7. Dissociation of periodic leg movements from arousals in restless legs syndrome

Sleep and Epilepsy Center, Neurocenter of the Southern Switzerland, Civic Hospital of Lugano, Via Tesserete 46, Lugano, Switzerland.
Annals of Neurology (Impact Factor: 11.91). 06/2012; 71(6):834-44. DOI: 10.1002/ana.23565
Source: PubMed

ABSTRACT The purpose of this study was to characterize the nature of the relation between periodic leg movements during sleep (PLMS) and cortical arousals to contribute to the debate on the clinical significance and treatment of PLMS.
A prospective, placebo-controlled, single-blind, parallel group study was carried out including 46 drug-naive patients with idiopathic restless legs syndrome (RLS). Each patient underwent 2 consecutive full-night polysomnographic studies. The first night was the baseline night. Prior to the second night, 1 group received a single oral dose of 0.25mg pramipexole, whereas a second group received a single oral dose of 0.5mg clonazepam, and the remaining patients received placebo. Sleep stages, cyclic alternating pattern (CAP), and leg movement activity were scored following standard criteria; symptoms of RLS were also assessed.
Pramipexole suppressed PLMS without affecting electroencephalographic (EEG) instability (CAP) and arousals (corresponding to CAP A3 and, partially, A2 subtypes), whereas clonazepam did the opposite, reducing non-rapid eye movement sleep EEG instability without effects on PLMS. Both drugs were effective on sensory RLS symptoms.
This study demonstrates that a selective pharmacological approach can disconnect PLMS from arousal events, suggesting an indirect relation between each other. These results might weaken the hypothesis of a direct pathological role of PLMS in sleep disruption and can be important for the discussion on the existence of a distinct entity called periodic limb movements disorder. Moreover, the study opens the doors to the possibility of a joint treatment for RLS targeting sensory and motor symptoms, as well as sleep instability.

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    • "Interestingly, the facts that experimentally induced arousals (i.e., sleep fragmentation) during sleep do not elicit PLMS in normal subjects (Ferri et al. 2013), and that arousals and PLMS can be dissociated Fig. 1 Mean R–R interval, standard deviation of the NN interval (SDNN), low-frequency components (LF), and high frequency components (HF) during different sleep stages (N1-N2, N3, REM) as well as during wakefulness before (W-pre) and after (W-post) sleep in PLMS patients, and control subjects. No statistical differences were observed pharmacologically (Manconi et al. 2012), suggest that the pathophysiology of PLMS is likely to be more complex than just a representation of an arousal response. "
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    ABSTRACT: The relationship between the autonomic nervous system and periodic leg movements during sleep (PLMS) is not completely understood. We aimed to determine whether patients with PLMS exhibit any changes in their basal heart rate variability (HRV), excluding episodes of leg movements and arousals. To investigate this, we conducted a cross-sectional study including 13 patients with PLMS (PLMS ≥ 20) and 13 matched controls, free of cardiovascular diseases and medications. Time-and frequency-domain HRV measures [mean R-R interval, low frequency (LF), high frequency (HF), LF/HF] were calculated across all sleep stages as well during wakefulness just before and after sleep during one-night polysomnography. We only took ECG segments of sleep without arousals and excluded periods of 30 s before and after the leg movements. No statistical differences between PLMS and control subjects were found in any of the time- or frequency-domain HRV measures across sleep stages. Basal cardiac autonomic modulation in patients with PLMS is similar to that of control subjects. Our results argue against a role for a basal disturbance of the cardiac autonomic nervous system in the pathogenesis of PLMS.
    Journal of Neural Transmission 11/2013; 121(4). DOI:10.1007/s00702-013-1116-8 · 2.87 Impact Factor
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    • "Furthermore, quinpirole had a deleterious effect on sleep parameters with a profound shortening of the animals' total sleep time and a dramatic increase in sleep latency, at least at the daily dosage we used in our protocol, thus confirming its arousal-inducing effect. Interestingly, it has been shown that D2/D3 agonists, although capable of reducing motor events during sleep, do not alleviate sleep arousal nor deepen sleep in patients with restless legs syndrome (Manconi et al., 2012). "
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    ABSTRACT: Both excessive daytime sleepiness (EDS) and rapid eye movement (REM) sleep deregulation are part of Parkinson's disease (PD) non-motor symptoms and may complicate dopamine replacement therapy. We report here that dopamine agonists act differentially on sleep architecture in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinemacaque monkey. Continuous sleep and wake electroencephalographic monitoring revealed no effect of the selective dopamine D2 receptor agonist quinpirole on EDS, whereas the selective dopamine D1 receptor agonist SKF38393 efficiently alleviated EDS and restored REM sleep to baseline values. The present results question the relevance of abandoning D1 receptor agonist treatment in PD as it might actually improve sleep-related disorders.
    Neurobiology of Disease 11/2013; 63. DOI:10.1016/j.nbd.2013.10.029 · 5.20 Impact Factor
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    • "In patients with RLS, the use of pharmacological interventions, such as pramipexole, can decrease the frequency of PLMS without a concomitant decrease in the frequency of arousals [14]. Conversely, reducing the number of arousals by agents such as clonazepam, is not associated with a decrease of PLMS [15]. Collectively, these findings suggest that interrelationships of cortical, motor, and autonomic events during sleep are likely complex and require further clarification. "
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    ABSTRACT: OBJECTIVE: To evaluate whether eliciting repetitive cortical and autonomic arousals during sleep is able to induce the occurrence of periodic leg movements during sleep (PLMS). METHODS: Fifteen normal subjects underwent one night of uninterrupted and two sequential nights of experimental sleep fragmentation achieved by auditory and mechanical stimuli eliciting frequent EEG arousals. Sleep was polygraphically recorded and subsequently used to determine the frequency of arousals and occurrence of leg movement (LM) activity during the first (baseline) and the second fragmentation night. Also, heart rate variability parameters were obtained to assess the autonomic changes induced by the stimulation. RESULTS: Sleep fragmentation was associated with an increase in the arousal index, percentage of sleep stage 1, and frequency of stage shifts. In addition, there was a decrease in sleep latency and in percentage of slow-wave sleep. Moreover, a significant increase in heart rate variability and especially of its sympathetic component, was also found. In contrast, parameters of the leg movement activity showed no significant change following experimental sleep fragmentation. The lack of an increase in leg movement activity was also observed in one subject who demonstrated PLMS at baseline. CONCLUSIONS: Experimental sleep fragmentation is not associated with an increase in PLMS in normal young adults.
    Sleep Medicine 11/2012; 14(1). DOI:10.1016/j.sleep.2012.09.021 · 3.10 Impact Factor
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