Multiple Sclerosis Research:
2002-2006
       
Expert Opin Pharmacother. 2006 Oct;7 Suppl 1:S1-9.
Disease-modifying drugs for multiple sclerosis: current and future aspects.
Freedman MS.
University of Ottawa and Ottawa Health Research Institute, Canada. mfreedman@ottawahospital.on.ca.

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

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Neurology. 2006 Sep 26;67(6):944-53. Comment in: Neurology. 2006 Sep 26;67(6):930-1.
Long-term subcutaneous interferon beta-1a therapy in patients with relapsing-remitting MS.
Kappos L, Traboulsee A, Constantinescu C, Eralinna JP, Forrestal F, Jongen P, Pollard J, Sandberg-Wollheim M, Sindic C, Stubinski B, Uitdehaag B, Li D.
University of Basel, Basel, Switzerland. lkappos@uhbs.ch

OBJECTIVE: To conduct systematic long-term follow-up (LTFU) of patients in the Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) study to provide up to 8 years of safety, clinical and MRI outcomes on subcutaneous (s.c.) interferon (IFN) beta-1a in relapsing-remitting multiple sclerosis (RRMS). METHODS: The original cohort of 560 patients was randomized to IFNbeta-1a, 44 or 22 microg three times weekly (TIW) or to placebo; after 2 years, patients on placebo were rerandomized to active treatment and the blinded study continued for a further 4 years. The LTFU visit was scheduled 7 to 8 years after baseline. RESULTS: LTFU was attended by 68.2% of the original PRISMS study cohort (382/560 patients). 72.0% (275/382) were still receiving IFNbeta-1a s.c. TIW. Patients originally randomized to IFNbeta-1a 44 microg s.c. TIW showed lower Expanded Disability Status Scale progression, relapse rate and T2 burden of disease up to 8 years compared with those in the late treatment group. Brain parenchymal volume did not show differences by treatment group. Overall, 19.7% of patients progressed to secondary progressive MS between baseline and LTFU (75/381). No new safety concerns were identified and treatment was generally well tolerated. CONCLUSIONS: Despite the limitations inherent in any long-term study (for example, potential differences between returning and nonreturning patients), these results indicate that patients with relapsing-remitting multiple sclerosis can experience sustained benefit over many years from early interferon beta-1a subcutaneous therapy three times weekly compared with patients whose treatment is delayed. This effect was more apparent in the patients receiving the higher dose.

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J Neurol. 2006 Sep;253 Suppl 5:v50-v58.
Intravenous immunoglobulins as therapeutic option in the treatment of multiple sclerosis.
Dudesek A, Zettl UK.
Department of Neurology, University of Rostock, Gehlsheimer Str. 20, 18147, Rostock, Germany, uwe.zettl@med.uni-rostock.de.

Treatment of neurological disorders with intravenous immunoglobulin (IVIG) is an increasing feature of practice for an expanding range of indications. This article reviews the current literature regarding the role of IVIG treatment in multiple sclerosis (MS) and summarizes recommendations for the use of IVIG in different courses and clinical subsets of the disease.Principally based on the results of four randomized, double-blind, placebo-controlled trials (RCTs) and a corresponding meta-analysis, the amount of evidence for the efficacy of IVIG treatment is currently most convincing for the relapsing-remitting course of MS (RRMS); nevertheless, it lags clearly behind that for beta interferon due to smaller study sizes, partial deficits in study design and not established optimal dosage. This prompted the basis for a consensus statement in some countries to recommend IVIG as second-line treatment in RRMS, when other licensed therapies (i. e., beta interferon, glatiramer acetate) are individually not tolerated due to side effects or concomitant disease. Recent evidence indicates that IVIG is also effective in clinically isolated syndrome (CIS) and should be considered as a therapeutic option, particularly when licensed immunotherapy can not be offered. During an acute relapse additional IVIG administration to established steroid treatment showed no benefit. Despite promising experimental data on promotion of remyelination, fixed chronic deficits were not reversed or improved by long-term IVIG treatment either. Currently there is no indication for IVIG treatment in the chronic progressive disease stages, since a large and well-designed RCT failed to show any beneficial effect in patients with secondary progressive MS (SPMS) and data derived from primary progressive MS (PPMS) are still pending. However, preliminary results of a so far unpublished RCT including patients with PPMS and SPMS suggest a strong trend towards a beneficial effect in PPMS. So far, IVIG is the only therapy investigated for reducing postpartum relapses, whereas immunomodulatory drugs are contraindicated during pregnancy and lactation period. Data evaluating the peripartal use of IVIG along with the positive results of the trials in RRMS justify postpartal IVIG treatment particularly for mothers, who choose to breastfeed, under consideration of the recommendations specified for the relapsing-remitting disease course. As recently shown IVIG administration right from the early weeks of pregnancy appears to be a promising strategy, but cannot be recommended from the viewpoint of evidence-based medicine.

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Neurol Sci. 2006 Sep;27(Supplement 5):s369-s372.
Interferon after 10 years in patients with multiple sclerosis.
Pozzilli C, Prosperini L, Sbardella E, Paolillo A.
Department of Neurological Sciences, "La Sapienza" University, Viale dell'Universita 30, I-00185, Rome, Italy, carlo.pozzilli@uniroma1.it.

Multiple sclerosis (MS) is a life-long disease that typically affects young adults. The introduction of disease-modifying therapy has changed the clinical and social burden of the disease. Safety, tolerability and efficacy profiles of Interferon beta (IFNbeta) therapy in MS have been widely highlighted both in trial settings and in daily clinical practice. However, there is a relative lack of information on the long-term period: all pivotal trials must be considered short-term in a disease with an average duration of 30-40 years and post-marketing studies suffer from some limitations. Moreover, current available IFNbeta preparations are only partially effective and are difficult to administer, which has led to poor patient compliance. Over the treatment period, a problem could be the development of neutralising antibodies (NAbs) against the drug, which have been related to lessening treatment benefits. Despite these restrictions, IFNbeta still remains the first choice treatment in MS.

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Neurol Sci. 2006 Sep;27(4):231-9.
Fertility in patients with multiple sclerosis: current knowledge and future perspectives.
Cavalla P, Rovei V, Masera S, Vercellino M, Massobrio M, Mutani R, Revelli A.
Department of Neurosciences, University of Turin, Turin, Italy.

The issue of fertility in patients with multiple sclerosis (MS) has not been exhaustively studied. Epidemiological data have suggested that spontaneous fecundity might be reduced; several endocrine and sexual disturbances potentially interfering with reproduction have been evidenced in MS patients of both sexes. Moreover, some medical treatments used in MS (e. g., mitoxantrone, cyclophosphamide) may exert detrimental effects on spermatozoa as well as on oocytes, leading to early impairment of fertility. This review illustrates the factors potentially interfering with fertility in MS and discusses the therapeutic tools that may be used to promote fertility in these patients. The safety of hormonal therapies in MS is also examined. The current applications of assisted reproductive technology (ART) are discussed, including in vitro fertilisation (IVF) techniques. Currently available methods to preserve fertility in patients that undergo cytotoxic treatments by means of sperm/oocyte cryostorage or by ovarian fragment cryopreservation and autografting are considered.

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Neurol Sci. 2006 Sep;27 Suppl 5:s365-8.
Treatment of multiple sclerosis with interferon beta in clinical practice: 2-year follow-up data from the South Italy Mobile MRI Project.
Bonavita S, Dinacci D, Lavorgna L, Savettieri G, Quattrone A, Livrea P, Bresciamorra V, Orefice G, Paciello M, Coniglio G, Di Costanzo A, Valentino P, Patti F, Salemi G, Simone I, Tedeschi G.
Department of Neurological Sciences, Second University of Naples, Piazza Miraglia 2, I-80138, Naples, Italy, gioacchino.tedeschi@unina2.it.

This follow-up study assessed the 2-year clinical and magnetic resonance imaging (MRI) outcomes of patients with multiple sclerosis (MS) originally enrolled in an MRI study conducted at eight centres in south Italy (the South Italy Mobile MRI Project). Of the 597 MS patients recruited at baseline, 391 returned for the follow-up study. Of these, 363 provided 2-year clinical and MRI follow-up data, and 215 were still undergoing treatment with one of four interferon beta regimens: Avonex, 30 mcg intramuscularly once weekly; Betaferon, 250 mcg subcutaneously (sc) every other day; Rebif 22 mcg sc three times weekly (tiw; Rebif 22); or Rebif 44 mcg sc tiw (Rebif 44). Over the 2-year follow-up period, patients receiving the higher dose of Rebif were more likely to remain free from relapses [odds ratio (OR) = 2.23] and from developing both new T2 (OR = 0.15) and new T1 black hole lesions (OR = 0.22), when compared with patients in the Avonex group. Despite some limitations in the trial design, the results from this follow-up study provide helpful clinical and MRI data on the efficacy of interferon beta regimens in MS patients treated in the clinical setting.

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J Neurol. 2006 Sep;253(9):1160-4. Epub 2006 Sep 21.
Sequential maintenance treatment with glatiramer acetate after mitoxantrone is safe and can limit exposure to immunosuppression in very active, relapsing remitting multiple sclerosis.
Ramtahal J, Jacob A, Das K, Boggild M.
The Walton Centre for Neurology and Neurosurgery, Lower Lane, Liverpool, L9 7LJ, UK, j.ramtahal@liverpool.ac.uk.

Mitoxantrone has been approved by the FDA for worsening relapsing remitting and secondary progressive Multiple Sclerosis. However the benefits of this agent in reducing disease progression and relapse rate cannot be sustained in the long-term, as treatment is limited by the potential for cumulative cardiotoxicity. We report our experience utilising Glatiramer Acetate as maintenance immuno-modulatory treatment following initial immunosuppression with Mitoxantrone in a consecutive series of 27 patients with very active relapsing remitting disease, eight of whom had experienced continuing relapse activity on first-line treatment. Duration of treatment with Mitoxantrone and thereby cumulative dose were reduced as our experience with the combination increased.No unanticipated side effects of combination treatment were encountered over a follow-up period of 66 months. A single patient developed therapy related acute leukaemia (TRAL) 9 months after completion of Mitoxantrone.A sustained 90% reduction in annualised relapse rate (p < 0.001) has been observed. Disability is stable or improved in all patients a mean of 36 (16-66) months from initiation of treatment. Early suppression of relapse activity with Mitoxantrone has been maintained at a mean of 22 months from last dose of this agent. Only two relapses have occurred in the cohort since withdrawal of Mitoxantrone, occurring in the two patients who had previously been treated with Glatiramer Acetate. In 9 of the first 10 patients treated, imaged a mean of 27 months after withdrawal of Mitoxantrone, no enhancing lesions were identified on MRI brain scans.Glatiramer Acetate appears a safe and effective option for continuing disease modification in patients with relapsing remitting multiple sclerosis treated with Mitoxantrone. The treatment protocol utilised in later patients in this series appears to have the potential to limit exposure to this agent.

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Neurol Sci. 2006 Sep;27 Suppl 4:s338-40.
Management of swallowing disorders in multiple sclerosis.
Restivo DA, Marchese-Ragona R, Patti F.
Department of Neurology, Garibaldi Hospital, Piazza S. Maria di Gesu, I-95100, Catania, Italy, dearestivo@tiscali.it.

Dysphagia can complicate multiple sclerosis (MS). Its real prevalence may be estimated to be around 30%-40%. Furthermore, dysphagia is life-threatening. In fact, its complications such as dehydration and aspiration pneumonia are a common cause of death and morbidity in late MS. The management of dysphagia should be focused on treatment of the specific dysphagic symptom and the underlying pathophysiology. The symptomatic management of dysphagia is based on two different types of approaches: the rehabilitative treatment and the pharmacological treatment. Botulinum toxin treatment may be a valid therapy in MS patients with oro-pharyngeal dysphagia associated with upper oesophageal sphincter hyperactivity.

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Acta Neurol Scand. 2006 Jun;113(6):378-386.
Glatiramer acetate in treatment-naive and prior interferon-beta-1b-treated multiple sclerosis patients*
Zwibel HL.
Multiple Sclerosis Center, Baptist/Health Doctors' Hospital, Coral Gables, FL, USA.

Objective - This prospective, open-label study evaluated the efficacy, safety, and tolerability of glatiramer acetate (GA) in treatment-naive relapsing-remitting multiple sclerosis (RRMS) patients and in patients who had previously received interferon-beta (IFN-beta)-1b therapy. Methods - Two treatment cohorts were defined based on prestudy IFN-beta-1b use. At entry, prior IFN-beta-1b patients (n = 247) were older, had longer disease duration, and had higher mean Expanded Disability Status Scale (EDSS) scores, relapse rates, and ambulation indexes than treatment-naive patients (n = 558). Safety was assessed every 3 months and EDSS every 6 months for up to 3.5 years. Results - Overall, 247 treatment-naive and 107 prior IFN-beta-1b patients discontinued before study end. Median GA treatment durations were 36 and 24 months in treatment-naive and prior IFN-beta-1b patients, respectively. At last observation, annual relapse rates had declined by 75% in both cohorts (0.42 +/- 0.84 and 0.34 +/- 0.71 in treatment-naive and prior IFN-beta-1b groups, respectively, P = 0.1482). Mean changes in EDSS were less than 0.5 in both cohorts, regardless of entry EDSS, at 12 and 18 months and at last observation. Conclusions - Prior IFN-beta-1b treatment does not negatively influence the efficacy, safety, or tolerability of subsequent GA therapy. Switching to GA can benefit patients who discontinue IFN-beta therapy.

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Ann Pharmacother. 2006 May 9; [Epub ahead of print]
The Role of Vitamin D in Multiple Sclerosis (June).
Brown SJ.
Drug Information Service, Skaggs School of Pharmacy, College of Health Professions and Biomedical Sciences, The University of Montana, 32 Campus Dr. Skaggs, Bldg 217, Missoula, MT 59812-1522, fax 406/243-4353, sherrill.brown@umontana.edu.

OBJECTIVE: To evaluate the literature about the role of vitamin D in the prevention and treatment of multiple sclerosis (MS). DATA SOURCES: MEDLINE (1966-April 2006) and International Pharmaceutical Abstracts (1970-April 2006) searches were performed. In addition, pertinent references from identified articles were obtained. Key search terms included vitamin D, 25-hydroxyvitamin D, vitamin D deficiency, and multiple sclerosis. DATA SYNTHESIS: Vitamin D supplementation prevented the development and progression of experimental autoimmune encephalitis, an animal model of MS, in mice. A large, prospective, cohort study found that vitamin D supplementation was associated with a 40% reduction in the risk of developing MS. Four small, noncontrolled studies suggested that vitamin D supplementation may decrease exacerbation of MS symptoms. CONCLUSIONS: Vitamin D supplementation may help prevent the development of MS and may be a useful addition to therapy. However, current studies are in small populations and are confounded by other variables, such as additional vitamin and mineral supplementation.

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J Neurol. 2006 May 12; [Epub ahead of print]
Levetiracetam for cerebellar tremor in multiple sclerosis : An open-label pilot tolerability and efficacy study.
Striano P, Coppola A, Vacca G, Zara F, Brescia Morra V, Orefice G, Striano S.
Department of Neurological Sciences, Federico II University, Via Pansini 5, 80131, Naples, Italy.

PURPOSE: Disabling tremor is frequent in multiple sclerosis (MS) and its treatment remains challenging. We conducted an open-label trial to evaluate the effect of levetiracetam (LEV) to treat cerebellar tremor in MS patients.PATIENTS AND METHODS: Fourteen MS patients, aged 27 to 57 years, with cerebellar tremor. Tremor duration ranged from 3 to 14 years. The tremor clinical rating scale, the spiral drawings scale, and ataxia clinical scale were used to assess the severity of tremor. Data about the tremor-induced disability were obtained by using the specific Activities of Daily Living Questionnaire (ADL). LEV was orally administered at a starting dose of 500 mg twice daily for one week followed by increments of 500 mg twice daily each week up to the target dose of 50 mg/Kg/day. Patients were evaluated at baseline and two weeks after the end of titration phase. The Wilcoxon matched-pairs test was used for statistical analysis.RESULTS: Eleven patients completed the trial. LEV administration was associated with subjective and objective improvement of the tremor, with significant lowering of all tremor measurements' sum of scores as well as of ADL mean score between the baseline and follow-up. No correlation was found between the degree of improvement of the tremor and the disease duration or progression. LEV was well tolerated by subjects who completed the study.CONCLUSIONS: LEV could be useful for the management of cerebellar tremor in MS and the good tolerability makes it easy to test. LEV long-term efficacy should be confirmed in extended studies.

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J Neurol Sci. 2006 May 2; [Epub ahead of print]
Pseudobulbar affect in multiple sclerosis: Toward the development of innovative therapeutic strategies.
Miller A.
Center for Multiple Sclerosis, Department of Neurology, Carmel Medical Center, Rappaport Faculty of Medicine and Research Institute, Technion, Haifa, Israel.

Pseudobulbar affect (PBA), a condition involving involuntary and uncontrollable episodes of crying and/or laughing, occurs frequently in patients with a variety of neurological disorders, including amyotrophic lateral sclerosis (ALS), stroke, traumatic brain injury, dementia including Alzheimer's disease, and multiple sclerosis (MS). Although PBA results in considerable distress for patients and caretakers, it is underrecognized and undertreated. Agents used to treat psychiatric disorders-particularly tricyclic antidepressants and selective serotonin reuptake inhibitors-are useful in alleviating PBA, but act on diffuse neural networks rather than targeting those involved in emotional motor expression. As a result of their nonspecific activity, these agents are associated with a range of unwanted effects that preclude many patients from using them. Dextromethorphan, a common cough suppressant, specifically targets sigma(1) receptors concentrated in the brainstem and cerebellum, thus providing the possibility of targeting regions implicated in emotional expression. When administered in a fixed combination with quinidine, dextromethorphan is effective in treating PBA in patients with ALS, and preliminary results suggest that this therapy also is effective in treating MS-related PBA.

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Neurol Res. 2006 Apr;28(3):320-5.
Neurosurgical treatment of multiple sclerosis.
Patwardhan RV, Minagar A, Kelley RE, Nanda A.
Department of Neurosurgery, Louisiana State University Health Sciences Center in Shreveport, Shreveport, LA, USA.

OBJECTIVES: To describe the role of neurosurgical techniques in treatment of symptoms of multiple sclerosis (MS).METHODS: A review of the existing world literature searching (using PubMed, August 22, 2005) for key words 'multiple sclerosis' and multiple symptoms associated with MS including trigeminal neuralgia, pain (pump and rhizotomy), spasticity, intrathecal pump, hydrocephalus and stimulation (brain and spinal).RESULTS: In total, 1,404 articles met selection criteria. These were narrowed based upon uniqueness of technique described, nature of information provided and avoidance of redundancy. Further, the methods listed were classified into groups of cranial and spinal techniques. Indications, brief description of technique and outcome/side effects were noted for each technique.DISCUSSION: A vast, growing body of literature exists for various neurosurgical applications for MS treatment. Older techniques such as rhizolysis for neuralgia and rhizotomy for spasticity have been modified using stereotactic radiosurgery and deep brain stimulation, along with central nervous system stimulation and intrathecal pumps. Other applications continue to be found with varying degrees of success.CONCLUSIONS: Neurosurgical techniques, based upon proper selection criteria, can significantly improve MS-related symptoms with low procedure-associated risk and therefore can substantially improve patients' quality of life.

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J Neurol Sci. 2006 Apr 25; [Epub ahead of print]
Are there protective treatments for cognitive decline in MS?
Pia Amato M, Portaccio E, Zipoli V.
Department of Neurology, University of Florence, Viale Morgagni 85, 50134 Florence, Italy.

Despite its frequency and high functional impact, very little is known about effective strategies for managing cognitive impairment in multiple sclerosis (MS). Disease-modifying drugs, such as beta-interferons and glatiramer acetate, may prevent or reduce the progression of cognitive dysfunction by containing the development of new cerebral lesions. To date, clinical trials have provided inconsistent results, with neuropsychological effects documented only in one trial. Moreover, pilot studies have tested symptomatic therapies for fatigue, a frequent symptom in MS, which may share a common physiopathological substrate with cognitive dysfunction. Small trials with amantadine, pemoline, 4-aminopyridine and 3-4 aminopyridine have provided mainly negative results. Acetylcholinesterase inhibitors (AChEI) used to treat Alzheimer's disease (AD)-such as donepezil, rivastigmine, and galantamine-have recently been tested in other cognitive disorders, including MS. The majority of pilot trials with AchEI in MS have provided promising results, and the donepezil study recently published by Krupp et al. represents a major development in this field. As for non-pharmacological interventions based on cognitive rehabilitation, few studies have used an experimental approach and, in general, results have been disappointingly negative. Further research is clearly needed in this area.

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Mult Scler. 2006 Feb;12(1):101-3.
Intrathecal baclofen for treatment of spasticity of multiple sclerosis patients.
Ben Smail D, Peskine A, Roche N, Mailhan L, Thiebaut I, Bussel B.
Service de Medecine Physique et Readaptation, Hopital R. Poincare, 104 Bd R. Poincare, 92380 Garches, France. djamel.bensmail@rpc.aphp.fr

We conducted a retrospective study of the case files of 64 multiple sclerosis (MS) patients presenting severe spasticity, who had received intrathecal (IT) baclofen test injections between 1992 and 2004 in a rehabilitation unit. In almost all cases of our series, IT baclofen was proposed to patients who were no longer able to walk. IT baclofen is a safe and effective treatment to reduce spasticity in MS patients. Despite an advanced stage of the disease at the time of pump placement, the complication rate was low and the efficacy of this treatment was maintained over time.

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Mult Scler. 2006 Feb;12(1):66-71.
No effect of intravenous immunoglobulins on cytokine-producing lymphocytes in secondary progressive multiple sclerosis.
Petereit HF, Reske D, Pukrop R, Maas-Enriquez M, Japp G, Jongen PJ, Kolmel HW, Merkelbach S, Hartung HP, Heiss WD, Hommes OR.
Department of Neurology and Psychiatry, University of Cologne, Josef-Stelzmann-Str. 9, 50924 Ko1n, Germany. hela.petereit@medizin.uni-koeln.de

Intravenous immunoglobulins (IVIG) have been effective in reducing multiple sclerosis (MS) disease activity and improving disability scores. However, the mechanism by which this beneficial effect is achieved remains unclear. An effect of IVIG on pro- and anti-inflammatory cytokines which are thought to play a role in the disease process - has been postulated in a number of animal and ex vivo studies. Hence, we performed a study on 34 patients with secondary progressive (SP) MS being treated with monthly IVIG or placebo for two years according to the protocol of the ESIMS study. Clinical outcome measures and cytokine production (interferon gamma, tumour necrosis factor alpha, interleukin-4 and -10) were recorded in all patients and compared with respect to the treatment group. Against our expectations, IVIG did not reduce the relapse rate or the progression of disability or cytokine production. Our data argue against an enduring immunomodulating effect of IVIG, at least in SPMS.

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Cochrane Database Syst Rev. 2006 Jan 25;(1):CD004431.
Psychological interventions for multiple sclerosis.
Thomas P, Thomas S, Hillier C, Galvin K, Baker R.

BACKGROUND: The unpredictable, variable nature of Multiple Sclerosis (MS), and the possibility of increasing disability, means that a diagnosis can have substantial psychological consequences. OBJECTIVES: To assess the effectiveness of psychological interventions for people with MS. SEARCH STRATEGY: We searched 19 databases up to December 2004; Cochrane MS Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PsychINFO, CINAHL and 14 others. We searched reference lists of articles, wrote to corresponding authors of the 13 papers identified by June 2004, and searched for trials in progress using 3 research registers. SELECTION CRITERIA: Randomised controlled trials of interventions described as wholly or mostly based on psychological theory and practice, in people with MS. Primary outcome measures were disease specific and general quality of life, psychiatric symptoms, psychological functioning, disability, and cognitive outcomes. Secondary outcome measures were number of relapses, pain, fatigue, health care utilisation, changes in medication, and adherence to other therapies. DATA COLLECTION AND ANALYSIS: Pertinent studies were identified from abstracts by one author. Full papers were independently compared to selection criteria by four authors. Key details were extracted from relevant papers using a standard format, and studies scored on three dimensions of quality. The review is organised into four mini-reviews (MR) dependent on the intervention's target population; people with cognitive impairments (MR1), people with moderate to severe disability (MR2), people with MS (no other criteria) (MR3), and people with depression (MR4). MAIN RESULTS: Overall 16 studies were identified and included. MR1: three trials (n=145). Some evidence of effectiveness of cognitive rehabilitation on cognitive outcomes, although this was difficult to interpret because of the large number of outcome measures used. MR2: three trials (n=80). One small trial suggesting psychotherapy may help with depression. MR3: seven studies (n=688). Some evidence that cognitive behavioural therapy may help people adjust to, and cope with, having MS (three trials). The other trials were diverse in nature and some difficult to interpret because of multiple outcome measures. MR4: three trials (n=93). Two small studies of cognitive behavioural therapy showed significant improvements in depression. AUTHORS' CONCLUSIONS: The diversity of psychological interventions identified indicates the many ways in which they can potentially help people with MS. No definite conclusions can be made from this review. However there is reasonable evidence that cognitive behavioural approaches are beneficial in the treatment of depression, and in helping people adjust to, and cope with, having MS.

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Adv Neurol. 2006;98:273-92.
The use of glatiramer acetate in the treatment of multiple sclerosis.
Wolinsky JS.
University of Texas Health Science Center at Houston, USA.

Glatiramer acetate is a collection of synthetic polypeptides indicated as therapy for relapsing a remitting multiple sclerosis (MS). Current understanding of the immunological and neuroprotective mechanisms of action of GA makes it unique among current MS therapies. The clinical efficacy of GA appears similar to that of the recombinant beta interferons. GA has a favorable side effect profile with excellent patient compliance and long-term acceptance. The results of pivotal controlled clinical trials and long-term data derived from organized extension studies are reviewed. Supportive data from open-label comparison, combination treatment and therapeutic switch studies are also provided to enable informed decisions on the appropriate place for GA among other immunomodulatory treatments for relapsing MS.

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Neurology. 2006 Jan 25; [Epub ahead of print]
IM interferon {beta}-1a delays definite multiple sclerosis 5 years after a first demyelinating event.
[No authors listed]

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

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Eur J Neurol. 2006 Jan;13(1):72-6.
Repeat intrathecal triamcinolone acetonide application is beneficial in progressive MS patients.
Hoffmann V, Kuhn W, Schimrigk S, Islamova S, Hellwig K, Lukas C, Brune N, Pohlau D, Przuntek H, Muller T.
Department of Neurology, Kamillus-Klinik, Asbach, Germany.

Available immunomodulatory and conventional steroid treatment regimens provide a limited symptomatic benefit for patients with progressive multiple sclerosis (MS). We performed an open trial on the short-term efficacy of repeated intrathecal application of the sustained release steroid triamcinolone acetonide (TCA) in 27 progressive MS patients. Six TCA administrations, performed every third day, reduced the Expanded Disability Status Scale (EDSS) score [initial: 5.4 +/- 1.3, 3-7.5 (mean +/- SD, range); end: 4.9 +/- 1.1; 2.5-6.5; P < 0.001] and significantly increased the walking distance and speed in particular after the fourth TCA injection. Concomitantly serially determined cerebrospinal fluid (CSF) markers of cell injury, neuron-specific enolase, total tau-protein, S-100, and beta-amyloid did not significantly change within the interval of TCA treatment. No serious side effects appeared. We conclude that repeat intrathecal injection of 40 mg TCA provides a substantial benefit in progressive MS patients with predominant spinal symptoms and does not alter CSF markers of neuronal cell injury.

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Clin Neurol Neurosurg. 2005 Dec 31; [Epub ahead of print]
Pregnancy and multiple sclerosis: The children of PRIMS.
Vukusic S, Confavreux C.
The European Database for Multiple Sclerosis (EDMUS) Coordinating Center and Service de Neurologie A, INSERM U 433, Hopital Neurologique Pierre Wertheimer, 59 Boulevard Pinel, 69677 Lyon-Bron CEDEX, France.

The influence of pregnancy on multiple sclerosis (MS) has long been a matter of controversy. Women with MS were often discouraged to consider pregnancy. The PRegnancy In Multiple Sclerosis (PRIMS) study was the first large prospective study aimed at assessing the possible influence of pregnancy and delivery on the clinical course of MS. Two hundred and fifty-four women with the diagnosis of MS were included during pregnancy and followed until the end of the second year post partum. The results were a reduction in the relapse rate during pregnancy, in comparison to the year before pregnancy, especially marked in the third trimester, and a significant increase in the relapse rate in the first trimester post partum. Starting in the second trimester post partum, the relapse rate did not significantly differ from the pre-pregnancy rate. About one third of the women experienced a post partum relapse. Pregnancy did not influence disability progression. Women with greater disease activity in the year before and during pregnancy had a higher risk of relapse in the first three months post partum. Neither breastfeeding, nor epidural analgesia correlated with the presence of a post partum relapse. When comparing predicted and observed status, 72% of the women were correctly classified by the multivariate model; it therefore seems unwise to use such a model to select women who would benefit from a putative preventive therapy. The PRIMS study had other major consequences: it fostered the development of specific therapeutic strategies to prevent post partum relapses (IV immunoglobulins, IV methylprednisolone), and suggested a potential role for sex hormones in the natural history of MS during pregnancy and the post partum. The preventive effect of progesterone combined with estradiol on post partum relapses is about to be tested in a large randomized and placebo-controlled European trial, the POPART'MUS study.

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Clin Neurol Neurosurg. 2005 Dec 31; [Epub ahead of print]
Neuroprotection in multiple sclerosis.
Karussis D, Grigoriadis S, Polyzoidou E, Grigoriadis N, Slavin S, Abramsky O.
Department of Neurology and the Agnes Ginges Center for Neurogenetics, Laboratory of Neuroimmunology, Hadassah University Hospital, Jerusalem, Ein-Karem IL-91120, Israel.

In chronic inflammatory diseases like multiple sclerosis (MS), neuroprotection refers to strategies aimed at prevention of the irreversible damage of various neuronal and glial cell populations, and promoting regeneration. It is increasingly recognized that MS progression, in addition to demyelination, leads to substantial irreversible damage to, and loss of neurons, resulting in brain atrophy and cumulative disability. One of the most promising neuroprotective strategies involves the use of bone marrow derived stem cells. Both hematopoietic and non-hematopoietic (stromal) cells can, under certain circumstances, differentiate into cells of various neuronal and glial lineages. Neuronal stem cells have also been reported to suppress EAE by exerting direct in situ immunomodulating effects, in addition to their ability to provide a potential source for remyelination and neuroregeneration. Preliminary results from our laboratory indicate that intravenous or intracerebral/intraventricular injection of bone marrow derived stromal cells could differentiate in neuronal/glial cells and suppress the clinical signs of chronic EAE. Both bone marrow and neuronal stem cells may therefore have a therapeutic potential in MS. It seems that future treatment strategies for MS should combine immunomodulation with neuroprotective modalities to achieve maximal clinical benefit.

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Int J Immunopathol Pharmacol. 2005 Oct-Dec;18(4):771-8.
A pilot, open label, clinical trial using hydroxyzine in Multiple Sclerosis.
Logothetis L, Mylonas IA, Baloyannis S, Pashalidou M, Orologas A, Zafeiropoulos A, Kosta V, Theoharides TC.
B Department of Neurology, Aristotle University, AHEPA Hospital, Thessaloniki, Greece.

Multiple sclerosis (MS) is an autoimmune disorder of myelin destruction. Blood-brain-barrier (BBB) disruption precedes pathological or clinical findings and could involve mediators from perivascular brain mast cells, such as histamine and vascular endothelial growth factor (VEGF). Mast cells could be activated by many triggers, including acute stress that has been correlated with MS exacerbations. We considered that the histamine-1 (H1) receptor antagonist hydroxyzine, which also partially inhibits brain mast cells and has anxiolytic properties, may reduce MS symptoms. This open label, pilot, clinical trial investigated the effect on MS of an oral solution of hydroxyzine (100 mg per day), together with caffeine (200 mg per day) to reduce sedation. Twenty patients (8 males; 12 females) with relapsing-remitting or relapsing-progressive MS completed the study (12 +/- 1 months) and were evaluated using disability scales. Most patients on hydroxyzine (75%) remained stable or improved neurologically and all but one showed improved mood. Hydroxyzine could be used as an adjuvant in MS, but the small number of patients enrolled and the short duration of the study precludes any definitive conclusions. A double-blind, placebo-controlled study is warranted.

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J Neurol Neurosurg Psychiatry. 2005 Dec;76(12):1664-9.
Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up.
Zajicek JP, Sanders HP, Wright DE, Vickery PJ, Ingram WM, Reilly SM, Nunn AJ, Teare LJ, Fox PJ, Thompson AJ.
Room N16, ITTC Building, Tamar Science Park, Plymouth, Devon PL6 8BX, UK. john.zajicek@phnt.swest.nhs.uk.

OBJECTIVE: To test the effectiveness and long term safety of cannabinoids in multiple sclerosis (MS), in a follow up to the main Cannabinoids in Multiple Sclerosis (CAMS) study. METHODS: In total, 630 patients with stable MS with muscle spasticity from 33 UK centres were randomised to receive oral Delta(9)-tetrahydrocannabinol (Delta(9)-THC), cannabis extract, or placebo in the main 15 week CAMS study. The primary outcome was change in the Ashworth spasticity scale. Secondary outcomes were the Rivermead Mobility Index, timed 10 metre walk, UK Neurological Disability Score, postal Barthel Index, General Health Questionnaire-30, and a series of nine category rating scales. Following the main study, patients were invited to continue medication, double blinded, for up to12 months in the follow up study reported here. RESULTS: Intention to treat analysis of data from the 80% of patients followed up for 12 months showed evidence of a small treatment effect on muscle spasticity as measured by change in Ashworth score from baseline to 12 months (Delta(9)-THC mean reduction 1.82 (n = 154, 95% confidence interval (CI) 0.53 to 3.12), cannabis extract 0.10 (n = 172, 95% CI -0.99 to 1.19), placebo -0.23 (n = 176, 95% CI -1.41 to 0.94); p = 0.04 unadjusted for ambulatory status and centre, p = 0.01 adjusted). There was suggestive evidence for treatment effects of Delta(9)-THC on some aspects of disability. There were no major safety concerns. Overall, patients felt that these drugs were helpful in treating their disease. CONCLUSIONS: These data provide limited evidence for a longer term treatment effect of cannabinoids. A long term placebo controlled study is now needed to establish whether cannabinoids may have a role beyond symptom amelioration in MS.

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Arch Neurol. 2005 Nov;62(11):1681-3.
Response to interferon beta-1a treatment in African American multiple sclerosis patients.
Cree BA, Al-Sabbagh A, Bennett R, Goodin D.
Multiple Sclerosis Center, University of California, San Francisco, 94117, USA. bcree@itsa.ucsf.edu

BACKGROUND: African Americans (AAs) with multiple sclerosis (MS) seem to have a more severe disease course than white Americans (WAs). To our knowledge, it is not known to what extent treatment with interferon beta-1a will effect the MS disease course within the AA population. OBJECTIVE: To compare the response to treatment with interferon beta-1a between AA and WA MS patients. DESIGN: This is an exploratory post hoc analysis of the Evidence of Interferon Dose-Response: European North American Comparative Efficacy (EVIDENCE) study. SETTING: The EVIDENCE study is a randomized controlled trial that compared the efficacy of once weekly, intramuscular, 30-microg interferon beta-1a treatment with thrice weekly, subcutaneous, 44-microg interferon beta-1a therapy in treatment-naive MS subjects. PARTICIPANTS: Thirty-six AA subjects were compared with 616 WA subjects. MAIN OUTCOME MEASURES: The number of MS exacerbations, the proportion of exacerbation-free subjects, and the number of new MS lesions present on brain magnetic resonance imaging were compared between AA and WA subjects at 24 and 48 weeks after initiating treatment with interferon beta-1a. RESULTS: The AA subjects experienced more exacerbations and were less likely to remain exacerbation free (statistical trends). The AA subjects developed more new MS lesions on T2-weighted brain magnetic resonance imaging at 48 weeks (P = .04). CONCLUSIONS: Despite the small sample size, AA subjects appeared less responsive to treatment than WA subjects on outcome measures, reaching significance only for T2-weighted lesion count at 48 weeks. However, it is difficult to base these differences solely on response to treatment given the potential differing in MS disease course in AA patients.

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Expert Rev Neurother. 2005 Nov;5(6):721-7.
Cladribine for multiple sclerosis: review and current status.
Sipe JC.
Department of Molecular and Experimental Medicine, The Scripps Research Institute, and Scripps Clinic, 10550 North Torrey Pines Road (MEM-215), LaJolla, CA 92037 USA. jcsipe@scripps.edu

In the 1990s, cladribine was developed as an adenosine deaminase-resistant nucleoside analog with selective lymphotoxic specificity in the hope that it might become useful in the treatment of some lymphoid neoplasms and autoimmune disorders. Several clinical trials demonstrated very significant effectiveness and safety of cladribine in the cure of hairy-cell leukemia, and the control of many other lymphoid malignancies. Cladribine was also extensively tested in selected autoimmune disorders, most notably in multiple sclerosis, with evidence of efficacy, tolerability and acceptable side effects/toxicity. The previous clinical studies and current status of cladribine for the treatment of multiple sclerosis are considered in this drug profile. In January 2005, Serono and IVAX announced plans to initiate a Phase III study of a specially formulated oral tablet of cladribine (Mylinax, Serono and IVAX) for the treatment of relapsing forms of multiple sclerosis. The proposed study will be the first large multicenter randomized controlled clinical trial of oral cladribine in multiple sclerosis.

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Expert Opin Emerg Drugs. 2005 Nov;10(4):797-816.
Emerging therapies in multiple sclerosis.
Farrell R, Heaney D, Giovannoni G.
Department of Neuroinflammation, Institute of Neurology, Queen Square, London, WC1N 3BG, UK. R.Farrell@ion.ucl.ac.uk

Multiple sclerosis (MS) is the most common neurological cause of disability in young people. The disease-modifying treatments, IFN-beta and glatiramer acetate, have been widely available over the last decade and have shown a beneficial effect on relapse rate and magnetic resonance imaging parameters of disease activity; however, their effect on disease progression and disability is modest. Therefore, the search for alternative treatment strategies continues. As understanding of the heterogeneous pathophysiology of MS has increased, emphasis has shifted to more selective therapy that targets components of the inflammatory cascade and the promotion of remyelination and neuroprotection. These agents target the blood-brain barrier, systemic immune dysfunction, local inflammation and neurodegeneration. Combination therapies are being investigated for patients who fail first-line treatments. Many new drugs are being developed and tested that address these issues with the aim of finding a more effective and convenient therapy. These include humanized monoclonal antibodies such as daclizumab (IL-2 antagonist), oral immunomodulators such as sirolimus and statins and neuroprotective agents such as NMDA antagonists and Na+-channel blockers. Many of the treatments discussed in this review are still at early stages of development, but provide exciting potential treatment options; others have proved disappointing in larger extended-phase studies.

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Ann Pharmacother. 2005 Nov;39(11):1833-43. Epub 2005 Oct 11.
Natalizumab for the treatment of multiple sclerosis and Crohn's disease.
Keeley KA, Rivey MP, Allington DR.
Pharmacy Practice Resident, The University of Montana and Community Medical Center, Missoula, MT (ImProving Health Among Rural Montanans) project, University of Montana.

OBJECTIVE: To review the pharmacology, pharmacokinetics, safety, and pivotal clinical trials for natalizumab in the treatment of multiple sclerosis (MS) and inflammatory bowel disease. DATA SOURCES: A PubMed/MEDLINE search was conducted (1966-June 2005), and information was obtained from Iowa Drug Information Services. Additional data sources included meeting abstracts, bibliographies from identified articles, and information from the manufacturer. STUDY SELECTION AND DATA EXTRACTION: Studies and review articles examining natalizumab were evaluated. All published, randomized clinical trials evaluating natalizumab in MS and IBD were included in this review. DATA SYNTHESIS: Natalizumab is the first drug in a new class of agents called selective adhesion molecule inhibitors. It has shown promising results in MS and inflammatory bowel disease and appears superior compared with current therapies in reducing relapse rates. However, 3 recent, confirmed case reports of progressive multifocal leukoencephalopathy (PML) create concern about natalizumab's use in combination with existing therapies or in undefined patient subgroups. Natalizumab was voluntarily withdrawn from the market in March 2005 while the drug's safety is further evaluated. CONCLUSIONS: Although long-term efficacy and safety of natalizumab have not been established, available data indicate that it is a novel drug for patients with MS or inflammatory bowel disease. Analysis of its possible association with PML will determine the risk-benefit evaluation and eventual place in therapy for natalizumab.

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South Med J. 2005 Oct;98(10):1024-7.
Vitamin D: important for prevention of osteoporosis, cardiovascular heart disease, type 1 diabetes, autoimmune diseases, and some cancers.
Holick MF.
Vitamin D, Skin and Bone Research Laboratory, and the Section of Endocrinology, Diabetes, and Nutrition, Department of Medicine, Boston University School of Medicine, Boston, MA, USA. mfholick@bu.edu

Vitamin D is very important for overall health and wellbeing. A major source of vitamin D comes from exposure to sunlight. Measurement of 25-hydroxyvitamin D in the blood and not 1,25-dihydroxyvitamin D is used to determine vitamin D status. A blood level of 25-hydroxyvitamin D of at least 20 ng/mL is considered to be vitamin D sufficient. Vitamin D deficiency increases the risk of many common cancers, multiple sclerosis, rheumatoid arthritis, hypertension, cardiovascular heart disease, and type I diabetes.

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Med Hypotheses. 2005 Oct 3; [Epub ahead of print]
A tale of two cannabinoids: The therapeutic rationale for combining tetrahydrocannabinol and cannabidiol.
Russo E.
GW Pharmaceuticals, Salisbury, UK; University of Washington School of Medicine, Seattle, WA, USA; University of Montana Department of Pharmaceutical Sciences, MT, USA.

This study examines the current knowledge of physiological and clinical effects of tetrahydrocannabinol (THC) and cannabidiol (CBD) and presents a rationale for their combination in pharmaceutical preparations. Cannabinoid and vanilloid receptor effects as well as non-receptor mechanisms are explored, such as the capability of THC and CBD to act as anti-inflammatory substances independent of cyclo-oxygenase (COX) inhibition. CBD is demonstrated to antagonise some undesirable effects of THC including intoxication, sedation and tachycardia, while contributing analgesic, anti-emetic, and anti-carcinogenic properties in its own right. In modern clinical trials, this has permitted the administration of higher doses of THC, providing evidence for clinical efficacy and safety for cannabis based extracts in treatment of spasticity, central pain and lower urinary tract symptoms in multiple sclerosis, as well as sleep disturbances, peripheral neuropathic pain, brachial plexus avulsion symptoms, rheumatoid arthritis and intractable cancer pain. Prospects for future application of whole cannabis extracts in neuroprotection, drug dependency, and neoplastic disorders are further examined. The hypothesis that the combination of THC and CBD increases clinical efficacy while reducing adverse events is supported.

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Cochrane Database Syst Rev. 2005 Oct 19;(4):CD002127.
Mitoxantrone for multiple sclerosis.
Martinelli BF, Rovaris M, Capra R, Comi G, Martinelli Boneschi F.

BACKGROUND: Mitoxantrone (MX) has been shown to be moderately effective in reducing the clinical outcome measures of disease activity in multiple sclerosis (MS) patients. OBJECTIVES: The objective was to assess the efficacy and safety of MX in relapsing-remitting MS (RRMS), progressive relapsing MS (PRMS) and secondary progressive MS (SPMS). SEARCH STRATEGY: We searched the Cochrane MS Group Trials Register (searched April 2005), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2004), MEDLINE (Pub Med) (January 1966 to April 2005), EMBASE (January 1974 to April 2005), and reference lists of articles. We also undertook hand searching and contacting trialists and pharmaceutical companies. SELECTION CRITERIA: The trials were selected if double-blinded, placebo-controlled, randomised, irrespective of eventual additive therapy (such as steroids). DATA COLLECTION AND ANALYSIS: Three reviewers independently selected articles for inclusion, assessed trials' quality and extracted data. MAIN RESULTS: Four trials involving 270 participants were included. MX was found to reduce the progression of disability at 2 years follow-up (proportion of participants with 6-months confirmed progression of disability: Odds Ratios (OR) 0.3, p = 0.05). Similar figures were found regarding the reduction in annualised relapse rate and the proportion of patients free from relapses at 1 and 2 years, as well as the number of patients with active MRI lesions at 6 months/ 1 year only. Side effects reported in the trials were more frequent in treated patients than in controls. Caution must be exercised in drawing conclusions from such data because of the heterogeneous quality and characteristics of the included trials, which are different in terms of treatment schedule and type of enrolled patients. More than half of the included patients came from a single study. Moreover, from the included trials, it was not possible to estimate the long-term efficacy and safety of MX, which may raise concerns about the risk of cardiotoxicity and therapy-related leukemias, which is increasingly reported in the literature. AUTHORS' CONCLUSIONS: MX is moderately effective in reducing the disease progression and the frequency of relapses in patients affected by RR, PR and SP MS in the short-term follow-up (2 years), even if the results are based on trials heterogeneous in terms of drug dosage and inclusion criteria. No major neoplastic or symptomatic cardiotoxicity related to MX have been reported from the trials. However, longer follow-up studies are highly warranted to better explore the efficacy and safety of the drug, mainly as regards the long-term risk of therapy-related leukemias and cardiotoxicity.As a conclusion, MX has a partial efficacy, but, due to its unclear long-term safety profile, it should be used to treat patients with worsening RR and SP MS with evidence of worsening disability.

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Pharmacol Ther. 2005 Oct 13; [Epub ahead of print]
Therapeutic role of beta-interferons in multiple sclerosis.
Javed A, Reder AT.
Department of Neurology, MC-2030, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS). In the last 12 years, there has been a proliferation of studies elucidating the immune mechanisms that mediate tissue damage in MS. Interferons (IFNs) have an important role in regulating innate and adaptive immune responses. They decrease pro-inflammatory responses such as the autoimmunity in MS, but other autoimmune responses such as systemic lupus erythematosus (SLE) may be exacerbated. This review offers a general overview of the biological properties of IFNs, effects on immune cells, and clinical effectiveness in MS treatment. IFN signaling is complex, from receptor binding events to the generation of effector mechanisms that dampen inflammation. Immune cell function is altered in MS. IFN treatment of MS patients ameliorates immune dysfunction, but not completely. The incomplete resolution of immune dysfunction by IFNs partly explains their significant, but modest therapeutic effects. This observation also suggests that there are immune mechanisms in MS that are resistant to IFN therapy. In MS, abnormalities may exist at several points along the IFN signaling pathway, including molecular defects in the IFN second messenger system. Currently, several studies are ongoing evaluating ways of potentiating IFN effects. IFNs were the first agents to show clinical efficacy in treatment of MS. More than a decade of experience with IFNs has showed continued clinical efficacy over time. In the near future, IFNs will continue to play a major role in MS.

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Neurology. 2005 Oct 12; [Epub ahead of print]
A randomized crossover study of bee sting therapy for multiple sclerosis.
Wesselius T, Heersema DJ, Mostert JP, Heerings M, Admiraal-Behloul F, Talebian A, van Buchem MA, De Keyser J.
>From the Department of Neurology, University Medical Center Groningen, Groningen (Drs. Wesselius, Heersema, Mostert, De Keyser, M. Heerings), Department of Radiology, Gemini Hospital, Den Helder (Dr. Wesselius), Department of Radiology, Leiden University Medical Center, Leiden (Drs. Admiraal-Behloul, Talebian, and van Buchem), The Netherlands.

Abstract-- BACKGROUND: Bee sting therapy is increasingly used to treat patients with multiple sclerosis (MS) in the belief that it can stabilize or ameliorate the disease. However, there are no clinical studies to justify its use. METHODS: In a randomized, crossover study, we assigned 26 patients with relapsing-remitting or relapsing secondary progressive MS to 24 weeks of medically supervised bee sting therapy or 24 weeks of no treatment. Live bees (up to a maximum of 20) were used to administer bee venom three times per week. The primary outcome was the cumulative number of new gadolinium-enhancing lesions on T1-weighted MRI of the brain. Secondary outcomes were lesion load on T2*-weighted MRI, relapse rate, disability (Expanded Disability Status Scale, Multiple Sclerosis Functional Composite, Guy's Neurologic Disability Scale), fatigue (Abbreviated Fatigue Questionnaire, Fatigue Impact Scale), and health-related quality of life (Medical Outcomes Study 36-Item Short Form General Health Survey). RESULTS: During bee sting therapy, there was no significant reduction in the cumulative number of new gadolinium-enhancing lesions. The T2*-weighted lesion load further progressed, and there was no significant reduction in relapse rate. There was no improvement of disability, fatigue, and quality of life. Bee sting therapy was well tolerated, and there were no serious adverse events. CONCLUSIONS: In this trial, treatment with bee venom in patients with relapsing multiple sclerosis did not reduce disease activity, disability, or fatigue and did not improve quality of life.

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Ann Readapt Med Phys. 2005 Sep 27; [Epub ahead of print]
[Multiple sclerosis and physical activities.]
[Article in French]
Kerdoncuff V, Durufle A, Le Tallec H, Lassalle A, Petrilli S, Nicolas B, Robineau S, Edan G, Gallien P.
Service de medecine physique et readaptation, CHRU de Pontchaillou, 2, rue Henri-Le-Guilloux, 35033 Rennes cedex 9, France.

Introduction. - Multiple sclerosis (MS) is a neurological disease of the central nervous system that most often affects young people. It is characterized by various debilitating symptoms. The aim of this study was to assess physical activities in patients with MS and how these affect their quality of life. Methods. - Forty-five patients were questioned about their physical activities. The following were taken into account: the characteristics of MS within each patient, the level of disease severity (EDSS score) and the quality of life (on the SEP-59 questionnaire). Results. - Fifteen patients had to give up a physical activity because of their illness but more so due to ataxia, fatigue and muscular weakness. Fifteen patients take part in a physical activity, the principal motivation being for their personal well-being. The mean EDSS was 4.2. Answers on the SEP-59 revealed found that patients with MS who took part in a physical activity had significantly better well-being in general. Discussion and conclusion. - Physical activities seem to improve the quality of life of patients with MS who, in general, already have a poor quality of life in relation to the general population. Knowing that muscular function is improved through exercise in patients with an EDSS less than 6, it would seem advantageous for them to take part in a regular physical activity.

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Lancet Neurol. 2005 Sep;4(9):556-66.
Quality of life and its assessment in multiple sclerosis: integrating physical and psychological components of wellbeing.
Mitchell AJ, Benito-Leon J, Gonzalez JM, Rivera-Navarro J.
Department of Liasion Psychiatry, Brandon Mental Health Unit, Leicester General Hospital, Leicester, UK.

Health-related quality of life (HRQoL) has been more intensively studied in multiple sclerosis (MS) than in any other neurological disorder. Traditional medical models of impairment and disability are an incomplete summary of disease burden. Quality of life can be thought of as the sum of all sources of satisfaction (including anticipated sources) minus all threats (including anticipated threats). Many psychosocial factors-including coping, mood, self-efficacy, and perceived support-influence the quality of life of patients with MS more than biological variables such as weakness or extent of MRI lesions. Neuropsychiatric complications such as cognitive impairment and fatigue are also important predictors, even in those patients in the early stages of the disease. We review generic and specific HRQoL measures to help clinicians choose the most appropriate therapies. Subjective (self-report) HRQoL measures may serve to alert clinicians to areas that would otherwise be overlooked. Studies of new interventions should include an assessment of HRQoL not just impairment or disability alone.

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J Neurol Neurosurg Psychiatry. 2005 Sep;76(9):1294-6.
A pilot study of oral calcitriol (1,25-dihydroxyvitamin D3) for relapsing-remitting multiple sclerosis.
Wingerchuk DM, Lesaux J, Rice GP, Kremenchutzky M, Ebers GC.
Mayo Clinic, Scottsdale, Arizona, USA. wingerchuk.dean@mayo.edu.

BACKGROUND: Epidemiological and ecological studies suggest links between vitamin D deficiency and increased multiple sclerosis (MS) prevalence. OBJECTIVE: To evaluate the safety and tolerability of oral calcitriol therapy in an open label pilot study. METHODS: 15 ambulatory patients with relapsing-remitting MS and at least one clinical relapse within the previous 12 months received oral calcitriol (target dose: 2.5 mug/d) for 48 weeks. Dietary calcium was restricted to 800 mg/d. Patients were monitored using frequent clinical and laboratory examinations, the expanded disability status scale (EDSS), and brain magnetic resonance imaging (MRI). RESULTS: Two patients withdrew because of symptomatic hypercalcaemia (serum calcium >3.35 mmol/l in each case) resulting from persistent dietary indiscretion. Two diet compliant patients required temporary dose adjustments for mild asymptomatic hypercalcaemia. Diet compliant patients experienced mild adverse effects. The on-study exacerbation rate (27%) was less than baseline. Four patients experienced five clinical relapses but only one patient worsened by >1 EDSS point. Brain MRI revealed enhancing lesions in five patients at baseline (33%) and in four (29%) at both 24 and 48 weeks. CONCLUSIONS: Oral calcitriol is safe and well tolerated for up to one year by diet compliant relapsing-remitting MS patients. Further study of vitamin D related mechanisms is warranted in MS.

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Fortschr Neurol Psychiatr. 2005 Aug;73(8):451-62.
[Alternative and complementary therapies in multiple sclerosis]
[Article in German]
Schwarz S, Leweling H, Meinck HM.
Neurologische Klinik, Klinikum Mannheim der Universitat Heidelberg, Mannheim. s.schwarz@neuro.ma.uni-heidelberg.de

Most MS patients use unconventional therapies, usually as complementary measures in addition to the conventional treatment. Only a few adequate clinical trials exist in this field. By definition, the efficacy of these therapies is unproven. Moreover, the possible risks are also largely unknown. Some therapies rely on rational pathophysiological considerations, other must be regarded as potentially harmful. The influence of diet on MS is unproven. Possibly, unsaturated fatty acids are beneficial. However, a few randomized trials yielded inconclusive results. Long-term supplementation of Vitamin D is associated with a decreased MS incidence. There is, however, insufficient evidence for an influence of Vitamin D on the course of the disease. Because of the high prevalence of osteoporosis in MS patients, prophylaxis with Vitamin D and Calcium is widely accepted. The effects of various minerals, selenium, antioxidant compounds, fish oil or vitamins remain speculative. Many patients use cannabis to alleviate spasticity and pain. Small series indicated positive effects, but randomized trials were negative for spasticity. However, many patients report subjective improvement under cannabis even if their objective parameters remain unchanged. Hyperbaric oxygenation was the subject of several small studies with heterogeneous results which, overall, do not support its use. Generally, physical therapies are perceived as an established therapy for MS. Short-term effects are probable, whereas the possible favourable long-term effects are unclear.

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Mult Scler. 2005 Aug;11(4):409-19.
Eight-year immunogenicity and safety of interferon beta-1a-Avonex treatment in patients with multiple sclerosis.
Herndon RM, Rudick RA, Munschauer FE 3rd, Mass MK, Salazar AM, Coats ME, Labutta R, Richert JR, Cohan SL, Genain C, Goodkin D, Toal M, Riester K.
University of Mississippi, VA Medical Center, Jackson, MS 39216, USA. rherndon@neurology.umsmed.edu

An open-label extension study of the phase III trial of intramuscular interferon beta-1a (IFNbeta-1a-Avonex) was conducted to evaluate the immunogenicity and safety of IFNbeta-1a-Avonex over six years in patients with relapsing multiple sclerosis (MS). Patients who participated in the pivotal phase III study were offered enrolment; entry was also open to patients who had not participated. All patients received IFNbeta-1a-Avonex 30 microg intramuscularly once weekly for six years, for a treatment duration of up to eight years in patients who received IFNbeta-1a-Avonex in the phase III trial. Serum levels of IFNbeta antibodies were measured every six months using a screening enzyme-linked immunosorbent assay (ELISA) followed by an antiviral cytopathic effect assay to detect neutralizing antibodies (NAbs) in serum samples positive on ELISA. The incidence of adverse events and laboratory test results assessed safety. Of 382 total patients, 218 had participated in the phase III study (103 placebo, 115 IFNbeta-1a-Avonex) and 164 had not participated; 24 of the 164 were IFNbeta-naive. At baseline, 281 patients were negative for IFNbeta antibodies (NAb-). NAbs (titre > or = 20) developed at any time over six years in 5% of these patients. Of 140 patients who had been on IFNbeta-1b-Betaseron, 49 were positive for NAbs (NAb+) at baseline; 11 of 115 who had been on IFNbeta-1a-Avonex were NAb+ at baseline. Thirty-nine of 49 patients who had been on Betaseron and were NAb+ had titres < 100; 36 of these 39 seroconverted to NAb- while on IFNbeta-1a-Avonex, with a median time of approximately six months. Ten patients who had been on Betaseron had NAb titres > or = 100; five remained NAb+ during six years on IFNbeta-1a-Avonex and five seroconverted to NAb-, but only after at least two years. Five patients who had been on IFNbeta-1a-Avonex during the clinical trial were NAb+ with titres < 100 at baseline; four seroconverted to NAb-, with a median time of two to three years. Six patients who had been on IFNbeta-1a-Avonex had NAb titres > or = 100; five of these remained NAb+ at six years. No patient with a NAb titre > 1000 seroconverted to NAb-, whether initially treated with IFNbeta-1a-Avonex or -Betaseron. Adverse events were similar to those observed in the pivotal phase III trial. Results from this trial indicated that IFNbeta-1a-Avonex was associated with a low incidence of NAbs and was well tolerated for up to eight years. Further, the results indicate that persistence of NAbs is dependent on titre and IFNbeta product.

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Neurology. 2005 Aug 10; [Epub ahead of print]
Pregnancy outcomes during treatment with interferon beta-1a in patients with multiple sclerosis.
Sandberg-Wollheim M, Frank D, Goodwin TM, Giesser B, Lopez-Bresnahan M, Stam-Moraga M, Chang P, Francis GS.
>From the Department of Neurology (Dr. Sandberg-Wollheim), University Hospital, Lund, Sweden; Serono, Inc. (Drs. Lopez-Bresnahan, Chang, and Francis, D. Frank), Rockland, MA; Serono (M. Stam-Moraga), Geneva, Switzerland; Department of Obstetrics and Gynecology (Dr. Goodwin), University of Southern California; and Department of Neurology (Dr. Giesser), University of California, Los Angeles.

Abstract-- BACKGROUND: Although patients with multiple sclerosis (MS) are advised to stop interferon (IFN) beta-1a therapy before becoming pregnant, some patients become pregnant while on treatment. METHODS: We examined individual patient data from eight clinical trials with IFNbeta-1a. RESULTS: Of 3,361 women in the studies, 69 pregnancies were reported, of which 41 were patients receiving (or who had stopped receiving within 2 weeks prior to conception) IFNbeta-1a (in utero exposure group), 22 were patients who discontinued IFNbeta-1a treatment more than 2 weeks before conception (previous exposure group), and six were patients receiving placebo. The 41 in utero exposure pregnancies resulted in 20 healthy full-term infants, one healthy premature infant, nine induced abortions, eight spontaneous abortions, one fetal death, and one congenital anomaly (hydrocephalus). One patient was lost to follow-up. The 22 previous exposure pregnancies resulted in 20 full-term healthy infants, one healthy premature infant, and one birth-related congenital anomaly (Erb palsy) CONCLUSIONS: The majority (21/31) of pregnancies that had the potential to go to full term produced healthy infants. The rate of spontaneous abortion was higher, but not significantly so, in the in utero exposure group compared to general population estimates. Until more exposure data become available, patients remain advised to stop IFNbeta therapy before becoming pregnant.

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Eur J Neurol. 2005 Aug;12(8):649-56.
The long-term safety and tolerability of high-dose interferon beta-1a in relapsing-remitting multiple sclerosis: 4-year data from the PRISMS study.
Gold R, Rieckmann P, Chang P, Abdalla J; PRISMS Study Group.
Institut fuer MS-Forschung, Bereich Humanmedizin der Universitaet Goettingen und Gemeinnuetzige Hertie-Stiftung, Waldweg, Goettingen, Germany. r.gold@med.uni-goettingen.de

In the prevention of relapses and disability by interferon subcutaneously in multiple sclerosis (PRISMS) study, 560 patients with relapsing-remitting multiple sclerosis were randomized to receive subcutaneous interferon (IFN) beta-1a, 22 or 44 mug three times weekly, or placebo, for 2 years. Patients receiving placebo were then re-randomized to one of the two doses of IFN beta-1a for a further 2 years, whilst patients receiving active treatment continued their original treatment. Safety assessments were performed throughout the study. The most common adverse events for patients originally randomized to active treatment were injection-site inflammation (72% of patients had at least one event), headache (71%) and influenza-like symptoms (69%). These were generally mild in nature and most frequent during the first month of treatment. The 4-year adverse event profiles for the two IFN beta-1a doses were comparable with those observed during the initial phase of the study and, for the most part, with each other. There was no association between IFN beta-1a and depression or suicide/attempted suicide. The most common laboratory abnormalities were asymptomatic lymphopenia and elevated serum liver transaminase levels. These were generally mild and resolved spontaneously. Therapy with subcutaneous IFN beta-1a three times weekly for up to 4 years was well tolerated without dose-limiting safety concerns.

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Am J Epidemiol. 2005 Aug 24; [Epub ahead of print]
Familial Risk of Multiple Sclerosis: A Nationwide Cohort Study.
Nielsen NM, Westergaard T, Rostgaard K, Frisch M, Hjalgrim H, Wohlfahrt J, Koch-Henriksen N, Melbye M.
Department of Epidemiology Research, Danish Epidemiology Science Centre, Statens Serum Institut, Copenhagen, Denmark.

Multiple sclerosis (MS) is known to accumulate within families. The magnitude of the familial risk, however, remains uncertain. Using a nationwide MS register and other national registers, the authors estimated relative and absolute risks of MS in a population-based cohort that included 19,615 first-degree relatives of 8,205 Danish MS patients followed from 1968 to 1997. The ratio of observed to expected numbers of MS cases served as the measure of the relative risk of MS. Lifetime risks of MS in first-degree relatives were estimated as the product of the relative risk and the national lifetime risk of MS. Overall, first-degree relatives had a sevenfold increased risk of MS (relative risk = 7.1, 95% confidence interval: 5.8, 8.8) (n = 90) compared with the background population. By modeling the individual incidence rate of MS as the sum of a familial component and a sporadic risk component, the familial excess lifetime risk was found to be 2.5% (95% confidence interval: 2.0, 3.2) among first-degree relatives of MS patients, irrespective of the gender of the proband and the relative. This percentage should be added to a sporadic absolute risk in the general population of 0.5% in women and 0.3% for men. Spouses of MS patients did not experience an increased risk of MS, suggesting no major role for environmental factors acting in adulthood.

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J Clin Neurosci. 2005 Aug;12(6):638-642.
Thalamotomy versus thalamic stimulation for multiple sclerosis tremor.
Bittar RG, Hyam J, Nandi D, Wang S, Liu X, Joint C, Bain PG, Gregory R, Stein J, Aziz TZ.
Department of Neurosurgery, Radcliffe Infirmary, Oxford, UK; Australasian Movement Disorder and Pain Surgery (AMPS) Clinic, Melbourne, Australia; Department of Neurosurgery, The Alfred Hospital, Melbourne, Australia; Department of Surgery, Montash University, Melbourne, Australia; Melbourne Neurosurgery, Melbourne, Australia.

Disabling intractable tremor occurs frequently in patients with multiple sclerosis (MS). There is currently no effective medical treatment available, and the results of surgical intervention have been variable. Thalamotomy has been the mainstay of neurosurgical therapy for intractable MS tremor, however the popularisation of deep brain stimulation (DBS) has led to the adoption of chronic thalamic stimulation in an attempt to ameliorate this condition. With the goal of examining the relative efficacy and adverse effects of these two surgical strategies, we studied twenty carefully selected patients with intractable MS tremor. Thalamotomy was performed in 10 patients, with chronic DBS administered to the remaining 10. Both thalamotomy and thalamic stimulation produced improvements in postural and intention tremor. The mean improvement in postural tremor at 16.2 months following surgery was 78%, compared with a 64% improvement after thalamic stimulation (14.6 month follow-up) (P>0.05). Intention tremor improved by 72% in the group undergoing thalamotomy, a significantly larger gain than the 36% tremor reduction following DBS (P<0.05). Early postoperative complications were common in both groups. Permanent complications related to surgery occurred in four patients overall. Following thalamotomy, long-term adverse effects were observed in three patients (30%), and comprised hemiparesis and seizures. Only one patient in the thalamic stimulation group experienced a permanent deficit (monoparesis). We conclude that thalamotomy is a more efficacious surgical treatment for intractable MS tremor, however the higher incidence of persistent neurological deficits in patients receiving lesional surgery may support the use of DBS as the preferred surgical strategy.

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Fortschr Neurol Psychiatr. 2005 Aug;73(8):463-9.
[Cannabinoids in multiple sclerosis -- therapeutically reasonable?]
[Article in German]
Trebst C, Stangel M.
Neurologische Klinik mit Klinischer Neurophysiologie, Medizinische Hochschule Hannover. trebst.corinna@mh-hannover.de

For centuries extracts from the Cannabis sativa plant have been used for recreational use and as remedies. Anecdotal reports from patients with multiple sclerosis (MS) experiencing relief of their spasticity and pain after smoking marihuana have prompted discussions about a potential therapeutic application of cannabis preparations in MS. Only recently the first large, multicenter, double-blind, placebo controlled study was conducted evaluating the use of cannabinoids for treatment of spasticity and other symptoms related to MS. Based on this trial and previous uncontrolled observations together with insights from basic research and animal experiments there is reasonable evidence for the therapeutical employment of cannabinoids in the treatment of MS related symptoms. Furthermore, data are arising that cannabinoids have immunomodulatory and neuroprotective properties. However, results from clinical trials do not allow the recommendation for the general use of cannabinoids in MS. This article summarizes the present knowledge of clinical and experimental research regarding the therapeutic potential of cannabinoids for the treatment of MS.

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Schweiz Rundsch Med Prax. 2005 Jul 27;94(30-31):1167-70.
[Multiple sclerosis—update]
[Article in German]
Mattle HP.
Neurologische Klinik und Poliklinik der Universitat, Inselspital, Bern. heinrich.mattle@insel.ch

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. Its etiology is not known, but it is well established that auto-reactive T-cells and monocytes play an important pathogenetic role. The inflammation causes focal demyelination and loss of axons, neurons and glial cells. Typical symptoms and signs are monocular blurred vision, double vision, sensory symptoms and motor weakness, and eventually also cognitive deficits and a disturbed micturition. In younger patients the neurological deficits tend to be present for a limited time and then to improve and disappear, only to be followed by new and different deficits later on. Each relapse may leave neurological deficits which in a later course tend to progress slowly, uninterrupted by remissions. When older patients present for the first time with MS, they tend to present with primary progressive spasticity. Important ancillary tests and findings to confirm the diagnosis are multiple focal lesions on MR images, oligoclonal bands in the cerebrospinal fluid, and slowed evoked potentials. Relapses are treated with corticosteroids. Immunomodulation with beta-interferons or glatiramer acetate reduce the number and severity of relapses and long-term disability. Very active forms can be treated with immunosuppression using mitoxantrone. Individual manifestations such as urinary tract infections or paroxysmal phenomena should be treated accordingly with medication.

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Curr Opin Investig Drugs. 2005 Jul;6(7):667-71.
The potential role for statins in the treatment of multiple sclerosis.
Darlington CL.
Department of Pharmacology and Toxicology, University of Otago Medical School, Dunedin, New Zealand. cynthia.darlington@stonebow.otago.ac.nz

In 1995, it was observed that the administration of statins to heart transplant patients resulted in fewer episodes of rejection, thus a role for statins in the treatment of inflammatory disease was suggested. To date, the results of a single, open-label trial in multiple sclerosis patients have demonstrated that treatment with one of the statins, simvastatin, reduced the number and volume of lesions, as observed using gadolinium-enhancing magnetic resonance imaging. While the results of this first study seem promising, the rationale for using a cholesterol-lowering drug in a demyelinating disease must be addressed, in addition to the potential problems that the side effects of statins may produce in multiple sclerosis patients.

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Curr Opin Neurol. 2005 Jun;18(3):237-244.
Promoting repair in multiple sclerosis: problems and prospects.
Lubetzki C, Williams A, Stankoff B.
aFederation de Neurologie, Hopital de la Salpetriere, Universite Pierre et Marie Curie, Paris, France bINSERM U-711, Hopital de la Salpetriere, Universite Pierre et Marie Curie, Paris, France cService de Pharmacologie, Hopital de la Salpetriere, Universite Pierre et Marie Curie, Paris, France.

PURPOSE OF REVIEW: Despite recent progress in treating the inflammatory component of multiple sclerosis, current therapies have no clear impact on progression of disability, which closely relates to tissue (myelin and axon) injury. Many scientists now focus their efforts on elucidating the mechanisms that lead to tissue injury, and on developing new strategies for tissue repair. We review recent breakthroughs in this field and discuss their putative applications to therapy. RECENT FINDINGS: Several hypotheses have been raised to explain the failure of remyelination, including depletion of remyelinating cells, quiescence of oligodendrocyte precursor cells and axonal inhibitory signals. Success in remyelination therapy may be achieved either by enhancing endogenous repair or by grafting exogenous remyelinating cells. Several neurotrophic factors have been shown to enhance endogenous remyelination, and many immature cells have been shown to induce efficient exogenous remyelination in animal models. Although effective remyelination probably represents the best way to prevent neurodegeneration, several alternative neuroprotective strategies are emerging. Statins, cyclins and immunophilin ligands are orally available immunomodulatory agents that may protect neurones. Other promising possibilities include the modulation of excitotoxicity, nitric oxide synthesis, or cationic channels. SUMMARY: Despite the increasing number of putative therapeutic targets, no treatment to achieve remyelination or neuroprotection has yielded positive clinical results in humans. Forging a link between basic biology and treatment of patients will require us to overcome several challenges, including assessment of efficacy of repair, improving tolerance to and delivery of neurotrophic factors, and better defining the indications for and limitations of transplantation.

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Nervenarzt. 2005 May 18; [Epub ahead of print]
[High-dose intravenous immunoglobulins in the treatment of multiple sclerosis An update.]
[Article in German]
Stangel M, Gold R.
Neurologische Klinik, Medizinische Hochschule Hannover, .

The immunomodulatory treatment of multiple sclerosis (MS) with high-dose intravenous immunoglobulins (IVIg) has been discussed with some controversy in the context of evidence-based medicine. The recent publication of eight trials investigating several aspects of MS has shed some more light on the role of IVIg treatment in MS. Here we summarize and critically discuss the new data in the context of previous studies on this treatment. In relapsing-remitting MS, IVIg remain a second-line treatment when other licensed treatments are not possible. Currently there is no role for IVIg in secondary progressive MS. Similarly, the use of IVIg during an acute relapse shows no benefit in addition to standard steroid treatment. The initiation of IVIg therapy after a clinically isolated syndrome has delayed the occurrence of definite MS, and this may become a new indication. Furthermore, previous data suggesting that IVIg can reduce the incidence of postpartal relapses have been substantiated. However, those trials unfortunately lack appropriate internal control groups. By and large, previous recommendations for the use of IVIg in MS are supported by the new data.

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Rev Neurol. 2005 May 16-31;40(10):594-7.
[Autoimmune diseases and multiple sclerosis.]
[Article in Spanish]
Alemany-Rodriguez MJ, Aladro Y, Amela-Peris R, Perez-Vieitez MC, Reyes-Yanez MP, Deniz-Naranjo MC, Sanchez-Garcia F.
Hospital de Gran Canaria Dr. Negrin, 35020 Las Palmas de Gran Canaria, Espana.

INTRODUCTION. Multiple sclerosis (MS) is a demyelinating disease affecting the central nervous system with an unknown origin, although the immunological system plays a crucial role in its pathogenesis. It has been observed that the relatives of MS patients very often have other autoimmune diseases (ADs) and it has been suggested that there may be susceptibility genes that are common to this group of diseases. AIMS. Our aim was to estimate the prevalence of ADs in first and second degree relatives of patients with MS and to determine the coexistence of other ADs in MS patients. PATIENTS AND METHODS. We selected 251 patients with MS defined by the Poser criteria and face-to-face interviews with the patients and/or their relatives were conducted to investigate the following ADs: MS, rheumatoid arthritis, systemic lupus erythematosus, polyarteritis nodosa, autoimmune thyroid disease (ATD), inflammatory bowel disease, myasthenia gravis, type I diabetes mellitus (DMI) and psoriasis. RESULTS. 29.9% of the patients with MS had a first and/or second degree relative with an AD. Prevalence of ADs in first degree relatives was 15.5%, 30% in familial MS and 40% if the patient had both MS and another AD. The most frequent ADs were: MS 27%, psoriasis 18%, ATD 16% and DMI 15%. 15 patients had MS and another AD: six ATD, three DMI, four psoriasis, one inflammatory bowel disease and one myasthenia gravis. CONCLUSIONS. These findings lend support to the existence of susceptibility genes that are common to the different ADs and would act as risk factors.

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J Neurol Sci. 2005 May 13; [Epub ahead of print]
The therapeutic use of stem cells for myelin repair in autoimmune demyelinating disorders.
Pluchino S, Martino G.
Neuroimmunology Unit-DIBIT and Department of Neurology and Neurophysiology, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy.

Spontaneous remyelination occurs in multiple sclerosis (MS) patients. However, this process is not robust enough to promote a functional and stable recovery of the myelin architecture in demyelinated areas of the central nervous system (CNS). As a consequence of this incomplete reparative process, the disease invariably progresses and patchy areas of demyelination-in which axonal damage and/or loss is a constant accompanying factor-increase over time and lead to the accumulation of irreversible neurological deficits. Thus, the development of cell-based therapies aimed to promote multifocal remyelination in MS represents one of the most challenging areas of investigation. Several cell-replacement strategies have been developed in the last few years. However, most of these therapeutic approaches-although consistently able to form new myelin sheaths around the transplantation site-are unrealistic owing to the mutifocality of the demyelinating process and the inability to in vitro growth and differentiate large number of myelin-forming cells. Recently, promising cell-replacement therapies based on the use of stem cells have been proposed. However, before envisaging any potential human applications of such therapies we need to confront with some preliminary and still unsolved questions: (i) the ideal stem cell source for transplantation, (ii) the route of cell administration, (iii) the differentiation and persistence of stem cells into the targeted tissue and, last but not least, (iv) the functional and long-lasting integration of transplanted cells into the host tissue.

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Drugs. 2005;65(9):1295-312.
Subcutaneous Recombinant Interferon-beta-1a (Rebif((R))): A Review of its Use in Relapsing-Remitting Multiple Sclerosis.
Murdoch D, Lyseng-Williamson KA.
Adis International Limited, Auckland, New Zealand.

Subcutaneous recombinant interferon-beta-1a (Rebif((R))) 22 or 44microg three times weekly is a valuable option in the first-line treatment in patients with relapsing-remitting multiple sclerosis (RRMS). It has shown benefits on outcome measures related to relapses, progression of disability and magnetic resonance imaging (MRI) in clinical trials. A significant efficacy advantage for subcutaneous interferon-beta-1a three times weekly over intramuscular interferon-beta-1a 30microg once weekly was shown at 24 and 48 weeks. The most common adverse events are generally mild and clinically manageable. Considering both direct and indirect comparative clinical trial data, an assessment suggests that subcutaneous interferon-beta-1a 44microg three times weekly has the best benefit-to-risk values of the available disease-modifying drugs used to treat RRMS.

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Complement Ther Med. 2005 Mar;13(1):25-33.
Functionality or aesthetics?A pilot study of music therapy in the treatment of multiple sclerosis patients.
Aldridge D, Schmid W, Kaeder M, Schmidt C, Ostermann T.
Chair for Qualitative Research in Medicine, University of Witten Herdecke, Alfred-Herrhausen-Str. 50, D-58448, Germany.

INTRODUCTION:: Neuro-degenerative diseases are, and will remain, an enormous public health problem. Interventions that could delay disease onset even modestly will have a major public health impact. The aim of this study is to see which components of the illness are responsive to change when treated with music therapy in contrast to a group of patients receiving standard medical treatment alone. MATERIAL AND METHODS:: Twenty multiple sclerosis patients (14 female, 6 male) were involved in the study, their ages ranging from 29 to 47 years. Ten participants formed the therapy group, and 10 the matched control group matched by age, gender and the standard neurological classification scheme Expanded Disability Status Scale (EDSS). Exclusion criteria were pregnancy and mental disorders requiring medication. Patients in the therapy group received three blocks of music therapy in single sessions over the course of the one-year project (8-10 sessions, respectively). Measurements were taken before therapy began (U1), and subsequently every three months (U2-U4) and within a 6-month follow-up without music therapy (U5) after the last consultation. Test battery included indicators of clinical depression and anxiety (Beck Depression Inventory and Hospital Anxiety and Depression Scale), a self-acceptance scale (SESA) and a life quality assessment (Hamburg Quality of Life Questionnaire in Multiple Sclerosis). In addition, data were collected on cognitive (MSFC) and functional (EDSS) parameters. RESULTS:: There was no significant difference between the music-therapy treatment group and the control group. However, the effect size statistics comparing both groups show a medium effect size on the scales measuring self-esteem (d, 0.5423), depression HAD-D (d, 0.63) and anxiety HAD-A (d, 0.63). Significant improvements were found for the therapy group over time (U1-U4) in the scale values of self-esteem, depression and anxiety. In the follow-up, scale values for fatigue, anxiety and self-esteem worsen within the group treated with music therapy. DISCUSSION:: A therapeutic concept for multiple sclerosis, which includes music therapy, brings an improvement in mood, fatigue and self-acceptance. When music therapy is removed, then scale scores worsen and this appears to intimate that msuic therapy has an influence.

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CNS Drugs. 2005;19(5):369-76.
Primary progressive multiple sclerosis : current and future treatment options.
Leary SM, Thompson AJ.
Institute of Neurology, University College London, London, UK.

Approximately 10% of patients with multiple sclerosis (MS) run a primary progressive course characterised by an accumulation of neurological deficits without relapse or remission. Designing therapeutic trials in primary progressive MS (PPMS) has presented several problems. Patient recruitment may be difficult because of the relative rarity of PPMS and historically has been hindered by the lack of specific diagnostic criteria. There has been a limited choice of validated outcome measures, although, in recent studies, the MS functional composite measure and magnetic resonance imaging measures of lesion load and atrophy have been widely used.Despite these problems, several trials have been designed specifically for PPMS, including exploratory randomised controlled trials of interferon-beta-1a and interferon-beta-1b and mitoxantrone, a phase III trial of glatiramer acetate, and an open-label study of riluzole. Patients with PPMS have also been included in randomised controlled trials of azathioprine, methotrexate, cladribine, intravenous immunoglobulin and cyclophosphamide, and open-label studies of haematopoietic stem cell transplantation and pirfenidone in progressive MS. However, no treatment has been proven definitively to modify the course of the disease. Looking to the future, therapeutic agents should aim to target the underlying pathogenic mechanisms in PPMS. As a result of the relative lack of inflammation in PPMS, neuroprotective agents that target neuronal loss directly, rather than inflammation, may be more worthwhile. However, further investigation into the pathogenic mechanisms in PPMS is required to guide the development of future therapeutic agents.

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Cochrane Database Syst Rev. 2005 Jan 25;(1):CD003980.
Exercise therapy for multiple sclerosis.
Rietberg M, Brooks D, Uitdehaag B, Kwakkel G.

BACKGROUND: No intervention has proven effective in modifying long-term disease prognosis in Multiple Sclerosis (MS) but exercise therapy is considered to be an important part of symptomatic and supportive treatment for these patients. OBJECTIVES: To assess the effectiveness of exercise therapy for patients with MS in terms of activities of daily living and health-related quality of life. SEARCH STRATEGY: We searched the Cochrane MS Group Specialised Register (searched: March 2004), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2004), MEDLINE (from 1966 to March 2004), EMBASE (from 1988 to March 2004 ), CINAHL (from 1982 to March 2004), PEDro (from 1999 to March 2004) . Manual search in the journal 'Multiple Sclerosis' and screening of the reference lists of identified studies and reviews. We also searched abstracts published in proceedings of conferences. SELECTION CRITERIA: Randomised Controlled Trials (RCTs) that reported on exercise therapy for adults with MS, not presently experiencing an exacerbation; outcomes that include measures of activity limitation or health-related quality of life or both. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and methodological quality of the included trials. Disagreements were resolved by discussion. The results were analysed using a best-evidence synthesis based on methodological quality. MAIN RESULTS: Nine high-methodological-quality RCTs(260 participants) met the inclusion criteria. Six trials focussed on comparison of exercise therapy versus no exercise therapy, whereas three trials compared two interventions that both met our definition of exercise therapy. Best evidence synthesis showed strong evidence in favour of exercise therapy compared to no exercise therapy in terms of muscle power function, exercise tolerance functions and mobility-related activities. Moderate evidence was found for improving mood. No evidence was observed for exercise therapy on fatigue and perception of handicap when compared to no exercise therapy. Finally, no evidence was found that specific exercise therapy programmes were more successful in improving activities and participation than other exercise treatments. No evidence of deleterious effects of exercise therapy was described in included studies. AUTHORS' CONCLUSIONS: The results of the present review suggest that exercise therapy can be beneficial for patients with MS not experiencing an exacerbation. There is an urgent need for consensus on a core set of outcome measures to be used in exercise trials. In addition, these studies should experimentally control for 'dose' of treatment, type of MS and should include sufficient contrast between experimental and control groups.

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Neurology. 2004 Dec 28;63(12 Suppl 6):S28-32.
Mitoxantrone treatment of multiple sclerosis: safety considerations.
Cohen BA, Mikol DD.
Davee Department of Neurology, Northwestern University, 710 North Lake Shore Drive, Abbott Hall 1121, Chicago, Illinois 60611, USA. bac106@northwestern.edu

Treatment of patients with mitoxantrone for worsening multiple sclerosis (MS) requires careful monitoring for possible adverse events. Common side effects that are minor and easily managed include transient leukopenia and elevated liver enzymes, nausea, alopecia, bluish discoloration of urine, and urinary tract infections. Amenorrhea, severe infection, cardiac toxicity, and toxic leukemias are more serious adverse events associated with mitoxantrone treatment but occur infrequently. The potential for clinically significant heart failure is low and is dose-related. Subclinical reductions in left ventricular ejection fraction may occur with serial doses, underscoring the importance of careful monitoring before initiating and during treatment. The risk for chronic cardiomyopathy limits the approved cumulative dose of mitoxantrone for treatment of MS to 140 mg/m2. Dexrazoxane has a cardioprotective effect when used with anthracycline in the treatment of patients with neoplasms. Studies under way address whether concomitant administration of dexrazoxane with mitoxantrone might decrease the risk for cardiac toxicity in MS patients and perhaps increase the allowable cumulative dose of mitoxantrone. A phase IV clinical study of mitoxantrone (RENEW) is in progress to assess the long-term safety and tolerability of treatment. Careful laboratory and cardiac monitoring can reduce the possibility of adverse events and enhance patient safety.

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J Long Term Eff Med Implants. 2004;14(6):467-80.
Strategies to reduce hyperthermia in ambulatory multiple sclerosis patients.
Edlich RF, Buschbacher RM, Cox MJ, Long WB, Winters KL, Becker DG.
Distinguished Professor Emeritus of Plastic Surgery and Biomedical Engineering, University of Virginia Health System; Director of Trauma Prevention, Research, and Education, Trauma Specialists, LLP, Legacy Emanual Hospital, Portland, Oregon.

Approximately 400,000 Americans have multiple sclerosis. Worldwide, multiple sclerosis affects 2.5 million individuals. Multiple sclerosis affects two to three times as many women as men. The adverse effects of hyperthermia in patients with multiple sclerosis have been known since 1890. While most patients with multiple sclerosis experience reversible worsening of their neurologic deficits, some patients experience irreversible neurologic deficits. In fact, heat-induced fatalities have been encountered in multiple sclerosis patients subjected to hyperthermia. Hyperthermia can be caused through sun exposure, exercise, and infection. During the last 50 years, numerous strategies have evolved to reduce hyperthermia in individuals with multiple sclerosis, such as photoprotective clothing, sunglasses, sunscreens, hydrotherapy, and prevention of urinary tract infections. Hydrotherapy has become an essential component of rehabilitation for multiple sclerosis patients in hospitals throughout the world. On the basis of this positive hospital experience, hydrotherapy has been expanded through the use of compact aquatic exercise pools at home along with personal cooling devices that promote local and systemic hypothermia in multiple sclerosis patients. The Multiple Sclerosis Association of America and NASA have played leadership roles in developing and recommending technology that will prevent hyperthermia in multiple sclerosis patients and should be consulted for new technological advances that will benefit the multiple sclerosis patient. In addition, products recommended for photoprotection by The Skin Cancer Foundation may also be helpful to the multiple sclerosis patient's defense against hyperthermia. Infections in the urinary tract, especially detrusor-external sphincter dyssynergia, are initially managed conservatively with intermittent self-catheterization and pharmacologic therapy. In those cases, refractory to conservative therapy, transurethral external sphincterotomy followed by condom catheter drainage is recommended. However, if external urethral sphincterotomy fails to reduce residual urine and detrusor pressure, urinary diversion or bladder reconstruction may be necessary.

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Neurology. 2004 Dec 28;63(12 Suppl 6):S8-14.
Current approved options for treating patients with multiple sclerosis.
Rizvi SA, Agius MA.
Department of Clinical Neurosciences Brown University, 2 Dudley Street, Suite 555, Providence, Rhode Island 02905, USA. srizvi@lifespan.org

Multiple sclerosis (MS), a neurologic disorder that affects 400,000 persons in the United States, consists of an inflammatory and a neurodegenerative phase. Treatment options now approved by the FDA specifically target the inflammatory phase of MS and include immunomodulators (i.e., interferon betas and glatiramer acetate) and an immunosuppressant, mitoxantrone. This article discusses the methods of monitoring disease progression using disability scales and MRI and reviews the clinical efficacy and tolerability of the FDA-approved therapies. All of the immunomodulators are approved for the treatment of relapsing forms of MS. Only mitoxantrone is approved for the treatment of worsening relapsing-remitting MS, secondary progressive MS, and progressive-relapsing MS. Early treatment with these disease-modifying agents is desirable to reduce the progression of the disease and to limit long-term disability.

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Neurology. 2004 Dec 28;63(12 Suppl 6):S47-54.
Other therapy options and future strategies for treating patients with multiple sclerosis.
Rizvi SA, Bashir K.
Department of Clinical Neurosciences, Brown University School of Medicine, 2 Dudley Street, Suite 555, Providence, Rhode Island 02905, USA. srizvi@lifespan.org

Research into therapy for multiple sclerosis (MS) is occurring at a rapid pace, and current treatment options approved by the FDA specifically target the inflammatory phase of MS. However, drugs that are not FDA-approved are routinely used to treat MS. One example is corticosteroids, which are commonly used to treat acute relapses. Other drugs that are commonly used to treat patients who do not respond to the FDA-approved agents include the following: methotrexate, azathioprine, cyclophosphamide, and pulse steroids. Drugs being studied as possible therapeutic agents include the statins, mycophenolate mofetil, various monoclonal antibodies (e.g., alemtuzumab, daclzumab, natalizumab, and rituximab), antibiotics and antivirals, and the pregnancy hormone estriol. Disease modifying agents (DMAs) that promote remyelination would be beneficial for preventing long-term disability, and such agents are also under active investigation (e.g., IV immunoglobulin G and stem cell transplantation). Combination therapy with DMAs with different mechanisms of action may be advantageous in the future for providing optimal treatment that both delays the progression of disability and promotes repair and remyelination.

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Neurology. 2004 Dec 28;63(12 Suppl 6):S41-6.
Use of combination therapy with immunomodulators and immunosuppressants in treating multiple sclerosis.
Jeffery DR.
Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA. djeffery@wfubmc.edu

Immunomodulating agents have beneficial effects in the treatment of multiple sclerosis (MS), decreasing the frequency of relapses, the progression of disability, and MRI measures of disease activity. Despite the efficacy of these agents, many patients continue to show progression of disability, breakthrough relapses, and active disease on MRI. Therefore, clinicians have employed a variety of combinations of agents in an attempt to decrease disease activity in those with active disease despite standard immunomodulatory therapy. Although a variety of combination therapies have been used in clinical practice, there is a paucity of data available to guide clinical decision-making. A major pitfall in using combination therapy in the absence of data demonstrating safety is the possibility that the agent added to the primary therapy may have no effect or, worse, may antagonize the effect of the primary agent. The combination of mitoxantrone and interferon beta (IFNbeta) appears safe in short-term studies from a toxicity standpoint and is associated with a reduction in relapse rates, a decrease in the frequency of enhancing lesions, and a decrease in T2 lesion burden. Other combinations that appear safe in preliminary studies include IFNbeta-1a and methotrexate, IFNbeta-1a and azathioprine, and mitoxantrone plus methylprednisolone. The decision to use combination therapy in patients with a suboptimal response to monotherapy should be considered early and not be delayed until disability becomes advanced. This review discusses the available data regarding the combination of standard immunomodulatory therapy with immunosuppressive agents.

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Ideggyogy Sz. 2004 Nov 20;57(11-12):401-16.
[Immunomodulatory treatment in multiple sclerosis]
[Article in Hungarian]
Tunde C, Daniel B.
Debreceni Egyetem, Altalanos Orvostudomanyi Kar, Neurologiai Klinika, Debrecen. csepany@jaguar.dote.hu

During the past decade, several disease-modifying agents have been established and have become available for the treatment of multiple sclerosis. The disease-modifying agents could be grouped into immunomodulatory and immunosuppressive therapies altering the long-term course of multiple sclerosis. Therapy is now available for relapsing-remitting, secondary progressive and progressive-relapsing multiple sclerosis. Different disease-modifying agents became also available for the treatment of relapsing-remitting multiple sclerosis in Hungary which makes the therapeutic decision difficult. This overview might help to give an answer for different questions in the management of multiple sclerosis: Which agent to choose? When to initiate the therapy? Which dose to apply? Are the drugs safe? How long to treat the patients with immunomodulatory drugs? We give a review from the literature to assess the efficacy of disease-modifying therapies and to compare the data from phase three trials of interferon beta1b, two preparations of interferon beta1a or glatiramer acetate for the treatment of multiple sclerosis. We analyzed the efficacy and safety of these agents on physical, inflammatory and cognitive measures of disease activity. Comparison of study results indicated similar effects of immunomodulatory agents on relapse-related and inflammatory measures in relapsing multiple sclerosis. Interferon beta1a slowed the progression of disability in relapsing multiple sclerosis. One interferon beta1a preparation (intramuscularly injected) demonstrated efficacy in slowing progression of cognitive dysfunction. The interferons reduced relapses at early phase of secondary progressive multiple sclerosis, but their efficacy have not yet been proven in the later phase of secondary progressive multiple sclerosis without relapses. Mitoxantrone demonstrated efficacy in slowing the progression of disability in secondary progressive multiple sclerosis. All of the disease modifying agents are safe and tolerable, if the indication is correct and the patients are strictly controlled.

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J Altern Complement Med. 2004 Oct;10(5):891-7.
Complementary and alternative medicine in multiple sclerosis: survey of licensed naturopaths.
Shinto L, Calabrese C, Morris C, Sinsheimer S, Bourdette D.
Department of Neurology, Oregon Health & Science University, Portland, OR 97239-3098, USA. shintol@ohsu.edu

OBJECTIVE: This paper describes the treatments and treatment outcome measures used by licensed naturopathic physicians in the United States who treat people with multiple sclerosis (MS). DESIGN: A cross-sectional mail survey was used. SUBJECTS: The participants were licensed naturopaths who were members of the American Association of Naturopathic Physicians. OUTCOME MEASURES: Outcome measures included practitioner demographics; patient demographics by practitioner report; recommended therapies; perceived effectiveness of treatments for MS; methods for measuring treatment effectiveness. RESULTS: Forty three percent (43%) of the respondents (166/385) had treated at least one patient with MS while 56.9% (291/385) had never treated MS. 63.3% had treated 1-10 patients with MS, 19.9% had treated 11-20 patients with MS, and 16.8% had treated > or =20 patients with MS. Among the naturopaths, 68.1% communicated with an M.D. about their patient(s)' care and the majority of patients with MS were diagnosed by an M.D. (mean % = 96.3). The mean number of therapies recommended for M.S. was 3.91 (standard deviation [SD] =2.01, range 1-10). The most frequently recommended therapies included, diet (52.4%), essential fatty acid supplementation (44.6%), vitamin/mineral supplementation (33.7%), homeopathy (30.7%), botanicals (22.3%), and antioxidants (18.1%). Respondents perceived their treatments as "very effective" for the following stages of MS: early stage (57.2%); middle stage (25.3%); and late stage (3.0%). Respondents perceived their treatments as "very effective" for the following disease-related outcomes: improved quality of life (59.0%); decrease relapse rates (48.2%); decreased symptom severity (45.8%); prevention of disease progression (41.6%). The methods used "most often" for measuring treatment effectiveness included, patient report (88.0%); physical examination (27.1%); medical records/laboratory testing (13.3%). The mean estimated percentage of patients not taking conventional disease-modifying medication was 51.2% (SD = 42.7%). CONCLUSIONS: Naturopaths use both a broad range and multiple complementary and alternative medicine CAM therapies for treating MS and report treatment effectiveness on the following outcomes: quality of life; symptom severity; relapse rates; and disease progression. Further research on single CAM therapies and holistic CAM systems is warranted in MS.

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Spinal Cord. 2004 Nov 16 [Epub ahead of print]
Intrathecal drug therapy using the Codman Model 3000 Constant Flow Implantable Infusion Pumps: experience with 17 cases.
Ethans KD, Schryvers OI, Nance PW, Casey AR.
1Section of Physical Medicine and Rehabilitation, Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.

OBJECTIVES:: The objective of this study was to evaluate the accuracy, reliability, safety, and efficacy of the Codman Model 3000 Constant Flow Implantable Infusion Pump for intrathecal baclofen delivery as a therapeutic option for the treatment of severe spasticity. The distinctive features of this pump include a raised, easily palpable septum, a safety valve protecting the bolus pathway, no programmer needed, and no battery to fail. DESIGN:: A total of 17 patients with spinal cord injury, multiple sclerosis, or cerebral palsy were implanted with this pump. The accuracy of the pump and drug treatment efficacy was determined at each visit and adjustments to the dosages were made as required. All the intrathecal drug delivery system complications were reviewed. RESULTS:: The expected efficacy was achieved. The accuracy of the implanted pumps ranged from 90-97% (average 94%). There were no complications due to primary pump problems. The complications reported are similar to other implantable infusion devices and include dehiscence of the suture line, pressure ulcer development, formation of seroma, inversion of the pump, baclofen overdose, and catheter failures. CONCLUSION:: The Codman Model 3000 Constant Flow Implantable Infusion Pump is an accurate, reliable, and convenient option for patients needing intrathecal baclofen therapy, with complications similar to other available pumps.Spinal Cord advance online publication, 16 November 2004; doi:10.1038/sj.sc.3101684.

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Neurology. 2004 Nov 9;63(9):1579-85.
Donepezil improved memory in multiple sclerosis in a randomized clinical trial.
Krupp LB, Christodoulou C, Melville P, Scherl WF, MacAllister WS, Elkins LE.
Department of Neurology, State University of New York at Stony Brook, HSC T12-020, Stony Brook, NY 11794-8121, USA. lauren.krupp@stonybrook.edu

OBJECTIVE: To determine the effect of donepezil in treating memory and cognitive dysfunction in multiple sclerosis (MS). METHODS: This single-center double-blind placebo-controlled clinical trial evaluated 69 MS patients with cognitive impairment who were randomly assigned to receive a 24-week treatment course of either donepezil (10 mg daily) or placebo. Patients underwent neuropsychological assessment at baseline and after 24 weeks of treatment. The primary outcome was change in verbal learning and memory on the Selective Reminding Test (SRT). Secondary outcomes included other tests of cognitive function, patient-reported change in memory, and clinician-reported impression of cognitive change. RESULTS: Donepezil-treated patients showed significant improvement in memory performance on the SRT compared to placebo (p = 0.043). The benefit of donepezil remained significant after controlling for various covariates including age, Expanded Disability Status Scale, baseline SRT score, reading ability, MS subtype, and sex. Donepezil-treated patients did not show significant improvements on other cognitive tests, but were more than twice as likely to report memory improvement than those in the placebo group (p = 0.006). The clinician also reported cognitive improvement in almost twice as many donepezil vs placebo patients (p = 0.036). No serious adverse events related to study medication occurred, although more donepezil (34.3%) than placebo (8.8%) subjects reported unusual/abnormal dreams (p = 0.010). CONCLUSIONS: Donepezil improved memory in MS patients with initial cognitive impairment in a single center clinical trial. A larger multicenter investigation of donepezil in MS is warranted in order to more definitively assess the efficacy of this intervention.

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BMC Neurol. 2004 Nov 7;4(1):18 [Epub ahead of print]
Efficacy of repeated intrathecal triamcinolone acetonide application in progressive multiple sclerosis patients with spinal symptoms.
Hellwig K, Stein FJ, Przuntek H, Muller T.

BACKGROUND: There are controversial results on the efficacy of the abandoned, intrathecal predominant methylprednisolone application in multiple sclerosis (MS) in contrast to the proven effectiveness in intractable postherpetic neuralgia. METHODS: We performed an analysis of the efficacy of the application of 40 mg of the sustained release steroid triamcinolone acetonide (TCA). We intrathecally injected in sterile saline dissolved TCA six times within three weeks on a regular basis every third day in 161 hospitalized primary and predominant secondary progressive MS patients with spinal symptoms. The MS patients did not experience an acute onset of exacerbation or recent distinct increased progression of symptoms. We simultaneously scored the MS patients with the EDSS and the Barthel index, estimated the walking distance and measured somatosensory evoked potentials. Additionally the MS patients received a standardized rehabilitation treatment. RESULTS: EDSS score and Barthel index improved, walking distance increased, latencies of somatosensory evoked potentials of the median and tibial nerves shortened in all MS patients with serial evaluation (p < 0.0001 for all variables). Side effects were rare, five patients stopped TCA application due to onset of a post lumbar puncture syndrome. CONCLUSIONS: Repeated intrathecal TCA application improves spinal symptoms, walking distance and SSEP latencies in progressive MS patients in this uncontrolled study. Future trials should evaluate the long-term benefit of this invasive treatment.

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Bone Marrow Transplant. 2004 Nov;34(10):877-81.
Consensus statement concerning cardiotoxicity occurring during haematopoietic stem cell transplantation in the treatment of autoimmune diseases, with special reference to systemic sclerosis and multiple sclerosis.
Saccardi R, Tyndall A, Coghlan G, Denton C, Edan G, Emdin M, Farge D, Fassas A, Finke J, Furst D, Lassus M, Mancardi G, Miniati I, Mini E, Pagliai F, Passweg J, Pignone A, van Laar JM, Bocelli-Tyndall C, Matucci-Cerinic M.
Haematology Unit, University of Florence, Italy. r.saccardi@dac.unifi.it

Autologous haematopoietic stem cell transplantation is now a feasible and effective treatment for selected patients with severe autoimmune diseases. Worldwide, over 650 patients have been transplanted in the context of phase I and II clinical trials. The results are encouraging enough to begin randomised phase III trials. However, as predicted, significant transplant-related morbidity and mortality have been observed. This is primarily due to complications related to either the stage of the disease at transplant or due to infections. The number of deaths related to cardiac toxicity is low. However, caution is required when cyclophosphamide or anthracyclines such as mitoxantrone are used in patients with a possible underlying heart damage, for example, systemic sclerosis patients. In November 2002, a meeting was held in Florence, bringing together a number of experts in various fields, including rheumatology, cardiology, neurology, pharmacology and transplantation medicine. The object of the meeting was to analyse existing data, both published or available, in the European Group for Blood and Marrow Transplantation autoimmune disease database, and to propose a safe approach to such patients. A full cardiological assessment before and during the transplant emerged as the major recommendation.

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Lancet. 2004 Oct 23;364(9444):1489-96.
Interferon beta-1a for brain tissue loss in patients at presentation with syndromes suggestive of multiple sclerosis: a randomised, double-blind, placebo-controlled trial.
Filippi M, Rovaris M, Inglese M, Barkhof F, De Stefano N, Smith S, Comi G.
Neuroimaging Research Unit, Department of Neurology, Scientific Institute and University Ospedale San Raffaele, Milan, Italy. filippi.massimo@hsr.it

BACKGROUND: In patients who present with clinically isolated syndromes suggestive of multiple sclerosis, interferon beta-1a is effective in delaying evolution to clinically definite disease and in reducing MRI-measured disease activity. We aimed to assess whether this drug can also reduce the rate of brain volume decrease in such patients enrolled in the ETOMS (early treatment of multiple sclerosis) trial. METHODS: MRI data for brain volume measurements at baseline, month 12, and month 24 were available from 131, 111, and 112 patients assigned treatment (22 microg interferon beta-1a), and 132, 98, and 99 patients assigned placebo respectively. Normalised brain parenchymal volume (NBV) at baseline and percentage brain volume changes (PBVC) were measured with a fully-automated segmentation technique. The primary endpoint was conversion to clinically definite multiple sclerosis due to clinical relapse. Analysis was by intention to treat. FINDINGS: 41 (31%) of 131 patients on interferon beta-1a and 62 (47%) of 132 on placebo converted to clinically definite multiple sclerosis (odds ratio 0.52 [95% CI 0.31-0.86], p=0.0115). Mean PBVC for patients on placebo was -0.83% during the first year, -0.67% during the second year, and -1.68% during the entire study period. Respective values for treated patients were -0.62%, -0.61%, and -1.18%. The changes in brain volume were significant in both groups at all timepoints. A significant treatment effect was detected for month 24 versus baseline values (p=0.0031). The number of new T2 lesions formed during the first year correlated weakly with PBVC during the second year. INTERPRETATION: Early treatment with interferon beta-1a is effective in reducing conversion to clinically definite multiple sclerosis and in slowing progressive loss of brain tissue in patients with clinically isolated syndromes. The modest correlation between new lesion formation and brain volume decrease suggests that inflammatory and neurodegenerative processes are, at least partly, dissociated from the earliest clinical stage of multiple sclerosis onwards.

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Ann Neurol. 2004 Oct 20 [Epub ahead of print]
Treatment of multiple sclerosis with an anti-interleukin-2 receptor monoclonal antibody.
Rose JW, Watt HE, White AT, Carlson NG.
Neurovirology Research Laboratory, VA Salt Lake City Health Care System.

We examined whether treatment with daclizumab, a humanized monoclonal antibody specific for the interleukin-2 receptor alpha chain, was safe and efficacious in relapsing-remitting and secondary progressive multiple sclerosis patients. Nineteen ambulatory patients with clinically active disease were treated for 5 to 25 months. Seventeen patients were not responding to other immunotherapies. Daclizumab was generally well tolerated. Sustained clinical improvement (10 patients) or stabilization (9 patients) was observed. Daclizumab treatment produced significant reduction in magnetic resonance imaging activity. Ann Neurol 2004.

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Arch Neurol. 2004 Oct;61(10):1515-20.
Intravenous immunoglobulin treatment following the first demyelinating event suggestive of multiple sclerosis: a randomized, double-blind, placebo-controlled trial.
Achiron A, Kishner I, Sarova-Pinhas I, Raz H, Faibel M, Stern Y, Lavie M, Gurevich M, Dolev M, Magalashvili D, Barak Y.
Multiple Sclerosis Center and Neuroradiology Unit, Sheba Medical Center, Tel-Hashomer 52621, Israel. achiron@post.tau.ac.il

BACKGROUND: Intravenous immunoglobulin (IVIg) has been reported to reduce disease activity in patients with relapsing-remitting multiple sclerosis. We assessed the effect of IVIg treatment in patients after the first neurological event suggestive of demyelinative disease and evaluated the occurrence of a second attack and dissemination in time demonstrated by brain magnetic resonance imaging within the first year from onset. METHODS: We conducted a randomized, placebo-controlled, double-blind study in 91 eligible patients enrolled within the first 6 weeks of neurological symptoms. Patients were randomly assigned to receive IVIg treatment (2-g/kg loading dose) or placebo, with boosters (0.4 g/kg) given once every 6 weeks for 1 year. Neurological and clinical assessments were done every 3 months, and brain magnetic resonance imaging was performed at baseline and the end of the study. RESULTS: The cumulative probability of developing clinically definite multiple sclerosis was significantly lower in the IVIg treatment group compared with the placebo group (rate ratio, 0.36 [95% confidence interval, 0.15-0.88]; P = .03). Patients in the IVIg treatment group had a significant reduction in the volume and number of T2-weighted lesions and in the volume of gadolinium-enhancing lesions as compared with the placebo group (P = .01, P = .01, and P = .03, respectively). Treatment was well tolerated, compliance was high, and incidence of adverse effects did not differ significantly between groups. CONCLUSIONS: Intravenous immunoglobulin treatment for the first year from onset of the first neurological event suggestive of demyelinative disease significantly lowers the incidence of a second attack and reduces disease activity as measured by brain magnetic resonance imaging.

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Drugs Today (Barc). 2004 Aug;40(8):663-76.
Towards cannabis and cannabinoid treatment of multiple sclerosis.
Croxford JL, Miller SD.
Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA. s-d-miller@northwestern.edu.

Multiple sclerosis is a common human demyelinating disease of the central nervous system (CNS), and it is thought to involve autoimmune responses to CNS myelin antigens. Current symptomatic therapies for multiple sclerosis are in some cases ineffective and may have a high risk of serious side effects. This has led some multiple sclerosis patients to self-medicate with cannabis, which anecdotal evidence suggests may be beneficial in controlling symptoms such as spasticity, pain, tremor and bladder dysfunction. In support of these claims, results from experimental studies have suggested that cannabinoid-based treatments may be beneficial in a wide number of diseases. Furthermore, recent research in animal models of multiple sclerosis has demonstrated the efficacy of cannabinoids in controlling disease-induced symptoms such as spasticity and tremor, as well as in ameliorating the severity of clinical disease. However, these initially promising results have not yet been fully translated into the clinic. Although cannabinoid treatment of multiple sclerosis symptoms has been shown to be both well tolerated and effective in a number of subjective tests in several small-scale clinical trials, objective measures demonstrating the efficacy of cannabinoids are still lacking. Currently, a number of large-scale phase III clinical trials are under way to further elucidate the use of cannabinoids in the symptomatic treatment of multiple sclerosis. This review highlights the recent advances in our understanding of the endocannabinoid system, discusses both the experimental and clinical evidence for the use of cannabinoids to treat multiple sclerosis and explores possible future strategies of cannabinoid therapy in multiple sclerosis. (c) 2004 Prous Science. All rights reserved.

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J Neurol Sci. 2004 Aug 15;223(1):1-11.
Immunosuppressive treatment in multiple sclerosis.
Weiner HL.
Department of Neurology, Partners Multiple Sclerosis Center, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.

Immunosuppressive therapy has been used to treat multiple sclerosis (MS) for over 30 years based on the hypothesis that MS is a T cell-mediated autoimmune disease. The most commonly used immunosuppressive agents in MS are azathioprine, cyclophosphamide, methotrexate, and mitoxantrone. Since the interferons and glatiramer acetate have become widely used in MS, immunosuppressive agents have found a role given as combination therapy or as monotherapy in instances where the interferons and glatiramer acetate are not effective in controlling the disease. Like the interferons and glatiramer acetate, immunosuppressive drugs are most efficacious in stages of MS that have an inflammatory component as evidenced by relapses and/or gadolinium-enhancing lesions on MRI or in patients in earlier stages of disease where inflammation predominates over degenerative processes in the CNS. There is no evidence of efficacy in primary progressive MS or later stages of secondary progressive MS. In our studies of cyclophosphamide, we have found that although it is a general immunosuppressant that affects both T cell and B cell functions, 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). Cyclophosphamide and mitoxantrone are the most common immunosuppressive drugs used in patients with rapidly worsening MS whose disease is not controlled by beta-interferon or glatiramer acetate.

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Proc Natl Acad Sci U S A. 2004 Aug 11 [Epub ahead of print]
Autoimmune concepts of multiple sclerosis as a basis for selective immunotherapy: From pipe dreams to (therapeutic) pipelines.
Hohlfeld R, Wekerle H.
Department of Neuroimmunology, Max Planck Institute for Neurobiology, Am Klopferspitz, D-82152 Martinsried, Germany.

Autoimmune T and B cell responses to CNS antigen(s) are thought to drive the pathogenesis of multiple sclerosis (MS), and thus are logical targets for therapy. Indeed, several immunomodulatory agents, including IFN-beta1b, IFN-beta1a, glatiramer acetate, and mitoxantrone, have had beneficial clinical effects in different forms of MS. However, because the available treatments are only partially effective, MS therapy needs to be further improved. Selective (antigen-specific) immunotherapies are especially appealing because in theory they combine maximal efficacy with minimal side effects. Indeed, several innovative immunotherapies have been successfully applied in experimental autoimmune encephalomyelitis. For example, autoreactive T cells can be selectively targeted by means of antigen, T cell receptor, or activation markers. However, experimental autoimmune encephalomyelitis is far from being a perfect approximation of MS because MS is more heterogeneous and the target antigen(s) is (are) not known. Further advances in MS therapy will depend on our growing understanding of the pathogenesis of this still incurable disease.

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Int MS J. 2004 Aug;11(2):36-42.
Multiple sclerosis in children.
Tardieu M, Mikaeloff Y.
aboratoire E0109 INSERM, Faculte de Medecine Paris-Sud, 63 rue Gabriel Peri, 94276 Le Kremlin Bicetre, Cedex, France E-mail: marc.tardieu@kb.u-psud.fr

Multiple sclerosis can develop during childhood, even among children under 10 years of age, and the initial diagnosis can be difficult. A first demyelinating event in children may be an episode of monophasic acute disseminated encephalomyelitis or a first episode of a macrophage activation syndrome, angiitis affecting the central nervous system or MS. The risk of developing MS is lower if: the child is younger than 10 years old; onset is associated with severely altered consciousness; presentation is polysymptomatic; or there are large and poorly limited lesions of the white matter. MS in children probably has a slightly better outcome than MS in adults. Initial treatment mainly relies on methylprednisolone, and there is little information on the results of beta interferon treatment in children with MS.

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J Neurol Sci. 2004 Aug 15;223(1):81-6.
Pixantrone (BBR2778): a new immunosuppressant in multiple sclerosis with a low cardiotoxicity.
Gonsette RE.
National Center for Multiple Sclerosis, Vanheylenstraat 16, B_1820, Melsbroek, Belgium.

Mitoxantrone (MX) has been approved by the Food and Drug Administration for the treatment of rapidly progressive multiple sclerosis (MS). Unfortunately, its long-term administration is prevented by the cardiotoxicity. Pixantrone (PIX) is an analogue of MX devoid of toxic effects on cardiac tissue and was developed as a replacement for other anthracenediones in cancer patients. With a view to an application in MS patients, experimental data demonstrated that PIX is as potent as MX in preventing acute experimental allergic encephalomyelitis development as well as the occurrence of relapses in the chronic model. Safety data from animal studies and from phase II trials in cancer patients confirm a very weak cardiotoxicity, if any. A phase I trial with PIX in patients with a rapidly progressive MS seems thus warranted.

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J Neurol Sci. 2004 Aug 15;223(1):47-51.
Corticosteroids treatment.
Pozzilli C, Marinelli F, Romano S, Bagnato F.
Department of Neurological Sciences, La Sapienza University, V.le Universita 30, 00185 Rome, Italy.

Corticosteroids (Cs) are widely used for treatment of multiple sclerosis (MS) acute relapses because of the potent immunosuppressive and anti-inflammatory properties. As for patients with relapsing-remitting (RR) MS, short-term administrations of Cs markedly less severity of symptoms and promote faster recovery of clinical attacks. Chronic administrations of Cs significantly diminish the formation of T1 hypointense lesions and the progression of brain atrophy. As for patients with secondary progressive MS treatment with Cs delays the time to onset of sustained disability. Finally the association between methylprednisolone and interferon beta (IFNbeta) leads the recovery of active lesions at greater extent and reduces the formation of neutralizing antibodies (NABs) against IFNbeta in patients with RRMS.

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J Neurol Sci. 2004 Aug 15;223(1):53-8.
Autologous hemopoietic stem cell transplantation in the treatment of multiple sclerosis: rationale and clinical experience.
Fassas A, Kimiskidis VK.
Department of Hematology and Bone Marrow Transplantation Unit, George Papanicolaou Hospital, 57010 Exokhi, Thessaloniki, Greece.

Based on the encouraging results of transplantation in animals with experimental autoimmune encephalomyelitis (EAE), small-scale phase I/II trials of autologous hematopoietic stem cell transplantation (autoHSCT) were initiated in 1995 for the treatment of severe cases of multiple sclerosis (MS). More than 200 patients with treatment-resistant multiple sclerosis have been transplanted so far, mainly in Europe and the USA. The results of these studies appear promising in terms of impact on MRI disease parameters and, to a lesser extent, clinical stabilization or even improvement. Despite concerns raised by the morbidity and mortality noted in the initial pilot studies, a controlled, randomized, phase III trial of autoHSCT against the best currently available treatment, i.e., mitoxantrone, seems justified and is under way.

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Curr Opin Investig Drugs. 2004 Jul;5(7):727-30.
Medicinal cannabis extracts for the treatment of multiple sclerosis.
Smith PF.
University of Otago, Department of Pharmacology and Toxicology, School of Medical Sciences, Dunedin, New Zealand. paul.smith@stonebow.otago.ac.nz

Prior to 2002, few clinical data were available to indicate whether cannabis extracts may be beneficial. However, in the last two years, results of several placebo-controlled clinical trials of orally administered compounds have been published, and these cast doubt on the efficacy of delta9-tetrahydrocannabinol (delta9-THC) in objectively reducing spasticity in MS. By contrast, it has been claimed that sublingually administered cannabis extracts that contain approximately equal concentrations of delta9-THC and cannabidiol, a natural cannabinoid that does not act on the CB1 receptor, can produce a statistically and clinically significant reduction in spasticity, although this claim has yet to be thoroughly validated. Nonetheless, results of preclinical trials also lend support to the hypothesis that the endogenous cannabinoid system may be involved in the regulation of spasticity and pain. A better indication of the clinical potential of the different cannabis extracts will have to await the publication of the most recent clinical trial data. This review critically evaluates the most recent evidence available on the potential use of medicinal extracts of cannabis to relieve pain and spasticity in multiple sclerosis.

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Best Pract Res Clin Haematol. 2004 Jun;17(2):247-62.
Multiple sclerosis.
Fassas A, Nash R.
Bone Marrow Transplantation Unit, Department of Haematology, George Papanicolaou Hospital, 57010 Exokhi, Thessaloniki, Greece.

Autologous transplants for severe and refractory multiple sclerosis (MS) were proposed in 1997 and have been performed on about 200 selected patients worldwide. Phase I/II clinical studies have shown that high-dose immunosuppressive therapy suppresses inflammation in the CNS and may delay the progression of clinical disease. The procedure is associated with toxicity from the high-dose cytotoxic therapy and a risk of serious infections. There is a transplant-related mortality risk of 1-5%, requiring careful patient selection before transplantation. Treatment should be reserved for patients who have a significant chance of response, i.e. young patients with low disability scores but rapidly progressing disease who have inflammatory rather than neurodegenerative changes in the CNS. The long term effect of high-dose immunosuppression after transplantation on the frequency of relapse or progression of MS is unclear, but the initial concept of immune ablation by high-dose therapy and the reconstitution of normal immunity and tolerance from transplant-derived lymphocyte progenitors has given way to the concept of 'resetting' the immune system. The clinical effect of transplantation remains to be demonstrated in comparative studies.

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CNS Drugs. 2004;18(10):653-69.
Management of secondary-progressive multiple sclerosis.
Giovannoni G.
Department of Neuroinflammation, Institute of Neurology, The National Hospital for Neurology and Neurosurgery, London, UK.

The majority of patients with relapse-onset multiple sclerosis (MS) will go on to develop secondary-progressive MS (SPMS) disease, with approximately 50% developing SPMS after 10 years. It remains unknown whether the relapsing and progressive phases of MS differ qualitatively. The pathogenesis of SPMS is poorly understood. The specific role that inflammation plays in disease progression is not well defined. Immunosuppressive therapies, which are capable of reducing or stopping clinical relapses and suppressing MRI activity, generally do not stop disease progression. Recent natural history studies suggest that disease progression occurs regardless of the presence of superimposed relapses. However, poor recovery from clinical relapses does account for the acquisition of disability. Therefore, stopping relapses with appropriate therapy delays the acquisition of disability but does not necessarily delay or prevent the development of SPMS.At present, the only disease-modifying therapies licensed for use in SPMS are interferon-beta-1b in Europe and the US, and mitoxantrone in the US. These agents can only be recommended for patients who continue to have relapses. Symptomatic therapies remain the cornerstone of treatment for patients with SPMS. Delivering high-quality, effective symptomatic therapies requires a multidisciplinary approach. The aim of symptomatic therapies should not only be to reduce neurological impairments but also to decrease disability and handicap and to improve the emotional well-being and health-related quality of life of patients with SPMS.

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Neurology. 2004 Apr 13;62(7):1105-9.
The effect of cannabis on tremor in patients with multiple sclerosis.
Fox P, Bain PG, Glickman S, Carroll C, Zajicek J.
Peninsula Medical School, Plymouth, UK. patrick.fox@virgin.net

BACKGROUND: Disabling tremor is common in patients with multiple sclerosis (MS). Data from animal model experiments and subjective and small objective studies involving patients suggest that cannabis may be an effective treatment for tremor associated with MS. To our knowledge, there are no published double-blind randomized controlled trials of cannabis as a treatment for tremor in MS patients. METHODS: The authors conducted a randomized double-blind placebo-controlled crossover trial to examine the effect of oral cannador (cannabis extract) on 14 patients with MS with upper limb tremors. There were eight women and six men, with a mean age of 45 years and mean Expanded Disability Status Scale score of 6.25. Patients were randomly assigned to receive each treatment and the doses escalated over a 2-week period before each assessment. The primary outcome was change on a tremor index, measured using a validated tremor rating scale. The study was powered to detect a functionally significant 50% improvement in the tremor index. Secondary outcomes included accelerometry, an ataxia scale, spiral drawing, finger tapping, and nine-hole pegboard test performance. RESULTS: Analysis of the data showed no significant improvement in any of the objective measures of upper limb tremor with cannabis extract compared to placebo. Finger tapping was faster on placebo compared to cannabis extract (p < 0.02). However, there was a nonsignificant trend for patients to experience more subjective relief from their tremors while on cannabis extract compared to placebo. CONCLUSIONS: Cannabis extract does not produce a functionally significant improvement in MS-associated tremor.

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Rev Neurol. 2004 Mar 16-31;38(6):524-9.
[Multiple sclerosis and depression]
[Article in Spanish]
Sanchez Lopez MP, Olivares Perez T, Nieto Barco A, Hernandez Perez MA, Barroso Ribal J.
Universidad de la Laguna. Facultad de Psicologia, La Laguna, Espana.

Introduction. Depression has frequently been reported in multiple sclerosis. However, prevalence rates must be interpreted in the light of the conceptual and methodological limitations of these studies. Depression has traditionally been associated with response to the diagnosis of this disease, the presence of physical and cognitive limitations, the damage of specific neural systems and inmunomodulatory therapy. Aims. To assess the evolution of emotional state and its relationship with motor and cognitive slowness, in relapsing remitting patients with minimal levels of neurological disability. Patients and methods. Data are reported for 35 patients with relapsing remitting multiple sclerosis, 27 treated with interferons and 8 without interferon treatment. Mood disturbance (Beck Depression Inventory, BDI), physical disability (Kurtzke Expanded Disability Status Scale, EDSS) and speed of information processing (reaction times) were assessed. The first testing was carried out before the start of treatment and the second testing one year later. Results and conclusions. The group of patients showed a total BDI score indicative of minimal depression associated with items expressing performance difficulties and somatic complaints. Emotional state was not related to physical disability but was related to processing speed measures. A significant improvement of depression was observed after one year of treatment with inmunomodulatory therapy.

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IDrugs. 2004 Feb;7(2):166-72.
Pirfenidone.
Lasky J.
Tulane University Health Sciences Center, 1430 Tulane Avenue, SL-9, New Orleans, LA 70112, USA. jlasky@tulane.edu

Pirfenidone, an antifibrotic tissue growth antagonist, is in development for the potential treatment of fibrotic diseases including renal, liver and pulmonary fibrosis and for multiple sclerosis.

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Prescrire Int. 2004 Feb;13(69):10-2.
Glatiramer: new preparation. No place in multiple sclerosis.
[No authors listed]

(1) Interferon beta-1a is the reference treatment for relapsing-remitting multiple sclerosis. It reduces the frequency of exacerbations and was the first interferon beta shown to delay the onset of disability. (2) Glatiramer, a peptide with certain structural similarities to myelin components, was recently approved for use in this indication. (3) Three randomised double-blind trials lasting a maximum of two years compared glatiramer with placebo. They showed that glatiramer has no impact on the progression of disability. Glatiramer increased slightly the interval between exacerbations: each patient avoided about one exacerbation after two years treatment. But the drug had no effect on the number of patients who experienced exacerbation. Glatiramer has not been compared with interferon beta in clinical trials. (4) The treatment withdrawal rates for adverse effects among patients treated with glatiramer and interferon beta are about the same, although the two drugs have different adverse effect profiles. Most patients using glatiramer have reactions at the injection site. Nearly half the patients given glatiramer have an immediate systemic reaction, and these can be serious. (5) Glatiramer therapy requires daily injections, unlike the more convenient interferon beta (which is given every three days). (6) Glatiramer is no cheaper than interferon beta. (7) In practice, the minor benefits of glatiramer are offset by its adverse effects and less convenient administration. There is currently no place for glatiramer in the treatment of multiple sclerosis.

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Exp Biol Med (Maywood). 2004 Jan;229(1):12-20.
Multiple sclerosis: etiological mechanisms and future directions.
Lutton JD, Winston R, Rodman TC.
Institute for Human Genetics and Biochemistry, Cabrini Medical Center, New York, New York 10003, USA. jdlut@frontiernet.net

Multiple sclerosis (MS) is a complex human autoimmune-type disease with a predominantly unknown etiology. Immunologic destruction of myelin basic protein (MBP) throughout the nervous system is the major pathology of multiple sclerosis. This review will attempt to update new information about basic mechanisms and therapeutic management of the disease. The significance of the structure of MBP is discussed with respect to the contribution of such structures to the disease process. A number of MBP peptides that serve as the immunodominant antigens in MS patients have been identified. These peptides have been studied in animal models for their antigenic characteristics and ability to induce disease. Evidence for genetic contributions is reviewed with multigenerational twin studies providing the best evidence for susceptible haplotypes. The role of microorganisms/viruses and environmental agents are discussed as potential etiological factors but are now thought to be of minor importance to the primary causal development of the disease. Of major consideration are immunological mechanisms that contribute to the development of autoimmunity. In particular, antigen expression, cytokine and leukocyte interactions, and regulatory T-cells are discussed. Particular attention is given to regulatory T-cells (Treg), which help balance/modulate other T-cells such as Th1 and Th2 cells, and how such Treg regulate autoimmunity is addressed. The importance of the role of Tregs is exemplified by the demonstration that administration of oral antigens can induce specific Tregs that counteract experimental autoimmune encephalomyelitis in animal models. The significance of animal studies to human multiple sclerosis is discussed. A potential role for natural antibodies and innate immune mechanisms to help provide resistance to disease development is also reviewed. Finally, a variety of therapeutic agents that have been and continue to be utilized for multiple sclerosis is reviewed. Trials with oral antigens, such as glatirmer acetate (copolymer 1) especially in combination with interferon-beta, have shown promise. Antibody therapy and bone marrow transplantation are also briefly discussed.

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Eur Neurol. 2004;51(1):15-20. Epub 2003 Nov 18.
Azathioprine and interferon beta(1a) in relapsing-remitting multiple sclerosis patients: increasing efficacy of combined treatment.
Lus G, Romano F, Scuotto A, Accardo C, Cotrufo R.
Department of Neurological Sciences, Faculty of Medicine of the Second University of Naples and the Centro Interuniversitario di Ricerca in Neuroscienze, Naples, Italy. giacomo.lus@unina2.it

Current treatments of relapsing-remitting multiple sclerosis (RRMS) with immunosuppressive or immunomodulatory drugs have been shown to modify the course of the disease in a significative number of patients. However, in many cases, the response to either interferon beta (IFN-beta) or azathioprine (AZA) treatments was not satisfactory and new therapeutic approaches are needed. We studied clinical and MRI efficacy, safety and tolerance of AZA and IFN-beta(1a) combined therapy in 23 patients with clinically definite RRMS, who had not previously been responsive to either monotherapies. Our cases were divided into three subgroups: 8 previously untreated patients (subgroup A) with at least 2 years of natural course of the disease, 8 patients (subgroup B) previously treated with AZA for 2 years and 7 patients (subgroup C) previously treated with IFN-beta(1a) for 2 years. The baseline Expanded Disability Status Scale (EDSS) ranged from 2 to 4 in all subgroups. All patients completed 2 years of combined treatment with a dose of AZA adjusted to reduce lymphocyte count down to 1,000 +/- 100/microl in association with IFN-beta(1a) at a dose of 6 MIU every other day. The mean number of relapses during the combined treatment period was significantly lower than that observed before combined therapy in all the three subgroups. Also, the mean Delta EDSS score was significantly lower during combined treatment than in monotherapy in subgroups B and C. Moreover, after 2 years of combined treatment, the number of new T(1) hypointense lesions, the number and volume of proton density/T(2) hyperintense lesions and the gadolinium enhancement of T(1) hypointense lesions were significantly lower than before combined treatment. After 2 years of treatment, this combination therapy appears to be safe and well tolerated and no serious side effects were reported. Despite some limitations of our study design, the information regarding efficacy, safety and tolerance of the association of AZA and IFN-beta is most encouraging. Copyright 2004 S. Karger AG, Basel

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Prog Brain Res. 2004;146:415-32.
Remyelination in multiple sclerosis: a new role for neurotrophins?
Althaus HH.
Max-Planck-Institute for Experimental Medicine, RU Neural Regeneration, H.-Reinstr. 3, D-37075 Gottingen, Germany. althaus@em.mpg.de

Multiple sclerosis (MS) is a common neurological disease, which affects young adults. Its course is unpredictable and runs over decades. It is considered as an autoimmune disease, and is neuropathologically characterized by demyelination, variable loss of oligodendroglial cells, and axonal degeneration. Demyelination provides a permitting condition for axonal degeneration, which seems to be causative of permanent neurological deficits. Hence, the current treatment, which works preferentially immunmodulatory, should be complemented by therapeutics, which improves remyelination not only for restoring conduction velocity but also for preventing an irreversible axonal damage. One strategy to achieve this aim would be to promote remyelination by stimulating oligodendroglial cells remaining in MS lesions. While central nervous system neurons were already known to respond to neurotrophins (NT), interactions with glial cells became apparent more recently. In vitro and in vivo studies have shown that NT influence proliferation, differentiation, survival, and regeneration of mature oligodendrocytes and oligodendroglial precursors in favor of a myelin repair. Two in vivo models provided direct evidence that NT can improve remyelination. In addition, their neuroprotective and anti-inflammatory role would support a repair. Hence, a wealth of data point to NT as promising therapeutical candidates.

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Mult Scler. 2003 Dec;9(6):585-91.
Glatiramer acetate (Copaxone): comparison of continuous versus delayed therapy in a six-year
organized multiple sclerosis trial.
Johnson KP, Brooks BR, Ford CC, Goodman AD, Lisak RP, Myers LW, Pruitt AA, Rizzo MA, Rose JW, Weiner LP, Wolinsky JS.
Department of Neurology, University of Maryland, Baltimore, MD 21201, USA. kjohnson@som.umaryland. edu

The aim of this study was to assess the long-term safety and efficacy of glatiramer acetate (GA) for patients with multiple sclerosis (MS) who received active treatment versus those on placebo for approximately 30 months (24-35 months) before receiving GA during a six-year organized, prospective open label study. Entry required two relapses in the previous two years and an Expanded Disability Status Scale (EDSS) score of 0-5. Patients (251) were equally randomized to daily subcutaneous GA, 20 mg, or to placebo. After approximately 30 months, 208 patients continued in an open label study: 101 continued on GA and 107 switched from placebo to active drug. Groups were well matched at randomization and entry to the open label study. Patients always on GA showed a steady decline in relapses: a mean of 1.5 per year at entry, a mean of 0.42 over the entire six years (95% CI = 0.34-0.51), a 72% reduction (P = 0.0001). They averaged a relapse every four + years (yearly rate 0.23 in year six) and 26/101 remain relapse free. Patients did less well if on placebo for 30 months, but relapses then declined, and by year six the rates were similar. Of patients always on GA, 69% showed neurological improvement of > or = 1 EDSS steps or remained stable compared with 57% if GA treatment was delayed. Of relapse-free patients always on GA over six years, only three of 26 (11%) were worse by > or = 1 EDSS steps, whereas nine of 21 (43%) in the placebo/active group were worse (P < 0.03). Disability, measured every six months, showed that the group of patients always on GA was relatively stable over the six years, while the group who received placebo for the first two-and-a-half years did significantly less well. Daily injections of GA were well tolerated. This longest ever organized MS treatment trial shows that delaying therapy with GA increases the risk of neurologic disability, reinforcing the rationale for using GA as a first-line treatment early in the course of relapsing-remitting MS.

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Neurol Sci. 2003 Dec;24 Suppl 5:S298-300.
Multiple sclerosis: rationale for early treatment.
Soderstrom M.
Department of Ophthalmology, Huddinge University Hospital, SE-1451 86, Stockholm, Sweden.

MS often presents as acute unilateral optic neuritis (ON). While it is clear that many patients with ON suffer from a generalized disease of the central nervous system that will go on to clinically definite MS (CDMS), it is also clear that others do not. As patients become increasingly wellinformed and with the development of effective pharmacotherapy for MS, the distinction between those patients with ON who have MS and those who do not has become ever more important. Recent randomized clinical trials in patients with ON or other clinically isolated syndromes (CIS) suggestive of MS and evidence of prior subclinical demyelination on magnetic resonance imaging of the brain found that treatment with recombinant interferon-beta-1a is beneficial in reducing the development of CDMS. Ophthalmologists and other non-neurologists should refer patients with acute ON or other CIS suggestive of MS to a neurologist for MS-directed investigations.

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Eur J Neurol. 2003 Nov;10(6):671-6.
A retrospective, observational study comparing the four available immunomodulatory treatments for relapsing-remitting multiple sclerosis.
Carra A, Onaha P, Sinay V, Alvarez F, Luetic G, Bettinelli R, San Pedro E, Rodriguez L.
Hospital Britanico Buenos Aires, Argentina. neuro@hbritanico.com.ar

We performed an observational, retrospective analysis of outcome in a sequential cohort of patients with relapsing-remitting multiple sclerosis (RRMS) in Argentina. Patients treated for 16 months with interferon beta-1a (Avonex; 30 micrograms intramuscularly, once a week), interferon beta-1a (Rebif); 44 micrograms subcutaneously, thrice weekly), interferon beta-1b (Betaferon; 250 micrograms subcutaneously, every other day) or glatiramer acetate (Copaxone; 20 mg subcutaneously daily) were compared with a non-treated group of patients. The different treatment groups were similar in baseline demographic and clinical variables. A significant fall in the annual relapse rate was observed for all four treatments, with the largest effect observed with glatiramer acetate (81% reduction in relapse rate, compared with pre-treatment values). The proportion of patients remaining relapse-free for the entire 16-month treatment period varied from 37% in untreated patients to 83% in the glatiramer acetate treated group. No statistically significant changes in disability scores were observed over the treatment period. This first such comparative study in Latin America shows that treatment of multiple sclerosis patients with immunomodulatory therapies in the context of current standards of care in Argentina provides clinically important benefit, and suggest that some of these therapies may be better than others.

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Neurology. 2003 Nov 25;61(10):1332-8.
The use of mitoxantrone (Novantrone) for the treatment of multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.
Goodin DS, Arnason BG, Coyle PK, Frohman EM, Paty DW; Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.
Therapeutics and Technology Assessment Subcommittee, American Academy of Neurology, St. Paul, MN 55116, USA.

Mitoxantrone is the first drug approved for the treatment of secondary progressive multiple sclerosis (SPMS) in the United States. This assessment considers use of mitoxantrone in the treatment of MS. Mitoxantrone probably reduces the clinical attack rate and reduces attack-related MRI outcomes in patients with relapsing MS (Type B recommendation). Also, mitoxantrone may have a beneficial effect on disease progression in patients with MS whose clinical condition is worsening (Type B recommendation). The potential for serious toxicity of mitoxantrone, however, must be taken into account when considering this therapy in individual patients. Moreover, because the potential clinical benefits on disease progression appear to be only modest, the results of the single phase III trial should be replicated in another (and hopefully much larger) clinical study before this agent is widely recommended for the treatment of patients with MS.

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Cas Lek Cesk. 2003;142(9):534-7.
[A neurologist's views on cellular and gene therapy in nervous system diseases]
[Article in Czech]
Bojar M.
Neurologicka klinika 2. LF UK a FNM, Praha. martin.bojar@lfmotol.cuni.cz

Lesional impairment of the brain and spinal cord is a serious and usually irreversible disorder. There is only a small chance of functionally significant compensation of lesions. Neurons and glia are marked by the minimal regeneration. Though plasticity and adaptability represent important mechanisms, which can contribute to the compensation of structural and functional CNS disorders, irreversible structural and functional deficits may develop. Transplantation of various cells incl. neurons from fetal brain or transplantation of genetically modified cells was therefore proposed. Clear verification of this method by animal tests and by clinically controlled trials is a necessary condition. Its application is expected in atrophic-degenerative and vascular diseases of CNS, tumors, injuries, seizure, inflammatory and demyelinating diseases in which the replacement of neurons, glia and enhancement of their regeneration play the key role. Transplantation of embryonic stem cells, fetal neural cells, and haematopoietic stem cells introduced by stereotaxic, hematogenic or intrathecal procedure gets the attention. Bioethical problems and the possible contribution of this method based on experience with transplantation of fetal cells into basal ganglia of 3 patients with Parkinson's disease and haematopoietic stem cell transplantation in multiple sclerosis (n 1) are discussed.

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J Neurol. 2003 Oct;250(10):1214-8.
Does neurorehabilitation have a role in relapsing-remitting multiple sclerosis?
Liu C, Playford ED, Thompson AJ.
Neurorehabilitation Unit, National Hospital for Neurology & Neurosurgery, Queen Square, London WC1N 3BG, UK.

Patients with relapsing-remitting multiple sclerosis (RR MS) often make incomplete recovery from disabling exacerbations, despite corticosteroid treatment. Inpatient rehabilitation has been shown to be valuable in progressive MS, but its role in RR MS is less clear. We evaluated the effect of rehabilitation in consecutive patients with RR MS admitted to a neurological rehabilitation unit. Outcome measures applied on admission and discharge included the Expanded Disability Status Scale (EDSS), the Barthel Index (BI) and the Functional Independence Measure (FIM), as well as a visual analogue scale (VAS) of the patients' perception of rehabilitation impact. Confounding factors including the timing of steroid therapy and re-admissions were also examined. RR patients showed considerable improvement following rehabilitation, with a median change of -0.5 on EDSS, +4 on BI and +12 on FIM (mean change of -0.8 EDSS, +4.5 BI and +15.6 FIM points; effect sizes of -1.01, 0.97 and 0.86, respectively), which was significantly greater than other MS subtypes. RR patients rated their admissions highly (median VAS 8.9, interquartile range 7.5-9.9), and the VAS scores correlated modestly with disability measures (Spearman's rho = -0.42, 0.31 and 0.24 versus EDSS, BI and FIM, respectively; p = 0.007-0.040). Repeat admissions and the timing of steroid treatment did not have a significant effect on outcome. This suggests that inpatient rehabilitation is useful in RR MS, particularly in patients with incomplete recovery from relapses who have accumulated moderate to severe disability.

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Br J Nurs. 2003 Oct 9-22;12(18):1075-80.
Results of a fatigue management programme in multiple sclerosis.
Ward N, Winters S.
University of Central England, Birmingham, UK.

Fatigue in patients with multiple sclerosis (MS) is a complex symptom that is notoriously difficult to treat, not least because it is extremely subjective and is experienced differently by each patient. Owing to the prevalence of this symptom, most patients with MS who are seen in outpatient settings complain of fatigue and experience the disabling effect it can have upon day-to-day living. Managing and treating this symptom is a challenge, although there is some evidence that applying fatigue management principles can potentially reduce the debilitating effect fatigue has on patients (Welham, 1995). This article reviews the evidence base surrounding the management and treatment of fatigue that is applied in clinical practice. It describes the fatigue management programme that had been introduced for people with MS at the authors' workplace, and evaluated whether applying fatigue management principles can make a difference to people's ability to self-care. The effect this symptom has upon people's quality of life will also be explored.

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J Neurol Neurosurg Psychiatry. 2003 Oct;74(10):1392-7.
Chronic deep brain stimulation for the treatment of tremor in multiple sclerosis: review and case reports.
Wishart HA, Roberts DW, Roth RM, McDonald BC, Coffey DJ, Mamourian AC, Hartley C, Flashman LA, Fadul CE, Saykin AJ.
Department of Psychiatry, Dartmouth Medical School, Lebanon, New Hampshire 03756-0001, USA. heather.wishart@dartmouth.edu

BACKGROUND: Deep brain stimulation (DBS) offers a non-ablative alternative to thalamotomy for the surgical treatment of medically refractory tremor in multiple sclerosis. However, relatively few outcomes have been reported. OBJECTIVE: To provide a systematic review of the published cases of DBS use in multiple sclerosis and to present four additional patients. METHODS: Quantitative and qualitative review of the published reports and description of a case series from one centre. RESULTS: In the majority of reported cases (n=75), the surgical target for DBS implantation was the ventrointeromedial nucleus of the thalamus. Tremor reduction and improvement in daily functioning were achieved in most patients, with 87.7% experiencing at least some sustained improvement in tremor control postsurgery. Effects on daily functioning were less consistently assessed across studies; in papers reporting relevant data, 76.0% of patients experienced improvement in daily functioning. Adverse effects were similar to those reported for DBS in other patient populations. CONCLUSIONS: Few of the studies reviewed used highly standardised quantitative outcome measures, and follow up periods were generally one year or less. Nonetheless, the data suggest that chronic DBS often produces improved tremor control in multiple sclerosis. Complete cessation of tremor is not necessarily achieved, there are cases in which tremor control decreases over time, and frequent reprogramming appears to be necessary.

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Schmerz. 2003 Oct;17(5):367-73.
[Therapeutic use of cannabinoids in neurology]
[Article in German]
Schwenkreis P, Tegenthoff M.
Neurologische Universitatsklinik, BG-Kliniken Bergmannsheil Bochum. peter.schwenkreis@ruhr-uni-bochum.de

This review gives insight into the potential therapeutical role of cannabinoids in neurology. Preclinical data are presented which could give a rationale for the clinical use of cannabinoids in the fields of multiple sclerosis, spasticity, epilepsy, movement disorders, and neuroprotection after traumatic head injury or ischemic stroke. Besides, clinical data (case reports, open-label and randomised controlled studies) dealing with the therapeutical use of cannabinoids in these fields are reported and discussed. At present, clinical data are insufficient to recommend the use of cannabinoids in any neurological disease as standard therapy. Several questions still have to be answered (which cannabinoid? which way of administration? stimulation of endogenous cannabinoids? separation between desired and undesired effects?), and controlled studies are still needed to clarify the potential therapeutical role of cannabinoids in neurology.

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Neurol Sci. 2003 Oct;24 Suppl 4:S227-30.
Treatment of multiple sclerosis with intravenous immunoglobulin: review of clinical trials.
Sorensen PS.
MS Research Unit, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

Intravenous immunoglobulin (IVIG) is an established therapy for a number of neuroimmune disorders, including Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy. IVIG exerts a number of effects that may be beneficial in multiple sclerosis (MS): reduction of inflammation, inhibition of macrophages, and promotion of remyelination. Four double-blind trials have been performed of IVIG in relapsing-remitting MS. A meta-analysis of the four trials has shown that IVIG reduces the relapse rate, new MRI lesions, and disease progression. IVIG does not seem to be of any benefit in chronic visual or motor symptoms in MS. In secondary progressive MS, IVIG has not shown effect on disease progression, relapses or new MRI lesions. In conclusion, IVIG is an alternative second-line treatment to approved therapies in relapsing-remitting MS, but the ideal dosage of IVIG still needs to be determined.

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Lancet Neurol. 2003 Sep;2(9):563-6.
New and emerging treatment options for multiple sclerosis.
Polman CH, Uitdehaag BM.
Department of Neurology, VU Medical Center, Amsterdam, Netherlands. ch.polman@vumc.nl

BACKGROUND: The use of interferon beta and glatiramer acetate for the treatment of multiple sclerosis (MS) has, to some extent, changed the course of the disease. The annual relapse rate of patients treated with these drugs is lower than that in placebo-treated patients, and more treated patients remain relapse-free compared with untreated patients. In addition, these compounds reduce the development of new lesions, as detected by MRI. RECENT DEVELOPMENTS: The limited effectiveness of approved treatments for MS, as well as reports of adverse events and toxicity, emphasise the need for the development of new therapies with improved efficacy and fewer side-effects. Clinical observations, increased understanding of the underlying pathophysiology of the disease, and advances in biotechnology have led to several new therapeutic approaches to the treatment of MS that are currently under investigation. WHERE NEXT? Mitoxantrone has recently been shown to produce benefit when used to treat patients with progressive MS; it may also be an effective second-line treatment for patients who do not respond to interferon beta or glatiramer acetate. Over the past few years, several studies have drawn attention to the potential of natalizumab, alemtuzumab, statins, and oestrogens as effective treatments for MS. These drugs are at different stages of clinical development and additional clinical data are needed to support their use and devise dosage regimens. However, they are important and attractive candidates for several reasons: they counteract a fundamental and well-defined pathophysiological process; they have a less cumbersome route of administration than interferon beta and glatiramer acetate; or they have a remarkable safety record.

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J Neurol Neurosurg Psychiatry. 2003 Sep;74(9):1225-30.
A randomised controlled trial comparing rehabilitation against standard therapy in multiple sclerosis patients receiving intravenous steroid treatment.
Craig J, Young CA, Ennis M, Baker G, Boggild M.
The Walton Centre for Neurology & Neurosurgery, Lower Lane, Liverpool, UK. jenny.craig@thewsltoncentre.nhs.uk

BACKGROUND: There is evidence to support both the use of intravenous methylprednisolone (IVMP) in multiple sclerosis (MS) relapse and physiotherapy in the management of MS, but no studies have investigated the combination of steroids and rehabilitation together. OBJECTIVES: To evaluate the benefits of IVMP with planned, comprehensive multidisciplinary team (MDT) care compared to IVMP with standard care. METHODS: In this randomised controlled trial, patients confirmed to have had a definite MS relapse severe enough to warrant IVMP (1 g daily for three days) were randomised to two groups. The control group was managed according to the standard ward routine; the treatment group received planned coordinated multidisciplinary team assessment and treatment. Baseline assessments, including demographics and Expanded Disability Status Scale (EDSS) were carried out on both groups. The primary outcome measures were Guy's Neurological Disability Scale (GNDS), and Amended Motor Club Assessment (AMCA). The secondary measures were the Barthel Index (BI), Human Activity Profile (HAP), and Short Form Item 36 Health Survey (SF-36). All measures have published data on reliability and validity. Measures were administered at one and three months. RESULTS: Forty subjects, including 27 females, completed data collection. There were no significant differences between the two groups at baseline. Results showed statistically significant differences in GNDS (p = 0.03), AMCA (p = 0.03), HAPM (p < 0.01), HAPA (p = 0.02), and BI (p = 0.02) at three months in favour of planned MDT care. CONCLUSION: This study indicates that combining steroids with planned MDT care is superior to administering them in a standard neurology or day ward setting. Further research is necessary in order to confirm this finding.

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Nippon Rinsho. 2003 Aug;61(8):1449-54.
[Immunologic therapy for secondary and primary progressive multiple sclerosis]
[Article in Japanese]
Ozawa K.
Department of Neurology, Utano National Hospital.

Immunological treatments of progressive multiple sclerosis are discussed. Recent trials of interferon-beta 1b(IFN beta-1b) and IFN beta-1a in secondary progressive MS (SPMS) have demonstrated treatment benefits on relapse rate and accumulation of MRI lesions, and one trial of IFN beta-1b showed significant slowing of disability progression. In another recent study, mitoxantrone, a potent immunosuppressive agent, was reported to reduce progression of disability in SPMS. As regards primary progressive MS, there is currently no convincing disease-modifying treatment. Pathologic studies have revealed that axonal injury is prominent in MS and may be the explanation for irreversible disability. It is hoped that therapeutic strategies will be aimed at axonal loss as well as inflammation and demyelination.

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Nippon Rinsho. 2003 Aug;61(8):1388-95.
[Therapeutic apheresis in multiple sclerosis]
[Article in Japanese]
Nomura K.
Department of Neurology, Saitama Medical School.

Therapeutic apheresis is divided in cytapheresis and plasmapheresis. And plasmapheresis(PP) is divided into three treatments, plasma exchange(PE), double filtration plasmapheresis(DFPP) and immunoadsorption plasmapheresis(IAPP). PE has been applied in the neuroimmunological disorders and the effectiveness of PP has been well established in some neuroimmunological disorders. In this article, PP treatment of multiple sclerosis(MS) was reviewed. PP is an effective means of removing the pathogenic immune-mediated factors, such as inflammatory cytokines, autoantibodies, immune complexes, and complements. PP may affect not only humoral immune responses but also cellular immune responses. Previous clinical reports suggested that PE might be effective in treating acute attacks of MS, but be no effective in patients with chronic progressive MS. IAPP may be superior to PE in the treatment of MS.

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Nippon Rinsho. 2003 Aug;61(8):1381-7.
[Newer disease—modifying drugs: glatiramer acetate and mitoxantrone]
[Article in Japanese]
Kohriyama T, Higaki M, Matsumoto M.
Third Department of Internal Medicine, Hiroshima University Hospital.

Glatiramer acetate(GA) is a synthetic molecule composed of four amino acids: glutamine, lysine, alanine, and tyrosine. These four amino acids are represented in myelin basic protein, which is a suspect antigen involved in the induction of autoimmunity in multiple sclerosis (MS). Subcutaneous GA 20 mg/day showed a reduction of the mean relapse rate and a slower decline of Expanded Disability Status Scale(EDSS) in patients with relapsing-remitting MS(RRMS). In addition, GA is effective in reducing magnetic resonance imaging(MRI) measured activity in patients with RRMS. The drug is generally well tolerated and is not associated with the influenza-like symptoms. Mitoxantrone(MX), a cytotoxic drug exhibiting very potent immunosuppressive properties, has been found effective on relapse rate and progression of disability in patients with worsening RRMS or secondary progressive MS. An induction phase with the monthly intravenous administration of 12 mg/m2 followed by a maintenance phase with 12 mg/m2 every 3 months for 2 years seems the most effective and safe treatment regimen, not exceeding the maximum cumulative dose of 140 mg/m2. Cardiotoxicity, the major long-term toxicity, is clearly dose-dependent and is a strict treatment duration limiting factor.

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Nippon Rinsho. 2003 Aug;61(8):1374-80.
[Intravenous immunoglobulin in multiple sclerosis]
[Article in Japanese]
Ota K.
Faculty of Science, Tokyo University of Science.

Intravenous immunoglobulin(IVIg) is a immunomodulating therapy to administer a relatively high dose of human immunoglobulins to a number of autoimmune diseases. Clinical trials of IVIg for neurological disorders including autoimmune peripheral neuropathy were carried out since the later of 1980's, and the efficacy of IVIg for such diseases was proved. In recent years the effectiveness of IVIg for multiple sclerosis(MS) has been reported in several randomized controlled trials(RCTs). MS patients in the trials were given immunoglobulin or placebo every month or two months for more than half a year. IVIg in particular is beneficial in prevention a recurrence of relapsing remitting MS and in improvement of MRI findings in a part of RCTs. However, IVIg does not recognize the distinct effectiveness in progression of secondary progressive MS yet. Some problems, for example, optimal dose or dosage frequency are unsolved. Generally a adverse effect of IVIg in MS patient is slightness and the continuation treatment of IVIg is tolerate for most patients. Now, in Europe where a clinical trial goes ahead, IVIg might be considered the therapy for MS when a already established treatment for MS such as interferon--beta is not effective or not be able to use. On the other hand, unfortunately the effectiveness of IVIg for MS could not be recognized by RCT executed in Japan.

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Nippon Rinsho. 2003 Aug;61(8):1367-73.
[Interferon beta treatment in multiple sclerosis]
[Article in Japanese]
Ochi H.
Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University.

Medical treatment of multiple sclerosis(MS) consists primarily of corticosteroid therapy to enhance recovery from relapse and drug interventions to help manage symptoms. However, disease-modifying drugs for the treatment of MS have been developed recent years, including interferon(IFN) beta, glatiramer acetate, and mitoxantrone. In addition to reductions in annual relapse rates and other measures of clinical disability, these drugs appear to reduce disease activity on MRI. In Japan, IFN beta-1b(Betaferon) is available as a disease-modifying drug from September 2000. This article focuses on the use of IFN beta for MS on the basis of available clinical data.

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Nippon Rinsho. 2003 Aug;61(8):1361-6.
[Steroid therapy for multiple sclerosis]
[Article in Japanese]
Oishi C, Sakuta M.
Department of Internal Medicine I, School of Medicine, Kyorin University.

The cause of multiple sclerosis(MS) is still obscure. However, recent therapy is making a dramatic progress. The steroid is traditional therapy, especially the common use of methylprednisolone in management of attacks of MS is based on high-dose intravenous methylprednisolone. This section are described steroid therapy of history(ACTH therapy, High-dose intravenous methylprednisolone therapy, ACTH therapy vs high-dose intravenous methylprednisolone therapy, and long term effects of steroid therapy), high-dose oral and intravenous methylprednisolone therapy, oral therapy after steroid pulse therapy and long term effects of steroid.

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Nippon Rinsho. 2003 Aug;61(8):1355-60.
[Symptomatic therapies for multiple sclerosis]
[Article in Japanese]
Honda H.
Department of Neurology, Jikei University School of Medicine.

In spite of the proven efficacy of the newer immunomodulative pharmacologic treatments for multiple sclerosis, such as steroid pulse therapy for exacerbation and beta-interferon subcutaneous injections for prevention, those treatments have not yet satisfied the criteria for direct management of the disease. Thus, even now, patients with multiple sclerosis still need symptomatic therapy to improve their quality of life and ameliorate the impairments in their activities of daily living due to their various neurologic deficits. This article reviews the management of a wide range of neurologic symptoms of multiple sclerosis, including spasticity, bladder dysfunction, paroxysmal symptoms, and chronic pain.

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Can J Neurol Sci. 2003 Aug;30(3):201-5.
Cannabis use as described by people with multiple sclerosis.
Page SA, Verhoef MJ, Stebbins RA, Metz LM, Levy JC.
Office of Medical Bioethics, University of Calgary, Calgary, AB, Canada.

BACKGROUND: Multiple sclerosis (MS) is one of the most common neurological diseases affecting young adults. The prevalence of MS in Alberta has been described as among the highest reported in the world, estimated at 217 per 100,000. Numerous anecdotal reports, and a few small empirical investigations have suggested that cannabis use may relieve the symptom experience of those with MS. The present study was undertaken to describe cannabis use by this patient group. Information on peoples' beliefs, practices and experiences related to use were investigated. METHODS: A questionnaire was mailed to a sample of 780 adults with MS in southern Alberta, Canada. RESULTS: Completed questionnaires were returned by 420/673 eligible subjects (response rate 62%). Mean sample age was 48 years and 75% were women. Respondents ranged from mildly to severely impaired. The majority of respondents (96%) was aware cannabis was potentially therapeutically useful for MS and most (72%) supported legalization for medicinal purposes. Forty-three percent had tried cannabis at some point in their lives, 16% for medicinal purposes. Symptoms reported to be ameliorated included anxiety/depression, spasticity and chronic pain. Reasons given for not trying cannabis were the fact that it is an illegal substance, concern about side effects and lack of knowledge on how to obtain it. CONCLUSIONS: Subjective improvements in symptom experience were reported by the majority of people with MS who currently use cannabis. Further evaluation of this substance is warranted.

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Mult Scler. 2003 Aug;9(4):356-61.
Reflexology treatment relieves symptoms of multiple sclerosis: a randomized controlled study.
Siev-Ner I, Gamus D, Lerner-Geva L, Achiron A.
Complementary Medicine Clinic, Department of Orthopedic Rehabilitation, Sheba Medical Center, Tel-Hashomer, Israel.

OBJECTIVE: To evaluate the effect of reflexology on symptoms of multiple sclerosis (MS) in a randomized, sham-controlled clinical trial. METHODS: Seventy-one MS patients were randomized to either study or control group, to receive an 11-week treatment. Reflexology treatment included manual pressure on specific points in the feet and massage of the calf area. The control group received nonspecific massage of the calf area. The intensity of paresthesias, urinary symptoms, muscle strength and spasticity was assessed in a masked fashion at the beginning of the study, after 1.5 months of treatment, end of study and at three months of follow-up. RESULTS: Fifty-three patients completed this study. Significant improvement in the differences in mean scores of paresthesias (P = 0.01), urinary symptoms (P = 0.03) and spasticity (P = 0.03) was detected in the reflexology group. Improvement with borderline significance was observed in the differences in mean scores of muscle strength between the reflexology group and the controls (P = 0.06). The improvement in the intensity of paresthesias remained significant at three months of follow-up (P = 0.04). CONCLUSIONS: Specific reflexology treatment was of benefit in alleviating motor; sensory and urinary symptoms in MS patients.

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Mult Scler. 2003 Aug;9(4):349-55.
Effects of glatiramer acetate on relapse rate and accumulated disability in multiple sclerosis: meta-analysis of three double-blind, randomized, placebo-controlled clinical trials.
Boneschi FM, Rovaris M, Johnson KP, Miller A, Wolinsky JS, Ladkani D, Shifroni G, Comi G, Filippi M.
Department of Neuroscience, Scientific Institute, University H San Raffaele, Milan, Italy.

Three randomized, double-blind, placebo-controlled trials have shown that glatiramer acetate (GA) is effective in reducing relapse rate in patients with relapsing-remitting (RR) multiple sclerosis (MS). Using raw data pooled from 540 patients, we performed a meta-analysis of these three trials, to investigate whether the extent of GA efficacy varies according to disease-related variables at study entry. Three regression models were developed to assess the efficacy of GA on the annualized relapse rate (primary outcome measure), on the total number of on-trial relapses and on the time to first relapse. We also explored the efficacy of GA on accumulated disability and the potential role of baseline clinical variables as predictors of relapse-rate variables and treatment efficacy. The mean adjusted annualized relapse rate on study was 1.14 in the pooled placebo-treated subjects and 0.82 in the pooled GA group (P = 0.004), indicating an average reduction in annualized relapse rate of 28%. About a one third reduction of the total number of on-trial relapses was also observed in patients receiving GA (P < 0.0001), who had a median time to the first relapse of 322 days versus a median time to the first relapse of 219 days seen in those receiving placebo (P = 0.01). A beneficial effect on accumulated disability was also found (risk ratio of 0.6; 95%; CI = 0.4-0.9; P = 0.02). The drug assignment (P = 0.004), baseline EDSS score (P = 0.02) and number of relapses during the two years prior to study entry (P = 0.002) were significant predictors of on-trial annualized relapse rate. No other demographic or clinical variable at baseline significantly influenced the treatment effect. This meta-analysis reaffirms the effectiveness of GA in reducing relapse rate and disability accumulation in RRMS, at a magnitude comparable to that of other available immunomodulating treatments. It also suggests that GA efficacy is not significantly influenced by the patients' clinical characteristics at the time of treatment initiation.

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Mult Scler. 2003 Aug;9(4):342-8.
Oral interferon beta-1a in relapsing-remitting multiple sclerosis: a double-blind randomized study.
Polman C, Barkhof F, Kappos L, Pozzilli C, Sandbrink R, Dahlke F, Jakobs P, Lorenz A; European Oral Interferon Beta-1a in Relapsing-Remitting MS Study Group.
Department of Neurology, Free University Medical Center, de Boelelaan 1117, NL-1007 MB Amsterdam, The Netherlands. ch.polman@vumc.nl

BACKGROUND: Interferon beta (IFNB) is available in parenteral formulations for treatment of multiple sclerosis (MS). The purpose of this study was to evaluate safety, tolerability and effects on MRI lesions of three different doses of oral IFNB-1a compared with placebo over six months in relapsing-remitting (RR) MS patients. METHODS: In this multicenter; double-blind randomized trial, RR-MS patients received 0.06, 0.6 or 6 million international units (MIU) IFNB-1a or placebo every other day for up to six months. Gadolinium DTPA-enhanced brain MRI scans were performed at screening and monthly during treatment. The primary variable was the cumulative number of newly active lesions. Secondary variables included volume of enhancing lesions on T1-weighted images each month and lesion volume on T2-weighted images at months three and six. Safety measures included adverse events, laboratory variables, vital signs, ECG, physical examination, EDSS and number of relapses. Neopterin was measured in 21 patients and neutralizing antibodies in 24 patients. RESULTS: Of 194 screened patients, 173 were randomized (42-44 patients per group) in 15 centers. Median cumulative numbers of newly active lesions over six months were 4.0 in the placebo and 0.6 MIU groups, compared with 7.5 and 9.0 in the 0.06 and 6 MIU groups (no significant differences). Secondary efficacy endpoints showed small and inconsistent differences between groups. Adverse events showed no notable group differences. Approximately two-thirds of patients in each group remained relapse free. No patients showed neutralizing antibodies. Neopterin levels were comparable between groups. CONCLUSION: Oral IFNB-1a showed neither beneficial effects in RRMS nor any systemic biological effects. Treatment was safe and well tolerated.

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Neurologia. 2003 Jul-Aug;18(6):318-23.
[Mitoxantrone]
[Article in Spanish]
Pericot I, Montalban X.
Unidad de Neuroinmunologia Clinica, Escuela de Enfermeria, Hospital Universitario Vall d'Hebron Barcelona, Spain. imma@comg.es

Mitoxantrone is an antineoplastic agent that exerts a potent immunosuppresive effect, including suppression of B cell immunity and reduction of T cell numbers. Clinical trials have shown that mitoxantrone has a statistically significant impact on reduction of relapse rate and delays disability progression in patients with relapsing remitting (RR) multiple sclerosis (MS) or secondary progressive (SP) MS. Treatment is well tolerated, but the risk of cardiotoxicity at higher cumulative doses is likely to limit the duration of treatment. The maximum cumulative dose recommended is 140 mg/m2. In 2000, the FDA (Food and Drug Administration) approved the use of mitoxantrone for the treatment of active RRMS, SPMS and progressing relapsing (PR) MS.

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Altern Ther Health Med. 2003 Jul-Aug;9(4):38-48.
Effects of a pulsed electromagnetic therapy on multiple sclerosis fatigue and quality of life: a double-blind, placebo controlled trial.
Lappin MS, Lawrie FW, Richards TL, Kramer ED.
Energy Medicine Developments, (North America), Inc., Burke, Va., USA.

CONTEXT: There is a growing literature on the biological and clinical effects of pulsed electromagnetic fields. Some studies suggest that electromagnetic therapies may be useful in the treatment of chronic illnesses. This study is a follow-up to a placebo controlled pilot study in which multiple sclerosis (MS) patients exposed to weak, extremely low frequency pulsed electromagnetic fields showed significant improvements on a composite symptom measure. OBJECTIVE: To evaluate the effects of a pulsed electromagnetic therapy on MS related fatigue, spasticity, bladder control, and overall quality of life. DESIGN: A multi-site, double-blind, placebo controlled, crossover trial. Each subject received 4 weeks of the active and placebo treatments separated by a 2-week washout period. SETTING: The University of Washington Medical Center in Seattle Wash, the Neurology Center of Fairfax in Fairfax, Va, and the headquarters of the Multiple Sclerosis Association of America in Cherry Hill, NJ. SUBJECTS: 117 patients with clinically definite MS. INTERVENTION: Daily exposure to a small, portable pulsing electromagnetic field generator. MAIN OUTCOME: The MS Quality of Life Inventory (MSQLI) was used to assess changes in fatigue, bladder control, spasticity, and a quality of life composite. RESULTS: Paired t-tests were used to assess treatment differences in the 117 subjects (81% of the initial sample) who completed both treatment sessions. Improvements in fatigue and overall quality of life were significantly greater on the active device. There were no treatment effects for bladder control and a disability composite, and mixed results for spasticity. CONCLUSIONS: Evidence from this randomized, double-bind, placebo controlled trial is consistent with results from smaller studies suggesting that exposure to pulsing, weak electromagnetic fields can alleviate symptoms of MS. The clinical effects were small, however, and need to be replicated. Additional research is also needed to examine the possibility that ambulatory patients and patients taking interferons for their MS may be most responsive to this kind of treatment.

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Cochrane Database Syst Rev. 2003;(3):CD003608.
Occupational therapy for multiple sclerosis.
Steultjens EM, Dekker J, Bouter LM, Cardol M, Van de Nes JC, Van den Ende CH.
Nivel; Netherlands Institute for Health Services Research, P.O. Box 1568, Utrecht, Netherlands.

BACKGROUND: Multiple sclerosis (MS) patients are referred to occupational therapy with complaints about fatigue, limb weakness, alteration of upper extremity fine motor coordination, loss of sensation and spasticity that causes limitations in performance of activities of daily living and social participation. The primary purpose of occupational therapy is to enable individuals to participate in self-care, work and leisure activities that they want or need to perform. OBJECTIVES: To determine whether occupational therapy interventions in MS patients improve outcome on functional ability, social participation and/or health related quality of life. SEARCH STRATEGY: Relevant full length articles were identified by electronical searches in Medline, Cinahl, Embase, Amed, Scisearch and The Cochrane MS Group Trials Register. The reference list of identified studies and reviews were examined for additional references. Date of last search: December 2002. SELECTION CRITERIA: Controlled (randomized and non-randomized) and other than controlled studies addressing occupational therapy for MS patients were eligible for inclusion. DATA COLLECTION AND ANALYSIS: The methodological quality of the included trials was independently assessed by two reviewers. Disagreements were resolved by discussion. A list proposed by Van Tulder et al. (Van Tulder 1997) was used to assess the methodological quality. For outcome measures, standardized mean differences were calculated. The results were analysed using a best-evidence synthesis based on type of design, methodological quality and the significant findings of outcome and/or process measures. MAIN RESULTS: Only one randomized clinical trial was identified. Two other included studies were a controlled clinical trial and a study with a pre-post test design. The studies included 271 patients in total. Two studies evaluated an energy-conservation course for groups of patients and one study evaluated a counselling intervention. The results of the energy conservation studies could be biased because of the designs used, the poor methodological quality and the small number of included patients. The high quality RCT on counselling reported non-significant results. REVIEWER'S CONCLUSIONS: On basis of this review no conclusions can be stated whether occupational therapy improves outcome in MS patients.The lack of (randomized controlled) efficacy studies in most intervention categories of OT shows an urgent need for future research in occupational therapy for multiple sclerosis. Initially, a survey of occupational therapy practice for MS patients including the characteristics and needs of these patients is necessary to develop a research agenda for efficacy studies.

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Rev Neurol (Paris). 2003 Jul;159(6-7 Pt 1):648-51.
[Intravenous immunoglobulins for relapsing-remitting multiple sclerosis after failure of treatment with other immuno-modulators]
[Article in French]
Lebrun C, Ghetau G, Bourg V, Chanalet S, Dumas S, Chatel M.
Service de Neurologie, Hopital Pasteur, Nice, France.

Intravenous immunoglobulins are used in the treatment of different autoimmune diseases. Recent trials suggest their efficacy in relapsing remitting multiple sclerosis. We report the results of an efficacy and safety trial using monthly intravenous injections of immunoglobulins for patients with secondary progressive multiple sclerosis. Eighteen patients in clinical progression, who have been previously treated with immunomodulatory or immunosuppressive drugs, were given monthly intravenous immunoglobulin infusions (0.4 g/kg/d for 5 days). At the beginning, the mean EDSS score was 6.77. At the end of the study, an improvement of EDSS was noted in 61.1 p. cent of patients, with less than 1 and 0.75 for secondary and primary progressive diseases respectively. No worsening was reported. Surprisingly, some patients had partial improvement of neurological functions which were considered as sequelae. Indications for intravenous immunoglobulins in the treatment of the multiple sclerosis need to be evaluated.

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J Neurol. 2003 Jul;250(7):861-6.
Effects of a short outpatient rehabilitation treatment on disability of multiple sclerosis patients--a randomised controlled trial.
Patti F, Ciancio MR, Cacopardo M, Reggio E, Fiorilla T, Palermo F, Reggio A, Thompson AJ.
Institute of Neurological Sciences, University of Catania, Via Santa Sofia 78, 95125 Catania, Italy. patti@mbox.unict.it

It is well known that neurorehabilitation can reduce disability or improve handicap of people with multiple sclerosis (MS). The aim of this study was to evaluate the effectiveness of a short period (6 weeks) of a tailored, individualised outpatient rehabilitation program in people with progressive MS. A randomised-controlled trial was undertaken in patients with primary and secondary progressive MS referred to the Centro Sclerosi Multipla of Catania. One hundred and eleven patients were assessed at baseline and at 12 weeks with validated measures of disability (Functional Independence Measure (FIM)) and impairment (Expanded Disability Status Scale (EDSS) and Functional Systems Scale). Of the 111, 58 were randomly assigned to the treatment group and 53 to the control group. All patients had been previously trained in a home exercise program. Both groups were well matched for age, sex, disease duration and severity, disability and quality of life (Short Form-36). At the end of 6 weeks patients allocated to the rehabilitation treatment group showed significant improvement in their level of disability compared with the control group,while the level of impairment did not change. Thirty-two patients of the treatment group and four of the control group improved on the FIM by two or more steps at 12 weeks (p<0.0001). An improvement by 1 EDSS step occurred in only two patients of the treatment group and in one patient of the control group. Benefits were maintained for a further six weeks. This study demonstrates that a short outpatient rehabilitation treatment improves disability of MS patients, without changing their impairment and confirms the effectiveness of rehabilitation in people with MS

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J Neurol Sci. 2003 Jul 15;211(1-2):81-4.
Efficacy and safety of repeated intrathecal triamcinolone acetonide application in progressive multiple sclerosis patients.
Hoffmann V, Schimrigk S, Islamova S, Hellwig K, Lukas C, Brune N, Pohlau D, Przuntek H, Muller T.
Department of Neurology, St. Josef-Hospital, Ruhr-University of Bochum, Gudrunstrasse 56, 44791 Bochum, Germany.

Available immunomodulatory and conventional steroid treatment options for patients with progressive multiple sclerosis (MS) only provide limited symptomatic benefit. We performed an open trial on the short-term and long-term efficacy and safety of repeated intrathecal application of the sustained release steroid triamcinolone acetonide (TCA) in 36 progressive MS patients. Six TCA administrations, performed every third day, reduced the EDSS score (initial: 5.6+/-0.93 [mean+/-S.D.]; end: 4.9+/-1.0; p<0.001) and increased the walking distance (WD) (initial: 294+/-314 m; end: 604+/-540 m; p<0.001). Twenty MS patients continued intrathecal TCA treatment with one TCA injection performed with a variable frequency ranging from 6 to 12 weeks. Both EDSS and walking distance remained stable in these patients until the end of the follow-up investigation period. No serious side effects occurred. We conclude that repeated intrathecal TCA injection provides substantial benefit for progressive MS patients with predominantly spinal symptoms.

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J Neurol. 2003 Jul;250(7):834-8.
Cyclophosphamide is effective in stabilizing rapidly deteriorating secondary progressive multiple sclerosis.
Perini P, Gallo P.
Multiple Sclerosis Center, First Neurology Clinic, Department of Neurological & Psychiatrical Sciences, University of Padova, Via Giustiniani 5, 35128 Padova, Italy.

The safety and efficacy of pulse cyclophosphamide (CTX) therapy was investigated in patients with very active secondary progressive multiple sclerosis, characterized by frequent relapses and rapid disability progression. For this purpose the clinical and MRI effects were assessed. Sixteen patients, 11 female and 5 male, were experiencing rapidly deteriorating disease, characterized by frequent and severe relapses as well as rapid progression (defined by an increase of more than 1 EDSS point in a period of 1 year). Mean relapse rate in the two years preceding CTX therapy was 3.0 +/-1.4. Mean EDSS was 4.0+/-1.4 one year before therapy and 5.6+/-1.0 at study entry. Treatment consisted in administration of high dose intravenous CTX every four weeks for one year and then every eight weeks for an additional twelve months. CTX dose was tailored to the patient's white blood cell response, and ranged from 800 to 1,200 mg/m(2) body surface. MRI was performed before therapy and then at 12 (Y1) and 24 (Y2) months. Eight patients with similar clinical features constituted a control group. CTX therapy was safe and well tolerated, and no severe side effects were observed. The EDSS decreased to 4.3+/-1.6 at Y1 (Y0 vs.Y1: p< 0.001) and to 4.1+/-1.6 at Y2 (Y0 vs.Y2: p< 0.001). Only four patients experienced relapses during the first year of therapy, while no relapses were observed during the second year of therapy. The mean relapse rate during therapy was 0.25 +/-0.45 (p< 0.0001).No increase in T2 lesion load was observed over the two years. A significant clinical and MRI deterioration was observed in the control group. Therapy with pulse CTX was able to stop disease activity and progression in patients with rapidly evolving secondary-progressive MS.

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Curr Opin Neurol. 2003 Jun;16(3):393-401.
Statins as potential therapeutic agents in neuroinflammatory disorders.
Stuve O, Youssef S, Steinman L, Zamvil SS.
Department of Neurology, University of California, San Francisco, California 94143, USA.

PURPOSE OF REVIEW: Multiple sclerosis is a central nervous system inflammatory demyelinating disease that is thought to have an autoimmune pathogenesis. Recent results indicate that 'statins', 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, which are the most commonly used oral cholesterol-lowering drugs, have immunomodulatory properties. In this article we will review those findings that indicate that statins may be beneficial in the treatment of multiple sclerosis, neurodegenerative disease, and ischemic stroke. RECENT FINDINGS: It was reported that statin treatment could either inhibit or reverse chronic and relapsing experimental autoimmune encephalomyelitis, a model of multiple sclerosis. Several immunomodulatory properties of statins may account for their beneficial clinical effect: Statins decreased the migration of leukocytes into the central nervous system, inhibited MHC class II and costimulatory signals required for activation of proinflammatory T cells, induced a T(H)2 phenotype in T cells, and decreased the expression of inflammatory mediators in the central nervous system, including nitric oxide and tumor necrosis factor alpha. It was also demonstrated that statin use significantly reduced beta-amyloid secretion in the cerebrospinal fluid of experimental animals. Clinically, there is emerging evidence that statins have beneficial effects in patients with multiple sclerosis, Alzheimer's disease, and ischemic stroke. SUMMARY: In-vitro studies have indicated that statins may have anti-inflammatory properties. Results from in-vivo animal models suggest that statins may be beneficial in treatment of different central nervous system conditions. Larger scale, randomized, double-blind trials are needed to validate the role of statins as a treatment of inflammatory central nervous system diseases.

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Curr Opin Neurol. 2003 Jun;16(3):299-305.
Hematopoietic stem cell transplantation for multiple sclerosis: current status and future challenges.
Muraro PA, Cassiani Ingoni R, Martin R.
Neuroimmunology Branch, National Institute of Neurological Diseases and Stroke, National Institutes of Health, MSC1400 Bethesda, MD 20892-1400, USA.

PURPOSE OF REVIEW: This article reviews recent advances in clinical trials of hematopoietic stem cell transplantation as a therapy for multiple sclerosis, and progress in exploring the potential for neural repair of hematopoietic-derived precursors. RECENT FINDINGS: Important recent findings are that hematopoietic stem cell transplantation can completely suppress the inflammatory component of multiple sclerosis, hematopoietic stem cells can migrate into the central nervous systems of rodents and humans, and can differentiate into cells expressing neural and glial markers. Hematopoietic stem cells also have neural and myelin repair potential. The heterogeneity of transplant regimens, the selection of patients at different stages of disease in clinical trials, and the limited duration of follow-up all currently preclude the evaluation of the long-term clinical benefits of hematopoietic stem cell transplantation for multiple sclerosis. SUMMARY: Hematopoietic stem cell transplantation is an experimental treatment that shows strong effects on the inflammatory component of multiple sclerosis. On the basis of experience acquired from initial pilot studies, controlled clinical trials are now being designed to verify long-term clinical efficacy. Selecting patients at high risk in the earlier stages of the disease that is dominated by inflammation, and monitoring objectively disease activity by magnetic resonance imaging will be critically important in these studies. Recent advances on the migratory potential and on the differentiation plasticity of hematopoietic stem cells have opened new opportunities for remyelination and axonal repair strategies for multiple sclerosis.

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Curr Opin Neurol. 2003 Jun;16(3):289-97.
Management of multiple sclerosis: current trials and future options.
Noseworthy JH.
Department of Neurology, Mayo Medical School, Clinic and Foundation, Rochester, Minnesota 55905, USA. Noseworthy.john@mayo.edu

PURPOSE OF THE REVIEW: The present review of multiple sclerosis (MS) therapeutic trials published in 2002 is intended to assist the reader in understanding the most current advances in the care of their patients. RECENT FINDINGS: A substantial number of pivotal and preliminary reports continue to demonstrate encouraging new evidence that advances are being made in the care of patients with MS. Several short-term studies in relapsing/remitting MS have demonstrated that it is possible to complete head-to-head comparison trials of active agents in MS (e.g. without a placebo control group). The findings of these trials remain open to interpretation and have generated considerable controversy, as expected. A phase 3 trial [the International MS Secondary Progressive Avonex Controlled Trial (IMPACT)] became the fourth study of the beta interferons (interferon-beta-1a, in this case) to demonstrate a partial effect on disease activity in secondary progressive MS. Two trials demonstrated apparent partial efficacy for the anthrecenedione mitoxantrone in active and progressive MS. Disappointing results were announced for a number of large pivotal trials, although those results have not yet been published (e.g. oral glatiramer acetate in relapsing/remitting MS, glatiramer acetate in primary progressive MS, and intravenous immunoglobulin in secondary progressive MS). SUMMARY: The MS research community needs to determine how best to address two key unanswered questions. Is late clinical deterioration often or invariably tied to the initial inflammatory/demyelinating phase of the disease? What is the optimal research design to address whether current and future experimental strategies affect the later phases of MS (e.g. does early treatment delay or prevent clinical disability)?

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Curr Opin Neurol. 2003 Jun;16(3):247-52.
Multiple paradigm shifts in multiple sclerosis.
Kieseier BC, Hartung HP.

PURPOSE OF REVIEW: The present article reviews the currently ongoing scientific debate of our changing views on the pathogenesis of multiple sclerosis and the therapeutic strategies currently available for multiple sclerosis. RECENT FINDINGS: The most important observations include that (a) axonal loss accounts for permanent disability in multiple sclerosis, (b) remyelination should be possible in theory but fails for unknown reasons in the multiple sclerosis lesion, (c) inflammation can be beneficial, (d) treatment should be initiated early, and (e) immunosuppressive strategies exhibit beneficial effects in progressive forms of the disease. SUMMARY: Our current understanding of the immunopathogenesis of multiple sclerosis has changed in the past. Whereas demyelination was originally thought to be relevant for the lasting neurological deficit, it is nowadays commonly accepted that the extent of axonal loss dictates the degree of permanent clinical disability. How axonal damage can be prevented remains elusive. The interaction between the myelinating cell and the neuron gains increasing attention, however the evolving knowledge has not yet yielded new treatment concepts. Hence for the time being, it seems prudent to make optimal use of current approved therapies. Recent trials underlined the need for early initiation of treatment with immunomodulatory drugs. The superiority of one of the interferons is still a matter of debate, and a conclusive answer cannot be given at present. Finally, with mitoxantrone we have a drug at hand which can be used in progressive forms of multiple sclerosis, especially when other disease modifying drugs are not or no longer effective.

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Neuropediatrics. 2003 Jun;34(3):120-6.
Glatiramer acetate treatment in patients with childhood and juvenile onset multiple sclerosis.
Kornek B, Bernert G, Balassy C, Geldner J, Prayer D, Feucht M.
Department of Neuropsychiatry of Childhood and Adolescence, University of Vienna, Vienna, Austria. barbara.kornek@univie.ac.at

BACKGROUND: Recent data indicate that in multiple sclerosis disease onset before the age of 16 is more common than previously assumed. However, current therapeutic options are limited to the treatment of acute attacks in these patients. Glatiramer acetate has been successfully applied in adults with relapsing-remitting multiple sclerosis, but there are no data available about the use of glatiramer acetate in childhood and juvenile onset multiple sclerosis. METHODS: Seven patients with relapsing-remitting multiple sclerosis and disease onset between 9 and 16 years of age were treated with daily subcutaneous injection of 20 mg glatiramer acetate (Copaxone). Patients were followed for 24 months. Treatment was initiated in all patients before the age of 18. RESULTS: The use of glatiramer acetate in our cohort of early onset multiple sclerosis patients was safe and well tolerated. Two out of seven patients remained relapse-free during the two year period. Clinical disability as measured by the EDSS remained stable in three out of seven patients. CONCLUSION: Due to the small number of patients the efficacy of the treatment has to be interpreted with caution. However, there might be a more pronounced treatment benefit in patients with low disability at treatment initiation and early treatment onset.

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Semin Neurol. 2003 Jun;23(2):147-58.
Future immunotherapies in multiple sclerosis.
Blevins G, Martin R.
Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 5B16, 10 Center Drive, Bethesda, MD 20892-1400, USA.

Immunotherapy of multiple sclerosis (MS) will continue to benefit from an increasing understanding of this disease. This knowledge results in newly defined targets for novel therapies. In this article the development of future immunotherapies will be discussed by classifying the approaches into three main types: (1) antigen-specific therapies; (2) agents with a defined target in pathogenic steps of the MS lesion; and (3) therapies with broad immunomodulatory activity. Success in developing new immunotherapies depends on understanding the underlying complexity and heterogeneity of the disease. The current practice of employing a single therapy across a heterogeneous group of MS patients is in part a likely reason for their modest efficacy. The mechanism of action of a single agent may target the appropriate defect in one individual but not others. The therapy of MS in the future will most likely use a combination of agents that are directed at the underlying disease state and stage in the individual patient.

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Semin Neurol. 2003 Jun;23(2):133-46.
Current disease-modifying therapies in multiple sclerosis.
Kieseier BC, Hartung HP.
Department of Neurology, Heinrich-Heine-University, Moorenstrasse 5, 40225 Dusseldorf, Germany.

In recent years, the usefulness of interferon beta and glatiramer acetate in the treatment of relapsing-remitting multiple sclerosis (RRMS) has been established. Interferon beta has also been shown to be efficacious in secondary-progressive multiple sclerosis (SPMS) as well as in patients with isolated syndromes at risk to develop clinically definite multiple sclerosis (MS). Mitoxantrone is another disease-modifying drug that is available for SPMS and severe cases of RRMS. The clinical utility of disease-modifying agents in MS will be reviewed with respect to the anti-inflammatory, immunomodulatory, and immunosuppressive treatments that are currently available. Symptomatic therapies will not be considered.

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Expert Opin Pharmacother. 2003 Jun;4(6):999-1001.
Is natalizumab a breakthrough in the treatment of multiple sclerosis?
Doggrell SA.
School of Biomedical Sciences, The University of Queensland, QLD 4072, Australia. s_doggrell@yahoo.com

In patients with either relapsing-remitting or secondary-progressive multiple sclerosis, there were fewer new lesions/patient with natalizumab (0.7 and 1.1 with natalizumab 3 and 6 mg/kg every 28 days, respectively) than in the placebo group (9.6 new lesions/patient) over 6 months. There were also fewer relapses in the natalizumab groups than the placebo group. However, there were no changes in the Expanded Disability Status Scale scores in any of the groups. Natalizumab was well-tolerated. Thus, the initial results with natalizumab treatment over 6 months in multiple sclerosis are encouraging.

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CNS Drugs. 2003;17(8):563-75.
Interventions for the prevention of brain atrophy in multiple sclerosis : current status.
Rovaris M, Filippi M.
Neuroimaging Research Unit, Department of Neurology, Scientific Institute and University Ospedale San Raffaele, Milan, Italy. rovaris.marco@hsr.it

The assessment of brain volume changes on serial magnetic resonance imaging (MRI) scans can provide an objective measure of the neurodegenerative component of multiple sclerosis (MS) pathology. Results from placebo-controlled and crossover clinical trials indicate that immunomodulating (e.g. recombinant interferon-beta [IFNbeta]-1a [Rebif] and IFNbeta-1b [Betaferon] and glatiramer acetate [Copaxone]) and immunosuppressive (e.g. cladribine and alemtuzumab) treatments for relapsing-remitting (RR) and secondary progressive MS lack substantial efficacy in preventing the development of brain atrophy, despite the marked effects of these treatments on clinical and MRI outcomes of disease activity. A modest but significant treatment effect on brain atrophy has been reported for patients with RRMS only in one trial of IFNbeta-1a (Avonex) and in another study of long-term corticosteroid therapy.Failure to find a significant treatment benefit in preventing brain atrophy might be the result of inadequate trial designs, including their relatively short durations, which may not be adequate to reveal beneficial effects in a chronic disease like MS. Alternatively, such a failure might indicate that treatments proven to be effective in reducing MS-related inflammation are unable to act with the same efficacy on the most severe and disabling pathological substrates of the disease. The modest correlation between MRI enhancement frequency and brain atrophy observed in the placebo groups of several trials also fits with the concept that the suppression of inflammatory activity in MS is not fully and rapidly associated with a similar effect on the global neurodegenerative process of the disease.

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Lik Sprava. 2003 Apr-Jun;(3-4):109-13.
[Effect of phlogenzym in long-term treatment of patients with multiple sclerosis]
[Article in Ukrainian]
Mialovyts'ka OA.

An assessment was carried out of clinical effectiveness of the drug phlogenzym in 74 patients with remitting, remitting-progressive, and secondary progressive course of multiple sclerosis. Phlogenzym intake for up to one to three years resulted in decline in the incidence of complications, with their degree having come to be lower, duration of remissions longer, progression of the illness slowed down. The data secured suggest to us that phlogenzym is a safe agent. It can, we believe used in a therapeutic regimen for those patients presenting with remitting and remitting-progressive types of the course of the disease.

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Am J Occup Ther. 2003 May-Jun;57(3):315-23.
Effects of an energy conservation course on fatigue impact for persons with progressive multiple sclerosis.
Vanage SM, Gilbertson KK, Mathiowetz V.
Replay Physical Therapy, 1202 West Havens Street, Kokomo, Indiana 46901, USA. smvanage@yahoo.com

OBJECTIVE: Fatigue is a common, troublesome symptom for persons with multiple sclerosis. This study evaluated the effects of an energy conservation course on fatigue impact for persons with multiple sclerosis whose symptoms cause moderate to severe disability. METHODS: Thirty-seven persons with progressive multiple sclerosis participated in an 8-week experimental energy conservation course treatment and an 8-week control period of traditional treatment using a crossover design. The Fatigue Impact Scale (FIS) was used to assess fatigue impact before and after the experimental and control periods, and 8 weeks post-energy conservation course. RESULTS: After participation in the energy conservation course, the average FIS total score and physical, cognitive, and psychosocial subscale scores decreased significantly, whereas the total and subscale scores did not change significantly during the control period. Additionally, decreased fatigue impact was maintained 8 weeks after course completion for evaluated participants. CONCLUSION: This study provides evidence that this energy conservation course can be a beneficial intervention for persons with progressive multiple sclerosis.

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Curr Opin Neurol. 2003 Jun;16(3):299-305.
Hematopoietic stem cell transplantation for multiple sclerosis: current status and future challenges.
Muraro PA, Ingoni RC, Martin R.
Neuroimmunology Branch, National Institute of Neurological Diseases and Stroke, National Institutes of Health, MSC1400 Bethesda, MD 20892-1400, USA.

PURPOSE OF REVIEW: This article reviews recent advances in clinical trials of hematopoietic stem cell transplantation as a therapy for multiple sclerosis, and progress in exploring the potential for neural repair of hematopoietic-derived precursors. RECENT FINDINGS: Important recent findings are that hematopoietic stem cell transplantation can completely suppress the inflammatory component of multiple sclerosis, hematopoietic stem cells can migrate into the central nervous systems of rodents and humans, and can differentiate into cells expressing neural and glial markers. Hematopoietic stem cells also have neural and myelin repair potential. The heterogeneity of transplant regimens, the selection of patients at different stages of disease in clinical trials, and the limited duration of follow-up all currently preclude the evaluation of the long-term clinical benefits of hematopoietic stem cell transplantation for multiple sclerosis. SUMMARY: Hematopoietic stem cell transplantation is an experimental treatment that shows strong effects on the inflammatory component of multiple sclerosis. On the basis of experience acquired from initial pilot studies, controlled clinical trials are now being designed to verify long-term clinical efficacy. Selecting patients at high risk in the earlier stages of the disease that is dominated by inflammation, and monitoring objectively disease activity by magnetic resonance imaging will be critically important in these studies. Recent advances on the migratory potential and on the differentiation plasticity of hematopoietic stem cells have opened new opportunities for remyelination and axonal repair strategies for multiple sclerosis.

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Neurochirurgie. 2003 May;49(2-3 Pt 2):265-70.
[Spasticity and botulinum toxin in 2003. An update]
[Article in French]
Feve A.
Service de Neurologie, Hopital Leopold-Bellan, Paris. Afeve@aol.com

After the spastic foot in cerebral palsy, there are now wider indications for botulinum toxin injections in spasticity. Post stroke upper limb spasticity has been usefully treated by botulinum toxin in several studies, including double blind placebo-controlled studies. Two serotypes and one serotype B are marketed, with various properties. Botulinum toxin has been studied in multiple etiologies of spasticity. In multiple sclerosis, few studies revealed an efficacy in angulations and comfort. In spinal cord injuries, gait and sphincter disorders can be improved. In post stroke spasticity, lower limb angulations are improved, but gait remained difficult to evaluate. In upper limb spasticity, angulation, function and quality of life were improved in double blind, placebo controlled studies. Comparisons of costs and efficacy are made between botulinum toxin and the other antispastic methods.

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J Neuroimmunol. 2003 Apr;137(1-2):140-3.
Immunomodulatory effects of orally administered cannabinoids in multiple sclerosis.
Killestein J, Hoogervorst EL, Reif M, Blauw B, Smits M, Uitdehaag BM, Nagelkerken L, Polman CH.
Department of Neurology, VU Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. J.Killestein@vumc.nl

Cannabinoids can modulate the function of immune cells. We here present the first human in vivo study measuring immune function in 16 MS patients treated with oral cannabinoids. A modest increase of TNF-alpha in LPS-stimulated whole blood was found during cannabis plant-extract treatment (p=0.037), with no change in other cytokines. In the subgroup of patients with high adverse event scores, we found an increase in plasma IL-12p40 (p=0.002). The results suggest pro-inflammatory disease-modifying potential of cannabinoids in MS.

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Expert Opin Investig Drugs. 2003 Apr;12(4):561-7.
The therapeutic potential of cannabis in multiple sclerosis.
Baker D, Pryce G.
Department of Neuroinflammation, Institute of Neurology, University College London, 1 Wakefield Street, London, WC1N 1PJ, UK. d.baker@ion.ucl.ac.uk

There has been renewed interest in the therapeutic applications of cannabis, and people, particularly those with multiple sclerosis, claim that it may offer benefit in symptom control. Cannabis exerts many of its effects because it taps into an endogenous cannabinoid system. Recent advances have begun to shine light on the biology of this system and may support some of the anecdotal medical claims. The problem with cannabis as a drug is that both the positive and negative aspects are largely the work of the same receptor. However, it may be possible to avoid these through modulation of the endogenous system. Cannabinoids provide a novel therapeutic target, not only for controlling symptoms, but also slowing disease progression through inhibition of neurodegeneration, which is the cause of accumulating irreversible disability.

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CNS Drugs. 2003;17(4):225-34.
Fatigue in multiple sclerosis: definition, pathophysiology and treatment.
Krupp LB.
Department of Neurology, State University of New York at Stony Brook, New York, New York 11794, USA.

Fatigue is a common disabling symptom of multiple sclerosis (MS). It is often considered a state of exhaustion distinct from depressed mood or physical weakness. Fatigue can be assessed by either self-report scales or performance-based measures; however, neither method captures all features of fatigue. Fatigue in MS frequently leads to unemployment. It is associated with a sense of loss of control over one's environment, low positive affect, psychological distress and neurological impairment. To date there is no reproducible neuroimaging marker or biological correlate that has been identified. Proposed pathological mechanisms of fatigue in MS include neuronal factors such as dysfunction of premotor, limbic, basal ganglia or hypothalamic areas; disruption of the neuroendrocrine axis leading to low arousal; alteration in serotoninergic pathways; changes in neurotransmitter levels; and altered CNS functioning caused by a disruption of the immune response. Treatment of fatigue is best approached in a multidisciplinary fashion that incorporates nonpharmacological interventions as well as medication. Amantadine and modafinil are among the most commonly used medications for fatigue associated with MS. Both medications have been studied with positive results in controlled clinical trials. Additional research towards measurement and pathogenesis of fatigue will hopefully lead to improved therapies.

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Expert Opin Investig Drugs. 2003 Apr;12(4):689-712.
Disease-modifying therapies in multiple sclerosis: an update on recent and ongoing trials and
future strategies.
Wiendl H, Kieseier BC.
Department of Neurology, University of Tubingen, Hoppe-Seyler-Strasse 3, D-72076 Tubingen, Germany. heinz.wiendl@uni-tuebingen.de

Multiple sclerosis (MS) is the prototype inflammatory autoimmune disorder of the central nervous system and the most common cause of neurological disability in young adults exhibiting considerable clinical, radiological and pathological heterogeneity. Novel insights in the immunopathological processes, advances in biotechnology, development of powerful magnetic resonance imaging technologies together with improvements in clinical trial design led to a variety of evaluable therapeutic approaches. Therapy has changed dramatically over the past decade, yielding significant progress for the treatment of relapsing-remitting and secondary progressive MS. A substantial number of pivotal and preliminary reports continue to demonstrate encouraging new evidence that advances are being made in the care of MS patients. This review summarises recent progress with currently available disease-modifying therapies and - on the basis of present immunopathogenetic concepts - outlines ongoing studies as well as future treatment strategies.

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Trends Pharmacol Sci. 2003 Mar;24(3):131-8.
Immunomodulation in multiple sclerosis: from immunosuppression to neuroprotection.
Neuhaus O, Archelos JJ, Hartung HP.
Department of Neurology, Heinrich-Heine-Universitat, Moorenstrasse 5, 40225 Dusseldorf, Germany. oliver.neuhaus@uni-duesseldorf.de

Multiple sclerosis (MS) is the most common disabling neurological disease of young adulthood. Following advances in the understanding of the immunological mechanisms that underlie the pathogenesis of MS, a growing arsenal of immunomodulatory agents is available. Two classes of immunomodulators are approved for long-term treatment of MS, the efficacy of several promising new concepts is being tested in clinical trials and classical immunosuppressive agents used in MS treatment have been shown to exert specific, immunomodulatory effects. Furthermore, two recent observations have changed our basic understanding of the pathogenesis of MS. First, immune cells in MS lesions have neuroprotective activity, which indicates a beneficial role of neuroinflammation. Second, there is evidence that axonal loss, rather than demyelination, underlies the progression of MS and, hence, constitutes a therapeutic target.

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Complement Ther Nurs Midwifery. 2003 Feb;9(1):5-9.
Homeopathy in multiple sclerosis.
Whitmarsh TE.
Glasgow Homeopathic Hospital, 1053 Great Western Road, Glasgow G12 9UY, Scotland, UK. tom.whitmarsh@virgin.net

Multiple sclerosis (MS) is the most common disease of the central nervous system affecting people between the ages of 20 and 40 years in the UK, Northern Europe and the USA. No definitive treatment yet exists to halt the almost inevitable decline in function and accumulation of disability over the years in sufferers. Management is largely directly of symptoms which arise variably in the course of the condition. Such problems as urinary incontinence, sexual dysfunction, cramps and spasms, tremor and trigeminal neuralgia can often be helped to some extent using conventional therapies. These treatments though are not effective in everyone, or cause unacceptable side-effects and there are some commonly reported symptoms, such as fatigue or emotional lability for which there are no generally accepted treatments. Here, a knowledge of complementary and alternative medicine (CAM) can bring benefits to the person with MS. CAM is widely used by people with MS and some studies in this area are briefly summarised. It is interesting to reflect what lies behind all this CAM use and what that might tell conventional medicine about just what it is the MS sufferer really wants from their carers.Homeopathy is a form of CAM unique in the UK in having been available in the NHS since the foundation in 1948. Medical homeopaths in the UK have always been concerned with the integration of the best of conventional and complementary treatments for the benefit of their patients. Glasgow Homeopathic Hospital has around 100 admissions each year of people with MS at different stages of the condition and aims at an integrated response to their distress. Different therapeutic modalities are employed, but a homeopathic approach in particular is of benefit in MS. By its nature, it is a whole-person approach and allows for complete individualisation of treatment, taking account of the minutiae of someone's life. This is discussed and some examples of homeopathic treatments, which seem to be more generalisable for commonly encountered MS symptoms, are given.

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J Neurol Sci. 2003 Feb 15;206(2):203-8.
Mitoxantrone in progressive multiple sclerosis: when and how to treat?
Gonsette RE.
National Center for MS, Melsbroek B 1820, Belgium. r.gonsette@skynet.be

Mitoxantrone (MX) has been approved by the Food and Drug Administration (FDA) for the treatment of patients with worsening relapsing-remitting (RR) or secondary progressive (SP) multiple sclerosis (MS). However, indications should be refined and mitoxantrone reserved as a rescue therapy to: (1) patients in the relapsing-remitting phase with frequent and disabling exacerbations likely leading to permanent severe disability and (2) to patients in the secondary progressive phase whose disability progression rate increases by one EDSS point or more per year and who do not respond to other current therapies. An induction phase with the monthly intravenous administration of 12 mg/m(2) followed by a maintenance phase with 12 mg/m(2) every 3 months for 2 years seems the most effective and safe treatment regimen, not exceeding the maximum cumulative dose of 140 mg/m(2). Given the potent myelosuppressive activity of mitoxantrone, dosage should be carefully adapted to the body surface and hematological changes. Long-term toxicities (amenorrhoea and therapy-related leukemia) seem acceptable but a valid evaluation will need a longer follow-up in more patients. Cardiotoxicity, the major long-term toxicity, is clearly dose-dependent and is a strict treatment duration limiting factor. To reduce the risk of cardiac events, the drug should be administered by slow infusion (over 30 min). Analogs of mitoxantrone with a much lower cardiotoxicity are currently investigated in animal experimental models.

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J Neurol Sci. 2003 Feb 15;206(2):199-202.
Interferon beta 1a for secondary progressive multiple sclerosis.
Hughes RA.
Department of Neuroimmunology, Guy's, King's and St. Thomas School of Medicine, Guy's Hospital, London SE1 1 UL, UK. richard.a.hughes@kcl.ac.uk

This non-systematic review identified four randomised trials that have tested the efficacy of interferon beta in secondary progressive multiple sclerosis (SPMS). Two were trials of interferon beta 1a (IFNb1a) and two of interferon beta 1b (IFNb1b). All have shown significant reductions in relapse rates and accumulation of new magnetic resonance imaging (MRI) lesions, but only one trial (of IFNb1b) showed significant slowing of disability progression. Post hoc analyses of these trials suggest that the differences in outcomes might be partly explained by the differences between the trials in the proportions of patients with relapsing disease. In one of the trials of IFNb1a (the SPECTRIMS trial), the hazard ratio for progression in the treated relapsing patients with relapses in the two pre-study years was 0.74 compared to placebo patients with pre-study relapses and 1.01 in the treated patients compared to the placebo patients without pre-study relapses. In the same trial, the treatment effects on MRI parameters were more marked in the patients who had recent pre-study relapses compared with those who had not. These observations have led to the recommendation in national guidelines that prescribing of IFNb in SPMS be limited to those patients who have had disabling relapses in the last 2 years. These conclusions should be reviewed when the full results of all four trials have been published.

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J Neurol Sci. 2003 Feb 15;206(2):123-30.
The role of intravenous immunoglobulin in the treatment of multiple sclerosis.
Sorensen PS.
MS Research Unit, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, DK-2100 Copenhagen, Denmark.

Intravenous immunoglobulin (IVIG) has several effects on the immune system that could have a beneficial influence on disease processes in multiple sclerosis (MS). Owing to its anti-inflammatory properties, IVIG may be beneficial in the treatment of acute relapses and in prevention of new relapses. By promoting remyelination, IVIG could have a beneficial effect on disability and disease progression. Four double-blind trials in relapsing-remitting MS have demonstrated that IVIG reduces the relapse rate and the number of gadolinium enhancing lesions, and in this respect seems comparable to established therapies in relapsing-remitting MS, i.e. interferon-beta and glatiramer acetate. The doses of IVIG that have been used for treatment in relapsing-remitting have varied 10-fold, and the ideal dosage of IVIG for treating MS still needs to be determined. Three studies have been performed to assess the effect of IVIG on chronic visual impairment or established motor symptoms in MS. None of these trials could confirm that established symptoms in MS can be reversed by IVIG. In secondary progressive MS, a large randomized placebo-controlled trial has recently shown that IVIG is without beneficial effects in this phase of the disease. In conclusion, IVIG is a valuable alternative for treatment of relapsing-remitting MS in patients who do not tolerate or are unwilling to take the approved injectable medications, but additional studies are needed to establish the role of IVIG in the management of multiple sclerosis.

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Acta Neurol Scand. 2003 Jan;107(1):7-11.
Clinical benefits of interferon beta-1a in relapsing-remitting MS: a phase IV study.
Fernandez O, Arbizu T, Izquierdo G, Martinez-Yelamos A, Gata JM, Luque G, de Ramon E.
Department of Neurology, Hospital Regional Universitario Carlos Haya, Malaga, Spain. ofernand@hch.sas.cica.es

OBJECTIVE: To evaluate the efficacy and safety of IFNbeta-1a (Avonex, Biogen, Inc., Cambridge, MA, USA) in patients with relapsing-remitting multiple sclerosis (MS). METHODS: In this multicenter, open-label, prospective clinical trial, 96 patients with relapsing-remitting MS received IFNbeta-1a 30 mcg intramuscularly once weekly for 2 years. Outcome variables included: change from baseline in mean number of exacerbations, proportion of exacerbation-free patients, and mean Expanded Disability Status Scale (EDSS) scores at Years 1 and 2. RESULTS: IFNbeta-1a significantly (P < 0.0001) reduced exacerbation rate at Years 1 and 2 of treatment. The percentage of exacerbation-free patients was 53% during Year 1 and 33% during Year 2. Mean EDSS scores were 2.96 +/- 1.26 at baseline, 2.89 +/- 1.42 at Year 1, and 3.00 +/- 1.62 at Year 2 (P = 0.116). EDSS scores improved in 35.4%, remained stable in 28.1%, and worsened in 36.5% of patients. IFNbeta-1a treatment was well tolerated. CONCLUSION: This study confirms and extends the beneficial clinical profile for IFNbeta-1a in relapsing MS.

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Clin Exp Immunol. 2003 Jan;131(1):155-68.
T cell vaccination in multiple sclerosis patients with autologous CSF-derived activated T cells: results
from a pilot study.
Van der Aa A, Hellings N, Medaer R, Gelin G, Palmers Y, Raus J, Stinissen P.
Biomedisch onderzoeksinstituut (BIOMED), Limburgs Universitair Centrum and School of Life Sciences, Transnational University Limburg (tUL), Diepenbeek, Belgium.

Myelin-reactive T cells are considered to play an essential role in the pathogenesis of multiple sclerosis (MS), an autoimmune disease of the central nervous system. We have previously studied the effects of T cell vaccination (TCV), a procedure by which MS patients are immunized with attenuated autologous myelin basic protein (MBP)-reactive T cell clones. Because several myelin antigens are described as potential autoantigens for MS, T cell vaccines incorporating a broad panel of antimyelin reactivities may have therapeutic effects. Previous reports have shown an accumulation of activated T cells recognizing multiple myelin antigens in the cerebrospinal fluid (CSF) of MS patients. We conducted a pilot clinical trial of TCV with activated CD4+ T cells derived from CSF in five MS patients (four RR, one CP) to study safety, feasibility and immune effects of TCV. CSF lymphocytes were cultured in the presence of rIL-2 and depleted for CD8 cells. After 5-8 weeks CSF T cell lines (TCL) were almost pure TCR alpha beta+CD4+ cells of the Th1/Th0 type. The TCL showed reactivity to MBP, MOG and/or PLP as tested by Elispot and had a restricted clonality. Three immunizations with irradiated CSF vaccines (10 million cells) were administered with an interval of 2 months. The vaccinations were tolerated well and no toxicity or adverse effects were reported. The data from this small open-label study cannot be used to support efficacy. However, all patients remained clinically stable or had reduced EDSS with no relapses during or after the treatment. Proliferative responses against the CSF vaccine were observed in 3/5 patients. Anti-ergotypic responses were observed in all patients. Anti-MBP/PLP/MOG reactivities remained low or were reduced in all patients. Based on these encouraging results, we recently initiated a double-blind placebo-controlled trial with 60 MS patients to study the effects of TCV with CSF-derived vaccines in early RR MS patients.

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N Engl J Med. 2003 Jan 2;348(1):15-23.
A controlled trial of natalizumab for relapsing multiple sclerosis.
Miller DH, Khan OA, Sheremata WA, Blumhardt LD, Rice GP, Libonati MA, Willmer-Hulme AJ, Dalton CM, Miszkiel KA, O'Connor PW; International Natalizumab Multiple Sclerosis Trial Group.
Department of Neuroinflammation, Institute of Neurology, London, United Kingdom. d.miller@ion.ucl.ac.uk

BACKGROUND: In patients with multiple sclerosis, inflammatory brain lesions appear to arise from autoimmune responses involving activated lymphocytes and monocytes. The glycoprotein alpha4 integrin is expressed on the surface of these cells and plays a critical part in their adhesion to the vascular endothelium and migration into the parenchyma. Natalizumab is an alpha4 integrin antagonist that reduced the development of brain lesions in experimental models and in a preliminary study of patients with multiple sclerosis. METHODS: In a randomized, double-blind trial, we randomly assigned a total of 213 patients with relapsing-remitting or relapsing secondary progressive multiple sclerosis to receive 3 mg of intravenous natalizumab per kilogram of body weight (68 patients), 6 mg per kilogram (74 patients), or placebo (71 patients) every 28 days for 6 months. The primary end point was the number of new brain lesions on monthly gadolinium-enhanced magnetic resonance imaging during the six-month treatment period. Clinical outcomes included relapses and self-reported well-being. RESULTS: There were marked reductions in the mean number of new lesions in both natalizumab groups: 9.6 per patient in the placebo group, as compared with 0.7 in the group given 3 mg of natalizumab per kilogram (P<0.001) and 1.1 in the group given 6 mg of natalizumab per kilogram (P<0.001). Twenty-seven patients in the placebo group had relapses, as compared with 13 in the group given 3 mg of natalizumab per kilogram (P=0.02) and 14 in the group given 6 mg of natalizumab per kilogram (P=0.02). The placebo group reported a slight worsening in well-being (a mean decrease of 1.38 mm on a 100-mm visual-analogue scale), whereas the natalizumab groups reported an improvement (mean increase of 9.49 mm in the group given 3 mg of natalizumab per kilogram and 6.21 mm in the group given 6 mg of natalizumab per kilogram). CONCLUSIONS: In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis. Copyright 2003 Massachusetts Medical Society

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Lancet. 2003 Feb 15;361(9357):545-52.
Interferons in relapsing remitting multiple sclerosis: a systematic review.
Filippini G, Munari L, Incorvaia B, Ebers GC, Polman C, D'Amico R, Rice GP.
Unita di Neuroepidemiologia, Istituto Nazionale Neurologico C Besta, Milan, Italy. gfilippini@istituto-besta.it

BACKGROUND: Recombinant interferons have been approved by many national regulatory agencies for treatment of relapsing remitting multiple sclerosis, but widespread discussion continues about their true effectiveness, benefits, side-effects, and costs. METHODS: With the Cochrane Collaboration methodology, we reviewed all published, randomised, placebo-controlled trials of recombinant interferons undertaken in patients with relapsing remitting multiple sclerosis between 1993 and 2002. Our primary aim was to find out whether recombinant interferons reduced the number of patients who had clinical exacerbations and disease progression, compared with placebo. FINDINGS: The seven trials that met our criteria included 1215 randomised patients: data from 667 (55%) were available for analysis at 1 year's and from 919 (76%) at 2 years' follow-up. Interferon seemed to reduce the number of patients who had exacerbations during the first year of treatment (relative risk 0.73, 95% CI 0.54-0.99), but results at 2 years' follow-up were not robust and were difficult to interpret because of the many dropouts. Although the number of patients who had exacerbations (0.81, 0.74-0.89) or progressed (0.70, 0.55-0.88) during the first 2 years fell significantly in the protocol analysis, results were inconclusive after sensitivity analyses for exacerbations (1.11, 0.73-1.68) and disease progression (1.31, 0.60-2.89). Data were insufficient to establish whether steroid use and admissions to hospital were reduced in the interferon group. Similarly, MRI outcome data could not be analysed quantitatively. Side-effects were common, and acute toxic effects adversely affected quality of life. INTERPRETATION: Recombinant interferons slightly reduce the number of patients who have exacerbations during first year of treatment. Their clinical effect beyond 1 year is uncertain and new trials are needed to assess their long-term effectiveness and side-effects.

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J Neurol. 2003 Feb;250(2):171-8.
Beta-Interferon treatment does not always slow the progression of axonal injury in multiple sclerosis.
Parry A, Corkill R, Blamire AM, Palace J, Narayanan S, Arnold D, Styles P, Matthews PM.
Centre for Functional Magnetic Resonance Imaging of the Brain, The John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK. paul@fmrib.ox.ac.uk

Progression of disability in multiple sclerosis (MS) appears related to axonal damage, which is at least in part associated with white matter lesions. Beta-interferon (BIFN) substantially reduces new inflammatory activity in MS and a recent report suggested that it may reverse a component of axonal injury. To test the generalisability of this conclusion, particularly in a population with relatively active disease, we used magnetic resonance spectroscopy measures to test whether BIFN can reverse or arrest progression of axonal injury in patients with MS. Eleven patients with a history of active (median, 1.5 relapses/year) relapsing-remitting MS were treated with BIFN and responses to treatment were monitored with serial MRI and single voxel magnetic resonance spectroscopic measurements of relative concentrations of brain N-acetylaspartate (NAA), a measure of axonal integrity from a central, predominantly white matter brain region. BIFN treatment was associated with a significant reduction in relapse rate (p = 0.007) and white matter water T2 relaxation time (p = 0.047) over 12 months. Also consistent with a treatment effect, white matter T2-hyperintense lesion loads did not increase. However, the central white matter NAA/creatine ratio (NAA/Cr, which was reduced over 16 % in patients relative to healthy controls at the start of treatment), continued to decrease in the patients over the period of observation (mean 6.2 % decrease, p = 0.02). For individual patients the magnitude of the NAA/Cr decrease was correlated with the frequency of relapses over the two years prior to treatment (r = -0.76, p = 0.006). These data suggest that reduction of new inflammatory activity with BIFN does not invariably halt progression of axonal injury. Nonetheless, there appears to be a relationship between the rate of progression of axonal injury and relapse rate over the previous two years. The consequences of reduced inflammation on pathological progression relevant to disability therefore may be present, but substantially delayed. Alternatively, distinct mechanisms may contribute to the two processes.

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Curr Drug Target CNS Neurol Disord. 2002 Feb;1(1):17-30.
Multiple sclerosis: emerging opportunities for therapeutic intervention.
Evans CF, Shriver LP.
Department of Integrative Biology, Digital Gene Technologies, Inc, 11149 North Torrey Pines Road, La Jolla, CA 92037, USA. cevans@dgt.com

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system of unknown etiology. Two of the major therapies for the treatment of MS, interferon-beta and glatiramer acetate, show only limited evidence that long-term treatment slows disability. There is a great need for new drugs that will halt, reverse, and prevent the development of MS. This article reviews therapies currently in use and describes innovative strategies being developed to alter the disease course. New technologies in gene expression profiling offer hopeful directions toward the design of successful drug therapies and diagnostic testing for MS. Additionally, the new fields of genomics and proteomics offer the promise of novel treatments, and should help to reveal the mechanisms of disease initiation and pathological progression.

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Folia Neuropathol. 2002;40(4):173-5.
Interleukin 12 and interleukin 10 are affected differentially by treatment of multiple sclerosis with glatiramer acetate (Copaxone).
Losy J, Michalowska-Wender G, Wender M.
Department of Clinical Neuroimmunology, University School of Medicine and Neuroimmunological Unit, Medical Research Centre, Polish Academy of Sciences, Poznan, Poland. jlosy@mail.usoms.poznan.pl

Proinflammatory cytokines produced by Th-1 cells and cytokines with immunosuppressive properties play an important role in the pathogenesis of multiple sclerosis (MS). Glatiramer acetate (GA) is one of the most important immunomodulatory agents used in the therapy of MS. The mechanism of action of GA in MS is not yet fully explained. In our previous study we found the significant down-regulation of interleukin 18 (IL-18), a proinflammatory cytokine inducing the production of interferon gamma during therapy with GA in MS patients. The purpose of this study was to evaluate the effect of GA in a dose 20 mg daily in a period of 6 months on interleukins IL-10 and IL-12. Thirty-one patients with definite MS and 30 control subjects were the subject of our study. The interleukins levels in sera were measured by the ELISA test. A significant increase was found of IL-12 and also of IL-10 levels in MS patients in comparison with control group. We also established a significant decrease of IL-12 after 3 and 6 months of GA therapy and some insignificant differences in the level of IL-10 (the decrease after 3 months and the increase after 6 months). IL-12 is a proinflammatory cytokine secreted by blood mononuclear cells, including dendritic cells in response to antigens and mitogens and is thought to contribute to the pathogenesis of MS. Therefore the established downregulation of IL-12 as well as that previously described of IL-18 suggest a marked relationship between the clinical effect and downregulatory action of GA on proinflammatory interleukins. The insignificant change of IL-10 level observed in the course of GA therapy seems to indicate that this cytokine is not connected with the immunomodulatory effect of GA in MS.

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Int J Clin Pract Suppl. 2002 Sep;(131):23-32.
Interferon beta and multiple sclerosis: look at the evidence.
Patti F, Reggio A.
Centro Sclerosis Multipla, Dipartmento di Neuroscienze, Universita di Catania, Italy.

Recent advances in therapy for multiple sclerosis (MS) have centred on the use of the disease-modifying drugs glatiramer acetate (GA) and interferon (IFN) beta. Several large-scale clinical trials have been carried out on the use of these compounds, but there have been few studies that have directly compared their efficacy in MS. Furthermore, there has been controversy and confusion over the IFN beta therapy regimen that will achieve the best possible clinical outcome for MS patients. This review focuses principally on clinical trials of IFN beta-1a, where data that allow direct comparison of different treatment regimens are now available. Current data indicate that IFN beta, and in particular IFN beta-1a, has important advantages over GA in the treatment of relapsing-remitting MS (RRMS). Additionally, IFN beta-1a (Rebif, Serono), 44 microg administered subcutaneously (s.c.) three times weekly (t.i.w.), is significantly more effective than IFN beta-1a (Avonex, Biogen), 30 microg administered intramuscularly once weekly. For optimal management of RRMS, treatment with IFN beta-1a, 44 microg s.c. t.i.w., should begin as early as possible after diagnosis.

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Int J Clin Pract Suppl. 2002 Sep;(131):17-22.
Early use of interferon beta patients with multiple sclerosis.
Bosley EB, Capildeo R.
Multiple Sclerosis Clinic, Basildon General Hospital, Basildon, Essex, UK.

In recent years, major advances have been made in the management of multiple sclerosis (MS) in the form of new disease-modifying therapies, the most widely used of which is interferon (IFN) beta. A growing body of evidence indicates that the beneficial effects of IFN beta are maximised if treatment is started as soon as possible after the diagnosis of MS, and if patients are given the highest possible dose. The argument in favour of early treatment is based primarily on the finding that the inflammation of the central nervous system characteristic of MS leads to irreversible axonal destruction starting very early in the course of the disease. Evidence that IFN beta should be given at high doses comes from preclinical and clinical studies showing that the effects of this drug are strongly dose-dependent. Three formulations of IFN beta are currently available for the treatment of MS: subcutaneous (s.c.) IFN beta-1a, intramuscular (i.m.) IFN beta-1a and s.c. IFN beta-1b. All are well tolerated, although IFN beta-1a appears to be less immunogenic than IFN beta-1b. IFN beta-1a, in s.c. formulation, has advantages over the other formulations in terms of convenience, and is approved for use at higher doses than i.m. IFN beta-1a.

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Int J Clin Pract Suppl. 2002 Sep;(131):3-7.
Disease-modifying therapy in relapsing--remitting multiple sclerosis: efficacy is paramount.
Cristiano E.
Departamento de Neurologia, Hospital Italiano de Buenos Aires, Argentina.

The primary objective in the management of a chronic disease is to maximise therapeutic effectiveness, according to the general consensus among specialists. Recent market research has confirmed that a treatment's effectiveness is the primary consideration for neurologists' choice of therapy for multiple sclerosis (MS). Of the available disease-modifying therapies, interferon (IFN) beta appears to be consistently more efficacious than glatiramer acetate. High doses of therapy, and frequent administration of IFN beta should be used to provide maximal effects. This has been supported by a recent Class I comparative trial of two commercial preparations of IFN beta-1a. Preliminary results indicated significantly greater efficacy for IFN beta-1a (Rebif, Serono) 44 microg administered subcutaneously three times weekly (t.i.w.), over IFN beta-1 (Avonex, Biogen) 30 microg administered intramuscularly once weekly IFN beta-1a, 44 microg t.i.w., provides maximal efficacy for patients with relapsing forms of MS.

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Prog Neurobiol. 2002 Dec;68(5):361-76.
Remyelinating strategies for the treatment of multiple sclerosis.
Stangel M, Hartung HP.
Department of Neurology, Medical School Hannover OE 7210, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. stangel.martin@mh-hannover.de

Demyelination is the pathological hallmark of multiple sclerosis (MS) lesions. The concept of remyelination has gained acceptance in recent years, but naturally occurring remyelination is incomplete. To improve repair processes, a number of strategies have been explored experimentally and clinical trials are being carried out. In principle, remyelination can be achieved by either promoting endogenous repair mechanisms or by providing an exogenous source of myelinating cells via transplantation. Both approaches have been successful in animal models of demyelination. Besides, many studies have elucidated principal mechanisms of oligodendrocyte biology and remyelination in the central nervous system (CNS). This progress in knowledge also allowed for more specific interventions. First clinical trials to enhance endogenous remyelination have been performed, unfortunately with disappointingly negative results. This illustrates that experimental data cannot be easily transferred to human disease, and more detailed knowledge on the regulatory mechanisms of remyelination in MS is required. Recently, the first MS patient received a transplant of autologous Schwann cells. Many other cell types are being studied experimentally, including stem cells. Despite the ethical problems associated with an embryonic cell source, new developments in stem cell biology indicate that adult stem cells or bone marrow-derived cells may substitute for embryonic cells in the future. In this review, we describe the current views on oligodendrocyte biology, myelination and remyelination, and focus on recent developments leading to reconstructing, remyelinating strategies in MS.

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Neurol Neurochir Pol. 2002 Sep-Oct;36(5):971-80.
[GABApentin--new therapeutic possibilities]
[Article in Polish]
Jagustyn P, Romaniak A.
Kliniki Neurologii Wojskowego Instytutu Medycyny Lotniczej.

The paper is a review of current experience with use of gabapentin--a new antiepileptic drug--in neurologic conditions others than epilepsy. Mechanism of action of the drug is not fully elucidated yet. However it proved to be effective in therapy of chronic pain, especially in neuropathic pain, neuralgia, low back pain, reflex sympathetic dystrophy and erythromelalgia. Gabapentin is also effective in pain and spasticity in multiple sclerosis. Clinical studies of gabapentin in movement disorders, such as Parkinson disease, essential tremor and atrophic lateral sclerosis are discussed in the paper. It can be summarized that gabapentin is a valuable medication and the use thereof in neurology is not limited to epilepsy.

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Cochrane Database Syst Rev. 2002;(4):CD002819.
Cyclophosphamide for multiple sclerosis.
La Mantia L, Milanese C, Mascoli N, Incorvaia B, D'Amico R, Weinstock-Guttman B.
MS Group, Istituto Nazionale Neurologico C. Besta, Via Celoria, 11, MIlano, Italy, 20133. msgroup@istituto-besta.it

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 CFX efficacy in patients with progressive MS. OBJECTIVES: The main objectives were to determine whether CFX slows the disease progression. SEARCH STRATEGY: Electronic databases (including MEDLINE, EMBASE, Cochrane Controlled Trials Register) were systematically searched. References list of retrieved studies and conference abstracts on the main meetings on Multiple Sclerosis were handsearched. 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 ACTH or steroids. The comparison group had to be placebo or no treatment or the same co intervention (ACTH or steroids) The main outcome criteria were : progression of disability (defined as an increase of 0.5 point in Kurtzke Extended Disability Status Scale (EDSS) for patients with baseline EDSS > or = 6 and 1 for EDSS < or = 5.5), differences of disability between treatment-control groups and the number of patients with side effects. DATA COLLECTION AND ANALYSIS: The identified references were reviewed by two reviewers who independently decided the eligibility of the study, extracted and summarized data and assessed the trial's quality. The statistical analysis was performed using the Cochrane RevMan software and analyzed using Cochrane MetaView. MAIN RESULTS: Of the 326 identified references, 80 were selected for full review, only four RCTs were selected 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) risk to evolution to a next step of EDSS. However, the mean change in disability (final disability subtracted from the baseline) significantly favoured the treated group at 12 (effect size - 0.21; C. I. - 0.24, - 0.17) and 18 months (- 0.19; C. I. - 0.24, - 0.14). We were not able to verify the efficacy of other schedules. Five patients died; sepsis and amenorrhea frequently occurred in treated patients (descriptive analysis). REVIEWER'S CONCLUSIONS: Only limited objectives were reached. This review shows a role of CFX in the treatment of progressive MS, but less toxic schedules must be considered, before its use in the clinical practice.

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Lancet. 2002 Dec 21-28;360(9350):2018-25.
Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised,
multicentre trial.
Hartung HP, Gonsette R, Konig N, Kwiecinski H, Guseo A, Morrissey SP, Krapf H, Zwingers T; Mitoxantrone in Multiple Sclerosis Study Group (MIMS).
Department of Neurology, Heinrich-Heine-Universitat, Dusseldorf, Germany. hans-peter.hartung@uni-duesseldorf.de

BACKGROUND: Treatment options for patients with secondary progressive multiple sclerosis are few. Encouraging results in open-label studies prompted this randomised trial of mitoxantrone in such patients. METHODS: 194 patients with worsening relapsing-remitting or secondary progressive multiple sclerosis were assigned placebo or mitoxantrone (5 mg/m(2) [exploratory group] or 12 mg/m(2) intravenously) every 3 months for 24 months. Clinical assessments were made every 3 months for 24 months. The primary endpoint was a multivariate analysis of five clinical measures. Analyses of mitoxantrone 12 mg/m(2) versus placebo were based on patients who received at least one dose and returned for at least one assessment of efficacy. FINDINGS: Of 194 patients enrolled, 188 were able to be assessed at 24 months. There were no drug-related serious adverse events or evidence of clinically significant cardiac dysfunction. At 24 months, the mitoxantrone group experienced benefits compared with the placebo group for the primary outcome (difference 0.30 [95% CI 0.17-0.44]; p<0.0001) and the preplanned univariate analyses of those measures: change in expanded disability status scale (0.24 [0.04-0.44]; p=0.0194), change in ambulation index (0.21 [0.02-0.40]; p=0.0306), adjusted total number of treated relapses (0.38 [0.18-0.59]; p=0.0002), time to first treated relapse (0.44 [0.20-0.69]; p=0.0004), and change in standardised neurological status (0.23 [0.03-0.43]; p=0.0268). INTERPRETATION: Mitoxantrone 12 mg/m(2) was generally well tolerated and reduced progression of disability and clinical exacerbations. Further studies are needed to identify the patients with these forms of multiple sclerosis who are most likely to respond to therapy, the best treatment protocols, and the frequency of long-term drug-related side-effects.

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Rev Neurol. 2002 Dec 16-31;35(12):1136-41.
[Transplantation of haematopoietic stem cells in multiple sclerosis]
[Article in Spanish]
Saiz A, Graus F.
Servicio de Neurologia, Institut d'Investigacio Biomedica August Pi i Sunyer, Hospital Clinic de Barcelona, Barcelona, Espana.

INTRODUCTION AND METHOD: The idea of treating auto immune diseases which are resistant to conventional immunodepressive treatment by autologous transplantation of haematopoietic stem cells obtained from peripheral blood (TAPH) is based on the hypothesis that immuno ablative treatment would destroy the patients anti self lymphocytes and the reinfusion of stem cells would give rise to lymphocytes which would be tolerant of the antigens responsible for the auto immune response. By July 2000 90 patients with multiple sclerosis (ES) had received a TAPH according to data of the European Group for Blood and Marrow Transplantation/European League against Rheumatism (EBMT/EULAR). In the literature there are reports of the results obtained in 43 patients in whom EM was the sole indication for treatment [30 secondary progressive (SP), 10 primary progressive (PP) and 3 progressive relapsing (PR) ES]. The transplant related mortality (death within the first 100 days) was 4.6% (2/43), in both cases caused by infection. In the study which included 24 patients, the TAPH was considered to have been effective, since 92% of the patients with SP MS had no further progression after 3 years. However, of the patients with PP EM only 40% scored the same or better on the EDSS, as compared to their basal scores, at the end of the study. In any case, this treatment cannot be considered to cure the MS since the probability of patients having no signs of active disease 3 years after transplantation is 12% in SP MS and 0% in PP MS. CONCLUSIONS: TAPH remains an experimental treatment. Only in the future will it be clear whether this treatment is really useful for patients with multiple sclerosis.

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S D J Med. 2002 Nov;55(11):477-81.
Current concepts in multiple sclerosis: Part II.
Hanson LJ, Cafruny WA.
USD School of Medicine, Vermillion, SD, USA.

Multiple sclerosis (MS) is a complex and challenging autoimmune disease of the central nervous system, affecting approximately 0.1% of the US population. Evidence to date suggests that viral infection triggers autoimmune attack against nerve cells in genetically-susceptible individuals. Neurologic deficits then appear, typically with a variable course and episodes of remission. Partial treatment success has been obtained with immunomodulating agents, such as interferon-beta and intravenous immunoglobulins. Current research is directed at elucidating potential viral causes of MS, as well as the interaction of host genes with the immunopathogenic mechanisms involved in MS. In the future, it may be possible to vaccinate susceptible individuals against MS, as well as refine immunomodulation therapy for the treatment of MS.

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