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or a disorder?
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Periodic leg movements in sleep and periodic limb movement disorder: a polysomnographic finding and/or a disorder? D.-K. Kaynaka a Istanbul University
Cerrahpasa Faculty of medicine Department of neurology Sleep Disorders Unit, Istanbul, Turkey. Correspondance : [email protected]
Summary Periodic leg movements in sleep (PLMS) are a sleep related phenomenon with periodic episodes of repetitive and highly stereotypical movements of the lower extremities. As the presence of PLMS is believed to be associated with the complaint of non-restorative sleep, it is recommended to routinely record PLMS for clinical purposes. PLMS occurring in patients with otherwise not explained insomnia and/or hypersomnia is defined as periodic limb movement disorder (PLMD). The largest epidemiological study evaluating the presence of PLMS and sleep complaints documented a 3.9% prevalence in general population.PLMS have also been documented in patients with various sleep and medical disorders. There are many hypotheses in respect to pathophysiology of PLMS and have been suggested to be related to dopaminergic systems. Besides clinical symptoms, PLMS may influence some physiological measures such as heart rate, blood pressure and EEG-spectra during sleep. Recommendations for therapy of PLMD originate mostly from studies in RLS patients, in which L-dopa and dopamine agonists are considered as first-line treatment.
Keywords Sleep, periodic leg movements, periodic limb movement disorder, prevalence, treatment.
MOUVEMENTS PÉRIODIQUES DES JAMBES AU COURS DU SOMMEIL ET SYNDROME DES MOUVEMENTS PÉRIODIQUES DES MEMBRES : UNE DÉCOUVERTE POLYSOMNOGRAPHIQUE ET/OU UNE PATHOLOGIE ?
Résumé Les mouvements périodiques des membres dans le sommeil (PLMS, pour periodic limb movements in sleep) sont des phénomènes liés au sommeil. Ils consistent en des mouvements périodiques et hautement stéréotypés des extrémités inférieures.La présence de mouvements périodiques des membres étant réputée être associée à une plainte de sommeil non restaurateur, on a l’habitude d’enregistrer ces mouvements en routine.L’association mouvements périodiques des membres – insomnie ou hypersomnie inexpliquées est désignée sous le terme de syndrome de mouvements périodiques des membres dans le sommeil. La plus large étude épidémiologique réalisée à ce jour,sur la prévalence de l’association mouvements périodiques des membres – plaintes sur le sommeil, a trouvé une prévalence de 3,9 % dans la population générale. Des mouvements périodiques des membres dans le sommeil ont également été décrits chez des patients atteints de troubles variés du sommeil et d’autres maladies. La physiopathologie des mouvements périodiques des membres a donné lieu à de nombreuses hypothèses impliquant les systèmes dopaminergiques.En plus des symptômes cliniques auxquels ils donnent lieu, les mouvements périodiques des membres dans le sommeil pourraient avoir un impact sur la fréquence cardiaque, la pression artérielle et les paramètres EEG, durant le sommeil. Les recommandations concernant le traitement du syndrome de mouvements périodiques des membres dans le sommeil proviennent surtout d’études réalisées chez des patients atteints du syndrome d’impatiences des membres inférieurs, chez lesquels la L-Dopa et les agonistes dopaminergiques sont recommandés comme traitement de première intention.
Mots-clés Sommeil,mouvements périodiques des membres inférieurs,syndrome de mouvements périodiques des membres,prévalence,traitement. MEDECINE DU SOMMEIL - Année 5 - Avril - Mai - Juin 2008
© 2008 – Elsevier Masson SAS – Tous droits réservés
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mise au point INTRODUCTION Periodic leg movements in sleep (PLMS) are a sleep related phenomenon with periodic episodes of repetitive and highly stereotypical movements of the lower extremities [1). The movements are characterized by dorsiflexion of the ankle, dorsiflexion of the toes and a partial flexion of the knee and sometimes the hip. PLMS were first described by Symonds as ‘nocturnal myoclonus’ [2]. Lugaresi et al. [3] reported the first polysomnographic (PSG) recording of PLMS. Coleman proposed the first scoring criteria of PLMS [4]. The new standards for recording and scoring periodic leg movements were proposed by the World Association of Sleep Medicine (WASM) in collaboration with a task force from the International Restless Legs Syndrome Study Group (IRLSSG) [1]. The necessities to change scoring criteria were: newly recognized pathologies to be associated with PLMS and occurrence of new sophisticated methods of signal analysis. These new guidelines apply to adults; they are expected to be valid also for children, but are recommended for cautious use with children pending further pediatric evaluations of PLMS. The criteria for the association with arousal and/or abnormal respiratory events were also described. According to the new criteria, duration of movement is defined as the time between onset and offset of the event which must be at least 0.5 seconds and no longer than 10 seconds (figure 1). The period length for two consecutive movements to be considered as PLM must be at least 5 and no more than 90 seconds.The number of consecutive movements meeting the period criteria must be four or more movements can occur in any stage of sleep or wake and the sequence of consecutive events continues across changes in sleep–wake state. Bilateral movements can include two or more unilateral movements separated (offset-to-onset) by less than 0.5 s from each other. An arousal and movement are considered associated with each other when there is less than 0.5 seconds between the end of one event and the onset of the other event, regardless of which is the first. Respiration must be recorded to accurately assess if movements are associated with respiratory events. These movements should not be included in PLM-related parameters. It should be noted that PLM and obstructive sleep apnea might coexist [1].
Figure 1 : Overview of the detection parameters of candidate PLM (1)
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PLMS may occur not only during sleep but also in wakefulness (periodic leg movements in wake-PLMW). PLMW occurring in RLS patients are phenotypically similar to PLMS but have a longer duration [4]. PLMW recordings may be used for the diagnosis of RLS in the ‘Suggested Immobilization Test’ [5]. In RLS, PLMW were found to have higher diagnostic specificity and sensitivity than PLMS [6]. Gender has no significant effect on PLMS indices, duration or periodicity.Movements of longer duration are seen during wakefulness, while REM sleep is characterized by the shorter duation and the lowest frequency. State of vigilance also modulates the periodicity of PLMS. Intervals are shorter during wakefulness and increase progressively from stage 1 to stage 2 and slow wave sleep [7]. In heathy subjects, the presence of PLMS was rare before the age of 40, but then the index increased dramatically. PLMW index was higher in younger subjects compared with middle-aged subjects. With advancing age, PLMS interval histograms show a peak around 15 to 35 seconds, which is not observed in younger subjects. On the other hand, despite high indexes, PLMW interval histograms do not show a clear peak for any age group [8]. As the presence of PLMS is believed to be associated with the complaint of non-restorative sleep, it is recommended to routinely record PLMS for clinical purposes [1, 9]. Due to night-tonight variability of PLMS, two-night PLMS recordings may be necessary for diagnostic purposes [10]. Recording PLMS by actigraphy can facilitate PLMS recording over multiple nights. However, the technique is currently not yet established and its validity still has to be demonstrated [11]. To determine the frequency of PLMS occurrence, the PLMS index, calculated as the number of PLMS per hour of total sleep time, is used. As PLMS followed by an arousal are considered to be relevant in the generation of sleep disturbances, it is recommended to additionally calculate the PLMS-arousal index that is the number of PLMS with arousals per hour of total sleep time [1]. Relative frequency of movements, their duration and their arousing effect appear to decrease during non-rapid eye movement sleep stages while the intermovement interval was found to increase. During rapid eye movement sleep, the duration of movements was found to be shortest and the intermovement interval longest [12]. The new approach for the analysis of quantity, type, and periodicity of the leg motor activity during sleep was also described in patients with restless legs syndrome. In this analysis, leg movement duration , amplitude, area under the curve, sleep stage, side, interval, and bilaterality were taken into consideration. In RLS patients' inter-LM interval distribution graph showed a wide peak with a maximum located at around 15 to 30 seconds and extending from 10 to 90 seconds, and another peak for intervals less than 8 seconds. Periodicity was not dependent on the periodic leg movement index.This new approach seems to be useful in a qualitative differentiation among patients with PLMS, hich is not possible by using the simple PLM index [13]. PLMS occurring in subjectswith otherwise not explained insomnia and/or hypersomnia with the PLMS index exceeds 5 in children and 15 in adults is defined as periodic limb movement disorder (PLMD) [14]. If PLMS are present without clinical sleep disturbance, they can be noted as polysomnographic finding.The diagnosis of PLMD requires PSG confirmation and is based on the exclusion of other causes of sleep disturbances. MEDECINE DU SOMMEIL - Année 5 - Juillet - Aôut - Septembre 2008
D.-K. Kaynak
Periodic leg movements in sleep and periodic limb movement disorder: a polysomnographic finding and/or a disorder ?
PREVALENCE OF PERIODIC LEG MOVEMENTS IN SLEEP To date, the largest epidemiological study evaluating the presence of PLMS and sleep complaints (PLMD) documented a 3.9% prevalence in 18,980 subjects from the general population aged 15–100 years [15]. The study identified several factors associated with PLMD such as female gender, caffeine intake, stress and the presence of mental disorders. In childhood and adolescence, PLMS rarely occur. In a study of children referred to a pediatric sleep laboratory, 5.6% of 591 subjects had a PLMS index of greater than 5. Only 1.2% of them had PLMS without sleep complaints or a comorbid disorder [16]. In an other study 23% of children were diagnosed as having PLMS on the basis of polysomnography. The presence of PLMS had usually been unrecognized clinically. The only clinical symptom that could be related to periodic limb movement disorder was a report of leg pains at morning awakening. Comorbidity seen with PLMS included neuropsychiatric syndromes, isolated sleep disordered breathing , and several other comorbid conditions [17]. Elevated PLMS indices have been reported also in children with obstructive sleep apnea syndrome (OSAS), juvenile fibromyalgia [18] and attention-deficit hyperactivity syndrome [19]. The prevalence of PLMS has been found to increase with advanced age [20, 21, 22, 23], and frequently have been observed in subjects without any sleep disturbance [20, 21, 22, 24, 25]. On the other hand, an elevated PLM index has been detected in over 80% of older patients with sleep complaints [26].
PLMS AND OTHER DISORDERS PLMS have been documented in patients with various sleep disorders. PLMS occur most frequently in patients with RLS. In a study of 133 cases of RLS, a PLMS index of more than 5 was found in 80% of the patients during one night PSG and in 88% with two PSG recordings [27]. An elevated rate of PLMS can also be observed in narcolepsy [28]. PLMS are a common finding in OSAS and may occur both in close temporal association with abnormal respiratory events or independently from them. During CPAP therapy, PLMS may increase or decrease depending on the severity of OSAS. In moderate to severe OSAS, PLMS were found to increase, probably due to ‘unmasking’ of an underlying PLMD. In mild OSAS, PLMS decrease due to resolution of the respiratory efforts and the related PLMS [29]. Classification of PLMS in OSAS into spontaneous (as in PLMD) and induced (secondary to respiratory effort-related arousals) PLMS has been suggested. According to current scoring criteria, leg movements occurring in association with respiratory events (apneas, hypopneas) should be counted separately, if respiratory signal is available [1]. In patients with significant abnormal respiratory events and elevated number of PLMS, the OSAS should be primarily treated before evaluating the clinical importance of PLMS. PLMS are also frequently recorded in patients with REM sleep behavior disorder (RBD). In a cohort of 40 RBD patients, 70% revealed a PLMS index more then 10 [30]. In RBD, PLMS may also frequently occur during REM sleep. Besides sleep disorders, an elevated PLMS index was found to be MEDECINE DU SOMMEIL - Année 5 - Juillet - Aôut - Septembre 2008
increased with severity or worsening of a medical disorder such as in patients with essential hypertension [31], end-stage renal disease [32], and alcohol dependency [33]. It is not known whether PLMS in these disorders are related to the basic pathophysiology of the disease as proposed for alcohol dependency or whether they are just a surrogate marker as presumed in end-stage renal disease. Observational studies described an increase of PLMS in depressed patients treated with psychoactive substances and antidepressants like clomipramine, lithium, fluoxetine or venlafaxine [34, 35, 36, 37, 38].A recent study on 274 patients treated with antidepressants found a significant increase of PLMS during treatment with selective serotonin reuptake inhibitors or with venlafaxine but normal values during bupropion therapy [39].
PATHOPHYSIOLOGY The exact pathophysiology of PLMS has not been elucidated yet. According to the common brainstem system (CBS) theory [40, 41], CBS exerts regulatory influences on the activities of peripheral visceral and somatomotor systems, synchronizing them to the activities of higher brain structures. However the neurons of the CBS also present an oscillatory rhythmic activity that is able to adjust the vascular, cardiac, respiratory and EEG delta–theta rhythms in case of altered internal or external stimuli (?) [40, 42]. Internal or external stimuli could be processed by the CBS, inducing the initial part of the arousal response, aimed at maintaining sleep, and mainly characterized by mild HR and EEG delta waves activation. Further activation of the CBS could induce an increase in the firing rate of this system, yielding major changes in autonomic and cerebral activities, as a survival defensive response. It has been shown that PLM onset is heralded by a significant activation of HR and delta activity power, beginning before the leg movement takes place. Faster EEG frequency bands showed an activation starting immediately just before the PLM onset. In averaged variations of tibial EMG, there was no presence of muscular activity able to induce the initial changes in EEG and ECG signals before PLM onset.The time evolution of alpha, sigma and beta frequency variations shows that their activation largely develops after the PLM onset. Moreover, there is a trend toward a progressive increase in the importance of activation from lower to faster frequencies. This study highlights that impressive cardiac and EEG changes take place before the onset of the motor phenomenon. The temporal relationship between delta activity, cardiac activation and PLM suggests that these phenomena are preparatory conditions, involving both central and autonomic nervous systems, exerting a permissive function on the activity of spinal motoneurons [43]. According to Sforza et al. [44] the rise of delta waves and HR could be considered as the first level of a transient activation from sleep. PLMS, and the subsequent progressive activation of the faster EEG frequencies, should be considered as the second phase in the continuum of the arousal response associated with these movements. These authors reported that, irrespective of the importance of EEG changes linked to PLMs, the pattern of arousal response consisted of an abrupt increase in delta activity and HR a few seconds before the onset of the PLM, followed by a progressive rise in fast EEG frequencies and tachycardia, peaking 25
mise au point from 1 to 3 seconds after the PLM onset. On the whole, these data give strong evidence that PLMs are not the trigger phenomenon of cardiac and EEG activation, but on the contrary seem ruled by a central oscillatory mechanism regulating both EEG and autonomic functions. Either spontaneous arousals or those related to motor phenomena, blood pressure variations or cardiac activations show a qualitatively common EEG spectral pattern, irrespective of the presence of a detectable arousing stimulus, its type or its strength. Since a stereotyped pattern of variations in HR and EEG spectral composition is present before and during spontaneous arousal, PLMS, respiratory efforts and cardiovascular variations, it is tempting to suggest, that oscillatory processes in autonomic and EEG activities might adjust in anticipation to the motor phenomenon. There are also other studies investigating the relationship between PLMS and cortical arousal, heart rate and EEG spectra. Our study addressed this point using inspective EEG techniques. Findings of a significantly higher number of arousals prior to leg movements suggest that arousals are not simply the consequence of PLMD but that, on the contrary, both EEG arousals and PLMD are manifestations of a common underlying arousal disorder [45]. On the other hand, the occurrence of PLMS in patients with spinal cord injury suggests that PLM may be directly generated in the spinal cord [54, 57]. Provini et al. suggested that activation (or disinhibition) of innervated skeletal muscles at medullar levels L4-S1 and to a lesser extent at C6–C7, is involved in generating PLMS. Another study has shown that lesion of the gracilis and cuneate fascicles were sufficient to generate this pattern of movement during sleep, regardless of the length or degree of histopathological lesion [58]. Another hypothesis for the involvement of the dorsal column in movements during sleep is the topographical location of the dopaminergic neurons in the dorsal column of the spinal cord. The dopaminergic system cells are located periventricularly in the dorsal hypothalamus and caudal thalamus, and their nerve endings have their synapses in the dorsal horn at all levels of the spinal cord and around the preganglionic sympathetic neurons in the thoracolumbar spinal cord. The data now available favor the participation of the spinal dopaminergic system in pain modulation and autonomic and motor responses. Dysfunction of spinal dopaminergic neurons may also be involved in the pathophysiology of certain conditions, such as Parkinson’s disease [59]. Because of frequent association with RLS narcolepsy or RBD in which the impairment of dopaminergic transmission have been suggested, PLMS are hypothesized to be related to dopaminergic systems [60]. In the rat model of RLS it has been shown that subcortical lesions to the A11 dopaminergic nuclei cause PLMS [61]. Furthermore, dopaminergic agents were reported to reduce the number of PLMS in RLS, narcolepsy and RBD patients. Functional neuroimaging studies may contribute to elucidate pathophysiological mechanisms of PLMS which still remain unclear. Functional MRI investigations of RLS patients revealed an activation in the red nuclei and brainstem close to the reticular formation during the symptomatic period, suggesting that subcortical cerebral generators are involved in the pathogenesis of RLS [62]. However this technique is not yet clinically relevant methods to differentiate PLMS or RLS from other movement disorders during sleep. 26
PLMS AND SLEEP DISTURBANCE The correlation of subjective sleep complaints and PLMS is contradictory. Periodic leg movements during sleep occur along with a wide variety of sleep-wake complaints such as sleep onset difficulty, nocturnal awakenings, early morning awakenings and also daytime sleepiness. They occur in 13.3% of patients complaining of insomnia, 6.9% of those being evaluated for excessive sleepiness [63]. It is generally accepted, from a clinical standpoint, that leg movements are frequently accompanied by electroencephalogram (EEG) signs of arousal which cause sleep fragmentation and in the absence of such arousals, patients do not have sleep-wake complaints. Insomnia and daytime sleepiness show different characteristics in these patients. It has been shown that PLMS patients with insomnia had more leg movements, a longer delay to sleep onset and to REM onset, more wakefulness after sleep onset and less total sleep time than those patients with daytime sleepiness [64]. Two studies compared PLMS parameters in patients with insomnia and daytime sleepiness proposed that the differences in symptomatic complaints represent points on a continuum of sleep fragmentation [65, 66]. The fragmentation of sleep was more severe in PLMS patients complaining of insomnia, who showed increased wakefulness, less total sleep time, a greater latency of SWS and impaired sleep efficiency index. In our patients, having consulted for an evaluation of insomnia and having PLMS, sleep analysis revealed an increased wake time after sleep onset, number of awakenings, shifts to sleep stage 1, and a decreased sleep efficiency continuity index. All these impaired sleep parameters resulted in disturbed nocturnal sleep and complaint of insomnia. On the other hand, we found no clear association between periodic leg movement index, periodic leg movement arousal index, inter-movement interval and various sleep parameters. The only significant relationship we found was that the longer the movement duration, the longer the wake time after sleep onset, and SWS latency, and the lower the sleep efficiency and continuity index [67]. In respect to daytime sleepiness, no correlation was found between PLMS index and poor sleep efficiency or daytime sleepiness as measured by the multiple sleep latency test (MSLT) [68]. Pollmacher and Schulz showed that the arousing effect of periodic leg movements depends on the duration of the movement [12]. This was suggested by the finding that the percentage of periodic leg movements followed by EEG arousals increases with the increasing duration of the movements. Based on the assumption that the arousing effect of the movements is probably crucial for the induction of sleep disturbance, our findings also support the assumption that the determining factor of sleep disturbance in PLMS patients was movement duration rather than frequency or inter-movement interval.The evaluation of sleep micro-structure revealed that the amount of EEG activities during sleep (alpha, theta, delta and spindles), with and without leg movements, did not show any significant difference. The lack of significant differences in both macro- and microstructure of sleep and EEG activity content, with respect to the association with movements, confirms the hypothesis that periodic leg movements did not primarily cause the sleep disturbance [67]. The relationship of periodic leg movements to both subjective complaint and also objective sleep disturbance is MEDECINE DU SOMMEIL - Année 5 - Juillet - Aôut - Septembre 2008
D.-K. Kaynak
Periodic leg movements in sleep and periodic limb movement disorder: a polysomnographic finding and/or a disorder ?
neither obvious nor simple. Besides clinical symptoms, PLMS may influence some physiological measures during sleep. There are investigations demonstrated PLMS-related changes in heart rate [69], EEGspectra [70] and in also of blood pressure [71]. However, these changes may be unspecific, at least for those PLMS not associated with an arousal, as they are comparable in magnitude to the changes in heart rate and blood pressure induced by a Kcomplex [72]. Moreover, in a recent study, it has been shown that changes of the EEG-spectra due to an arousal (whether associated with a PLMS or not) are by far more prominent than that of a PLMS not associated with an arousal [73]. This finding questions the pathophysiological relevance of PLMS and indicates that it is not the PLMS but rather the associated arousals that influence cortical activity in sleep and may be related to the subjective impression of nonrestorative sleep. On the other hand, recently, it has been shown that in NREM sleep the primary cardiac effect of the PLMS consists in a strong increase in sympathetic activity associated with a weak reduction in parasympathetic tonus [74]. In a study of Pennestri MH et al, blood pressure was shown to be increased significantly in association with all PLMS. Blood pressure changes associated with PLMS with arousals were greater than those associated with PLMS without arousals. Systolic and diastolic blood pressure changes increased with age and the duration of illness [75]. Thus PLMS-related repetitive nocturnal blood pressure fluctuations could contribute to the risk of cardiovascular diseases especially in the elderly. Further studies are needed to evaluate the relationship of PLMS and cardiovascular disorders. While in stages 1 and 2 of NREM sleep, the PLM was preceded by a rise in slow EEG activity paralleling the rise in HR, in wakefulness and REM sleep, the changes in cerebral activity appeared simultaneously with the PLM onset.In addition the EEG variations were strong and persistent during sleep but the EEG activation was almost absent during wakefulness. The differences between wakefulness and sleep appear to be similar in RLS and PLMD suggesting an underlying common pathogenetic mechanism. In addition typical pattern of cardiac response was present during NREM and REM sleep, the autonomic activation was smaller but prolonged during wakefulness. These results suggest that the mechanisms triggering PLMS are different between NREM sleep, REM sleep and wakefulness, suggesting that the occurrence of PLMS may be underlie by specific sleep state-dependent mechanisms. In an other study it has been observed significant differences in the time course of cerebral and cardiac activation during PLMS in relation to different sleep states and wakefulness. Wakefulness appears to induce smaller changes in both systems indicating a mechanism different from that implicated during sleep. The differences across sleep stages in the EEG and cardiac variations suggest that more a sleep stage dependence of arousal response to motor event rather than a common generator may be implicated in the occurrence of PLMS [76]. The clinical relevance of these findings remains questionable. To further elucidate the relationship of subjective sleep perception and PLMS, the temporal relationship of PLMS, arousal and CAP as well as their periodicity should be more closely examined. Additionally, the sleep stage during which PLMS occur and the time course of PLMS during the night should be considered. MEDECINE DU SOMMEIL - Année 5 - Juillet - Aôut - Septembre 2008
TREATMENT OF PLMS IN PATIENTS WITH INSOMNIA AND/OR HYPERSOMNIA (PLMD) Recommendations for therapy of PLMD originate mostly from studies in RLS patients, in which L-dopa and dopamine agonists are considered as first-line treatment [77]. However, there is no controlled clinical study investigating the effect of L-dopa on PLMS and/or the related sleep complaints.To date, only a handful of clinical studies on the treatment of PLMS in PLMD patients have been published. Most trials were open studies in small patient groups evaluating the effect of various substances on PLMS.The results of these studies should be verified in controlled randomized studies assessing both PLMS and subjective sleep parameters. n
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[51]Parrino L, Boselli M, Buccino GP, et al. The cyclic alternating pattern plays a gatecontrol on periodic limb movements during non-rapid eye movement sleep. J Clin Neurophysiol 1996;13:314-23. [52]El-Ad B, Chervin RD.The case of a missing PLM. Sleep 2000;23: 450-1. [53]Riva L,Bianchi AM,Castronovo V,et al.Heart Rate variability in relation to periodic limb movement (PLM) disorder and cyclic alternating pattern (CAP). Sleep 2002;25:A63. [54]De Mello M.T, Silva A.C, Rueda A.D, et al.. Correlation between K complex, periodic leg movements (PLM), and myoclonus during sleep in paraplegic adults before and after an acute physical activity, Spinal Cord 1997;35:248-52. [55]De Mello M.T, Poyares D.L, Tufik S. Treatment of periodic leg movements with a dopaminergic agonist in subjects with total spinal cord lesions, Spinal Cord 1999;37:634-7. [56]Lee M.S, Choi Y.C, Lee S.H, Lee S.B. Sleep-related periodic leg movements associated with spinal cord lesions, Mov. Disord. 1996;11:719- 22. [57]Yokota T,Hirose K,Tanabe H,Tsukagoshi H.Sleep-related periodic leg movements (nocturnal myoclonus) due to spinal cord lesion, J. Neurol. Sci. 1991;104:13-18. [58]Provini F, Vetruno R., Meletti S, et al. Motor pattern of periodic limb movements during sleep, Neurology 2001; 57:300-304. [59]Lindvall O, Bjorklund A, Skagerberg G. Dopamine-containing neurons in the spinal cord: anatomy and some functional aspects, Ann. Neurol. 1983;14:255-260. [60]Trenkwalder C, Paulus W. Why do restless legs occur at rest? Pathophysiology of neuronal structures in RLS. Neurophysiology of RLS (part 2). Clin Neurophysiol 2004;115:1975-88. [61]Ondo W.G, He Y, Rajasekaran S, Le W.D. Clinical correlates of 6- hydroxydopamine injections into A11 dopaminergic neurons in rats: a possible model for restless legs syndrome, Mov. Disord. 2000;15:154-158. [62]Wetter TC,Eisensehr I,Trenkwalder C.Functional neuroimaging studies in restless legs syndrome.Sleep Med. 2004;5(4):401-406. [63]Coleman RM, Bliwise DL, Sabjen N et al. Epidemiology of periodic movement during sleep. In: Guilleminault C, Lugarasi E, eds. Sleep wake disorders: natural History, epidemiology and long term evaluation. Raven Press, New York, 1983;217229. [64]Mendelson WB. Are periodic leg movements associated with clinical sleep disturbance? Sleep 1996;19:219-23. [65]Rosenthal L, Roehrs T, Sicklesteel J, et al...Periodic movements during sleep, sleep fragmentation and sleep wake complaints. Sleep 1984;7:326-30. [66]Saskin P, Moldofsky HA, Lue F. Periodic movements in sleep and sleep-wake complaint. Sleep 1985;8:319-24. [67]Karadeniz D, Ondze B, Besset A, Billiard M. Are periodic leg movements during sleep (PLMS) responsible for sleep disruption in insomnia patients? Eur. J Neurol, 2000;7,331-6. [68]Nicolas A, Lesperance P, Montplaisir J. Is excessive daytime sleepiness with periodic leg movements during sleep a specific diagnostic category? European Neurology, 1998;40:22-26. [69]Winkelman JW. The evoked heart rate response to periodic leg movements of sleep. Sleep 1999;22:575-80. [70]Sforza E, Nicolas A, Lavigne G, et al.. EEG and cardiac activation during periodic leg movements in sleep: support for a hierarchy of arousal responses. Neurology 1999;52:786-91. [71]Ali NJ, Davies RJ, Fleetham JA, Stradling JR. Periodic movements of the legs during sleep associated with rises in systemic blood pressure. Sleep 1991;14:163-5. [72]Hornyak M, Cejnar M, Elam M, Matousek M,Wallin BG. Sympathetic muscle nerve activity during sleep in man. Brain 1991;114(Pt 3):1281-95. [73]Hornyak M, Feige B, Voderholzer U, Reimann D. Spectral analysis of sleep EEG in patients with restless legs syndrome. Clin Neurophysiol 2005;116(6):1265-72. [74]Sforza E, Pichot V, Barthelemy JC, et al.. Cardiovascular variability during periodic leg movements: a spectral analysis approach. Clin Neurophysiol, 2005;116 :1096-104. [75]Pennestri MH, Montplaisir J, Colombo R, et al.. Nocturnal blood pressure changes in patients with restless legs syndrome.Neurology 2007;68(15):1213-8. [76]Lavoie S, de Bilbao F, Haba-Rubio J , et al. Influence of sleep stage and wakefulness on spectral EEG activity and heart rate variations around periodic leg movements. Clin Neurophysiol 2004;115:2236-46. [77]Hening WA, Allen RP, Earley CJ, et al.. Restless legs syndrome task force of the standards of practice committee of the American academy of sleep medicine. An update on the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. Sleep 2004;27:560-83.
MEDECINE DU SOMMEIL - Année 5 - Juillet - Aôut - Septembre 2008
Periodic leg movements in sleep and periodic limb movement disorder: a polysomnographic finding and/or a disorder? D.-K. Kaynaka a Istanbul University
Cerrahpasa Faculty of medicine Department of neurology Sleep Disorders Unit, Istanbul, Turkey. Correspondance : [email protected]
Summary Periodic leg movements in sleep (PLMS) are a sleep related phenomenon with periodic episodes of repetitive and highly stereotypical movements of the lower extremities. As the presence of PLMS is believed to be associated with the complaint of non-restorative sleep, it is recommended to routinely record PLMS for clinical purposes. PLMS occurring in patients with otherwise not explained insomnia and/or hypersomnia is defined as periodic limb movement disorder (PLMD). The largest epidemiological study evaluating the presence of PLMS and sleep complaints documented a 3.9% prevalence in general population.PLMS have also been documented in patients with various sleep and medical disorders. There are many hypotheses in respect to pathophysiology of PLMS and have been suggested to be related to dopaminergic systems. Besides clinical symptoms, PLMS may influence some physiological measures such as heart rate, blood pressure and EEG-spectra during sleep. Recommendations for therapy of PLMD originate mostly from studies in RLS patients, in which L-dopa and dopamine agonists are considered as first-line treatment.
Keywords Sleep, periodic leg movements, periodic limb movement disorder, prevalence, treatment.
MOUVEMENTS PÉRIODIQUES DES JAMBES AU COURS DU SOMMEIL ET SYNDROME DES MOUVEMENTS PÉRIODIQUES DES MEMBRES : UNE DÉCOUVERTE POLYSOMNOGRAPHIQUE ET/OU UNE PATHOLOGIE ?
Résumé Les mouvements périodiques des membres dans le sommeil (PLMS, pour periodic limb movements in sleep) sont des phénomènes liés au sommeil. Ils consistent en des mouvements périodiques et hautement stéréotypés des extrémités inférieures.La présence de mouvements périodiques des membres étant réputée être associée à une plainte de sommeil non restaurateur, on a l’habitude d’enregistrer ces mouvements en routine.L’association mouvements périodiques des membres – insomnie ou hypersomnie inexpliquées est désignée sous le terme de syndrome de mouvements périodiques des membres dans le sommeil. La plus large étude épidémiologique réalisée à ce jour,sur la prévalence de l’association mouvements périodiques des membres – plaintes sur le sommeil, a trouvé une prévalence de 3,9 % dans la population générale. Des mouvements périodiques des membres dans le sommeil ont également été décrits chez des patients atteints de troubles variés du sommeil et d’autres maladies. La physiopathologie des mouvements périodiques des membres a donné lieu à de nombreuses hypothèses impliquant les systèmes dopaminergiques.En plus des symptômes cliniques auxquels ils donnent lieu, les mouvements périodiques des membres dans le sommeil pourraient avoir un impact sur la fréquence cardiaque, la pression artérielle et les paramètres EEG, durant le sommeil. Les recommandations concernant le traitement du syndrome de mouvements périodiques des membres dans le sommeil proviennent surtout d’études réalisées chez des patients atteints du syndrome d’impatiences des membres inférieurs, chez lesquels la L-Dopa et les agonistes dopaminergiques sont recommandés comme traitement de première intention.
Mots-clés Sommeil,mouvements périodiques des membres inférieurs,syndrome de mouvements périodiques des membres,prévalence,traitement. MEDECINE DU SOMMEIL - Année 5 - Avril - Mai - Juin 2008
© 2008 – Elsevier Masson SAS – Tous droits réservés
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mise au point INTRODUCTION Periodic leg movements in sleep (PLMS) are a sleep related phenomenon with periodic episodes of repetitive and highly stereotypical movements of the lower extremities [1). The movements are characterized by dorsiflexion of the ankle, dorsiflexion of the toes and a partial flexion of the knee and sometimes the hip. PLMS were first described by Symonds as ‘nocturnal myoclonus’ [2]. Lugaresi et al. [3] reported the first polysomnographic (PSG) recording of PLMS. Coleman proposed the first scoring criteria of PLMS [4]. The new standards for recording and scoring periodic leg movements were proposed by the World Association of Sleep Medicine (WASM) in collaboration with a task force from the International Restless Legs Syndrome Study Group (IRLSSG) [1]. The necessities to change scoring criteria were: newly recognized pathologies to be associated with PLMS and occurrence of new sophisticated methods of signal analysis. These new guidelines apply to adults; they are expected to be valid also for children, but are recommended for cautious use with children pending further pediatric evaluations of PLMS. The criteria for the association with arousal and/or abnormal respiratory events were also described. According to the new criteria, duration of movement is defined as the time between onset and offset of the event which must be at least 0.5 seconds and no longer than 10 seconds (figure 1). The period length for two consecutive movements to be considered as PLM must be at least 5 and no more than 90 seconds.The number of consecutive movements meeting the period criteria must be four or more movements can occur in any stage of sleep or wake and the sequence of consecutive events continues across changes in sleep–wake state. Bilateral movements can include two or more unilateral movements separated (offset-to-onset) by less than 0.5 s from each other. An arousal and movement are considered associated with each other when there is less than 0.5 seconds between the end of one event and the onset of the other event, regardless of which is the first. Respiration must be recorded to accurately assess if movements are associated with respiratory events. These movements should not be included in PLM-related parameters. It should be noted that PLM and obstructive sleep apnea might coexist [1].
Figure 1 : Overview of the detection parameters of candidate PLM (1)
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PLMS may occur not only during sleep but also in wakefulness (periodic leg movements in wake-PLMW). PLMW occurring in RLS patients are phenotypically similar to PLMS but have a longer duration [4]. PLMW recordings may be used for the diagnosis of RLS in the ‘Suggested Immobilization Test’ [5]. In RLS, PLMW were found to have higher diagnostic specificity and sensitivity than PLMS [6]. Gender has no significant effect on PLMS indices, duration or periodicity.Movements of longer duration are seen during wakefulness, while REM sleep is characterized by the shorter duation and the lowest frequency. State of vigilance also modulates the periodicity of PLMS. Intervals are shorter during wakefulness and increase progressively from stage 1 to stage 2 and slow wave sleep [7]. In heathy subjects, the presence of PLMS was rare before the age of 40, but then the index increased dramatically. PLMW index was higher in younger subjects compared with middle-aged subjects. With advancing age, PLMS interval histograms show a peak around 15 to 35 seconds, which is not observed in younger subjects. On the other hand, despite high indexes, PLMW interval histograms do not show a clear peak for any age group [8]. As the presence of PLMS is believed to be associated with the complaint of non-restorative sleep, it is recommended to routinely record PLMS for clinical purposes [1, 9]. Due to night-tonight variability of PLMS, two-night PLMS recordings may be necessary for diagnostic purposes [10]. Recording PLMS by actigraphy can facilitate PLMS recording over multiple nights. However, the technique is currently not yet established and its validity still has to be demonstrated [11]. To determine the frequency of PLMS occurrence, the PLMS index, calculated as the number of PLMS per hour of total sleep time, is used. As PLMS followed by an arousal are considered to be relevant in the generation of sleep disturbances, it is recommended to additionally calculate the PLMS-arousal index that is the number of PLMS with arousals per hour of total sleep time [1]. Relative frequency of movements, their duration and their arousing effect appear to decrease during non-rapid eye movement sleep stages while the intermovement interval was found to increase. During rapid eye movement sleep, the duration of movements was found to be shortest and the intermovement interval longest [12]. The new approach for the analysis of quantity, type, and periodicity of the leg motor activity during sleep was also described in patients with restless legs syndrome. In this analysis, leg movement duration , amplitude, area under the curve, sleep stage, side, interval, and bilaterality were taken into consideration. In RLS patients' inter-LM interval distribution graph showed a wide peak with a maximum located at around 15 to 30 seconds and extending from 10 to 90 seconds, and another peak for intervals less than 8 seconds. Periodicity was not dependent on the periodic leg movement index.This new approach seems to be useful in a qualitative differentiation among patients with PLMS, hich is not possible by using the simple PLM index [13]. PLMS occurring in subjectswith otherwise not explained insomnia and/or hypersomnia with the PLMS index exceeds 5 in children and 15 in adults is defined as periodic limb movement disorder (PLMD) [14]. If PLMS are present without clinical sleep disturbance, they can be noted as polysomnographic finding.The diagnosis of PLMD requires PSG confirmation and is based on the exclusion of other causes of sleep disturbances. MEDECINE DU SOMMEIL - Année 5 - Juillet - Aôut - Septembre 2008
D.-K. Kaynak
Periodic leg movements in sleep and periodic limb movement disorder: a polysomnographic finding and/or a disorder ?
PREVALENCE OF PERIODIC LEG MOVEMENTS IN SLEEP To date, the largest epidemiological study evaluating the presence of PLMS and sleep complaints (PLMD) documented a 3.9% prevalence in 18,980 subjects from the general population aged 15–100 years [15]. The study identified several factors associated with PLMD such as female gender, caffeine intake, stress and the presence of mental disorders. In childhood and adolescence, PLMS rarely occur. In a study of children referred to a pediatric sleep laboratory, 5.6% of 591 subjects had a PLMS index of greater than 5. Only 1.2% of them had PLMS without sleep complaints or a comorbid disorder [16]. In an other study 23% of children were diagnosed as having PLMS on the basis of polysomnography. The presence of PLMS had usually been unrecognized clinically. The only clinical symptom that could be related to periodic limb movement disorder was a report of leg pains at morning awakening. Comorbidity seen with PLMS included neuropsychiatric syndromes, isolated sleep disordered breathing , and several other comorbid conditions [17]. Elevated PLMS indices have been reported also in children with obstructive sleep apnea syndrome (OSAS), juvenile fibromyalgia [18] and attention-deficit hyperactivity syndrome [19]. The prevalence of PLMS has been found to increase with advanced age [20, 21, 22, 23], and frequently have been observed in subjects without any sleep disturbance [20, 21, 22, 24, 25]. On the other hand, an elevated PLM index has been detected in over 80% of older patients with sleep complaints [26].
PLMS AND OTHER DISORDERS PLMS have been documented in patients with various sleep disorders. PLMS occur most frequently in patients with RLS. In a study of 133 cases of RLS, a PLMS index of more than 5 was found in 80% of the patients during one night PSG and in 88% with two PSG recordings [27]. An elevated rate of PLMS can also be observed in narcolepsy [28]. PLMS are a common finding in OSAS and may occur both in close temporal association with abnormal respiratory events or independently from them. During CPAP therapy, PLMS may increase or decrease depending on the severity of OSAS. In moderate to severe OSAS, PLMS were found to increase, probably due to ‘unmasking’ of an underlying PLMD. In mild OSAS, PLMS decrease due to resolution of the respiratory efforts and the related PLMS [29]. Classification of PLMS in OSAS into spontaneous (as in PLMD) and induced (secondary to respiratory effort-related arousals) PLMS has been suggested. According to current scoring criteria, leg movements occurring in association with respiratory events (apneas, hypopneas) should be counted separately, if respiratory signal is available [1]. In patients with significant abnormal respiratory events and elevated number of PLMS, the OSAS should be primarily treated before evaluating the clinical importance of PLMS. PLMS are also frequently recorded in patients with REM sleep behavior disorder (RBD). In a cohort of 40 RBD patients, 70% revealed a PLMS index more then 10 [30]. In RBD, PLMS may also frequently occur during REM sleep. Besides sleep disorders, an elevated PLMS index was found to be MEDECINE DU SOMMEIL - Année 5 - Juillet - Aôut - Septembre 2008
increased with severity or worsening of a medical disorder such as in patients with essential hypertension [31], end-stage renal disease [32], and alcohol dependency [33]. It is not known whether PLMS in these disorders are related to the basic pathophysiology of the disease as proposed for alcohol dependency or whether they are just a surrogate marker as presumed in end-stage renal disease. Observational studies described an increase of PLMS in depressed patients treated with psychoactive substances and antidepressants like clomipramine, lithium, fluoxetine or venlafaxine [34, 35, 36, 37, 38].A recent study on 274 patients treated with antidepressants found a significant increase of PLMS during treatment with selective serotonin reuptake inhibitors or with venlafaxine but normal values during bupropion therapy [39].
PATHOPHYSIOLOGY The exact pathophysiology of PLMS has not been elucidated yet. According to the common brainstem system (CBS) theory [40, 41], CBS exerts regulatory influences on the activities of peripheral visceral and somatomotor systems, synchronizing them to the activities of higher brain structures. However the neurons of the CBS also present an oscillatory rhythmic activity that is able to adjust the vascular, cardiac, respiratory and EEG delta–theta rhythms in case of altered internal or external stimuli (?) [40, 42]. Internal or external stimuli could be processed by the CBS, inducing the initial part of the arousal response, aimed at maintaining sleep, and mainly characterized by mild HR and EEG delta waves activation. Further activation of the CBS could induce an increase in the firing rate of this system, yielding major changes in autonomic and cerebral activities, as a survival defensive response. It has been shown that PLM onset is heralded by a significant activation of HR and delta activity power, beginning before the leg movement takes place. Faster EEG frequency bands showed an activation starting immediately just before the PLM onset. In averaged variations of tibial EMG, there was no presence of muscular activity able to induce the initial changes in EEG and ECG signals before PLM onset.The time evolution of alpha, sigma and beta frequency variations shows that their activation largely develops after the PLM onset. Moreover, there is a trend toward a progressive increase in the importance of activation from lower to faster frequencies. This study highlights that impressive cardiac and EEG changes take place before the onset of the motor phenomenon. The temporal relationship between delta activity, cardiac activation and PLM suggests that these phenomena are preparatory conditions, involving both central and autonomic nervous systems, exerting a permissive function on the activity of spinal motoneurons [43]. According to Sforza et al. [44] the rise of delta waves and HR could be considered as the first level of a transient activation from sleep. PLMS, and the subsequent progressive activation of the faster EEG frequencies, should be considered as the second phase in the continuum of the arousal response associated with these movements. These authors reported that, irrespective of the importance of EEG changes linked to PLMs, the pattern of arousal response consisted of an abrupt increase in delta activity and HR a few seconds before the onset of the PLM, followed by a progressive rise in fast EEG frequencies and tachycardia, peaking 25
mise au point from 1 to 3 seconds after the PLM onset. On the whole, these data give strong evidence that PLMs are not the trigger phenomenon of cardiac and EEG activation, but on the contrary seem ruled by a central oscillatory mechanism regulating both EEG and autonomic functions. Either spontaneous arousals or those related to motor phenomena, blood pressure variations or cardiac activations show a qualitatively common EEG spectral pattern, irrespective of the presence of a detectable arousing stimulus, its type or its strength. Since a stereotyped pattern of variations in HR and EEG spectral composition is present before and during spontaneous arousal, PLMS, respiratory efforts and cardiovascular variations, it is tempting to suggest, that oscillatory processes in autonomic and EEG activities might adjust in anticipation to the motor phenomenon. There are also other studies investigating the relationship between PLMS and cortical arousal, heart rate and EEG spectra. Our study addressed this point using inspective EEG techniques. Findings of a significantly higher number of arousals prior to leg movements suggest that arousals are not simply the consequence of PLMD but that, on the contrary, both EEG arousals and PLMD are manifestations of a common underlying arousal disorder [45]. On the other hand, the occurrence of PLMS in patients with spinal cord injury suggests that PLM may be directly generated in the spinal cord [54, 57]. Provini et al. suggested that activation (or disinhibition) of innervated skeletal muscles at medullar levels L4-S1 and to a lesser extent at C6–C7, is involved in generating PLMS. Another study has shown that lesion of the gracilis and cuneate fascicles were sufficient to generate this pattern of movement during sleep, regardless of the length or degree of histopathological lesion [58]. Another hypothesis for the involvement of the dorsal column in movements during sleep is the topographical location of the dopaminergic neurons in the dorsal column of the spinal cord. The dopaminergic system cells are located periventricularly in the dorsal hypothalamus and caudal thalamus, and their nerve endings have their synapses in the dorsal horn at all levels of the spinal cord and around the preganglionic sympathetic neurons in the thoracolumbar spinal cord. The data now available favor the participation of the spinal dopaminergic system in pain modulation and autonomic and motor responses. Dysfunction of spinal dopaminergic neurons may also be involved in the pathophysiology of certain conditions, such as Parkinson’s disease [59]. Because of frequent association with RLS narcolepsy or RBD in which the impairment of dopaminergic transmission have been suggested, PLMS are hypothesized to be related to dopaminergic systems [60]. In the rat model of RLS it has been shown that subcortical lesions to the A11 dopaminergic nuclei cause PLMS [61]. Furthermore, dopaminergic agents were reported to reduce the number of PLMS in RLS, narcolepsy and RBD patients. Functional neuroimaging studies may contribute to elucidate pathophysiological mechanisms of PLMS which still remain unclear. Functional MRI investigations of RLS patients revealed an activation in the red nuclei and brainstem close to the reticular formation during the symptomatic period, suggesting that subcortical cerebral generators are involved in the pathogenesis of RLS [62]. However this technique is not yet clinically relevant methods to differentiate PLMS or RLS from other movement disorders during sleep. 26
PLMS AND SLEEP DISTURBANCE The correlation of subjective sleep complaints and PLMS is contradictory. Periodic leg movements during sleep occur along with a wide variety of sleep-wake complaints such as sleep onset difficulty, nocturnal awakenings, early morning awakenings and also daytime sleepiness. They occur in 13.3% of patients complaining of insomnia, 6.9% of those being evaluated for excessive sleepiness [63]. It is generally accepted, from a clinical standpoint, that leg movements are frequently accompanied by electroencephalogram (EEG) signs of arousal which cause sleep fragmentation and in the absence of such arousals, patients do not have sleep-wake complaints. Insomnia and daytime sleepiness show different characteristics in these patients. It has been shown that PLMS patients with insomnia had more leg movements, a longer delay to sleep onset and to REM onset, more wakefulness after sleep onset and less total sleep time than those patients with daytime sleepiness [64]. Two studies compared PLMS parameters in patients with insomnia and daytime sleepiness proposed that the differences in symptomatic complaints represent points on a continuum of sleep fragmentation [65, 66]. The fragmentation of sleep was more severe in PLMS patients complaining of insomnia, who showed increased wakefulness, less total sleep time, a greater latency of SWS and impaired sleep efficiency index. In our patients, having consulted for an evaluation of insomnia and having PLMS, sleep analysis revealed an increased wake time after sleep onset, number of awakenings, shifts to sleep stage 1, and a decreased sleep efficiency continuity index. All these impaired sleep parameters resulted in disturbed nocturnal sleep and complaint of insomnia. On the other hand, we found no clear association between periodic leg movement index, periodic leg movement arousal index, inter-movement interval and various sleep parameters. The only significant relationship we found was that the longer the movement duration, the longer the wake time after sleep onset, and SWS latency, and the lower the sleep efficiency and continuity index [67]. In respect to daytime sleepiness, no correlation was found between PLMS index and poor sleep efficiency or daytime sleepiness as measured by the multiple sleep latency test (MSLT) [68]. Pollmacher and Schulz showed that the arousing effect of periodic leg movements depends on the duration of the movement [12]. This was suggested by the finding that the percentage of periodic leg movements followed by EEG arousals increases with the increasing duration of the movements. Based on the assumption that the arousing effect of the movements is probably crucial for the induction of sleep disturbance, our findings also support the assumption that the determining factor of sleep disturbance in PLMS patients was movement duration rather than frequency or inter-movement interval.The evaluation of sleep micro-structure revealed that the amount of EEG activities during sleep (alpha, theta, delta and spindles), with and without leg movements, did not show any significant difference. The lack of significant differences in both macro- and microstructure of sleep and EEG activity content, with respect to the association with movements, confirms the hypothesis that periodic leg movements did not primarily cause the sleep disturbance [67]. The relationship of periodic leg movements to both subjective complaint and also objective sleep disturbance is MEDECINE DU SOMMEIL - Année 5 - Juillet - Aôut - Septembre 2008
D.-K. Kaynak
Periodic leg movements in sleep and periodic limb movement disorder: a polysomnographic finding and/or a disorder ?
neither obvious nor simple. Besides clinical symptoms, PLMS may influence some physiological measures during sleep. There are investigations demonstrated PLMS-related changes in heart rate [69], EEGspectra [70] and in also of blood pressure [71]. However, these changes may be unspecific, at least for those PLMS not associated with an arousal, as they are comparable in magnitude to the changes in heart rate and blood pressure induced by a Kcomplex [72]. Moreover, in a recent study, it has been shown that changes of the EEG-spectra due to an arousal (whether associated with a PLMS or not) are by far more prominent than that of a PLMS not associated with an arousal [73]. This finding questions the pathophysiological relevance of PLMS and indicates that it is not the PLMS but rather the associated arousals that influence cortical activity in sleep and may be related to the subjective impression of nonrestorative sleep. On the other hand, recently, it has been shown that in NREM sleep the primary cardiac effect of the PLMS consists in a strong increase in sympathetic activity associated with a weak reduction in parasympathetic tonus [74]. In a study of Pennestri MH et al, blood pressure was shown to be increased significantly in association with all PLMS. Blood pressure changes associated with PLMS with arousals were greater than those associated with PLMS without arousals. Systolic and diastolic blood pressure changes increased with age and the duration of illness [75]. Thus PLMS-related repetitive nocturnal blood pressure fluctuations could contribute to the risk of cardiovascular diseases especially in the elderly. Further studies are needed to evaluate the relationship of PLMS and cardiovascular disorders. While in stages 1 and 2 of NREM sleep, the PLM was preceded by a rise in slow EEG activity paralleling the rise in HR, in wakefulness and REM sleep, the changes in cerebral activity appeared simultaneously with the PLM onset.In addition the EEG variations were strong and persistent during sleep but the EEG activation was almost absent during wakefulness. The differences between wakefulness and sleep appear to be similar in RLS and PLMD suggesting an underlying common pathogenetic mechanism. In addition typical pattern of cardiac response was present during NREM and REM sleep, the autonomic activation was smaller but prolonged during wakefulness. These results suggest that the mechanisms triggering PLMS are different between NREM sleep, REM sleep and wakefulness, suggesting that the occurrence of PLMS may be underlie by specific sleep state-dependent mechanisms. In an other study it has been observed significant differences in the time course of cerebral and cardiac activation during PLMS in relation to different sleep states and wakefulness. Wakefulness appears to induce smaller changes in both systems indicating a mechanism different from that implicated during sleep. The differences across sleep stages in the EEG and cardiac variations suggest that more a sleep stage dependence of arousal response to motor event rather than a common generator may be implicated in the occurrence of PLMS [76]. The clinical relevance of these findings remains questionable. To further elucidate the relationship of subjective sleep perception and PLMS, the temporal relationship of PLMS, arousal and CAP as well as their periodicity should be more closely examined. Additionally, the sleep stage during which PLMS occur and the time course of PLMS during the night should be considered. MEDECINE DU SOMMEIL - Année 5 - Juillet - Aôut - Septembre 2008
TREATMENT OF PLMS IN PATIENTS WITH INSOMNIA AND/OR HYPERSOMNIA (PLMD) Recommendations for therapy of PLMD originate mostly from studies in RLS patients, in which L-dopa and dopamine agonists are considered as first-line treatment [77]. However, there is no controlled clinical study investigating the effect of L-dopa on PLMS and/or the related sleep complaints.To date, only a handful of clinical studies on the treatment of PLMS in PLMD patients have been published. Most trials were open studies in small patient groups evaluating the effect of various substances on PLMS.The results of these studies should be verified in controlled randomized studies assessing both PLMS and subjective sleep parameters. n
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