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Clinical Significance of Gastrointestinal and Flushing Events in Patients with Multiple Sclerosis Treated with Delayed-Release Dimethyl Fumarate

The ability to reliably monitor disease progression in patients with multiple sclerosis (MS) is integral to patient care. The Expanded Disability Status Scale (EDSS) is a commonly used tool to assess the disability status of patients with MS; however, it has limited sensitivity in detecting subtle changes in disability levels and, as a result, does not consistently provide clinicians with accurate insight into disease progression. At the 2019 European Committee for Treatment and Research in Multiple Sclerosis meeting in Stockholm, Sweden, a panel of neurologists met to discuss the limitations of the EDSS as a short-term predictor of MS progression. Before this panel discussion, a targeted literature review was conducted to evaluate published evidence on prognostic measures such as fatigue, physical assessments, and measures that are more taxing for patients, all of which may be useful to clinicians at different stages of the course of MS. This article summarizes currently available evidence in support of these measures. In addition, this article highlights the current state of expert clinical consensus regarding the current approaches used to predict and monitor disease progression and offers insight for future studies to assist clinicians in accurately monitoring disease progression in patients with MS.

From the Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA (BW-G); Department of Health Sciences, University of Genoa, Genoa, Italy (MPS); IRCCS Ospedale Policlinico San Martino, Genoa, Italy (MPS); and Swedish Medical Center at Seattle, Seattle, WA, USA (PR). 

 Bianca Weinstock-Guttman, MD, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, 1010 Main St, Buffalo, NY 14202, USA; 

 Dr Weinstock-Guttman has received grant/research support from, participated in speakers’ bureaus for, and/or served as a consultant for Biogen, EMD Serono, Novartis, Genentech, Celgene, AbbVie, Sanofi Genzyme, and Mallinckrodt and serves on the editorial board for 

. Dr Sormani has received consulting fees from Biogen, Merck, Novartis, Roche, Sanofi, Celgene, MedDay, GeNeuro, and Mylan. Dr Repovic declares no conflicts of interest.

 Financial support for the preparation of this review was provided by Celgene.

Multiple sclerosis (MS) is a chronic neurologic disease wherein overactive immune cells cause inflammation, demyelination, and axonal damage in the central nervous system. The resulting degenerative disease course requires accurate, sensitive, and comprehensive measures for the purposes of monitoring progression and making patient care decisions.

The Expanded Disability Status Scale (EDSS), an ordinal, clinician-administered assessment scale with scores ranging from 0 to 10, is widely used to assess the status of patient disability in MS. Short-term sustained changes in disability status are often reported in terms of confirmed disability progression (CDP), the presence of which corresponds to an increase in EDSS score maintained on repeated evaluation at 3 to 6 months. However, several studies have criticized the EDSS and CDP for limitations related to their prognostic value, including lack of accuracy, limited sensitivity to change at certain disability levels of the disease, focus on physical ability, and nonstandardized interpretability.

 As a binary indicator, CDP in particular may offer limited value for prediction of disability progression. Although the EDSS does have some predictive value, certain aspects, such as intrarater and interrater variability, leave room for improvement.

 Given these limitations, there is a need for expansion in the tools used to gauge disease progression in clinical practice as well as clinical trials evaluating the efficacy of new MS treatments.

In this narrative review, we first summarize the available evidence of the predictive power of a select number of commonly used measures to assess MS progression. The goal of this review is not a systematic assessment but rather a targeted review of recent literature that focuses on specific end points related to MS progression. We then discuss available evidence on key limitations of the EDSS as a prognostic measure and highlight some measures that may assist in improving the sensitivity of this scale in the clinical management of MS. We highlight general viewpoints from a panel of 4 experts in MS research (the authors [B.W.-G., M.P.S., P.R.] and Dr Enrique Alvarez of the University of Colorado) convened at the 2019 European Committee for Treatment and Research in Multiple Sclerosis meeting in Stockholm, Sweden, held September 13 to 19, 2019. At this meeting, the panel discussed the utility of clinical methods currently used to predict and monitor MS progression and suggested general directions for future studies that might help clinicians effectively monitor MS disease worsening.

Targeted Literature Review of Prognostic Measures

Before the expert panel discussion, a targeted literature review using ProQuest and Google Scholar was conducted to identify evidence on prognostic measures other than the EDSS that may be predictive of long-term MS disease progression. The targeted literature review largely focused on articles published between 2014 and 2019, although articles published before 2014 were included to capture relevant evidence. Articles not published in English were excluded from consideration. All identified studies were screened, reviewed, and synthesized based on the following measures: no evidence of disease activity; EDSS and CDP; brain volume loss; gray matter; white matter; lesions; serum neurofilament light; cognitive impairment; pregnancy and demographics, specifically age, sex, and education; relapse and annualized relapse rate; disease duration; macular volume; and Montgomery-Åsberg Depression Rating Scale. A summary of key search terms associated with each measure is provided in 

The impact of each measure used to assess the progression of MS and the patient populations evaluated are summarized in 

, which is published in the online version of this article at IJMSC.org. The evidence varied regarding each measure’s utility in assessing disease progression. Among the studies that met the inclusion criteria, the evidence regarding the predictive power of no evidence of disease activity and minimal evidence of disease activity was generally inconsistent.

 Brain volume loss generally showed positive predictive power on long-term MS progression, particularly regarding increases in EDSS score

 and assessments that combine brain atrophy and retinal thinning.

 Although assessments of gray matter reductions were also predictive of MS progression, the evidence was partially based on associations and correlations.

 Similarly, there was some evidence supporting the predictive power of white matter on long-term disease progression, but it was based on associations.

 Limited evidence was available in favor of the predictive power of other measures of brain volume, such as cerebrospinal fluid, parenchyma,

 demographic characteristics (age, sex, education),

 did not consistently predict disease progression, particularly in the long-term. Although the evidence was mixed regarding the predictive power of annualized relapse rate,

 there was some evidence to support the predictive power of relapse on long-term disease progression.

 There was also some evidence to support the predictive power of pregnancy on long-term disease progression; however, the research was largely based on congress presentations.

 The Montgomery-Åsberg Depression Rating Scale was found to have no predictive power in long-term assessments of MS progression.

There is ample evidence supporting the limitations of the EDSS as a prognostic measure. Foremost, the EDSS is meant to function as a measure of irreversible disability in MS; however, the literature shows that it fails to serve this basic purpose.

 Recently, the placebo arms of 31 randomized controlled trials in relapsing-remitting MS and secondary progressive MS patient populations were analyzed, and the results showed significant rates of EDSS score improvement, sometimes as high as rates of EDSS score worsening.

 To further illustrate the inaccuracy and instability of this instrument, the EDSS has been shown to overestimate the accumulation of permanent disability by up to 30%.

 The EDSS also has plateau scores at 6.0 and 6.5, that, over time, has discouraged researchers from including patients with these scores in clinical trials, given the need to quantify change in progression.

Further evidence shows that increases in EDSS scores do not accurately identify patients with irreversible long-term disease progression. A study conducted in persons with relapsing-remitting MS assessed multiple definitions of sustained progression using the EDSS.

 Between 15.8% and 42.2% of these individuals had sustained progression across 3.7 years, but nearly 50% of them did not maintain progression for the duration of follow-up.

 Relapses or changes in provider could not explain the poor performance of the EDSS,

 suggesting that the use of the EDSS score and the CDP to measure outcomes for clinical trials or observational studies could lead to incorrect conclusions due to the potential instability of EDSS scores.

The EDSS has also been criticized for not being a comprehensive measure of all dimensions of MS.

 Whereas lower scale values are influenced by impairments detected by a neurologic examination, values higher than 4 are mainly based on walking ability, and values higher than 6 are based on patient handicaps.

 The EDSS does not adequately capture the dimensions of cognition, upper extremity function, or fatigue, which are believed to be relevant predictors of long-term disease progression in MS.

 Moreover, studies recommend separate consideration of the lower and upper value ranges of the EDSS because EDSS scores of 6 and higher are less sensitive to change in disease severity.

 The evidence on the prognostic limitations of the EDSS across several domains highlights the scope for improved prediction of long-term disease progression in MS.

Panel’s Viewpoints on Alternative Prognostic Measures to the EDSS

Because of the potential prognostic limitations of the EDSS, it is the panel’s opinion that alternative measures are needed to better classify disease severity and assess disease progression in patients with MS. Although there is a large and growing body of evidence on the prognostic value of factors beyond the EDSS, there is no widely held understanding of whether these factors improve predictions of long-term disability beyond the EDSS. To detect clinically meaningful changes in patients with MS, prognostic measures will need increased reliability and sensitivity. To these ends, current research suggests that approaches incorporating fatigue and lower limb function, as well as combination measures, either as a supplement or alternative to the EDSS, may be promising avenues to explore. In the following sections, we provide literature to support the panel’s viewpoints on alternative prognostic measures to the EDSS.

Incorporation of Fatigue and Lower Limb Function

The related matters of fatigue and lower extremity dysfunction, including patient-reported leg weakness as well as functional limitation identified via examination, may be of particular interest among alternative measures of disease progression with promising predictive value.

 A preliminary study found that in older people with MS, fatigue and limited lower extremity function predicted conversion from relapsing-remitting MS to secondary progressive MS within 5 years.

 The study evaluated 155 persons aged 50 years or older with relapsing-remitting MS and a disease duration of at least 15 years. Fatigue was reported to be 4 times as likely in people with disease progression (92%) as compared to those without progression (68%).

 In addition, limitations in lower extremity function were reported to be 3 times as likely in people with disease progression at the beginning of the study (53%) compared with those who did not progress (22%).

 Researchers noted that although the precise cause of fatigue in patients with MS has not been fully established, it is most likely a result of the underlying complex inflammatory and neurodegenerative processes that characterize the disease, including sequelae from MS—demyelination, axonal injury, and inflammatory response—in addition to factors such as depression and sleep disturbances.

 Consequently, fatigue and lower extremity dysfunction may be more sensitive indicators of the extent of central nervous system injury, but they may not be fully assessed or gauged with high sensitivity during a short neurologic examination.

Use of Combination Measures to Supplement the EDSS 

An alternative approach to improved prediction of disease progression could involve supplementing the EDSS with physical measures such as the Nine-Hole Peg Test (NHPT), the Timed 25-Foot Walk test, or the low-contrast letter acuity test.

 For example, the NHPT is commonly used in MS research and clinical practice and is considered to be a gold standard measure of manual dexterity, a frequent symptom reported by patients with worsening MS.

 Studies have indicated the consistently high interrater and test-retest reliability of the NHPT as well as its ability to distinguish patients with MS who have different levels of upper limb impairment.

 A 20% change in NHPT score is used to define clinically meaningful worsening; however, this definition needs further validation in all stages of the disease.

Another potential avenue for future research is combining cognitive measures such as the Symbol Digit Modalities Test (SDMT) or the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) with taxing motor tasks and walking tests.

 A 10-year retrospective longitudinal study reported cognitive impairment, measured by the SDMT, as a predictor of disability progression and secondary progressive MS conversion in patients with newly diagnosed relapsing-remitting MS.

 The study included 155 persons with relapsing-remitting MS, of whom 67 (43.2%) reached an EDSS score of 4.0, and 34 (21.9%) converted to secondary progressive MS during follow-up.

 Individuals with cognitive impairment at MS diagnosis were 3 times as likely to reach an EDSS score of 4.0 and 2 times as likely to convert to secondary progressive MS compared with cognitively preserved individuals.

Last, the predictive validity of magnetic resonance imaging and clinical scoring assessments may help clinicians identify treatment failure and potentially assist with treatment optimization.

 For example, the Rio scoring system, which combines evidence of magnetic resonance imaging lesions, presence of relapse, and increases in EDSS scores within 12 months of treatment initiation, has been used to predict ongoing disease activity and, ultimately, which patients are at risk for a suboptimal response to therapy over time.

 The sum of each parameter (0–3) distinguishes a patient’s risk from low to high.

 The modified Rio score, a simplified version of the Rio score that excludes the EDSS score and modifies relapse and magnetic resonance imaging lesion criteria, has been reported to have a high positive predictive value of disease progression within 3 years of treatment initiation.

 Results from a longitudinal study validating the utility of the scoring system found that in 222 patients with relapsing-remitting MS treated with interferon, patients with a risk score of 0 had a 24% probability of MS progression, whereas those with a score of 2 or higher had their risk of progression increase to 65%.

Although our current understanding of MS disease progression does not allow for a single most promising measure to be identified, research should continue to explore promising themes and measures to improve clinical and real-world assessments of MS treatments in the near term.

 An improved understanding of individuals at higher risk for disease progression may eventually result in more tailored treatment options for patients and establish an advanced approach to economic evaluations in MS.

Using prognostic factors beyond the EDSS may improve patient care and inform future trials in MS. Specifically, supplementing the EDSS with patient-reported physical measures, assessing fatigue, and using simultaneous cognitive and motor function testing may help in gauging MS disease progression.

Predicting Long-term Disability in Multiple Sclerosis: A Narrative Review of Current Evidence and Future Directions

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

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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.

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

Eva Havrdova, MD

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