Limited evidence suggests that modafil or respiratory exercise may reduce fatigue compared to placebo or usual care in patients with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND); however, these results were very uncertain. Resistance exercise may also improve total functional status and lower extremity function compared to placebo. No methodological concerns were noted. Further high quality research is needed to develop and test effective treatments for fatigue in patients with ALS/MND.
Overall summary Low risk of bias in the review
All domains were considered at low concern.
|A. Did the interpretation of findings address all of the concerns identified in Domains 1 to 4?||Probably yes|
|B. Was the relevance of identified studies to the review's research question appropriately considered?||Probably yes|
|C. Did the reviewers avoid emphasizing results on the basis of their statistical significance?||Probably yes|
|Risk of bias in the review||Low|
|Number of studies||4|
|Number of participants||86|
|Last search date||5th September 2017|
|Objective||To determine the effects of pharmacological and non-pharmacological interventions for fatigue in amyotrophic lateral sclerosis/motor neuron disease.|
|Population||Patients diagnosed with possible, probable or definite amyotrophic lateral sclerosis/motor neuron disease (ALS/MND)|
|Interventions||Any intervention that aimed to reduce fatigue in people with ALS/MND (pharmacological or non-pharmacological)|
|Comparator||Placebo, standard care or a different intervention aiming to reduce fatigue|
|Outcome||Primary outcome: level of fatigue at the end of the follow-up period.
Secondary outcomes: sleepiness, depression, quality of life, functional status or adverse events.
|Study design||Randomised and quasi-randomised controlled trials.|
When modafil was compared to placebo, a single randomised controlled trial (RCT) reported a reduction in fatigue (mean difference [MD] - 11.00, 95% confidence interval (CI) -23.08 to 1.08; 1 study, n=32 participants) and sleepiness (MD -2.00, 95% CI -4.46 to 0.46; 1 study, n=32 participants) for modafil compared to placebo after 4 weeks; however, this result was associated with a large degree of uncertainty. The same study reported no difference in depression severity (MD 0.00, 95% CI -4.38 to 4.38; 1 study, n=32 participants) for modafil compared to placebo after 4 weeks.
When resistance exercise was compared to usual care, a single RCT reported an improvement in total functional status (MD 5.70, 95% CI 1.29 to 10.11; 1 study, n=18 participants) and lower extremity function (MD 5.30, 95% CI 1.82 to 8.78; 1 study, n=18 participants) for resistance exercise compared to usual care after 6 months. However, the same study reported no difference in fatigue (MD -0.2, 95% CI -10.98 to 11.38; 1 study, n=18 participants), mental health (MD -1.70, 95% CI -5.50 to 2.10; 1 study, n= 18 participants), physical role (MD 0.20, 95% CI -1.06 to 1.46; 1 study, n=18 participants), pain (MD -0.10, 95% CI -2.01 to 1.81; 1 study, n=18 participants), general health (MD 0.40, 95% CI -4.32 to 5.12; 1 study, n=18 participants), vitaility (MD 1.60, 95% CI -1.87 to 5.07; 1 study, n=18 participants), social function (MD 0.70, 95% CI -0.97 to 2.37; 1 study, n=18 participants) or emotional role (MD 0.60, 95% CI -0.47 to 1.67; 1 study, n=18 participants) for resistance exercise compared to usual care after 6 months.
When respiratory exercise was compared with sham intervention, a single RCT reported a reduction in depression severity (MD 1.77, 95% CI 0.02 to 3.52; 1 study, n=24 participants) for respiratory exercise compared to sham intervention. The same study also reported a reduction in fatigue levels (MD -9.65, 95% CI -22.04 to 2.73; 1 study, n=24 participants) for respiratory exercise compared with sham intervention; however, this result was associated with a large degree of uncertainty. No difference was reported in sleepiness (MD 0.31, 95% CI -3.48 to 4.10; 1 study, n=24 participants), quality of life (MD 0.77, 95% CI -17.10 to 18.64; 1 study, n=24 participants), overall functional status (MD 0.85, 95% CI -2.16 to 3.85; 1 study, n=24 participants), bulbar functional status (MD -0.39, 95% CI -1.38 to 0.61; 1 study, n=24 participants) or respiratory functional status (MD 0.08, 95% CI -0.25 to 0.41; 1 study, n=24 participants) following respiratory exercise compared to sham intervention.
The research objective was clearly stated and appropriate inclusion criteria were defined. No restrictions were reported based on study characteristics or sources of information.
|1.1 Did the review adhere to pre-defined objectives and eligibility criteria?||Probably yes|
|1.2 Were the eligibility criteria appropriate for the review question?||Probably yes|
|1.3 Were eligibility criteria unambiguous?||Probably yes|
|1.4 Were all restrictions in eligibility criteria based on study characteristics appropriate (e.g. date, sample size, study quality, outcomes measured)?||Probably yes|
|1.5 Were any restrictions in eligibility criteria based on sources of information appropriate (e.g. publication status or format, language, availability of data)?||Probably yes|
|Concerns regarding specification of study eligibility criteria||Low|
Literature searches were conducted in CENTRAL via the Cochrane Register of Studies (CRS-Web), MEDLINE, EMBASE, PsycINFO, CINAHL Plus and ERIC databases. In addition the reference lists of the included studies, conference abstracts from International ALS/MND Symposia and trial registries (US National Institutes of Health trials registry, ClinicalTrials.gov (clinicaltrials.gov/) and the World Health Organisation International Clinical Trials Registry Platform (ICTRP; apps.who.int/trialsearch/)) were searched to identify additional studies. The search strategy was reported in full and appeared to be adequate. No restrictions were reported based on date, publication format or language. Three reviewers were independently involved in the study selection and disagreements were resolved by discussion.
|2.1 Did the search include an appropriate range of databases/electronic sources for published and unpublished reports?||Probably yes|
|2.2 Were methods additional to database searching used to identify relevant reports?||Probably yes|
|2.3 Were the terms and structure of the search strategy likely to retrieve as many eligible studies as possible?||Probably yes|
|2.4 Were restrictions based on date, publication format, or language appropriate?||Probably yes|
|2.5 Were efforts made to minimise error in selection of studies?||Yes|
|Concerns regarding methods used to identify and/or select studies||Low|
Two review authors independently extracted the data from the eligible studies using a standardised data extraction form. Sufficient individual study characteristics were extracted to allow for the interpretation of the results. Relevant study results appear to have been extracted. Two review authors independently assessed the risk of bias for each study using the Cochrane ’Risk of bias’ tool, and disagreements were resolved by discussion and consensus,
|3.1 Were efforts made to minimise error in data collection?||Probably yes|
|3.2 Were sufficient study characteristics considered for both review authors and readers to be able to interpret the results?||Probably yes|
|3.3 Were all relevant study results collected for use in the synthesis?||Probably yes|
|3.4 Was risk of bias (or methodological quality) formally assessed using appropriate criteria?||Yes|
|3.5 Were efforts made to minimise error in risk of bias assessment?||Yes|
|Concerns regarding methods used to collect data and appraise studies||Low|
The synthesis appeared include all relevant studies. A narrative synthesis was performed to summarise the findings; this was considered appropriate due to the small number of included studies. The quality of the individual studies was considered in the synthesis.
|4.1 Did the synthesis include all studies that it should?||Probably yes|
|4.2 Were all pre-defined analyses reported or departures explained?||Probably yes|
|4.3 Was the synthesis appropriate given the degree of similarity in the research questions, study designs and outcomes across included studies?||Probably yes|
|4.4 Was between-study variation minimal or addressed in the synthesis?||Probably yes|
|4.5 Were the findings robust, e.g. as demonstrated through funnel plot or sensitivity analyses?||Probably yes|
|4.6 Were biases in primary studies minimal or addressed in the synthesis?||Yes|
|Concerns regarding synthesis and findings||Low|
Background: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is terminal, progressive neurological condition for which there are no curative treatments. Among people with ALS/MND, fatigue is a common and debilitating symptom, which is characterised by reversible motor weakness and whole-body tiredness that is only partially relieved by rest. The effectiveness of pharmacological or non-pharmacological treatments for fatigue in ALS/MND is not yet established.Objectives: To assess the effects of pharmacological and non-pharmacological interventions for fatigue in ALS/MND.Search methods: We searched the following databases on 5 September 2017: Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL Plus, and ERIC. We also searched two clinical trials registries.Selection criteria: We selected randomised and quasi-randomised controlled trials of any intervention which sought to reduce fatigue for people with ALS/MND. We included studies if reduction in fatigue was a primary or secondary outcome of the trial.Data collection and analysis: We used the standard methodological procedures expected by Cochrane.Main results: We included one pharmacological (modafinil) study and three non-pharmacological studies (resistance exercise, respiratory exercise, and repetitive transcranial magnetic stimulation (rTMS)), involving a total of 86 participants with ALS/MND. None of the included studies were free from risk of bias. Since there was only one trial for each intervention, no meta-analysis was possible. All studies assessed fatigue using the Fatigue Severity Scale (FSS; scale from 9 to 63, higher scores indicate more fatigue). Information for assessing bias was often lacking in study reports, making the risk of bias unclear across several domains in all trials. Blinding of participants was not possible in exercise trials, but the outcome assessment was blinded.We found very low-quality evidence suggesting possible improvements in fatigue for modafinil treatment versus placebo (MD -11.00, 95% CI -23.08 to 1.08), respiratory exercise versus a sham intervention (MD -9.65, 95% CI -22.04 to 2.73), and rTMS versus sham rTMS (data not provided), which warrant further investigation to clarify the efficacy of these treatments for fatigue in ALS/MND. We found no clear improvements in fatigue for resistance exercise versus usual care (MD 0.20, 95% CI -10.98 to 11.38; very low-quality evidence).Three participants in the modafinil group dropped out of the modafinil study, two citing issues with headache and one with chest tightness; other adverse effects were anxiety, nausea, dizziness, and sialorrhoea (probably ALS-related). The trials reported no adverse effects of exercise or rTMS.We cannot be certain about the effects of any of the interventions studied because of imprecision (small numbers of participants, wide CI), and possible study limitations.Authors' conclusions: It is impossible to draw firm conclusions about the effectiveness of interventions to improve fatigue for people with ALS/MND as there are few randomised studies, and the quality of available evidence is very low.