ORIGINAL ARTICLES
Motor Dyscontrol in Narcolepsy: Rapid-Eye-Movement (REM) Sleep without Atonia and REM Sleep Behavior Disorder Carlos H. Schenck, MD,” and Mark W. Mahowald, MD-F
Narcolepsy involves abnormalities of rapid-eye-movement (REM) sleep, including a short latency to the onset of REM sleep, hypnagogic hallucinations, and sleep paralysis. In addition, persistence of muscle tone by electromyographic criteria or excessive muscle twitching during REM sleep or both have been’reported in treated and untreated narcoleptic patients. We report that another previously described abnormality of REM sleep, REM sleep behavior disorder, may also be a symptom of narcolepsy. This disorder was found in 10 narcoleptic patients during routine clinical evaluations involving polysomnography and multiple sleep latency tests. During REM sleep, 7 additional narcoleptic patients displayed persistent muscle tone and/or excessive twitching, which we believe to be subclinical components of REM sleep behavior disorder. These 17 patients, diagnosed by established criteria for narcolepsy and for REM sleep behavior disorder, ranged in age from 8 to 74 years. Seventy-one percent were male. Narcolepsy and REM sleep behavior disorder most commonly emerged in tandem. In 3 patients, treatment of narcolepsy-cataplexy with stimulants and tricyclics either induced or exacerbated REM sleep behavior disorder. Schenck CH, Mahowald MW. Motor dyscontrol in narcolepsy: rapid-eye-movement (REM) sleep without atonia and REM sleep behavior disorder. Ann Neurol 1992;32:3-10
Narcolepsy El-4) is a syndrome characterized by excessive daytime sleepiness, cataplexy {5-71, sleep paralysis, and hypnagogic hallucinations 15, 6, 8, 9). Abnormalities of rapid-eye-movement (REM) sleep and of motor control are common in narcolepsy: The latency to the onset of REM sleep is usually very short. Sleep paralysis and hypnagogic hallucinations are frequent and represent the intrusion of REM sleep into wakefulness or light sleep {6). Motor dyscontrol may involve not only cataplexy and sleep paralysis, but also (1) periodic limb movements during non-rapideye-movement (NREM) sleep and during REM sleep [lo-131, and (2) persistence of electromyographic (EMG) tone throughout REM sleep (i.e., REM sleep without atonia) and/or excessive aperiodic EMG twitching during REM sleep in patients with untreated narcolepsy or in patients receiving clomipramine treatment for cataplexy E13-20). We now present data suggesting that the “REM sleep behavior disorder” (RBD) can also be associated with narcolepsy. RBD is a form of motor dyscontrol characterized by complex, vigorous, and frequently violent, dream-enacting behaviors during REM sleep. It
From the Minnesota Regional Sleep Disorders Center, the *Department of Psychiatry, and the tDepartment of Neurology, Hennepin County Medical Center and the University of Minnesota Medical
School, Minneapolis, MN. Received May 9, 1991, and in revised form Sep 4, Nov 12, and Dec 4. Accepted for publication Dec 6, 1991.
may be idiopathic or symptomatic of diverse neurological disorders, and usually affects older men [Z, 2 1-30).
Patients and Methods Over a 4.5-year period (1986-1991), clinical polysomnographic (PSG) evaluations at our sleep disorders center identified 17 narcoleptic patients with extensive motor dysregulation during REM sleep. Ten of these patients met established criteria for RBD [2, 251. The 17 patients comprised nearly 12% of all narcoleptics undergoing PSG studies during that period. The chief complaint pertained to RBD and narcolepsy jointly in 35.396 (6/17) and to narcolepsy primarily in 64.7% (11/17) of patients. RBD complaints typically concerned sleep-related injuries (ecchymoses, lacerations). Narcolepsy complaints were related to excessive daytime sleepiness and cataplexy. All patients (usually with family members) were interviewed by staff physicians at our center, completed comprehensive medical and sleep-wake questionnaires, and underwent neurological and other clinical examinations. Standard methods were employed in recording and scoring the PSG studies [311, with allowance for intermittent or persistent loss of REM sleep atonia, including electrooculography, submental and anterior tibialis EMG (and occasionally
Address correspondence to Dr Schenck, Minnesota Regional Sleep Disorders Center, Department of Psychiatry (844), Hennepin County Medical Center, 701 Park Ave South, Minneapolis, MN 55415.
Copyright 0 1992 by the American Neurological Association 3
posterior tibialis, and extensor and flexor digitorum EMG), electroencephalography (EEG) (C, and C4 sleep stage scoring channels, and also a seizure montage [F,-T3, T,-T,, T5-01, F8-T4, T4-T6, T6-02,F,-P,, F4-P4] with faster paper speeds of 15 and 30 mm/sec in 43.79% [7/17) of patients), electrocardiography (EKG), nasal-oral airflow determinations using thermistors, and more extensive apnea monitoring (respiratory effort by inductance plethysmography and hemoglobin oxygen saturation by oximetry) whenever indicated. All PSG studies were continuously videotaped. Patients were free of psychoactive medication for at least 10 days prior to the PSG studies, with four exceptions reported below. Each patient completed a multiple sleep latency test (MSLT) according to established procedures E32J The diagnostic criteria for RBD [25] included: 1. PSG abnormality during REM sleep: elevated submental EMG tone and/or excessive phasic submental and/or limb EMG twitching. 2. Documentation of abnormal REM sleep behaviors during PSG studies (prominent limb or truncal jerking; complex, vigorous, or violent behaviors), or a history of injurious or disruptive sleep behaviors.
All patients satisfied strict criteria for narcolepsy E12) by the presence of at least three of the following:
1. Definite history of excessive daytime sleepiness. 2. Definite history of cataplexy. 3. Mean sleep latency index of less than 5 minutes on the MSLT.
4. Two or more sleep-onset REM periods on the MSLT; or one or more sleep-onset REM period on nocturnal PSG study (i.e., appearance of REM sleep within 20 minutes of sleep onset), and one or more sleep-onset REM period on the MSLT. The diagnostic criteria for both RBD and narcolepsy listed above conform to the criteria contained in the current international classification of sleep disorders [2].Although narcolepsy has been strongly associated with the HLA-DR2/ DQwl haplotype [33-351, human leukocyte antigen (HLA) typing was not routinely performed since all subjects met the clinical, PSG, and MSLT criteria for narcolepsy.
Results Table 1 documents the diagnosis of narcolepsy in our patients. There was a short mean sleep latency o n the MSLT, and a nearly 75% incidence of sleep-onset REM periods during MSLT naps. Table 2 classifies the narcoleptic patients according to types of REM sleep motor disturbances. Males were affected preferentially, and most age groups were represented. There was strong expression of the narcolepsy tetrad: 47% (8/17) had the full tetrad, 88.2% (15/17) had cataplexy, 52.9% (9117) had sleep paralysis, and 58.8% (10/17) had hypnagogic hallucinations. Six (42.8%) of the 14 adult patients suffered work disability on account of the narcolepsy. REM sleep without atonia and excessive REM sleep limb twitching were seen in the non-RBD group either separately or together (see Table 2). In the RBD group, 6 patients (5 males) had preserved submental EMG atonia throughout most of their REM sleep periods despite repeated intrusions of complex and vigorous behaviors, while 4 patients ( 3 males) had augmented submental EMG tone throughout most of their REM sleep periods. These two subgroups of RBD did not differ in mean age: 40.7 21.2 years (standard deviation), and 36.0 f 21.5 years (t test, not significant). Of the 3 patients receiving stimulants and tricyclics, 2 had preservation of and 1 had loss of REM sleep atonia. Figure 1 indicates how bursts of limb EMG twitching during REM sleep can occur either with intact submental EMG atonia or with augmented submental EMG tone. Figure 2 reveals a prominent form of motor dyscontrol during REM sleep in a 13-year-old boy (Patient 5) whose mother had noticed frequent irregular jerking movements of his arms, legs, and head during sleep. However, he did not meet the criteria for RBD because he had no history of sleep disruption or of sleeprelated injury. During PSG studies, patients with RBD displayed complex, vigorous, or violent behaviors ( e g , punching or kicking) within REM sleep, and not during arousals from REM sleep. RBD behaviors reported by history
*
Table 1. Multiple Sleep Latency Test (MSLT) Data in 17 Consecutive Patients with Narcolepsy and REM Sleep Motor Dyscontrol Category of REM Sleep Motor Dyscontrol
MSLT Mean (2SD) Sleep Latency (min)
Sleep-Onset REM Periods/ Total MSLT Nap Opportunities"
= 7) (tonic and/or phasic electromyographic abnormalities) 11. RBD (n = 10) 111. Total (n = 17)
3.0 (21.1)
21/23 (91.3%Ib
4.2 (*3.4) 3.7 ('2.7)
29/45 (64.4%) 50/68 (73.5%)b
I. Non-RBD (n
"The MSLT for each patient consisted of 4 or 5 nap opportunities. bData from 2 patients were excluded from this analysis because of ambiguous REM-NREM sleep boundaries.
RBD = REM sleep behavior disorder.
4 Annals of Neurology Vol 32 No 1 July 1992
Table 2. Clinical Data from 17 Narcoleptic Patients at the Time of Polysomnographic Documentation of REM Sleep Motor Dyscontrol Category of REM Sleep Motor Dyscontrol
Patient No.
I. Non-RBD (n = 7 ) a. Loss of sub-
Female Female Male Male
mental EMG atonia
b. Excessive limb EMG twitching c. Loss of submental EMG atonia and excessive limb EMG twitching Mean 2 SD 11. RBD (n = 10)
Male Female
Male
57.1% ( 4/7)b 8
Male
9
Male Male Male
10 11 12 13 14 15 16 17 Mean ? SD Total
Sex
Female Female Male Male
Male Male 80.0% ( 8/10)b 70.6% (12117)b
Age (yr)
Age at Narcolepsy Onset (yr)
Narcolepsy Tetrad” (no. of features present)
23 46 8 45 13 49 53
21 16 8 18 11 19 13
114 314 214 414 214 414 414
33.8 ( 218.6) 12 17 19 24 37 42 45 46 63 74 37.9 ( k 2 0 . 3 ) 36.2 (k19.2)
15.1 (k 4.7) 12 14 17 19 19 13 41 16 18 59 22.8 ( k 1 5 . 1 ) 19.6 ( 2 1 2 . 3 )
2.914.0 (21.2) 214 314 414 214 414 414 414 414 214 214 3.114.0 ( k 1 . 0 ) 3.014.0 (rl.1)
‘Excessive somnolence, cataplexy, sleep paralysis, and hypnagogic hallucinations. All (17/ 17) of the patients had excessive somnolence. bPercentageof males (no. of males/totaI).
RBD = REM sleep behavior disorder; EMG = electromyographic.
included running in bed; using a wrestling maneuver (hammerlock) on a spouse; “clawing” at a spouse on the abdomen, causing deep lacerations; repeated kicking and elbowing; arm waving; talking or arguing during sleep; and other behaviors that often represented attempted dream enactments. Treatment of narcolepsy-cataplexy either induced or aggravated Rl3D in 3 patients: nortriptyline, 100 mg/ day, and methylphenidate, 35 mg/day (Patient 12); imipramine, 225 mg/day, and methylphenidate, 110 mg/day (Patient 13); and imipramine, 30 mg/day, and pemoline, 112 mg/day (Patient 14). The mean age at RBD onset was 28.4 (k17.3) years. RBD emerged in tandem with narcolepsy in 5 patients, and early in the course of narcolepsy in 3. The 10 patients with narcolepsy and RBD comprised 12.5% of 80 consecutive patients with RBD, with narcolepsy and neurodegenerative disorders being the most frequently identified medical disorders etiologically associated with RBD at our sleep disorders center (C. H. Schenck, M. W. Mahowald, unpublished data, 1991). Table 3 presents the first-night PSG data for the 13 mmedicated patients. These data for the RBD and non-RBD groups were not significantly different. The distribution of sleep stages was unremarkable, apart from an increased proportion of stage 1 sleep and a mild reduction in sleep efficiency. The REM sleep latency was very brief, consistent with narcolepsy. The
customary cycling among NREM and REM sleep stages [36} occurred in each patient. Short periods of ambiguous NREM-REM sleep were commonly found (e.g., sudden intrusions of submental EMG atonia or REMs into NREM sleep). The 4 patients receiving medications, who are not included in Table 3, had substantial sleep disruption, decreased REM sleep percentage, and prolonged REM sleep latencies during their PSG studies. Periodic limb movements of NREM sleep, usually associated with arousals, were present in 58.8% (10117) of the patients. The mean PMS index (i.e., limb movements per hour) for NREM periodic limb movements was 29.4 (k18.7). Patients with NREM periodic movements (n = 10) were not significantly different in age from patients without NREM periodic movements (n = 7) (two-tailed t test: mean age, 42.7 k 20.1 versus 27.0 % 14.3 years; t = 1.77, df = 15, not significant). Comparison of NREM periodic limb movements in the non-RF3D and RBD groups revealed a similar prevalence (4/7 and 6/10) and mean hourly index (34.5 k 27.7 and 26.0 k 12.4; t test, not significant). The prevalence of NREM periodic limb movements with narcolepsy in this series was consistent with that in previous reports [lo-131. Mild obstructive sleep apnea, with minimal oxygen desaturation, was present in 11.8% (2/17) of patients. Sleep walking and sleep terror (consisting of complex
Schenck and Mahowald: Narcolepsy and REM Behavior Disorder
5
D.E. 3-6-90 45 y.0. male
3-6-90 45 y.0. male
A Fig I . (A)REM sleep polysomnogramfrom a man with narcolepsy and REM sleep behavior disorder. Intense electromyographic (EMG) twitching of the lower extremities (12- 15) and dense REMs in the electrooculogram (1, 2 ) are present throughout the tracing despite preservation of background REM sleep atonia in the submental EMG (7). 8 , 10 = lejt and right extensor digitorum EMG; 9,11 = ldt and right jexor digitorum EMG; 12, 14 = ldt and right anterior tibialis EMG; 13, 15 = ldt and right posterior tibialis EMG. (B) Polysomnogram from 2 hours after that in A, during a subsequent REM sleep period. Bursts of EMG twitching of the limbs (10-1 5)-which in A had appeared during submental EMG atonia-now emerge during an interval of augmented tone (i.e., loss of REM sleep atonia) in the submental EMG (71,with superimposed phasic twitching ( 7 , arrow).
behaviors and/or screaming arising abruptly from NREM sleep 121) were never detected. Nocturnal psychogenic dissociative disorder (consisting of elaborate behaviors arising from sustained EEG wakefulness after awakenings from epochs of NREM or REM sleep 137, 38)) likewise was not suggested by any PSG study. In 7 patients monitored with a seizure montage during PSG studies, neither EEG epileptiform nor clinical seizure activity was detected. The findings on neurological and general physical examinations were unremarkable, and no patient had a history of neurological disorder, other than narcolepsy, except 1 patient (Patient 2) who had a subarachnoid hemorrhage 12 years after the onset of narcolepsy. This patient had the HLA-DR2/DQwl haplotype. Valproic acid had been prescribed subsequent to the subarachnoid hemorrhage on account of recurrent confusional episodes. Patient 8 had HLA typing because of the fulminance of the onset of narcolepsy, and was found to have the DR2/DQwl haplotype. 6 Annals of Neurology Vol 32 No 1 July 1992
12) L. Ant. Tib. EMG 13) L. Post. Tib. EMG 14) R. Ant. Tib. EMG 15) I?.Post. Tib. EMG 16) EKG -IrJsJ7-lr-t”cJc-t-w 17) Nasal-Oral Airflow - 0 5
B
Discussion Narcolepsy and REM Sleep Behavior Disorder This report identifies RBD as another category of
REM sleep motor dyscontrol that can be closely associated with narcolepsy and its treatment. A chance association between RBD and narcolepsy is unlikely, since RBD is uncommon and rarely begins before the sixth decade 12, 28), whereas the mean age at RBD onset in patients with narcolepsy in this report was only 28.4 years. Furthermore, the male preponderance in this series is typical for RBD 12, 281, but is atypical for narcolepsy El-41. The treatment of narcolepsy-cataplexy apparently induced or promoted RBD in 3 patients who were receiving tricyclic antidepressants and stimulants. Clomipramine, a tricyclic antidepressant, has been reported to induce REM sleep without submental EMG atonia in narcoleptics 114, 15, 171. Clomipramine treatment of narcolepsy-cataplexy has also induced violent limb jerking during REM sleep, despite
3-4-91 13 y.0. male 1) 2)
3) 7) L Ant l i b EMG 8) R An1 l i b EMG -
-
A 3-4-91 13 Y.O. male
L
6) Submental EMG 7) L Ant Tib EMG 8) R Ant Tib EMG
Fig 2. (A) The first of three sequentialpolysomnograms covering an interval of 90 seconds during REM sleep in a narcoleptic boy. REM sleep is characterized by REMs in the electrooculogram (1, 2), and by a desynchronized,fast-frequency, activated electroencephalogram(EEG) (3-5). However, the customary background atonia of REM sleep in the submental electromyogram (EMG) is interrupted episodically by excessive twitching (6). Phasic dyscontrol in REM sleep is also indicated by the prominent, bilateral anterior tibialis twitch activity (7, 8). (B) Initially, there is complete release from REM sleep atonia which lasts 10 seconds and is marked by high-amplitudeaugmentation of background tone in the submental EMG (6, large arrow). REM sleep atonia emerges abruptly and persists for 4 seconds (6, bracket). Intrusion of excessive twitching then occurs, primarily in the submental EMG (6, small arrow). (C) The EMG pattern present in B is now fully reversed, as REM sleep atonia is continuously maintained throughout the submental EMG (61, despite the presence of dense, highamplitude twitcbing of the ltft anterior tibialis (7).
Table 3. Sleep Architecture Data from Nocturnal PolysomnographicStudies Documenting REM Sleep Motor Dyscontrol in 13 Unmedicated Narcoleptic Patients” Totalb (n = 13)
Sleep Parameters
Non-RBD (n = 6)
RBD (n
1. Total sleep time (min) 2. Sleep efficiency (% of total sleep time/time in bed) 3. Stage 1 (% of total sleep time) 4. Stage 2 (% of total sleep time) 5. Stage 314 (% of total sleep time) 6. Stage REM (% of total sleep time) 7. REM sleep latency (min) 8. No. of awakenings (260 sec)
402.5 (k127.8) 84.3‘ (2 7.7)
455.7 (rt70.1) 89.8 (2 5.5)
431.1 (L107.8) 87.5‘ (L 7.7)
10.7 (a 7.4) 45.8 (* 6.7) 20.3 ( 2 7.1) 23.2 (k 10.8) 23.2 (f 28.6) 14.5 (2 8.3)
12.6 (% 7.7) 43.1 (*10.5) 17.7 (2 5.1) 26.4 (211.7) 36.8 (L 8.3) 7.8 (? 3.1)
11.7 (L 8.5) 44.3 (2 8.7) 17.0 (L 5.9) 24.9 (2 11.0) 30.5d (e33.0) 10.7 (* 6.9)
=
7)
“Mean age, 34.3 (k21.6) yr; range, 8-74 yr; males, 84.6% (11/13).Data were obtained from first-night polysomnographic studies. All data are means -C SD. bStudent’st test did not reveal significant differences in sleep parameter scores between the two groups. outlying sleep efficiency score of 44.7% was excluded from this analysis. dRange of REM latency, 2.5-70.0 min.
RED = REM sleep behavior disorder.
Schenck and Mahowald: Narcolepsy and REM Behavior Disorder
7
maintenance of submental EMG atonia 1161. The mechanisms by which clomipramine can promote RBD are unknown. Three patients in this study were receiving methylphenidate, pemoline, or valproic acid at the time of their PSG and MSLT studies. None of these medications is known to reduce REM sleep latency or to induce REM sleep motor abnormalities 137-46). Childhood-onset RBD has been reported in 4 patients, all associated with a neurological disorder, including 3 with brainstem involvement 125, 47-50). The case of Patient 8 in this report identifies narcolepsy as another neurological disorder presenting with childhood RBD. The 7 patients without RBD listed in Table 2 may be at risk for developing frank RBD, since they all displayed prominent tonic and/or phasic PSG abnormalities during REM sleep, and since it is known that RBD can be preceded by a lengthy prodrome of sleep motor dyscontrol c28). Thus, these non-RBD forms of motor dyscontrol during REM sleep may be considered as “subclinical RBD’ and are most likely symptoms of narcolepsy (and its treatment), since they have been a very uncommon finding at our center 151). The most extreme form of sleep-related motor dyscontrol in narcolepsy involves prolonged behavioral release with a complete loss of recognizable sleep-wake state markers throughout nocturnal PSG monitoring 152). This phenomenon, “status dissociatus,” extends the concept of narcolepsy as a disorder of “state boundary control” in which the physiological components of REM and NREM sleep can become inappropriately admixed or can repeatedly intrude into wakefulness c3, 531. Tonic and Phasic REM Sleep Processes and the Pathophysiology of REM Sleep Behavior Disorder Separate brainstem control mechanisms underlying the tonic (continuous) and phasic (intermittent) processes of REM sleep have been identified 154-59). A recent study in dogs revealed colocdzation of the atonia and locomotor systems of REM sleep in the pons [60), providing an anatomical basis for the dysregulation of these two systems in RBD. Furthermore, suprapontine structures may also influence REM sleep atonia 1611, which may be relevant to human RBD whose associated neuropathology, when present, primarily involves iuprapontine regions 128). RJ3D may result primarily ?om excessive excitation of locomotor systems activated during REM sleep 162-641, which can become sufficiently powerful as to overcome the preserved customary atonia of REM sleep (as shown in Figs l A , 2C), although loss of REM sleep atonia probably facilitates the release of RBD behaviors. REM sleep without atonia was previously found not only in narcoleptics receiving clomipramine, but also 8 Annals of Neurology Vol 32 No 1 July 1992
in (1) non-narcoleptics receiving clomipramine, various other tricyclic antidepressants, phenelzine, or fluoxetine 114, 17, 65-69]; and in ( 2 ) patients with parlunsonism and Shy-Drager syndrome C70, 711. An animal model of RBD that exists involves dorsolateral pontine tegmental lesions 163, 72). Four categories of RBD behaviors were found in this model, with the location and extent of the pontine lesions determining the category of released behaviors [63]: (1) a minimal syndrome of REM sleep without atonia accompanied by minor movements, (2) orienting and exploratory behaviors, ( 3 ) fighting behaviors, and ( 4 ) locomotion. The behavioral repertoire of human Rl3D is identical among its various clinical populations (idiopathic, neurological), and also mirrors the repertoire found in animals with experimental Rl3D 163, 72) or with clinical RBD (idiopathic, neurological) 173, 74). This suggests that final common pathways exist for behavioral release in mammalian RBD. In conclusion, narcoleptic patients should be questioned about disturbed sleep and dream-related behaviors at the time of initial diagnosis and throughout the course of treatment, especially since clonazepam is very effective in controlling RBD 128). This work was supported in part by a grant from Hennepin Faculty Associates. We acknowledge the ongoing contributions of Scott R. Bundlie, MD, Gerald Rosen, MD, Thomas D. Hurwitz, MD, Andrea L. Patterson, RPSGT, and Jan Schluter, RN, and are indebted to Susan Phelps and Traci Oletzke for their secretarial support. Robert Sherman, PhD, provided statistical assistance. Presented at the third annual meeting of the Association of Professional Sleep Societies, Washington, DC, June 23, 1989.
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characteristics of healthy elderly subjects with somnambulismlike behaviors. Biol Psychiatry 1991;30:4-14 3 1. Rechtschaffen A, Kales AA. A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. Bethesda, MD: National Institute of Neurological Diseases and Blindness, 1968 32. Richardson GS, Carskadon MA, Flagg W, et al. Excessive daytime sleepiness in man: multiple sleep latency measurement in narcoleptic and control subjects. Electroencephalogr Clin Neuroph ysiol 1978;45:62 1-62 7 33. Langdon N, Welsh KI, Van Dam M, et al. Genetic markers in narcolepsy. Lancet 1984;2:1178-1180 34. Billiard M, Seignalet J, Besset A, Cadilhac J. HLA-DR2 and narcolepsy. Sleep 1986;9:149-1 52 35. Guilleminault C, Mignot E, Gnunet FC. Familial patterns of narcolepsy. Lancet 1989;2:1376- 1379 36. Carskadon MA, Dement WC. Normal human sleep: an overview. In: Kryger MH, Roth T, Dement WC, eds. Principles and practice of sleep medicine. Philadelphia: WB Saunders, 1989: 3-13 37. Schenck CH, Milner DM, Hurwin TD, et al. A polysomnographic and clinical report on sleep-related injury in 100 adult patients. Am J Psychiatry 1989;146:1166-1173 38. Schenck CH, Milner DM, Hurwitt TD, et al. Dissociative disorders presenting as somnambulism: polysomnographic, video and clinical documentation (8 cases). Dissociation 1989;2:194-204 39. Haig JR, Schroeder CS, Schroeder SR. Effects of methylphenidate on hyperactive children's sleep. Psychopharmacologia 1974;37:185-188 40. Nahas AD, Krynicki V. Effect of merhylphenidate on sleep stages and ultradian rhythms in hyperactive children. J Nerv Ment Dis 1977;164:66-69 41. Okuma T, Honda H . Model insomnia, noise, and methylphenidate, used for the evaluation of hypnotic drugs. PsychopharmaCology 1978;57: 127- 132 42. Okuma T, Matsuoka H , Matsue Y, Toyomura K. Model insomnia by methylphenidate and caffeine and use in the evaluation of temazepam. Psychopharmacology 1982;76:201-208 43. Greenhill L, Puig-Antich J, Goetz R, et al. Sleep architecture and REM sleep measures in prepubertal children with attention deficit disorder with hyperactivity. Sleep 1983;6:91-101 44. Nicholson AN, Stone BM, Jones MMC. Wakefulness and reduced rapid eye movement sleep: studies with prolintane and pemoline. Br J Clin Pharmacol 1980;10:465-472 45. Puca FM, Genco S, Minervini MG, et al. I1 sonno di coreici cronici dopo terapia con valproato di sodio. Boll SOCItal Biol Sper 1984;60:989-992 46. Pies R, Adler DA, Ehrenberg BL. Sleep disorders and depression with atypical features: response to valproate. J Clin Psychopharmacol 1989;9:352-3 5 7 47. Barros-Ferreira M, Chodkiewicz J-P, Lairy GC, Salzarulo P. Disorganized relations of tonic and phasic events of REM sleep in a case of brain-stem tumour. Electroencephalogr Clin Neurophysiol 1975;38:203-207 48. Schenck CH, Bundlie SR, Smith SA, et al. REM behavior disorder in a 10 year old girl and aperiodic REM and NREM deer movements in an 8 year old brother. Sleep Res 1986;15:162 49. Herman JH, Blaw ME, Steinberg JB. REM behavior disorder in a two year old male with evidence of brainstem pathology. Sleep Res 1989;18:242 50. Blaw ME, Leroy RF, Steinberg JB, Herman J. Hereditary quivering chin and REM behavioral disorder. Ann Neurol 1989; 26:471 5 1. Schenck CH, Mahowald MW. Pre-clinical tonic and phasic REM motor disturbances in 19 patients. Sleep Res 1991;20322 52. Mahowald MW, Schenck CH. Status dissociams-a perspective on states of being. Sleep 1991;14:69-79
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10 Annals of Neurology Vol 32 No 1 July 1992
64. Morrison AR. Paradoxical sleep without atonia. Arch Ital Biol 1988;126:275-289 65. Akindele MO, Evans JI, Oswald I. Mono-amine oxidase inhibitors, sleep and mood. Electroencephalogr Clin Neurophysiol 1970;29:47-56 66. Dunleavy DLF, Bretinova V, Oswald I, et al. Changes during weeks in effects of tricyclic drugs on the human sleeping brain. Br J Psychiatry 1972;120:663-672 67. k e y JH, Crisp AH, Crutchfield M, et al. Clomipramine and sleep: a preliminary communication. Postgrad Med J 1977; 5 ~(SUPPI 4):35-40 68. Shimizu T, Ookawa M, Iijima S, et al. Effect of clomipramine on nocturnal sleep of normal human subjects. Ann Rep Pharmacopsychiatr Res Found (Jpn) 1985;16:138 69. Schenck CH, Mahowald MW, Kim SW, et al. Prominent eye movements during NREM sleep and REM sleep behavior disorder associated with fluoxetine treatment of depression and obsessive-compulsive disorder. Sleep 1992 (in press) 70. Mouret J. Differences in sleep in patients with Parkinson’s disease. Electroencep halogr Clin Neurophysiol 1975 ;38:6 5 3-6 5 7 71. Jouvet M, Sastre J-P, Sakai K. Toward an etho-ethnology of dreaming. In: Karacan I, ed. Psychophysiological aspects of sleep. Park Ridge, NJ: Noyes Medical Publications, 1981: 204-2 14 72. Jouvet M, Delorme F. Locus coeruleus et sommeil paradoxal. C R Soc Biol (Paris) 1965;159:895-899 73. Hendricks JC, Morrison AR, Farnbach GL, et al. A disorder of rapid eye movement sleep in a cat. J Am Vet Med Assoc 1981;178:55-57 74. Hendricks JC, Lager A, OBrien D, Morrison AR. Movement disorders during sleep in cats and dogs. J Am Vet Med Assoc 1989;194:686-689
Motor Dyscontrol in Narcolepsy: Rapid-Eye-Movement (REM) Sleep without Atonia and REM Sleep Behavior Disorder Carlos H. Schenck, MD,” and Mark W. Mahowald, MD-F
Narcolepsy involves abnormalities of rapid-eye-movement (REM) sleep, including a short latency to the onset of REM sleep, hypnagogic hallucinations, and sleep paralysis. In addition, persistence of muscle tone by electromyographic criteria or excessive muscle twitching during REM sleep or both have been’reported in treated and untreated narcoleptic patients. We report that another previously described abnormality of REM sleep, REM sleep behavior disorder, may also be a symptom of narcolepsy. This disorder was found in 10 narcoleptic patients during routine clinical evaluations involving polysomnography and multiple sleep latency tests. During REM sleep, 7 additional narcoleptic patients displayed persistent muscle tone and/or excessive twitching, which we believe to be subclinical components of REM sleep behavior disorder. These 17 patients, diagnosed by established criteria for narcolepsy and for REM sleep behavior disorder, ranged in age from 8 to 74 years. Seventy-one percent were male. Narcolepsy and REM sleep behavior disorder most commonly emerged in tandem. In 3 patients, treatment of narcolepsy-cataplexy with stimulants and tricyclics either induced or exacerbated REM sleep behavior disorder. Schenck CH, Mahowald MW. Motor dyscontrol in narcolepsy: rapid-eye-movement (REM) sleep without atonia and REM sleep behavior disorder. Ann Neurol 1992;32:3-10
Narcolepsy El-4) is a syndrome characterized by excessive daytime sleepiness, cataplexy {5-71, sleep paralysis, and hypnagogic hallucinations 15, 6, 8, 9). Abnormalities of rapid-eye-movement (REM) sleep and of motor control are common in narcolepsy: The latency to the onset of REM sleep is usually very short. Sleep paralysis and hypnagogic hallucinations are frequent and represent the intrusion of REM sleep into wakefulness or light sleep {6). Motor dyscontrol may involve not only cataplexy and sleep paralysis, but also (1) periodic limb movements during non-rapideye-movement (NREM) sleep and during REM sleep [lo-131, and (2) persistence of electromyographic (EMG) tone throughout REM sleep (i.e., REM sleep without atonia) and/or excessive aperiodic EMG twitching during REM sleep in patients with untreated narcolepsy or in patients receiving clomipramine treatment for cataplexy E13-20). We now present data suggesting that the “REM sleep behavior disorder” (RBD) can also be associated with narcolepsy. RBD is a form of motor dyscontrol characterized by complex, vigorous, and frequently violent, dream-enacting behaviors during REM sleep. It
From the Minnesota Regional Sleep Disorders Center, the *Department of Psychiatry, and the tDepartment of Neurology, Hennepin County Medical Center and the University of Minnesota Medical
School, Minneapolis, MN. Received May 9, 1991, and in revised form Sep 4, Nov 12, and Dec 4. Accepted for publication Dec 6, 1991.
may be idiopathic or symptomatic of diverse neurological disorders, and usually affects older men [Z, 2 1-30).
Patients and Methods Over a 4.5-year period (1986-1991), clinical polysomnographic (PSG) evaluations at our sleep disorders center identified 17 narcoleptic patients with extensive motor dysregulation during REM sleep. Ten of these patients met established criteria for RBD [2, 251. The 17 patients comprised nearly 12% of all narcoleptics undergoing PSG studies during that period. The chief complaint pertained to RBD and narcolepsy jointly in 35.396 (6/17) and to narcolepsy primarily in 64.7% (11/17) of patients. RBD complaints typically concerned sleep-related injuries (ecchymoses, lacerations). Narcolepsy complaints were related to excessive daytime sleepiness and cataplexy. All patients (usually with family members) were interviewed by staff physicians at our center, completed comprehensive medical and sleep-wake questionnaires, and underwent neurological and other clinical examinations. Standard methods were employed in recording and scoring the PSG studies [311, with allowance for intermittent or persistent loss of REM sleep atonia, including electrooculography, submental and anterior tibialis EMG (and occasionally
Address correspondence to Dr Schenck, Minnesota Regional Sleep Disorders Center, Department of Psychiatry (844), Hennepin County Medical Center, 701 Park Ave South, Minneapolis, MN 55415.
Copyright 0 1992 by the American Neurological Association 3
posterior tibialis, and extensor and flexor digitorum EMG), electroencephalography (EEG) (C, and C4 sleep stage scoring channels, and also a seizure montage [F,-T3, T,-T,, T5-01, F8-T4, T4-T6, T6-02,F,-P,, F4-P4] with faster paper speeds of 15 and 30 mm/sec in 43.79% [7/17) of patients), electrocardiography (EKG), nasal-oral airflow determinations using thermistors, and more extensive apnea monitoring (respiratory effort by inductance plethysmography and hemoglobin oxygen saturation by oximetry) whenever indicated. All PSG studies were continuously videotaped. Patients were free of psychoactive medication for at least 10 days prior to the PSG studies, with four exceptions reported below. Each patient completed a multiple sleep latency test (MSLT) according to established procedures E32J The diagnostic criteria for RBD [25] included: 1. PSG abnormality during REM sleep: elevated submental EMG tone and/or excessive phasic submental and/or limb EMG twitching. 2. Documentation of abnormal REM sleep behaviors during PSG studies (prominent limb or truncal jerking; complex, vigorous, or violent behaviors), or a history of injurious or disruptive sleep behaviors.
All patients satisfied strict criteria for narcolepsy E12) by the presence of at least three of the following:
1. Definite history of excessive daytime sleepiness. 2. Definite history of cataplexy. 3. Mean sleep latency index of less than 5 minutes on the MSLT.
4. Two or more sleep-onset REM periods on the MSLT; or one or more sleep-onset REM period on nocturnal PSG study (i.e., appearance of REM sleep within 20 minutes of sleep onset), and one or more sleep-onset REM period on the MSLT. The diagnostic criteria for both RBD and narcolepsy listed above conform to the criteria contained in the current international classification of sleep disorders [2].Although narcolepsy has been strongly associated with the HLA-DR2/ DQwl haplotype [33-351, human leukocyte antigen (HLA) typing was not routinely performed since all subjects met the clinical, PSG, and MSLT criteria for narcolepsy.
Results Table 1 documents the diagnosis of narcolepsy in our patients. There was a short mean sleep latency o n the MSLT, and a nearly 75% incidence of sleep-onset REM periods during MSLT naps. Table 2 classifies the narcoleptic patients according to types of REM sleep motor disturbances. Males were affected preferentially, and most age groups were represented. There was strong expression of the narcolepsy tetrad: 47% (8/17) had the full tetrad, 88.2% (15/17) had cataplexy, 52.9% (9117) had sleep paralysis, and 58.8% (10/17) had hypnagogic hallucinations. Six (42.8%) of the 14 adult patients suffered work disability on account of the narcolepsy. REM sleep without atonia and excessive REM sleep limb twitching were seen in the non-RBD group either separately or together (see Table 2). In the RBD group, 6 patients (5 males) had preserved submental EMG atonia throughout most of their REM sleep periods despite repeated intrusions of complex and vigorous behaviors, while 4 patients ( 3 males) had augmented submental EMG tone throughout most of their REM sleep periods. These two subgroups of RBD did not differ in mean age: 40.7 21.2 years (standard deviation), and 36.0 f 21.5 years (t test, not significant). Of the 3 patients receiving stimulants and tricyclics, 2 had preservation of and 1 had loss of REM sleep atonia. Figure 1 indicates how bursts of limb EMG twitching during REM sleep can occur either with intact submental EMG atonia or with augmented submental EMG tone. Figure 2 reveals a prominent form of motor dyscontrol during REM sleep in a 13-year-old boy (Patient 5) whose mother had noticed frequent irregular jerking movements of his arms, legs, and head during sleep. However, he did not meet the criteria for RBD because he had no history of sleep disruption or of sleeprelated injury. During PSG studies, patients with RBD displayed complex, vigorous, or violent behaviors ( e g , punching or kicking) within REM sleep, and not during arousals from REM sleep. RBD behaviors reported by history
*
Table 1. Multiple Sleep Latency Test (MSLT) Data in 17 Consecutive Patients with Narcolepsy and REM Sleep Motor Dyscontrol Category of REM Sleep Motor Dyscontrol
MSLT Mean (2SD) Sleep Latency (min)
Sleep-Onset REM Periods/ Total MSLT Nap Opportunities"
= 7) (tonic and/or phasic electromyographic abnormalities) 11. RBD (n = 10) 111. Total (n = 17)
3.0 (21.1)
21/23 (91.3%Ib
4.2 (*3.4) 3.7 ('2.7)
29/45 (64.4%) 50/68 (73.5%)b
I. Non-RBD (n
"The MSLT for each patient consisted of 4 or 5 nap opportunities. bData from 2 patients were excluded from this analysis because of ambiguous REM-NREM sleep boundaries.
RBD = REM sleep behavior disorder.
4 Annals of Neurology Vol 32 No 1 July 1992
Table 2. Clinical Data from 17 Narcoleptic Patients at the Time of Polysomnographic Documentation of REM Sleep Motor Dyscontrol Category of REM Sleep Motor Dyscontrol
Patient No.
I. Non-RBD (n = 7 ) a. Loss of sub-
Female Female Male Male
mental EMG atonia
b. Excessive limb EMG twitching c. Loss of submental EMG atonia and excessive limb EMG twitching Mean 2 SD 11. RBD (n = 10)
Male Female
Male
57.1% ( 4/7)b 8
Male
9
Male Male Male
10 11 12 13 14 15 16 17 Mean ? SD Total
Sex
Female Female Male Male
Male Male 80.0% ( 8/10)b 70.6% (12117)b
Age (yr)
Age at Narcolepsy Onset (yr)
Narcolepsy Tetrad” (no. of features present)
23 46 8 45 13 49 53
21 16 8 18 11 19 13
114 314 214 414 214 414 414
33.8 ( 218.6) 12 17 19 24 37 42 45 46 63 74 37.9 ( k 2 0 . 3 ) 36.2 (k19.2)
15.1 (k 4.7) 12 14 17 19 19 13 41 16 18 59 22.8 ( k 1 5 . 1 ) 19.6 ( 2 1 2 . 3 )
2.914.0 (21.2) 214 314 414 214 414 414 414 414 214 214 3.114.0 ( k 1 . 0 ) 3.014.0 (rl.1)
‘Excessive somnolence, cataplexy, sleep paralysis, and hypnagogic hallucinations. All (17/ 17) of the patients had excessive somnolence. bPercentageof males (no. of males/totaI).
RBD = REM sleep behavior disorder; EMG = electromyographic.
included running in bed; using a wrestling maneuver (hammerlock) on a spouse; “clawing” at a spouse on the abdomen, causing deep lacerations; repeated kicking and elbowing; arm waving; talking or arguing during sleep; and other behaviors that often represented attempted dream enactments. Treatment of narcolepsy-cataplexy either induced or aggravated Rl3D in 3 patients: nortriptyline, 100 mg/ day, and methylphenidate, 35 mg/day (Patient 12); imipramine, 225 mg/day, and methylphenidate, 110 mg/day (Patient 13); and imipramine, 30 mg/day, and pemoline, 112 mg/day (Patient 14). The mean age at RBD onset was 28.4 (k17.3) years. RBD emerged in tandem with narcolepsy in 5 patients, and early in the course of narcolepsy in 3. The 10 patients with narcolepsy and RBD comprised 12.5% of 80 consecutive patients with RBD, with narcolepsy and neurodegenerative disorders being the most frequently identified medical disorders etiologically associated with RBD at our sleep disorders center (C. H. Schenck, M. W. Mahowald, unpublished data, 1991). Table 3 presents the first-night PSG data for the 13 mmedicated patients. These data for the RBD and non-RBD groups were not significantly different. The distribution of sleep stages was unremarkable, apart from an increased proportion of stage 1 sleep and a mild reduction in sleep efficiency. The REM sleep latency was very brief, consistent with narcolepsy. The
customary cycling among NREM and REM sleep stages [36} occurred in each patient. Short periods of ambiguous NREM-REM sleep were commonly found (e.g., sudden intrusions of submental EMG atonia or REMs into NREM sleep). The 4 patients receiving medications, who are not included in Table 3, had substantial sleep disruption, decreased REM sleep percentage, and prolonged REM sleep latencies during their PSG studies. Periodic limb movements of NREM sleep, usually associated with arousals, were present in 58.8% (10117) of the patients. The mean PMS index (i.e., limb movements per hour) for NREM periodic limb movements was 29.4 (k18.7). Patients with NREM periodic movements (n = 10) were not significantly different in age from patients without NREM periodic movements (n = 7) (two-tailed t test: mean age, 42.7 k 20.1 versus 27.0 % 14.3 years; t = 1.77, df = 15, not significant). Comparison of NREM periodic limb movements in the non-RF3D and RBD groups revealed a similar prevalence (4/7 and 6/10) and mean hourly index (34.5 k 27.7 and 26.0 k 12.4; t test, not significant). The prevalence of NREM periodic limb movements with narcolepsy in this series was consistent with that in previous reports [lo-131. Mild obstructive sleep apnea, with minimal oxygen desaturation, was present in 11.8% (2/17) of patients. Sleep walking and sleep terror (consisting of complex
Schenck and Mahowald: Narcolepsy and REM Behavior Disorder
5
D.E. 3-6-90 45 y.0. male
3-6-90 45 y.0. male
A Fig I . (A)REM sleep polysomnogramfrom a man with narcolepsy and REM sleep behavior disorder. Intense electromyographic (EMG) twitching of the lower extremities (12- 15) and dense REMs in the electrooculogram (1, 2 ) are present throughout the tracing despite preservation of background REM sleep atonia in the submental EMG (7). 8 , 10 = lejt and right extensor digitorum EMG; 9,11 = ldt and right jexor digitorum EMG; 12, 14 = ldt and right anterior tibialis EMG; 13, 15 = ldt and right posterior tibialis EMG. (B) Polysomnogram from 2 hours after that in A, during a subsequent REM sleep period. Bursts of EMG twitching of the limbs (10-1 5)-which in A had appeared during submental EMG atonia-now emerge during an interval of augmented tone (i.e., loss of REM sleep atonia) in the submental EMG (71,with superimposed phasic twitching ( 7 , arrow).
behaviors and/or screaming arising abruptly from NREM sleep 121) were never detected. Nocturnal psychogenic dissociative disorder (consisting of elaborate behaviors arising from sustained EEG wakefulness after awakenings from epochs of NREM or REM sleep 137, 38)) likewise was not suggested by any PSG study. In 7 patients monitored with a seizure montage during PSG studies, neither EEG epileptiform nor clinical seizure activity was detected. The findings on neurological and general physical examinations were unremarkable, and no patient had a history of neurological disorder, other than narcolepsy, except 1 patient (Patient 2) who had a subarachnoid hemorrhage 12 years after the onset of narcolepsy. This patient had the HLA-DR2/DQwl haplotype. Valproic acid had been prescribed subsequent to the subarachnoid hemorrhage on account of recurrent confusional episodes. Patient 8 had HLA typing because of the fulminance of the onset of narcolepsy, and was found to have the DR2/DQwl haplotype. 6 Annals of Neurology Vol 32 No 1 July 1992
12) L. Ant. Tib. EMG 13) L. Post. Tib. EMG 14) R. Ant. Tib. EMG 15) I?.Post. Tib. EMG 16) EKG -IrJsJ7-lr-t”cJc-t-w 17) Nasal-Oral Airflow - 0 5
B
Discussion Narcolepsy and REM Sleep Behavior Disorder This report identifies RBD as another category of
REM sleep motor dyscontrol that can be closely associated with narcolepsy and its treatment. A chance association between RBD and narcolepsy is unlikely, since RBD is uncommon and rarely begins before the sixth decade 12, 28), whereas the mean age at RBD onset in patients with narcolepsy in this report was only 28.4 years. Furthermore, the male preponderance in this series is typical for RBD 12, 281, but is atypical for narcolepsy El-41. The treatment of narcolepsy-cataplexy apparently induced or promoted RBD in 3 patients who were receiving tricyclic antidepressants and stimulants. Clomipramine, a tricyclic antidepressant, has been reported to induce REM sleep without submental EMG atonia in narcoleptics 114, 15, 171. Clomipramine treatment of narcolepsy-cataplexy has also induced violent limb jerking during REM sleep, despite
3-4-91 13 y.0. male 1) 2)
3) 7) L Ant l i b EMG 8) R An1 l i b EMG -
-
A 3-4-91 13 Y.O. male
L
6) Submental EMG 7) L Ant Tib EMG 8) R Ant Tib EMG
Fig 2. (A) The first of three sequentialpolysomnograms covering an interval of 90 seconds during REM sleep in a narcoleptic boy. REM sleep is characterized by REMs in the electrooculogram (1, 2), and by a desynchronized,fast-frequency, activated electroencephalogram(EEG) (3-5). However, the customary background atonia of REM sleep in the submental electromyogram (EMG) is interrupted episodically by excessive twitching (6). Phasic dyscontrol in REM sleep is also indicated by the prominent, bilateral anterior tibialis twitch activity (7, 8). (B) Initially, there is complete release from REM sleep atonia which lasts 10 seconds and is marked by high-amplitudeaugmentation of background tone in the submental EMG (6, large arrow). REM sleep atonia emerges abruptly and persists for 4 seconds (6, bracket). Intrusion of excessive twitching then occurs, primarily in the submental EMG (6, small arrow). (C) The EMG pattern present in B is now fully reversed, as REM sleep atonia is continuously maintained throughout the submental EMG (61, despite the presence of dense, highamplitude twitcbing of the ltft anterior tibialis (7).
Table 3. Sleep Architecture Data from Nocturnal PolysomnographicStudies Documenting REM Sleep Motor Dyscontrol in 13 Unmedicated Narcoleptic Patients” Totalb (n = 13)
Sleep Parameters
Non-RBD (n = 6)
RBD (n
1. Total sleep time (min) 2. Sleep efficiency (% of total sleep time/time in bed) 3. Stage 1 (% of total sleep time) 4. Stage 2 (% of total sleep time) 5. Stage 314 (% of total sleep time) 6. Stage REM (% of total sleep time) 7. REM sleep latency (min) 8. No. of awakenings (260 sec)
402.5 (k127.8) 84.3‘ (2 7.7)
455.7 (rt70.1) 89.8 (2 5.5)
431.1 (L107.8) 87.5‘ (L 7.7)
10.7 (a 7.4) 45.8 (* 6.7) 20.3 ( 2 7.1) 23.2 (k 10.8) 23.2 (f 28.6) 14.5 (2 8.3)
12.6 (% 7.7) 43.1 (*10.5) 17.7 (2 5.1) 26.4 (211.7) 36.8 (L 8.3) 7.8 (? 3.1)
11.7 (L 8.5) 44.3 (2 8.7) 17.0 (L 5.9) 24.9 (2 11.0) 30.5d (e33.0) 10.7 (* 6.9)
=
7)
“Mean age, 34.3 (k21.6) yr; range, 8-74 yr; males, 84.6% (11/13).Data were obtained from first-night polysomnographic studies. All data are means -C SD. bStudent’st test did not reveal significant differences in sleep parameter scores between the two groups. outlying sleep efficiency score of 44.7% was excluded from this analysis. dRange of REM latency, 2.5-70.0 min.
RED = REM sleep behavior disorder.
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maintenance of submental EMG atonia 1161. The mechanisms by which clomipramine can promote RBD are unknown. Three patients in this study were receiving methylphenidate, pemoline, or valproic acid at the time of their PSG and MSLT studies. None of these medications is known to reduce REM sleep latency or to induce REM sleep motor abnormalities 137-46). Childhood-onset RBD has been reported in 4 patients, all associated with a neurological disorder, including 3 with brainstem involvement 125, 47-50). The case of Patient 8 in this report identifies narcolepsy as another neurological disorder presenting with childhood RBD. The 7 patients without RBD listed in Table 2 may be at risk for developing frank RBD, since they all displayed prominent tonic and/or phasic PSG abnormalities during REM sleep, and since it is known that RBD can be preceded by a lengthy prodrome of sleep motor dyscontrol c28). Thus, these non-RBD forms of motor dyscontrol during REM sleep may be considered as “subclinical RBD’ and are most likely symptoms of narcolepsy (and its treatment), since they have been a very uncommon finding at our center 151). The most extreme form of sleep-related motor dyscontrol in narcolepsy involves prolonged behavioral release with a complete loss of recognizable sleep-wake state markers throughout nocturnal PSG monitoring 152). This phenomenon, “status dissociatus,” extends the concept of narcolepsy as a disorder of “state boundary control” in which the physiological components of REM and NREM sleep can become inappropriately admixed or can repeatedly intrude into wakefulness c3, 531. Tonic and Phasic REM Sleep Processes and the Pathophysiology of REM Sleep Behavior Disorder Separate brainstem control mechanisms underlying the tonic (continuous) and phasic (intermittent) processes of REM sleep have been identified 154-59). A recent study in dogs revealed colocdzation of the atonia and locomotor systems of REM sleep in the pons [60), providing an anatomical basis for the dysregulation of these two systems in RBD. Furthermore, suprapontine structures may also influence REM sleep atonia 1611, which may be relevant to human RBD whose associated neuropathology, when present, primarily involves iuprapontine regions 128). RJ3D may result primarily ?om excessive excitation of locomotor systems activated during REM sleep 162-641, which can become sufficiently powerful as to overcome the preserved customary atonia of REM sleep (as shown in Figs l A , 2C), although loss of REM sleep atonia probably facilitates the release of RBD behaviors. REM sleep without atonia was previously found not only in narcoleptics receiving clomipramine, but also 8 Annals of Neurology Vol 32 No 1 July 1992
in (1) non-narcoleptics receiving clomipramine, various other tricyclic antidepressants, phenelzine, or fluoxetine 114, 17, 65-69]; and in ( 2 ) patients with parlunsonism and Shy-Drager syndrome C70, 711. An animal model of RBD that exists involves dorsolateral pontine tegmental lesions 163, 72). Four categories of RBD behaviors were found in this model, with the location and extent of the pontine lesions determining the category of released behaviors [63]: (1) a minimal syndrome of REM sleep without atonia accompanied by minor movements, (2) orienting and exploratory behaviors, ( 3 ) fighting behaviors, and ( 4 ) locomotion. The behavioral repertoire of human Rl3D is identical among its various clinical populations (idiopathic, neurological), and also mirrors the repertoire found in animals with experimental Rl3D 163, 72) or with clinical RBD (idiopathic, neurological) 173, 74). This suggests that final common pathways exist for behavioral release in mammalian RBD. In conclusion, narcoleptic patients should be questioned about disturbed sleep and dream-related behaviors at the time of initial diagnosis and throughout the course of treatment, especially since clonazepam is very effective in controlling RBD 128). This work was supported in part by a grant from Hennepin Faculty Associates. We acknowledge the ongoing contributions of Scott R. Bundlie, MD, Gerald Rosen, MD, Thomas D. Hurwitz, MD, Andrea L. Patterson, RPSGT, and Jan Schluter, RN, and are indebted to Susan Phelps and Traci Oletzke for their secretarial support. Robert Sherman, PhD, provided statistical assistance. Presented at the third annual meeting of the Association of Professional Sleep Societies, Washington, DC, June 23, 1989.
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