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. Author manuscript; available in PMC: 2021 Aug 1.
Published in final edited form as: Mult Scler Relat Disord. 2020 May 18;43:102176. doi: 10.1016/j.msard.2020.102176

Restless legs syndrome, sleep quality, and perceived cognitive impairment in adults with multiple sclerosis

Katie LJ Cederberg a,*, Brenda Jeng a, Jeffer E Sasaki b, Robert W Motl a
PMCID: PMC7363523  NIHMSID: NIHMS1600142  PMID: 32498034

Abstract

Background:

Restless legs syndrome (RLS) is a prominent sleep disorder that often worsens sleep quality and perhaps cognitive function in adults with multiple sclerosis (MS). The present study examined the relationships among RLS prevalence and severity, sleep quality, and perceived cognitive impairment in adults with MS.

Methods:

Participants (N=275) completed the Cambridge-Hopkins Restless Legs Syndrome Questionnaire, the International Restless Legs Syndrome Study Group (IRLS) Scale, the Multiple Sclerosis Neuropsychological Screening Questionnaire (MSNQ), the Pittsburgh Sleep Quality Index (PSQI), the Patient Determined Disease Steps (PDDS), and a demographic and clinical characteristics questionnaire.

Results:

Persons with MS who had RLS (i.e., MS+RLS; n=74) reported significantly worse perceived cognitive impairment compared with those who did not have RLS (n=201; p=0.015). Bivariate correlation analyses within the MS+RLS group indicated that greater RLS severity was significantly associated with more severe perceived cognitive impairment (r=0.274) and sleep quality (r=0.380), and worse perceived cognitive impairment was significantly associated with worse sleep quality (r=0.438). Linear, step-wise regression analyses indicated that RLS severity significantly predicted perceived cognitive impairment (β=0.274), but the inclusion of sleep quality (β=0.391) accounted for the relationship between RLS severity and perceived cognitive impairment (β=0.126).

Conclusions:

Our results suggest that sleep impairment may be an intermediary factor in the association between RLS severity and cognitive impairment in persons with MS who present with RLS. The diagnosis and treatment of RLS symptoms and other effectors of sleep quality could improve neuropsychological consequences of MS.

Keywords: restless legs syndrome, multiple sclerosis, cognitive function, sleep quality

1. Introduction

Restless legs syndrome (RLS) is an idiopathic sensorimotor disorder that has a higher prevalence in persons with neurological diseases such as multiple sclerosis (MS; 26%)(Ning et al., 2018) than the general population of adults (15%)(Ohayon, O’Hara, & Vitiello, 2012). The pathology related to RLS in MS is unknown, however research to date suggests a correlation between cervical lesions and symptoms of RLS (Manconi et al., 2008; Minar, Petrlenicova, & Valkovic, 2017)implying the descending and/or ascending tracts may be interrupting proper signaling (Foschi et al., 2019). The defining features of RLS include the uncontrollable urge to move the extremities that is accompanied by uncomfortable or unpleasant sensations that begin or worsen during periods of rest or inactivity, most notably in the evening (American Academy of Sleep Medicine, 2015; Walters et al., 2003). RLS symptoms, in particular the severity of symptoms, can significantly impair a person’s ability to fall asleep and stay asleep. Indeed, RLS symptom severity has been correlated with sleep quality in adults with MS, wherein greater severity of symptoms is associated with greater reductions in sleep quality (Cederberg, Jeng, et al., 2019; Giannaki et al., 2018).

Adults with MS have an increased risk for sleep disturbances with approximately half of adults with MS reporting sleep-related problems (Bamer, Johnson, Amtmann, & Kraft, 2008; Tachibana et al., 1994). Such sleep problems might impact other consequences of MS, including cognitive function. Importantly, sleep deprivation effects a number of cognitive functions in the general population (Durmer & Dinges, 2005), and a recent study demonstrated that sleep disturbances may be directly associated with subjective cognitive problems in adults with MS (van Geest, Westerik, van der Werf, Geurts, & Hulst, 2017). Additionally, the negative influence of RLS symptoms on sleep quality could further exacerbate the neuropsychological impairments associated with MS. Thus, RLS may be directly or indirectly associated with cognitive function in persons with MS through impairments in sleep quality. However, there is a lack of understanding regarding the relationships among RLS, sleep quality, and cognitive function in adults with MS.

Our interest in the relationships among RLS, sleep quality, and cognitive function in adults with MS is based, in part, on recent data for adults with Parkinson’s disease (PD) (Cederberg, Brinkley, et al., 2019). That study indicated that greater RLS symptom severity was associated with greater deficits in cognitive function; however, this relationship was not accounted for by impaired sleep quality, suggesting that other variables may be influencing the relationship between RLS and cognition in PD(Cederberg, Brinkley, et al., 2019). The pathophysiology of RLS in MS likely differs from that in PD, as RLS may be a secondary consequence of the damage to the central nervous system associated with these disorders(Ferini- Strambi, Carli, Casoni, & Galbiati, 2018; Foschi et al., 2019; Minar et al., 2017). Thus, RLS may influence sleep and cognitive function differently in MS than PD.

The present study examined the relationships among RLS prevalence and severity, perceived sleep quality, and perceived cognitive impairment in a large sample of adults with MS. We anticipated that adults with MS who present with RLS would report significantly worse perceived cognitive impairment and worse sleep quality than persons with MS who did not present with RLS based on the aforementioned literature. We further expected a negative association between RLS symptom severity and perceived cognitive impairment in those with MS who present with RLS that would be partially accounted for by a deficit in self-reported sleep quality.

2. Materials and Methods

2.1. Participants

We recruited a sample of persons with MS through the North American Research Committee on Multiple Sclerosis(NARCOMS) patient registry. NARCOMS staff distributed printed letters among a random sample of 1,000 persons with MS who completed the Fall 2017 biannual survey. Those who were interested in participating contacted the research team and completed a brief screening interview for inclusion criteria including: (a)age 18 years or older; (b)self-reported diagnosis of MS; and (c)member of the NARCOMS registry. Of the 1,000 persons with MS recruited through NARCOMS, 316 contacted the research team and 296 were screened for eligibility; one person declined participation after the description of the study. The research team distributed study materials to 295 persons, and 284 individuals returned study materials. Of those who returned materials, nine declined participation. The final sample consisted of 275 persons with MS who completed all measures.

2.2. Restless Legs Syndrome

2.2.1. Diagnosis.

The diagnosis of RLS was based on the Cambridge-Hopkins Restless Legs Syndrome Questionnaire(CH-RLSq) that has demonstrated validity and sensitivity for diagnosing RLS via survey form(Allen, Burchell, MacDonald, Hening, & Earley, 2009). The CH-RLSq includes items that exclude common mimics of RLS (i.e., leg cramps and positional discomfort) and assesses the five criteria for a positive diagnosis of RLS: (1) the desire to move the legs in association with uncomfortable sensations; (2) the need to move the legs in response to these sensations; (3) the worsening of the sensations at rest; (4) the partial or complete relief of sensations with movement; and (5) the sensations occurring most frequently during the evening or early part of the night. The item scores were reviewed by a researcher and scored as positive for RLS (i.e., MS+RLS group) if responses were consistent with the aforementioned RLS diagnostic criteria or as negative for RLS (i.e., MS group) if any item was inconsistent with RLS diagnostic criteria.

2.2.2. Symptom Severity.

RLS symptom severity was measured using the International Restless Legs Syndrome Study Group (IRLS) Scale(Walters et al., 2003). The IRLS is a validated, 10-item survey that provides a global score of overall severity of RLS symptoms over the previous seven days(Abetz et al., 2006). The items were rated on a scale ranging between 0 (e.g., none) and 4 (e.g., very severe), and individual item scores were summed for a measure of overall symptom severity ranging between 0 and 40 with higher scores indicating more severe RLS severity. Additionally, we included item four in analyses as it relates to sleep disturbance specifically regarding RLS symptoms.

2.3. Sleep Quality

Subjective sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI)(Buysse, Reynolds, Monk, Berman, & Kupfer, 1989). The PSQI consists of 19 items that measure the quality of one’s sleep and sleep disturbances over the past month including items assessing bedtime, sleep onset latency, wake time, and sleep duration. Time in bed (TIB) was calculated as the number of hours from bedtime through wake time and sleep efficiency was calculated by dividing sleep duration by TIB and multiplying by 100. The item scores yield seven component scores reflective of a number of factors associated with sleep quality. Each component was scored between 0 (fairly good) and 3 (very bad) and component scores were summed for a global score ranging between 0 and 21; higher scores reflect worse sleep quality. Of note, scores greater than 5 are indicative of a poor sleeper with severe difficulties in at least two domains or moderate difficulties in more than three areas(Buysse et al., 1989). Scores from the PSQI have demonstrated evidence for validity and reliability in assessing sleep quality in the general population(Buysse et al., 1989) and is a commonly used measure in adults with MS.

2.4. Perceived Cognitive Impairment

Perceived cognitive impairment was measured using the Multiple Sclerosis Neuropsychological Questionnaire (MSNQ) (Benedict et al., 2003). The MSNQ contains 15 statements describing cognitive problems encountered by persons with MS in the course of daily life, including processing speed, dual task processing, attention, memory, executive function, and psychosocial comportment. Participants reported cognitive problems on a 4-point scale ranging between 0 (problem not encountered) and 4 (severe, occurs very frequently). The items scores were summed with a range between 0 and 60, and higher scores reflected more severe perceived cognitive impairment. There is evidence of reliability, validity, and reasonable accuracy of MSNQ scores for predicting neuropsychological impairment in persons with MS(Benedict et al., 2003; Benedict & Zivadinov, 2006).

2.5. Demographics and Clinical Characteristics

Participants completed a demographic and clinical characteristics questionnaire for information regarding age, gender, education level, employment status, race, MS subtype, and disease duration. The questionnaire included a section for participants to list current medications including MS modifying medications (i.e., DMTs). Participants further completed the Patient Determined Disease Steps (PDDS), a single item measure of self-reported disability status(Hohol, Orav, & Weiner, 1995, 1999). PDDS scores ranged between 0 (normal) and 8 (bedridden), and the scores have demonstrated evidence for validity and strong correlations with the Expanded Disability Status Scale (EDSS), pyramidal and cerebellar functional scores, and walking ability in persons with MS(Learmonth, Motl, Sandroff, Pula, & Cadavid, 2013).

2.6. Procedures

The University’s Institutional Review Board approved this study and all participants provided written informed consent. After initial telephone contact and screening, all participants who verbally volunteered were mailed a packet containing the informed consent document, questionnaire battery, and a pre-stamped and pre-addressed envelope for return service through the United Stats Postal Service(USPS). After completing the questionnaires, participants returned a copy of the signed informed consent along with the study materials through the USPS. Upon receipt of research materials, a member of the research team checked for missing answers and, in the event of missing answers, called the participant and acquired missing information over the phone. All participants received $10 for voluntary participation.

2.7. Statistical Analysis

All statistical analyses were conducted using SPSS version 25, and descriptive data are presented as mean and standard deviations (SD) or as frequency and percentage of individuals, unless otherwise specified. A p-value of less than 0.05 was adopted for interpreting statistical significance with all inferential analyses. Skewness and kurtosis values along with assessment of frequency distributions were inspected for establishing normality of the variables. Of note, all outcome variables other than sleep latency were normally distributed and demonstrated acceptable values of skewness and kurtosis(Field, 2009; Gravetter & Wallnau, 2014; Trochim & Donnelly, 2006). The differences in outcome measures between groups (MS+RLS vs. MS) were determined using an independent t-test for normally distributed continuous variables, Mann-Whitney U for non-normally distributed continuous variables (i.e., sleep latency), and Chi Squared (χ2) test for nominal variables. Cohen’s d was utilized to estimate the magnitude of difference between groups on continuous variables, and effect sizes of 0.2, 0.5, and 0.8 were interpreted as small, moderate, and large, respectively(Cohen, 1988).

We examined associations among the presence of RLS, variables related to MS disease course (i.e., disease duration, type of MS, DMTs), and perceived cognitive impairment using Spearman’s rho (ρ) bivariate correlation analyses. Within the MS+RLS group, the associations among RLS severity, perceived cognitive impairment (i.e., MSNQ), sleep quality, and outcomes that may influence cognitive function in this population (i.e., age, disability status, disease duration, and level of education(Borghi et al., 2013; Ruano et al., 2017)) were examined by means of bivariate Pearson product-moment (r) correlation coefficients. Values of 0.1, 0.3, and 0.5 were interpreted as small, moderate, and large, respectively(Cohen, 1988). We further evaluated the relationship between RLS symptom severity and perceived cognitive impairment in the MS+RLS group using multivariate linear regressions with forward stepwise selection (α = 0.05). We regressed MSNQ scores on IRLS scores in Step 1, and IRLS plus variables that were significantly correlated with both MSNQ and IRLS scores in bivariate correlation analyses in Step 2. We examined the change in the standardized beta-coefficient for IRLS scores predicting MSNQ scores between Steps 1 and 2 for judging the variables that may be intermediary factors in the associations between RLS and perceived cognitive impairment in persons with MS and RLS. This approach was adopted from our previous examination of this relationship in adults with PD(Cederberg, Brinkley, et al., 2019) and is consistent with the Baron and Kenny approach for statistical mediation in cross-sectional data(Baron & Kenny, 1986).

3. Results

3.1. Participant Characteristics

The summary of participant demographic and clinical characteristics for the overall sample (N=275) is presented in Table 1. The sample was primarily female (81%) and Caucasian (95%) with a mean age of 59.7±10.1 years. Participants mostly had relapsing-remitting MS (66%) with moderate disability (median [interquartile range] PDDS score: 3.0 [5.0]), an average disease duration of 20.4±9.7 years, and most participants were using an MS-specific disease modifying therapy (DMT; 74%). Of note, 27%(n=20) of our sample with MS who had RLS were taking a medication that could reduce RLS severity (e.g., pramipexole, gabapentin, and rotigotine(Restless Legs Syndrome Foundation, 2018) and 19%(n=14) were taking medications that could exacerbate RLS severity (e.g., antidepressants, first-generation antihistamines(Buchfuhrer, 2012)). The sample reported scores consistent with moderate-to-severe sleep disturbances (PSQI global score: 7.2±3.6) and 173 (63%) reported a global PSQI score of greater than 5, indicating poor sleeper status(Buysse et al., 1989). Participants reported an average of 8.7±1.3 hours spent in bed, 23.9±25.0 minutes to fall asleep, and 7.3±1.3 hours spent sleeping resulting in an average sleep efficiency of 85%.

Table 1:

Participant characteristics (N = 275)

All Participants (N = 275)
Age (years) 59.7 ± 10.1
Gender (n (%)) 223 (81.1%) F / 52 (18.9%) M
Education (years) 16.9 ± 2.2
Employed (n (%)) 91 (33.1%) Y / 181 (65.8%) N
Race (n (%))
Caucasian 261 (94.9%)
Latino/Latina 5 (1.8%)
Black/African American 4 (1.5%)
American Indian 1 (0.4%)
Other 3 (1.1%)
MS Type (n (%))
Relapsing-Remitting MS 181 (65.8%)
Progressive MS 91 (33.1%)
Unknown 3 (1.1%)
Disease Duration (years) 20.4 ± 9.7
MS DMT (n (%)) 202 (73.5%)
PDDS (median [IQR]) 3.0 [5]
MSNQ 19.1 ± 11.3
RLS (n (%)) 74 (26.9%)
None 9 (12.2%)
Mild 26 (35.1%)
Moderate 28 (37.8%)
Severe 10 (13.5%)
Very Severe 1 (1.4%)
PSQI Global Score 7.2 ± 3.6
Time in Bed (hours) 8.7 ± 1.3
Sleep Latency (min) 23.9 ± 25.0
Sleep Duration (hours) 7.3 ± 1.3
Sleep Efficiency (%) 85.1 ± 14.2
Poor Sleepers (n (%)) 173 (62.9%)
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Note: Data are presented in mean ± standard deviation unless otherwise specified. MS multiple sclerosis; RLS restless legs syndrome; RRMS relapsing-remitting MS; SPMS secondary progressive MS; PPMS primary progressive MS; DMT Disease Modifying Treatment; PDDS Patient Determined Disease Status; IQR interquartile range; MSNQ Multiple Sclerosis Neuropsychological Questionnaire; IRLS International Restless Legs Syndrome Study Group Scale; PSQI Pittsburgh Sleep Quality Index.

3.2. Restless Legs Syndrome in Multiple Sclerosis

The summary of participant characteristics for subsamples of participants with and without RLS is presented in Table 2. Approximately 27% of our sample fit the criteria for a positive diagnosis of RLS based on the CH-RLSq diagnostic questionnaire; this is consistent with population estimates for RLS in MS (Ning et al., 2018). Persons with MS who presented with RLS reported significantly worse perceived cognitive impairment than persons with MS who did not present with RLS (mean difference=−3.9; p<0.05). The presence of RLS had a small effect on perceived cognitive impairment in this sample (d=0.43). The sample of persons with MS who had RLS reported an average IRLS score of 11.4±7.6 indicating moderate RLS severity with a median [interquartile range] of 1.0 [1.0] on item four of the IRLS indicating mild sleep disturbance due to RLS(Walters et al., 2003). The two groups (i.e., MS+RLS and MS) were not significantly different in age, gender, level of education, employment status, race, MS type, disease duration, self-reported clinical disability status, number of participants on DMTs, or global sleep quality.

Table 2:

Participant characteristics for subsamples of participants with and without restless legs syndrome.

MS+RLS (n = 74) MS (n = 201) p-value d
Age (years) 59.4 ± 9.9 59.9 ± 10.2 0.744 --
Gender (n (%)) 60 (81%) F / 14 (19%) M 163 (81%) F / 38 (19%) M 0.998+ --
Education (years) 16.8 ± 2.2 16.9 ± 2.3 0.626
Employed (n (%)) 20 (72.0%) 71 (35.3%) 0.200+
Race (n (%)) 0.422+ --
Caucasian 73 (98.6%) 188 (93.5%) -- --
Latino/Latina 0 (0.0%) 5 (2.5%) -- --
Black/African American 0 (0.0%) 4 (2.0%) -- --
American Indian 0 (0.0%) 1 (0.5%) -- --
Other 1 (1.4%) 2 (1.0%) -- --
MS Type (n (%)) 0.731+ --
Relapsing-Remitting MS 48 (64.9%) 133 (66.2%) -- --
Secondary Progressive MS 17 (23.0%) 41 (20.4%) -- --
Primary Progressive MS 9 (12.2%) 24 (11.9%) -- --
Unknown 0 (0.0%) 3 (1.5%) -- --
Disease Duration (years) 20.0 ± 9.7 20.5 ± 9.7 0.687 --
MS DMT (n (%)) 53 (71.6%) 149 (74.1%) 0.676+ --
PDDS (median [IQR]) 3.5 [3] 3.0 [5] 0.318 --
MSNQ 21.9 ± 11.7 18.0 ± 11.0 0.015 0.343
IRLS 11.4 ± 7.6 -- -- --
Sleep disturbance from RLS (IRLS-4) 1.0 [1.0] -- -- --
PSQI Global Score 7.6 ± 4.0 7.0 ± 3.4 0.176 0.070
Time in Bed (hours) 8.9 ± 1.6 8.6 ± 1.2 0.168 0.212
Sleep Latency (min) 26.3 ± 31.8 23.0 ± 22.0 0.354# 0.121
Sleep Duration (hours) 7.3 ± 1.4 7.3 ± 1.3 0.850 0.000
Sleep Efficiency (%) 83.8 ± 16.2 85.6 ± 13.4 0.366 0.121
Poor Sleeper (n (%)) 49 (66.2) 124 (61.7) 0.493+ --
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Note: Data are presented in mean ± standard deviation unless otherwise specified. MS multiple sclerosis; RLS restless legs syndrome; RRMS relapsing-remitting MS; SPMS secondary progressive MS; PPMS primary progressive MS; DMT Disease Modifying Treatment; PDDS Patient Determined Disease Status; IQR interquartile range; MSNQ Multiple Sclerosis Neuropsychological Questionnaire; IRLS International Restless Legs Syndrome Study Group Scale; PSQI Pittsburgh Sleep Quality Index.

+

Chi Square Analysis

#

Mann-Whitney U Test

We further analyzed the difference in perceived cognitive impairment between groups with similar levels of sleep impairment by including only persons categorized as poor sleepers (i.e., PSQO score of >5 (Buysse et al., 1989)). Persons with MS who presented with RLS and categorized as poor sleepers (n=49) had significantly worse perceived cognitive impairment than persons with MS who categorized as poor sleepers (n=124; mean difference=−5.01; p<0.01).

3.3. Relationship among Restless Legs Syndrome, Perceived Cognitive Impairment, and Sleep Quality

Bivariate Spearman’s rho correlation analyses indicated that the presence of RLS was associated with more severe perceived cognitive impairment (ρ=0.14). There were no significant correlations between MS disease duration, MS type, or DMTs and the presence of RLS or perceived cognitive impairment. The summary of bivariate Pearson product-moment correlation analysis for RLS severity, perceived cognitive impairment, sleep quality, age, disability status, disease duration, and years of education for the subsample of participants with MS who had RLS (n=74) is presented in Table 3. Worse RLS severity was significantly associated with more severe perceived cognitive impairment (r = 0.27), worse overall sleep quality (r = 0.38), and greater sleep disturbance related to RLS symptoms (r = 0.83). More severe perceived cognitive impairment was significantly associated with worse sleep quality (r = 0.44), younger age (r = −0.24), and shorter MS disease duration (r = −0.29). Greater sleep disturbance related to RLS symptoms was associated with worse sleep quality (r = 0.35); however, sleep disturbance related to RLS was not associated with perceived cognitive impairment.

Table 3:

Summary of bivariate Pearson’s correlation analysis for restless legs syndrome severity, perceived cognitive impairment, sleep quality, age, disability status, disease duration, and years of education for the subsample of participants with restless legs syndrome and multiple sclerosis (n = 74)

IRLS MSNQ PSQI RLS_4 Age PDDS Disease Duration Education
IRLS --
MSNQ 0.274* --
PSQI 0.380* 0.438** --
IRLS_4 0.832** 0.114 0.352** --
Age −0.072 −0.241* −0.318* −0.059 --
PDDS 0.194 −0.028 0.081 0.218 0.344** --
Disease −0.215 −0.005 0.455** 0.209 --
Duration (years) −0.088 −0.289*
Education (years) 0.044 −0.224 −0.044 0.071 −0.043 −0.052 0.010 --
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Note: IRLSInternational Restless Legs Syndrome Study Group Scale; MSNQ Multiple Sclerosis Neuropsychological Questionnaire; PSQI Pittsburgh Sleep Quality Index; PDDS Patient Determined Disease Status.

The summary of linear regression analyses for evaluating the relationships among RLS severity, perceived cognitive impairment, and sleep quality in persons with MS who had RLS is presented in Table 4. RLS severity explained a significant amount of the variance in perceived cognitive impairment in Step 1 (F=5.86, p<0.05; R2=0.075; β=0.274), but the inclusion of sleep quality (β=0.391) attenuated the relationship between RLS severity and perceived cognitive impairment (β=0.126) based on the magnitude of the standardized beta-coefficient in Step 2 (F=9.19, p<0.01; ΔR2=0.131). The reduction in the effect of RLS severity on perceived cognitive impairment after including PSQI in the model was significant based on the Sobel test (p<0.05), and the mediation effect (i.e., indirect effect) was 0.230(MacKinnon, Fairchild, & Fritz, 2007).

Table 4:

Summary of linear regression analysis for the relationship between restless legs syndrome severity, perceived cognitive impairment, and sleep quality in adults with restless legs syndrome and multiple sclerosis (n = 74).

MSNQ
B SE B β
Step 1
IRLS 0.423 0.175 0.274*
Step 2
IRLS 0.194 0.176 0.126
PSQI 1.148 0.336 0.391*
R2 = 0.075 for Step 1; ΔR2 = 0.131 for Step 2
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Note: MSNQ Multiple Sclerosis Neuropsychological Questionnaire; IRLS International Restless Legs Syndrome Study Group Scale; PSQI Pittsburgh Sleep Quality Index.

4. Discussion

The present study evaluated the relationships among RLS, sleep quality, and perceived cognitive impairment in adults with MS. Our sample was representative of the population of adults with MS for age (i.e., peak prevalence in the United States 55–64 years) and sex(Wallin et al., 2019), MS type (“Atlas of MS: Mapping multiple sclerosis around the world.,” 2013), and prevalence of RLS (i.e., 27%) (Ning et al., 2018). Our sample of adults with MS who had RLS reported significantly worse perceived cognitive impairment compared with adults with MS who did not have RLS. We further observed that worse RLS severity was significantly associated with more severe perceived cognitive impairment in the sample of adults with MS who had RLS; however, the inclusion of sleep quality mitigated the relationship between RLS and perceived cognitive impairment. This suggests that sleep impairment may be an intermediary factor in the association between RLS severity and cognitive impairment in persons with MS who present with RLS.

To our knowledge, this was the first study to evaluate the association between RLS and cognitive function in adults with MS. Our results suggest that the presence of RLS had a small, yet significant effect on cognitive function, whereby adults who had both MS and RLS reported significantly worse perceived cognitive impairment compared with adults who had MS without RLS. This is similar to our findings in adults with PD(Cederberg, Brinkley, et al., 2019) and consistent with current literature in the general population, wherein persons with RLS demonstrated significantly greater cognitive deficits compared with controls without RLS(Fulda, Beitinger, Reppermind, Winkelman, & Wetter, 2010; Pearson et al., 2006). Such results may inform current theories regarding the pathological link between MS and RLS. One recent study suggested that the inflammatory process involved in MS may disrupt dopamine regulation related to RLS symptomology(Foschi et al., 2019). This link in dopamine dysregulation may explain cognitive impairment related to RLS and MS as a different study in healthy adults reported dopamine dysregulation with cognitive impairment (Volkow et al., 1998). These results suggest that the presence of RLS may influence cognitive function, and this highlights the importance of diagnosing and treating RLS in adults with MS.

We further observed in our sample of adults with MS who had RLS that more severe RLS symptomology was associated with worse perceived cognitive impairment; however, this relationship was mitigated by the inclusion of sleep quality. This differs from our previous findings in PD, wherein the relationship between RLS and cognition was not attenuated when controlling for sleep quality suggesting other factors responsible for the influence of RLS on cognition in PD(Cederberg, Brinkley, et al., 2019). Importantly, in the present study, RLS severity was associated with sleep quality, whereby worse symptom severity was associated with reduced sleep quality in MS and sleep quality was associated with greater sleep disturbance specifically related to RLS symptoms. This is consistent with current literature in patients on hemodialysis(Orsal, Unsal, Balci-Alparslan, & Duru, 2017) and persons with heart failure(Yatsu et al., 2019) and suggest that disruption of sleep quality associated with increased severity of RLS symptoms may impair cognitive function in adults with MS and RLS. This notion is consistent with current literature that demonstrated a reduction in cognitive function with sleep disturbances, namely visual memory, verbal memory, executive function, attention, processing speed, and working memory(Braley, Kratz, Kaplish, & Chervin, 2016). Another study demonstrated similar results with self-reported sleep being significantly and independently associated with perceived cognitive impairment in adults with MS(Hughes et al., 2017). However, our sample of persons with MS who have RLS did not report worse sleep quality compared with persons with MS who do not have RLS, suggesting that RLS may not impact overall sleep quality more than MS alone. Future research should consider the evaluation of different domains of cognitive function using neuropsychological outcomes in the relationship among RLS severity, sleep quality, and cognitive impairment.

There are limitations to consider when interpreting our results. The cross-sectional design of this study precludes inferences on causality in the relationship among RLS, sleep, and cognition; additional research should consider longitudinal designs to further explore the causality of this relationship. We did not include other sleep measures, such as polysomnography or actigraphy or the Epworth Sleepiness Scale, which could provide further data on the relationship between sleep dysfunction, RLS and cognitive performance. The protocol included outcome measures that were self-reported and were not verified by a physician or medical records. Additionally, the self-report nature of outcomes could introduce bias associated with self-reported outcomes in adults with cognitive impairment that may include selection bias. Of note, previous research suggests that MSNQ scores may be reduced in adults with severe cognitive impairment(Benedict et al., 2004) suggesting that persons with more severe cognitive impairment may underestimate perceived cognitive impairment; however, this measure was necessary for the current study as all data were collected remotely through the USPS. Although the questionnaire for RLS diagnosis includes items for the five diagnostic criteria and exclusion of common mimics of RLS in persons with MS, there is a risk for identifying false positive or false negative screening of RLS. Our sample of persons with MS who had RLS reported an average IRLS score consistent with moderate severity, which may not be representative of the population of adults with MS and RLS. Additionally, 27% of our sample with MS who had RLS were taking a medication that could reduce RLS severity and 19%(n=14) were taking medications that could exacerbate RLS severity presenting an important limitation when assessing RLS symptom severity in this population, as a number of prescriptions for symptoms and consequences of MS can treat or exacerbate symptoms of RLS. Additionally, the MSNQ is a global cognitive scale used to detect overall cognitive impairment in adults with MS; thus, this scale did not allow for the evaluation of the impact of RLS on neuropsychological outcomes or specific domains of cognition (e.g., attention). However, this measure provides a good starting point to design future studies to better address that question. Participants in this study were older and with longer disease duration, thus these results may not apply to younger adults or adults in early disease progression.

Our results offer important clinical and practical relevance for the consideration of physicians, rehabilitation specialists, and researchers, as it highlights the importance of diagnosing and treating sleep disorders and sleep impairments in adults with MS. To date, sleep disorders including RLS remains largely undiagnosed in adults with MS, and sleep impairments are often overlooked or attributed to other symptoms or consequences in persons with MS(Brass, Li, & Auerbach, 2014). Sleep impairments negatively impact cognitive function, and considering cognitive impairment is amongst the most common consequence of MS with an estimated prevalence of 40–60%(Jongen, Ter Horst, & Brands, 2012), our results highlight the importance of diagnosing sleep disorders and treating sleep impairments in this population, as managing sleep disturbance may offer additional opportunities to reduce cognitive impairment in adults with MS.

5. Conclusions

Our results suggest that adults with MS who have RLS may experience worse cognitive impairment compared with adults with MS who do not have RLS. Of note, among adults with MS who have RLS, more severe RLS symptomology was associated with worse cognitive impairment; however, this relationship was mitigated by the inclusion of sleep quality. Additional research is necessary to evaluate the relationship between RLS and objective cognitive function, including various domains that may include visual memory, verbal memory, executive function, attention, processing speed, and working memory that have been associated with sleep disturbances in this population.

Highlights.

  • People with MS and RLS reported worse perceived cognitive impairment

  • More severe RLS was associated with worse perceived cognitive impairment

  • Sleep quality may mediate the relationship between RLS and cognitive function in MS

Acknowledgments

Funding Sources: This work was supported, in part, by a pilot grant from the National Multiple Sclerosis Society [PP 1412] and a mentor-based post-doctoral fellowship from the National Multiple Sclerosis Society [MB 0011]. Research reported in this publication was supported, in part, by the Eunice Kennedy Shriver National Institute Of Child Health & Human Development of the National Institutes of Health [F31HD097903]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding source had no involvement in (a) the study design; (b) data collection, analysis or interpretation; (c) in writing of the report; or in the decision to submit the article for publication.

Abbreviations

CH-RLSq

Cambridge-Hopkins Restless Legs Syndrome Questionnaire

DMT

Disease Modifying Treatment

EDSS

Expanded Disability Status Scale

IRLS

International Restless Legs Syndrome Study Group Scale

MS

Multiple Sclerosis

MSNQ

Multiple Sclerosis Neuropsychological Screening Questionnaire

NARCOMS

North American Research Committee on Multiple Sclerosis

PD

Parkinson’s Disease

PDDS

Patient Determined Disease Steps

PSQI

Pittsburgh Sleep Quality Index

RLS

Restless Legs Syndrome

SD

Standard Deviation

USPS

United States Postal Service

Footnotes

Declaration of Interest Statement: The authors have no conflicts of interest to disclose.

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