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: 9.98). 06/2012; 71(6):834-44. DOI: 10.1002/ana.23565
Source: PubMed


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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    • "PLMS may also occur in the absence of cortical arousal and the two phenomena may be pharmacologically dissociated [14], but PLMS always entail changes in both HR and ABP. These cardiovascular changes are not solely caused by the movement or the cortical activation, despite being potentiated by the co-occurrence of cortical arousals [12] [13] [14] [15]. The PLMS-related temporal pattern of autonomic and EEG changes suggests a hierarchy in the arousal response, from autonomic activation, representing the earliest marker of brain arousal, to cortical involvement under more-powerful arousing stimuli [8,13,16]. "
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    ABSTRACT: Studies involving genetic engineering on animal models and mathematical analysis of cardiovascular signals on humans are shedding new light on the interactions between the arterial baroreceptor reflex (baroreflex) and arousal. Baroreceptor stimulation, if very mild or performed under anaesthesia, may inhibit cortical arousal. However, substantial increases or decreases in baroreflex activation cause arousal in animal models and human subjects in physiological conditions. On the other hand, cardiovascular changes during autonomic arousals and between the states of wakefulness and sleep involve changes in the baroreflex set point and balance with central autonomic commands. Neural connectivity and functional data suggest that the nucleus of the solitary tract, adrenergic C1 neurons of the medulla, and the parabrachial nucleus of the pons mediate the bidirectional interactions between the baroreflex and arousal. These interactions may constitute a positive feedback loop that facilitates sharp and coordinated brain state and autonomic transitions upon arousal: upon arousal, central autonomic commands may increase blood pressure, thereby loading baroreceptors and further increasing arousal. Anomalies of this feedback loop may play a role in the pathophysiology of disease conditions associated with cardiovascular and wake-sleep cycle alterations. These conditions include: obstructive sleep apnoea syndrome, with its association with excessive daytime sleepiness and baroreflex impairment; and insomnia, with its association with autonomic hyperarousal and hypertension. When faced with disorders associated with cardiovascular and sleep-wake cycle alterations, clinical reasoning should entertain the possibility that both conditions are strongly influenced by anomalies of baroreflex function.
    Sleep Medicine 12/2014; 16(2). DOI:10.1016/j.sleep.2014.10.011 · 3.15 Impact Factor
    • "Few studies have objectively assessed the prevalence of PLMS in demented patients but an increase of twitches or jerks in sleep reported by the patient or his family has been described [85] [91]. The role of PLMS in sleep disruption is equivocal and a recent study demonstrates a dissociation of periodic leg movements from arousals in restless legs syndrome [92]. Presently, pharmacologic treatment of PLMS is not recommended if not associated with RLS, but PLMS triggered by sleep respiratory events may decrease after CPAP treatment [93]. "
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    ABSTRACT: Sleep disorders are frequent in Alzheimer's disease (AD), with a significant impact on patients and caregivers and a major risk factor for early institutionalization. Micro-architectural sleep alterations, nocturnal sleep fragmentation, decrease in nocturnal sleep duration, diurnal napping and even inversion of the sleep-wake cycle are the main disorders observed in patients with AD. Experimental and epidemiological evidence for a close reciprocal interaction between cognitive decline and sleep alterations is growing. Management of sleep disorders in AD is pre-eminently behavioral. Association of melatonin and bright light treatment seems to be promising as well. The presence of sleep complaints, especially excessive somnolence in demented patients, should draw attention to possible associated sleep pathologies such as sleep apnea syndrome or restless legs syndrome.
    Sleep Medicine Reviews 04/2014; 19. DOI:10.1016/j.smrv.2014.03.007 · 8.51 Impact Factor
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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 · 2.40 Impact Factor
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