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Proteomic Biomarker Panel for Gauging Multiple Sclerosis Disease Activity: A Case Series From Real-World Use

Although the COVID-19 quarantine required everyone to make lifestyle changes, it may have had especially profound implications for individuals who experience multiple sclerosis (MS)–related fatigue. Individuals with MS who suffer from fatigue are at risk of worsening symptoms and already predisposed to inactivity and social isolation. The objective of this study was to examine the impact of the COVID-19 national quarantine and related restrictions on mental, emotional, and physical fatigue in persons with MS in the United States.

We conducted a survey open to all adults (>18 years) with MS within the United States. The survey gathered demographic information and asked how the COVID-19 pandemic impacted their physical, mental, and emotional fatigue.

The survey was completed by 600 individuals, 478 with relapsing MS and 122 with progressive MS. There was a significant 2-way interaction of time by fatigue type; both physical and emotional fatigue significantly increased during the pandemic (

 <.01) and remained significantly higher after the pandemic than prior to the pandemic (

 <.01). Mental fatigue increased significantly during the pandemic (

 <.01) and although it remained higher, on average, after the pandemic, it was not significantly different from the level before the pandemic.

Individuals with MS experienced increases in physical, mental, and emotional fatigue over the course of the COVID-19 quarantine. Even after the lifting of quarantine restrictions, these levels have not returned to baseline. To adequately address fatigue, it is critical that health care professionals inquire about all types of fatigue in persons with MS.

From the Neuroimaging and Neurorehabilitation Laboratory, Wayne State University, Detroit, MI (ZAR,JF,NEF); the Department of Health Care Sciences, Wayne State University, Detroit, MI (JF, NEF); the Department of Physical Therapy, MGH Institute of Health Professions, Boston, MA (PP,NEF); and the Department of Neurology, Wayne State University, Detroit, MI (NEF). 

Nora E. Fritz, 259 Mack Ave #2324, Detroit, MI, 48201; 

Fatigue is one of the most common and debilitating symptoms of multiple sclerosis (MS)

; it is present in 64% to 81% of people with MS.

 Fatigue is commonly reported across disease subtypes and at all stages of the disease. It may arise both from central nervous system damage (primary fatigue) or as a result of accumulation of disease burden (secondary fatigue).

 Regardless of cause, fatigue contributes to a downward spiral of inactivity and social isolation

 and is the primary reason for job loss in persons with MS.

To limit the spread of COVID-19, a national emergency was declared in the United States on March 13, 2020, prompting a national quarantine. Although the quarantine forced all residents to make lifestyle changes, it may have had especially profound implications for individuals who experience MS-related fatigue. People with MS who have fatigue are at risk for symptom worsening and are predisposed to inactivity and social isolation. Thus, it is possible that prolonged isolation due to the pandemic may have further diminished physical activity and exacerbated symptoms of MS–related fatigue among people with MS. Indeed, in Turkey, people with MS reported greater fatigue, anxiety, and depression during quarantine than adults without MS

; however, a critical limitation of this study was the cross-sectional assessment of fatigue, anxiety, and depression during the pandemic without directly assessing the impact of COVID-19 on these symptoms. Whether the pandemic affected self-reported fatigue in people with MS is unclear.

In Italy, when compared with the 12 months prior, the 3-month lockdown resulted in perceived worsening of fatigue and overall disability in 32.4% of individuals with progressive MS, worsening depressive symptoms in 30.4%, and a shift to a more sedentary lifestyle, with 47.1% completely stopping exercise.

 Although this study describes COVID-19–related changes in fatigue in people with progressive MS, the study fails to report data on the severity and type of fatigue before or after lockdown. Despite these findings from recent European studies, the impact of the COVID-19 quarantine and the subsequent lifting of quarantine restrictions on fatigue in people with MS in the United States has not been examined. Thus, the objective of this study was to examine the impact of the COVID-19 national quarantine and its related restrictions on the mental, emotional, and physical fatigue experienced by people with MS in the United States.

We conducted a nationwide survey using REDCap (Vanderbilt University), a secure, Health Insurance Portability and Accountability Act–compliant, browser-based database and survey platform. Part of a larger cross-sectional study evaluating fatigue in people with MS, the survey was distributed through the National Multiple Sclerosis Society monthly newsletter and was available from November 1, 2021 through January 30, 2022. The Impact of COVID-19 survey was open to all adults (>18 years) with MS within the United States and took approximately 20 minutes to complete. All study procedures were approved by the Wayne State University Institutional Review Board.

The survey gathered demographic information and asked questions regarding fatigue severity, fatigue impact on daily activities, other MS symptoms, and how the COVID-19 pandemic impacted physical, mental, and emotional fatigue. Physical fatigue was defined as a lack of energy, weakness, or feeling “drained”; mental fatigue was defined as a lack of energy to think, brain fog, or feeling mentally tired; emotional fatigue was defined as feeling emotionally overwhelmed, burned out, or defeated.

 Each type of fatigue was rated using a scale ranging from 0 (no fatigue) to 10 (extreme fatigue). The survey asked for ratings of fatigue in 3 periods: (1) prior to March 2020; (2) March 2020 through May 2021; and (3) June 2021 to the present (ie, the day the survey was submitted), representing before the quarantine, during the quarantine, and the period after the easing of quarantine restrictions. Demographic information included age, sex, race, living situation, and employment status. Additionally, we collected information about current disease-modifying therapy, fatigue medication use, ambulatory status, assistive device use, and comorbidities. Disease severity was characterized with the self-reported Patient Determined Disease Steps (PDDS). The PDDS is a valid and reliable measure of disease disability in MS.

Descriptive data were examined for all variables. Participants who identified as having primary progressive MS or secondary progressive MS were pooled for analysis into a single progressive MS group. This is consistent with the most recent revisions of the MS phenotype descriptions, which consider primary and secondary progressive MS to fall under the umbrella of “progressive MS.”

 To determine whether fatigue levels and fatigue types were significantly different among the 3 time periods, a 2-way analysis of variance (ANOVA) was applied. We explored differences in fatigue across disease subtypes using ANOVA. Tukey post hoc comparisons were used to examine significant interaction effects.

Six hundred individuals living in the United States completed the survey, 478 with relapsing-remitting MS (RRMS) and 122 with progressive MS. Respondents had an average age of 50.9 ±12.5 years. The sample was largely female (82.8%), White (88.1%), living alone (83%), working full- or part-time (53.3%), ambulatory (96%) with relatively low disability (PDDS ≤ 3) (71%), and taking disease-modifying therapies (83.3%). In this sample, only 31.3% reported current use of medications to manage fatigue (

When asked to rate their physical, mental, and emotional fatigue levels, individuals reported greater fatigue (0-10 scale) during lockdown than before lockdown, and although the level of physical, mental, and emotional fatigue declined following the lifting of quarantine restrictions, fatigue levels did not return to previous levels. Physical fatigue was 0.6 points higher, mental fatigue 1.0 point higher, and emotional fatigue 0.8 points higher (

) than before the pandemic. There was a significant 2-way interaction of time by fatigue type; physical fatigue significantly increased during the pandemic (P <.01) and it remained significantly higher after the pandemic than before it (P <.01). Emotional fatigue also significantly increased during the pandemic (P <. 01) and it remained significantly higher after the pandemic than before it (P <.01). Mental fatigue increased significantly during the pandemic (P <.01), and although it remained higher, on average, after the pandemic, it was not significantly different after the pandemic than before it. Before the pandemic, physical fatigue was significantly greater than emotional (P <.01) and mental fatigue (P <.01), which did not differ from each other. During the pandemic, there was no difference between severity of physical and emotional fatigue, and both were significantly greater than mental fatigue. After the pandemic, physical fatigue was again significantly greater than both emotional (P <.01) and mental fatigue (P <.01), which did not differ from each other (

Differences in Fatigue Across Disease Subtypes 

There was a significant 2-way interaction of disease subtype by fatigue type; within progressive MS, there was a main effect of fatigue, such that physical fatigue was greater than mental (P <.01) or emotional (P <.01) fatigue, which did not differ from each other. There were no significant differences in the severity of fatigue subtypes in RRMS. Physical fatigue in individuals with progressive MS was also significantly greater than all types of fatigue in individuals with RRMS (

Impact of COVID-19 on Work and Self-Reported Exercise 

Of those individuals with MS who were employed (53.3%), 78.7% reported that their working arrangement (remote/in-person, hybrid) remained stable from before quarantine through quarantine. Only 20.7% reported some shift from remote back to in-person or to hybrid after quarantine (Table S1). A greater number of persons with RRMS (60.9%) reported working than did the participants with progressive MS (23.8%) (Table 1). Regardless of MS subtype, approximately 50% of individuals with MS reported that the pandemic impacted the amount they exercised; 82.7% reported that the pandemic affected the amount of social interaction they experienced weekly, but only 39.5% endorsed that the pandemic had negatively impacted their relationships (

The main finding of this study was that physical, mental, and emotional fatigue levels of people with MS in the United States increased during the COVID-19 lockdown, and although they declined slightly with the lifting of lockdown restrictions, these levels did not return to previous levels, which represents an overall worsening of fatigue for people with MS during this time period. Compared with the general population of adults aged 45 to 86 years, people with MS report 43% to 60% greater fatigue.

 Although all adults may have experienced a change in fatigue levels as a result of pandemic-related lockdowns, it is possible that the impact on people with MS was even greater. Indeed, 46% of nonhospitalized adults reported fatigue 6 months after having COVID-19. In comparison, all participants in this study reported at least some level of fatigue in the physical, mental, and emotional domains. Current evidence indicates that although fatigue is common in chronic diseases, the prevalence of severe and chronic fatigue is remarkably similar across chronic diseases, except for MS, Parkinson disease, and liver disease, in which the prevalence of severe and chronic fatigue was significantly higher.

A possible explanation for the increased mental and emotional fatigue levels may be changes in routine and responsibilities. The average age of our sample was 50.9 years and 83% lived with another person, so they may have been responsible for caring for young children who were suddenly home from school while also trying to work (53% of the sample was working). The intermingling of tasks and demands on time may contribute to the perception of greater fatigue. A possible explanation for a rise in physical fatigue levels may be related to an increase in sedentary behavior. In this study, individuals reported that the pandemic changed their level of exercise (52%) and social interactions (83%), which may have contributed to leaving the house less and sitting more. In addition, a prior study showed an association between higher self-reported fatigue levels and low activity levels, as well as an increased fall risk and lower quality of life in people with MS.

 Reports of exercising less during the pandemic suggest that before the pandemic, home-based exercise was not the regular mode of most participants. Thirty-three percent of physical therapists reported that aerobic training was reduced or unavailable during the pandemic and, despite 15% of physical therapists reporting increased use of relaxation/mind-body techniques or fatigue management techniques during the pandemic,

 fatigue in our sample still rose. There is an ongoing need for exercise services and skilled therapies at major medical centers; thus, clinicians should provide resources to wellness and exercise programming that can be successfully completed at home.

There was some discrepancy in how pandemic periods were defined. We defined 3 periods: before quarantine, prior to March 2020; quarantine, March 2020 through May 2021; and easing of quarantine restrictions, June 2021 to the present (ie, the day the survey was completed). Other studies either did not define the lockdown or quarantine periods,

 defined a single year (ie, 2020) for consideration,

 or defined only the lockdown period (March 2020 to May 2020) but allowed for tests within 3 (August 2020) and 6 (November 2020) months of lockdown to be considered in the dataset.

 Our results build on these studies by extending the focus beyond the immediate lockdown period to determine changes in the perception of fatigue over time.

While our sample was large, findings cannot be extrapolated to the general population of individuals with MS due to both survey bias (median PDDS score of 2 with an average age of 50.9) and participant recall bias; recall of fatigue levels over time would be more accurate with a longitudinal study design. Of course, in 2020, we did not anticipate that quarantine and restrictions would persist for such a long period of time. A longitudinal design of periodic surveys and the inclusion of a follow-up survey would potentially better capture fatigue and further our understanding of how long elevated perceptions of fatigue persist. Our data overcome some of these limitations by capturing different types of fatigue (physical, mental, emotional), albeit with simple survey questions created for this study that rank fatigue on a 0 to 10 scale. We did not differentiate whether fatigue was due to the pandemic or the worsening of disease and/or symptoms due to reduced activity levels, or whether it might be due to a combination of these factors. Finally, we did not ask participants whether they had a positive COVID-19 test, so we are unable to determine whether elevated fatigue levels may have been, in part, due to post–COVID-19 condition.

Fatigue is a common and debilitating symptom that can negatively impact quality of life. People with MS experienced increases in physical, mental, and emotional fatigue over the course of the COVID-19 quarantine and levels of fatigue did not return to baseline levels even after quarantine restrictions were lifted. Interestingly, prior work suggests that fatigue ratings tend to remain relatively stable over an 18-month period,

 which suggests that changes reported during COVID-19 lockdown may exceed natural disease progression. Persons with progressive MS reported higher levels of fatigue than those with RRMS. Providers who are attuned to the impact of fatigue can intervene with timely management strategies, but to adequately address fatigue, it is critical that health care professionals ask people with MS about all fatigue domains, which aligns with recent best-practice recommendations to use the Modified Fatigue Impact Scale to assess multiple domains of fatigue for comprehensive fatigue management in people with MS.

 This work was presented at the Wayne State University Eugene Applebaum College of Pharmacy and Health Sciences College Research Day in 2022.

The Impact of COVID-19 on Fatigue in Multiple Sclerosis

 Apathy, a neuropsychiatric symptom characterized by a lack of motivation and affecting cognitive, emotional, and behavioral domains, is being increasingly recognized in multiple sclerosis (MS), with an estimated prevalence of 19% to 43%. However, apathy remains underinvestigated in early MS. In this study, we aim to evaluate apathy in people with relapsing-remitting MS (RRMS) whose disease duration has been less than 5 years.

 The study included 38 people with RRMS with a disease duration of less than 5 years and 38 matched controls. Clinical and comprehensive neuropsychological evaluations were performed. Apathy was evaluated using the Apathy Evaluation Scale, Clinician Version (AES-C).
Depressive symptoms, anxiety, fatigue, and quality of life were also assessed.

 Apathy prevalence was 42.1%. Apathy scores correlated with depressive symptoms, anxiety, fatigue, lower quality of life, younger age, and worse performance in frontal lobe tests (Trail Making Test-A [TMT-A] and Symbol Digit Modalities Test). Independent apathy predictors were depressive symptoms (OR, 4.05; 95% CI, 1.22-13.5; 

 = .023), global quality of life (OR, 1.7; 95% CI, 1.08-2.64; 

 = .021), and TMT-A score (OR, 1.14; 95% CI, 1.02-1.27; 

 Apathy is a disabling symptom that is present in a significant percentage of people in the first years after they have been diagnosed with RRMS. Thus, people with MS should should be routinely screened for apathy, and symptoms should be managed when it occurs. We identified depressive symptoms, low quality of life, and executive dysfunction as predictors of apathy in this population.

From the Department of Neurology, Hospital da Luz Lisboa, Lisbon, Portugal. 

 Inês Brás Marques, MD, Hospital da Luz Lisboa, Avenida Lusíada 100, 1500-650 Lisbon, Portugal; 

 The authors acknowledge Renato Oliveira for his assistance in the initial setup of this study.

The author(s) declare no potential conflicts of interest.

This project (Reference LH.INV.F2019013) was partially financed by Hospital da Luz Lisboa under the initiative “Luz investigação—Bolsas Luz Saúde.” Hospital da Luz Lisboa was not involved in the scientific aspects of the study or the publication.

The content of this work was presented as an e-poster at the 10th Congress of the European Academy of Neurology; June 29-July 2, 2024; Helsinki, Finland.

Apathy is a behavioral and psychological syndrome characterized by a lack of motivation that impacts cognitive, emotional, or behavioral domains.

 Apathy is defined as a quantitative reduction of goal-directed activity compared with previous functioning that persists for a minimum of 4 weeks and affects at least 2 of the dimensions of behavior, cognition, emotionality, and social interaction.

This decline in initiative or interest in usual activities and emotional expression or responsiveness may cause clinically significant functional impairments that cannot be fully explained by other factors, such as physical disability, diminished consciousness, substance effects, and major changes in the patients’ environment.

Apathy is recognized as a neuropsychiatric manifestation of many neurological disorders, including Parkinson disease, Alzheimer disease, frontotemporal dementia, Huntington disease, cerebrovascular disease, and mild cognitive impairment.

 This disabling symptom is also being increasingly recognized in patients with multiple sclerosis (MS), with an estimated prevalence of 19% to 43%.

 Some studies in MS have also identified a correlation between apathy and cognitive dysfunction, particularly in executive functions, with apathy severity being a predictor of cognitive dysfunction at follow-up.

Despite these findings, apathy is still not part of the routine clinical assessment of people with MS, and its impact on patients’ lives is probably being underestimated. Additionally, studies evaluating apathy in the early stages of MS are lacking in the literature, and its prevalence in these initial phases is still underinvestigated. Thus, this study aims to evaluate the prevalence of apathy in people in the early phase of relapsing-remitting MS (RRMS). The association between apathy and clinical characteristics, cognitive functions, neuropsychiatric symptoms, and quality of life will also be assessed.

This study included a group of people aged 18 to 49 years with RRMS, as defined by the 2017 McDonald Criteria,

 with a disease duration of less than 5 years, who were followed in a neuroimmunology outpatient clinic of a tertiary center. Exclusion criteria included a diagnosis of progressive forms of MS, individuals under 18 or over 50 years of age, steroid treatment in the 4 weeks before the evaluation, a history of severe mental disorder (eg, major depression, psychosis, or schizoaffective disorder), other neurological conditions adversely affecting cognitive functions (eg, dementia, severe traumatic brain injury, stroke), and a history of substance abuse. Healthy controls (HCs) matched to patient demographics, including age, sex, and years of education, were also recruited. The protocol of the research project was approved by the ethics committee of our institution (Comissão de Ética do Hospital da Luz), and it conforms to the provisions of the Declaration of Helsinki. Written informed consent was obtained from all participants prior to assessments.

All participants underwent a clinical evaluation, including a full medical history and a complete neurological examination. Data collection included demographic variables such as age, sex, and years of education, as well as disease-specific information, including duration of MS, age at MS diagnosis, history of MS relapses, and current pharmacological treatment. Physical disability was assessed using the Expanded Disability Status Scale (EDSS).

Apathy was assessed through a clinical interview using the Apathy Evaluation Scale, Clinician Version (AES-C).

 This 18-item clinician-administered scale assesses various aspects of affective, behavioral, and cognitive apathy during the preceding 4 weeks. Each item has 4 possible answers rated from 0, 

, with a total score ranging from 18 to 72. Higher scores indicate more severe apathetic symptoms. Scoring guidelines provided by the original author are based on a clinician’s best judgment of the subject’s thoughts, feelings, and actions, evaluating both verbal and nonverbal data. The AES-C has been validated for the Portuguese population with defined cutoff points.

 In this study, participants with AES-C scores higher than the cutoff scores adjusted for educational level were categorized as apathetic.

A comprehensive formal neuropsychological assessment was performed by 2 trained neuropsychologists (CC and DS) with the following battery of tests: Montreal Cognitive Assessment,

a screening tool for global cognitive functioning; California Verbal Learning test

 for verbal learning and memory; Controlled Oral Word Association Test

 for verbal fluency; Digit Span Test Forward and Digit Span Test Backward

for immediate attention and working memory; Rey-Osterrieth complex Figure Test

 for visuo-constructional ability, planning, and spatial orientation; Stroop Color-Word Interference test

 for flexibility and inhibitory control; Symbol Digit Modalities Test (SDMT)

 for information processing speed and attention; Trail Making test Parts A (TMT-A) and B (TMT-B)

 for attention, information processing speed, and set-shifting ability; Wisconsin Card Sorting Test (WCST)

 for abstract reasoning, monitoring, and cognitive flexibility; and Judgment of Line Orientation test

Depression, Anxiety, Fatigue, and Quality-of-Life Assessment

Severity of depressive symptoms and anxiety were evaluated by the Patient Health Questionnaire (PHQ-9)

 and the General Anxiety Disorder Assessment (GAD-7),

 respectively. Fatigue was evaluated using the Modified Fatigue Impact Scale (MFIS)

 and quality of life was assessed with the 12-Item Short Form Survey (SF-12).

Descriptive statistics were utilized to present absolute and relative frequencies for categorical variables, while continuous variables were summarized using mean with SD or medians, as appropriate. Group comparisons were conducted using an independent-samples 

 test, depending on the variable type. Correlational analysis was performed using Spearman correlation and 2-tailed Pearson correlation to examine the relationship between apathy and clinical characteristics, cognition, mood disorders, fatigue, or quality of life. Variables found to be significant in the univariate analysis were selected for inclusion in a multivariate logistic regression model to identify predictors of apathy. All reported 

 values were 2-sided, and statistical significance was considered for values less than .05.

In total, 38 people with MS and 38 matched HCs were included in the study. 

 presents participant demographic and clinical data. People with MS had a mean disease duration of 1.9±1.3 years and a median EDSS score of 1.8.

We found a prevalence of apathy in people with MS of 42.1% (n = 16); they had a statistically significant higher score on the AES-C than controls (30 ± 9.69 vs 25.13 ± 5.43; 

 = .009). Apathy with no significant depressive symptoms associated, or 

, was present in 43.8% (n = 7) of patients with apathy.

shows the correlations between AES-C scores and disease characteristics, neuropsychiatric symptoms, and cognitive functions of people with MS.

In the correlation analysis, AES-C scores exhibited negative correlations with SF-12 scores (

 = .003). Positive correlations were observed between AES-C scores and PHQ-9 scores (

 = .008). No significant correlations were found between apathy and years of education, disease duration, or physical disability.

For cognitive functions, a correlation was found between apathy and performance on the TMT-A (

In the multivariate analysis, PHQ-9 scores (OR, 4.05; 95% CI, 1.22-13.5; 

 = .023), SF-12 total scores (OR, 1.7; 95% CI, 1.08-2.64; 

 = .021), SF-12-mental scores (OR, 0.603; 95% CI, 0.39-0.93; 

 = .022), and TMT-A scores (OR, 1.139; 95% CI, 1.02-1.27; 

 = .020) were independent predictors of apathy.

In this study, we assessed the prevalence of apathy and the correlational and predictive relationship with clinical, neuropsychiatric, and cognitive measures in people with early RRMS. We found the overall prevalence of apathy was 42.1%, consistent with reported prevalence rates in other studies focusing on apathy in MS.

 To the best of our knowledge, this is the first study evaluating apathy prevalence in early RRMS, suggesting that it occurs early in the disease course in a substantial proportion of patients.

This study revealed a negative correlation between apathy and quality of life, with higher apathy scores associated with lower global and mental quality of life, as also reported in another study in MS.

 Additionally, we identified lower quality of life as an independent predictor of the presence of apathy, which underscores the impact apathy may exert on the lives of people with MS from the earlier stages of the disease.

We also identified a correlation between apathy and depressive symptoms, consistent with other studies,

 and depressive symptoms were an independent predictor of apathy.

Although apathy and depression symptoms may overlap, many patients present with pure apathy, as did 43.8% of our population. This supports the findings that apathy can manifest independently of depression, as previously reported.

While symptoms such as loss of interest, lack of initiative, and social withdrawal may be present in both apathy and depression, distinctions exist. In depression, the loss of motivation is usually linked to feelings of hopelessness, sadness, and pessimism.

 Apathy is characterized by difficulties in planning and executing voluntary actions, resulting in decreased goal-oriented behavior in response to external stimuli. This differentiation underscores apathy as a distinct entity from depression, with different underlying pathophysiological mechanisms.

Regarding cognitive functions, higher apathy scores correlated with worse performance in frontal lobe tests, namely TMT-A and SDMT, which evaluate attention, information processing speed, and set-shifting ability. Further, a higher TMT-A score emerged as an independent predictor of apathy. These results suggest an association between apathy and executive dysfunction, which has also been reported in other MS studies.

Abnormalities in frontal-subcortical circuits are proposed to underlie both motor and cognitive impairments that result in apathy, suggesting that apathy might be a behavioral disorder associated with cognitive dysexecutive syndrome.

 Studies indicate that apathy may be associated with disruptions in the medial frontal cortex (including the anterior cingulate cortex and orbitofrontal cortex) and subcortical structures (such as the ventral striatum, medial thalamus, and ventral tegmental area).

 identified microstructural damage within the frontal cortex, caudate nucleus, and frontostriatal white matter bundles as significant pathological substrates of apathy in MS.

We observed a significant correlation between apathy and fatigue, with elevated apathy scores being associated with higher levels of global, cognitive, and social fatigue. Previous research also reported an association between apathy and fatigue.

 In addition, our study identified a correlation between apathy and anxiety symptoms, as reported in another study in MS.

However, apathy is an independent neuropsychiatric syndrome, distinct from depression, fatigue, and anxiety. The co-occurrence of these symptoms in some patients may be explained by overlapping aspects in their pathophysiology

; further research is needed to fully understand the pathophysiological mechanisms underlying their associations.

Anxiety, cognitive deficits, and apathy often present simultaneously in patients, frequently exacerbating each other and contributing to a complex clinical picture that is challenging to disentangle. Each condition may affect motivation and behavior through distinct mechanisms.

Anxiety disrupts motivation by reallocating cognitive resources to threat-related stimuli, thereby impairing the efficient functioning of the goal-directed attentional system.

 Cognitive processes such as attention, working memory, and decision-making are particularly susceptible to the effects of anxiety, leading to avoidance behaviors and a reduced capacity for effective planning and problem-solving.

Cognitive deficits further exacerbate both anxiety and apathy by undermining executive functions critical for planning, problem-solving, and maintaining goal-oriented focus.

 Apathy, in turn, can reinforce cognitive deficits, as it is often associated with disruptions in executive functioning, as previously discussed.

This intricate interplay between anxiety, cognitive deficits, and apathy poses a significant challenge in understanding and addressing their combined impact on motivation and behavior. Effective intervention requires a comprehensive approach that accounts for their overlapping mechanisms and distinct manifestations.

We also observed a correlation between apathy and younger age, which has not been previously reported in the literature, although some studies in MS reported an association between apathy and longer disease duration.

 This study evaluated a population of younger people with MS with short disease durations and low physical disability, which may have revealed that a younger age at MS onset could be linked to higher levels of apathy.

 have reported an association between apathy and higher disability levels in MS patients. However, our study did not replicate this finding, likely due to the characteristics of our sample, where all patients exhibited low physical disability levels.

The strengths of our study include the comprehensive neuropsychological evaluation, the use of the clinician version of the apathy scale, and the assessment of multiple outcome measures, all of which provide a better understanding of the factors associated with apathy in MS.

The limitations were the relatively small sample size and a select population of young patients with low physical disability, which may limit the generalizability of our findings to all people with early MS. In addition, the study did not explore the relationship between apathy and
disease-modifying treatments; imaging correlates of apathy were also not assessed.

Recognition of apathy in clinical practice is crucial, as this neuropsychiatric symptom can significantly affect disease management. Apathetic individuals may not adhere to appointments, medication regimens, and treatment instructions, alongside a reduced willingness to exert effort in their own care. Moreover, they often display a diminished concern for their health and a decline in social interactions. Thus, apathy is associated with a reduction in quality of life, as well as with depression, anxiety, and cognitive executive dysfunction.

Our results highlight the need to develop rehabilitation strategies to address apathy early in the MS disease course to minimize the significant impact it has on patients’ daily lives and activities and ultimately improve their well-being and quality of life.

A multidisciplinary approach, including rehabilitation programs designed to encourage engagement and activity, cognitive behavioral therapy to encourage positive behavioral changes and structured goal-setting, along with the pharmacological management of comorbid conditions such as depression, anxiety, and fatigue, can be useful in managing apathy and improving overall patient outcomes.

The impact of apathy on various facets of patients’ lives, including social adaptation, quality of life, adherence to therapy, and caregiver distress is likely being underestimated. We identified depressive symptoms, diminished quality of life, and executive dysfunction as predictors of apathy in this population. Early recognition and management of apathy in MS is crucial because a significant percentage of people with RRMS present with apathy in the first years of the disease.

Apathy in Early Relapsing-Remitting Multiple Sclerosis: Prevalence and Predictors

 To access the article and evaluation online, go to 

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

Recognize the unmet need for effective and direct intervention strategies for individuals with MS that correctly target specific stigma type.

Describe the 3 major stigma types in order to be able to select a stigma instrument that allows the clinician to differentiate among experienced, anticipated, and internalized stigma.

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 AMA PRA Category 1 Credit(s). 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 (none in the area of pharmacology).

: This activity is awarded 1.0 CE credits.

 As a Jointly Accredited Organization, the CMSC is approved to offer social work continuing education by the Association of Social Work Boards Approved Continuing Education program. Organizations, not individual courses, are approved under this program. Regulatory boards are the final authority on courses accepted for continuing education credit. Social workers completing this course receive 1.0 general continuing education credits.

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

, editor in chief of the International Journal of MS Care (

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

, associate editor of IJMSC, has disclosed no relevant financial relationships. Author 

, has disclosed a financial relationship with Adelphi Values (employee). Authors 

Brian C. Healy, PhD, Jonathan D. Zurawski, MD

Tarun Singhal, MBBS, MD, Sydney B. Kehoe, BS

 have disclosed no relevant financial relationships.

The staff at IJMSC, 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: May 1, 2024; Valid for Credit through: May 1, 2025

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

(3) Complete the evaluation, which is available at 

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

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Stigma is an undesired differentness associated with a particular characteristic or condition that distinguishes a person as being outside the norm and cueing stereotypes. Stigma is common in people with multiple sclerosis (MS) and is associated with several disease variables including disease duration, age, age of onset, and disease course. Stigma is also associated with psychological and psychosocial variables such as depression, anxiety, and quality of life. This article reviews our current understanding of stigma in people with MS with a focus on the various stigma types including anticipated, experienced, and internalized stigma, and the lack of consistent definitions across studies. It also describes the 7 instruments that are most commonly used to measure stigma in people with MS, and the limitations of each measure. We conclude that a better understanding of stigma that includes standard definitions of stigma types could lead to more direct intervention strategies aimed at reducing particular stigma concepts and resulting in improved health-related quality of life in people with MS.

From the Brigham MS Center, Brigham and Women’s Hospital, Boston, MA (SIW-K, BCH, SBK, JDZ, TS, BIG); Department of Neurology, Harvard Medical School, Boston, MA (BCH, JDZ, TS, BIG); Biostatistics Center, Massachusetts General Hospital, Boston, MA (BCH). 

 Bonnie I. Glanz, PhD, 60 Fenwood Road, Boston, MA 02115; 

 Sasha I. Winston-Khan, BS, has disclosed a financial relationship with Adelphi Values (employee). All other authors report no relevant disclosures.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that is characterized by early neurological relapses and risk for transition to a progressive disease phase where gradual disability may accrue.

 It is the most common nontraumatic cause of disability in young adults with onset typically occurring in young to middle adulthood.

 Approximately 85% of people with MS are diagnosed with relapsing-remitting MS (RRMS), and 15% are diagnosed with a primary progressive form of the disease (PPMS).

 Within 10 years, approximately half of those with RRMS experience progressive worsening of symptoms that is consistent with secondary progressive disease.

 Although many people with MS may initially have clinical recovery from early neurological attacks, disability tends to accrue over time and many individuals develop visible symptoms (eg, tremors, poor balance, and loss of coordination) as their disease progresses.

 describes stigma as an undesired differentness or flaw, often associated with a particular characteristic, quality, or condition (such as race, religion, mental illness, physical disability, or chronic disease) that often cues stereotypes and marks a person as outside the norm or different from the majority.

 may use this mark of disgrace to identify and disaffiliate from 

 This process of identifying and labeling a person as different from the majority and then dismissing or treating them differently is a phenomenon Goffman calls stigmatization.

Stigma is characterized by cognitive, emotional, and behavioral components that are reflected by both experiences and attitudes. 

 stigma refers to the stigma one may face in interpersonal interactions; this includes discriminatory attitudes or behaviors from other people because of a person's stigmatized condition. 

 stigma is an intrapersonal experience, chiefly involving one's fear of facing discrimination from others in the future and the internalized sense of shame associated with having a quality that others deem inferior.

Early views of stigma held that felt stigma stemmed from enacted stigma.

Yang Mao-Draayer, MD, PhD

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