CLINICAL LUNG AND HEART/LUNG TRANSPLANTATION
Restless Legs Syndrome in Lung Transplant Recipients Omar A. Minai, MD, FCCP,a Joseph A. Golish, MD, FCCP,a,b Jose C. Yataco, MD,a Marie M. Budev, MD,a Holli Blazey, RN,a and Carmen Giannini, RNa Background: Given the increased incidence of steroid-induced diabetes and drug-induced anemia, renal dysfunction and neuropathy, we believed that lung transplant recipients would be at an increased risk of developing restless legs syndrome (RLS). We performed a cross-sectional, observational study to determine the prevalence and characteristics of RLS in this population. Methods: Patients filled out two questionnaires during a routine visit: (1) a diagnostic tool for RLS, based on the core clinical features; and (2) a 10-question rating scale used to assess severity. Data were obtained by medical record review with regard to demographics, lung transplant characteristics and known risk factors for RLS. Results: Forty-two lung transplant recipients (age 46.6 ⫾ 15.4 years [mean ⫾ SD]; 24 women, 18 men) without a family history of RLS were recruited. RLS was found in 47.6% (20 of 42) of the patients and 80% had moderate or severe RLS. Seventy-five percent of those with RLS were women ( p ⫽ 0.03). RLS patients had a serum calcium level that was higher than those without RLS ( p ⫽ 0.05) and were more likely to be recipient ( p ⫽ 0.02) or donor positive ( p ⫽ 0.07) for cytomegalovirus (CMV). All 4 hypothyroid patients on replacement therapy were in the RLS group. The prevalence of diabetes mellitus and chronic renal failure were not significantly different between the RLS and non-RLS groups. Conclusions: There was a very high prevalence of RLS in our lung transplant population and most patients had moderate or severe symptoms. RLS patients were more likely to be women, donor or recipient positive for CMV, hypothyroid, and to have an elevated serum calcium level. J Heart Lung Transplant 2007;26:24 –9. Copyright © 2007 by the International Society for Heart and Lung Transplantation.
Restless legs syndrome (RLS) is a neurologic disorder with a prevalence of between 3% and 19% in the general population.1– 4 RLS usually involves the lower extremities and is characterized by a “crawling” sensation at rest, relieved by movement.1 Sub-cortical central nervous system dysfunction, mainly via the dopaminergic pathway, has been suggested as the mechanism responsible for the development of RLS.4 Symptoms of RLS may begin in childhood or adulthood, but the prevalence of RLS increases with age and appears to be higher among women than men.5–7 The diagnosis of RLS is a clinical one3,4,8,9 and polysomnography should be performed if there is clinical suspicion of sleep apnea or if sleep is still disrupted after treatment of RLS. Multiple known risk factors for RLS include uremia, pregnancy, iron deficiency,7,10 peripheral neuropathy, From the aDepartment of Pulmonary, Allergy, and Critical Care, and b Sleep Disorders Center, Cleveland Clinic, Cleveland, Ohio. Submitted April 25, 2006; revised October 3, 2006; accepted October 19, 2006. Reprint requests: Omar A. Minai, MD, Department of Pulmonary, Allergy, and Critical Care Medicine, Cleveland Clinic, 9500 Euclid Avenue, A90, Cleveland, OH 44195-5038. Tel: 216-445-2610. Fax: 216-445-1878. E-mail: [email protected]
Copyright © 2007 by the International Society for Heart and Lung Transplantation. 1053-2498/07/$–see front matter. doi:10.1016/ j.healun.2006.10.014
hyper- and hypothyroidism, folic acid deficiency and electrolyte abnormalities, among others.3,4,11 There are very few epidemiologic data on RLS among solid-organ transplant recipients. In a cross-sectional study of 45 heart transplant recipients, 45% of patients with periodic limb movements were found to have RLS.12 Given the increased incidence of steroid-induced diabetes and drug-induced anemia, renal dysfunction and neuropathy, we suspected that lung transplant recipients would be at an increased risk of developing RLS. We performed a cross-sectional, observational study to determine the prevalence and characteristics of RLS in the lung transplant recipient population followed at our institution. METHODS The protocol was approved by the institutional review board at the Cleveland Clinic. Lung transplant recipients who attended the outpatient lung transplant clinic between February 2005 and June 2005 were recruited for the study. A total of 42 patients agreed to participate in the study. All of these patients were routinely followed by the lung transplant team and were clinically stable on standard therapy for lung transplantation, including immunosuppressants and prophylactic medications, as previously described.13
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The patients were asked to fill out two questionnaires during a routine visit to the clinic. The first questionnaire was the diagnostic tool for RLS, based on the core clinical features of the disorder, which was found to have a sensitivity of 82.3% and a specificity of 89.9% in an epidemiologic study.3,14 The second questionnaire was a 10-question rating scale used to assess the severity of RLS. The score ranged from 0 to 40 points with 0 to 10 indicating mild, 11 to 20 indicating moderate, 21 to 30 indicating severe and 31 to 40 indicating very severe RLS. This rating scale has been validated and published by the International RLS Study Group (IRLSSG).9 Patient medical records were reviewed to obtain demographic data; reason and date of lung transplantation; weight; renal function; presence of diabetes or anemia; information indicating iron, folate or vitamin B12 deficiency; acute rejection episodes; and immunosuppressant regimen. No specific examination or laboratory testing was performed for the purposes of the study to look for potential risk factors such as iron deficiency, neuropathy, etc. Patients found to have RLS were compared to those without RLS (non-RLS) to determine risk factors associated with the prevalence of RLS in this population. In this analysis, Wilcoxon’s test was used when comparing groups for continuous measures, and Fisher’s exact test or Pearson’s chi-square test was used when comparing groups for categoric measures. RESULTS A total of 42 lung transplant recipients were recruited in this study between February 2005 and June 2005. Subjects were 46.6 ⫾ 15.4 (mean ⫾ SD) years of age (Table 1) and there were 24 (57%) women and 18 (43%) men. Ethnic breakdown was 40 (95%) whites and 2 (5%) blacks. The reasons for lung transplantation in the overall group were emphysema (N ⫽ 19; 45%), cystic fibrosis (N ⫽ 11; 26%), lung fibrosis (N ⫽ 6; 14%) and others (N ⫽ 6; 14%). In the overall group, time since lung transplantation was 149 ⫾ 143 days, most recent forced expiratory in 1 second (FEV1) was 58 ⫾ 19 percent predicted, and only 1 patient was on hemodialysis for renal failure. Electrolytes, hemoglobin, thyroid-stimulating hormone (TSH), erythrocyte sedimentation rate (ESR) and IgG levels were normal in the overall group. Four patients were hypothyroid and were receiving replacement therapy. None of the patients were known to have a family history of RLS. RLS was found in 20 of 42 lung transplant recipients, resulting in a prevalence of 47.6%. Among the patients diagnosed with RLS, 4 (20%) had mild RLS, 11 (55%) had moderate RLS, 5 (25%) had severe RLS and 0 had very severe RLS according to the IRLSSG rating scale. A comparison of RLS and non-RLS groups for continuous and categoric variables is shown in Tables 2 and 3,
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Table 1. Overall Descriptive Summary of the Study Population Factor Age, years (mean ⫾ SD) Gender Male Female BMI, kg/m2 (mean ⫾ SD) Reason for lung transplant, N (%) COPD CF IPF Type of lung transplant, N (%) Single Double CMV status, N (%) D⫹ R⫹ Time since transplant, days (mean ⫾ SD) Most recent FEV1 Percent predicted (mean ⫾ SD) Hb, g/dl (mean ⫾ SD) Diabetes mellitis, N (%) Potassium, mmol/liter (mean ⫾ SD) Magnesium, mmol/liter (mean ⫾ SD) Calcium, mmol/liter (mean ⫾ SD) Serum creatinine, mg/dl (mean ⫾ SD) Creatinine clearance, ml/min TSH IgG level Prednisone, N (%) Azathioprine, N (%)
Value 46.62 ⫾ 15.36 18 (43) 24 (57) 25.05 ⫾ 4.21 19 (45) 11 (26) 6 (14) 22 (52) 20 (48) 25 (61) 17 (41) 148.82 ⫾ 143.27 57.98 ⫾ 19.5 11.80 ⫾ 1.44 19 (45) 4.34 ⫾ 0.50 1.86 ⫾ 0.27 9.47 ⫾ 0.97 1.36 ⫾ 0.53 69.07 ⫾ 30.64 2.12 ⫾ 1.44 744.26 ⫾ 239.24 40 (95) 17 (40)
BMI, body mass index; CMV, cytomegalovirus; FEV1, forced expiratory volume in 1 second; Hb, hemoglobin; TSH, thyroid-stimulating hormone; IgG, immunoglobulin G; COPD, chronic obstructive pulmonary disease; CF, cardiac failure; IPF, idiopathic pulmonary fibrosis.
respectively. There was no significant difference in age or race between the RLS and non-RLS groups. Of those with RLS (N ⫽ 20), 4 (20%) were ⬎60 years old and 11 (55%) were ⬎50 years old, as opposed to 5 (23%) and 12 (55%) of 22, respectively, in the non-RLS group. There were only 2 patients ⬍20 years of age and both were in the RLS group. The RLS group had a higher serum calcium level than the non-RLS group, showing a trend toward statistical significance ( p ⫽ 0.05; Table 2). There was a significant female preponderance in the RLS group and 75% of those with RLS were women ( p ⫽ 0.03; Table 3). Among patients with RLS, 9 were CMV donor and recipient positive, compared with only 2 patients without RLS, and only 2 patients were CMV donor and recipient negative, compared with 8 of those without RLS (Table 3). Because CMV donor- and recipientnegative patients do not receive CMV prophylaxis, patients with RLS were more likely to be exposed to ganciclovir than patients without RLS. Those with RLS were significantly more likely to be CMV recipient
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Table 2. Comparison of RLS and Non-RLS Groups for Several Continuous Measures RLS Factor Age, years BMI, kg/m2 Time since lung transplant, days Most recent FEV1, percent predicted Hb, g/dl Calcium, mmol/liter Magnesium, mmol/liter Potassium, mmol/liter TSH CEA ESR Creatinine, mg/dl Creatinine clearance, ml/min
N 20 20 20 20 20 20 20 20 18 17 16 20 20
Median (q1, q3) 52 (34, 57.5) 25.9 (21.3, 29) 90 (75.5, 188) 52 (43, 65.5) 11.2 (10.8, 12.7) 9.9 (9.3, 10.2) 1.8 (1.6, 2.1) 4.5 (4.1, 4.6) 2.1 (1.2, 3.5) 3.5 (2.7, 4.0) 34.5 (10.5, 57) 1.3 (1.1, 1.4) 67.4 (50.7, 80.2)
N 22 22 22 22 22 22 22 22 19 19 18 22 22
Median (q1, q3) 53.5 (35, 60) 25.1 (21.1, 27.2) 96.5 (57, 207) 57.5 (50, 69) 12.2 (10.6, 13.1) 9.5 (8.8, 9.9) 1.9 (1.8, 1.9) 4.3 (3.8, 4.6) 1.6 (1.0, 2.1) 4.5 (3.9, 7.6) 36 (22, 44) 1.2 (1.0, 1.8) 65.8 (46.5, 82.6)
p -valuea 0.88 0.40 0.66 0.27 0.63 0.05 0.89 0.93 0.34 0.06 0.76 0.94 0.95
q1, first quartile; q3, third quartile; BMI, body mass index; TSH, thyroid-stimulating hormone; CEA, carcinoembryonic antigen; ESR, erythrocyte sedimentation rate. a Comparison done using Wilcoxon’s test. p ⬍ 0.05 considered statistically significant.
positive ( p ⫽ 0.02) and there was a trend toward positive CMV donor status in the RLS group ( p ⫽ 0.07; Table 3). There was no level of IgG that predicted a significantly increased likelihood of having RLS. Fourteen of 20 (70%) RLS and non-RLS patients had a history
of either Grade A1 or ⬎A1 acute transplant rejection. These data were not available for 2 non-RLS patients. All 4 hypothyroid patients on replacement therapy were in the RLS group. There was no other clinically or statistically significant difference between the two
Table 3. Comparison of RLS and Non-RLS Groups for Several Categoric Measures RLS Factor Level Gender Male Female Type of lung transplant Single Double Reason for lung transplant COPD Cystic fibrosis IPF Silicosis CMV donor status Negative Positive CMV recipient status Negative Positive Diabetes mellitis Absent Present Dialysis No Yes
19 11 6 2
10 4 2 1
50.0 20.0 10.0 5.0
9 7 4 1
40.9 31.8 18.2 4.6
p -valuea 0.03
0.99a 41 1
COPD, chronic obstructive pulmonary disease; IPF, idiopathic pulmonary fibrosis; CMV, cytomegalovirus. a Using Fisher’s exact test, otherwise, Pearson’s chi-square test was used.
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groups with regard to: reason for lung transplantation; single- vs double-lung transplant; time since transplantation; diabetic status; immunosuppressive (or other) medications used; or laboratory investigations, such as TSH, carcinoembryonic antigen, ESR, hemoglobin, electrolytes, serum creatinine or creatinine clearance. Data were also analyzed for known risk factors for RLS. Diabetes mellitus had a prevalence of 45% in the overall group and was more prevalent in those with RLS, but this did not reach statistical significance ( p ⫽ 0.23; Table 3). Nine of 20 patients with RLS were on insulin as opposed to only 5 of 22 non-RLS patients, but this was not statistically significant ( p ⫽ 0.13). Chronic renal failure, defined for the present analysis as a creatinine clearance ⬍50 ml/hour, was found in 43% of patients in the overall group, but had a similar distribution in the RLS and non-RLS groups (45% vs 41%). One patient with RLS and 3 without RLS were known to have iron deficiency and were receiving oral iron replacement therapy. Anti-nuclear antibody levels were checked in all patients and 4 of 20 patients with RLS were anti-nuclear antibody positive as opposed to 2 of 22 of those without RLS. Other possible risk factors, vitamin B12 or folic acid deficiency, were not present in any of the lung transplant recipients as a result of routine vitamin and folic acid supplementation and close laboratory monitoring of patients. DISCUSSION This is the first study of transplant patients that has evaluated the association between RLS and factors and complications associated with transplantation. In this pilot study of RLS in lung transplant recipients followed at our institution, we found a much higher prevalence of RLS (47.6%) compared with the 3% to 19% prevalence of RLS in the general population reported in prior studies.1– 4 This prevalence is similar to that found in a study of heart transplant recipients that reported a prevalence of 45% among patients with periodic limb movements.12 Those investigators found no association between RLS and anemia, electrolyte imbalance or renal failure. Unfortunately, the study included very few patients with RLS and did not look more deeply into factors associated with the transplant population and their possible linkage with RLS. Previous studies1,6,7,15 have indicated that, although RLS may begin in childhood or adulthood, its prevalence increases significantly with age. In our group, there was no significant difference in age between the RLS and non-RLS groups, yet 55% of patients with RLS were ⬎50 years of age. Population-based studies have indicated a significant female preponderance.6,16 Similar to these studies, our study also indicated a significantly higher prevalence of RLS in female patients. End-stage renal disease has been identified as a signifi-
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cant risk factor for RLS. In a prospective study, the long-term course of RLS in 11 hemodialysis patients was investigated. In all patients, RLS symptoms disappeared after kidney transplantation within 1 to 21 days after transplantation, emphasizing the importance of uremia in the pathogenesis of secondary RLS.17 In a separate study, Molnar et al18 found a significantly lower prevalence of RLS in kidney-transplanted patients compared with patients maintained on dialysis. Among our group of patients renal failure was no more common in those with RLS versus those without RLS. The reason for this may be sampling bias, because, although our study included patients with renal dysfunction, only 1 patient was on hemodialysis. Diabetes mellitus and chronic renal failure were very prevalent in the lung transplant recipients in this study but had a similar distribution in patients with or without RLS. Other possible risk factors, such as iron, vitamin B12 and folic acid deficiency, were not seen in our patients. Electrolyte abnormalities such as magnesium deficiency have been associated with an increased prevalence of RLS.1 In our study there was no significant difference in serum magnesium levels between those with and without RLS. We did find that patients with RLS had higher serum calcium levels, although this difference was not statistically significant. A case of RLS occurring in a patient with primary hyperparathyroidism and hypercalcemia has been reported.19 The patient’s serum calcium levels were only mildly elevated (between 10.6 and 11.1 mg/dl). Symptoms in that case resolved completely after parathyroidectomy and resolution of hypercalcemia. The pathophysiologic significance of this finding, if any, remains unclear, although it may underlie some of the “idiopathic” cases of RLS. We recommend that serum calcium levels be routinely performed as part of the work-up of RLS so that a potentially treatable metabolic disturbance causing RLS can be detected. All 4 hypothyroid patients receiving replacement therapy were in the RLS group. Patients with RLS are believed to have impairment of the dopaminergic pathway,4 and the hypothyroid state has been associated with abnormalities in catecholamine levels20 and with dopaminergic dysfunction in animal models.21 A higher incidence of acquired hypothyroidism has been reported previously in female patients with RLS22 and 2 of our patients had acquired hypothyroidism (1 after sub-total thyroidectomy and 1 after I-133 therapy for hyperthyroidism). One study of 146 consecutive patients with thyroid disorders,23 using the IRLSSG criteria, found no significant difference in the prevalence of RLS in patients with thyroid disorders compared with euthyroid controls. They did find a higher (8.2%; 12 of 146) prevalence of RLS-like symptoms compared with the controls (0.9%; 4 of 434; p ⬍ 0.0001).
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We also found an increased prevalence of RLS in those who were donor and/or recipient positive for CMV. Again, the significance of this finding remains to be defined through further study. A positive CMV status is associated with neuropathy,24,25 but there are no reports suggesting a link between CMV and RLS. Some reports suggested that the prevalence of RLS may be higher among patients with neuropathy,11,26 yet other studies have failed to show such an association.27,28 Because this was an observational study, neurologic examination and testing was not performed on our patients and none had a known history of peripheral neuropathy. Hypogammaglobulinemia has been associated with peripheral neuropathies and IgG levels were routinely checked in all our patients as part of their transplant follow-up. There was no significant difference in IgG levels between RLS and non-RLS groups in our study. Nineteen of 20 RLS patients and 20 of 22 non-RLS patients had IgG levels ⬎400 IU. A number of medications are believed to either induce or exacerbate the symptoms of RLS.29,30 These include selective serotonin re-uptake inhibitors, tricyclic anti-depressants, nonopioid analgesics, lithium, beta-blockers, histamine-2 blockers and ethanol. There was no significant increase in the use of these medications in the RLS group compared with the non-RLS group. There was also no significant difference between these groups with regard to medications used to treat RLS, such as clonazepam, gabapentin, carbidopa–levodopa or pergolide. Because of the sensory symptoms or associated periodic limb movements of sleep, RLS may have profound negative effects on sleep.12,31 Eighty percent of the patients with RLS in our study had moderate to severe symptoms based on the IRLSSG. This indicates that most patients had significantly debilitating symptoms as a result of their RLS, which would likely have resulted in sleep disruption, although sleep studies were not done to document this as part of this observational pilot study. In view of the efficacy of medical therapy, it is also possible that medical intervention for RLS in these patients may result in improvement in their sleep quality. Insomnia or fatigue may be the initial symptoms reported. Reduced concentration and memory, decreased motivation and drive and depression and anxiety may also occur.32 The limitations of our study include its relatively small size and that it was questionnaire-based and physical examination and laboratory testing specifically targeted to RLS risk factors was not performed. In conclusion, there was a very high prevalence of RLS in our lung transplant population and most patients had moderate or severe symptoms. RLS patients were more likely to be women, CMV donor or recipient positive and hypothyroid, and to have an elevated serum calcium level. More awareness of the higher
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prevalence of RLS in lung transplant recipients is needed because this disorder can significantly affect the quality of life of this population. Careful selection of therapy for RLS is necessary due to the potential interactions with the numerous medications taken by lung transplant recipients. Further studies with larger populations are needed to identify risk factors and the impact of RLS therapy in lung transplant recipients. REFERENCES 1. Avecillas J, Golish JA, Giannini C, Yataco J. Restless legs syndrome: keys to recognition and treatment. Cleve Clin J Med 2005;72:769 – 87. 2. Allen RP, Earley CJ. Defining the phenotype of the restless legs syndrome (RLS) using age-of-symptom-onset. Sleep Med 2000;1: 11–9. 3. Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi J. 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;4:101–19. 4. Earley CJ. Clinical practice. Restless legs syndrome. N Engl J Med 2003;348:2103–9. 5. Berger K, Luedemann J, Trenkwalder C, John U, Kessler C. Sex and the risk of restless legs syndrome in the general population. Arch Intern Med 2004;164:196 –202. 6. Ohayon MM, Roth T. Prevalence of restless legs syndrome and periodic limb movement disorder in the general population. J Psychosom Res 2002;53:547–54. 7. Phillips B, Young T, Finn L, et al. Epidemiology of restless legs symptoms in adults. Arch Intern Med 2000;160:2137– 41. 8. Hening WA, Allen RP, Thanner S, et al. The Johns Hopkins telephone diagnostic interview for the restless legs syndrome: preliminary investigation for validation in a multi-center patient and control population. Sleep Med 2003;4:137– 41. 9. Walters AS, LeBrocq C, Dhar A, et al. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med 2003;4:121–32. 10. Ulfberg J, Nystrom B, Carter N, Edling C. Prevalence of restless legs syndrome among men aged 18 to 64 years: an association with somatic disease and neuropsychiatric symptoms. Mov Disord 2001;16:1159 – 63. 11. Rutkove SB, Matheson JK, Logigian EL. Restless legs syndrome in patients with polyneuropathy. Muscle Nerve 1996;19:670 –2. 12. Javaheri S, Abraham WT, Brown C, Nishiyama H, Giesting R, Wagoner LE. Prevalence of obstructive sleep apnoea and periodic limb movement in 45 subjects with heart transplantation. Eur Heart J 2004;25:260 – 6. 13. Lee P, Minai OA, Mehta AC, DeCamp MM, Murthy S. Pulmonary nodules in lung transplant recipients: etiology and outcome. Chest 2004;125:165–72. 14. Nichols DA, Kushida CA, Allen RP, et al. Validation of RLS diagnostic questions in a primary care practice. Sleep 2003;26:A346. 15. Egan D, O’Dubhghaill C, McNamee S, Mulkerrin E, O’Keefe ST. A community study of the prevalence of restless legs syndrome. Ir Med J 2003;96:153. 16. Ulfberg J, Nystrom B, Carter N, Edling C. Restless legs syndrome among working-aged women. Eur Neurol 2001;46:17–9. 17. Winkelman JW, Chertow GM, Lazarus JM. Restless legs syndrome in end-stage renal disease. Am J Kidney Dis 1996;28:372– 8. 18. Molnar MZ, Novak M, Ambrus C, et al. Restless legs syndrome in patients after renal transplantation. Am J Kidney Dis 2005;45: 388 –96.
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19. Lim LL, Dinner D, Tham KW, Siraj E, Shields R Jr. Restless legs syndrome associated with primary hyperparathyroidism. Sleep Med 2005;6:283–5. 20. Mano T, Sakamoto H, Fujita K, et al. Effects of thyroid hormone on catecholamine and its metabolite concentrations in rat cardiac muscle and cerebral cortex. Thyroid 1998;8:353– 8. 21. Kincaid AE. Spontaneous circling behavior and dopamine neuron loss in a genetically hypothyroid mouse. Neuroscience 2001;105: 891– 8. 22. Banno K, Delaive K, Walid R, Kryger MH. Restless legs syndrome in 218 patients: associated disorders. Sleep Med 2000;1:221–9. 23. Tan EK, Ho SC, Eng P, Loh LM, et al. Restless legs symptoms in thyroid disorders. Parkinsonism Rel Disord 2004;10:149 –51. 24. Kolson DL, Gonzalez-Scarano F. HIV-associated neuropathies: role of HIV-1, CMV, and other viruses. J Periph Nerv Syst 2001;6:2–7. 25. Anders HJ, Goebel FD. Neurological manifestations of cytomegalovirus infection in the acquired immunodeficiency syndrome. Int J STD AIDS 1999;10:151–9.
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26. Ianaccone S, Zucconi M, Marchettini P, et al. Evidence of peripheral axonal neuropathy in primary restless legs syndrome. Mov Disord 1995;10:2–9. 27. Olsen TS, Hogenhaven H, Thage O. Epilepsy after stroke. Neurology 1987;37:1209 –11. 28. Mohr JP, Caplan LR, Melski JW, et al. The Harvard Cooperative Stroke Registry: a prospective registry. Neurology 1978;28: 754 – 62. 29. Kraus T, Schuld A, Pollmacher T. Periodic leg movements in sleep and restless legs syndrome probably caused by olanzapine. J Clin Psychopharmacol 1999;19:478 –9. 30. Hargrave R, Beckley DJ. Restless legs syndrome exacerbated by sertraline. Psychosomatics 1998;39:177– 8. 31. Rama AN, Kushida CA. Restless legs syndrome and periodic limb movement disorder. Med Clin N Am 2004;88:653– 67. 32. Coleman RM, Pollak CP, Weitzman ED. Periodic movements in sleep (nocturnal myoclonus): relation to sleep disorders. Ann Neurol 1980;8:416 –21.