Amantadine for fatigue in multiple sclerosis.

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

Why physicians need to look more closely at the use of complementary and alternative medicine by multiple sclerosis patients.

With the aim of contributing to the knowledge of attitudes, patterns and motivations for the use of complementary and alternative medicine (CAM) for multiple sclerosis (MS), 109 MS outpatients, or their close relative in cases of mental status impairment, were interviewed using a semi-structured questionnaire. The main results are: (i). 35.7% used at least one CAM at least once; (ii). homeopathy and diets were the most common; (iii). 39.4% showed a positive attitude towards CAM; (iv). a perceived benefit was recorded in 61.5% of cases; (v). the referral source was a physician in only 12.8% of cases; (vi). caring neurologist was not consulted in 82% and generalist was not consulted in 67% of cases; (vii). of 61 CAM interventions, 21 were expected to be disease-modifying and 40 symptomatic; (viii). CAM negatively influenced compliance with conventional medical management in very few cases (2/39); (ix). a higher expanded disability status scale (EDSS) was observed in CAM users; and (x). in those who used CAM during last 3 years (21.1%), the approximate mean cost per year per person was 483 euro. In Italy, the use of CAM in MS is widespread but costly. This study has provided further baseline data on which to assess trends in CAM use and has highlighted issues for patients and conventional doctors about the use of CAM to deal with health problems. More research into the implications of concurrent use of CAM with conventional medicine on public health care is required.

Amantadine for fatigue in multiple sclerosis.

BACKGROUND: Fatigue is one of the most common and disabling symptoms of people with Multiple Sclerosis (MS). The effective management of fatigue has an important impact on the patient's functioning, abilities, and quality of life. Although a number of strategies have been devised for reducing fatigue, treatment recommendations are based on a limited amount of scientific evidence. Many textbooks report amantadine as a first-choice drug for MS-related fatigue because of published randomised controlled trials (RCTs) showing some benefit. We performed a systematic review in order to gather existing evidence, and contribute to the topic. OBJECTIVES: To determine the effectiveness and safety of amantadine in reducing fatigue in people with MS. SEARCH STRATEGY: RCTs of amantadine were identified using MEDLINE, EMBASE, bibliographies of relevant articles, personal communications, manual searches of relevant journals, and information from drug companies. SELECTION CRITERIA: Randomised, placebo or other drugs-controlled, double-blind trials of amantadine in MS people with fatigue. DATA COLLECTION AND ANALYSIS: Three reviewers selected studies for inclusion in the review and they extracted the data reported in the original articles. Missing and unclear data were requested by correspondence with the trial's principal investigator. A meta-analysis was not performed due to the inadequacy of available data, heterogeneity of outcome measures. MAIN RESULTS: Out of twelve pertinent publications, four trials met the criteria for inclusion in this review: one study was a parallel arms study, and 3 were crossover trials. The number of randomised participants ranged between 10 and 115, and a total of 236 MS patients had been studied. Overall the quality of the studies considered was poor and all trials were open to bias. All studies reported small and inconstant improvements in fatigue, whereas the clinical relevance of these findings and the impact on patient's functioning and health related quality of life remains undetermined. The number of participants reporting side effects during amantadine therapy ranged from 10% to 57%, without significant differences between treatment and placebo. The side effects reported were generally mild, and discontinuation of the drug due to side effects occurred in less than 10% of the patients. REVIEWER'S CONCLUSIONS: Amantadine treatment is overall well tolerated, however its efficacy in reducing fatigue in people with MS is poorly documented and there is insufficient evidence to make recommendations to guide prescribing. It is advisable to (a) improve knowledge on the underlying mechanisms of MS-related fatigue; (b) achieve an agreement on accurate, reliable and responsive outcome measures of fatigue; (c) perform good quality RCTs.

Aminopyridines for symptomatic treatment in multiple sclerosis.

BACKGROUND: The potassium channel blockers 4-aminopyridine (AP) and 3,4-diaminopyridine (DAP) increase nerve conduction in demyelinated nerve fibers, and have been proposed as a symptomatic therapy for people with multiple sclerosis (MS). OBJECTIVES: To determine the efficacy and safety of aminopyridines for neurological deficits in MS people. SEARCH STRATEGY: We searched CENTRAL (Issue 2, 2002), MEDLINE (January 1966-July 2002), EMBASE (1974-July 2002), and the Cochrane MS Group's Specialised Register. We hand searched bibliographic references from retrieved studies and recent MS symposia reports, and contacted known studies' investigators. SELECTION CRITERIA: We included trials fulfilling all following criteria: randomised controlled trials (RCTs); adults with MS, out of exacerbation; AP or DAP treatment versus placebo; clinical endpoints. DATA COLLECTION AND ANALYSIS: We identified 26 potentially pertinent studies. Three reviewers independently extracted data and assessed trial quality from 17 full-paper studies. MAIN RESULTS: Six studies (eight publications, 198 participants, all crossover trials) were considered. Five studies assessed the efficacy of AP versus placebo, one compared DAP with active placebo. Treatment duration ranged from hours to six months. Median quality score of the studies was 3. Heterogeneity of outcome assessment and absence of information on individual study periods allowed quantitative pooling of results for few categorical variables. Of the 198 treated patients, there were six major side effects: one acute encephalopathy, three episodes of confusion, and two seizures. Three studies (54 patients) assessed manual muscle testing, with 29 patients (54%) improving in at least one muscular district during study treatment versus four patients (7%) during placebo (odds ratio [OR] 14.5, 95% confidence interval [CI] 4.7-43.7). Nine out of 54 participants (17%) improved in ambulation during study treatment versus none during placebo (p<0.001). A lower EDSS score was found in 13/198 participants during study treatment (7%) versus none during placebo (p<0.001). No improvement in neuropsychological tests was found in three trials assessing cognitive function. Finally, 47/136 MS people (35%) felt better when receiving the study drug, against 7(5%) on placebo (OR 9.7, 95% CI 4.3-22.0). REVIEWER'S CONCLUSIONS: Currently available information allows no unbiased statement about safety or efficacy of aminopyridines for treating MS symptoms. Furthermore, we could not obtain any data on three unpublished RCTs (more than 300 participants). We conclude that publication bias remains a pervasive problem in this area, and that until the results of these unpublished studies are available to the scientific community, no confident estimate of effectiveness of aminopyridines in the management of MS symptoms is possible.

Aminopyridines for symptomatic treatment in multiple sclerosis.

BACKGROUND: Because of their ability to increase nerve conduction in demyelinated nerve fibers, potassium channel blockers 4-aminopyridine (AP) and 3,4-diaminopyridine (DAP) have been proposed as a symptomatic therapy for people with multiple sclerosis (MS). OBJECTIVES: To determine the efficacy and safety of aminopyridines in improving neurological deficits in people with MS. SEARCH STRATEGY: Computerised general (MEDLINE, EMBASE) and specialised databases (Cochrane MS Group's trials register, CCTR). Hand search of bibliographic references from retrieved studies and recent MS symposia reports. Contact with principal investigators of known studies. SELECTION CRITERIA: Trials were included if they fulfilled all following criteria: randomised controlled trials (RCTs); adults with MS, out of exacerbation; AP or DAP treatment versus placebo; clinical endpoints. DATA COLLECTION AND ANALYSIS: We identified 26 potentially pertinent studies. Three reviewers independently extracted data and assessed trial quality from the 16 studies available as full papers. MAIN RESULTS: Five studies (six publications) and 144 participants were considered in this review. Two more abstracts are awaiting assessment. All five studies were single-centre, double-blind, crossover trials. Four studies assessed the efficacy of AP versus placebo, one compared DAP with active placebo. The duration of treatment ranged from hours to three months. The median quality score of the studies was 3 (range 2-5). The heterogeneity of outcome assessment and the absence of information on individual study periods, allowed quantitative pooling of results for few categorical variables. Of the 144 treated patients, there were six major side effects: one acute encephalopathy, three episodes of confusion, and two seizures. Manual muscle testing was assessed in three studies (54 patients), with 29 patients (54%) improving in at least one muscular district during study treatment versus four patients (7%) during placebo (odds ratio [OR] 14.5, 95% confidence interval [CI] 4.7-43.7). Ambulation was assessed in three studies (54 patients): 9 patients (17%) improved during study treatment versus none during placebo (p<0.001). An improvement in EDSS score was found in 13 of the 144 participants during study treatment (9%) versus none during placebo (p<0.001). No improvement in neuropsychological tests was found in the two trials that evaluated cognitive function. Finally, 47 of 136 people with MS (35%) felt improved when receiving the study drug, against 7(5%) on placebo (OR 9.7, 95% CI 4.3-22.0). REVIEWER'S CONCLUSIONS: Based on currently available information, no unbiased statement can be made about the safety or efficacy of aminopyridines for treating MS symptoms. Furthermore, we could not obtain any data on three unpublished RCTs involving more than 300 participants. We conclude that publication bias remains a pervasive problem in this area, and that until the results of these unpublished studies are available to the scientific community, no confident estimate of effectiveness of aminopyridines in the management of MS symptoms is possible.

Absence of HHV-6 and HHV-7 in cerebrospinal fluid in relapsing-remitting multiple sclerosis.

OBJECTIVE: To contribute to clarifying the controversy on the association between Human Herpesviruses 6 and 7 (HHV-6, HHV-7) and multiple sclerosis (MS) studying patients with relapsing-remitting MS (RRMS) with or without evidence of disease activity (clinically or radiologically evaluated). MATERIAL AND METHODS: In 25 RRMS patients, 7 suspected MS patients and 9 patients with other neurological diseases, the following parameters were analysed: i) antibody titers (IgM and IgG) against HHV-6 by indirect immunofluorescence both in serum and cerebrospinal fluid (CSF) samples; ii) PCR-detection of HHV-6 DNA and HHV-7 DNA in CSF and HHV-6 DNA in peripheral blood mononuclear cells (PBMCs). MS patients in remission underwent a gadolinium-enhanced magnetic resonance imaging in proximity of sample collections. RESULTS: No viral DNA was found in any CSF sample, HHV-6 DNA frequency in PBMCs of MS patients and controls was not statistically different. Antibody titers against HHV-6 were comparable to those of the general population. Some 30.4% of MS patients were seronegative to HHV6. CONCLUSION: Our data suggest that there is no relationship between HHV-6 or HHV-7 and MS.