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Latest Research on
Multiple Sclerosis
     
Lancet Neurol. 2008 Feb;7(2):173-83.
Intense immunosuppression in patients with rapidly worsening multiple sclerosis: treatment guidelines for the clinician.
Boster A, Edan G, Frohman E, Javed A, Stuve O, Tselis A, Weiner H, Weinstock-Guttman B, Khan O.
The Multiple Sclerosis Clinical Research Center, Department of Neurology, Wayne State University School of Medicine, and The Detroit Medical Center, Detroit, MI, USA.

Several lines of evidence link immunosuppression to inflammation in patients with multiple sclerosis (MS) and provide a rationale for the increasing use of immunosuppressive drugs in the treatment of MS. Treatment-refractory, clinically active MS can quickly lead to devastating and irreversible neurological disability and treating these patients can be a formidable challenge to the clinician. Patients with refractory MS have been treated with intense immunosuppression, such as cyclophosphamide or mitoxantrone, or with autologous haematopoeitic stem cell transplants. Evidence shows that intense immunosuppression might be effective in patients who are unresponsive to immunomodulating therapy, such as interferon beta and glatiramer acetate. Natalizumab, a new addition to the armamentarium for treating MS, might also have a role in the treatment of this MS phenotype. This Review describes the use of intense immunosuppressant drugs and natalizumab in patients with rapidly worsening MS and provides clinicians with guidelines for the use of these drugs in this patient group.

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J Autoimmun. 2008 Jan 25 [Epub ahead of print]
Will hematopoietic stem cell transplantation cure human autoimmune diseases?
Marmont AM.
II Division of Hematology and Stem Cell Transplantation Center, Azienda Ospedaliera-Universitaria S. Martino, Genova, Italy.

Hematopoietic stem cell transplantation is becoming an accepted therapy for severe autoimmune diseases, and over 1000 patients have been transplanted worldwide. Diseases include neurological (multiple sclerosis, others), rheumatological (systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis, vasculitis), haematological (aplastic anemia, single line immune mediated cytopenias) and others. The aim of this article is not to review the copious specific literature, but to analyze whether the up to now existing evidence satisfies the requirements of cure. Prospective randomized trials have been launched by the European Group of Blood and Marrow Transplantation (EBMT). Autologous transplantation, by far the most widely utilized because of its safety, has been shown to possess a powerful disease-arresting effect, but whether the attendant immune reconstitution ("re-education") will finally lead to cure is not demonstrated. The experience with allogeneic transplantation is too limited to draw even tentative conclusions. A Graft-versus-Autoimmunity effect has been ascertained both experimentally and clinically, but cure of autoimmunity by this procedure has not been demonstrated. Unexpected relapses in spite of full donor chimerism have been published. Further experience and studies are necessary.

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Nervenarzt. 2008 Jan 5 [Epub ahead of print]
[Fumaric acid and its esters in the treatment of multiple sclerosis : Studies and effects.]
[Article in German]
Stangel M, Moharregh-Khiabani D, Linker RA, Gold R.
Klink für Neurologie, Medizinische Hochschule Hannover, Carl-Neuberg-Straße 1, 30625, Hannover, Deutschland, stangel.martin@mh-hannover.de.

The currently licensed medications for relapsing-remitting multiple sclerosis (RRMS) are only partially effective and require a parenteral route of administration. Thus there is a need for new, preferably orally available therapeutics. Such a substance could be fumaric acid and its esters (FAE). These compounds are already in use for treatment of psoriasis and are known to have an immunomodulatory effect. In addition there is a potential for neuroprotective effects as suggested by in vitro studies and experiments in the animal model of experimental autoimmune encephalomyelitis. A phase II clinical study in RRMS patients with the modified fumaric acid ester BG-12 showed as "proof of principle" in a frequent MRI design that FAE significantly reduce the number of gadolinium-enhancing lesions after 24 weeks of treatment. Further phase III studies have been started to explore the long-term efficacy of this substance. The results of these studies will show if FAE can be another treatment option, maybe for combination therapy, in patients with MS.

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Mult Scler. 2008 Jan 21 [Epub ahead of print]
A longitudinal study on effects of a six-week course for energy conservation for multiple sclerosis patients.
Sauter C, Zebenholzer K, Zeitlhofer J, Vass K, Hisakawa J.
University Clinic of Neurology, Medical University of Vienna, Vienna, Austria and Department of Psychiatry and Psychotherapy, Charité – University Medicine Berlin, Campus Benjamin Franklin, Berlin,Germany.

Objective Fatigue management and energy conservation are effective strategies to minimize fatigue in multiple sclerosis (MS). Sustained results have not yet been reported. Methods A fatigue management course was provided for 32 MS patients. They were tested prior to, directly after participation in the course and in a 7-9 month follow-up with the Fatigue Severity Scale, the MS-specific Fatigue Scale, the Modified Fatigue Impact Scale (MFIS), the Pittsburgh Sleep Quality Index and a self-rating scale for depression. The Expanded Disability Status Score (EDSS) and the MS functional composite (MSFC) were evaluated before and after participation in the course. Results The total score and the Cognitive and Physical subscores of the MFIS showed significant improvements on both points of time. Scores in the Fatigue Severity Scale, MS-specific Fatigue Scale and Psychosocial Fatigue Impact Scale did not improve significantly. MS functional composite and EDSS remained unchanged after six weeks o
f course participation. Subjective sleep quality improved directly after participation in the course and after 7-9 months. The depression score decreased significantly to a normal level at the end of training and in the 7-9 month follow-up. Conclusion Fatigue management enables MS patients to cope with their fatigue and energy more effectively. Follow-up evaluations showed stable results after 7-9 months.

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Mult Scler. 2008 Jan 21 [Epub ahead of print]
Long-term (up to 22 years), open-label,compassionate-use study of glatiramer acetatein relapsingremitting multiple sclerosis.
Miller A, Spada V, Beerkircher D, Kreitman RR.
Mount Sinai School of Medicine, New York, NY, USA.

To evaluate the safety and efficacy of long-term glatiramer acetate (GA) therapy, 46 patients with relapsing remitting multiple sclerosis (RRMS) were treated for up to 22 years in an ongoing, open-label study. Kurtzke expanded disability status scale (EDSS) was measured every six months, relapses were reported at occurrence and patients self-reported adverse events (AEs). At GA initiation, disease durations ranged from 020 years (median 6.0 years) and at data cut-off (October 2004), GA therapy duration ranged from 122 years (median 12.0 years). Mean EDSS score increased 0.9 +/-1.9 from the pretreatment score (3.0 +/- 1.8; P =0.076). Only 10/28 (36%) patients with baseline EDSS <4.0 had a last observed value >/=4.0 and 8/34 (24%) with entry EDSS <6.0 reached EDSS >/=6.0. A majority (57%) maintained improved or unchanged EDSS scores. Annualized relapse rate decreased to 0.1 +/- 0.2 from 2.9 +/- 1.4 prestudy (P <0.0001). Of the 18 remaining patients in October 2004 (average disease duration 23 years), 17% with baseline EDSS scores <4.0 reached EDSS >/=4.0 and 28% with baseline scores <6.0 reached EDSS >/=6.0. Adverse events were similar to those reported in short-term clinical trials. This study shows a low rate of relapses and EDSS progression in RRMS patients on GA for up to 22 years.

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Acta Neurol Scand. 2008 Jan 16 [Epub ahead of print]
Reproductive counselling, treatment and course of pregnancy in 73 German MS patients.
Hellwig K, Brune N, Haghikia A, Müller T, Schimrigk S, Schwödiauer V, Gold R.
Department of Neurology, St Josef Hospital, Ruhr University Bochum, Bochum, Germany.

Multiple sclerosis (MS) often affects women during the reproductive years of their life. During this period, issues such as choice of immunomodulatory treatment, seeking advice from specialists, relapse-induced steroid application before, during or after pregnancy in combination with breastfeeding gain importance. The objective was to investigate these issues retrospectively using a questionnaire among 73 MS patients with a total of 88 pregnancies. Eighty per cent of the participants consulted their neurologists before and 60% during pregnancy. The annual relapse rate decreased during pregnancy and significantly increased during the first 3 months after delivery. Immunomodulatory treatment was stopped due to desired pregnancy for a mean of 4 years. Fourteen of the MS patients received intravenous immunoglobulin treatment post-natal. Ninety per cent of the study subjects started breastfeeding. However, nearly 30% ablactated, as they received steroids due to a relapse. Weight and height of the full-term children of singleton pregnancies from MS patients were significantly lower compared with the ones of age-matched healthy controls. Our results confirm the known reduced relapse rate during pregnancy, which is followed by an increased relapse rate after delivery. They shed light on the epidemiology of childbirth in patients with MS.

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Endocr Metab Immune Disord Drug Targets. 2007 Dec;7(4):292-9.
Multiple sclerosis: current and future treatment options.
Rizvi S.
Department of Neurology, Brown Medical School, Providence, 2 Dudley Street, Suite 555 Providence RI, 02905, USA. srizvi@lifespan.org.

Multiple Sclerosis is an inflammatory and degenerative disorder involving the central nervous system. It primarily affects young adults and may result in significant long-term disability. The most common initial presentation is relapsing remitting, followed by a chronic progressive course. In a small number of patients the disease tends to be progressive from onset. Multiple sclerosis has traditionally been described as a demylinating disorder. There is now overwhelming evidence pointing to a very significant degenerative component. Current treatment options include immunomodulating and immunosuppressive agents as well as monoclonal antibodies and target the inflammatory component of the disease resulting in significant reduction in relapses, decrease in MRI lesion load and a modest effect on disability. There are several other biological agents being developed which target different aspects of the immunopathology of multiple sclerosis. This article will review the agents currently used in the treatment of MS and also discuss agents currently under development.

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Rev Neurol Dis. 2007;4(4):184-193.
Treating Multiple Sclerosis in the Natalizumab Era: Risks, Benefits, Clinical Decision Making, and a Comparison Between North American and European Union Practices.
Giovannoni G, Kinkel P, Vartanian T.
Neuroimmunology Unit, Neuroscience Centre, Institute of Cell and Molecular Science, Queen Mary’s School of Medicine and Dentistry, Whitechapel, London.

Multiple sclerosis (MS) is the most common cause of nontraumatic severe neurological disability in young adults. If left untreated, most individuals with MS will accumulate significant physical and/or cognitive disability as the consequence of demyelination and axonal injury. Treatment has focused on disease-modifying therapies (DMTs) and questions remain about timing and indications for their use. Natalizumab is a humanized monoclonal antibody directed against alpha4-integrin that prevents migration of leukocytes into the brain parenchyma. The clinical and radiological efficacy of natalizumab has been shown in several randomized trials; however, adverse events associated with natalizumab have limited its use as a first-line agent. In this review we compare current recommendations for the use of first-line DMTs, adverse events associated with MS therapies, and differences between the practices in North American and the European Union.

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Clin Immunol. 2007 Oct 2; [Epub ahead of print]
TNFalpha blockade in human diseases: An overview of efficacy and safety.
Lin J, Ziring D, Desai S, Kim S, Wong M, Korin Y, Braun J, Reed E, Gjertson D, Singh RR.
UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA.

Tumor necrosis factor-alpha (TNFalpha) antagonists including antibodies and soluble receptors have shown remarkable efficacy in various immune-mediated inflammatory diseases (IMID). As experience with these agents has matured, there is an emerging need to integrate and critically assess the utility of these agents across disease states and clinical sub-specialties. Their remarkable efficacy in reducing chronic damage in Crohn's disease and rheumatoid arthritis has led many investigators to propose a new, 'top down' paradigm for treating patients initially with aggressive regimens to quickly control disease. Intriguingly, in diseases such as rheumatoid arthritis and asthma, anti-TNFalpha agents appear to more profoundly benefit patients with more chronic stages of disease but have a relatively weaker or little effect in early disease. While the spectrum of therapeutic efficacy of TNFalpha antagonists widens to include diseases such as recalcitrant uveitis and vasculitis, these agents have failed or even exacerbated diseases such as heart failure and multiple sclerosis. Increasing use of these agents has also led to recognition of new toxicities as well as to understanding of their excellent long-term tolerability. Disconcertingly, new cases of active tuberculosis still occur in patients treated with all TNFalpha antagonists due to lack of compliance with recommendations to prevent reactivation of latent tuberculosis infection. These safety issues as well as guidelines to prevent treatment-associated complications are reviewed in detail in this article. New data on mechanisms of action and development of newer TNFalpha antagonists are discussed in a subsequent article in the Journal. It is hoped that these two review articles will stimulate a fresh assessment of the priorities for research and clinical innovation to improve and extend therapeutic use and safety of TNFalpha antagonism.

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Surg Neurol. 2007 Oct;68(4):394-9.
Gamma knife thalamotomy for multiple sclerosis tremor.
Mathieu D, Kondziolka D, Niranjan A, Flickinger J, Lunsford LD.
Department of Neurological Surgery, University of Pittsburgh, Center for Image-Guided Neurosurgery, Pittsburgh, PA 15213, USA; Department Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.

BACKGROUND: Some patients with MS suffer from disabling tremor. Improvement with medical treatment is modest, at best. Stereotactic surgery targeting the vim nucleus of the thalamus has been successful in alleviating MS tremor. Gamma knife radiosurgery represents a minimally invasive alternative to radiofrequency lesioning and DBS that can provide improvement in patients suffering from essential and parkinsonian tremor. We reviewed our experience with GK thalamotomy in the management of six consecutive patients suffering from disabling MS tremor. METHODS: The median age at the time of radiosurgery was 46 years (range, 31 to 57 years). Intention tremor had been present for a median of three years (range 8 months to 12 years). One 4-mm isocenter was used to deliver a median maximum dose of 140 Gy (range, 130-150 Gy) to the vim nucleus of the thalamus opposite the side of the most disabling tremor. Clinical outcome was assessed using the Fahn-Tolosa-Marin scale. RESULTS: The med
ian follow-up was 27.5 months (range, 5-46 months). All patients experienced improvement in tremor after a median latency period of 2.5 months. More improvement was noted in tremor amplitude than in writing and drawing ability. In four patients, the tremor reduction led to functional improvement. One patient suffered from transient contralateral hemiparesis, which resolved after brief corticosteroid administration. No other complication was seen. CONCLUSION: Gamma knife radiosurgical thalamotomy is effective as a minimally invasive alternative to stereotactic surgery for the palliative treatment of disabling MS tremor.

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Lancet Neurol. 2007 Oct;6(10):903-12.
Primary-progressive multiple sclerosis.
Miller DH, Leary SM.
Department of Neuroinflammation, Institute of Neurology, University College London, London, UK.

About 10-15% of patients with multiple sclerosis (MS) present with gradually increasing neurological disability, a disorder known as primary-progressive multiple sclerosis (PPMS). Compared with relapse-onset multiple sclerosis, people with PPMS are older at onset and a higher proportion are men. Inflammatory white-matter lesions are less evident but diffuse axonal loss and microglial activation are seen in healthy-looking white matter, in addition to cortical demyelination, and quantitative MRI shows atrophy and intrinsic abnormalities in the grey matter and the white matter. Spinal cord atrophy corresponds to the usual clinical presentation of progressive spastic paraplegia. Although neuroaxonal degeneration seems to underlie PPMS, the pathogenesis and the extent to which immune-mediated mechanisms operate is unclear. MRI of the brain and spinal cord, and examination of the CSF, are important investigations for diagnosis; conventional immunomodulatory therapies, such as interferon beta and glatiramer acetate, are ineffective. Future research should focus on the clarification of the mechanisms of axonal loss, improvements to the design of clinical trials, and the development of effective neuroprotective treatments.

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Lancet Neurol. 2007 Oct;6(10):887-902.
Multiple sclerosis in children: clinical diagnosis, therapeutic strategies, and future directions.
Banwell B, Ghezzi A, Bar-Or A, Mikaeloff Y, Tardieu M.
Department of Paediatrics, Division of Neurology, The Hospital for Sick Children, University of Toronto, Toronto, Canada.

The onset of multiple sclerosis (MS) in childhood poses diagnostic and therapeutic challenges, particularly if the symptoms of the first demyelinating event resemble acute disseminated encephalomyelitis (ADEM). MRI is an invaluable diagnostic tool but it lacks the specificity to distinguish ADEM from the first attack of MS. Advanced MRI techniques might have the required specificity to reveal whether the loss of integrity in non-lesional tissue occurs as a fundamental feature of MS. Although the onset of MS in childhood typically predicts a favourable short-term prognosis, some children are severely disabled, either physically or cognitively, and more than 50% are predicted to enter the secondary-progressive phase of the disease by the age of 30 years. Immunomodulatory therapies for MS and their safe application in children can improve long-term prognosis. Genetic and environmental factors, such as viral infection, might be uniquely amenable to study in paediatric patients with MS. Understanding the immunological consequences of these putative exposures will shed light on the early pathological changes in MS.

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AJNR Am J Neuroradiol. 2007 Sep 20; [Epub ahead of print]
A Three-Year Study of Brain Atrophy after Autologous Hematopoietic Stem Cell Transplantation in Rapidly Evolving Secondary Progressive Multiple Sclerosis.
Rocca MA, Mondria T, Valsasina P, Somrani MP, Flach ZH, Te Boekhorst PA, Comi G, Hintzen RQ, Filipi M.
Neuroimaging Research Unit, Department of Neurology, Scientific Institute and University San Raffaele, Milan, Italy; Departments of Neurology, Radiology, and Haematology, Erasmus Medical Center, Rotterdam, the Netherlands; Biostatistics Unit, Department of Health Sciences, University of Genoa, Genoa, Italy.

BACKGROUND AND PURPOSE: In multiple sclerosis (MS), autologous hematopoietic stem cell transplantation (AHSCT) induces a profound suppression of clinical activity and MR imaging-detectable inflammation, but it may be associated with a rapid brain volume loss in the months subsequent to treatment. The aim of this study was to assess how AHSCT affects medium-term evolution of brain atrophy in MS. MATERIALS AND METHODS: MR imaging scans of the brain from 14 patients with rapidly evolving secondary-progressive MS obtained 3 months before and every year after AHSCT for 3 years were analyzed. Baseline normalized brain volumes and longitudinal percentage of brain volume changes (PBVCs) were assessed using the Structural Image Evaluation of Normalized Atrophy software. RESULTS: The median decrease of brain volume was 1.92% over the first year after AHSCT and then declined to 1.35% at the second year and to 0.69% at the third year. The number of enhancing lesions seen on the pretreatment scans was significantly correlated with the PBVCs between baseline and month 12 (r = -0.62; P = .02); no correlation was found with the PBVCs measured over the second and third years. CONCLUSIONS: After AHSCT, the rate of brain tissue loss in patients with MS declines dramatically after the first 2 years. The initial rapid development of brain atrophy may be a late consequence of the pretransplant disease activity and/or a transient result of the intense immunoablative conditioning procedure.

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Ann N Y Acad Sci. 2007 Sep;1110:455-464.
Autologous Stem Cell Transplantation for Severe Autoimmune Diseases: A 10-Year Experience.
Gualandi F, Bruno B, VAN Lint MT, Luchetti S, Uccelli A, Capello E, Mancardi GL, Bacigalupo A, Marmont A.
Divisione Ematologia Padiglione 6, Ospedale S. Martino 16132, Genova, Italy. alberto.marmont@hsanmartino.it.

The first autologous hematopoietic stem cell transplantation in Europe for a patient with severe refractory systemic lupus erythematosus (SLE) was performed in Genoa in 1996. Since then, 32 patients with a wide spectrum of autoimmune diseases (ADs) received autologous transplants, 22 of them with multiple sclerosis (MS). There were no fatal adverse events. All patients had complete or very good partial remissions, but relapses were frequent, especially in SLE, though never as aggressive as pretransplant. The mechanism of action of this intervention remains not completely understood, as briefly discussed here.

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J Neurol Sci. 2007 Sep 26; [Epub ahead of print]
Autologous mesenchymal bone marrow stem cells: Practical considerations.
Scolding N, Marks D, Rice C.
University of Bristol Institute of Clinical Neurosciences, Department of Neurology, Frenchay Hospital, Bristol BS16 1LE, UK.

A number of practical problems need to be addressed before any form of cell therapy can be widely applied in patients with multiple sclerosis. The choice of cell type is one considered elsewhere in this issue; others include the question of axon loss, that of continuing inflammatory disease activity, the mode of delivery of cells (bearing in mind the presence of innumerable lesions scattered throughout the CNS), the problem of measuring directly or indirectly the impact (if any) of an intervention, the timing of any treatment and perhaps above all the safety of the patient. All converge on the one increasingly relevant underlying question: when should stem cell treatments begin to be tested in patients? Here we review the progress in various of these practical problems in order to explain how we have arrived at the conclusion that the clinical science has progressed to a stage where the 'translation threshold' can be safely and appropriately crossed, and therefore why we have already commenced in Bristol a small pilot/feasibility study of autologous bone marrow cell treatment in patients with multiple sclerosis.

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Cell Tissue Res. 2007 Sep 28; [Epub ahead of print]
Human stem cells for CNS repair.
Zietlow R, Lane EL, Dunnett SB, Rosser AE.
Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, CF10 3US, UK, zietlowr@cf.ac.uk.

Although most peripheral tissues have at least a limited ability for self-repair, the central nervous system (CNS) has long been known to be relatively resistant to regeneration. Small numbers of stem cells have been found in the adult brain but do not appear to be able to affect any significant recovery following disease or insult. In the last few decades, the idea of being able to repair the brain by introducing new cells to repair damaged areas has become an accepted potential treatment for neurodegenerative diseases. This review focuses on the suitability of various human stem cell sources for such treatments of both slowly progressing conditions, such as Parkinson's disease, Huntington's disease and multiple sclerosis, and acute insult, such as stroke and spinal cord injury. Despite stem cell transplantation having now moved a step closer to the clinic with the first trials of autologous mesenchymal stem cells, the effects shown are moderate and are not yet at the stage of development that can fulfil the hopes that have been placed on stem cells as a means to replace degenerating cells in the CNS. Success will depend on careful investigation in experimental models to enable us to understand not just the practicalities of stem cell use, but also the underlying biological principles.

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J Neurol Sci. 2007 Sep 24; [Epub ahead of print]
Short-term combination of glatiramer acetate with IV steroid treatment preceding treatment with GA alone assessed by MRI-disease activity in patients with relapsing-remitting multiple sclerosis.
De Stefano N, Filippi M, Hawkins C; (and the 9011 study group).
Department of Neurological and Behavioral Sciences, University of Siena, Italy.

OBJECTIVES: To assess if short-term combination of glatiramer acetate (GA) and IV steroid in patients with relapsing-remitting multiple sclerosis (RRMS) is safe and sustains the effect of GA treatment on MRI-disease activity. METHODS: RRMS patients with >/=2 gadolinium (Gd)-enhancing lesions on screening MRI and EDSS score </=4.0 received GA injection (20 mg subcutaneously once daily) and monthly 1 g IV Methylprednisolone (IVMP) for 6 months. Afterwards, all subjects received GA injections daily alone for additional 6 months. Neurological evaluations were performed at screening, baseline and every 3 months. Laboratory tests for safety were performed at screening, baseline, months 1, 6 and 12. Brain MRIs were performed at screening, baseline, months 5, 6, 11, and 12 to assess the change in the number of Gd-enhancing lesions i) from baseline to month 6, and ii) from baseline to month 12 compared with the change from baseline to month 6. RESULTS: 89 subjects were eligible for the study. In this group, GA in combination with IVMP resulted in 65% (95% CI=0.25-0.49, p<0.0001) reduction in the number of Gd-enhancing lesions. This reduction was sustained for additional 6 months when patients received GA alone. The analysis for change achieved in the second 6 month period showed no difference from the change achieved in the first six months (ratio 0.75, 90% CI=0.468-1.197). Overall, treatment was well tolerated and adverse events reported were similar to the known safety profile of GA. CONCLUSIONS: Short-term combination of GA with 1 g monthly IVMP, preceding treatment with GA alone, is safe. MRI data suggest that this combination therapy may result in an early and sustained reduction of disease activity in RRMS patients.

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Curr Opin Neurol. 2007 Jun;20(3):286-93.
Treatment and treatment trials in multiple sclerosis.
Kieseier BC, Wiendl H, Hemmer B, Hartung HP.
aDepartment of Neurology, Heinrich-Heine-University, Duesseldorf bDepartment of Neurology, Julius-Maximilians-University, Wuerzburg, Germany.

PURPOSE OF REVIEW: This review focuses on advances in current and novel treatment approaches in multiple sclerosis. RECENT FINDINGS: New therapeutic approaches in multiple sclerosis are emerging. Orally available treatment strategies are more acceptable for patients and may improve adherence to therapy. An oral formulation of glatiramer acetate failed to demonstrate efficacy in a clinical trial, but other promising compounds are on the horizon, such as FTY720. Advances are currently being made in use of therapeutic monoclonal antibodies that specifically target key molecules involved in the immunopathogenesis of multiple sclerosis. Natalizumab directed against the adhesion molecule very late antigen-4 represents the first specific antibody to be added to our therapeutic armamentarium for multiple sclerosis. Further evidence that immunomodulation should be initiated as early as possible has been reported. SUMMARY: Treatment of multiple sclerosis has changed dramatically over the past decade. Enhanced understanding of the immunopathological processes that underlie the disease, advances in biotechnology and development of powerful magnetic resonance imaging technologies, together with improvements in clinical trial design have led to a variety of valuable therapeutic approaches, which are currently being studied in detail.

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Curr Opin Neurol. 2007 Jun;20(3):281-285.
Combination therapies for multiple sclerosis: scientific rationale, clinical trials, and clinical practice.
Costello F, Stüve O, Weber MS, Zamvil SS, Frohman E.
aDepartments of Medicine (Neurology) and Ophthalmology, The University of Ottawa, Ottawa, Ontario, Canada bNeurology Section, VA North Texas Healthcare System, Medical Service, Dallas, Texas, USA cDepartment of Neurology, University of Texas Southwestern Medical Center at Dallas, Texas, USA dDepartment of Neurology, University of California, San Francisco, California, USA eProgram in Immunology, University of California, San Francisco, California, USA fDepartment of Ophthalmology, University of Texas Southwestern Medical Center at Dallas, Texas, USA.

PURPOSE OF REVIEW: To outline the scientific rationale for combination therapy in multiple sclerosis and to discuss the evidence for combination treatment strategies from animal models and clinical trials of multiple sclerosis. RECENT FINDINGS: Experiments conducted in experimental autoimmune encephalomyelitis have recently shown beneficial effects of numerous combination therapies. The combination of approved and experimental drugs and two or more experimental agents may positively impact clinical disease activity, inflammation within the central nervous system, and neurorepair. Clinical trials are currently underway to establish the therapeutic efficacy and safety of various combination therapies for multiple sclerosis patients. SUMMARY: More effective therapies are needed to treat multiple sclerosis. There are good scientific rationales for the use of combination therapy in multiple sclerosis, and the pharmacologic principles for evaluating and understanding their actions are available. The evaluation of specific combination therapies in the controlled setting of clinical trials should be a priority in clinical multiple sclerosis research.

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Int Rev Neurobiol. 2007;79:303-21.
Multiple sclerosis as a painful disease.
Kenner M, Menon U, Elliott DG.
Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71103, USA.

Pain is a common problem of patients with multiple sclerosis (MS) and may be due to central/neuropathic or peripheral/somatic pathology. Rarely MS may present with pain, or pain may herald an MS exacerbation, such as in painful tonic spasms or Lhermitte's sign. In other patients, pain may become chronic as a long-term sequela of damage to nerve root entry zones (trigeminal neuralgia) or structures in central sensory pathways. Migraine headache may develop as a consequence of MS, and headache can also be a side effect of interferon treatment. The pathophysiology of pain in MS may be linked to certain plaque locations which disrupt the spinothalamic and quintothalamic pathways, abnormal impulses through motor axons, development of an acquired channelopathy in affected nerves, or involve glial cell inflammatory immune mechanisms. At this time, the treatment of pain in MS employs the use of antiepileptic drugs, muscle relaxers/antispasmodic agents, anti-inflammatory drugs, and nonpharmacological measures. Research concerning cannabis-based treatments shows promising results, and substances which block microglial or astrocytic involvement in pain processing are also under investigation.

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CNS Drugs. 2007;21(6):483-502.
Oral disease—modifying treatments for multiple sclerosis: the story so far.
Kieseier BC, Wiendl H.
Department of Neurology, Heinrich-Heine University, Düsseldorf, Germany.

Multiple sclerosis (MS) represents the prototypic inflammatory autoimmune disorder of the CNS. It is the most common cause of neurological disability in young adults and exhibits considerable clinical, radiological and pathological heterogeneity. Increased understanding of the immunopathological processes underlying this disease, advances in biotechnology and the development of powerful magnetic resonance imaging (MRI) technologies, together with improvements in clinical trial design, have led to a variety of valuable therapeutic approaches to MS.Therapy for MS has changed dramatically over the past decade, yielding significant progress in the treatment of relapsing remitting and secondary progressive forms; however, most of the clinically relevant therapeutic approaches are not yet available as oral formulations. A substantial number of preliminary and pivotal reports have provided promising results for oral therapies, and various phase III clinical trials are currently being initiated or are already underway evaluating the efficacy of a variety of orally administered agents, including cladribine, teriflunomide, laquinimod, fingolimod and fumaric acid. It is hoped that these trials will advance the development of oral therapies for MS.

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J Neurol Sci. 2007 May 14; [Epub ahead of print]
Combination therapy in multiple sclerosis.
Fernández O.
Institute of Clinical Neurosciences, Hospital Regional Universitario Carlos Haya, Avda. Carlos Haya s/n, 29010 Málaga, Spain.

Multiple sclerosis is an inflammatory/demyelinating and neurodegenerative disease. Treatment of MS is currently based on various different therapeutic algorithms of a sequential or escalating therapy with immunomodulators or immunosuppressants, generated partly from evidence based medicine and partly from expert's consensus. However, these therapies are not always effective as monotherapies. An alternative would be the combination of agents which already have some proven efficacy in MS therapy, are directed against different mechanisms of the pathogenic chain, and ideally result in synergic effects and a profile of reduced toxicity. Combination therapy in multiple sclerosis can be: Combination of two or more anti-inflammatory agents or combination of anti-inflammatory agents plus neuroprotective agents. Many combinations of drugs have been or are being tested in multiple sclerosis. Clinical trials have included a low number of patients for short periods of time. Preliminary studies on safety suggest that some combination therapies might be safe and efficacious. Ongoing and new phase III clinical trials involving a greater number of patients for longer periods of time are needed to verify this hypothesis. A wise balance between efficacy and safety and extremely clear information to patients should drive clinical decisions.

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Expert Opin Drug Saf. 2007 May;6(3):279-88.
The safety and efficacy of IFN-beta products for the treatment of multiple sclerosis.
Kremenchutzky M, Morrow S, Rush C.
University of Western Ontario, Department of Clinical Neurological Sciences, London Health Sciences Centre, Canada.

Multiple sclerosis, a chronic demyelinating disease of the CNS, is now a treatable disease. Phase III clinical trials of three recombinant IFN-beta products conducted in relapsing-remitting multiple sclerosis have shown, albeit modest, significant effects on relapses and short-term progression of disability, and a more substantial effect on MRI parameters. However, these effects do not correlate well with clinical disease activity or long-term disability. Overall, IFN-beta is safe and generally well tolerated, and reported adverse events were comparable between preparations. Systemic side effects can be effectively managed by dose escalation, use of an auto-injector and careful clinical monitoring.

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Curr Neurol Neurosci Rep. 2007 May;7(3):259-64.
New directions in optic neuritis and multiple sclerosis.
Gilbert ME, Sergott RC.
Department of Neuro-ophthalmology, Wills Eye Hospital, 840 Walnut Street, Philadelphia, PA 19107, USA.

Optic neuritis (ON) is the initial presentation in 15% to 20% of cases of multiple sclerosis (MS). Thirty-eight percent to 50% of patients with MS develop ON at some point during the course of their disease. The Optic Neuritis Treatment Trial (ONTT) provided much prospective data about the clinical presentation, clinical course with respect to treatment, and development of MS in patients with ON. The clinical course of MS initially involves episodes of demyelination followed by full recovery; however, later attacks often leave persistent deficits that lead to secondary progression of the disease. The risk of developing progressive neurologic deficits can be reduced by starting therapy with immunomodulating drugs early in the course of the disease. Optical coherence tomography is a noninvasive way to monitor patients with ON to determine if they are undergoing subclinical axonal loss of ganglion cells. Progression of axonal loss on optical coherence tomography may prompt a change in therapy or further imaging.

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J Neurol. 2007 May;254 Suppl 2:II112-II115.
Complementary and alternative medicine and coping in neuroimmunological diseases.
Apel A, Greim B, Zettl UK.
Dept. of Neurology, University of Rostock, Gehlsheimer Str. 20, 18147, Rostock, Germany, annett.apel@med.uni-rostock.de.

The utilisation of complementary and alternative medicine (CAM) is widespread in neuroimmunological diseases like multiple sclerosis (MS) but has been disregarded in research until lately. After describing the problems of definition in CAM, different categories will be described.Various confounding factors on CAM utilisation exist, though hardly investigated. Besides sociodemographic variables like education, income, gender and age, illness-related factors like severity of disease are discussed. Furthermore, the important role of coping and CAM utilisation has not been investigated in neuroimmunological diseases, yet. Results derived from our investigations on CAM utilisation in MS indicate that users of CAM apply coping strategies, such as "rumination", "search for information" and "search for meaning in religion", more frequently than non-users and that current CAM utilisation is related to depression. Further research is needed in this field, as well as in other neuroimmunological diseases.

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Arch Neurol. 2007 May;64(5):683-8.
Testosterone treatment in multiple sclerosis: a pilot study.
Sicotte NL, Giesser BS, Tandon V, Klutch R, Steiner B, Drain AE, Shattuck DW, Hull L, Wang HJ, Elashoff RM, Swerdloff RS, Voskuhl RR.
Division of Brain Mapping, Department of Neurology, The David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

OBJECTIVE: To study the effect of testosterone supplementation on men with multiple sclerosis (MS). DESIGN, SETTING, AND PARTICIPANTS: Men are less susceptible to many autoimmune diseases, including MS. Possible causes for this include sex hormones and/or sex chromosome effects. Testosterone treatment ameliorates experimental allergic encephalomyelitis, an animal model of MS, but the effect of testosterone supplementation on men with MS is not known. Therefore, 10 men with relapsing-remitting MS were studied using a crossover design whereby each patient served as his own control. There was a 6-month pretreatment period followed by a 12-month period of daily treatment with 10 g of the gel containing 100 mg of testosterone. MAIN OUTCOME MEASURES: Clinical measures of disability and cognition (the Multiple Sclerosis Functional Composite and the 7/24 Spatial Recall Test) and monthly magnetic resonance imaging measures of enhancing lesion activity and whole brain volumes. RESULTS: One year of treatment with testosterone gel was associated with improvement in cognitive performance (P = .008) and a slowing of brain atrophy (P <.001). There was no significant effect of testosterone treatment on gadolinium-enhancing lesion numbers (P = .31) or volumes (P = .94). Lean body mass (muscle mass) was increased (P = .02). CONCLUSION: These exploratory findings suggest that testosterone treatment is safe and well tolerated and has potential neuroprotective effects in men with relapsing-remitting MS.

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J Neuroimmunol. 2007 May 10; [Epub ahead of print]
Expert opinion: Guidelines for the use of natalizumab in multiple sclerosis patients previously treated with immunomodulating therapies.
Gold R, Jawad A, Miller DH, Henderson DC, Fassas A, Fierz W, Hartung HP.
Department of Neurology at St. Josef-Hospital, University of Bochum, Gudrunstrasse 56, D-47901 Bochum, Germany.

Natalizumab (Tysabri(R)) (anti-VLA4) is a novel agent for treatment of relapsing multiple sclerosis (MS) [Polman C.H., O'Connor P.W., Havrdova E. et al., 2006. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 354, 899-910.]. Controlled trials have shown considerable efficacy in preventing relapses, in excess of that seen for other EMEA-approved disease modulating drugs. While well-tolerated and generally safe, three cases of progressive multifocal leukoencephalopathy (PML) occurred in the context of 3 clinical trials encompassing some 3300 patients using this drug in multiple sclerosis and Crohn's disease. Immune compromised patients, such as those receiving immunosuppressive medications, are at a higher risk of developing PML. Natalizumab was recently approved for the treatment of relapsing forms of MS. This includes patients who had an inadequate response to other therapies and some of these patients will have already received immunosuppressants. These agents have the potential to cause prolonged effects on the immune system, even after dosing has been discontinued. Determining that these patients are not immunocompromised will be an important safety issue to consider prior to the initiation of natalizumab therapy. This short report summarizes interdisciplinary practical recommendations from specialists in neuroimmunology, rheumatology, transplantation medicine and clinical immunology.

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Expert Rev Neurother. 2007 May;7(5):453-61.
Fampridine—SR for multiple sclerosis and spinal cord injury.
Hayes KC.
The University of Western Ontario, Department of Physical Medicine & Rehabilitation, London, Ontario, Canada. kchayes@uwo.ca

Fampridine-SR is a sustained-release tablet form of the K(+) channel-blocking compound 4-aminopyridine that has been shown to restore conduction in focally demyelinated axons, to enhance synaptic transmission in many types of neurons and to potentiate muscle contraction. The present review describes the mechanism of action and chemistry of Fampridine-SR, its pharmacokinetics and safety, and the outcomes of clinical trials of its safety and efficacy for enhancing neuromuscular function in patients with multiple sclerosis or spinal cord injury. Randomized clinical trials completed to date indicate that this form of K(+) channel blockade may be useful for the improvement of walking ability in patients with multiple sclerosis.

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Ann Readapt Med Phys. 2007 Apr 20; [Epub ahead of print]
Physical training and multiple sclerosis.
Gallien P, Nicolas B, Robineau S, Pétrilli S, Houedakor J, Durufle A.
Centre MPR, Notre-Dame-de-Lourdes, 54, rue Saint-Hélier, 35000 Rennes, France; Clinique de la sclérose en plaques, CHU de Pontchaillou, rue Henri-Le-Guilloux, 35033 Rennes cedex, France.

For many years, patients with multiple sclerosis (MS) were advised to avoid exercise because of the risk of increased neurological impairment. This article reviews the literature related to MS and physical exercise. Physical exercise depends on patients' physiological tolerance and response to exercise. MS patients can exhibit dysfunction of cardiovascular adjustment accompanied by respiratory involvement, which can alter aerobic capacity. These abnormalities tend to increase with the neurological impairment. Muscle weakness is the consequence of not only altered central motor drive but also disuse. Several studies have shown the benefits of physical training, with improvements in aerobic capacity, gait parameters and fatigue, and an influence on quality of life. Regular aerobic physical activity is necessary to maintain the benefit of physical training.

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Semin Neurol. 2007 Feb;27(1):78-85.
Multiple sclerosis.
Benedict RH, Bobholz JH.
Department of Neurology, State University of New York (SUNY) at Buffalo, Jacobs Neurological Institute, Buffalo, New York.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that commonly leads to inflammatory and atrophic brain pathology, often causing cognitive impairment. MS-associated cognitive impairment was first described over a century ago. However, with the advent of standardized neuropsychological testing and quantitative brain imaging, the frequency, quality, and correlates of cognitive impairment are better understood. Dementia is rare in MS, although it is known to occur in 10 to 25% of patients. Our data suggest a frequency of 22% among clinic attendees. In addition to the cognitive impairments evident in MS dementia, changes in personality and social behavior also occur. For example, some patients develop euphoria sclerotica and marked deficiency in social empathy, conditions that in combination with executive dysfunction cause considerable hardship for patients and caregivers. These neuropsychiatric manifestations of MS dementia are correlated with magnetic resonance imaging indicators of brain atrophy, including ventricle enlargement, neocortical volume, and normalized whole brain volume. Recent developments in pharmacological treatment for disease progression and management of cognitive symptoms hold promise for patients suffering from the degenerative aspects of MS.

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Ann Neurol. 2007 Jan 29;61(1):14-24 [Epub ahead of print]
Glatiramer acetate in primary progressive multiple sclerosis: Results of a multinational, multicenter, double-blind, placebo-controlled trial.
Wolinsky JS, Narayana PA, O'connor P, Coyle PK, Ford C, Johnson K, Miller A, Pardo L, Kadosh S, Ladkani D.
Department of Neurology, The University of Texas Health Science Center at Houston, Houston, TX.

OBJECTIVE: To determine whether glatiramer acetate (GA) slows accumulation of disability in primary progressive multiple sclerosis. METHODS: A total of 943 patients with primary progressive multiple sclerosis were randomized to GA or placebo (PBO) in this 3-year, double-blind trial. The primary end point was an intention-to-treat analysis of time to 1- (entry expanded disability status scale, 3.0-5.0) or 0.5-point expanded disability status scale change (entry expanded disability status scale, 5.5-6.5) sustained for 3 months. The trial was stopped after an interim analysis by an independent data safety monitoring board indicated no discernible treatment effect on the primary outcome. Intention-to-treat analyses of disability and magnetic resonance imaging end points were performed. RESULTS: There was a nonsignificant delay in time to sustained accumulated disability in GA- versus PBO-treated patients (hazard ratio, 0.87 [95% confidence interval, 0.71-1.07]; p = 0.1753), with significant decreases in enhancing lesions in year 1 and smaller increases in T2 lesion volumes in years 2 and 3 versus PBO. Post hoc analysis showed that survival curves for GA-treated male patients diverged early from PBO-treated male subjects (hazard ratio, 0.71 [95% confidence interval, 0.53-0.95]; p = 0.0193). INTERPRETATION: The trial failed to demonstrate a treatment effect of GA on primary progressive multiple sclerosis. Both the unanticipated low event rate and premature discontinuation of study medication decreased the power to detect a treatment effect. Post hoc analysis suggests GA may have slowed clinical progression in male patients who showed more rapid progression when untreated. Ann Neurol 2007;61:14-24.

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Curr Med Res Opin. 2007 Jan;23(1):17-24.
Meta-analysis of cannabis based treatments for neuropathic and multiple sclerosis-related pain.
Iskedjian M, Bereza B, Gordon A, Piwko C, Einarson TR.
PharmIdeas Research & Consulting Inc., Oakville, ON, Canada; PharmIdeas USA Inc., Charlotte, NC, USA.

OBJECTIVE: Debilitating pain, occurring in 50-70% of multiple sclerosis (MS) patients, is poorly understood and infrequently studied. We summarized efficacy and safety data of cannabinoid-based drugs for neuropathic pain. Data sources: Studies were identified from Medline, Embase, and Cochrane databases; Bayer Healthcare provided additional trials. STUDY SELECTION: Accepted were randomized, double-blinded placebo-controlled trials of cannabinoid-based treatments for MS-related/neuropathic pain in adults >/= 18 years of age. Data extraction: Two reviewers identified studies and extracted data; a third adjudicated disagreements. Data included baseline and endpoint pain scores on visual analog or 11-point ordinal scales. DATA SYNTHESIS: Of 18 articles and three randomized controlled trial (RCT) reports identified, 12 articles and two reports were rejected (9 = inappropriate disease or outcome, 1 = duplicate, 1 = review, and 1 = abstract); six accepted articles and one RCT-report involved 298 patients (222 treated, 76 placebo); four examined Sativex (a cannabidiol/delta-9-tetrahydrocannabinol (THC) buccal spray) (observations = 196), five cannabidiol (n = 41), and three dronabinol (n = 91). Homogeneity chi(2) values were non-significant, allowing data combination. Analyses focused on baseline-endpoint score differences. The cannabidiol/THC buccal spray decreased pain 1.7 +/- 0.7 points (p = 0.018), cannabidiol 1.5 +/- 0.7 (p = 0.044), dronabinol 1.5 +/- 0.6 (p = 0.013), and all cannabinoids pooled together 1.6 +/- 0.4 (p < 0.001). Placebo baseline-endpoint scores did not differ (0.8 +/- 0.4 points, p = 0.023). At endpoint, cannabinoids were superior to placebo by 0.8 +/- 0.3 points (p = 0.029). Dizziness was the most commonly observed adverse event in the cannabidiol/THC buccal spray arms (39 +/- 16%), across all cannabinoid treatments (32.5 +/- 16%) as well as in the placebo arms (10 +/- 4%). CONCLUSION: Cannabinoids including the cannabidiol/THC buccal spray are effective in treating neuropathic pain in MS. LIMITATIONS: This review was based on a small number of trials and patients. Pain related to MS was assumed to be similar to neuropathic pain.

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Cochrane Database Syst Rev. 2007 Jan 24;(1):CD005029.
Treatment for ataxia in multiple sclerosis.
Mills R, Yap L, Young C.

BACKGROUND: Disabling tremor or ataxia is common in multiple sclerosis (MS) and up to 80% of patients experience tremor or ataxia at some point during their disease. A variety of treatments are available, ranging from pharmacotherapy or stereotactic neurosurgery to neurorehabilitation. OBJECTIVES: To assess the efficacy and tolerability of both pharmacological and non-pharmacologic treatments of ataxia in patients with MS. SEARCH STRATEGY: The following electronic resources were searched: Cochrane MS Group trials register (June 2006), the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2, 2006), National Health Service National Research Register (NRR) including the Medical Research Council Clinical Trials Directory (Issue 2, 2006), MEDLINE (January 1996 to June 2006), and EMBASE (Jan 1988 to June 2006). Manual searches of bibliographies of relevant articles, pertinent medical and neurology journals and abstract books of major neurology and MS conferences (2001-2006) were also performed. Direct communication with experts and drug companies was sought. SELECTION CRITERIA: Blinded, randomised trials which were either placebo-controlled or which compared two or more treatments were included. Trials testing pharmacological agents must have had both participant and assessor blinding. Trials testing surgical interventions or effects of physiotherapy, where participants could not have been blinded to the treatment, must have had independent assessors who were blinded to the treatment. Cross-over trials were included. DATA COLLECTION AND ANALYSIS: Three independent reviewers extracted data and the findings of the trials were summarised. A meta-analysis was not performed due to the inadequacy of outcome measures and methodological problems with the studies reviewed. MAIN RESULTS: Ten randomised controlled trials met the inclusion criteria. Six placebo-controlled studies (pharmacotherapy) and four comparative studies (one stereotactic neurosurgery and three neurorehabilitation) were reviewed. No standardised outcome measures were used across the studies. In general, pharmacotherapies were unrewarding and data on neurosurgery or rehabilitation is insufficient to lead to a change in practice. AUTHORS' CONCLUSIONS: The absolute and comparative efficacy and tolerability of pharmacotherapies to treat ataxia in MS are poorly documented and no recommendations can be made to guide prescribing. Although studies on neurosurgery and neurorehabilitation showed promising results, the absolute indications for treating with those methods cannot be developed. Standardised, well validated measures of ataxia and tremor need to be developed and employed in larger randomised controlled trials with careful blinding.

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Cochrane Database Syst Rev. 2007 Jan 24;(1):CD004192.
Dietary interventions for multiple sclerosis.
Farinotti M, Simi S, Di Pietrantonj C, McDowell N, Brait L, Lupo D, Filippini G.

BACKGROUND: Clinical and experimental data suggest that certain dietary regimens, particularly those including polyunsaturated fatty acids (PUFAs) and vitamins might improve outcomes in people with multiple sclerosis (MS). Diets and dietary supplements are much used by people with MS in the belief that they might improve disease outcomes. OBJECTIVES: We performed a Cochrane review of all randomised trials of dietary regimens for MS with the aim of answering MS consumers' questions regarding the efficacy and safety of these interventions. SEARCH STRATEGY: We searched the Cochrane MS Group trial register (February 2006), Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Library, Issue 1, 2006, MEDLINE (PubMed) (1966 to March 2006), EMBASE (1974 to March 2006) and the bibliographies of papers found. SELECTION CRITERIA: All randomised controlled trials comparing a specific dietary intervention, diet plan or dietary supplementation, with no dietary modification or placebo, were eligible. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected articles, assessed trial quality and extracted data. Trial quality was poor, particularly as regards descriptions of randomisation, blinding and adverse event reporting. Some studies had large numbers of drop-outs; dropouts were never included in the analyses. MAIN RESULTS: PUFAs did not have a significant effect on disease progression, measured as worsening of Disability Status Scale. Omega-6 fatty acids (11-23 g/day linoleic acid) had no benefit in 75 relapsing remitting (RR) MS patients (progression at two years: relative risk (RR)=0.78, 95% CI [0.45 to 1.36]) or in 69 chronic progressive (CP) MS patients (RR=1.67, 95% CI [0.75 to 3.72]. Linoleic acid (2.9-3.4 g/day) had no benefit in CPMS (progression at two years: RR=0.78, 95% CI [0.43 to 1.42]). Slight decreases in relapse rate and relapse severity were associated with omega-6 fatty acids in some small studies, however these findings are limited by the limited validity of the endpoints.Omega-3 fatty acids had no benefit on progression at 12 months in 14 RRMS patients or at 24 months in 292 RRMS patients (RR=0.15, 95% CI [0.01 to 3.11], p= 0.22 at 12 months, and 0.82 95% CI [0.65 to 1.03], p=0.08, at 24 months).The low frequency of reported adverse events suggests no major toxicity associated with PUFA administration.No studies on vitamin supplementation and allergen-free diets were analysed as none met the eligibility criteria. AUTHORS' CONCLUSIONS: PUFAs seem to have no major effect on the main clinical outcome in MS (disease progression), and does not substantially affect the risk of clinical relapses over 2 years. However, the data available are insufficient to assess any potential benefit or harm from PUFA supplementation. Evidence bearing on the possible benefits and risks of vitamin supplementation and antioxidant supplements in MS is lacking. More research is required to assess the effectiveness of diets interventions in MS.

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Cochrane Database Syst Rev. 2007 Jan 24;(1):CD002819.
Cyclophosphamide for multiple sclerosis.
La Mantia L, Milanese C, Mascoli N, D'Amico R, Weinstock-Guttman B.

BACKGROUND: Multiple sclerosis is a presumed cell-mediated autoimmune disease of the central nervous system. Cyclophosphamide (CFX) is a cytotoxic and immunosuppressive agent, used in systemic autoimmune diseases. Controversial results have been reported on its efficacy in MS. We conducted a systematic review of all relevant trials, evaluating the efficacy of CFX in patients with progressive MS. OBJECTIVES: The main objective was to determine whether CFX slows the progression of MS. SEARCH STRATEGY: We searched the Cochrane MS Group Trials Register (searched June 2006), Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3 2006), MEDLINE (January 1966 to June 2006), EMBASE (January 1988 to June 2006) and reference lists of articles. We also contacted researchers in the field. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating the clinical effect of CFX treatment in patients affected by clinically definite progressive MS.CFX had to be administered alone or in combination with adrenocorticotropic hormone (ACTH) or steroids. The comparison group had to be placebo or no treatment or the same co-intervention (ACTH or steroids) DATA COLLECTION AND ANALYSIS: Two reviewers independently decided the eligibility of the study, assessed the trial quality and extracted data. We also contacted study authors for original data. MAIN RESULTS: Of the 461identified references, we initially selected 70: only four RCTs were included for the final analysis. Intensive immunosuppression with CFX (alone or associated with ACTH or prednisone) in patients with progressive MS compared to placebo or no treatment (152 participants) did not prevent the long-term (12, 18, 24 months) clinical disability progression as defined as evolution to a next step of Expanded Disability Status Scale (EDSS) score. However, the mean change in disability (final disability subtracted from the baseline) significantly favoured the treated group at 12 (effect size - 0.21, 95% confidence interval - 0.25 to -0.17) and 18 months (- 0.19, 95% confidence interval - 0.24 to - 0.14) but favoured the control group at 24 months (0.14, CI 0.07 to 0.21). We were unable to verify the efficacy of other schedules. Five patients died; sepsis and amenorrhea frequently occurred in treated patients (descriptive analysis). AUTHORS' CONCLUSIONS: We were unable to achieve all of the objectives specified for the review. This review shows that the overall effect of CFX (administered as intensive schedule) in the treatment of progressive MS does not support its use in clinical practice.

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Cochrane Database Syst Rev. 2007 Jan 24;(1):CD002818.
Amantadine for fatigue in multiple sclerosis.
Pucci E, Branas P, D'Amico R, Giuliani G, Solari A, Taus C.

BACKGROUND: Fatigue is one of the most common and disabling symptoms of people with Multiple Sclerosis (MS). The effective management of fatigue has an important impact on the patient's functioning, abilities, and quality of life. Although a number of strategies have been devised for reducing fatigue, treatment recommendations are based on a limited amount of scientific evidence. Many textbooks report amantadine as a first-choice drug for MS-related fatigue because of published randomised controlled trials (RCTs) showing some benefit. OBJECTIVES: To determine the effectiveness and safety of amantadine in treating fatigue in people with MS. SEARCH STRATEGY: We searched The Cochrane MS Group Trials Register (July 2006), The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 1, 2006), MEDLINE (January 1966 to July 2006), EMBASE (January 1974 to July 2006), bibliographies of relevant articles and handsearched relevant journals. We also contacted drug companies and researchers in the field. SELECTION CRITERIA: Randomised, placebo or other drugs-controlled, double-blind trials of amantadine in MS people with fatigue. DATA COLLECTION AND ANALYSIS: Three reviewers selected studies for inclusion in the review and they extracted the data reported in the original articles. We requested missing and unclear data by correspondence with the trial's principal investigator. A meta-analysis was not performed due to the inadequacy of available data and heterogeneity of outcome measures. MAIN RESULTS: Out of 13 pertinent publications, 5 trials met the criteria for inclusion in this review: one study was a parallel arms study, and 4 were crossover trials. The number of randomised participants ranged between 10 and 115, and a total of 272 MS patients were studied. Overall the quality of the studies considered was poor and all trials were open to bias. All studies reported small and inconsistent improvements in fatigue, whereas the clinical relevance of these findings and the impact on patient's functioning and health related quality of life remained undetermined. The number of participants reporting side effects during amantadine therapy ranged from 10% to 57%. AUTHORS' CONCLUSIONS: The efficacy of amantadine in reducing fatigue in people with MS is poorly documented, as well as its tolerability. It is advisable to: (1) improve knowledge on the underlying mechanisms of MS-related fatigue; (2) achieve anagreement on accurate, reliable and responsive outcome measures of fatigue; (3) perform good quality RCTs.

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Mult Scler. 2006 Dec;12(6):814-23.
Autologous stem cell transplantation for progressive multiple sclerosis: update of the European Group for Blood and Marrow Transplantation autoimmune diseases working party database.
Saccardi R, Kozak T, Bocelli-Tyndall C, Fassas A, Kazis A, Havrdova E, Carreras E, Saiz A, Lowenberg B, te Boekhorst PA, Gualandio F, Openshaw H, Longo G, Pagliai F, Massacesi L, Deconink E, Ouyang J, Nagore FJ, Besalduch J, Lisukov IA, Bonini A, Merelli E, Slavino S, Gratwohl A, Passweg J, Tyndall A, Steck AJ, Andolina M, Capobianco M, Martin JL, Lugaresi A, Meucci G, Saez RA, Clark RE, Fernandez MN, Fouillard L, Herstenstein B, Koza V, Cocco E, Baurmann H, Mancardi GL; Autoimmune Diseases Working Party of EBMT.
BMT Unit Department of Hematology, Ospedale di Careggi, Florence, Italy. r.saccardi@DAC.UNIFI.IT

Over the last decade, hematopoietic stem cells transplantation (HSCT) has been increasingly used in the treatment of severe progressive autoimmune diseases. We report a retrospective survey of 183 multiple sclerosis (MS) patients, recorded in the database of the European Blood and Marrow Transplantation Group (EBMT). Transplant data were available from 178 patients who received an autologous graft. Overall, transplant related mortality (TRM) was 5.3% and was restricted to the period 1995-2000, with no further TRM reported since then. Busulphan-based regimens were significantly associated with TRM. Clinical status at the time of transplant and transplant techniques showed some correlations with toxicity. No toxic deaths were reported among the 53 patients treated with the BEAM (carmustine, etoposide, cytosine-arabinoside, melphalan)/antithymocyte globulin (ATG) regimen without graft manipulation, irrespective of their clinical condition at the time of the transplant. Improvement or stabilization of neurological conditions occurred in 63% of patients at a median follow-up of 41.7 months, and was not associated with the intensity of the conditioning regimen. In this large series, HSCT was shown as a promising procedure to slow down progression in a subset of patients affected by severe, progressive MS; the safety and feasibility of the procedure can be significantly improved by appropriate patient selection and choice of transplant regimen.  
 

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