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FIGURE 1 Periodic limb movements of sleep in polysomnographic record. To be scored as periodic

leg movements, events should have amplitude equal or greater than 25% of the tonic anterior tibialis

bio-calibration signal. Duration should be between 0.5 and 5 seconds, and occur in a sequence of at

least four consecutive movements. The interval between each independent movement should be 4 to

90 seconds. Abbreviations: EEG, electroencephalogram; L EOG, left electrooculogram; R EOG, right

electrooculogram; CHIN EMG, chin electromyogram; ECG, electrocardiogram; SA O2, saturation of

oxygen.



PLMS are also frequent in normal subjects without sleep disorders complaints, especially in the elderly (13– 16). The prevalence increases with age in

healthy subjects. Furthermore, PLMS have a night-to-night variability. PLMS are

rare in normal subjects younger than 30 years; however, when polysomnography

is performed across several nights, approximately 30% of subjects between 40

and 60 years and over 50% of those over 65 years show a significant number of

PLMS (16 –19).



CLINICAL FEATURES OF PERIODIC LEG MOVEMENTS

IN SLEEP AND WAKEFULNESS

PLMW are the basis of the suggested immobilization test (SIT), particularly in

patients with RLS. PLMW during SIT are scored according to the same criteria as

those used for PLMS (4), but include a few modifications. Any movements

lasting between 0.5 and 10 seconds, with an intermovement interval of 4 to 90

seconds are scored.

PLMs are scored as bilateral if the interval between the offset of movement in

one leg and the onset of movement in the other leg is lower than four seconds. The

use of these criteria differentiates PLMW from myoclonia (due to their duration)



Periodic Leg Movements of Sleep



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FIGURE 2 Hypnogram showing sleep disruption with multiple periodic limb movements of sleep

(PLMS). Periodic leg movements (PLMs) occur more commonly during stages 1 and 2 and tend to

be more abundant during the first half of the night. PLMs may precipitate an electroencephalogram

arousal with sleep disruption. Abbreviations: PLMS, periodic limb movements of sleep; REM, rapid

eye movement.



and from continued EMG tonic bursts (due to the required intermovement intervals). Furthermore, according to Coleman’s criteria, any leg movements to be

scored have to be part of series of at least four consecutive movements and thus

be periodic. However, during wakefulness, the longest duration for leg movement

to be scored as such is 10 seconds, whereas during sleep the maximal duration is

five seconds. The longer duration of leg movements during wakefulness is justified

as being the result of a voluntary contraction of leg muscles that follows the shorter,

involuntary one, in order to relieve the dysesthesias, which usually take place

within two seconds of the onset of PLMW (20).

Periodic Limb Movements of Sleep Disorder

Periodic limb movements disorder (PLMD) is defined as the presence of an abnormal number of PLM in PSG studies with the simultaneous presence of insomnia

(difficulties in initiating and/or maintaining sleep) and/or, occasionally, daytime

fatigue or sleepiness, and with the exclusion of other causes of sleep disturbances

(21). The main criterion used for the diagnosis of PLMD is the index of PLM per

hour (PLMI) on PSG recording in the sleep laboratory or ambulatory sleep recording. Usually, an additional measure of severity is the index of PLMS associated with

arousal (PLMAI) (22). Classically, a PLMI greater than five per hour was considered

abnormal. However, some doubts have risen on the clinical validity of this

threshold: although it may be maintained for children, later reports suggested

that in adults the normative abnormal minimal value of PLMI should be greater

than 15 per hour (21). Furthermore, sleep-related breathing disorders and, more

specifically, upper airway resistance syndrome (UARS) need to be excluded

using a pressure transducer airflow monitoring or esophageal pressure, before

the diagnosis of PLMD can be made (23 –25). The classical classification of severity

for PLMD is: mild (PLMI between 15 and 24 associated with mild insomnia or



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sleepiness), moderate (PLMI between 25 and 50 associated with moderate insomnia

or sleepiness), and severe (PLMI greater than 50 or PLMAI greater than 25 associated with severe insomnia or sleepiness).

Actigraphy is also a valid method for the detection of PLMs. While EMG

detects electrical potentials, actigraphy records movements. More recent actigraphs

with high sampling rates can determine whether movements meet criteria for

PLMs and include light detectors or position detectors that helps to distinguish

PLMs from repetitive voluntary limb movements (26). The main advantage of

actigraphy is that it is more economic than PSG, can be performed in any environment, and is easily used on a long-term basis (22). Its main disadvantage is that it

provides less information about the context of the movement.

The prevalence of PLMD is not well-determined; in a recent cross-sectional

study performed in five European countries with telephone interviews of subjects

aged 15 to 100 years old, the prevalence of PLMD was 3.9%. Specific associated

factors were: being a shift- and/or a night-worker, snoring, high daily coffee

intake, use of hypnotics, and stress (27). No sex difference has been described, and

a typical age range is not known (21), although PLMD is probably more frequent

in the elderly. It is a matter of ongoing discussion whether PLMD is a preclinical

form of RLS or a completely separate entity (28– 30).

Periodic Limb Movements of Sleep Associated with Other Conditions

The first descriptions of PLMS were made in patients diagnosed with RLS (31,32).

In fact, 70% to 87% of the patients with RLS studied by PSG have a significant

number of PLMS (five per hour of sleep or more) (10,33) and RLS is the most

common condition associated with PLMS (22). In RLS, the mean PLMS index

increases with age (34,35). Furthermore, independently of the age factor, PLMS

index increases with RLS severity (5).

In RLS, the temporal pattern of PLMS index across the night is the “decrescendo type” (36,37): most movements take place during the initial part of the

sleep period and their frequency decreases as the night progresses. Furthermore,

according to several reports, in RLS, PLMS are more frequent and longer during

non-REM sleep stages (34). The individual night to night variability of PLMS is

most frequent and occur to the highest extent in RLS patients than in non-RLS

patients (38).

PLMS are a habitual finding in other primary sleep disorders, most frequently

narcolepsy and REM sleep behavior disorder (RBD). PLMS are very common in

narcoleptic subjects (33,39 –41), with an estimate of PLMI of five or more in 45%

to 60% of the subjects. This percentage varies with age, and increases to 90% in

narcoleptic individuals older than 60 years (42). The linkage PLMS – RBD is also

well-documented (43,44), with a reported PLMI greater than 10 per hour in about

70% of the patients. Both, narcolepsy and RBD have frequent PLMS in all stages

of sleep, with a trend to have more PLMs during REM sleep. These features are

probably a manifestation of motor control dysfunction with a lack of REM sleep

motor inhibition, presumably secondary to an impaired dopaminergic system.

PLMS has also a well-documented relationship with the obstructive sleep

apnea (45,46). It occurs most frequently in association with respiratory events but

can be independent, in which case the intermovement interval of PLMS is reported

to be shorter (47). The PLMS index can decrease after treatment with nasal continuous positive airway pressure (N-CPAP), although it frequently remains elevated



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(48); an increase of PLMS after N-CPAP treatment has also been reported (45,49).

Furthermore, an increased PLMAI might be predictive for decreasing sleepiness

in obstructive sleep apnea syndrome (OSAS), perhaps because sleepiness may

reduce the likelihood of arousal before each PLMS (50). The association of PLMs

to UARS has also been recently reported (24).

Precipitation or, most probably, aggravation of PLMS has been linked to

treatment with antidepressants. Among these, it has been linked most frequently

to tricyclics, venlafaxine, and other selective serotonin reuptake inhibitors. Also

neuroleptics, lithium, and dopamine-receptor antagonists tend to precipitate or

exacerbate PLMS (21,51 –53).

PLMS are found in medical conditions such as essential hypertension (54),

rheumatoid arthritis (55), Parkinson’s disease (56,57), or chronic sarcoidosis (58)

and are also reported in spinal cord lesions (7,59). A probable association

between attention deficit and hyperactivity disorder has been reported (60,61).

Pathophysiology of Periodic Limb Movements of Sleep

Although most studies have been performed on patients with PLMS that also had

RLS, it is thought that both conditions (PLMD and RLS/PLMS) share the same

pathophysiology, as they frequently coexist and both respond to the same therapeutic agents (62,63). The final common pathway mediating PLMs are neural pathways within the spinal cord, as lesions below the pons (infarction, transaction, or

other spinal pathology) can contribute to their occurrence (7,64 –66).

A single neurophysiologic mechanism underlying PLMS is unlikely. In

general, the main deficit manifests as brainstem or spinal reflex “hyperexcitability”

(67– 69). The origin of this enhancement of motor excitability is not known, but

must derive from a source that accounts for the circadian variation and for the

state dependency of spinal cord excitability. In that sense, state dependent

changes have been described in spinal cord excitability (68). These changes manifest as a decreased threshold of the FR and as a segmental spread of the FR (from

proximal to distal muscles). It should be noted that the FR can be modified by

muscle and cutaneous afferents, Renshaw cells, presynaptic inhibition of afferents

by intraspinal interneurons, and multiple supraspinal pathways (70– 74).

Periodic limb movements do not reside in the principal sensory and motor

elements, as waking EMG activity, resting motoneuron excitability, simple reflexes,

and sensory evoked potentials are generally normal (67,75 –78). However, diffuse

peripheral nerve dysfunction is common and may be an important modifier of

PLMS expression (79– 82). The most powerful and consistent influences originate

from outside the spinal cord in supraspinal, premotor circuits of the central

nervous system. In spinal cord injury, pharmacologic agents effective in treating

RLS/PLMS and dampening FR responses via local spinal circuits are generally,

but not universally, ineffective (63,83). Thus, the primary benefit is mediated by

dopamine-sensitive pathways that are located supraspinally. However, although

some brain imaging studies have shown reductions in dopamine uptake into

presynaptic axons and D2 receptor binding, suggesting a relative excess of extracellular dopamine, the magnitude of these changes is small (84 – 86).

Periodic limb movements also occur when the striatum is depleted of

dopamine axons (13,57). This can occur either in experimental setting or in neurodegeneration such as in Parkinson’s disease. Nevertheless, it is surprising that the

prevalence of RLS in Parkinson’s disease (PD) lacking nigrostriatal pathways does



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not differ substantially from that observed in the general population (87,88), and

could point out to the main pathophysiology residing in alternative dopaminergic

pathways such as the diencephalo-spinal pathways. These pathways terminate in

the dorsal horn where they inhibit superficial and deep tissue afferents.

PLMs can be modified by other central pathways. Rather than exhibiting a

unique pathologic condition, PLMs can arise from several central sources. Factors

favouring PLMs expression can be categorized into two groups: the first reflecting

disinhibition resulting from interruption of descending inhibitory pathways, for

example, through modulation by the pyramidal motor system, as patients with

hemiplegia due to cerebrovascular disease exhibit PLMs that predominate in

the hemiplegic limbs (89).

The second mechanism would consist in facilitation from direct enhancement

of neural activity, such as is the case during administration of monamines. For

example, PLMS can be exacerbated by serotonin reuptake inhibitors (90). The

specific neural substrates mediating these effects are not known, given the ubiquitous nature of monaminergic innervation, but they could be mediated by direct

enhancement of motoneuron responsiveness, serotonin (5HT2)-receptor mediated

facilitation of the FR (91), or medullary raphe-mediated enhancement of spinal

nociceptive transmission (92). It remains also possible that decrements in monoaminergic neural integrity with aging (specially dopaminergic nigrostriatal cells) might

also play a role, given the fact that the prevalence of PLMs increases steadily across

the life-span. In summary, the heterogeneity of causes for PLMs and in treatment

responses could be due to a redundancy in sensori-motor networks as well as a

lack of neurons necessary and sufficient to generate PLMs.

Treatment of Periodic Limb Movements of Sleep

There is a general consensus that the presence of PLMS per se, when not

accompanied by insomnia, fragmented sleep, daytime symptoms (fatigue, somnolence), does not necessarily require treatment. Most studies on the treatment of

PLMD have been performed in patients with RLS. In any case, treatment should

only be considered when PLMS is part of a broader disorder in which sleep complaints (PLMD) are present. Although no large studies have been performed on

the treatment of PLMD, most agents have been used in PLMS associated to RLS.

Many agents have been suggested to be effective in PLMS (Table 1). Among

these, the non-ergot dopamine-agonists are the most often recommended agents

for PLMS (93,94). Ropirinole at 1.5 to 4 mg/day has a high efficacy in reducing

TABLE 1 Effective Medications for the Treatment of PLMS in Restless Legs Syndrome

Dopaminergic agents

L-DOPA

Dopamine agonists

Nonergot derivatives: ropinirole, pramipexol

Ergot derivatives: cabergoline, pergolide, bromocriptine

Benzodiacepines

Clonazepam

Opioids

Oxycodone, codeine

Anticonvulsants

Gabapentine

Abbreviations: PLMS, periodic limb movements of sleep; L-DOPA, levodopa.



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PLMI in relation to placebo (76% vs. 14%) (95). Pramipexole at 0.375 to 1.5 mg

before bedtime is also effective in reducing PLMS (96). Common side effects are

somnolence, nausea, dyspepsia, muscle weakness, and headache. Ergotamine

derivatives like cabergoline 0.5 to 2 mg/day or pergolide 0.4 to 0.55 mg/day can

also be used to treat PLMS (97,98). Bromocryptine 7.5 mg/day was reported as

effective in PLMD associated with narcolepsy (99). During long-term treatment

with ergotamine derivatives, an increased risk of valvular heart disease and fibrotic

reactions has been reported. L-DOPA seems to be effective for PLMS (associated or

not to arousals) (100– 102), but is less frequently used by sleep specialists. Gabapentin at 600 to 1800 mg/day has been reported as effective, reducing the PLM index by

9.8 events (103,104). Minor side effects like dizziness, drowsiness, and enhanced

alcohol effects were reported. Clonazepam at 0.5 to 1 mg/daily also has been

reported effectively in reduce PLMS and PLM associated to arousals (by 32%)

(105,106). The side effects of benzodiazepines should be considered (morning sedation, tolerance, memory dysfunction, somnolence, dizziness) before administering

cloazepam. Opiates like oxycodone can improve PLMS reducing PLMI (by 34%)

and PLMA (by 23%) (107). Other agents—baclofen, iron sulfate, magnesium, melatonin, erythropoietin, selegiline, apomorphine—used for the treatment of PLMD

associated or not to RLS have no demonstrated efficacy.



REFERENCES

1. Hening WA, Allen RP, Walters AS, Chokroverty S. Motor function and dysfunctions of

sleep. In: Chokroverty S, Daroff RB, eds. Sleep Medicine Disorders: Basic Science, Technical Considerations, and Clinical Aspects. Boston: Butterworth Heinemann,

1999:441–508.

2. Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisir J. Restless

legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report

from the restless legs syndrome diagnosis and epidemiology workshop at the National

Institutes of Health. Sleep Med 2003; 4(2):101–119.

3. Symonds CP. Nocturnal myoclonus. J Neurol Neurosurg Psychiatry 1953; 16(3):

166 –171.

4. Coleman RM, Pollak CP, Weitzman ED. Periodic movements in sleep (nocturnal myoclonus): relation to sleep disorders. Ann Neurol 1980; 8(4):416– 421.

5. Chabli A, Michaud M, Montplaisir J. Periodic arm movements in patients with the restless legs syndrome. Eur Neurol 2000; 44(3):133– 138.

6. Atlas Task Force of the American Sleep Disorders Association. Recording and scoring

leg movements. Sleep 1993; 16(8):748–759.

7. 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(1):13– 18.

8. Provini F, Vetrugno R, Meletti S, et al. Motor pattern of periodic limb movements

during sleep. Neurology 2001; 57(2):300–304.

9. de Weerd AW, Rijsman RM, Brinkley A. Activity patterns of leg muscles in periodic

limb movement disorder. J Neurol Neurosurg Psychiatry 2004; 75(2):317– 319.

10. Lugaresi E, Cirignotta F, Coccagna F, Montagna P. Nocturnal myoclonus and restless

legs syndrome. In: Fahn S, Marsden CD, van Woert M, eds. Myoclonus. New York:

Raven Press, 1986:295.

11. Coccagna G. Restless legs syndrome/periodic movements in sleep. In: Thorpy MJ, ed.

Handbook of Sleep Disorders. New York: Marcel Dekker, 1990:457– 478.

12. Hening WA. Restless legs syndrome: a sensorimotor disorder of sleep/wake motor

regulation. Curr Neurol Neurosci Rep 2002; 2(2):186– 196.

13. Bliwise D, Rye D, Dihenia B, et al. Periodic leg movements in elderly patients with

parkinsonism. Sleep 1998; 21(suppl):196–200.



200



Garcia-Borreguero et al.



14. Dickel MJ, Renfrow SD, Moore PT, Berry RB. Rapid eye movement sleep periodic leg

movements in patients with spinal cord injury. Sleep 1994; 17:733– 738.

15. Ancoli-Israel S, Kripke DF, Klauber MR, Mason WJ, Fell R, Kaplan O. Periodic limb

movements in sleep community dwelling elderly. Sleep 1991; 14(6):496– 500.

16. Youngstedt SD, Kripke DF, Klauber MR, Sepulveda RS, Mason WJ. Periodic leg movements during sleep and sleep disturbances in elders. J Gerontol A Biol Sci Med Sci 1998;

53(5):M391–M394.

17. Carrier J, Frenette S, Montplaisir J, Paquet J, Drapeau C, Morettini J. Effects of periodic

leg movements during sleep in middle-aged subjects without sleep complaints. Mov

Disord 2005; 20(9):1127 –1132.

18. Gosselin N, Lanfranchi P, Michaud M, et al. Age and gender effects on heart rate activation associated with periodic leg movements in patients with restless legs syndrome.

Clin Neurophysiol 2003; 114(11):2188–2195.

19. Mosko SS, Dickel MJ, Paul TA, et al. Sleep apnea and sleep-related periodic leg movements in community resident seniors. J Am Geriatr Soc 1988; 36(6):502– 508.

20. Michaud M, Lavigne G, Desautels A, Poirier G, Montplaisir J. Effects of immobility

on sensory and motor symptoms of restless legs syndrome. Mov Disord 2002; 17(1):

112 –115.

21. American Academy of Sleep Medicine. International classification of sleep disorders.

2nd ed. Diagnostic and Coding Manual. Westchester, Illinois: American Academy of

Sleep Medicine, 2005:182 –187.

22. Hening W. The clinical neurophysiology of the restless legs syndrome and periodic

limb movements. Part I: diagnosis, assessment, and characterization. Clin Neurophysiol 2004; 115(9):1965–1974.

23. Hosselet JJ, Norman RG, Ayappa I, Rapoport DM. Detection of flow limitation with

a nasal cannula/pressure transducer system. Am J Respir Crit Care Med 1998; 157(5

Pt 1):1461–1467.

24. Exar EN, Collop NA. The association of upper airway resistance with periodic limb

movements. Sleep 2001; 24(2):188–192.

25. Epstein MD, Chicoine SA, Hanumara RC. Detection of upper airway resistance syndrome using a nasal cannula/pressure transducer. Chest 2000; 117(4):1073– 1077.

26. Jean-Louis G, Kripke DF, Mason WJ, Elliott JA, Youngstedt SD. Sleep estimation from

wrist movement quantified by different actigraphic modalities. J Neurosci Methods

2001; 105(2):185–191.

27. Ohayon MM, Roth T. Prevalence of restless legs syndrome and periodic limb

movement disorder in the general population. J Psychosom Res 2002; 53(1):

547 –554.

28. Walters AS. Toward a better definition of the restless legs syndrome. The International

Restless Legs Syndrome Study Group. Mov Disord 1995; 10(5):634– 642.

29. Walters AS, Hening WA, Chokroverty S. Review and videotape recognition of idiopathic restless legs syndrome. Mov Disord 1991; 6(2):105 –110.

30. Walters A, Hening W, Cote L, Fahn S. Dominantly inherited restless legs with myoclonus and periodic movements of sleep: a syndrome related to the endogenous opiates?

Adv Neurol 1986; 43:309–319.

´

31. Lugaresi E, Tassinari CA, Coccagna G, Ambrossetto C. Particularites cliniques et

´

polygraphiques du syndrome d’impatience des membres inferieurs. Rev Neurol

(Paris) 1965; 113:545–555.

32. Ambrosetto C, Lugaresi E, Coccagna G, Tassinari CA. Clinical and polygraphic

remarks in the syndrome of restless legs. Riv Patol Nerv Ment 1965; 86(2):244– 252.

33. Montplaisir J, Lorrain D, Godbout R. Restless legs syndrome and periodic leg movements in sleep: the primary role of dopaminergic mechanism [abstr]. Eur Neurol

1991; 31(1):41 –43.

34. Nicolas A, Michaud M, Lavigne G, Montplaisir J. The influence of sex, age and sleep/

wake state on characteristics of periodic leg movements in restless legs syndrome

patients. Clin Neurophysiol 1999; 110(7):1168 –1174.

35. Michaud M, Paquet J, Lavigne G, Desautels A, Montplaisir J. Sleep laboratory diagnosis of restless legs syndrome. Eur Neurol 2002; 48(2):108– 113.



Periodic Leg Movements of Sleep



201



36. 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(1):102–110.

37. Sforza E, Jouny C, Ibanez V. Time course of arousal response during periodic leg movements in patients with periodic leg movements and restless legs syndrome. Clin Neurophysiol 2003; 114(6):1116–1124.

38. Hornyak M, Kopasz M, Feige B, Riemann D, Voderholzer U. Variability of periodic leg

movements in various sleep disorders: implications for clinical and pathophysiologic

studies. Sleep 2005; 28(3):331 –335.

39. Wittig R, Zorick F, Piccione P, Sicklesteel J, Roth T. Narcolepsy and disturbed nocturnal

sleep. Clin Electroencephalogr 1983; 14(3):130–134.

40. Baker TL, Guilleminault C, Nino-Murcia G, Dement WC. Comparative polysomnographic study of narcolepsy and idiopathic central nervous system hypersomnia.

Sleep 1986; 9(1 Pt 2):232–242.

41. Okura M, Fujiki N, Ripley B, et al. Narcoleptic canines display periodic leg movements

during sleep. Psychiatry Clin Neurosci 2001; 55(3):243– 244.

42. Montplaisir J, Lapierre O, Warnes H, Pelletier G. The treatment of the restless leg syndrome with or without periodic leg movements in sleep. Sleep 1992; 15(5):391– 395.

43. Lapierre O, Montplaisir J. Polysomnographic features of REM sleep behavior disorder:

development of a scoring method. Neurology 1992; 42(7):1371–1374.

44. Fantini ML, Michaud M, Gosselin N, Lavigne G, Montplaisir J. Periodic leg movements

in REM sleep behavior disorder and related autonomic and EEG activation. Neurology

2002; 59(12):1889–1894.

45. Fry JM, DiPhillipo MA, Pressman MR. Periodic leg movements in sleep following treatment of obstructive sleep apnea with nasal continuous positive airway pressure. Chest

1989; 96(1):89 –91.

46. Briellmann RS, Mathis J, Bassetti C, Gugger M, Hess CW. Patterns of muscle activity in

legs in sleep apnea patients before and during nCPAP therapy. Eur Neurol 1997;

38(2):113–118.

47. Carelli G, Krieger J, Calvi-Gries F, Macher JP. Periodic limb movements and obstructive

sleep apneas before and after continuous positive airway pressure treatment. J Sleep

Res 1999; 8(3):211–216.

48. Yamashiro Y, Kryger MH. Acute effect of nasal CPAP on periodic limb movements

associated with breathing disorders during sleep. Sleep 1994; 17(2):172– 175.

49. Guilleminault C, Philip P. Tiredness and somnolence despite initial treatment of

obstructive sleep apnea syndrome (what to do when an OSAS patient stays hypersomnolent despite treatment). Sleep 1996; 19(suppl 9):S117 –S122.

50. Chervin RD. Periodic leg movements and sleepiness in patients evaluated for sleepdisordered breathing. Am J Respir Crit Care Med 2001; 164(8 Pt 1):1454– 1458.

51. Bedard MA, Montplaisir J, Godbout R, Lapierre O. Nocturnal gamma-hydroxybutyrate. Effect on periodic leg movements and sleep organization of narcoleptic patients.

Clin Neuropharmacol 1989; 12(1):29–36.

52. Yang C, White DP, Winkelman JW. Antidepressants and periodic leg movements of

sleep. Biol Psychiatry 2005; 58(6):510–514.

53. Schulz H, Walther BW. Diagnosis and classification of sleep disorders. Z Arztl Fortbild

Qualitatssich 2001; 95(1):4–10.

54. Espinar-Sierra J, Vela-Bueno A, Luque-Otero M. Periodic leg movements in sleep in

essential hypertension. Psychiatry Clin Neurosci 1997; 51(3):103– 107.

55. Lavie P, Epstein R, Tzischinsky O, et al. Actigraphic measurements of sleep in rheumatoid arthritis: comparison of patients with low back pain and healthy controls. J Rheumatol 1992; 19(3):362–365.

¨gl

56. Wetter TC, Brunner H, Ho B, Yassouridis A, Trenkwalder C, Friess E. Increased alpha

activity in REM Sleep in de novo patients with Parkinson’s disease. Mov Disord 2001;

16(5):928–933.

¨

57. Wetter TH, Collado-Seidel V, Pollmacher T, Yassouridis A, Trenkwalder C. Sleep and

periodic leg movement patterns in drug-free patients with Parkinson’s disease and

multiple system atrophy. Sleep 2000; 23(3):361–367.



202



Garcia-Borreguero et al.



58. Verbraecken J, Hoitsma E, van der Grinten CP, Cobben NA, Wouters EF, Drent M.

Sleep disturbances associated with periodic leg movements in chronic sarcoidosis.

Sarcoidosis Vasc Diffuse Lung Dis 2004; 21(2):137– 146.

59. Nogues M, Cammarota A, Leiguarda R, Rivero A, Pardal A, Encabo H. Periodic limb

movements in syringomyelia and syringobulbia. Mov Disord 2000; (15):113 – 119.

60. Picchietti DL, Underwood DJ, Farris WA, Walters AS, Shah MM, Dahl RE et al. Further

studies on periodic limb movement disorder and restless legs syndrome in children

with attention-deficit hyperactivity disorder. Mov Disord 1999; 14(6):1000– 1007.

61. Chervin RD, Archbold KH, Dillon JE, Pituch KJ, Panahi P, Dahl RE et al. Associations

between symptoms of inattention, hyperactivity, restless legs, and periodic leg movements. Sleep 2002; 25(2):213–218.

62. Allen RP. The resurrection of periodic limb movements (PLM): leg activity monitoring

and the restless legs syndrome (RLS). Sleep Med 2005; 6(5):385– 387.

63. de Mello MT, Poyares DL, Tufik S. Treatment of periodic leg movements with a dopaminergic agonist in subjects with total spinal cord lesions. Spinal Cord 1999; 37(9):

634 –637.

64. Mello MT, Silva AC, Rueda AD, Poyares D, Tufik S. 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(4):248– 252.

65. de Mello MT, Lauro FA, Silva A, Tufik S. Incidence of periodic leg movements and of

the restless legs syndrome during sleep following acute physical activity in spinal cord

injury subjects. Spinal Cord 1996; 34(5):294–296.

66. Tings T, Baier PC, Paulus W, Trenkwalder C. Restless legs syndrome induced by

impairment of sensory spinal pathways. J Neurol 2003; 250(4):499– 500.

67. Wechsler LR, Stakes JW, Shahani BT, Busis NA. Periodic leg movements of sleep (nocturnal myoclonus): an electrophysiological study. Ann Neurol 1986; 19(2):168– 173.

68. 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.

69. Rye DB. Parkinson’s disease and RLS: the dopaminergic bridge. Sleep Med 2004;

5(3):317–328.

70. Eccles JC, Eccles RM, Iggo A, Lundberg A. Electrophysiological studies on gamma

motoneurones. Acta Physiol Scand 1960; 50:32– 40.

71. Eccles JC, Eccles RM, Iggo A, Lundberg A. Electrophysiological investigations on

Renshaw cells. J Physiol (Paris) 1961; 159:461 –478.

72. Eccles JC, Eccles RM, Magni F. Monosynaptic excitatory action on motoneurones regenerated to antagonistic muscles. J Physiol 1960; 154:68– 88.

´

73. Eccles RM. Inhibition by Renshaws cells. Actual Neurophysiol (Paris) 1962; 43:55– 66.

74. Ellrich J, Treede RD. Convergence of nociceptive and non-nociceptive inputs onto

spinal reflex pathways to the tibialis anterior muscle in humans. Acta Physiol Scand

1998; 163(4):391–401.

75. Bucher S, Trenkwalder C, Oertel W. Reflex studies and MRI in the restless legs

syndrome. Acta Neurol Scand 1996; 94:145–150.

76. Bucher SF, Seelos KC, Oertel WH, Reiser M, Trenkwalder C. Cerebral generators

involved in the pathogenesis of the restless legs syndrome. Ann Neurol 1997;

41(5):639–645.

77. Trenkwalder C, Bucher SF, Oertel WH, Proeckl D, Plendl H, Paulus W. Bereitschafts

potential in idiopathic and symptomatic restless legs syndrome. Electroenceph Clin

Neurophysiol 1993; 89:95–103.

78. Trenkwalder C, Bucher SF, Oertel WH. Electrophysiological pattern of involuntary

limb movements in the restless legs syndrome. Muscle Nerve 1996; 19:155– 159.

79. Iannaccone S, Zucconi M, Marchettini P, et al. Evidence of peripheral axonal neuropathy in primary restless legs syndrome. Mov Disord 1995; 10(1):2– 9.

80. Ondo W, Jankovic J. Restless Legs Syndrome: Clinicoethiologic correlates. Neurology

1996; 47(6):1435–1441.

81. Rutkove SB, Matheson JK, Logigian EL. Restless legs syndrome in patients with polyneuropathy. Muscle Nerve 1996; 19(5):670–672.



Periodic Leg Movements of Sleep



203



82. Gemignani F, Marbini A, Di Giovanni G, Salih S, Terzano MG. Charcot – Marie– Tooth

disease type 2 with restless legs syndrome. Neurology 1999; 52(5):1064– 1066.

83. Lee M, Choi YC, Lee SH, Lee SB. Sleep-related periodic leg movements associated with

spinal cord lesions. Mov Disord 1996; (11):719–722.

84. Allen RP, Earley CJ. Restless legs syndrome: a review of clinical and pathophysiologic

features. J Clin Neurophysiol 2001; 18(2):128–147.

85. Turjanski N, Lees AJ, Brooks DJ. Striatal dopaminergic function in restless legs

syndrome: 18F-dopa and 11C-raclopride PET studies. Neurology 1999; 52(5):932– 937.

86. Ruottinen HM, Partinen M, Hublin C, et al. An FDOPA PETstudy in patients with periodic

limb movement disorder and restless legs syndrome. Neurology 2000; 54(2):502–504.

87. Ondo WG, Vuong KD, Jankovic J. Exploring the relationship between Parkinson

disease and restless legs syndrome. Arch Neurol 2002; 59(3):421– 424.

88. Garcia-Borreguero D, Odin P, Serrano C. Restless legs syndrome and PD: a review of

the evidence for a possible association. Neurology 2003; 6(suppl 3):S49 – S55.

89. Anderson KN, Bhatia KP, Losseff NA. A case of restless legs syndrome in association

with stroke. Sleep 2005; 28(1):147–148.

90. Morgan JL, Brown TM, Wallace ER. Monoamine oxidase inhibitors and sleep movements. Am J Psychiatry 1994; 151(5):782.

91. Skarsfeldt T, Arnt J, Hyttel J. L-5-HTP facilitates the electrically stimulated flexor reflex

in pithed rats: evidence for 5-HT2-receptor mediation. Eur J Pharmacol 1990;

176(2):135–142.

92. Zhuo M, Sengupta JN, Gebhart GF. Biphasic modulation of spinal visceral nociceptive

transmission from the rostroventral medial medulla in the rat. J Neurophysiol 2002;

87(5):2225–2236.

93. Hening WA, Allen RP, Earley CJ, Picchietti DL, Silber MH. An update on the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. Sleep

2004; 27(3):560–583.

94. Silber MH, Ehrenberg BL, Allen RP, et al. An algorithm for the management of restless

legs syndrome. Mayo Clin Proc 2004; 79(7):916 –922.

95. Allen R, Becker PM, Bogan R, et al. Ropinirole decreases periodic leg movements and

improves sleep parameters in patients with restless legs syndrome. Sleep 2004;

27(5):907–914.

96. Partinen M, Hirvonen K, Alakuijala A, Jama L, Tertunnen J. Pramipexole is safe and

efficacious in the treatment of idiopathic restless legs syndrome: results of a large randomized double-blind placebo-controlled dose-finding study [abstr]. Sleep 2004;

27(suppl):A293.

97. Stiasny-Kolster K, Benes H, Peglau I, et al. Effective cabergoline treatment in idiopathic

restless legs syndrome. Neurology 2004; 63(12):2272 – 2279.

98. Trenkwalder C, Hundemer HP, Lledo A, et al. Efficacy of pergolide in treatment of

restless legs syndrome: the PEARLS study. Neurology 2004; 62(8):1391– 1397.

99. Boivin DB, Montplaisir J, Poirier G. The effects of L-dopa on periodic leg movements

and sleep organization in narcolepsy. Clin Neuropharmacol 1989; 12(4):339– 345.

100. Benes H, Kurella B, Kummer J, Kazenwadel J, Selzer R, Kohnen R. Rapid onset of action

of levodopa in restless legs syndrome: a double-blind, randomized, multicenter, crossover trial. Sleep 1999; 22(8):1073–1081.

101. Montplaisir J, Godbout R, Poirier G, Bedard MA. Restless legs syndrome and periodic

movements in sleep: physiopathology and treatment with L-dopa. Clin Neuropharmacol 1986; 9(5):456–463.

102. Saletu M, Anderer P, Hogl B, et al. Acute double-blind, placebo-controlled sleep

laboratory and clinical follow-up studies with a combination treatment of rr-L-dopa

and sr-L-dopa in restless legs syndrome. J Neural Transm 2003; 110(6):611 – 626.

103. Ehrenberg B, Wagner AK, Corbett K, Rogers WH. Double-blind trial of gabapentin for

periodic limb movements of sleep: preliminary results [abstr]. Neurology 1998;

50(suppl 4):A276.

104. Garcia-Borreguero D, Larrosa O, De la Llave Y, Verger K, Masramon X, Hernandez

G. Treatment of restless legs syndrome with gabapentin: a double-blind, cross-over

study. Neurology 2002; 59(10):1573–1579.



204



Garcia-Borreguero et al.



105. Saletu M, Anderer P, Saletu-Zyhlarz G, et al. Restless legs syndrome (RLS) and periodic

limb movement disorder (PLMD): acute placebo-controlled sleep laboratory studies

with clonazepam. Eur Neuropsychopharmacol 2001; 11(2):153– 161.

106. Horiguchi J, Inami Y, Sasaki A, Nishimatsu O, Sukegawa T. Periodic leg movements in

sleep with restless legs syndrome: effect of clonazepam treatment. Jpn J Psychiatry

Neurol 1992; 46(3):727–732.

107. Walters AS, Wagner ML, Hening WA, et al. Successful treatment of the idiopathic restless legs syndrome in a randomized double-blind trial of oxycodone versus placebo.

Sleep 1993; 16(4):327–332.