evaluate an additional or alternative remyelinating agent, based on a 40% treatment effect, revealed that a relatively small sample size (78 patients) would be required to demonstrate efficacy in future trials of remyelination therapies.

Conclusions: Given its known sensitivity for latency changes and the stability found in this RRMS population, the mfVEP represents an ideal biomarker to assess the degree of latency recovery that may be achieved by remyelination in multiple sclerosis.
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http://dx.doi.org/10.1097/WNP.0000000000000757DOI Listing
November 2020

Expansion of chronic lesions is linked to disease progression in relapsing-remitting multiple sclerosis patients.

Authors:
Samuel Klistorner Michael H Barnett Con Yiannikas Joshua Barton John Parratt Yuyi You Stuart L Graham Alexander Klistorner

Mult Scler 2020 Nov 20:1352458520974357. Epub 2020 Nov 20.

Sydney Medical School, Save Sight Institute, The University of Sydney, Sydney, NSW, Australia/Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia.

Background: Slow-burning inflammation is putatively associated with lesion expansion and leads to progressive loss of axons and disability worsening.

Objective: To investigate the incidence and extent of chronic white matter lesion expansion in relapsing-remitting multiple sclerosis (RRMS) patients and to evaluate its relationship with biomarkers of disease progression.

Methods: Pre- and post-gadolinium T1, fluid-attenuated inversion recovery (FLAIR) and diffusion tensor images were acquired from 33 patients. Lesional activity were analysed between baseline and 48 months using custom-designed software.

Results: A total of 569 lesions were identified as chronic at baseline, of which 261 were expanding, 236 were stable and 72 were shrinking. In addition, 139 new lesions (both confluent and free-standing) were observed. Chronic lesion expansion was associated with patient's age and accounted for the bulk (67.3%) of total brain lesion volume increase, while only 32.7% was attributable to new lesion formation. Change in chronic lesion volume correlated with the rate of brain atrophy ( = -0.57,  = 0.001), change of Expanded Disability Status Scale (EDSS;  = 0.38,  = 0.03) and an increase of isotropic diffusivity inside the lesions ( = 0.75,  < 0.001).

Conclusion: Expansion of chronic lesions in RRMS patients is the primary determinant of increased T2 total lesion load. It significantly contributes to disease progression and partially driving axonal loss inside the lesions and brain damage outside of lesional tissue.
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http://dx.doi.org/10.1177/1352458520974357DOI Listing
November 2020

The neuro-otology of Susac syndrome.

Authors:
Todd A Hardy Rachael L Taylor Jessica Qiu Billy O'Brien Sumana Gopinath Benjamin Trewin Penelope J Spring Mohamed Shaffi Sam J Bolitho Roger J Garsia Richard Roxburgh Deborah F Mason Jerome Ip Fiona Chan Luke Chen Ian Wilson Heidi N Beadnall Michael H Barnett John D E Parratt John D G Watson Miriam S Welgampola Stephen W Reddel Benjamin Tsang G Michael Halmagyi

J Neurol 2020 Dec 21;267(12):3711-3722. Epub 2020 Jul 21.

Department of Neurology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.

Objective: We characterised the clinical and neuro-otological characteristics of patients with Susac syndrome.

Methods: The medical records of 30 patients with Susac syndrome were reviewed for details of their clinical presentation and course, neuro-otological symptoms, investigation results including audiology and vestibular function tests, treatment and outcomes.

Results: Our findings demonstrate that 29 of our 30 patients with Susac syndrome developed neuro-otological symptoms such as hearing loss, disequilibrium, tinnitus or vertigo during their disease course. Hearing loss was the most common neuro-otological symptom occurring in 93% of patients. A rising configuration of low-frequency greater than the high-frequency sensorineural hearing loss was the most characteristic finding on audiological testing (37% of reviewed audiograms). Disproportionately poor speech discrimination was identified in 20% of cases, and one case demonstrated a retrocochlear pattern on electrophysiological testing. Four patients required hearing aids and a further two patients required a cochlear implant due to severe hearing loss. Two out of two treated patients had improvements in hearing after the prompt administration of corticosteroids, indicating the potential for recoverable hearing loss if relapses are treated early. Effects on vestibular function were variable in ten patients who were tested, with most showing preservation of function despite significant hearing loss.

Conclusions: Neuro-otological symptoms in Susac syndrome are almost universal. In the correct clinical context, a rising configuration of low to high-frequency sensorineural hearing loss should prompt consideration of Susac syndrome. Treatment of inner ear symptoms in Susac syndrome requires further research as early immunotherapy may be beneficial.
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http://dx.doi.org/10.1007/s00415-020-10086-0DOI Listing
December 2020

Relapse Patterns in NMOSD: Evidence for Earlier Occurrence of Optic Neuritis and Possible Seasonal Variation.

Authors:
Elham Khalilidehkordi Laura Clarke Simon Arnett Wajih Bukhari Sofia Jimenez Sanchez Cullen O'Gorman Jing Sun Kerri M Prain Mark Woodhall Roger Silvestrini Christine S Bundell David Abernethy Sandeep Bhuta Stefan Blum Mike Boggild Karyn Boundy Bruce J Brew Matthew Brown Wallace Brownlee Helmut Butzkueven William M Carroll Celia Chen Alan Coulthard Russell C Dale Chandi Das Marzena J Fabis-Pedrini David Fulcher David Gillis Simon Hawke Robert Heard Andrew P D Henderson Saman Heshmat Suzanne Hodgkinson Trevor J Kilpatrick John King Chris Kneebone Andrew J Kornberg Jeannette Lechner-Scott Ming-Wei Lin Christopher Lynch Richard A L Macdonell Deborah F Mason Pamela A McCombe Jennifer Pereira John D Pollard Sudarshini Ramanathan Stephen W Reddel Cameron Shaw Judith Spies James Stankovich Ian Sutton Steve Vucic Michael Walsh Richard C Wong Eppie M Yiu Michael H Barnett Allan G Kermode Mark P Marriott John Parratt Mark Slee Bruce V Taylor Ernest Willoughby Fabienne Brilot Angela Vincent Patrick Waters Simon A Broadley

Front Neurol 2020 16;11:537. Epub 2020 Jun 16.

Menzies Health Institute Queensland, Gold Coast Campus, Griffith University, Southport, QLD, Australia.

Neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) show overlap in their clinical features. We performed an analysis of relapses with the aim of determining differences between the two conditions. Cases of NMOSD and age- and sex-matched MS controls were collected from across Australia and New Zealand. Demographic and clinical information, including relapse histories, were recorded using a standard questionnaire. There were 75 cases of NMOSD and 101 MS controls. There were 328 relapses in the NMOSD cases and 375 in MS controls. Spinal cord and optic neuritis attacks were the most common relapses in both NMOSD and MS. Optic neuritis ( < 0.001) and area postrema relapses ( = 0.002) were more common in NMOSD and other brainstem attacks were more common in MS ( < 0.001). Prior to age 30 years, attacks of optic neuritis were more common in NMOSD than transverse myelitis. After 30 this pattern was reversed. Relapses in NMOSD were more likely to be treated with acute immunotherapies and were less likely to recover completely. Analysis by month of relapse in NMOSD showed a trend toward reduced risk of relapse in February to April compared to a peak in November to January ( = 0.065). Optic neuritis and transverse myelitis are the most common types of relapse in NMOSD and MS. Optic neuritis tends to occur more frequently in NMOSD prior to the age of 30, with transverse myelitis being more common thereafter. Relapses in NMOSD were more severe. A seasonal bias for relapses in spring-summer may exist in NMOSD.
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http://dx.doi.org/10.3389/fneur.2020.00537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308484PMC
June 2020

Disability outcomes of early cerebellar and brainstem symptoms in multiple sclerosis.

Authors:
Minh Le Charles Malpas Sifat Sharmin Dana Horáková Eva Havrdova Maria Trojano Guillermo Izquierdo Sara Eichau Serkan Ozakbas Alessandra Lugaresi Alexandre Prat Marc Girard Pierre Duquette Catherine Larochelle Raed Alroughani Roberto Bergamaschi Patrizia Sola Diana Ferraro Pierre Grammond Francois Grand' Maison Murat Terzi Cavit Boz Raymond Hupperts Helmut Butzkueven Eugenio Pucci Franco Granella Vincent Van Pesch Aysun Soysal Bassem I Yamout Jeannette Lechner-Scott Daniele LA Spitaleri Radek Ampapa Recai Turkoglu Gerardo Iuliano Cristina Ramo-Tello Jose Luis Sanchez-Menoyo Youssef Sidhom Riadh Gouider Vahid Shaygannejad Julie Prevost Ayse Altintas Yara Dadalti Fragoso Pamela Ann McCombe Thor Petersen Mark Slee Michael H Barnett Steve Vucic Anneke Van Der Walt Tomas Kalincik

Mult Scler 2021 Apr 15;27(5):755-766. Epub 2020 Jun 15.

CORe, Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia; Department of Neurology, The Royal Melbourne Hospital, Melbourne, VIC, Australia.

Background: Cerebellar and brainstem symptoms are common in early stages of multiple sclerosis (MS) yet their prognostic values remain unclear.

Objective: The aim of this study was to investigate long-term disability outcomes in patients with early cerebellar and brainstem symptoms.

Methods: This study used data from MSBase registry. Patients with early cerebellar/brainstem presentations were identified as those with cerebellar/brainstem relapse(s) or functional system score ⩾ 2 in the initial 2 years. Early pyramidal presentation was chosen as a comparator. Andersen-Gill models were used to compare cumulative hazards of (1) disability progression events and (2) relapses between patients with and without early cerebellar/brainstem symptoms. Mixed effect models were used to estimate the associations between early cerebellar/brainstem presentations and expanded disability status scale (EDSS) scores.

Results: The study cohort consisted of 10,513 eligible patients, including 2723 and 3915 patients with early cerebellar and brainstem symptoms, respectively. Early cerebellar presentation was associated with greater hazard of progression events (HR = 1.37,  < 0.001) and EDSS (β = 0.16,  < 0.001). Patients with early brainstem symptoms had lower hazard of progression events (HR = 0.89,  = 0.01) and EDSS (β = -0.06,  < 0.001). Neither presentation was associated with changes in relapse risk.

Conclusion: Early cerebellar presentation is associated with unfavourable outcomes, while early brainstem presentation is associated with favourable prognosis. These presentations may be used as MS prognostic markers and guide therapeutic approach.
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http://dx.doi.org/10.1177/1352458520926955DOI Listing
April 2021

Real-world effectiveness of cladribine for Australian patients with multiple sclerosis: An MSBase registry substudy.

Authors:
Nathaniel Lizak Suzanne Hodgkinson Ernest Butler Jeannette Lechner-Scott Mark Slee Pamela Ann McCombe Cameron Shaw Olga Skibina Steve Vucic Neil Shuey Michael H Barnett John Parratt Helmut Butzkueven Dominic Jack Jessica Fabris Tomas Kalincik

Mult Scler 2021 03 12;27(3):465-474. Epub 2020 Jun 12.

CORe, Department of Medicine, University of Melbourne, Melbourne, VIC, Australia/Department of Neurology, Royal Melbourne Hospital, Melbourne, VIC, Australia.

Background/objective: Observational clinical data from cladribine-treated patients with relapsing forms of multiple sclerosis (MS) were recorded in the Australian MS registry powered by the MSBase registry platform (5-year follow-up) and analysed to complement information from the pivotal cladribine clinical trials in MS.

Methods: A cohort of 90 cladribine-treated patients with follow-up data reported by treating physicians and recorded in the Australian MSBase registry (database lock February 2016) were examined. Clinical data included Expanded Disability Status Scale (EDSS) scores, relapses and other disease-modifying drugs (DMDs) administered before and after cladribine treatment.

Results: Mean age on starting cladribine was 47 years; mean age at MS onset was 34 years, and median baseline EDSS score was 5.25. Disability trajectories in patients with sufficient follow-up suggested an overall increasing trend prior to cladribine treatment which was reduced during the 2-year post-treatment. Approximately 80% of patients were EDSS progression-free, 65% remained relapse-free after 2 years and median time to next DMD was 1.7 years.

Conclusion: These observational data suggest a disease-modifying effect in this cohort of relapsing MS patients characterised by older and more disabled patients. Since these data represent a single-arm cohort, clinical trials and larger comparative post-marketing studies are needed to validate and extend these findings.
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http://dx.doi.org/10.1177/1352458520921087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897790PMC
March 2021

Precision therapy for neuromyelitis optica spectrum disorder: A retrospective analysis of the use of class-switched memory B-cells for individualised rituximab dosing schedules.

Authors:
Benjamin P Trewin Stephen Adelstein Judith M Spies Heidi N Beadnall Joshua Barton Nicholas Ho Kerri J Gallagher Michael H Barnett

Mult Scler Relat Disord 2020 Aug 11;43:102175. Epub 2020 May 11.

Neurology, Royal Prince Alfred Hospital (RPAH), Australia; Brain & Mind Centre, University of Sydney (USyd), Australia; Faculty of Medicine & Health, USyd, Australia. Electronic address:

Background: B-cell depleting treatments are widely used to modify the course of neuromyelitis optica spectrum disorder (NMOSD). Despite recent successful Phase 3 trials of several novel NMOSD therapies, limited availability and high cost constrains their clinical use, and rituximab (RTX) remains a core treatment in many centres. Since 2013, the Royal Prince Alfred Hospital Neuroimmunology Clinic (NIC) has regularly measured class-switched memory B-cells (SMB-cells) in the peripheral blood of patients with NMOSD, who have been treated with RTX, in order to guide retreatment intervals.

Objective: To assess the management and outcomes of the treated patients, and to determine the effect of SMB-cell monitoring in guiding retreatment intervals.

Methods: A retrospective analysis of hospital records, clinic letters and laboratory data was performed.

Results: Sixteen patients with NMOSD received individualised rituximab dosing at NIC between 2013 and 2018. Fourteen (87.5%) were aquaporin-4 antibody (AQP4-Ab) positive; 1 (6.25%) was myelin oligodendrocyte glycoprotein antibody (MOG-Ab) positive and 1 (6.25%) was seronegative. After commencement of RTX, individually dosed according to regular measurements of serum SMB-cells, there was a 77.5% reduction in annualised relapse rate over a mean follow-up time of 46.1 months in our recently active NMOSD patients. Their mean retreatment interval was 50.9 weeks.

Conclusions: This study provides real-world evidence supporting individualised rituximab dosing in the treatment of NMOSD.
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http://dx.doi.org/10.1016/j.msard.2020.102175DOI Listing
August 2020

Alemtuzumab: Rare serious adverse events of a high-efficacy drug.

Authors:
Hans-Peter Hartung Jan Mares Michael H Barnett

Mult Scler 2020 05 16;26(6):737-740. Epub 2020 Apr 16.

Department of Neurology, Royal Prince Alfred Hospital and Brain and Mind Centre, The University of Sydney, Sydney, NSW, Australia.

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http://dx.doi.org/10.1177/1352458520913277DOI Listing
May 2020

MRI biomarkers of disease progression in multiple sclerosis: old dog, new tricks?

Authors:
Yael Barnett Justin Y Garber Michael H Barnett

Quant Imaging Med Surg 2020 Feb;10(2):527-532

Sydney Neuroimaging Analysis Centre, Camperdown, NSW, Australia.

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http://dx.doi.org/10.21037/qims.2020.01.04DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063292PMC
February 2020

Chronic demyelination exacerbates neuroaxonal loss in patients with MS with unilateral optic neuritis.

Authors:
Yuyi You Michael H Barnett Con Yiannikas John Parratt Jim Matthews Stuart L Graham Alexander Klistorner

Neurol Neuroimmunol Neuroinflamm 2020 05 13;7(3). Epub 2020 Mar 13.

From the Save Sight Institute (Y.Y., A.K.), The University of Sydney; Faculty of Medicine and Health Sciences (Y.Y., S.L.G., A.K.), Macquarie University; Brain and Mind Centre (M.H.B.), The University of Sydney; Sydney Neuroimaging Analysis Centre (M.H.B., A.K.); Department of Neurology (C.Y., J.P.), Royal North Shore Hospital; and Sydney Informatics and Data Science Hub (J.M.), The University of Sydney, NSW, Australia.

Objective: To examine the effect of chronic demyelination in the optic nerve of patients with MS on progressive loss of retinal ganglion cell (RGC) axons.

Methods: Progressive retinal nerve fiber layer (RNFL) loss, as measured by optical coherence tomography, was longitudinally examined in 51 patients with MS with a history of unilateral optic neuritis (ON) and 25 normal controls. Patients were examined annually with a median of 4-year follow-up. Pairwise intereye comparison was performed between ON and fellow non-ON (NON) eyes of patients with MS using the linear mixed-effects model and survival analysis. The latency asymmetry of multifocal visual evoked potential (mfVEP) was used to determine the level of demyelination in the optic nerve.

Results: Although both ON and NON eyes demonstrate significantly faster loss of RGC axons compared with normal subjects, ON eyes with severe chronic demyelination show accelerated thinning in the RNFL in the temporal sector of the optic disc (temporal RNFL [tRNFL]) compared with fellow eyes (evidenced by both the linear mixed-effects model and survival analysis). Furthermore, progressive tRNFL thinning is associated with the degree of optic nerve demyelination and reflects the topography of pathology in the optic nerve. More rapid axonal loss in ON eyes is also functionally evidenced by mfVEP amplitude reduction, which correlates with the level of optic nerve demyelination.

Conclusions: Although the effect of demyelination on axonal survival has been demonstrated in experimental studies, our results provide first clinically meaningful evidence that chronic demyelination is associated with progressive axonal loss in human MS.
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http://dx.doi.org/10.1212/NXI.0000000000000700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136042PMC
May 2020

Effects of the Positive Threshold and Data Analysis on Human MOG Antibody Detection by Live Flow Cytometry.

Authors:
Fiona Tea Deepti Pilli Sudarshini Ramanathan Joseph A Lopez Vera Merheb Fiona X Z Lee Alicia Zou Ganesha Liyanage Chelsea B Bassett Selina Thomsen Stephen W Reddel Michael H Barnett David A Brown Russell C Dale Fabienne Brilot

Front Immunol 2020 6;11:119. Epub 2020 Feb 6.

Brain Autoimmunity Group, Kids Neuroscience Centre, Kids Research at the Children's Hospital at Westmead, Sydney, NSW, Australia.

Human autoantibodies targeting myelin oligodendrocyte glycoprotein (MOG Ab) have become a useful clinical biomarker for the diagnosis of a spectrum of inflammatory demyelinating disorders. Live cell-based assays that detect MOG Ab against conformational MOG are currently the gold standard. Flow cytometry, in which serum binding to MOG-expressing cells and control cells are quantitively evaluated, is a widely used observer-independent, precise, and reliable detection method. However, there is currently no consensus on data analysis; for example, seropositive thresholds have been reported using varying standard deviations above a control cohort. Herein, we used a large cohort of 482 sera including samples from patients with monophasic or relapsing demyelination phenotypes consistent with MOG antibody-associated demyelination and other neurological diseases, as well as healthy controls, and applied a series of published analyses involving a background subtraction (delta) or a division (ratio). Loss of seropositivity and reduced detection sensitivity were observed when MOG ratio analyses or when 10 standard deviation (SD) or an arbitrary number was used to establish the threshold. Background binding and MOG ratio value were negatively correlated, in which patients seronegative by MOG ratio had high non-specific binding, a characteristic of serum that must be acknowledged. Most MOG Ab serostatuses were similar across analyses when optimal thresholds obtained by ROC analyses were used, demonstrating the robust nature and high discriminatory power of flow cytometry cell-based assays. With increased demand to identify MOG Ab-positive patients, a consensus on analysis is vital to improve patient diagnosis and for cross-study comparisons to ultimately define MOG Ab-associated disorders.
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http://dx.doi.org/10.3389/fimmu.2020.00119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016080PMC
March 2021

Effects of disease-modifying therapy on peripheral leukocytes in patients with multiple sclerosis.

Authors:
F Schweitzer S Laurent G R Fink Michael H Barnett H P Hartung C Warnke

J Neurol 2020 Feb 8. Epub 2020 Feb 8.

Department of Neurology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany.

Modern disease-modifying therapies (DMTs) in multiple sclerosis (MS) have variable modes of action and selectively suppress or modulate the immune system. In this review, we summarize the predicted and intended as well as unwanted adverse effects on leukocytes in peripheral blood as a result of treatment with DMTs for MS. We link changes in laboratory tests to the possible therapeutic risks that include secondary autoimmunity, infections, and impaired response to vaccinations. Profound knowledge of the intended effects on leukocyte counts, in particular lymphocytes, explained by the mode of action, and adverse effects which may require additional laboratory and clinical vigilance or even drug discontinuation, is needed when prescribing DMTs to treat patients with MS.
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http://dx.doi.org/10.1007/s00415-019-09690-6DOI Listing
February 2020

The clinical profile of NMOSD in Australia and New Zealand.

Authors:
Wajih Bukhari Laura Clarke Cullen O'Gorman Elham Khalilidehkordi Simon Arnett Kerri M Prain Mark Woodhall Roger Silvestrini Christine S Bundell Sudarshini Ramanathan David Abernethy Sandeep Bhuta Stefan Blum Mike Boggild Karyn Boundy Bruce J Brew Wallace Brownlee Helmut Butzkueven William M Carroll Celia Chen Alan Coulthard Russell C Dale Chandi Das Keith Dear Marzena J Fabis-Pedrini David Fulcher David Gillis Simon Hawke Robert Heard Andrew P D Henderson Saman Heshmat Suzanne Hodgkinson Sofia Jimenez-Sanchez Trevor J Kilpatrick John King Chris Kneebone Andrew J Kornberg Jeannette Lechner-Scott Ming-Wei Lin Christopher Lynch Richard A L Macdonnell Deborah F Mason Pamela A McCombe Jennifer Pereira John D Pollard Stephen W Reddel Cameron Shaw Judith Spies James Stankovich Ian Sutton Steve Vucic Michael Walsh Richard C Wong Eppie M Yiu Michael H Barnett Allan G Kermode Mark P Marriott John Parratt Mark Slee Bruce V Taylor Ernest Willoughby Robert J Wilson Fabienne Brilot Angela Vincent Patrick Waters Simon A Broadley

J Neurol 2020 May 31;267(5):1431-1443. Epub 2020 Jan 31.

Menzies Health Institute Queensland, School of Medicine, Griffith University, Gold Coast Campus, Gold Coast, QLD, 4222, Australia.

Neuromyelitis optica spectrum disorders (NMOSD) are an inflammation of the central nervous system associated with autoantibodies to aquaporin-4. We have undertaken a clinic-based survey of NMOSD in the Australia and New Zealand populations with the aim of characterising the clinical features and establishing the value of recently revised diagnostic criteria. Cases of possible NMOSD and age and sex-matched controls with multiple sclerosis (MS) were referred from centres across Australia and New Zealand. Cases were classified as NMOSD if they met the 2015 IPND criteria and remained as suspected NMOSD if they did not. Clinical and paraclinical data were compared across the three groups. NMOSD was confirmed in 75 cases and 89 had suspected NMOSD. There were 101 controls with MS. Age at onset, relapse rates and EDSS scores were significantly higher in NMOSD than in MS. Lesions and symptoms referable to the optic nerve were more common in NMOSD whereas brainstem, cerebellar and cerebral lesions were more common in MS. Longitudinally extensive spinal cord lesions were seen in 48/71 (68%) of cases with NMOSD. Elevations of CSF, white cell count and protein were more common in NMOSD. We have confirmed a clinical pattern of NMOSD that has been seen in several geographical regions. We have demonstrated the clinical utility of the current diagnostic criteria. Distinct patterns of disease are evident in NMOSD and MS, but there remains a large number of patients with NMOSD-like features who do not meet the current diagnostic criteria for NMOSD and remain a diagnostic challenge.
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http://dx.doi.org/10.1007/s00415-020-09716-4DOI Listing
May 2020

Pre-treatment T-cell subsets associate with fingolimod treatment responsiveness in multiple sclerosis.

Authors:
Mahtab Ghadiri Ayman Rezk Rui Li Ashley Evans Paul S Giacomini Michael H Barnett Jack Antel Amit Bar-Or

Sci Rep 2020 01 15;10(1):356. Epub 2020 Jan 15.

Montreal Neurological Institute, McGill University, Montreal, QC, Canada.

Biomarkers predicting fingolimod (FTY) treatment response in relapsing-remitting multiple sclerosis (RRMS) are lacking. Here, we performed extensive functional immunophenotyping using multiparametric flow cytometry to examine peripheral immune changes under FTY treatment and explore biomarkers of FTY treatment response. From among 135 RRMS patients who initiated FTY in a 2-year multicentre observational study, 36 were classified as 'Active' or 'Stable' based on clinical and/or radiological activity on-treatment. Flow cytometric analysis of immune cell subsets was performed on pre- and on-treatment peripheral blood mononuclear cells (PBMC) samples. Decreased absolute counts of B cells and most T-cell subsets were seen on-treatment. Senescent CD8 + T cells, CD56 + T cells, CD56 natural killer cells, monocytes and dendritic cells were not reduced in number and hence relatively increased in frequency on-treatment. An unbiased multiparametric and traditional manual analysis of T-cell subsets suggested a higher pre-treatment frequency of CD4 + central memory T cells (TCM) in patients who were subsequently Active versus Stable on-treatment. Lower pre-treatment terminally differentiated effector memory (TEMRA) cell frequencies were also seen in the subsequently Active cohort. Together, our data highlight differential effects of FTY on peripheral immune cell subsets and suggest that pre-treatment T-cell subset frequencies may have value in predicting FTY treatment response.
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http://dx.doi.org/10.1038/s41598-019-57114-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962338PMC
January 2020

Serum Exosome MicroRNAs Predict Multiple Sclerosis Disease Activity after Fingolimod Treatment.

Authors:
Saeideh Ebrahimkhani Heidi N Beadnall Chenyu Wang Catherine M Suter Michael H Barnett Michael E Buckland Fatemeh Vafaee

Mol Neurobiol 2020 Feb 12;57(2):1245-1258. Epub 2019 Nov 12.

School of Biotechnology and Biomolecular Sciences, University of New South Wales (UNSW Sydney), 2106, L2 West, Bioscience South E26, UNSW, Sydney, NSW, 2052, Australia.

We and others have previously demonstrated the potential for circulating exosome microRNAs to aid in disease diagnosis. In this study, we sought the possible utility of serum exosome microRNAs as biomarkers for disease activity in multiple sclerosis patients in response to fingolimod therapy. We studied patients with relapsing-remitting multiple sclerosis prior to and 6 months after treatment with fingolimod. Disease activity was determined using gadolinium-enhanced magnetic resonance imaging. Serum exosome microRNAs were profiled using next-generation sequencing. Data were analysed using univariate/multivariate modelling and machine learning to determine microRNA signatures with predictive utility. Accordingly, we identified 15 individual miRNAs that were differentially expressed in serum exosomes from post-treatment patients with active versus quiescent disease. The targets of these microRNAs clustered in ontologies related to the immune and nervous systems and signal transduction. While the power of individual microRNAs to predict disease status post-fingolimod was modest (average 77%, range 65 to 91%), several combinations of 2 or 3 miRNAs were able to distinguish active from quiescent disease with greater than 90% accuracy. Further stratification of patients identified additional microRNAs associated with stable remission, and a positive response to fingolimod in patients with active disease prior to treatment. Overall, these data underscore the value of serum exosome microRNA signatures as non-invasive biomarkers of disease in multiple sclerosis and suggest they may be used to predict response to fingolimod in future clinical practice. Additionally, these data suggest that fingolimod may have mechanisms of action beyond its known functions.
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http://dx.doi.org/10.1007/s12035-019-01792-6DOI Listing
February 2020

AQP4 Antibody Assay Sensitivity Comparison in the Era of the 2015 Diagnostic Criteria for NMOSD.

Authors:
Kerri Prain Mark Woodhall Angela Vincent Sudarshini Ramanathan Michael H Barnett Christine S Bundell John D E Parratt Roger A Silvestrini Wajih Bukhari Fabienne Brilot Patrick Waters Simon A Broadley

Front Neurol 2019 4;10:1028. Epub 2019 Oct 4.

School of Medicine, Gold Coast Campus, Griffith University, Southport, QLD, Australia.

We have compared five different assays for antibodies to aquaporin-4 in 181 cases of suspected Neuromyelitis optica spectrum disorders (NMOSD) and 253 controls to assess their relative utility. As part of a clinically-based survey of NMOSD in Australia and New Zealand, cases of suspected NMOSD were referred from 23 centers. Clinical details and magnetic imaging were reviewed and used to apply the 2015 IPND diagnostic criteria. In addition, 101 age- and sex-matched patients with multiple sclerosis were referred. Other inflammatory disease ( = 49) and healthy controls ( = 103) were also recruited. Samples from all participants were tested using tissue-based indirect immunofluorescence assays and a subset were tested using four additional ELISA and cell-based assays. Antibodies to myelin oligodendrocyte glycoprotein (MOG) were also assayed. All aquaporin-4 antibody assays proved to be highly specific. Sensitivities ranged from 60 to 94%, with cell-based assays having the highest sensitivity. Antibodies to MOG were detected in 8/79 (10%) of the residual suspected cases of NMOSD. Under the 2015 IPND diagnostic criteria for NMOSD, cell-based assays for aquaporin-4 are sensitive and highly specific, performing better than tissue-based and ELISA assays. A fixed cell-based assay showed near-identical results to a live-cell based assay. Antibodies to MOG account for only a small number of suspected cases.
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http://dx.doi.org/10.3389/fneur.2019.01028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787171PMC
October 2019

Characterization of the human myelin oligodendrocyte glycoprotein antibody response in demyelination.

Authors:
Fiona Tea Joseph A Lopez Sudarshini Ramanathan Vera Merheb Fiona X Z Lee Alicia Zou Deepti Pilli Ellis Patrick Anneke van der Walt Mastura Monif Esther M Tantsis Eppie M Yiu Steve Vucic Andrew P D Henderson Anthony Fok Clare L Fraser Jeanette Lechner-Scott Stephen W Reddel Simon Broadley Michael H Barnett David A Brown Jan D Lunemann Russell C Dale Fabienne Brilot

Acta Neuropathol Commun 2019 09 3;7(1):145. Epub 2019 Sep 3.

Brain Autoimmunity Group, Kids Neuroscience Centre, Kids Research at the Children's Hospital at Westmead, Locked Bag 4001, Sydney, NSW, 2145, Australia.

Over recent years, human autoantibodies targeting myelin oligodendrocyte glycoprotein (MOG Ab) have been associated with monophasic and relapsing central nervous system demyelination involving the optic nerves, spinal cord, and brain. While the clinical relevance of MOG Ab detection is becoming increasingly clear as therapeutic and prognostic differences from multiple sclerosis are acknowledged, an in-depth characterization of human MOG Ab is required to answer key challenges in patient diagnosis, treatment, and prognosis. Herein, we investigated the epitope, binding sensitivity, and affinity of MOG Ab in a cohort of 139 and 148 MOG antibody-seropositive children and adults (n = 287 patients at baseline, 130 longitudinal samples, and 22 cerebrospinal fluid samples). MOG extracellular domain was also immobilized to determine the affinity of MOG Ab. MOG Ab response was of immunoglobulin G1 isotype, and was of peripheral rather than intrathecal origin. High affinity MOG Ab were detected in 15% paediatric and 18% adult sera. More than 75% of paediatric and adult MOG Ab targeted a dominant extracellular antigenic region around Proline42. MOG Ab titers fluctuated over the progression of disease, but affinity and reactivity to Proline42 remained stable. Adults with a relapsing course intrinsically presented with a reduced immunoreactivity to Proline42 and had a more diverse MOG Ab response, a feature that may be harnessed for predicting relapse. Higher titers of MOG Ab were observed in more severe phenotypes and during active disease, supporting the pathogenic role of MOG Ab. Loss of MOG Ab seropositivity was observed upon conformational changes to MOG, and this greatly impacted the sensitivity of the detection of relapsing disorders, largely considered as more severe. Careful consideration of the binding characteristics of autoantigens should be taken into account when detecting disease-relevant autoantibodies.
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http://dx.doi.org/10.1186/s40478-019-0786-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724269PMC
September 2019

Lesion activity and chronic demyelination are the major determinants of brain atrophy in MS.

Authors:
Chenyu Wang Michael H Barnett Con Yiannikas Joshua Barton John Parratt Yuyi You Stuart L Graham Alexander Klistorner

Neurol Neuroimmunol Neuroinflamm 2019 09 16;6(5). Epub 2019 Jul 16.

From the Brain and Mind Centre (C.W., M.H.B., J.B.), Sydney Medical School, University of Sydney; Sydney Neuroimaging Analysis Centre (C.W., M.H.B.); Royal North Shore Hospital (C.Y., J.P.); Save Sight Institute (Y.Y., A.K.), Sydney Medical School, University of Sydney; and Faculty of Medicine and Health Sciences (S.L.G., A.K.), Macquarie University, Sydney, NSW, Australia.

Objective: To evaluate the combined effect of lesion activity and pathologic processes occurring in both chronically demyelinated lesions and normal-appearing white matter (NAWM) on brain atrophy in MS.

Methods: Pre- and post-gadolinium T1, fluid attenuation inversion recovery, and diffusion tensor imaging images were acquired from 50 consecutive patients with relapsing-remitting MS (all, but one, on disease-modifying therapy) at baseline and 5 years. Brain atrophy was measured using structural image evaluation, using normalization of atrophy percent brain volume change (PBVC) analysis.

Results: During follow-up, brain volume diminished by 2.0% ± 1.1%. PBVC was not associated with patient age, disease duration, sex, or type of treatment. PBVC moderately correlated with baseline lesion load ( = -0.38, = 0.016), but demonstrated strong association with new lesion activity ( = -0.63, < 0.001). Brain atrophy was also strongly linked to the increase of water diffusion within chronic MS lesions ( = -0.62, < 0.001). In normal-appearing white matter (NAWM), PBVC demonstrated a significant correlation with both baseline and longitudinal increase of demyelination as measured by radial diffusivity (RD, = -0.44, = 0.005 and = -0.35, = 0.026, respectively). Linear regression analysis explained 62% of the variance in PBVC. It confirmed the major role of new lesion activity ( = 0.002, standardized beta-coefficient -0.42), whereas change in diffusivity inside chronic lesions and NAWM RD at baseline also contributed significantly ( = 0.04 and 0.02, standardized beta-coefficient -0.31 and -0.29, respectively), increasing predictive power of the model by 55%.

Conclusion: In addition to new lesion activity, progressive loss of demyelinated axons in chronic lesions and the degree of demyelination in NAWM significantly contribute to accelerated loss of brain tissue in patients with MS receiving immunomodulatory therapy.
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http://dx.doi.org/10.1212/NXI.0000000000000593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705629PMC
September 2019

The spectrum of immune-mediated and inflammatory lesions of the brainstem: Clues to diagnosis.

Authors:
Lai Yin Law D Sean Riminton MaiAnh Nguyen Michael H Barnett Stephen W Reddel Todd A Hardy

Neurology 2019 08;93(9):390-405

From the Neuroimmunology Clinic, Concord Hospital (L.Y.L., D.S.R., M.N., S.W.R., T.A.H.), Brain and Mind Centre (M.H.B., S.W.R., T.A.H.), and Department of Neurology, Royal Prince Alfred Hospital (M.H.B.), University of Sydney, NSW, Australia.

The presentation of a patient with brainstem symptoms and signs invokes a number of common and less common differential diagnoses, and accurate diagnosis can be challenging. We review the major immune-mediated and inflammatory syndromes that can affect the brainstem including multiple sclerosis, neuromyelitis optica spectrum disorder, neuro-Behçet disease, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids, neurosarcoidosis, Susac syndrome, and the histiocytic disorders. We focus on clinical features and MRI clues that help to distinguish among the different brainstem conditions. Accurate diagnosis is important to guide appropriate treatment and limit neurologic disability.
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http://dx.doi.org/10.1212/WNL.0000000000008015DOI Listing
August 2019

Investigation of tumefactive demyelination is associated with higher economic burden and more adverse events compared with conventional multiple sclerosis.

Authors:
Matthew Silsby Pedro Sánchez Judith M Spies Jane Frith Joshua Barton Heidi N Beadnall Michael H Barnett Stephen W Reddel Todd A Hardy

Mult Scler Relat Disord 2019 Oct 20;35:104-107. Epub 2019 Jul 20.

Neurology Department, Concord Repatriation General Hospital, Sydney, New South Wales, Australia; Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia. Electronic address:

Background: Tumefactive demyelinating lesions occur as part of the spectrum of multiple sclerosis (MS), but can be difficult to distinguish from other large cerebral lesions such as neoplasm or abscess.

Objectives: To estimate the cost associated with diagnostic investigation of patients with tumefactive demyelination (TD), including associated morbidity, and compare this to more typical relapsing-remitting MS.

Methods: Retrospective review of medical records of patients seen between 2013 and 2018 in clinics at the Brain and Mind Centre, Sydney, Australia; a center with tertiary referral expertise in MS.

Results: Thirty-one patients with TD and 31 patients with MS were compared. The cost of investigating TD was more than 7.5 times higher per patient than MS ($18,300 vs $2418, p < 0.01). More patients in the TD group were admitted to hospital (22/31 versus 10/31) and ICU admissions only occurred in the TD group (10/22 versus 0/10). Brain biopsy was performed only in the TD group (7 patients), which contributed to cost differences and also accounted for differences in adverse outcomes.

Conclusion: The cost and morbidity related to investigating TD is higher than in typical MS. Improvements in the diagnosis of TD have the potential to improve health and economic outcomes.
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http://dx.doi.org/10.1016/j.msard.2019.07.013DOI Listing
October 2019

Computerized Cognitive Training in Multiple Sclerosis: A Systematic Review and Meta-analysis.

Authors:
Amit Lampit Josephine Heine Carsten Finke Michael H Barnett Michael Valenzuela Anna Wolf Isabella H K Leung Nicole T M Hill

Neurorehabil Neural Repair 2019 09 22;33(9):695-706. Epub 2019 Jul 22.

1 University of Melbourne, Parkville, Victoria, Australia.

. Cognitive impairments are common in people with multiple sclerosis (MS). Systematic reviews reported promising evidence for various cognitive interventions in this population. Computerized cognitive training (CCT) has strong evidence for safety and efficacy in several populations, but its effects in MS have yet to be specified. . We aimed to synthesize the evidence from randomized controlled trials (RCTs) investigating the effects of CCT on cognitive, psychosocial, and functional outcomes in adults with MS. . We searched MEDLINE, EMBASE, PsycINFO, CINAHL, and CENTRAL from inception to March 2019. We calculated standardized mean difference (Hedges' ) of change from baseline in untrained measures of cognition, individual domains, psychosocial functioning, and daily function between CCT and control groups using a random-effects model. . A total of 20 RCTs encompassing 982 participants (78% with relapsing-remitting MS) were included. The overall cognitive effect size was moderate ( = 0.30; 95% CI = 0.18-0.43), with no evidence of small-study effect or between-study heterogeneity (prediction interval = 0.17-0.44). Small to moderate effect sizes were found for attention/processing speed, executive functions, and verbal and visuospatial memory. Evidence for working memory, fatigue, and psychosocial and daily functioning were inconclusive. Cognitive effects waned without further training. . CCT is efficacious for overall and key cognitive domains in adults with MS, but efficacy on other outcomes and in progressive subtypes remains unclear. Long-term and well-powered trials with diverse cohorts are needed to optimize and maintain the efficacy of CCT, investigate transfer to daily living, and determine who can benefit and whether CCT is a cost-effective strategy to attenuate cognitive decline in MS.
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http://dx.doi.org/10.1177/1545968319860490DOI Listing
September 2019

Salient Central Lesion Volume: A Standardized Novel Fully Automated Proxy for Brain FLAIR Lesion Volume in Multiple Sclerosis.

Authors:
Michael G Dwyer Niels Bergsland Deepa P Ramasamy Bianca Weinstock-Guttman Michael H Barnett Chenyu Wang Davorka Tomic Diego Silva Robert Zivadinov

J Neuroimaging 2019 09 1;29(5):615-623. Epub 2019 Jul 1.

Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY.

Background And Purpose: Quantitative neuroimaging is an important part of multiple sclerosis research and clinical trials, and measures of lesion volume (LV) and brain atrophy are key clinical trial endpoints. However, translation of these endpoints to heterogeneous historical datasets and nonstandardized clinical routine imaging has been difficult. The NeuroSTREAM technique was recently introduced as a robust and broadly applicable surrogate for brain atrophy measurement, but no such surrogate currently exists for conventional T2-LV. Therefore, we sought to develop a fully automated proxy for T2-LV with similar analytic value but increased robustness to common issues arising in clinical routine imaging.

Methods: We created an algorithm to identify salient central lesion volume (SCLV), comprised of the subset of lesion voxels within a specific distance to the lateral ventricles (centrality) and with intensity at least a quantitatively-derived amount brighter than normal appearing tissue (salience). We evaluated this method on four datasets (clinical, inter-scanner, scan-rescan, and real-world multi-center), including 1.5T, 3T, Philips, Siemens, and GE scanners with heterogeneous protocols, to assess agreement with conventional T2-LV, comparative relationship with disability, reliability across scanners and between scans, and applicability to real-world scans.

Results: SCLV correlated strongly with conventional T2-LV in both research-quality (r = .90, P < .001) and real-world (r = 0.87, P < 0.001) datasets. It also showed similar correlations with Expanded Disability Status Scale, as conventional T2-LV (r = 0.48 for T2-LV vs. r = 0.45 for SCLV). Inter-scanner reproducibility (ICC) was 0.86, p < 0.001 for SCLV compared to 0.84, p < 0.001 for conventional T2-LV, whereas scan-rescan ICC was 0.999 for SCLV versus 0.997 for T2-LV.

Conclusions: SCLV is a robust, fully-automated proxy for T2-LV in situations where conventional T2-LV is not easily or reliably calculated.
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http://dx.doi.org/10.1111/jon.12650DOI Listing
September 2019

The evaluation of an online mindfulness program for people with multiple sclerosis: study protocol.

Authors:
Amy-Lee Sesel Louise Sharpe Heidi N Beadnall Michael H Barnett Marianna Szabo Sharon L Naismith

BMC Neurol 2019 Jun 14;19(1):129. Epub 2019 Jun 14.

School of Psychology, University of Sydney, Sydney, NSW, 2006, Australia.

Background: Multiple sclerosis (MS) is a neurological disease of the central nervous system and is associated with many psychosocial symptoms that are difficult to manage including low mood, anxiety, fatigue and pain, as well as low health-related quality of life. Internet-based psychosocial interventions that use mindfulness-based approaches are gathering much attention in recent literature, particularly in the treatment of chronic illnesses. However, no large randomized controlled trials have been done examining the efficacy of such interventions for people with MS (PwMS).

Methods/design: This study is a randomised controlled trial of an online mindfulness-based intervention (MBI) for PwMS. Participants will be randomised to receive either the MBI or offered the intervention after a waiting period. All participants will be assessed to determine whether they have a history of recurrent depressive disorder. The primary outcome will be severity of depression, according to the Centre of Epidemiology Depression Scale. Secondary outcomes will be anxiety severity, fatigue, pain and quality of life. Assessments will be conducted pre, post-treatment, at three and six-month follow-up. The online mindfulness-based program was developed in collaboration with end-users (n = 19 PwMS) who gave feedback about what would be feasible and acceptable, and the draft program was reviewed by both experts and patients.

Discussion: Multiple sclerosis is the most common acquired chronic neurological disease amongst young adults and is associated with a range of symptoms that can be difficult to cope with. In face-to-face interventions, a MBI demonstrated the largest effect in a recent meta-analysis of psychological treatments for PwMS, but MBIs for PwMS have not been delivered online. Hence, this trial will confirm whether MBIs can be efficacious when delivered online. A range of symptoms are assessed as outcomes so that the nature of benefits associated with the online MBI can be ascertained.

Trial Registration: ACTRN12618001260213 . Date of Registration: 25/07/2018.
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http://dx.doi.org/10.1186/s12883-019-1356-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567500PMC
June 2019

The electrophysiological assessment of visual function in Multiple Sclerosis.

Authors:
Joshua L Barton Justin Y Garber Alexander Klistorner Michael H Barnett

Clin Neurophysiol Pract 2019 8;4:90-96. Epub 2019 May 8.

Brain & Mind Centre, University of Sydney, NSW, Australia.

The assessment of vision is integral to the diagnosis and monitoring of patients with multiple sclerosis (MS). Visual electrophysiology, previously a critical investigation in patients with suspected MS, has in large part been supplanted by magnetic resonance imaging in clinical routine. However, the development of multi-focal visual evoked potentials and the advent of putative re-myelinating therapies that can be monitored with these techniques has led to a resurgence of interest in the field. Here, we review the clinical applications, technical considerations and limitations of visual evoked potentials in the management of patients with MS.
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http://dx.doi.org/10.1016/j.cnp.2019.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539333PMC
May 2019