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Leg movements during wakefulness in restless legs syndrome: Time structure and relationships with periodic leg movements during sleep
Sleep Medicine 13 (2012) 529–535
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Original Article
Leg movements during wakefulness in restless legs syndrome: Time structure and relationships with periodic leg movements during sleep Raffaele Ferri a,⇑, Mauro Manconi b, Giuseppe Plazzi c, Oliviero Bruni d, Filomena I.I. Cosentino a, Luigi Ferini-Strambi e, Marco Zucconi e a
Sleep Research Centre, Department of Neurology I.C., Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Troina, Italy Sleep and Epilepsy Centre, Neurocenter of Southern Switzerland, Lugano, Switzerland Department of Neurological Sciences, University of Bologna, Bologna, Italy d Centre for Pediatric Sleep Disorders, Department of Developmental Neurology and Psychiatry, University of Rome ‘‘La Sapienza’’, Rome, Italy e Sleep Disorders Center, Department of Neurology, Scientific Institute and University Ospedale San Raffaele, Vita-Salute University, Milan, Italy b c
a r t i c l e
i n f o
Article history: Received 19 July 2011 Received in revised form 25 July 2011 Accepted 31 August 2011 Available online 15 February 2012 Keywords: Periodic leg movements during sleep Periodic leg movements during wakefulness Restless legs syndrome Dopamine agonist Time structure Periodicity Index
a b s t r a c t Background and objective: Approximately one third of patients with restless legs syndrome (RLS) also show periodic leg movements (PLM) during relaxed wake fulness (PLMW). In contrast with the large amount of data published on periodic leg movements during sleep (PLMS), PLMW have received less attention from the scientific community. The objective of this study was to evaluate the correlations/differences of time–structure and response to a dopamine-agonist between PLMW and PLMS in patients with RLS. Methods: Ninety idiopathic RLS patients and 28 controls were recruited. Subjects underwent clinical and neurophysiological evaluation, hematological screening, and one or two consecutive full-night polysomnographic studies. A subset of patients received 0.25 mg of pramipexole or placebo before the second recording. Polysomnographic recordings were scored and LM activity was analyzed during sleep and during the epochs of wakefulness occurring during the first recording hour. Results: RLS patients had higher LM activity during wakefulness than controls, but with a similar periodicity. Even if correlated, the ability of the PLMW index to predict the PLMS index decreased with increasing LM activity. Intermovement intervals during wakefulness showed one peak only at approximately 4 s, gradually decreasing with increasing interval in both patients and controls. The effect of pramipexole was very limited and involved the small periodic portion of LM activity during wakefulness. Conclusions: PLMW index and PLMS index were correlated; however, the magnitude of this correlation was not sufficient to suggest that PLMW can be good predictors of PLMS. Short-interval LM activity during wakefulness and sleep might be linked to the severity of sleep disruption in RLS patients and the differences between their features obtained during wakefulness or sleep might be relevant for the diagnosis of sleep disturbances in RLS. Ó 2012 Elsevier B.V. All rights reserved.
1. Introduction Formerly reported by Symmonds in 1953 [1], and first clinically described and polysomnographically detailed by Lugaresi et al. in 1965 [2,3], periodic leg movements (PLM) in restless legs syndrome (RLS) now represent one of the most common findings in routine polysomnographic studies. PLM during sleep (PLMS) are repetitive leg jerks characterized by a triple flexion movement at ankle, knee, and hip, which arise from sleep, especially during NREM sleep. According to the standard criteria, leg movements (LM) are scored ⇑ Corresponding author. Address: Sleep Research Centre, Department of Neurology I.C., Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Via C. Ruggero 73, 94018 Troina, Italy. Tel.: +39 0935 936111; fax: +39 0935 936694. E-mail address: [email protected] (R. Ferri). 1389-9457/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2011.08.007
as PLM when the electromyographic signal derived from the tibialis anterior shows activations longer than 0.5 and shorter than 10 s, separated by an inter-movement interval ranging from 5 to 90 s from each other, and occurring in series of at least four [4,5]. The periodic occurrence represents the most important feature in differentiating PLMS from other physiological LM activity during sleep, while duration and amplitude are not peculiar features. Interesting information has been obtained from the distribution histogram of LM intermovement-intervals in patients with RLS. This distribution has a consistent bimodal profile, showing one first peak at approximately 2–4 s and a second prominent peak covering, especially, the 16–30 s range [6]. PLMS are temporally associated with cortical (electroencephalographic) arousals and autonomic (heart rate variability, arterial blood pressure) activations. However, the pathological role of PLMS in sleep disruption
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and in autonomic stress is strongly suspected but still controversial; moreover, the acute pharmacological suppression of PLMS reduces the amplitude of the PLMS-related heart rate variability fluctuations [7], but it seems to exert no significant action on the electro-cortical arousal instability [8]. PLMS are highly sensitive markers for RLS but much less specific; in fact, they frequently occur in other sleep disorders such as narcolepsy [9] and REM sleep behavior disorder (RBD) [10], or even in healthy subjects, especially in the elderly [11]. Indeed, PLMS in RBD and narcolepsy show some significant differences compared to those observed in RLS when parameters more advanced than the simple PLMS index (number of PLMS per hour of sleep) are considered, such as their degree of periodicity, the shape of their intermovement–intervals distribution, and their distribution across the night and across the different sleep stages [9,10]. Thus, the simple quantification of PLMS by using the old-fashioned PLMS index can be considered to be insufficient to capture the different and complex aspects of the PLMS phenomenon. In RLS patients PLMS, as well as the typical sensory symptoms, respond immediately to a single low dosage of dopamine-agonists such as pramipexole or ropinirole [12,13]. The suppressive action of dopamine-agonists on PLMS is proportional to the degree of periodicity of LM: it is almost absent for isolated LM and, within the periodic LM range, it is particular evident for those PLMS with a period of approximately 10–20 s (second peak of the intermovement–intervals distribution curve) [14,15]. These results support a heterogeneous physiopathology for LM, at least in RLS, with a nondopaminergic mechanism involved in isolated LM and a dopaminedependent mechanism in PLMS. Recent evidence suggests that this powerful drug inhibition on PLMS might be mediated by the D3 dopaminergic receptor subtype. Approximately one third of RLS patients show PLM also during relaxed wake fulness (periodic leg movements during wakefulness, PLMW). In contrast with the large amount of data published on PLMS, PLMW have received less attention from the scientific community. Their diagnostic value has been evaluated in the context of the so-called suggested immobilization test, which was validated in 1998 as a polygraphic test able to identify and score PLMW [16,17]. However, even though this test is less expensive than polysomnography, it is still time consuming and significantly uncomfortable for the patient. Finally, PLMW can show significant variability, being under the combined effects of time of the day and rest [18]. For this reason, our attention, in the present study, was focused on PLMW naturally occurring during the relaxed wakefulness recorded during the first hour of time in bed (the time of the night when PLMS tend to be highest) [9,19] in patients and controls undergoing a standard polysomnographic recording in the sleep lab. The main scope of the present investigation was to evaluate possible correlations and differences between PLMW and PLMS in terms of their time–structure and in terms of response to a dopamine-agonist in patients with RLS.
2. Subjects and methods 2.1. Subjects Ninety untreated consecutive patients affected by idiopathic RLS were included in this study (mean age 58.2 years, 11.84 SD; 37 males, mean age 57.1 years and 53 females, mean age 58.9 years). The patients were recruited at the Sleep Research Centres of the Department of Neurology I.C., Oasi Institute, Troina (Italy) and of the Department of Neurology, H San Raffaele Scientific Institute, Milan (Italy). In agreement with the International RLS Study Group [20], the minimal criteria accepted for the diagnosis of RLS were: (a) an urge to move the legs, usually accompanied
or caused by uncomfortable and unpleasant sensations in the legs; (b) the urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity such as lying or sitting; (c) the urge to move or unpleasant sensations are partially or totally relieved by movement, such as walking or stretching; (d) the urge to move or unpleasant sensations are worse in the evening or night than during the day or only occur in the evening or night. A mean score of 26.2 (range 13–38) was obtained at the International RLS Study Group rating scale [21]. The sleep respiratory pattern of each patient was assessed by means of oral and nasal airflow (thermistor or nasal pressure cannula), thoracic and abdominal respiratory effort (strain gauge), and oxygen saturation (pulse-oxymetry) in a previous recording (within one week) or during this study recording; patients with an apnea/hypopnea index >5 were not included. Neurological examination showed unremarkable results in all patients. Routine blood tests (including serum iron and ferritin) and neurophysiological investigation (EMG and electroneurography of the lower limbs) were also normal. All subjects were free of medication for at least two weeks before polysomnography. A subgroup of 35 patients were randomly subdivided into two treatment subgroups and underwent one additional nocturnal polysomnographic recording; before the 2nd night recording, subjects included in the treatment group (n = 17) received a single oral dose of 0.25 mg pramipexole at 9.00 p.m., while the remaining patients (n = 18) received placebo. No medication was administered before the 1st night recording (baseline). Additional details on these subgroups can be found elsewhere [12,14]. Twenty-eight normal subjects (12 males and 16 females, mean age 53.1 years, SD 19.55) were also included in the study and used as a control group. Control subjects were screened to exclude those with any current or prior symptoms suggestive of RLS by using the same minimal criteria set by the International RLS Study Group for the diagnosis of RLS [20] and had to be in general good health; they were excluded from the study if any of the following were present: diagnosis of any other significant sleep disorder(s), major mental illness including any indications of cognitive problems as determined by history, any history of neuroleptic-induced akathisia or use of any neuroleptic in the past year. This study was approved by the local ethics committee and all subjects provided informed consent before entering the study. 2.2. Polygraphic sleep recording Each subject underwent a polysomnographic full night recording, after an adaptation night, carried out in a standard sound-attenuated (noise level to a maximum of 30 dB nHL) sleep laboratory. Subjects were not allowed to have beverages containing caffeine during the afternoon preceding the recording and were allowed to sleep until their spontaneous awakening in the morning. The following parameters were included in the polysomnographic study: EEG (at least three channels, one frontal, one central and one occipital, referred to the contralateral earlobe); electrooculogram (electrodes placed 1 cm above the right outer cantus and 1 cm below the left outer cantus and referred to A1), electromyogram (EMG) of the submentalis muscle, EMG of the right and left tibialis anterior muscles (bipolar derivations with two electrodes placed 3 cm apart on the belly of the anterior tibialis muscle of each leg, impedance was kept less than 10 kX), and ECG (one derivation). Sleep signals were sampled at 200 Hz and stored on hard disk in European data format (EDF, see Kemp et al. [22] for details) for further analysis. EMG signals, in particular, were digitally bandpass filtered at 10–100 Hz, with a notch filter at 50 Hz. At the beginning of each session and before the start of recording the sleep technician checked that the amplitude of the EMG signal from the two tibialis anterior muscles was below 2 lV at rest and exceeded 7–10 lV for small voluntary dorsiflexions of the foot.
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2.3. Sleep scoring and detection of LMs Sleep stages were visually scored following standard criteria [23] on 30-s epochs by means of the sleep analysis software Hypnolab 1.2 (SWS Soft, Italy). LMs during sleep were first detected by the same software which allows their computer-assisted detection. With this software, the detection is performed by means of a human-supervised automatic approach controlled by the scorer. The performances of this system have been evaluated and validated [24], but for this study one scorer (RF) visually edited the detections proposed by the automatic analysis before the computation of the various parameters which were automatically generated by the same software, adopting the new criteria set by the International RLS Study Group and endorsed by the World Association of Sleep Medicine [4] and by the American Academy of Sleep Medicine [5]. In particular, a total LM index was calculated to represent the total number of leg movements per hour of sleep, the PLMS index was calculated as the number of LMs included in a series of four or more, separated by more than five and less than 90 s per hour of sleep and, finally, we also computed the number of isolated LMs (not included in these series) per hour of sleep. Similar to our previous studies on PLMS intervals, we also obtained a distribution histogram of all inter-LM intervals and [6], subsequently, the number of intervals included in sequences of at least three, all 10–90 s long, was divided by the total number of intervals and we will refer to this ratio as the periodicity index (PI); this index can vary between 0 (absence of periodicity, with none of the intervals having a length between 10 and 90 s) to 1 (complete periodicity, with all intervals having a length between 10 and 90 s) [6]. PI is independent on the absolute number of LMs recorded and was calculated for all the subjects included in this study. After the detection of PLMS, we also detected and analyzed in the same way all LMs occurring during all wakefulness epochs during the first recording hour after lights off. For this, we applied the rules suggested by the International RLS Study Group and endorsed by the World Association of Sleep Medicine [4] for detecting and scoring LMs during wakefulness.
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parameters correlated with periodicity were higher in RLS patients than in controls during sleep (total LM index, PLMS index, number of PLMS sequences, and PI). During wakefulness the same parameters, excepting PI, were also higher in the patient group than in controls; however, in this case, isolated LM were higher as well. Fig. 1 displays the correlation between the PLMW index and the PLMS index in the group of patients with idiopathic RLS; a significant correlation coefficient of 0.310 was obtained (p < 0.00003). However, all patients (n = 90) had a PLMS index >5, but only 74 of them (positive predictive value, PPV 82.2%) also had a PLMW index >5; similarly, only 68 out of the 88 patients (PPV 77.3%) who had PLMS index >10 also had a PLMW index >10 and, finally, 59 out of the 78 patients (PPV 75.6%) who had a PLMS index >15 also had a PLMW index >15. Table 3 reports, in detail, sensitivity, specificity, positive predictive value, and negative positive value of the PLMW index for the same value of PLMS index during the night in controls and RLS patients. Overall, sensitivity is lower and specificity is higher in controls than in RLS patients. In particular, the specificity in RLS patients is extremely low. In both groups of subjects, PPV shows a clear decrease with increasing PLMW/PLMS index values. Taken together, these data show that the capability of the PLMW index during the first recording hour to predict the level of the PLMS index during the night decreases with increasing LM activity. Fig. 2 depicts the distribution of inter-LM intervals during wakefulness preceding sleep (top panel) and during sleep (bottom panel) in the groups of subjects included in this study. During sleep, it is possible to observe a typical and similar bimodal distribution in both groups of subjects, with a first peak at approximately 4 s and a second, higher peak at approximately 18–22 s. However, the graph obtained in patients is significantly higher than that of controls for most of the graph points. During wakefulness, a single main peak is present in both groups at approximately 4 s that gradually decreases with increasing inter-LM interval. In this case the graph obtained in patients is significantly higher than that of controls only for inter-LM intervals 630 s. 3.3. Effects of pramipexole
2.4. Statistical data analysis The comparisons between the two different subject groups were carried-out using the Student’s t-test for independent data sets. The comparisons between the same RLS subgroup before and after treatment (pramipexole or placebo) were carried out by means of the Student’s t-test for paired data sets. Differences were considered significant when they reached a p < 0.05 level for most analyses but a p < 0.005 level was used to take into account multiple comparisons when appropriate (see below). The data analysis software system STATISTICA (StatSoft, Inc., 2004, version 6. www.statsoft.com) was used for statistical analysis. 3. Results 3.1. Sleep scoring parameters Sleep scoring parameters obtained from patients affected by idiopathic RLS and control subjects included in this study are reported in Table 1; sleep efficiency, wakefulness after sleep onset, and sleep stage 1 percentage were higher in RLS patients, while REM sleep percentage was lower. 3.2. Leg movement parameters during wakefulness and sleep Table 2 shows the comparison between LM parameters found during wakefulness or sleep in the two groups of subjects. All
Table 4 reports the comparison between LM parameters found during wakefulness in two subgroups of RLS patients at baseline or after the first administration of pramipexole or placebo. None of the parameters was modified by the administration of placebo while, after pramipexole, all parameters, excepting isolated LM, were reduced, reaching statistical significance for the number of PLMW sequences and PI. Finally, Fig. 3 shows the inter-LM interval histograms during wakefulness preceding sleep at baseline and after the first night of treatment with pramipexole (top panel) or placebo (bottom panel) in two subgroups of RLS patients. Pramipexole exerted a small effect only in the range approximately from 28 to 56 s, but this did not reach statistical significance at the p level that we used for this analysis involving multiple comparisons (0.005); however, some of the differences would have been considered significant if a classical p level of 0.5 was used. Of note, the peak at 4 s was not modified by pramipexole. 4. Discussion In normal subjects PLMW show a decrease up to the 5th decade of age, with a subsequent increase in older ages [11]. In patients with RLS they have been reported to show significant variability, being under the combined effects of time of the day and rest [18]; moreover, they probably have low night-to-night variability [25], but, unlike PLMS, PLMW parameters have been reported to
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Table 1 Comparison between the sleep scoring parameters found in the two groups of subjects.
Time in bed (min) Sleep period time (min) Total sleep time (min) Sleep latency (min) First REM period latency (min) Stage shifts (h) Awakenings (h) Sleep efficiency (%) Wakefulness after sleep onset (%) Sleep stage 1 (%) Sleep stage 2 (%) Slow-wave sleep (%) REM sleep (%)
RLS (n = 90)
Controls (n = 28)
Student’s t-test
Mean
SD
Mean
SD
515.7 481.7 383.4 23.9 118.2
86.94 91.97 106.75 27.76 70.47
483.2 461.0 391.9 16.5 88.4
61.32 61.07 47.76 13.77 73.12
1.835 1.113 0.410 1.356 1.934
NS NS NS NS NS
11.8 4.8 73.9 21.0
4.32 2.49 15.66 15.05
11.6 4.7 81.8 14.3
3.67 3.39 10.31 10.75
0.270 0.065 2.499 2.208
NS NS 0.014 0.029
7.3 42.5 14.9 14.2
5.59 10.82 8.07 6.22
4.4 46.6 16.0 18.8
4.24 9.53 7.39 7.49
2.534 1.762 0.603 3.281
0.013 NS NS 0.001
t
p<
Fig. 1. Correlation between PLMW index and PLMS index in the group of patients with idiopathic RLS; also the regression line is shown (continuous line, correlation coefficient = 0.310, p < 0.00003) together with the 95% confidence intervals (dashed lines).
show significant differences, with different definitions for duration, inter-movement interval, and bilaterality [26]. The potential diagnostic value of PLMW for RLS is not clear; PLMW during the SIT (SIT-PLMW) seem to correlate with polysomnographic PLMS but not with the International RLS Study Group rating scale [21], which correlates better with the subjective motor discomfort score (SITMDS) [27]. Both SIT-PLMW and SIT-MDS have been reported to be as good as PLMS in differentiating uremic from RLS patients [28]; however, SIT has also been reported to show a significant test-to-test variability [29]. Additional problems limit the practical and extensive application of SIT because validation data are limited to non-consecutive selected patients with generally severe RLS symptoms and are based on a low number of patients, and even a lower number of controls, and do not include symptomatic RLS [16,17]. Finally, SIT is under important subjective influences, such as distraction/attention level, that are difficult to control and, therefore, it cannot be considered a purely objective tool [30].
Table 2 Comparison between the leg movement parameters found during wakefulness or sleep in the two groups of subjects. RLS (n = 90)
Controls (n = 28)
Student’s t-test
Mean
Mean
t
SD
LM parameters during wakefulness Total LM index 85.8 53.93 PLMW index 56.6 49.15 Isolated LM index 29.2 40.10 Number of PLMW 2.1 1.74 sequences Duration of PLMW 55.1 114.06 sequences (s) Periodicity index 0.241 0.210
SD
p<
38.3 24.6 13.7 1.2
34.35 31.99 13.25 1.71
4.384 3.234 2.004 2.448
16.2
60.65
1.726 NS
0.264
0.319
LM parameters during sleep Total LM index 51.8 37.70 16.5 16.39 PLMS index 43.8 37.27 8.7 14.31 Isolated LM index 8.0 3.24 7.8 3.78 Number of PLMS 12.6 6.72 5.1 5.04 sequences Duration of PLMS 112.5 160.08 49.2 156.06 sequences (s) Periodicity index 0.704 0.160 0.400 0.311
0.00003 0.0016 0.047 0.016
0.447 NS 4.798 4.862 0.207 5.470
0.000005 0.000004 NS 0.000001
1.838 NS 6.820 0.000001
As introduced above, for this series of reasons, our attention in the present study was focused on PLMW naturally occurring during the relaxed wakefulness recorded during the first hour of time in bed (the time of the night when PLMS tend to be highest) [9,19] in patients and controls undergoing a standard polysomnographic recording in the sleep lab. We then decided to use all epochs of relaxed wakefulness occurring during the first hour of time in bed. It is known that RLS patients are most likely to have PLM activity in the period from 23:00 p.m. to 3:00 a.m. [25,31,32], during the first half of their usual sleep period; moreover, RLS seems to be worst on the falling phase of the core temperature cycle, but the timing of the circadian cycle is relatively normal [31]. RLS patients also seem to have normal circadian profiles of melatonin, prolactin, cortisol, and growth hormone [33,34], and some authors have suggested that RLS may be activated by some process varying with circadian time, such as blood levels of iron or dopamine [31,32]. In this study we found that most LM parameters during wakefulness were higher in RLS patients than in controls and this is in agreement with the clinical expression of this disease and with previous reports on PLMW [16,35]. However, we also found that the increase in LM activity involved not only their periodic portion, (PLMW) but also isolated LM (intermovement interval >90 s); moreover, the PI was not different between patients and controls and was much lower than that exhibited by PLMS in the same patients during the night. Even if at an individual level, some patients seemed to show a clearly periodic LM activity during wakefulness, at the group level this periodicity was not evident and was characterized by a low PI. This is also evident in the distribution histograms of LM intermovement intervals during wakefulness that show a single main peak, in both groups, at approximately 4 s that gradually decreases with increasing inter-LM interval, which is clearly much higher in RLS patients. These histograms lack the evident peak at approximately 18–22 s that dominates the corresponding histograms of PLMS and are similar to those reported earlier by Pennestrì et al. [11] in normal controls who, however, started their drawings at 5 s intermovement interval and could not define the peak at 4 s clearly evident in our histograms. Also, during sleep it is possible to observe a secondary early peak at the same interval range, at approximately 4 s, as the main peak of wakefulness. This is an important coincidence that allows us to speculate that this peak observed during sleep might be related to the movement occurring during the frequent arousals
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R. Ferri et al. / Sleep Medicine 13 (2012) 529–535 Table 3 Sensitivity, specificity, positive predictive value and negative positive value of the PLMW index for the same value of PLMS index during the night in controls and RLS patients. Sensitivity Controls
RLS
Specificity
PPV
NPV
PLMW/PLMS >5 PLMW/PLMS >10 PLMW/PLMS >15
52.9 38.5 23.1
90.0 85.7 85.7
90.0 71.4 60.0
52.9 60.0 54.5
PLMW/PLMS >5 PLMW/PLMS >10 PLMW/PLMS >15
100.0 97.1 88.1
0.0 0.0 17.4
82.2 77.3 75.6
n.a. 0.0 33.3
PPV = positive predictive value and NPV = negative predictive value.
Table 4 Comparison between the leg movement parameters found during wakefulness in two subgroups of RLS patients at baseline or after the first administration of pramipexole or placebo. Baseline Mean Pramipexole (n = 17) Total LM index PLMW index Isolated LM index Number of PLMW sequences Duration of PLMW sequences (s) Periodicity index Wakefulness during the 1st recording hour Placebo (n = 18) Total LM index PLMW index Isolated LM index Number of PLMW sequences Duration of PLMW sequences (s) Periodicity index Wakefulness during the 1st recording hour
SD
Treatment
Student t-test (paired)
Mean
SD
t
p<
90.5 58.3 32.1 2.4
29.10 38.24 27.79 1.77
82.1 45.6 36.5 1.1
51.12 45.92 48.56 0.99
0.807 0.886 0.281 2.452
NS NS NS 0.026
58.1
99.91
9.4
27.59
1.841
NS
0.277 71.3
0.204 39.54
0.180 52.5
0.209 27.94
2.437 1.864
0.027 NS
61.7 45.6 16.8 1.7
45.07 43.88 14.74 1.41
79.2 47.7 33.6 1.8
54.34 41.97 49.59 2.01
1.307 0.169 1.276 0.233
NS NS NS NS
67.3
165.95
20.2
52.02
1.128
NS
0.242 53.5
0.268 37.15
0.081 1.300
NS NS
0.248 69.2
0.236 43.03
Fig. 2. Inter-LM intervals during wakefulness preceding sleep (top panel) and during sleep (bottom panel) in the groups of subjects included in this study. Grayshaded areas indicate statistically significant differences between the graphs (p < 0.005).
characterizing the nocturnal sleep of RLS [8]. Similarly, the same peak observed during wakefulness might related to sleep fragmentation and finally to the severity of insomnia; however, this intriguing relationship needs to be demonstrated by further appropriate analysis. Concerning this point, it should be underlined that the current scoring rules to recognize and quantify PLMW and PLMS do not consider movements occurring with an intermovement-interval <5 s [4,5]. However, our results clearly demonstrate that LM activity during wakefulness is mostly composed of movements with intermovement-interval <5 s, while this is less true for LM activity during sleep. This reinforces the idea that the simple PLMW index is too restrictive, excluding the major LM activity during wakefulness, in favor of the less prominent activities. Moreover, PI takes into account intermovement intervals as short as 2 s [6] and can reliably pick up the degree of periodicity of this activity.
Fig. 3. Inter-LM intervals during wakefulness preceding sleep at baseline and after the first night of treatment with pramipexole (top panel) or placebo (bottom panel) in two subgroups of RLS patients.
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We found that the correlation between PLMW index and PLMS index was statistically significant; however, the magnitude of this correlation was not sufficient to suggest that PLMW can be good predictors of PLMS. This conclusion was further reinforced by the computation of sensitivity, specificity, and positive and negative predictive values. While PLMW seem to have a high sensitivity for the level of PLMS, they lack specificity and their positive predictive value for PLMS rapidly declines with increasing level of LM activity. It has already been reported that PLMS are sensitive to the effects of treatment with pramipexole [36] and do not seem to be affected by the placebo effect [37]. Our results after the first administration of pramipexole in a subgroup of RLS patients are in full agreement with these observations and complete our previous reports on the effects of dopamine agonists in RLS patients [7,12–14]. Additionally, our analysis of intermovement intervals confirms that the action of pramipexole is strictly limited to the periodic portion of the whole LM activity during wakefulness, with significant reductions in the approximate interval range of 28–56 s. This is in line with our previous report on PLMS and strengthens the idea that different neurotransmitter mechanisms might subserve PLMS and short-interval LM activity of wakefulness (and arousal) [14]. It is also interesting to note that PLMS occurring during the first hour of sleep are reduced by pramipexole [14,15] while LM activity during wakefulness is not. Finally, it has already been reported that dopamine agonists, such as pramipexole or ropinirole, induce only minor beneficial effects on sleep architecture [12–14,38]; this might reinforce our suggestion that short-interval LM activity, which is little modified by pramipexole, might be linked in some way to the severity of sleep disruption in RLS patients, and the differences between the features of LM activity during wakefulness or sleep analyzed in this study might, as a result, be relevant for the diagnosis of sleep disturbances in RLS.
Conflict of Interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: doi:10.1016/j.sleep.2011.08.007.
Acknowledgment This study was supported by the Italian Ministry of Health (‘‘Ricerca Corrente’’ and ‘‘Cinque per Mille’’). References [1] Symmonds CP. Nocturnal myoclonus. J Neurol Neurosurg Psychiatry 1953;16:166–71. [2] Lugaresi E, Coccagna G, Tassinari CA, Ambrosetto C. Rilievi poligrafici sui fenomeni motori nella sindrome delle gambe senza riposo. Riv Neurol 1965;35:550–61. [3] Lugaresi E, Tate L, Coccagna G, Ambrosetto C. Particularités cliniques et polygraphiques du syndrome d’impatience des membres inferieurs. Rev Neurol (Paris) 1965;113:545–55. [4] Zucconi M, Ferri R, Allen R, et al. The official World Association of Sleep Medicine (WASM) standards for recording and scoring periodic leg movements in sleep (PLMS) and wakefulness (PLMW) developed in collaboration with a task force from the International Restless Legs Syndrome Study Group (IRLSSG). Sleep Med 2006;7:175–83. [5] Iber C, Ancoli-Israel S, Chesson AL, Quan SF. The AASM manual for the scoring of sleep and associated events: rules, terminology, and technical specifications. 1st ed. Westchester, IL: American Academy of Sleep Medicine; 2007. [6] Ferri R, Zucconi M, Manconi M, Plazzi G, Bruni O, Ferini-Strambi L. New approaches to the study of periodic leg movements during sleep in restless legs syndrome. Sleep 2006;29:759–69.
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Clinical characteristics of restless legs syndrome in end-stage renal failure and idiopathic RLS patients. Mov Disord 2008;23:811–6. [29] Haba-Rubio J, Sforza E. Test-to-test variability in motor activity during the suggested immobilization test in restless legs patients. Sleep Med 2006;7:561–6. [30] Ondo W. Sensory immobilization testing and polysomnogram testing are useful research tools for restless legs syndrome. Sleep Med 2003;4: 159–60. [31] Hening WA, Walters AS, Wagner M, et al. Circadian rhythm of motor restlessness and sensory symptoms in the idiopathic restless legs syndrome. Sleep 1999;22:901–12. [32] Trenkwalder C, Hening WA, Walters AS, Campbell SS, Rahman K, Chokroverty S. Circadian rhythm of periodic limb movements and sensory symptoms of restless legs syndrome. Mov Disord 1999;14:102–10. [33] Wetter TC, Collado-Seidel V, Oertel H, Uhr M, Yassouridis A, Trenkwalder C. Endocrine rhythms in patients with restless legs syndrome. J Neurol 2002;249:146–51. 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Sleep Medicine journal homepage: www.elsevier.com/locate/sleep
Original Article
Leg movements during wakefulness in restless legs syndrome: Time structure and relationships with periodic leg movements during sleep Raffaele Ferri a,⇑, Mauro Manconi b, Giuseppe Plazzi c, Oliviero Bruni d, Filomena I.I. Cosentino a, Luigi Ferini-Strambi e, Marco Zucconi e a
Sleep Research Centre, Department of Neurology I.C., Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Troina, Italy Sleep and Epilepsy Centre, Neurocenter of Southern Switzerland, Lugano, Switzerland Department of Neurological Sciences, University of Bologna, Bologna, Italy d Centre for Pediatric Sleep Disorders, Department of Developmental Neurology and Psychiatry, University of Rome ‘‘La Sapienza’’, Rome, Italy e Sleep Disorders Center, Department of Neurology, Scientific Institute and University Ospedale San Raffaele, Vita-Salute University, Milan, Italy b c
a r t i c l e
i n f o
Article history: Received 19 July 2011 Received in revised form 25 July 2011 Accepted 31 August 2011 Available online 15 February 2012 Keywords: Periodic leg movements during sleep Periodic leg movements during wakefulness Restless legs syndrome Dopamine agonist Time structure Periodicity Index
a b s t r a c t Background and objective: Approximately one third of patients with restless legs syndrome (RLS) also show periodic leg movements (PLM) during relaxed wake fulness (PLMW). In contrast with the large amount of data published on periodic leg movements during sleep (PLMS), PLMW have received less attention from the scientific community. The objective of this study was to evaluate the correlations/differences of time–structure and response to a dopamine-agonist between PLMW and PLMS in patients with RLS. Methods: Ninety idiopathic RLS patients and 28 controls were recruited. Subjects underwent clinical and neurophysiological evaluation, hematological screening, and one or two consecutive full-night polysomnographic studies. A subset of patients received 0.25 mg of pramipexole or placebo before the second recording. Polysomnographic recordings were scored and LM activity was analyzed during sleep and during the epochs of wakefulness occurring during the first recording hour. Results: RLS patients had higher LM activity during wakefulness than controls, but with a similar periodicity. Even if correlated, the ability of the PLMW index to predict the PLMS index decreased with increasing LM activity. Intermovement intervals during wakefulness showed one peak only at approximately 4 s, gradually decreasing with increasing interval in both patients and controls. The effect of pramipexole was very limited and involved the small periodic portion of LM activity during wakefulness. Conclusions: PLMW index and PLMS index were correlated; however, the magnitude of this correlation was not sufficient to suggest that PLMW can be good predictors of PLMS. Short-interval LM activity during wakefulness and sleep might be linked to the severity of sleep disruption in RLS patients and the differences between their features obtained during wakefulness or sleep might be relevant for the diagnosis of sleep disturbances in RLS. Ó 2012 Elsevier B.V. All rights reserved.
1. Introduction Formerly reported by Symmonds in 1953 [1], and first clinically described and polysomnographically detailed by Lugaresi et al. in 1965 [2,3], periodic leg movements (PLM) in restless legs syndrome (RLS) now represent one of the most common findings in routine polysomnographic studies. PLM during sleep (PLMS) are repetitive leg jerks characterized by a triple flexion movement at ankle, knee, and hip, which arise from sleep, especially during NREM sleep. According to the standard criteria, leg movements (LM) are scored ⇑ Corresponding author. Address: Sleep Research Centre, Department of Neurology I.C., Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Via C. Ruggero 73, 94018 Troina, Italy. Tel.: +39 0935 936111; fax: +39 0935 936694. E-mail address: [email protected] (R. Ferri). 1389-9457/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2011.08.007
as PLM when the electromyographic signal derived from the tibialis anterior shows activations longer than 0.5 and shorter than 10 s, separated by an inter-movement interval ranging from 5 to 90 s from each other, and occurring in series of at least four [4,5]. The periodic occurrence represents the most important feature in differentiating PLMS from other physiological LM activity during sleep, while duration and amplitude are not peculiar features. Interesting information has been obtained from the distribution histogram of LM intermovement-intervals in patients with RLS. This distribution has a consistent bimodal profile, showing one first peak at approximately 2–4 s and a second prominent peak covering, especially, the 16–30 s range [6]. PLMS are temporally associated with cortical (electroencephalographic) arousals and autonomic (heart rate variability, arterial blood pressure) activations. However, the pathological role of PLMS in sleep disruption
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and in autonomic stress is strongly suspected but still controversial; moreover, the acute pharmacological suppression of PLMS reduces the amplitude of the PLMS-related heart rate variability fluctuations [7], but it seems to exert no significant action on the electro-cortical arousal instability [8]. PLMS are highly sensitive markers for RLS but much less specific; in fact, they frequently occur in other sleep disorders such as narcolepsy [9] and REM sleep behavior disorder (RBD) [10], or even in healthy subjects, especially in the elderly [11]. Indeed, PLMS in RBD and narcolepsy show some significant differences compared to those observed in RLS when parameters more advanced than the simple PLMS index (number of PLMS per hour of sleep) are considered, such as their degree of periodicity, the shape of their intermovement–intervals distribution, and their distribution across the night and across the different sleep stages [9,10]. Thus, the simple quantification of PLMS by using the old-fashioned PLMS index can be considered to be insufficient to capture the different and complex aspects of the PLMS phenomenon. In RLS patients PLMS, as well as the typical sensory symptoms, respond immediately to a single low dosage of dopamine-agonists such as pramipexole or ropinirole [12,13]. The suppressive action of dopamine-agonists on PLMS is proportional to the degree of periodicity of LM: it is almost absent for isolated LM and, within the periodic LM range, it is particular evident for those PLMS with a period of approximately 10–20 s (second peak of the intermovement–intervals distribution curve) [14,15]. These results support a heterogeneous physiopathology for LM, at least in RLS, with a nondopaminergic mechanism involved in isolated LM and a dopaminedependent mechanism in PLMS. Recent evidence suggests that this powerful drug inhibition on PLMS might be mediated by the D3 dopaminergic receptor subtype. Approximately one third of RLS patients show PLM also during relaxed wake fulness (periodic leg movements during wakefulness, PLMW). In contrast with the large amount of data published on PLMS, PLMW have received less attention from the scientific community. Their diagnostic value has been evaluated in the context of the so-called suggested immobilization test, which was validated in 1998 as a polygraphic test able to identify and score PLMW [16,17]. However, even though this test is less expensive than polysomnography, it is still time consuming and significantly uncomfortable for the patient. Finally, PLMW can show significant variability, being under the combined effects of time of the day and rest [18]. For this reason, our attention, in the present study, was focused on PLMW naturally occurring during the relaxed wakefulness recorded during the first hour of time in bed (the time of the night when PLMS tend to be highest) [9,19] in patients and controls undergoing a standard polysomnographic recording in the sleep lab. The main scope of the present investigation was to evaluate possible correlations and differences between PLMW and PLMS in terms of their time–structure and in terms of response to a dopamine-agonist in patients with RLS.
2. Subjects and methods 2.1. Subjects Ninety untreated consecutive patients affected by idiopathic RLS were included in this study (mean age 58.2 years, 11.84 SD; 37 males, mean age 57.1 years and 53 females, mean age 58.9 years). The patients were recruited at the Sleep Research Centres of the Department of Neurology I.C., Oasi Institute, Troina (Italy) and of the Department of Neurology, H San Raffaele Scientific Institute, Milan (Italy). In agreement with the International RLS Study Group [20], the minimal criteria accepted for the diagnosis of RLS were: (a) an urge to move the legs, usually accompanied
or caused by uncomfortable and unpleasant sensations in the legs; (b) the urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity such as lying or sitting; (c) the urge to move or unpleasant sensations are partially or totally relieved by movement, such as walking or stretching; (d) the urge to move or unpleasant sensations are worse in the evening or night than during the day or only occur in the evening or night. A mean score of 26.2 (range 13–38) was obtained at the International RLS Study Group rating scale [21]. The sleep respiratory pattern of each patient was assessed by means of oral and nasal airflow (thermistor or nasal pressure cannula), thoracic and abdominal respiratory effort (strain gauge), and oxygen saturation (pulse-oxymetry) in a previous recording (within one week) or during this study recording; patients with an apnea/hypopnea index >5 were not included. Neurological examination showed unremarkable results in all patients. Routine blood tests (including serum iron and ferritin) and neurophysiological investigation (EMG and electroneurography of the lower limbs) were also normal. All subjects were free of medication for at least two weeks before polysomnography. A subgroup of 35 patients were randomly subdivided into two treatment subgroups and underwent one additional nocturnal polysomnographic recording; before the 2nd night recording, subjects included in the treatment group (n = 17) received a single oral dose of 0.25 mg pramipexole at 9.00 p.m., while the remaining patients (n = 18) received placebo. No medication was administered before the 1st night recording (baseline). Additional details on these subgroups can be found elsewhere [12,14]. Twenty-eight normal subjects (12 males and 16 females, mean age 53.1 years, SD 19.55) were also included in the study and used as a control group. Control subjects were screened to exclude those with any current or prior symptoms suggestive of RLS by using the same minimal criteria set by the International RLS Study Group for the diagnosis of RLS [20] and had to be in general good health; they were excluded from the study if any of the following were present: diagnosis of any other significant sleep disorder(s), major mental illness including any indications of cognitive problems as determined by history, any history of neuroleptic-induced akathisia or use of any neuroleptic in the past year. This study was approved by the local ethics committee and all subjects provided informed consent before entering the study. 2.2. Polygraphic sleep recording Each subject underwent a polysomnographic full night recording, after an adaptation night, carried out in a standard sound-attenuated (noise level to a maximum of 30 dB nHL) sleep laboratory. Subjects were not allowed to have beverages containing caffeine during the afternoon preceding the recording and were allowed to sleep until their spontaneous awakening in the morning. The following parameters were included in the polysomnographic study: EEG (at least three channels, one frontal, one central and one occipital, referred to the contralateral earlobe); electrooculogram (electrodes placed 1 cm above the right outer cantus and 1 cm below the left outer cantus and referred to A1), electromyogram (EMG) of the submentalis muscle, EMG of the right and left tibialis anterior muscles (bipolar derivations with two electrodes placed 3 cm apart on the belly of the anterior tibialis muscle of each leg, impedance was kept less than 10 kX), and ECG (one derivation). Sleep signals were sampled at 200 Hz and stored on hard disk in European data format (EDF, see Kemp et al. [22] for details) for further analysis. EMG signals, in particular, were digitally bandpass filtered at 10–100 Hz, with a notch filter at 50 Hz. At the beginning of each session and before the start of recording the sleep technician checked that the amplitude of the EMG signal from the two tibialis anterior muscles was below 2 lV at rest and exceeded 7–10 lV for small voluntary dorsiflexions of the foot.
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2.3. Sleep scoring and detection of LMs Sleep stages were visually scored following standard criteria [23] on 30-s epochs by means of the sleep analysis software Hypnolab 1.2 (SWS Soft, Italy). LMs during sleep were first detected by the same software which allows their computer-assisted detection. With this software, the detection is performed by means of a human-supervised automatic approach controlled by the scorer. The performances of this system have been evaluated and validated [24], but for this study one scorer (RF) visually edited the detections proposed by the automatic analysis before the computation of the various parameters which were automatically generated by the same software, adopting the new criteria set by the International RLS Study Group and endorsed by the World Association of Sleep Medicine [4] and by the American Academy of Sleep Medicine [5]. In particular, a total LM index was calculated to represent the total number of leg movements per hour of sleep, the PLMS index was calculated as the number of LMs included in a series of four or more, separated by more than five and less than 90 s per hour of sleep and, finally, we also computed the number of isolated LMs (not included in these series) per hour of sleep. Similar to our previous studies on PLMS intervals, we also obtained a distribution histogram of all inter-LM intervals and [6], subsequently, the number of intervals included in sequences of at least three, all 10–90 s long, was divided by the total number of intervals and we will refer to this ratio as the periodicity index (PI); this index can vary between 0 (absence of periodicity, with none of the intervals having a length between 10 and 90 s) to 1 (complete periodicity, with all intervals having a length between 10 and 90 s) [6]. PI is independent on the absolute number of LMs recorded and was calculated for all the subjects included in this study. After the detection of PLMS, we also detected and analyzed in the same way all LMs occurring during all wakefulness epochs during the first recording hour after lights off. For this, we applied the rules suggested by the International RLS Study Group and endorsed by the World Association of Sleep Medicine [4] for detecting and scoring LMs during wakefulness.
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parameters correlated with periodicity were higher in RLS patients than in controls during sleep (total LM index, PLMS index, number of PLMS sequences, and PI). During wakefulness the same parameters, excepting PI, were also higher in the patient group than in controls; however, in this case, isolated LM were higher as well. Fig. 1 displays the correlation between the PLMW index and the PLMS index in the group of patients with idiopathic RLS; a significant correlation coefficient of 0.310 was obtained (p < 0.00003). However, all patients (n = 90) had a PLMS index >5, but only 74 of them (positive predictive value, PPV 82.2%) also had a PLMW index >5; similarly, only 68 out of the 88 patients (PPV 77.3%) who had PLMS index >10 also had a PLMW index >10 and, finally, 59 out of the 78 patients (PPV 75.6%) who had a PLMS index >15 also had a PLMW index >15. Table 3 reports, in detail, sensitivity, specificity, positive predictive value, and negative positive value of the PLMW index for the same value of PLMS index during the night in controls and RLS patients. Overall, sensitivity is lower and specificity is higher in controls than in RLS patients. In particular, the specificity in RLS patients is extremely low. In both groups of subjects, PPV shows a clear decrease with increasing PLMW/PLMS index values. Taken together, these data show that the capability of the PLMW index during the first recording hour to predict the level of the PLMS index during the night decreases with increasing LM activity. Fig. 2 depicts the distribution of inter-LM intervals during wakefulness preceding sleep (top panel) and during sleep (bottom panel) in the groups of subjects included in this study. During sleep, it is possible to observe a typical and similar bimodal distribution in both groups of subjects, with a first peak at approximately 4 s and a second, higher peak at approximately 18–22 s. However, the graph obtained in patients is significantly higher than that of controls for most of the graph points. During wakefulness, a single main peak is present in both groups at approximately 4 s that gradually decreases with increasing inter-LM interval. In this case the graph obtained in patients is significantly higher than that of controls only for inter-LM intervals 630 s. 3.3. Effects of pramipexole
2.4. Statistical data analysis The comparisons between the two different subject groups were carried-out using the Student’s t-test for independent data sets. The comparisons between the same RLS subgroup before and after treatment (pramipexole or placebo) were carried out by means of the Student’s t-test for paired data sets. Differences were considered significant when they reached a p < 0.05 level for most analyses but a p < 0.005 level was used to take into account multiple comparisons when appropriate (see below). The data analysis software system STATISTICA (StatSoft, Inc., 2004, version 6. www.statsoft.com) was used for statistical analysis. 3. Results 3.1. Sleep scoring parameters Sleep scoring parameters obtained from patients affected by idiopathic RLS and control subjects included in this study are reported in Table 1; sleep efficiency, wakefulness after sleep onset, and sleep stage 1 percentage were higher in RLS patients, while REM sleep percentage was lower. 3.2. Leg movement parameters during wakefulness and sleep Table 2 shows the comparison between LM parameters found during wakefulness or sleep in the two groups of subjects. All
Table 4 reports the comparison between LM parameters found during wakefulness in two subgroups of RLS patients at baseline or after the first administration of pramipexole or placebo. None of the parameters was modified by the administration of placebo while, after pramipexole, all parameters, excepting isolated LM, were reduced, reaching statistical significance for the number of PLMW sequences and PI. Finally, Fig. 3 shows the inter-LM interval histograms during wakefulness preceding sleep at baseline and after the first night of treatment with pramipexole (top panel) or placebo (bottom panel) in two subgroups of RLS patients. Pramipexole exerted a small effect only in the range approximately from 28 to 56 s, but this did not reach statistical significance at the p level that we used for this analysis involving multiple comparisons (0.005); however, some of the differences would have been considered significant if a classical p level of 0.5 was used. Of note, the peak at 4 s was not modified by pramipexole. 4. Discussion In normal subjects PLMW show a decrease up to the 5th decade of age, with a subsequent increase in older ages [11]. In patients with RLS they have been reported to show significant variability, being under the combined effects of time of the day and rest [18]; moreover, they probably have low night-to-night variability [25], but, unlike PLMS, PLMW parameters have been reported to
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Table 1 Comparison between the sleep scoring parameters found in the two groups of subjects.
Time in bed (min) Sleep period time (min) Total sleep time (min) Sleep latency (min) First REM period latency (min) Stage shifts (h) Awakenings (h) Sleep efficiency (%) Wakefulness after sleep onset (%) Sleep stage 1 (%) Sleep stage 2 (%) Slow-wave sleep (%) REM sleep (%)
RLS (n = 90)
Controls (n = 28)
Student’s t-test
Mean
SD
Mean
SD
515.7 481.7 383.4 23.9 118.2
86.94 91.97 106.75 27.76 70.47
483.2 461.0 391.9 16.5 88.4
61.32 61.07 47.76 13.77 73.12
1.835 1.113 0.410 1.356 1.934
NS NS NS NS NS
11.8 4.8 73.9 21.0
4.32 2.49 15.66 15.05
11.6 4.7 81.8 14.3
3.67 3.39 10.31 10.75
0.270 0.065 2.499 2.208
NS NS 0.014 0.029
7.3 42.5 14.9 14.2
5.59 10.82 8.07 6.22
4.4 46.6 16.0 18.8
4.24 9.53 7.39 7.49
2.534 1.762 0.603 3.281
0.013 NS NS 0.001
t
p<
Fig. 1. Correlation between PLMW index and PLMS index in the group of patients with idiopathic RLS; also the regression line is shown (continuous line, correlation coefficient = 0.310, p < 0.00003) together with the 95% confidence intervals (dashed lines).
show significant differences, with different definitions for duration, inter-movement interval, and bilaterality [26]. The potential diagnostic value of PLMW for RLS is not clear; PLMW during the SIT (SIT-PLMW) seem to correlate with polysomnographic PLMS but not with the International RLS Study Group rating scale [21], which correlates better with the subjective motor discomfort score (SITMDS) [27]. Both SIT-PLMW and SIT-MDS have been reported to be as good as PLMS in differentiating uremic from RLS patients [28]; however, SIT has also been reported to show a significant test-to-test variability [29]. Additional problems limit the practical and extensive application of SIT because validation data are limited to non-consecutive selected patients with generally severe RLS symptoms and are based on a low number of patients, and even a lower number of controls, and do not include symptomatic RLS [16,17]. Finally, SIT is under important subjective influences, such as distraction/attention level, that are difficult to control and, therefore, it cannot be considered a purely objective tool [30].
Table 2 Comparison between the leg movement parameters found during wakefulness or sleep in the two groups of subjects. RLS (n = 90)
Controls (n = 28)
Student’s t-test
Mean
Mean
t
SD
LM parameters during wakefulness Total LM index 85.8 53.93 PLMW index 56.6 49.15 Isolated LM index 29.2 40.10 Number of PLMW 2.1 1.74 sequences Duration of PLMW 55.1 114.06 sequences (s) Periodicity index 0.241 0.210
SD
p<
38.3 24.6 13.7 1.2
34.35 31.99 13.25 1.71
4.384 3.234 2.004 2.448
16.2
60.65
1.726 NS
0.264
0.319
LM parameters during sleep Total LM index 51.8 37.70 16.5 16.39 PLMS index 43.8 37.27 8.7 14.31 Isolated LM index 8.0 3.24 7.8 3.78 Number of PLMS 12.6 6.72 5.1 5.04 sequences Duration of PLMS 112.5 160.08 49.2 156.06 sequences (s) Periodicity index 0.704 0.160 0.400 0.311
0.00003 0.0016 0.047 0.016
0.447 NS 4.798 4.862 0.207 5.470
0.000005 0.000004 NS 0.000001
1.838 NS 6.820 0.000001
As introduced above, for this series of reasons, our attention in the present study was focused on PLMW naturally occurring during the relaxed wakefulness recorded during the first hour of time in bed (the time of the night when PLMS tend to be highest) [9,19] in patients and controls undergoing a standard polysomnographic recording in the sleep lab. We then decided to use all epochs of relaxed wakefulness occurring during the first hour of time in bed. It is known that RLS patients are most likely to have PLM activity in the period from 23:00 p.m. to 3:00 a.m. [25,31,32], during the first half of their usual sleep period; moreover, RLS seems to be worst on the falling phase of the core temperature cycle, but the timing of the circadian cycle is relatively normal [31]. RLS patients also seem to have normal circadian profiles of melatonin, prolactin, cortisol, and growth hormone [33,34], and some authors have suggested that RLS may be activated by some process varying with circadian time, such as blood levels of iron or dopamine [31,32]. In this study we found that most LM parameters during wakefulness were higher in RLS patients than in controls and this is in agreement with the clinical expression of this disease and with previous reports on PLMW [16,35]. However, we also found that the increase in LM activity involved not only their periodic portion, (PLMW) but also isolated LM (intermovement interval >90 s); moreover, the PI was not different between patients and controls and was much lower than that exhibited by PLMS in the same patients during the night. Even if at an individual level, some patients seemed to show a clearly periodic LM activity during wakefulness, at the group level this periodicity was not evident and was characterized by a low PI. This is also evident in the distribution histograms of LM intermovement intervals during wakefulness that show a single main peak, in both groups, at approximately 4 s that gradually decreases with increasing inter-LM interval, which is clearly much higher in RLS patients. These histograms lack the evident peak at approximately 18–22 s that dominates the corresponding histograms of PLMS and are similar to those reported earlier by Pennestrì et al. [11] in normal controls who, however, started their drawings at 5 s intermovement interval and could not define the peak at 4 s clearly evident in our histograms. Also, during sleep it is possible to observe a secondary early peak at the same interval range, at approximately 4 s, as the main peak of wakefulness. This is an important coincidence that allows us to speculate that this peak observed during sleep might be related to the movement occurring during the frequent arousals
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R. Ferri et al. / Sleep Medicine 13 (2012) 529–535 Table 3 Sensitivity, specificity, positive predictive value and negative positive value of the PLMW index for the same value of PLMS index during the night in controls and RLS patients. Sensitivity Controls
RLS
Specificity
PPV
NPV
PLMW/PLMS >5 PLMW/PLMS >10 PLMW/PLMS >15
52.9 38.5 23.1
90.0 85.7 85.7
90.0 71.4 60.0
52.9 60.0 54.5
PLMW/PLMS >5 PLMW/PLMS >10 PLMW/PLMS >15
100.0 97.1 88.1
0.0 0.0 17.4
82.2 77.3 75.6
n.a. 0.0 33.3
PPV = positive predictive value and NPV = negative predictive value.
Table 4 Comparison between the leg movement parameters found during wakefulness in two subgroups of RLS patients at baseline or after the first administration of pramipexole or placebo. Baseline Mean Pramipexole (n = 17) Total LM index PLMW index Isolated LM index Number of PLMW sequences Duration of PLMW sequences (s) Periodicity index Wakefulness during the 1st recording hour Placebo (n = 18) Total LM index PLMW index Isolated LM index Number of PLMW sequences Duration of PLMW sequences (s) Periodicity index Wakefulness during the 1st recording hour
SD
Treatment
Student t-test (paired)
Mean
SD
t
p<
90.5 58.3 32.1 2.4
29.10 38.24 27.79 1.77
82.1 45.6 36.5 1.1
51.12 45.92 48.56 0.99
0.807 0.886 0.281 2.452
NS NS NS 0.026
58.1
99.91
9.4
27.59
1.841
NS
0.277 71.3
0.204 39.54
0.180 52.5
0.209 27.94
2.437 1.864
0.027 NS
61.7 45.6 16.8 1.7
45.07 43.88 14.74 1.41
79.2 47.7 33.6 1.8
54.34 41.97 49.59 2.01
1.307 0.169 1.276 0.233
NS NS NS NS
67.3
165.95
20.2
52.02
1.128
NS
0.242 53.5
0.268 37.15
0.081 1.300
NS NS
0.248 69.2
0.236 43.03
Fig. 2. Inter-LM intervals during wakefulness preceding sleep (top panel) and during sleep (bottom panel) in the groups of subjects included in this study. Grayshaded areas indicate statistically significant differences between the graphs (p < 0.005).
characterizing the nocturnal sleep of RLS [8]. Similarly, the same peak observed during wakefulness might related to sleep fragmentation and finally to the severity of insomnia; however, this intriguing relationship needs to be demonstrated by further appropriate analysis. Concerning this point, it should be underlined that the current scoring rules to recognize and quantify PLMW and PLMS do not consider movements occurring with an intermovement-interval <5 s [4,5]. However, our results clearly demonstrate that LM activity during wakefulness is mostly composed of movements with intermovement-interval <5 s, while this is less true for LM activity during sleep. This reinforces the idea that the simple PLMW index is too restrictive, excluding the major LM activity during wakefulness, in favor of the less prominent activities. Moreover, PI takes into account intermovement intervals as short as 2 s [6] and can reliably pick up the degree of periodicity of this activity.
Fig. 3. Inter-LM intervals during wakefulness preceding sleep at baseline and after the first night of treatment with pramipexole (top panel) or placebo (bottom panel) in two subgroups of RLS patients.
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We found that the correlation between PLMW index and PLMS index was statistically significant; however, the magnitude of this correlation was not sufficient to suggest that PLMW can be good predictors of PLMS. This conclusion was further reinforced by the computation of sensitivity, specificity, and positive and negative predictive values. While PLMW seem to have a high sensitivity for the level of PLMS, they lack specificity and their positive predictive value for PLMS rapidly declines with increasing level of LM activity. It has already been reported that PLMS are sensitive to the effects of treatment with pramipexole [36] and do not seem to be affected by the placebo effect [37]. Our results after the first administration of pramipexole in a subgroup of RLS patients are in full agreement with these observations and complete our previous reports on the effects of dopamine agonists in RLS patients [7,12–14]. Additionally, our analysis of intermovement intervals confirms that the action of pramipexole is strictly limited to the periodic portion of the whole LM activity during wakefulness, with significant reductions in the approximate interval range of 28–56 s. This is in line with our previous report on PLMS and strengthens the idea that different neurotransmitter mechanisms might subserve PLMS and short-interval LM activity of wakefulness (and arousal) [14]. It is also interesting to note that PLMS occurring during the first hour of sleep are reduced by pramipexole [14,15] while LM activity during wakefulness is not. Finally, it has already been reported that dopamine agonists, such as pramipexole or ropinirole, induce only minor beneficial effects on sleep architecture [12–14,38]; this might reinforce our suggestion that short-interval LM activity, which is little modified by pramipexole, might be linked in some way to the severity of sleep disruption in RLS patients, and the differences between the features of LM activity during wakefulness or sleep analyzed in this study might, as a result, be relevant for the diagnosis of sleep disturbances in RLS.
Conflict of Interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: doi:10.1016/j.sleep.2011.08.007.
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