Mark S Freedman's research while affiliated with Ottawa Hospital Research Institute and other places

Publications (433)

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Objective We report a case of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) who achieved durable and steroid-free remission after IV cladribine. Methods A 25 year-old man presented with progressively worsening headaches, polydipsia, dysarthria, diplopia and vertigo, and obtundation requiri...
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Background: People with moderate to severe multiple sclerosis (MS) and their family care partners do not engage in sufficient physical activity (PA) for health benefits. Dyadic PA interventions need to be developed to benefit each individual and the dyad. The objective of this study was to engage expert stakeholders in prioritizing and refining key...
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Background Slowed processing speed is the most frequently reported cognitive deficit for people with multiple sclerosis (MS). However, measures used to assess processing speed may also recruit other cognitive abilities. The present objective was to determine the contributions of different cognitive functions to performance on two commonly used proc...
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Background: White matter lesions and brain atrophy are both present early in multiple sclerosis. However, the spatio-temporal relationship between atrophy and lesion processes remains unclear. Methods: Yearly magnetic resonance images were analyzed in 392 patients with clinically isolated syndrome from the 5-year REFLEX/REFLEXION studies. Patien...
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Objective To evaluate the dose-response relationship of 10, 20 and 40-mg ponesimod and long-term efficacy and safety of ponesimod 20 mg using an analysis of combined data from the phase 2 Core and Extension studies in relapsing-remitting multiple sclerosis (RRMS) patients. Methods In the Core study, 464 patients were randomized (1:1:1:1): placebo...
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Autologous hematopoietic stem cell transplantation (aHSCT) is increasingly used to treat patients with highly active multiple sclerosis (MS) refractory to disease‐modifying therapy. Briefly, cyclophosphamide and filgrastim are used to mobilize autologous hematopoietic stem cells (HSC) into the circulation. HSC are harvested by leukapheresis, purifi...
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Background Mesenchymal stem cell (MSC) therapies are being evaluated in multiple sclerosis (MS) for possible neural repair. To date, the potential benefits on cognition have received little attention. The objective of the current study was to comprehensively evaluate cognition before and after MSC therapy in those with MS as part of a double-blind,...
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Background and purpose: In the REFLEX trial (ClinicalTrials.gov identifier: NCT00404352), patients with a first clinical demyelinating event (FCDE) displayed significantly delayed onset of multiple sclerosis (MS; McDonald criteria) when treated with subcutaneous interferon β-1a (scIFNβ-1a) versus placebo. This post hoc analysis evaluated the effec...
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Objective To report on neurophysiological outcomes derived from transcranial magnetic stimulation (TMS) following autologous mesenchymal stem cells (aMSCs) therapy in patients with multiple sclerosis (MS). Methods 20 adults with confirmed MS were recruited to participate in a phase II randomized control trial to assess the safety and potential ben...
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Background One-off serum levels of neurofilament light chain (sNfL) is an established predictor of emerging disease activity in multiple sclerosis (MS). However, the importance of longitudinal increases in sNfL is yet to be enumerated, an important consideration as this test is translated for serial monitoring. Glial Fibrillary Acidic Protein (sGFA...
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Background There is a lack of studies on the association between obesity and conversion from a clinically isolated syndrome (CIS) to multiple sclerosis (MS). Objective The aim of this study was to determine whether obesity predicts disease activity and prognosis in patients with CIS. Methods Body mass index (BMI) at baseline was available for 464...
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The complement system is a tightly controlled signaling network that plays a role in innate immune surveillance. However, abnormal signaling through this pathway contributes to tissue damage in several inflammatory, autoimmune, and degenerative diseases. Myasthenia gravis (MG) and neuromyelitis optica spectrum disorders (NMOSD) have complement dysf...
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Background Mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells, have been proposed as a promising therapeutic option for people with multiple sclerosis on the basis of their immunomodulatory and neuroprotective properties. The MEsenchymal StEm cells for Multiple Sclerosis (MESEMS) study was devised to evaluate the safety, tolerab...
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Background: Prognostic biomarkers are badly needed to direct MS treatment intensity early in the condition Levels of serum neurofilament light chains (sNfL) result from the destruction of central nervous system axons in MS and correlate with the aggressiveness of the disease. Methods: In this prospective cohort study, we identified patients with se...
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Background: Objective markers of disease progression are needed for patients with multiple sclerosis (MS). Increased randomness in neural networks is hypothesized to be an important cause of morbidity that can be objectified using graph theory. Methods: We use voxel-based structural similarity determined from T1-weighted MRI scans of 23 patients wi...
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Background : In accordance with expert guidance, patients have typically continued to receive treatment with subcutaneous interferon beta-1a (sc IFN β-1a) for relapsing multiple sclerosis (MS) during the COVID-19 pandemic. Methods : We provide a summary of outcomes among sc IFN β-1a-treated patients with adverse events related to confirmed or susp...
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This post-hoc analysis evaluated candidate biomarkers of long-term efficacy of subcutaneous interferon beta-1a (sc IFN β-1a) in REFLEX/REFLEXION studies of clinically isolated syndrome. Samples from 507 REFLEX and 287 REFLEXION study participants were analyzed. All investigated biomarkers were significantly upregulated 1.5–4-fold in response to sc...
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Background Many patients with multiple sclerosis (MS) experience suboptimal disease control despite the use of disease-modifying therapy (DMT). Objective To assess the efficacy and safety of ocrelizumab (OCR) in patients with relapsing-remitting MS (RRMS) and suboptimal response to prior DMTs. Methods Patients with RRMS and suboptimal responses (...
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Background: Prolonged-release fampridine (PR-FAM) 10-mg tablet twice daily is the only approved pharmacological treatment for improvement of walking ability in adults with multiple sclerosis (MS). LIBERATE assessed the safety/effectiveness of PR-FAM in the real-world. Objectives: The aim of this study was to collect additional safety data, inclu...
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Background Physical activity (PA) is beneficial for all people; however, people affected by multiple sclerosis (MS) find regular PA challenging. These people may include individuals with advanced disabilities and their care partners. Objective The objective of this study is to determine the feasibility of a dyadic PA intervention for people with a...
Article
Fingolimod (Gilenya) received regulatory approval from the US FDA in 2010 as the first-in-class sphingosine 1-phosphate (S1P) receptor (S1PR) modulator and was the first oral disease-modifying therapy (DMT) used for the treatment of the relapsing forms of multiple sclerosis (MS). Development of this new class of therapeutic compounds has continued...
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Background : Highly active MS may warrant higher efficacy treatments for disease control. However, these often confer more risk and have not been compared in head-to-head clinical trials, making relative efficacy and safety difficult to interpret. Alemtuzumab and cladribine are two high-efficacy treatments given as discrete courses separated by one...
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Importance To our knowledge, the Oral Ponesimod Versus Teriflunomide In Relapsing Multiple Sclerosis (OPTIMUM) trial is the first phase 3 study comparing 2 oral disease-modifying therapies for relapsing multiple sclerosis (RMS). Objective To compare the efficacy of ponesimod, a selective sphingosine-1-phosphate receptor 1 (S1P1) modulator with ter...
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Measurement of serum neurofilament light chain concentration (sNfL) promises to become a convenient, cost effective and meaningful adjunct for multiple sclerosis (MS) prognostication as well as monitoring disease activity in response to treatment. Despite the remarkable progress and an ever-increasing literature supporting the potential role of sNf...
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Background In the Phase 3, 96-week ORACLE-MS study, cladribine tablets 10 mg (3.5 or 5.25 mg/kg cumulative dosage over two years) significantly reduced lesions associated with multiple sclerosis versus placebo in participants following a first clinical demyelinating event (FCDE). Objective To determine the timing of effects of cladribine tablets o...
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Background: Autologous haematopoietic stem cell transplantation (AHSCT) is an effective treatment for patients with multiple sclerosis (MS) who have highly active disease, despite the use of standard disease-modifying therapies (DMTs). However, the optimal time for offering AHSCT to patients with 'aggressive' MS is yet to be established. Objectiv...
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A simple blood-derived biomarker is desirable in the routine management of multiple sclerosis (MS) patients and serum neurofilament light chain (sNfL) is the most promising candidate. Although its utility was first shown in cerebrospinal fluid (CSF), technological advancements have enabled reliable detection in serum and less frequently plasma, obv...
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Background: Subcutaneous (sc) interferon (IFN) β-1a reduces relapse rates and delays disability progression in patients with MS. We examined the association of the year 1 Magnetic Resonance Imaging in MS (MAGNIMS) score with long-term clinical disease activity (CDA) -free status and confirmed disability progression in patients treated with sc IFN β...
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The judicious use of autologous hematopoietic stem cell transplantation (AHSCT) for MS requires understanding the potential benefits, identifying the most appropriate patient, and acknowledging the risks and differences between different protocols. Recently, AHSCT for MS is occurring more frequently, with a better safety profile than earlier studie...
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Background Few data exist concerning conversion to secondary progressive MS in patients treated with disease-modifying therapies. Objective Determine the proportion of alemtuzumab-treated patients converting from relapsing-remitting to secondary progressive MS during the CARE-MS core and extension studies. Methods Patients ( N = 811) were analyze...
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Background There is an unmet need to develop therapeutic interventions directed at the neurodegeneration that underlies progression in multiple sclerosis. High-dose, pharmaceutical-grade biotin (MD1003) might enhance neuronal and oligodendrocyte energetics, resulting in improved cell function, repair, or survival. The MS-SPI randomised, double-blin...
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Cognitive fatigability (CF) can be defined as an inability to maintain performance throughout a sustained cognitive task. Individuals with multiple sclerosis (MS) are more susceptible to CF than healthy controls (HCs); however, the neural correlates underlying CF are still under investigation. Arterial spin labeling (ASL) perfusion imaging provides...
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Background: There is an unmet need to develop therapeutic interventions directed at the neurodegeneration that underlies progression in multiple sclerosis. High-dose, pharmaceutical-grade biotin (MD1003) might enhance neuronal and oligodendrocyte energetics, resulting in improved cell function, repair, or survival. The MS-SPI randomised, double-bli...
Preprint
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Blood neurofilament light chain (NfL) is a marker of neuro-axonal injury showing promising associations with outcomes of interest in several neurological conditions. Although initially discovered and investigated in the cerebrospinal fluid (CSF), the recent development of ultrasensitive digital immunoassay technologies has enabled reliable detectio...
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Neurofilaments are intracellular cytoskeletal proteins that leak into cerebrospinal fluid (CSF) and blood as a result of neuronal damage. 1 Blood and CSF neurofilament levels are elevated in a number of neurologic diseases such as multiple sclerosis (MS), amyotrophic lateral sclerosis, and Parkinson disease, as well as in traumatic brain injury.2,3...
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Background: In this pooled, post hoc analysis of a phase 2 trial and the phase 3 TEMSO, TOWER, and TENERE clinical trials, long-term efficacy and safety of teriflunomide were assessed in subgroups of patients with relapsing multiple sclerosis (MS) defined by prior treatment status. Methods: Patients were classified according to their prior treat...
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The outbreak of a severe acute respiratory syndrome caused by a novel coronavirus (COVID-19), has raised health concerns for patients with multiple sclerosis (MS) who are commonly on long-term immunotherapies. Managing MS during the pandemic remains challenging with little published experience and no evidence-based guidelines. We present five terif...
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Background: Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). Shortening the 600 mg infusion to 2 hours reduces the total site stay from 5.5-6 hours (approved infusion duration including mandatory pre-medication and post-infusion observation) to 4 hours. The safety profile of shorter-duration ocr...
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Background : In the phase 3 TOWER core study (NCT00751881), the efficacy and safety of teriflunomide compared with placebo were demonstrated in patients with relapsing forms of multiple sclerosis (RMS). Here, the long-term safety and efficacy outcomes from the TOWER extension study (NCT00751881) are reported. Methods : All patients who entered the...
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Serum neurofilament light chain (NfL) is emerging as an important biomarker in multiple sclerosis (MS). Our objective was to evaluate the prognostic value of serum NfL levels obtained close to the time of MS onset with long-term clinical outcomes. In this prospective cohort study, we identified patients with serum collected within 5 years of first...
Preprint
Full-text available
The outbreak of a severe acute respiratory syndrome caused by a novel coronavirus (COVID-19), has raised health concerns for patients with multiple sclerosis (MS) who are commonly on long-term immunotherapies. Managing MS during the pandemic remains challenging with little published experience and no evidence-based guidelines. We present five terif...
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The most effective treatment at halting inflammation in patients with highly active multiple sclerosis (MS) is immune ablation followed by autologous hematopoietic stem cell transplantation (AHSCT). Better patient selection and supportive management, as well as advances in conditioning regimens have resulted in improved safety with AHSCT. However,...
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Objective Accelerated brain volume loss has been noted following immunoablative autologous hematopoietic stem cell transplantation (IAHSCT) for multiple sclerosis. As with other MS treatments, this is often interpreted as ‘pseudoatrophy’, related to reduced inflammation. Treatment‐related neurotoxicity may be contributory. We sought objective evide...
Article
Objective To investigate whether vitamin D, smoking, and anti-Epstein-Barr virus (EBV) antibody concentrations predict long-term cognitive status and neuroaxonal injury in multiple sclerosis (MS). Methods This study was conducted among 278 patients with clinically isolated syndrome who participated in the clinical trial BENEFIT (Betaferon/Betasero...
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The Canadian Multiple Sclerosis Working Group has updated its treatment optimization recommendations (TORs) on the optimal use of disease-modifying therapies for patients with all forms of multiple sclerosis (MS). Recommendations provide guidance on initiating effective treatment early in the course of disease, monitoring response to therapy, and m...
Preprint
BACKGROUND Physical activity (PA) is beneficial for all people; however, people affected by multiple sclerosis (MS) find regular PA challenging. These people may include individuals with advanced disabilities and their care partners. OBJECTIVE The objective of this study is to determine the feasibility of a dyadic PA intervention for people with a...
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Background Defining the transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive multiple sclerosis (SPMS) can be challenging and delayed. A digital tool (MSProDiscuss) was developed to facilitate physician-patient discussion in evaluating early, subtle signs of multiple sclerosis (MS) disease progression representing...
Article
Multiple sclerosis (MS) is a chronic, inflammatory disease of the central nervous system (CNS), affecting patients of all ages, causing neurologic disability if inadequately treated. Some patients have a relatively benign disease course without significant disability after decades, while a more aggressive course ensues in others and disability prog...
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Background Diroximel fumarate (DRF) is a novel oral fumarate approved in the USA for relapsing forms of multiple sclerosis. DRF is converted to monomethyl fumarate, the pharmacologically active metabolite of dimethyl fumarate (DMF). DRF 462 mg and DMF 240 mg produce bioequivalent exposure of monomethyl fumarate and are therefore expected to have si...
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This study evaluated efficacy of subcutaneous (sc) interferon beta-1a (IFN β-1a) 44 µg 3 × weekly (tiw) in patients appearing to transition from relapsing–remitting multiple sclerosis (RRMS) to secondary progressive MS (SPMS). The PRISMS study included 560 patients with RRMS (EDSS 0–5.0; ≥ 2 relapses in previous 2 years), and the SPECTRIMS study in...
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Background: Clinically isolated syndrome (CIS) is defined as a monophasic clinical episode highly suggestive of multiple sclerosis (MS). Regardless, studies have shown that treatment at this early stage of MS can delay a second event and prolong the transition to clinically diagnosed MS. The objective of this post-hoc analysis was to determine the...
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Background: Diroximel fumarate (DRF) is a novel oral fumarate for patients with relapsing-remitting multiple sclerosis (RRMS). DRF and the approved drug dimethyl fumarate yield bioequivalent exposure to the active metabolite monomethyl fumarate; thus, efficacy/safety profiles are expected to be similar. However, DRF's distinct chemical structure m...
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Background Alemtuzumab is administered as two annual courses for relapsing–remitting multiple sclerosis (MS). Patients may relapse before completing the two-course regimen. Objective The objective was to evaluate 6-year outcomes in patients who relapsed between alemtuzumab Courses 1 and 2 (early relapsers). Methods Post hoc analysis of patients f...
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Neuroanatomical pattern classification using support vector machines (SVMs) has shown promising results in classifying Multiple Sclerosis (MS) patients based on individual structural magnetic resonance images (MRI). To determine whether pattern classification using SVMs facilitates predicting conversion to clinically definite multiple sclerosis (CD...
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Background: Enhanced prediction of progression in secondary progressive multiple sclerosis (SPMS) could improve clinical trial design. Machine learning (ML) algorithms are methods for training predictive models with minimal human intervention. Objective: To evaluate individual and ensemble model performance built using decision tree (DT)-based a...
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Multiple sclerosis is the leading non-traumatic cause of disability in young adults, affecting up to 100,000 Canadians. This chronic inflammatory and neurodegenerative disease of the central nervous system leads to irreversible neurologic disability if inadequately controlled. Though many current medications are available that reduce inflammatory d...
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Objective: To evaluate neurofilament light chain (NfL) levels in serum and CSF of patients with aggressive MS pre- and post-treatment with immunoablation followed by autologous hematopoietic stem cell transplantation (IAHSCT) and examine associations with clinical and MRI outcomes. Methods: Paired serum and CSF in addition to MRI and clinical me...
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Background: Opicinumab is a human monoclonal antibody against LINGO-1, an inhibitor of oligodendrocyte differentiation and axonal regeneration. Previous findings suggested that opicinumab treatment might enhance remyelination in patients with CNS demyelinating diseases. We aimed to assess the safety and efficacy of opicinumab in patients with rela...
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Background: In Phase 3 studies, teriflunomide reduced relapse rates and disability progression compared with placebo; however, decreases in lymphocyte counts were also observed. Objective: To describe the effect of long-term teriflunomide treatment on lymphocyte counts and infection rates among patients in pooled analyses of Phase 3 core and ext...