Multiple Sclerosis: Freedman M

Feasby T, Banwell B, Benstead T, Bril V, Brouwers M, Freedman M, Hahn A, Hume H, Freedman J, Pi D, Wadsworth L. · IVIG Hematology and Neurology Expert Panels. · Transfus Med Rev. · Pubmed #17397768 No free full text.

Abstract: Canada's per capita use of intravenous immune globulin (IVIG) grew by approximately 115% between 1998 and 2006, making Canada one of the world's highest per capita users of IVIG. It is believed that most of this growth is attributable to off-label usage. To help ensure IVIG use is in keeping with an evidence-based approach to the practice of medicine, the National Advisory Committee on Blood and Blood Products (NAC) and Canadian Blood Services convened a panel of national experts to develop an evidence-based practice guideline on the use of IVIG for neurologic conditions. The mandate of the expert panel was to review evidence regarding use of IVIG for 22 neurologic conditions and formulate recommendations on IVIG use for each. A panel of 6 clinical experts, one expert in practice guideline development and 4 representatives from the NAC met to review the evidence and reach consensus on the recommendations for the use of IVIG. The primary sources used by the panel were 2 recent evidence-based reviews. Recommendations were based on interpretation of the available evidence and, where evidence was lacking, consensus of expert clinical opinion. A draft of the practice guideline was circulated to neurologists in Canada for feedback. The results of this process were reviewed by the expert panel, and modifications to the draft guideline were made where appropriate. This practice guideline will provide the NAC with a basis for making recommendations to provincial and territorial health ministries regarding IVIG use management. Recommendations for use of IVIG were made for 14 conditions, including acute disseminated encephalomyelitis, chronic inflammatory demyelinating polyneuropathy, dermatomyositis, diabetic neuropathy, Guillain-Barré syndrome, Lambert-Eaton myasthenic syndrome, multifocal motor neuropathy, multiple sclerosis, myasthenia gravis, opsoclonus-myoclonus, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, polymyositis, Rasmussen's encephalitis, and stiff person syndrome; IVIG was not recommended for 8 conditions including adrenoleukodystrophy, amyotropic lateral sclerosis, autism, critical illness polyneuropathy, inclusion body, myositis, intractable childhood epilepsy, paraproteinemic neuropathy (IgM variant), and POEMS syndrome. Development and dissemination of evidence-based clinical practice guidelines may help to facilitate appropriate use of IVIG.

Karussis D, Biermann LD, Bohlega S, Boiko A, Chofflon M, Fazekas F, Freedman M, Gebeily S, Gouider R, Havrdova E, Jakab G, Karabudak R, Miller A, Anonymous00555. · Department of Neurology, Hadassah Hebrew University Hospital, Ein-Karem, Jerusalem, Israel. · Eur J Neurol. · Pubmed #16420394 No free full text.

Abstract: An International Working Group for Treatment Optimization in MS met to recommend evidence-based therapeutic options for the management of suboptimal responses or intolerable side-effects in patients treated with disease-modifying drugs (DMDs) for multiple sclerosis (MS). Several DMDs are now available for the treatment of MS that have been shown to alter the clinical course of the disease by decreasing disease activity and delaying the progression of disability. Nevertheless, many patients continue to experience disease activity whilst on treatment, and recommendations have been made on how the success of therapy in an individual patient can be assessed. However, even after having identified criteria for a suboptimal response to current treatments, clinicians require guidance on how to improve the outcomes. This report summarizes the conclusions from a workshop at which this issue was addressed. We suggest treatment pathways for optimizing therapy for those patients with suboptimal responses to DMDs, and therapeutic options for patients with unacceptable side-effects on their current therapy.

Atkins H, Freedman M. · Ottawa Hospital Blood and Marrow Transplant Program, General Campus, University of Ottawa, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada. · Neurol Clin. · Pubmed #15661098 No free full text.

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Oger J, Freedman M. · Canadian MS Clinics Network, Canada. · Can J Neurol Sci. · Pubmed #10610197 No free full text.

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Atkins H, Freedman M. · The Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, Ontario, ON, Canada. · Methods Mol Biol. · Pubmed #19378207 No free full text.

Abstract: Complete abrogation of the inflammatory response by high-dose cytotoxic therapy at an early stage of MS, when the nervous system has not yet sustained irreparable damage may be successful at preventing the inexorable progression. Immunological and hematological reconstitution follows abrogation through bone marrow transplantation. The issues are complex, and many factors, including baseline disability, the timing of this intervention, the intensity of the immune ablation, and depletion of lymphocytes from the graft, are all likely to influence treatment outcome. This article describes the immune ablation regimen for treatment of patients with poor prognosis MS, as performed in the Canadian MS-BMT study.

Costello F, Hodge W, Pan YI, Freedman M, DeMeulemeester C. · Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada. · J Neurol Sci. · Pubmed #19303605 No free full text.

Abstract: OBJECTIVES: To determine whether retinal nerve fiber layer (RNFL) atrophy in the afferent visual pathway may complement existing tools used to describe and characterize differences across MS subtypes. METHODS: Optical coherence tomography-measured RNFL values were compared over two years in 35 patients (70 eyes) with optic neuritis (ON) as a clinically isolated syndrome (CIS); 39 patients (78 eyes) with relapsing remitting MS (RRMS); and 7 patients (14 eyes) with secondary progressive MS (SPMS). RESULTS: RNFL comparisons involving eyes without ON yielded greater differences between MS subtypes than ON-affected eyes. Overall RNFL values in non-affected eyes were reduced in SPMS patients (83.4 microm), relative to CIS (101.2 microm) (p=0.0009), and RRMS patients (103.7 microm) (p=0.001); and temporal RNFL atrophy was greater in RRMS (64.4 microm) eyes as compared to CIS eyes (73.2 microm) (p=0.02). In ON-affected eyes, RNFL atrophy was greater in SPMS patients (39.5 microm) than CIS patients (58.1 microm) (p=0.03), and in RRMS patients (48.2 microm) relative to CIS patients (p=0.05). RNFL values did not change significantly for any MS subtype during the two-year duration of the study. INTERPRETATION: RNFL thickness may represent a structural marker, which can help distinguish MS subtypes, because the extent of atrophy is commensurate with disease progression. RNFL comparisons between non-affected eyes revealed greater differences between CIS, RRMS, and SPMS patients relative to ON-affected eyes, because the impact of prior ON may supplant the effects of disease subtype.

Darlington PJ, Podjaski C, Horn KE, Costantino S, Blain M, Saikali P, Chen Z, Baker KA, Newcombe J, Freedman M, Wiseman PW, Bar-Or A, Kennedy TE, Antel JP. · Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. · J Neuropathol Exp Neurol. · Pubmed #18520777 No free full text.

Abstract: Neuronal injury and loss are recognized features of neuroinflammatory disorders, including acute and chronic encephalitides and multiple sclerosis; destruction of astrocytes has been demonstrated in cases of Rasmussen encephalitis. Here, we show that innate immune cells (i.e. natural killer [NK] and gammadelta T cells) cause loss of neurons from primary human neuron-enriched cultures by destroying the supporting astrocytes. Interleukin 2-activated NK cells caused loss of astrocytes within 1 hour, whereas neurons were lost at 4 hours. Time-lapse imaging indicated that delayed neuron loss was due to early destruction of supporting astrocytes. Selective blocking of astrocyte death with anti-NKG2D antibodies reduced neuron loss, as did blocking of CD54 on astrocytes. gammadelta T cells also induced astrocyte cytotoxicity, leading to subsequent neuronal displacement. In astrocytes, NK cells caused caspase-dependent fragmentation of the intermediate filament proteins glial fibrillary acidic protein and vimentin, whereas anti-CD3-activated T cells produced fragmentation to a lesser extent and without measurable cytotoxicity. Glial fibrillary acidic protein fragmentation was also demonstrated in lysates from chronic multiple sclerosis plaques but not from normal control white matter. These data suggest that non-major histocompatibility complex-restricted immune effector cells may contribute to neuron loss in neuroinflammatory disorders indirectly through injury of glia.

Banwell B, Krupp L, Kennedy J, Tellier R, Tenembaum S, Ness J, Belman A, Boiko A, Bykova O, Waubant E, Mah JK, Stoian C, Kremenchutzky M, Bardini MR, Ruggieri M, Rensel M, Hahn J, Weinstock-Guttman B, Yeh EA, Farrell K, Freedman M, Iivanainen M, Sevon M, Bhan V, Dilenge ME, Stephens D, Bar-Or A. · Division of Neurology, The Hospital for Sick Children, University of Toronto, ON, Canada. · Lancet Neurol. · Pubmed #17689148 No free full text.

Abstract: BACKGROUND: The full spectrum of clinical manifestations and outcome, and the potential importance of regional or demographic features or viral triggers in paediatric multiple sclerosis (MS), has yet to be fully characterised. Our aim was to determine some of these characteristics in children with MS. METHODS: 137 children with MS and 96 control participants matched by age and geographical region were recruited in a multinational study. They underwent structured clinical-demographic interviews, review of academic performance, physical examination, disability assessment (MS patients only), and standardised assays for IgG antibodies directed against Epstein-Barr virus, cytomegalovirus, parvovirus B19, varicella zoster virus, and herpes simplex virus. FINDINGS: MS was relapsing-remitting at diagnosis in 136 (99%) children. The first MS attack resembled acute disseminated encephalomyelitis (ADEM) in 22 (16%) of the children, most under 10 years old (mean age 7.4 [SD 4.2] years). Children with ADEM-like presentations were significantly younger than were children with polyfocal (11.2 [4.5] years; p<0.0001) or monofocal (12.0 [3.8] years; p=0.0005) presentations. Permanent physical disability (EDSS>or=4.0) developed within 5 years in 15 (13%) of the 120 children for whom EDSS score was available. 23 (17%) had impaired academic performance, which was associated with increasing disease duration (p=0.02). Over 108 (86%) of the children with MS, irrespective of geographical residence, were seropositive for remote EBV infection, compared with only 61 (64%) of matched controls (p=0.025, adjusted for multiple comparisons). Children with MS did not differ from controls in seroprevalence of the other childhood viruses studied, nor with respect to month of birth, sibling number, sibling rank, or exposure to young siblings. INTERPRETATION: Paediatric MS is a relapsing-remitting disease, with presenting features that vary by age at onset. MS in children might be associated with exposure to EBV, suggesting a possible role for EBV in MS pathobiology.

Duddy M, Niino M, Adatia F, Hebert S, Freedman M, Atkins H, Kim HJ, Bar-Or A. · Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, and Department of Neurology, Ottawa General Hospital, Canada. · J Immunol. · Pubmed #17475834 links to  free full text

Abstract: Although recent animal studies have fuelled growing interest in Ab-independent functions of B cells, relatively little is known about how human B cells and their subsets may contribute to the regulation of immune responses in either health or disease. In this study, we first confirm that effector cytokine production by normal human B cells is context dependent and demonstrate that this involves the reciprocal regulation of proinflammatory and anti-inflammatory cytokines. We further report that this cytokine network is dysregulated in patients with the autoimmune disease multiple sclerosis, whose B cells exhibit a decreased average production of the down-regulatory cytokine IL-10. Treatment with the approved chemotherapeutic agent mitoxantrone reciprocally modulated B cell proinflammatory and anti-inflammatory cytokines, establishing that the B cell cytokine network can be targeted in vivo. Prospective studies of human B cells reconstituting following in vivo depletion suggested that different B cell subsets produced distinct effector cytokines. We confirmed in normal human B cell subsets that IL-10 is produced almost exclusively by naive B cells while the proinflammatory cytokines lymphotoxin and TNF-alpha are largely produced by memory B cells. These results point to an in vivo switch in the cytokine "program" of human B cells transitioning from the naive pool to the memory pool. We propose a model that ascribes distinct and proactive roles to memory and naive human B cell subsets in the regulation of memory immune responses and in autoimmunity. Our findings are of particular relevance at a time when B cell directed therapies are being applied to clinical trials of several autoimmune diseases.

Saikali P, Antel JP, Newcombe J, Chen Z, Freedman M, Blain M, Cayrol R, Prat A, Hall JA, Arbour N. · Neuroimmunology Unit, Montreal Neurological Institute, Montreal, Quebec, Canada H3A 2B4. · J Neurosci. · Pubmed #17267578 links to  free full text

Abstract: NKG2D is an activating or coactivating receptor expressed on human natural killer (NK) cells, CD8+ T cells, and gamma/delta T cells. NKG2D ligands have been detected on many tumor cell types and can be induced on nontransformed cells by environmental signals including DNA damage and inflammation. We investigated the contribution of NKG2D-NKG2D ligand interaction on CNS-directed immune responses. We observed that primary cultures of human adult oligodendrocytes and fetal astrocytes expressed ligands for NKG2D in vitro whereas neurons, microglia, and adult astrocytes did not. Disruption of the NKG2D-NKG2D ligand interaction using blocking antibodies significantly inhibited killing of primary human oligodendrocytes mediated by activated human NK cells, gamma/delta T cells, and allo-reactive CD8+ T cells. NKG2D ligands [major histocompatibility complex class I chain-related molecules A and B (MICA/B)] were detected in groups of cells and colocalized with an oligodendrocyte marker (adenomatous polyposis coli) in white matter sections obtained from multiple sclerosis lesions but not in normal control samples. CD8+ T cells could be detected in close proximity to MICA/B+ cells within multiple sclerosis lesions, supporting an in vivo interaction between these immune effectors and stressed MICA/B-expressing oligodendrocytes. These results imply that NKG2D-NKG2D ligand interaction can potentially contribute to cytotoxic responses mediated by activated immune effector cells in the inflamed CNS, as observed in multiple sclerosis.

O'Connor KC, McLaughlin KA, De Jager PL, Chitnis T, Bettelli E, Xu C, Robinson WH, Cherry SV, Bar-Or A, Banwell B, Fukaura H, Fukazawa T, Tenembaum S, Wong SJ, Tavakoli NP, Idrissova Z, Viglietta V, Rostasy K, Pohl D, Dale RC, Freedman M, Steinman L, Buckle GJ, Kuchroo VK, Hafler DA, Wucherpfennig KW. · Center for Neurologic Diseases, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA. · Nat Med. · Pubmed #17237795 No free full text.

Abstract: The role of autoantibodies in the pathogenesis of multiple sclerosis (MS) and other demyelinating diseases is controversial, in part because widely used western blotting and ELISA methods either do not permit the detection of conformation-sensitive antibodies or do not distinguish them from conformation-independent antibodies. We developed a sensitive assay based on self-assembling radiolabeled tetramers that allows discrimination of antibodies against folded or denatured myelin oligodendrocyte glycoprotein (MOG) by selective unfolding of the antigen domain. The tetramer radioimmunoassay (RIA) was more sensitive for MOG autoantibody detection than other methodologies, including monomer-based RIA, ELISA or fluorescent-activated cell sorting (FACS). Autoantibodies from individuals with acute disseminated encephalomyelitis (ADEM) selectively bound the folded MOG tetramer, whereas sera from mice with experimental autoimmune encephalomyelitis induced with MOG peptide immunoprecipitated only the unfolded tetramer. MOG-specific autoantibodies were identified in a subset of ADEM but only rarely in adult-onset MS cases, indicating that MOG is a more prominent target antigen in ADEM than MS.

Banwell B, Reder AT, Krupp L, Tenembaum S, Eraksoy M, Alexey B, Pohl D, Freedman M, Schelensky L, Antonijevic I. · The Hospital for Sick Children, University of Toronto, Ontario, Canada. · Neurology. · Pubmed #16505297 No free full text.

Abstract: BACKGROUND: Immunomodulatory therapies are widely used in adults with multiple sclerosis (MS) and safety and tolerability is well-established. Although at least 5% of all patients with MS experience the clinical onset of their disease prior to age 18 years, the available literature on safety and tolerability of immunomodulatory therapies for pediatric-onset MS is limited. METHODS: The authors retrospectively reviewed safety and tolerability of interferon beta-1b (IFNbeta-1b) in a cohort of 43 children and adolescents treated for a mean of 29.2 months (SD 22.3 months). RESULTS: Mean age at start of IFNbeta-1b treatment was 13 years. Eight children were < or =10 years. Most common adverse events included flu-like syndrome (35%), abnormal liver function test (26%), and injection site reaction (21%). No serious or unexpected adverse events were reported. CONCLUSIONS: Although data on long-term effects on the maturing organ systems are lacking, the safety profile supports the safety and tolerability of interferon beta-1b (IFNbeta-1b) in children with multiple sclerosis and related diseases. All patients treated with IFNbeta-1b should undergo regular monitoring of liver function.

Kinkel RP, Kollman C, O'Connor P, Murray TJ, Simon J, Arnold D, Bakshi R, Weinstock-Gutman B, Brod S, Cooper J, Duquette P, Eggenberger E, Felton W, Fox R, Freedman M, Galetta S, Goodman A, Guarnaccia J, Hashimoto S, Horowitz S, Javerbaum J, Kasper L, Kaufman M, Kerson L, Mass M, Rammohan K, Reiss M, Rolak L, Rose J, Scott T, Selhorst J, Shin R, Smith C, Stuart W, Thurston S, Wall M, Anonymous00246. · No affiliation provided · Neurology. · Pubmed #16436649 No free full text.

Abstract: BACKGROUND: The Controlled High Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) showed that IM interferon beta-1a (IFNbeta-1a) significantly slows the rate of development of clinically definite multiple sclerosis (CDMS) over 2 years in high-risk patients who experience a first clinical demyelinating event. This report highlights the primary results of a 5-year, open-label extension of CHAMPS (the Controlled High Risk Avonex Multiple Sclerosis Prevention Study in Ongoing Neurologic Surveillance [CHAMPIONS Study]). OBJECTIVE: To determine if the benefits of IFNbeta-1a observed in CHAMPS are sustained for up to 5 years. METHODS: CHAMPS patients at participating CHAMPIONS sites were enrolled in the study. All patients were offered, but not required to take, IFNbeta-1a 30 microg IM once weekly for up to 5 years (from CHAMPS randomization). Patients who received placebo in CHAMPS were considered the delayed treatment (DT) group, and patients who received IFNbeta-1a in CHAMPS were considered the immediate treatment (IT) group. The primary outcome measure was the rate of development of CDMS. Additional outcomes included disease state classification at 5 years, annualized relapse rates, disability level at 5 years (Expanded Disability Status Scale), and MRI measures at 5 years. RESULTS: Fifty-three percent (203/383) of patients enrolled in CHAMPIONS (n = 100, IT group; n = 103, DT group) and 64% (32/50) of CHAMPS study sites participated in CHAMPIONS. The median time to initiation of IFNbeta-1a therapy in the DT group was 29 months. The cumulative probability of development of CDMS was significantly lower in the IT group compared with the DT group (5-year incidence 36 +/- 9 vs 49 +/- 10%; p = 0.03). Multivariate analysis suggested that the only factors independently associated with an increased rate of development of CDMS were randomization to the DT group and younger age at onset of neurologic symptoms. Few patients in either group developed major disability within 5 years. CONCLUSIONS: These results support the use of IM interferon beta-1a after a first clinical demyelinating event and indicate that there may be modest beneficial effects of immediate treatment compared with delayed initiation of treatment.

Dyment DA, Willer CJ, Scott B, Armstrong H, Ligers A, Hillert J, Paty DW, Hashimoto S, Devonshire V, Hooge J, Kastrukoff L, Oger J, Metz L, Warren S, Hader W, Power C, Auty A, Nath A, Nelson R, Freedman M, Brunet D, Paulseth JE, Rice G, O'Connor P, Duquette P, Lapierre Y, Francis G, Bouchard JP, Murray TJ, Bhan V, Maxner C, Pryse-Phillips W, Stefanelli M, Sadovnick AD, Risch N, Ebers GC. · The Wellcome Trust Center for Human Genetics, Oxford, UK. · Neurogenetics. · Pubmed #11523565 No free full text.

Abstract: Four published genome screens have identified a number of markers with increased sharing in multiple sclerosis (MS) families, although none has reached statistical significance. One hundred and five markers previously identified as showing increased sharing in Canadian, British, Finnish, and American genome screens were genotyped in 219 sibling pairs ascertained from the database of the Canadian Collaborative Project on Genetic Susceptibility to MS (CCPGSMS). No markers examined met criteria for significant linkage. Markers located at 5p14 and 17q22 were analyzed in a total of 333 sibling pairs and attained mlod scores of 2.27 and 1.14, respectively. The known HLA Class II DRB1 association with MS was confirmed (P<0.0001). Significant transmission disequilibrium was also observed for D17S789 at 17q22 (P=0.0015). This study highlights the difficulty of searching for genes with only mild-to-moderate effects on susceptibility, although large effects of specific loci may still be present in individual families. Future progress in the genetics of this complex trait may be helped by (1) focussing on more ethnically homogeneous samples, (2) using an increased number of MS families, and (3) using transmission disequilibrium analysis in candidate regions rather than the affected relative pair linkage analysis.

Freedman M, King J, Oger J, Sharief M, Hartung HP, Anonymous00117. · No affiliation provided · Lancet. · Pubmed #12781558 No free full text.

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Jeffery D, Bashir K, Buchwald L, Coyle P, Freedman M, Markowitz C, Rammohan K, Reder T, Sharief M, Wolinsky J. · No affiliation provided · J Neurol Sci. · Pubmed #12163200 No free full text.

This publication has no abstract.