Elsevier

Sleep Medicine

Volume 12, Issue 1, January 2011, Pages 47-55
Sleep Medicine

Original Article
Effects of acute dopamine-agonist treatment in restless legs syndrome on heart rate variability during sleep

https://doi.org/10.1016/j.sleep.2010.03.019Get rights and content

Abstract

Objective

To compare heart rate variability (HRV) changes in patients with restless legs syndrome (RLS) and in healthy subjects, and to evaluate HRV before and after treatment with pramipexole in RLS patients.

Methods

A prospective, polysomnographic, single-blind, placebo-controlled study was performed in 23 patients with RLS and 10 healthy subjects. Basal spectral analysis of HRV and phasic heart rate (HR) changes during PLMS were compared between the two groups and, within the RLS group, before and after treatment with placebo or pramipexole.

Results

No differences were found in the basal sympathovagal balance outside of PLMS between RLS and controls and, in the RLS group, before and after treatment. The amplitude of PLMS-related HR changes was higher in patients than in controls. Treatment with pramipexole decreased the number of PLMS and normalized the increased PLMS-related HR response in RLS subjects.

Conclusions

The repetitive abnormal autonomic response to PLMS might play a role in the increased cardiovascular risk proposed for RLS patients. Pramipexole reduced the number of PLMS and the amplitude of the autonomic response to residual PLMS, without effects on the tonic sympathovagal regulation. D3 receptors in the sympathetic pre-ganglionic neurons of the spinal intermediolateral columns might be a target of pramipexole. The normalization of the HR response could be relevant in reducing the risk of cardiovascular diseases and associated autonomic dysfunctions in patients with RLS.

Introduction

Restless legs syndrome (RLS) is a common sensorimotor disorder which affects up to 10% of the general adult population [1]. Patients with RLS experience an unpleasant sensation in the limbs that appears or worsens during rest and night-time and disappears or improves after movement [2]. Other frequently associated features are represented by insomnia, positive family history, periodic leg movements during sleep (PLMS) and response to dopamine-agonist treatment. Preferential D3 selective dopamine-agonists significantly improve the sensitive and motor components of the syndrome also at very low doses and since the first night of administration [3], [4].

PLMS are repetitive leg jerks characterized by a flexion movement at ankle, knee and hip, which arise from sleep, especially during NREM stages 1 and 2, disclosed by the polysomnographic investigation. Contractions lasting from 0.5 to 10 s, separated by an inter-movement interval ranging between 5 and 90 s, and occurring at least four in a row, belong to the PLMS category [5]. More than 80% of RLS patients present PLMS; however, PLMS can also be observed in other neurological or sleep disorders and in healthy elderly people [6].

In RLS, PLMS are associated with cortical (electroencephalography, EEG) arousals and autonomic (heart rate variability, HRV; arterial blood pressure) activations [7]. Analysis of HRV gives quantitative information on the sympathovagal balance [8]. The pathological meaning of PLMS is still controversial [9]. Previous studies proved that EEG and heart rate (HR) changes may start some seconds before the beginning of PLMS [7], [10], [11], [12]. Furthermore, periodic HR activations and EEG arousals occur spontaneously during NREM sleep also in the absence of leg movements [13], [14]. These findings weakened the hypothesis that PLMS per se might cause sleep disruption or have a significant autonomic impact. However, significantly greater cardiac activations can be observed when leg movements are coupled with the end of obstructive sleep apnea episodes, compared to respiratory events without leg movements [15]. Moreover, bilateral PLMS are accompanied by more important changes in HR and EEG activity than unilateral ones [11]. Therefore, even if PLMS are not the direct cause, they might amplify the EEG and autonomic fluctuations, and the three components may reinforce each other in a positive feedback loop. The phasic repetitive PLMS-related nocturnal autonomic activations might play a critical role in determining a higher cardiovascular risk in the RLS population, observed by recent epidemiological studies [16].

The first aim of the present study was to assess HRV in patients with RLS in comparison to healthy subjects, in baseline conditions; two types of HRV were considered: during periods without PLMS or around single PLMS events. The second aim was to evaluate the effects of treatment with placebo or pramipexole on the same parameters in patients with RLS.

Section snippets

Subjects and methods

A double-step, clinical and polysomnographic, prospective, single blind, placebo-controlled study was carried out. In the first step a group of healthy controls (four males and six females, mean age 58.9 ± 13.36 years) was compared to a group of untreated patients affected by RLS (six males and 17 females, mean age 57.3 ± 11.33 years); in the second step the results obtained from the basal night in the RLS group were compared with those regarding a second night after a single administration of

Results

Twenty-three patients (six males and 17 females, mean age 57.3 ± 11.33 years) and 10 control subjects (four males and six females, mean age 58.9 ± 13.36 years) were included in the study. As introduced above, in the second step the results obtained from the basal night in the RLS group were compared with those regarding a second night after a single administration of pramipexole (13 patients) or placebo (10 patients).

Fig. 1 reports an example of a polysomnographic recording obtained from a patient

Discussion

The present study is focused on the autonomic function during sleep of patients affected by RLS, as reflected by HRV in terms of sympathovagal balance, in relatively long sleep epochs without PLMS, and in terms of phasic HR rises coupled with the occurrence of PLMS.

Concerning the first point, we found no differences between RLS and healthy controls for HRV during NREM sleep, outside of the occurrence of PLMS. This result indicates that during normal sleep the basic mechanisms for heart rate

Future directions

Additional research is needed to understand both the long- and short-term effects of pharmacological treatment on motor and autonomic components of RLS. In particular, future short-term studies should consider the effect of pramipexole on PLMS associated blood pressure changes; prospective long-term investigations should focus on the effect of pramipexole on PLMS in association with pulse rate and blood pressure changes in RLS. Moreover, it would be interesting to perform additional research on

Conflicts of interest

There are no financial interests that represent potential conflict of interest for individual authors.

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