Movement Disorders Vol. 6, NO. 2, 1991, pp. 105-110, 0 1991 Movement Disorder Society
Review and Videotape Recognition of Idiopathic Restless Legs Syndrome Arthur S. Walters, Wayne A. Hening, and Sudhansu Chokroverty Movement Disorder Group, Department of Neurology, Universily of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, and Neurology Service, Veterans Administration Medical Center, Lyons, New Jersey, U.S.A.
Summary: The motor phenomena associated with idiopathic restless legs syndrome (RLS) are infrequently seen in the physician’s office because they are present only after prolonged sitting or lying and usually at night. These motor phenomena are captured on videotape in four unrelated patients with idiopathic RLS. The clinical features of idiopathic RLS are reviewed in detail, and therapeutic advances in its treatment are summarized. Key Words: Restless legs syndrome-Myoclonus-Periodic movements in sleep-L-Dopa-Opioid drugs-Benzodiazepine drugs.
of primary idiopathic RLS and summarizes advances in therapy. Videotapes displaying the clinical characteristics of idiopathic RLS have not been previously published, and we present four unrelated patients with idiopathic RLS in videotape form. All four patients were in their 60s at the time of the study and met the criteria for diagnosis of RLS (Table 1). All four patients had symptoms of RLS that were progressively getting worse for many years, and all four patients also demonstrated polysomnographic evidence of the additional features of “resting dyskinesias while awake,’’ periodic movements in sleep (PMS), and sleep disturbance. Three of four had a family history of RLS (patients 1, 3, and 4). Ten sections of videotape are delineated in order in the text and in Table 2. Six sections depict motor restlessness and four sections of videotape follow that depict “resting dyskinesias while awake” and PMS. Of the six sections depicting motor restlessness, five of the sequences are captured spontaneously. The leg-stretching sequence from patient 3 illustrates the type of knowledge that can be obtained by asking a patient to demonstrate restless movements. At the time of the video, the patient is markedly restless and has done what RLS patients
Restless legs syndrome (RLS) may exist to varying degrees of severity in as much as 2% of the population (1) and yet it goes largely unrecognized by clinicians. Because the movements associated with RLS occur only after prolonged sitting or lying and mostly at night (1-7), physicians usually examine a movement-free patient and, except in secondary forms of RLS, e.g., those associated with peripheral neuropathy, the neurological examination is normal (1,6,7). Under these circumstances, clinicians must rely on a history of the presence of movements, other historical information, or polysomnography to make a diagnosis. The criteria for diagnosis of idiopathic RLS are paresthesias and motor restlessness aggravated by nightfall and rest (1-3,5-10) (Table 1). Depending on the additional feature involved, approximately 30-90% of RLS patients will show additional features that also help to make the diagnosis of RLS (1,2,5,8,9,10) (Table 1). This review concentrates on the clinical features A videotape segment accompanies this article. Address correspondence and reprint requests to A. S. Walters at 408B MEB, Department of Neurology CN 19, UMDNJRobert Wood Johnson Medical School, New Brunswick, NJ 08903-0019, U.S.A.
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A . S. WALTERS ET AL. TABLE 1. Clinical features of idiopathic restless legs syndrome (RLS)
Autosomal dominant inheritance in more than one-third of cases Paresthesias" Motor restlessness" Aggravation by nightfall" Aggravation by rest' Resting dyskinesias while awake Periodic movements in sleep Sleep disturbances Clinical course (usually progressive/severe >50 yrs of age) Neurological examination-normal
" Criteria for diagnosis of RLS.
normally do spontaneously, i.e., he has switched from another strategy to the videotaped strategy in an attempt to relieve paresthesias. Because the restless movements in idiopathic RLS are transient, usually present at night and therefore inaccessible to most clinicians, their demonstration may provide important diagnostic information. A detailed description of the clinical features of idiopathic RLS and appropriate videotapes follow.
CLINICAL CHARACTERISTICS OF IDIOPATHIC RLS Autosomal Dominant Family History An autosomal dominant family history is present in one-third or more of patients with RLS (1,2,5-8). Patient report cannot be relied on to establish that a family history is absent, but instead the relatives must be questioned in detail (11). Paresthesias Uncomfortable sensations, most often present in the legs, lead to a desire to move. These sensations have been described as creeping, crawling, tingling, burning, pins and needles, cramping, painful, aching, or indescribable (1-3,5-7). Paresthesias sometimes occur in the arms (1,2,12). Motor Restlessness The paresthesias lead to an urge to move the affected limbs, and the less severely affected patients get relief in motion (1-3,5-7). The motor restlessness occurs during wakefulness. The motor restlessness is temporarily suppressible, and patients choose a variety of creative ways of trying to relieve the paresthesias; also, they may switch at will from one strategy to another. To relieve the paresthesias, patients most often pace the floor. Tossing
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TABLE 2. Guide to videotape Motor restlessness during wakefulness 1. Tossinghrning in bed (patient 1) 2. Foot rubbing (patient 2) 3. Leg flexions (patient 2) 4. Leg stretching (patient 3) 5. Body rocking (patient 3) 6. Marching in place (patient 2) Resting dyskinesias while awake and periodic movements in sleep 7. Periodic myoclonus while awake (patient 1) 8. Clustered myoclonus while awake (patient 3) 9. Periodic movements in sleep involving legs (patient 4) 10. Periodic movements in sleep involving arm and legs (patient 4)
and turning in bed is captured in the videotape of patient 1. Patients may also try to alter sensory input to relieve paresthesias by rubbing their feet, as captured in the videotape of patient 2, or they may take baths. Leg flexions and leg stretching are captured in the videotapes of patients 2 and 3, respectively. Patients may also do leg flexions with their feet dependent (deep kneebends), or they may stretch their legs by standing with their feet flat on the floor and try to touch their toes with their knees locked for a prolonged period. Body rocking and marching in place are the classic motor movements seen in neuroleptic-induced akathisia (motor restlessness caused by antipsychotic agents). In a recent survey we also found body rocking and marching in place in 6 of 10 patients with RLS (2). In RLS, the body rocking and marching in place usually occur only at night and even then they occur only intermittently. This distinguishes them from the all-day-long body rocking and marching in place of neuroleptic-induced akathisia (1,2). Body rocking is captured in the videotape of patient 3 and marching in place is captured in the videotape of patient 2.
Aggravation by Nightfall and Rest The signs and symptoms of RLS can be present during the day but are classically worse at night (1-7,9,10). Although it is clear that these signs and symptoms are worse at night because the patients are more at rest (i.e., lying or sitting) during the night than during the day, there is also probably a separate diurnal variation that is independent of rest (4).Aggravation by both nightfall and rest is a highly distinctive pattern that may be unique for RLS.
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Resting Dyskinesias While Awake (DWA) These are involuntary, stereotypic, repetitive flexions typically of the hips, knees, or ankles that occur during nighttime wakefulness (1-9). The more severely affected patients may have hundreds of these jerking movements while attempting to lie down and go to sleep. They are typically present at rest, disappear with action (1,2,11), range in speed from myoclonic (fast) to dystonic (slow and sustained) (1-3), and may be of large or small amplitude. Lugaresi et al. estimated that of 100 RLS patients whose condition was severe enough to seek medical attention, approximately 50% had movements of this kind (1,5). Ekbom (6,7), Boghen and Peyronnard (8), Brodeur et al. (9), and Walters et al. (2,13) have also reported these movements. There is no uniform terminology for the jerking movements of the legs seen during wakefulness in RLS. The groups of Lugaresi (5) and Montplaisir (9) prefer to call them by the term “nocturnal myoclonus” or “periodic leg movements,” respectively, which is the same terminology they use for similar movements during sleep. We prefer the term “resting dyskinesias while awake” (DWA) because the movements can occur during the night or day, can be myoclonic or slower than true myoclonus, can be periodic or aperiodic, and can simultaneously involve the legs and arms (1,2). In addition, our terminology stresses the resting component and distinguishes these movements from similar movements during sleep (PMS). The videotape of patient 1 shows myoclonic jerks of the legs that recur periodically at approximately every 9-10 s. The videotape of patient 3 shows myoclonic jerks of the legs that occur in a clustered fashion. Resting DWA are markedly decreased in number by opioid therapy and reappear when opioid-treated patients are challenged with the opiate receptor blocker, naloxone. The involuntary movements seen in the two sections of videotape are characteristic of those seen in the untreated patient or in the opioid-treated patient who is challenged with naloxone.
during stages I and I1 of non-REM sleep (5) and, unlike resting DWA, they are usually too slow to be considered myoclonic (10,14). The legs are involved at approximately every 12-14 s in the first videotape of patient 4, but the arms plus the legs are involved at the same periodicity in another sequence from the same patient.
PMS These are involuntary, stereotypic, repetitive flexions typically of the hips, knees, or ankles that occur during sleep (1-3,5,9,10,14). They form a continuum with and are similar in form to the resting DWA. They may number in the hundreds, and most patients with RLS have PMS (1-3,5,9,10,14). PMS recur at intervals of between 5 and 120 s (10)
THERAPY FOR IDIOPATHIC RLS L-Dopa and dopamine agonists (9,15-19), benzodiazepine drugs (12,2&28), opioid drugs (3,13,2932), clonidine (33-33, carbamazepine (36,37), and baclofen (38) have all been claimed to be successfui in RLS, leading to speculations that the endogenous dopaminergic, GABAergic, serotonergic, opioid, and adrenergic symptoms might be involved in the
Sleep Disturbances The paresthesias, motor restlessness, and resting DWA may keep the patient from going to sleep (133-7,9, lo). Patients may complain of disorders of initiating and maintaining sleep and excessive daytime somnolence. Polysomnographic recording in severely affected RLS patients consistently show prolonged sleep latencies (difficulty getting to sleep), decreases in sleep efficiency (few hours of sleep), and an increased number of awakenings (3,9,10). Although awakenings in the middle of the night are associated with PMS, it is controversial as to whether the PMS cause the awakenings (1,5,14). It is our belief that large-amplitude PMS do cause arousals and awakenings in RLS. Clinical Course In the majority of cases the condition progresses with age, and the bulk of the patients seeking medical attention are middle to older aged (2,3,9). Generally once a person has RLS, it is a lifelong condition. However, the symptoms can begin in childhood or in old age and may be mild or severe, static or progressive, and remitting or unremitting. Neurological Examination The signs and symptoms of primary RLS may be absent during the day, at which time the neurological examination is normal (1,6,7). In more severe cases of RLS, the signs and symptoms are present during the day as well. Secondary forms of RLS may show evidence on examination of an associated condition, e.g., a peripheral neuropathy (1,6,7).
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pathogenesis of RLS (1). Evidence suggesting the efficacy of these agents is described below. L-Dopa and Bromocriptine In the various studies, total effective doses of LDopa ranged from 50 to 625 mg/day in combination with a dosage of decarboxylase inhibitor in the ration of 4:1 (e.g., Sinemet) (9,15-17). Statistically significant subjective improvements in motor restlessness and paresthesias have been consistently reported (9,15-17). Although giving a single dose of the drug 1 h before bedtime suppresses PMS in the first third of the night as measured by polysomnography, there is a rebound with greater numbers of PMS occurring later in the night (17). L-Dopa can, therefore, probably be most effectively given in divided doses 1 h before bedtime and again on awakening in the middle of the night. Brodeur et al. used this protocol in a double-blind study to show that L-Dopa significantly decreased PMS (9). Although double-blind studies indicate that there is a statistically significant subjective improvement of sleep with L-Dopa (9,15), polysomnographic analyses have shown the improvement in sleep to be modest (9,17). A more recent study shows that there are long-term beneficial effects of L-Dopa in RLS (18). Akpinar was the first to suggest that the dopamine agonist bromocriptine (Parlodel) might be helpful in relieving the symptoms of RLS (15). In a double-blind study of 7.5 mg of the drug before h.s., we found that five of six patients experienced partial, subjective improvement in restlessness and paresthesias with the drug as compared with placebo, and that there was a statistically significant decrease in the number of PMS. Objective improvement in sleep as measured by polysomnography was modest (19). Benzodiazepine Drugs Benzodiazepine drugs are thought to act either through GABAergic or serotonergic mechanisms (1). Diazepam (Valium) at 5-15 mg h.s. subjectively improved the symptoms of RLS in 19 patients (12). In a double-blind crossover trial of six patients with RLS, clonazepam (Klonopin) 1 mg h.s. subjectively improved leg paresthesias, restlessness, and quality of sleep (20). In a nonblinded polysomnographic study of RLS, paresthesias, restlessness, and PMS disappeared in two patients at doses of 0.5 mg clonazepam h.s. in one patient and 4 mg h.s. in the other (21). Two other nonblinded, nonpolysomnographic studies suggest the efficacy of clonazepam
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in RLS (22,23). There have been at least four polysomnographic studies documenting the beneficial effect of clonazepam 0.5-2 mg h.s. on sleep disturbance and PMS (24-27). One of these four studies was a double-blind, parallel group design with 10 patients in each group (25). The majority of the patients in these four studies did not have RLS, but a minority of the patients in some of these studies did have RLS. No difference in therapeutic response was noted in any of the studies between the RLS and non-RLS patients with PMS (24-27). Other benzodiazepine drugs such as nitrazepam 5 mg h.s. (28) and temazepam (Restoril) 30 mg h.s. (24) also improve sleep and decrease PMS, as documented by polysomnography . Opioid Drugs Sir Thomas Willis (1,3,13) and later Ekbom (7) suggested that opioid drugs are successful in RLS. However, no studies of opioid drugs were done on RLS until 1984 (29). All the studies are consistent in reporting the efficacy of various opioid drugs, including codeine 30 mg, propoxyphene 65 mg, oxycodone 4.5 mg, and methadone 10 mg in relieving paresthesias and motor restlessness as well as in subjectively improving sleep (3,13,29,30,32). Polysomnographic analysis documents a dramatic decrease in resting DWA and PMS and a dramatic improvement in sleep in some opioid-treated patients (3,13), but only a modest change in these parameters in other patients (3,13). Opioid drugs may also improve sleep and suppress PMS in patients without RLS (31). Although a double-blind study of opioid drugs in RLS has not been done, intravenous naloxone (an opiate receptor blocker) was administered to two opioid-treated patients in a blinded fashion, and this resulted in the reappearance of large numbers of myoclonic jerks (3,13). Naloxone placebo (saline) had no effect (3,13). Most clinicians who treat RLS prefer to give one tablet of opioid, usually codeine, propoxyphene, or oxycodone, just before or at h.s., but we have found it necessary to give higher doses in some nonresponsive patients. A typical regimen we use is one tablet 2 h before h.s., one at h.s., and one in the middle of the night if the patient awakens. In the last 7 years we have had few problems with addiction or tolerance at these higher dosages. The beneficial effects of opioid drugs in RLS appear to be long term ( 3 2 ) . Clonidine Clonidine (Catapres), which works on the adrenergic and noradrenergic system (l), ameliorates par-
IDIOPATHIC RESTLESS LEGS SYNDROME esthesias, restlessness, and sleep disturbances at the dosages of 0.1-0.3 mg at h.s. according to two reports in which 3 and 15 patients were treated, respectively (33,34). However, neither of these studies was blinded and neither employed polysomnography to quantitatively document improvements in sleep or a decrement in resting DWA and PMS. A third study that also depended on subjective patient response reported negative results in seven patients (35). Our personal experience with clonidine on the East Coast of the U.S. has not been positive, but we have interviewed all of John C. Steiner’s midwestern RLS patients and we are convinced of the therapeutic benefit of clonidine in at least some patients with RLS. Perhaps there are different biochemical subtypes of RLS with similar phenotypic expression. Carbamazepine In a double-blind crossover study of 200-600 mg/ day carbamazepine (Tegretol) in six patients with RLS, three reported fewer and less severe attacks of paresthesias when taking medication as opposed to placebo, and these three preferred to continue the drug after completion of the study (36). None of the six patients preferred placebo to carbamazepine (36). The authors comment that they have subsequently treated nonresponders at higher doses of 800-1,000 mg/day, with good success (36). In another double-blind study of 174 patients who were divided into a drug and a placebo group, the patients reported that the number of attacks of RLS symptoms per week were diminished and that the severity of sleep disturbances was less with 100-300 mg carbamazepine at h.s. (37). These results were statistically significant (37). Neither of these studies of carbamazepine in RLS has employed polysomnography . Baclofen Baclofen (Lioresal) is postulated to produce its effect through its influence on the GABAergic system (1). There has been one double-blind polysomnographic study that measured the effect of 20-160 mg/day of baclofen on PMS (38). Each patient was studied multiple times at multiple dosages. Only one of the patients had RLS. Although baclofen increased the number of PMS, it decreased their force and amplitude, thus decreasing sleep fragmentation (38). Deep sleep increased with baclofen as compared with placebo. Dosages of 20-40 mg h.s. were most effective (38).
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THERAPEUTIC RECOMMENDATIONS To date there have been no studies comparing the efficacies of the various therapeutic agents for RLS, but there have been many studies looking at single agents. At a recent symposium on RLS in which sleep disorder specialists were surveyed, L-Dopa, opioid drugs, and benzodiazepine drugs either singly or in combination were most frequently mentioned as useful (39), and these are our preferences as well. Our experience is that medications should be given 1 or 2 h before h.s. and again at h.s. to allow for proper absorption and peak effect. A third dose may be given in the middle of the night if the patient awakens. For severe RLS in which symptoms are also prominent during the day, morning and afternoon dosages may be necessary as well. LEGEND TO THE VIDEOTAPE See Table 2. REFERENCES 1 . Walters AS, Hening W. Review of the clinical presentation
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6. 7. 8. 9.
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and neuropharmacology of restless legs syndrome. Clin Neuropharmacol 1987;10:225-237; erratum in 10:482. Walters AS, Hening WA, Chokroverty S. Frequent occurrence of myoclonus while awake and at rest, body rocking and marching-in-place in a subpopulation of patients with restless legs syndrome. Acra Neurol Scand 1988;77:418421. Hening W, Walters A, Kavey N, Gidro-Frank S, CBt6 L, Fahn S. Dyskinesias while awake and periodic movements in sleep in restless legs syndrome: treatment with opioids. Neurology 1986;36:1363-1366. Hening W, Walters A, Chokroverty S. A test for circadian variability of the restless leg syndrome in patients treated with opioids. Neurosci Abstr 1988;14:908. Lugaresi E, Cirignotta F , Coccagna G, Montagna P. Nocturnal myoclonus and restless legs syndrome. In: Fahn S , Marsden CD, Van Woert MH, eds. Myoclonus. New York: Raven Press, 1986:295-307. (Advances in Neurology; vol 43). Ekbom KA. Restless legs: a clinical study. Acta Med Scand 1945;158:1-123. Ekbom KA. Restless legs syndrome. Neurology 1960;lO: 868-873. Boghen D, Peyronnard JM. Myoclonus in familial restless legs syndrome. Arch Neurol 1976;33:368-370. Brodeur C, Montplaisir J, Godbout R, Marinier R. Treatment of restless legs syndrome and periodic movements during sleep with L-Dopa: a double-blind, controlled study. Neurology 1988;38:1845-1848. Coleman RM. Periodic movements in sleep (nocturnal myoclonus) and restless legs syndrome. In: Guilleminault C, ed. Sleeping and waking Disorders: indications and techniques. Menlo Park, California: Addison Wesley, 1982:265295. Walters A, Picchietti D, Hening W, Lazzarini A. Variable expressivity in familial restless legs syndrome. Arch Neurol 1990;47:1219-1220. Morgan LK. Restless limbs: a commonly overlooked symptom controlled by “Valium.” Med J Aust 1967;2:589-594. Walters A, Hening W, CBt6 L, Fahn S. Dominantly inherited restless legs with myoclonus and periodic movements in
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sleep: a syndrome related to the endogenous opiates? In: Fahn S, Marsden CD, Van Woert MH, eds. Myoclonus. New York: Raven Press, 1986:30%319. (Advances in neurology; vol 43). 14. Coleman RM, Pollak CP, Weitzman ED. Periodic movements in sleep (nocturnal myoclonus): relation to sleep disorders. Ann Neurol 1980;8:416-421. 15. Akpinar S . Restless legs syndrome treatment with dopaminergic drugs. Clin Neuropharmacol 1987;10:69-79. 16. Von Scheele C. Levodopa in restless legs. Lancet 1986;2: 426-427, 17. Montplaisir J, Godbout R, Poirier G, Bedard MA. Restless legs syndrome and periodic movements in sleep: pathophysiology and treatment with L-Dopa. Clin Neuropharmacol 1986;9:456463. 18. Von Scheele C, Kempi V. Long-term effect of dopaminergic drugs in restless legs. Arch Neurol 1990;47:1223-1224. 19. Walters A, Hening W, Kavey N, Chokroverty S, GidroFrank S. A double-blind randomized crossover trial of bromocriptine and placebo in restless legs syndrome. Ann Neurol 1988;24:455-458. 20. Montagna P, Sassoli de Bianchi L, Zucconi M, Cirignotta F, Lugaresi E. Clonazepam and vibration in restless legs syndrome. Acra Neurol Scand 1984;69:428430. 21., Montplaisir J, Godbout R, Boghen D, De Champlain J, Young SN, Lapierre G. Familial restless legs with periodic movements in sleep: electrophysiological, biochemical, and pharmacological study. Neuroiogy 1985;35:130-134. m" LL. Boghen D. Successful treatment of restless legs with clonazepam. Ann Neurol 1980;8:341. 23. Matthews WB. Treatment of restless legs syndrome with clonazepam. Br Med J 1979;1:751. 24. Mitler MM, Browman CP, Menn SJ, Gujavarty K, Timms RM. Nocturnal myoclonus: treatment efficacy of clonazepam and temazepam. Sleep 1986;9:385-392. 25. Peled R, Lavie P. Double-blind evaluation of clonazepam in periodic movements in sleep. J Neurol Neurosurg Psychiatry 1987;50:1679-1681.
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26. Oshtory MA, Vijayan N. Clonazepam treatment of insomnia due to sleep myoclonus. Arch Neurol 1980;37:119-120. 27. Ohanna N, Peled R, Rubin AE, Zomer J, Lavie P. Periodic leg movements in sleep: effect of clonazepam treatment. Neurology 1985;35:408411. 28. Modolfsky H,Tullis C, Quance G, Lue FA. Nitrazepam for periodic movements in sleep (sleep related myoclonus). Can J Neurol Sci 1986;13:52-54. 29. Trzepacz PT,Violette EJ, Sateia MJ. Response to opioids in three patients with restless legs syndrome. Am J Psychiatry 1984;141:993-996. 30. Sandyk R, Bamford CR, Gillman MA. Opiates in the restless legs syndrome. Znt J Neurosci 1987;36:99-104. 31. Kavey N, Walters AS, Hening W, Gidro-Frank S. Opioid treatment of periodic movements in sleep in patients without restless legs. Neuropeptides 1988;11:181-184. 32. Hening WA, Walters AS. Successful long-term therapy of the restless legs syndrome with opioid medication. Sleep Res 1989;18:241. 33. Handwerker JV, Palmer RF. Clonidine in the treatment of restless leg syndrome. New Engl J Med 1985;313:1228-1229. 34. Steiner JC. Clonidine in restless legs syndrome. Neurology 1987;37(suppl1):278. 35. Bamford CR, Sandyk R. Failure of clonidine to ameliorate the symptoms of the restless legs syndrome. Sleep 1987;lO: 398-399. 36. Lundvall 0,Abom PE, Holm R. Carbamazepine in restless legs: a controlled pilot study. Eur J Clin Pharmacol 1983;25:323-324. 37. Telstad W, Sorensen 0, Larsen S, Lillevold PE, Stensrud P, Nyberg-Hansen R. Treatment of the restless legs syndrome with carbamazepine: a double-blind study. Br Med J 1984;288:444-446. 38. Guilleminault C, Flagg W. Effect of baclofen on sleeprelated periodic leg movements. Ann Neurol 1984;15:234239. 39. Buchholz DW. Wrestling with restless legs and periodic movements in sleep. 4th Annual Meeting of the Association of Professional Sleep Societies, Minneapolis, Minnesota, June 27-July I , 1990 (not published).
Review and Videotape Recognition of Idiopathic Restless Legs Syndrome Arthur S. Walters, Wayne A. Hening, and Sudhansu Chokroverty Movement Disorder Group, Department of Neurology, Universily of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, and Neurology Service, Veterans Administration Medical Center, Lyons, New Jersey, U.S.A.
Summary: The motor phenomena associated with idiopathic restless legs syndrome (RLS) are infrequently seen in the physician’s office because they are present only after prolonged sitting or lying and usually at night. These motor phenomena are captured on videotape in four unrelated patients with idiopathic RLS. The clinical features of idiopathic RLS are reviewed in detail, and therapeutic advances in its treatment are summarized. Key Words: Restless legs syndrome-Myoclonus-Periodic movements in sleep-L-Dopa-Opioid drugs-Benzodiazepine drugs.
of primary idiopathic RLS and summarizes advances in therapy. Videotapes displaying the clinical characteristics of idiopathic RLS have not been previously published, and we present four unrelated patients with idiopathic RLS in videotape form. All four patients were in their 60s at the time of the study and met the criteria for diagnosis of RLS (Table 1). All four patients had symptoms of RLS that were progressively getting worse for many years, and all four patients also demonstrated polysomnographic evidence of the additional features of “resting dyskinesias while awake,’’ periodic movements in sleep (PMS), and sleep disturbance. Three of four had a family history of RLS (patients 1, 3, and 4). Ten sections of videotape are delineated in order in the text and in Table 2. Six sections depict motor restlessness and four sections of videotape follow that depict “resting dyskinesias while awake” and PMS. Of the six sections depicting motor restlessness, five of the sequences are captured spontaneously. The leg-stretching sequence from patient 3 illustrates the type of knowledge that can be obtained by asking a patient to demonstrate restless movements. At the time of the video, the patient is markedly restless and has done what RLS patients
Restless legs syndrome (RLS) may exist to varying degrees of severity in as much as 2% of the population (1) and yet it goes largely unrecognized by clinicians. Because the movements associated with RLS occur only after prolonged sitting or lying and mostly at night (1-7), physicians usually examine a movement-free patient and, except in secondary forms of RLS, e.g., those associated with peripheral neuropathy, the neurological examination is normal (1,6,7). Under these circumstances, clinicians must rely on a history of the presence of movements, other historical information, or polysomnography to make a diagnosis. The criteria for diagnosis of idiopathic RLS are paresthesias and motor restlessness aggravated by nightfall and rest (1-3,5-10) (Table 1). Depending on the additional feature involved, approximately 30-90% of RLS patients will show additional features that also help to make the diagnosis of RLS (1,2,5,8,9,10) (Table 1). This review concentrates on the clinical features A videotape segment accompanies this article. Address correspondence and reprint requests to A. S. Walters at 408B MEB, Department of Neurology CN 19, UMDNJRobert Wood Johnson Medical School, New Brunswick, NJ 08903-0019, U.S.A.
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A . S. WALTERS ET AL. TABLE 1. Clinical features of idiopathic restless legs syndrome (RLS)
Autosomal dominant inheritance in more than one-third of cases Paresthesias" Motor restlessness" Aggravation by nightfall" Aggravation by rest' Resting dyskinesias while awake Periodic movements in sleep Sleep disturbances Clinical course (usually progressive/severe >50 yrs of age) Neurological examination-normal
" Criteria for diagnosis of RLS.
normally do spontaneously, i.e., he has switched from another strategy to the videotaped strategy in an attempt to relieve paresthesias. Because the restless movements in idiopathic RLS are transient, usually present at night and therefore inaccessible to most clinicians, their demonstration may provide important diagnostic information. A detailed description of the clinical features of idiopathic RLS and appropriate videotapes follow.
CLINICAL CHARACTERISTICS OF IDIOPATHIC RLS Autosomal Dominant Family History An autosomal dominant family history is present in one-third or more of patients with RLS (1,2,5-8). Patient report cannot be relied on to establish that a family history is absent, but instead the relatives must be questioned in detail (11). Paresthesias Uncomfortable sensations, most often present in the legs, lead to a desire to move. These sensations have been described as creeping, crawling, tingling, burning, pins and needles, cramping, painful, aching, or indescribable (1-3,5-7). Paresthesias sometimes occur in the arms (1,2,12). Motor Restlessness The paresthesias lead to an urge to move the affected limbs, and the less severely affected patients get relief in motion (1-3,5-7). The motor restlessness occurs during wakefulness. The motor restlessness is temporarily suppressible, and patients choose a variety of creative ways of trying to relieve the paresthesias; also, they may switch at will from one strategy to another. To relieve the paresthesias, patients most often pace the floor. Tossing
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TABLE 2. Guide to videotape Motor restlessness during wakefulness 1. Tossinghrning in bed (patient 1) 2. Foot rubbing (patient 2) 3. Leg flexions (patient 2) 4. Leg stretching (patient 3) 5. Body rocking (patient 3) 6. Marching in place (patient 2) Resting dyskinesias while awake and periodic movements in sleep 7. Periodic myoclonus while awake (patient 1) 8. Clustered myoclonus while awake (patient 3) 9. Periodic movements in sleep involving legs (patient 4) 10. Periodic movements in sleep involving arm and legs (patient 4)
and turning in bed is captured in the videotape of patient 1. Patients may also try to alter sensory input to relieve paresthesias by rubbing their feet, as captured in the videotape of patient 2, or they may take baths. Leg flexions and leg stretching are captured in the videotapes of patients 2 and 3, respectively. Patients may also do leg flexions with their feet dependent (deep kneebends), or they may stretch their legs by standing with their feet flat on the floor and try to touch their toes with their knees locked for a prolonged period. Body rocking and marching in place are the classic motor movements seen in neuroleptic-induced akathisia (motor restlessness caused by antipsychotic agents). In a recent survey we also found body rocking and marching in place in 6 of 10 patients with RLS (2). In RLS, the body rocking and marching in place usually occur only at night and even then they occur only intermittently. This distinguishes them from the all-day-long body rocking and marching in place of neuroleptic-induced akathisia (1,2). Body rocking is captured in the videotape of patient 3 and marching in place is captured in the videotape of patient 2.
Aggravation by Nightfall and Rest The signs and symptoms of RLS can be present during the day but are classically worse at night (1-7,9,10). Although it is clear that these signs and symptoms are worse at night because the patients are more at rest (i.e., lying or sitting) during the night than during the day, there is also probably a separate diurnal variation that is independent of rest (4).Aggravation by both nightfall and rest is a highly distinctive pattern that may be unique for RLS.
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Resting Dyskinesias While Awake (DWA) These are involuntary, stereotypic, repetitive flexions typically of the hips, knees, or ankles that occur during nighttime wakefulness (1-9). The more severely affected patients may have hundreds of these jerking movements while attempting to lie down and go to sleep. They are typically present at rest, disappear with action (1,2,11), range in speed from myoclonic (fast) to dystonic (slow and sustained) (1-3), and may be of large or small amplitude. Lugaresi et al. estimated that of 100 RLS patients whose condition was severe enough to seek medical attention, approximately 50% had movements of this kind (1,5). Ekbom (6,7), Boghen and Peyronnard (8), Brodeur et al. (9), and Walters et al. (2,13) have also reported these movements. There is no uniform terminology for the jerking movements of the legs seen during wakefulness in RLS. The groups of Lugaresi (5) and Montplaisir (9) prefer to call them by the term “nocturnal myoclonus” or “periodic leg movements,” respectively, which is the same terminology they use for similar movements during sleep. We prefer the term “resting dyskinesias while awake” (DWA) because the movements can occur during the night or day, can be myoclonic or slower than true myoclonus, can be periodic or aperiodic, and can simultaneously involve the legs and arms (1,2). In addition, our terminology stresses the resting component and distinguishes these movements from similar movements during sleep (PMS). The videotape of patient 1 shows myoclonic jerks of the legs that recur periodically at approximately every 9-10 s. The videotape of patient 3 shows myoclonic jerks of the legs that occur in a clustered fashion. Resting DWA are markedly decreased in number by opioid therapy and reappear when opioid-treated patients are challenged with the opiate receptor blocker, naloxone. The involuntary movements seen in the two sections of videotape are characteristic of those seen in the untreated patient or in the opioid-treated patient who is challenged with naloxone.
during stages I and I1 of non-REM sleep (5) and, unlike resting DWA, they are usually too slow to be considered myoclonic (10,14). The legs are involved at approximately every 12-14 s in the first videotape of patient 4, but the arms plus the legs are involved at the same periodicity in another sequence from the same patient.
PMS These are involuntary, stereotypic, repetitive flexions typically of the hips, knees, or ankles that occur during sleep (1-3,5,9,10,14). They form a continuum with and are similar in form to the resting DWA. They may number in the hundreds, and most patients with RLS have PMS (1-3,5,9,10,14). PMS recur at intervals of between 5 and 120 s (10)
THERAPY FOR IDIOPATHIC RLS L-Dopa and dopamine agonists (9,15-19), benzodiazepine drugs (12,2&28), opioid drugs (3,13,2932), clonidine (33-33, carbamazepine (36,37), and baclofen (38) have all been claimed to be successfui in RLS, leading to speculations that the endogenous dopaminergic, GABAergic, serotonergic, opioid, and adrenergic symptoms might be involved in the
Sleep Disturbances The paresthesias, motor restlessness, and resting DWA may keep the patient from going to sleep (133-7,9, lo). Patients may complain of disorders of initiating and maintaining sleep and excessive daytime somnolence. Polysomnographic recording in severely affected RLS patients consistently show prolonged sleep latencies (difficulty getting to sleep), decreases in sleep efficiency (few hours of sleep), and an increased number of awakenings (3,9,10). Although awakenings in the middle of the night are associated with PMS, it is controversial as to whether the PMS cause the awakenings (1,5,14). It is our belief that large-amplitude PMS do cause arousals and awakenings in RLS. Clinical Course In the majority of cases the condition progresses with age, and the bulk of the patients seeking medical attention are middle to older aged (2,3,9). Generally once a person has RLS, it is a lifelong condition. However, the symptoms can begin in childhood or in old age and may be mild or severe, static or progressive, and remitting or unremitting. Neurological Examination The signs and symptoms of primary RLS may be absent during the day, at which time the neurological examination is normal (1,6,7). In more severe cases of RLS, the signs and symptoms are present during the day as well. Secondary forms of RLS may show evidence on examination of an associated condition, e.g., a peripheral neuropathy (1,6,7).
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pathogenesis of RLS (1). Evidence suggesting the efficacy of these agents is described below. L-Dopa and Bromocriptine In the various studies, total effective doses of LDopa ranged from 50 to 625 mg/day in combination with a dosage of decarboxylase inhibitor in the ration of 4:1 (e.g., Sinemet) (9,15-17). Statistically significant subjective improvements in motor restlessness and paresthesias have been consistently reported (9,15-17). Although giving a single dose of the drug 1 h before bedtime suppresses PMS in the first third of the night as measured by polysomnography, there is a rebound with greater numbers of PMS occurring later in the night (17). L-Dopa can, therefore, probably be most effectively given in divided doses 1 h before bedtime and again on awakening in the middle of the night. Brodeur et al. used this protocol in a double-blind study to show that L-Dopa significantly decreased PMS (9). Although double-blind studies indicate that there is a statistically significant subjective improvement of sleep with L-Dopa (9,15), polysomnographic analyses have shown the improvement in sleep to be modest (9,17). A more recent study shows that there are long-term beneficial effects of L-Dopa in RLS (18). Akpinar was the first to suggest that the dopamine agonist bromocriptine (Parlodel) might be helpful in relieving the symptoms of RLS (15). In a double-blind study of 7.5 mg of the drug before h.s., we found that five of six patients experienced partial, subjective improvement in restlessness and paresthesias with the drug as compared with placebo, and that there was a statistically significant decrease in the number of PMS. Objective improvement in sleep as measured by polysomnography was modest (19). Benzodiazepine Drugs Benzodiazepine drugs are thought to act either through GABAergic or serotonergic mechanisms (1). Diazepam (Valium) at 5-15 mg h.s. subjectively improved the symptoms of RLS in 19 patients (12). In a double-blind crossover trial of six patients with RLS, clonazepam (Klonopin) 1 mg h.s. subjectively improved leg paresthesias, restlessness, and quality of sleep (20). In a nonblinded polysomnographic study of RLS, paresthesias, restlessness, and PMS disappeared in two patients at doses of 0.5 mg clonazepam h.s. in one patient and 4 mg h.s. in the other (21). Two other nonblinded, nonpolysomnographic studies suggest the efficacy of clonazepam
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in RLS (22,23). There have been at least four polysomnographic studies documenting the beneficial effect of clonazepam 0.5-2 mg h.s. on sleep disturbance and PMS (24-27). One of these four studies was a double-blind, parallel group design with 10 patients in each group (25). The majority of the patients in these four studies did not have RLS, but a minority of the patients in some of these studies did have RLS. No difference in therapeutic response was noted in any of the studies between the RLS and non-RLS patients with PMS (24-27). Other benzodiazepine drugs such as nitrazepam 5 mg h.s. (28) and temazepam (Restoril) 30 mg h.s. (24) also improve sleep and decrease PMS, as documented by polysomnography . Opioid Drugs Sir Thomas Willis (1,3,13) and later Ekbom (7) suggested that opioid drugs are successful in RLS. However, no studies of opioid drugs were done on RLS until 1984 (29). All the studies are consistent in reporting the efficacy of various opioid drugs, including codeine 30 mg, propoxyphene 65 mg, oxycodone 4.5 mg, and methadone 10 mg in relieving paresthesias and motor restlessness as well as in subjectively improving sleep (3,13,29,30,32). Polysomnographic analysis documents a dramatic decrease in resting DWA and PMS and a dramatic improvement in sleep in some opioid-treated patients (3,13), but only a modest change in these parameters in other patients (3,13). Opioid drugs may also improve sleep and suppress PMS in patients without RLS (31). Although a double-blind study of opioid drugs in RLS has not been done, intravenous naloxone (an opiate receptor blocker) was administered to two opioid-treated patients in a blinded fashion, and this resulted in the reappearance of large numbers of myoclonic jerks (3,13). Naloxone placebo (saline) had no effect (3,13). Most clinicians who treat RLS prefer to give one tablet of opioid, usually codeine, propoxyphene, or oxycodone, just before or at h.s., but we have found it necessary to give higher doses in some nonresponsive patients. A typical regimen we use is one tablet 2 h before h.s., one at h.s., and one in the middle of the night if the patient awakens. In the last 7 years we have had few problems with addiction or tolerance at these higher dosages. The beneficial effects of opioid drugs in RLS appear to be long term ( 3 2 ) . Clonidine Clonidine (Catapres), which works on the adrenergic and noradrenergic system (l), ameliorates par-
IDIOPATHIC RESTLESS LEGS SYNDROME esthesias, restlessness, and sleep disturbances at the dosages of 0.1-0.3 mg at h.s. according to two reports in which 3 and 15 patients were treated, respectively (33,34). However, neither of these studies was blinded and neither employed polysomnography to quantitatively document improvements in sleep or a decrement in resting DWA and PMS. A third study that also depended on subjective patient response reported negative results in seven patients (35). Our personal experience with clonidine on the East Coast of the U.S. has not been positive, but we have interviewed all of John C. Steiner’s midwestern RLS patients and we are convinced of the therapeutic benefit of clonidine in at least some patients with RLS. Perhaps there are different biochemical subtypes of RLS with similar phenotypic expression. Carbamazepine In a double-blind crossover study of 200-600 mg/ day carbamazepine (Tegretol) in six patients with RLS, three reported fewer and less severe attacks of paresthesias when taking medication as opposed to placebo, and these three preferred to continue the drug after completion of the study (36). None of the six patients preferred placebo to carbamazepine (36). The authors comment that they have subsequently treated nonresponders at higher doses of 800-1,000 mg/day, with good success (36). In another double-blind study of 174 patients who were divided into a drug and a placebo group, the patients reported that the number of attacks of RLS symptoms per week were diminished and that the severity of sleep disturbances was less with 100-300 mg carbamazepine at h.s. (37). These results were statistically significant (37). Neither of these studies of carbamazepine in RLS has employed polysomnography . Baclofen Baclofen (Lioresal) is postulated to produce its effect through its influence on the GABAergic system (1). There has been one double-blind polysomnographic study that measured the effect of 20-160 mg/day of baclofen on PMS (38). Each patient was studied multiple times at multiple dosages. Only one of the patients had RLS. Although baclofen increased the number of PMS, it decreased their force and amplitude, thus decreasing sleep fragmentation (38). Deep sleep increased with baclofen as compared with placebo. Dosages of 20-40 mg h.s. were most effective (38).
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THERAPEUTIC RECOMMENDATIONS To date there have been no studies comparing the efficacies of the various therapeutic agents for RLS, but there have been many studies looking at single agents. At a recent symposium on RLS in which sleep disorder specialists were surveyed, L-Dopa, opioid drugs, and benzodiazepine drugs either singly or in combination were most frequently mentioned as useful (39), and these are our preferences as well. Our experience is that medications should be given 1 or 2 h before h.s. and again at h.s. to allow for proper absorption and peak effect. A third dose may be given in the middle of the night if the patient awakens. For severe RLS in which symptoms are also prominent during the day, morning and afternoon dosages may be necessary as well. LEGEND TO THE VIDEOTAPE See Table 2. REFERENCES 1 . Walters AS, Hening W. Review of the clinical presentation
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