Article type
Year
Abstract
Background: Multiple sclerosis (MS) is the most important non-traumatic cause of neurological disability in young adults. Despite advance in curative treatment, symptomatic therapies also play an important role in the MS management. The potassium channel blockers 4-aminopyridine (AP) and 3,4-diaminopyridine (DAP) increase action potential amplitude and duration thus improving nerve conduction. Several randomised clinical trials of AP and DAP have been published and the drugs have been proposed as effective symptomatic drugs for MS, especially in temperature-sensitive patients, but side effects have been reported. Objective: The objective of this review was to determine the efficacy and safety of aminopyridines in improving neurological deficits in MS patients.
Methods: All RCTs, comparing AP and DAP with placebo in clinically definite MS patients were identified (Collaborative Review Group search strategy) and considered for inclusion in the review. A qualitative review was be undertaken to assess the methodological quality of the trials. The main outcomes of interest were: changes in disability and impairment scales assessing motor function and visual acuity, cognition, fatigue, quality of life, and patient's subjective response (efficacy); the number of drop outs and side effects (safety). The Review Manager software developed by the Cochrane Collaboration was used for data management.
Results: Electronic and manual search identified 73 titles. Of these 13 were RCTs, but 4 were excluded since they were duplicate, or AP vs DAP comparative trials or only paraclinical endpoints were considered. All 9 eligible RCTs had a crossover design (6 full text articles); we contacted the investigators of all included RCTs for further information. Due to lack of data on the first study period we could not perform yet quantitative analyses. Three RCTs (54 patients) considered motor function testing as study outcome, with 29 patients (54%) improving in at least one district during drug vs 4 patients (7%) during placebo. Eye movement registration was performed in 2 studies where the same patients was evaluated after IV infusion and over a 3-month period: authors found mean changes in smooth pursuit gain for both eyes during both acute and non acute treatment in favour of AP. The efficacy of aminopyridines on ambulation was assessed on 3 studies (54 patients): overall, 9 patients (17%) improved in ambulation during study drug vs none during placebo. Five RCTs considered EDSS as study outcome (144 patients): 13 patients were improved (9%) during drug vs none during placebo. Two trials assessed visual function by means of mean changes in contrast sensitivity, flicker fusion frequency, and evoked potentials latency. Significant changes in favour of treatment were reported for evoked potential latency in one study, and for contrast sensitivity in the other. No improvement in neuropsychological tests was detected in 2 trials that evaluated it. Patient's subjective impression was assessed in 4 studies (136 patients). Overall, 47 patients (35%) felt improved when receiving the study drug vs 7 patients (5%) during placebo. Out of 144 treated patients 6 major side effects were reported: one acute encephalopathy, 3 episodes of confusion, and 2 seizures. Four major side effects were reported during treatment with DAP (11%), and 2 during AP (2%). Withdrawals and dropouts were reported in 4 studies, with 13 attritions in 80 patients treated with AP (16%), and 8 in 36 patients with DAP (22%).
Conclusion: The methodological quality of RCTs was generally low and data available did not allow quantitative analyses. A general trend favours AP and DAP could be suggested but in consideration of possible side effects there is not enough evidence of important benefits from the drug to LEFT routine use.
Methods: All RCTs, comparing AP and DAP with placebo in clinically definite MS patients were identified (Collaborative Review Group search strategy) and considered for inclusion in the review. A qualitative review was be undertaken to assess the methodological quality of the trials. The main outcomes of interest were: changes in disability and impairment scales assessing motor function and visual acuity, cognition, fatigue, quality of life, and patient's subjective response (efficacy); the number of drop outs and side effects (safety). The Review Manager software developed by the Cochrane Collaboration was used for data management.
Results: Electronic and manual search identified 73 titles. Of these 13 were RCTs, but 4 were excluded since they were duplicate, or AP vs DAP comparative trials or only paraclinical endpoints were considered. All 9 eligible RCTs had a crossover design (6 full text articles); we contacted the investigators of all included RCTs for further information. Due to lack of data on the first study period we could not perform yet quantitative analyses. Three RCTs (54 patients) considered motor function testing as study outcome, with 29 patients (54%) improving in at least one district during drug vs 4 patients (7%) during placebo. Eye movement registration was performed in 2 studies where the same patients was evaluated after IV infusion and over a 3-month period: authors found mean changes in smooth pursuit gain for both eyes during both acute and non acute treatment in favour of AP. The efficacy of aminopyridines on ambulation was assessed on 3 studies (54 patients): overall, 9 patients (17%) improved in ambulation during study drug vs none during placebo. Five RCTs considered EDSS as study outcome (144 patients): 13 patients were improved (9%) during drug vs none during placebo. Two trials assessed visual function by means of mean changes in contrast sensitivity, flicker fusion frequency, and evoked potentials latency. Significant changes in favour of treatment were reported for evoked potential latency in one study, and for contrast sensitivity in the other. No improvement in neuropsychological tests was detected in 2 trials that evaluated it. Patient's subjective impression was assessed in 4 studies (136 patients). Overall, 47 patients (35%) felt improved when receiving the study drug vs 7 patients (5%) during placebo. Out of 144 treated patients 6 major side effects were reported: one acute encephalopathy, 3 episodes of confusion, and 2 seizures. Four major side effects were reported during treatment with DAP (11%), and 2 during AP (2%). Withdrawals and dropouts were reported in 4 studies, with 13 attritions in 80 patients treated with AP (16%), and 8 in 36 patients with DAP (22%).
Conclusion: The methodological quality of RCTs was generally low and data available did not allow quantitative analyses. A general trend favours AP and DAP could be suggested but in consideration of possible side effects there is not enough evidence of important benefits from the drug to LEFT routine use.