Periodic Leg Movement, L-Dopa, 5-Hydroxytryptophan, and L-Tryptophan

Transcription

1 Sleep 10(4): , Raven Press, New York 1987, Association of Professional Sleep Societies Short Report Periodic Leg Movement, L-Dopa, 5-Hydroxytryptophan, and L-Tryptophan C. Guilleminault, S. Mondini, J. Montplaisir, J. Mancuso, D. Cobasko, and W. C. Dement Sleep Disorders Clinic, Stanford University School of Medicine, Stanford, California, U.S.A. Periodic leg movement (PLM) or nocturnal myoclonus consists of repetitive, stereotypic discharges of varying intensity in the anterior tibialis muscles, resulting in extension of the big toe. The muscle discharges are generally bilateral but may randomly involve a single leg. Akpinar (1) has suggested that L-Dopa may be helpful in restless legs syndrome, a condition where PLMs are also noted during sleep; movements are worsened by a dopamine antagonist, pimozide. Our preliminary study investigates PLM in elderly subjects free of restless legs syndrome or other neurological disorder. PATIENT POPULATION Two groups of patients were investigated. Group A consisted of five patients: two women and three men, mean age 62.2 years, range years. Group B consisted of six patients: three men and three women, mean age 56 years, range years. All patients were referred to the sleep clinic with a complaint of nocturnal sleep disturbances and early morning awakening. None of the patients had received hypnotic medications for at least 6 weeks prior to entering the study. During nocturnal sleep, all patients had undergone polygraphic monitoring that confirmed the diagnosis of PLM and presented a minimum movement index (PLM index), i.e., number of PLMs per hour of total sleep time (TST), as defined by Coleman (2). Leg movements, to be considered as "periodic," must have a duration of s; the interval between events must be s, and a series of at least three consecutive movements must be present; isolated, individual movements do not qualify as PLMs (2). POLYGRAPHIC RECORDINGS For each recording the monitored variables were electroencephalogram (EEG) (C3/A2-C4/Al), electrooculogram, chin electromyogram (EMG), electrocardiogram (modified V2 lead), thoracoabdominal movements, and airflow. Right and left anterior tibialis EMGs were monitored using Beckman surface electrodes (3). Polygraphic Accepted for publication March 1987, Address correspondence and reprint requests to Dr. C. Guilleminault at Sleep Disorders Center, Stanford University School of Medicine, Stanford, CA 94305, U.S.A. 393

2 394 C. GUILLEMINAULT ET AL. monitoring was begun between 2200 and 2230 h. Lights-out time was left to the patient's dis~retion, ~s was time of arising, when the monitoring ended. No daytime monitoring was done. QUESTIONNAIRE On each morning of the study, patients were asked to fill out a questionnaire on which they rated nocturnal sleep and any side effects subjectively. As the investigation was open trial, patients had full knowledge of the medication and dosage administered. GROUP A PATIENTS AND 5-HYDROXYTRYPTOPHAN The five patients of group A were monitored in the Clinical Research Center (CRC) for a total of 6 nights. Each patient had 2 baseline nights and 2 initial drug nights. Patients returned home from drug day 3 until drug day 14 and were again monitored on nights 14 and 15 in the CRC. Patients received 500 mg 5-hydroxytryptophan (5-HTP) in capsule form at 2215 h on the nights of objective monitoring and were instructed to follow the same medication schedule at home. Two men, aged 51 and 55 years, received 1,000 mg for 4 nights (nights 16-19) and 1,500 mg for 7 nights (nights 20-26) at the conclusion of the standard protocol. They were again monitored polygraphically on nights 19, 25, and 26. GROUP B PATIENTS AND L-TRYPTOPHAN/L-DOPA Group B patients were monitored in the same manner as group A and received two different drugs with a 15-day drug-free interval between the administration of each drug. Patients were randomly distributed into subgroup 1, which received L-tryptophan as the first drug, and subgroup 2, which initially received L-Dopa with Dopa decarboxylase inhibitor. (Dopa decarboxylase inhibitor was administered only with L-Dopa.) L-Tryptophan was administered in 500-mg tablets, each patient taking a total of 3 g at bedtime in a single dose. L-Dopa was administered using the commercially available L-Dopa plus Dopa decarboxylase inhibitor (carbidopa) preparation , which contains 100 mg L-Dopa and 25 mg carbidopa. L-Dopa was administered in combination with a small snack to minimize any gastrointestinal side effects. Each drug was administered at 2215 h during patient monitoring. Patients were asked to follow a regular schedule at home between objective monitorings. Patients were polygraphically monitored for a total of 7 nights: 2 baseline nights, 2 initial drug nights (nights 1-2), and nights 7,14, and 15 of each drug trial. DATA ANALYSIS All records were scored by 30-s epochs, using the Rechtschaffen and Kales scoring system (4). Sleep disturbances and short EEG arousals immediately following PLMs were also identified and scored within each epoch. The PLM index and the movement arousal index (number of PLMs associated with arousals per hour of TST) were calculated. A two-way analysis of variance for repeated measure and matched-pairs t tests were performed on the data obtained.

3 PERIODIC LEG MOVEMENT 395 RESULTS No significant side effects were noted with the drugs tested. In particular, no abnormal movements or gastrointestinal problems were noted with 5-HTP or L-Dopa during the IS-day trial. The administration of 5-HTP had no effect on the number of PLMs, with or without arousal. In the two subjects who agreed to take 1,000 and 1,500 mg, no improvement was seen with the higher dosage. All statistical analyses were nonsignificant. In group B, there was no difference in the results between the two subgroups that had drug administration counterbalanced; therefore, the analyses are presented for the total patient group independently of the order of drug administration. Like 5-HTP, L-tryptophan had no statistically significant effects on PLM. The combination of L-Dopa with carbidopa, however, definitely reduced the number of PLMs. The PLM index differed from baseline when drug condition was investigated. There is spontaneous variation in PLM from night to night that is reflected in movement index (MI) and movement arousal index (MAL). On baseline night the mean MI was 42.7 ± 21.4 and the mean MAL was 34.5 ± 18. The large standard deviation can explain the absence of statistical results when MAL was analyzed under different conditions, despite the fact that the mean MAIs on nights 7 and were 20.3 ± 12.6 and 21 ± 14, respectively. When MI was statistically analyzed, there was a difference between baseline and night 7 (p < 0.04, t = 2.843) and a clear trend between baseline and nights (p < 0.06, t = 2.401). Once again, standard deviations were large, despite use of index (x MI night 7 = 24.5 ± 14.2; x MI nights = 25.7 ± 16.4). None of the sleep variables (TST, percentage of stage I NREM sleep, percentage REM sleep, time spent awake after sleep onset, sleep latency) was statistically significant. Table 1 outlines the mean results and standard deviations. Despite the fact that there was a significant difference in MI between baseline and night 7 and the overall trends, evaluation of individual results indicated that one subject (patient 4, a 61-year-old man) showed no improvement over time with L-Dopa and Dopa decarboxylase inhibitor (MI: baseline = 50, nights 1-2 = 52, night 7 = 47, nights = 54.5). Clinical interviews and TABLE 1. L-Dopa plus Dopa decarboxylase inhibitor and periodic leg movements Baseline Nights 1-2 Nights Variable ex 2 nights) ex 2 nights) Night 7 ex 2 nights) Ml x SO MAl x SO SL x SO WASO x 82, SO %SI x SO %REM x SO TST x SO Ml, movement index; MAl, movement arousal index; SL, sleep latency (min); WASO, wake after sleep onset (min, s); %SI, % stage I sleep; %REM, % REM sleep; TST, total sleep time (min).

4 396 C. GUILLEMINAULT ET AL. reviews of clinical information revealed that although his PLM patterns did not differ from those of other patients, he was the only one in the group who complained of cold feet on a near-nightly basis. He frequently wore socks during sleep and presented a poor venous return, suggestive of a possible mild vascular problem involving the lower extremities. Clinical evaluation, however, revealed no diabetes mellitus, peripheral neuropathy, or valvular deficiencies. COMMENTS This short report presents the results of open trials investigating the possible role of putative neurotransmitters, or their precursors, in the appearance ofplm. None of the patients studied presented any accompanying syndrome that has been reported in association with PLM. No restless legs syndrome, narcolepsy, or sleep apnea was noted in any of the subjects. Baclofen has previously been reported to decrease the amplitude of PLM but not its frequency (5). Akpinar (1) and Montplaisir et al. (6) recently reported the beneficial effect of L-Dopa on restless legs syndrome. Montplaisir et al. (6) also noted a significant reduction in PLM seen in association with the syndrome. Our findings confirm that PLM, even in the absence of restless legs syndrome, can be improved by L-Dopa with carbidopa. Several points must be emphasized. a. We never succeeded in completely eliminating PLM or PLM-associated arousals. As noted by Montplaisir et al. (6), PLMs had a tendency to cluster at the end of the night in patients receiving L-Dopa; i.e., there was less movement observed during the first two-thirds of the night than during the last third; but the difference between the first and third segments of the night was not statistically significant. PLM persistence may be related to the limited dosage administered to our patients (25 mg carbidopa with 100 mg L-Dopa). The risks of central nervous system and gastrointestinal side effects are well known with L-Dopa, however, and may limit the use of this drug. b. If MI and MIA improvement ensued within 48 h of drug intake, as indicated by mean data, still better results were seen on day 7, but no further improvement was noted on nights recordings as compared with that of night 7. Subjectively, patients mentioned only a "better sleep" on night 7 and nights of L-Dopa ingestion, and not on nights 1-2. c. Despite L-Dopa administration, patient 4's condition remained surprisingly unchanged compared with baseline. One may argue, once again, for a too-low L-Dopa dosage in this case; but one cannot rule out the possibility of a different etiology of PLM syndrome to account for patient 4's total lack of response over time. Peripheral vascular problems may be a significant clue, as beneficial effects of vasodilators have previously been reported (7). Ancoli-Israel and colleagues (8,9) have also hypothesized that poor circulation may be responsible for PLM syndrome in a subgroup of patients, and have used thermal biofeedback as a therapeutic agent in this case (8). We studied four pregnant women who developed a marked PLM syndrome during their third trimester of pregnancy. Because of the fetus's position, all of the women had great difficulty in sleeping other than on their back and presented important venous return problems exacerbated during sleep. PLM disappeared completely after delivery in all four cases. Investigation of peripheral vascular problems, as reported by Ware et al. (7), and/or foot skin temperature (10) may help us dissociate this subgroup from others and lead to a more symptomatic treatment. d. Last but not least, results with L-Dopa were much more evident in patients with

5 PERIODIC LEG MOVEMENT 397 numerous leg jerks; those with mild forms of PLM appeared to benefit less from treatment. This open trial indicates the need for better definition of the clinical problems presented by patients recognized with PLM syndrome during sleep. Objective evaluation may try to document changes in foot skin temperature or, even better, evaluate lower extremity blood circulation during sleep. It also indicates that L-Dopa with a Dopa decarboxylase inhibitor may be helpful in a subgroup of patients with PLM, and that further investigation of L-Dopa is needed. Acknowledgment: This work was aided by National Institute of Aging grant no. AG and by General Clinical Research grant no. RR funded by the National Institutes of Health. We thank Joan Mancuso, Wayne Flagg, and Roger Baldwin for providing technical assistance and Alison Grant for editing the manuscript. REFERENCES 1. Akpinar S. Treatment of restless legs syndrome with levodopa plus benzerazide. Arch Neurol 1982;39: Coleman RM. Periodic movements in sleep (nocturnal myoclonus) and restless leg syndrome. In: Guilleminault C, ed. Sleep and waking disorders: indications and techniques. Menlo Park, CA: Addison Wesley, 1982: Guilleminault C, Montplaisir J, Dement WC. 5 HTP and nocturnal myoclonus. Neurosci Abstr 1974;2: Rechtschaffen A, Kales A. A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. Brain Information Service/Brain Research Institute, UCLA, Los Angeles, Guilleminault C, Flagg W. Effects of Badofen on sleep-related periodic leg movements. Ann Neurol 1984;15: Montplaisir J, Godbout R, Poirier G, Be'dart MA. Restless legs syndrome and periodic movements in sleep: physiopathy and treatment with L-dopa. Clin PharmacoI1986;5: Ware JC, Pittard JT, Blumoss RL. Treatment of sleep-related myoclonus with an alpha-receptor blocker [Abstract]. Sleep Res 1981;10: Lemon ME, Seifert AR, Ancoli-Israel S. Periodic movements in sleep and foot temperature: subjective reports [Abstract]. Sleep Res 1985;14: Seifert AR, Ancoli-Israel S, Lemon M. Periodic movements in sleep and foot temperature: a case for thermal biofeedback [Abstract]. Biofeedback Self Regul 1986;11 : Ancoli-Israel S, Seifert AR, Lemon M. Thermal biofeedback and periodic movements in sleep: patients' subjective reports and a case study. Biofeedback Self Regul (in press).