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Polysomnographic findings in restless legs syndrome (RLS) patients with severe augmentation
Accepted Manuscript Polysomnographic findings in restless legs syndrome (RLS) patients with severe augmentation Sophia Stephanie Steinke, Claudia Trenkwalder, MD, Johannes Zimmermann, Friederike Sixel-Döring, MD, Maria-Lucia Muntean, MD, PhD PII:
S1389-9457(18)30161-8
DOI:
10.1016/j.sleep.2018.04.010
Reference:
SLEEP 3688
To appear in:
Sleep Medicine
Received Date: 27 December 2017 Revised Date:
22 April 2018
Accepted Date: 25 April 2018
Please cite this article as: Steinke SS, Trenkwalder C, Zimmermann J, Sixel-Döring F, Muntean M-L, Polysomnographic findings in restless legs syndrome (RLS) patients with severe augmentation, Sleep Medicine (2018), doi: 10.1016/j.sleep.2018.04.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Original article
Polysomnographic findings in restless legs syndrome (RLS) patients with severe augmentation Sophia Stephanie Steinke a,b, Claudia Trenkwalder MD a,b, Johannes Zimmermann c, Friederike SixelDöring MD b,d, Maria-Lucia Muntean MD, PhD b a
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Department of Neurosurgery, University Medical Center, Göttingen, Germany Paracelsus Elena Hospital, Kassel, Germany c Psychologische Hochschule Berlin, Germany d Department of Neurology, Philips University, Marburg, Germany b
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Title character count: 92 Word count: Abstract: 205 Article: 3498 References: 24 Tables: 7 Figures: 3 Running title: PSG findings in RLS augmentation
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*Corresponding author: Maria-Lucia Muntean, [email protected]
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ACCEPTED MANUSCRIPT Abstract Background and objectives: Augmentation can occur frequently in restless legs syndrome (RLS) patients treated with dopaminergic agents. Video-polysomnographic (PSG) data from augmented RLS patients are scant. The aim of this study was to evaluate PSG findings in augmented RLS patients and compare them with those of non-augmented RLS patients.
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Patients and methods: Valid PSG data were analyzed from 99 augmented and 84 non-augmented RLS inpatients who underwent one night PSG.
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Results: Both patient groups showed a high subjective burden of RLS symptoms. The mean scores on the International RLS Study Group Rating Scale (IRLS) were significantly higher in the group with augmentation than in the group without. The periodic leg movement index (PLMI) was increased in both groups, mostly on account of the PLM in wakefulness (PLMW). Both groups presented a reduced sleep efficiency and an increased sleep latency. The levodopa equivalent dose (LED) was significantly higher in the augmented group.
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Conclusions: Our study confirms that RLS patients with augmentation have disturbed sleep due to high amount of leg movements and fragmented sleep. Overall, however, polysomnographic characteristics were not different between insufficiently treated RLS and severely augmented RLS patients, implying that augmentation could represent a severe form of RLS and not a different phenomenon.
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Key words: Restless Legs Syndrome, Augmentation, Polysomnography
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1. Introduction
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Restless legs syndrome (RLS) is a common neurological disorder with severe sleep disturbance, which has a clinically significant negative impact on 2-3% of the general adult population.[1] Augmentation is characterized by a worsening of symptom severity; ie, an earlier onset of symptoms in the afternoon or evening compared to before treatment initiation, a shorter latency of symptoms at rest and a spreading of symptoms to other body parts.[2] Augmentation is currently a therapeutic challenge for neurologists and sleep medicine specialists. Long-term treatment with dopaminergic agents results in an increased rate of augmentation for up to 42-68% of those patients who are monitored for 10 years. [3, 4]
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There are scant video-polysomnographic (PSG) data in RLS patients with augmentation, and the data that are available come either from case reports [5] or from the limited number of studies that compared small numbers of patients with and without augmentation.[6,7,8] It has been assumed that periodic limb movements (PLMs), and motor activity in general, increase during augmentation. [9] However, one study failed to show the expected increase in the number of PLMs in augmented patients, implying that dopaminergic agents still act on PLMs in these patients. [6] Studies using the suggested immobilization test (SIT) have reported higher motor activity during wake periods, implying that RLS augmentation is a phenomenon that manifests mostly in wakefulness. [6]
2. Patients and methods 2.1. Patients
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The aim of the present study was to compare the PSG characteristics of a large cohort of augmented RLS patients to a cohort of RLS patients without augmentation. In particular, we sought to compare sleep parameters and motor activity in relation to the medication taken, and to elucidate the relation between PLMS and dopaminergic dosages in augmentation.
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Two hundred and eleven inpatients with a definite diagnosis of RLS consecutively admitted to the Paracelsus Elena Hospital in Kassel between January 2016 and February 2017 were included in this study and underwent one night of PSG. Neurologists from the ambulatory setting referred RLS patients to the clinic due to severe RLS, refractory RLS, augmentation, or severe side effects of the medications used to treat RLS. Board-certified sleep medicine specialists (CT, FSD, MLM) interviewed all patients on admission to assess RLS diagnosis. The International RLS Study Group (IRLSSG) 2014 essential diagnostic criteria were used to confirm RLS. 10 Patients who had less than 3 hours time in bed (TIB) during the night in the sleep laboratory or a sleep efficiency (SE) of less than 30% were excluded from the statistical analysis of the extended sleep parameters, but included in the cohort.
2.2. Methods
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ACCEPTED MANUSCRIPT Augmentation was defined according to the NIH criteria [1] and was assessed in each patient individually. The RLS patients were subsequently divided into two groups for further comparisons: RLS patients with augmentation and without augmentation. The group without augmentation consisted of RLS patients who proved to be refractory to treatment in the ambulatory setting, who were severely affected, or who had side effects of the medication previously used for treating RLS.
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All patients gave their written informed consent before being enrolled in the study and prior to the sleep study. The study was approved by the Ethical Committee of the Landesärztekammer Hessen, Germany in the context of RLS in polysomnographic and sleep studies. All patients were inpatients and PSG was recorded within 3 days of admission. Patients filled out the International RLS Study Group Rating Scale(IRLS) 11, Restless Legs Syndrome-6 Scale (RLS-6) 12 and the Medical Outcomes Study sleep scale (MOS)13 on the day of the PSG study.
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Demographic characteristics and concomitant diseases (including polyneuropathy and sleep apnea) were collected. Medications used for RLS on the day of the PSG was recorded, which tended to be the medication previously prescribed by the neurologists in the ambulatory setting.
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Ferritin, transferrin, and transferrin saturation were measured as part of the routine laboratory examination upon admission.
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Standard cardiorespiratory PSG (PSG; Xltec: Excel Tech Ltd; Oakville, Ontario; Canada) was applied according to AASM criteria 14. All patients were documented with an infrared video recording synchronized to the PSG. Sleep (including sleep stages), PLMs, and apneas were scored manually by a trained sleep technician. PLMs were scored in sleep and in wakefulness only if they occurred in a series of at least four consecutive movements lasting 0.5 to 5 seconds each with an intermovement interval of 4 to 90 seconds, in accordance with international scoring rules. [14] Sleep efficiency was defined as total sleep time (TST) / TIB. Quantitative analysis of sleep stages was calculated as a percentage of TST. Sleep apneas were defined as an apnea-hypnea index (AHI) of 5 or more in accordance with Ruehland et al. 15 For patients already undergoing ventilation therapy for sleep apnea, the PSG was performed with ongoing ventilation and efficacy of CPAP therapy was controlled.
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All sleep evaluations were reviewed and supervised by board-certified sleep specialists (FSD, CT or MLM).
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2.3. Statistical analysis
The abovementioned parameters were compared between RLS patients with and without augmentation. For categorical variables, we compared frequencies using Pearson’s chi square test or Fisher’s exact test. For continuous variables, we compared mean values using t-tests, or (in the case of non-normally distributed variables) Mann-Whitney-u tests. To control the family-wise error rate the Holm-Bonferroni method was used. The program used for the calculation is Statistica version 13.1 by Dell Inc.
3. Results The final study population consisted of 116 RLS patients with augmentation and 95 RLS patients without augmentation who fulfilled the inclusion criteria. The complete analysis of the PSG parameters was performed in 99 RLS patients with augmentation and 84 RLS patients without augmentation. The study tree is presented in Fig.1. 4
ACCEPTED MANUSCRIPT The two groups were similar in terms of demographics: there were no statistically significant differences between the two groups regarding age, body mass index (BMI), sex, and concomitant diseases (polyneuropathy, sleep apnea) (Table 1).
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Total scores of the IRLS rating scale demonstrated severe disease burden in both groups. The mean score on the IRLS in the group with augmentation was 32.13 ± 4.47, which was significantly higher than in the group without augmentation (29.97 ± 7.54, p=0.01). The RLS-6 and MOS sleep scores were high in both groups, but not significantly different. In fact, the RLS-6 mean score in the augmentation group was 35.61 ± 10.11 compared to 34.91 ± 11.89 in the group without augmentation, p=0.66; and MOS-sleep mean score in the augmentation group was 39.46 ± 5.14 compared to 39.39± 4.88 in the group without augmentation, p=0.93.
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When the amount of daily RLS (item 8 of IRLS) was used as a measure of daytime RLS symptoms, no statistically significant difference was noticed between RLS patients with and without augmentation (p=0.295) (Table 2).
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Serum ferritin levels were lower in the RLS group with augmentation but this difference failed to reach statistical significance (Table 1). The levels of transferrin and transferrin saturation did not differ between the two groups.
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Medications taken by patients during the day when the PSG was performed are presented in Tables 3 and 4. A combination of two or more medications to treat RLS symptoms was used more often in RLS patients with augmentation than in those without (p<0.001). Significantly more RLS patients with augmentation took levodopa and dopamine agonists compared to RLS patients without augmentation (p=0.053 and p<0.001, respectively) (Table 4). When the dopamine agonists were considered separately, we determined that more patients in the augmented group took rotigotine alone or in combination treatment compared to the group without augmentation (p=0.003). But out of the 51 patients with treatment of rotigotine in the RLS group, only seven were on monotherapy with rotigotine. These seven patients were treated with a dosage of 2 ± 1mg rotigotine.
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For the other dopamine agonists no statistically significant differences were observed (Table 5) (Mann-Whitney-u Test for non-normally distributed variables). The mean levodopa equivalent dose (LED) was significantly higher in the augmentation group (68.76 ± 154.22mg), than in the group without augmentation (29.93 ± 43.23mg) (p< 0.005). There were no significant differences in the number of patients using α-2-δ ligands or opioids in the two groups (Table 4). The results of the PSG studies are shown in Table 6. Both groups presented reduced sleep efficiency and increased sleep latency. There was no difference regarding REM sleep between the groups. RLS patients with and without augmentation showed an increased amount of light sleep and a reduced amount of slow-wave sleep. The PLMI was increased in both groups, mostly on account of the PLM in wakefulness (PLMW). PLMW index was greatly increased in all RLS patients, and while it was greater in those with augmentation compared to the non-augmented patients this difference did not reach statistical significance (p>0.05). (Table 6, Figure 2). We subsequently analyzed the PLMI of all RLS patients, including those with sleep efficiency of less than 30%, and still found no difference between the augmented (65.65 ± 54.64) and the non augmented group (61.51 ± 54.64) (p=0.592) (Table 7).
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ACCEPTED MANUSCRIPT No correlation was noted between IRLS and PLMW index or PLMS index in either of the groups (p>0.20) (Figure 3)
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The awakening index did not differ between the groups (p=0.487). The AHI was slightly increased in both groups and was not significantly different between them (p=0.868). When we excluded the patients with insufficiently- or untreated sleep apnea, no significant difference in PLMS index between the groups (PLMS index: RLS patients with augmentation (n=35): 23.05 ± 34.46, RLS patients without augmentation (n=43): 39.74 ± 45.47, p= 0.077) was noted. 4. Discussion
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We investigated the PSG characteristics of 99 RLS inpatients with augmentation compared to 84 severely affected RLS inpatients without augmentation. This is, to the best of our knowledge, the largest study of RLS patients with augmentation who underwent video PSG.
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The results of this study confirmed the disturbed sleep and high amount of leg movements in RLS patients with augmentation, but failed to show a significant difference compared to RLS patients without augmentation. PLMW index was higher than PLMS index in RLS patients regardless of the presence of augmentation. It has been shown in other polysomnographic studies that RLS patients have increased PLMW compared to controls. [16] In our study, even though it did not reach statistical significance, there was a trend to more PLMW in augmented patients compared to those without augmentation, suggesting that augmentation is more a problem of wakefulness than of sleep. Mitterling et al. also implied in their study using the suggested immobilization test (SIT) that RLS augmentation seems to be a phenomenon that manifests predominantly during wakefulness, both during the day and at night. [6]
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The PLMW index values in our study population were higher than those published by Mitterling et al. [6]: PLMW index in RLS patients with augmentation in our study (93.11 [6-218] vs. 34.8 [7.2–259.4]). The PLMW index in non-augmented patients was also higher: 78.75 [3-281] vs. 36.2 [7.9–155.7]. This could be partly explained by the fact that the patients in the present study had more severe RLS than those in the study by Mitterling et al. (IRLS scores: RLS with augmentation 31.75 [10-39] vs. 29 [18– 39], RLS without augmentation 29.63 [0-39] vs. 11 [0–32]). [6] Another explanation could be the night-to-night variability in the PLMI in RLS patients. This has been well established in previous studies. [17, 18] The periodicity index was not accounted for in our study. Mitterling et al. who calculated the index in their study did not find any difference in periodicity of leg movements between RLS patients with and without augmentation. [6] The patients in the control group had severe RLS. This explains the high number of limb movements in these patients. The correlation between the severity of RLS measured by the IRLS and the PLMS index was previously demonstrated by Garcia-Borreguero et al. [9] In the present study, however we could not demonstrate this correlation. In our study, the subjective severity of RLS measured by the IRLS was worse in patients with augmentation than in those without. The results are in line with other studies that showed a correlation between the presence of augmentation and higher scores on RLS-specific scales. [6, 19] The PSG data in the current study objectively confirm the subjective complaints of augmented RLS
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ACCEPTED MANUSCRIPT patients). The number of hours with RLS symptoms per 24 h period did not differ in RLS patients with augmentation compared to severely affected RLS patients without augmentation.
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For the validity of the PSG data, RLS patients with and without augmentation who had less than 3 hours TIB or less than 30% sleep efficiency where excluded from the analysis of the sleep parameters. Altogether, 17 (14.65%) augmented patients and 11 (11.58%) patients without augmentation showed such a poor quality of sleep that the complete PSG data were not exploitable. This further proves that the high impact of very severe RLS and augmentation on quality of sleep. In these patients only PLMI and sleep efficiency were considered for analysis.
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All RLS patients showed a reduced amount of slow wave sleep, consistent with previous findings [6]. The amount of slow wave sleep was lower than the values published in healthy adults, regardless of age or gender (≤ 30 y 20.7 (15.2–37.5)% and > 60 y: 14.9 (2.4–35.6)%. 20
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Overall, the augmented group showed a more complex therapeutic concept (multi-drug treatment), higher amount of dopamine agonists, and a higher levodopa-equivalent dose than the patients in the non-augmented group, which is in line with the definition of augmentation as a dopaminergic overtreatment in RLS. [2] Levodopa, having the shortest half-life from all the dopaminergic agents was significantly associated with augmentation even in combination with long-acting dopamine agonists. The dose of rotigotine in RLS patients with augmentation was significantly higher than in those without augmentation. Also, most of the patients treated with rotigotine (44/51; 86,28%) in the group of RLS patients with augmentation received a combination therapy with additional dopaminergic substances. This finding is in line with previous studies which show that rotigotine could induce augmentation only in higher dosages. [21] Our data support the theory that augmentation is a syndrome characterized by a severely increased concentration of dopamine in the central nervous system. [22]
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The treatment protocol for augmentation used in our clinic is to reduce the dopamine agonists to the level of the recommended dose or change the medication to a long-acting dopamine agonist. Opioids are also added when needed. For all RLS patients, secondary causes and aggravating factors are searched for and managed.
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The serum ferritin levels were slightly reduced in the augmented group but did not reach statistical significance. This is in contrast with other studies that showed lower serum ferritin levels in patients with augmentation. [23,24] Limitations
One potential limitation is the patient selection bias, especially of the non-augmented group. Our hospital is a national specialized center for RLS, therefore, the most severe cases are referred to us. The fact that the patients in the control group had such severe RLS could be a possible bias and explain the lack of statistically significant difference between the groups. It is also possible that some patients with mild early augmentation were included in the control group. All augmented patients had daytime RLS symptoms. We unfortunately did not have data on the exact time of day that symptoms occurred. Since not all patients filled the augmentation severity
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ACCEPTED MANUSCRIPT ratinge scale (ASRS), we used item 8 from the IRLS to account for the amount of daytime RLS symptoms. Due to organizational reasons the PSG was performed within the first three days after admission in the hospital, and the augmentation criteria very evaluated upon admission. 5. Conclusion
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In conclusion, our study confirms that RLS patients with augmentation have disturbed sleep due to the high amount of leg movements and fragmented sleep. The leg movements are increased, especially in wakefulness, despite high dopaminergic medication dosages. Overall, however, polysomnographic characteristics were not different between insufficiently treated RLS and severely augmented RLS patients, implying that augmentation represents a severe form of RLS, but is also characterized by a distinct phenotype of paradoxical response to dose increase during long-term therapy, whereas short-term increases of dopaminergic drugs temporarily improve symptoms.
Funding source
The publication of the study was supported by an unrestricted grant from UCB Pharma. Financial disclosure related to research covered in this article:
Table and figure legends
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Full financial disclosures for the last 12 months:
Figure 1. Study tree of RLS patients
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Figure 2. Representation of PLM index in sleep and wakefulness for the RLS patients with and without augmentation
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Figure 3. Representation of PLM index in sleep and wakefulness in relation to severity of RLS on the IRLS
Table 1. Demographic and clinical characteristics of the study population Table 2. Severity of the RLS symptoms according to IRLS-item 8 Table 3. Overview of the medication combinations taken by the RLS patients on the day when the PSG was performed Table 4. Distribution of the RLS patients according to the different classes of medication used (alone or in combination) on the day when the PSG was performed Table 5. Doses of the dopamine agonists (in mono- and combination therapy) used by RLS patients on the day when the PSG was performed
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ACCEPTED MANUSCRIPT Table 6. PSG parameters of the RLS patients with valid PSG
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Table 7. PSG parameters of the all 221 RLS patients
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ACCEPTED MANUSCRIPT References
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1 Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisir J. Restless Legs Syndrome Diagnosis and Epidemiology workshop at the National Institutes of Health; International Restless Legs Syndrome Study Group. 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.
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2 Garcia-Borreguero D, Silber MH, Winkelman JW, Högl B, Bainbridge J, Buchfuhrer M, Hadjigeorgiou G, Inoue Y, Manconi M, Oertel W, Ondo W, Winkelmann J, Allen RP. Guidelines for the first-line treatment of restless legs syndrome/ Willis–Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and theRLSfoundation. Sleep Med 2016;21:1-11.
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3 Trenkwalder C, Beneš H, Grote L, García-Borreguero D, Högl B, Hopp M, Bosse B, Oksche A, Reimer K, Winkelmann J, Allen RP, Kohnen R; RELOXYN Study Group. Prolonged release oxycodonenaloxone for treatment of severe restless legs syndrome after failure of previous treatment: a double-blind, randomised, placebo-controlled trial with an open-label extension. Lancet Neurol. 20;12(12):1141-50. 4 Högl B, Garcia-Borreguero D, Trenkwalder C, Ferini-Strambi L, Hening W, Poewe W, Brenner SS, Fraessdorf M, Busse M, Albrecht S, Allen RP. Efficacy and augmentation during 6 months of doubleblind pramipexole for restless legs syndrome. Sleep Med 2011;12(4):351-60.
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5 Vetrugno R, Contin M, Baruzzi A, Provini F, Plazzi G, Montagna P. Polysomnographic and pharmacokinetic findings in levodopa-induced augmentation of restless legs syndrome. Mov Disord. 2006 Feb;21(2):254-8.
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6 Mitterling T, Frauscher B, Falkenstetter T, Gschliesser V, Ehrmann L, Gabelia D, Brandauer E, Poewe W, Högl B. Is there a polysomnographic signature of augmentation in restless legs syndrome? Sleep Med. 2014 Oct;15(10):1231-40.
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7 Allen RP, Earley CJ. Augmentation of the restless legs syndrome with carbidopa/levodopa. Sleep. 1996;19(3):205-13. 8 Maestri M, Fulda S, Ferini-Strambi L, Zucconi M, Marelli S, Staedler C, Bassetti CL, Manconi M. Polysomnographic record and successful management of augmentation in restless legs syndrome/Willis-Ekbom disease. Sleep Med 2014;15(5):570-5. 9 Garcia-Borreguero D, Larrosa O, de la Llave Y, Granizo JJ, Allen R. Correlation between rating scales and sleep laboratory measurements in restless legs syndrome. Sleep Med 2004;5(6):561-5. 10 Allen RP, Picchietti DL, Garcia-Borreguero D, Ondo WG, Walters AS, Winkelman JW, et al. Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group [IRLSSG] consensus criteria e history, rationale, description, and significance. Sleep Med 2014;15:860-73. 11 Walters AS1, LeBrocq C, Dhar A, Hening W, Rosen R, Allen RP, Trenkwalder C; International Restless Legs Syndrome Study Group. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome Sleep Med 2003;4(2):121-32.
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ACCEPTED MANUSCRIPT 12 Kohnen R et al.: Rating of daytime and nighttime symptoms in RLS: validation of the RLS-6 scale of restless legs syndrome/Willis-Ekbom disease. Sleep Med 2016; 20: 116-22 13 Hays RD, Stewart AL. Sleep Measures. In: Stewart AL, Ware JEJ, editor. Measuring functioning and well-being; the medical outcomes study approach Duke edition. Duke University Press; 1992. pp. 235–259.
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14 American Academy of Sleep Medicine. International classification of sleep disorders, 2nd ed.; diagnostic and coding manual. Westchester, IL: American Academy of Sleep Medicine, 2005. 15 W. R. Ruehland, P.D. Rochford, F. J.O’Donoghue, R. J. Pierce, P. Singh, and A. T.Thornton, “The new AASMcriteria for scoring hypopneas: impact on the apnea hypopnea index,” Sleep 2009;32(2):150–157.
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16 Ferri R, Manconi M, Plazzi G, Bruni O, Cosentino FI, Ferini-Strambi L, Zucconi M. Leg movements durings wakefulness in restless legs syndrome: time structure and relationships with periodic movements during sleep. Sleep Med 2012;13(5):539-35.
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17 HornyakM, Kopasz M, Feige B, Riemann D, Voderholzer U. Variability of periodic leg movements in various sleep disorders: implications for clinical and pathophysiologic studies. Sleep 2005;28:331–5. 18 Ferri R, Fulda S, Manconi M, Högl B, Ehrmann L, Ferini-Strambi L, et al. Night-to-night variability of periodic leg movements during sleep in restless legs syndrome and periodic limb movement disorder: comparison between the periodicity index and the PLMS index. Sleep Med 2013;14:293–6.
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19 Frauscher B, Gschliesser V, Brandauer E, El-Demerdash E, Kaneider M, Rücker L, et al. The severity range of restless legs syndrome (RLS) and augmentation in a prospective patient cohort: association with ferritin levels. Sleep Med 2009;10:611–15. 20 Mitterling T, Högl B, Schönwald SV, Hackner H, Gabelia D, Biermayr M, Frauscher B. Sleep and Respiration in 100 Healthy Caucasian Sleepers--A Polysomnographic Study According to American Academy of Sleep Medicine Standards. Sleep 2015 ;38(6):867-75.
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21 Oertel W, Trenkwalder C, Benes H, Ferini-Strambi L, Högl B, Poewe W et al. Long-term safety and efficacy of rotigotine transdermal patch for moderate-to-severe idiopathic restless legs syndrome: a 5-year open-label extension study. The Lancet Neurology 2011:10(8):710 – 720. 22 Paulus W, Trenkwalder C. Less is more: pathophysiology of dopaminergic-therapy-related augmentation in restless legs syndrome. Lancet Neurol 2006;5:878–86. 23 Trenkwalder C, Högl B, Benes H, Kohnen R. Augmentation in restless legs syndrome is associated with low ferritin. Sleep Med 2008;9:572–4. 24 Frauscher B, Gschliesser V, Brandauer E, El-Demerdash E, Kaneider M, Rücker L, et al. The severity range of restless legs syndrome (RLS) and augmentation in a prospective patient cohort: association with ferritin levels. Sleep Med 2009;10:611–15.
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ACCEPTED MANUSCRIPT Table 1. Demographic and clinical characteristics of the study population
62.91 (12.64) 74 (63.79) 29.53 (6.50)
Polyneuropathy, n (%)
34 (29.31)
20 (21.05)
p-value 0.036 0.237 0.141
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Age (years), mean(SD) Sex, F (%) BMI (kg/m2), mean(SD)
Patients with severe RLS without augmentation (N=95) 59.06 (13.87) 53 (55.79) 28.21 (6.35)
RLS patients with augmentation (N=116)
0.171
Sleep apnea, n (%)
52 (44.82)
33 (34.74)
Sleep apnea efficiently treated, n (%)
4 (3.45)
3 (3.16)
Serum ferritin (ng/ml), mean (SD)
110.09 (99.48)
126.07 (94.66)
Transferrin (ng/ml), mean (SD)
277.34 (44.91) (N=95)
271.10 (43.95) (N=82)
0.353
Transferrin saturation (%), mean (SD)
22.50 (9.45) (N=93)
23.89 (9.30) (N=80)
0.332
IRLS, mean (SD)
32.13 (4.47)
29.97 (7.54)
0.011
0.137
0.569
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0.237
Table 2. Severity of the RLS symptoms according to IRLS-item 8
0 1 2 3 4
RLS patients with augmentation (N=116)
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IRLS item 8 (points)
Patients with severe RLS without augmentation (N=95)
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0 (0%) 2 (2.11%) 2 (1.72%) 4 (4.21%) 15 (12.93%) 14 (14.74%) 53 (45.69%) 41 (43.16%) 46 (39.66%) 34 (35.79%) All the data is presented as absolute frequency (% of respective group), 0 = no symptoms, 1= symptoms less than 1 hour per day, 2= symptoms 1-3 hours per day, 3= symptoms 3-8 hours per day, 4 = symptoms 8 hours per day or more
ACCEPTED MANUSCRIPT Table 3: Overview of the medication combinations taken by the RLS patients on the day when the PSG was performed
Patients with severe RLS without augmentation (N=95)
0
4
0 10 4 7 21
1 14 10 14 39
No therapy Mono therapy L-Dopa Dopamine agonists α-2-δ ligands Opioids Total Double therapy L-Dopa + Dopamine agonists L-Dopa + α-2-δ ligands L-Dopa + Opioids Dopamine agonists + α-2-δ ligands Dopamine agonists + Opioids α-2-δ agonists + Opioids Total Triple therapy L-Dopa + Dopamine agonists+ α-2-
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2 2 2 18 40 11 75
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RLS patients with augmentation (N=116)
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Medication
δ ligands
2
0
5
2
3
2
9
8
19
12
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L-Dopa + Dopamine agonists+ Opioids L-Dopa + α-2-δ ligands+ Opioids Dopamine agonists + α-2-δ ligands+ Opioids Total Quadruple therapy L-Dopa + dopamine agonists + α2-δ agonists + Opioids
1 0 0 8 16 15 40
1
0
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Table 4: Distribution of the RLS patients according to the different classes of medication used (alone or in combination) on the day when the PSG was performed
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RLS patients with augmentation (N=116)
L-Dopa Dopamine agonists α-2-δ ligands Opioids
17 87 50 78
Patients with severe RLS without augmentation (N=95) 6 49 43 57
p-value p= 0.053 P< 0.001 p= 0.753 p= 0.276
ACCEPTED MANUSCRIPT Table 5. Doses of the dopamine agonists (in mono- and combination therapy) used by RLS patients on the day when the PSG was performed
Ropinirole, mean (SD) Pramipexole, mean (SD) Rotigotine, mean (SD) Piribedil, mean (SD) Cabergoline, mean (SD)
N=12 5.15(11.01) N=23 0.42 (0.17) N=51 1.96 (0.66) N=0 0 N=1 0.50
LED (mg)
102.92 (220.27) 41.65 (16.84) 58.82 (19.86) 0 33.50
N=7 1.25 (0.72) N=17 0.28 (0.15) N=23 1.78 (0.74) N=1 100 N=1 1
LED (mg)
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SD=standard deviation, LED=Levodopa equivalent dose
Dosage (mg)
p-value
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Patients with severe RLS without augmentation (N=95)
25.00 (4.43)
0.400
27.71 (14.80)
0.511
53.48 (22.08)
0.002
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RLS patients with augmentation (N=116)
100
0.273
67
0.887
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p-value
70.60 (14.55)
72.27 (13.22)
0.421
275.33 (56.66)
281.83 (51.48)
0.991
28.45 (33.83)
29.21 (28.93)
0.391
71.74 (13.21) 9.95 (10.9) 18.33 (9.03)
76.85 (10.58) 6.84 (7.72) 16.30 (7.9)
0.005 0.030 0.111
114.05 (78.38)
101.75 (65.58)
0.263
54.09 (43.09) 37.36 (53.22) 93.11 (60.07)
53.86 (51.97) 45.24 (54.24) 78.75 (58.92)
0.973 0.324 0.105
6.83 (15.15)
5.66 (3.43)
0.487
25.95 (13.65)
27.29 (14.39)
0.520
6.43 (9.07)
6.07 (18.61)
0.868
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Sleep latency (min) Stage 1+2 (%) Stage 3 (%) REM (%) REM latency (min) PLMI PLMS PLMW Awakening index Awakenings number AHI
Patients with severe RLS without augmentation (N=84)
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Sleep efficiency (%) TST (min)
RLS patients with augmentation (N=99)
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Table 6. PSG parameters of the RLS patients with valid PSG
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All the data is presented as mean (SD), SD= standard deviation, TST=total sleep time. Sleep efficiency was calculated as % of sleep during time in bed; sleep stages were calculated as % of TST; index of periodic leg movements (PLM) was calculated per hour of time in bed (PLMI), per hour of sleep (PLMS index), and per hour of wakefulness (PLMW index), Awakening index= total number of awakenings in TST
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Patients with severe RLS without augmentation (N=95)
p-value
Sleep efficiency (%) TST (min)
62.30 (24.53) 241.50 (98.35)
65.97 (22.43)
0.262 0.306
PLMI PLMI > 15, n (%)
65.65 (54.64)
61.51 (56.64)
96 (82.75)
72 (75.79%)
0.592 0.211
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254.97 (90.60)
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Data is presented as mean (SD), SD= standard deviation, TST=total sleep time, Sleep efficiency was calculated as % of sleep during time in bed; index of periodic leg movements (PLM) was calculated per hour of time in bed (PLM index)
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RLS-augmentation
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n=95
17 patients
11 patients
SE<30%
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SE<30% TIB<3h
RLS+augmentation valid PSG n=99
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RLS-augmentation valid PSG n=84
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Figure 1. Study tree of RLS patients
SE=sleep efficiency, TIB= time in bed, RLS=restless legs syndrome, PSG=video polysomnography, “RLS+augmentation” =RLS patients with augmentation, “RLS-augmentation”=patients with severe RLS without augmentation
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Figure 2. Representation of PLM index in sleep and wakefulness for the RLS patients with and without augmentation
PLMS=periodic limb movements in sleep index, PLMW=periodic limb movements in wakefulness index
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PLM Index in wakefulness in RLS patients with augmentation 250
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Figure 3. Representation of PLM index in sleep and wakefulness in relation to severity of RLS on the IRLS
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PLM Index in sleep in RLS patients with augmentation 400 350 300 200 150
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PLMS=periodic limb movements in sleep index, PLMW=periodic limb movements in wakefulness index, IRLS=International restless legs syndrome rating scale
ACCEPTED MANUSCRIPT • RLS patients with augmentation have very disturbed sleep • ·
Leg movements increased, mainly in wakefulness, despite high
dopaminergic doses Insufficiently treated RLS and severely augmented RLS had similar
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• ·
PSG results
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Augmentation could represent a severe form of RLS and not a
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different phenomenon
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S1389-9457(18)30161-8
DOI:
10.1016/j.sleep.2018.04.010
Reference:
SLEEP 3688
To appear in:
Sleep Medicine
Received Date: 27 December 2017 Revised Date:
22 April 2018
Accepted Date: 25 April 2018
Please cite this article as: Steinke SS, Trenkwalder C, Zimmermann J, Sixel-Döring F, Muntean M-L, Polysomnographic findings in restless legs syndrome (RLS) patients with severe augmentation, Sleep Medicine (2018), doi: 10.1016/j.sleep.2018.04.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Original article
Polysomnographic findings in restless legs syndrome (RLS) patients with severe augmentation Sophia Stephanie Steinke a,b, Claudia Trenkwalder MD a,b, Johannes Zimmermann c, Friederike SixelDöring MD b,d, Maria-Lucia Muntean MD, PhD b a
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Department of Neurosurgery, University Medical Center, Göttingen, Germany Paracelsus Elena Hospital, Kassel, Germany c Psychologische Hochschule Berlin, Germany d Department of Neurology, Philips University, Marburg, Germany b
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Title character count: 92 Word count: Abstract: 205 Article: 3498 References: 24 Tables: 7 Figures: 3 Running title: PSG findings in RLS augmentation
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*Corresponding author: Maria-Lucia Muntean, [email protected]
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ACCEPTED MANUSCRIPT Abstract Background and objectives: Augmentation can occur frequently in restless legs syndrome (RLS) patients treated with dopaminergic agents. Video-polysomnographic (PSG) data from augmented RLS patients are scant. The aim of this study was to evaluate PSG findings in augmented RLS patients and compare them with those of non-augmented RLS patients.
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Patients and methods: Valid PSG data were analyzed from 99 augmented and 84 non-augmented RLS inpatients who underwent one night PSG.
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Results: Both patient groups showed a high subjective burden of RLS symptoms. The mean scores on the International RLS Study Group Rating Scale (IRLS) were significantly higher in the group with augmentation than in the group without. The periodic leg movement index (PLMI) was increased in both groups, mostly on account of the PLM in wakefulness (PLMW). Both groups presented a reduced sleep efficiency and an increased sleep latency. The levodopa equivalent dose (LED) was significantly higher in the augmented group.
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Conclusions: Our study confirms that RLS patients with augmentation have disturbed sleep due to high amount of leg movements and fragmented sleep. Overall, however, polysomnographic characteristics were not different between insufficiently treated RLS and severely augmented RLS patients, implying that augmentation could represent a severe form of RLS and not a different phenomenon.
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Key words: Restless Legs Syndrome, Augmentation, Polysomnography
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1. Introduction
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Restless legs syndrome (RLS) is a common neurological disorder with severe sleep disturbance, which has a clinically significant negative impact on 2-3% of the general adult population.[1] Augmentation is characterized by a worsening of symptom severity; ie, an earlier onset of symptoms in the afternoon or evening compared to before treatment initiation, a shorter latency of symptoms at rest and a spreading of symptoms to other body parts.[2] Augmentation is currently a therapeutic challenge for neurologists and sleep medicine specialists. Long-term treatment with dopaminergic agents results in an increased rate of augmentation for up to 42-68% of those patients who are monitored for 10 years. [3, 4]
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There are scant video-polysomnographic (PSG) data in RLS patients with augmentation, and the data that are available come either from case reports [5] or from the limited number of studies that compared small numbers of patients with and without augmentation.[6,7,8] It has been assumed that periodic limb movements (PLMs), and motor activity in general, increase during augmentation. [9] However, one study failed to show the expected increase in the number of PLMs in augmented patients, implying that dopaminergic agents still act on PLMs in these patients. [6] Studies using the suggested immobilization test (SIT) have reported higher motor activity during wake periods, implying that RLS augmentation is a phenomenon that manifests mostly in wakefulness. [6]
2. Patients and methods 2.1. Patients
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The aim of the present study was to compare the PSG characteristics of a large cohort of augmented RLS patients to a cohort of RLS patients without augmentation. In particular, we sought to compare sleep parameters and motor activity in relation to the medication taken, and to elucidate the relation between PLMS and dopaminergic dosages in augmentation.
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Two hundred and eleven inpatients with a definite diagnosis of RLS consecutively admitted to the Paracelsus Elena Hospital in Kassel between January 2016 and February 2017 were included in this study and underwent one night of PSG. Neurologists from the ambulatory setting referred RLS patients to the clinic due to severe RLS, refractory RLS, augmentation, or severe side effects of the medications used to treat RLS. Board-certified sleep medicine specialists (CT, FSD, MLM) interviewed all patients on admission to assess RLS diagnosis. The International RLS Study Group (IRLSSG) 2014 essential diagnostic criteria were used to confirm RLS. 10 Patients who had less than 3 hours time in bed (TIB) during the night in the sleep laboratory or a sleep efficiency (SE) of less than 30% were excluded from the statistical analysis of the extended sleep parameters, but included in the cohort.
2.2. Methods
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ACCEPTED MANUSCRIPT Augmentation was defined according to the NIH criteria [1] and was assessed in each patient individually. The RLS patients were subsequently divided into two groups for further comparisons: RLS patients with augmentation and without augmentation. The group without augmentation consisted of RLS patients who proved to be refractory to treatment in the ambulatory setting, who were severely affected, or who had side effects of the medication previously used for treating RLS.
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All patients gave their written informed consent before being enrolled in the study and prior to the sleep study. The study was approved by the Ethical Committee of the Landesärztekammer Hessen, Germany in the context of RLS in polysomnographic and sleep studies. All patients were inpatients and PSG was recorded within 3 days of admission. Patients filled out the International RLS Study Group Rating Scale(IRLS) 11, Restless Legs Syndrome-6 Scale (RLS-6) 12 and the Medical Outcomes Study sleep scale (MOS)13 on the day of the PSG study.
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Demographic characteristics and concomitant diseases (including polyneuropathy and sleep apnea) were collected. Medications used for RLS on the day of the PSG was recorded, which tended to be the medication previously prescribed by the neurologists in the ambulatory setting.
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Ferritin, transferrin, and transferrin saturation were measured as part of the routine laboratory examination upon admission.
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Standard cardiorespiratory PSG (PSG; Xltec: Excel Tech Ltd; Oakville, Ontario; Canada) was applied according to AASM criteria 14. All patients were documented with an infrared video recording synchronized to the PSG. Sleep (including sleep stages), PLMs, and apneas were scored manually by a trained sleep technician. PLMs were scored in sleep and in wakefulness only if they occurred in a series of at least four consecutive movements lasting 0.5 to 5 seconds each with an intermovement interval of 4 to 90 seconds, in accordance with international scoring rules. [14] Sleep efficiency was defined as total sleep time (TST) / TIB. Quantitative analysis of sleep stages was calculated as a percentage of TST. Sleep apneas were defined as an apnea-hypnea index (AHI) of 5 or more in accordance with Ruehland et al. 15 For patients already undergoing ventilation therapy for sleep apnea, the PSG was performed with ongoing ventilation and efficacy of CPAP therapy was controlled.
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All sleep evaluations were reviewed and supervised by board-certified sleep specialists (FSD, CT or MLM).
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2.3. Statistical analysis
The abovementioned parameters were compared between RLS patients with and without augmentation. For categorical variables, we compared frequencies using Pearson’s chi square test or Fisher’s exact test. For continuous variables, we compared mean values using t-tests, or (in the case of non-normally distributed variables) Mann-Whitney-u tests. To control the family-wise error rate the Holm-Bonferroni method was used. The program used for the calculation is Statistica version 13.1 by Dell Inc.
3. Results The final study population consisted of 116 RLS patients with augmentation and 95 RLS patients without augmentation who fulfilled the inclusion criteria. The complete analysis of the PSG parameters was performed in 99 RLS patients with augmentation and 84 RLS patients without augmentation. The study tree is presented in Fig.1. 4
ACCEPTED MANUSCRIPT The two groups were similar in terms of demographics: there were no statistically significant differences between the two groups regarding age, body mass index (BMI), sex, and concomitant diseases (polyneuropathy, sleep apnea) (Table 1).
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Total scores of the IRLS rating scale demonstrated severe disease burden in both groups. The mean score on the IRLS in the group with augmentation was 32.13 ± 4.47, which was significantly higher than in the group without augmentation (29.97 ± 7.54, p=0.01). The RLS-6 and MOS sleep scores were high in both groups, but not significantly different. In fact, the RLS-6 mean score in the augmentation group was 35.61 ± 10.11 compared to 34.91 ± 11.89 in the group without augmentation, p=0.66; and MOS-sleep mean score in the augmentation group was 39.46 ± 5.14 compared to 39.39± 4.88 in the group without augmentation, p=0.93.
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When the amount of daily RLS (item 8 of IRLS) was used as a measure of daytime RLS symptoms, no statistically significant difference was noticed between RLS patients with and without augmentation (p=0.295) (Table 2).
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Serum ferritin levels were lower in the RLS group with augmentation but this difference failed to reach statistical significance (Table 1). The levels of transferrin and transferrin saturation did not differ between the two groups.
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Medications taken by patients during the day when the PSG was performed are presented in Tables 3 and 4. A combination of two or more medications to treat RLS symptoms was used more often in RLS patients with augmentation than in those without (p<0.001). Significantly more RLS patients with augmentation took levodopa and dopamine agonists compared to RLS patients without augmentation (p=0.053 and p<0.001, respectively) (Table 4). When the dopamine agonists were considered separately, we determined that more patients in the augmented group took rotigotine alone or in combination treatment compared to the group without augmentation (p=0.003). But out of the 51 patients with treatment of rotigotine in the RLS group, only seven were on monotherapy with rotigotine. These seven patients were treated with a dosage of 2 ± 1mg rotigotine.
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For the other dopamine agonists no statistically significant differences were observed (Table 5) (Mann-Whitney-u Test for non-normally distributed variables). The mean levodopa equivalent dose (LED) was significantly higher in the augmentation group (68.76 ± 154.22mg), than in the group without augmentation (29.93 ± 43.23mg) (p< 0.005). There were no significant differences in the number of patients using α-2-δ ligands or opioids in the two groups (Table 4). The results of the PSG studies are shown in Table 6. Both groups presented reduced sleep efficiency and increased sleep latency. There was no difference regarding REM sleep between the groups. RLS patients with and without augmentation showed an increased amount of light sleep and a reduced amount of slow-wave sleep. The PLMI was increased in both groups, mostly on account of the PLM in wakefulness (PLMW). PLMW index was greatly increased in all RLS patients, and while it was greater in those with augmentation compared to the non-augmented patients this difference did not reach statistical significance (p>0.05). (Table 6, Figure 2). We subsequently analyzed the PLMI of all RLS patients, including those with sleep efficiency of less than 30%, and still found no difference between the augmented (65.65 ± 54.64) and the non augmented group (61.51 ± 54.64) (p=0.592) (Table 7).
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The awakening index did not differ between the groups (p=0.487). The AHI was slightly increased in both groups and was not significantly different between them (p=0.868). When we excluded the patients with insufficiently- or untreated sleep apnea, no significant difference in PLMS index between the groups (PLMS index: RLS patients with augmentation (n=35): 23.05 ± 34.46, RLS patients without augmentation (n=43): 39.74 ± 45.47, p= 0.077) was noted. 4. Discussion
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The results of this study confirmed the disturbed sleep and high amount of leg movements in RLS patients with augmentation, but failed to show a significant difference compared to RLS patients without augmentation. PLMW index was higher than PLMS index in RLS patients regardless of the presence of augmentation. It has been shown in other polysomnographic studies that RLS patients have increased PLMW compared to controls. [16] In our study, even though it did not reach statistical significance, there was a trend to more PLMW in augmented patients compared to those without augmentation, suggesting that augmentation is more a problem of wakefulness than of sleep. Mitterling et al. also implied in their study using the suggested immobilization test (SIT) that RLS augmentation seems to be a phenomenon that manifests predominantly during wakefulness, both during the day and at night. [6]
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The PLMW index values in our study population were higher than those published by Mitterling et al. [6]: PLMW index in RLS patients with augmentation in our study (93.11 [6-218] vs. 34.8 [7.2–259.4]). The PLMW index in non-augmented patients was also higher: 78.75 [3-281] vs. 36.2 [7.9–155.7]. This could be partly explained by the fact that the patients in the present study had more severe RLS than those in the study by Mitterling et al. (IRLS scores: RLS with augmentation 31.75 [10-39] vs. 29 [18– 39], RLS without augmentation 29.63 [0-39] vs. 11 [0–32]). [6] Another explanation could be the night-to-night variability in the PLMI in RLS patients. This has been well established in previous studies. [17, 18] The periodicity index was not accounted for in our study. Mitterling et al. who calculated the index in their study did not find any difference in periodicity of leg movements between RLS patients with and without augmentation. [6] The patients in the control group had severe RLS. This explains the high number of limb movements in these patients. The correlation between the severity of RLS measured by the IRLS and the PLMS index was previously demonstrated by Garcia-Borreguero et al. [9] In the present study, however we could not demonstrate this correlation. In our study, the subjective severity of RLS measured by the IRLS was worse in patients with augmentation than in those without. The results are in line with other studies that showed a correlation between the presence of augmentation and higher scores on RLS-specific scales. [6, 19] The PSG data in the current study objectively confirm the subjective complaints of augmented RLS
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For the validity of the PSG data, RLS patients with and without augmentation who had less than 3 hours TIB or less than 30% sleep efficiency where excluded from the analysis of the sleep parameters. Altogether, 17 (14.65%) augmented patients and 11 (11.58%) patients without augmentation showed such a poor quality of sleep that the complete PSG data were not exploitable. This further proves that the high impact of very severe RLS and augmentation on quality of sleep. In these patients only PLMI and sleep efficiency were considered for analysis.
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All RLS patients showed a reduced amount of slow wave sleep, consistent with previous findings [6]. The amount of slow wave sleep was lower than the values published in healthy adults, regardless of age or gender (≤ 30 y 20.7 (15.2–37.5)% and > 60 y: 14.9 (2.4–35.6)%. 20
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Overall, the augmented group showed a more complex therapeutic concept (multi-drug treatment), higher amount of dopamine agonists, and a higher levodopa-equivalent dose than the patients in the non-augmented group, which is in line with the definition of augmentation as a dopaminergic overtreatment in RLS. [2] Levodopa, having the shortest half-life from all the dopaminergic agents was significantly associated with augmentation even in combination with long-acting dopamine agonists. The dose of rotigotine in RLS patients with augmentation was significantly higher than in those without augmentation. Also, most of the patients treated with rotigotine (44/51; 86,28%) in the group of RLS patients with augmentation received a combination therapy with additional dopaminergic substances. This finding is in line with previous studies which show that rotigotine could induce augmentation only in higher dosages. [21] Our data support the theory that augmentation is a syndrome characterized by a severely increased concentration of dopamine in the central nervous system. [22]
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The serum ferritin levels were slightly reduced in the augmented group but did not reach statistical significance. This is in contrast with other studies that showed lower serum ferritin levels in patients with augmentation. [23,24] Limitations
One potential limitation is the patient selection bias, especially of the non-augmented group. Our hospital is a national specialized center for RLS, therefore, the most severe cases are referred to us. The fact that the patients in the control group had such severe RLS could be a possible bias and explain the lack of statistically significant difference between the groups. It is also possible that some patients with mild early augmentation were included in the control group. All augmented patients had daytime RLS symptoms. We unfortunately did not have data on the exact time of day that symptoms occurred. Since not all patients filled the augmentation severity
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ACCEPTED MANUSCRIPT ratinge scale (ASRS), we used item 8 from the IRLS to account for the amount of daytime RLS symptoms. Due to organizational reasons the PSG was performed within the first three days after admission in the hospital, and the augmentation criteria very evaluated upon admission. 5. Conclusion
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In conclusion, our study confirms that RLS patients with augmentation have disturbed sleep due to the high amount of leg movements and fragmented sleep. The leg movements are increased, especially in wakefulness, despite high dopaminergic medication dosages. Overall, however, polysomnographic characteristics were not different between insufficiently treated RLS and severely augmented RLS patients, implying that augmentation represents a severe form of RLS, but is also characterized by a distinct phenotype of paradoxical response to dose increase during long-term therapy, whereas short-term increases of dopaminergic drugs temporarily improve symptoms.
Funding source
The publication of the study was supported by an unrestricted grant from UCB Pharma. Financial disclosure related to research covered in this article:
Table and figure legends
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Full financial disclosures for the last 12 months:
Figure 1. Study tree of RLS patients
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Figure 2. Representation of PLM index in sleep and wakefulness for the RLS patients with and without augmentation
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Figure 3. Representation of PLM index in sleep and wakefulness in relation to severity of RLS on the IRLS
Table 1. Demographic and clinical characteristics of the study population Table 2. Severity of the RLS symptoms according to IRLS-item 8 Table 3. Overview of the medication combinations taken by the RLS patients on the day when the PSG was performed Table 4. Distribution of the RLS patients according to the different classes of medication used (alone or in combination) on the day when the PSG was performed Table 5. Doses of the dopamine agonists (in mono- and combination therapy) used by RLS patients on the day when the PSG was performed
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Table 7. PSG parameters of the all 221 RLS patients
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ACCEPTED MANUSCRIPT References
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17 HornyakM, Kopasz M, Feige B, Riemann D, Voderholzer U. Variability of periodic leg movements in various sleep disorders: implications for clinical and pathophysiologic studies. Sleep 2005;28:331–5. 18 Ferri R, Fulda S, Manconi M, Högl B, Ehrmann L, Ferini-Strambi L, et al. Night-to-night variability of periodic leg movements during sleep in restless legs syndrome and periodic limb movement disorder: comparison between the periodicity index and the PLMS index. Sleep Med 2013;14:293–6.
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19 Frauscher B, Gschliesser V, Brandauer E, El-Demerdash E, Kaneider M, Rücker L, et al. The severity range of restless legs syndrome (RLS) and augmentation in a prospective patient cohort: association with ferritin levels. Sleep Med 2009;10:611–15. 20 Mitterling T, Högl B, Schönwald SV, Hackner H, Gabelia D, Biermayr M, Frauscher B. Sleep and Respiration in 100 Healthy Caucasian Sleepers--A Polysomnographic Study According to American Academy of Sleep Medicine Standards. Sleep 2015 ;38(6):867-75.
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21 Oertel W, Trenkwalder C, Benes H, Ferini-Strambi L, Högl B, Poewe W et al. Long-term safety and efficacy of rotigotine transdermal patch for moderate-to-severe idiopathic restless legs syndrome: a 5-year open-label extension study. The Lancet Neurology 2011:10(8):710 – 720. 22 Paulus W, Trenkwalder C. Less is more: pathophysiology of dopaminergic-therapy-related augmentation in restless legs syndrome. Lancet Neurol 2006;5:878–86. 23 Trenkwalder C, Högl B, Benes H, Kohnen R. Augmentation in restless legs syndrome is associated with low ferritin. Sleep Med 2008;9:572–4. 24 Frauscher B, Gschliesser V, Brandauer E, El-Demerdash E, Kaneider M, Rücker L, et al. The severity range of restless legs syndrome (RLS) and augmentation in a prospective patient cohort: association with ferritin levels. Sleep Med 2009;10:611–15.
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ACCEPTED MANUSCRIPT Table 1. Demographic and clinical characteristics of the study population
62.91 (12.64) 74 (63.79) 29.53 (6.50)
Polyneuropathy, n (%)
34 (29.31)
20 (21.05)
p-value 0.036 0.237 0.141
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Age (years), mean(SD) Sex, F (%) BMI (kg/m2), mean(SD)
Patients with severe RLS without augmentation (N=95) 59.06 (13.87) 53 (55.79) 28.21 (6.35)
RLS patients with augmentation (N=116)
0.171
Sleep apnea, n (%)
52 (44.82)
33 (34.74)
Sleep apnea efficiently treated, n (%)
4 (3.45)
3 (3.16)
Serum ferritin (ng/ml), mean (SD)
110.09 (99.48)
126.07 (94.66)
Transferrin (ng/ml), mean (SD)
277.34 (44.91) (N=95)
271.10 (43.95) (N=82)
0.353
Transferrin saturation (%), mean (SD)
22.50 (9.45) (N=93)
23.89 (9.30) (N=80)
0.332
IRLS, mean (SD)
32.13 (4.47)
29.97 (7.54)
0.011
0.137
0.569
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0.237
Table 2. Severity of the RLS symptoms according to IRLS-item 8
0 1 2 3 4
RLS patients with augmentation (N=116)
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IRLS item 8 (points)
Patients with severe RLS without augmentation (N=95)
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0 (0%) 2 (2.11%) 2 (1.72%) 4 (4.21%) 15 (12.93%) 14 (14.74%) 53 (45.69%) 41 (43.16%) 46 (39.66%) 34 (35.79%) All the data is presented as absolute frequency (% of respective group), 0 = no symptoms, 1= symptoms less than 1 hour per day, 2= symptoms 1-3 hours per day, 3= symptoms 3-8 hours per day, 4 = symptoms 8 hours per day or more
ACCEPTED MANUSCRIPT Table 3: Overview of the medication combinations taken by the RLS patients on the day when the PSG was performed
Patients with severe RLS without augmentation (N=95)
0
4
0 10 4 7 21
1 14 10 14 39
No therapy Mono therapy L-Dopa Dopamine agonists α-2-δ ligands Opioids Total Double therapy L-Dopa + Dopamine agonists L-Dopa + α-2-δ ligands L-Dopa + Opioids Dopamine agonists + α-2-δ ligands Dopamine agonists + Opioids α-2-δ agonists + Opioids Total Triple therapy L-Dopa + Dopamine agonists+ α-2-
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2 2 2 18 40 11 75
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RLS patients with augmentation (N=116)
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Medication
δ ligands
2
0
5
2
3
2
9
8
19
12
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L-Dopa + Dopamine agonists+ Opioids L-Dopa + α-2-δ ligands+ Opioids Dopamine agonists + α-2-δ ligands+ Opioids Total Quadruple therapy L-Dopa + dopamine agonists + α2-δ agonists + Opioids
1 0 0 8 16 15 40
1
0
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Table 4: Distribution of the RLS patients according to the different classes of medication used (alone or in combination) on the day when the PSG was performed
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RLS patients with augmentation (N=116)
L-Dopa Dopamine agonists α-2-δ ligands Opioids
17 87 50 78
Patients with severe RLS without augmentation (N=95) 6 49 43 57
p-value p= 0.053 P< 0.001 p= 0.753 p= 0.276
ACCEPTED MANUSCRIPT Table 5. Doses of the dopamine agonists (in mono- and combination therapy) used by RLS patients on the day when the PSG was performed
Ropinirole, mean (SD) Pramipexole, mean (SD) Rotigotine, mean (SD) Piribedil, mean (SD) Cabergoline, mean (SD)
N=12 5.15(11.01) N=23 0.42 (0.17) N=51 1.96 (0.66) N=0 0 N=1 0.50
LED (mg)
102.92 (220.27) 41.65 (16.84) 58.82 (19.86) 0 33.50
N=7 1.25 (0.72) N=17 0.28 (0.15) N=23 1.78 (0.74) N=1 100 N=1 1
LED (mg)
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SD=standard deviation, LED=Levodopa equivalent dose
Dosage (mg)
p-value
RI PT
Dosage (mg)
Patients with severe RLS without augmentation (N=95)
25.00 (4.43)
0.400
27.71 (14.80)
0.511
53.48 (22.08)
0.002
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RLS patients with augmentation (N=116)
100
0.273
67
0.887
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p-value
70.60 (14.55)
72.27 (13.22)
0.421
275.33 (56.66)
281.83 (51.48)
0.991
28.45 (33.83)
29.21 (28.93)
0.391
71.74 (13.21) 9.95 (10.9) 18.33 (9.03)
76.85 (10.58) 6.84 (7.72) 16.30 (7.9)
0.005 0.030 0.111
114.05 (78.38)
101.75 (65.58)
0.263
54.09 (43.09) 37.36 (53.22) 93.11 (60.07)
53.86 (51.97) 45.24 (54.24) 78.75 (58.92)
0.973 0.324 0.105
6.83 (15.15)
5.66 (3.43)
0.487
25.95 (13.65)
27.29 (14.39)
0.520
6.43 (9.07)
6.07 (18.61)
0.868
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Sleep latency (min) Stage 1+2 (%) Stage 3 (%) REM (%) REM latency (min) PLMI PLMS PLMW Awakening index Awakenings number AHI
Patients with severe RLS without augmentation (N=84)
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Sleep efficiency (%) TST (min)
RLS patients with augmentation (N=99)
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Table 6. PSG parameters of the RLS patients with valid PSG
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All the data is presented as mean (SD), SD= standard deviation, TST=total sleep time. Sleep efficiency was calculated as % of sleep during time in bed; sleep stages were calculated as % of TST; index of periodic leg movements (PLM) was calculated per hour of time in bed (PLMI), per hour of sleep (PLMS index), and per hour of wakefulness (PLMW index), Awakening index= total number of awakenings in TST
ACCEPTED MANUSCRIPT Table 7. PSG parameters of the all 221 RLS patients RLS patients with augmentation (N=116)
Patients with severe RLS without augmentation (N=95)
p-value
Sleep efficiency (%) TST (min)
62.30 (24.53) 241.50 (98.35)
65.97 (22.43)
0.262 0.306
PLMI PLMI > 15, n (%)
65.65 (54.64)
61.51 (56.64)
96 (82.75)
72 (75.79%)
0.592 0.211
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254.97 (90.60)
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Data is presented as mean (SD), SD= standard deviation, TST=total sleep time, Sleep efficiency was calculated as % of sleep during time in bed; index of periodic leg movements (PLM) was calculated per hour of time in bed (PLM index)
ACCEPTED MANUSCRIPT Severe RLS inpatients who underwent PSG
RLS-augmentation
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RLS+augmentation
n=95
17 patients
11 patients
SE<30%
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n=116
SE<30% TIB<3h
RLS+augmentation valid PSG n=99
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TIB<3h
RLS-augmentation valid PSG n=84
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Figure 1. Study tree of RLS patients
SE=sleep efficiency, TIB= time in bed, RLS=restless legs syndrome, PSG=video polysomnography, “RLS+augmentation” =RLS patients with augmentation, “RLS-augmentation”=patients with severe RLS without augmentation
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Figure 2. Representation of PLM index in sleep and wakefulness for the RLS patients with and without augmentation
PLMS=periodic limb movements in sleep index, PLMW=periodic limb movements in wakefulness index
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PLM Index in wakefulness in RLS patients with augmentation 250
150
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PLMW
200
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Figure 3. Representation of PLM index in sleep and wakefulness in relation to severity of RLS on the IRLS
100
0 0
5
10
15
20
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50 25
30
35
40
PLMW
45
IRLS
PLM Index in wakefulness in RLS patients without augmentation
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300 250
150
PLMW
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100 50 0
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PLMW
200
0
5
10
15
20
IRLS
25
30
35
40
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PLM Index in sleep in RLS patients with augmentation 400 350 300 200 150
RI PT
PLMS
250
PLMS
100 50 0 0
5
10
15
20
25
30
35
40
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IRLS
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PLM Index in sleep in RLS patients without augmentation 250
150 100 50 0 0
5
10
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PLMS
200
15
20
25
30
35
PLMS
40
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IRLS
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PLMS=periodic limb movements in sleep index, PLMW=periodic limb movements in wakefulness index, IRLS=International restless legs syndrome rating scale
ACCEPTED MANUSCRIPT • RLS patients with augmentation have very disturbed sleep • ·
Leg movements increased, mainly in wakefulness, despite high
dopaminergic doses Insufficiently treated RLS and severely augmented RLS had similar
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• ·
PSG results
·
Augmentation could represent a severe form of RLS and not a
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different phenomenon
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•