Multiple Sclerosis
Multiple sclerosis (MS) (1) is a chronic immune-mediated inflammatory demyelinating disease of the central nervous system. Three main courses have been identified: Relapsing-remitting multiple sclerosis (RRMS, ICD 8A40.0) (1); Primary progressive multiple sclerosis (PPMS, ICD) (1); and Secondary progressive multiple sclerosis (RRMS) (1). All classifications result in accumulated disability over time (2,3).
MS is acquired following an unknown trigger (thought to be an unidentified virus) causing the immune system to respond to myelin as an antigen, attacking the myelin sheath. Demyelination, inflammation, gliosis and axonal injury combine to cause white matter brain and spinal cord damage (4). Multiple plaques are formed, affecting the ability of the axons to relay nerve signals. White matter plaques occur within subcortical areas, frequently within periventricular and frontal lobe regions. The size and location of plaques is highly individual resulting in variable symptom presentation. First reported symptoms are most commonly sensory changes, optic neuritis, weakness or balance problems (5). There is no definitive diagnostic test, and the process of diagnosis can be prolonged, as more than one relapse must be recorded.
This review focuses on presenting problems and symptoms in order to review the scientific evidence of what may work to ameliorate these symptoms. It is important to note that many people living with MS continue to live fulfilling, meaningful and active lives despite the challenges the condition can bring. Practitioners delivering psychological therapies should consider individual variability and potentially interacting physical, mood and cognitive symptoms presenting in MS (5). Physical symptoms often include muscle spasms, weakness, pain, paraesthesia, visual disturbances, fatigue, gait, balance and urinary problems. Physical disability and disease progression are highly variable between individuals and over time (6) and there may be symptom recovery as well as decline (7,8). In RRMS, 33% will have minimal disease outcome even after 20 years, but 10% experience significant disability within five years of onset (associated with risks of older age, motor symptoms at onset and progressive classification) (5,7,9).
MS and Mood: MS symptoms are unpredictable and inconsistent, making day-to-day life a challenge and often impacting on mood and quality of life (10,11). The unpredictability and individual differences in symptom presentation can be particularly emotionally challenging, and clinicians should consider mood as part of the comprehensive assessment during routine reviews and at transition points in disease presentation. There is some evidence that those with greater uncertainty in regard to MS diagnosis and symptoms may be more susceptible to adjustment difficulties and depression (for a brief review see BPS Evidence-based guidance on psychological interventions: Huntington’s disease, Parkinson’s disease, motor neurone disease and multiple sclerosis (10). A recent meta-analysis of 58 studies reported prevalence of 30.5% for depression and 22.1% for anxiety, compared to general population prevalence of 6% in the same review (12). The summarised literature reports 50% lifetime risk for depression (11).
MS and Cognition: Individuals living with MS are often faced with cognitive changes in processing speed and executive function; which may typically present as problems finding the right word in conversation, doing two things at once (multi-tasking), paying attention for long periods and/or processing conversations in busy environments. Reduced speed of processing may be the first cognitive symptom to emerge (13,14) and serve as a sensitive indicator of MS-related cognitive change (15,16). In the presence of more widespread subcortical lesions, associated difficulties can emerge in working memory, recall, word finding and executive function (cognitive inflexibility, disinhibition, multi-tasking and abstraction deficits) (17,18). Memory problems are typically associated with underlying subcortical-based changes, and typically caused by primary changes in speed, attention and recall, which combine to reduce memory efficiency. In progressive cases with significant and widespread axonal loss, cortical atrophy may result in primary memory and language deficits and severe dysexecutive function (19,20).
Cognitive dysfunction in MS can impact activity and participation in occupational, social and parenting/caring roles. Changes in speed, planning and multitasking may limit activities of daily living (5); in turn affecting routine household tasks such as cooking a meal for the family (which involves attention, timing and multi-tasking). Quality of life has been shown to be independently impacted by speed of processing (21). Those with MS-related cognitive problems have poorer prognosis, engage in fewer social and vocational activities, are less likely to be in employment and can have problems driving (22-24). The literature highlights the importance of a holistic approach to assessment and intervention; considering potentially treatable factors of fatigue, pain and mood (22,25-27).
A recent meta-analysis (28) reported prevalence at 32.5% in RRMS for cognitive impairment (defined as reduced performance across at least two cognitive domains relative to normative samples; where reduced performance was defined as 1.5 to 2.0 standard deviations [SDs] below the mean). Prevalence estimates of cognitive difficulties range more widely from 35–70%, likely due to the individual nature of underlying pathology and varying definitions of “cognitive difficulties” (5,29,30). Evidence indicates mostly mild-moderate problems, but with impact on day-to-day function; often compounded by fatigue, pain, anxiety, depression and adjustment issues (30,31). Risks for greater cognitive impairment include white matter lesion load, grey matter volume loss, male sex, older age, disease duration and Primary Progressive MS (20,28,29,32-34). Greater white matter lesion load and grey matter structural damage at baseline (at the time of diagnosis) are risks for cognitive decline (34,35). Cognitive reserve is hypothesised to play a protective role, with greater premorbid capacity (evidenced via education, occupation and intellectual enrichment) allowing more potential for functional reorganisation (36-38).
MS-related Fatigue: Symptoms of fatigue were reported in 36–78% of individuals living with MS in a recent systematic review (39). MS-related fatigue can have a significant impact on family and working life and has been associated with reduced participation in employment (39).
Prevalence of MS diagnosis
MS occurs most often in adulthood between 20 and 50 years of age. The condition is likely to be acquired before puberty, but symptom onset comes later. MS occurs three times more often in northern countries, north of 40 degrees latitude (40); with evidence that the condition results from a complex interaction between genetic and environmental risk factors. Prevalence of MS is higher in Scotland (estimated >200 per 100,000 (9), than in England (estimated 190 per 100,000) (41). Higher incidence rates are reported in the north than in the south of Scotland (PHS, 2024). Environmental factors, such as smoking and obesity have been shown to effect level of disability (42,43), with smoking rates higher in people with MS than in the general population (41).
This topic covers evidence-based psychological interventions used to treat mood, cognitive and fatigue presentations in adults living with MS. Children and young people under the age of 16 years are more rarely diagnosed with MS (9). Evidence of interventions with this age group is beyond the scope of this document. Non-psychological and/or pharmacological interventions are beyond the scope of this topic page.
This academic review may be most relevant to healthcare professionals (in primary, community, secondary, tertiary settings) who have direct contact with those living with MS and make decisions concerning evidence-based interventions and provision of care. More broadly, the review information is relevant to commissioners, managers and trainers to consider the evidence base for the delivery of psychological and neuropsychological interventions for adults living with MS.
The review information is also relevant to adults living with MS. Additional resources are reported to be valuable to those living with MS in managing symptoms of the condition. These include third sector, wellbeing and peer support services which are beyond the scope of this review; but which are signposted here: MS Society Scotland community support page and NHS Inform.
A note on NHS service provision is important. Dedicated/tertiary clinical health psychology or neuropsychology services for specialist MS input are rare, and relevant presentations will often be referred into general adult primary, secondary and acute mental health and neuropsychology services depending on the local area and service availability (10). NICE guidelines (5) do not make specific specialist recommendations about the context for treatment of commonly presenting mental health and cognitive symptoms in the context of MS. The intended audience of this guideline includes all psychological therapy practitioners working across all relevant primary and secondary care settings to guide the effectiveness of psychological therapies applied in the context of those presenting with psychological symptoms (cognition, emotional and behavioural) in the context of MS diagnosis. Comorbid mental health diagnoses should be treated in line with relevant Matrix recommendations and NICE guidelines for depression in chronic physical health conditions (44). The MS Society also provides information on MS for health professionals https://www.mssociety.org.uk/supporting-someone-with-ms/for-professionals.
Detailed guidelines on principles for best clinical practice can be found in the following guidance:
The evidence is synthesised from clinical guidance, systematic reviews and meta-analyses published between 2014 and 2024. These reviews summarise data reported from RCTs on psychological interventions in the context of MS; updating the evidence base previously published in Matrix evidence (2014). The overview and tables of evidence are presented by psychological interventions for (1) mental health problems, (2) cognitive problems; and (3) fatigue presenting in the context of MS.
Psychological therapies for mental health problems presenting for adults living with MS
Conclusions are drawn based on synthesis of evidence from 15 systematic reviews, meta-analyses and clinical guidance documents published between 2014 and 2024.(5,10,44-56). These papers provide best practice clinical guidelines and summarise data reported within RCTs on the effectiveness of psychological therapies for adults living with MS; including cognitive behavioural therapy (CBT) and mindfulness based approaches. All reviews highlighted limitations to quality of RCTs, with heterogeneity of intervention approaches and patient groups.
High quality evidence indicated the effectiveness of a variety of CBT-based approaches and intensities; including computerised, remote, face to face (FTF), group and individual modalities. There was a consistent finding of small to medium effect sizes (0.29 to 0.59) (46-53) for CBT-based approaches to treating depression, anxiety or psychological distress. CBT is included as a first line recommendation. Effectiveness of mindfulness-based approaches was demonstrated, but with less evidence in regard to longer term efficacy (10,48,52,54). Mindfulness interventions are included as alternative approaches.
Wider multidisciplinary rehabilitation programmes may incorporate physical therapy / exercise interventions alongside psychological interventions such as psychoeducation, CBT, goal setting and/or behavioural activation approaches (5). RCT evidence indicates moderate quality evidence for CBT components of comprehensive rehabilitation (55). Psychological therapies for MS-related mood changes are often embedded within rehabilitation programmes, and the component parts of intervention may be hard to separate in a critical review of the evidence. In consideration of the way in which NHS rehabilitation services are delivered, the Matrix evidence tables provide recommendations for a whole systems approach to identifying and treating psychological distress, anxiety and depression in the context of MS (informed and skilled levels); as well as enhanced or specialist psychological therapy treatment approaches.
Psychological interventions for common cognitive problems for adults living with MS
Definitions and rehabilitation approaches
Neuropsychological and cognitive rehabilitation approaches aim to ameliorate cognitive difficulties by supporting increased patient and family awareness of cognitive strengths and weaknesses; providing psychoeducation to improve adjustment; and teaching coping strategies for cognitive problems. A compensatory approach aims to introduce strategies to aid daily living, working around underlying impairment to improve adaptation by teaching the integrated use of external aids and internal meta-cognitive strategies. A restoration or remediation training approach focuses on targeting underlying impairment in a specific cognitive domain through drill and repeated practice exercises, delivered either by manual or computerised training sometimes termed “brain training”. The wider intention of neuropsychological and cognitive rehabilitation is to improve quality of life, independence, function, activity and participation (International Classification of Functioning, Disability and Health, ICF, World Health Organisation, WHO, 2001) (57).
Psychological interventions are often incorporated as one component within comprehensive rehabilitation programmes, and it can be difficult to identify key factors influencing intervention outcomes. In a whole systems approach to psychological intervention, rehabilitation incorporates informed and skilled psychology practice from all multi-disciplinary team (MDT) members; and highlights the importance of an MDT approach to rehabilitation including psychoeducation, goal setting, exercise and behavioural activation approaches from various professionals. Exercise and psychoeducation interventions have demonstrated small to moderate effects in ameliorating cognitive and mood symptoms in MS and an MDT approach has been shown to result in longer term gains in activity and participation (5,55,56,58,59). An evidence-based practice recommendation can be made for a holistic and comprehensive MDT approach to assessment and tailored management options for those living with MS and cognitive difficulties. Psychology roles include both direct and indirect patient work, supporting rehabilitation programmes more widely.
Current clinical practice for neuropsychological/cognitive rehabilitation in MS draws extensively from the evidence base for cognitive rehabilitation in acquired brain injury (ABI) (60) and clinicians are guided to consider the Matrix evidence tables for ABI interventions (see Matrix ABI evidence tables: https://www.matrix.nhs.scot/evidence-summaries/populations-requiring-special-considerations-and-adjustments/). Where they have proved effective in ABI, approaches for domains of speed, such as Time Pressure Management Training (61,62) or executive function, such as Goal Management Training (63), could be applied to treat these prevalent cognitive symptoms in MS; but there is little published evidence within MS-specific populations (5) and methodological issues affecting the quality of existing RCTs.
Caution is highlighted in the interpretation of synthesised results on cognitive training or “brain training” remediation approaches targeting underlying impairment. The utility of restorative (training) versus compensatory (strategy) approaches in MS are debated (64,65). Study quality in the recent NICE review of brain training was consistently reported as very low, with small population sizes, risk of study bias and uncertainty about findings when confidence intervals were considered (66). The intervention approaches aim to repeatedly practice tasks which mirror the later objective measurement of cognitive function used to determine intervention effectiveness (traditional neuropsychological assessments measuring underlying impairment). Concerns have been raised about passive control groups frequently used in “brain training” studies, which may not account for placebo or other active effects (67). Consideration may be required about whether continuous ongoing training would be required to sustain any potential remediation benefits in MS, akin to the administration of a pharmacological treatment effect which ceases when the medication is no longer taken (64). Recent studies in non-MS publications have highlighted concerns that “brain training” intervention may result in practice effects on trained tasks, with no evidence of transfer effects to other similar or unrelated cognitive tasks (68). Further research is required to determine generalisability of brain training remediation approaches to the wider aims of cognitive/neuropsychological rehabilitation in daily activity, participation and quality of life (5,69).
Summary of main results and recommendations
Conclusions are drawn based on synthesis of MS-specific evidence from 14 clinical practice guidelines, systematic reviews and meta-analyses/meta-syntheses published between 2014 and 2024 (5,59,60,66,70-79). These papers summarise studies of the effectiveness of psychological interventions (neuropsychological and cognitive rehabilitation) for cognitive problems presenting for adults living with MS, with a focus on RCT evidence.
Aligned with the NICE evidence review (66), three further systematic reviews found insufficient evidence to support or refute the effectiveness of cognitive rehabilitation techniques in MS (60,70,71) also highlighting poor reporting of intervention protocols and active treatment components (71).
Compensatory strategies alone or combined with comprehensive rehabilitation and/or computerised training demonstrated high quality evidence of small to medium effect sizes for outcomes in subjective memory report (SMD=0.16-0.32) and quality of life (SMD=0.17-0.42) (72,73). Low quality evidence reported small effect sizes for reduction on self-report measures of anxiety (-0.30) and depression (-0.23) (74). Low quality evidence was reported for outcomes on objective measures (cognitive testing) of immediate verbal memory (SMD=0.13-0.40) (59,75) delayed verbal memory (SMD=0.22) (59), processing speed (SMD=0.23-0.51) (72,73) and working memory (0.31) (74). The Story Memory Technique (SMT) was a practice recommendation in one review (76) based on just one high quality RCT demonstrating improvements on self-report and memory testing (list learning).
In the context of quality limitations described above, very low quality evidence indicates cognitive remediation approaches may have small to medium effect sizes on objective measures (cognitive testing) of verbal memory (SMD=0.54) (59), working memory (SMD=0.33) (59), attention (MD=3.74) (77) and visual memory (MD=2.72) (77). Higher quality evidence is lacking. In wider generalisability of practice training, one systematic review (59) reported no effect on mood, participation, quality of life or subjective cognition measures; and one other (77) reported low quality evidence of reduced self-reported depression scores (MD=-3.27) (77). There is a lack of evidence for longer term effects. Due to study quality and practice limitations, no recommendation for use of this approach alone is made in evidence tables at this time; but it may be considered an adjunct to compensatory rehabilitation approaches.
Qualitative synthesis of self-report from MS participants in neuropsychological/rehabilitation programmes (78) found evidence of increased awareness, understanding and reflection around cognitive difficulties; and increased strategy use, transferability of skills, improved confidence, perseverance, social, emotional and quality of life. Group approaches invoked a beneficial sense of community and sharing/learning from others in the same situation. The authors highlighted the limitations of currently available quantitative measures of subjective cognitive difficulties and potential insensitivity of cognitive measures to the targets for rehabilitation.
One systematic review examined mindfulness and acceptance-based RCTs, reporting moderate effects on self-report measures of quality of life (SMD=0.56), attention (SMD=0.56) and coping (SMD=0.45) post-intervention; with large effects for self-reported and objective tests of memory in three RCTs (SMD=0.81) and self-reported quality of life (SMD=0.81) at follow-up (79). Mindfulness is recommended as an alternative approach, but further high quality evidence is required.
Psychological therapies for MS-related fatigue
Conclusions are drawn based on synthesis of evidence from eleven practice guidance papers, systematic reviews or meta-analyses published between 2014 and 2024 (5,10,54,80-87). These papers summarise data reported within RCTs on the effectiveness of psychological interventions for fatigue presenting for adults living with MS; including CBT and mindfulness based approaches.
Evidence indicated the effectiveness of a variety of CBT-based approaches and intensities; including remote, FTF, group and individual modalities (5,10,54,80,81). CBT in this context aims to identify and manage cognitive, behavioural, emotional and external factors that may perpetuate MS-related fatigue (80,81), where fatigue-targeted CBT has been found to be superior to distress-targeted CBT and to pacing/energy conservation fatigue management methods (81,83). There is high quality evidence that CBT-based approaches have a medium effect in reducing self-reported fatigue immediately post-discharge (SMD=0.47-0.60) (80,81,83,85), but with reduced effects observed by follow-up (SMD=0.30-0.39) (80,81,83,85).
Meta-analyses indicate high certainty of a small overall effect size of traditional energy conservation approaches (classed as behavioural therapy interventions) on fatigue severity at discharge (0.19-0.37) (81-84); Education approaches alone (0.17-0.20) (81,83,84); And self-management approaches where results were mixed and effect sizes could not be calculated (86). Mindfulness-based approaches for MS-related fatigue indicated small effect sizes when compared with any control group (0.24) and against active control groups (0.10) (87). Only a small number of available RCTs indicated mixed evidence supporting effectiveness making it difficult to draw over-arching conclusions on mindfulness-based approaches to MS-related fatigue (10,87).
Physical rehabilitation programmes may incorporate informed and skilled PT concepts, such as goal setting and behavioural activation (5). Physical therapy and exercise interventions have demonstrated moderate to high improvement of MS-related fatigue symptoms (82,83,88). These studies are not incorporated in the evidence detailed above where PT evidence is more clearly described. Comprehensive rehabilitation combining CBT, neuropsychological rehabilitation approaches (psychoeducation, compensatory and coping strategies) and physical exercise may optimise pooled success for rehabilitation across mood, cognition and fatigue symptoms in MS.
Overview of Evidence for Harms and Adverse Effects
Psychological therapies have the potential to have adverse effects. Until recently, information on potential harms and rates of adverse effects has not been gathered systematically. Although reports of adverse effects are increasingly included in research trials and gathered as part of service provision, we do not know if psychological interventions cause more, fewer or similar numbers of adverse effects than no treatment or another treatment, because the evidence in this area is of very low quality at present. Based on the limited available reports on adverse effects, the systematic reviews included in this Matrix review reported few side effects of intervention and concluded the approaches to be safe.
| Recommendation | Who for? | List of Interventions | Type of psychological practice | Evidence | Efficacy |
| First line recommendations | Adults with MS and depression (low mood, mild and/or moderate) | Rehabilitation programmes: incorporating psychoeducation, goal setting, CBT-informed practice, physical therapy and behavioural activation (5,10,51,52,55,56) | Skilled - Enhanced | A | Low -Medium |
| Enhanced psychological interventions (computerised CBT, group-based peer support, or self-help based on CBT principles; remote and in-person (10,46-52,54 | Enhanced | A | Low - Medium | ||
| CBT based interventions (Individual and Group-based; remote and in person) 10,43-47,49-54) | Enhanced/Specialist | A | Low - Medium | ||
| First line recommendation | Adults with MS and moderate- severe depression | Specialist interventions (group or individual CBT) are advised for severe or complex depression, or mild to moderate depression that has not responded to low-intensity interventions (10,44,46,47) | Specialist | A | Medium |
| First line recommendations | Anxiety (all presentations: psychological distress, mild, moderate and/or severe) | Enhanced or specialist interventions based on CBT principles; including self-help, guided self-help, or psychoeducational groups; remote and in person (10,44,48-50,52-54) | Enhanced/Specialist | A | N/A |
| CBT based group interventions (44,46,48) | Enhanced/Specialist | A | Low | ||
| Alternative (evidence less established; long term efficacy less established) | Adults with MS and mild to moderate Anxiety or Depression | Mindfulness based interventions (Individual and Group-based) (10,48,49,52,54) | Enhanced/Specialist | B | N/A |
| Recommendation | Who for? | List of Interventions | Type of psychological practice | Evidence | Efficacy |
| Professional practice approach | All adult presentations | All professionals should be aware that cognitive problems present in MS. Person-centred routine review of individual needs should include interview/screening to assess any presenting cognitive problems (5) | Informed - Skilled | C | N/A |
| Anxiety, depression, difficulty sleeping, fatigue and medication can all impact on cognition. Individual assessment and management of these factors should be considered to alleviate cognitive impact (5) | Informed - Specialist | C | N/A | ||
| First line recommendations | Persistent cognitive problems | Tailored management planned according to identified individual needs (5) | Skilled - Specialist | C | N/A |
| Comprehensive cognitive assessment to identify individual profile of strengths and weaknesses (5) | Specialist | C | N/A | ||
| Compensatory strategies (alone or combined with comprehensive rehabilitation and/or computerised training tailored to individual needs) (59,72-78) These may incorporate: - Aim to increase patient and family awareness of cognitive strengths and weaknesses; - Psychoeducation to improve awareness and adjustment; - Teaching coping strategies for cognitive problems; - Compensatory strategies (external and aids internal meta-cognitive strategies such as the Story Memory Technique); - Cognitive training approaches (only when incorporated within one or more compensatory rehabilitation approaches)] |
Specialist | A | Low- Medium | ||
| Alternative (evidence less established) | All adult cognitive problems | Mindfulness and acceptance-based approaches (79) | Enhanced - Specialist | B | Medium |
| Recommendation | Who for? | List of Interventions | Type of psychological practice | Evidence | Efficacy |
| Professional practice approach | All adult presentations | All professionals should be aware that fatigue problems present in MS. Information should be offered, including identification of potential triggers; including heat, biological, physical and emotional stress factors (5) | Informed - Skilled | C | N/A |
| Sleep, pain, spasticity, bladder function, medication, illness, anxiety and depression can all impact on fatigue. Individual assessment and management of these factors should be considered to alleviate fatigue (5) | Informed - Specialist | C | N/A | ||
| First line recommendations | Persistent fatigue | Cognitive behavioural therapy (CBT) approaches for fatigue management (including in person and remote (5,6,55,81-84) | Enhanced - Specialist | A | Medium |
| Alternative approaches (evidence less established and/or evidence of lower effectiveness) | All adult presentations | Additional management approaches tailored to identified individual needs (5). This may incorporate: - Self-management approaches (86) - Education (81-84) - Identifying goals and priorities (5) - Reviewing lifestyle factors (e.g. exercise) (5) |
Skilled -Specialist | B | Low |
| Behavioural therapy approaches - i.e. Energy conservation/behavioural activation (81-84) | Enhanced - Specialist | B | Low | ||
| Mindfulness and acceptance-based approaches (5,10,87) | Enhanced - Specialist | B | N/A |
With thanks to representatives from Heads of Neuropsychology Scotland and the MS Society Scotland for their involvement and feedback.
Advisory group members: Emma Burton, Tracey Harrison, Sarah McNeish, Lauren MacLean, Leeanne Nicklas, Ruth Sumpter, Lesley Williams.
Technical group members: Ruth Sumpter, Leeanne Nicklas.
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