16

Electroencephalography and Clinical Neurophysiology, 1978, 4 5 : 1 6 - - 2 5 © Elsevier/North-Holland Scientific Publishers, Ltd.

SLEEP DISTURBANCES IN PROGRESSIVE SUPRANUCLEAR PALSY * R.A. GROSS, R. SPEHLMANN and J.C. DANIELS

Veterans Administration Lakeside Hospital, and Departments of Neurology and Pharmacology, Northwestern University Medical School, Chicago, Ill. 60611 (U.S.A.) (Accepted for publication: November 15, 1977)

It is now believed that sleep is the result of coordinated neuronal activity of structures located within the brain stem. Ablative and pharmacological studies in animals have demonstrated that non-rapid eye movement (NREM) sleep is dependent upon activity of midline raphe nuclei in the central gray core of the brain stem tegmentum (Batini et al. 1959; Kostowski et al. 1968; Mouret et al. 1968; Weitzman et al. 1968). Similar studies have shown that the locus coeruleus, located dorsolaterally in the pontine tegmentum, plays an important role in the production of rapid eye movement (REM) sleep (Jouvet 1969, 1973). Much of the present knowledge regarding sleep mechanisms has been derived from experiments on animals. Analogous information regarding human sleep mechanisms remains sparse. Reports have implicated the raphe nuclei as being important for duration of NREM sleep (Guilleminault et al. 1973; Freemon et al. 1974). It has been postulated that the locus coeruleus plays a role in coordination of components (Barros-Ferreira et al. 1975; Mouret 1975) and duration (Mouret 1975) of REM sleep. Abnormalities of both NREM and REM sleep have been demonstrated in patients with the 'locked-in' syndrome associated with bilateral pontine tegmental damage (Feldman 1971; Markand and Dyken 1976). While these studies tend to * This paper was presented in part at the 31st annual meeting of the American Electroencephalographic Society, Miami, Fla., June 1977.

confirm that brain stem structures are important for human sleep, more information is required for a better understanding of the mechanisms underlying normal and disturbed sleep in man. Progressive supranuclear palsy (PSP) is a disease leading to degeneration of nuclei within the pontine and mesencephalic tegmentum. The locus coeruleus is almost invariably involved; damage within the central gray core of the pons and mesencephalon, including regions occupied by raphe nuclei, has been reported (Steele et al. 1964; Behrman et al. 1969). The disease also produces damage within the globus pallidus, dentate nuclei of the cerebellum and nuclei at the mesodiencephalic junction. The cerebral cortex, subcortical white matter and thalamus tend to be spared, or involved only to a minimal degree (Steele et al. 1964; Behrman et al. 1969). In an effort to explore the role of brain stem structures in human sleep, we studied four patients with PSP of varying degrees of severity, using prolonged polygraphic recordings.

Methods Four male patients, aged 62--67, were admitted to the Veterans Administration Lakeside Hospital, Chicago, Ill., between June and October, 1976. All had the characteristic features of PSP as verified by three neurologists in each case. An estimate of severity of

SLEEP IN PROGRESSIVE SUPRANUCLEAR PALSY clinical involvement was based upon the physical findings. Case 1, considered to have severe clinical involvement, was unable to stand without aid. His eye movements on c o m m a n d and pursuit were almost totally paralyzed in all directions. He showed marked dysarthria, and marked tonic extensor rigidity of the neck, trunk and upper extremities. Cases 2 and 3 were considered to exhibit moderate clinical involvement. They were unable to take more than one or two steps unaided before losing their balance. Ophthalmoplegia was complete for willed vertical gaze; willed lateral eye movements were slow. Each of these patients had moderate dysarthria and tonic extensor rigidity. Case 4, judged to have the mildest degree of clinical involvement, was able to ambulate with a cane. He was unable to move the eyes vertically, but horizontal gaze was intact. Mild dysarthria and tonic extensor rigidity were present. The oculocephalic reflex (doll's eye maneuver) resulted in full vertical and horizontal excursions of the eyes in all patients. Dementia was felt to be present to a mild or moderate degree in all cases. None of the patients exhibited weakness, tremor, or cerebellar ataxia. Brain scan, skull X-ray, cerebrospinal fluid examination, and routine biochemical and hematological tests were within normal limits in all cases. Two of the patients (cases 3 and 4) were receiving carbidopa (30--75 mg) and levodopa ( 3 0 0 - - 7 5 0 m g ) daily in divided doses, taking their final daily dose at least 2 h before their all-night polygraphic studies. Three patients (cases 2, 3 and 4) received diphenhydramine, 50 or 100 mg/day. Three age-matched patients without evidence of central nervous system disease served as control subjects. Informed consent was obtained from all patients. Each patient with PSP received a routine electroencephalogram (EEG), and several brief (3--6 h) polygraphic recordings, usually at night, followed by two prolonged polygraphic recording sessions (12 or 24 h). Total recording time was 240 h. During the

17 brief recordings, patients were frequently addressed, asked questions, or given commands in order to assess their level of behavioral arousal and to make correlations with the EEG patterns. The 3--6 h recordings also served to familiarize the patients with the apparatus in order to help eliminate the 'first night' effect (Agnew et al. 1966) in the subsequent 12 or 24 h recordings. Control subjects underwent 12 h all-night polygraphic recording sessions. All recordings were performed in the patients' own hospital rooms. Lights were turned off at the usual times. One of the authors or an experienced technician observed the patients throughout the recording periods and d o c u m e n t e d observations regarding their behavior. A Grass Model 6 8-channel electroencephalograph was employed, using paper speeds of 15 and 30 mm/sec, and conventional gain and filter settings. Gold-plated cup electrodes, secured with collodion and filled with conductive jelly, were placed on the scalp and ears according to the international 10/20 system. During polygraphic studies, 4 EEG channels were used to monitor activity from the parieto-occipital and central regions (P3-O1 or P 4 - O 2 , C4--CZ, CZ--C3, and C4--A1). Gold-plated cup electrodes were also placed near the lateral canthi for the electrooculogram (EOG) and submental muscles for the surface electromyogram (EMG), following electrode placement recommendations of the Manual of Standardized Terminology for Sleep Stages of Human Subjects (Rechtschaffen and Kales 1968). The last channel was used to monitor the electrocardiogram (ECG). The paper tracings were subsequently interpreted and scored in 20 sec epochs for sleep stages according to conventional criteria (Rechtschaffen and Kales 1968) except when modified in Results. Results

(I) Wakefulness Routine EEGs in three patients (cases 2, 3 and 4) showed only minor abnormalities, con-

18

sisting of slow transients on the temporal areas. The background consisted of fairly well organized alpha rhythms, 8--9 c/sec in frequency and 2 5 - - 3 5 g V in amplitude. The EEG of the most severely affected patient {case 1) contained a well organized background r h y t h m of 7 c/sec, best developed posteriorly (Fig. 1A). This patient's EEG often showed bursts of bilaterally synchronous waves of 1.5--2c/sec, maximal on the temporal areas.

(II) NREM sleep NREM sleep stages could be identified in three of the patients (cases 2, 3 and 4). Approximately one-fourth of stage 1 sleep differed morphologically from the 2--7 c/ sec background characteristic of stage 1 sleep (Rechtschaffen and Kales 1968), showing instead a predominantly monorhythmic background consisting of waves of 6 c/sec (Fig. 2A). This monorhythmic pattern was considered to be stage 1 sleep because it often appeared at the onset of sleep, was associated with slow eye movements characteristic of stage 1 sleep, and was often intermixed with patterns typical of stage 1 sleep. Stage 1 sleep accounted for 34.7% of total sleep time (TST) in these three patients. This proportion was 3.6 times that seen in our control patients, in whom stage 1 sleep accounted for 9.7% of TST. Sleep was scored stage 2 when a K-complex or a sleep spindle of at least 0.5 sec in duration was identified. Spindles occurred infrequently in the patients with PSP, and consisted of poorly formed waves of 12--15 c/ sec with low amplitude (5--20 uV) (Fig. 2B). Activity resembling rudimentary K-complexes and vertex sharp transients appeared infrequently. Positive occipital sharp transients of sleep appeared only in the record of the patient with the mildest degree of clinical involvement (case4), and occurred infrequently. As sleep progressed, high-amplitude (above 75 uV in the C4--A1 derivation) slow (below

R.A. GROSS ET AL. A.

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2 c/sec) activity appeared. When this activity occupied greater than 20% or greater than 50% of an epoch, sleep was scored stage 3 or

SLEEP IN PROGRESSIVE SUPRANUCLEAR PALSY

19

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Fig. 2. EEG patterns in patients with scorable sleep (cases 2, 3 and 4). A: case 4, stage 1 sleep. Atypical pattern with monorhythmic background of 6 c/sec waves. B: case 3, stage 2 sleep. Note low amplitude of sleep spindles and activity resembling K-complexes and vertex sharp transients. C : case 2. Abnormal sleep pattern dominated by rhythm in the alpha frequency range. D: case 3, REM sleep. Bursts of eye movements are represented by out of phase pen deflections in the fifth and sixth channels. Calibrations: 20 pV and 1 sec.

4, respectively, according to conventional criteria (Rechtschaffen and Kales 1968). Details regarding NREM sleep stages are presented in Table I. Rhythms in the alpha frequency range appeared frequently throughout NREM sleep in cases 2 and 3. Waves of 8--9 c/sec, occurring in bursts of 1--3 sec, occupied 25--50% of the tracing in over half of the stage 2 and stage 3 sleep epochs in these patients. The waves were of the same frequency, amplitude and distribution as the patients' background rhythms recorded during wakefulness. During sleep, the 8--9c/sec waves were usually superimposed upon a background of slow waves and sleep spindles. On several occasions, the 8--9 c/sec rhythm dominated the record for periods of up to 3 min, without evidence of

behavioral arousal (Fig. 2C). In the three patients with scorable sleep, single sporadic eye movements appeared occasionally during NREM stages 2 and 3.

(III)REMsleep Table I summarizes details of REM sleep in patients and controls. REM sleep did not occur in case 1. In cases 2, 3 and 4, REM sleep accounted for 6% of TST, a value significantly (P < 0.01) below that obtained from control subjects (24.8%). Patients exhibited a total of 15.3 min/night of REM sleep, which was significantly (P < 0.01) below that in controls, who had 101.9 min/night of REM sleep. Patients 2, 3 and 4 had an average of 3 REM periods per night, a value not signifi-

20

R.A. GROSS ET AL.

TABLE I Quantitative aspects of sleep in progressive supranuclear palsy. Values represent mean -+ S.D. TST = total sleep time. Values under headings NREM sleep and REM sleep apply to the three patients with scorable sleep (cases 2, 3 and 4). Values under the heading Hyposomnia apply to all four patients. Number of controls, 3. Controls

PSP

NREM sleep (1) Stage 1 sleep (per cent of TST) (2) Stage 2 sleep (per cent of TST) (3) Stage 3 + 4 sleep (per cent of TST)

9.7 _+ 2.32 56.4 _+ 5.27 9.1 _+ 2.44

34.7 _+ 20.42 50.2 +- 19.78 9.1 -+ 5.53

REM sleep (1) (2) (3) (4)

Stage Mean Mean Mean

REM (per cent of TST) total duration (min/night) number of REM periods REM period duration (min)

24.8 101.9 5.0 22.9

_+ 2.19 + 20.54 _+ 1.73 _+ 6.89

6.0 15.3 3.0 5.0

_+ 3.39 ** +_ 10.18 ** + 1.79 _+ 2.21 *

Hyposomnia (1) Total sleep time (min) (2) Mean number of awakenings/night (3) Mean duration of awakenings (rain)

411.1 + 66.49 5.7 + 0.57 4.4 + 1.21

242.9 _+44.79 * 13.1 _+ 2.39 ** 15.1 _+ 1.53 **

* Significantly different at P < 0.02 (Student's t-test). ** Significantly different at P < 0.01.

cantly different from that obtained in controls, who had 5 REM periods per night. Mean duration of a REM period, however, was significantly (P < 0.02) decreased in patients (5min) compared to control subjects (22.9 min). Compared to control subjects, frequency of eye movements in REM sleep appeared to be decreased in patients with PSP. However, clusters of fairly rapid eye movements appeared at times (Fig. 2D). EEG patterns and level of EMG activity during REM sleep in patients did not appear different from those observed in control subjects. (IV) Sleep in case 1

Case 1, clinically more advanced than the other patients, showed severely disturbed sleep patterns which could not be scored. During approximately one-half of this patient's sleep, EEG patterns were not distinguishable from those observed during wakefulness (Fig. 1B). Therefore, sleep was recognized and

quantified in part by constant observation of the patient. During wakefulness, he was markedly bradyphrenic but kept his eyes open, displayed purposeful movements, made verbal requests and responded appropriately, albeit slowly, to commands. This wakeful state could be distinguished from sleep, during which the eyes closed, purposeful movements ceased, the patient failed to respond when addressed (tested during the 3-6 h recordings only), and his breathing became deep, at times irregular, and associated with snoring. This constellation of findings was termed 'behavioral sleep' and generally occurred in brief periods (10-15 min) with 12--14 spontaneous awakenings per night. Several longer periods of behavioral sleep (mean duration 67 min) occurred each night. During these periods, the EEG pattern changed. After 15--20min of behavioral sleep, all electrocerebral activity faster than 2c/sec underwent a marked reduction in amplitude. The stereotyped bursts of 1.5--

SLEEP IN PROGRESSIVE SUPRANUCLEAR PALSY

21

2 c/sec waves ceased. The record became dominated by activity of 0.5--2 c/sec, with variable amplitudes ranging from 15 to 60 gV. The 7 c/sec rhythm continued to appear intermittently; however, the amplitude of the waves was reduced to 5--15~V (Fig. 1C). Waves of 12--15 c/sec and of 5/~V appeared occasionally. No activity resembling K-complexes or vertex sharp transients was seen. Submental muscular atonia occurred twice (mean duration 8 min) during the prolonged sleep periods, without accompanying change in the EEG pattern, or appearance of eye movements. No eye movements appeared throughout sleep in case 1.

tended to have a late onset of sleep and awakened early. In addition, patients had a mean of 13 spontaneous awakenings throughout the night, compared to 5.7 for controls. Mean duration of individual awakenings was 15.1 min for patients and 4.4 min for controls. Both of these differences were significant (P < 0.01). One-third of the wakeful periods exceeded 30 min in the patients with PSP. The hypnograms shown in Fig. 3 illustrate sleep characteristics in cases 2, 3 and 4, compared to a control subject, and pertinent values are given in Table I. Two 12 h daytime recordings were contiguous with two all-night recordings and produced a mean TST of 26 min, indicating that nocturnal hyposomnia was not compensated during the day. Quantitative aspects of NREM sleep stages, REM sleep, TST and nocturnal awakenings of control subjects were in good agreement with

(V) Total sleep time Mean TST for all four patients with PSP 'was 242.9 min, a value significantly (P < 0.02) below the mean TST of 411.1 min obtained for control subjects. Patients with PSP

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22

data obtained from normal males, aged 60-69 (Williams et al. 1974).

Discussion

Our results indicate that PSP may lead to marked disturbances of sleep, consisting of hyposomnia, disorganization of NREM sleep patterns and absent or markedly reduced REM sleep. These findings are in general agreement with a recent report (Leygonie et al. 1976) of sleep patterns in PSP. Other reports relating human sleep abnormalities to lesions within the central nervous system have implicated structures within the brain stem tegmentum. Thus, decreased TST with normal per cent REM sleep was reported in one case with autopsy-verified lesions of the pontine and mesencephalic raphe nuclei (Freemon et al. 1974); decreased TST was the major abnormality in a patient in whom clinical findings suggested brain stem involvement and in whom biochemical and pharmacological studies were consistent with a lesion of the raphe system (Guilleminault et al. 1973). Decreased REM sleep (Mouret 1975) or faulty coordination of REM sleep components (Barros-Ferreira et al. 1975; Mouret 1975) have been associated with suspected damage in the locus coeruleus. Prolonged recordings from patients with extensive bilateral pontine lesions and clinical features of the 'locked-in' syndrome (Plum and Posner 1972) have shown insomnia or hyposomnia, abnormalities of NREM sleep patterns, and absent to markedly reduced REM sleep (Feldman 1971; Markand and Dyken 1976). The constellation of rather unusual sleep abnormalities that characterized the 'lockedin' syndrome is quite similar to that observed in PSP. The site of pathology common to both conditions and relevant to sleep is restricted to the pontine tegmentum. Because of these similarities, we feel that our results support the hypothesis that proper functioning of structures within the pontine tegmentum is necessary for normal initiation

R.A. G R O S S E T AL.

and maintenance of NREM and REM sleep in man.

Increases in the amount of stage 1 sleep and in the number of nocturnal awakenings are accepted consequences of aging and have been attributed to a general weakening of the sleep process (Feinberg 1969; Williams et al. 1974). In PSP, these increases exceed those which can be attributed to the aging process. We feel that such changes may be the result of damage to structures which are essential to the sleep process, and possibly situated within the central gray core of the pontine or mesencephalic tegmentum, or both. A striking feature of the nocturnal awakenings was their long duration, some persisting for up to 90 min. Although no explanation is readily available on the basis of our data, we noted that the most prolonged wakeful periods occurred immediately or very soon after REM periods, suggesting that our patients suffer some disturbance in the maintenance of sleep during the transition from REM sleep to NREM sleep. Our patients showed a dissociation between electrographic and behavioral manifestations of sleep. This dissociation was most apparent in case 1, in whom one-half of behavioral sleep was accompanied by the EEG pattern seen during wakefulness. Cases 2 and 3 displayed rhythms in the alpha frequency range throughout sleep. These rhythms were considered to represent a persistence of EEG activity normally present only in wakefulness, and not a manifestation of unusually slow sleep spindles, because (1) the frequency and distribution of the waves were very similar to the alpha rhythms recorded during wakefulness in these patients, and (2) the alpha-like rhythms were intermixed with sleep spindles of 12--15 c/sec. The finding of EEG patterns of wakefulness during behavioral sleep suggests that the neurophysiological mechanisms responsible for behavioral manifestations of sleep are functionally separable from the mechanisms that subserve the production of EEG patterns associated with sleep; and that these mechanisms,

SLEEP IN PROGRESSIVE SUPRANUCLEARPALSY usually tightly interlocked, may become uncoupled in the course of PSP. Two of our patients (cases 3 and 4) were receiving small doses of levodopa, and three (cases 2, 3 and 4) received diphenhydramine. Levodopa is believed to produce a decrease in REM sleep when given 30 min before bedtime, but not when given 2 h before bedtime (Wyatt et al. 1970). Diphenhydramine has been associated with a mild decrease of REM sleep in a few healthy subjects (Kales et al. 1969), but these results were not considered definitive (Kay et al. 1976). In our patients, the final daily dose of medications was given at least 2 h before sleep studies. No difference in proportion of REM sleep was seen in case 4 when studied while taking medications and studied again several weeks after withdrawal. Per cent of REM sleep was the same in two patients (cases 2 and 3) with similar degree of clinical involvement, although only case 3 was receiving levodopa. In view of the profound and unusual sleep disturbances in our patients, including one (case 1) on no medications, we conclude that these abnormalities were not due to drug effects. Structural brain damage is usually detected in the EEG while the patient is awake. Our results show that prolonged polygraphic sleep recordings can demonstrate severe abnormalities due to lesions of the brain stem in patients whose EEGs during wakefulness show only mild non-specific abnormalities. It appears that prolonged polygraphic recordings in patients with brain stem lesions, especially when accompanied by pathological correlations, may lead to a more complete understanding of the mechanisms underlying human sleep.

Summary Prolonged polygraphic sleep recordings were obtained from four patients with progressive supranuclear palsy (PSP), a disease which produces degenerative changes in the pontine and mesencephalic tegmentum, globus

23 pallidus, dentate nuclei of the cerebellum and nuclei at the mesodiencephalic junction. All patients had hyposomnia, with mean total sleep time of 243 min. REM sleep was absent or markedly reduced in all patients. Non-REM sleep patterns were abnormal, showing a decrease in number and amplitude of sleep spindles, and infrequent activity resembling rudimentary K-complexes and vertex sharp transients. Rhythms in the alpha frequency range appeared throughout non-REM sleep. EEG patterns of wakefulness persisted into behavioral sleep. EEG patterns of sleep in PSP are similar to those reported in patients with lesions of vascular origin involving the pons bilaterally. Involvement of structures relevant to sleep and common to both conditions is restricted to the pontine tegmentum. Our results strongly suggest that structures within this area are necessary for the initiation and maintenance of sleep in man. The appearance of EEG patterns characteristic of wakefulness during behavioral sleep suggests that functionally separable mechanisms account for the EEG patterns and the behavioral manifestations of sleep, and that these may become uncoupled in PSP. Rdsumd-

Perturbations du sommeil dans la paralysie supra-nucldaire progressive Des enregistrements polygraphiques prolongds du sommeil ont dt~ obtenus chez 4 malades avec paralysie supra-nucl~aire progressive (PSP), une maladie qui produit des modifications ddg~ndratives du tegmentum pontin et m~senc~phalique, du globus pallidus, des noyaux dentel~s du cervelet et des noyaux de la jonction mdsodiencdphalique. Tous ces malades pr~sentent une hyposomnie avec temps de sommeil total moyen de 243 min. Le sommeil paradoxal est absent ou tr~s r~duit chez tous. Les patterns du sommeil lent sont anormaux, montrant une diminution du nombre et de l'amplitude des spindles,

24

et des activitds peu fr~quentes ressemblant des complexes K rudimentaires et aux ondes transitoires pointues au vertex. Des rythmes de fr~quence alpha apparaissent t o u t au long du sommeil lent. Des patterns EEG de veille persistent au cours du sommeil comportemental. Les patterns EEG de sommeil dans la PSP sont similaires ~ ceux qui o n t ~td rapp o r t , s chez des malades atteints de l~sion d'origine vasculaire impliquant bilatdralement le pont. L'implication des structures concernant le sommeil, communes ~ ces deux types d'affections se limite au tegmentum pontin. Nos r~sultats sugg~rent f o r t e m e n t que ces structures, ~ l'intArieur de cette rdgion, sont ndcessaires ~ l'initiation et au maintien du sommeil chez l'homme. L'apparition de patterns EEG caract~ristiques de la veille au cours du sommeil comportemental sugg~re que des m~canismes fonctionnellement distincts rendent c o m p t e des patterns EEG et des manifestations comportementales du sommeil et que ceux-ci peuvent se dissocier dans la PSP. The authors thank Clifford Smathers and Calvin Meineke for expert technical assistance, and Karyl Norcross for reviewing the manuscript. This study was supported by the Medical Research Service of the Veterans Administration and by NIH Research Grant NS 06820.

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R.A. GROSS ET AL. pathological study of four cases. Brain, 1969, 92: 663--678. Feinberg, I. Effects of age on human sleep patterns. In: A. Kales (Ed.), Sleep. Physiology and Pathology: a Symposium. Lippincott, Philadelphia, Pa., 1969: 39--52. Feldman, M.H. Physiological observations in a chronic case of 'locked-in' syndrome. Neurology (Minneap.), 1971, 21: 459--478. Freemon, F.R., Salinas-Garcia, R.F. and Ward, J.W. Sleep patterns in a patient with a brain stem infarction involving the raphe nucleus. Electroenceph, clin. Neurophysiol., 1974, 36: 657---660. Guilleminault, C., Cathala, J.P. and Castaigne, P. Effects of 5-hydroxytryptophan on sleep of a patient with a brain-stem lesion. Electroenceph. clin. Neurophysiol., 1973, 34: 177--184. Jouvet, M. Biogenic amines and the states of sleep. Science, 1969, 163: 32--41. Jouvet, M. Role of catecholamines in the control of the sleep-waking cycle. In: E. Usdin and S. Snyder (Eds.), Frontiers in Catecholamine Research. Pergamon Press, New York, 1973: 751--757. Kales, A., Heuser, G., Kales, J.D., Rickles, Jr., W.H., Rubin, R.T., Scharf, M.B., Ungerleider, J.T. and Winters, W.D. Drug dependency: investigations of stimulants and depressants. Ann. intern. Med., 1969, 70: 591--614. Kay, D.C., Blackburn, A.B., Buckingham, J.A. and Karacan, I. Human pharmacology of sleep. In: R.L. Williams and I. Karacan (Eds.), Pharmacology of Sleep. Wiley, New York, 1976: 83--105. Kostowski, W., Giacalone, E., Garattini, S. and Valzelli, L. Studies on behavioral and biochemical changes in rats after lesions of midbrain raphe. Europ. J. Pharmacol., 1968, 4: 371--376. Leygonie, F., Thomas, J., Degos, J.D., Bouchareine, A. et Barbizet, J. Troubles du sommeil dans la maladie de Steele-Richardson. Etude polygraphique de 3 cas. Rev. neurol., 1976, 132: 125--136. Markand, O.N. and Dyken, M.L. Sleep abnormalities in patients with brain stem lesions. Neurology (Minneap.), 1976, 26: 769--776. Mouret, J. Differences in sleep in patients with Parkinson's disease. Electroenceph. clin. Neurophysiol., 1975, 38: 653--657. Mouret, J., Bobillier, P. and Jouvet, M. Insomnia following para-chlorophenylalanine in the rat. Europ. J. Pharmacol., 1968, 5: 17--22. Plum, F. and Posner, J.B. The Diagnosis of Stupor and Coma. Davis, Philadelphia, Pa., 1972: 24--25. Rechtschaffen, A. and Kales, A. A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. Public Health Service, U.S. Government Printing Office, Washington, D.C., 1968. Steele, J.C., Richardson, J.C. and Olszewski, J. Progressive supranuclear palsy. Arch. Neurol.

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25 encephalography (EEG) of Human Sleep: Clinical Applications. Wiley, New York, 1974. Wyatt, R.J., Chase, T.N., Scott, J., Snyder, F. and Engleman, K. Effect of L-DOPA on the sleep of man. Nature (Lond.), 1970, 228: 999--1001.