- Email: [email protected]
Effects of STN DBS for Parkinson’s disease on restless legs syndrome and other sleep-related measures
Parkinsonism and Related Disorders 17 (2011) 208e211
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Short communication
Effects of STN DBS for Parkinson’s disease on restless legs syndrome and other sleep-related measuresq L.M. Chahine*, A. Ahmed, Z. Sun Cleveland Clinic, Cleveland, OH, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 29 July 2010 Received in revised form 19 October 2010 Accepted 23 November 2010
Restless legs syndrome (RLS) and other sleep abnormalities are common in Parkinson’s Disease (PD). We prospectively examined sleep measures in PD patients undergoing subthalamic nucleus (STN) deep brain stimulation (DBS). An RLS questionnaire, Epworth Sleepiness Scale (ESS), and Parkinson’s Disease Sleep Scale (PDSS) were administered through telephone interviews preoperatively and postoperatively. Seventeen patients were included. Mean preoperative and 4 weeks postoperative ESS scores were 11.6 and 6.4 respectively (p < 0.001) and PDSS scores were 94.2 and 122.9 respectively (p < 0.001). The improvement was sustained at 6 months. Six patients were diagnosed with RLS preoperatively. Mean preoperative International Restless Legs Syndrome Study Group rating scale score was 23.0. Mean 4 week and 6 month postoperative IRLSSG rating scale scores were 14.8 and 13.8 respectively, significantly improved compared to preoperative scores (p ¼ 0.027 and p ¼ 0.037 respectively). No patients developed new-onset RLS postoperatively. STN DBS improves daytime sleepiness, sleep quality, and RLS. Ó 2010 Elsevier Ltd. All rights reserved.
Keywords: Restless legs syndrome Parkinson’s disease Sleep Deep brain stimulation Subthalamic nucleus
1. Introduction Abnormalities in sleep occur in 80% of patients with Parkinson’s Disease (PD) [1]. Restless legs syndrome (RLS) is more common in PD patients than the general population [2]. Several sleep parameters improve in PD patients after DBS [3e5], but there are limited and conflicting data on the effects of DBS on RLS [3,6,7] with some studies showing improvement [6] and others showing emergence of RLS postoperatively [7]. The objectives of this study were to prospectively assess subjective changes in the quality of sleep, extent of daytime sleepiness, and RLS symptoms in PD patients early and after several months of STN DBS and to determine whether some patients with PD who do not have RLS pre-DBS develop RLS postoperatively. 2. Methods This was a longitudinal cohort study conducted from November 2008 to April 2010. All consecutive patients at our institution undergoing first-time STN DBS were approached for participation in the study. Data were collected through 6 telephone interviews. The paradigm of questions for epidemiologic studies of RLS proposed by the International Restless Legs Syndrome Study Group (IRLSSG) [8] were used to synthesize the questionnaire used to identify
q The review of this paper was entirely handled by an Associate Editor, J. Carr. * Corresponding author. S90, Department of Neurology, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA. Tel.: þ1 216 444 2000; fax: þ1 216 444 0230. E-mail address: [email protected] (L.M. Chahine). 1353-8020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2010.11.017
RLS patients (see Part 1 of the E-Supplement). Estimates of the sensitivity of the four essential diagnostic criteria for RLS vary from 82% to 97% [9]. In the general population, the false-positive rate for RLS diagnosis may be more than 10% when only the four essential criteria are used during interview [9], and these criteria have not been specifically validated in the diagnosis of RLS in PD patients, in whom distinguishing RLS from PD symptomatology may be challenging [10,11]. Therefore, additional questions, by means of a structured interview, were asked to ensure exclusion of patients with RLS mimickers (specifically, to exclude nocturnal leg cramps, arthritic pain, neuropathic pain, painful legs and moving toes, or vascular or neurogenic claudication; see Part 2 of the E-Supplement). The relation of RLS symptoms to motor fluctuations was also probed. Further questions tailored to specific patient symptoms were asked to confirm the diagnosis and exclude other conditions. Patients diagnosed with PD and RLS were administered the IRLSSG rating scale [12]. All patients were administered the Epworth Sleepiness Scale (ESS) [13] (in which higher scores indicate greater daytime sleepiness) and Parkinson’s Disease Sleep Scale (PDSS) [1] (in which higher scores indicate better sleep). Study participants were contacted 2 weeks preoperatively then at 1 week, 2 weeks, approximately 4 weeks (7 days after 1st programming), 3 months, and 6 months following surgery for readministration of the questionnaire for RLS diagnosis, the IRLSSG rating scale if RLS was present, ESS, and PDSS. PD patients with bilateral staged procedures were contacted 2 weeks prior to their first DBS surgery and after their second surgery they then had similar time points as patients with unilateral or bilateral simultaneous procedures. Other data collected for all study participants through medical record review included: demographics, year of symptom onset, family history of RLS, medications preoperatively and at each postoperative time point, with dopaminergic medication converted into levodopa equivalents (LE) (LE ¼ levodopa þ 0.75 dose of levodopa CR þ 1.3 dose of levodopa/entacapone þ 100 dose of pramipexole þ 20 dose of ropirinole), preoperative off-medication motor UPDRS score, and off-medication, on-stimulation motor UPDRS scores at 4 weeks postoperatively. All interviews were carried out with the adequate understanding and consent of the subjects involved. This study was approved by the institutional review board at our institution.
L.M. Chahine et al. / Parkinsonism and Related Disorders 17 (2011) 208e211
3. Statistical analysis Among RLS and non-RLS patients, categorical patient characteristics and preoperative values were compared using Chi-square test or Fisher’s exact test. Continuous patient characteristics and preoperative values were compared using independent t-tests. Independent t-tests were used to compare preoperative and postoperative (at 4 weeks) differences in UPDRS, PDSS, and ESS between patients who underwent unilateral versus bilateral DBS. All tests were two-tailed and performed at a significance level of 0.05. A mixed model was used to assess differences among repeated measures preoperatively, at 4 weeks, and at 6 months. These measures included ESS, PDSS, and IRLSGG, levodopa equivalents, and scores for PDSS question 1 (how would you rate the overall quality of your night’s sleep?), question 3 (how would you rate your difficulty staying asleep), question 8 (do you get up at night to pass urine?), and question 14 (have you unexpectedly fallen asleep during the day?). The 4 PDSS questions were selected as representatives of the different components of sleep dysfunction in PD patients (overall quality, sleep fragmentation, nocturia, excessive daytime sleepiness). Multiple comparisons among the 3 time points were performed using a Bonferroni adjusted significance level of 0.0167(0.05/3). All tests were two-tailed.
4. Results Thirty-nine patients underwent STN DBS during the recruiting period. Eleven declined participation, 4 could not be contacted prior to their procedure, and 7 participated in one or more interviews but did not complete all 6. Seventeen patients were included in the final analysis, 11 males and 6 females. Mean patient age at first interview was 62 8.8 years. Mean disease duration was 13.1 years 8 (range: 4e39 years). Twelve patients underwent unilateral and 5 patients bilateral STN DBS. There was not a significant difference in the change in preoperative and 4 weeks postoperative UPDRS scores among patients who underwent unilateral versus bilateral DBS (change in UPDRS was 14.9 10.6 for the unilateral group vs. 18.5 10.7 for the bilateral group; p ¼ 0.59), so all patients were analyzed in combination. For the 17 patients combined, mean preoperative motor UPDRS off medications was 39.5 9.4 and mean motor UPDRS off medications and on stimulation at 4 weeks postoperatively was 22.4 6.3 (p < 0.001). Mean LE were 1193.8 600.7 preoperatively and 920.9 624.7 at 4 weeks postoperatively (p ¼ 0.005), a 22.9% of reduction. Mean LE at 6 months postoperatively were 599.6 369.7, a 50% reduction
209
compared to preoperative LE. There was not a significant difference between LE among patients who underwent unilateral versus bilateral DBS at 4 weeks postoperatively (unilateral group 870.8 619.8 vs. bilateral group 1041.0 692.0, p ¼ 0.65) and 6 months postoperatively (unilateral group 625.8 425.2 vs. bilateral group 537.0 206.3, p ¼ 0.57). ESS and PDSS scores, and scores on questions 1, 3, 8, and 14 of the PDSS preoperatively and at 6 months are shown in Table 1 and plots in Fig. 1. In comparing the change in scores for patients with unilateral versus bilateral DBS preoperatively and at 4 weeks, there were no significant differences in the change in ESS scores (unilateral group: 4.5 3.9 vs. bilateral group: 7 4.3, p ¼ 0.30) and PDSS scores (unilateral group: 25.8 24.3 vs. bilateral group: 35.8 8.1, p ¼ 0.22). Therefore, all 17 patients were analyzed in combination. For these 17 patients, significant improvement in ESS, PDSS, and PDSS subscores 1, 3, and 14 were noted at 4 weeks postoperatively, and this was sustained at 6 months. PDSS8 subscores were not significantly improved when multiple comparisons were conducted between preoperative, 4 week, and 6 month scores. However, using a two-tailed t-test at a significance level of 0.05, there was a significant improvement in PDSS8 scores comparing preoperative scores to 4 weeks (p ¼ 0.038) and 6 months (p ¼ 0.020) scores separately. Six patients met diagnostic criteria for RLS preoperatively; all 6 patients met all 4 essential diagnostic criteria for RLS, and structured interview did not reveal any evidence to suggest presence of an RLS mimicker. Two had a prior diagnosis, and 4 were newly diagnosed based on telephone interview. Two of the patients with RLS and one without RLS had a family history of RLS in at least one relative. There was no significant difference between patients with and without preoperative RLS in age, disease duration, off-medication motor UPDRS, antidepressant use, preoperative LE, or preoperative PDSS or ESS. IRSLGG rating scale scores were not significantly improved when multiple comparisons were conducted between preoperative, 4 week, and 6 month scores. However, using a two-tailed paired t-test at a significance level of 0.05, there was a significant improvement in comparing preoperative IRLSSG rating scale scores to 4 weeks (p ¼ 0.027) and 6 months (p ¼ 0.037) scores separately (Table 1). RLS symptoms resolved in 1 patient by the 5th interview. None of the 11 patients without preoperative RLS developed RLS postoperatively.
5. Discussion We found significant improvement in sleep quality and daytime sleepiness in this group of PD patients who underwent unilateral or bilateral STN DBS. Improvement occurred early on, at 4 weeks, and
Table 1 Comparisons of preoperative, 4 week, and 6 month IRLSSG, ESS, and PDSS scores. p values were from paired comparisons based on mixed model. A Bonferroni adjusted significance level of 0.05/3 ¼ 0.0167 was used. p values < 0.0167 were considered as significant. Mean(SD) Patients
Variable
Preoperatively
RLS patients (n ¼ 6)
IRLSSG
All PD patients (n ¼ 17)
ESS PDSS PDSS1a PDSS3b PDSS8c PDSS14d
a b c d
PDSS PDSS PDSS PDSS
question question question question
4 weeks vs. preoperative
6 months vs. preoperative
6 months vs. 4 weeks
Estimated difference (SE)
Estimated difference (SE)
Estimated difference (SE)
At 4 weeks
At 6 months
23.0(5.8)
14.8(5.0)
13.8(8.6)
8.2(2.6)
0.027
9.2(3.2)
0.037
1.0(2.6)
11.6(5.0) 94.2(20.8) 5.7(1.7) 3.8(2.7) 3.2(3.6) 4.6(3.0)
6.4(3.4) 122.9(17.1) 7.4(1.6) 6.0(2.7) 4.8(3.6) 8.3(1.9)
6.8(4.4) 124.9(18.0) 7.4(1.6) 7.2(1.7) 5.6(3.4) 7.9(2.4)
5.2(1.0) 28.7(5.1) 1.7(0.5) 2.2(0.8) 1.6(0.7) 3.6(0.7)
<0.001 <0.001 0.004 0.016 0.038 <0.001
4.8(0.9) 30.7(6.6) 1.7(0.5) 3.4(0.8) 2.5(1.0) 3.3(0.8)
<0.001 <0.001 0.003 <0.001 0.020 <0.001
0.4(0.8) 2.0(3.6) 0(0.39) 1.2(0.7) 0.8(1.0) 0.4(0.5)
1: how would you rate the overall quality of night’s sleep? 3: how would you rate your difficulty staying asleep? 8: do you get up at night to pass urine? 14: have you unexpectedly fallen asleep during the day?
p value
p value
p value 0.72 0.61 0.59 >0.99 0.13 0.40 0.48
210
L.M. Chahine et al. / Parkinsonism and Related Disorders 17 (2011) 208e211
Fig. 1. (a) Mean Epworth Sleepiness Scale (ESS) scores plot preoperatively and at 5 postoperative interviews, (b) Mean total Parkinson’s Disease Sleep Scale (PDSS) scores plot preoperatively and at 5 postoperative interviews, and (c) Mean International Restless Legs Syndrome Study Group (IRLSGG) rating scale score preoperatively and at 5 postoperative interviews.
was sustained at 6 months. Unlike the findings of others [4], we found significant improvements in daytime sleepiness (demonstrated on two separate measures, ESS and PDSS question 14). This improvement likely results from reductions in dopaminergic therapy and improved sleep quality, as has been demonstrated by polysomnography [3,5]. For assessment of nocturia, we utilized PDSS question 8, and improvement was noted postoperatively. Our study
had a small sample size, and larger studies using a validated questionnaire for nocturia are needed to further examine this symptom that significantly affects quality of life in PD patients [14], but improvements in nocturia following STN DBS would be consistent with the improvement in bladder capacity seen with STN stimulation, postulated to result from improved integration of afferent bladder signals by the basal ganglia with subsequent modulation of activation of the lateral frontal and anterior cingulate cortex [15]. We found improvement in RLS symptoms postoperatively, similar to a previously published retrospective study [6]. Improvement in RLS postoperatively has been suggested to relate to changes in basal ganglia neuronal firing with downstream effects on the thalamus and diencephalo-spinal (A11) dopaminergic pathways [6,16]. None of the patients had new-onset RLS at 6 months postoperatively, similar to findings of others [3] despite a mean 50% reduction in LE. In contrast, in a series of 195 PD patients who underwent bilateral STN DBS, 11 patients reported new-onset RLS postoperatively [7]. Mean levodopa reduction was 79% in the patients who developed RLS compared to 40% in those who did not [7]. One possibility in explaining this discordance of observed new-onset RLS postoperatively is that in that study [7], RLS was misdiagnosed. We used rigorous diagnostic criteria to exclude RLS mimics. The second possibility is that, as has been suggested [3,6], the reduction in LE in our patient population was not sufficient enough to bring out RLS symptoms. Given the negative impact of this treatable disorder on quality of life, assessment for RLS in PD patients undergoing reductions of dopaminergic medications following DBS is important, particularly with reductions of >50% in LE from preoperative doses given the possibility that such reductions unmask RLS symptoms. The limitations of this study include the small sample size which likely accounts for lack of significant improvement in PDSS8 and IRLSSG rating scale scores when performing multiple comparisons, and limited our ability to assess the effects of the DBS programming parameters on sleep. Improved polysomnographic findings, not documented in this study, would have supported the subjective improvements documented through the PDSS and ESS. In addition, the diagnostic criteria for RLS set forth by the IRLSGG have not been validated in PD, and while rigorous questioning to establish the diagnosis of RLS and exclude mimickers was used, it is possible that some of the patients were misdiagnosed with RLS. The IRLSSG rating scale has also not been validated among PD patients. Future studies validating diagnostic criteria for RLS and RLS severity assessments among PD patients, and utility of ancillary testing such as the suggested immobility test and polysomnogram [8,17], will be needed in order to better study RLS in PD patients in general and effects of DBS in this patient population. The ESS and PDSS are typically self-administered patient questionnaires, but telephone administration was conducted to ensure patient participation at specific time points. This may have influenced patient response, particularly since PDSS presents a visual analogue. Despite these limitations, our findings reflect the beneficial effects of STN DBS on sleep quality, and indicate that this change occurs early on. Our results suggest that nocturia improves, which requires further investigation. In addition, it is likely based on our findings and those of others that RLS does not emerge following halving of dopaminergic therapy following DBS, though it is not yet clear if further reductions will unmask RLS symptoms.
Acknowledgements Fees for statistical analysis were funded by a grant from the Cleveland Clinic Research Programs Council and Cleveland Clinic Neurological Institute.
L.M. Chahine et al. / Parkinsonism and Related Disorders 17 (2011) 208e211
Appendix. Supplementary material Supplementary material related to this article can be found online at doi:10.1016/j.parkreldis.2010.11.017. References [1] Chaudhuri KR, Pal S, DiMarco A, Whately-Smith C, Bridgman K, Mathew R, et al. The Parkinson’s disease sleep scale: a new instrument for assessing sleep and nocturnal disability in Parkinson’s disease. J Neurol Neurosurg Psychiatr 2002 Dec;73(6):629e35. [2] Ondo WG, Vuong KD, Jankovic J. Exploring the relationship between Parkinson disease and restless legs syndrome. Arch Neurol 2002 Mar;59(3):421e4. [3] Iranzo A, Comella CL, Santamaria J, Oertel W. Restless legs syndrome in Parkinson’s disease and other neurodegenerative diseases of the central nervous system. Mov Disord 2007;22(Suppl. 18):S424e30. [4] Hjort N, Ostergaard K, Dupont E. Improvement of sleep quality in patients with advanced Parkinson’s disease treated with deep brain stimulation of the subthalamic nucleus. Mov Disord 2004 Feb;19(2):196e9. [5] Cicolin A, Lopiano L, Zibetti M, Torre E, Tavella A, Guastamacchia G, et al. Effects of deep brain stimulation of the subthalamic nucleus on sleep architecture in parkinsonian patients. Sleep Med 2004 Mar;5(2):207e10. [6] Driver-Dunckley E, Evidente VG, Adler CH, Hillman R, Hernandez J, Fletcher G, et al. Restless legs syndrome in Parkinson’s disease patients may improve with subthalamic stimulation. Mov Disord 2006 Aug;21(8):1287e9. [7] Kedia S, Moro E, Tagliati M, Lang AE, Kumar R. Emergence of restless legs syndrome during subthalamic stimulation for Parkinson disease. Neurology 2004 Dec 28;63(12):2410e2.
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[8] Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi J, 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 Mar;4(2):101e19. [9] Benes H, Walters AS, Allen RP, Hening WA, Kohnen R. Definition of restless legs syndrome, how to diagnose it, and how to differentiate it from RLS mimics. Mov Disord 2007;22(Suppl. 18):S401e8. [10] Peralta CM, Wolf E, Seppi K, Wenning GK, Hogl B, Poewe W. Restless legs in idiopathic Parkinson’s disease. Mov Disord 2005;20(Suppl. 10):S108. [11] Wilson R, Simuni T, Stern MB. Prevalence of restless legs syndrome in Parkinson’s disease. Mov Disord 2000;15:1043e4. [12] Walters AS, LeBrocq C, Dhar A, Hening W, Rosen R, Allen RP, et al. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med 2003 Mar;4(2):121e32. [13] Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991 Dec;14(6):540e5. [14] Barone P, Antonini A, Colosimo C, Marconi R, Morgante L, Avarello TP, et al. The PRIAMO study: a multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson’s disease. Mov Disord 2009 Aug 15;24(11):1641e9. [15] Herzog J, Weiss PH, Assmus A, Wefer B, Seif C, Braun PM, et al. Subthalamic stimulation modulates cortical control of urinary bladder in Parkinson’s disease. Brain 2006 Dec;129(Suppl. 12):3366e75. [16] Rye DB. Parkinson’s disease and RLS: the dopaminergic bridge. Sleep Med 2004 May;5(3):317e28. [17] Montplaisir J, Boucher S, Nicolas A, Lesperance P, Gosselin A, Rompre P, et al. Immobilization tests and periodic leg movements in sleep for the diagnosis of restless leg syndrome. Mov Disord 1998 Mar;13(2):324e9.
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Short communication
Effects of STN DBS for Parkinson’s disease on restless legs syndrome and other sleep-related measuresq L.M. Chahine*, A. Ahmed, Z. Sun Cleveland Clinic, Cleveland, OH, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 29 July 2010 Received in revised form 19 October 2010 Accepted 23 November 2010
Restless legs syndrome (RLS) and other sleep abnormalities are common in Parkinson’s Disease (PD). We prospectively examined sleep measures in PD patients undergoing subthalamic nucleus (STN) deep brain stimulation (DBS). An RLS questionnaire, Epworth Sleepiness Scale (ESS), and Parkinson’s Disease Sleep Scale (PDSS) were administered through telephone interviews preoperatively and postoperatively. Seventeen patients were included. Mean preoperative and 4 weeks postoperative ESS scores were 11.6 and 6.4 respectively (p < 0.001) and PDSS scores were 94.2 and 122.9 respectively (p < 0.001). The improvement was sustained at 6 months. Six patients were diagnosed with RLS preoperatively. Mean preoperative International Restless Legs Syndrome Study Group rating scale score was 23.0. Mean 4 week and 6 month postoperative IRLSSG rating scale scores were 14.8 and 13.8 respectively, significantly improved compared to preoperative scores (p ¼ 0.027 and p ¼ 0.037 respectively). No patients developed new-onset RLS postoperatively. STN DBS improves daytime sleepiness, sleep quality, and RLS. Ó 2010 Elsevier Ltd. All rights reserved.
Keywords: Restless legs syndrome Parkinson’s disease Sleep Deep brain stimulation Subthalamic nucleus
1. Introduction Abnormalities in sleep occur in 80% of patients with Parkinson’s Disease (PD) [1]. Restless legs syndrome (RLS) is more common in PD patients than the general population [2]. Several sleep parameters improve in PD patients after DBS [3e5], but there are limited and conflicting data on the effects of DBS on RLS [3,6,7] with some studies showing improvement [6] and others showing emergence of RLS postoperatively [7]. The objectives of this study were to prospectively assess subjective changes in the quality of sleep, extent of daytime sleepiness, and RLS symptoms in PD patients early and after several months of STN DBS and to determine whether some patients with PD who do not have RLS pre-DBS develop RLS postoperatively. 2. Methods This was a longitudinal cohort study conducted from November 2008 to April 2010. All consecutive patients at our institution undergoing first-time STN DBS were approached for participation in the study. Data were collected through 6 telephone interviews. The paradigm of questions for epidemiologic studies of RLS proposed by the International Restless Legs Syndrome Study Group (IRLSSG) [8] were used to synthesize the questionnaire used to identify
q The review of this paper was entirely handled by an Associate Editor, J. Carr. * Corresponding author. S90, Department of Neurology, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA. Tel.: þ1 216 444 2000; fax: þ1 216 444 0230. E-mail address: [email protected] (L.M. Chahine). 1353-8020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2010.11.017
RLS patients (see Part 1 of the E-Supplement). Estimates of the sensitivity of the four essential diagnostic criteria for RLS vary from 82% to 97% [9]. In the general population, the false-positive rate for RLS diagnosis may be more than 10% when only the four essential criteria are used during interview [9], and these criteria have not been specifically validated in the diagnosis of RLS in PD patients, in whom distinguishing RLS from PD symptomatology may be challenging [10,11]. Therefore, additional questions, by means of a structured interview, were asked to ensure exclusion of patients with RLS mimickers (specifically, to exclude nocturnal leg cramps, arthritic pain, neuropathic pain, painful legs and moving toes, or vascular or neurogenic claudication; see Part 2 of the E-Supplement). The relation of RLS symptoms to motor fluctuations was also probed. Further questions tailored to specific patient symptoms were asked to confirm the diagnosis and exclude other conditions. Patients diagnosed with PD and RLS were administered the IRLSSG rating scale [12]. All patients were administered the Epworth Sleepiness Scale (ESS) [13] (in which higher scores indicate greater daytime sleepiness) and Parkinson’s Disease Sleep Scale (PDSS) [1] (in which higher scores indicate better sleep). Study participants were contacted 2 weeks preoperatively then at 1 week, 2 weeks, approximately 4 weeks (7 days after 1st programming), 3 months, and 6 months following surgery for readministration of the questionnaire for RLS diagnosis, the IRLSSG rating scale if RLS was present, ESS, and PDSS. PD patients with bilateral staged procedures were contacted 2 weeks prior to their first DBS surgery and after their second surgery they then had similar time points as patients with unilateral or bilateral simultaneous procedures. Other data collected for all study participants through medical record review included: demographics, year of symptom onset, family history of RLS, medications preoperatively and at each postoperative time point, with dopaminergic medication converted into levodopa equivalents (LE) (LE ¼ levodopa þ 0.75 dose of levodopa CR þ 1.3 dose of levodopa/entacapone þ 100 dose of pramipexole þ 20 dose of ropirinole), preoperative off-medication motor UPDRS score, and off-medication, on-stimulation motor UPDRS scores at 4 weeks postoperatively. All interviews were carried out with the adequate understanding and consent of the subjects involved. This study was approved by the institutional review board at our institution.
L.M. Chahine et al. / Parkinsonism and Related Disorders 17 (2011) 208e211
3. Statistical analysis Among RLS and non-RLS patients, categorical patient characteristics and preoperative values were compared using Chi-square test or Fisher’s exact test. Continuous patient characteristics and preoperative values were compared using independent t-tests. Independent t-tests were used to compare preoperative and postoperative (at 4 weeks) differences in UPDRS, PDSS, and ESS between patients who underwent unilateral versus bilateral DBS. All tests were two-tailed and performed at a significance level of 0.05. A mixed model was used to assess differences among repeated measures preoperatively, at 4 weeks, and at 6 months. These measures included ESS, PDSS, and IRLSGG, levodopa equivalents, and scores for PDSS question 1 (how would you rate the overall quality of your night’s sleep?), question 3 (how would you rate your difficulty staying asleep), question 8 (do you get up at night to pass urine?), and question 14 (have you unexpectedly fallen asleep during the day?). The 4 PDSS questions were selected as representatives of the different components of sleep dysfunction in PD patients (overall quality, sleep fragmentation, nocturia, excessive daytime sleepiness). Multiple comparisons among the 3 time points were performed using a Bonferroni adjusted significance level of 0.0167(0.05/3). All tests were two-tailed.
4. Results Thirty-nine patients underwent STN DBS during the recruiting period. Eleven declined participation, 4 could not be contacted prior to their procedure, and 7 participated in one or more interviews but did not complete all 6. Seventeen patients were included in the final analysis, 11 males and 6 females. Mean patient age at first interview was 62 8.8 years. Mean disease duration was 13.1 years 8 (range: 4e39 years). Twelve patients underwent unilateral and 5 patients bilateral STN DBS. There was not a significant difference in the change in preoperative and 4 weeks postoperative UPDRS scores among patients who underwent unilateral versus bilateral DBS (change in UPDRS was 14.9 10.6 for the unilateral group vs. 18.5 10.7 for the bilateral group; p ¼ 0.59), so all patients were analyzed in combination. For the 17 patients combined, mean preoperative motor UPDRS off medications was 39.5 9.4 and mean motor UPDRS off medications and on stimulation at 4 weeks postoperatively was 22.4 6.3 (p < 0.001). Mean LE were 1193.8 600.7 preoperatively and 920.9 624.7 at 4 weeks postoperatively (p ¼ 0.005), a 22.9% of reduction. Mean LE at 6 months postoperatively were 599.6 369.7, a 50% reduction
209
compared to preoperative LE. There was not a significant difference between LE among patients who underwent unilateral versus bilateral DBS at 4 weeks postoperatively (unilateral group 870.8 619.8 vs. bilateral group 1041.0 692.0, p ¼ 0.65) and 6 months postoperatively (unilateral group 625.8 425.2 vs. bilateral group 537.0 206.3, p ¼ 0.57). ESS and PDSS scores, and scores on questions 1, 3, 8, and 14 of the PDSS preoperatively and at 6 months are shown in Table 1 and plots in Fig. 1. In comparing the change in scores for patients with unilateral versus bilateral DBS preoperatively and at 4 weeks, there were no significant differences in the change in ESS scores (unilateral group: 4.5 3.9 vs. bilateral group: 7 4.3, p ¼ 0.30) and PDSS scores (unilateral group: 25.8 24.3 vs. bilateral group: 35.8 8.1, p ¼ 0.22). Therefore, all 17 patients were analyzed in combination. For these 17 patients, significant improvement in ESS, PDSS, and PDSS subscores 1, 3, and 14 were noted at 4 weeks postoperatively, and this was sustained at 6 months. PDSS8 subscores were not significantly improved when multiple comparisons were conducted between preoperative, 4 week, and 6 month scores. However, using a two-tailed t-test at a significance level of 0.05, there was a significant improvement in PDSS8 scores comparing preoperative scores to 4 weeks (p ¼ 0.038) and 6 months (p ¼ 0.020) scores separately. Six patients met diagnostic criteria for RLS preoperatively; all 6 patients met all 4 essential diagnostic criteria for RLS, and structured interview did not reveal any evidence to suggest presence of an RLS mimicker. Two had a prior diagnosis, and 4 were newly diagnosed based on telephone interview. Two of the patients with RLS and one without RLS had a family history of RLS in at least one relative. There was no significant difference between patients with and without preoperative RLS in age, disease duration, off-medication motor UPDRS, antidepressant use, preoperative LE, or preoperative PDSS or ESS. IRSLGG rating scale scores were not significantly improved when multiple comparisons were conducted between preoperative, 4 week, and 6 month scores. However, using a two-tailed paired t-test at a significance level of 0.05, there was a significant improvement in comparing preoperative IRLSSG rating scale scores to 4 weeks (p ¼ 0.027) and 6 months (p ¼ 0.037) scores separately (Table 1). RLS symptoms resolved in 1 patient by the 5th interview. None of the 11 patients without preoperative RLS developed RLS postoperatively.
5. Discussion We found significant improvement in sleep quality and daytime sleepiness in this group of PD patients who underwent unilateral or bilateral STN DBS. Improvement occurred early on, at 4 weeks, and
Table 1 Comparisons of preoperative, 4 week, and 6 month IRLSSG, ESS, and PDSS scores. p values were from paired comparisons based on mixed model. A Bonferroni adjusted significance level of 0.05/3 ¼ 0.0167 was used. p values < 0.0167 were considered as significant. Mean(SD) Patients
Variable
Preoperatively
RLS patients (n ¼ 6)
IRLSSG
All PD patients (n ¼ 17)
ESS PDSS PDSS1a PDSS3b PDSS8c PDSS14d
a b c d
PDSS PDSS PDSS PDSS
question question question question
4 weeks vs. preoperative
6 months vs. preoperative
6 months vs. 4 weeks
Estimated difference (SE)
Estimated difference (SE)
Estimated difference (SE)
At 4 weeks
At 6 months
23.0(5.8)
14.8(5.0)
13.8(8.6)
8.2(2.6)
0.027
9.2(3.2)
0.037
1.0(2.6)
11.6(5.0) 94.2(20.8) 5.7(1.7) 3.8(2.7) 3.2(3.6) 4.6(3.0)
6.4(3.4) 122.9(17.1) 7.4(1.6) 6.0(2.7) 4.8(3.6) 8.3(1.9)
6.8(4.4) 124.9(18.0) 7.4(1.6) 7.2(1.7) 5.6(3.4) 7.9(2.4)
5.2(1.0) 28.7(5.1) 1.7(0.5) 2.2(0.8) 1.6(0.7) 3.6(0.7)
<0.001 <0.001 0.004 0.016 0.038 <0.001
4.8(0.9) 30.7(6.6) 1.7(0.5) 3.4(0.8) 2.5(1.0) 3.3(0.8)
<0.001 <0.001 0.003 <0.001 0.020 <0.001
0.4(0.8) 2.0(3.6) 0(0.39) 1.2(0.7) 0.8(1.0) 0.4(0.5)
1: how would you rate the overall quality of night’s sleep? 3: how would you rate your difficulty staying asleep? 8: do you get up at night to pass urine? 14: have you unexpectedly fallen asleep during the day?
p value
p value
p value 0.72 0.61 0.59 >0.99 0.13 0.40 0.48
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Fig. 1. (a) Mean Epworth Sleepiness Scale (ESS) scores plot preoperatively and at 5 postoperative interviews, (b) Mean total Parkinson’s Disease Sleep Scale (PDSS) scores plot preoperatively and at 5 postoperative interviews, and (c) Mean International Restless Legs Syndrome Study Group (IRLSGG) rating scale score preoperatively and at 5 postoperative interviews.
was sustained at 6 months. Unlike the findings of others [4], we found significant improvements in daytime sleepiness (demonstrated on two separate measures, ESS and PDSS question 14). This improvement likely results from reductions in dopaminergic therapy and improved sleep quality, as has been demonstrated by polysomnography [3,5]. For assessment of nocturia, we utilized PDSS question 8, and improvement was noted postoperatively. Our study
had a small sample size, and larger studies using a validated questionnaire for nocturia are needed to further examine this symptom that significantly affects quality of life in PD patients [14], but improvements in nocturia following STN DBS would be consistent with the improvement in bladder capacity seen with STN stimulation, postulated to result from improved integration of afferent bladder signals by the basal ganglia with subsequent modulation of activation of the lateral frontal and anterior cingulate cortex [15]. We found improvement in RLS symptoms postoperatively, similar to a previously published retrospective study [6]. Improvement in RLS postoperatively has been suggested to relate to changes in basal ganglia neuronal firing with downstream effects on the thalamus and diencephalo-spinal (A11) dopaminergic pathways [6,16]. None of the patients had new-onset RLS at 6 months postoperatively, similar to findings of others [3] despite a mean 50% reduction in LE. In contrast, in a series of 195 PD patients who underwent bilateral STN DBS, 11 patients reported new-onset RLS postoperatively [7]. Mean levodopa reduction was 79% in the patients who developed RLS compared to 40% in those who did not [7]. One possibility in explaining this discordance of observed new-onset RLS postoperatively is that in that study [7], RLS was misdiagnosed. We used rigorous diagnostic criteria to exclude RLS mimics. The second possibility is that, as has been suggested [3,6], the reduction in LE in our patient population was not sufficient enough to bring out RLS symptoms. Given the negative impact of this treatable disorder on quality of life, assessment for RLS in PD patients undergoing reductions of dopaminergic medications following DBS is important, particularly with reductions of >50% in LE from preoperative doses given the possibility that such reductions unmask RLS symptoms. The limitations of this study include the small sample size which likely accounts for lack of significant improvement in PDSS8 and IRLSSG rating scale scores when performing multiple comparisons, and limited our ability to assess the effects of the DBS programming parameters on sleep. Improved polysomnographic findings, not documented in this study, would have supported the subjective improvements documented through the PDSS and ESS. In addition, the diagnostic criteria for RLS set forth by the IRLSGG have not been validated in PD, and while rigorous questioning to establish the diagnosis of RLS and exclude mimickers was used, it is possible that some of the patients were misdiagnosed with RLS. The IRLSSG rating scale has also not been validated among PD patients. Future studies validating diagnostic criteria for RLS and RLS severity assessments among PD patients, and utility of ancillary testing such as the suggested immobility test and polysomnogram [8,17], will be needed in order to better study RLS in PD patients in general and effects of DBS in this patient population. The ESS and PDSS are typically self-administered patient questionnaires, but telephone administration was conducted to ensure patient participation at specific time points. This may have influenced patient response, particularly since PDSS presents a visual analogue. Despite these limitations, our findings reflect the beneficial effects of STN DBS on sleep quality, and indicate that this change occurs early on. Our results suggest that nocturia improves, which requires further investigation. In addition, it is likely based on our findings and those of others that RLS does not emerge following halving of dopaminergic therapy following DBS, though it is not yet clear if further reductions will unmask RLS symptoms.
Acknowledgements Fees for statistical analysis were funded by a grant from the Cleveland Clinic Research Programs Council and Cleveland Clinic Neurological Institute.
L.M. Chahine et al. / Parkinsonism and Related Disorders 17 (2011) 208e211
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