Multiple Sclerosis: Freedman MS

Polman CH, Reingold SC, Barkhof F, Calabresi PA, Clanet M, Cohen JA, Cutter GR, Freedman MS, Kappos L, Lublin FD, McFarland HF, Metz LM, Miller AE, Montalban X, O'Connor PW, Panitch H, Richert JR, Petkau J, Schwid SR, Sormani MP, Thompson AJ, Weinshenker BG, Wolinsky JS. · Department of Neurology, Free University Medical Center in Amsterdam, PO Box 4075, 1007 MB Amsterdam, The Netherlands. · Neurology. · Pubmed #18362273 No free full text.

Abstract: The increasing number of established effective therapies for relapsing multiple sclerosis (MS) and emerging consensus for early treatment raise practical concerns and ethical dilemmas for placebo-controlled clinical trials in this disease. An international group of clinicians, ethicists, statisticians, regulators, and representatives from the pharmaceutical industry convened to reconsider prior recommendations regarding the ethics of placebo-controlled trials in MS. The group concluded that placebo-controlled trials can still be done ethically, with restrictions. For patients with relapsing MS for which established effective therapies exist, placebo-controlled trials should only be offered with rigorous informed consent if the subjects refuse to use these treatments, have not responded to them, or if these treatments are not available to them for other reasons (e.g., economics). Suggestions are provided to protect subject autonomy and improve informed consent procedures. Recommendations are tighter than previously suggested for placebo-controlled trials in "resource-restricted" environments where established therapies may not be available. Guidance is also provided on the ethics of alternative trial designs and the balance between study subject burden and risk, scientific rationale and interpretability of trial outcomes.

Freedman MS, Thompson EJ, Deisenhammer F, Giovannoni G, Grimsley G, Keir G, Ohman S, Racke MK, Sharief M, Sindic CJ, Sellebjerg F, Tourtellotte WW. · Department of Medicine (Neurology), University of Ottawa, Multiple Sclerosis Research Clinic, The Ottawa Hospital, Ottawa, Ontario, Canada. · Arch Neurol. · Pubmed #15956157 links to  free full text

Abstract: New criteria for the diagnosis of multiple sclerosis (MS) were published as the result of an internationally formed committee. To increase the specificity of diagnosis and to minimize the number of false diagnoses, the committee recommended the use of both clinical and paraclinical criteria, the latter involving information obtained from magnetic resonance imaging, evoked potentials, and cerebrospinal fluid (CSF) analysis. Although rigorous magnetic resonance imaging requirements were provided, the "new criteria paper" fell short in terms of guidelines as to how the CSF analysis should be performed and simply equated the IgG index with isoelectric focusing, without any justification. The spectrum of parameters analyzed and methods for CSF analysis differ worldwide and often yield variable results in terms of sensitivity, specificity, accuracy, and reliability, with no decided "optimal" CSF test for the diagnosis of MS. To address this question specifically, an international panel of experts in MS and CSF diagnostic techniques was convened and the result was this article, representing a consensus of all the participants. These recommendations for establishing a standard for the evaluation of CSF in patients suspected of having MS should greatly complement the new criteria in ensuring that a correct diagnosis of MS is being made.

Freedman MS, Pachner AR. · No affiliation provided · Neurology. · Pubmed #17909150 No free full text.

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Freedman MS, Atkins HL. · No affiliation provided · Neurology. · Pubmed #14745045 No free full text.

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MacLean HJ, Freedman MS. · The Ottawa Hospital-General Campus, 501 Smyth Road, Ottawa, Ontario, Canada, K1H 8L6. · Lancet Neurol. · Pubmed #19081501 No free full text.

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Freedman MS. · Multiple Sclerosis Research Unit, The Ottawa Hospital General Campus, University of Ottawa, Ottawa, Canada. · Neurol Sci. · Pubmed #18690508 No free full text.

Abstract: Not all patients presenting with their first attack of multiple sclerosis (MS) or early thereafter are necessarily in the same phase of disease; some truly present early with minimal disease, whereas others present late, having accumulated already considerable damage to the central nervous system (CNS). This beckons a different approach to therapy depending on "where" a patient may be in the course of disease. If early, then any of the current first line immunomodulating agents may be appropriate, whereas later disease calls for a more aggressive approach entailing either induction with a more powerful but riskier treatment or an escalation approach, moving through first line agents and stepping up to more aggressive treatments. This paper discusses the rationale for either regimen.

Freedman MS, Hughes B, Mikol DD, Bennett R, Cuffel B, Divan V, LaVallee N, Al-Sabbagh A. · Department of Medicine (Neurology), University of Ottawa, Ottawa, Ontario, Canada. · Eur Neurol. · Pubmed #18437041 links to  free full text

Abstract: The treatment of relapsing-remitting multiple sclerosis (RRMS) has become more effective over the last decade with the advent of the currently available disease-modifying therapies (DMTs). Pivotal clinical studies differ in many characteristics, such that cross-comparisons of relative risk reductions are of limited value and can be misleading. Our objective was to compare the clinical efficacy of currently approved first-line DMTs in patients with RRMS, applying an evidence-based medicine approach. We reviewed all phase III pivotal trials of DMTs. Six clinical trials of Avonex, Betaseron, Copaxone, Rebif and Tysabri in patients with RRMS were identified for analysis. Only randomized, placebo-controlled, double-blind studies were included. The clinical efficacy endpoints compared were: proportion of relapse-free patients at 1 and 2 years; annualized relapse rate at 2 years; proportion of progression-free patients at 2 years, and proportion of patients free of gadolinium-enhancing lesions at 1 year or 9 months. Based on these analyses, Betaseron, Rebif, and Tysabri show comparable effects, whereas for several endpoints Avonex or Copaxone did not significantly differ from placebo. In the absence of head-to-head studies for all products used to treat RRMS, it still may be possible to compare treatment effects by applying evidence-based medicine principles.

Freedman MS. · University of Ottawa, The Ottawa Hospital, General Campus, Ottawa, Ontario, Canada. · J Neurol Sci. · Pubmed #17560611 No free full text.

Abstract: Based upon the theory that MS is an acquired autoimmune disease and not purely genetically defined, complete ablation of the defective immune system and replacement with a naive non-disease-causing system de novo from stem cells autologously-obtained should lead to a long-lasting remission of disease. The rationale and methodology are discussed along with recommendations for patient selection. Results of several small studies are presented along with some preliminary results from the ongoing Canadian effort.

Freedman MS. · University of Ottawa and Ottawa Health Research Institute, Canada. · Expert Opin Pharmacother. · Pubmed #17020427 No free full text.

Abstract: Multiple sclerosis (MS) is the most common inflammatory demyelinating disorder of the human CNS, affecting an estimated 2.5 million people in the world. Until the 1990s, treatment was mainly symptomatic, but a new era began with the introduction of disease-modifying therapy that seems to alter the natural course of MS. Current drugs include three interferons (IFNs): IFN-beta1a (Avonex intramuscular; Biogen, Cambridge, USA; Rebif subcutaneous; Serono, Geneva, Switzerland), IFN-beta1b (Betaseron subcutaneous; Schering, Berlin, Germany) and glatiramer acetate (Copaxone subcutaneous; Teva, Petach Tikva, Israel). Ongoing research targeting a variety of mechanisms and processes means there is much promise for the future treatment of MS.

Thompson EJ, Freedman MS. · Department of Neuroimmunology, National Hospital for Neurology & Neurosurgery, Queen Square, London, Ontario, Canada. · Adv Neurol. · Pubmed #16400832 No free full text.

This publication has no abstract.

Freedman MS. · Department of Medicine (Neurology), University of Ottawa, Ottawa Hospital General Campus, 501 Smith Road, Box 601, Ottawa, Ontario K1H 8L6, Canada. · Mult Scler. · Pubmed #15218807 No free full text.

Abstract: Diagnosing the 'primary progressive' form of multiple sclerosis (PPMS) requires assurance that other conditions that might cause a chronic inflammatory neurodegenerative central nervous system (CNS) disease have been ruled out. Both imaging and pathological studies have shown that this form of MS tends to be less inflammatory compared with either the relapsing-remitting or secondary progressive types. There are therefore many conditions that cause a slowly progressive wasting of the CNS that might be confused with MS. The new MS diagnostic scheme has made the presence of 'typical' MS abnormalities in the cerebrospinal fluid (CSF) a mandatory first criterion, but there may well be individuals that still have PPMS even in the absence of a typical MS CSF. Here we explore what the CSF can tell about an individual's disease process and outline the current state of the art in terms of CSF analysis. Used properly, the CSF can be very helpful in clarifying a diagnosis of PPMS.

Freedman MS, Patry DG, Grand'Maison F, Myles ML, Paty DW, Selchen DH, Anonymous00249. · MS Research Clinic, University of Ottawa, Ottawa Hospital General Campus, Ottawa, Ontario, Canada. · Can J Neurol Sci. · Pubmed #15198439 No free full text.

Abstract: The treatment of multiple sclerosis has finally become possible with the advent of the current disease-modifying therapies (DMTs) that have had a significant impact on those living with this disease. Though demonstrating clear efficacy on a number of short-term outcome measures, unfortunately, these agents are not "cures" and many patients with multiple sclerosis continue to experience disease activity in spite of treatment. Clinicians are becoming more comfortable initiating therapy with DMTs, but it is now important to focus attention on monitoring the results of the chosen therapy and deciding whether or not a patient is responding well to treatment. At present, however, clinicians lack criteria for defining optimal versus suboptimal responses to DMTs as well as evidence-based guidelines on how to improve treatment outcomes. Using a recently published model as a framework, The Canadian Multiple Sclerosis Working Group developed practical recommendations on how neurologists can assess the status of patients on DMTs and decide when it may be necessary to modify treatment in order to optimize outcomes. The Canadian Multiple Sclerosis Working Group's recommendations are based on monitoring relapses, neurological progression and MRI activity. Other possible causes of suboptimal treatment responses or treatment failure are also considered.

MacLean HJ, Freedman MS. · Multiple Sclerosis Clinic, University of Ottawa, Ottawa Hospital-General Campus, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada. · Curr Neurol Neurosci Rep. · Pubmed #11898530 No free full text.

Abstract: The treatment of relapsing-remitting multiple sclerosis (RRMS), the most common form of multiple sclerosis, has been revolutionized in recent years. In addition to effective treatment of acute relapses, therapies are now available to prevent relapses, reduce the burden of disease as seen on magnetic resonance imaging, and possibly even slow the course of disease. There are now several agents either approved, awaiting approval, or in various stages of development in many countries. Evidence suggests that early intervention with these agents will yield the best results in the long run. The current approach to treatment of RRMS is the focus of this discussion.

Chen JT, Collins DL, Atkins HL, Freedman MS, Arnold DL, Anonymous00222. · McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada. · Ann Neurol. · Pubmed #18257039 No free full text.

Abstract: OBJECTIVE: To assess demyelination and remyelination in vivo in acute gadolinium (Gd)-enhancing lesions of multiple sclerosis (MS). METHODS: We measured significant changes in magnetization transfer ratio (MTR) consistent with demyelination and remyelination of individual lesion voxels, as well as the mean normalized MTR over all lesion voxels during and after contrast enhancement, in MS patients participating in a 3-year Canadian trial assessing immunoablation and autologous stem cell transplantation for treatment of MS. RESULTS: The average mean normalized lesion MTR over all lesions exhibited partial recovery over 2 to 4 months after Gd enhancement. Voxel-based analysis demonstrated that approximately 70% of the initially enhancing lesion volume (GdLV) was left with stably low MTR over 39 months of evaluation. The percentage of the GdLV undergoing significant increases in MTR consistent with remyelination increased for approximately 7 months after enhancement and then stabilized at 21 %GdLV. Significant decreases in MTR consistent with demyelination were ongoing for approximately 33 months after enhancement, stabilizing at 9 %GdLV. The estimated error of these measurements, based on scan/rescan analysis, was less than 0.4 %GdLV. INTERPRETATION: We found significant changes in MTR consistent with demyelination and remyelination that followed different temporal evolutions and were ongoing in different lesion regions for at least 3 years after lesion formation.

Polman C, Kappos L, Freedman MS, Edan G, Hartung HP, Miller DH, Montalbán X, Barkhof F, Selmaj K, Uitdehaag BM, Dahms S, Bauer L, Pohl C, Sandbrink R, Anonymous00310. · Vrije Universiteit Medical Centre, Amsterdam, The Netherlands. · J Neurol. · Pubmed #18004635 No free full text.

Abstract: BACKGROUND : The BENEFIT study examined interferon beta (IFNB)-1b treatment in patients with clinically isolated syndrome (CIS) and > or = 2 clinically silent brain MRI lesions. METHODS : Subgroups of 468 patients (IFNB-1b: n = 292; placebo: n = 176) were created for demographics, clinical, laboratory, and MRI findings at onset. The 'natural' risk of clinically definite MS (CDMS) over 2 years was estimated by Kaplan Meier statistics in placebo-treated patients; the IFNB-1b treatment effect was analysed by Cox proportional hazards regression. RESULTS : The risk of CDMS was increased in placebo-treated patients (overall 45 %) if they were younger (< 30 years: 60%), were cerebrospinal fluid (CSF)-positive (49 %), or had received steroid treatment (48 %). MRI parameters implied a higher risk in placebo-treated patients with > or = 9 T2-lesions (48%) or > or = 1 gadolinium (Gd)-enhancing lesions (52 %). The CDMS risk was highest (75 %) in placebo-treated patients with monofocal disease onset displaying MRI disease activity (> or = 1 Gd-lesion) and dissemination (> or = 9 T2-lesions). Treatment effects were significant across almost all subgroups including patients with less disease dissemination/activity at onset (monofocal: 55%; < 9 T2-lesions: 60%; no Gd-lesions: 57%) and patients without steroid treatment for the CIS (62 %). Monofocal patients had greater treatment effects if they had > or = 9 T2-lesions (61 %), Gd-lesions (58 %), or both (65 %). CONCLUSIONS : This study confirms the impact of age of onset, CSF and MRI findings on risk of conversion from CIS to CDMS. IFNB-1b treatment effect was robust across the study population including patients without MRI disease activity and less clinical or MRI disease dissemination at onset and patients not receiving steroids for the CIS.

Barkhof F, Polman CH, Radue EW, Kappos L, Freedman MS, Edan G, Hartung HP, Miller DH, Montalbán X, Poppe P, de Vos M, Lasri F, Bauer L, Dahms S, Wagner K, Pohl C, Sandbrink R. · Department of Diagnostic Radiology and Image Analysis Center, Vrije Universiteit Medical Center, PO Box 7057, 1007 MB Amsterdam, the Netherlands. · Arch Neurol. · Pubmed #17846268 links to  free full text

Abstract: BACKGROUND: In the Betaseron/Betaferon in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT) study, interferon beta-1b delayed conversion to multiple sclerosis in patients with a first clinical event and at least 2 clinically silent brain magnetic resonance imaging (MRI) lesions. OBJECTIVE: To examine detailed MRI findings from the first 2 years of this trial. DESIGN: Double-blind, placebo-controlled, randomized, parallel-group, multicenter, phase 3 study. SETTING: Ninety-eight centers worldwide. PATIENTS: A total of 404 individuals with a first demyelinating event suggestive of multiple sclerosis. INTERVENTIONS: Patients were randomized to receive interferon beta-1b, 250 microg subcutaneously every other day, or placebo. After 24 months of treatment or on conversion to clinically definite multiple sclerosis, open-label interferon beta-1b treatment was offered. MAIN OUTCOME MEASURES: Reported MRI data from patients completing 2 years of follow-up. RESULTS: Data were analyzed from 248 patients taking interferon beta-1b and 156 taking placebo. Across 2 years the cumulative number of newly active lesions was lower in patients receiving interferon beta-1b vs placebo (median, 2.0 vs 5.0 [reduction of 60%]; P < .001). This corresponded to lower cumulative numbers of new T2 lesions (median, 1.0 vs 3.0 [reduction of 66%]; P < .001) and new gadolinium-enhancing lesions (median, 0.0 vs 1.0; P < .001) in patients receiving interferon beta-1b vs placebo. From screening to month 24, T2 lesion volume decreased and was more pronounced in patients receiving interferon beta-1b (P = .02). CONCLUSIONS: Interferon beta-1b treatment had a robust effect on MRI measures, supporting its value as an early intervention in this patient group. This effect was maintained despite including patients who switched from placebo to interferon beta-1b in the active treatment group. Trial Registration clinicaltrials.gov Identifier: NCT00185211.

Kuhle J, Pohl C, Mehling M, Edan G, Freedman MS, Hartung HP, Polman CH, Miller DH, Montalban X, Barkhof F, Bauer L, Dahms S, Lindberg R, Kappos L, Sandbrink R. · Department of Research, University Hospital, Basel, Switzerland. · N Engl J Med. · Pubmed #17251533 links to  free full text

Abstract: BACKGROUND: Patients with a single episode of neurologic dysfunction and brain magnetic resonance imaging (MRI) scans suggestive of multiple sclerosis are at high risk for clinically definite multiple sclerosis, but the outcome for individual patients is unpredictable. An increased risk of progression to clinically definite multiple sclerosis in patients with serum antibodies against myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP) has been reported. METHODS: We measured serum anti-MOG and anti-MBP IgG and IgM antibodies in 462 patients with a first clinical event suggestive of multiple sclerosis and at least two clinically silent lesions on brain MRI. The patients were participating in a multicenter trial of treatment with interferon beta-1b. Antibodies were assessed by Western blot analysis at baseline, and the results compared with the time and rate of progression to clinically definite multiple sclerosis or a diagnosis of multiple sclerosis as defined by an international panel (the McDonald criteria). Regular visits were scheduled for the assessment of neurologic impairment and for MRI before treatment and at months 3, 6, 9, 12, 18, and 24. RESULTS: No associations were found between the presence of anti-MOG and anti-MBP IgM and IgG antibodies and progression to clinically definite multiple sclerosis or a diagnosis of multiple sclerosis according to the McDonald criteria, either in the entire cohort or in any subgroups of the study population. CONCLUSIONS: Serum antibodies against MOG and MBP, as detected by Western blot analysis, are not associated with an increased risk of progression to clinically definite multiple sclerosis in patients who have had a clinically isolated syndrome suggestive of multiple sclerosis.

O'Connor PW, Li D, Freedman MS, Bar-Or A, Rice GP, Confavreux C, Paty DW, Stewart JA, Scheyer R, Anonymous00137, Anonymous00138. · University of Toronto, Ontario, Canada. · Neurology. · Pubmed #16567708 No free full text.

Abstract: BACKGROUND: Teriflunomide, a dihydro-orotate dehydrogenase inhibitor, has immunomodulatory effects, including the ability to suppress experimental allergic encephalomyelitis. In this randomized, double-blind, placebo-controlled Phase II study, the authors examined the safety and efficacy of oral teriflunomide in multiple sclerosis (MS) with relapses. METHODS: Patients (n = 179) with relapsing-remitting MS (n = 157) or secondary progressive MS with relapses (n = 22) were randomized to receive placebo, teriflunomide 7 mg/day, or teriflunomide 14 mg/day for 36 weeks. MRI brain scans were performed every 6 weeks. The primary endpoint was the number of combined unique active lesions per MRI scan. Secondary endpoints included MRI-defined disease burden, relapse frequency, and disability increase. RESULTS: The median number of combined unique active lesions per scan was 0.5, 0.2, and 0.3 in the placebo, teriflunomide 7 mg/day (p < 0.03 vs placebo), and teriflunomide 14 mg/day (p < 0.01 vs placebo) groups during the 36-week double-blind treatment phase. Teriflunomide-treated patients also had significantly fewer T1 enhancing lesions per scan, new or enlarging T2 lesions per scan, and new T2 lesions. Patients receiving teriflunomide 14 mg/day had significantly reduced T2 disease burden. Teriflunomide treatment resulted in trends toward a lower annualized relapse rate and fewer relapsing patients (14 mg/day only) vs placebo. Significantly fewer patients receiving teriflunomide 14 mg/day vs placebo demonstrated disability increase. Treatment was well tolerated; numbers of adverse events and serious adverse events were similar in all treatment groups. CONCLUSION: Oral teriflunomide was effective in reducing MRI lesions and was well tolerated in patients with relapsing multiple sclerosis.

Chen JT, Collins DL, Freedman MS, Atkins HL, Arnold DL, Anonymous00328. · McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada H3A 2B4. · Neuroimage. · Pubmed #15850745 No free full text.

Abstract: Multiple sclerosis (MS) lesions show differing degrees of demyelination and remyelination. Changes in myelin content are associated with changes in magnetization transfer on MRI. Since acute inflammation and demyelination are spatially and temporally inhomogeneous, we hypothesized that local magnetic transfer ratio (MTR) heterogeneity might be predictive of subsequent changes in MTR. To test this hypothesis, we analyzed MTR images obtained in 14 subjects, at baseline and after 2 months follow-up. We segmented lesions and normal-appearing white-matter (NAWM), calculated MTR signal inhomogeneity maps at baseline and MTR lesion difference maps between baseline and follow-up. We found that regions with low MTR inhomogeneity at baseline experienced little further change in MTR on follow-up. The mean change in lesion MTR between baseline and follow-up was 0.10 +/- 3.70; in NAWM it was -0.09 +/- 2.02. We found that regions with high MTR inhomogeneity at baseline would change MTR on follow-up: (1) voxels with significantly high MTR in regions of high MTR inhomogeneity at baseline showed a mean decrease in MTR between baseline and follow-up of -2.51 +/- 4.68 in lesions and -1.41 +/- 3.00 in NAWM; (2) voxels with low MTR in regions of high MTR inhomogeneity at baseline showed a mean increase in MTR between baseline and follow-up of 2.61 +/- 6.07 in lesions. These changes in MTR were significantly different (P < 0.001). These results suggest that calculation of MTR signal inhomogeneity may provide a method for quantifying the potential for remyelination and demyelination, and thus could provide an important MRI biomarker for assessing the efficacy of therapies targeting remyelination.

Uitdehaag BM, Kappos L, Bauer L, Freedman MS, Miller D, Sandbrink R, Polman CH. · Department of Neurology, VU University Medical Centre, Amsterdam, The Netherlands. · Mult Scler. · Pubmed #15794398 No free full text.

Abstract: The new McDonald diagnostic criteria for multiple sclerosis (MS) incorporate detailed criteria for the interpretation and classification of magnetic resonance imaging (MRI) findings, but, in contrast, provide no instructions for the interpretation of clinical findings. Because MS according to the McDonald criteria is one of the primary endpoints in a large trial enrolling patients after the first manifestation suggestive for a demyelinating disease (BENEFIT study), it was decided to organize a centralized eligibility assessment for this trial. During this eligibility assessment it was observed that there were marked inconsistencies in the decisions of participating neurologists with respect to the classification of clinical symptoms as being caused by one or more lesions provoking discussions in about one in every five patients. This paper describes these inconsistencies and their sources, and recommends a systematic approach that attempts to reduce the variability in interpreting clinical findings.

Freedman MS, Francis GS, Sanders EA, Rice GP, O'Connor P, Comi G, Duquette P, Metz L, Murray TJ, Bouchard JP, Abramsky O, Pelletier J, O'Brien F, Anonymous00096, Anonymous00097. · Ottawa Hospital - General Campus, Ottawa, Ontario, Canada. · Mult Scler. · Pubmed #15732265 No free full text.

Abstract: BACKGROUND: Once weekly interferon beta-1a for multiple sclerosis (OWIMS) demonstrated modest, but significant, magnetic resonance imaging (MRI) benefit of once-weekly (qw) interferon (IFN) beta-1a at 48 weeks, but no significant effect on relapses. Objective: An OWIMS extension permitted assessment of longer-term efficacy/safety of qw IFN beta-1a in relapsing-remitting multiple sclerosis (RRMS). METHODS: Placebo patients were rerandomized to IFN beta-1a, 22 or 44 mcg qw, for two additional 48-week intervals. Primary outcome was MRI lesion activity. Relapse rate and other MRI measures were secondary outcomes. RESULTS: After three years, median (mean) T2 lesion count/patient/scan was 1.3 (2.6) for 44 mcg, 1.7 (3.3) for 22 mcg, 1.7 (3.4) for placebo/22 mcg, 2.0 (3.6) for placebo/44 mcg (all differences not significant). Annualized relapse rates were lowest for 44 mcg (0.77) versus other groups (0.83-0.86, not significant). Persistent neutralizing antibodies did not affect relapse rates, but MRI active lesions were increased in antibody-positive patients receiving 44 mcg compared to antibody negative patients. CONCLUSIONS: In RRMS, once weekly IFN beta-1a, particularly 44 mcg, can induce a significant MRI, but not relapse, effect, compared with placebo. No significant dose effect was seen. In contrast to the significant effect observed with three-times-weekly dosing of subcutaneous IFN beta-1a compared with placebo, this study confirms the lack of meaningful clinical benefit with once-weekly dosing.

Phillips JT, Rice G, Frohman E, Vande Gaer L, Scott T, Haas J, Eggenberger E, Freedman MS, Stuart W, Cunha L, Jacobs L, Oger J, Arnold D, Murray TJ, DiBiase M, Jethwa V, Goelz S. · Multiple Sclerosis Center at Texas Neurology, Baylor University Medical Center, 6301 Gaston Avenue, Suite 400 West Tower, Dallas, TX 75214, USA. · Clin Ther. · Pubmed #15189748 No free full text.

Abstract: BACKGROUND: A new liquid formulation of Avonex (interferon beta-1a [IFNbeta-1a]) in a prefilled syringe has been developed to make administration of the drug easier for patients with multiple sclerosis (MS). This formulation does not contain human serum albumin (HSA), often added to interferon (IFN) products for stabilization. However, formulation changes may alter the secondary, tertiary, and quaternary structures of IFNbeta products. These kinds of structural changes could lead to the formation of antibodies directed against IFNbeta. Some of these anti-IFN antibodies may neutralize the biologic activity of IFNbeta. OBJECTIVE: This study was designed to determine the immunogenicity and safety of the new prefilled syringe (liquid) HSA-free formulation of Avonex in patients with relapsing MS. METHODS: This was a multicenter, single-arm, open-label study. Patients with relapsing MS received liquid, HSA-free Avonex 30 microg by IM injection from a prefilled syringe once weekly for up to 24 months. Immunogenicity and safety were assessed every 3 months. Serum levels of neutralizing antibodies (NAbs) were measured at baseline and every 3 months using a 2-step enzyme-linked immunosorbent assay and antiviral cytopathic effect assay. RESULTS: A total of 153 patients (121 women, 32 men; mean [SD] age, 39.6 [9.9] years; age range, 19.0-59.0 years) were enrolled in the study. Sera were available for analysis from 125 and 119 patients after 18 and 24 months of treatment, respectively. By 18 months, 1 patient (1%) had > or =2 consecutive titers of > or =20, a level at which the persistent presence of NAbs has been shown in some studies to have clinical consequences. By 24 months, 1 additional patient (total 2%) had > or =2 consecutive titers of > or =20. At 18 months, 5 patients (4%) had > or =1 NAb titer of > or =5; at 24 months, 6 patients (5%) had > or =1 NAb titer of > or =5. The safety profile of liquid Avonex was comparable to the lyophilized form containing HSA. CONCLUSIONS: The prefilled syringe (liquid) HSA-free formulation of Avonex was well tolerated and showed a low level of immunogenicity. Over 24 months, 2% of patients developed persistent NAbs (> or =2 consecutive titers of > or =20).

Nielsen JM, Pohl C, Polman CH, Barkhof F, Freedman MS, Edan G, Miller DH, Bauer L, Sandbrink R, Kappos L, Uitdehaag BM. · MS Center, Department of Neurology, VU Medical Center, Amsterdam, the Netherlands. · BMC Neurol. · Pubmed #19457248 links to  free full text

Abstract: BACKGROUND: To diagnose multiple sclerosis (MS), evidence for dissemination in space and time is required. There is no clear definition on how symptoms and signs of a patient indicate clinical dissemination in space. To provide a uniform approach on this subject, a clinical classification system was described recently differentiating patients with mono- and multifocal clinical presentation. Here we assess the predictive value of clinically defined dissemination in space at first presentation for time to clinically definite MS (CDMS). METHODS: Four hundred and sixty-eight patients with a first episode suggestive of MS were classified as clinically mono- or multifocal by two neurologists blinded to magnetic resonance imaging (MRI) results. These patients were part of the BENEFIT study in which 292 patients were randomized to interferon beta-1b (IFNB-1b) and 176 to placebo. By using Kaplan-Meier statistics the risk for CDMS was studied in mono- and multifocal patients of the placebo group, both with and without taking into account MRI measures of potential prognostic relevance. RESULTS: Time to CDMS was similar in monofocal and multifocal patients. In monofocal patients, the risk for CDMS over 2 years was significantly higher when >or= 9 T2 lesions or at least one Gd-enhancing lesion were present at the first event or 3 or 6 months after the first event. In patients with multifocal presentation, these MRI measures had no significant added value in predicting time to CDMS. CONCLUSION: These data indicate that a carefully performed neurological assessment of symptoms and signs, combined with lesions on MRI, is important for defining the risk of conversion to CDMS. TRIAL REGISTRATION: The Benefit trial has been registered under NCT00185211 http://www.clinicaltrials.gov.

Smith AM, Walker LA, Freedman MS, DeMeulemeester C, Hogan MJ, Cameron I. · School of Psychology, University of Ottawa, Ottawa, Canada. · J Neurol Sci. · Pubmed #19344919 No free full text.

Abstract: Although deficits in executive functioning are well known cognitive sequelae of multiple sclerosis (MS), less is known about patients' performance on response inhibition tasks in particular. Behavioural observation of cognitively impaired MS patients often reveals impulsivity. However, knowledge about associated neural activity during response inhibition measurable with functional magnetic resonance imaging (fMRI) is lacking. In the current study the performance and fMRI activation patterns of patients with MS on a response inhibition task (Go/No-Go) were investigated. METHODS: Ten cognitively impaired patients with MS (with little or no physical disability) and 10 sex-, age- and education-matched healthy controls performed a Go/No-Go task while in the MR scanner. RESULTS: MS patients had significantly more commission errors than controls but did not demonstrate longer reaction times. Controlling for this difference, whole brain random effects analyses revealed that patients demonstrated more activation than controls in the fusiform gyrus, cingulate gyrus (including the anterior cingulate gyrus), cerebellum and putamen. Patients demonstrated less activity than controls in the supramarginal gyrus. CONCLUSIONS: MS patients exhibited significant neural compensation during response inhibition when compared with controls. The specific results provide new insight into the neural processing underlying the impulsivity often observed in cognitively impaired individuals with MS.

Freedman MS, Laks J, Dotan N, Altstock RT, Dukler A, Sindic CJ. · University of Ottawa, The Ottawa Hospital-General Campus, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6. · Mult Scler. · Pubmed #19324980 No free full text.

Abstract: BACKGROUND: There is no specific serum-based biomarker for the diagnosis or prognosis of relapsing-remitting multiple sclerosis (RRMS). OBJECTIVE: We investigated whether levels of IgM antibodies to Glc(alpha1,4)Glc(alpha) (GAGA4) or to a panel of four glucose-based glycans could differentiate MS from other neurological diseases (OND) or predict risk of early relapse following first presentation (FP) of RRMS. METHODS: Retrospective analysis of 440 sera samples of three cohorts: A) FP-RRMS (n = 44), OND (n = 44); B) FP-RRMS (n = 167), OND (n = 85); and C) FP (n = 100). Anti-GAGA4 IgM levels were measured by enzyme immunoassay in cohort-A and cohort-B. Cohort-C IgM antibodies to glucose-based glycan panel were measured by immunofluorescence. RESULTS: FP-RRMS had higher levels of anti-GAGA4 IgM than OND patients (cohort-A, P = 0.01; cohort-B, P = 0.0001). Sensitivity and specificity were 27% and 97% for cohort-A; and 26% and 90% for cohort-B, respectively. In cohort-C, 58 patients experienced early relapse (<24 months), 31 had late relapse (> or =24 months), and 11 did not experience second attack during follow-up. Kaplan-Meier curves demonstrated decrease in time to next relapse for patients positive for the antibody panel (P = 0.02, log rank). CONCLUSIONS: Serum anti-GAGA4 IgM discerns FP-RRMS patients from OND patients. Higher levels of serum anti-alpha-glucose IgM in FP patients predict imminent early relapse.