Journal of

Neurology

J. Neurol. 221, 1--13 (1979)

© by Springer-Verlag 1979

Original Investigations Hypersomnia with Simultaneous Waking and Sleep Patterns in the Electroencephalogram A Case Report with Neurotransmitter Studies E. Niedermeyer, H. S. Singer, S. E. Folstein, R. P. Allen, F. Miranda, F. Fineyre, and B. L. Bird Departments of Neurology and Neurological Surgery and of Psychiatry, The Johns Hopkins University School of Medicine and Hospital and of Neurology, Baltimore City Hospital, Baltimore, Maryland, U.S.A.

Summary. A mildly dyslexic boy of 11 years, with no neurological deficit or history of epileptic seizures, had marked hypersomnia for 2 years, which was most pronounced in the morning hours. Repeated E E G studies and power spectral analysis revealed simultaneous posterior alpha rhythm and sleep patterns (spindles, vertex waves, K complexes) over vertex and frontocentral regions, while the patient was behaviorally awake. Bilateral synchronous anterior spikes were frequently noted in association with sleep patterns. A polysomnogram over 24h confirmed excessive sleep, night and day (especially morning hours) and there was evidence of a large REM sleep percentage (on E M G and EOG basis) while the E E G had predominantly non-REM sleep patterns. Special neurotransmitter studies were performed in view of a presumed disturbance affecting the neurobiochemical sleep regulation. These studies were based on CSF metabolite levels and provided evidence for a high serotonin metabolite (5HIAA) level. It is tempting to hypothesize that the biochemical disturbance has led to encroachment of non-REM sleep patterns on both wakefulness and REM sleep. Further discussion deals with the bilateral-synchronous spike activity and its relationship to arousal patterns in sleep. Key words: Sleep disorder - E E G (sleep patterns) - Neurotransmitters - Sleep regulation.

Zusammenfassung. Es wird tiber einen 1 lj~ihrigen Knaben berichtet, der seit 2Jahren an ausgepr~igter Schl~ifrigkeit leidet, die besonders in den Vormittagsstunden bemerkbar ist. Der Patient zeigt eine leichte Lesest6rung, aber es Address for offprint requests: E. Niedermeyer, M.D., The Johns Hopkins Hospital, 601 N. Broad-

way, Baltimore, Maryland 21205, U.S.A. 0340-5354/79/0221/0001/$ 02.60

2

E. Niedermeyer et al. liegen keine neurologischen Ausf~ille vor, und die Vorgeschichte ist negativ ffir epileptische Anf~ille. Wiederholte EEG-Untersuchungen mit Spektralanalyse zeigten im Wachzustand das gleichzeitige Vorkommen eines Alpharhythmus fiber der hinteren Schadelhalfte und typischer Schlafmuster (Spindelzfige, Vertex-Potentiale, KKomplexe) fiber Vertex und der Frontozentralregion. AufSerdem wurden h~iufige bilateral-synchrone Spitzen fiber den vorderen Regionen beobachtet. Ein 24-Std-Polysomnogramm best~itigte exzessiven Schlaf, nachts wie auch tagsfiber (besonders am Vormittag), und es zeigte sich ein hoher Prozentsatz von REM-Schlaf (basierend auf elektromyographischen und elektrooculographischen Befunden), wobei jedoch die EEG-Muster des langsamen (NichtREM)Schlafs persistierten. In Hinblick auf eine vermutete neurobiochemische Schlafregulationsst6rung wurden spezielle Neurotransmitter-Studien durchgeffihrt. Diese Untersuchungen basierten auf Metabolitenwerten im Liquor und zeigten erh6hte Werte ffir den Serotonin-Metaboliten 5HIAA. Es bietet sich daher die Hypothese an, dab eine biochemische St6rung zu einer ,,Expansion" des langsamen Schlafes geffihrt hat mit ,Eindringen" in die elektrophysiologischen Muster des Wachzustandes und des REM-Schlafes. Aul3erdem wird die bilateral-synchron e Spitzenaktivit~it besprochen und deren Beziehung zu Weckmustern im Schlaf.

Increasing interest in sleep disorders coupled with a refined technological approach has resulted in the introduction of "polysomnography" and the establishment o f special nocturnal sleep laboratories. This work has elucidated many hitherto unknown or poorly understood sleep disorders (Rechtschaffen and Dement, 1969; Guilleminautt and Dement, 1974, 1977; Dement et al., 1975). During the past decade there has also been enormous progress in the basic research on sleep mechanisms which has led to the discovery of crucial brainstem regions (pontine raphe nuclei, locus coeruleus) and specifically involved neurotransmitter substances (Jouvet, 1969, 1972). This bulk of recent knowledge of basic and clinical sleep research could not provide us with the key for the understanding of an unusual and perhaps unique case with the simultaneous occurrence of alpha rhythm and physiological sleep pattern (spindles, vertex waves, K complexes) and occasional abnormal activity such as bilateral-synchronous spikes. Even a most recent presentation of this case at the American E E G Society Meeting (San Francisco, 7 to 9 September, 1978) has left us with unanswered questions and the lack of similar observations.

Case Report A boy, aged 11, was admitted to the Johns Hopkins Hospital Child Psychiatry Unit because of daytime hypersomnia characterized by falling asleep in school and some difficulty in getting to sleep at night. His developmental milestones were normal--he walked at about one year and his speech developed normally. Infancy (including pregnancy and delivery) and early childhood were unremarkable. He has no siblings; his parents are well adjusted individuals.

Hypersomnia with Simultaneous Waking and Sleep Patterns

3

Hyperactive behavior became manifest at the age of 5 years. His hyperactivity was characterized by constantly getting out of his chair and moving around at the dinner table. He would even not watch television very long at one time. These behavioral changes improved when, at the age of 5, a physician prescribed methylphenydate hydrochloride (Ritalin), 10mg twice daily, which he took for 4 years. The patient performed satisfactorily in the first grade of elementary school but, in second grade (age 7), his work became inconsistent and he needed extra help. He had to repeat second grade and was then transferred to a special school for children with learning difficulties. At about age 9, the child began to have mild difficulties with failing asleep in school and also had increasing learning problems. A neurological evaluation revealed normal findings except for an abnormal EEG with frequent bilateral spikes. In the following years, the child had great difficulty getting up in the morning and would fall asleep at breakfast. He would fall asleep numerous times in the morning classes but seemed awake in the afternoon. In the evening hours, the boy was in his bed and had considerable difficulty falling asleep at night (about 22.30 to 23.30 h). The morning sleepiness has become progressively worse and occurs on school days as well as on weekends when he is allowed to sleep as late as he wishes. He usually awakens at

F~h-F~' . ~,~ •~iv,,~'~.~,.%.,,.,~:~,,'~'~-....,-,~:,.~,..,..-~ dw~! F~-%

~'

~/~h

~ ~ ~ . > ~ /

~

'

,

~~,~~t~%~,~,~%%~@¢:~¢ , T 5 ~ I~

~

~

~

~

'

~

,

~

~

~

0 2 - "1"~

~o~~~,,7~<>.~.-,,,~.~:'.v~.~r>%~%

~ ~

"

.

Te-T4

~

~

'

~

'

7

T4-F8

~-~

a

~

FP2- P~

' v

&

'

~~

~

~ ~ ~

Fz-Cz

~

~

Cz-Pz q

~

r~-c~.

.

.C ~

C

R v

~

~

4 ~j~ ~ ~-,~

,

~

E~

~ m ~ v

~ ~

a HF 70, LF 1 (TC 0,16s~) ~

~

.....

...........

~"~ .i~ A~" Q~ ~ ~ ~

Fig. 1. Waking record obtained during afternoon h while patient was more alert. Note welt developed posterior alpha rhythm while spindle frequencies (around 12w14/s) predominate in superior frontal, central and parietal leads (six channels at the bottom). Even two K complexes occur over this area

4

E. Niedermeyer et al.

11.00 or 11.30h. He has no history of abrupt narcoleptic sleep attacks, cataplexy or sleep paralysis. In December 1977, a neurological reevaluation at this hospital was normal except for mild clumsiness performing rapidly alternating movements. Because of spike activity in the EEG, diphenylhydantoin was prescribed but was taken for a short period of time only. The child was admitted for a psychiatric evaluation in March 1978 when unusual electroencephalographic patterns revealed, for the first time, a profound deviation in the sequential structure of the waking-sleeping cycle. The child's psychiatric assessment itself did not reveal a psychiatric basis for the disorder but confirmed the reported hypersomnia in the morning hours.

Neurological Findings. No gross deficit; mild clumsiness with alternating movements. Evidence of dyslexia, IQ (WISC): verbal 78, performance 92, full scale of 84. Reading, spelling and arithmetic skill at about 3rd grade level (age 8). Very poor visual sequencing memory (at the 5 ~2year level). Skull films normal. Computed tomography (with contrast) normal. Blood chemistry normal. Evaluation of thyroid functions unremarkable.

Fp t -F 3

Fp2.- F8

T4-T6

I

.

Y

.

~

.

.

.

~"

~

~eye ol:~n ~flg

TC 0.16 sec (LF 1)

Fig. 2. Recording of the morning h. The patient is awake; he opens and closes his eyes associated with appearance and blocking of posterior alpha rhythm (channels 4, 8, 11, 12, 15, 16 from top). The rest of tracing, especially the fronto-centro-parietal regions, shows marked slowing with sleep spindles. Note high voltage output (see voltage parameter)

Hypersomnia with Simultaneous Waking and Sleep Patterns

5

Electroencephalographic Evaluation EEG recordings were made on 29 March in the morning as well as in the afternoon hours. The general x)oltage output was unusually high; the posterior 9--11/s alpha rhythm consistently reached 100--2001aV. Considerable diffusely intermixed high voltage 2--7/s activity (with frontal maximum) was noted and there was also a lot of scattered tow to medium voltage 14--20/s activity. The entire tracings showed unusually high voltage output. While still awake (posterior alpha being present), runs of medium to high voltage 12--14/s spindles were frequently noted, maximal over frontal midline; there were also runs of large K complexes; maximal over frontal midline, often associated with spikes in frontal leads (slightly lateralized to the right) (Figs. 1,2 and 3). The posterior alpha rhythm was most prominent in the afternoon hours (Fig. 1), but even then there was considerable spindle and K complex activity with subtle spikes in frontal-central leads (Fig. 1). Figure 2 shows persistent alpha and response to eye closure and opening (demonstrating wakefulness) while the rest of the record was completely dominated by slow activity and sleep pattern. Figure 3 shows a marginal waking state (evidenced by fragments of alpha in occipital leads) following arousal from light sleep (stage 2) with spindles. Nearly generalized synchronous spikes and spike-wave with frontal maximum are seen during arousal. Such arousal

HF 7'0, LF 1

Fig. 3. Recording of morning h. Following arousal response in center of illustration, there are fragments of occipital alpha rhythm while sleep patterns generally prevail. Arousal is associated with large bilateral-synchronous anterior spike (slightly more prominent on right) followed by few spike-wave-like discharges. Note again high voltage output

6

E. Niedermeyer et al.

..~-~ ~ ° ~ / ~ ;~~. ~ / ~ ~ . ~ ~ ~

~'c~ 5 ~ ~ ~ 5 ~ , ~ ~ 33~,~ ~ ~ ~ ~ , . ~ - ~ ~ : ~ -

N2-F4

m-~

~

~

~

,

~

~

~

~

~

~

,

....

~

~

~

~

~ . ~ . . , ~ .

~ , ~ ~ ' ~ ~ ~ - ~ ~ ~~ ~ ~ ~ -

~

~~

~

Jz ~ v

~

w

~

~

~

~

Cz-C4

, ~ ~ v % ~ r ~ ~

~

~

~

~

~light noise

~

~

~

~

A

~

~

~

~

~ttght noise

~

HF 7~ I F~

Fig. 4. Recording in morning h. Three arousal responses (spontaneous or elicited by light noise) are shown, two of them in conjunction with bilateral-synchronous anterior spikes and spikewave-like discharges

responses are shown in Figure 4. The coexistence of posterior alpha and sleep spindles was also demonstrated with power spectral analysis (Fig. 5). Following a period of slow sleep, a REM sleep period was recorded with a striking dissociation between the oculographic REM pattern and the EEG which showed persisting slow sleep (Fig. 6). These perplexing findings in the EEG laboratory prompted apotysomnographic study in the Sleep Laboratory of the Baltimore City Hospital. A study, which was carried out over 24 h, revealed the following distribution of polygraphic patterns: Waking 3.89%, REM 34.98%, Stage 1 0.4%, Stage 2 11.45%, Stage 3 28.46%, Stage 4 20.82%. This indicates excess of REM sleep and an extremely small segment of wakefulness. Both of these findings must be taken with a grain of salt in view of the reported dissociation syndrome. With the small number of EEG channels, most of the waking periods were considered slow sleep because of coexisting spindles whereas REM periods were determined on oculographic and EMG basis (Fig. 7). Marked bradycardia was also noted during polysomnography.

A further workup at a research unit of Johns Hopkins Hospital included an investigation of the neurotransmitter acid metabotites of dopamine, serotonin and norepinephrine in the cerebrospinal fluid (CSF). CSF was obtained by lumbar puncture in the lateral decubitus position after 12h of bed rest and fasting with plentiful fluid intake. The initial 4ml of CSF was collected in glass tubes containing ascorbic acid (2 mg/ml) as preservative, transported on ice and stored at 70°C. Probenecid (125mg/kg), which blocks the egress of metabolites from CSF, was administered orally in three divided doses. A second sample of lumbar CSF was obtained 18 h

Hypersomnia with Simultaneous Waking and Sleep Patterns

7

o~

0

,'-

m

~'~

~..~ xS.- =

o

o~'~

o ~

~

¢'~ ._~'~ ~

.~'~

o

o

¢~ ~

. ~ e g o

I

0

~

~

~'~ .¢

~

~

~

~

~"~

0

×

Z

<

.= .

8

E. Niedermeyer et al.

FpI-A1 FpEA z F -A t

Fs-A2

~'

F4-A2

!'

T3-A I

A1

Ts-A~ T6-A2

1 sec ] 2ooj,v

P3-A~

O~-A~

~_~. -

~

LF 1 (TC 0.16sec)

~

~

^

Fig. 6. Patient asleep during morning h. REM activity is shown oculographically (bottom channel) while stage 3 non-REM sleep patterns dominate the EEG. Again note high voltage output

after starting probenicid and 6h after the last dose. Homovanillic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) were assayed by a quantitative gas chromatographic/mass spectrometric method (Swahn, 1976) and probenicid was assayed by a modified gas chromographic method (Watson and Wilk, 1973; Zacchei and Weidner, 1973). The results of SEM HVA 105.9ng/ml 5HIAA 57.5ng/ml MHPG 18.5ng/ml

baseline metabolites were as follows: (normal: 100.7=+8.1, after Butler et al., 1978) (normal: 32.1+3.3) (normal: 11.9+ 0.6)

Results of the second CSF examination with a probenicid level of 20ng/ml (more than adequate to block metabolite uptake) were: 5HA 556 ng/ml 5HIAA 214 ng/ml Serotonin turnover, as reflected by the ratio of post/pre probenicid 5HIAA, was 3.7-minimally below the 4--12 fold increase reported (Tamarkin et al., 1970; Goodwin et al., 1973; Parel et al., 1974).

Hypersomnia with Simultaneous Waking and Sleep Patterns

9

E.O.G.

i

Sub-m~ntot EMG

Ai~r

Fs-T6 ~'~.

~ .~.

EKG

~

I

t

"

"

!

~ ~

I ~

l

Fig. 7. Polysomnogram, 24h. Note REM episode with unabated large K complexes and delta activity in frontal leads. (Slow paper speed)

CSF opening pressure was 150 mm HzO, protein 29 mg/dl, IgG 1.1 mg/dl. A screening urine for 5HIAA was normal. Cardiac consultation was obtained because of sleep activated bradycardia and disclosed no evidence of organic disease. EKG, echocardiogram, chest X-ray and 24h Holter monitor recordings were normal. Repeat electroencephalogram and EEG telemetry again showed simultaneous waking and sleep patterns as well as bilateral-synchronous anterior spikes. A therapeutic trial with dextroamphetamine sulfate (Dexedrine) was initiated and has resulted in a dramatic improvement. On a dose of 15 mg taken in the morning, the patient has returned to school without lethargy or sleepiness. His teachers have confirmed a marked

10

E. Niedermeyer et al.

improvement in alertness and scholastic performance. Difficulty falling asleep at night persists. This improvement has persisted over the past 5 months. A recent EEG evaluation, however, was unchanged.

Discussion

The case reported is characterized by coexistence (or simultaneous occurrence) of a) E E G waking patterns and EEG slow sleep (non-REM sleep) patterns, and b) REM sleep activity (oculographically and electromyographically documented) and slow sleep EEG patterns. This combination of waking and sleep activity and dissociation of sleep patterns suggests an encroachment of slow sleep with its EEG correlates on both waking state and REM sleep. Clinically, this unusual constellation has led to marked hypersomnia (especially in the morning hours) and some degree of nocturnal insomnia with difficulty falling asleep. Another puzzling feature of this slow sleep EEG is recurrent bilateral synchronous spike activity over the frontal areas. This introjects an element of epileptological interest notwithstanding the fact that the patient never had seizures. The epileptic discharges could be viewed as merely coincidental (or as the expression of predisposition) but there is also a possibility that the spike discharges represent a part of the disturbance of sleep mechanisms. We will not review the experimental basis of the neuronal circuitry and neurobiochemistry of slow sleep and REM sleep. The discussion of these topics in the Bruges Symposium on Sleep (Chase, 1972) and the review of Morgane and Stern (1974) will familiarize the reader with these subjects. The upshot of this work is as follows: 1) The locus coeruleus (laterodorsal tegmental nucleus) has been demonstrated as the most important brainstem structure in the organization of REM sleep (Dahlstrom and Fuxe, 1964; Jouvet and Delorme, 1965; Shute and Lewis, 1967). Its neurons are noradrenergic as well as cholinergic; important noradrenergic outflowing fiber systems to the diencephalon and telencephalon have been identified (Ungerstedt, 1971). 2) The raphe nuclear complex of the pons is presumed to be the most important structure in the governance of slow sleep. The anterior complex of the raphe nuclei (reaching well into the midbrain) gives rise to a serotonergic pathway (5-HT system) via the medial forebrain bundle to the limbic forebrain area. The case reported makes us wonder if the imbalance of the waking-sleep system is due to an excessively potent slow sleep producing serotinergic system which even invades the domain of the waking and REM-sleep-state. If this hypothesis is true, a state of "hyperserotonergia" ought to be presumed. Neurotransmitter studies in our case permit indirect inferences based on the level of metabolities in the CSF. There is indeed evidence of a high serotoninmetabolite (5 HIAA) level in the CSF which could provide support for our hypothesis. It must be kept in mind, however, that the assessment of neurotransmitter activity is a tedious procedure, thus far scantily used and hardly serving as the basis for convincing conclusions.

Hypersomnia with Simultaneous Waking and Sleep Patterns

11

A further problem stems from discrepancies between experimental work in animals and studies in the human. According to Wyatt et al. (1969), PCPA (parachlorophenylalanine), a drug which inhibits 5-HT synthesis, has relatively little effect on human non-REM sleep in therapeutic dosages (up to 4g/24 h). There was even a decrease of REM sleep from 10 to 70% baseline over a 2 to 3 week period in 16 patients. On the basis of further studies (Wyatt et al., 1970a), these authors assumed that a nonserotonergic tryptophan derivative is capable of increasing non-REM sleep in humans. In another study, Wyatt et al. (1971), focused their attention on the noradrenergic system in human sleep with the use of tyrosine hydroxylase inhibitors, alpha-methylalanine and AMPT, both of which increased REM sleep. AMPT also produced marked daytime drowsiness for the first days of administration. L-Dopa, a precursor of the catecholamines, decreased REM sleep by 5--46% in the human (Wyatt et al., 1970b). In the light of these data, our basic concept of hyperserotonergia may be doubtful but there is reason to presume that the neurophysiological mechanisms of non-REM sleep are overactive (regardless of the neurotransmitter substance involved). There is, however, no explanation for the basis of the patient's daytime hypersomnia and his difficulties falling asleep at night; this is also true for the patient's dyslexia and the previously existing hyperactive behavior. In clinical electroencephalography, spindle activity may occasionally occur in the waking records of children (usually below the age of 5 years) who show "extreme spindles" (Gibbs and Gibbs, 1964) with non-REM sleep. Extreme spindles are of unusually high voltage and of wider distribution then regular spindle activity. This pattern has been associated mainly with mental retardation. In contrast with our case, there is no evidence of vertex waves or K complexes in the waking records of children with extreme spindles. In our patient, the configuration of spindle activity also clearly differs from the patterns of extreme spindles. The bilateral-synchronous anterior spike activity in the EEG poses another question. These spike discharges (in a nonepileptic child with no known genetic predisposition) may be directly related to the massive generation of arousal responses (K complexes) which punctuate the EEG patterns of non-REM sleep. These K complexes have frontal midline rather than vertex maximum. Both types of K complexes are essentially physiological (Davis et al., 1939; Brazier, 1949) but it is the frontal midline K complex which tends to be associated with paroxysmal discharges in predisposed individuals (Niedermeyer, 1972). The "epileptic K complex" (Passouant et al., 1954) represents a classical finding in the sleep records of patients with primary generalized epilepsy (Niedermeyer, 1965, 1966, 1972). These discharges, however, are seen mostly in non-REM sleep (Passouant and Cadilhac, 1970) but are not completely incompatible with REM sleep (Ross et al., 1966; Tomka et al., 1971; Passouant, 1975). Such a presumed linkage between arousal responses in non-REM sleep and bilateral-synchronous seizure discharges has been supported by recent experimental work in the cat by Gloor and his co-workers (Quesney et al., 1977; Gloor et al., 1977; Gloor, 1978). With the use of intramuscular injection of penicillin, resulting bilateral spike-wave activity can be retriggered by electrical stimulation of deep structures and chiefly from areas where electrical stimulation also produces spindles (midline and intralaminar nuclei of the thalamus, parts of the

12

E. Niedermeyer et al.

nucleus reticularis t h a l a m i a n d the nucleus lateralis p o s t e r i o r t h a l a m i , p u l v i n a r a n d n e o s t r i a t u m ) (Quesney et al., 1977). S t i m u l a t i o n o f these areas also precipitates diffuse cortical spike-wave bursts following the a p p l i c a t i o n o f a very weak penicillin s o l u t i o n to the cortex in the cat ( G l o o r et al., 1977). In a d d i t i o n to the spike discharges, the excessive EEG voltage output deserves a b r i e f c o m m e n t . H y p e r s y n c h r o n i z a t i o n due to overactive p o n t i n e reticular structures ( d e m o n s t r a t e d by M a g n e s et al., 1961) c o u l d a c c o u n t for these changes but this is strictly h y p o t h e t i c a l . In conclusion, the case r e p o r t e d seems to be c h a r a c t e r i z e d by a basic b r a i n s t e m d y s f u n c t i o n a s s o c i a t e d with overactive n e u r o p h y s i o l o g i c a l (and p r o b a b l y also n e u r o b i o c h e m i c a l ) m e c h a n i s m s o f n o n - R E M sleep d i s t u r b i n g the p a t i e n t ' s w a k ing-sleep cycle. Precise b i o c h e m i c a l d a t a c a n n o t be p r o v i d e d a n d the n a t u r e o f the t h e r a p e u t i c effect o f d e x t r o - a m p h e t a m i n e (after failure o f m e t h y l p h e n y d a t e ) r e m a i n s obscure.

Acknowledgements. Neurotransmitter metabolite determinations were performed in the Department of Biochemistry, University of Texas, Medical School of Houston, Houston, Texas. We extend our gratitude to Drs. Seifert, Butler and Caprioli. The patient's evaluation at the Johns Hopkins Research Unit was aided by the General Clinical Research Center's Grant RR 52.

References Brazier, M. A. B.: The electrical fields at the surface of the head during sleep. Electroencephalogr. Clin. Neurophysiol. 1, 195--204 (1949) Butler, I. J., Seifert, W. E., Koslow, S. H., Caprioli, R. M., Singer, H. S.: Neurotransmitters in neurological disorders of childhood. Proc. Fourth Int. Catecholamine Symposium of Pacific Groove, California, September 1978 Chase, M. H. (ed.): The sleeping brain. Brain Information Service, University of California, Los Angeles, 1972 Dahlstrom, A., Fuxe, K.: Evidence for the existence of monoamine-containing neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brain stem neurons. Acta Physiol. Scand. [Suppl.] 232, 1--55 (1964) Davis, H., Davis, P. H., Loomis, A. L., Harvey, E. N., Hobart, G.: Electrical reactions to the human brain to auditory stimuli during sleep. J. Neurophysiol. 2, 500--514 (1939) Dement, W., Guilleminault, C., Zarcone, V.: The pathologies of sleep. A case series approach. In: The nervous system, D. B. Tower (ed.), Vol. 2, pp. 501--512. New York: Raven 1975 Gibbs, F. A., Gibbs, E. L.: Atlas of electroencephalography, 2nd ed., Vol. 3. Reading: AddisonWesley 1964 Gloor, P.: Evaluation of the concept of the mechanism of generalized epilepsy with bilateral spike and wave discharge. In: Modern perspectives in epilepsy, J. A. Wada (ed.), pp. 99--137. St. Albans: Eden 1978 Gloor, P., Quesney, L. F., Zumstein, H.: Pathophysiology of generalized penicillin epilepsy in the cat: The role of cortical and subcortical structures. II. Topical application of penicillin to the cerebral cortex and to subcortical structures. Electroencephalogr. Clin. Neurophysiol. 43, 79--94 (1977) Goodwin, F. H., Post, R. M., Donner, D. L., Gorden, E. K.: Cerebrospinal fluid amine metabolites in affective illness: the probenecid technique. Am. J. Psychiatry 130, 73--79 (1973) Guilleminault, C., Dement, W. C.: Pathologies of excessive sleep. In: Advances in sleep research, E. D. Weizman (ed.), Vol. 1, pp. 345--390. Flushing, N.Y.: Spectrum 1974 Guilleminault, C., Dement, W. C.: 235 cases of excessive daytime sleepiness. Diagnosis and tentative classification. J. Neurol. Sci. 31, 13--27 (1977) Jouvet, M.: Biogenic amines and the states of sleep. Science 163, 32--41 (1969)

Hypersomnia with Simultaneous Waking and Sleep Patterns

13

Jouvet, M.: Some monoaminergic mechanisms controlling sleep and wakirig. In: Brain and human behavoir, A. G. Karczmar, J. C. Eccles (eds.), pp. 131--t61. New York: Springer 1972 Jouvet, M., Delorme, F.: Locus coeruleus et sommeil parodoxal. C.R. Soc. Biol. (Paris) 159, 895m899 (1965) Magnes, J., Moruzzi, G., Pompeiano, O.: EEG-synchronizing structures in the lower brain stem. In: The nature of sleep, G. E. W. Wolstenholme, M. O'Connor (eds.), pp. 57--72. London: Churchill 1961 Morgane, P. J., Stern, W.: Chemical anatomy of brain circuits in relation to sleep and wakefulness. In: Advances in sleep research, E. D. Weizman (ed.), Vol. 1, pp. 1--131. Flushing, N.Y.: Spectrum 1974 Mouret, J., Debilly, G., Renaud, B., Blois, R.: Narcolepsy and hypersomnia: diseases or symptoms. In: Narcolepsy, C. Guilleminault, P. Passouant, W. Dement (eds.), pp. 571--584. Flushing, N.Y.: Spectrum 1976 Niedermeyer, E.: Sleep electroencephalograms in petit mat. Arch. Neurol. 12, 625--630 (1965) Niedermeyer, E.: Generalized seizure discharges and. possible precipitating mechanisms. Epilepsia (Amsterdam) 7, 23--29 (1966) Niedermeyer, E.: The generalized epilepsies. Springfield: Thomas 1972 Passouant, P.: Neurological diseases and sleep. In: Handbook of electroencephatography and clinical neurophysiology, A. Remond (ed.), Vol. 7A, pp. 66m73. Amsterdam: Elsevier 1975 Passouant, P., Cadilhac, J., Labauge, R.: La locatisation 61ectroencrphalographique d'un foyer anatomique au cours du sommeil. Montpellier M~d. ~15,581--598 (1954) Passouant, P., Cadilhac, J.: Drcharges 6pileptiques et sommeil. In: Epilepsy, E. Niedermeyer (ed.), pp. 87--104. Basel: Karger 1970 Quesney, L. F., Gloor, P., Kratzenberg, E., Zumstein, H.: Pathophysiology of generalized penicillin epilepsy in the cat: The role of cortical and subcortical structures. I, Systemic application of penicillin. Electroencephalogr. Clin. Neurophysiol. 42, 640--655 (1977) Rechtschaffen,A., Dement, W.: Narcolepsy and hypersomnia. In: Sleep--physiology and pathology, A. Kales (ed.), pp. 119--130. Philadelphia: Lippincott 1969 Ross, J. J., Johnson, L. C., Walter, R. D.: Spike and wave discharges during states of sleep. Arch. Neurol. 14, 399--407 (1966) Shute, C. C. D., Lewis, P. R.: The ascending cholinergic reticular system: neocortical, olfactory and subcorticaI projections. Brain 90, 497--520 (1967) Swahn, C. G., Sandgarde, B., Wiesel, F. A., Sedvall, G.: Simultaneous determination of the three major monoamine metabolites in brain tissue and body fluids by a mass fragmentographic method. PsychopharmacoI. 48, 147--152 (1976) Tamarkin, N. R., Goodwin, F. H., Axelrod, J.: Rapid elevation of biogenic amine metabolites in human CSF following probenecid. Life Sci. 9 (part I), 1397--1408 (1970) Tomka, I., Passouant, P., Baldy-Moulinier, M.: REM sleep and petit mal epilepsy. Quoted after Passouant, P., 1975 Ungerstedt, U.: Stereotaxic mapping of the monoamine pathway in the rat brain. Acta Physiol. Scand. [Suppl.] 367, 1--48 (1971) Watson, E., Wilk, S.: Determination of probenecid in small volumes of cerebrospinal fluid. J. Neurochem. 21, 1569--1571 (1973) Wyatt, R. 3"., Engelman, K., Kupfer, D. J., Scott, J., Sjoerdsma, A., Snyder, F.: Effects ofparachlorophenylalanine in man. Electroencephalogr. Clin. Neurophysiol. 27, 529--532 (1969) Wyatt, R. J., Engelman, K., Kupfer, D. J., Fram, D. H., Sjoerdsma, A., Snyder, F.: Effects of L-Tryptophan (a natural sedative) on human sleep. Lancet 197tla II, 842m846 Wyatt, R. J., Chase, T. N., Scott, J., Snyder, F., Engelman, K.: Effect of L-Dopa on the sleep of man. Nature (Lond.) 228, 999--1001 (1970b) Wyatt, R. J., Chase, T. N., Kupfer, D. J., Scott, J., Snyder, F., Sjoerdsma, A., Engelman, K.: Brain catecholamines and human sleep. Nature 233, 63m68 (1971) Zacchei, A. G., Weidner, L.: GLC determination ofprobenecid in biological fluids. J, Pharmacol. Sci. 62, 1972--1975 (1973) Received December 27, 1978