European Journal of Neurology 2014
doi:10.1111/ene.12409
SHORT COMMUNICATION
Restless legs syndrome and multiple sclerosis: a population based case control study in Catania, Sicily E. Brunoa,*, A. Nicolettia,*, S. Messinaa, S. Lo Fermoa, L. Racitia, G. Quattrocchia, V. Dibilioa, V. Paradisib, on behalf of the SIMG General Practitioners, D. Maimonec, F. Pattia and M. Zappiaa a
Section of Neurosciences, Department GF Ingrassia, University of Catania, Catania; bCatania Municipality Section, Italian Society of
General Medicine (SIMG), Catania; and cDivision of Neurology, Garibaldi Hospital, Catania, Italy
Keywords:
case control, multiple sclerosis, prevalence, restless legs syndrome Received 24 October 2013 Accepted 7 February 2014
Background and purpose: A population-based case control study in the city of Catania, Sicily, was carried out to determine restless legs syndrome (RLS) prevalence and its association with multiple sclerosis (MS). Methods: Patients were randomly selected from a cohort of MS patients resident in the study area and a group of age and sex matched controls was enrolled from the general population. RLS was diagnosed according to the International Restless Legs Syndrome Study Group criteria. Results: In total, 152 MS patients and 431 controls were included in the study. A significantly higher prevalence of RLS amongst MS patients (14.5%) compared with controls (6.0%) was detected, corresponding to an almost threefold increased risk (odds ratio 2.7, 95% confidence interval 1.4–5.0) of developing RLS. Spinal cord lesions in MS patients were associated with a higher risk of RLS (odds ratio 3.7, 95% confidence interval 1.1–13.5). Conclusion: RLS was strongly associated with MS, with a significantly higher risk in patients presenting spinal cord lesions.
Introduction Restless legs syndrome (RLS) is a sensorimotor disorder characterized by a distressing urge to move the limbs [1]. Prevalence in the general population ranges between 2.5% and 18.3% [2] but a higher prevalence (from 12.1% to 57.5%) and increased risk have been observed amongst patients with multiple sclerosis (MS) [3]. However, to date, case control studies conducted to investigate the association between RLS and MS have often reported contrasting results, limiting conclusions about the association of these two conditions and a possible pathogenic explanation [4,5]. To determine RLS prevalence in MS patients and the influence of MS characteristics, including the role of cervical cord demyelination and of MS disease modifying therapies, on RLS, a population-based case control study was carried out in the city of Catania, Sicily. Correspondence: M. Zappia, Section of Neurosciences, Department GF Ingrassia, University of Catania, via Santa Sofia 78, Catania 95123, Italy (tel.: +0039 095 3782783; fax: +0039 39 95 3782900; e-mail: [email protected]). *These authors contributed equally to this work.
© 2014 The Author(s) European Journal of Neurology © 2014 EFNS
Methods Study population
Multiple sclerosis patients were randomly selected from a previously defined cohort of 367 patients diagnosed according to Poser’s criteria [6] in the period between the 1 January 1975 and 31 December 2004 in the city of Catania, Sicily [7]. Age and sex group matched controls were enrolled from the general population using a multistage sampling method on the General Practitioners cabinet list [8]. Exclusion criteria were applied: Mini Mental State Examination score 10), N (%)
Multivariate analysis
MS cases
Controls
OR
95% CI
P value
OR
95% CI
P value
152 46.0 10.8
431 47.0 14.9
1.0
0.9–1.1
0.4
1.0
0.9–1.0
0.3
55 (36.2) 97 (63.8) 31.7 10.4 14.3 9.3 2.8 2.4 22 (14.5) N = 22 3 (13.6) 12 (54.5) 4 (18.3) 3 (13.6) 9 (5.9)
139 (32.3) 292 (67.7) / / / 26 (6.0) N = 26 8 (30.8) 15 (57.7) 3 (11.5) 0 (0.0) 12 (2.8)
1.0 0.8 / / / 2.6
/ 0.6–1.2 / / / 1.4–4.8
0.4 / / / 0.002
1.0 0.8 / / / 2.7
/ 0.5–1.2 / / / 1.4–5.0
0.3 / / / 0.001
1.0 2.6 2.1 2.3 2.2
/ 0.5–11.3 0.3–11.4 1.4–12.0 0.9–5.3
0.04
/
/
/
0.08
2.2
0.9–5.4
0.09
CI, confidence interval; EDSS, Expanded Disability Status Scale; ESS, Epworth Sleepiness Scale; F, female; IRLS-RS, International Restless Legs Syndrome Rating Scale; M, male; MS, multiple sclerosis; N, number; OR, odds ratio; RLS, restless legs syndrome; SD, standard deviation.
© 2014 The Author(s) European Journal of Neurology © 2014 EFNS
Restless legs syndrome and multiple sclerosis
Table 2 Characteristics of 152 patients with MS with and without RLS No. of cases, N (%) Age (mean SD) Gender, N (%) M F Age at onset (mean SD) MS duration (mean SD) MS clinical course, N (%) RR SP PP EDSS score (mean SD) MRI cervical cord lesions Absent Present Number of cervical lesions (mean SD) MS therapies, N (%) Immunosuppressant Immunomodulator Monoclonal antibody None ESS, N (%) GNDS (mean SD) AI (mean SD)
MS/RLS+
MS/RLS
OR
95% CI
22 (14.5) 46.9 9.9
130 (85.5) 45.9 11.0
1.0
0.9–1.1
0.7
7 (31.8) 15 (68.2) 31.4 12.4 15.5 10.6
48 (36.9) 82 (63.1) 31.7 10.1 14.1 9.1
1.0 1.2 1.0 1.0
/ 0.5–3.3 0.9–1.1 0.9–1.1
0.6 0.9 0.5
18 (81.8) 4 (18.2) 0 (0.0) 2.8 2.3 (19/22) 3 (15.8) 16 (84.2) 2.1 1.8
103 (79.2) 20 (15.4) 7 (5.4) 2.8 2.4 (114/130) 47 (41.2) 67 (58.8) 1.2 1.6
1.0 1.1 / 1.0
/ 0.3–3.7 /
1.0 3.7 1.3
/ 1.1–13.5 1.1–1.6
5 (22.7) 13 (59.1) 0 (0.0) 4 (18.2) 2 (9.1) 8.1 7.5 1.5 2.2
20 (15.4) 72 (55.4) 2 (1.5) 36 (27.7) 7 (5.4) 6.8 7.1 1.6 2.6
2.5 1.9 / 1.0 1.7 1.0 1.0
0.6–10.3 0.6–6.2 / / 0.3–9.0 0.9–1.1 0.9–1.1
3
P value
0.5 0.9
0.04 0.05
0.2 0.3
0.5 0.5 0.9
AI, ambulatory index; CI, confidence interval; EDSS, Expanded Disability Status Scale; ESS, Epworth Sleepiness Scale; F, female; GNDS, Guy’s Neurological Disability Scale; M, male; MS, multiple sclerosis; N, number; OR, odds ratio; PP, primary progressive; RLS, restless legs syndrome; RR, relapsing remitting; SD, standard deviation; SP, secondary progressive.
Discussion Multiple sclerosis patients presented a significantly higher prevalence of RLS (14.5%) compared with healthy controls (6.0%), corresponding to an almost threefold increased risk (OR 2.7, 95% CI 1.4–5.0) of developing RLS. Our prevalence and OR were similar to those reported in previous surveys [4,5] and in a recent meta-analysis [3]. The presence of cervical cord damage was an important risk factor for RLS (OR 3.7, 95% CI 1.1–13.5), significantly associated with the number of lesions (OR 1.3, 95% CI 1.1–1.6). These results could be related to the hypothesized spinal pathogenesis of RLS in MS that attributes the occurrence of the symptoms to an interruption of descending and ascending hypothalamic-spinal pathways [11]. In this context, the observed increased RLS risk linked to the presence of more lesions could be attributed to an increased chance of damaging pathways involved in RLS aetiology. Moreover the symptomatic nature of RLS in MS subjects could be supported by the subsequent onset of RLS and by the higher severity of RLS symptoms reported amongst MS/RLS+ compared with CTR/RLS+. Except for cervical cord lesions, clinical characteristics and MS therapies did not appear to be related to the occurrence of RLS amongst MS patients. © 2014 The Author(s) European Journal of Neurology © 2014 EFNS
In conclusion, due to the cross-sectional nature of the study, our results should be interpreted with caution. Nevertheless, some peculiar findings regarding the possible role of spinal cord lesions in the pathogenesis of RLS in MS are highlighted.
Acknowledgements We would like to thank the SIMG General Practitioners Dr Salvatore Amato, Dr Giovanni Cappello, Dr Marco Ciancio, Dr Carmelo Di Gregorio, Dr Maurizio D’Urso, Dr Melchiorre Fidelbo, Dr Giovanni Marotta, Dr Concetta Persano, Dr Valeria Polizzi, Dr Gaetano Profeta, Dr Antonino Rizzo, Dr Anna Salvo, Dr Giuseppa Spada and Dr Guglielmo Travaglianti for their cooperation in the study. There is no funding.
Disclosure of conflicts of interest The authors declare no financial or other conflicts of interest.
References 1. Earley CJ. Restless legs syndrome. N Engl J Med 2003; 348: 2103–2109.
4
E. Bruno et al.
2. Hening W, Walter AS, Allen RP, et al. Impact, diagnosis and treatment of restless legs syndrome in a primary care population: the REST (RLS epidemiology, symptoms and treatment) primary care study. Sleep Med 2004; 5: 237–246. 3. Sch€ urks M, Bussfeld P. Multiple sclerosis and restless legs syndrome: a systematic review and meta-analysis. Eur J Neurol 2013; 20: 605–615. 4. Manconi M, Rocca MA, Ferini-Strambi L, et al. Restless legs syndrome is a common finding in multiple sclerosis and correlates with cervical cord damage. Mult Scler 2008; 14: 86–93. 5. Deriu M, Cossu G, Molari A, et al. Restless legs syndrome in multiple sclerosis: a case control study. Mov Disord 2009; 24: 697–701. 6. Poser CM, Party DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13: 227–231.
7. Nicoletti A, Patti F, Lo Fermo S, et al. Increasing frequency of multiple sclerosis in Catania, Sicily: a 30-year survey. Mult Scler 2011; 17: 273–280. 8. Patti F, Nicoletti A, Leone C, et al. Multiple sclerosis and CCSVI: a population-based case control study. PLoS One 2012; 7: e41227. 9. Allen RP, Picchietti D, Hening WA, et al. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the Restless Legs Syndrome Diagnosis and Epidemiology workshop at the National Institutes of Health. Sleep Med 2003; 4: 101– 119. 10. Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep 1991; 14: 540– 545. 11. Clemens S, Rye D, Hochman S. Restless legs syndrome: revisiting the dopamine hypothesis from the spinal cord perspective. Neurology 2006; 67: 125–130.
© 2014 The Author(s) European Journal of Neurology © 2014 EFNS
doi:10.1111/ene.12409
SHORT COMMUNICATION
Restless legs syndrome and multiple sclerosis: a population based case control study in Catania, Sicily E. Brunoa,*, A. Nicolettia,*, S. Messinaa, S. Lo Fermoa, L. Racitia, G. Quattrocchia, V. Dibilioa, V. Paradisib, on behalf of the SIMG General Practitioners, D. Maimonec, F. Pattia and M. Zappiaa a
Section of Neurosciences, Department GF Ingrassia, University of Catania, Catania; bCatania Municipality Section, Italian Society of
General Medicine (SIMG), Catania; and cDivision of Neurology, Garibaldi Hospital, Catania, Italy
Keywords:
case control, multiple sclerosis, prevalence, restless legs syndrome Received 24 October 2013 Accepted 7 February 2014
Background and purpose: A population-based case control study in the city of Catania, Sicily, was carried out to determine restless legs syndrome (RLS) prevalence and its association with multiple sclerosis (MS). Methods: Patients were randomly selected from a cohort of MS patients resident in the study area and a group of age and sex matched controls was enrolled from the general population. RLS was diagnosed according to the International Restless Legs Syndrome Study Group criteria. Results: In total, 152 MS patients and 431 controls were included in the study. A significantly higher prevalence of RLS amongst MS patients (14.5%) compared with controls (6.0%) was detected, corresponding to an almost threefold increased risk (odds ratio 2.7, 95% confidence interval 1.4–5.0) of developing RLS. Spinal cord lesions in MS patients were associated with a higher risk of RLS (odds ratio 3.7, 95% confidence interval 1.1–13.5). Conclusion: RLS was strongly associated with MS, with a significantly higher risk in patients presenting spinal cord lesions.
Introduction Restless legs syndrome (RLS) is a sensorimotor disorder characterized by a distressing urge to move the limbs [1]. Prevalence in the general population ranges between 2.5% and 18.3% [2] but a higher prevalence (from 12.1% to 57.5%) and increased risk have been observed amongst patients with multiple sclerosis (MS) [3]. However, to date, case control studies conducted to investigate the association between RLS and MS have often reported contrasting results, limiting conclusions about the association of these two conditions and a possible pathogenic explanation [4,5]. To determine RLS prevalence in MS patients and the influence of MS characteristics, including the role of cervical cord demyelination and of MS disease modifying therapies, on RLS, a population-based case control study was carried out in the city of Catania, Sicily. Correspondence: M. Zappia, Section of Neurosciences, Department GF Ingrassia, University of Catania, via Santa Sofia 78, Catania 95123, Italy (tel.: +0039 095 3782783; fax: +0039 39 95 3782900; e-mail: [email protected]). *These authors contributed equally to this work.
© 2014 The Author(s) European Journal of Neurology © 2014 EFNS
Methods Study population
Multiple sclerosis patients were randomly selected from a previously defined cohort of 367 patients diagnosed according to Poser’s criteria [6] in the period between the 1 January 1975 and 31 December 2004 in the city of Catania, Sicily [7]. Age and sex group matched controls were enrolled from the general population using a multistage sampling method on the General Practitioners cabinet list [8]. Exclusion criteria were applied: Mini Mental State Examination score 10), N (%)
Multivariate analysis
MS cases
Controls
OR
95% CI
P value
OR
95% CI
P value
152 46.0 10.8
431 47.0 14.9
1.0
0.9–1.1
0.4
1.0
0.9–1.0
0.3
55 (36.2) 97 (63.8) 31.7 10.4 14.3 9.3 2.8 2.4 22 (14.5) N = 22 3 (13.6) 12 (54.5) 4 (18.3) 3 (13.6) 9 (5.9)
139 (32.3) 292 (67.7) / / / 26 (6.0) N = 26 8 (30.8) 15 (57.7) 3 (11.5) 0 (0.0) 12 (2.8)
1.0 0.8 / / / 2.6
/ 0.6–1.2 / / / 1.4–4.8
0.4 / / / 0.002
1.0 0.8 / / / 2.7
/ 0.5–1.2 / / / 1.4–5.0
0.3 / / / 0.001
1.0 2.6 2.1 2.3 2.2
/ 0.5–11.3 0.3–11.4 1.4–12.0 0.9–5.3
0.04
/
/
/
0.08
2.2
0.9–5.4
0.09
CI, confidence interval; EDSS, Expanded Disability Status Scale; ESS, Epworth Sleepiness Scale; F, female; IRLS-RS, International Restless Legs Syndrome Rating Scale; M, male; MS, multiple sclerosis; N, number; OR, odds ratio; RLS, restless legs syndrome; SD, standard deviation.
© 2014 The Author(s) European Journal of Neurology © 2014 EFNS
Restless legs syndrome and multiple sclerosis
Table 2 Characteristics of 152 patients with MS with and without RLS No. of cases, N (%) Age (mean SD) Gender, N (%) M F Age at onset (mean SD) MS duration (mean SD) MS clinical course, N (%) RR SP PP EDSS score (mean SD) MRI cervical cord lesions Absent Present Number of cervical lesions (mean SD) MS therapies, N (%) Immunosuppressant Immunomodulator Monoclonal antibody None ESS, N (%) GNDS (mean SD) AI (mean SD)
MS/RLS+
MS/RLS
OR
95% CI
22 (14.5) 46.9 9.9
130 (85.5) 45.9 11.0
1.0
0.9–1.1
0.7
7 (31.8) 15 (68.2) 31.4 12.4 15.5 10.6
48 (36.9) 82 (63.1) 31.7 10.1 14.1 9.1
1.0 1.2 1.0 1.0
/ 0.5–3.3 0.9–1.1 0.9–1.1
0.6 0.9 0.5
18 (81.8) 4 (18.2) 0 (0.0) 2.8 2.3 (19/22) 3 (15.8) 16 (84.2) 2.1 1.8
103 (79.2) 20 (15.4) 7 (5.4) 2.8 2.4 (114/130) 47 (41.2) 67 (58.8) 1.2 1.6
1.0 1.1 / 1.0
/ 0.3–3.7 /
1.0 3.7 1.3
/ 1.1–13.5 1.1–1.6
5 (22.7) 13 (59.1) 0 (0.0) 4 (18.2) 2 (9.1) 8.1 7.5 1.5 2.2
20 (15.4) 72 (55.4) 2 (1.5) 36 (27.7) 7 (5.4) 6.8 7.1 1.6 2.6
2.5 1.9 / 1.0 1.7 1.0 1.0
0.6–10.3 0.6–6.2 / / 0.3–9.0 0.9–1.1 0.9–1.1
3
P value
0.5 0.9
0.04 0.05
0.2 0.3
0.5 0.5 0.9
AI, ambulatory index; CI, confidence interval; EDSS, Expanded Disability Status Scale; ESS, Epworth Sleepiness Scale; F, female; GNDS, Guy’s Neurological Disability Scale; M, male; MS, multiple sclerosis; N, number; OR, odds ratio; PP, primary progressive; RLS, restless legs syndrome; RR, relapsing remitting; SD, standard deviation; SP, secondary progressive.
Discussion Multiple sclerosis patients presented a significantly higher prevalence of RLS (14.5%) compared with healthy controls (6.0%), corresponding to an almost threefold increased risk (OR 2.7, 95% CI 1.4–5.0) of developing RLS. Our prevalence and OR were similar to those reported in previous surveys [4,5] and in a recent meta-analysis [3]. The presence of cervical cord damage was an important risk factor for RLS (OR 3.7, 95% CI 1.1–13.5), significantly associated with the number of lesions (OR 1.3, 95% CI 1.1–1.6). These results could be related to the hypothesized spinal pathogenesis of RLS in MS that attributes the occurrence of the symptoms to an interruption of descending and ascending hypothalamic-spinal pathways [11]. In this context, the observed increased RLS risk linked to the presence of more lesions could be attributed to an increased chance of damaging pathways involved in RLS aetiology. Moreover the symptomatic nature of RLS in MS subjects could be supported by the subsequent onset of RLS and by the higher severity of RLS symptoms reported amongst MS/RLS+ compared with CTR/RLS+. Except for cervical cord lesions, clinical characteristics and MS therapies did not appear to be related to the occurrence of RLS amongst MS patients. © 2014 The Author(s) European Journal of Neurology © 2014 EFNS
In conclusion, due to the cross-sectional nature of the study, our results should be interpreted with caution. Nevertheless, some peculiar findings regarding the possible role of spinal cord lesions in the pathogenesis of RLS in MS are highlighted.
Acknowledgements We would like to thank the SIMG General Practitioners Dr Salvatore Amato, Dr Giovanni Cappello, Dr Marco Ciancio, Dr Carmelo Di Gregorio, Dr Maurizio D’Urso, Dr Melchiorre Fidelbo, Dr Giovanni Marotta, Dr Concetta Persano, Dr Valeria Polizzi, Dr Gaetano Profeta, Dr Antonino Rizzo, Dr Anna Salvo, Dr Giuseppa Spada and Dr Guglielmo Travaglianti for their cooperation in the study. There is no funding.
Disclosure of conflicts of interest The authors declare no financial or other conflicts of interest.
References 1. Earley CJ. Restless legs syndrome. N Engl J Med 2003; 348: 2103–2109.
4
E. Bruno et al.
2. Hening W, Walter AS, Allen RP, et al. Impact, diagnosis and treatment of restless legs syndrome in a primary care population: the REST (RLS epidemiology, symptoms and treatment) primary care study. Sleep Med 2004; 5: 237–246. 3. Sch€ urks M, Bussfeld P. Multiple sclerosis and restless legs syndrome: a systematic review and meta-analysis. Eur J Neurol 2013; 20: 605–615. 4. Manconi M, Rocca MA, Ferini-Strambi L, et al. Restless legs syndrome is a common finding in multiple sclerosis and correlates with cervical cord damage. Mult Scler 2008; 14: 86–93. 5. Deriu M, Cossu G, Molari A, et al. Restless legs syndrome in multiple sclerosis: a case control study. Mov Disord 2009; 24: 697–701. 6. Poser CM, Party DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13: 227–231.
7. Nicoletti A, Patti F, Lo Fermo S, et al. Increasing frequency of multiple sclerosis in Catania, Sicily: a 30-year survey. Mult Scler 2011; 17: 273–280. 8. Patti F, Nicoletti A, Leone C, et al. Multiple sclerosis and CCSVI: a population-based case control study. PLoS One 2012; 7: e41227. 9. Allen RP, Picchietti D, Hening WA, et al. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the Restless Legs Syndrome Diagnosis and Epidemiology workshop at the National Institutes of Health. Sleep Med 2003; 4: 101– 119. 10. Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep 1991; 14: 540– 545. 11. Clemens S, Rye D, Hochman S. Restless legs syndrome: revisiting the dopamine hypothesis from the spinal cord perspective. Neurology 2006; 67: 125–130.
© 2014 The Author(s) European Journal of Neurology © 2014 EFNS
