A Solari1, B Uitdehaag, G Giuliani, E Pucci, C Taus. 1. Laboratory of Epidemiology, National Neurological Institute Carlo Besta, Via Celoria 11, Milan, Italy. solari@istituto-besta.it
Abstract
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.
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.
Authors: Rishyashring R Iyer; Yuan-Zhi Liu; Carlos A Renteria; Brian E Tibble; Honggu Choi; Mantas Žurauskas; Stephen A Boppart Journal: iScience Date: 2022-04-27