Publications by authors named "Anthony Traboulsee"

175 Publications

Elevated levels of serum CD5 antigen-like protein distinguish secondary progressive multiple sclerosis from other disease subtypes.

Mult Scler Relat Disord 2021 Sep 20;56:103269. Epub 2021 Sep 20.

Department of Pathology & Laboratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, Canada; International Collaboration on Repair Discoveries (ICORD), Faculty of Medicine, University of British Columbia, Vancouver, Canada. Electronic address:

CD5 antigen-like (CD5L) protein is a macrophage-secreted protein with roles in immunomodulation and lipid homeostasis. We compared serum CD5L levels in healthy controls to individuals diagnosed with clinically isolated syndrome, relapsing remitting (RR), secondary progressive (SP), and primary progressive (PP) multiple sclerosis (MS). CD5L was increased in SPMS relative to controls, RRMS, and PPMS. SPMS CD5L was associated with longer disease duration independent of age, sex, or disease severity. The positive relationship between CD5L and disease duration in SPMS suggests a chronic peripheral inflammatory profile compared to other subtypes, particularly PPMS, warranting investigation of functional roles for CD5L in MS.
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http://dx.doi.org/10.1016/j.msard.2021.103269DOI Listing
September 2021

Myelin-oligodendrocyte glycoprotein antibody-associated disease.

Lancet Neurol 2021 09;20(9):762-772

Brain Institute of Rio Grande do Sul and School of Medicine, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil.

Myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently identified autoimmune disorder that presents in both adults and children as CNS demyelination. Although there are clinical phenotypic overlaps between MOGAD, multiple sclerosis, and aquaporin-4 antibody-associated neuromyelitis optica spectrum disorder (NMOSD) cumulative biological, clinical, and pathological evidence discriminates between these conditions. Patients should not be diagnosed with multiple sclerosis or NMOSD if they have anti-MOG antibodies in their serum. However, many questions related to the clinical characterisation of MOGAD and pathogenetic role of MOG antibodies are still unanswered. Furthermore, therapy is mainly based on standard protocols for aquaporin-4 antibody-associated NMOSD and multiple sclerosis, and more evidence is needed regarding how and when to treat patients with MOGAD.
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http://dx.doi.org/10.1016/S1474-4422(21)00218-0DOI Listing
September 2021

Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double-blind, placebo-controlled trial.

Lancet Neurol 2021 09;20(9):729-738

Department of Medicine, University of British Columbia, Vancouver, BC, Canada.

Background: Tolebrutinib is an oral, CNS-penetrant, irreversible inhibitor of Bruton's tyrosine kinase, an enzyme expressed in B lymphocytes and myeloid cells including microglia, which are major drivers of inflammation in multiple sclerosis. We aimed to determine the dose-response relationship between tolebrutinib and the reduction in new active brain MRI lesions in patients with relapsing multiple sclerosis.

Methods: We did a 16-week, phase 2b, randomised, double-blind, placebo-controlled, crossover, dose-finding trial at 40 centres (academic sites, specialty clinics, and general neurology centres) in ten countries in Europe and North America. Eligible participants were adults aged 18-55 years with diagnosed relapsing multiple sclerosis (either relapsing-remitting or relapsing secondary progressive multiple sclerosis), and one or more of the following criteria: at least one relapse within the previous year, at least two relapses within the previous 2 years, or at least one active gadolinium-enhancing brain lesion in the 6 months before screening. Exclusion criteria included a diagnosis of primary progressive multiple sclerosis or a diagnosis of secondary progressive multiple sclerosis without relapse. We used a two-step randomisation process to randomly assign eligible participants (1:1) to two cohorts, then further randomly assign participants in each cohort (1:1:1:1) to four tolebrutinib dose groups (5, 15, 30, and 60 mg administered once daily as an oral tablet). Cohort 1 received tolebrutinib for 12 weeks, then matched placebo (ie, identical looking tablets) for 4 weeks; cohort 2 received 4 weeks of placebo followed by 12 weeks of tolebrutinib. Participants and investigators were masked for dose and tolebrutinib-placebo administration sequence; investigators, study team members, and study participants did not have access to unmasked data. MRI scans were done at screening and every 4 weeks over 16 weeks. The primary efficacy endpoint was the number of new gadolinium-enhancing lesions detected on the scan done after 12 weeks of tolebrutinib treatment (assessed at week 12 for cohort 1 and week 16 for cohort 2), relative to the scan done 4 weeks previously, and compared with the lesions accumulated during 4 weeks of placebo run-in period in cohort 2. Efficacy data were analysed in a modified intention-to-treat population, using a two-step multiple comparison procedure with modelling analysis. Safety was assessed for all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03889639), EudraCT (2018-003927-12), and WHO (U1111-1220-0572), and has been completed.

Findings: Between May 14, 2019, and Jan 2, 2020, we enrolled and randomly assigned 130 participants to tolebrutinib: 33 to 5 mg, 32 to 15 mg, 33 to 30 mg, and 32 to 60 mg. 129 (99%) completed the treatment regimen and 126 were included in the primary analysis. At treatment week 12, there was a dose-dependent reduction in the number of new gadolinium-enhancing lesions (mean [SD] lesions per patient: placebo, 1·03 [2·50]; 5 mg, 1·39 [3·20]; 15 mg, 0·77 [1·48]; 30 mg, 0·76 [3·31]; 60 mg, 0·13 [0·43]; p=0·03). One serious adverse event was reported (one patient in the 60 mg group was admitted to hospital because of a multiple sclerosis relapse). The most common non-serious adverse event during tolebrutinib treatment was headache (in one [3%] of 33 in the 5 mg group; three [9%] of 32 in the 15 mg group; one [3%] of 33 in the 30 mg group; and four [13%] of 32 in the 60 mg group). No safety-related discontinuations or treatment-related deaths occurred.

Interpretation: 12 weeks of tolebrutinib treatment led to a dose-dependent reduction in new gadolinium-enhancing lesions, the 60 mg dose being the most efficacious, and the drug was well tolerated. Reduction of acute inflammation, combined with the potential to modulate the immune response within the CNS, provides a scientific rationale to pursue phase 3 clinical trials of tolebrutinib in patients with relapsing and progressive forms of multiple sclerosis.

Funding: Sanofi.
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http://dx.doi.org/10.1016/S1474-4422(21)00237-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8434816PMC
September 2021

Preliminary testing of a patient decision aid for patients with relapsing-remitting multiple sclerosis.

Mult Scler J Exp Transl Clin 2021 Jul-Sep;7(3):20552173211029966. Epub 2021 Jul 15.

Division of Neurology, University of British Columbia, Vancouver, Canada.

Background: Multiple first-line disease modifying therapies (DMTs) are available for relapsing-remitting multiple sclerosis (RRMS), each with different characteristics. We developed an interactive patient decision aid (PtDA) to promote informed shared decision-making (SDM).

Objective: To test the preliminary effectiveness of the PtDA in participants with RRMS.

Methods: Knowledge, and decisional conflict were measured pre- and post- implementation of the PtDA, SDM after the consultation, and 6-month treatment patterns were observed. Differences in scores were analyzed using descriptive statistics and paired t-tests. Qualitative interviews with patients and neurologists were analyzed using thematic analysis.

Results: 52 participants were recruited: most were female (81%), 40 years of age or younger (62%), and had experienced MS for less than 5 years (56%). After participants used the PtDA, there was a significant improvement in decisional conflict (change = 1.00;  < 0.001) and knowledge (change = 2.15, p < 0.001). Nearly all patients wanted SDM, and 25 (56%) reported this occurred in their consult. Qualitative results suggested the PtDA supported both patients and neurologists in making decisions.

Conclusion: This pilot study suggests that PtDA use helps RRMS patients and their clinician select a DMT. Future studies will assess the feasibility of implementation and the impact of the PtDA on timely DMT initiation and longer-term adherence.
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http://dx.doi.org/10.1177/20552173211029966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287362PMC
July 2021

Water content changes in new multiple sclerosis lesions have a minimal effect on the determination of myelin water fraction values.

J Neuroimaging 2021 Jul 26. Epub 2021 Jul 26.

Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada.

Background And Purpose: Myelin water fraction (MWF) is a histopathologically validated in vivo myelin marker. As MWF is the proportion of water with a short T relative to the total water, increases in water from edema and inflammation may confound MWF determination in multiple sclerosis (MS) lesions. Total water content (TWC) measurement enables calculation of absolute myelin water content (MWC) and can be used to distinguish edema/inflammation from demyelination. We assessed what influence changes in total water might have on MWF by calculating MWC values in new MS lesions.

Methods: 3T 32-echo T relaxation data were collected monthly for 6 months from six relapsing-remitting MS participants. TWC was determined and multiplied with MWF images to calculate corrected MWC images. The effect of this water content correction was examined in 20 new lesions by comparing mean MWF and MWC over time.

Results: On average, at lesion first appearance, lesion TWC increased by 6.4% (p = .003; range: -1% to +21%), MWF decreased by 24% (p = .006; range: -70% to +12%), and MWC decreased by 20% (p = .026; range: -68% to +21%), relative to prelesion values. Average TWC in lesions then gradually decreased, whereas MWF and MWC remained low. The shape of the MWF and MWC lesion evolution curves was nearly identical, differing only by an offset.

Conclusion: MWF mirrors MWC and is able to monitor myelin in new lesions. Even after taking into account water content increases, MWC still decreased at lesion first appearance attributed to demyelination.
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http://dx.doi.org/10.1111/jon.12908DOI Listing
July 2021

2021 MAGNIMS-CMSC-NAIMS consensus recommendations on the use of MRI in patients with multiple sclerosis.

Lancet Neurol 2021 08 14;20(8):653-670. Epub 2021 Jun 14.

Section of Neuroradiology, Department of Radiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. Electronic address:

The 2015 Magnetic Resonance Imaging in Multiple Sclerosis and 2016 Consortium of Multiple Sclerosis Centres guidelines on the use of MRI in diagnosis and monitoring of multiple sclerosis made an important step towards appropriate use of MRI in routine clinical practice. Since their promulgation, there have been substantial relevant advances in knowledge, including the 2017 revisions of the McDonald diagnostic criteria, renewed safety concerns regarding intravenous gadolinium-based contrast agents, and the value of spinal cord MRI for diagnostic, prognostic, and monitoring purposes. These developments suggest a changing role of MRI for the management of patients with multiple sclerosis. This 2021 revision of the previous guidelines on MRI use for patients with multiple sclerosis merges recommendations from the Magnetic Resonance Imaging in Multiple Sclerosis study group, Consortium of Multiple Sclerosis Centres, and North American Imaging in Multiple Sclerosis Cooperative, and translates research findings into clinical practice to improve the use of MRI for diagnosis, prognosis, and monitoring of individuals with multiple sclerosis. We recommend changes in MRI acquisition protocols, such as emphasising the value of three dimensional-fluid-attenuated inversion recovery as the core brain pulse sequence to improve diagnostic accuracy and ability to identify new lesions to monitor treatment effectiveness, and we provide recommendations for the judicious use of gadolinium-based contrast agents for specific clinical purposes. Additionally, we extend the recommendations to the use of MRI in patients with multiple sclerosis in childhood, during pregnancy, and in the post-partum period. Finally, we discuss promising MRI approaches that might deserve introduction into clinical practice in the near future.
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http://dx.doi.org/10.1016/S1474-4422(21)00095-8DOI Listing
August 2021

Characterization of multiple sclerosis neuroinflammation and neurodegeneration with relaxation and diffusion basis spectrum imaging.

Mult Scler 2021 Jun 16:13524585211023345. Epub 2021 Jun 16.

Department of Radiology, The University of British Columbia, Vancouver, BC, Canada/International Collaboration on Repair Discoveries (ICORD), The University of British Columbia, Vancouver, BC, Canada/Department of Physics & Astronomy, The University of British Columbia, Vancouver, BC, Canada/Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, Canada.

Background: Advanced magnetic resonance imaging (MRI) methods can provide more specific information about various microstructural tissue changes in multiple sclerosis (MS) brain. Quantitative measurement of T and T relaxation, and diffusion basis spectrum imaging (DBSI) yield metrics related to the pathology of neuroinflammation and neurodegeneration that occurs across the spectrum of MS.

Objective: To use relaxation and DBSI MRI metrics to describe measures of neuroinflammation, myelin and axons in different MS subtypes.

Methods: 103 participants (20 clinically isolated syndrome (CIS), 33 relapsing-remitting MS (RRMS), 30 secondary progressive MS and 20 primary progressive MS) underwent quantitative T, T, DBSI and conventional 3T MRI. Whole brain, normal-appearing white matter, lesion and corpus callosum MRI metrics were compared across MS subtypes.

Results: A gradation of MRI metric values was seen from CIS to RRMS to progressive MS. RRMS demonstrated large oedema-related differences, while progressive MS had the most extensive abnormalities in myelin and axonal measures.

Conclusion: Relaxation and DBSI-derived MRI measures show differences between MS subtypes related to the severity and composition of underlying tissue damage. RRMS showed oedema, demyelination and axonal loss compared with CIS. Progressive MS had even more evidence of increased oedema, demyelination and axonal loss compared with CIS and RRMS.
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http://dx.doi.org/10.1177/13524585211023345DOI Listing
June 2021

Efficacy and safety of alemtuzumab over 6 years: final results of the 4-year CARE-MS extension trial.

Ther Adv Neurol Disord 2021 23;14:1756286420982134. Epub 2021 Apr 23.

Department of Neurology, University of Warmia and Mazury, Olsztyn, Poland.

Background: In the 2-year CARE-MS I and II trials, alemtuzumab 12 mg administered on 5 consecutive days at core study baseline and on 3 consecutive days 12 months later significantly improved outcomes subcutaneous interferon beta-1a (SC IFNB-1a) in relapsing-remitting multiple sclerosis patients. Here, we present the final 6-year CARE-MS extension trial results (CAMMS03409), and compare outcomes over 6 years in patients randomized to both treatment groups at core study baseline.

Methods: Over a 4-year extension, alemtuzumab patients (alemtuzumab-only) received as-needed additional alemtuzumab (⩾12 months apart) for disease activity after course 2. SC IFNB-1a patients who entered the extension discontinued SC IFNB-1a and received 2 alemtuzumab 12 mg courses (IFN-alemtuzumab), followed by additional, as-needed, alemtuzumab.

Results: Through year 6, 63% of CARE-MS I and 50% of CARE-MS II alemtuzumab-only patients received neither additional alemtuzumab nor other disease-modifying therapy, with lasting suppression of disease activity, improved disability, and slowing of brain volume loss (BVL). In CARE-MS I patients (treatment-naive; less disability; shorter disease duration), disease activity and BVL were significantly reduced in IFN-alemtuzumab patients, similar to alemtuzumab-only patients at year 6. Among CARE-MS II patients (inadequate response to prior treatment; more disability; longer disease duration), alemtuzumab significantly improved clinical and magnetic resonance imaging outcomes, including BVL, in IFN-alemtuzumab patients; however, disability outcomes were less favorable alemtuzumab-only patients. Safety profiles, including infections and autoimmunities, following alemtuzumab were similar between treatment groups.

Conclusion: This study demonstrates the high efficacy of alemtuzumab over 6 years, with a similar safety profile between treatment groups.

Clinicaltrialsgov Identifiers: NCT00530348; NCT00548405; NCT00930553.
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http://dx.doi.org/10.1177/1756286420982134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072102PMC
April 2021

Corpus callosum lesions are not inextricably linked to CNS symptoms in reported cases of susac syndrome.

Mult Scler Relat Disord 2021 Jun 10;51:102883. Epub 2021 Mar 10.

Department of Neurology, University of British Columbia, Canada.

Objective: To evaluate whether corpus callosum (CC) lesions are inextricably linked to CNS symptoms of Susac Syndrome (SuS) by reviewing published cases to find instances where: 1) CC lesions occur without CNS symptoms, and 2) whether patients with CNS symptoms lack CC lesions.

Methods: 100 reported cases of SuS were identified in PubMed. Clinical symptoms, para-clinical testing and MRI data were collected both at presentation and for any available follow-up and analyzed. Cases were reviewed to evaluate how they met European diagnostic criteria for SuS (EuSaC) both at first presentation and at most recent evaluation after followup, if available.

Results: Limited disease is a common finding in the 100 recently published cases and 56/100 cases did not meet EuSaC probable or definite criteria at first evaluation. CC lesions were not inextricably linked with encephalopathy, as 8 cases presented with CC lesions without CNS symptoms and 6 cases had encephalopathy without CC lesions. In five patients with both eye and ear involvement, isolated CC lesions or CNS symptoms could enhance diagnostic certainty. This may reduce specificity, but would increase sensitivity, ultimately benefitting patient care.

Conclusion: Patients with early SuS rarely meet diagnostic criteria at presentation. Future diagnostic criteria could make use of unlinked CC lesions or CNS symptoms.
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http://dx.doi.org/10.1016/j.msard.2021.102883DOI Listing
June 2021

Cervical cord myelin abnormality is associated with clinical disability in multiple sclerosis.

Mult Scler 2021 Mar 22:13524585211001780. Epub 2021 Mar 22.

Division of Neurology, Department of Medicine, The University of British Columbia, Vancouver, BC, Canada; Department of Radiology, The University of British Columbia, Vancouver, BC, Canada/Department of Physics and Astronomy, The University of British Columbia, Vancouver, BC, Canada; International Collaboration on Repair and Discoveries, Vancouver, BC, Canada.

Background: Myelin water imaging (MWI) was recently optimized to provide quantitative in vivo measurement of spinal cord myelin, which is critically involved in multiple sclerosis (MS) disability.

Objective: To assess cervical cord myelin measurements in relapsing-remitting multiple sclerosis (RRMS) and progressive multiple sclerosis (ProgMS) participants and evaluate the correlation between myelin measures and clinical disability.

Methods: We used MWI data from 35 RRMS, 30 ProgMS, and 28 healthy control (HC) participants collected at cord level C2/C3 on a 3 T magnetic resonance imaging (MRI) scanner. Myelin heterogeneity index (MHI), a measurement of myelin variability, was calculated for whole cervical cord, global white matter, dorsal column, lateral and ventral funiculi. Correlations were assessed between MHI and Expanded Disability Status Scale (EDSS), 9-Hole Peg Test (9HPT), timed 25-foot walk, and disease duration.

Results: In various regions of the cervical cord, ProgMS MHI was higher compared to HC (between 9.5% and 31%,  ⩽ 0.04) and RRMS (between 13% and 26%,  ⩽ 0.02), and ProgMS MHI was associated with EDSS ( = 0.42-0.52) and 9HPT ( = 0.45-0.52).

Conclusion: Myelin abnormalities within clinically eloquent areas are related to clinical disability. MWI metrics have a potential role for monitoring subclinical disease progression and adjudicating treatment efficacy for new therapies targeting ProgMS.
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http://dx.doi.org/10.1177/13524585211001780DOI Listing
March 2021

Multimodal peripheral fluid biomarker analysis in clinically isolated syndrome and early multiple sclerosis.

Mult Scler Relat Disord 2021 May 3;50:102809. Epub 2021 Feb 3.

Departments of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

Background: Increasing evidence suggests that various inflammatory, immunological and metabolic pathways are altered in the clinically isolated syndrome (CIS) of multiple sclerosis (MS). Moreover, recent diagnostic criteria have made possible the very early diagnosis of MS. We evaluated multiple fluid biomarkers in people with early MS and CIS.

Methods: We measured blood levels of cytokines, matrix metalloproteinases (MMPs), serum metabolomics and immune cell immunophenotyping in participants in the Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis.

Results: When compared with healthy controls, people with early MS/CIS had higher levels of eotaxin, MCP-3, IL-1 receptor antagonist, IL-1β, IL-9 and IP-10, as well as MMPs 1, 8 and 9. In metabolomics analysis, the alanine, aspartate and glutamate metabolism and the synthesis and degradation of ketone bodies pathways were altered compared to healthy controls. There were no differences in lymphocyte subpopulation numbers. Out of all these biomarkers, only MMP-1 was able to differentiate between early MS and CIS, and was found to correlate with lesion volume and gadolinium enhancing lesions on MRI.

Conclusion: The immunological and metabolic profile of CIS and early MS is remarkably similar, supporting that these are a continuum of a common underlying pathophysiological process.
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http://dx.doi.org/10.1016/j.msard.2021.102809DOI Listing
May 2021

Myelin Oligodendrocyte Glycoprotein (MOG) Antibody Positive Patients in a Multi-Ethnic Canadian Cohort.

Front Neurol 2020 12;11:525933. Epub 2021 Jan 12.

UBC MS/NMO Clinic, University of British Columbia, Vancouver, BC, Canada.

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease is a recently described central nervous system (CNS) inflammatory disorder with phenotypic overlap with Neuromyelitis Optica Spectrum Disorder (NMOSD). NMOSD seronegative patients, and those with limited forms of the disorder, become suspects for MOG antibody-associated disease. We describe a multi-ethnic population with MOG antibody seropositivity from the University of British Columbia MS/NMO clinic. AQP4-antibody seronegative patients presenting 2005-2016 with CNS inflammatory disease suspicious for NMOSD, as well as 20 MS controls, were retrospectively tested for MOG-IgG1 antibodies by live cell-based assay at Oxford Autoimmune Neurology Diagnostic Laboratory (UK) and by a commercial fixed cell-based assay at MitogenDx (Calgary, Canada). Additional MOG seropositive cases were identified through routine clinical interaction (2016-2018) using one of these laboratories. Clinical data was reviewed retrospectively. Retrospective testing identified 21 MOG seropositives (14 by live assay only, 3 by fixed assay only and 4 by both) representing 14% of the "NMOSD suspects" cohort. One multiple sclerosis (MS) control serum was MOG seropositive. Twenty additional MOG positive cases were identified prospectively. Of 42 patients (27 female), median disease onset age was 29 years (range 3-62; 9 pediatric cases), 20 (47%) were non-Caucasian, and 3 (7%) had comorbid autoimmune disease. Most common onset phenotypes were optic neuritis (23, 55%; 8 bilateral) and myelitis (9, 21%; 6 longitudinally extensive) Three of the patients in our cohort experienced cortical encephalitis; two presented with seizures. Onset was moderate-severe in 64%, but 74% had good response to initial steroid therapy. Cumulative relapse probability for the MOG positive group at 1 year was 0.428 and at 4 years was 0.628. Most had abnormal brain imaging, including cortical encephalitis and poorly demarcated subcortical and infratentorial lesions. Few "classic MS" lesions were seen. Optic nerve lesions (frequently bilateral) were long and predominantly anterior, but 5 extended to the chiasm. Spinal cord lesions were long and short, with involvement of multiple spinal regions simultaneously, including the conus medullaris. Our MOG seropositive patients display phenotypes similar to previous descriptions, including cortical lesions with seizures and conus medullaris involvement. Many patients relapsed, predominantly in a different CNS location from onset. Serologic data from two different cell-based antibody assays highlight the discrepancies between live and fixed testing for MOG antibodies.
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http://dx.doi.org/10.3389/fneur.2020.525933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835710PMC
January 2021

Comparison of multi echo T relaxation and steady state approaches for myelin imaging in the central nervous system.

Sci Rep 2021 01 14;11(1):1369. Epub 2021 Jan 14.

Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada.

The traditional approach for measuring myelin-associated water with quantitative magnetic resonance imaging (MRI) uses multi-echo T relaxation data to calculate the myelin water fraction (MWF). A fundamentally different approach, abbreviated "mcDESPOT", uses a more efficient steady-state acquisition to generate an equivalent metric (f). Although previous studies have demonstrated inherent instability and bias in the complex mcDESPOT analysis procedure, f has often been used as a surrogate for MWF. We produced and compared multivariate atlases of MWF and f in healthy human brain and cervical spinal cord (available online) and compared their ability to detect multiple sclerosis pathology. A significant bias was found in all regions (p < 10), albeit reversed for spinal cord (f-MWF =  - 3.4%) compared to brain (+ 6.2%). MWF and f followed an approximately linear relationship for regions with MWF <  ~ 10%. For MWF >  ~ 10%, the relationship broke down and f no longer increased in tandem with MWF. For multiple sclerosis patients, MWF and f Z score maps showed overlapping areas of low Z score and similar trends between patients and brain regions, although those of f generally had greater spatial extent and magnitude of severity. These results will guide future choice of myelin-sensitive quantitative MRI and improve interpretation of studies using either myelin imaging approach.
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http://dx.doi.org/10.1038/s41598-020-80585-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809349PMC
January 2021

An atlas for human brain myelin content throughout the adult life span.

Sci Rep 2021 01 11;11(1):269. Epub 2021 Jan 11.

Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada.

Myelin water imaging is a quantitative neuroimaging technique that provides the myelin water fraction (MWF), a metric highly specific to myelin content, and the intra-/extra-cellular T (IET2), which is related to water and iron content. We coupled high-resolution data from 100 adults with gold-standard methodology to create an optimized anatomical brain template and accompanying MWF and IET2 atlases. We then used the MWF atlas to characterize how myelin content relates to demographic factors. In most brain regions, myelin content followed a quadratic pattern of increase during the third decade of life, plateau at a maximum around the fifth decade, then decrease during later decades. The ranking of mean myelin content between brain regions remained consistent across age groups. These openly available normative atlases can facilitate evaluation of myelin imaging results on an individual basis and elucidate the distribution of myelin content between brain regions and in the context of aging.
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http://dx.doi.org/10.1038/s41598-020-79540-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801525PMC
January 2021

Diagnosis of Progressive Multiple Sclerosis From the Imaging Perspective: A Review.

JAMA Neurol 2021 Mar;78(3):351-364

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, Istituto di Ricovero e di Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy.

Importance: Although magnetic resonance imaging (MRI) is useful for monitoring disease dissemination in space and over time and excluding multiple sclerosis (MS) mimics, there has been less application of MRI to progressive MS, including diagnosing primary progressive (PP) MS and identifying patients with relapsing-remitting (RR) MS who are at risk of developing secondary progressive (SP) MS. This review addresses clinical application of MRI for both diagnosis and prognosis of progressive MS.

Observations: Although nonspecific, some spinal cord imaging features (diffuse abnormalities and lesions involving gray matter [GM] and ≥2 white matter columns) are typical of PPMS. In patients with PPMS and those with relapse-onset MS, location of lesions in critical central nervous system regions (spinal cord, infratentorial regions, and GM) and MRI-detected high inflammatory activity in the first years after diagnosis are risk factors for long-term disability and future progressive disease course. These measures are evaluable in clinical practice. In patients with established MS, GM involvement and neurodegeneration are associated with accelerated clinical worsening. Subpial demyelination and slowly expanding lesions are novel indicators of progressive MS.

Conclusions And Relevance: Diagnosis of PPMS is more challenging than diagnosis of RRMS. No qualitative clinical, immunological, histopathological, or neuroimaging features differentiate PPMS and SPMS; both are characterized by imaging findings reflecting neurodegeneration and are also impacted by aging and comorbidities. Unmet diagnostic needs include identification of MRI markers capable of distinguishing PPMS from RRMS and predicting the evolution of RRMS to SPMS. Integration of multiple parameters will likely be essential to achieve these aims.
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http://dx.doi.org/10.1001/jamaneurol.2020.4689DOI Listing
March 2021

An International Standardized Magnetic Resonance Imaging Protocol for Diagnosis and Follow-up of Patients with Multiple Sclerosis: Advocacy, Dissemination, and Implementation Strategies.

Int J MS Care 2020 Sep-Oct;22(5):226-232. Epub 2020 Oct 27.

Standardized magnetic resonance imaging (MRI) protocols are important for the diagnosis and monitoring of patients with multiple sclerosis (MS). The Consortium of Multiple Sclerosis Centers (CMSC) convened an international panel of MRI experts to review and update the current guidelines. The objective was to update the standardized MRI protocol and clinical guidelines for diagnosis and follow-up of MS and develop strategies for advocacy, dissemination, and implementation. Conference attendees included neurologists, radiologists, technologists, and imaging scientists with expertise in MS. Representatives from the CMSC, Magnetic Resonance Imaging in MS (MAGNIMS), North American Imaging in Multiple Sclerosis Cooperative, US Department of Veteran Affairs, National Multiple Sclerosis Society, Multiple Sclerosis Association of America, MRI manufacturers, and commercial image analysis companies were present. Before the meeting, CMSC members were surveyed about standardized MRI protocols, gadolinium use, need for diffusion-weighted imaging, and the central vein sign. The panel worked to make the CMSC and MAGNIMS MRI protocols similar so that the updated guidelines could ultimately be accepted by international consensus. Advocacy efforts will promote the importance of standardized MS MRI protocols. Dissemination will include publications, meeting abstracts, educational programming, webinars, "meet the expert" teleconferences, and examination cards. Implementation will require comprehensive and coordinated efforts to make the protocol easy to access and use. The ultimate vision, and goal, is for the guidelines to be universally useful, usable, and used as the standard of care for patients with MS.
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http://dx.doi.org/10.7224/1537-2073.2020-094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643842PMC
October 2020

Associations Between Findings From Myelin Water Imaging and Cognitive Performance Among Individuals With Multiple Sclerosis.

JAMA Netw Open 2020 09 1;3(9):e2014220. Epub 2020 Sep 1.

Department of Medicine (Neurology), The University of British Columbia, Vancouver, British Columbia, Canada.

Importance: Cognitive impairment is a debilitating symptom of multiple sclerosis (MS) that affects up to 70% of patients. An improved understanding of the underlying pathology of MS-related cognitive impairment would provide considerable benefit to patients and clinicians.

Objective: To determine whether there is an association between myelin damage in tissue that appears completely normal on standard clinical imaging, but can be detected by myelin water imaging (MWI), with cognitive performance in MS.

Design, Setting, And Participants: In this cross-sectional study, participants with MS and controls underwent cognitive testing and magnetic resonance imaging (MRI) from August 23, 2017, to February 20, 2019. Participants were recruited through the University of British Columbia Hospital MS clinic and via online recruitment advertisements on local health authority websites. Cognitive testing was performed in the MS clinic, and MRI was performed at the adjacent academic research neuroimaging center. Seventy-three participants with clinically definite MS fulfilling the 2017 revised McDonald criteria for diagnosis and 22 age-, sex-, and education-matched healthy volunteers without neurological disease were included in the study. Data analysis was performed from March to November 2019.

Exposures: MWI was performed at 3 T with a 48-echo, 3-dimensional, gradient and spin-echo (GRASE) sequence. Cognitive testing was performed with assessments drawn from cognitive batteries validated for use in MS.

Main Outcomes And Measures: The association between myelin water measures, a measurement of the T2 relaxation signal from water in the myelin bilayers providing a specific marker for myelin, and cognitive test scores was assessed using Pearson correlation. Three white matter regions of interest-the cingulum, superior longitudinal fasciculus (SLF), and corpus callosum-were selected a priori according to their known involvement in MS-related cognitive impairment.

Results: For the 95 total participants, the mean (SD) age was 49.33 (11.44) years. The mean (SD) age was 50.2 (10.7) years for the 73 participants with MS and 46.4 (13.5) for the 22 controls. Forty-eight participants with MS (66%) and 14 controls (64%) were women. The mean (SD) years of education were 14.7 (2.2) for patients and 15.8 (2.5) years for controls. In MS, significant associations were observed between myelin water measures and scores on the Symbol Digit Modalities Test (SLF, r = -0.490; 95% CI, -0.697 to -0.284; P < .001; corpus callosum, r = -0.471; 95% CI, -0.680 to -0.262; P < .001; and cingulum, r = -0.419; 95% CI, -0.634 to -0.205; P < .001), Selective Reminding Test (SLF, r = -0.444; 95% CI, -0.660 to -0.217; P < .001; corpus callosum, r = -0.411; 95% CI, -0.630 to -0.181; P = .001; and cingulum, r = -0.361; 95% CI, -0.602 to -0.130; P = .003), and Controlled Oral Word Association Test (SLF, r = -0.317; 95% CI, -0.549 to -0.078; P = .01; and cingulum, r = -0.335; 95% CI, -0.658 to -0.113; P = .006). No significant associations were found in controls.

Conclusions And Relevance: This study used MWI to demonstrate that otherwise normal-appearing brain tissue is diffusely damaged in MS, and the findings suggest that myelin water measures are associated with cognitive performance. MWI offers an in vivo biomarker feasible for use in clinical trials investigating cognition, providing a means for monitoring changes in myelination and its association with symptom worsening or improvement.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.14220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525360PMC
September 2020

Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis: The VELOCE study.

Neurology 2020 10 29;95(14):e1999-e2008. Epub 2020 Jul 29.

From the Department of Neurology and Center for Neuroinflammation and Experimental Therapeutics (A.B.-O.), Perelman School of Medicine, University of Pennsylvania, Philadelphia; The Minneapolis Clinic of Neurology (J.C.C.), MN; F. Hoffmann-La Roche Ltd (C.C., J.E., M.M., D.S.), Basel, Switzerland; Central Texas Neurology Consultants (E.J.F.), Round Rock; Genentech, Inc (A.H.), South San Francisco, CA; John McNamara Consulting Ltd (J.M.), Cambridge, UK; Department of Neurology (D.S.R.), Multiple Sclerosis Division, University of South Florida College of Medicine, Tampa; Territory Neurology and Research Institution (J.K.W.), Tucson, AZ; Division of Infectious Diseases (K.L.W.), Oregon Health & Science University, Portland; and University of British Columbia (A.T.), Vancouver, Canada.

Objective: The phase IIIb A Study to Evaluate the Effects of Ocrelizumab on Immune Responses in Participants With Relapsing Forms of Multiple Sclerosis (VELOCE) study (NCT02545868) assessed responses to selected vaccines in ocrelizumab (OCR)-treated patients with relapsing multiple sclerosis.

Methods: Patients were randomized 2:1 into the OCR group (n = 68; OCR 600 mg) or control group (n = 34; interferon beta or no disease-modifying therapy). All received tetanus toxoid (TT)-containing vaccine, Pneumovax (23-valent pneumococcal polysaccharide vaccine [23-PPV]), and keyhole limpet hemocyanin (KLH). The OCR group was subdivided into OCR1 (n = 33) and OCR2 (n = 35) at randomization. The OCR1 group received Prevnar (13-valent conjugate pneumococcal vaccine) 4 weeks after 23-PPV; the OCR2 and control groups received influenza vaccine. Vaccinations started 12 weeks after OCR initiation (OCR group) or on day 1 (control group).

Results: Positive response rate to TT vaccine at 8 weeks was 23.9% in the OCR vs 54.5% in the control group. Positive response rate to ≥5 serotypes in 23-PPV at 4 weeks was 71.6% in the OCR and 100% in the control group. Prevnar did not enhance response to pneumococcal serotypes in common with Pneumovax. Humoral response to KLH was decreased in the OCR vs control group. Seroprotection rates at 4 weeks against 5 influenza strains ranged from 55.6% to 80.0% in the OCR2 group and 75.0% to 97.0% in the control group.

Conclusion: Peripherally B-cell-depleted OCR recipients mounted attenuated humoral responses to clinically relevant vaccines and the neoantigen KLH, suggesting that use of standard nonlive vaccines while on OCR treatment remains a consideration. For seasonal influenza vaccines, it is recommended to vaccinate patients on OCR because a potentially protective humoral response, even if attenuated, can be expected.

Classification Of Evidence: This study provides Class II evidence confirming that the humoral response to nonlive vaccines in patients with relapsing multiple sclerosis after OCR treatment is attenuated compared with untreated or interferon beta-treated patients, but they can still be expected to be protective.

Clinicaltrialsgov Identifier: NCT02545868.
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http://dx.doi.org/10.1212/WNL.0000000000010380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843152PMC
October 2020

Efficacy and Safety of Alemtuzumab Through 9 Years of Follow-up in Patients with Highly Active Disease: Post Hoc Analysis of CARE-MS I and II Patients in the TOPAZ Extension Study.

CNS Drugs 2020 09;34(9):973-988

MS Center for Innovations in Care, Missouri Baptist Medical Center, St. Louis, MO, USA.

Background: Alemtuzumab efficacy versus subcutaneous interferon-β-1a (SC IFNB-1a) was demonstrated over 2 years in patients with relapsing-remitting multiple sclerosis, with continued efficacy over 7 additional years. Alemtuzumab is included as a recommended treatment for patients with highly active disease (HAD) by the American Academy of Neurology Practice Guidelines, and the label indication in Europe was recently restricted to the treatment of HAD patients. There is currently no consensus definition for HAD, and alemtuzumab efficacy across various HAD definitions has not been explored previously.

Objectives: In this post hoc analysis, we assess the efficacy and safety of alemtuzumab in Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) trial patients who met criteria for at least one of four separate definitions of HAD (one primary and three alternatives). Over 2 years, alemtuzumab-treated HAD patients were compared with SC IFNB-1a-treated HAD patients, with additional 7-year follow-up in patients from the alemtuzumab arm.

Methods: Patients in the CARE-MS studies received either alemtuzumab (baseline: 5 days; 12 months later: 3 days) or SC IFNB-1a (3 times weekly). Alemtuzumab-treated patients who enrolled in the extensions could receive additional courses ≥ 12 months apart. Four definitions of HAD were applied to assess alemtuzumab efficacy: the pre-specified primary definition (two or more relapses in the year prior to baseline and at least one gadolinium [Gd]-enhancing lesion at baseline) and three alternative definitions that focused on relapse, magnetic resonance imaging (MRI), or prior treatment response criteria. Efficacy outcomes were annualized relapse rate, change in Expanded Disability Status Scale score, 6-month confirmed disability worsening, 6-month confirmed disability improvement, MRI disease activity, and brain volume change. Adverse events were summarized for HAD patients meeting the primary definition.

Results: In the pooled CARE-MS population, 208 alemtuzumab-treated patients met the primary HAD definition. Annualized relapse rate was 0.27 in years 0-2 and 0.16 in years 3-9. Over 9 years, 62% of patients were free of 6-month confirmed disability worsening, 50% had 6-month confirmed disability improvement, and median cumulative change in brain volume was - 2.15%. During year 9, 62% had no evidence of disease activity, and 69% were free of MRI disease activity. Similar efficacy outcomes were observed using an alternative relapse-driven HAD definition. For patients meeting alternative HAD definitions focused on either higher MRI lesion counts or disease activity while on prior therapy, reduced efficacy for some endpoints was seen. Safety was consistent with the overall CARE-MS population through year 9.

Conclusions: Over 9 years, alemtuzumab efficacy was maintained in CARE-MS HAD patients based on four HAD definitions. These results support intervention with alemtuzumab in patients with early indicators of HAD, including frequent relapse without high MRI activity. No safety signals were observed over 9 years that were unique to the HAD populations. CLINICALTRIALS.

Gov Identifiers: NCT00530348; NCT00548405; NCT00930553; NCT02255656.
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http://dx.doi.org/10.1007/s40263-020-00749-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447657PMC
September 2020

Five years of ocrelizumab in relapsing multiple sclerosis: OPERA studies open-label extension.

Neurology 2020 09 20;95(13):e1854-e1867. Epub 2020 Jul 20.

From the Department of Neurology (S.L.H.), University of California, San Francisco; Neurologic Clinic and Policlinic (L.K.), Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital Basel, University of Basel, Switzerland; NeuroRx Research (D.L.A.); Departments of Neurology and Neurosurgery (D.L.A.), McGill University, Montreal, Canada; Department of Neurology and Center for Neuroinflammation and Experimental Therapeutics (A.B.-O.), University of Pennsylvania, Philadelphia; Department of Neurology (B.B.), CHU de Bordeaux, France; Department of Neurology (R.T.N.), Washington University School of Medicine, St. Louis, MO; Division of Neurology (A.T.), Department of Medicine, University of British Columbia, Vancouver, Canada; Department of Neurology (J.S.W.), McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth); F. Hoffmann-La Roche Ltd (S.B., H.K., M.M., F.M., S.H.), Basel, Switzerland; Genentech, Inc. (V.L., L.M.), South San Francisco, CA; Division of Neurology (X.M.), University of Toronto, Canada; and Department of Neurology-Neuroimmunology (X.M.), Vall d'Hebron University Hospital, Barcelona, Spain. During completion of the work related to this article, S.B. and L.M. were employees of F. Hoffmann-La Roche Ltd; current affiliations are Biogen (S.B.), Cambridge, MA; and Alder Biopharmaceuticals Inc. (L.M.), Bothell, WA.

Objective: To assess over 3 years of follow-up the effects of maintaining or switching to ocrelizumab (OCR) therapy on clinical and MRI outcomes and safety measures in the open-label extension (OLE) phase of the pooled OPERA: I/II studies in relapsing multiple sclerosis.

Methods: After 2 years of double-blind, controlled treatment, patients continued OCR (600 mg infusions every 24 weeks) or switched from interferon (IFN)-β-1a (44 μg 3 times weekly) to OCR when entering the OLE phase (3 years). Adjusted annualized relapse rate, time to onset of 24-week confirmed disability progression (CDP)/improvement (CDP), brain MRI activity (gadolinium-enhanced and new/enlarging T2 lesions), and percentage brain volume change were analyzed.

Results: Of patients entering the OLE phase, 88.6% completed year 5. The cumulative proportion with 24-week CDP was lower in patients who initiated OCR earlier vs patients initially receiving IFN-β-1a (16.1% vs 21.3% at year 5; = 0.014). Patients continuing OCR maintained and those switching from IFN-β-1a to OCR attained near complete and sustained suppression of new brain MRI lesion activity from years 3-5. Over the OLE phase, patients continuing OCR exhibited less whole brain volume loss from double-blind study baseline vs those switching from IFN-β-1a (-1.87% vs -2.15% at year 5; < 0.01). Adverse events were consistent with past reports and no new safety signals emerged with prolonged treatment.

Conclusion: Compared with patients switching from IFN-β-1a, earlier and continuous OCR treatment up to 5 years provided sustained benefit on clinical and MRI measures of disease progression.

Classification Of Evidence: This study provides Class III evidence that earlier and continuous treatment with OCR provided sustained benefit on clinical and MRI outcomes of disease activity and progression compared with patients switching from IFN-β-1a. The study is rated Class III because of the initial treatment randomization disclosure that occurred after inclusion in OLE.

Clinical Trial Identifiers: NCT01247324/NCT01412333.
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http://dx.doi.org/10.1212/WNL.0000000000010376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682822PMC
September 2020

Short-term outcomes of pediatric multiple sclerosis patients treated with alemtuzumab at a Canadian University multiple sclerosis clinic.

Mult Scler J Exp Transl Clin 2020 Apr-Jun;6(2):2055217320926613. Epub 2020 Jul 1.

Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, Canada.

There is a lack of literature documenting the use of alemtuzumab in pediatric multiple sclerosis (MS) patients. Here we describe a 16-year-old and a 17-year-old patient receiving alemtuzumab and being followed for 37 months and 20 months, respectively. Both patients experienced a 1.0 decrease in Expanded Disability Status Scale since initial alemtuzumab infusion and had stable disease. No serious infusion reactions, infections, or definite relapses were recorded on follow-up. Alemtuzumab has been relatively well-tolerated and effective; however, larger, longer-term studies are necessary to understand the specific risks and benefits of alemtuzumab in pediatric MS.
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http://dx.doi.org/10.1177/2055217320926613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333501PMC
July 2020

Long-term efficacy and safety of alemtuzumab in patients with RRMS: 12-year follow-up of CAMMS223.

J Neurol 2020 Nov 24;267(11):3343-3353. Epub 2020 Jun 24.

University of Cambridge, Cambridge, UK.

Background: In the phase 2 CAMMS223 trial (NCT00050778), alemtuzumab significantly improved clinical and MRI outcomes versus subcutaneous interferon beta-1a over 3 years in treatment-naive patients with relapsing-remitting MS. Here, we assess efficacy and safety of alemtuzumab over 12 years in CAMMS223 patients who enrolled in the CAMMS03409 extension (NCT00930553), with available follow-up through the subsequent TOPAZ extension (NCT02255656).

Methods: In CAMMS223, patients received 2 alemtuzumab courses (12 mg/day; baseline: 5 days; 12 months later: 3 days); 22% received a third course. In the open-label, nonrandomized extensions, patients could receive as-needed additional alemtuzumab or other disease-modifying therapies.

Results: Of 108 alemtuzumab-treated patients in CAMMS223, 60 entered the CAMMS03409 extension; 33% received a total of 2 alemtuzumab courses, and 73% received no more than 3 courses through Year 12. Over 12 years, annualized relapse rate was 0.09, 71% of patients had stable or improved Expanded Disability Status Scale scores, and 69% were free of 6-month confirmed disability worsening. In Year 12, 73% of patients were free of MRI disease activity. Cumulatively throughout the extensions (Years 7-12), 34% of patients had no evidence of disease activity. Adverse event (AE) incidence declined through Year 12. Infusion-associated reactions peaked at first course and declined thereafter. Cumulative thyroid AE incidence was 50%; one immune thrombocytopenia event occurred, and there were no autoimmune nephropathy cases.

Conclusions: Alemtuzumab efficacy was maintained over 12 years in CAMMS223 patients, with 73% receiving no more than three courses. The safety profile in this cohort was consistent with other alemtuzumab clinical trials.
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http://dx.doi.org/10.1007/s00415-020-09983-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578137PMC
November 2020

Both Stationary and Dynamic Functional Interhemispheric Connectivity Are Strongly Associated With Performance on Cognitive Tests in Multiple Sclerosis.

Front Neurol 2020 4;11:407. Epub 2020 Jun 4.

Graduate Program in Neuroscience, University of British Columbia, Vancouver, BC, Canada.

Although functional connectivity has been extensively studied in MS, robust estimates of both stationary (static connectivity at the time) and dynamic (connectivity variation across time) functional connectivity has not been commonly evaluated and neither has its association to cognition. In this study, we focused on interhemispheric connections as previous research has shown links between anatomical homologous connections and cognition. We examined functional interhemispheric connectivity (IC) in MS during resting-state functional MRI using both stationary and dynamic strategies and related connectivity measures to processing speed performance. Twenty-five patients with relapsing-remitting MS and 41 controls were recruited. Stationary functional IC was assessed between homologous Regions of Interest (ROIs) using correlation. For dynamic IC, a sliding window approach was used to quantify changes between homologous ROIs across time. We related IC measures to cognitive performance with correlation and regression. Compared to control subjects, MS demonstrated increased IC across homologous regions, which accurately predicted performance on the symbol digit modalities test (SDMT) ( = 0.96) and paced auditory serial addition test (PASAT) ( = 0.59). Dynamic measures were not different between the 2 groups, but dynamic IC was related to PASAT scores. The associations between stationary/dynamic connectivity and cognitive tests demonstrated that different aspects of functional IC were associated with cognitive processes. Processing speed measured in SDMT was associated with static interhemispheric connections and better PASAT performance, which requires working memory, sustain attention, and processing speed, was more related to rigid IC, underlining the neurophysiological mechanism of cognition in MS.
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http://dx.doi.org/10.3389/fneur.2020.00407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287147PMC
June 2020

Repopulation of T, B, and NK cells following alemtuzumab treatment in relapsing-remitting multiple sclerosis.

J Neuroinflammation 2020 Jun 15;17(1):189. Epub 2020 Jun 15.

Department of Neurology, University of British Columbia, Vancouver, CA, USA.

Objective: To characterize long-term repopulation of peripheral immune cells following alemtuzumab-induced lymphopenia in relapsing-remitting MS (RRMS), with a focus on regulatory cell types, and to explore associations with clinical outcome measures.

Methods: The project was designed as a multicenter add-on longitudinal mechanistic study for RRMS patients enrolled in CARE-MS II, CARE-MS II extension at the University of Southern California and Stanford University, and an investigator-initiated study conducted at the Universities of British Columbia and Chicago. Methods involved collection of blood at baseline, prior to alemtuzumab administration, and at months 5, 11, 17, 23, 36, and 48 post-treatment. T cell, B cell, and natural killer (NK) cell subsets, chemokine receptor expression in T cells, in vitro cytokine secretion patterns, and regulatory T cell (Treg) function were assessed. Clinical outcomes, including expanded disability status score (EDSS), relapses, conventional magnetic resonance imaging (MRI) measures, and incidents of secondary autoimmunity were tracked.

Results: Variable shifts in lymphocyte populations occurred over time in favor of CD4+ T cells, B cells, and NK cells with surface phenotypes characteristic of regulatory subsets, accompanied by reduced ratios of effector to regulatory cell types. Evidence of increased Treg competence was observed after each treatment course. CD4+ and CD8+ T cells that express CXCR3 and CCR5 and CD8+ T cells that express CDR3 and CCR4 were also enriched after treatment, indicating heightened trafficking potential in activated T cells. Patterns of repopulation were not associated with measures of clinical efficacy or secondary autoimmunity, but exploratory analyses using a random generalized estimating equation (GEE) Poisson model provide preliminary evidence of associations between pro-inflammatory cell types and increased risk for gadolinium (Gd+) enhancing lesions, while regulatory subsets were associated with reduced risk. In addition, the risk for T2 lesions correlated with increases in CD3+CD8+CXCR3+ cells.

Conclusions: Lymphocyte repopulation after alemtuzumab treatment favors regulatory subsets in the T cell, B cell, and NK cell compartments. Clinical efficacy may reflect the sum of interactions among them, leading to control of potentially pathogenic effector cell types. Several immune measures were identified as possible biomarkers of lesion activity. Future studies are necessary to more precisely define regulatory and effector subsets and their contributions to clinical efficacy and risk for secondary autoimmunity in alemtuzumab-treated patients, and to reveal new insights into mechanisms of immunopathogenesis in MS.

Trial Registration: Parent trials for this study are registered with ClinicalTrials.gov: CARE-MS II: NCT00548405, CARE-MS II extension: NCT00930553 and ISS: NCT01307332.
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http://dx.doi.org/10.1186/s12974-020-01847-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296935PMC
June 2020

Genetic analysis of nucleotide-binding leucine-rich repeat (NLR) receptors in multiple sclerosis.

Immunogenetics 2020 09 11;72(6-7):381-385. Epub 2020 Jun 11.

Department of Medical Genetics, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada.

Genetic and functional analyses of the inflammasome suggest a role for this multiprotein complex in the biological mechanisms leading to the onset and progression of multiple sclerosis (MS). Nucleotide-binding, leucine-rich repeat (NLR) receptors trigger the activation and assembly of specific inflammasomes in response to danger signals. Mining exome sequencing data from 326 MS patients identified 17 rare missense or nonsense variants in NLR family pyrin domain containing 1 (NLRP1), NLRP3, NLRP6, NLRP7 and NLR family CARD domain containing 4 (NLRC4). Genotyping these variants in 2503 MS cases and 1076 healthy controls did not result in statistically significant differences between groups, and segregation analysis within MS families was largely unsupportive of co-segregation of these variants with disease. However, the identification of MS patients harboring rare homozygote variants in NLRP1 (p.Ile601Phe and p.Ser1387Ile), a variant in NLRP3 (p.Leu832Ile) resulting in the substitution of a critical amino acid for the formation of its leucine-rich repeat domain, and several MS patients with NLRC4 variants (p.Arg310Ter and p.Glu600Ter) causing protein truncations suggest that rare protein-altering variants in inflammasome-activating NLR receptors may contribute to MS risk.
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http://dx.doi.org/10.1007/s00251-020-01170-wDOI Listing
September 2020

Safety and efficacy of satralizumab monotherapy in neuromyelitis optica spectrum disorder: a randomised, double-blind, multicentre, placebo-controlled phase 3 trial.

Lancet Neurol 2020 05;19(5):402-412

Department of Neurology, Mayo Clinic, Rochester, MN, USA.

Background: Satralizumab, a humanised monoclonal antibody targeting the interleukin-6 receptor, reduced the risk of relapse in patients with neuromyelitis optica spectrum disorder (NMOSD) when added to immunosuppressant therapy. This study assessed the safety and efficacy of satralizumab monotherapy in patients with the disorder.

Methods: In this phase 3, double-blind, placebo-controlled, parallel-group trial, we enrolled adults aged 18-74 years with aquaporin-4 antibody seropositive or seronegative NMOSD at 44 investigational sites in 13 countries. Eligible participants had experienced at least one documented NMOSD attack or relapse in the past 12 months and had a score of 6·5 or less on the Expanded Disability Status Scale. Exclusion criteria included clinical relapse 30 days or fewer before baseline. Participants were randomly assigned (2:1) to receive satralizumab 120 mg or visually matched placebo subcutaneously at weeks 0, 2, 4, and every 4 weeks thereafter. Taking immunosuppressants concomitantly was prohibited. The primary endpoint was time to the first protocol-defined relapse, based on the intention-to-treat population and analysed with stratification for two randomisation factors (previous therapy for prevention of attacks and nature of the most recent attack). Safety was assessed in all participants who received at least one dose of satralizumab or placebo. The double-blind phase was due to last until 44 protocol-defined relapses occurred or 1·5 years after random assignment of the last patient enrolled, whichever occurred first; participants could enter an open-label phase after the occurrence of a protocol-defined relapse or at the end of the double-blind phase. The study is registered with ClinicalTrials.gov, NCT02073279.

Findings: 95 (57%) of 168 screened participants were randomly assigned to treatment (63 to satralizumab; 32 to placebo) between Aug 5, 2014, and April 2, 2017. Protocol-defined relapses occurred in 19 (30%) patients receiving satralizumab and 16 (50%) receiving placebo (hazard ratio 0·45, 95% CI 0·23-0·89; p=0·018). 473·9 adverse events per 100 patient-years occurred in the satralizumab group, as did 495·2 per 100 patient-years in the placebo group; the incidence of serious adverse events and adverse events leading to withdrawal was similar between groups.

Interpretation: Satralizumab monotherapy reduced the rate of NMOSD relapse compared with placebo in the overall trial population, with a favourable safety profile. The patient population included a ratio of aquaporin-4 antibody seropositive and seronegative patients that was reflective of clinical practice. Satralizumab has the potential to become a valuable treatment option for patients with NMOSD.

Funding: Chugai Pharmaceutical (Roche).
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http://dx.doi.org/10.1016/S1474-4422(20)30078-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935419PMC
May 2020

Long-Term Stability of Neuroaxonal Structure in Alemtuzumab-Treated Relapsing-Remitting Multiple Sclerosis Patients.

J Neuroophthalmol 2020 03;40(1):37-43

Department of Medicine (Neurology) (JKC, VD, A-LS, RC, AT), University of British Columbia, Vancouver, Canada; Department of Neurology (EHMdL, SA-A), Center of Neuroimmunology, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; Department of Statistics (CT), University of British Columbia, Vancouver, Canada; Department of Neruology (A-LN), University of Melbourne, Melbourne, Australia; Royal Melbourne Hospital (A-LN), Melbourne, Australia; and Departments of Clinical Neurosciences and Surgery (Ophthalmology) (FC), University of Calgary, Clinician Scientist with the Hotchkiss Brain Institute (HBI), Calgary, Canada.

Background: Patients with multiple sclerosis (MS) experience progressive thinning in optical coherence tomography (OCT) measures of neuroaxonal structure regardless of optic neuritis history. Few prospective studies have investigated the effects of disease-modifying therapies on neuroaxonal degeneration in the retina. Alemtuzumab is a monoclonal antibody shown to be superior to interferon β-1a in treating relapsing-remitting MS (RRMS). The purpose of this study was to assess the effects of alemtuzumab and first-line injectable treatments on OCT measures of neuroaxonal structure including peripapillary retinal nerve fiber layer (RNFL) thickness and combined ganglion cell-inner plexiform (GCIP) layer volume in RRMS patients followed up over 5 years.

Methods: In this retrospective pilot study with prospectively collected double cohort data, spectral domain OCT measures of RNFL thickness and GCIP volume were compared between alemtuzumab-treated RRMS patients (N = 24) and RRMS patients treated with either interferon-β or glatiramer acetate (N = 21).

Results: Over a median of 60 months (range 42-60 months), the alemtuzumab cohort demonstrated a change in the mean RNFL thickness (thinning from baseline) of -0.88 μm (95% confidence interval [CI] -2.63 to 0.86; P = 0.32) and mean GCIP volume of +0.013 mm (95% CI -0.006 to 0.032; P = 0.18). Over the same time period, the first-line therapy-treated cohort demonstrated greater degrees of RNFL thinning (mean change in RNFL thickness was -3.65 μm [95% CI -5.40 to -1.89; P = 0.0001]). There was also more prominent GCIP volume loss relative to baseline in the first-line therapy group (-0.052 mm [95% CI -0.070 to -0.034; P < 0.0001]).

Conclusions: Alemtuzumab-treated patients with RRMS demonstrated relative stability of OCT-measured neuroaxonal structure compared with RRMS patients treated with either interferon-β or glatiramer acetate over a 5-year period. These findings, along with previous demonstration of improved brain atrophy rates, suggest that alemtuzumab may offer long-term preservation of neuroaxonal structure in patients with RRMS.
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http://dx.doi.org/10.1097/WNO.0000000000000802DOI Listing
March 2020

Myelin water imaging data analysis in less than one minute.

Neuroimage 2020 04 21;210:116551. Epub 2020 Jan 21.

Physics & Astronomy, University of British Columbia, Canada; International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Canada; Radiology, University of British Columbia, Canada; Pathology & Laboratory Medicine, University of British Columbia, Canada. Electronic address:

Purpose: Based on a deep learning neural network (NN) algorithm, a super fast and easy to implement data analysis method was proposed for myelin water imaging (MWI) to calculate the myelin water fraction (MWF).

Methods: A NN was constructed and trained on MWI data acquired by a 32-echo 3D gradient and spin echo (GRASE) sequence. Ground truth labels were created by regularized non-negative least squares (NNLS) with stimulated echo corrections. Voxel-wise GRASE data from 5 brains (4 healthy, 1 multiple sclerosis (MS)) were used for NN training. The trained NN was tested on 2 healthy brains, 1 MS brain with segmented lesions, 1 healthy spinal cord, and 1 healthy brain acquired from a different scanner.

Results: Production of whole brain MWF maps in approximately 33 ​s can be achieved by a trained NN without graphics card acceleration. For all testing regions, no visual differences between NN and NNLS MWF maps were observed, and no obvious regional biases were found. Quantitatively, all voxels exhibited excellent agreement between NN and NNLS (all R>0.98, p ​< ​0.001, mean absolute error <0.01).

Conclusion: The time for accurate MWF calculation can be dramatically reduced to less than 1 ​min by the proposed NN, addressing one of the barriers facing future clinical feasibility of MWI.
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http://dx.doi.org/10.1016/j.neuroimage.2020.116551DOI Listing
April 2020

Efficacy of alemtuzumab in relapsing-remitting MS patients who received additional courses after the initial two courses: Pooled analysis of the CARE-MS, extension, and TOPAZ studies.

Mult Scler 2020 12 25;26(14):1866-1876. Epub 2019 Nov 25.

Division of Neurology, Department of Medicine, The University of British Columbia, Vancouver, BC, Canada.

Background: Alemtuzumab is given as two annual courses. Patients with continued disease activity may receive as-needed additional courses.

Objective: To evaluate efficacy and safety of additional alemtuzumab courses in the CARE-MS (Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis) studies and their extensions.

Methods: Subgroups were based on the number of additional alemtuzumab courses received. Exclusion criteria: other disease-modifying therapy (DMT); <12-month follow-up after last alemtuzumab course.

Results: In the additional-courses groups, Courses 3 and 4 reduced annualized relapse rate (12 months before: 0.73 and 0.74, respectively; 12 months after: 0.07 and 0.08). For 36 months after Courses 3 and 4, 89% and 92% of patients were free of 6-month confirmed disability worsening, respectively, with 20% and 26% achieving 6-month confirmed disability improvement. Freedom from magnetic resonance imaging (MRI) disease activity increased after Courses 3 and 4 (12 months before: 43% and 53%, respectively; 12 months after: 73% and 74%). Safety was similar across groups; serious events occurred irrespective of the number of courses.

Conclusion: Additional alemtuzumab courses significantly improved outcomes, without increased safety risks, in CARE-MS patients with continued disease activity after Course 2. How this compares to outcomes if treatment is switched to another DMT instead remains unknown.
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http://dx.doi.org/10.1177/1352458519888610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720359PMC
December 2020

Myelin Damage in Normal Appearing White Matter Contributes to Impaired Cognitive Processing Speed in Multiple Sclerosis.

J Neuroimaging 2020 03 24;30(2):205-211. Epub 2019 Nov 24.

Department of Medicine (Neurology), Radiology, Physics & Astronomy, University of British Columbia, Vancouver, British Columbia, Canada.

Background And Purpose: Cognitive impairment is a core symptom in multiple sclerosis (MS). Damage to normal appearing white matter (NAWM) is likely involved. We sought to determine if greater myelin heterogeneity in NAWM is associated with decreased cognitive performance in MS.

Methods: A total of 27 participants with MS and 13 controls matched for age, sex, and education underwent myelin water imaging (MWI) from which the myelin water fraction (MWF) was calculated. Corpus callosum, superior longitudinal fasciculus, and cingulum were chosen as regions of interest (ROIs) a priori based on their involvement in MS-related cognitive impairment. Cognitive performance was assessed using the Symbol Digit Modalities Test (SDMT). Pearson ́s product moment correlations were performed to assess relationships between cognitive performance and myelin heterogeneity (variance of MWF within an ROI).

Results: In MS, myelin heterogeneity in all three ROIs was significantly associated with performance on the SDMT. These correlations ranged from moderate (r = -.561) to moderately strong (r = -.654) and were highly significant (P values ranged from .001 to .0002). Conversely, myelin heterogeneity was not associated with SDMT performance in controls in any ROI (P > .108).

Conclusion: Increased myelin heterogeneity in NAWM is associated with decreased cognitive processing speed performance in MS.
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http://dx.doi.org/10.1111/jon.12679DOI Listing
March 2020
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