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Safety and Tolerability of Delayed-Release Dimethyl Fumarate Administered with Interferon Beta or Glatiramer Acetate in Relapsing-Remitting Multiple Sclerosis

The John A. Schafer, MD Multiple Sclerosis Achievement Center (MSAC) conducts wellness programs that include exercise, cognitive stimulation, education, emotional support, and socialization for people with multiple sclerosis and their care partners. Patient-reported outcomes (PROs) are collected annually. Four-year outcomes encompass the COVID-19 pandemic when some of these programs were offered virtually.

Beginning in 2017, baseline data were collected for 110 MSAC day wellness program participants through PRO measures. Of those 110, 52 completed PROs annually through 2021. Outcome measures included the Multiple Sclerosis Impact Scale (MSIS-29); Multiple Sclerosis Self-Efficacy Scale (MSSE-10); Godin Leisure-Time Exercise Questionnaire (GLTEQ); and the Neurology Quality of Life domains of Anxiety, Depression, Emotional and Behavioral Dysregulation, Positive Affect, Cognition, Ability to Participate in and Satisfaction with Social Roles and Activities, and Satisfaction with Social Roles and Activities. Analysis using t tests compared baseline with 4-year data. A separate analysis compared outcomes collected in January 2020 and January 2021.

Analysis of 4-year data demonstrated statistically significant improvement in MSIS-29 and GLTEQ. Statistically significant improvements noted at years 2 and 3 in the Ability to Participate in Social Roles and Activities were no longer significant at year 4. Other notable changes included significant decreases in MSSE at year 4 when compared with baseline and year 3.

Individuals who participated in a weekly, structured day wellness program showed improvements in self-reported disease impact and physical activity at year 4 vs baseline. Decreases in self-efficacy and social domains were seen, corresponding with disruptions caused by the COVID-19 pandemic. Further analysis is needed to understand the effects of the pandemic on program participants.

From the Dignity Health John A. Schafer, MD Multiple Sclerosis Achievement Center, Citrus Heights, CA. 

Tiffany Malone, MSW, MSCS; Dignity Health John A. Schafer, MD Multiple Sclerosis Achievement Center, 7777 Greenback Lane, Suite 108,Citrus Heights, CA 95610; 

Multiple sclerosis (MS) is a chronic disease of the central nervous system most commonly diagnosed in people between 20 and 50 years old. MS debilitates normal body function and can cause serious disruptions to daily living, including “work, physical independence, mobility, social interaction, and participation in leisure activities.”

 In general, people with MS have a normal life span; therefore, many, particularly those who receive a diagnosis early in life, must live a long time with the physical, cognitive, and psychological effects of MS. They often experience isolation from family and friends. As such, interventions to enhance quality of life are essential to helping people with MS live well.

The John A. Schafer, MD Multiple Sclerosis Achievement Center (MSAC) in Sacramento, California, provides adult day services, which, broadly, encompass a system of professionally delivered, integrated, home- and community-based therapeutic, social, and health-related services for individuals to sustain living in the community.

 The wellness programs include individual and group exercise programs, individual cognitive stimulation using activities and applications on a tablet, group discussions in areas of overall health and MS-specific management that are facilitated by a health care professional, emotional support, and socialization with other people with MS. In addition to the day wellness programs, community outings provide other social and recreational opportunities. Some people have been participating since the program's inception in 2014.

Adult day programs also offer respite for caregivers.

 The MSAC provides a professionally facilitated support group for caregivers and loved ones of people with MS. Since its inception in 2016, 91% to 95% of participants in the MSAC support partner program report that they agree or strongly agree that the program is beneficial to their health and well-being.

Research results on day programs are mixed. A scoping review of older adults who participate in activities at adult day centers (ADCs) concluded that ADCs have positive impacts on health-related, social, psychological, and behavioral outcomes.

 In addition, a study found that caregivers showed significant decreases in depression, improvement in their ability to manage memory lapses and difficult behaviors, and improvement in self-perception of overall well-being with participation in an Adult Day Services (ADS) Plus program (a community-based program for adults living at home plus care management services). All these changes were seen at 3 months, but no statistically significant differences were seen long term (up to 12 months).

Investigators in another study did not find clinically significant effects on standardized measures of physical and mental health-related quality of life (HRQOL) or health care utilization after 1 year.

 Scores on the physical component scale of the 12-Item Short Form Health Survey were statistically significant for those with MS attending ADS, but the difference was not considered clinically meaningful. Investigators in a qualitative study from the same data set did conclude that these programs have a profound influence on the participants’ psychosocial health, which the authors attribute to membership in a socially cohesive community.

An evaluation of a concentrated 4-day wellness program for people with MS showed improvements in self-efficacy and self-perceived health-related outcomes. Improvement in these health-related outcomes was not dependent on initial disability as measured by the Expanded Disability Status Scale.

The COVID-19 pandemic affected people with MS in many ways. Several studies have reported increases in depression

 However, results of another study showed improvements in social interactions.

 In a survey of 1145 people with MS, many reported delays in and difficulties with several aspects of their medical care due to the pandemic, including delays to disease-modifying therapy administration and non–MS-related medical procedures, delays to medications and complementary and alternative medicine services, and postponement or cancellation of medical appointments. In addition, more than those who did not self-quarantine, respondents who self-quarantined reported that the pandemic had a significantly negative impact on their diet, personal finances, and exercise.

 Finally, as patients returned to in-clinic visits after isolation due to the pandemic, clinicians noted increased weakness, spasticity, balance issues, and pain related to deconditioning.

Results of a recent study evaluating a virtual wellness program during the pandemic showed an association between participation and improved quality of life.

 The wellness program was offered 17 times over 6 months and included exercise, mindfulness programs, and guest speakers. Those with higher attendance rates demonstrated improvements in emotional well-being and pain measures at 6 months when compared with baseline.

At MSAC, participants report that they are “more confident,” “more active,” and “more connected” to others through engagement in our programs. Because many people have attended for multiple years, we have had the ability to analyze outcome measures longitudinally, something that has not been previously reported in the literature. In comparison with the COVID-19 pandemic data, our participants also reported increases in anxiety and depression but disagreed with the research results above, indicating that their social interactions decreased and they felt more isolated.

The purpose of this analysis was to review the results of the outcome measures regarding the impact a day wellness program may have on participants’ quality of life, the impact of their MS, mood, and level of physical activity, with a particular focus on learning more about the results and any changes that may be noted during, and perhaps because of, the pandemic. The primary purpose of this data collection was to assess program gaps and guide the development of program content.

Program measures were collected annually for all individuals enrolled in the program at the time and those who had left the program. Data analysis was retrospective. The chairman of Dignity Health's Sacramento/Sierra regional institutional review board reviewed our project proposal and determined it to be a quality improvement project; therefore, board review and approval were not required.

Initial measures were collected in January 2017 (baseline) and then annually through January 2021. Measures collected in January 2021 reflect a little more than 8 months of the pandemic. During that time, the MSAC offered only virtual programs (April and May 2020) and hybrid in-person and virtual programs (June through December 2020). All participants were offered 5 hours of weekly programming during the virtual-only and hybrid programs, but they were spread throughout the week instead of in a single 5-hour day per week.

Multiple Sclerosis Self-Efficacy Scale-10 (MSSE-10)

The MSSE-10 was developed and is validated for measuring self-efficacy in function maintenance and control over MS from the patient's perspective. The MSSE-10 is highly correlated with the original MSSE.

Multiple Sclerosis Impact Scale-29 (MSIS-29)

The MSIS-29 is a physical (20 items) and psychological (9 items) measure and has been found to be an accurate, valid, and reliable patient-based outcome measure of the impact of MS from the patient's perspective.

Godin Leisure-Time Exercise Questionnaire (GLTEQ)

The GLTEQ is a valid self-reported measure of physical activity in people with MS and is an appropriate, simple, and effective tool to describe patterns of physical activity and examine correlates and outcomes of physical activity, thereby providing an outcome for measuring change in physical activity after an intervention.

The Neuro-QoL instrument includes 13 scales that assess physical, emotional, cognitive, and social domains and is used for a variety of neurological illnesses.

 The Neuro-QoL assesses several domains of well-being not typically assessed using traditional MS-specific patient-reported outcome (PRO) measures. Analysis examined the domains of Anxiety, Depression, Emotional and Behavioral Dyscontrol, Positive Affect, Cognition, Ability to Participate in Social Roles and Activities, and Satisfaction with Social Roles and Activities.

The above PRO measures were collected on an annual basis beginning in January 2017. Data were analyzed using paired t tests for the different outcome measures at baseline (ie, 2017, even though some individuals had participated prior to that date), 1 year, 2 years, 3 years, and 4 years. An additional analysis was done comparing years 3 and 4 (ie, 2020 and 2021), which includes the first 8 months of the COVID-19 pandemic. Raw scores were analyzed and reported for the MSSE-10, MSIS-29, and GLTEQ; t scores were reported for the Neuro-QoL scales. The paired t tests were taken without correction based on an a priori hypothesis. Significance was accepted at 

Data were collected from 119 people with MS who participated in the MSAC's day wellness programs from 2017 to 2021. Of the 119 individuals, data analysis was limited to 52 individuals for whom all 4 years of data were available. At baseline, the average length of MSAC participation was 16 months since some participated in MSAC programs prior to initial data collection in 2017. 

 reflects the baseline demographic characteristics of those individuals.

The mean MSSE-10 scores were 71.76 (SD, 19.66) at baseline, 78.18 (SD, 18.47) at year 3, and 67.70 (SD, 24.47) at year 4. A statistically significant improvement was seen at year 3 when compared with baseline (

 = .02). No statistically significant difference was seen at year 4 when compared with baseline (

 = .18). However, when comparing years 3 and 4 there was a statistically significant decrease in MSSE-10 scores (

 = .0001). MSIS-29 mean scores were 39.08 (SD, 20.72) at baseline, 31.96 (SD, 14.99) at year 3, and 32.89 (SD, 14.65) at year 4. A statistically significant improvement was seen at year 3 (

 = .01). However, when comparing years 3 and 4, there was not a statistically significant change in MSIS-29 scores (

Scores in the Ability to Participate in Social Roles and Activities and Satisfaction with Social Roles and Activities domains of the Neuro-QoL had statistically significant improvement at years 2 and 3. As with the MSSE-10, statistically significant changes were not maintained at year 4. Mean scores at baseline and years 2, 3, and 4 P values are included in 

. Scores on other domains of the Neuro-QoL did not show statistical significance at any point during the 4-year period. Cognition in year 3 approached significance (

 < .001), results from the GLTEQ showed some increase in participation in physical activity during leisure time during year 3 (

 = .14) and a statistically significant improvement in year 4, as well as between years 3 and 4 (

No significant changes, positive or negative, were observed in other outcome measures compared with baseline unless otherwise noted.

Over 4 years of data collection and analysis, we saw that individuals who participate in a weekly, structured day wellness program have had significant improvements in overall quality of life.

ADS participants at MSAC who have been enrolled and completed PROs over the course of 4 years have demonstrated improvements in disease impact and participation in physical activity during leisure time. Improvements were also noted in areas of self-efficacy and Ability to Participate in and Satisfaction with Social Roles and Activities through year 3; however, negative changes were noted in year 4 during the pandemic.

Changes in social domain scores occurred first and may be directly related to the social interaction inherent in the MSAC wellness program. The program encourages, promotes, and teaches the benefits of being socially engaged and this may have directly impacted self-efficacy. Increases in physical activity were noted in years 2 and 3 but were not statistically significant until year 4. These data are similar to the study results of another wellness program that demonstrated improvements in self-efficacy after 6 months, but no change in physical activity measures.

 Although self-efficacy has been correlated with physical activity,

 we saw a decrease in self-efficacy with the greatest increases in physical activity. This may be, in part, due to the MSSE being a scale that measures an individual's perspective of self-efficacy in function maintenance and control over MS,

 not specific to one's ability to engage in physical activity.

The results of this study are similar to and different from other studies of adults with MS in day programs. Results from our study and the study done by Gasper et al

 show statistically significant positive effects on quality of life. However, in the Gasper study, the statistically significant improvements in the SF-12 physical component scale were not clinically meaningful. In our analysis, unlike the Gasper study, we did see significant improvements in social domains; however, changes were not detected until the second year of program participation.

Qualitative results reported by Marrow et al

 demonstrated that MS ADP programs have a profound effect on psychosocial health due to the socially cohesive environment. These results are consistent with our results in the social domains of the Neuro-QoL. These scores were the first to improve with participation in our programs, and this improvement could certainly be attributed to the group environment.

Our study's reported changes in self-efficacy were similar to those reported by Ng et al,

 although ours did not occur as quickly. This may be due to differences in program design and/or because we may not have captured some of the initial changes because the beginning of data collection did not occur until many participants had already taken part in the program for up to 3 years.

Presumed Implications of the COVID-19 Pandemic 

Changes in some domains between years 3 and 4, as well as between baseline and year 4, may be due to the COVID-19 pandemic. Statistically significant at year 3, quality-of-life and self-efficacy measures were no longer statistically significant at year 4 when compared with baseline. The social domains of the Neuro-QoL returned to baseline, whereas the self-efficacy measures fell below baseline measures. The traditional format of our programs encourages socialization, which may provide greater internal motivation for behavior change. Although further analysis is necessary in order to confirm, we believe the significant improvements in both physical activity and disease impact during year 4 correspond with people learning to access other avenues for physical activity, such as videos and virtual exercise sessions, while being sheltered at home. Both the GLTEQ and the MSIS-29 address questions related to physical activity, and both showed statistically significant improvements in year 4. Although the MSIS-29 also addresses mood, we believe the reductions in our other measures of self-efficacy and quality of life, combined with a decreased self-reported impact on the MSIS-29, support our hypothesis that the year 4 changes on this scale reflect an increase in physical activity, not changes in mood. However, a subanalysis of the MSIS-29 was not conducted to confirm this hypothesis. These data are also contrary to those from a recent study that reported a decrease in physical activity during the pandemic for people with MS.

 Activities based in physiotherapy centers, gyms, or pools decreased, whereas walking increased. A majority of participants did not use technology as part of their physical activity program. Since we did not specifically ask about the type of exercise, we do not know which types of activity impacted the GLTEQ scores. However, we are aware that many of our participants were active in the virtual exercise programs we offered during COVID-19 lockdowns.

Future analysis will include data collected after returning to the type of in-person programming offered prepandemic. The results will help inform whether the reductions in quality of life and self-efficacy measures during the pandemic return to levels seen at years 2 and 3. In addition, we can assess whether behavior changes were sustained.

The MSAC opened in February 2014, and some of our participants have been enrolled in the day wellness program since the first day. However, the outcome measures that have been used for our reports of baseline data and throughout this reporting period did not begin until 2017, which does not reflect a true baseline for all participants.

Additionally, the data only include information for individuals who have been participants of the day wellness program for the duration of the 4-year reporting period. The data do not include individuals who were participants for only a portion of that time. Although the analysis did not include a control group, the period leading up to the pandemic (2017-2020) could be considered a control for purposes of post-COVID-19 data analysis. Although this was not a preplanned analysis, the pandemic did provide an interruption to our time-series data collection approach. Considering the time prior to the pandemic as a control provides greater confidence that significant changes during and after the pandemic are, at least in part, due to COVID-19 restrictions.

The wellness programs offered at the MSAC are voluntary. Individuals enroll in programs open to anyone in the community with MS and, therefore, may include selection bias. The outcomes collected were primarily for purposes of program development and monitoring individual progress toward their goals, not as data for a prospective research study. The authors acknowledge that statistical analysis was performed without correction and is therefore subject to type 1 error.

In year 4, because of the pandemic and the need for portions of our program to be provided virtually, the outcome measures were collected online. Prior to that time, they were collected onsite during program hours via pen and paper. Outcome measures for year 4 were emailed to program participants and completed online. Every precaution was taken to send the measures directly to the program participant; however, because staff were not present at the time of completion, we cannot guarantee that a family member or caregiver did not respond on behalf of the participant.

Lastly, our participants do not engage exclusively in MSAC activities. Some participate in other interventions, including rehabilitation services, gym memberships, and other medical treatments. Their participation in these additional interventions may be reflected in their responses to our outcome measures.

The estimated total economic burden for people with MS in 2019 was $85.4 billion, and this figure is expected to increase to $108.1 billion by 2039. When compared with matched controls without MS, the average excess medical cost per person for someone with MS was $65,612; for someone older than 65 years, the excess cost per person increased to $66,356.

Research assessing adult day programs concludes that the various services provided can address health system challenges such as providing appropriate care for older individuals and enabling them to age in place while also providing low-cost services for a growing demographic group.

 Additional research assessing adult day programs during the COVID-19 pandemic recommends better support of community-based programs and those they serve, including classifying adult day programs as essential and exploring new ways to finance them.

The results of this analysis support day wellness programs as an effective means for improving quality of life and, ultimately, physical activity for people with MS. Regarding quality-of-life measures, the impact of in-person programs appears to be more substantial than virtual programs. However, the virtual format may have maintained some areas of quality of life above baseline and resulted in increased physical activity because of the challenges presented by the COVID-19 pandemic. Future analysis will be important to determine whether the return to in-person programming impacted measures of quality of life and self-efficacy while maintaining increases in physical activity.

 The authors report no conflicts of interest.

 No financial support was provided for this project.

 This information was presented during a platform presentation at the Consortium of Multiple Sclerosis Centers Annual Meeting; June 1-4, 2022; National Harbor, MD.

Outcomes of a Day Wellness Program for People With Multiple Sclerosis Before and During the COVID-19 Pandemic

 To access the article and evaluation online, go to https://www.highmarksce.com/mscare.

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

Review current research, including limitations, of the potential cognitive impacts of polypharmacy and anticholinergic burden in individuals with MS.

Evaluate potential cognitive risks associated with polypharmacy and anticholinergic burden using tools such as the Drug Burden Index to guide decision-making in the development of comprehensive treatment plans.

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, the Accreditation Council for Pharmacy Education, and the American Nurses Credentialing Center, to provide continuing education for the health care team.

This activity was planned by and for the health care team, and learners will receive 1.0 Interprofessional Continuing Education credit for learning and change.

 The CMSC designates this journal-based activity for a maximum of 1.0 

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

 The CMSC designates this enduring material for 1.0 contact hour of nursing continuing professional development (1.0 in the area of pharmacology).

This knowledge-based activity (UAN JA4008165-9999-24-004-H01-P) qualifies for 1.0 contact hour (.01 CEUs) of continuing pharmacy education credit.

 The CMSC has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. The activity is designated for 1.0 AAPA Category 1 CME credits. PAs should only claim credit commensurate with the extent of their participation.

 It is the policy of the CMSC 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.

, has served as physician planner for this activity. He has disclosed no relevant financial relationships. 

, has disclosed not relevant financial relationships. 

, has disclosed financial relationships with Atara Biotherapeutics, Biogen, Bristol Myers Squibb, Immunic, Novartis, Pipeline, Roche, Sanofi, TG Therapeutics, and UCB (researcher). Authors 

Joanie Huebner, PhD; Jade Robichaud, BA; Julia S. Cozart, MA;

, have disclosed no relevant financial relationships.

At the time of this research and authorship, author 

, disclosed no relevant financial relationships. Subsequent to the selection of this paper for publication and continuing education credit, she began an employee relationship with Astra Zeneca.

, 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: March 1, 2024; Valid for Credit through: March 1, 2025

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

(3) Complete the evaluation, which is available at https://www.highmarksce.com/mscare.

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 US Food and Drug Aadministration. 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.

Polypharmacy, or the use of 5 or more daily medications, is common in adults with multiple sclerosis (MS), and is often due to various physical, cognitive, and emotional symptoms. However, research regarding the association between polypharmacy and cognitive outcomes in MS is sparse. Furthermore, individuals with MS often use medications with anticholinergic properties, which are commonly associated with cognitive impairment and other central nervous system adverse effects. Currently, the utility of scales measuring anticholinergic burden in MS is unknown. This study aims to investigate the relationship between polypharmacy, anticholinergic burden, and objective cognitive performance in MS.

We recruited 90 individuals with MS during routine visits at an MS specialty clinic in Kansas City. Participants completed a brief, virtual cognitive assessment and answered questions about their health. Participants provided their medication lists from which we determined polypharmacy and scores on several anticholinergic burden scales. Statistical analyses included Spearman correlations and linear regression models.

Approximately 44% of the individuals surveyed met the criteria for polypharmacy. The number of daily medications was negatively correlated with cognitive performance (

 < .001). Further, the Drug Burden Index accounted for additional variance in cognitive performance beyond that explained by age, education, MS disease duration, and comorbidities [ΔR

Clinicians should consider the possible negative consequences of polypharmacy when addressing cognitive concerns in MS. Anticholinergic burden scales may be valuable in this regard. Future investigations could explore behavioral and pharmacological interventions aimed at reducing polypharmacy in MS.

From the Department of Community and Family Medicine, University Health Lakewood Medical Center, University of Missouri–Kansas City, Kansas City, MO (JH); Department of Biomedical and Health Informatics, School of Medicine, University of Missouri–Kansas City, Kansas City, MO (JR, JSC, JMB); Department of Psychology, University of Missouri–Kansas City, Kansas City, MO (JSC); Department of Pharmacy Practice, University of Kansas Medical Center, Kansas City, MO (CB); Department of Neurology, University of Kansas Medical Center, Kansas City, KS (SGL); and the Departments of Neurology and Psychiatry, University Health Truman Medical Center, Kansas City, MO (JMB). 

Joanie Huebner, PhD, University Health Lakewood Medical Center, 7900 Lee’s Summit Rd, Kansas City, MO 64139, USA; 

The authors would like to express our thanks to those who worked alongside us to make this research possible. In particular, we extend our gratitude to Joan McDowd, PhD, and Joah Williams, PhD, for their support, suggestions, and feedback.

Sharon Lynch, MD, has reported receiving funding in multicenter MS drug trials from Anokion, Atara Bio, Bristol Myers Squibb, Celgene, EMD Serono, Novartis, Roche, Sanofi, and TG Therapeutics. All other authors disclosed no relevant financial relationships at the time of the research and writing of this publication. Subsequent to the selection of this paper for publication and continuing education credit, Crystal Burkhardt, PharmD, began an employee relationship with Astra Zeneca.

This study was financially supported by awards from the UMKC Women’s Council Graduate Assistance Fund: the Mary F. Merryman Award in Memory of Grace Greenwood Duncan, the Martha Jane Starr Award, and Frances E. Clark Merit Recipient award.

Portions of the results of this study were presented as a poster at the European Committee for Treatment and Research in Multiple Sclerosis; October 2022; Amsterdam, The Netherlands.

Individuals with multiple sclerosis (MS) experience a wide array of symptoms caused by focal lesions and diffuse neurodegeneration in the central nervous system. It is common for patients to use a disease-modifying therapy (DMT) to slow disease progression as well as treatments for a variety of physical, cognitive, and emotional symptoms.

 For this reason, polypharmacy is a considerable concern for individuals with MS.

Polypharmacy refers to the concurrent use of multiple medications

; it is most commonly quantified in the literature as 5 or more daily medications. Evidence suggests that polypharmacy is associated with adverse health outcomes in those of advanced age, including increased falls, cognitive impairment, and hospitalizations due to drug adverse events.

 Certain types of medications, including those with anticholinergic properties, are particularly hazardous.

 Compared to older adults, individuals with MS represent a similar yet unique population that is vulnerable to polypharmacy effects, yet the literature on this topic is sparse. Our previous research suggests that polypharmacy is associated with subjective cognitive difficulties in MS; however, a consistent relationship with objective cognitive measures was not observed.

Cognitive abnormalities often emerge as a direct consequence of MS disease pathology, affecting between 40% to 70% of patients.

 Notably, difficulties with cognition can arise at any stage of the disease and tend to persist or worsen over time.

 Common cognitive domains affected in MS include information progressing speed, executive function, and working memory, and these deficits can consequently impair visuospatial abilities and verbal fluency.

 Cognitive symptoms are linked to a range of adverse outcomes in MS, such as problems with activities of daily living, employment, and completing daily household tasks.

The present study examines the relationship between polypharmacy and objective cognitive performance in adults with MS while accounting for demographic and disease-related factors. We hypothesized that polypharmacy would be negatively associated with cognitive performance, such that people taking more medications would demonstrate poorer performance on objective measures of cognition. We also explored whether anticholinergic burden scales could predict cognitive performance after controlling for relevant covariates.

We recruited 90 participants with MS through a large MS specialty clinic affiliated with the University of Kansas Medical Center. Additional recruitment methods included referrals and flyers posted in the clinic. Participants received a $25 Amazon gift card as compensation for their participation. Criteria for inclusion included (1) a confirmed MS diagnosis based on established criteria

 from a board-certified neurologist; (2) no nervous system disorder other than MS; (3) no severe sensory, motor, physical, or neurological impairment that would make participation in the study insurmountable; (4) no history of learning disability; (5) no MS relapse and/or corticosteroid treatment within 4 weeks of evaluation; and (6) access to stable internet in a private location for Zoom teleconferences.

Study personnel approached patients with MS while they were attending their routine clinical visits. Upon introduction and a brief description of the research, study personnel assessed patients’ interest in study participation and asked additional screening questions. Eligible and interested patients provided written informed consent, gave their contact information, and scheduled a time to complete the study assessment and questionnaires with the researcher. Out of an abundance of caution during the COVID-19 pandemic, all data collection occurred via telehealth. A battery that could be administered virtually was compiled and included measures across several domains of cognitive functioning that are commonly affected in patients with MS, such as information processing speed, executive functioning, and working memory. The validity and reliability of online assessments using our selected measures has been established in adults with and without cognitive impairment,

 Participants completed the cognitive assessment portion via Zoom or by telephone if online audio/video connectivity was poor. To ensure that mode of test administration did not unduly influence participant test performance, method of participation was examined as a covariate in analyses. Study data were collected and managed using Research Electronic Data Capture (REDCap) tools hosted at the University of Missouri–Kansas City.

 All procedures were approved by the institutional review boards of the University of Missouri–Kansas City and the University of Kansas Medical Center.

Participants provided a complete list of all medications used daily (including both prescription and over-the-counter drugs), which were tallied to yield the total number of medications (med count). Medications prescribed as prn were only included in analyses if the participant reported taking the medication within 24 hours prior to the testing session. For each medication, participants provided the dosage, frequency, route of administration, date/time of last dose taken, and percentage of doses missed.

The Anticholinergic Burden Calculator (www.anticholinergicscales.es) was used to derive numerical values and qualitative labels (eg, low/medium/high risk) for 3 rating scales thought to be associated with cognitive functioning

 the Anticholinergic Cognitive Burden (ACB) Scale,

 For each scale, higher scores indicate increased possibility of anticholinergic impact.

Verbal memory was assessed using the Hopkins Verbal Learning Test-Revised (HVLT-R).

 We assessed sequential set-shifting with the oral Trail Making Test (OTMT), trials A (processing speed; OTMT-A) and B (executive functioning; OTMT-B).

 The Digit Span test is a subtest of the Wechsler Adult Intelligence Scale–Fourth Edition (WAIS-IV).

 Measures of verbal fluency included both semantic and phonemic fluency tasks.

 All measures utilized have been validated for use in individuals with MS.

Participants completed the Patient-Determined Disease Steps (PDDS),

 a self-reported measure of disability based on motor and ambulatory dysfunction. The PDDS has 9 levels that range from 0 (normal) to 8 (bedridden). PDDS scores correlate strongly with the Expanded Disability Status Scale (EDSS) and are a valid patient-reported outcome of disability in individuals with MS.

We assessed the presence of comorbid health conditions via the Comorbidity Questionnaire for MS, which is validated for use in individuals with MS.

 A supplementary list of comorbidities was also produced to account for other common conditions experienced in the MS population, such as sleep disorder and genitourinary disease; the additional comorbidities were drawn from Cumulative Illness Rating Scale

; Comorbid Medical Conditions Questionnaire

; Self-Administered Comorbidity Questionnaire

; and the discussion section of “Validation of a Self-Report Comorbidity Questionnaire for MS.”

 For each patient-reported comorbid condition, follow-up questions included, “What year were you diagnosed?” and “Is this condition currently being treated?” The total number of comorbid conditions per person was tallied to yield a comorbidity score.

Participants reported the month and year of their MS diagnosis as well as their MS subtype (subtype confirmed by SGL). Demographic information included age, sex, education, ethnicity, and employment status.

A composite variable was created for all cognitive measures (ie, HVLT-R Learning, digit span forward [DSF], digit span backward [DSB], OTMT-A, OTMT-B, Phonemic Fluency, and Semantic Fluency) to reduce the number of analyses and thereby decrease the likelihood of family-wise error. This was achieved by transforming the raw scores to standardized z scores, summing the z scores for each measure, and dividing by 7 (ie, the total number of tests). We used negative z scores for OTMT-A and OTMT-B, as higher scores indicate slower performance. This statistical approach has been used frequently in the literature.

 We obtained zero-order correlations using Spearman rank correlation (

); bootstrapping was performed for 1000 samples, yielding 95% CIs for each correlation. Stepwise regression analyses estimated the predictive utility of the polypharmacy indices on the objective cognitive measures. For each model, multiple checks for potential violations of the assumptions for regression analysis were performed. We assessed the normality of residuals by examining predicted probability plots. The assumption of independent errors was checked by examining the Durbin-Watson test statistic. Homoscedasticity was assessed by visual inspection of scatterplots of the predicted values and residuals. We assessed multicollinearity by examining variance inflation factor values.

Analyses were conducted using IBM SPSS Statistics for Windows, Version 27.0. The threshold for statistical significance was set at 

 (all supplemental material is available in a PDF at the end of the online article) illustrates the enrollment of participants in the study. Demographic and clinical data are presented in 

, respectively. The study sample included 90 adults with MS. Participants were mostly female (78.9%), White (87.8%), and diagnosed with RRMS (73.3%). Average participant age was 50.71 ± 11.68 years. The median level of disability as measured by PDDS was 2 (IQR = 1, 4). On average, participants took 4.78 ± 3.67 daily medications (range 0-14), and 44.4% (n = 40) met the criteria for polypharmacy. The most common drug categories reported in the sample were DMTs (n = 50, 55.6%), analgesics (n = 42, 46.7%), and antidepressants (n = 40, 44.4%). The most common specific medications in the sample were baclofen (n = 26, 28.9%), gabapentin (n = 17, 18.9%), and levothyroxine (n = 14, 15.6%).

On average, participants reported 3.39 ± 2.87 comorbidities (range 0-13). The most frequent comorbidities were hypertension (n = 28, 31.1%), depression (n = 28, 31.1%), hyperlipidemia (n = 27, 30%), anxiety (n = 17, 18.9%), and migraine (n = 16, 17.8%).

All polypharmacy indices were significantly correlated with each other, with moderately strong (

 displays the correlations between the polypharmacy indices and cognitive performance. Six participants completed the cognitive testing by telephone due to connectivity problems. There were no significant differences in performance based on mode of administration. A greater degree of polypharmacy and anticholinergic burden was associated with worse cognitive performance, with values ranging from 

 < .001 (DBI). Post hoc correlations (Table 1) between the polypharmacy scales and each cognitive test were performed to assess whether specific domains of cognition were driving the significant relationships. The polypharmacy indices were more consistently associated with measures of processing speed, attention, and phonemic fluency.

A linear regression was used to examine whether polypharmacy indices predicted composite cognitive performance while controlling for other variables known to be associated with both polypharmacy and cognition. Age, education, disease duration, and comorbidities were entered as covariates in the first block. Polypharmacy indices were entered in the second block using a stepwise method (

). The initial model containing the covariates was significant and explained nearly 20% of the variance in cognitive composite scores, 

 = .003) were both significant predictors in the model. In the second model, DBI was retained and associated with an additional 12% of explained variance (

 = .119). These results suggest that an individual’s score on the DBI can predict a significant portion of variance in the cognitive composite score, such that for every unit of increase on the DBI index, the cognitive composite z score decreases by .209.

Few studies have directly examined polypharmacy in the MS population, and none have examined the potential utility of anticholinergic burden scales in predicting objective cognitive performance. Approximately 44% of the present sample met the criteria for polypharmacy, and DMTs were the most frequently used medications. However, the most commonly reported medication was baclofen, a skeletal muscle relaxant that is commonly used to treat spasticity in MS (and, notably, has considerable anticholinergic properties).

The relationship between anticholinergic medications and cognitive adverse effects in advanced age is well documented across a variety of clinical conditions.

 However, this phenomenon warrants further attention in the MS population. Anticholinergic medications are the first-line treatment for common MS symptoms, such as bladder dysfunction. In a comparison of patients with MS who were and were not using anticholinergic medication for bladder symptoms, Cruce and colleagues reported that anticholinergic users performed significantly worse on measures of processing speed and verbal learning when compared with nonusers.

 This effect remained robust after controlling for age, gender, and disability. More recently, Morrow et al

 used a prospective matched-cohort study to examine the effect of anticholinergic medication on objective cognitive performance in an MS sample. Cases and controls completed a comprehensive neurocognitive battery prior to starting anticholinergic medications and again after 12 weeks. While controls improved on the cognitive measures (consistent with practice effects), the performance of individuals taking anticholinergic medication remained unchanged.

This is the first study to utilize anticholinergic burden scales in the MS population. We compared the number of daily medications to scales that estimate the amount of anticholinergic burden in each participant’s medication regimen. While the ACB and ADS apply numeric ratings to broad lists of medications based on relative anticholinergic activity, the DBI accounts for both sedative and anticholinergic effects and adjusts for medication dosages. We anticipated that scores on these scales (as well as the number of medications) would be highly correlated. This was confirmed, with Spearman correlation coefficients yielding large effect sizes. Of the 3 anticholinergic scales utilized in this study, the DBI yielded the strongest relationship with total number of medications (

Each anticholinergic scale was significantly correlated with the cognitive composite score with moderate to large effect sizes. When examining the relationships between the polypharmacy indices and individual cognitive measures, all scales were correlated with measures of processing speed, attention, and phonemic fluency. This is consistent with the patterns of impaired cognitive performance reported in the studies by Cruce et al

We then entered all 4 polypharmacy indices in a linear regression to predict cognition, while accounting for the effects of age, disease duration, education, and number of health comorbidities, as these factors are known to be associated with cognitive performance. Our results suggest that the DBI may be useful in predicting objective cognitive performance in adults with MS, as it accounted for roughly 12% of additional variance in cognition above and beyond known covariates. No other polypharmacy index was retained in the regression analysis. Compared to the other polypharmacy indices, the DBI may be best suited to predict cognitive problems due to the inclusion of sedative effects and medication dosage in its calculation of anticholinergic burden.

The relationship between DBI and cognitive performance is inconsistent in the literature. One report found that higher DBI scores were associated with poorer performance on a brief cognitive screening tool in a sample of community-dwelling men ages 70 and older.

 However, another study with a very similar sample found no significant relationship between the DBI and measures of cognitive performance.

 In a sample of diabetic adults, researchers found that DBI scores were associated with poorer memory performance, but only among older adults (> 55 years) in the sample.

 It is possible that such heterogeneous results are attributable to variance in study samples and methods of cognitive assessment.

The current findings are somewhat contrary to our previous work, which found very few differences in objective cognition based on polypharmacy status.

 This discrepancy may be a function of the different cognitive measures utilized in the studies. In our 2014 study, participants completed a battery of assessments during a traditional paper-and-pencil testing session.

 Of these measures, polypharmacy was associated with poorer performance on a measure of prospective memory; however, no other cognitive measures were significantly related to polypharmacy. Due to safety concerns during the COVID-19 pandemic, the present study utilized a different set of cognitive tasks that were appropriate for virtual administration.

Robert J. Fox, MD, FAAN

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