Multiple Sclerosis: Cohen JA

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.

Goldman MD, Cohen JA. · No affiliation provided · Neurology. · Pubmed #18955682 No free full text.

This publication has no abstract.

Cohen JA, Antel JP. · No affiliation provided · Neurology. · Pubmed #15557486 No free full text.

This publication has no abstract.

Bermel RA, Fisher E, Cohen JA. · Mellen Center for MS Treatment and Research, Neurological Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. · Neuroimaging Clin N Am. · Pubmed #19068409 No free full text.

Abstract: MR imaging is an integral part of multiple sclerosis (MS) clinical trials. It provides the primary efficacy outcome of preliminary proof-of-concept studies and important corroborating data as secondary and exploratory outcomes in pivotal trials. At all stages of drug development, MR imaging provides important information on the kinetics and magnitude of treatment effect and insight into potential mechanisms of action. Attention to issues in scan acquisition, quantitative image processing, and statistical analysis is critical to generate high-quality data. Although it is unlikely that one single outcome measure can capture all aspects of the MS disease process, there is potential for MR imaging outcomes to evaluate inflammatory and degenerative components within clinical trials.

Boissy AR, Cohen JA. · Cleveland Clinic Foundation, Mellen Center U-10, 9500 Euclid Avenue, Cleveland, OH 44195, USA. · Expert Rev Neurother. · Pubmed #17868019 No free full text.

Abstract: Multiple sclerosis (MS) is the most common cause of nontraumatic disability in young adults. The increasing emphasis on early treatment with disease-modifying therapies has the goal of preventing long-term disability. However, current disease treatments are only partially effective, and most patients experience a variety of neurologic symptoms at various times during their disease course. Because these symptoms often have a profound impact on social, occupational and physical performance, effective symptom management is an important component of therapy to maintain quality of life. Effective symptom management often requires a multidisciplinary team approach. This review outlines general principles of the management of MS symptoms.

Goldman MD, Cohen JA, Fox RJ, Bethoux FA. · Mellen Center for Multiple Sclerosis Treatment and Research, Department of Neurology, Cleveland Clinic Foundation, OH 44195, USA. · Cleve Clin J Med. · Pubmed #16478042 links to  free full text

Abstract: Multiple sclerosis (MS) has protean manifestations, and the care of people with MS presents many unique challenges. Clinicians can have an important impact on health, quality of life, and daily functioning by participating in open dialogue, tailoring focused treatment plans, and anticipating general medical needs.

Fox RJ, Bethoux F, Goldman MD, Cohen JA. · Mellen Center for Multiple Sclerosis Treatment and Research, Department of Neurology, The Cleveland Clinic Foundation, OH 44195, USA. · Cleve Clin J Med. · Pubmed #16444920 links to  free full text

Abstract: Recent advances in our understanding of the diagnosis, imaging, pathology, and clinical monitoring of multiple sclerosis (MS) have significantly increased our ability to successfully treat this often perplexing neurologic disorder. Magnetic resonance imaging (MRI) is now integral to the diagnostic process. Treatment of MS can be considered as three parallel pathways: treatment of relapses, symptom management, and long-term prevention of tissue injury.

Weiner HL, Cohen JA. · Multiple Sclerosis Center, Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School, Boston 02115, USA. · Mult Scler. · Pubmed #11990872 No free full text.

Abstract: Cyclophosphamide is an alkylating agent used to treat malignancies and immune-mediated inflammatory non-malignant processes such as lupus nephritis and immune-mediated neuropathies. It has been studied as a treatment for multiple sclerosis (MS) for the past 30 years and is used by physicians in selected cases of progressive or worsening MS. Review of published reports suggests that it is efficacious in cases of worsening MS that have an inflammatory component as evidenced by relapses and/or gadolinium (Gd)-enhancing lesions on magnetic resonance imaging (MRI) or in patients in earlier stages of disease where inflammation predominates over degenerative processes in the central nervous system (CNS). There is no evidence of efficacy in primary progressive MS or later stages of secondary progressive MS. Although a general immunosuppressant that affects both T- and B-cell function, cyclophosphamide has selective immune effects in MS by suppressing IL-12 and Th1-type responses and enhancing Th2/Th3 responses (IL-4, IL-10, TGF-beta; eosinophils in peripheral blood). Side effects include nausea, alopecia, infertility, bladder toxicity and risk of malignancy. The most commonly used regimens involve every 4- to 8-week outpatient i.v. pulse therapy given with or without corticosteroids and are usually well-tolerated by patients. Cyclophosphamide is currently used in patients whose disease is not controlled by beta-interferon or glatiramer acetate and those with rapidly worsening MS.

Cohen JA, Fisher RS, Brigell MG, Peyster RG, Sze G. · Mellen Center for Multiple Sclerosis Treatment and Research, Department of Neurology, Cleveland Clinic Foundation, Ohio 44195, USA. · Epilepsia. · Pubmed #10691111 No free full text.

Abstract: PURPOSE: Vigabatrin (Sabril, Hoechst Marion Roussel) is an antiepilepsy drug (AED) presently marketed in 64 countries for the treatment of partial and secondarily generalized seizures. Vigabatrin (VGB) is marketed in a subset of these countries for the treatment of infantile spasms. Clinical experience in humans has shown that VGB provides effective seizure control with a wide margin of safety. However, animal toxicity studies raised concern when prolonged administration of VGB was shown to induce intramyelinic edema (IME) in some laboratory animal species. METHODS: Animal and human data were reviewed with respect to the potential for VGB-induced IME. Surveillance of patients receiving VGB in clinical trials or by prescription has been conducted for >15 years to identify patients developing clinical abnormalities that might be IME related. RESULTS: The histologic lesions of VGB-induced IME in animals are reliably reproduced and correlate with changes in multimodality evoked potentials (EPs) and magnetic resonance imaging (MRI). Numerous studies of the effects of VGB on EP and MRI in epilepsy patients have demonstrated no clear-cut IME-related changes in these modalities. Additionally, autopsy and surgical brain samples from VGB-treated patients have been scrutinized for potential IME histopathology. In an estimated 350,000 patient-years of VGB exposure (approximately 175,000 patients exposed for 2 years at an average dose of 2 g/day), no definite case of VGB-induced IME has been identified. CONCLUSIONS: Comprehensive review of a variety of sources of data failed to identify any definite case of IME in humans treated with VGB.

Cohen JA, Carter JL, Kinkel RP, Schwid SR. · Mellen Center for Multiple Sclerosis Treatment and Research, Department of Neurology, Cleveland Clinic Foundation, OH 44195, USA. · J Neuroimmunol. · Pubmed #10426359 No free full text.

Abstract: There is increasing impetus to begin disease-modifying therapy for relapsing multiple (R-MS) early, before the development of irreversible tissue damage and resultant permanent disability. However, all of the currently-approved therapies for relapsing multiple sclerosis are only partially effective for patients as a group. Treatment failure can be due to noncompliance with therapy, intolerable adverse effects, the development of neutralizing antibodies, or non-responsive disease. Neurologists managing patients on disease-modifying therapy for R-MS must remain vigilant for these issues and take appropriate action when necessary.

Goodman AD, Brown TR, Cohen JA, Krupp LB, Schapiro R, Schwid SR, Cohen R, Marinucci LN, Blight AR, Anonymous00326. · Multiple Sclerosis Center, Chief Neuroimmunology Unit, Department of Neurology, University of Rochester Medical Center, 601 Elmwood Ave., Room 6-8521, Box 605, Rochester, NY 14642, USA. · Neurology. · Pubmed #18672472 No free full text.

Abstract: OBJECTIVE: To examine the efficacy and safety of three different doses of sustained-release fampridine in people with multiple sclerosis (MS). METHOD: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study recruited 206 participants at 24 centers in the United States and Canada. After a single-blind, 2-week placebo run-in, participants were randomly assigned to receive fampridine (10, 15, or 20 mg twice daily) or placebo for 15 weeks. The primary efficacy variable was percent change in walking speed based on the timed 25-foot walk. RESULTS: Trends for increased walking speed were consistent across dose groups vs placebo, but not significant, on the prospective analysis. An increase from baseline in lower extremity strength during the 12-week stable-dose period was seen in the groups receiving 10- and 15-mg doses, compared with placebo (p = 0.018 and 0.003). There were no significant changes in other secondary assessments. Post hoc analysis revealed subsets of participants in each dose group with walking speeds during the treatment period that were consistently faster than during the nontreatment period. There were significantly more "consistent responders" in the drug-treated groups than in the placebo group (36.7% compared with 8.5%). Consistent responders showed significantly greater improvement in self-assessed ambulation on the 12-Item MS Walking Scale than did nonresponders. Fampridine was generally well tolerated. Severe and serious adverse events were more frequent at the highest dose. CONCLUSIONS: This phase 2 study suggests that a subgroup of patients, when treated with fampridine, experiences a clinically relevant improvement in walking ability, which is sustained for at least 14 weeks.

Cohen JA, Calabresi PA, Chakraborty S, Edwards KR, Eickenhorst T, Felton WL, Fisher E, Fox RJ, Goodman AD, Hara-Cleaver C, Hutton GJ, Imrey PB, Ivancic DM, Mandell BF, Perryman JE, Scott TF, Skaramagas TT, Zhang H, Anonymous00159. · Mellen Center, Cleveland Clinic Foundation, Cleveland, OH 44195, USA. · Mult Scler. · Pubmed #18208877 No free full text.

Abstract: OBJECTIVE: To review the rationale, design and baseline data of the Avonex Combination Trial (ACT), an investigator-run study of intramuscular interferon beta-1a (IM IFNbeta-1a) combined with methotrexate (MTX) and/or IV methylprednisolone (IVMP) in relapsing-remitting multiple sclerosis (RRMS) patients with continued disease activity on IM IFNbeta-1a monotherapy. METHODS: Eligibility criteria included RRMS, Expanded Disability Status Scale score 0-5.5, and >or=1 relapse or gadolinium-enhancing MRI lesion in the prior year while on IM IFNbeta-1a monotherapy. Subjects continued IFNbeta-1a 30 mcg IM weekly and were randomized in a 2 x 2 factorial design to adjunctive weekly placebo or MTX 20 mg PO, with or without IVMP 1,000 mg/day for three days every other month. ACT was industry-supported, and collaboratively designed and governed by an Investigator Steering Committee with independent Advisory and Data Safety Monitoring Committees. Study operations, MRI analysis and aggregated data were managed by the Cleveland Clinic MS Academic Coordinating Center. RESULTS: In total 313 subjects were enrolled with clinical and MRI characteristics typical of RRMS. Most subjects (86.9%) qualified with a clinical relapse, with or without an enhancing MRI lesion, in the preceding year. At baseline, 21.4% had enhancing lesions, and 5.1% had anti-IFNbeta neutralizing antibodies. ACT's management and operational structures functioned well. CONCLUSION: This study provides an innovative model for academic-industry collaborative MS research and will enhance understanding of the utility of combination therapy for RRMS patients with continued disease activity on an established first-line treatment.

Goldman MD, Marrie RA, Cohen JA. · Department of Neurology, University of Virginia, Charlottesville, VA 22908, USA. · Mult Scler. · Pubmed #17942508 No free full text.

Abstract: OBJECTIVE: To assess the characteristics of the 6-min walk (6MW) in multiple sclerosis (MS) subjects of varied disability, and controls. To assess the correlation of 6MW to subjective measures of fatigue, health status and ambulation using the modified fatigue impact scale (MFIS), short form-36 Health Questionnaire physical component score and MS walking scale (MSWS). METHODS: Forty MS expanded disability status scale [(EDSS) 0-6.5] and 20 control subjects were recruited from a MS outpatient clinic. Subjects completed survey material and three 6MWs with 1-h interval rest in a single study visit. RESULTS: There was no practice effect or fatigability with repeat 6MW tests with a one-h rest period between test sessions. The 6MW had excellent intra-[intraclass correlation coefficient (ICC) = 0.95] and inter-rater (ICC = 0.91) reliability. MS subjects demonstrated reduced 6MW distance and speed compared with controls (P < 0.0001). Within the MS population 6MW distance was significantly reduced with increasing disability (P = 0.05). Compared with the EDSS, the 6MW had a stronger correlation to subjective measures of ambulation and physical fatigue: MSWS (r = -0.81 versus 0.69) and MFISphy (0.66 versus 0.63). CONCLUSIONS: The 6MW is a feasible, reproducible, and reliable measure in MS. MS subjects demonstrate motor fatigue in both 6MW distance and speed compared with controls. In MS subjects there is an inverse relationship between motor fatigue and disability. 6MW has a strong correlation to subjective measures of ambulation and physical fatigue.

Smith DR, Weinstock-Guttman B, Cohen JA, Wei X, Gutmann C, Bakshi R, Olek M, Stone L, Greenberg S, Stuart D, Orav J, Stuart W, Weiner H. · Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA. · Mult Scler. · Pubmed #16193896 No free full text.

Abstract: OBJECTIVE: To evaluate the efficacy and safety of combination therapy with pulse cyclophosphamide given with methylprednisolone (MP) and interferon beta (IFNbeta)-Ia in multiple sclerosis (MS) patients with active disease during IFNbeta monotherapy. METHODS: This was a randomized, single-blind, parallel-group, multicenter trial in MS patients with a history of active disease during IFNbeta treatment. Patients were randomized to either cyclophosphamide 800 mg/m2 plus methylprednisolone 1 g IV (CY/MP) or methylprednisolone once a month for six months and then followed for an additional 18 months. All patients received three days of methylprednisolone 1 g IV at screening and 30 mcg IFNbeta-Ia IM weekly for the entire 24 months. The primary endpoint was change from baseline in the mean number of gadolinium-enhancing (Gd+) lesions. Secondary clinical endpoints included time to treatment failure. RESULTS: Fifty-nine patients were randomized to treatment: 30 to CY/MP and 29 to MP Change from baseline in the number of Gd+ lesions was significantly different between treatment groups at three (P =0.01), six (P =0.04) and 12 months (P =0.02), with fewer lesions in the CY/MP group. The cumulative rate of treatment failure was significantly lower in the CY/MP group compared with the MP group (rate ratio =0.30; 95% confidence interval, 0.12-0.75; P =0.011). CY/MP treatment was well tolerated. CONCLUSION: Combination therapy with CY/MP and IFNbeta-Ia decreased the number of Gd+ lesions and slowed clinical activity in patients with previously active disease on IFNbeta alone.

Fox RJ, Fisher E, Tkach J, Lee JC, Cohen JA, Rudick RA. · Department of Neurology (Mellen Center), Cleveland Clinic Foundation, Cleveland, OH 44195, USA. · Mult Scler. · Pubmed #15794385 No free full text.

Abstract: BACKGROUND: The short-term effect of corticosteroids on MRI measures of multiple sclerosis (MS) is not well understood and may have a significant impact when using these quantitative measures to evaluate disease activity and changes following other therapeutic interventions. OBJECTIVE: To determine the impact of a course of intravenous methylprednisolone (IVMP) on quantitative measures of disease activity and tissue injury in MS patients. METHODS: We prospectively measured brain parenchymal fraction (BPF), magnetization transfer ratio (MTR, lesional and whole brain), and lesion volumes on nine weekly brain MRI studies in ten MS patients receiving a course of IVMP. A group of nine MS patients not receiving IVMP served as controls. RESULTS: In comparison to untreated controls, BPF declined over the eight weeks following IVMP treatment (P <0.02). BPF decline was most prominent in patients with secondary progressive MS (SPMS, P <0.03), and was not seen in relapsing-remitting (RR) MS patients. Short-term change in BPF correlated with baseline BPF (r =0.62, P =0.05) and short-term change in lesional MTR (r = -0.55, P =0.03), but not with change in enhancing lesion volume. Short-term change in lesional MTR inversely correlated with baseline lesional and whole brain MTR (r = -0.79, P =0.04 for both). There was no significant difference between treated and control patients in measures of MTR or T2, T1 or enhancing lesion volumes. CONCLUSIONS: Patients with SPMS showed a greater decline in BPF following IVMP than RRMS patients. A correlation between changes in BPF and MTR suggest that these changes are secondary to altered water content within MS lesions. Differential response to a standardized therapeutic intervention in RRMS and SPMS suggests that responses to therapy may differ due to a fundamental pathologic difference between early and late stage MS.

Baier ML, Cutter GR, Rudick RA, Miller D, Cohen JA, Weinstock-Guttman B, Mass M, Balcer LJ. · Center for Research Methodology and Biometrics, Cooper Institute, 14023 Denver West Parkway, 100, Golden, CO 80401, USA. · Neurology. · Pubmed #15781814 No free full text.

Abstract: OBJECTIVE: To evaluate concurrent and predictive validity for low-contrast letter acuity (L-CLA) testing as a candidate visual component for the Multiple Sclerosis Functional Composite (MSFC). METHODS: L-CLA testing was conducted in two MS patient cohorts. In the MSFC Validation Study, 137 participants from a Phase III trial of inteferon beta-1a (Avonex) for relapsing-remitting MS were followed. A second cohort included 65 patients with secondary progressive MS who participated in a substudy of the International MS Secondary Progressive Avonex Controlled Trial (IMPACT). The total number of letters read correctly at four contrast levels (100, 5, 1.25, and 0.6%) was correlated with Expanded Disability Status Scale (EDSS), MSFC, Sickness Impact Profile, Multiple Sclerosis Quality of Life Inventory, and brain parenchymal fraction (BPF), as determined by MRI. RESULTS: Low- and high-contrast letter acuity scores correlated with BPF at follow-up in the MSFC Validation Study (5%: r = 0.40, p < 0.0001; 100%: r = 0.31, p = 0.0002). L-CLA also correlated with EDSS (5%: r = -0.35, p < 0.0001; 1.25%: r = -0.26, p = 0.0003) and MSFC (5%: r = 0.47, p < 0.0001; 1.25%: r = 0.45, p < 0.0001). In the IMPACT Substudy, change in L-CLA scores from baseline to year 1 predicted subsequent change in the EDSS from year 1 to 2 at the 5% (p = 0.0142) and the 1.25% (p = 0.0038) contrast levels, after adjusting for change in MSFC scores from baseline to year 1. CONCLUSIONS: Low-contrast letter acuity (L-CLA) scores demonstrate concurrent and predictive validity in patients with relapsing-remitting and secondary progressive multiple sclerosis (MS). L-CLA testing provides additional information relevant to the MS disease process that is not entirely captured by the Multiple Sclerosis Functional Composite.

Cohen JA, Cutter GR, Fischer JS, Goodman AD, Heidenreich FR, Kooijmans MF, Sandrock AW, Rudick RA, Simon JH, Simonian NA, Tsao EC, Whitaker JN, Anonymous00071. · Mellen Center for Multiple Sclerosis Treatment and Research, Department of Neurology, Cleveland Clinic Foundation, OH 44195, USA. · Neurology. · Pubmed #12221157 No free full text.

Abstract: BACKGROUND: Interferon beta-1a (IFNbeta-1a, Avonex) is efficacious in relapsing forms of MS. Studies of other IFNbeta preparations in secondary progressive MS (SPMS) yielded conflicting results. This study was undertaken to determine whether IFNbeta-1a slowed disease progression in SP-MS. METHODS: A total of 436 subjects with SPMS and Expanded Disability Status Scale (EDSS) score 3.5 to 6.5 were randomized to receive IFNbeta-1a (60 micro g) or placebo by weekly intramuscular injection for 2 years. The primary outcome measure, used for the first time in a large-scale MS trial, was baseline to month 24 change in the MS Functional Composite (MSFC), comprising quantitative tests of ambulation (Timed 25-Foot Walk), arm function (Nine-Hole Peg Test [9HPT]), and cognition (Paced Auditory Serial Addition Test [PASAT]). RESULTS: Median MSFC Z-score change was reduced 40.4% in IFNbeta-1a subjects (-0.096 vs -0.161 in placebo subjects, p = 0.033), an effect driven mainly by the 9HPT and PASAT. There was no discernible benefit on the EDSS, which in this range principally reflects walking ability. IFNbeta-1a subjects had 33% fewer relapses (p = 0.008). There was significant benefit on eight of 11 MS Quality of Life Inventory subscales. New or enlarging T2-hyperintense brain MRI lesions and gadolinium-enhancing lesions were reduced at months 12 and 24 (both p < 0.001). IFNbeta-1a was well tolerated by the majority of subjects. Neutralizing antibodies developed in 3.3% of IFNbeta-1a-treated subjects. CONCLUSIONS: IFNbeta-1a demonstrated benefit on MSFC progression, relapses, quality of life, and MRI activity in SPMS.

Cohen JA, Cutter GR, Fischer JS, Goodman AD, Heidenreich FR, Jak AJ, Kniker JE, Kooijmans MF, Lull JM, Sandrock AW, Simon JH, Simonian NA, Whitaker JN. · The Mellen Center-U10, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195, USA. · Arch Neurol. · Pubmed #11405811 links to  free full text

Abstract: BACKGROUND: The Multiple Sclerosis Functional Composite (MSFC) is a multidimensional clinical outcome measure that includes quantitative tests of leg function/ambulation (Timed 25-Foot Walk), arm function (9-Hole Peg Test), and cognitive function (Paced Auditory Serial Addition Test). The MSFC is the primary outcome measure in the ongoing multinational phase 3 trial of interferon beta-1a (Avonex) in patients with secondary progressive MS. OBJECTIVE: To assess the practice effects, reliability, and validity of the MSFC clinical outcome measure. DESIGN: Examining technicians underwent formal training using standardized materials. The MSFC was performed according to a standardized protocol. The 436 patients enrolled in the International Multiple Sclerosis Secondary Progressive Avonex Controlled Trial underwent 3 prebaseline MSFC testing sessions before randomization. RESULTS: Practice effects were evident initially for the MSFC but stabilized by the fourth administration. The Paced Auditory Serial Addition Test demonstrated the most prominent practice effects. The reliability of the MSFC was excellent, with an intraclass correlation coefficient for session 3 (final prebaseline session) vs session 4 (baseline) of 0.90. The MSFC at baseline correlated moderately strongly with the Kurtzke Expanded Disability Status Scale. Among the MSFC components, the Timed 25-Foot Walk correlated most closely. Correlations among the 3 MSFC components were weak, suggesting they assess distinct aspects of neurologic function in patients with MS. CONCLUSIONS: The MSFC demonstrated excellent intrarater reliability in this multinational phase 3 trial. Three prebaseline testing sessions were sufficient to compensate for practice effects. The pattern of correlations among the MSFC, its components, and the Kurtzke Expanded Disability Status Scale supported the validity of the MSFC.

Cohen JA. · Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, Ohio 44195, USA. · Arch Neurol. · Pubmed #19597083 No free full text.

Abstract: Six agents are currently approved by regulatory agencies to treat relapsing multiple sclerosis. Although these agents are effective and generally safe, some patients have continued disease activity or adverse effects. A sizable number of new agents are under investigation currently. This article reviews emerging agents that have shown promise in phase 2 trials.

Mehta LR, Schwid SR, Arnold DL, Cutter GR, Aradhye S, Balcer LJ, Calabresi PA, Cohen JA, Cole PE, Glanzman R, Goelz S, Inglese M, Kapoor R, Kappos L, Kreitman R, Lublin FD, Mann A, Marrie RA, O'Looney P, Polman CH, Ravina BM, Reingold SC, Richert JR, Sandrock AW, Waubant E. · University of Rochester Department of Neurology, Rochester, NY, USA. · Mult Scler. · Pubmed #19389749 No free full text.

Abstract: BACKGROUND: There is considerable interest in tissue-protective treatments for multiple sclerosis (MS). METHODS AND OBJECTIVES: We convened a group of MS clinical trialists and related researchers to discuss designs for proof of concept studies utilizing currently available data and assessment methods. RESULTS: Our favored design was a randomized, double-blind, parallel-group study of active treatment versus placebo focusing on changes in brain volume from a post-baseline scan (3-6 months after starting treatment) to the final visit 1 year later. Study designs aimed at reducing residual deficits following acute exacerbations are less straightforward, depending greatly on the anticipated rapidity of treatment effect onset. CONCLUSIONS: The next step would be to perform one or more studies of potential tissue-protective agents with these designs in mind, creating the longitudinal data necessary to refine endpoint selection, eligibility criteria, and sample size estimates for future trials.

Cohen JA, Imrey PB, Calabresi PA, Edwards KR, Eickenhorst T, Felton WL, Fisher E, Fox RJ, Goodman AD, Hara-Cleaver C, Hutton GJ, Mandell BF, Scott TF, Zhang H, Apperson-Hansen C, Beck GJ, Houghtaling PL, Karafa MT, Stadtler M, Anonymous00019. · Mellen Center U-10, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. · Neurology. · Pubmed #19204263 No free full text.

Abstract: OBJECTIVE: To assess the safety, tolerability, and efficacy of interferon beta-1a (IFNbeta-1a) combined with methotrexate (MTX), i.v. methylprednisolone (IVMP), or both in patients with relapsing-remitting multiple sclerosis (RRMS) with continued disease activity on IFNbeta-1a monotherapy. METHODS: Eligibility criteria included RRMS, Expanded Disability Status Scale score 0-5.5, and > or = 1 relapse or gadolinium-enhancing MRI lesion in the prior year on IFNbeta-1a monotherapy. Participants continued weekly IFNbeta-1a 30 microg i.m. and were randomized in a 2 x 2 factorial design to adjunctive weekly placebo or MTX 20 mg p.o., with or without bimonthly IVMP 1,000 mg/day for 3 days. The primary endpoint was new or enlarged T2 lesion number at month 12 vs baseline. The study was industry-supported, collaboratively designed, and governed by an investigator Steering Committee with independent Advisory and Data Safety Monitoring committees. Study operations, MRI analyses, and aggregated data were managed by an academic coordinating center. RESULTS: The 313 participants had clinical and MRI characteristics typical of RRMS. Combinations of IFNbeta-1a with MTX or IVMP were generally safe and well tolerated. Although trends suggesting modest benefit were seen for some outcomes for IVMP, the results did not demonstrate significant benefit for either adjunctive therapy. The data suggested IVMP reduced anti-IFNbeta neutralizing antibody titers. CONCLUSIONS: This trial did not demonstrate benefit of adding low-dose oral methotrexate or every other month IV methylprednisolone to interferon beta-1a in relapsing-remitting multiple sclerosis.

Cohen JA. · Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic Foundation, Cleveland, OH, USA. · J Neurol Sci. · Pubmed #19200869 No free full text.

Abstract: Recent years have seen considerable evolution and increasing sophistication of our concepts of the pathophysiology of multiple sclerosis. These new notions include the increased recognition of the importance of extralesional pathology, of the interplay between inflammation and neurodegenerative changes, pathophysiological heterogeneity and additional immune cell populations contributing to disease. These advances have driven the development and evaluation of new therapeutic strategies and outcome measures for clinical trials. A sizeable number of new immunomodulatory and immunosuppressive agents are under development and attracting great attention. These may offer potential advantages over existing treatments in terms of convenience and efficacy, but certain agents may raise safety concerns. In addition, neuroprotective and repair strategies are beginning to be considered. Not all of these agents will eventually be marketed but they will all help us gain insight into the pathophysiology of multiple sclerosis and decipher the mechanisms that underlie its heterogeneity. The place that these therapies will come to occupy in future years will depend on their relative benefits and risks.

Cohen JA. · Cleveland Clinic Lerner College of Medicine, Cleveland, OH 44195, USA. · Nat Clin Pract Neurol. · Pubmed #18852726 No free full text.

Abstract: Intravenous immunoglobulin (IVIg) has been extensively used to treat humoral immunodeficiency states and various immune-mediated conditions. Several studies indicate that the benefits of IVIg with respect to relapses and MRI lesion activity compare favorably with those of interferon beta and glatiramer acetate in relapsing-remitting multiple sclerosis (RRMS) or clinically isolated syndromes. Fazekas et al. recently reported the results of a multinational, randomized, double-blind, placebo-controlled phase II trial of a new preparation of IVIg in 127 participants with RRMS. No significant benefit was demonstrated for IVIg compared with placebo for the primary end point (proportion of relapse-free participants), the main secondary end point (cumulative number of unique newly active brain MRI lesions), or a number of clinical and MRI tertiary end points. Neither the previous positive studies nor the negative results reported by Fazekas et al. can be considered to be definitive, and the utility of IVIg in RRMS remains uncertain at present.

Miller DH, Weinshenker BG, Filippi M, Banwell BL, Cohen JA, Freedman MS, Galetta SL, Hutchinson M, Johnson RT, Kappos L, Kira J, Lublin FD, McFarland HF, Montalban X, Panitch H, Richert JR, Reingold SC, Polman CH. · Department of Inflammation, Institute of Neurology, NMR Research Unit, University College London, UK. · Mult Scler. · Pubmed #18805839 No free full text.

Abstract: BACKGROUND AND OBJECTIVES: Diagnosis of multiple sclerosis (MS) requires exclusion of diseases that could better explain the clinical and paraclinical findings. A systematic process for exclusion of alternative diagnoses has not been defined. An International Panel of MS experts developed consensus perspectives on MS differential diagnosis. METHODS: Using available literature and consensus, we developed guidelines for MS differential diagnosis, focusing on exclusion of potential MS mimics, diagnosis of common initial isolated clinical syndromes, and differentiating between MS and non-MS idiopathic inflammatory demyelinating diseases. RESULTS: We present recommendations for 1) clinical and paraclinical red flags suggesting alternative diagnoses to MS; 2) more precise definition of "clinically isolated syndromes" (CIS), often the first presentations of MS or its alternatives; 3) algorithms for diagnosis of three common CISs related to MS in the optic nerves, brainstem, and spinal cord; and 4) a classification scheme and diagnosis criteria for idiopathic inflammatory demyelinating disorders of the central nervous system. CONCLUSIONS: Differential diagnosis leading to MS or alternatives is complex and a strong evidence base is lacking. Consensus-determined guidelines provide a practical path for diagnosis and will be useful for the non-MS specialist neurologist. Recommendations are made for future research to validate and support these guidelines. Guidance on the differential diagnosis process when MS is under consideration will enhance diagnostic accuracy and precision.

Koff MD, Cohen JA, McIntyre JJ, Carr CF, Sites BD. · Department of Anesthesiology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 03756-0001, USA. · Anesthesiology. · Pubmed #18212578 links to  free full text

Abstract: DESPITE the known benefits of regional anesthesia for patients undergoing joint arthroplasty, the performance of peripheral nerve blocks in patients with multiple sclerosis (MS) remains controversial. MS has traditionally been described as an isolated disease of the central nervous system, without involvement of the peripheral nerves, and peripheral nerve blockade has been suggested to be safe. However, careful review of the literature suggests that MS may also be associated with involvement of the peripheral nervous system, challenging traditional teachings. There is a paucity of evidence with regard to safety in using peripheral nerve regional anesthesia in these patients. This makes it difficult to provide adequate "informed consent" to these patients. This case report describes a patient with MS who sustained a severe brachial plexopathy after a total shoulder arthroplasty during combined general anesthesia and interscalene nerve block.