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Trigeminal Neuralgia Commonly Precedes the Diagnosis of Multiple Sclerosis

The role of conformity to masculine gender norms in health behaviors in men with multiple sclerosis (MS) has not received attention. This cross-sectional study explores these issues and their relationship to coping and health behaviors.

Eighty-one men with MS completed the Conformity to Masculine Norms Inventory-46 and the Ways of Coping Questionnaire and provided demographic and clinical variables. These results were used to predict subscale scores of the Health Behavior Inventory-20 in multivariable regression models.

Models for the Preventive Self-care and Avoiding Anger and Stress subscales were successfully fit. For the former, respondents endorsing lower levels of masculine conformity related to Emotional Control and higher levels of Heterosexual Self-presentation predicted greater self-care, as did higher use of Positive Reappraisal as a coping strategy. For men reporting low levels of Positive Reappraisal as a coping strategy, increasing Heterosexual Self-presentation was associated with higher levels of self-care. For those with high levels of coping with Positive Reappraisals, increased Heterosexual Self-presentation was associated with modest declines in self-care. For the Avoiding Anger and Stress subscale score, men endorsing Violence or Heterosexual Self-presentation as important aspects of masculinity also reported less efforts in controlling stress and anger.

Masculinity adherence to traditional gender norms was a significant predictor of how men engaged in health behaviors and, in the case of Preventive Self-care, was found to interact with Positive Reappraisal as a coping strategy. Such information is novel and important to providers serving male patients with MS and can improve provider awareness/conceptualization of male patient needs.

From the Mellen Center for Multiple Sclerosis (BD [now at Norton Healthcare], ABS) and Department of Quantitative Health Sciences (RH), Cleveland Clinic, Cleveland, OH, USA. 

 Bryan Davis, PsyD, 3991 Dutchmans Lane Suite 310, Louisville, KY 40207; 

 Dr Davis has been a consultant for Novartis. Dr Sullivan has been a consultant and speaker for Novartis, Biogen, Bristol Myers Squibb, and Medscape. Dr Honomichl declares no conflicts of interest.

 This study was supported by a Cleveland Clinic Neurological Institute Research Project Pilot Funding Award.

Although men have lower prevalence rates of multiple sclerosis (MS) than women,

 it is still important to understand their experience with an MS diagnosis. Previous research has demonstrated sex differences in a variety of relevant psychological domains: higher self-efficacy in women,

 higher levels of depression in men with MS,

 typically worse prognosis in men with MS, and more of an effect of disability on health-related quality of life in men.

Given these findings, some data cite evidence that men differ from women in how they experience MS, but this difference is not overwhelming. Male socialized gender norms, such as Western culture gender roles, may be a contributor to such discrepancies. These socialized gender norms are established at a young age and guide young men in how to be masculine, which is socially reinforced by peers, caregivers, and society at large.

 Although such gender norms do not seem to be inherently detrimental and can also teach helpful behaviors (eg, independence, toughness, provision), some behaviors may contribute to differences in health behaviors and disease management.

Previous research suggests that the difficulty men have utilizing health care services is an effect of gender norm socialization.

 Traditionally dominant masculine ideals often include toughness, resiliency, independency, and stoicism.

 Specifically, young men may not practice help-seeking behaviors due to the contradictions to gender norms (vulnerability, weakness, and dependence).

 It has been found that men also allocate less time towards their personal health and practice less preventative health behaviors when compared to women (eg, increased substance/nicotine use and poorer diets).

 Furthermore, Robertson and Williams found that men within the age range of 16 to 44 years perceive the medical setting as more feminine and therefore underutilize health services.

 examined the relationship of male gender norms and male health behaviors in a sample of college- and community-dwelling men. They found that certain subscale scores of the Conformity to Masculine Norms Inventory-46 (CMNI-46)

 seemed to act as protective buffers of health-promoting behaviors, whereas others were risk factors. Specifically, men who self-reported higher levels of masculinity related to Emotional Control were also better at Avoiding Anger and Stress and Avoiding Substance Use. However, men who reported a stronger belief in a drive to win in life as an important component of masculinity showed a poorer ability to avoid stress and anxiety. These men also reported lower use of health care resources and less focus on diet as a health-promoting strategy. Men who endorse risk-taking and being a “playboy” as important components of masculinity were also less likely to avoid substance abuse. Risk-taking was also associated with lower health care use. However, men viewing success in life as an important aspect of masculinity were more likely to use health care properly and to see diet as an important component of health. Finally, men who viewed violence as being key to masculinity, as well as men who emphasized self-reliance, were less likely to report diet as a focus.

Although findings such as these have contributed to additional research on men’s health and other chronic conditions have been highlighted, no studies have focused exclusively on MS.

 Given this, the relationship between masculinity and health behaviors in men with MS may also be nuanced and deserves exploration. If socialized gender norms are particularly important in health behaviors and support seeking, they warrant focus to understand the relationship between how men with MS conceptualize their own masculinity and the behaviors they engage in to promote their health.

The present study explored the relationship between socialized gender norms and health behaviors in a cross-sectional survey study of men with MS receiving treatment at a large academic hospital. Specifically, the association between conformity to masculinity and health-promoting behaviors was examined. We predicted that higher levels of conformity to masculinity would be related to more negative health behaviors (anger/stress, lack of self-care, improper use of health care, poor diet, increased substance use).

In addition to exploring masculinity and health behaviors, we were interested in measuring the effect that such relationships may have on the coping styles of men with MS. Previous research suggests that differences may exist between men and women in terms of adjustment and ways of coping.

 Specifically, men with MS were found to be less likely than women with MS to seek support, practice coping skills/acceptance, or attend a support goup.

 We predicted that higher levels of conformity to masculinity would also be related to limited/rigid coping styles (nonsupport seeking, distancing, confrontive, avoidant, etc).

The institutional review board–approved study took place from January 1 through May 31, 2020, at the Cleveland Clinic Mellen Center for MS. The study protocol involved patients completing a series of survey measures at a single time point. Potential participants were contacted based on their completion of a previous survey regarding their research interest. Inclusion criteria for the study included being a man older than 18 years, being diagnosed as having MS, and receiving treatment for MS at the Mellen Center. Approximately 500 men qualified as potential participants and were sent a message via a web-based patient portal (MyChart; Epic Systems Corp) inviting them to participate in the study. Interested patients were sent an email to access the electronic surveys in a REDCap (Research Electronic Data Capture) database. Completion of the surveys qualified them for a $25 stipend.

 was used to assess conformity to 9 masculine norms: Emotional Control (6 items) (ie, emotional restriction and suppression), Winning (6 items) (ie, drive to win), Playboy (4 items) (ie, desire for multiple non-committed sexual relationships), Violence (6 items) (ie, penchant for violence), Self-reliance (5 items) (ie, desire to solve problems on one’s own), Risk-Taking (5 items) (ie, inclination toward risky behaviors), Power Over Women (4 items) (ie, perceived control over women), Primacy of Work (4 items) (ie, viewing work as the primary focus in life), and Heterosexual Self-presentation (6 items) (ie, importance of presenting oneself as heterosexual). Items are indicated on a 4-point Likert scale (1 = strongly disagree to 4 = strongly agree). Higher scores reflect greater conformity to masculine norms.

In the Ways of Coping Questionnaire (WCQ),

 respondents are asked to rate how much they used a particular strategy in response to a stressor. Items are scored on a 4-point Likert scale (0 = does not apply or not used, 1 = used somewhat, 2 = used quite a bit, 3 = used a great deal) and measure 8 coping styles: Confrontive Coping (6 items) (ie, aggressive efforts to alter the situation, suggesting some degree of hostility and risk-taking), Distancing (6 items) (ie, cognitive efforts to detach oneself and to minimize the significance of the situation), Self-controlling (7 items) (ie, efforts to regulate one’s feelings and actions), Seeking Social Support (6 items) (ie, efforts to seek informational support, tangible support, and emotional support), Accepting Responsibility (4 items) (ie, acknowledges one’s own role in the problem with a concomitant theme of trying to put things right), Escape-Avoidance (8 items) (ie, wishful thinking and behavioral efforts to escape or avoid the problem), Planful Problem-Solving (6 items) (ie, deliberate problem-focused efforts to alter the situation, coupled with an analytic approach to solving the problem), and Positive Reappraisal (7 items) (ie, efforts to create positive meaning by focusing on personal growth, includes a religious dimension). Higher scores reflect a greater reliance on a coping style.

The Health Behavior Inventory-20 (HBI-20)

 was used to measure health behaviors and consists of 20 items and 5 subscales. Three subscales reflect health-promoting behaviors: Diet (5 items), Preventive Self-care (7 items), and Proper Use of Health Care Resources (2 items). Two subscales reflect health risk behaviors: Avoiding Anger and Stress (3 items) and Avoiding Substance Use (3 items). Participants were asked to rate the extent to which each item describes themselves using a 7-point Likert scale (1 = always to 7 = never). Higher scores reflect greater efforts at health promotion.

Subscale scores are obtained by averaging response scores. A total scale score is obtained by averaging the scores of all the items. Levant et al

 reported Cronbach α values for the subscales and the full scale ranging from 0.68 to 0.79.

Disease impact was evaluated using the Patient-Determined Disease Steps (PDDS) scale,

 a self-assessment that subjectively scales personal MS disease status. Higher scores reflect higher perceived disability related to MS (normal = 0, mild disability = 1, moderate disability = 2, gait disability = 3, early cane = 4, late cane = 5, bilateral support = 6, wheelchair/scooter = 7, bedridden = 8).

The following patient demographic and clinical characteristics were collected: age, race, marital status, educational status, and years since MS diagnosis.

Descriptive statistics are used to summarize demographic and clinical characteristics (including the PDDS scale score) and subscale scores on the CMNI-46, WCQ, and HBI-20. Frequency counts with percentages are used to present categorical data, and mean ± SD is used to present continuous variables.

To examine the relationships among demographic and clinical characteristics, conformity to masculinity, and coping, Pearson correlation coefficients were generated for all variables. The associations between these variables and each of the HBI-20 subscale scores were determined using univariate linear regression models. Conformity to masculinity and coping sub-scale scores that were associated with the outcome at least at the 

 < .10 level were added to multivariate linear regression models, controlling for age, race, marital status, educational status, PDDS scale score, and years since MS diagnosis. Additional interaction effects were also evaluated between masculinity conformity and coping variables in the model.

Given the exploratory nature of the study, there was no correction for multiple testing. Missing data were handled using complete case analysis. Computations were performed in R, version 3.6.3.

Eighty-one patients completed the study protocol. Descriptive statistics are provided in 

. Race lacked variability and was, therefore, eliminated from future analyses. Also, PDDS scale scores were highly variable, with some categories showing low frequency. Therefore, this variable was dichotomized to reflect whether a patient had a score higher than 3 (gait disability). Finally, 2 subscale scores, WCQ Self-controlling and HBI-20 Avoiding Substance Use, were not found to be internally consistent (Cronbach α < 0.60) and were eliminated from further analyses.

Correlation coefficients between demographic and clinical characteristics, as well as conformity to masculinity and coping subscale scores, are presented in 

, which is published in the online version of this article at IJMSC.org. Age was related to lower levels of Self-reliance, as well as to Distancing and Escape-Avoidance as coping strategies. Being married was related to lower scores on the Confrontive Coping, Distancing, Accepting Responsibility, and Escape-Avoidance subscales. Length of diagnosis, PDDS scale score, and educational level were not related to subscale scores for conformity to masculinity or coping. For adherence to masculine norms, respondents high on Emotional Control were lower on Seeking Social Support and Accepting Responsibility. Winning was correlated with more Confrontive Coping. Men reporting higher Self-reliance reported lower levels of Seeking Social Support, as did those with higher levels of Power Over Women.

Univariate linear regression models on Diet identified the Planful Problem-Solving and Positive Reappraisal coping styles for further analyses in multivariable models. For modeling on the Preventive Self-care subscale, Emotional Control, Heterosexual Self-presentation, Planful Problem-solving, and Positive Reappraisal were retained (

). For modeling on the Proper Use of Health Care Resources subscale, Primacy of Work, Seeking Social Support, Planful Problem-solving, and Positive Reappraisal met the threshold to remain in the multivariable model. Finally, for the Avoiding Anger and Stress subscale, conformity to the masculine norms of Winning, Violence, and Heterosexual Self-presentation as well as Confrontive Coping were retained as multivariable predictors (

For the multivariable linear regression model for each of the 4 previously mentioned HBI-20 subscale scores, the following patient demographic and clinical characteristics were controlled for: age, race, marital status, educational status, and years since MS diagnosis. In addition, all CMNI-46 and WCQ subscale scores identified as predictors in the univariate analyses were added to the models. Because Planful Problem-solving and Positive Reappraisal were strongly correlated, the potential for multicollinearity was evident. Therefore, after initial examination of the impact of each subscale score on the first 3 outcomes, Positive Reappraisal was retained.

No significant model could be fit for the Diet or Proper Use of Health Care Resources subscale scores. For Preventive Self-care, only Emotional Control and Heterosexual Self-presentation were significant predictors. However, after adding an interaction between Heterosexual Self-presentation and Positive Reappraisal, a main effect for the latter also emerged. The interaction effect was also significant (

). Men reporting higher levels of Emotional Control reported worse efforts at Preventive Self-care. In contrast, men endorsing stronger beliefs in Heterosexual Self-presentation reported more efforts. In addition, engaging in Positive Reappraisal as a coping strategy was also positively associated with self-care efforts., With high and low Positive Reappraisal levels split at the median, the interaction is presented in 

. For men with low levels of Positive Reappraisal, increasing Heterosexual Self-presentation was associated with higher levels of Preventive Self-care. For those with low levels of Positive Reappraisal, increased Heterosexual Self-presentation was associated with declines in Preventive Self-care.

For the Avoiding Anger and Stress subscale score, having a PDDS scale score greater than 3 was associated with greater efforts to control negative emotions (

). In addition, CMNI-46 subscale scores for Violence and Heterosexual Self-presentation were negatively associated with controlling stress and anger. No interaction effect was found.

The present study investigated the relationship between adherence to traditional gender norms in men with MS and their health behaviors. After examining correlation coefficients and univariate regression analyses, candidate predictors in the areas of coping and conformity to masculinity were identified for multivariable models of health behaviors. Of the 5 domains of the HBI-20, 3 could not be successfully modeled. Avoiding Substance Use exhibited very poor reliability (α = 0.50) and was, therefore, eliminated from further analyses. In addition, models for Diet and Proper Use of Health Care Resources were not significant.

For Preventive Self-care, controlling for demographic and clinical characteristics, aspects of masculinity conformity related to Emotional Control and Heterosexual Self-presentation were significant predictors, as was the Positive Reappraisal coping strategy. Men reporting stronger adherence to the masculine norm of Emotional Control reported poorer Preventive Self-care. Men endorsing Heterosexual Self-presentation as a key aspect of masculinity reported greater efforts in self-care. Positive Reappraisal was also associated with higher reported self-care. In addition, the interaction between Heterosexual Self-presentation and Positive Reappraisal was significant. For men reporting low levels of Positive Reappraisal as a coping strategy, increasing Heterosexual Self-presentation was associated with higher levels of Preventive Self-care. For those with high levels of coping with Positive Reappraisals, increased Heterosexual Self-presentation was associated with modest declines in self-care.

For the Avoiding Anger and Stress subscale, having a PDDS scale score greater than 3 positively predicted efforts to control negative emotions. Related to conformity to masculine gender norms, men endorsing Violence or Heterosexual Self-presentation as important aspects of masculinity also reported less effort in controlling stress and anger. No interaction was found between conformity to masculinity and coping.

 found that the coping strategies of women with MS may differ from the coping strategies of men with MS (eg, men are less likely to accept the condition, adopt productive coping strategies, and seek social support). The present study showed that men with MS are in fact coping but may be doing so in a way that is influenced by their gender norms. Specifically, men who endorsed the gender norm of Heterosexual Self-presentation (importance of presenting oneself as heterosexual) reported greater efforts in self-care. In contrast, men with MS who endorsed the gender norm of Emotional Control (emotional restriction and suppression) reported poorer Preventive Self-care. Specific to coping, men with MS who used the strategy of positive appraisal (create positive meaning by focusing on personal growth) also reported greater effort in self-care.

The present study showed commonalities with and differences to the findings of Levant and Wimer.

 For Avoiding Anger and Stress, they found that Emotional Control was a positive predictor, as did the present study. However, they also found that Winning and Risk-Taking were predictive. For Preventive Self-care, no aspects of conformity to masculine norms were significant predictors, whereas the present study identified Emotional Control and Heterosexual Self-presentation. They also found a variety of predictive relationships between aspects of conformity to masculine norms and the subscale scores of Avoiding Substance Use, Diet, and Proper Use of Health Care Resources. A variety of factors may have contributed to these differences. First, their sample consisted of both college students and community members, with an average age of 23 years. In contrast, the sample for the present study was significantly older at nearly 52 years on average. Issues related to masculinity may have differed greatly between these 2 groups due to this difference. Perhaps also related to this, more respondents in the present study reported being married (21%) compared with only 12% reporting being married, partnered, or engaged in the sample from Levant and Wimer. Finally, approximately 13% of respondents in the sample from Levant and Wimer reported having a college degree or higher compared with nearly 50% in the present study.

Overall, the results of the present study show that aspects of conformity to masculine gender norms are associated with health behaviors in men with MS. In the case of Preventive Self-care, there was also evidence of interaction between masculinity conformity and coping strategies. However, contrary to expectations, several demographic and clinical characteristics were not found to be predictive of health behaviors at a univariate or multivariable level (ie, age, educational level, marital status, PDDS scale score, and years since diagnosis). This may be due to a restricted range of patients in terms of age and disease duration. Having a larger portion of younger men with MS in a sample may allow examination of age differences in some of these issues.

 Furthermore, the present sample consisted largely of patients with long-term disease duration (mean ± SD time since diagnosis of 12.24 ± 8.47 years). It may be that the earlier years of disease duration are critical to the examination of these issues. In addition, we did not look at sexual orientation or gender identification, which would have enhanced the study. This study population identified as 93% White, and recent studies have focused on the underrepresentation of ethnic minorities in MS.

 It is well-known that racial and ethnic diversity can play a significant role in how people with chronic disease, specifically MS, cope with their health and how health care disparities play a role in disease and progression. Finally, the cross-sectional nature of this study limits the strength of inferences that can be made about the interrelationships among conformity to masculinity, coping strategies, and health behaviors. Longitudinal data analyses would allow a clearer examination of whether and how adherence to traditional male gender norms is related to health behaviors and the mediating role that coping strategies may play.

In future research, it may be helpful to look at how men with MS differ from men living with other chronic illnesses. Also of particular interest would be an assessment of gender norms and their correlation with predicting male-identifying patients and a study of treatment approaches.

The present study displayed the nuanced relationship between masculine gender norms and specific coping strategies and male health behaviors.

Effects of Conformity to Masculine Norms and Coping on Health Behaviors in Men With Multiple Sclerosis

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.

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

Ahmad Fallata, MD

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