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Recruitment of African American Adults With Multiple Sclerosis Into Randomized Controlled Trials of Exercise Training: Lessons Learned From Project TEAAMS

 People with multiple sclerosis (MS) often experience psychiatric symptoms, such as anxiety and depression, that impact disease progression and quality of life. Cognitive impairment, particularly in processing speed and episodic memory, is common in MS. There are several studies studying the relationship between anxiety and cognition in the population with MS. This study reviews that literature.

This bibliographic review covers publications in Spanish and English from January 2006 to June 2022. It focuses on quantitative investigations of the relationship between anxiety symptoms and cognitive variables in people with MS.

A majority of studies found an association between anxiety and cognition in people with MS. Anxiety significantly affects information processing speed, learning, memory, attention, working memory, and verbal fluency in people with MS. However, some studies find no association. The impact of depressive symptoms and the bidirectional relationship between anxiety and cognition are highlighted.

Anxiety in people with MS is associated with cognitive impairment. Further research is needed to understand the mechanisms and establish causal relationships between anxiety and cognition in this population.

From the Demyelinating Diseases Working Group (CUEM), Neurology Division, Ramos Mejía Hospital, Buenos Aires, Argentina (RMS, NC, ALM, RA, MBE); and the Research Institute in Psychology, School of Psychology, Buenos Aires University, Buenos Aires, Argentina (NC, MBE). 

 María Bárbara Eizaguirre, JD, Perón 3051, La Matanza, Buenos Aires, Argentina. ZC: 1754; 

We extend our gratitude to the authors of the studies included in this review, whose work has greatly enriched our understanding of the subject.

Multiple sclerosis (MS) is a chronic immune-mediated, inflammatory, demyelinating, and neurodegenerative disease of the central nervous system. It is the most common cause of neurologic disability in young adults.

 Psychiatric manifestations, such as symptoms of anxiety and depression, are prevalent in people with MS and are associated with disease progression and a poorer quality of life.

 Although these manifestations are present in up to 60% of people with MS, they are often not adequately treated.

 In contrast, the prevalence of cognitive impairment in adults with MS ranges from 34% to 65% and symptoms vary according to the course of the disease.

 Cognitive impairment is also a neglected but common symptom with a profound effect on essential activities of daily living. Neuropsychological research suggests that cognitive processing speed and episodic memory are the most frequently affected cognitive domains.

MS can be described as a pathology with an uncertain outcome: a chronic, unpredictable neurological disorder with recurrent relapses (the most common form of MS, the relapsing-remitting MS phenotype) that seem to occur at random; it carries the risk of eventual progression to a chronic progressive disease after years or decades of stability. Therefore, it is quite possible that the unpredictable nature of this disease, particularly with regard to relapses and the potential for future progression and disability, causes anxiety.

Clinical anxiety is defined as an intermittent or persistent feeling of apprehension or fear that can be associated with physical symptoms, including tachycardia, sweating, palpitations, dizziness, and autonomic gastrointestinal symptoms.

 The severity of anxiety symptoms can be assessed in 2 ways: (1) via self-report scales or questionnaires that measure the patient's current self-perceive1d mood, such as the Hospital Anxiety and Depression Scale (HADS),

 or (2) through clinical reporting, such as the Structured Clinical Interview for the 

Diagnostic and Statistical Manual of Mental Disorders

 (SCID), which uses more formal diagnostic criteria to establish the presence of a possible or proven anxiety disorder.

 Studies indicate that between 30% and 50% of people with MS present with clinically significant anxiety

 and it is associated with negative health-related outcomes, such as lower adherence to treatment

; increased fatigue; physical, psychiatric, and social dysfunction

Depression is known to be a common comorbid symptom with anxiety in people with MS, and anxiety was found to be a strong predictor of depression through both direct and indirect pathways, suggesting a possible causal relationship.

 Although the role of each variable has been studied separately, recently, the presence of multiple comorbidities in people with MS has drawn the attention of clinicians and researchers, which has led to mediation studies

 that seek to understand the interaction of both variables and their relationship with cognition.

There is evidence of prefrontal cortical atrophy in people with MS who have anxiety, involving structures that resemble known neurobiological circuits of anxiety. MRI studies found an association between atrophy in the superior and middle gyri of the right frontal lobe and anxiety scores in people with MS.

 These findings clarify the appearance of anxiety as part of the pathology of the disease.

It is known that the influence of emotional stimuli—especially stimuli of a threatening or anxiogenic nature—interferes with performance in attention tasks, working memory, and cognitive inhibition.

 This is important for understanding the relationship between anxiety and cognition in MS; some authors have proposed that it is bidirectional or synergistic, which would imply that anxiety can negatively affect domains such as complex attention and processing speed, thus interrupting cognition. In addition, anxiety contributes to slower processing speed, which creates anxiety symptoms and, therefore, negatively affects cognition.

 The neuropsychological findings regarding the relationship between anxiety and cognition are not consistent, both those that refer to people without MS

 Is it possible to identify a neuropsychological profile and establish a characteristic pattern of functioning across the different cognitive domains in people with anxiety and MS? We conducted a narrative review of the bibliography available to date on the relationship between anxiety and cognition in people with MS to investigate.

We searched for the following terms in PubMed and the Scientific Electronic Library online (SciELO): 

anxiety symptoms, neuropsychiatric disorders

. We selected articles published from January 2006 to June 2022 that quantitatively investigated the relationship between anxiety symptoms and 1 or more cognitive variables in people with MS. The search yielded 53 articles. After discarding 10 papers that addressed anxiety and cognition outside the scope of MS and 8 that addressed anxiety and MS but did not include cognitive variables, 35 studies remained (

Anxiety is a complex construct that implies a multidimensional conceptualization. It includes physiological, behavioral, cognitive, and affective variables; thus, its evaluation requires the assessment of multiple dimensions.

 Indeed, in the MS clinic, anxiety symptoms can be measured in many ways, for example, indirectly by taking standardized interviews that complement psychopathology and mental health manuals, such as the Schedules for Clinical Assessment in Neuropsychiatry

 Another possibility is using scales, questionnaires, and inventories, including subjective measures such as the patient's self-report, to complete what is referenced in the medical records and in the direct objective measures of the physiological and behavioral dimension of the anxiety spectrum.

 Some of these scales and questionnaires are used as early detection or screening tools and may require additional evaluation to confirm a diagnosis.

 Several of these instruments have been validated to measure anxiety in people with MS: the Hamilton Anxiety Rating Scale,

 the State-Trait Anxiety Inventory (STAI),

 Because some common symptoms of MS, eg, tingling, dizziness, or muscle tension, can overlap with the somatic symptoms of anxiety and lead to misclassification or overestimation of anxiety presentations or criterion contamination, investigators of the Canadian Institutes of Health Research

 evaluated the validity and reliability of dimensional measures of anxiety in people with MS and concluded that the HADS anxiety subscale (HADS-A) is a reliable assessment with greater sensitivity and specificity for people with MS than other tools, such as the BAI or the Generalized Anxiety Disorder 7-Item scale.

 We found that the HADS-A cutoff points used for other medical populations were also appropriate for those with MS. Scores greater than or equal to 8 indicate clinically significant anxiety, while scores greater than or equal to 11 indicate an anxiety disorder with a sensitivity of 88.5% and a specificity of 80.7%.

 Of the 35 articles reviewed, 21 used the HADS-A to measure clinically significant anxiety,

 1 used the Mental Health Inventory with the Neuroticism scale from the NEO Five-Factor Inventory,

 1 used the Depression Anxiety Stress Scales,

 and 1 used the Zung Self-Rating Anxiety Scale.

 Only 5 of the studies supplemented the anxiety measures with evaluations from standardized neuropsychiatric interviews for anxiety disorders (SCID)

 and only 2 added a second tool to measure anxiety, the Symptom Checklist-90-Revised with the HADS

 and the Penn State Worry Questionnaire with the STAI.

Prevalence of Anxiety Disorders and Anxiety Symptoms in MS: Associated Factors

According to previous studies, the prevalence of anxiety is 3 times higher in people with MS than in the general population.

 A prevalence rate close to 30% was replicated in a cross-sectional study from 2018 in a sample of 244 people with MS in Canada. That study found that higher odds of anxiety were associated with depression, low levels of education, and impaired quality of life.

 The RELACCEM study, a multicenter investigation that evaluated neuropsychiatric symptoms among participants from Argentina, Chile, Colombia, Mexico, Uruguay, and Venezuela, found that anxiety symptoms were present in up to 33% of people with MS.

 An Argentinian cross-sectional study that evaluated 88 people with MS found that 45% of their sample presented with anxiety and anxiety was significantly associated with younger age, shorter time from diagnosis, history of other psychiatric disorders, depression, and poor quality of life.

 A recent systematic review with a meta-analysis found that the overall prevalence of anxiety in people with MS is 35.19%, which is higher than the prevalence reported in previous studies.

 This review also found that anxiety is more prevalent in different clinical forms of MS—21.40% in relapsingremitting MS (RRMS) and 24.07% in progressive MS (PMS)—than depression (15.78% in RRMS and 19.13% in PMS).

Relationship Between Anxiety and Cognition in MS

In the field of MS, neuropsychological batteries are used to assess cognition, including the classic Brief Repeatable Battery for Neuropsychological evaluation (BRB-N) by Rao,

 or the Minimal Assessment of Cognitive Function in MS (MACFIMS),

 which assess attention, working memory, learning, and verbal and visual episodic memory, as well as verbal fluency. MACFIMS can also be used to assess executive functions and visuospatial processing. In 2012, a committee of experts proposed the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) as a brief, practical, and universal cognitive assessment instrument.

 Some of the studies included in this review used one of these cognitive assessment batteries: 8 used the BRB-N,

 Other studies used different neuropsychological batteries or combinations of tests to measure 1 or more domains in particular: Three used tests from the Behavioural Assessment of the Dysexecutive Syndrome (BADS),

 3 evaluated using portions of the Test of Everyday Attention (TEA),

 2 used the Montreal Cognitive Assessment,

 2 used the Neuropsychological Screening Battery for MS,

 1 used the Luria–Nebraska Neuropsychological Battery,

 11 used a set of tests selected ad hoc or as a screening method,

 2 evaluated only 1 area or cognitive domain,

 and lastly, 2 used computerized batteries.

Studies investigating the association between anxiety and cognition in MS trend toward 3 different conclusions: confirming that anxiety is a predictor of cognitive functioning (12 cross-sectional studies

); finding that anxiety predicts subjective cognitive functioning, ie, the perception of cognitive impairment or cognitive difficulties (12 cross-sectional studies

); and finding no association between anxiety and cognition (5 cross-sectional studies

Studies confirming the association between anxiety and cognition in MS

. Several studies found that cognitive dysfunction correlates significantly with an increase in anxiety,

 or that anxiety independently predicts objective cognitive performance.

 One longitudinal study even suggests that anxiety is a significant predictor of cognitive changes over time.

 A recent article, with a 2-year follow-up, found that correlations between scores on anxiety and cognitive measures (HADS and BICAMS) were not significant at baseline, but weak to moderate negative correlations were found at follow-ups after 1 and 2 years.

 A subsequent article, with a 3-year follow-up, found that at any point in time, individuals with high anxiety symptoms exhibited lower performance in processing speed, verbal learning, and working memory.

 Other current cross-sectional studies also confirm that anxiety correlates with certain measures of cognitive functioning.

Information processing speed appears in several investigations as the function most affected by anxiety.

 Cross-sectional studies that included the Symbol Digit Modalities Test,

 to measure information processing speed, reported that people with MS who had anxiety were less efficient on executive tasks, particularly tasks that included a processing speed component.

 Another study that controlled for associated demographic and clinical factors, such as depression and fatigue, reported that anxiety in people with MS was independently related to lower information processing speed.

 Similarly, a significant difference was found in measures of processing speed in people with MS who had anxiety compared with people with MS who did not have anxiety.

 Another study found that lower disability, shorter disease duration, and lower levels of anxiety predicted performance in processing speed.

 This relationship was also found in a longitudinal study that followed the evolution of cognitive measures and values of associated clinical factors for 3 years in 4 cohorts of people with inflammatory diseases, including MS.

 These authors concluded that, at any point in time, individuals with high symptoms of anxiety exhibited lower processing speed. Vissicchio et al

 conducted 2 mediation analyses to explore the relationships between anxiety, processing speed, and verbal learning. The first analysis revealed that anxiety affects verbal learning through processing speed. The second analysis established that processing speed influences verbal learning while being mediated by anxiety. The results suggest a bidirectional relationship between anxiety and processing speed, with both factors influencing performance in verbal learning.

Different findings confirm that verbal episodic memory and visual episodic memory are 2 of the cognitive domains affected or interfered with by anxiety.

 A longitudinal study exploring cognitive changes in people with MS, who were assessed at baseline and after 1 year of followup, found that baseline measures of negative affect, including depressed mood and anxiety, tended to more strongly predict changes (25% of variability) in verbal and visuospatial episodic memory measures; however, the relationship between negative affect and cognition was not reciprocal.

 Another cross-sectional study showed that, in combination with gender, age, and disability, anxiety explained 24% of the variance in the memory domain in people with MS.

 A study that investigated the established relationship between anxiety and verbal learning and memory in people with MS found that anxiety was a significant predictor of deficits in verbal learning.

 Likewise, other studies found that high anxiety present in people with RRMS or in the early stages of the disease was associated with cognitive memory impairment and language disorders.

 A recent paper that studied the relationship between cognitive impairment, sleep disorders, and the role of anxiety and depression among people with MS established that memory scores were negatively correlated with state anxiety, whereas a high level of trait anxiety moderated the relationship between waking up at night and worse memory performance.

 Recent studies also report that a current diagnosis of anxiety disorder or elevated anxiety symptoms, even in the absence of a diagnosed anxiety disorder, were associated with reduced information processing speed, lower working memory performance, and lower learning and verbal memory performance.

 A 2016 study agreed that there was a relationship between anxiety and visual episodic memory and concluded that levels of impairment measured by the HADS-A were significantly related to measures of visual episodic memory, as well as visual episodic memory processing speed and working memory.

 Other articles identify strong relationships between cognition and mood and suggest that both anxiety and depression correlate with cognition in MS, even though they both have dissociable cognitive patterns: A lower level of anxiety is associated with better visual memory while a lower level of depression is related to better attention and information processing speed.

Several studies concluded that complex attention—either sustained or divided attention—and working memory are also affected by anxiety.

 Previous research examining the impact of anxiety on the cognitive performance of people with MS found that anxiety as a state, measured by the STAI, predicted performance on the executive functioning index.

 Likewise, anxiety has been independently related to lower performance in complex attention tasks and information speed processing

 as well as alterations in inhibition processes, verbal fluency, and practical-constructive problem solving.

 Other studies also found a significant difference between loading measures for working memory in anxious and nonanxious people with MS.

 A recent study showed that disease duration, physical disability, and high levels of state anxiety significantly and negatively predict performance on the Paced Auditory Serial Addition Test (PASAT), a test validated among the population with MS that requires complex attention and working memory.

 Similarly, 2 of the papers cited above found that self-reported anxiety symptoms were associated with lower working memory performance and processing speed.

Most of the aforementioned studies included language tests, but only 2

 found that anxiety measures were associated with language measures, and more specifically, with verbal fluency tasks. One concluded that high levels of anxiety and depression can be predictors of alterations in phonological and semantic verbal fluency.

 The other, seeking to establish cognitive phenotypes in people with MS, indicated that elevated anxiety are present in people with RRMS, people in the early stages of the disease, and people with memory and language disorders.

Studies that find association between anxiety and subjective cognitive impairment in MS. 

Twelve articles indicate that anxiety, along with other clinical variables (depression, fatigue, etc), in people with MS makes them more likely to report cognitive difficulties.

 In 10 of these studies, depression was present, suggesting that this variable could be involved in subjective rather than objective measures of cognition. Cross-sectional and longitudinal research studies have investigated the relationship between anxiety and subjective measures of cognitive impairment in MS using, for the most part, self-report questionnaires such as the Multiple Sclerosis Neuropsychological Questionnaire (MSNQ),

 the Cognitive Failures Questionnaire (CFQ),

 the Prospective and Retrospective Memory Questionnaire (PRMQ),

 or the Cognitive Emotion Regulation Questionnaire (CERQ).

 Of all the studies in this review, 3 used the MSNQ,

 and 1 used the 8-item Short Form Health Survey.

 Finally, the last and most current study used a computerized cognitive battery,

 the Mindstreams computerized cognitive assessment system,

 which yields a composite of global cognitive functioning. A pioneering study from 2006 found that levels of education, depression, anxiety, fatigue, and disability were significantly related to how people with MS perceived their cognitive functioning.

 The authors found that anxiety predicted perceptions of cognitive functioning at a daily global performance, but not an objective cognitive performance assessed by a battery of cognitive tests. They concluded that perceived cognitive functioning is subject to a number of noncognitive influences such as the patient's emotional state (depression and anxiety) and mental and physical state (fatigue and disability), which account for a considerable proportion of the variability (approximately 40%) of such perceived cognitive functioning. Subsequent studies also found that anxiety in concert with depression predicts self-reported cognitive decline in people with different clinical forms of MS.

 In contrast, an investigation that evaluated the subjective perception of memory problems found that they are associated with more reports of depression, anxiety, and neuroticism. The same investigation also found that the relationship between anxiety and self-reported memory is stronger than that between depression and self-reported memory.

 Other studies have also shown that self-reported executive dysfunction by people with MS predicts greater depression, stress severity, trait anxiety, mental health, and general quality of life.

 A more recent study that investigated the possible relationship between cognitive impairment, mood disorders (eg, anxiety and depression), and falls in people with MS found that those who were depressed and anxious were almost 4 times more likely to perceive cognitive alterations than those who were not depressed or anxious. It also noted that anxiety without depression was associated with a lower risk of falls, even when compared with people with MS who do not have depression or anxiety.

 In line with these findings, a 2019 study also found a significant correlation among anxiety, depressive symptoms, fatigue, cognitive difficulties, and psychiatric history,

 with only depressive symptoms and cognitive issues remaining significantly related to anxiety. Even though the latter search indicated that anxiety was associated with cognitive difficulties in people with MS, none of the objective neuropsychological tests showed significant correlations with anxiety.

Studies that find no association between anxiety and cognition in MS. 

 concluded that there is no association between anxiety and cognition.

One of the cross-sectional studies compared cognitive performance between people with MS both with and without anxiety and found no significant differences on the neuropsychological measures administered.

 Another study examined anxiety as a trait and a state via the STAI inventory in a sample of 50 people with MS and 45 subjects without MS, and also found no associations with neuropsychological functioning.

 A final study reported that anxiety is not associated with cognitive deficits, but that depressive symptoms may have a more disabling impact on the functional results of people with MS.

Longitudinal design studies also report that anxiety does not correlate with neuropsychological performance over time. One study found a significant association between anxiety and depression with perceived cognitive deterioration at the beginning of the study, however, in the follow-up measures, no relationship was found with neuropsychological performance.

 Another study, which followed a cohort of 608 people with MS for 1 year, found no clinically significant relationship between cognitive functioning and anxiety, even though other clinical variables were related.

 Likewise, a longitudinal study followed 165 people with RRMS for a period of 3 years and reported that only depression was significantly associated with an increased risk of cognitive impairment.

This literature review presents studies supporting the association between anxiety and cognitive performance in individuals with MS; there were 12 cross-sectional studies

 Anxiety significantly affects cognitive domains such as information processing speed, learning, verbal and visual episodic memory, attention, working memory, and verbal fluency. These findings are consistent with existing literature showing poorer cognitive performance in patients with anxiety disorders compared with the general population.

Notably, some researchers highlight a bidirectional relationship between anxiety and cognition, suggesting that higher anxiety levels impair information processing speed, while lower processing speed is associated with higher anxiety. This supports Eysenck's theory of attentional control,

 which posits that anxiety disrupts cognitive processes by increasing attention to both internal and external distractors, thereby affecting cognitive performance.

Despite these insights, the mechanisms linking anxiety and cognitive performance in people with MS are not fully understood. Research is needed to establish a causal relationship between these variables. This review also indicates that while anxiety can influence cognitive difficulties, depression is a stronger predictor of cognitive impairment in MS.

Given these data, it is reasonable to increase efforts to study the correlation between anxiety and its impact on cognition in people with MS. The conclusions drawn from this review have some limitations. It is important to be aware of the variability in the characteristics of the samples (eg, demographics, measure of cognitive impairment before evaluation). Another variable is the techniques used for measuring anxiety and for assessing cognitive components. Finally, the different methods for comparing data and measuring their effects and directions may influence the differences between the findings of the reviewed studies. It is also worth noting that only 17% of the reviewed papers were longitudinal studies (6 of 35). Despite these limitations, this review confirms that the association between anxiety and cognition in MS is validated by numerous studies that aim to expand knowledge about the impact of 1 variable on the other. Future research might consider discrepancies among the findings of the studies to provide a more precise understanding of the main mechanisms at play between anxiety and cognitive functioning. Prioritizing the study of the effects of anxiety in people with MS would optimize management and treatment, and likely lead to improvements in depressive symptoms and other comorbidities such as fatigue or cognitive impairment. Similarly, addressing cognitive problems could have a beneficial impact on mood symptoms, contributing to greater stability over the disease course and, consequently, a better quality of life.

Anxiety and Cognition in Multiple Sclerosis: A Narrative Review

The experience with spasticity varies among individuals with multiple sclerosis and spasticity (MSS), as they may not recognize it as spasticity or have the language to describe their symptoms. This can lead to potential delays in diagnosis and treatment.

Symptoms and Emotions Exploration Needed in Multiple Sclerosis Spasticity was an online survey completed by 1177 individuals with MSS in 2021. It sought to capture symptoms of spasticity, variability of symptoms, specific spasticity triggers, and how conversations with physicians were initiated.

The mean age of the cohort was 56.8 years and it was 78% women. Prior to spasticity onset, 65% of respondents felt minimally prepared or unprepared for possibly developing spasticity and were unaware that spasticity manifests as part of MS. Eighty percent experienced spasticity daily, which was variable in severity and duration. Spasticity was triggered by a range of factors and 90% of those surveyed were unable to predict when it would occur or its severity. Day-to-day variability of spasticity prevented 65% of respondents from doing things they wished to do. Sixty percent were confused by their symptoms, not recognizing them as spasticity. Although 91% reported experiencing muscle spasms, only 69% used “muscle spasms” to describe their symptoms. Other descriptors included “muscle tightness,” “stiffness,” “cramping,” and “pain.” After recognizing spasticity, 78% proactively initiated discussions with their physicians, 52% wished they had done so sooner, and 42% delayed the conversation by up to or more than a year.

Results emphasize the variable nature of spasticity and the lack of a common language to describe symptoms, underscoring the importance of education, earlier recognition, and customized treatments tailored to the severity and duration of spasticity symptoms.

From the Andrew C. Carlos Multiple Sclerosis Institute, Shepherd Center, Atlanta, GA (BT); Johns Hopkins University School of Medicine, Baltimore, MD (SDN); Department of Neurology, University of Arizona College of Medicine, Tucson, AZ (BH); Outcomes Insights, Ventura County, CA (SD); Jazz Pharmaceuticals, Inc, Seattle, WA (JP, RC). 

Ben Thrower, MD, Andrew C. Carlos Multiple Sclerosis Institute, Shepherd Center, 2020 Peachtree Road NW, Atlanta, GA, 30309, USA; 

The authors would like to thank all survey participants and those who assisted in the development of the survey. Formatting and editorial assistance was provided to the authors by April Ingram of Outcomes Insights and funded by Jazz Pharmaceuticals, Inc. All authors met the International Committee of Medical Journal Editors authorship criteria and had full access to relevant data. The authors had full editorial control of the data presented and provided final approval of all content.

 Dr Thrower has received consultant fees from Sanofi Genzyme and is a member of the speakers’ bureaus of Bristol Myers Squibb, Genentech, and Horizon Therapeutics. Dr Newsome has received consultant fees for scientific advisory boards from Biogen, Bristol Myers Squibb, EMD Serono, Genentech, Greenwich Biosciences, Horizon Therapeutics, and Novartis; is an advisor for Autobahn Therapeutics; is the study lead primary investigator for a Roche clinical trial; was a clinical adjudication committee member for a MedDay Pharmaceuticals clinical trial; and has received research funding (paid directly to institution) from Biogen, the Department of Defense, Genentech, the National Multiple Sclerosis Society, the Patient-Centered Outcomes Research Institute, Roche, and The Stiff Person Syndrome Research Foundation. Dr Hendin has received research funding and consultant fees for advisory boards from and is a member of the speakers’ bureaus of Biogen, Bristol Myers Squibb, EMD Serono, Genentech, Novartis, and Sanofi Genzyme. Dr Chinnapongse was an employee of Jazz Pharmaceuticals, Inc. Ms Danese has received consultant fees from Jazz Pharmaceuticals, Inc. Ms Patterson was an employee of Jazz Pharmaceuticals, Inc.

 This work was sponsored by Jazz Pharmaceuticals.

 Portions of this work were previously presented as an oral presentation and a poster presentation at the Consortium of Multiple Sclerosis Centers Annual Meeting; June 1-4, 2022; National Harbor, Maryland.

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system that can have a highly variable and unpredictable clinical course. It is estimated that 2.8 million people are living with MS globally.

 The overall burden and neurological symptoms of MS can be experienced differently, based on location, size, and number of central nervous system lesions. For those with MS, symptoms can occur concurrently, in various combinations, potentially exacerbating each other, further compounding its unpredictability and management complexity.

Spasticity involves the involuntary stimulus of muscles to contract or shorten and is a complicated, multidimensional symptom, contributing to disability in up to 84% of individuals with MS.

 The muscle contractions that characterize spasticity can occur spontaneously or continuously.

 Generally, spasticity may result in potentially debilitating musculoskeletal issues, including focal or diffuse pain, involuntary shaking, joint stiffness, muscle contractures, and limited range of movement, leading to multiple concurrent symptoms that negatively impact daily functioning and quality of life.

 For those with MS, it has been well documented that spasticity can result in physical disability and mobility issues, profoundly impacting quality of life, functioning, and performing activities of daily living, more so as the disease progresses.

As the experience of spasticity varies among individuals with MSS, the spectrum of its signs and symptoms has made quantifiable assessment challenging. Although clinician-assessed scales do exist, including the pendulum test, Ashworth Scale, modified Ashworth Scale, and the Tardieu and Modified Tardieu Scales, they are not widely used in the clinical setting. Patient-reported measures or scales have also been developed, including the 88-question MS Spasticity Scale and the Numeric Rating Scale for Spasticity. Despite the availability of assessment tools, most often, spasticity is included as a component of the standard MS neurological examination that is briefly documented in the patient’s chart. In addition, individuals with MSS may not recognize the characteristics of spasticity, have the language to describe their symptoms, or feel they are worth speaking to their physician about. All these factors may lead to potential delays in the clinician-patient dialogue resulting in delayed spasticity diagnosis and treatment.

To address this need and better understand the clinician-patient dialogue surrounding spasticity in individuals with MS, we conducted the Symptoms and Emotions Exploration Needed in Multiple Sclerosis Spasticity (SEEN-MSS) survey.

 The aim was to provide a more comprehensive understanding of how individuals with MSS experience and describe their symptoms associated with spasticity, the variability of those symptoms, specific spasticity triggers, and how they initiate conversations with physicians.

Survey methodology, eligibility, and a subset of analyses of SEEN-MSS have been previously published.

 A cross-sectional, observational, online survey, SEEN-MSS was developed by Greenwich Biosciences, now a part of Jazz Pharmaceuticals, Inc, and Scott Newsome, DO, in collaboration with 3 United States–based advocacy organizations for individuals with MS: the Multiple Sclerosis Association of America, the Multiple Sclerosis Foundation, and the National Multiple Sclerosis Society. These organizations assisted with online recruitment of survey participants.

The SEEN-MSS survey was conducted from February 4, 2021, to May 3, 2021. Prior to survey initiation, all materials were reviewed, and a waiver was granted by Advarra, an independent review board. All participants completed an online consent form prior to participating in the survey and all screening and survey details were self-reported.

Continuous variables were summarized as means, medians, and ranges; categorical variables were summarized as frequency distributions and percentages.

During the study period, the SEEN-MSS survey was completed by 1177 adults with MSS. Most participants were White (85%) and female (78%) with a mean age of 56.8 years (SD ± 10.7) (

). Of those who reported their specific MS diagnosis, 70% had been diagnosed with relapsing-remitting MS and 73% were receiving treatment with a disease-modifying therapy. A high proportion (80%) of participants reported that they experience spasticity at least daily, and applying the Numeric Rating Scale for Spasticity score, 18% reported their spasticity as mild, 40% as moderate, and 40% as severe. Eighty-seven percent were receiving treatment for their spasticity, most commonly an oral medication (Table 1). Additional characteristics of survey participants have been previously published.

Survey respondents reported that there was a period of approximately 5 years between MS diagnosis, occurring 16.8 years (mean, SD ± 10.0) prior to taking the survey, and onset of spasticity symptoms, occurring 11.5 years (mean, SD ± 9.7) prior to taking the survey. While 91% reported that they experience muscle spasms, only 69% specifically used the phrase 

). Other commonly used descriptors used by respondents included 

Spasticity does not appear to be a symptom that is immediately recognized by individuals with MS. When asked to look back, 60% reported that they were confused by the symptoms that they were experiencing and 70% recognized that they had been experiencing spasticity symptoms earlier than they had realized. Because specific symptoms may not have been recognized or acknowledged by the individual, this may have contributed to delays in clinician-patient dialogue.

Within the survey, 65% of respondents reported that they were either 

not at all prepared or minimally prepared

 for the possibility of developing spasticity, as their physician had not discussed this likelihood with them.

Following their MS diagnosis, physicians initiated a general discussion on possible MS symptoms with respondents within 3 months (30%), within 3 to 6 months (23%), within 7 to 11 months (4%), and after more than a year (30%). Of those who had had a discussion about spasticity specifically, it was started proactively by 78% of respondents while, for 22%, the physician was the one to initiate the discussion about spasticity. Interestingly, of the total cohort, 13% reported that they have never had a discussion with their physician about the symptoms of MS. Two-thirds (66%) of respondents stated that their physician used the word spasticity while discussing MS symptoms with them.

Although 87% of individuals with MSS had spoken with their physician about spasticity, 52% of those wished they had done so sooner. Among those wishing they had discussed spasticity sooner, 51% stated that it might have provided them with a better understanding of what was happening to their bodies, 48% might have sought treatment for their spasticity symptoms sooner, 34% shared that they may have had a name to explain what they were feeling, and 16% felt that earlier discussion might have given them more trust in their physician’s overall management plan for their MS.

Looking back, the majority of respondents (70%) somewhat agreed or strongly agreed that they were experiencing spasticity symptoms earlier than they originally thought and 60% somewhat agreed or strongly agreed that they were confused by their symptoms because they did not recognize them for what they were.

The survey identified 3 key barriers that prevented an earlier discussion about spasticity between participants and their physicians (

). The most common barrier, noted by more than half (52%) of the individuals, was that they lacked the vocabulary to describe spasticity; they did not know how to describe their symptoms. They also assumed that spasticity was simply a part of their MS and not worthy of mentioning (29%) and, similarly, they made the presumption that their spasticity could not be treated (18%), so again, it was not worth mentioning.

For 80%, spasticity is a once-daily occurrence. For 34%, spasticity is constant, while 40% describe multiple periods of spasticity during each day (Table 1). Spasticity is also variable throughout the day in severity and duration for 70% and from day to day for 63%. They reported that their spasticity is often worse in the evening (31%) and throughout the day (30%), compared with overnight (18%), in the morning (17%), or in the afternoon (4%).

Spasticity is triggered by a range of factors, most commonly fatigue (52%), physical activity (49%), heat (45%), and stress (43%) (

Implications of the Variable Nature of Spasticity

Recognition, Description, and Variability of Spasticity in Individuals With Multiple Sclerosis and Potential Barriers to Clinician-Patient Dialogue: Results From SEEN-MSS, a Large-Scale, Self-Reported Survey

Denise Gomez, BA

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