Fatigue is a commonly reported symptom in patients with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) (Ramirez 2008), with a large proportion of patients reporting 'clinically significant' levels of fatigue (McElhiney 2009). Fatigue in ALS/MND has been defined as "reversible motor weakness and whole-body tiredness that was predominantly brought on by muscular exertion and was partially relieved by rest" (Gibbons 2013a). In ALS/MND, fatigue is distinguished from sleepiness by feelings of weariness or exhaustion that do not necessarily beget a desire to sleep. This fatigue appears to be experienced predominantly as general (feelings of whole-body tiredness) and physical (reversible motor weakness), whereas in other neurological diseases such as multiple sclerosis, cognitive fatigue (reversible reduction in concentration or mental performance) is experienced alongside generalised physical fatigue (Lou 2003; Mills 2008).
In ALS/MND, fatigue can be experienced as a pervasive feeling of tiredness or lethargy, or as an objective decline in the ability of a muscle to contract to maximum force (Gibbons 2011; Lou 2012). The first type of fatigue is ubiquitous in humans and may have been experienced by the patient before diagnosis; however, following development of ALS/MND, the severity of this fatigue and precipitating factors substantially change. Objective motor fatigue, known as physical fatigability, is unique to the disease state and is not normally within a patient’s previous experience. Both types of fatigue have been shown to be important to patients with ALS/MND (Gibbons 2011), and fatigue, more generally, impacts negatively upon quality of life (Lou 2003).
Evidence for the relationship between fatigue and functional ability is conflicting. Although some studies have suggested that fatigue is related to functional capacity (Lo Coco 2012; McElhiney 2009), others have been unable to support this claim (Gibbons 2011; Ramirez 2008). Fatigue appears to be related to common nighttime complaints in MND including muscle cramps and nocturia (Lo Coco 2012). Fatigue is related to psychological distress, social withdrawal and reduced quality of life for patients with MND (Gibbons 2013b; Lou 2003).
Description of the condition
ALS/MND is a progressive, terminal neurodegenerative disease of unknown aetiology that is currently without a cure. The incidence of ALS/MND is around 2.16 per 100,000 person-years (Logroscino 2010). At any one time, approximately 5000 patients in the United Kingdom are affected (Shaw 1999) and 25,000 in North America (McGuire 1996).
Rapid progression of the disease causes weakness and muscular atrophy, impacting upon an individual's ability to carry out activities of daily living such as dressing, bathing and eating. Problems with speech and swallowing often occur as the result of weakness in bulbar musculature. As the disease progresses, breathing issues, including nocturnal hypoventilation and reduced sleep quality, become apparent and may progress until respiratory failure occurs (Bourke 2004). Death has been reported in most patients within two to five years following diagnosis, usually from respiratory failure caused by respiratory muscle weakness (Rowland 2001).
Description of the intervention
Currently, no evidence-based intervention is available for fatigue in patients with ALS/MND. Several drugs have been investigated as treatment for fatigue in this population, including amantadine, pemoline and bupropion, although evidence regarding their efficacy is lacking (Jackson 2006). Modafinil, a novel wakefulness-promoting agent that has been approved for the treatment of excessive sleepiness associated with narcolepsy, may also be an effective treatment for fatigue (Carter 2005; McElhiney 2009; Rabkin 2009).
Dietary supplementation of creatine may increase, or at least preserve, muscular strength and reduce levels of fatigue (Rosenfeld 2008).
Other non-pharmacological therapies may be used to ameliorate fatigue. Studies have evaluated the potential benefits of supported treadmill ambulation (Sanjak 2010), muscular exercise (Drory 2001) and repetitive transcranial magnetic stimulation (rTMS) (Guo 2012; Zanette 2008) for this purpose.
How the intervention might work
Pharmacological interventions that stimulate the central nervous system (CNS) may reduce generalised fatigue for patients with ALS. Modafinil stimulates the release of norepinephrine and dopamine from synaptic terminals and elevates hypothalamic levels of histamine (Ishizuka 2008). Creatine, which increases maximum availability for energy output in anaerobic activities, may also have a positive effect on muscle strength and fatigue (Ellis 2004; Kley 2013; Rosenfeld 2008). Different treatments may be effective for different forms of fatigue.
Non-pharmacological interventions may focus on light exercise including supported or unsupported exercises (e.g. walking) or resistance training using weights (Bello-Haas 2007).
Why it is important to do this review
Fatigue is prevalent in patients with ALS/MND and has a significant impact on quality of life. Presently, clarity regarding the best management of fatigue in this population is lacking. To date, no systematic review of pharmacological and non-pharmacological interventions for fatigue in ALS/MND has been conducted. This review will allow us to thoroughly assess the evidence for and against potential interventions.
Depending on the number of primary studies, we will examine differential effects concerning the type of intervention (pharmacological versus non-pharmacological). We will explore sources of heterogeneity in the results of identified studies, which may help provide suggestions for the design of future studies. By continuously updating this review, we will be able to integrate new evidence. We will incorporate into this review information on current and planned trials.
To assess the effects of pharmacological and non-pharmacological interventions for fatigue in ALS/MND.
Criteria for considering studies for this review
Types of studies
We will include randomised and quasi-randomised controlled trials in the review.
Types of participants
For studies to be included in the review, study participants should have been diagnosed with possible, probable or definite ALS/MND according to recognised criteria, preferably the El Escorial criteria (Brooks 2000).
Types of interventions
We will include all interventions that aim to reduce fatigue in people with ALS/MND, either as a primary or a secondary objective of a trial. We will include any intervention that successfully reduced fatigue in ALS/MND, even if reduction of fatigue was not the original aim of the trial. We will compare pharmacological and/or non-pharmacological treatments versus each other, placebo or standard care. Examples of such treatments include drug treatments (e.g. modafinil) and behavioural interventions. Studies that have reported fatigue as a secondary outcome will be considered for inclusion as long as sufficient data are available for meta-analyses to be conducted.
Types of outcome measures
The primary outcome for the review will be level of fatigue at the end of the follow-up period. Fatigue can be evaluated using any validated patient- or clinician-administered fatigue questionnaire that measures general fatigue, including the Modified Fatigue Impact Scale (MFIS) (Fisk 1994) and the Fatigue Severity Scale (FSS) (Krupp 1989). Questionnaires that measure general fatigue and reversible muscle weakness, such as the Neurological Fatigue Index–MND (NFI-MND) (Gibbons 2011), will also be included.
Secondary outcomes will be assessed at the end of the follow-up period and include the following.
- Sleepiness of participants measured by a validated scale including the Epworth Sleepiness Scale (ESS) (Johns 1991).
- Functional status of participants measured by a validated scale such as the ALS Functional Rating Scale-Revised (ALSFRS-R) (Cedarbaum 1999).
- Adverse effects.
Search methods for identification of studies
We will search the Cochrane Neuromuscular Disease Group Specialized Register, The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (January 1966 to present) and EMBASE (January 1980 to present), as well as SCOPUS, PsycINFO, Web of Science, ERIC and CINAHL.
Searching other resources
We will scan available conference abstracts from International ALS/MND Symposiums (starting 1989) for relevant studies. We will check all references in the identified trials and will contact trial authors to identify additional published or unpublished data, thus reducing publication bias. We will search trial registries (in particular, the US National Institutes of Health trials registry, clinicaltrials.gov (http://clinicaltrials.gov/), and the World Health Organization International Clinical Trials Registry Platform (ICTRP) (http://apps.who.int/trialsearch/)) to identify ongoing trials. We will include papers in languages other than English and will translate them as necessary.
Data collection and analysis
Selection of studies
Three review authors (CAY, CG and FP) will check titles and abstracts identified during the electronic searches. These review authors will obtain the full text of all potentially relevant studies for independent assessment. All review authors will decide which trials fit the inclusion criteria and will grade their risk of bias. We will resolve disagreements about inclusion criteria by discussion and consensus.
We will identify and exclude duplicates and will collate multiple reports of the same study so that each study rather than each report is the unit of interest in the review. We will record the selection process in sufficient detail to complete a PRISMA flow diagram and a 'Characteristics of excluded studies' table.
Data extraction and management
Two review authors (CG and FP) will independently extract data onto a specially designed form; the other two review authors (CAY and TF) will check the data extraction. One review author will enter the data into the software (CG), another will check the data entered (FP). We will obtain missing data from trial authors when possible.
We will extract the following study characteristics.
- Methods: study design, total duration of study, details of any 'run-in' period, number of study centres and locations, study settings, withdrawals and date of study.
- Participants: N, mean age, age range, gender, severity of condition, diagnostic criteria, baseline characteristics, inclusion criteria and exclusion criteria.
- Interventions: intervention, comparison, concomitant medications and excluded medications.
- Outcomes: primary and secondary outcomes specified and collected and time points reported.
- Notes: funding for trial and notable conflicts of interest of trial authors.
Assessment of risk of bias in included studies
Two review authors (CG and FP) will independently assess risk of bias for each study using the Cochrane 'Risk of bias' tool, as described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). All review authors will discuss disagreements related to risk of bias until we reach consensus. We will assess the risk of bias according to the following domains.
- Random sequence generation.
- Allocation concealment.
- Blinding of participants and personnel.
- Blinding of outcome assessment.
- Incomplete outcome data.
- Selective outcome reporting.
- Other sources of bias.
We will grade studies as having high, low or unclear risk of bias in each of these domains and will provide a justification for our judgements in the 'Risk of bias' table, with a quote from the study when appropriate.
When considering treatment effects, we will take into account the risk of bias for studies that contribute to that outcome.
Measures of treatment effect
To evaluate treatment effects for continuous outcomes, we will use mean differences (MDs) or standardised mean differences (SMDs) for results across studies with outcomes that are conceptually the same but measured in different ways. In the event that studies present dichotomous data (e.g. responder analyses), we will use risk ratios (RRs). We will calculate 95% confidence intervals (CIs) for the measures of treatment effect.
We will undertake meta-analyses only when this is meaningful, that is, when treatments, participants and the underlying clinical question are similar enough for pooling to make sense.
Unit of analysis issues
The unit of analysis will be the participant, which is typically also the unit of randomisation in the sort of trials that we will consider. We will take into account the level at which randomisation occurred, including cross-over trials, cluster-randomised trials and multiple observations from the same outcome.
Dealing with missing data
We will contact study authors to gather missing data. We will analyse dropout rates as a secondary outcome. In cases of between-trial heterogeneity, we will investigate whether this can be explained by varying quantities of missing data across trials.
Assessment of heterogeneity
We will test for heterogeneity across trials; if we find heterogeneity, we will undertake sensitivity analyses by repeating the calculation and omitting the trials that have low scores on individual risk of bias items.
Assessment of reporting biases
If we identify a large number of studies as eligible for inclusion in the review, we will create and analyse a funnel plot to assess the potential existence of small-study bias.
We plan to use SMDs for continuous data and RRs for binary data for individual study and summary results, with the random-effects model used for the summary effect measure. The weights for the studies will be inverse to the variances. If appropriate, we will combine data from cross-over trials and parallel-group designs. The random-effects model incorporates possible between-study variation as well as within-study differences and so is more conservative. The fixed-effect model assumes that no between-study differences exist. Both models yield very similar results unless significant between-study differences are noted (heterogeneity). If the review includes more than one comparison, which cannot be included in the same analysis, we will report the results for each comparison separately.
'Summary of findings' table
We will create a 'Summary of findings' table using fatigue as the outcome. We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of a body of evidence (studies that contribute data for the prespecified outcomes). We will also include adverse events. We will use methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) using GRADEpro software (GRADEpro 2008). We will justify all decisions to down-grade or up-grade the quality of studies using footnotes, and we will make comments to aid readers' understanding of the review when necessary.
Subgroup analysis and investigation of heterogeneity
We will assess the level of functional impairment, measured using the ALSFRS-R (Cedarbaum 1999), for heterogeneity and eventually will use this scale to create subgroups of participants that we will analyse and compare separately.
If a study is of doubtful eligibility for the systematic review, appears to be an outlier or has missing data that are impossible to retrieve, the review authors will perform analyses with and without inclusion of the trial and will compare these results with each other.
The editorial base of the Cochrane Neuromuscular Disease Group is supported by the Motor Neurone Disease Assocation and the MRC Centre for Neuromuscular Diseases.
The Methods section includes sections of standard text provided by the Cochrane Neuromuscular Disease Group.
The search strategy was developed by the Cochrane Neuromuscular Disease Group Trials Search Co-ordinator in collaboration with the review authors.
Appendix 1. MEDLINE (Ovid SP) search strategy
Database: Ovid MEDLINE(R) <1946 to April Week 1 2013>
1 randomized controlled trial.pt. (346027)
2 controlled clinical trial.pt. (85689)
3 randomized.ab. (248679)
4 placebo.ab. (137234)
5 drug therapy.fs. (1600078)
6 randomly.ab. (178008)
7 trial.ab. (256433)
8 groups.ab. (1158187)
9 or/1-8 (2986519)
10 exp animals/ not humans.sh. (3800175)
11 9 not 10 (2538086)
12 exp Motor Neuron Disease/ (18172)
13 (moto$1 neuron$1 disease$1 or moto?neuron$1 disease$1).mp. (6025)
14 ((Lou Gehrig$1 adj5 syndrome$1) or (Lou Gehrig$1 adj5 disease)).mp. (68)
15 charcot disease.tw. (14)
16 amyotrophic lateral sclerosis.tw. (11779)
17 or/12-16 (21942)
18 Fatigue/ or fatigue.mp. (58258)
19 (tired$ or weariness or weary or exhaust$ or lacklustre or astheni$ or lethargic or languidness or languor or lassitude or listlessness).mp. (39740)
20 ((lack or loss or lost) adj2 (energy or vigour or vigour)).mp. (2715)
21 18 or 19 or 20 (97006)
22 17 and 21 (223)
23 exp Exercise Therapy/ (27104)
24 exp Physical Therapy Modalities/ (116223)
25 rehabilitation.mp. or Rehabilitation/ (104628)
26 (exercise or train or activity or physical or exercise or strength or sports or isometric or isotonic or isokinetic or endurance or kinesiotherap$).mp. (2591893)
27 relaxation therapy/ (5562)
28 (exercise adj2 (grading or pacing)).mp. (171)
29 behavior therapy/ (22682)
30 orthotic devices/ (4846)
31 exp drug therapy/ (1022397)
32 cognitive therapy/ (13993)
33 or/23-32 (3637271)
34 11 and 22 and 33 (36)
35 exp *neoplasms/ (2085089)
36 34 not 35 (36)
37 remove duplicates from 36 (35)
Appendix 2. EMBASE (Ovid SP) search strategy
Database: EMBASE <1980 to 2013 Week 14>
1 crossover-procedure.sh. (36574)
2 double-blind procedure.sh. (113926)
3 single-blind procedure.sh. (17193)
4 randomized controlled trial.sh. (339824)
5 (random$ or crossover$ or cross over$ or placebo$ or (doubl$ adj blind$) or allocat$).tw,ot. (943332)
6 trial.ti. (143089)
7 or/1-6 (1075151)
8 (animal/ or nonhuman/ or animal experiment/) and human/ (1250445)
9 animal/ or nonanimal/ or animal experiment/ (3372851)
10 9 not 8 (2790892)
11 7 not 10 (986059)
12 limit 11 to embase (770715)
13 Motor Neuron Disease/ or Amyotrophic Lateral Sclerosis/ (24625)
14 (moto$1 neuron$1 disease$1 or moto?neuron$1 disease).mp. (8932)
15 ((Lou Gehrig$1 adj5 syndrome$1) or (Lou Gehrig$1 adj5 disease)).mp. (116)
16 charcot disease.tw. (21)
17 amyotrophic lateral sclerosis.tw. (15324)
18 or/13-17 (27373)
19 Fatigue/ or fatigue.mp. (132583)
20 (tired$ or weariness or weary or exhaust$ or lacklustre or astheni$ or lethargic or languidness or languor or lassitude or listlessness).mp. (74052)
21 ((lack or loss or lost) adj2 (energy or vigour or vigour)).mp. (4327)
22 19 or 20 or 21 (200002)
23 18 and 22 (625)
24 exp Exercise Therapy/ (42671)
25 exp Physical Therapy Modalities/ (48245)
26 rehabilitation.mp. or Rehabilitation/ (160354)
27 (exercise or train or activity or physical or exercise or strength or sports or isometric or isotonic or isokinetic or endurance or kinesiotherap$).mp. (3536728)
28 relaxation therapy/ (8024)
29 (exercise adj2 (grading or pacing)).mp. (189)
30 behavior therapy/ (35737)
31 orthotic devices/ (4191)
32 exp drug therapy/ (1489453)
33 cognitive therapy/ (29878)
34 or/24-33 (4941823)
35 12 and 23 and 34 (70)
36 exp *neoplasm/ (2389065)
37 35 not 36 (65)
38 remove duplicates from 37 (65)
Contributions of authors
Professor Carolyn Young conceived of the review.
All authors assisted in designing the review and the search strategies detailed in this protocol.
All authors assisted in drafting and providing critical appraisal of this protocol.
Declarations of interest
Tim Friede is a consultant to Novartis, Biogen Idec and Pharmalog, but not for the indication concerned (fatigue in ALS).
Chris Gibbons has published on fatigue in MND and stroke.
Francesco Pagnini has reported no conflicts.
Prof Young has published on fatigue in various neurological conditions, including MND, and has advised a pharmaceutical company (Multicell) about a potential trial for fatigue in multiple sclerosis. She has provided consultancy advice to Biogen Idec, Genzyme, Novartis and Teva in the past two years but not for the indication concerned (fatigue in ALS/MND).
Sources of support
- National Institute for Health Care and Research Greater Manchester Collaboration for Leadership in Applied Health Research and Care (NIHR CLAHRC-GM), UK.Chris Gibbons is supported by the NIHR-CLAHRC-GM.
- No sources of support supplied