Current Perspectives on Daytime Sleepiness: The Issues

Transcription

1 Sleep, 5:S56-S Raven Press, New York Current Perspectives on Daytime Sleepiness: The ssues William C. Dement and Mary A. Carskadon Stanford University Sleep Research Center, Stanford, California Although sleep and wakefulness are complementary phases in the daily cycle of human existence, they are usually considered as entirely separate entities and studied in isolation from one another. All-night sleep, in particular, is typically examined in its entirety and minutely dissected with total disregard of either the prior or following hours of wakefulness. A more rational approach is to consider these two phases as mutually interactive. The most obvious interaction between sleep and wakefulness other than their sequential occurrence in each succeeding 24-h period is the predictable fluctuation in daytime alertness as a function primarily of the amount of nocturnal sleep. n general, the more we sleep at night, the more alert or the less sleepy we are in the daytime. Everyone realizes that overwhelming drowsiness in the daytime is the inevitable consequence of failing to sleep at night. n spite of this, sleepiness was virtually ignored as an experimental variable by sleep researchers for many years, even in studies ofthe consequences of experimental sleep deprivation. There- was, of course, an implicit acknowledgment of this consequence in terms of the great care taken to prevent inadvertent dozing during prolonged wakefulness. Yet, one can search through monographs and books on sleep fruitlessly for a single mention of the word sleepiness. nstead, sleep researchers have obsessively focused on other potential consequences: toxicity, psychomotor impairment, biochemical changes, and so forth. From today's vantage point, the conclusion recently reached by Webb (1) seems ironic: " have been watching people perform deprivation experiments for at least 10 years... have been able to come to only one conclusion, that we know one thing and only one thing about total sleep deprivation: it makes you sleepy." Although we cannot fully understand the historical fact that sleep researchers refused to notice one of the core processes in their field, we can give credit to those who finally confronted the problem of daytime sleepiness. t remained for the sleep disorders clinicians to move sleepiness to stage center as the major complaint and disability associated with narcolepsy and sleep apnea syndromes (2-5), and as the dependent variable in clinical trials designed to provide alleviation of the symptom (6-8). One of the first systematic attempts to measure sleepiness quantitatively involved the Stanford Sleepiness Scale (9). This led directly to the development of S56

2 THE SSUES S57 the multiple sleep latency test, a reliable, simple, and straightforward objective approach to the study of sleepiness, which in tum stimulated further research, some of which will be reported later in this volume. n this introductory paper, we will attempt to outline some of the issues involving sleepiness as a phenomenon, as an object of investigation, and as a very important clinical symptom. ssue 1: What is sleepiness? What is alertness? We shall frequently use the terms sleepiness and alertness. n general, they are reciprocal. At our current state of knowledge, we can only speculate whether they are two reciprocal mechanisms, or whether alertness is simply the lack of sleepiness, or vice versa. Given this caveat, the first issue that must be considered is the nature of sleepiness. Most people can quite readily answer the question: Are you sleepy? But the feeling of sleepiness is somewhat difficult to put into words. To some extent sleepiness is a constellation of sensations that can be described. Some involve the eyes-a mild itching or burning-and heaviness of the eyelids requiring a conscious effort to hold them open. We may feel a heaviness in our limbs and bodies and a kind of reluctance to move. There is a loss of initiative and a loss of interest in what we are doing. Concentration becomes increasingly difficult. Sleepiness is a craving or desire for sleep in the same way that hunger is a desire or craving for food. Although it is difficult to describe sleepiness as a subjective feeling, it is possible to add behavioral and objective indicators to the description. Observed behavioral changes are consonant with some of the subjective attributes. There is a general decrease in the amount of movement and a tendency for the body to become quiet. There is a tendency for speech to become slower or to stop altogether, and there is a lack of animation of the facial expression, so that smiling and frowning tend to cease. The sleepy person typically has a glazed or "dopey" expression. Other "sleepy" behaviors include rubbing the eyes and yawning. Finally, when the tendency to fall asleep is virtually irresistible, the head begins to drop and the eyelids begin to close. At this point, it is obvious to even the most casual observer that one is sleepy. The terminology of the Stanford Sleepiness Scale provides a verbal framework for the subjective state of sleepiness. A consensus definition of sleepiness might be desirable. Finally, there is the issue of whether sleepiness is unidimensional or multidimensional. s sleepiness merely the absence of alertness or vice versa? Are there factors that promote sleepiness and entirely independent factors that promote alertness? f there are two reciprocal systems, they must interact smoothly over the entire "vertical" contiluum from behavioral sleep and zero alertness to maximum alertness with zero sleepiness. s there such a thing as being too alert (in the daytime, of course)? A question that might be asked is whether mania is the natural extension of optimal alertness or the introduction of a new quality. Sleepiness is also a reversible quality. A temporary subjective alerting can usually be produced in the most sleepy person by intense stimulation, startle, excitement, and so forth. ssue 2: How should daytime sleepiness be measured? t is already clear that subjective sleepiness and objective sleepiness are not exactly parallel. n addition to the usual problems with any SUbjective response, Sleep. Vol. 5 (Suppl. 2). 1982

3 S58 w. C. DEMENT AND M. A. CARSKADON these two aspects of sleepiness may not simply be two sides of the same coin. Rather, objective sleepiness should probably be thought of as a fairly long-lasting and stable physiological tendency to fall asleep. This underlying tendency may always be present, although moment-to-moment changes, particularly in the way we feel, occur often. The latter probably correspond more closely to subjective sleepiness. We think that a variety offactors can affect how sleepy we feel at any given moment. These factors include excitement, hilarity, pain, stimulation in general, muscular activity, hunger, thirst, fear, high motivation, and so forth. These factors are also related to our ability to avoid actually falling asleep when we are sleep-deprived. We can imagine that if we are very sleepy after a night of sleep loss, a period of vigorous exercise and excitement would make us feel that we are wide awake and alert, whereas if we are just sitting in a chair, we would continue to experience intense drowsiness. Behavioral indications would probably more closely parallel subjective sleepiness, but not always. There is probably no quarrel about how to measure subjective sleepinesssome sort of introspective scale. On the other hand, although the Multiple Sleep Latency Test is widely used in sleep disorder centers, some clinicians and investigators have not accepted it. Another measure is pupillometry. Yet another might be the use of evoked potentials. t seems reasonable, however, that the Multiple Sleep Latency Test (MSLT) is consonant with the notion that we are trying to measure an underlying physiological state. The standard conditions of the test are designed to minimize transient alerting. t might fairly be said that under the conditions of the MSL T, subjective sleepiness should approach physiological sleepiness. ssue 3: What are the determinants of daytime sleepiness? There is solid evidence (10-13) that daytime sleepiness measured by the MSLT is a function of prior sleep and wakefulness. There is also evidence that sleepiness is part of the circadian system in that it fluctuates rhythmically, with a period length of approximately 24 h (14-16). An important issue is how these two major determinants interact. For example, does alertness give way to sleepiness at the end of the day because fatigue is developing, or because the circadian clock commands the change? Reciprocally, does the ability to remain asleep at the end of the night end because we have discharged the sleep need, or because the clock says it is time to be alert? There is evidence (see Fig. 1) that the sleepy phase of the daily rhythm will give way to the alert phase even though a minimal amount of sleep has occurred. To be sure, this may only occur in very special circumstances. Nonetheless, it suggests that the reversal of the sleepy phase, or phase alternation, is not absolutely dependent on a specific amount of sleep. On the other hand, in the total sleep deprivation studies ofcarskadon et al. (10,13), once the phase of maximum sleepiness had occurred, it persisted unchanged regardless of clock time (see Fig. 2). This was true even during the day after the first night when sleep loss was minimal. To make the problem even more complicated, however, severe sleepiness persisted even after recovery sleep, and only gradually changed to alertness as the day wore on in the complete absence of additional sleep (Fig. 2). Another aspect of this issue is the question, whether there are additional determinants of sleepiness. The gist of this question is whether a number of factors- Sleep. Vol. 5 (Suppl. 2). 1982

4 THE SSUES S59 TME 30 FG. 1. The sequence of sleep latencies (top) and accumulation of sleep (bottom) in one subject across 11 consecutive 90-min time blocks during the 9O-min day study. At the start of the graph (2230), the subject was alert (maximal sleep latency) and became progressively sleepier, and finally extremely sleepy (minimal sleep latency) at The arrow at A indicates a reversal in sleep tendency, which was accomplished at 0900, even though only 2.5 h of sleep had accumulated. Full alertness is indicated by arrow B after only 3 h of total sleep time. c E - 20 o >- z w!:i..j Q" W ~ 10 Ul Q" W W..J Ul w 2h > ~ ::: h ::E ~ o Or ~ r_ _; r r- J CUMULATVE SLEEP TME AND SSS SCORE ON A 90 - MNUTE DAY including heat, food, boredom, and such chemicals as alcohol, antihistamines, and barbiturates-are specific in inducing drowsiness, or "unmask" drowsiness, This would relate to the question of whether sleepiness is unidimensional Finding that these factors cannot induce sleepiness in the fully alert person, but only in the partially sleepy person, would suggest the presence of another factor that offsets the various manifestations of sleepiness or enables one to resist sleepiness, The issue most difficult to challenge at the present time is the frequent statement that daytime sleepiness is also a result of "too much sleep" at night, Although many people claim that this happens to them, the putative phenomenon has never been studied systematically with objective measurements, ssue 4: Sleepiness as a motivator A fair amount is known about the neurological substrates of thirst, hunger, and the reproductive drive. n the case of the first two, there are presumed to be central receptors that respond to metabolic changes as a result of reduced fluid and food intake, t is widely assumed that there are internal signals of these changes in metabolic state. n the sense that sleepiness is a response to deprivation of sleep, there may be analogous mechanisms; however, there is no certainty about identifying either ens receptors or internal signals of the deprived state.

5 S60 W. C. DEMENT AND M. A. CARSKADON ~ 15r BASEL.iNE~-_i T, c 10 en ~ 0 ASLEEP ASLEEP e ~ 15 SLEEP DEPRVATON SD-1 C 15 e RECOVERY R-1 ~ 10 z... ~ 5 oj o ASLEEP ASLEEP B-2 ~. SD-2 1 T R-2 N1V-f j TME OF DAY FG. 2. Average (±SD) of sleep latencies on the Multiple Sleep Latency Test in six subjects before. during, and after 2 nights of sleep deprivation. Sleep latencies became minimal during the 1st night of sleep loss and remained extremely low throughout the deprivation period. After a single night of sleep (R- ), sleep latency did not achieve basal values until the evening tests; values in the morning and early afternoon were minimal. Further, whereas the response to deprivation is to intensify and motivate attempts to reverse the deprivation, thirst and hunger differ markedly from sleepiness in that they motivate behavior that prevents death. t is widely believed that prolonged sleep loss does not lead to a harmful consequence, although the absolute prevention of all sleep is so difficult to accomplish that the results of experimental sleep deprivation are not entirely certain. f we put aside the controversy about whether sleep is vitally necessary, certainly the analogy between sleepiness on the one hand and hunger and thirst on the other is valid. t is also entirely true that we simply cannot do without sleep. (Anyone who doubts this should try it.) To be fully alert we must sleep. Since there are so many advantages to being fully alert, we must assume that a motivational system has evolved that prevents sleep loss to an extent that would impair alert/waking function. ssue 5: What is optimal alertness? Sleepiness is so pervasive in adult life that it is certainly considered normal and inevitable. There is no such thing as a dull committee meeting without at least one member nodding off, struggling to hold his or her eyes open, etc. We suggested earlier that this pervasiveness has led to the notion that certain things like eating, drinking, boredom, warm rooms, and so forth cause sleepiness. Now we feel that the physiological state of sleepiness is already present, and that these factors merely inhibit the other factors and motivations which offset physiological sleepiness. This leads to the question, what will happen if there is no physiological sleepiness? Preadolescent children seem to fit this model. As reported by Carskadon (17), these children typically sleep about 9 h at night, and have no tendency

6 THE SSUES S61 whatsoever to fall asleep in the daytime. Anecdotal observations suggest that heavy meals, boring sedentary activities, warm rooms, and the like do not lead to either subjective sleepiness or reduced sleep latencies on MSLT. Their daily sleepiness rhythm appears to be of maximum amplitude, with long, uninterrupted, deep sleep at night, giving way quickly to continuous, full alertness all day long. They cannot nap; they never fall asleep during MSLT testing. t thus appears that there may be an optimal amount of sleep that makes optimal prolonged alertness possible within the constraints of an underlying circadian organization. This leads to another question: May we assume that sleep at night is less than optimal whenever there is even the smallest manifestation of daytime drowsiness? The preadolescent model also suggests that 24-h function is optimal when scheduled bedtime hours and the underlying 24-h rhythm are completely synchronous. This is true in the case of the children, and they are consequently able to go to bed when they are sleepy, and get up when they are fully restored. What is responsible for this synchrony? Extreme regularity? Central nervous maturation? s it possible that at this age the human being is socially more in tune with his chronobiological function? ndeed, these children are so alert and energetic all day long, and sleep so well at night, it seems to provide a glimpse of paradise. n this sense, puberty, as Carskadon will point out, is paradise lost. ssue 6: How does sleep reverse sleepiness? We have said that after sleep loss, maximal sleepiness persists until sleep occurs. n other words, sleep, or a certain amount of sleep, is necessary to alleviate sleepiness. How does the state of sleep discharge this function? Must sleep be continuous? s the reversal of sleepiness solely a function of the overall amount of sleep? To what extent is the complex architecture of states and stages through the night involved in promoting daytime alertness? Are there any differences between REM sleep and NREM sleep in this regard? These are very interesting questions. At the moment there are no final answers, but there are some tantalizing hints. For example, have already mentioned that sleepiness can be reversed even though the sleep prior to the reversal is fraught with discontinuities. On the other hand, hundreds of transient arousals are as likely to be associated with sleepiness as a single reduced sleep period. Carskadon has published evidence that REM sleep may be more important in reversing sleepiness, minute for minute, than NREM sleep (15). Another interesting phenomenon is the time course of the sleep reversal under certain circumstances. Thus, after 60 h of sleep loss and a single 8-h period of recovery sleep, daytime sleepiness is totally unreversed and alertness recovers through the day (see Fig. 2) without any additional sleep. These data certainly do not fit the model of' 'recharging the batteries." A caveat to this may be that subjective sleepiness and objective sleepiness are not exactly parallel. Thus, one may wake up after sleeping through the night following a period of prolonged wakefulness feeling quite refreshed, yet one could return to sleep very easily. n this peculiar recovery pattern actually due to a phase shift of the circadian oscillator that paces the daily rhythm of sleepiness and alertness? t could also mean that the organism is intended to sleep longer. Sleep. Vol. 5 (Suppl. 2), 1982

7 S62 W. C. DEMENT AND M. A. CARSKADON ssue 7: What about napping? An issue that is related to much of the foregoing is daytime napping. f they sleep their usual amount at night, preadolescents will not, or cannot, nap. Certainly they do not need to nap. However, if their sleep at night is gradually reduced, a remarkable phenomenon occurs: sleepiness develops in the daytime in a very specific way. n effect, the sleep latency profile becomes a catenary curve. A midday dip develops, and reverses towards evening with no sleep whatsoever. As sleep loss continues, the dip becomes a chasm, and then the ends drop. Obviously, the best time for a nap would appear to be at the time of the dip. This also suggests a CNS program for the response to sleep loss rather than a global fatigue process. ssue 8: The central nervous system f sleepiness has an objective, physiological dimension, what are its specific neurological substrates? At the macro level, we can specify certain electrophysiological events, such as EEG microsleeps, and the very interesting phenomenon reported by Rechtschaffen and his colleagues (18,19), the hippocampal spike. EEG micro sleeps and hippocampal spikes appear in behaviorally awake humans and animals, respectively, as a function of sleep deprivation. At the micro level, nothing is known, because we have not specifically defined sleepiness in animals. However, if we can infer that an animal is sleepy immediately prior to falling asleep, then neurons designated "on" cells for the transition from wakefulness to sleep might be involved (20). We would also, then, presuppose that the operation of a sleep system must begin in the waking state, and could theoretically continue in the waking state; thus the initiation of sleep and the cause of sleepiness would be identical. What about neurochemical correlates? nsofar as neurochemical analysis following sleep deprivation has produced no conclusive results, little can be said. However, pharmacological studies have been more productive. The clearest link between neurochemistry and sleepiness involves pharmacological agents that produce alerting, i.e., the central nervous stimulants like amphetamine, whose mechanism of action is apparently to block uptake of catecholamines at the synapse. Further, chemical (6-hydroxydopamine) and electrolytic destruction of central catecholaminergic systems predisposes to greater amounts of sleep. Thus, it is possible that what underlies the production of drowsiness is a reduction of activity in dopaminergic and noradrenergic neuronal systems. f this is true, we must ask what causes a reduction of adrenergic activity? Once again we must invoke the notion of two reciprocal systems. s there another system that causes sleep or inhibits arousal? t was once thought that serotonergic neurons constituted such a "sleep" system; however, discharge patterns of raphe neurons (21) are exactly the opposite of what one would predict-i.e., a system coming into activity as sleep approaches, with maximal activity near the transition. Serotonin neurons are most active during wakefulness, and their discharge diminishes as sleep approaches.

8 THE SSUES 563 The most potent compounds that induce drowsiness appear to be several of the benzodiazepines. For example, triazolam at a dose of approximately mg/kg reliably produces drowsiness in a human subject. n addition, the brain is rich in high-affinity benzodiazepine receptors. There is also some evidence that barbiturates affect the sensitivity ofthese neural structures. Do benzodiazepine receptors modulate the dimension of sleepiness/alertness? What must be asked in this regard is whether or not sleep and sleepiness are the same process. An approach to this problem would be to test sleep inducers in totally alert subjects. nsofar as anesthesia can be induced in anyone, it is likely that a quasi-sleep state would be induced if the dose of any so-called hypnotic were high enough. What we want to know is whether sleepiness and/or sleep can be triggered by a "physiological" dose in a fully alert subject. This would imply specificity. Exactly how receptor-ligand interaction would produce sleepiness and sleep is entirely uncertain. There are no clear cellular neurophysiological correlates of the sleep onset. The most common speculation is that it would involve reduced activity; however, this has not been convincingly demonstrated. We must also account for all the remarkable ways in which daytime sleepiness runs its course. The circadian clock and the amount of prior sleep interact in some way at the cellular level. Perhaps the underlying circadian process is fundamentally biphasic. Something keeps very close track of the total sleep time per 24 h. How else can we account for the changes in daytime sleepines over several consecutive days in response to relatively small increments or decrements in sleep? ssue 9: What is the functional significance of sleepiness/alertness? Perhaps the most important issue from a practical point of view is the degree to which being sleepy impairs or diminishes other functions. As will be described later in this volume, there is an age at which sleep and wakefulness appear naturally to be optimal. Carskadon and her colleagues (22) have reported 24-h studies in prepubertal adolescence in which nocturnal sleep was highly synchronous, highly efficient, highly continuous, and of substantial amounts, e.g., 9 h. During the day, the subjects failed to show any sleepiness whatsoever. t is tempting to conclude that these children were also functioning at peak levels in other ways: learning, remembering, initiative, creativity, enthusiasm, and so forth. t is certainly true that inducing sleepiness during the day in these subjects by partial sleep loss was associated with behavioral change, mood change, and even decrements in laboratory performance. t is widely believed that extreme sleepiness will impair performance (23,24); however, it is difficult to document this belief, and essentially impossible when sleepiness is mild. Laboratory performance aside, insofar as sleepiness can be measured with precision and changes have been reported as a function of sleep deprivation, age, clinical sleep disorders, and drugs, it would be extremely desirable to specify the consequences of diminished alertness. s alertness desirable and "good," or is it good only up to a point when it begins to change into anxiety, tension, and even mania? s it possible that some individuals find alertness uncomfortable and sleepiness more akin to tranquility? As with all other motivational phenomena, it seems that postponement of the consumatory response {going Sleep. Vol. 5 (Suppl. 2). 1982

9 S64 W. C. DEMENT AND M. A. CARSKADON to sleep) is unpleasant and consumation is pleasant. s drug-induced sleepiness the same as the sleepiness that occurs normally in the course of the unraveling of the circadian oscillation or in response to a reduction in prior sleep? t is likely that the above issues regarding functional sigqificance can come only from a different approach to the problem eschewing the conventional laboratory test batteries and trying to examine function over a long period of time in the field. Does a sleepy child do more poorly in school? Does the alert student get better grades? Does the alert employee do better on the job? Can these things be measured? Finally, and perhaps most important, does the fully alert human being simply enjoy life more, go through the day with more zest, and so on? ssue 10: Changes with age f we accept that sleepiness is what underlies the timing and occurrence of sleep, then we can assume marked changes across the life span. The newborn infant must be quite sleepy generally, with relatively brief periods of alertness. Daytime sleepiness must continue through the period of napping until finally, some time before age 10, the daily cycle is fully consolidated and has maximum amplitude. (There is no indication that the optimally alert children described above are in any way tense or anxious.) Then, as we continue to age, this optimal fluctuation begins to break down again, so that daytime sleepiness increases with age (25). To what extent is this a reversal of the apparent consolidation seen in children-a gradual dispersion of sleeping and waking tendencies? n this regard, we might ask the question, how much sleep, and of what kind, is required to produce h of continuous alertness? t is interesting in this regard that suprachiasmatic nucleus lesions that render animals aperiodic do not change total sleep time: rather, they change maximally consolidated phases of alertness into maximum dispersion. ssue 11: Clinical usefulness There is no question that the measure of daytime sleepiness is an important, if not indispensable, clinical test (26,27). The major application to date has been in the diagnostic evaluation of patients complaining of excessive daytime sleepiness. For extension of the clinical usefulness of this approach, two directions come to mind. The first would be routine evaluation of daytime sleepiness in patients with chronic insomnia. This could give additional insight into the meaning of the nocturnal sleep parameters, particularly when they do not seem to be excessively disturbed. The second direction would involve the use of MSLT or other measures to evaluate treatment, i.e., to follow the patients. This would involve the documentation of improved daytime alertness after prescribing stimulants in narcolepsy, after surgery in upper airway sleep apnea, and after hypnotics or sleep hygiene in chronic insomnia. With regard to the use of hypnotics, there are several issues involving daytime sleepiness. One is whether "improved" sleep following bedtime medication is normal in the sense that it would be followed by improved daytime alertness. Another is the use of MSLT measures to evaluate the degree of daytime sedation produced by long-acting hypnotics. t is likely that improved alertness would only

10 THE SSUES S65 be possible with short-acting hypnotics that had no direct effect in the daytime. Finally, are sedation and physiological sleepiness the same? t is certainly easier to induce sleep with a benzodiazepine at midnight than at 10 a.m. after a very good night of sleep. Seidel (28) has presented results showing that diurnally active sleeping medications increase daytime sleepiness. s there a consistent relationship between daytime plasma levels and daytime sleepiness? n some studies where very high plasma levels acccumulated over time, subjects were not overwhelmingly sleepy (28). A final practical issue of great importance is the need to devise methods that would lead to substantial cost reduction in the evaluation of daytime sleepiness. t is likely that widespread clinical application will occur only if the measures are much more inexpensive. Then, we can envisage weekly testing of patients with narcolepsy while we titrate the daily dosage of medication, or weekly testing to monitor for the development of daytime sedation in elderly patients being treated symptomatically for insomnia. Conclusion Daytime sleepiness and nighttime sleep appear to be closely and causally related. This relationship with its various ramifications is one of the most fundamental concerns of the discipline of sleep research. Given the severe impairment caused by pathological sleepiness, as in narcolepsy and upper airway sleep apnea syndrome, or prolonged total sleep loss, and the excellent functioning and zest of being fully alert, it is not an exaggeration to say that sleepiness/alertness is one of the most important dimensions of human function. t is therefore appropriate to review our knowledge about sleepiness as carefully and comprehensively as possible. The collection of papers in this issue is the first such attempt. Acknowledgments: This work was supported in part by National nstitute on Aging Grant AG W. C. Dement is supported in part by National nstitute of Mental Health Research Scientist Award MH REFERENCES 1. Webb W. Sleep deprivation: total, partial, and selective. n: Chase M, ed, The sleeping brain. Los Angeles: UCLA Brain nformation Service, 1972: Dement W. Daytime sleepiness and sleep "attacks." n: Guilleminault C. Dement W, Passouant P, eds, Narcolepsy. New York: Spectrum Publications, 1976: Guilleminault C, Dement W. 235 cases of excessive daytime sleepiness: diagnosis and tentative classification. J Neural Sci 1977; 31: Guilleminault C, Billiard M, Montplaisir J, Dement W. Altered states of consciousness in disorders of daytime sleepiness. J Neural Sci 1975; 26: Dement W, Carskadon M, Richardson G. Excessive daytime sleepiness in the sleep apnea syndrome. n: Guilleminault C, Dement W, eds, Sleep Apnea Syndromes. New York: Alan R. Liss, nc., 1978: Zarcone V, Dement W, Smythe H, Hoddes E, Phillips R. Oral L-5-hydroxytryptophan in narcolepsy. Sleep Res 1972; 1: Billiard M, Guilleminault C, Dement W. A menstruation-linked periodic hypersomnia (Kleine Levin syndrome or new clinical entity). Neurology 1975; 25: Roth T, Hartse K, Zorick F, Conway W. Multiple naps and the evaluation of daytime sleepiness in patients with upper airway sleep apnea. Sleep 1980; 3: Hoddes E, Zarcone V, Smythe H, Phillips R, Dement W. Quantification of sleepiness: a new approach. Psychophysiology 1973; 10:431-6.

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