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High false-positive rate of questionnaire-based restless legs syndrome diagnosis in multiple sclerosis

Sleep Medicine, In Press, Corrected Proof, Available online 6 March 2015

Highlights

 

  • Questionnaire-based diagnosis of restless legs syndrome (RLS) in multiple sclerosis has a high false-positive rate.
  • The high false-positive rate is mostly due to multiple sclerosis-related sensorimotor symptoms.
  • The periodic leg movements index (PLMI) during wakefulness may provide useful diagnostic information.

Abstract

Background/Objectives

Restless legs syndrome (RLS) is diagnosed by self-reported symptoms. Multiple sclerosis (MS) patients have disease-related symptoms which could mimic RLS. This study assessed the: (1) false-positive rate for questionnaire-based RLS diagnosis in MS patients and (2) utility of periodic leg movements during wakefulness (PLMW) on overnight polysomnography (PSG) in identifying true-positive RLS patients.

Methods

Ambulatory MS patients without known sleep disorders were recruited. Subjects completed the International RLS Study Group (IRLSG) diagnostic questionnaire (IRLDQ) and underwent full overnight PSG. IRLDQ-positive patients underwent clinical evaluation to confirm the diagnosis and completed the RLS severity scale (IRLS).

Results

Seventy-one MS patients (mean age 46.8 ± 10.4 years) were evaluated. Thirty-eight had a positive IRLDQ. RLS diagnosis was confirmed in 22, yielding a false-positive rate of 42% [95% confidence interval (CI) 26–59%], predominantly attributable to paresthesiae (n = 7), and cramps and/or muscle spasms (n = 4). IRLS scores were not significantly different between subjects with confirmed and nonconfirmed RLS. The PLMW index was significantly higher in patients with confirmed RLS (55.4 ± 41.9 vs. 29.7 ± 18.8,p = 0.03). The sensitivity of a PLMW index >70/h for true-positive IRLDQ was 8/22 = 36%, 95% CI: 17.2–59.3, and the specificity was 16/16 = 100%, 95% CI: 79.4–100.

Conclusions

MS patients have a high false-positive rate of RLS diagnosis using a standardized questionnaire largely attributable to MS-related sensorimotor symptoms. While detailed clinical evaluation is essential for confirming RLS diagnosis, the PLMW index may provide useful adjunctive information.

Keywords: Multiple sclerosis, Restless legs syndrome, Polysomnography, Periodic leg movements, International Restless Legs Syndrome Study Group questionnaire.

Abbreviations: AASM - American Academy of Sleep Medicine, AHI - apnea–hypopnea index, CI - confidence interval, EDSS - Expanded Disability Status Scale, IRLS - International Restless Legs Scale, IRLDQ - International Restless Legs Syndrome Group Diagnostic Questionnaire, IRLSSG - International Restless Legs Syndrome Study Group, MS - multiple sclerosis, NREM - non-rapid eye movement sleep, OSAH - obstructive sleep apnea–hypopnea, PLM - periodic leg movements, PLMS - periodic leg movements during sleep, PLMS-A - PLMS associated with arousal, PLMS-NA - PLMS not associated with arousal, PLMW - periodic leg movements during wakefulness, PP-MS - primary progressive MS, PSG - polysomnography, RLS - restless legs syndrome, PR-MS - progressive relapsing MS, RR-MS - relapsing remitting MS, REM - rapid eye movements, SDB - Sleep-disordered breathing, SR-MS - secondary progressive MS, SNRI - serotonin–noradrenalin reuptake inhibitor, SSRI - selective serotonin reuptake inhibitor, TSP - total sleep period, TST - total sleep time, WASO - wake after sleep onset.

1. Introduction

Restless legs syndrome (RLS), also known as Willis–Ekbom disease, is a sensorimotor disorder. The diagnosis is based on self-reported symptoms and there is no diagnostic test. The International Restless Legs Syndrome Study Group (IRLSSG) has established four minimal diagnostic criteria to define the disease: (1) Urge to move the legs usually associated with uncomfortable and unpleasant sensations, (2) symptoms beginning or worsening during periods of rest or inactivity, (3) partial or total relief by activity, and 4) worsening of symptoms in the evening or night[1] and [2].

To diagnose RLS in the general population, standardized questionnaires such at the IRLSSG diagnostic questionnaire (IRLDQ) have been developed based on these four main clinical features[3] and [4]. Using these questionnaires, RLS prevalence varies between 5% and 15% of the general population[5] and [6]. However, several conditions can mimic RLS, and false-positive diagnoses based only on screening questionnaires can be as high as 16% in the general population [4] .

Multiple sclerosis (MS) is a condition that can result in sensorimotor symptoms that can mimic RLS. MS is an autoimmune inflammatory demyelinating and neurodegenerative disease of the central nervous system. MS is characterized by relapsing and remitting or progressive neurological symptoms which can include weakness, numbness, muscle spasm, pain, vertigo, cognitive changes, and blindness. The symptoms of MS can complicate RLS diagnosis based on screening questionnaires. Despite this, an increased frequency of RLS has been consistently described in MS patients using RLS diagnostic questionnaires based on the four main clinical criteria[7], [8], [9], [10], and [11]. Given the implications for patient management, the validity of RLS diagnosis is an important issue and any useful supporting diagnostic tool would be of substantial value.

Most patients affected by RLS also present with periodic leg movements during sleep (PLMS) [12] . PLMS are involuntary, highly stereotyped, repetitive movements characterized by toe extension and ankle dorsiflexion with occasional knee and hip flexion, which arise from non-rapid eye movement (NREM) sleep[13], [14], and [15]. PLMS occur on nocturnal polysomnography (PSG) in the general population [16] , but are frequently seen in RLS. PLMS are sensitive, but not specific for RLS[13] and [14]. They are more frequent in MS patients than in the general population [17] .

Periodic leg movements during wakefulness (PLMW) can also occur on nocturnal PSG in RLS patients[12] and [18]. They provide an objective motor sign and may be more strongly associated with RLS considering the time frame of the disease [19] . However, they have been much less explored than PLMS. PLMW have been evaluated as a diagnostic tool for RLS in the Suggested Immobilization Test (SIT) [20] . A positive correlation with PLMS in normal subjects and in RLS patients has been described[12] and [18]. However, in MS patients, where sensorimotor disease-related symptoms obscure the diagnosis, the relationship between RLS and PLMS, or PLMW on nocturnal PSG has not been investigated.

The main objectives of this study were: (1) to assess the accuracy of the IRLDQ for RLS diagnosis compared with the clinical diagnosis by a specialist physician in MS patients, and (2) to assess the utility of PLMW from nocturnal PSG in identifying true-positive RLS patients in an MS population.

2. Methods

2.1. Patient selection

We used MS patient data from two prior consecutive studies performed by our group, both with similar inclusion and exclusion criteria, and clinical evaluation of subjects[21] and [22]. These studies included 71 MS patients recruited from the Montreal Neurological Institute and Hospital MS Clinic. All 71 patients were included in this analysis. Recruitment occurred between July 2007 and February 2010.

Our institutional Research Ethics Board approved the study. All subjects provided written informed consent to participate.

The inclusion criteria for MS patients were: MS diagnosis according to McDonald criteria [23] , Expanded Disability Status Scale (EDSS; assesses MS disability on a 0–10 scale, a higher score indicating greater disability) score of 0–7.0 [24] ; relapse-free for at least 30 days prior to screening and during the study; and no chronic steroid treatment (for more than 30 days) for the last six months prior to study. Exclusion criteria included: active treatment for RLS-PLM and any significant medical condition or cognitive disorder that could preclude compliance with the study. Detailed inclusion and exclusion criteria were published previously[21] and [22].

2.2. Study design

This was a cross-sectional study. All subjects underwent a comprehensive baseline clinical evaluation, including screening blood tests (with serum ferritin and vitamin B12 levels), and sleep and symptom questionnaires, and a full overnight laboratory PSG[21] and [22]. Based on questionnaire and PSG results, subjects were referred to a board-certified sleep physician for clinical evaluation and management.

2.3. RLS evaluation

All subjects completed the IRLDQ with a physician member of the study team (DT). Patients with a positive IRLDQ, defined as answering positively to all first three questions, underwent a clinical evaluation with a sleep specialist and/or neurologist within three months after completing the questionnaire to evaluate the responses and confirm true-positive cases of RLS versus “RLS-Mimics” or false-positive responses. The symptoms accounting for the false-positive responses were characterized.

In cases of uncertainty, both specialists made the decision. When there was no agreement between specialists, a therapeutic trial with dopaminergic drugs was performed based on published literature suggesting therapeutic response as a useful supportive diagnostic tool [25] .

RLS severity was assessed with the International Restless Legs Scale (IRLS) version 2.2 [26] . Patients were classified into three subgroups: (1) Patients with positive IRLDQ and confirmed RLS (IRLDQ+/RLS+), (2) patients with positive IRLDQ and without RLS (IRLDQ+/RLS–), and (3) patients with negative IRLDQ (IRLDQ–).

2.4. Baseline assessment

This evaluation included a detailed medical history and physical examination, medication data, and study questionnaires. The MS disease type, relapsing-remitting (RR), secondary progressive (SP), primary progressive (PP), or progressive-relapsing (PR), was noted. EDSS was calculated.

2.5. Polysomnography

PSG was performed in-laboratory, with lights out targeted for the patients' usual bedtime (typically 9:30–11:00 PM). We used the Harmonie System (Natus Inc, Mississauga, ON, Canada), with recording from standard electroencephalographic leads (C4/C3/F3/F4/O1/O2/M1/M2); bilateral electrooculogram; chin, anterior tibialis, and extensor digitorum electromyograms (EMG); airflow via nasal pressure cannula; thoracoabdominal movements via inductive plethysmography; single-lead EKG; pulse oximetry; snoring; digital video recording; and body position. Tibialis anterior muscle EMG activity was monitored with bipolar derivations with two surface electrodes placed 3 cm apart on the greater surface of the tibialis anterior muscle of each leg. Electrode impedance was verified at <10 kΩ. Calibration was performed at the beginning of the recording.

2.6. Scoring

All PSGs were scored manually by one of two scorers blinded to the questionnaires and clinical diagnosis. The reliability between scorers was evaluated. The average inter-scorer intra-class correlation coefficient (ICC) across respiratory and sleep variables was 0.93, and for the PLM indices in particular was 0.94. The scoring of sleep stages was based on American Academy of Sleep Medicine (AASM) criteria [27] . The respiratory analyses were done using standard AASM research criteria [28] . There was no discordance for sleep-disordered breathing (SDB) diagnosis (defined as an apnea–hypopnea index – AHI ≥ 15/h) between scorers.

2.7. PLMS and PLMW scoring

PLM analysis was performed manually using standard AASM criteria [29] . Specifically, PLM were defined as leg movements (LM) lasting 0.5–10 s with inter-movement intervals of 5–90 s in series of at least four consecutive movements across sleep and wake states. LM that occurred during a period from 0.5 s preceding or following an SDB event were not considered. LM were considered to be associated with an arousal when there was <0.5 s between the end of one event and the onset of the other event regardless of which was first. In addition, as recommended by the World Association of Sleep Medicine (WASM)/IRLSSG, for PLMW, the resting EMG baseline could be transiently changed if the EMG did not return to baseline within 15 s [30] .

We measured PLMW, PLMS, PLMS associated with arousal (PLMS-A), and PLMS not associated with arousal (PLMS-NA). We calculated the index for each type of PLM defined as the number of PLM per hour of sleep or wakefulness. The PLMW index included all PLM during wakefulness throughout the total recording time. For sleep, we calculated PLMS total index: PLMS/total sleep time, PLMS-A index: PLMS-A/total sleep time and PLMS-NA index: PLMS-NA/total sleep time.

2.8. Statistical analysis

We used standard descriptive statistics to summarize clinical characteristics of all subjects and subgroups. To compare sleep parameters and PLMs between groups we used two sidedt-tests. For comparison of nonparametric demographic data between groups, we used chi-squared tests or Fisher's exact tests, as appropriate. Exact binomial 95% confidence intervals (CI) were calculated around estimates of the false-positive rate, and sensitivity and specificity.

Ap-value of <0.05 was considered to be statistically significant. We used the statistical program SPSS.15 for data analysis.

3. Results

3.1. Patient clinical characteristics

Seventy-one MS patients (48 women, 23 men: age mean ± SD 46.6 ± 10.6 years) were included in the study. The median MS duration was 8.2 years (range 0.9–27.2, SD 6.36) and the median EDSS score was 3 (range 1–6.5, SD 1.6). Fifty-six (78.8%) of the patients had RR-MS, 13 (18.3%) had SP-MS, two (2.8%) had PR-MS, while no patient with PP-MS participated.

Forty-four patients (61.9%) were using MS-immunomodulating therapy: 18 glatiramer, 14 interferon, four natalizumab, three cyclophosphamide, three fingolimod, and two mitoxantrone.

Thirty-four patients (47.8%) were taking medications that have been reported to be associated with RLS or used for its treatment: 15 α-2-δ calcium channel ligands, 12 benzodiazepines, 10 baclofen, nine selective serotonin reuptake inhibitors (SSRI), two serotonin–noradrenalin reuptake inhibitors (SNRI), six tricyclic anti-depressants, three stimulants, four antiepileptics, three hypnotics, and two neuroleptics.

Thirty-eight (53.5%) of MS subjects were positive for obstructive sleep apnea–hypopnea (OSAH; AHI ≥ 15).

3.2. IRLDQ and IRLS score

Thirty-eight MS subjects (53.5%) had a positive IRLDQ. After an expert medical evaluation (JK and/or YL), the diagnosis was confirmed in 22 of 38 (57.8%), yielding a false-positive rate of 42% (95% CI 26–59%). All subjects with a positive questionnaire reported a frequency of symptoms of at least once per week. In three subjects, there was no agreement between specialists and a therapeutic trial with dopaminergic drugs was used to support or reject the diagnosis. In all three subjects, the diagnosis was accepted. All patients were evaluated by a physician-researcher and no IRLDQ– patient had RLS.

As shown in Table 1 , subjects in IRLDQ+/RLS+ group had a significantly higher proportion of females (p = 0.01) and milder disability scores compared to the IRLDQ+/RLS– group (p = 0.04). There were no differences in terms of MS disease type, proportion of patients receiving immunomodulating therapy or other medication, or in OSAH prevalence. The IRLS severity score for IRLDQ+/RLS+ patients was 19.5 ± 5.7, with no significant difference in mean severity scores between IRLDQ+/RLS+ and IRLDQ+/RLS– subjects (IRLS = 15.5 ± 9.8,p = 0.43).

Table 1 Clinical Characteristics of MS Subjects With or Without Confirmed RLS.

Variable IRLDQ+/RLS+ (n = 22) IRLDQ+/RLS– (n = 16) IRLDQ– (n = 33)
Sex-female n (%) 19 (86.3) 8 (50) 21 (63.6)
Age (years) 50.6 (10.6) 47.2 (9.7) 43.7 (10.2)
BMI (kg/m2) 27.8 (5.7) 26.4 (7.6) 25.3 (5.5)
MS duration (years) 9.9 (5.7) 11.4 (7.8) 8.6 (5.7)
MS form (RR/SP/PP/PR) 18/4/0/0 11/3/0/2 27/6/0/0
EDSS 3.5 (1.4) 4.5 (1.9) 3.1 (1.6)
Immunomodulating agents n (%) 10 (45.5%) 9 (56.3%) 25 (75.7%)
Other medications
α-2-δ ligands (n) 7 5 3
SSRI/SNRI (n) 3/0 3/0 3/2
Benzodiazepines (n) 2 5 5
Tricyclics (n) 1 2 3
Stimulants (n) 0 2 1

Legend:RLS: MS: multiple sclerosis; restless leg syndrome; IRLDQ: International Restless Leg Study Group Diagnostic questionnaire; BMI: body mass index; RR: relapsing-remitting; SP: secondary progressive; PP: primary progressive; PR: progressive-relapsing; EDSS: Expanded Disability Status Scale; α-2-δ ligands: α-2-δ ligands of voltage-dependent calcium channel; SSRI: serotonin reuptake inhibitors; SNRI: serotonin–noradrenalin reuptake inhibitors. Data presented as mean (SD) unless otherwise stated.

When comparing patients who were IRLDQ+/RLS+ versus IRLDQ–, patients with RLS were significantly older (50.5 ± 10.9 vs. 43.7 ± 10.2 years,p = 0.02) and were less likely to be receiving immunomodulating therapy (45.4% vs. 75.7%,p = 0.04). There were no differences in terms of sex, body mass index (BMI), MS disease duration, disability, or proportion of patients with OSAH.

When comparing subjects with RLS to all subjects without RLS (ie, including IRLDQ+ and IRLDQ– subjects), subjects with RLS were significantly older (50.5 ± 10.9 vs. 44.8 ± 10.1 years,p = 0.03), had a higher proportion of females (86.3% vs. 40.8%,p = 0.02), and tended to be less likely to be receiving immunomodulating therapy (45.4% vs. 69.3%,p = 0.055).

We found reduced serum ferritin (below normal range for our laboratory) in eight of our 71 subjects; four of these eight were IRLDQ+/RLS+. Twenty-two of 71 subjects had serum ferritin below 50 ug/L; four of these were IRLDQ+/RLS+. We found reduced vitamin B12 (below normal range for our laboratory) in 10 of 71 subjects; three of these were IRLDQ+/RLS+. Fifty-three of 71 subjects had vitamin B12 levels below 300; three of these were IRLDQ+/RLS+. We found no significant differences in the proportion of patients with reduced ferritin or vitamin B12 levels in the IRLDQ+/RLS+ and IRLDQ– groups.

3.3. RLS mimics

Sixteen subjects were found to have a positive IRLDQ without RLS. Figure 1 shows the main symptoms and interactions between symptoms accounting for the false-positive responses. The most frequent symptoms accounting for the mimic were paresthesiae in the context of MS sensory symptoms, and leg cramps. Five patients reported more than one of these symptoms. Of note, three patients did not report any RLS symptoms at the time of the clinical visit. One was on caffeine initially and his symptoms disappeared with caffeine discontinuation. The other two subjects were receiving glatiramer immunomodulating therapy. They reported infrequent symptoms in the first interview (less than once a month, and less than once a year) and one was using clonazepam 0.5 mg at night. They did not remember any symptoms at the time of the clinical visit.

sleep2702-fig-0001

Fig. 1 Symptoms accounting for restless legs syndrome mimics.

3.4. Sleep parameters and PLM

When comparing sleep data from MS patients with positive IRLDQ with or without RLS ( Table 2 ), no differences were found in terms of sleep architecture, sleep efficiency, sleep latency, or proportion of patients with OSAH.

Table 2 Sleep Parameters in MS Subjects With and Without RLS.

Sleep Parameter IRLDQ+/RLS+ n = 22 IRLDQ+/RLS– n = 16 IRLDQ– n = 33
TSP (min) 381.1 (75.0) 366.4 (54.0) 382.5 (52.0)
TST (min) 309.6 (83.4) 291.6 (59.0) 309.9 (71.6)
Sleep efficiency (%) 75 (12.3) 75.3 (14.8) 76.8 (15.9)
Sleep-onset latency (min) 26.1 (24.7) 23.6 (17.5) 20.3 (20.2)
WASO (min) 71.4 (35.9) 74.8 (50.1) 72.5 (55.8)
Number of stage shifts 145.7 (56.3) 151.6 (57.7) 142.4 (43.8)
Total arousal index (n/h) 39.3 (16.9) 39.1 (14) 41.1 (17.6)
Stage 1 (%) 10.7 (8.7) 13.0 (10.1) 10.3 (6.8)
Stage 2 (%) 46.4 (9.5) 50.2 (9.3) 50.2 (9.4)
Stage 3 (%) 28.3 (11.6) 21.6 (11.5) 26.0 (10.1)
REM (%) 14.5 (6.9) 15.1 (6.3) 13.4 (6.9)
AHI (n/h) 21.8 (19.8) 21.7 (15.1) 20.7 (17.2)
OSAH n (%) 10 (45.5%) 9 (56.3%) 18 (54.5%)

Legend:MS: multiple sclerosis; RLS: restless legs syndrome; IRLDQ: International Restless Leg Study Group Diagnostic questionnaire; TSP: total sleep period; TST: total sleep time; WASO: wake after sleep onset; REM: rapid eye movements; AHI: apnea–hypopnea index; OSA: obstructive sleep apnea–hypopnea. Data presented as mean (SD) unless otherwise specified.

When evaluating PLM in more detail ( Table 3 ), we found a significantly higher PLMW index among IRLDQ+/RLS+ patients versus IRLDQ+/RLS– patients (p = 0.03). We did not find differences in any of the other PLM indices measured. When comparing RLS subjects with subjects without RLS including IRLDQ+ and IRLDQ– subjects, PLMW index remained significantly higher in subjects with RLS (p = 0.04), and there was a trend for a higher total PLM index among RLS subjects (p = 0.058).

Table 3 PLM Indices in MS Subjects With and Without RLS.

PLM Index IRLDQ+/RLS+ n = 22 IRLDQ+/RLS– n = 16 IRLDQ- n = 33 p *
PLMW index 55.4 (41.9) 29.7 (18.8) 36.8 (45.6) 0.03
PLMS – A index 3.9 (4.9) 4.1 (5.6) 2.8 (4.4) 0.93
PLMS – NA index 21.8 (23.2) 22.4 (31.2) 15.1 (34.1) 0.95
PLMS – total index 25.7 (27.5) 26.5 (36.5) 17.9 (35.6) 0.94
PLM total index 33.8 (26.5) 27.3 (25.9) 18.5 (23.3) 0.46

* p value for comparison of IRLDQ+/RLS+ vs. IRLDQ+/RLS–.

Legend:PLM: periodic leg movements; MS: multiple sclerosis; RLS: restless legs syndrome; IRLDQ: International Restless Leg Study Group Diagnostic questionnaire; PLMW: periodic leg movements during wakefulness; PLMS-A: periodic leg movements during sleep associated with arousal; PLMS-NA: periodic leg movements during sleep not associated with arousal; PLMS: periodic leg movements during sleep.

The individual values for PLMW index in the IRLDQ+/RLS+ and IRLDQ+/RLS– subjects are shown in Fig. 2 . There was a sub-group of IRLDQ+/RLS+ with PLMW values >70/h, while no IRLDQ+/RLS– subjects demonstrated PLMW values in this range. Using a cutoff value of 70 events/hour for the PLMW index, the specificity for true RLS among positive IRLDQ respondents was 100% (95% CI 79.4–100), with a sensitivity of 36% (95% CI 17.2–59.3) ( Table 4 ). Of note, there was no difference in terms of SSRI, α-2-δ ligand, or benzodiazepine use between confirmed RLS subjects with or without PLMW index >70.

sleep2702-fig-0002

Fig. 2 PLMW index distribution in IRLDQ+/RLS– and IRLDQ+/RLS+ Subjects. No RLS– subjects had a PLMW index of >70. PLMW: periodic leg movements during wakefulness; IRLDQ: International Restless Legs Syndrome Diagnostic questionnaire; RLS: restless legs syndrome.

Table 4 Relationship Between PLMW Indices and RLS in IRLDQ+ Subjects.

  PLMW Index >70 PLMW Index <70 Total
RLS (+) 8 14 22
RLS (–) 0 16 16
Total 8 30 38

Legend:PLMW: periodic leg movements during wakefulness; RLS: restless legs syndrome, confirmed clinically if +; IRLDQ: International Restless Legs Syndrome Study Group Diagnostic Questionnaire.

We reviewed PLM indices among IRLDQ– patients. We found four patients with a PLMW index >70/h, and reviewed their characteristics. Three of the subjects were male and were using the immunomodulating agent glatiramer. The fourth one was not using an immunomodulating agent, but was taking an SSRI (paroxetine). The MS and demographic characteristics of these patients were similar to the rest of the group. With regard to their sleep parameters, they had higher PLMW and total PLM indices than the other IRLDQ– subjects, but the other PLM indices and sleep parameters were similar. We verified their negative responses to all IRLDQ questions both on the initial questionnaire and by subsequent interview.

We evaluated the association of PLMW indices with reduced serum ferritin and vitamin B12. We found no significant differences in PLMW indices between patients with and without reduced serum ferritin and vitamin B12 levels in our entire patient population.

4. Discussion

We found a very high rate of RLS mimics among MS patients. The false-positive rate for questionnaire-based RLS in our MS population was 42% (95% CI 26–59 %) compared to 16% reported in the general population [5] . We were unable to identify previous studies evaluating false-positive rates for RLS in MS. As expected, most false-positive responses to the IRLDQ were related to MS-associated sensorimotor symptoms. The evaluation of symptoms in this subgroup of patients in some instances was difficult even after expert medical evaluation. A therapeutic trial was required in a small portion of subjects. Thus, diagnostic tools to support the diagnosis of RLS could have substantial value in the care of these patients. We believe this to be the first report that PLMW values from nocturnal PSG may be a useful diagnostic tool for RLS in MS. PLMS were not found to be useful in this regard.

Since completion of our study, new diagnostic criteria for RLS have recently been introduced in 2014. These criteria now include a fifth major criterion that the RLS symptoms should not be confused with similar symptoms due to other conditions such as edema, leg cramps, arthritis, etc. Our results emphasize the importance of excluding RLS mimics in the diagnosis of RLS, and provide support for use of the new diagnostic criteria [31] .

In contrast to some previous reports, we found no association with MS severity and RLS[11] and [32], perhaps due to the absence of PP MS patients in our population. Two studies reported a higher proportion of PP MS subjects in those who were RLS positive[11] and [32]. These individuals usually have higher degrees of motor disability. The REstless legs syndrome in Multiple Sclerosis study also found that pyramidal and sensory EDSS account for the difference in MS severity [11] . Our findings were consistent with other studies which showed no association between RLS and MS severity [9] . These studies did not find a higher proportion of PP subjects among RLS-positive MS subjects. It is noteworthy that our false-positive group had more severe EDSS scores than the true-positive RLS group. Our finding of a high rate of RLS mimicry in MS suggests that previous questionnaire-based studies may have overestimated the prevalence of RLS in MS, with overestimation potentially more likely in patients with greater sensorimotor disability.

Our true RLS population was older than all RLS-negative subjects. In addition, we found a greater proportion of males among our false-positive patients (IRLDQ+/RLS–) and all RLS– subjects compared with true RLS subjects. Of interest, three of the four IRLDQ– subjects with high PLMW indices were also male. This age relationship and female gender predominance in RLS has been previously reported in the general population and in MS patients[5], [6], [7], [10], and [11].

PLMW have been explored in RLS subjects. However, the PLMW index among our MS patients with and without RLS was much higher than in subjects without MS, with or without RLS[12] and [16]. Most studies of RLS and leg movements have focused on their relationship with PLMS[13] and [30]. In addition, most studies on PLMW have focused on their correlation with PLMS[16] and [18]. However, PLMS are highly sensitive markers for RLS but have a low specificity [33] . In addition, considering the time frame of RLS symptoms (ie, occurring early in the night and disrupting sleep onset), PLMW could be more useful in RLS diagnosis. We observed that a PLMW index >70 on PSG is highly specific, although not very sensitive, for the diagnosis of RLS in MS subjects with a positive IRLDQ questionnaire. This finding could be potentially useful in establishing a diagnosis of RLS among MS patients.

We and others have found that MS patients may suffer from a diversity of sleep disorders which can profoundly affect their quality of life[8], [21], [22], and [34]. We have previously reported a high prevalence of OSAH among MS patients, and its strong association with fatigue [22] . Others have reported insomnia, narcolepsy, and REM sleep behavior disorder [34] . Overnight PSG should be considered routine in the evaluation of sleep complaints in MS, and our findings indicate that it can also be helpful for RLS evaluation.

Our study had several limitations. First, our patient population came from a specialized MS Clinic at a tertiary care institution, and may not be representative of the general MS population. Second, we did not utilize a newer questionnaire for RLS diagnosis, such as the Cambridge–Hopkins RLS questionnaire, which includes several questions that attempt to exclude conditions which mimic RLS [35] . However, this questionnaire was not available when we initiated subject recruitment and may pose similar difficulties to the IRLDQ for RLS diagnosis in MS. To our knowledge, it has not yet been tested in MS subjects.

In conclusion, we report a high rate of RLS mimics among MS subjects, mostly attributable to their sensorimotor symptoms. This finding underscores the need for careful clinical assessment of MS patients in establishing a diagnosis of RLS, rather than reliance solely on standardized questionnaires. While confirmation in further studies will be required, our findings indicate that a PLMW index of >70 assessed during overnight PSG may be a useful tool in differentiating true RLS patients from patients with RLS-like symptoms in the MS population.

Conflict of interest

The authors declare no conflicts of interest for this study.

The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2015.02.529 .

 

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Acknowledgments

This study was funded but the Multiple Sclerosis Society of Canada; the Fonds de recherche du Québec - Santé (15098); and the Montreal Neurological Institute. The funding agencies had no role in study design, data collection, analysis, and interpretation, and in the preparation and submission of the manuscript. We appreciate the help of Gustavo Torres and Allen Olha for conducting the polysomnographies. We thank Drs. Jack Antel, Michel Aubé, and Douglas Arnold for referring patients for the study. We are grateful to the patients who donated their time and effort to participate in this study.

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Footnotes

a Respiratory Division and Sleep Laboratory, McGill University Health Centre, 687 Pine Ave. West, Montreal, QC H3A 1A1, Canada

b Department of Medicine, McGill University Health Centre, 687 Pine Ave West, Montreal, QC H3A 1A1, Canada

c Department of Epidemiology, Biostatistics & Occupational Health, McGill University, 1020 Pine Ave. West, Montreal, QC H3A 1A2, Canada

d Respiratory Epidemiology and Clinical Research Unit, Montreal Chest Institute, McGill University, 3650 St. Urbain St, Montreal, QC H2X 2P4, Canada

e Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University Health Centre, 3801 University St., Montreal, QC H3A 2B4, Canada

* Corresponding author. Montreal Neurological Institute and Hospital, 3801 University St., Montreal QC H3A 2B4, Canada. Tel.: +514 398 8911; fax: +514 398 2745.


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  • Prof Timothy Vartanian

    dsc_0787_400x400.jpg Timothy Vartanian, Professor at the Brain and Mind Research Institute and the Department of Neurology, Weill Cornell Medical College,...
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    headshotcsr1_185x250.jpg Claire S. Riley, MD is an assistant attending neurologist and assistant professor of neurology in the Neurological Institute, Columbia...
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