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The Prevalence of Comorbidities and Their Association With Disability Progression in Individuals With Multiple Sclerosis: A Study From Brazil

Older adults with multiple sclerosis (MS) face unique issues related to the combined effects of MS and age-related changes, which often present with overlapping symptoms that complicate assessment and treatment decisions. In this review, based on the Consortium of MS Centers’ Aging and MS Consensus Statement committee meeting in 2024, we address the contributions of aging in MS by focusing on direct, biological aging effects on MS pathology and comorbid age-related changes in physical and cognitive function. Features of biological aging include cellular senescence and immune dysregulation, which may drive disease progression in MS through a variety of proinflammatory mediators that may maintain low levels of chronic inflammation in the immune and central nervous system compartments and offset regulatory processes, ultimately impairing remyelination and increasing neurodegeneration. Measuring biological aging in MS may help identify individuals at risk of worse MS outcomes and support gerotherapeutic treatments that target aging mechanisms. Compounding any direct effects of aging on MS pathology, aging-related impairments in neuromuscular function and cognition can worsen functional outcomes in people with MS. Characteristics of cognitive impairments in MS affecting attention and processing speed occur early in the disease course and are distinct from other age-associated neurodegenerative disorders, such as Alzheimer disease, that commonly affect language and executive function domains. As MS clinicians care for growing numbers of older adults with MS, a more comprehensive understanding of the interplay between aging and MS-related changes can improve the timing and modality of treatments to optimize MS neurogeriatric care.

From the Division of MS/Neuroimmunology, The Ohio State University, Wexner Medical Center, Columbus, OH (YZ); UCHealth Yampa Valley Medical Center, Steamboat Springs, CO (PB); Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada (SAM); Department of Neurology, Georgetown University Medical Center, Washington, DC, (JW); Departments of Medicine and Community Health and Epidemiology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada (RAM); Nova Scotia Health, Halifax, Nova Scotia, Canada (RAM); Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Neurology, University of Colorado Anschutz School of Medicine, Aurora, CO (JB); Department of Neurological Sciences, University of Nebraska, Omaha, NE (RStewart); Independence Care System, Brooklyn, NY (RStacom); private practice, Greensboro, NC (MDB); Departments of Internal Medicine and Geriatrics, University of Nebraska Medical Center, Omaha, NE (MTC); Ferkauf Graduate School of Psychology, Yeshiva University, Bronx, NY (FWF); Multiple Sclerosis Center, Holy Name Medical Center, Teaneck, NJ (FWF); Department of Neurology, University of Colorado Anschutz School of Medicine, Aurora, CO (JRC); Department of Clinical Neurology, Johns Hopkins School of Medicine, Baltimore, MD (SDN); Department of Neurology, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV (LHH); Department of Neurosciences, University of California San Diego, San Diego, CA (JSG). 

Yinan Zhang, MD, 395 West 12th Ave, 7th Floor, Columbus, OH 43210; 

This manuscript stems from presentations and discussions at the Consortium of Multiple Sclerosis Centers (CMSC) Aging and Multiple Sclerosis Consensus Conference held June 1-2, 2024, and is based on the CMSC publication “MS and Aging: A Summary Statement From a CMSC Consensus Conference.”

 Jeffrey Wilken, PhD, has been a speaker for Biogen, EMD Serono, and Sanofi; a paid consultant for Bayer and Sanofi; and has received research funding from Biogen and Sanofi. Ruth Ann Marrie, PhD, MD, receives research funding from the Arthritis Society, the Canadian Institutes of Health Research, Children’s Hospital Research Institute of Manitoba, Consortium of Multiple Sclerosis Centers, Crohn’s and Colitis Canada, Manitoba Medical Service Foundation, MS Canada, National Multiple Sclerosis Society, Pfizer Foundation, Public Health Agency of Canada, and the US Department of Defense. She is a coinvestigator on studies receiving funding from Biogen Idec and Roche Canada, and holds the Multiple Sclerosis Clinical Research Chair at Dalhousie University. Jacquelyn Bainbridge, PharmD, has served on advisory boards for EMD Serono, Novartis, and TG Therapeutics. Renee Stewart, APRN-DNP, has been on an advisory board for Genentech. Rachael Stacom, NP, has served on advisory boards for Genentech and TG Therapeutics. Frederick W. Foley, PhD, has been on advisory boards for Bayer and Biogen; has been a paid consultant for Biogen; and has been a speaker for EMD Serono and Sanofi. John R. Corboy, MD, MA, has received compensation as the medical director of the Rocky Mountain MS Center and associate editor of the 

. He has received research support from EMD Serono, the National Institute of Health via the Immune Tolerance Network, and the National Multiple Sclerosis Society. Le H. Hua, MD, has received personal fees for speaking, consulting, and advisory board activities from Alexion, EMD Serono, Genentech, Genzyme, Horizon, Novartis, and TG Therapeutics, and has had research support paid to her institution from Genentech outside the submitted work. Authors Yinan Zhang, MD; Patty Bobryk, MHS, PT, MSCS, ATP; Sarah A. Morrow, MD, FRCPC, MS; Mona D. Bostick, RDN; Maureen T. Choman, MD; Scott D. Newsome, DO; and Jennifer S. Graves, MD, PhD, MAS, have nothing to disclose.

Disease activity in multiple sclerosis (MS) diminishes with age, with fewer relapses and decreased new T2 lesion formation on brain and spine MRI.

 Concurrently, age increases the risk and rate of developing nonrelapse-related disability accumulation.

 Age strongly correlates with declines in physical and cognitive function in MS, and there is overlap between MS progression and non-MS age-related changes. Older adults experience the combined effects of MS and age-related changes (

). Providers and patients often face challenges in distinguishing whether neurological symptoms are due to aging, MS-specific decline, or an interaction of the two. In this review, we discuss pathophysiological changes and biomarkers of aging in MS and describe age-related changes in physical and cognitive function in people with MS. Understanding aging processes and their role in the MS disease course may lead to improved markers of disease progression and uncover new targets for therapy.

Pathophysiological Changes of Aging and MS

Although chronological age is the greatest risk factor for MS disease progression, the age at which people experience progression or reach disability milestones varies. Individual differences in biological age may explain this variation. Biological age reflects the cellular, molecular, and genetic mechanisms of aging, and emerging evidence suggests accelerated biological aging in people with MS.

 Aging mechanisms are related to damage accumulation, response to damage, and loss of reserve and compensatory ability, which collectively drive the irreversible decline in function from accumulation of cellular and molecular damage over time.

Aging is associated with cellular senescence and age-related immune exhaustion and dysregulation, referred to as immunosenescence.

 When cells permanently exit the cell cycle and become senescent in response to damage and stressors, the accumulation of senescent cells produces mediators of inflammation through the senescence-associated secretory phenotype (SASP).

 SASP mediators hinder remyelination and contribute to neurodegeneration and functional decline.

 In MS, particularly in progressive MS, senescent cells are in the tertiary lymphoid aggregates within the brain meninges and contribute to widespread microglial activation and SASP expression.

 In postmortem MS brain tissues, there is elevated expression of the senescence marker 

 in MS lesions compared with normal white matter.

 One senotherapeutic approach is to try to remove senescent cells using senolytic agents that disrupt their antiapoptotic pathways. Studies in experimental autoimmune encephalomyelitis, the widely used animal model of MS, have shown that some senolytics lead to improved function and survival.

 A clinical trial of senolytics in MS is underway (NCT07270120).

Immunosenescence in MS results in a shift of immune cells toward terminally differentiated lymphocytes and activated microglia.

 Thymic involution occurs with aging and results in decreased naive T cells and increased memory T cells, which leads to decreased T-cell receptor repertoire and impaired antigen recognition.

 Compared with controls, people with MS tend to have a lower frequency of naive T cells and a higher frequency of terminally differentiated effector memory T cells.

 B cells also decline with age, with a decrease in naive B cells and an increase in dysfunctional antigen-experienced B cells.

 Microglia are activated in chronic active MS lesions and drive neuroinflammation by secreting SASP mediators.

Other aging processes also play a role in MS progression. Aging-induced oxidative stress drives cellular senescence and mitochondrial dysfunction that damage neurons.

 Increased production of reactive oxygen species promotes oxidative stress and hinders energy production.

 Age-associated increases in gastrointestinal permeability lead to gut dysbiosis, resulting in the release of pathogen-associated molecular patterns, which are central nervous system penetrant and contribute to microglial activation.

 Aging also alters the gut microbiome, which may also contribute to MS progression.

Aging biomarkers reflect mechanisms of aging and provide insights into the processes that drive the onset and progression of age-related diseases. There are a variety of biomarkers reflecting the different hallmarks of aging, and several have been studied in people with MS. Multiple studies have measured telomere length in people with MS, where the progressive shortening of the protective endcaps of genomic DNA contributes to genomic instability and the DNA damage response and, ultimately, to replicative senescence.

 Several studies, but not all, have found shorter telomere lengths in people with MS compared with a control group, and there appears to be an association between shorter telomere length and greater disability in MS.

Aging has also been associated with epigenetic alterations. Epigenetic clocks have been derived from differential methylation patterns to predict life span (mortality) or health span–based outcomes.

 In people with MS, epigenetic age acceleration can be seen in both adults and children.

 As clinically accessible tools, composite biomarkers such as the National Health and Nutrition Examination Survey Biological Age Index (NHANES BAI), comprised of a 10-item clinical index of physiological measures and routine lab tests, may also be useful. The NHANES BAI has been shown to be elevated in people with MS compared with controls.

 Reproductive aging, marked by age-related decline in sex steroid hormones, has been shown to contribute to disability accumulation in women with MS, as measured by levels of anti-Müllerian hormone.

Although the precise mechanisms by which biological aging drives MS disease activity and progression are unclear, measuring biological aging in MS may advance clinical practice by informing clinical trial design of drugs that target processes, referred to as gerotherapeutics, which are studied in age-related diseases. Aging biomarkers also have the potential to stratify disease severity in MS if strong associations can be determined between biological aging and MS disease outcomes.

MS impacts overall physical function, neuromuscular performance, and physical activity levels, but there is only a modest understanding of the contribution of normal aging processes to these measures in older populations. Aging leads to reduced physiological reserve and performance,

 and there is overlap between MS disease-specific mechanisms and age-related health changes. The ability to identify and understand the similarities and distinctions between aging and the impact of MS on physical functioning may enable appropriate, targeted, and timely clinical interventions.

Physical function is divided into basic activities that are essential for independent living and complex activities that are discretionary and not required for independent living, but may affect quality of life.

 Many factors contribute to overall physical functioning beyond the presence or absence of disease, including perceptual, environmental, and behavioral considerations. The Short Physical Performance Battery (SPPB) is a tool that measures physical function and mobility in older adults.

 It includes assessments of balance, gait speed, and lower extremity strength, with a higher summary score indicating greater functional ability. The SPPB score typically declines with age in the general population.

 This tool has also been validated as a measure of lower-extremity physical function in people with MS across the life span.

 In a study that compared 345 people with MS and 174 controls across 6 age groups, SPPB scores declined along the life span in people with MS to a greater extent than those of controls.

 Strength was a robust component of physical functioning across most age groups.

Further support for the amplified decline of physical functioning in people with MS was demonstrated in a study that included 698 people with MS (aged 29-71 years) and 226 controls (aged 18-72 years).

 Performance tests were administered, including ambulation (Timed 25-Foot Walk Test) and upper extremity function (9-Hole Peg Test). The progression of motor decline increased synergistically in individuals with MS as they aged.

Accelerated decline in physical functioning during middle age was observed in people with MS in a longitudinal study. The 10-Item Physical Functioning Scale (PF-10) was used to assess various aspects of physical functioning in 733 women with MS over the course of 25 years.

 PF-10 scores declined in both the controls and in people with MS, but the decline was 3 to 4 times faster in midlife for those with MS. Specifically, a 45-year-old woman with MS exhibited physical function levels comparable to those of a 75-year-old woman without MS, suggesting a 30-year acceleration in functional decline due to the disease.

Physical activity declines with age in the general population, but this decline is more pronounced in people with MS.

 Recent study data confirm that older adults with MS are much less physically active than age-matched individuals without MS, and this can lead to compounding deleterious effects on physical function and worsening overall health.

 Older adults with MS exhibited lower step counts and greater sedentary time compared with controls without MS, despite adjusting for age, sex, and comorbidities. These differences may reflect not only the impact of aging but also MS-specific factors such as fatigue, balance issues, and reduced motor function.

Frailty is an age-related state characterized by decreased physiological reserve and increased vulnerability to adverse health outcomes. Common frailty measurements include the frailty phenotype, which assesses the presence of 3 or more out of 5 clinical manifestations, including weight loss, slow walking speed, low physical activity, exhaustion, and weak grip strength, and the Frailty Index, which evaluates the accumulation of deficits across a list of health-related variables that can be customized to the relevant clinical or research setting.

 In people with MS, frailty is associated with high disability, disease duration, and progressive MS.

 Although frailty may overlap with neurological disability in MS, its additional elements help capture the clinical complexity in MS and guide management and prognosis.

Muscle performance naturally declines with age due to physiological changes, such as decreased muscle mass, strength, and endurance.

 Neuromuscular function is the muscle’s ability to generate force and power, including the underlying neural and muscular determinants (such as voluntary activation and contractile properties). The combination of neural function (central) and muscular properties (peripheral) provides neuromuscular function, which then yields physical function and health-related outcomes, such as quality of life. In MS, age and the disease itself combine to reduce neuromuscular function.

 The rate of force development, which represents the ability to rapidly generate muscle force at the start of a maximal contraction, was up to 70% lower in people with MS than in controls across age groups. This becomes important in functional skills, where speed of contraction is essential, for example, a quick balance correction to prevent a fall.

 The study data also revealed that this decline begins early in the disease course and accelerates through middle age, with the most pronounced reductions seen in older adults with MS. An additional study investigated muscle power (work over time) and found a similar pattern of loss that was most evident in early to middle age, where changes in controls occurred later in the life span.

The authors suggest that this should be an area of targeted therapy early in the disease trajectory.

People with MS experience more pronounced and complex alterations in muscle function. Research has shown that people with MS exhibit substantial impairment compared with controls in isometric and dynamic muscle strength, particularly in knee extensors and plantar flexors, with deficits ranging from 18% to 38%.

 Plantar flexors of the ankle were preferentially affected in people with MS vs age-matched controls, and these deficits are linked to limitations in walking and stair climbing. In addition, people with MS demonstrate an altered muscle oxidative mechanism, leading to impaired exercise tolerance at the muscle level.

Aging is associated with worsening cognition, specifically in executive function, prospective memory, learning and retrieval, information processing speed, shifting attention, and visuoperceptual judgment.

 Cognitive impairment (CI) in people with MS most commonly involves slowed cognitive processing speed and deficits in episodic memory, executive function, and verbal fluency.

 Visuospatial ability is affected less frequently.

 Aging results in increased prevalence of CI in people with MS, which, in one study, was seen in 77.4% of adults over age 55 compared with 42.8% of younger patients,

 and CI was found in 48% of people with MS who had 3 decades of disease duration.

Only a few studies have directly examined the interaction between aging and cognitive decline in MS. For the most part, these studies have not demonstrated accelerated cognitive worsening or an interaction between the aging process and cognition in older people with MS.

 However, in late-onset MS, working memory and visuospatial memory (learning and recall) were more frequently and severely impaired than in people with earlier-onset MS, suggesting that MS-associated cognitive changes may be exacerbated by age-related brain changes, leading to reduced reserve and accelerated cognitive decline.

CI usually presents differently in older people with MS than in people with other degenerative diseases, such as amnestic mild cognitive impairment (aMCI) and Alzheimer disease (AD). Studies have found there may be a similar decrease in semantic fluency in people with MS and people with aMCI.

 However, people with aMCI typically perform much worse on delayed memory measures than people with MS. In addition, people with progressive MS have greater deficits in attention, episodic memory, and information processing speed, whereas people with AD have impaired learning, memory, and verbal skills.

 CI in older people with MS, as well as the potential overlap with other neurogenerative diseases such as AD, is still understudied and poorly understood. Other age-related conditions, such as vascular comorbidities, further contribute to CI in MS.

 There is still much to learn regarding the impact of aging on the MS disease course, the risk of other causes of cognitive impairment in people with MS, and the impact of other common comorbidities.

With improved disease management and increased life span, more individuals with MS are entering older age and are experiencing the dual burden of MS-related impairments and age-related decline. MS introduces disease-specific impairments that often result in functional limitations earlier and more severely than those seen in typical aging. As the MS population ages, clinicians must consider the interaction between age and MS-related decline and incorporate assessments and interventions that address both processes.

Understanding age-related changes in multiple sclerosis (MS) may help inform treatment decisions that address normal aging and MS-related aging processes.

Age-Related Changes in Multiple Sclerosis Pathophysiology and Clinical Function

 To access the article and evaluation online, go to 

 The target audience for this activity is nursing professionals, advanced practice clinicians, physicians, rehabilitation professionals, mental health professionals, social workers, and other health care providers involved in the management of patients with multiple sclerosis (MS).

Distinguish between the concepts of self-management and self-efficacy and effectively apply them in the promotion of rehabilitation care for patients with MS.

Select best instruments to measure patients’ self-management skills which can improve selection of intervention factors (theory, satisfaction, duration) necessary in the development and refinement of effective self-management interventions.

In support of improving patient care, this activity has been planned and implemented by the Consortium of Multiple Sclerosis Centers (CMSC) and Intellisphere, LLC. The CMSC is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the health care team.

This activity was planned by and for the healthcare team, and learners will receive .5 Interprofessional Continuing Education (IPCE) credit for learning and change.

 The CMSC designates this enduring material for .5 contact hour of nursing continuing professional development (NCPD) (none in the area of pharmacology).

 The CMSC designates this journal-based activity for a maximum of .5 

. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

 As a Jointly Accredited Organization, the CMSC is approved to offer social work continuing education by the Association of Social Work Boards (ASWB) Approved Continuing Education (ACE) program. Organizations, not individual courses, are approved under this program. State and provincial regulatory boards have the final authority to determine whether an individual course may be accepted for continuing education credit. The CMSC maintains responsibility for this course. Social workers completing this course receive .5 continuing education credits.

 It is the policy of the Consortium of Multiple Sclerosis Centers to mitigate all relevant financial disclosures from planners, faculty, and other persons that can affect the content of this CE activity. For this activity, all relevant disclosures have been mitigated.

), and planner for this activity has disclosed no relevant financial relationships. 

, has disclosed no relevant financial relationships. Authors 

Rouven Brenner, MScN; Verena Witzig-Brändli, MScN; Janine Vetsch, PhD

, have disclosed no relevant financial relationships.

, CMSC, and Intellisphere, LLC who are in a position to influence content have disclosed no relevant financial relationships. 

, CMSC continuing education director, has served as a planner and reviewer for this activity. She has disclosed no relevant financial relationships.

Release Date: July 1, 2022; Valid for Credit through: July 1, 2023

In order to receive CE credit, participants must:

1) Review the continuing education information, including learning objectives and author disclosures.

3) Complete the posttest and evaluation, which are available at 

Statements of Credit are awarded upon successful completion of the evaluation. There is no fee to participate in this activity.

 This educational activity may contain discussion of published and/or investigational uses of agents that are not approved by the FDA. The CMSC and Intellisphere, LLC do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the CMSC or Intellisphere, LLC.

 Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any medications, diagnostic procedures, or treatments discussed in this publication should not be used by clinicians or other health care professionals without first evaluating their patients’ conditions, considering possible contraindications or risks, reviewing any applicable manufacturer’s product information, and comparing any therapeutic approach with the recommendations of other authorities.

Rehabilitative nursing interventions are vital in the treatment of multiple sclerosis (MS), but there is a lack of evidence on the effectiveness of such interventions. This review aims to summarize outcomes of nurse-led rehabilitation interventions for patients with MS, focusing on patients' self-efficacy and self-management and their satisfaction with the intervention. This review is the first step of our overarching goal of developing, implementing, and evaluating a research-supported nursing consultation intervention in inpatient rehabilitation.

We searched 3 databases from their dates of inception until April 2020 (and performed another search in August 2021) for studies involving adult patients diagnosed as having MS. We focused on studies with interventions aimed at self-efficacy and self-management of MS and studies on intervention satisfaction. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

We included 4 studies in this review with a total of 271 participants. All interventions were educational and included training programs. All studies assessed self-efficacy, and all identified an improvement in self-efficacy, particularly through group training interventions. One study focused on self-management, reporting an improvement resulting from the intervention. Two studies evaluating satisfaction with the intervention obtained good overall satisfaction scores from participants, and 1 study's program was strongly recommended by participants.

This review indicates that self-efficacy and self-management abilities may be effectively promoted, particularly through group training interventions. An intervention tailored and adapted to the needs of patients with MS may promote satisfaction with the intervention and might consequently improve adherence to rehabilitation interventions.

We thank Vanessa Gasser (Eastern Switzerland University of Applied Sciences, School of Health Professions) for useful discussion and her support in the data extraction.

 The authors declare no conflicts of interest.

 The authors disclosed receipt of the following financial support for the research, authorship, and publication of this article: Swiss MS Society.

Multiple sclerosis (MS) is a demyelinating, chronic, inflammatory disease of the central nervous system, and it is the leading cause of disability in young and middle-aged adults in the developed world.

 It has an unpredictable disease course and can be classified into different patterns with different prevalence rates.

 Globally, MS affected approximately 2.8 million people in 2020, and incidence and prevalence rates are increasing

 due to longer life expectancy and an increased average age because of medical advancements in MS treatment

 and management of the superimposed comorbidities often diagnosed in patients with MS.

 Structured, multidisciplinary rehabilitation programs are essential to address symptom burden and disability associated with the disease and its comorbidities.

The World Health Organization defines rehabilitation as “a set of interventions designed to optimize functioning and reduce disability in individuals with health conditions in interaction with their environment.”

 Rehabilitation thus aims to improve functional independence and increase participation through promotion of self-management abilities.

The International Classification of Functioning, Disability and Health, a World Health Organization conceptual framework, offers a common approach to describe patients’ health conditions and health-related domains, such as bodily functions, activities, and participation.

 Not only does it describe body, individual, and societal perspectives, it also lists environmental factors that interact with all these components.

 Self-management and self-efficacy are key factors in the domains of participation (eg, in work, family) and activities (eg, self-care, daily routines).

 Based on the International Classification of Functioning, Disability and Health model, the desired outcome for rehabilitation is improved functional independence and enhanced participation in society. This can be achieved by emphasizing patient education and self-management.

Rehabilitation of individuals with MS often requires repeated inpatient stays in specialized rehabilitation clinics with 24-hour care.

 However, depending on the needs of the individuals, rehabilitation may be accessed in outpatient clinics.

 There are also international differences between patients with MS being inpatients or outpatients. In the western part of Europe, patients with MS are more likely to be treated in outpatient settings, and in the eastern part more inpatient rehabilitation services are available.

 Regardless of the setting, nurses are key players in the multidisciplinary rehabilitation team and are part of all aspects of the rehabilitation process. Due to their continuous, robust patient relationships and their 24/7 presence, they have the best insight into patients’ situations.

 For example, nurses can detect changes in a patient’s state of health immediately and initiate appropriate interventions. Or, as nurses gain more in-depth patient information, they can support their self-management in a patient-centered way to maintain holistic care

 In the outpatient setting, nurses assist patients in making the transition from the perspective of their disease needs in a clinical context to integrating those disease needs into their daily lives.

 This was recently highlighted by the Association of Rehabilitation Nurses in a competency model for professional rehabilitation nursing. One of the model’s 4 main domains is promotion of successful patient living, which includes fostering their ability to live independently at home or in a community living situation.

 Self-management is “the individual’s ability to manage the symptoms, treatment, physical and psychosocial consequences and lifestyle changes inherent in living with a chronic condition.”

 Self-management interventions are an important part of the rehabilitation process and are seen as key to active and effective disease management, especially after inpatient rehabilitation stays.

 A Cochrane review demonstrated that multidisciplinary inpatient rehabilitation leads to short-term gains for patients with MS; however, there was no evidence of long-term gains.

 Data about the successful implementation of self-management interventions into daily routines to achieve long-term behavior change are limited. A small study demonstrated that patients with MS in an outpatient setting had significantly higher self-efficacy for health promotion activities than the control group after an 8-week multidisciplinary health promotion education intervention.

 Another study in an outpatient setting found increased self-efficacy after 5 cognitive behavioral group sessions. The study group demonstrated a significant increase in self-efficacy after the intervention compared with the control group.

 However, these interventions were delivered by different health care professionals.

According to Bandura, successful self-management interventions that support a patient’s ability to change the way they live with a chronic condition require an underlying mechanism of self-efficacy.

 Self-efficacy is defined as a person’s belief in their ability to succeed in a particular situation.

 Translated to the rehabilitation of individuals with MS, self-efficacy describes how confident an individual with MS feels when implementing self-management interventions in their daily routine. Self-efficacy is a crucial psychological factor that reflects a patient’s confidence in managing their disease and is a strong predictor of self-management abilities.

Previous studies with nursing interventions reported positive effects on self-efficacy and/or self-management in patients with neurologic

 Evidence of effective interventions to increase self-efficacy and self-management is also available for patients with MS. However, these interventions were performed by health professionals,

 and, if they were implemented by nurses, they did not occur in the rehabilitative setting.

 Therefore, little is known about the effectiveness of nursing interventions focusing on self-efficacy and self-management of rehabilitation patients with MS.

Besides the summative outcomes of self-efficacy and self-management, satisfaction with the intervention is an important process outcome. Only when patients accept an intervention are they willing to use it continously.

 Understanding patient satisfaction with an intervention at an early stage will enhance the understanding of successful intervention implementation.

 Therefore, we focus on patient satisfaction with the intervention in this review, too.

This review is the first step of our overarching goal of developing, evaluating, and implementing a research-supported nursing consultation intervention using the Medical Research Council (MRC) framework.

 This intervention aims to continuously improve the self-efficacy and disease self-management abilities of individuals with MS through continuous contact with rehabilitation nurses regardless of inpatient or outpatient status. The renowned MRC framework will support the development process of this complex intervention. This intervention is considered complex because it has different interacting components (continuous nurse-patient relationship, self-management goal setting, etc). The intervention targets various patient-centered self-management behaviors based on the individual patient’s goals. Due to the patient-centered self-management goals, this intervention must be quite adaptive.

 The systematic review of research evidence in the development phase of an intervention is a main part of the MRC framework. A systematic review supports the identification of existing interventions to understand the evidence base.

 Therefore, this review summarizes the outcomes of nurse-led rehabilitation interventions focusing on the individual with MS’s self-efficacy and self-management and their satisfaction with the intervention.

We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)

We used a search string to search MEDLINE (via PubMed), the Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Library from their inception through April 15, 2020. These databases were seen as the optimal combination to identify all relevant studies answering the research question.

 Two authors also handsearched Google Scholar (R.B., J.V.) using different search terms and screened the first 10 pages to identify any studies answering the research question that are not indexed in the databases. As a supplementary search method, we screened all reference lists of included studies to identify additional articles. The database searches were repeated on August 3, 2021, but no additional relevant studies were identified.

The search strategy was developed by 3 of us (R.B., J.V., M.K.) and was adapted according to the requirements of each database (see 

, which are published in the online version of this article at IJMSC.org). The search was built with 4 main components: nursing, specific outcomes according to the study aims, MS, and rehabilitation. We used Medical Subject Headings where appropriate and free-text terms.

After duplicate article removal, 2 of us (R.B., J.V.) independently screened titles and abstracts for their eligibility using Rayyan (a free web and mobile app).

 The same authors independently screened the articles included for full-text screening. If consensus was not met, a third author (M.K.) was consulted. We retrieved all full texts and stored them using reference management software (Citavi; Swiss Academic Software GmbH).

All German- or English-language articles that focused on interventions to improve self-efficacy, self-management, and patient satisfaction in patients diagnosed as having MS who were older than 18 years were included. Studies with nursing interventions or interventions that could be performed by registered nurses (ie, educational interventions, counseling, or consultations) in inpatient and outpatient settings were included. We defined nursing interventions according to the National Institutes of Health guidelines for the systematic and progressive testing of nursing interventions.

 We included quantitative studies and mixed-method studies and excluded qualitative studies.

Two of us (R.B., V.W.) independently extracted the following data: author, year, country, study design, setting, participants, participants’ sociodemographic characteristics, intervention description (randomization, frequency, time point, etc), measurements, primary and secondary outcome measures, and primary and secondary outcome results related to study aims.

We used the Joanna Briggs Institute critical appraisal tools for quasi-experimental studies

 (qualitative part of any mixed-methods studies). Two of us (R.B., V.W.) independently assessed the quality of each article. Each item was judged with “yes,” “no,” or “unclear.” Any disagreements between reviewers were discussed and resolved by consensus. If consensus was not possible, a third author (M.K.) was integrated to reach a consensus. We did not exclude any study based on its quality.

The risk of bias was covered by questions in the Joanna Briggs Institute critical appraisal tools. These questions addressed selection bias (ie, similarity of participants), performance bias (ie, similarity of treatment of participants), attrition bias (ie, completeness of follow-up), detection bias (ie, equality of outcome measures across participants), and reporting bias (ie, reporting of all outcomes measured).

After the data were gathered, they were synthesized using an integrative approach, a narrative summary was written, and the findings were grouped according to the outcomes of interest related to the objectives of the review (ie, self-efficacy, self-management, and satisfaction with the intervention).

After identifying 846 studies, we removed 77 duplicates (9%) and screened all remaining 769 studies. After screening titles and abstracts against the review’s inclusion criteria, 86 studies (11%) were eligible for full-text screening. Of those, 4 were included in the review (

All included studies achieved a “Yes” of at least 50%. All the studies’ investigators described their inclusion criteria for the participants, and the groups were comparable at baseline. In addition, several outcome measures were used in all the studies before and after the intervention.

 Half of the studies had a control group.

 All of the studies completed some follow-up, but no studies completed or described any actions taken to reduce attrition rates.

 All results were measured comparably, but detailed information on the measures used was missing. All included studies used appropriate statistical analysis to calculate their results (

All assessed studies had a low risk of selection, detection, and reporting bias.

 The performance bias was unclear in 3 studies.

 However, according to the Cochrane Handbook, it may be possible to consider that risk of bias as low rather than high.

 For the 3 applicable studies, the risk of attrition bias was high (

In total, 271 patients with MS (203 female, 68 male) were included in the 4 studies. The mean ± SD patient age was 48.2 ± 7.9 years. The included studies were conducted in different settings: 1 inpatient study,

 and 2 studies with a mix of inpatients and outpatients.

 Two studies were conducted in rehabilitative settings.

 In the remaining 2 studies, rehabilitation is mentioned solely in the conclusion

 or in the description of the intervention.

All 4 studies were published after 2014. One study was conducted in Canada

 and the other 3 were conducted in Germany.

 Three studies used a quasi-experimental design,

 Two studies combined quantitative data with qualitative data.

"We encourage rehabilitation nurses from around the world to develop and distribute a comprehensive and generally accepted definition of rehabilitation nursing."

Maria Cecília Aragon de Vecino, MD

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