- Email: [email protected]
Increased frequency and severity of restless legs syndrome in patients with neuromyelitis optica spectrum disorder
Sleep Medicine 17 (2016) 121–123
Contents lists available at ScienceDirect
Sleep Medicine j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / s l e e p
Brief Communication
Increased frequency and severity of restless legs syndrome in patients with neuromyelitis optica spectrum disorder Jae-Won Hyun a, Su-Hyun Kim a, In Hye Jeong a, AeRan Joung a, Ji-Hee Kim a, Hyo Jin Cho a, Jee Hyun Kim b, Ho Jin Kim a,* a b
Department of Neurology, Research Institute and Hospital of National Cancer Center, Goyang, Republic of Korea Department of Neurology, Dankook University College of Medicine, Dankook University Hospital, Cheonan, Republic of Korea
A R T I C L E
I N F O
Article history: Received 29 May 2015 Received in revised form 27 July 2015 Accepted 20 August 2015 Available online 22 October 2015 Keywords: Restless legs syndrome Neuromyelitis optica spectrum disorder
A B S T R A C T
Objectives: To investigate the comorbidity of restless legs syndrome (RLS) and neuromyelitis optica spectrum disorder (NMOSD). Methods: This study enrolled 159 NMOSD patients and 153 age- and gender-matched healthy controls. All participants completed a questionnaire based on the updated International Restless Legs Syndrome Study Group consensus criteria, the International RLS Severity scale, Epworth Sleepiness Scale, Fatigue Severity Scale, and Pittsburgh Sleep Quality Index, and were subsequently interviewed by a neurologist. The frequency and features of RLS were compared between NMOSD patients and healthy controls. The clinical and radiological characteristics of the NMOSD patients with and without RLS were also compared. Results: The frequency and severity of RLS were significantly higher in NMOSD patients than in healthy controls (p = 0.015 for both) and NMOSD patients with RLS had a longer disease duration and more severe disability than those without RLS. Conclusions: This study indicated importance of considering RLS in NMOSD patients. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Restless legs syndrome (RLS) is characterized by the distressing urge to move one’s legs that is often accompanied by uncomfortable sensations [1]. The exact cause of RLS remains unknown, but there are idiopathic and secondary forms of RLS that are associated with variety of medical conditions, such as anemia, pregnancy, uremia, neuropathies, rheumatoid arthritis, and neurological disorders, including Parkinson’s disease, spinocerebellar ataxia, and multiple sclerosis [2]. Neuromyelitis optica (NMO) is a severe inflammatory disease of central nervous system [3]. Once considered a variant of multiple sclerosis, NMO is now considered as a distinct disease entity [3,4]. The discovery of disease-specific autoantibodies that target aquaporin-4 (AQP4) has led to refinement of a wide spectrum of disorders (NMO spectrum disorder: NMOSD) [4,5]. Patients with NMOSD often complain of leg restlessness as a sensory symptom, but the relationship between RLS and NMOSD has yet to be investigated. Therefore, this study estimated the prevalence of RLS in a large cohort of NMOSD patients and compared the RLS features of these patients with those of
* Corresponding author. Department of Neurology, Research Institute and Hospital of National Cancer Center, 410-719, 323 Ilsan-ro, Ilsandong-gu, Goyang, Republic of Korea. Tel.: +82 31 920 2438; fax: +82 31 925 5524. E-mail address: [email protected] (H.J. Kim). http://dx.doi.org/10.1016/j.sleep.2015.08.023 1389-9457/© 2015 Elsevier B.V. All rights reserved.
age- and gender-matched healthy controls. The clinical and magnetic resonance imaging (MRI) findings of the NMOSD patients with and without RLS were also compared. 2. Methods This study enrolled 159 NMOSD patients and 153 age- and gender-matched healthy controls. The enrollment and evaluation of RLS was performed between June 2014 and January 2015. All NMOSD patients either fulfilled the 2006 NMO diagnostic criteria [6], or were positive for AQP4 antibody and had at least one cardinal features of NMO: 90% of patients were positive for AQP4 antibody and 10% of the patients without AQP4 antibody had both optic neuritis and longitudinally extensive transverse myelitis with brain MRI not meeting the diagnostic criteria for multiple sclerosis. All participants completed a questionnaire based on the updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria and the Korean version of the International RLS Severity scale (IRLS) [1,7]. To diagnose RLS more accurately, subjects fulfilling the first to fourth criteria were subsequently interviewed by a neurologist to evaluate their eligibility regarding the fifth criterion, which was that the occurrence of the features could not be accounted for solely as symptoms primary to another medical or behavioral condition. Based on this interview, subjects with symptoms mimicking RLS, including paresthesia (six patients), spasm (five patients), and myoclonus (two patients), were
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excluded from the final analyses. The Epworth Sleepiness Scale (ESS), Fatigue Severity Scale (FSS), and Pittsburgh Sleep Quality Index (PSQI) were included in the questionnaire [8–10]. All the evaluations were performed when patients were in remission status at least for six months. None of the patients took medications known to cause RLS. Patients with conditions known to be associated with RLS, such as anemia [hemoglobin (Hb) levels < 12 mg/mL], pregnancy, uremia, neuropathies, rheumatoid arthritis, and neurological diseases other than NMOSD, were excluded; ultimately, 153 NMOSD patients remained. First, the frequencies of RLS in the NMOSD patients were estimated. Second, the features of RLS were compared between the NMOSD patients with RLS (RLS/NMOSD) and healthy controls with RLS (RLS/HC). Lastly, the characteristics of the NMOSD patients with (NMOSD/RLS+) and without (NMOSD/RLS−) RLS were compared to evaluate the clinical relationship between these two diseases. In three patients, the RLS preceded the onset of NMOSD and these subjects were excluded from the final comparison.
The Institutional Review Board of the National Cancer Center approved the study protocol and all subjects gave informed consent. All data were analyzed using the chi-square test, Student’s t-test, or Mann–Whitney U-test. Logistic regression was used to establish the relationship between RLS and NMOSD. A p-value < 0.05 was considered to indicate a significant difference. 3. Results Table 1 compares the NMOSD patients and healthy controls. RLS was significantly more frequent in the NMOSD patients than in the healthy controls (17% vs. 7.8%, p = 0.015) and the odds ratio (OR) was 2.4 (95% confidence interval 1.2–5.0; p = 0.018). The median scores on the IRLS (p = 0.015), FSS (p = 0.036), and PSQI (p = 0.018) were significantly higher in the RLS/NMOSD group than the RLS/ HC group, suggesting that RLS was more severe in NMOSD patients. Of the 26 RLS/NMOSD patients, 23 (88.5%) developed RLS at or after
Table 1 Demographics, RLS natures of NMOSD patients/healthy controls and the comparison of the 150 patients with/without secondary RLS.
Gender (male:female) Current age (years) Body mass index (kg/m2) Aquaporin-4 antibody (+) (years) NMOSD disease duration Current median EDSS [range] Presence of RLS (n, %)
RLS severity scale Preceding RLS (years) RLS disease duration Benefit with dopamine agonist (only in treated patients) ESS (median, range) ESS > 10, % FSS (median, range) FSS ≥ 4, % PSQI (median, range) PSQI > 5, %
Gender (male:female) Current age (years) Age of NMOSD onset (years) Age of RLS onset (years) Delay between NMOSD to RLS onset (years) Disease duration of RLS (years) Disease duration of NMOSD (years) Current median EDSS [range] Aquaporin-4 antibody (+) Menopause Immunosuppressive therapy Azathioprine Mycophenolate mofetil Rituximab Past spinal cord lesion on MRI Past pyramidal system involvement Past sensory system involvement ESS (median, range) ESS > 10 (n, %) FSS (median, range) FSS ≥ 4 (n, %) PSQI (median, range) PSQI > 5 (n, %)
NMOSD (n = 153)
Healthy controls (HC) (n = 153)
p-value
17:136 42.3 ± 11.5 22.8 ± 3.5 137/153 (89.5%) 8.7 ± 5.2 3 [0–8] 26 (17%)
17:136 42.4 ± 11.5 22.6 ± 2.9 N/A N/A N/A 12 (7.8%)
NS NS NS – – – 0.015
RLS/NMOSD (n = 26)
RLS/HC (n = 12)
p-value
22.6 ± 10.2 3/26 (11.5%) 7.1 ± 5.5 13/17 (76.5%)
14.3 ± 6.9 N/A 6.6 ± 3.1 N/A
0.015 – NS –
8.5 [1–19] 5 (19%) 5.1 [1.7–6.2] 17 (65%) 9 [4–18] 21 (81%)
6.5 [0–15] 4 (33%) 3.9 [1–5.3] 6 (50%) 6 [3–9] 9 (75%)
NS NS 0.036 NS 0.018 NS
NMOSD/RLS(+) n = 23
NMOSD/RLS(−) n = 127
p-values
3:20 44.1 ± 9.8 33.1 ± 11.4 36.9 ± 12.6 3.8 ± 5.5 7.3 ± 5.8 11.0 ± 6.1 4.5 [0–8] 20/23 (87%) 9/20(45%) 23 (100%) 4 (17%) 10 (44%) 9 (39%) 19 (83%) 19 (83%) 20 (87%) 7 [0–19] 4 (17%) 5.1 [1.7–6.2] 16 (70%) 9 [1–18] 20 (87%)
13:114 42.0 ± 11.8 33.6 ± 12.0 N/A N/A N/A 8.4 ± 4.9 3.0 [0–7.5] 115/127 (91%) 39/114(34%) 127 (100%) 11 (9%) 43 (34%) 73 (57%) 106 (83%) 88 (69%) 107 (84%) 7 [0–24] 27 (21%) 4.2 [1–6.7] 72 (57%) 7 [1–20] 93 (73%)
NS NS NS – – – 0.028 0.001 NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS
Abbreviations. NS: not significant, EDSS: expanded disability status scale, ESS: Epworth sleepiness scale, FSS: fatigue severity scale, PSQI: Pittsburgh sleep quality index.
J.-W. Hyun et al./Sleep Medicine 17 (2016) 121–123
the onset of NMOSD, while RLS preceded the onset of NMOSD in a few patients (11.5%). Of the 26 RLS/NMOSD patients, 17 were prescribed ropinirole (0.25–0.5 mg) and 13 of these patients (76.5%) reported marked benefits. A comparison of the NMOSD/RLS+ and NMOSD/RLS− groups (Table 1) revealed that the NMOSD/RLS+ patients had higher scores on the Expanded Disability Status Scale (EDSS) and longer disease duration of NMOSD than the NMOSD/RLS− patients. Although the results did not reach the statistical significance, the median FSS and PSQI scores were higher in the NMOSD/RLS+ group than the NMOSD/ RLS− group. The clinical and MRI features of the two groups did not differ significantly.
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Author contributions Dr Kim HJ had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Hyun, Kim HJ, Kim SH. Drafting of the manuscript: Hyun, Kim SH, Kim JH, Kim HJ. Acquisition, analysis and interpretation of data: Hyun, Kim HJ, Kim SH, Jeong, Joung, Kim J-H, Cho. Statistical analysis: Hyun, Kim HJ, Kim SH, Jeong. Critical revision of the manuscript for important intellectual content: Hyun, Kim SH, Jeong, Kim JH, Kim HJ.
Funding sources 4. Discussion There is no funding source to develop this research. This study found that RLS was more common and more severe in NMOSD patients than healthy controls. The reported prevalence of RLS in general populations from various countries is 1.1– 10.8% and 1.1–4.5% in Korea [2,11]. We applied the updated IRLSSG consensus criteria [1] to increase diagnostic accuracy and the prevalence of RLS in healthy controls was found to be 7.8%. Although subjects with symptoms that mimicked RLS were rigorously excluded from our study, the relatively high observed prevalence of RLS can be explained by the fact that the study population was dominated by middle-aged women. In those over 35 years of age, women are twice as likely to suffer RLS as are men in later life [12]. A majority of the RLS/NMOSD patients (88.5%) in our series began to exhibit RLS symptoms either simultaneously with or subsequent to the clinical onset of NMOSD. The NMOSD/RLS+ patients were also in the later stages of NMOSD and had more severe disabilities than the NMOSD/RLS− patients. Recent studies have demonstrated that increases in cortical motor excitability can compensate for reduced sensorimotor plasticity, which could increase one’s vulnerability to RLS [13]. Sensorimotor plasticity is more likely to be altered in patients with a longer disease duration or more severe attacks and RLS may be more common in these patients. However, the dopaminergic hypothalamic-spinal pathway, which descends from the A11 nucleus to the dorsal horn, is suspected as a potential cause of RLS [14], in our study, the NMOSD/RLS+ and NMOSD/RLS− groups did not differ significantly in terms of past spinal cord or sensorimotor involvement. Additional studies are required to verify the pathophysiological relevance of RLS in NMOSD patients. Other studies have demonstrated that sleep disturbances are a common distressing symptom associated with RLS [2]. In our study, the median FSS and PSQI scores were significantly higher in the RLS/ NMOSD group than the RLS/HC group. The median FSS and PSQI scores were also higher in the NMOSD/RLS+ group than the NMOSD/ RLS− group, but this difference was not statistically significant. Therefore the impact of RLS on the sleep quality of NMOSD patients is yet undetermined. Further studies using advanced diagnostic tools such as polysomnography may better characterize the comorbidity of sleep disorders and NMOSD. Although the future studies are required to confirm the treatment effect, benefits of the dopamine agonist were reported in some of the RLS/NMOSD patients. Therefore, clinicians should be aware of the presence of RLS in NMOSD patients and could consider treatment after carefully determining that these symptoms are not due to other conditions. Our findings highlight the importance of considering RLS in NMOSD patients, particularly in those who complain of poor sleep quality.
Conflict of interest Dr. Hyun, Jeong, Kim SH, Kim JH, RN. Joung, Ms. Kim JH, Cho report no disclosures. Dr. Kim HJ has given talks, consulted and received honoraria from Bayer Schering Pharma, Biogen Idec, Genzyme, Merck Serono, Novartis, Teva-Handok, and UCB and received research grants from Genzyme, Kael-GemVax, and Merck Serono. He serves on a steering committee for MedImmune and editorial board member for Multiple Sclerosis Journal – Experimental, Translational and Clinical. 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.2015.08.023.
References [1] Allen RP, Picchietti DL, Garcia-Borreguero D, et al. Restless legs syndrome/ Willis-Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria – history, rationale, description, and significance. Sleep Med 2014;15:860–73. [2] Garcia-Borreguero D, Williams AM. An update on restless legs syndrome (Willis-Ekbom disease): clinical features, pathogenesis and treatment. Curr Opin Neurol 2014;27:493–501. [3] Kim W, Kim SH, Kim HJ. New insights into neuromyelitis optica. J Clin Neurol 2011;7:115–27. [4] Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 2004;364:2106–12. [5] Wingerchuk DM, Lennon VA, Lucchinetti CF, et al. The spectrum of neuromyelitis optica. Lancet Neurol 2007;6:805–15. [6] Wingerchuk DM, Lennon VA, Pittock SJ, et al. Revised diagnostic criteria for neuromyelitis optica. Neurology 2006;66:1485–9. [7] Yang JG, Kim DH, Lee JH, et al. The reliability and validity of the Korean versions of the international restless legs scale and the restless legs syndrome quality of life questionnaire. J Korean Neurol Assoc 2010;28:263–9. [8] Cho YW, Lee JH, Son HK, et al. The reliability and validity of the Korean version of the Epworth sleepiness scale. Sleep Breath 2011;15:377–84. [9] Lee JH, Jeong HS, Lim SM, et al. Reliability and validity of the fatigue severity scale among university student in South Korea. Korean J Biol Psychiatry 2013;20:6–11. [10] Sohn SI, Kim do H, Lee MY, et al. The reliability and validity of the Korean version of the Pittsburgh Sleep Quality Index. Sleep Breath 2012;16:803–12. [11] Yun CH, Lee SK, Kim H, et al. Association between irritable bowel syndrome and restless legs syndrome in the general population. J Sleep Res 2012;21:569– 76. [12] Manconi M, Ulfberg J, Berger K, et al. When gender matters: restless legs syndrome. Report of the “RLS and woman” workshop endorsed by the European RLS Study Group. Sleep Med Rev 2012;16:297–307. [13] Rizzo V, Arico I, Mastroeni C, et al. Dopamine agonists restore cortical plasticity in patients with idiopathic restless legs syndrome. Mov Disord 2009;24:710–15. [14] Clemens S, Rye D, Hochman S. Restless legs syndrome: revisiting the dopamine hypothesis from the spinal cord perspective. Neurology 2006;67:125–30.
Contents lists available at ScienceDirect
Sleep Medicine j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / s l e e p
Brief Communication
Increased frequency and severity of restless legs syndrome in patients with neuromyelitis optica spectrum disorder Jae-Won Hyun a, Su-Hyun Kim a, In Hye Jeong a, AeRan Joung a, Ji-Hee Kim a, Hyo Jin Cho a, Jee Hyun Kim b, Ho Jin Kim a,* a b
Department of Neurology, Research Institute and Hospital of National Cancer Center, Goyang, Republic of Korea Department of Neurology, Dankook University College of Medicine, Dankook University Hospital, Cheonan, Republic of Korea
A R T I C L E
I N F O
Article history: Received 29 May 2015 Received in revised form 27 July 2015 Accepted 20 August 2015 Available online 22 October 2015 Keywords: Restless legs syndrome Neuromyelitis optica spectrum disorder
A B S T R A C T
Objectives: To investigate the comorbidity of restless legs syndrome (RLS) and neuromyelitis optica spectrum disorder (NMOSD). Methods: This study enrolled 159 NMOSD patients and 153 age- and gender-matched healthy controls. All participants completed a questionnaire based on the updated International Restless Legs Syndrome Study Group consensus criteria, the International RLS Severity scale, Epworth Sleepiness Scale, Fatigue Severity Scale, and Pittsburgh Sleep Quality Index, and were subsequently interviewed by a neurologist. The frequency and features of RLS were compared between NMOSD patients and healthy controls. The clinical and radiological characteristics of the NMOSD patients with and without RLS were also compared. Results: The frequency and severity of RLS were significantly higher in NMOSD patients than in healthy controls (p = 0.015 for both) and NMOSD patients with RLS had a longer disease duration and more severe disability than those without RLS. Conclusions: This study indicated importance of considering RLS in NMOSD patients. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Restless legs syndrome (RLS) is characterized by the distressing urge to move one’s legs that is often accompanied by uncomfortable sensations [1]. The exact cause of RLS remains unknown, but there are idiopathic and secondary forms of RLS that are associated with variety of medical conditions, such as anemia, pregnancy, uremia, neuropathies, rheumatoid arthritis, and neurological disorders, including Parkinson’s disease, spinocerebellar ataxia, and multiple sclerosis [2]. Neuromyelitis optica (NMO) is a severe inflammatory disease of central nervous system [3]. Once considered a variant of multiple sclerosis, NMO is now considered as a distinct disease entity [3,4]. The discovery of disease-specific autoantibodies that target aquaporin-4 (AQP4) has led to refinement of a wide spectrum of disorders (NMO spectrum disorder: NMOSD) [4,5]. Patients with NMOSD often complain of leg restlessness as a sensory symptom, but the relationship between RLS and NMOSD has yet to be investigated. Therefore, this study estimated the prevalence of RLS in a large cohort of NMOSD patients and compared the RLS features of these patients with those of
* Corresponding author. Department of Neurology, Research Institute and Hospital of National Cancer Center, 410-719, 323 Ilsan-ro, Ilsandong-gu, Goyang, Republic of Korea. Tel.: +82 31 920 2438; fax: +82 31 925 5524. E-mail address: [email protected] (H.J. Kim). http://dx.doi.org/10.1016/j.sleep.2015.08.023 1389-9457/© 2015 Elsevier B.V. All rights reserved.
age- and gender-matched healthy controls. The clinical and magnetic resonance imaging (MRI) findings of the NMOSD patients with and without RLS were also compared. 2. Methods This study enrolled 159 NMOSD patients and 153 age- and gender-matched healthy controls. The enrollment and evaluation of RLS was performed between June 2014 and January 2015. All NMOSD patients either fulfilled the 2006 NMO diagnostic criteria [6], or were positive for AQP4 antibody and had at least one cardinal features of NMO: 90% of patients were positive for AQP4 antibody and 10% of the patients without AQP4 antibody had both optic neuritis and longitudinally extensive transverse myelitis with brain MRI not meeting the diagnostic criteria for multiple sclerosis. All participants completed a questionnaire based on the updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria and the Korean version of the International RLS Severity scale (IRLS) [1,7]. To diagnose RLS more accurately, subjects fulfilling the first to fourth criteria were subsequently interviewed by a neurologist to evaluate their eligibility regarding the fifth criterion, which was that the occurrence of the features could not be accounted for solely as symptoms primary to another medical or behavioral condition. Based on this interview, subjects with symptoms mimicking RLS, including paresthesia (six patients), spasm (five patients), and myoclonus (two patients), were
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excluded from the final analyses. The Epworth Sleepiness Scale (ESS), Fatigue Severity Scale (FSS), and Pittsburgh Sleep Quality Index (PSQI) were included in the questionnaire [8–10]. All the evaluations were performed when patients were in remission status at least for six months. None of the patients took medications known to cause RLS. Patients with conditions known to be associated with RLS, such as anemia [hemoglobin (Hb) levels < 12 mg/mL], pregnancy, uremia, neuropathies, rheumatoid arthritis, and neurological diseases other than NMOSD, were excluded; ultimately, 153 NMOSD patients remained. First, the frequencies of RLS in the NMOSD patients were estimated. Second, the features of RLS were compared between the NMOSD patients with RLS (RLS/NMOSD) and healthy controls with RLS (RLS/HC). Lastly, the characteristics of the NMOSD patients with (NMOSD/RLS+) and without (NMOSD/RLS−) RLS were compared to evaluate the clinical relationship between these two diseases. In three patients, the RLS preceded the onset of NMOSD and these subjects were excluded from the final comparison.
The Institutional Review Board of the National Cancer Center approved the study protocol and all subjects gave informed consent. All data were analyzed using the chi-square test, Student’s t-test, or Mann–Whitney U-test. Logistic regression was used to establish the relationship between RLS and NMOSD. A p-value < 0.05 was considered to indicate a significant difference. 3. Results Table 1 compares the NMOSD patients and healthy controls. RLS was significantly more frequent in the NMOSD patients than in the healthy controls (17% vs. 7.8%, p = 0.015) and the odds ratio (OR) was 2.4 (95% confidence interval 1.2–5.0; p = 0.018). The median scores on the IRLS (p = 0.015), FSS (p = 0.036), and PSQI (p = 0.018) were significantly higher in the RLS/NMOSD group than the RLS/ HC group, suggesting that RLS was more severe in NMOSD patients. Of the 26 RLS/NMOSD patients, 23 (88.5%) developed RLS at or after
Table 1 Demographics, RLS natures of NMOSD patients/healthy controls and the comparison of the 150 patients with/without secondary RLS.
Gender (male:female) Current age (years) Body mass index (kg/m2) Aquaporin-4 antibody (+) (years) NMOSD disease duration Current median EDSS [range] Presence of RLS (n, %)
RLS severity scale Preceding RLS (years) RLS disease duration Benefit with dopamine agonist (only in treated patients) ESS (median, range) ESS > 10, % FSS (median, range) FSS ≥ 4, % PSQI (median, range) PSQI > 5, %
Gender (male:female) Current age (years) Age of NMOSD onset (years) Age of RLS onset (years) Delay between NMOSD to RLS onset (years) Disease duration of RLS (years) Disease duration of NMOSD (years) Current median EDSS [range] Aquaporin-4 antibody (+) Menopause Immunosuppressive therapy Azathioprine Mycophenolate mofetil Rituximab Past spinal cord lesion on MRI Past pyramidal system involvement Past sensory system involvement ESS (median, range) ESS > 10 (n, %) FSS (median, range) FSS ≥ 4 (n, %) PSQI (median, range) PSQI > 5 (n, %)
NMOSD (n = 153)
Healthy controls (HC) (n = 153)
p-value
17:136 42.3 ± 11.5 22.8 ± 3.5 137/153 (89.5%) 8.7 ± 5.2 3 [0–8] 26 (17%)
17:136 42.4 ± 11.5 22.6 ± 2.9 N/A N/A N/A 12 (7.8%)
NS NS NS – – – 0.015
RLS/NMOSD (n = 26)
RLS/HC (n = 12)
p-value
22.6 ± 10.2 3/26 (11.5%) 7.1 ± 5.5 13/17 (76.5%)
14.3 ± 6.9 N/A 6.6 ± 3.1 N/A
0.015 – NS –
8.5 [1–19] 5 (19%) 5.1 [1.7–6.2] 17 (65%) 9 [4–18] 21 (81%)
6.5 [0–15] 4 (33%) 3.9 [1–5.3] 6 (50%) 6 [3–9] 9 (75%)
NS NS 0.036 NS 0.018 NS
NMOSD/RLS(+) n = 23
NMOSD/RLS(−) n = 127
p-values
3:20 44.1 ± 9.8 33.1 ± 11.4 36.9 ± 12.6 3.8 ± 5.5 7.3 ± 5.8 11.0 ± 6.1 4.5 [0–8] 20/23 (87%) 9/20(45%) 23 (100%) 4 (17%) 10 (44%) 9 (39%) 19 (83%) 19 (83%) 20 (87%) 7 [0–19] 4 (17%) 5.1 [1.7–6.2] 16 (70%) 9 [1–18] 20 (87%)
13:114 42.0 ± 11.8 33.6 ± 12.0 N/A N/A N/A 8.4 ± 4.9 3.0 [0–7.5] 115/127 (91%) 39/114(34%) 127 (100%) 11 (9%) 43 (34%) 73 (57%) 106 (83%) 88 (69%) 107 (84%) 7 [0–24] 27 (21%) 4.2 [1–6.7] 72 (57%) 7 [1–20] 93 (73%)
NS NS NS – – – 0.028 0.001 NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS
Abbreviations. NS: not significant, EDSS: expanded disability status scale, ESS: Epworth sleepiness scale, FSS: fatigue severity scale, PSQI: Pittsburgh sleep quality index.
J.-W. Hyun et al./Sleep Medicine 17 (2016) 121–123
the onset of NMOSD, while RLS preceded the onset of NMOSD in a few patients (11.5%). Of the 26 RLS/NMOSD patients, 17 were prescribed ropinirole (0.25–0.5 mg) and 13 of these patients (76.5%) reported marked benefits. A comparison of the NMOSD/RLS+ and NMOSD/RLS− groups (Table 1) revealed that the NMOSD/RLS+ patients had higher scores on the Expanded Disability Status Scale (EDSS) and longer disease duration of NMOSD than the NMOSD/RLS− patients. Although the results did not reach the statistical significance, the median FSS and PSQI scores were higher in the NMOSD/RLS+ group than the NMOSD/ RLS− group. The clinical and MRI features of the two groups did not differ significantly.
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Author contributions Dr Kim HJ had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Hyun, Kim HJ, Kim SH. Drafting of the manuscript: Hyun, Kim SH, Kim JH, Kim HJ. Acquisition, analysis and interpretation of data: Hyun, Kim HJ, Kim SH, Jeong, Joung, Kim J-H, Cho. Statistical analysis: Hyun, Kim HJ, Kim SH, Jeong. Critical revision of the manuscript for important intellectual content: Hyun, Kim SH, Jeong, Kim JH, Kim HJ.
Funding sources 4. Discussion There is no funding source to develop this research. This study found that RLS was more common and more severe in NMOSD patients than healthy controls. The reported prevalence of RLS in general populations from various countries is 1.1– 10.8% and 1.1–4.5% in Korea [2,11]. We applied the updated IRLSSG consensus criteria [1] to increase diagnostic accuracy and the prevalence of RLS in healthy controls was found to be 7.8%. Although subjects with symptoms that mimicked RLS were rigorously excluded from our study, the relatively high observed prevalence of RLS can be explained by the fact that the study population was dominated by middle-aged women. In those over 35 years of age, women are twice as likely to suffer RLS as are men in later life [12]. A majority of the RLS/NMOSD patients (88.5%) in our series began to exhibit RLS symptoms either simultaneously with or subsequent to the clinical onset of NMOSD. The NMOSD/RLS+ patients were also in the later stages of NMOSD and had more severe disabilities than the NMOSD/RLS− patients. Recent studies have demonstrated that increases in cortical motor excitability can compensate for reduced sensorimotor plasticity, which could increase one’s vulnerability to RLS [13]. Sensorimotor plasticity is more likely to be altered in patients with a longer disease duration or more severe attacks and RLS may be more common in these patients. However, the dopaminergic hypothalamic-spinal pathway, which descends from the A11 nucleus to the dorsal horn, is suspected as a potential cause of RLS [14], in our study, the NMOSD/RLS+ and NMOSD/RLS− groups did not differ significantly in terms of past spinal cord or sensorimotor involvement. Additional studies are required to verify the pathophysiological relevance of RLS in NMOSD patients. Other studies have demonstrated that sleep disturbances are a common distressing symptom associated with RLS [2]. In our study, the median FSS and PSQI scores were significantly higher in the RLS/ NMOSD group than the RLS/HC group. The median FSS and PSQI scores were also higher in the NMOSD/RLS+ group than the NMOSD/ RLS− group, but this difference was not statistically significant. Therefore the impact of RLS on the sleep quality of NMOSD patients is yet undetermined. Further studies using advanced diagnostic tools such as polysomnography may better characterize the comorbidity of sleep disorders and NMOSD. Although the future studies are required to confirm the treatment effect, benefits of the dopamine agonist were reported in some of the RLS/NMOSD patients. Therefore, clinicians should be aware of the presence of RLS in NMOSD patients and could consider treatment after carefully determining that these symptoms are not due to other conditions. Our findings highlight the importance of considering RLS in NMOSD patients, particularly in those who complain of poor sleep quality.
Conflict of interest Dr. Hyun, Jeong, Kim SH, Kim JH, RN. Joung, Ms. Kim JH, Cho report no disclosures. Dr. Kim HJ has given talks, consulted and received honoraria from Bayer Schering Pharma, Biogen Idec, Genzyme, Merck Serono, Novartis, Teva-Handok, and UCB and received research grants from Genzyme, Kael-GemVax, and Merck Serono. He serves on a steering committee for MedImmune and editorial board member for Multiple Sclerosis Journal – Experimental, Translational and Clinical. 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.2015.08.023.
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