Periodic Limb Movements: Diagnosis and Clinical Associations

Periodic limb movements (PLMs) are characterized by stereotyped, repetitive, non-epileptic movements of the limbs, more frequently in legs. They occur during wakefulness preceding sleep onset (PLMW) and during sleep (PLMS). The first polygraphically documented cases occurred in restless legs syndrome (RLS).¹ In fact, most of what we know about PLMs derives from studies of patients with RLS. In their simplest form, PLMs consist of withdrawal-like dorsiflexion of the big and other toes and of the ankle, resembling the spinal flexor-reflex, occurring more frequently at the beginning of the night and exponentially declining across sleep cycles according to circadian influence(s)^2-4 (Figure 1). However, although the leg muscles are the most frequently affected, followed by the upper limb muscles, which are sometimes involved, and by axial muscles that are rarely involved, the movements are less stereotyped than previously believed, with individual variations of the movement patterns.^5-7 What's more, the EMG activity during PLMS may assume different forms. They include: a tonic activity lasting several hundreds of milliseconds possibly followed by myoclonic activity, an initial myoclonic jerk followed by tonic activity or several myoclonic jerks in clusters sometimes followed by tonic activity. Sometimes PLMS may be seen to occur only in one leg or on one side of the body or to alternate between the two sides.¹

From a polysomnographic point of view, PLMS are scored only if they occur in series of at least four consecutive movements each lasting 0.5-5 seconds and separated by intervals of 4-90 seconds. These criteria have recently undergone re-evaluation;^8,9 An index (number of PLMS per hour of sleep) greater than five for the entire night is considered pathologic, but data supporting this contention are rather limited.

The standard method to detect PLMs is a polysomnography recording. However, there have been efforts to detect PLMs by means of actigraphy, which is more convenient for both patient and investigator, since it permits multiple-night recordings in an outpatient setting. Actigraphy offers a convenient and economical alternative to polysomnography in the study of large populations to increase our understanding of the epidemiology and clinical significance of the PLMs.¹⁰ Physicians must note that actigraphy alone should not be used for diagnostic decisions.¹¹ Periodic limb movement disorder (PLMD) is defined as a PLMS index of five or greater that is associated with otherwise unexplained sleep-wake complaint and requiring a polysomnographic confirmation along with the exclusion of other causes of sleep disturbances.

PHYSIOLOGY AND PATHOGENESIS
PLMS are frequently associated with arousal and transient autonomic activation (tachycardia, tachypnea, and an increase in blood pressure) (Figure 2). The link between this common sleep-related motor phenomenon and the intrinsic periodic fluctuations of the nervous system affecting motor, autonomic and vigilance systems during light sleep suggested the existence of a common brainstem generator. This generator modulates their periodicity by descending, probably reticular, influences.^12,13 Later the physiologic fluctuations that reoccur every 20-40 seconds during NREM sleep were termed the "cyclic alternating pattern," infraslow oscillations whose periodicity is embraced with motor and autonomic fluctuations.¹⁴ The concept of a brain stem oscillator received some support from functional MRI studies implicating the red nucleus and other brainstem regions in the generation of the PLMS.¹⁵ Other MRI studies showed changes in thalamic structures at voxel-based morphometry analysis.¹⁶

Altogether, the findings support an involuntary mechanism of induction and a subcortical origin for PLMs. This is also suggested by transcranial magnetic stimulation investigations¹⁷ and the lack of EEG cortical potentials prior to PLMS1 and PLMW.¹⁸ However, clinical and neurophysiological observations demonstrate that PLMS are actually generated within the spinal cord from the activation of several central spine generators, most likely set into motion by state-dependent descending supraspinal modulating influences.^19-25

Impairment in brain iron availability^26,27 and the link between iron deficiency and reduction in central dopaminergic tone^28,29 coupled with the knowledge that central dopamine signaling exhibits a daily rhythm with a nadir in the evening,³⁰ support the pathophysiologic role of brain dopaminergic hypoactivity in PLMS.³¹ It may also explain the circadian recurrence and the efficacy of dopaminergic drugs in PLMD.³² In particular, a dysfunction or atrophy of a supraspinally located dopaminergic region in the hypothalamus (hypothalamic A11 nucleus) with descending pathways that target the preganglionic sympathetic neurons—the dorsal horn region, the interneurons, and the somatic motor neurons, has been hypothesized as being intimately involved in the etiology of PLMS.^33,34 Striatal regions29 and thalamic structures16 also may be involved.

PLMS still appear as a complex and multivarious movement disorder that implicates many brain areas, including regions belonging to the medial pain system (thalamus, anterior cingulate and insula) where abnormal dopamine and opioid activity has been found.^35,36 Several genetic variants associated with susceptibility to PLMS have also been recently discovered.³⁷

PREVALENCE
The prevalence of PLMS is four to 11 percent in the general population with an age-associated increase up to ^25-58 percent in the elderly population.^38-40 PLMS are present in 80 percent of patients with RLS.⁴¹ PLMS may also occur in children, with prevalence rates from 3.9 percent to 50 percent, although the coexistence of other medical conditions like sleep apnea, attention-deficit hyperactivity syndrome, migraine, seizures, narcolepsy and other neuropsychiatric conditions may raise the rate (ICSD-2, 2005).^42,43 The highest prevalence of PLMS was 85 percent, reported in a community-based study of elderly patients with a mean age of 67 years.⁴⁴ The latter finding underscores the controversy about the clinical relevance of the PLMS. Some authors contend that PLMs are associated with adverse consequences for health,⁴⁵ whereas others do not.⁴⁶ PLMs have been reported to occur predominantly during the activation phase of the "cyclic alternating pattern" of sleep,⁴⁷ associated with transient tachycardia and blood pressure increase.^48-52 These findings led some authors to maintain that PLMs imply a cardiovascular risk and should be treated even in the absence of any subjective impairment. Other authors cast doubt about the clinical significance of the PLMs and their associated arousals: arousals are not a well-defined phenomenon and, since the exact arousal index leading to clinical manifestations remains nebulous, PLMs should not need attention.⁴⁶ It thus remains to be seen whether PLMs constitute an incidental observation linked to developmental maturation or aging, or a defined medical entity with sequels.

CLINICAL CONDITIONS ASSOCIATED WITH PLMS
Besides RLS, PLMs occur with a wide range of sleep-related pathologies, especially in patients with difficulties starting and maintaining sleep and in patients with excessive daytime sleepiness. To date, the largest epidemiological study evaluating the simultaneous presence of PLMs and sleep complaints reported a 3.9 percent prevalence in 18,980 subjects from the general population between 15 and 100 years of age.³⁸ PLMS indeed occurs in various sleep disorders such as obstructive sleep apnea syndrome (OSA),^53,54 insomnia⁵⁵, hypersomnia,⁵⁶ narcolepsy,⁵⁵ REM sleep behavior disorders,⁵⁷ sleep bruxism,⁵⁸ and sleep-related eating disorders,⁵⁹ In OSA, they may increase or decrease after continuous positive airway (CPAP) therapy. In moderate to severe OSA, the PLMs may increase due mainly to the "unmasking" of an underlying spontaneous PLMD, and may decrease post-CPAP in mild OSA due to resolution of secondary PLMS associated with respiratory effort-related arousals.⁶⁰

PLMs have also been reported in disorders not primarily affecting sleep, such as severe congestive heart failure, essential hypertension, end-stage renal disease, post-traumatic stress disorders, sarcoidosis, spinal cord injury, syringomyelia, multiple sclerosis, alcohol dependence, peripheral neuropathies sometimes associated with primary amyloidosis, diabetes mellitus, uremia, chronic lung disease, leukemia, rheumatoid arthritis, fibromyositis, Isaac syndrome, stiff-man syndrome, Huntington chorea, amyotrophic lateral sclerosis, anemia with iron/ferritin deficiency, Parkinson disease, multiple system atrophy, Gilles de la Tourette syndrome, spinocerebellar ataxia, or after medical procedure (epidural and spinal cord anesthesia, gastric surgery). They may also be related to medication intake, in particular psychoactive substances such as lithium, clomipramine, fluoxetine, venlafaxine and other serotonin reuptake inhibitor antidepressants, and neuroleptics.^61,62

Psychiatric illness. Psychiatric illness such as depression and anxiety have been associated with chronic sleep loss^63,64 and appear to be more prevalent in patients with PLMS (and RLS.)^65,66 Reports of depression varied from 20 percent up to 70 percent in patients with PLMS (and RLS), and the initiation of antidepressant therapy often provides a worsening of the PLMS. Remarkably, some epidemiologic studies have suggested an association of cardiovascular disease and PLMS-RLS^67-69 leading to claims of an association between PLMS-related repetitive EEG arousals and autonomic hyperactivity and/or to sleep fragmentation as the causal link.^51,52

Cardiovascular diseases. A number of studies suggest that PLMS may be a risk factor for cardiac diseases. PLMs are common in people with essential hypertension.⁷⁰ EEG and autonomic activations are greater during PLMs than during other types of leg movements.⁷¹ PLMs have been associated with elevated systolic as well as diastolic blood pressure. An increase in systolic blood pressure by almost 17mmHg and 11mmHg was found during PLMS respectively with and without cortical arousals.⁵² Similar findings have been reported in another study,⁵¹ heralding the possibility that PLMS-related repetitive nocturnal EEG and blood pressure fluctuations could contribute to the risk of cardiovascular diseases. However, these changes may be unspecific, as they are comparable in magnitude to the changes in heart rate and blood pressure induced by a K-complex.⁷² Moreover, these changes may occur physiologically even in the absence of PLMS during light sleep.¹³ The latter findings question the pathophysiological relevance of the PLMS and do not exclude that PLMS represents an epiphenomenon of physiological arousal that, like sleep perturbations, ubiquitously increases with age.

It is important to remember clinical investigations addressing the correlations between PLMS and increased risk for hypertension and coronary artery disease are still contradictory. A possibility is also that sympathetic dysfunction is causally related to the PLMS and that the PLMS-related repetitive autonomic changes may have a potential clinical relevance.⁷¹ However, the recurrence of PLMS in multiple system atrophy, in which the central autonomic network is degenerated without the attendant heart-rate, blood pressure and EEG changes^73-75 challenge any hypothesis of a direct provocation of the PLMS by an abnormal autonomic discharge. Further large-scale studies are needed to fully assess the extent of the PLMS to autonomic system relationships.

Excessive daytime sleepiness. PLMS may be responsible for difficulties in initiating and maintaining sleep and for sleep fragmentation with consequent daytime somnolence. Clinical investigations addressing the correlations of excessive daytime sleepiness and PLMS are, however, contradictory. Indeed, when searched for in patients with PLMD, no significant correlation may be found between polysomnographically scored PLMS and the subjective complaint of disturbed sleep, the objective measures of daytime sleepiness, or a sense of refreshed sleep on awakening.⁷⁶ In 149 older subjects with complaints of excessive daytime sleepiness, PLMs were detected at in-laboratory sleep study, but they were not found to represent a significant risk factor associated with sleepiness.⁷⁷ On the other hand, in another study PLMs (not scored in the sleep laboratory but according to a telephone interview) were among the factors having a significant relationship with subjective sleepiness.⁷⁸

A limitation of these studies may be the semantic distinction between sleepiness, tiredness, and fatigue. Though distinguishable on theoretical ground, these constructs may be too subtle to be adequately taken into account by the individual patient and to be distinguished.^79-81

THERAPEUTIC OPTIONS
Several medications have been reported to influence PLMS. L-dopa and dopamine agonists are considered as the first-line treatments.³² However, due to the fact that the clinical significance of PLMS/PLMD is still debated, as many studies have failed to demonstrate an association between PLMS/PLMD and symptoms of sleep and non-sleep disturbances,^82,44 it is not possible to indicate specific treatments for this sleep-related motor phenomenon. There are no established guidelines for treatment of PLMs, and those that exist remain undecisive.32 Moreover, recommendations for therapy of PLMs originate mostly from studies in RLS patients^83,84, and only a few trials investigated the effect of dopaminergic substances on the PLMS/PLMD.⁸⁵ Clinical experience indicates also that therapy of the PLMS and its associated disorder may diverge. For instance, hypersomniacs with PLMS respond positively to psychostimulants but not to treatment of the PLMS with dopaminergic agents (personal communication). It is also noteworthy that dopaminergic therapy for PLMS may even trigger RLS symptoms in the same patient,⁸⁶ representing a complication of long-term dopaminergic treatment today called "augmentation."⁸⁷

In patients who present with symptoms of sleep disturbance such as excessive daytime sleepiness, insomnia or frequent awakening, the clinician is thus faced with deciding whether or not to treat those that display a high PLMS index. The PLMS night-to-night variability makes the therapeutic decision still more complicated.⁸⁸ The individual patient and his/her attending physician must make the final decision whether or not to treat the PLMs.

1. Lugaresi E, Cirignotta F, Coccagna G, Montagna P. Nocturnal myoclonus and restless legs syndrome. Adv Neurol 1986; 43: 295-307.
2. 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: 102-110.
3. Hening WA, Walters AS, Wagner M, Rosen R, Chen V, Kim S, Shah M, Thai O. Circadian rhythm of motor restlessness and sensory symptoms in idiopathic restless legs syndrome. Sleep 1999; 22: 901-912.
4. Michaud M, Dumont M, Selmaoui B, Paquet J, Fantini ML, Montplaisir J. Circadian rhythm of restless legs syndrome: relationship with biological markers. Ann Neurol 2004; 55: 372-380.
5. Provini F, Vetrugno R, Meletti S, Plazzi G, Solieri L, Lugaresi E, Coccagna G, Montagna P. Motor pattern of periodic limb movements durino sleep. Neurology 2001; 57: 300-304.
6. De Weerd AW, Rijsman RM, Brinkley A. Activity patterns of leg muscles in periodic limb movement disorder. J Neurol Neurosurg Psychiatry 2004; 75: 317-319.
7. Vetrugno R, Provini F, Plazzi G, Cortelli P, Montagna P. Propriospinal myoclonus: a motor phenomenon found in restless legs syndrome different from periodic limb movements during sleep. Mov Disord 2005; 20: 1323-1329.
8. Zucconi M, Ferri R, Allen R, Baier PC, Bruni O, Chokroverty S, Ferini-Strambi L, Fulda S, Garcia-Borreguero D, Hening WA, Hirshkowitz M, Hšgl B, Hornyak M, King M, Montagna P, Parrino L, Plazzi G, Terzano MG; International Restless Legs Syndrome Study Group (IRLSSG). 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: 175-183.
9. Walters AS, Lavigne G, Hening W, Picchietti DL, Allen RP, Chokroverty S, Kushida CA, Bliwise DL, Mahowald MW, Schenck CH, Ancoli-Israel S. The scoring of movements in sleep. J Clin Sleep Med 2007; 3: 155-167.
10. King MA, Jaffre MO, Morrish E, Shneerson JM, Smith IE. The validation of a new actigraphy system for measurement of periodic leg movements in sleep. Sleep Med 2005; 6: 507-513.
11. Gschliesser V, Frauscher B, Brandauer E, Kohnen R, Ulmer H, Poewe W, Hogl B. PLM detection by actigraphy compared to polysomnography: a validation and comparison of two actigraphs. Sleep Med 2008; Epub ahead of print.
12. Moruzzi G. The physiological propertoies of the brainstem reticular system. In: Adrian AD, Bremer F, Jasper HH, editors. Brain mechanisms and consciousness. Oxford Blackwell, 1954: 21-48.
13. Lugaresi E, Coccagna G, Mantovani M, Lebrun R. Some periodic phenomena arising durino drowsiness and sleep in man. Electroencephalogr Clin Neurophysiol 1972; 32: 701-705.
14. Terzano MG, Mancia D, Salati MR, Costani G, Decembrino A, Parrino L. The cyclic alternatine pattern as a physiological component of normal NREM sleep. Sleep 1985; 8: 137-145.
15. Bucher SF, Seeleos KC, Oertel WH, Reiser M, Trenkwalder C. Cerebral generators involved in the pathogenesis of the restless legs syndrome. Ann Neurol 1997; 5: 639-645.
16. Etgen T, Draganski B, Ilg C, Schršder M, Geisler P, Hajak G, Eisensehr I, Sander D, May A. Bilateral thalamic gray matter changes in patients with restless legs syndrome. Neuroimage 2005; 24: 1242-1247.
17. Tergau F, Wischer S, Paulus W. Motor system excitability in patients with restless legs syndrome. Neurology 1999; 52: 1060-1063.
18. Trenkwalder C, Bucher SF, Oertel WH, Proeckl D, Plendl H, Paulus W. Bereitschaftspotential in idiopathic and symptomatic restless legs syndrome. Electroenceph Clin Neurophysiol 1993; 89: 95-103.
19. Yokota T, Hirose K, Tanabe H, Tsugagoshi H. Sleep-related periodic leg movements (nocturnal myoclonus) due to spinal cord lesion. J Neurol Sci 1991; 104: 13-18.
20. Lee MS, Choi YC, Lee SH, Lee SB. Sleep related periodic leg movements associated with spinal cord lesions. Mov Disord 1996; 11: 719-722.
21. Watanabe S, Sakai K, Ondo Y, Seino H, Naito H. Alternating periodic leg movement induced by spinal cord anesthesia in a elderly male. Anesth Analg 1987; 66: 1031-1032.
22. Lee MS, Lyoo CH, Kim WC, Kang HJ. Periodic bursts or rhythmic dyskinesia associated with spinal anesthesia. Mov Disord 1997; 12: 816-817.
23. Bara-Jimenez W, Aksu M, Graham B, Sato S, Hallett M. Periodic limb movements in sleep: state-dependent excitability of the spinal flexor reflex. Neurology 2000; 54: 1609-1616.
24. Rijsman RM, Stam CJ, Weerd AW. Abnormal H-reflexes in periodic limb movements disorder: impact on understanding the pathophysiology of the disorder. Clin Neurophysiol 2005; 116: 204-210.
25. Scaglione C,Vetrugno R, Plazzi G, Rizzo G, Provini F, Montagna P, Martinelli P. Group I nonreciprocal inhibition in primary restless legs syndrome. Mov Disord 2008; 23:96-100.
26. Earley C, Allen R, Beard J, Connor J. Insight into the pathophysiology of restless legs syndrome. J Neurosci Res 2000; 62: 623-628.
27. Connor JR, Boyer PJ, Menzies SL, Dellinger B, Allen RP, Ondo WG, Earley CJ. Neuropathological examination suggests impaired brain iron acquisition in restless legs sindrome. Neurology 2003; 61: 304-309.
28. Allen R. Dopamine and iron in the pathophysiology of restless legs syndrome (RLS). Sleep Med 2004; 5: 385-391.
29. Cervenka S, Palhagen SE, Comley RA, Panagiotidis G, CselŽnyi Z, Matthews JC, Lai RY, Halldin C, Farde L. Support for dopaminergic hypoactivity in restless legs syndrome: a PET study on D2-receptor binding. Brain 2006; 129: 2017-2028.
30. Khaldy H, Leon J, Escames G, Bikjdaouene L, Garc'a JJ, Acu–a-Castroviejo D. Circadian rhythms of dopamine and dihydroxyphenyl acetic acid in the mouse striatum: effects of pinealectomy and melatonin treatment. Neuroendocrinology 2002; 75: 201-208.
31. Clemens S, Rye D, Hochman S, Restless legs syndrome. Revisiting the dopamine hypothesis from the spinal cord perspective. Neurology 2006; 67: 125-130.
32. Vignatelli L, Billiard M, Clarenbach P, Garcia-Borreguero D, Kaynak D, Liesiene V, Trenkwalder C, Montagna P; EFNS Task Force. EFNS guidelines on management of restless legs syndrome and periodic limb movement disorder in sleep. Eur J Neurol 2006; 13: 1049-1065.
33. Ondo WG, He Y, Rajasekaran S, Le WD. Clinical correlates of 6-hydroxydopamine injections into A11 dopaminergic neurons in rats: a possible model for restless legs syndrome. Mov Disord 1998; 13: 271-275.
34. Qu S, Ondo WG, Zhang X, Xie WJ, Pan TH, Le WD. Projections of diencephalic dopamine neurons into the spinal cord in mice. Exp Brain Res 2006; 168: 152-156.
35. Sewards TV, Sewards MA. The medial pain system: neural representations of the motivational aspect of pain. Brain Res Bull 2002; 59: 163-180.
36. von Spiczak S, Whone AL, Hammers A, Asselin MC, Turkheimer F, Tings T, Happe S, Paulus W, Trenkwalder C, Brooks DJ. The role of opioids in restless legs syndrome: an [11C]diprenorphine PET study. Brain. 2005; 128: 906-917.
37. Stefansson H, Rye DB, Hicks A, Petursson H, Ingason A, Thorgeirsson TE, Palsson S, Sigmundsson T, Sigurdsson AP, Eiriksdottir I, Soebech E, Bliwise D, Beck JM, Rosen A, Waddy S, Trotti LM, Iranzo A, Thambisetty M, Hardarson GA, Kristjansson K, Gudmundsson LJ, Thorsteinsdottir U, Kong A, Gulcher JR, Gudbjartsson D, Stefansson K. A genetic risk factor for periodic limb movements in sleep. N Engl J Med 2007; 357: 639-647.
38. Ohayon MM, Roth T. Prevalence of restless legs syndrome and periodic limb movement disorder in the general population. J Psychosom Res 2002; 53: 547-554.
39. Hornyak M, Trenkwalder C. Restless legs syndrome and periodic limb movement disorder in the elderly. J Psychosom Res 2004; 56: 543-548.
40. Pennestri MH, Whittom S, Adam B, Petit D, Carrier J, Montplaisir J. PLMS and PLMW in healthy subjects as a function of age: prevalence and interval distribution. Sleep 2006; 29: 1183-1187.
41. Montplaisir J, Boucher S, Poirier G, Lavigne G, Lapierre O, LespŽrance P. Clinical, polysomnographic, and genetic characteristics of restless legs syndrome: a study of 133 patients diagnosed with new standard criteria. Mov Disord 1997; 12: 61-65.
42. Hornyak M, Feige B, Riemann D, Voderholzer U. Periodic leg movements in sleep and periodic limb movement disorder: prevalence, clinical significance and treatment. Sleep Med Rev 2006; 10: 169-177.
43. Bokkala S, Napalinga K, Pinninti N, Carvalho KS, Valencia I, Legido A, Kothare SV. Correlates of periodic limb movements of sleep in the pediatric population. Pediatr Neurol 2008; 39: 33-39.
44. Youngstedt SD, Kripke DF, Klauber MR, Sepulveda RS, Mason WJ. Periodic leg movements during sleep and sleep disturbances in elders. J Gerontol Biol Sci Med Sci 1998; 53: 391-394.
45. Hogl B. Periodic limb movements are associated with disturbed sleep. J Clin Sleep Med 2007; 3: 12-14.
46. Mahowald MW. Periodic limb movements are not associated with disturbed sleep. J Clin Sleep Med 2007; 3: 15-17.
47. Terzano MG, Parrino L. Origin and significance of the cyclic alternatine pattern (CAP). Review article. Sleep Med Rev 2000; 4: 101-123.
48. Sforza E, Juony C, Ibanez V. Time-dependent variation in cerebral and autonomic activity during periodic leg movements in sleep: implications for arousal mechanisms. Clin Neurophysiol 2002; 113: 883-891.
49. Winkelman JW. The evoked heart rate response to periodic leg movements of sleep. Sleep 1999; 22: 575-580.
50. Ali NJ, Davies RJ, Freetham JA, Stradling JR. Periodic movements of the legs during sleep associated with rises in systemic blood pressure. Sleep 1991; 14: 163-165.
51. Pennestri MH, Montplaisir J, Colombo R, Lavigne G. Nocturnal blood pressure changes in patients with restless legs syndrome. Neurology 2007; 68: 1213-1218.
52. Siddiqui F, Strus J, Ming X, Lee IA, Chokroverty S, Walters AS. Rise of blood pressure with periodic limb movements in sleep and wakefulness. Clin Neurophysiol 2007; 118: 1923-1930.
53. Ancol-Israel S, Kripke DF, Mason W, Kaplan OJ. Sleep apnea and periodic movements in sleep in a aging population. J Gerontol 1985; 40: 419-425.
54. Fry JM, DiPillipo MA, Pressman MR. Periodic leg movements in sleep following treatment of obstructive sleep apnea with nasal continuous positive pressure. Chest 1989; 96: 89-91.
55. Montplaisir J, Michaud M, Denesle R, Gosselin A. Periodic leg movements are not more prevalent in insomnia or hypersomnia but are specifically associated with sleep disorders involving a dopamine impairment. Sleep Med 2000; 1: 163-167.
56. Coleman RM, Pollak CP, Weitzman ED. Periodic movements in sleep (nocturnal myoclonus): relation to sleep disorders. Ann Neurol 1980; 8: 416-421.
57. Fantini ML, Michaud M, Gosselin N, Lavigne G, Montplaisir J. Periodic leg movements in REM sleep behaviour disorder and related autonomic and EEG activation. Neurology 2002; 59: 1889-1894.
58. Lavigne G, Montplaisir JV. Restless legs syndrome and sleep bruxism: prevalence and association among Canadian. Sleep 1994; 17: 739-743.
59. Vetrugno R, Manconi M, Ferini-Strambi L, Provini F, Plazzi G, Montagna P. Nocturnal eating: sleep-related eating disorder or night eating syndrome? A videopolysomnographic study. Sleep 2006; 29: 949-54.
60. Baran AS, Richert AC, Douglass AB, May W, Ansarin K. Change in periodic limb movement index during treatment of obstructive sleep apnea with continuous positive airway pressure. Sleep 2003; 26: 717-720.
61. Vetrugno R, Provini F, Montagna P. Restless Legs Sindrome and periodic limb movements. Rev Neurol Diseases 2006; 3: 61-70.
62. Iranzo A, Comella CL, Santamaria J, Oertel W. Restless legs sindrome in Parkinson's disease and other neurodegenerative diseases of the central nervous system. Mov Disord 2007; 22 (Suppl 18): 424-430.
63. Lustberg L, Reynolds CF. Depression and insomnia: questions of cause and effect. Sleep Med Rev 2000; 4: 253-262.
64. Neckelmann D, Mykletun A, Dahl AA. Chronic insomnia as a risk factor for developing anxiety and depression. Sleep 2007; 30: 873-880.
65. Saletu B, Anderer P, Saletu M, Hauer C, Lindeck-Pozza L, Saletu-Zyhlarz G. EEG mapping, psychometric, and polysomnographic studies in restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) patients as compared with normal controls. Sleep Med 2002; 3 Suppl: S35-S42.
66. Picchietti D, Winkelman JW. Restless legs syndrome, periodic limb movements in sleep, and depression. Sleep 2005; 28: 891-898.
67. Ulfberg J, Nystrom B, Carter N, Edling C. Prevalence of restless legs syndrome among men aged 18 to 64 years: an association with somatic disease and neuropsychiatric symptoms. Mov Disord 2001; 16: 1159-1163.
68. Winkelman JW, Finn L, Young T. Prevalence and correlates of restless legs sindrome symptoms in the Wisconsin Sleep Cohort. Sleep Med 2006; 7: 545-552.
69. Winkelman JW, Shahar E, Sharif I, Gottlieb DJ. Association of restless legs syndrome and cardiovascular disease in the sleep heart health study. Neurology 2008; 70: 35-42.
70. Espinar-Sierra J, Vela-Bueno A, Luque-otero M. Periodic leg movements in sleep and essential hypertension. Psychiatry Clin Neurosci 1997; 51: 103-107.
71. Guggisberg AG, Hess CW, Mathis J. The significance of the sympathetic nervous system in the pathophysiology of periodic leg movements in sleep. Sleep 2007; 30: 755-766.
72. Hornyak M, Cejnar M, Elam M, Matousek M, Wallin BG. Sympathetic muscle nerve activity during sleep in man. Brain 1991; 114: 1281-1295.
73. Vetrugno R, Provini F, Cortelli P, Plazzi G, Lotti EM, Pierangeli G, Canali C, Montagna P. Sleep disorders in multiple system atrophy: a correlative video-polysomnographic study. Sleep Med 2004; 5: 21-30.
74. Vetrugno R, Liguori R, Cortelli P, Plazzi G, Vicini C, Campanini A, D'Angelo R, Provini F, Montagna P. Sleep-related stridor due to dystonic vocal cord motion and neurogenic tachipnea/tachicardia in multiple system atrophy. Mov Disord 2007; 22: 673-678.
75. Vetrugno R, D'Angelo R, Cortelli P, Plazzi G, Vignatelli G, Montagna P. Impaired cortical and autonomic arousal during sleep in multiple system atrophy. Clin Neurophysiol 2007; 118: 2512-2518.
76. Mendelson WB. Are periodic limb movements associated with clinical disturbance? Sleep 1996; 19: 219-223.
77. Pack AI, Dinges DF, Gehrman PR, Staley B, Pack FM, Maislin G. Risk factors for excessive sleepiness in older adults. Ann Neurol 2006; 59: 893-904.
78. Pallesen S, Nordhus IH, Sivertsen B, Tell GS, Bjorvatn B. Prevalence and risk factors of subjective sleepiness in the general adult population. Sleep 2007; 30: 619-624.
79. Hossain JL, Ahmad P, Reinish LW, Kayumov L, Hossain NK, Shapiro CM. Subjective fatigue and subjective sleepiness: two independent consequences of sleep disorders? J Sleep Res 2005; 14: 245-253.
80. Merkelbach S, Schulz H, Fatigue Collaborative Study Group. What have fatigue and sleepiness in common? J Sleep Res 2006; 15: 105-106.
81. Shen J, Barbera J, Shapiro CM. Distinguishing sleepiness and fatigue: focus on definition and measurement. Sleep Med Rev 2006; 10: 63-76.
82. Nicolas A, Lesperance P, Montplaisir J. Is excessive daytime sleepiness with periodic leg movements during sleep a specific diagnostic category? Eur Neurol 1998; 40: 22-26.
83. Hening WA, Allen RP, Earley CJ, Picchietti DL, Silber MH. 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: 560-583.
84. Oertel WH, Trenkwalder C, Zucconi M, Benes H, Garcia-Borreguero D, Bassetti C, Partinen M, Ferini-Strambi L, Stiasny-Kolster K. State of the art in restless legs syndrome therapy: practice recommendations for treating restless legs syndrome. Mov Disord 2007; 22 (Suppl 18): 466-475.
85. Manconi M, Ferri R, Zucconi M, Oldani A, Fantini ML, Castronovo V, Ferini-Strambi L. First night efficacy of pramipexole in restless legs syndrome and periodic leg movements. Sleep Med 2007; 8: 491-497.
86. Santamaria J, Iranzo A, Tolosa E. Development of restless legs syndrome after dopaminergic treatment in a patients with periodic leg movements in sleep. Sleep Med 2003; 4: 153-155.
87. Garcia-Borreguero D, Allen RP, Benes H, Earley C, Happe S, Hogl B, Kohnen R, Paulus W, Rye D, Winkelmann J. Augmentation as a treatment complication of restless legs syndrome: concept and management. Mov Disord 2007; 22 (Suppl 18): 476-484.
88. Sforza E, Haba-Rubio J. Night-to-night variability in periodic leg movements in patients with restless legs syndrome. Sleep Med 2005; 6: 259-267.