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Corresponding author at: Physical Medicine & Rehabilitation, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Room H390 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada.
Physical Medicine & Rehabilitation, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Room H390 2075 Bayview Avenue, Toronto, ON M4N 3M5, CanadaGeneral Practice and Primary Care, Institute of Health and Wellbeing, University of Glasgow, Glasgow, United Kingdom
Mindfulness-based interventions (MBIs) are complex interventions.
•
The optimal MBI for people with multiple sclerosis (PwMS) is not known.
•
MBIs appear to be moderately effective in improving fatigue in PwMS.
•
Evidence for MBIs for relieving pain in PwMS is inconsistent.
Abstract
Background
Physical wellbeing is commonly impaired in people with multiple sclerosis (PwMS). This study aims to update our previous systematic review (2014) and conduct a meta-analysis on the efficacy of Mindfulness-based interventions (MBIs) for improving physical symptoms in PwMS.
Methods
In November 2017 we carried out systematic searches for eligible randomised controlled trials (RCTs) in seven major databases, updating our search in July 2018. We used medical subject headings and key words. Two independent reviewers used pre-defined criteria to screen, data extract, quality appraise, and analyse studies. The Cochrane Collaboration risk of bias tool was used to determine study quality. Physical wellbeing was the main outcome of interest. We used the random effects model for meta-analysis, reporting effect sizes as Standardised Mean Difference (SMD). This study is registered with PROSPERO: CRD42018093171.
Results
We identified 10 RCTs as eligible for inclusion in the systematic review (including 678 PwMS), whilst seven RCTs (555 PwMS) had data that could be used in our meta-analyses. In general, comorbidity, disability, ethnicity and socio-economic status were poorly reported. MBIs included manualised and tailored interventions, treatment duration 6-9 weeks, delivered face-to-face and online in groups and also individually. For fatigue, against any comparator SMD was 0.24 (0.08 – 0.41), I2=0%; against active comparators only, SMD was 0.10 (-0.14 – 0.34), I2=0%. For pain SMD was 0.16 (-0.46 – 0.79), I2=77%. Three adverse events occurred across all studies.
Conclusions
MBIs appear to be an effective treatment for fatigue in PwMS. The optimal MBI in this context remains unclear. Further research into MBI optimisation, cost- and comparative-effectiveness is required.
). Common physical symptoms include difficulties with vision, speech, swallow, bowel, bladder and sexual function, chronic pain, spasticity and limited mobility (
Physical and mental health comorbidity is common in people with multiple sclerosis: nationally representative cross-sectional population database analysis.
). Physical comorbidities in MS are associated with more CNS lesions on Magnetic Resonance Imaging (MRI), greater levels of disability, increased hospitalisations, and higher mortality rates (
). Furthermore, having additional physical conditions in MS is associated with more stress and worse quality of life (QoL); as the number of additional physical conditions increase, so does the prevalence of mental health impairment (
Physical and mental health comorbidity is common in people with multiple sclerosis: nationally representative cross-sectional population database analysis.
). The UK National Institute for Care and Clinical Excellence (NICE) recommends offering PwMS cognitive behavioural therapy (CBT), aerobic exercise, yoga, or amantadine for fatigue, as well as avoiding stress and treating comorbid anxiety and depression ((
(2014) NIfHaCE. Multiple sclerosis: management of multiple sclerosis in primary and secondary care2014Available from: https://www.nice.org.uk/guidance/cg186.
(2014) NIfHaCE. Multiple sclerosis: management of multiple sclerosis in primary and secondary care2014Available from: https://www.nice.org.uk/guidance/cg186.
An outpatient program in behavioral medicine for chronic pain patients based on the practice of mindfulness meditation: Theoretical considerations and preliminary results.
). MBIs have been applied and researched in a range of health conditions and found to be effective treatments for anxiety, stress, recurrent depression and somatisation disorders (
) we found limited evidence from two randomised controlled trials (RCTs) and a controlled trial to support MBIs as a potential treatment for comorbid fatigue and comorbid pain in the condition, as well as improving standing balance (
). Since 2014, several more RCTs have been published and it is important to determine more definitively whether MBIs are effective treatments for fatigue and pain in PwMS, besides other commonly encountered physical symptoms.
The aim of this review is to conduct a meta-analysis of RCTs testing the efficacy of MBIs in improving physical symptoms in PwMS.
2. Methods
2.1 Protocol and registration
Our protocol was registered prospectively with the Centre for Reviews and Dissemination, University of York, Prospero ID: CRD42018093171. This body of work also included a meta-analysis of MBI effects on mental wellbeing in PwMS, reported separately (
Mindfulness-based interventions for mental well-being among people with multiple sclerosis: a systematic review and meta-analysis of randomised controlled trials.
J. Neurol., Neurosur. Psych.2019; (jnnp-2018-320165)
). To be eligible for inclusion, studies had to be RCTs, (comparing MBI vs active comparator or care as usual), with no limit placed on sample size. Participants had to be PwMS (of any phenotype), aged 18 years or older. The intervention(s) being tested had to be a recognisable MBI that included core practices of mindful breathing, mindful body awareness, and mindful movement; Mindfulness-based stress reduction (MBSR) and Mindfulness-based cognitive therapy (MBCT) served as reference guides in this regard. Outcomes had to be appropriately validated and report on a definable aspect of physical wellbeing experienced by PwMS (e.g. symptoms such as fatigue, pain, standing balance).
2.3 Search strategy
We employed a search strategy from our previous systematic review for use in: Allied and Complementary Medicines Database (AMED), Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing and Allied Health Literature (CINAHL), ExcerptaMedicadataBASE (EMBASE), Medical Literature Analysis and Retrieval System Online (MEDLINE), and PsycINFO. As our previous systematic review found the first study in this area was published in 2000, we set our ‘years’ delimiter to 2000 – 2018. In addition, we also searched ProQuest Dissertations & Theses, reviewed key references from identified studies, searched the grey literature, and approached experts in the field. We carried out our initial search in November 2017 and repeated this in July 2018. Our search strategy as used in MEDLINE is available in Appendix A.
2.4 Study selection, storage and screening
We imported search results into COVIDENCE, a data storage package for systematic reviews. Title/abstracts were screened by two reviewers (RS, SS) for potential eligibility using keywords like ‘mindfulness’ and ‘multiple sclerosis’. Selected studies were then assessed against SPIO criteria by two reviewers (JB, RS) to assess ultimate eligibility. A senior, third party reviewer (SM) was available to arbitrate any disagreements.
2.5 Data collection/data items
Data from the final list of included studies was extracted guided by CONSORT (
) to summarise risk for individual outcomes in selected studies, graded as high, unclear, or low risk. This assessed generation of sequence, concealment of allocation, blinding of participants, outcome assessors and personnel, incomplete outcomes, selective reporting of outcomes, and any other bias. Finally, as outlined by
, an overall RoB within each trial was determined based on the number of individual outcomes falling in to the high, unclear, and low risk categories:
Low = Low RoB for all key domains
Unclear = Low or unclear RoB for all key domains
High = High RoB for one or more key domains
2.7 Principal summary measures
The main outcome for this study was impact of MBI on physical symptoms. Main outcome measures were all reported as continuous with mean, standard deviation (SD) values and the number of participants for each treatment group extracted. “Effect size” is reported as the unbiased standardised mean difference (SMD), a positive SMD indicating a finding in support of the intervention having a positive treatment effect (TE). The standardised mean difference was calculated by difference in means between the MBI and the control group at last point of follow-up divided by the pooled last point of follow-up SD. Where effect estimates were reported from adjusted regression models, we extracted these as the SMD with their corresponding SD.
2.8 Synthesis of results
Throughout this study we adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (
) to determine SMD, as outcome measures were known to vary widely. We report estimates with corresponding 95% confidence intervals (CI) and ‘p’ values. We used the I2 statistic to determine variability between studies (
); I2 representing the percentage of total variability in effect size estimates due to heterogeneity. An I2 of 0% indicates that all heterogeneity is consistent with sampling error, whilst an I2 of 100% suggests all variability may be attributable to studies being truly heterogenous.
To assess for evidence of publication bias, we undertook Funnel plots and Egger's Test for asymmetry (
We identified ten RCTs as eligible for inclusion in the systematic review, with seven studies reporting endpoint data usable in meta-analysis (Fig. 1). We sought additional information from several study authors; one (
Investigating the combined effect of pelvic floor muscle exercise and mindfulness on sexual function in women with multiple sclerosis: a randomized controlled trial.
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
Investigating the combined effect of pelvic floor muscle exercise and mindfulness on sexual function in women with multiple sclerosis: a randomized controlled trial.
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
). Number of study participants ranged from 24 – 150 (median 62). Eight studies reported measuring outcomes at three points in time (baseline, immediately post MBI, and at further follow-up, which varied from 1 month post MBI to 1 year later) (
Investigating the combined effect of pelvic floor muscle exercise and mindfulness on sexual function in women with multiple sclerosis: a randomized controlled trial.
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
Center for Epidemiological Studies Depression, Spielberger Trait Anxiety Inventory, Modified Fatigue Impact Scale, Hamburg Quality of life Questionnaire in Multiple Sclerosis, Profile of health-related Quality Of Life in Chronic disorders, Goal setting, Neuropsychology assessment
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
Investigating the combined effect of pelvic floor muscle exercise and mindfulness on sexual function in women with multiple sclerosis: a randomized controlled trial.
There were 678 participants between the 10 RCTs included in the systematic review, versus 555 participants in the seven studies included in the meta-analysis. Participant ethnicity was described in three studies (
), most were Caucasian. Between all 10 RCTs, the majority of participants were female (76%; n=517). The extractable mean participant age was 46.0 years (not reported in
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
), most having school level education as a minimum. The majority (a minimum of 414 or 61%) had a relapsing-remitting phenotype, a minimum of 112 (17%) a secondary progressive phenotype, and a minimum of 27 (4%) had a primary progressive phenotype. Degree of disability was reported in six studies (
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
Investigating the combined effect of pelvic floor muscle exercise and mindfulness on sexual function in women with multiple sclerosis: a randomized controlled trial.
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
Investigating the combined effect of pelvic floor muscle exercise and mindfulness on sexual function in women with multiple sclerosis: a randomized controlled trial.
Investigating the combined effect of pelvic floor muscle exercise and mindfulness on sexual function in women with multiple sclerosis: a randomized controlled trial.
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
Investigating the combined effect of pelvic floor muscle exercise and mindfulness on sexual function in women with multiple sclerosis: a randomized controlled trial.
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
Investigating the combined effect of pelvic floor muscle exercise and mindfulness on sexual function in women with multiple sclerosis: a randomized controlled trial.
Investigating the combined effect of pelvic floor muscle exercise and mindfulness on sexual function in women with multiple sclerosis: a randomized controlled trial.
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
Investigating the combined effect of pelvic floor muscle exercise and mindfulness on sexual function in women with multiple sclerosis: a randomized controlled trial.
Investigating the combined effect of pelvic floor muscle exercise and mindfulness on sexual function in women with multiple sclerosis: a randomized controlled trial.
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
). Weekly MBI session lengths varied between 1–3 h. There were between five to 25 participants per MBI class across the studies, sessions being administered by 1-2 MBI instructors. The core MBI components were delivered in all studies. However, in six studies the MBI was tailored for PwMS (
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
), where mindful movement was simplified to accommodate high levels of disability. Another study pre-emptively removed mindful movement following stakeholder consultation (
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
Investigating the combined effect of pelvic floor muscle exercise and mindfulness on sexual function in women with multiple sclerosis: a randomized controlled trial.
Develop moment to moment awareness of breath, posture, movement with compassion
Cultivate interested, accepting, non-judgmental attitude to experience, including difficult sensations, emotions, thoughts and behavior
Adaptation of MBSR. Focus on negative thinking, engaging low mood, changing relationship with thoughts, feelings, sensations, no longer avoiding/ reacting to them automatically
Adaptation of MBSR. Focus on negative thinking, engaging low mood, changing relationship with thoughts, feelings, sensations, no longer avoiding/ reacting to them automatically
Facilitate the compliance with and adaptation to medical conditions. Pay attention to being present in a non-judgmental manner
Cultivate interested, accepting, non-judgmental attitude to experience, including difficult sensations, emotions, thoughts and behavior
Cultivation of mindful awareness, loving kindness, enrichment of listening, self-compassion, sensorimotor psychotherapy principles ‘window of tolerance’
Cultivate interested, accepting, non-judgmental attitude to experience, including difficult sensations, emotions, thoughts and behavior
Non- judgmental present moment awareness
Cultivate interested, accepting, non-judgmental attitude to experience, including difficult sensations, emotions, thoughts and behavior
3. What -Materials provided to participants?
Written handout, audio and video aids
Not reported
Headset, webcam, compact discs for home practice
Not reported
Leaflets for each session and compact discs for home practice
Course manual, compact discs for home practice Book - Full Catastrophe Living
Not reported
Dedicated website with online multimedia for home practices
Not reported
Not reported
4. What - Procedures -Pre-session?
Had to make a commitment to regular practice
Personal intake interview; goal planning
Screened for evidence of distress on General Health Questionnaire
Personal intake interview
Personal intake interview
Not reported
Not reported
Not reported
Not reported
Score of at least 1ten on Perceived Stress Scale
4. What - Procedures –In session?
General description only-
Body awareness, breath awareness, mindful movement, Tui Na self-massage
General description only-
Observation of sensory, cognitive and affective experience in lying, siting, and dynamic yoga postures
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
Investigating the combined effect of pelvic floor muscle exercise and mindfulness on sexual function in women with multiple sclerosis: a randomized controlled trial.
Investigating the combined effect of pelvic floor muscle exercise and mindfulness on sexual function in women with multiple sclerosis: a randomized controlled trial.
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
), where the SMD against any comparator was 0.24 (0.08 – 0.41) p<0.01, I2=0% (low heterogeneity) (Fig. 2); against active comparators only the SMD for fatigue was 0.10 (-0.14 – 0.34), p=0.40, I2=0% (low heterogeneity) (Fig. 3). Three studies also evaluated MBI effect on pain (besides fatigue) (
), where the SMD was 0.16 (-0.46 – 0.79), p=0.61, I2=77% (substantial heterogeneity) (Fig. 4).
Fig. 2SMD for fatigue vs any comparator. TE - Treatment effect; seTE - standard error of the TE; SMD – Standardised mean difference; 95%CI - 95% confidence interval; Weight - weight contributed by each study.
Fig. 3SMD for fatigue vs active comparators. TE - Treatment effect; seTE - standard error of the TE; SMD – Standardised mean difference; 95%CI - 95% confidence interval; Weight - weight contributed by each study.
Fig. 4SMD for pain vs any comparator. TE - Treatment effect; seTE - standard error of the TE; SMD – Standardised mean difference; 95%CI - 95% confidence interval; Weight - weight contributed by each study.
Using the I2 statistic, heterogeneity was low for fatigue (0%), but substantial for pain (77%). The funnel plot for fatigue identified no evidence of publication bias (Fig. 5). The p-value from Egger's Test of asymmetry from fatigue studies was 0.256.
) (n=40) versus usual care, where effect size for fatigue was 0.29 (-0.18 – 0.76), p=0.30 and the effect size for pain was 0.59 (0.14 – 1.04), p<0.05. Compared to a psychoeducation control, a study using Body-Affective Mindfulness (n=90) (
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
) had an effect size of 0.19 (-0.22 – 0.60), p=0.37 for effect on fatigue.
3.3 Study quality
Study quality was highly variable. Assessment was frequently made challenging by scanty reporting. For unclear reasons, those studies of highest quality (lowest RoB) originated from European countries and the United States. Eight studies outlined random sequence generation (
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
Investigating the combined effect of pelvic floor muscle exercise and mindfulness on sexual function in women with multiple sclerosis: a randomized controlled trial.
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
Investigating the combined effect of pelvic floor muscle exercise and mindfulness on sexual function in women with multiple sclerosis: a randomized controlled trial.
Investigating the combined effect of pelvic floor muscle exercise and mindfulness on sexual function in women with multiple sclerosis: a randomized controlled trial.
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
Investigating the combined effect of pelvic floor muscle exercise and mindfulness on sexual function in women with multiple sclerosis: a randomized controlled trial.
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
Investigating the combined effect of pelvic floor muscle exercise and mindfulness on sexual function in women with multiple sclerosis: a randomized controlled trial.
). Across trials, overall RoB was low for random sequence allocation, unclear for allocation concealment, low for assessor blinding, low for blinding of outcome assessment, unclear for incomplete outcome assessment, low for selective outcome reporting, and low for other sources of bias. Overall, there is an unclear RoB across trials.(Table 4). Appendix C details rationale for RoB assessments.
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
Investigating the combined effect of pelvic floor muscle exercise and mindfulness on sexual function in women with multiple sclerosis: a randomized controlled trial.
As all the pain studies were in the low RoB group, Fig. 6 illustrates only the SMD for all trials able to be analysed for fatigue, arranged by RoB categories (low, unclear and high). Low RoB (n=5) SMD was 0.29 (0.09 – 0.49): I2=0% (low heterogeneity); p<0.01. Unclear RoB (n=1) SMD was -0.01 (-0.37 – 0.35); p=0.95. High RoB (n=1) SMD was 0.80 (-0.04 – 1.64); p=0.06. Effect estimates did not vary significantly between RoB allocation in the overall RoB analysis, p=0.15. The low RoB studies are most likely to approximate the true effect of an MBI on PwMS who have fatigue, with (generally) larger sample sizes, a higher standard of trial procedures and hence less chance of inadvertent bias.
Fig. 6Risk of Bias Forest plot for fatigue studies. TE - Treatment effect; seTE - standard error of the TE; SMD – Standardised mean difference; 95%CI - 95% confidence interval; Weight - weight contributed by each study.
Ten RCTs that assessed the effects of an MBI on physical symptom outcomes in PwMS were eligible for inclusion in our systematic review; seven of these had data extractable for use in our meta-analysis. Four studies tested an MBI against an active comparator, four tested against treatment as usual, whilst the control condition was unclear in the remaining two studies. Intervention fidelity was reliably assessed in only one study. Sample sizes were frequently small. Follow-ups took place from immediately post-MBI to up to 1 year following course completion.
Six hundred and seventy-eight PwMS were included in these studies. Most (58%) had relapsing phenotypes. Most participants were female; mostly of Caucasian ethnicity. In general, comorbidity and disability levels were poorly reported.
Four studies used MBSR, two were loosely modeled on MBSR; two explicitly used MBCT, one ‘Mindfulness of Movement’, and in one case the basis for the MBI was unclear. Most interventions were provided as groups (n=5-25), delivering core MBI practices in and between sessions. Level of teacher training and experience were not well reported. MBI session attendance +/- home practice (treatment adherence) was described in six studies. Rates of attrition varied considerably (0–39%). Although very few adverse events were described from MBI training, few studies explicitly reported on this outcome.
Five RCTs were categorised as overall low RoB using the Cochrane Collaboration tool, three as high and two as unclear, signifying an overall improvement in study quality since we last assessed this in 2014 (
Our meta-analysis indicates that MBIs are modestly effective treatments for fatigue in PwMS, but evidence to support improvements in pain is inconsistent. No MBI is clearly optimal for treating impairment of fatigue in PwMS.
4.2 Comparison with existing literature
In this study we found MBIs moderately effective for improving fatigue (SMD 0.24; 0.08 – 0.41), but inconsistent with regards to effects on pain (SMD 0.16; -0.46 – 0.79) in PwMS.
) of psychological interventions for treating fatigue in PwMS reported CBT to be moderately effective (SMD 0.32; 0.01 – 0.63) and MBIs to be considerably more effective (SMD 0.62; 0.12 – 1.12), but only included two (
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
) RCTs identified in our current review, likely reflecting an earlier search cut-off date in their study (April 2017).
No previous meta-analysis has assessed the impact of MBI training on pain in PwMS, but in chronic pain populations at large, several meta-analyses have been conducted. A 2014 meta-analysis (
) reported moderate overall treatment effects (Cohen's d) from MBI training (0.33; 0.03 – 0.62), a finding that diminished to a null effect when examining the effect against active comparators. A 2015 meta-analysis (
) comprising painful musculoskeletal conditions reported small effects (Hedge's g) versus usual care following MBI training on pain intensity (0.16; 0.03 – 0.36; the effect attenuated when compared against active comparators to 0.09; -0.13 – 0.31), moderate effects on perceived pain control (0.58; 0.23 – 0.93), but larger effects on pain acceptance versus usual care (1.58; -0.57 – 3.74). Finally, a 2017 meta-analysis (
), our multidisciplinary team of experienced reviewers used robust search, appraisal and analysis techniques for extracting and analysing data in this systematic review and meta-analysis.
4.4 Limitations of this review
Although we assessed quality using a reference standard, the Cochrane Collaboration RoB tool, we did not estimate the strength of any recommendation for use of MBIs in PwMS. Future studies could do so by applying the GRADE criteria (
Meta-analyses of RCTs by design exclude other potentially relevant data, such as that deriving from observational or qualitative research. When considering intervention feasibility, such as acceptability, accessibility and implementability, these alternate study designs can provide important insights into how and why interventions succeed or fail in a given context. However, in this current study, the use of SPIO, the TIDieR checklist and Cochrane Collaboration tool for RoB, means that our evidence synthesis has covered other, related aspects of trial feasibility and execution.
4.5 Strengths and Limitations of the included studies
When considering the strength of evidence for the use of MBIs in PwMS, most studies which assessed impact on fatigue (n=5/7) and all that assessed impact on pain (n=3) were adjudged low RoB. However, despite all studies being RCTs, participant numbers were low (n=<50) in four. Although all MS phenotypes were represented, most participants had relapsing-remitting MS. Furthermore, mean sample age was relatively low (46.0), whilst ethnicity, SES and comorbidity were poorly covered, limiting the generalisability of findings. To complicate matters, several studies tailored their MBIs with minimal/absent prior justification. Only four compared an MBI against an active comparator condition. Observed effects were mostly small, with a wide range of confidence intervals. Heterogeneity, overall, was low.
Given the well documented high levels of physical comorbidity in PwMS, it is notable that our meta-analysis has only been able to quantify the effects of MBI training on two, albeit common, facets of physical wellbeing, namely fatigue and pain. Other aspects of physical wellbeing were measured in individual studies (e.g. standing balance, sleep and sexual function), where beneficial effects were reported, but meta-analysis was not possible. Future studies could address this evidence gap by measuring the impact of MBI training on other common physical symptoms associated with MS, for example dysarthria, dysphagia, bowel and bladder dysfunction, dynamic balance, in-coordination and spasticity. Although MBSR and MBCT both appear to be effective treatments for fatigue, it is not currently possible to recommend one approach over the other.
4.6 Implications for research
The quality of evidence for MBIs as effective treatments for fatigue in PwMS has improved considerably since our systematic review in 2014. However, adherence to CONSORT (
) reporting was poor in several studies included in the meta-analysis, with three studies assessed overall as high risk and two as unclear according to the Cochrane Collaboration (
) checklists when reporting studies of MBIs for PwMS, the knowledge base in this area could be further enhanced, helping to clarify where further research efforts should focus.
It remains unclear which type of MBI may be best for PwMS with impaired physical wellbeing in general, or fatigue or pain more specifically. Future research could test either MBSR or MBCT against established treatments in this area; by involving people affected with the condition in this endeavor, the co-design, delivery and ongoing development of an optimised MBI course for PwMS could take place (
MBIs appear to be modestly effective at improving fatigue in PwMS.
5. Conclusions
Meta-analytic evidence supports the use of MBIs in PwMS to improve fatigue. Evidence to support the use of MBIs for treating pain in this population is inconsistent. Although the quality of study reporting has become better, room still exists for enhanced reporting in this area. No clear optimal MBI exists for improving impaired physical wellbeing in PwMS.
Role of the funding source
The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Funding
This study was funded by the RS McDonald Trust (SC012710)
Declaration of Competing Interest
We declare no competing interests.
Acknowledgments
We wish to thank the RS McDonald trust for funding this study.
. "Mindfulness of movement as a coping strategy in multiple sclerosis: a pilot study."
Risk of bias assessment
Random sequence generation
Unclear – First matched on basis of activities of daily living (ADL) scores, then randomly allocated from that pair only
Allocation concealment
Unclear – Not mentioned in the paper
Blinding of assessors
Unclear – Not mentioned in the paper
Blinding of outcome assessment
High – Paper suggests in discussion that study would be enhanced by including a ‘blind or more objective rater’
Incomplete outcome data addressed
Unclear – Some data is reported in methods, but participant data has been omitted on the basis of not being ‘complete’. Unclear what this means.
Selective outcome reporting
High – This study is also reported in another paper with different outcome data:Mills N, Allen J, Carey-Morgan S. Does tai chi/qi gong help patients with multiple sclerosis? Journal of Bodywork and Movement Therapies. 2000 Jan 1;4(1):39-48.
. "MS quality of life, depression, and fatigue improve after mindfulness training A randomized trial."
Risk of bias assessment
Random sequence generation
Low – Baseline assessments prior to randomisation. PI randomised blind, using www.randomizer.org in blocks of 4 - 6
Allocation concealment
Low – PI sent allocation list to coordinator who informed participants in writing of their assignment. This was then re-checked by PI, no deviations found
Blinding of assessors
Low – Investigators blinded to assignment
Blinding of outcome assessment
Low – All PRO measures were entered into a database by blinded personnel
Incomplete outcome data addressed
Low – Consort flow diagram included in report with n randomised, ‘n’ analysed etc. Intention to Treat (ITT) employed. Missing data imputed by multiple linear regression that adjusted for age, gender, and disease progression
. "Distress improves after mindfulness training for progressive MS: A pilot randomised trial."
Risk of bias assessment
Random sequence generation
Low – Randomisation took place once cohort of 10 participants consented, screened and baseline data collected. Independent unit at KCL Clinical Trials Unit (CTU) handled randomisation, with fixed block sizes of 2
Allocation concealment
Low – As above. Then CTU sent assignment list to PI
Blinding of assessors
Low – Trial assessor blinded to allocation
Blinding of outcome assessment
Low – Statistician, health economist blinded to assignment
Incomplete outcome data addressed
Low – Consort flow diagram included in report with n randomised, ‘n’ analysed etc. ITT employed. Informative missingness processes explored by sensitivity analysis. Missing baseline variables handled using the missing indicator method
. "The Effectiveness of Mindfulness-Based Cognitive Therapy in Reducing Psychological Symptoms, Meta-Worry and Thought Fusion of Multiple Sclerosis Patients."
Risk of bias assessment
Random sequence generation
Unclear – Paper only states that participants were selected using a random sampling method
Allocation concealment
Unclear - Paper only states that participants were selected using a random sampling method
Blinding of assessors
Unclear – Not reported in the paper
Blinding of outcome assessment
Unclear – Not reported in the paper
Incomplete outcome data addressed
Unclear – Attrition not reported, nor numbers included in analyses or details regarding missing data. No consort flow diagram.
Selective outcome reporting
Low – All pre-specified outcomes were reported
Other sources of bias
High – No reporting of baseline participant characteristics at all
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
. "The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial."
Risk of bias assessment
Random sequence generation
Low – Randomly assigned on 1:1 ratio using a block wise randomisation sequence
Allocation concealment
Low – Sequence determined by an independent researcher blinded to initial assessment. Study co-ordinator communicated assignment to participants
Blinding of assessors
Low – Clinical Psychologists performing assessments were blinded to participant ID
Blinding of outcome assessment
Low – Clinical Psychologists performing assessments were blinded to participant ID
Incomplete outcome data addressed
Low – Both Per Protocol (PP) and ITT performed - ITT explored missing data – data imputation was used for two participants. Consort flow diagram detailing numbers analysed and dropping out. Comparison between completers and dropouts baseline measures and socio-demographics undertaken.
. "Online meditation training for people with multiple sclerosis: A randomized controlled trial."
Risk of bias assessment
Random sequence generation
Low – Participants were randomly assigned 1:1 to MBI and control using www.random.org
Allocation concealment
Unclear – Paper only states that participants were randomly assigned to MBI and control
Blinding of assessors
Unclear – Not reported in the paper
Blinding of outcome assessment
Unclear – Not reported in the paper
Incomplete outcome data addressed
Unclear – Although consort flow diagram included, detailing attrition, reasons accounting for this were insufficiently described. No mention of missing data
Investigating the combined effect of pelvic floor muscle exercise and mindfulness on sexual function in women with multiple sclerosis: a randomized controlled trial.
. "Investigating the combined effect of pelvic floor muscle exercise and mindfulness on sexual function in women with multiple sclerosis: a randomized controlled trial."
Risk of bias assessment
Random sequence generation
Low – Block randomisation of six blocks of three patients (ABC, ACB, BAC, BCA, CAB, CBA), then replacement random sampling used to select blocks
Allocation concealment
Unclear – Not discernable from paper
Blinding of assessors
Low – Data collected by third author blinded to group assignment
Blinding of outcome assessment
Low – Data analysed by second author, blinded to group assignment
Incomplete outcome data addressed
Unclear – Consort flow diagram detailing attrition and numbers analysed, but no mention of missing data
"acute disseminated encephalomyelitis".mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
8
encephalomyelitis.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
9
"multiple sclerosis".mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
10
"neuromyelitisoptica".mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
11
"optic neuritis".mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
12
"transverse myelitis".mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
13
demyelinat*.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
14
myelitis.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
15
((clinically or radiologically) and isolated syndrome).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
16
(demyelinating and (disease or disorder)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
17
1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16
18
exp Mindfulness/
19
exp Meditation/
20
exp Breathing Exercises/
21
(MBSR or MBCT).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
22
relaxation.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
23
(breathing and (exercis* or techniqu*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
24
vipassana.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
25
yoga.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
26
mindful*.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
27
meditat*.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
28
18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27
29
17 and 28
30
limit 29 to (english language and humans and yr="2000 -Current")
Appendix B. Data Extraction Sheet v.1 Simpson et al. (2018)
Appendix C. Cochrane Collaboration Risk of Bias assessment - justifications
References
(2014) NIfHaCE. Multiple sclerosis: management of multiple sclerosis in primary and secondary care2014Available from: https://www.nice.org.uk/guidance/cg186.
The effectiveness of a body-affective mindfulness intervention for multiple sclerosis patients with depressive symptoms: a randomized controlled clinical trial.
An outpatient program in behavioral medicine for chronic pain patients based on the practice of mindfulness meditation: Theoretical considerations and preliminary results.
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