Mark S Freedman

Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

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Publications (202)1357.18 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Multiple sclerosis (MS) is a CNS disorder characterized by inflammation, demyelination and neurodegeneration, and is the most common cause of acquired nontraumatic neurological disability in young adults. The course of the disease varies between individuals: some patients accumulate minimal disability over their lives, whereas others experience a rapidly disabling disease course. This latter subset of patients, whose MS is marked by the rampant progression of disability over a short time period, is often referred to as having 'aggressive' MS. Treatment of patients with aggressive MS is challenging, and optimal strategies have yet to be defined. It is important to identify patients who are at risk of aggressive MS as early as possible and implement an effective treatment strategy. Early intervention might protect patients from irreversible damage and disability, and prevent the development of a secondary progressive course, which thus far lacks effective therapy.
    Nature Reviews Neurology 06/2015; DOI:10.1038/nrneurol.2015.85 · 14.10 Impact Factor
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    ABSTRACT: Few biomarkers of progressive multiple sclerosis (MS) are sensitive to change within the two-year time frame of a clinical trial. To identify biomarkers of MS disease progression with magnetic resonance spectroscopy (MRS) in secondary progressive MS (SPMS). Forty-seven SPMS subjects were scanned at baseline and annually for two years. Concentrations of N-acetylaspartate, total creatine, total choline, myo-inositol, glutamate, glutamine, and the sum glutamate+glutamine were measured in a single white matter voxel. Glutamate and glutamine were the only metabolites to show an effect with time: with annual declines of (95% confidence interval): glutamate -4.2% (-6.2% to -2.2%, p < 10(-4)), glutamine -7.3% (-11.8% to -2.9%, p = 0.003), and glutamate+glutamine -5.2% (-7.6% to -2.8%, p < 10(-4)). Metabolite rates of change were more apparent than changes in clinical scores or brain atrophy measures. The high rates of change of both glutamate and glutamine over two years suggest they are promising new biomarkers of MS disease progression. © The Author(s), 2015.
    Multiple Sclerosis 05/2015; DOI:10.1177/1352458515586086 · 4.86 Impact Factor
  • Moeber Mahzari, Amel Arnaout, Mark S Freedman
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    ABSTRACT: Alemtuzumab, an anti-CD52 monoclonal antibody, was recently approved for treatment of MS in Canada, having shown to significantly reduce relapses and disability in patients, particularly those who relapsed despite first line treatment. Offsetting its benefit however, is the development of novel secondary autoimmune disease, particularly affecting the thyroid gland in up to 36% of patients. The incidence of Alemtuzumab induced thyroid dysfunction (AITD) will likely rise as alemtuzumab becomes more widely used for treating MS. We review the clinical and investigational cues that help delineate the aetiology and management of thyrotoxicosis and hypothyroidism in ATID. AITD can be easily managed and we present a simple approach for its evaluation and management by neurologists that should be implemented prior to considering a referral to an internist or endocrinologist for further opinion or treatment.
    The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 05/2015; DOI:10.1017/cjn.2015.48 · 1.60 Impact Factor
  • Value in Health 05/2015; 18(3):A279-A280. DOI:10.1016/j.jval.2015.03.1633 · 2.89 Impact Factor
  • Value in Health 05/2015; 18(3):A279. DOI:10.1016/j.jval.2015.03.1631 · 2.89 Impact Factor
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    ABSTRACT: A definitive diagnosis of multiple sclerosis (MS), as distinct from a clinically isolated syndrome, requires one of two conditions: a second clinical attack or particular magnetic resonance imaging (MRI) findings as defined by the McDonald criteria. MRI is also important after a diagnosis is made as a means of monitoring subclinical disease activity. While a standardized protocol for diagnostic and follow-up MRI has been developed by the Consortium of Multiple Sclerosis Centres, acceptance and implementation in Canada have been suboptimal. To improve diagnosis, monitoring, and management of a clinically isolated syndrome and MS, a Canadian expert panel created consensus recommendations about the appropriate application of the 2010 McDonald criteria in routine practice, strategies to improve adherence to the standardized Consortium of Multiple Sclerosis Centres MRI protocol, and methods for ensuring effective communication among health care practitioners, in particular referring physicians, neurologists, and radiologists. This article presents eight consensus statements developed by the expert panel, along with the rationale underlying the recommendations and commentaries on how to prioritize resource use within the Canadian healthcare system. The expert panel calls on neurologists and radiologists in Canada to incorporate the McDonald criteria, the Consortium of Multiple Sclerosis Centres MRI protocol, and other guidance given in this consensus presentation into their practices. By improving communication and general awareness of best practices for MRI use in MS diagnosis and monitoring, we can improve patient care across Canada by providing timely diagnosis, informed management decisions, and better continuity of care.
    The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 04/2015; DOI:10.1017/cjn.2015.24 · 1.60 Impact Factor
  • Mark S Freedman, Mohammad Abdoli
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    ABSTRACT: Despite the broadening range of available treatments, the response of multiple sclerosis patients to disease-modifying therapies remains quite heterogeneous, thus a scheme is required in order to flag individuals achieving a suboptimal treatment response, so that they may switch to a different, possibly more effective disease-modifying therapy. There are several treatment outcomes that can be defined as surrogate markers for continued treatment efficacy and can be used for optimizing disease-modifying therapy. As no single marker is validated, we must make use of all available potential surrogates to help predict the future course of the disease. Only by putting all of the outcome measures together can a true picture be derived that will indicate an optimal response to treatment.
    Expert Review of Neurotherapeutics 03/2015; 15(4):1-17. DOI:10.1586/14737175.2015.1023711 · 2.83 Impact Factor
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    ABSTRACT: Background: Anti-John Cunningham (JCV) antibodies have been detected in approximately 50% to 60% of multiple sclerosis (MS) patients. Age, sex, and geographic location have been associated with seroprevalence differences. We describe anti-JCV antibody prevalence in the Canadian cohort of patients enrolled in the JCV Epidemiology in MS study. Methods: This cross-sectional multicenter study evaluated the effects of demographic and disease characteristics on anti-JCV antibody seroprevalence in MS patients irrespective of disease type and treatment. A single blood sample was collected for analysis of anti-JCV antibodies using a two-step enzyme-linked immunosorbent assay (ELISA). Chi-square and logistic regression tests were used to determine significance. Results: A total of 4198 Canadian MS patients participated in the study; the overall anti-JCV antibody prevalence was 56.3% (95% confidence interval: 54.8% to 57.8%). Seroprevalence was significantly associated with age (increasing from 45% in young to 61% in those >60 years), sex, and region (p<0.0001 for age and sex; p=0.005 for region). No significant differences in anti-JCV antibody prevalence were associated with race, MS disease type and duration, or number and duration of treatments. Immunosuppressant use was associated with a higher seroprevalence rate (63.4%) compared with no immunosuppressant use (55.9%; p=0.040). Conclusions: Canadian MS patients had an overall anti-JCV antibody seroprevalence that was consistent with previous studies using the two-step ELISA. Significant associations of anti-JCV antibody positivity were found with age, sex, region, and immunosuppressant therapy, whereas seroprevalence was not associated with race, MS type, MS duration, or number or duration of MS treatments.
    The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 11/2014; DOI:10.1017/cjn.2014.32 · 1.60 Impact Factor
  • Mark S Freedman
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    ABSTRACT: The BEtaferon®/BEtaseron® in Newly Emerging MS For Initial Treatment (BENEFIT) trial assessed the efficacy of early versus delayed treatment with interferon beta-1b for patients with clinically isolated syndrome (CIS). Patients were randomly assigned to receive either interferon beta-1b 250 μg every other day (early treatment, n = 292) or placebo (delayed treatment, n = 176) for 2 years or until progression to clinically definite multiple sclerosis. Clinical and magnetic resonance imaging (MRI) outcomes were assessed after 2 years (at the end of the placebo-controlled phase) and then again at 3, 5, and 8 years post randomization. MRI assessments were made after 2, 3, and 5 years. The results showed a consistent advantage of early treatment across most clinical and MRI variables, although median Expanded Disability Status Scale scores remained consistently low, with no differences between groups. These findings suggest that early treatment with interferon beta-1b improves long-term outcomes for patients presenting with CIS.
    Therapeutic Advances in Neurological Disorders 11/2014; 7(6):279-88. DOI:10.1177/1756285614549554
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    ABSTRACT: Background Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing-remitting multiple sclerosis. We aimed to assess the efficacy and safety of teriflunomide in patients with a first clinical episode suggestive of multiple sclerosis. Methods In this randomised, double-blind, placebo-controlled, parallel-group study, we enrolled patients aged 18–55 years with clinically isolated syndrome (defined as a neurological event consistent with demyelination, starting within 90 days of randomisation, and two or more T2-weighted MRI lesions ≥3 mm in diameter) from 112 centres (mostly hospitals) in 20 countries. Participants were randomly assigned (1:1:1) in a double-blind manner (by an interactive voice response system) to once-daily oral teriflunomide 14 mg, teriflunomide 7 mg, or placebo, for up to 108 weeks. Patients, staff administering the interventions, and outcome assessors were masked to treatment assignment. The primary endpoint was time to relapse (a new neurological abnormality separated by ≥30 days from a preceding clinical event, present for ≥24 h in the absence of fever or known infection), which defined conversion to clinically definite multiple sclerosis. The key secondary endpoint was time to relapse or new gadolinium-enhancing or T2 lesions on MRI, whichever occurred first. The primary outcome was analysed for the modified intention-to-treat population; safety analyses included all randomised patients who were exposed to the study drug, as treated. This trial is registered with, number NCT00622700. Findings Between Feb 13, 2008, and Aug 22, 2012, 618 patients were enrolled and randomly assigned to teriflunomide 14 mg (n=216), teriflunomide 7 mg (n=205), or placebo (n=197). Two patients in each of the teriflunomide groups did not receive the study drug, so the modified intention-to-treat population comprised 214 patients in the teriflunomide 14 mg group, 203 in the teriflunomide 7 mg group, and 197 in the placebo group. Compared with placebo, teriflunomide significantly reduced the risk of relapse defining clinically definite multiple sclerosis at the 14 mg dose (hazard ratio [HR] 0·574 [95% CI 0·379–0·869]; p=0·0087) and at the 7 mg dose (0·628 [0·416–0·949]; p=0·0271). Teriflunomide reduced the risk of relapse or a new MRI lesion compared with placebo at the 14 mg dose (HR 0·651 [95% CI 0·515–0·822]; p=0·0003) and at the 7 mg dose (0·686 [0·540–0·871]; p=0·0020). During the study, six patients who were randomly assigned to placebo accidently also received teriflunomide at some point: four received 7 mg and two received 14 mg. Therefore, the safety population comprised 216 patients on teriflunomide 14 mg, 207 on teriflunomide 7 mg, and 191 on placebo. Adverse events that occurred in at least 10% of patients in either teriflunomide group and with an incidence that was at least 2% higher than that with placebo were increased alanine aminotransferase (40 [19%] of 216 patients in the 14 mg group, 36 [17%] of 207 in the 7 mg group vs 27 [14%] of 191 in the placebo group), hair thinning (25 [12%] and 12 [6%] vs 15 [8%]), diarrhoea (23 [11%] and 28 [14%] vs 12 [6%]), paraesthesia (22 [10%] and 11 [5%] vs 10 [5%]), and upper respiratory tract infection (20 [9%] and 23 [11%] vs 14 [7%]). The most common serious adverse event was an increase in alanine aminotransferase (four [2%] and five [2%] vs three [2%]). Interpretation TOPIC is to our knowledge the first study to report benefits of an available oral disease-modifying therapy in patients with early multiple sclerosis. These results extend the stages of multiple sclerosis in which teriflunomide shows a beneficial effect. Funding Genzyme, a Sanofi company.
    The Lancet Neurology 10/2014; 13(10). DOI:10.1016/S1474-4422(14)70191-7 · 21.82 Impact Factor
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    ABSTRACT: Background In pivotal phase 3 studies, fingolimod treatment initiation was associated with a transient reduction in heart rate (HR). Atrioventricular (AV) conduction delays, which were typically asymptomatic, were detected in a small minority of patients. Objective We report the first-dose effects of fingolimod in patients who switched from injectable therapies during the Evaluate Patient OutComes (EPOC) study ( Identifier: NCT01216072). Methods This was a phase 4, 6-month, randomized, active-comparator, open-label, multicenter study. It included over 900 fingolimod-treated patients with relapsing multiple sclerosis, with subgroups of individuals who were receiving common concomitant HR-lowering medications or had pre-existing cardiac conditions (PCCs). Vital signs were recorded hourly for 6 hours post-dose. A 12-lead electrocardiogram was obtained at baseline and at 6 hours post-dose. Results A transient decrease in mean HR and blood pressure occurred within 6 hours of the first fingolimod dose. The incidence of symptomatic bradycardia was low (1%); eight patients reported dizziness and there was one case each of fatigue, palpitations, dyspnea, cardiac discomfort, and gait disturbance. These symptomatic events were typically mild or moderate in severity and all resolved spontaneously, without intervention or fingolimod discontinuation. Conclusion First-dose effects in patients with PCCs and in those receiving concomitant HR-lowering medications were consistent with effects observed in the overall study population and with results from previous clinical trials. The EPOC study provides additional data demonstrating the transient and generally benign nature of fingolimod first-dose effects on HR and AV conduction in a large population that is more representative of patients encountered in routine clinical practice than in the pivotal trials.
    09/2014; 3(5). DOI:10.1016/j.msard.2014.06.006
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    ABSTRACT: Objective Some previous studies suggest modest to strong effects of 25-hydroxyvitamin D (25(OH)D) on multiple sclerosis (MS) activity. The objective of this study was to explore the mechanistic rationale that may explain potential clinical effects of 25(OH)D.Methods This study measured serum 25(OH)D levels and global gene expression profiles over a course of up to 2 years in patients starting treatment with interferon beta-1b (IFNB-1b) after a clinically isolated syndrome. MS disease activity was assessed by the number of gadolinium-enhancing lesions present on repeated magnetic resonance imaging (MRIs).ResultsThe number of gadolinium-enhancing lesions was highly significantly associated with 25(OH)D levels. Conducting various systems-level analyses on the molecular level, multiple lines of evidence indicated that 25(OH)D regulates expression dynamics of a large gene–gene interaction system which primarily regulates immune modulatory processes modulating MS activity. The vitamin D response element was significantly enriched in this system, indicating a direct regulation of this gene interaction network through the vitamin D receptor. With increasing 25(OH)D levels, resulting regulation of this system was associated with a decrease in MS activity. Within the complex network of genes that are regulated by 25(OH)D, well-described targets of IFNB-1b and a regulator of sphingosine-1-phosphate bioavailability were found. The 25(OH)D effects on MS activity were additively enhanced by IFNB-1b.InterpretationHere, we provide mechanistic evidence that an unbalanced 25(OH)D gene expression system may affect MS activity. Our findings support a potential benefit of monitoring and managing vitamin D levels (e.g., through supplementation) in early MS patients treated with IFN-beta-1b.
    08/2014; 1(8). DOI:10.1002/acn3.91
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    ABSTRACT: Infusion of PDA-001, a preparation of mesenchymal-like cells derived from full-term human placenta, is a new approach in the treatment of patients with multiple sclerosis. This safety study aimed to rule out the possibility of paradoxical exacerbation of disease activity by PDA-001 in patients with multiple sclerosis. This was a phase 1b, multicenter, randomized, double-blind, placebo-controlled, 2-dose ranging study including patients with relapsing-remitting multiple sclerosis or secondary progressive multiple sclerosis. The study was conducted at 6 sites in the United States and 2 sites in Canada. Patients were randomized 3:1 to receive 2 low-dose infusions of PDA-001 (150×10(6) cells) or placebo, given 1 week apart. After completing this cohort, subsequent patients received high-dose PDA-001 (600×10(6) cells) or placebo. Monthly brain magnetic resonance imaging scans were performed. The primary end point was ruling out the possibility of paradoxical worsening of MS disease activity. This was monitored using Cutter׳s rule (≥5 new gadolinium lesions on 2 consecutive scans) by brain magnetic resonance imaging on a monthly basis for six months and also the frequency of multiple sclerosis relapse. Ten patients with relapsing-remitting multiple sclerosis and 6 with secondary progressive multiple sclerosis were randomly assigned to treatment: 6 to low-dose PDA-001, 6 to high-dose PDA-001, and 4 to placebo. No patient met Cutter׳s rule. One patient receiving high-dose PDA-001 had an increase in T2 and gadolinium lesions and in Expanded Disability Status Scale score during a multiple sclerosis flare 5 months after receiving PDA-001. No other patient had an increase in Expanded Disability Status Scale score >0.5, and most had stable or decreasing Expanded Disability Status Scale scores. With high-dose PDA-001, 1 patient experienced a grade 1 anaphylactoid reaction and 1 had grade 2 superficial thrombophlebitis. Other adverse events were mild to moderate and included headache, fatigue, infusion site reactions, and urinary tract infection. PDA-001 infusions were safe and well tolerated in relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis patients. No paradoxical worsening of lesion counts was noted with either dose. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.
    08/2014; 3(6). DOI:10.1016/j.msard.2014.08.002
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    ABSTRACT: Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing–remitting multiple sclerosis. This post hoc analysis of the Phase III TOWER study evaluated the effects of teriflunomide treatment on five severe relapse outcomes: relapses with sequelae defined by an increase in Expanded Disability Status Scale (EDSS)/functional system (FS) score (sequelae-EDSS/FS) 30 days post relapse; relapses with sequelae defined by the investigator (sequelae-investigator); relapses leading to hospitalization; relapses treated with intravenous corticosteroids; and intense relapses using the definition of Panitch et al. from the EVIDENCE study based on specified increases in EDSS for severe relapses. Adjusted annualized rates for the five severe relapse outcomes were derived using a Poisson model with robust error variance, with treatment, baseline EDSS strata and region as covariates. Compared with placebo, teriflunomide significantly reduced annualized rates of relapses with sequelae-EDSS/FS [14 mg, 36.6 % (p = 0.0021); 7 mg, 31.3 % (p = 0.0104)] and sequelae-investigator [14 mg only, 53.5 % (p = 0.0004)], relapses leading to hospitalization [14 mg only, 33.6 % (p = 0.0155)], relapses requiring intravenous corticosteroids [14 mg, 35.7 % (p = 0.0002); 7 mg, 21.5 % (p = 0.0337)], and intense relapses [14 mg only, 52.5 % (p = 0.0015)]. Patients treated with teriflunomide 14 mg spent significantly fewer nights in hospital for relapse (p = 0.009) and had lower annualized rates of all hospitalizations (p = 0.030). Taken together, the positive effects of teriflunomide on severe relapses indicate that teriflunomide may reduce relapse-related healthcare costs. Electronic supplementary material The online version of this article (doi:10.1007/s00415-014-7395-7) contains supplementary material, which is available to authorized users.
    Journal of Neurology 06/2014; 261(9). DOI:10.1007/s00415-014-7395-7 · 3.84 Impact Factor
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    Mark S Freedman
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    ABSTRACT: Introduction Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. Evidence suggests that MS should be treated as early as possible in order to maximize the benefit of treatment. Areas covered This review details current understanding about the treatment of relapsing–remitting MS (RRMS). The pharmacological and clinical data on the use of subcutaneous (s.c.) interferon β-1a (IFN-β-1a) as a therapeutic option for RRMS are covered, with a focus on the importance of treating patients with MS as early as possible in the course of the disease, in order to delay permanent axonal damage that is responsible for the signs and symptoms of disease progression. Expert opinion There is a wealth of data on the treatment of RRMS with s.c. IFN-β-1a indicating that patients treated during the early inflammatory stages of the disease have significantly improved short-term outcomes compared with patients who commence treatment late. It remains to be determined whether the short-term effects of early treatment will translate into long-lasting benefits, although it is hoped that ongoing research will help to answer this question.
    Expert Opinion on Biological Therapy 06/2014; 14(8):1-8. DOI:10.1517/14712598.2014.924496 · 3.65 Impact Factor
  • Mark S Freedman
    Nature Reviews Neurology 06/2014; 10(7). DOI:10.1038/nrneurol.2014.98 · 14.10 Impact Factor
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    ABSTRACT: Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined. Open access full paper at //
    Neurology 05/2014; DOI:10.1212/WNL.0000000000000560 · 8.30 Impact Factor
  • Joint Congress of European Neurology; 05/2014
  • Arianna Sartori, Dawn Carle, Mark S Freedman
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    ABSTRACT: Introduction: Multiple sclerosis is a disabling chronic inflammatory disease of the CNS. New emerging oral treatments can offer efficacy with higher levels of therapeutic adherence. Teriflunomide is one such oral agent that has recently been approved for the treatment of relapsing multiple sclerosis (RMS). Areas covered: The aim of this review is to describe the pharmacological profile of teriflunomide and review the vast clinical development program that paved the way for its approval, with emphasis on its safety and tolerability. Expert opinion: Teriflunomide is a safe new oral medication for treating RMS. It is effective at reducing relapses, MRI activity and slowing disability progression. It is well tolerated, with mild and transitory side effects. Although teriflunomide is given a pregnancy category 'X' by the FDA and an effective contraception is needed, to date, there has been no evidence of teratogenicity in humans and a rapid washout procedure can lead to a virtually complete elimination. Its effectiveness appeared to be at least comparable to that of high-dose IFN-β-1a, and although direct comparisons with other orals are still lacking, its tolerability and encouraging safety data suggest that teriflunomide could be considered an ideal first-line medication for RMS.
    Expert Opinion on Pharmacotherapy 04/2014; DOI:10.1517/14656566.2014.902936 · 3.09 Impact Factor

Publication Stats

6k Citations
1,357.18 Total Impact Points


  • 2012–2015
    • Ottawa Hospital Research Institute
      Ottawa, Ontario, Canada
  • 1997–2015
    • University of Ottawa
      • • Department of Biochemistry, Microbiology and Immunology
      • • Department of Medicine
      Ottawa, Ontario, Canada
  • 2014
    • Università degli Studi di Trieste
      Trst, Friuli Venezia Giulia, Italy
  • 2011–2014
    • Multiple Sclerosis Society of Canada
      Ottawa, Ontario, Canada
  • 1994–2014
    • The Ottawa Hospital
      • Department of Neurology
      Ottawa, Ontario, Canada
  • 2009
    • VU University Medical Center
      Amsterdamo, North Holland, Netherlands
  • 2008
    • Collateral Analytics
      Honolulu, Hawaii, United States
    • Ottawa University
      اوتاوا، کانزاس, Kansas, United States
  • 1989–2008
    • McGill University
      • • Neuroimmunology Unit
      • • Department of Neurology and Neurosurgery
      Montréal, Quebec, Canada
  • 2007
    • VU University Amsterdam
      Amsterdamo, North Holland, Netherlands
    • Universitätsspital Basel
      Bâle, Basel-City, Switzerland
  • 2006
    • The National Institute of Neurology and Neurosurgery
      Tlalpam, The Federal District, Mexico
  • 2002–2005
    • University of Milan
      Milano, Lombardy, Italy
  • 1998
    • Montreal Heart Institute
      Montréal, Quebec, Canada
  • 1990
    • Université de Montréal
      • Department of Medicine
      Montréal, Quebec, Canada