Clinical Disorders of Sleep
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Clinical Disorders of SleepISMET KARACAN, M.D., (Med.) D.Sc., PATRICIA J. SALIS, M.A. AND
ROBERT L. WILLIAMS, M.D.
The modem era of sleep research can beconsidered to have begun in 1935, whenLoomis, Harvey, and Hobart! first describedfive stages into which electroencephalographic(EEG) activity during sleep could be cate-gorized. The next major discovery did notoccur until 1953, when Aserinsky and Kleit-man2 reported that bursts of conjugate, rapideye movements (REM) periodically appearduring sleep. The later report of these sameauthors:! that subjects awakened during REMperiods recalled dreaming much more oftenthan when they were awakened from otherstages of sleep, was the primary stimulus forthe truly immense activity which has charac-terized the field of sleep research during thelast 20 years.
As a result of this activity, it has beenlearned that normal, healthy individuals alter-nate between REM and the other, non-REM(NREM), stages of sleep throughout eachnight. NREM sleep consists of stages 1, 2, 3,and 4 sleep, with each successive stage repre-senting progressively more synchronized EEGactivity. REM sleep consists of stage 1 lowvoltage, fast activity in the EEG and REM inthe eye movement channels. S!ages 3 and 4sleep are typically concentrated during thefirst part of the night, while REM sleep pre-
The preparation of this review and some of thework described were aided by Public Health Servicegrant MH 15508, Veterans Administration researchfunds, and Clinical Research Center grant FR-82.
This paper was presented at the Annual Meeting ofthe Academy of Psychosomatic Medicine, San Diego,California, October, 1972.
Dr. Karacan is from Department of Psychiatry,University of Florida, and Psychiatry Service, Vet-erans Administration Hospital, Gainesville, Florida.
Patricia Salis is from Department of Psychiatry,University of Florida, and Research Service, VeteransAdministration Hospital, Ganesville, Florida.
Dr. Williams is from Department of Psychiatry,Baylor College of Medicine, Texas Medical Center,Houston, Texas.
dominates during the later part of the night.4
Each individual exhibits a relatively consistentand characteristic sleep pattern from night tonight. However, the precise sleep pattern isvery much dependent upon the individual's age,for there are quite definite changes in character-istic sleep patterns with increasing age.48 Itis presently believed that REM and slow-wavestages 3 and 4 sleep serve particularly impor-tant functions, because selective deprivation ofthem is followed by compensatory increases intheir amounts on recovery nights.9,lo REMsleep is the parameter which has been mostconsistently found to be affected by pharma-cological agents: A vast majority of the com-pounds evaluated suppress REM sleep to atleast a mild extenLll-13
In addition to the studies which have pro-vided this type of information, a great numberof sleep researchers have been engaged in anintensive exploration of the relevance of sleepdisturbances to the understanding of the etiol-ogy and process of numerous disease states.These efforts have produced literally thousandsof miles of EEG data. As you will shortly see,they have also provided many intriguing piecesof information, and hypotheses concerningthem. However, perhaps more so than in manyother fields, much of this information has yetto become understood by the general popula-tion of physicians, and thus it has yet to makethe widest possible contribution to the diag-nosis, prognosis, and treatment of patients.
In the hopes of helping correct this situation,we will spend the next several minutes reviewingsome of the major findings ~rom the sleeplaboratory concerning various clinical condi-tions. As in other fields, obtaining the mostcoherent picture of such data would be greatlyaided by a satisfactory classification system.Such a system does not yet exist in the field ofsleep research. We believe that the most efficientmanner of deriving a useful system would be to
construct a sort of "Periodic Table" of sleepdisorders, with various neurophysiological,physiological, biochemical and psychologicalvariables listed along one axis and the clinicalsyndromes listed along the other. Naturally, theEEG characteristics would be the most impor-tant neurophysiological variables to consider.We should include categories not only relat-ing to the conventional measures of sleep,such as the percentages of each sleep stage,total sleep time, etc., but also categories relat-ing to the basic waveforms of the sleep EEG.Numbers and distributions of sleep spindlesand delta activity are examples of these vari-ables. With recent advances in the computeranalysis of the sleep EEG, the derivation ofsuch quantities is becoming more and morefeasible. With these same computer techniques,we could also derive information on quali-tative changes in the various waveforms of thesleep EEG. Among the other variables whichwe might include are measures of electromyo-graphic (EMG) activity, eye movement activ-ity, including eye movement density, nocturnalpenile tumescence, blood pressure, heart rate,and respiration rate. Changes in the variousbiochemical and neurohormonal concomitantsof sleep should also be noted, as well as findingsrelated to the personality characteristics of thepatients, the natural history of each clinicalcondition, and the type and outcome of re-sponses to different treatment modalities.
If we were to construct such a table today,we would quickly see that most of the cellswould be blank. However, preparing this tablenow might not be a wasted effort, for it wouldcertainly graphically illustrate the areas inwhich further research should be concentrated.When enough information had been gatheredto complete this table, an evaluation of thesimilarities and dissimilarities among and be-tween the clinical syndromes on all of the vari-ables would form the logical empirical basisfor a useful classification system.
But since we are not yet able to constructa complete table of sleep disorders, we mustmake do with rather arbitrarily determinedclassification systems which seem to best ac-count for the data we possess at present. The
classification scheme we will employ here issuch an attempt. It is presented in Table I. Forconvenience, we have divided the diseases onwhich we currently have data into four generalcategories. The first, which we have called Pri-mary Sleep Disorders, includes conditions inwhich abnormalities of sleep constitute theprincipal, and frequently only, symptoms.In the Secondary Sleep Disorders, specific ornon-specific sleep disturbances may accompanythe chronic clinical problem. The Parasomniasrepresent sleeping behaviors or automatismswhich are normal during wakefulness but con-sidered abnormal, or at least unusual, duringthe sleeping state. The last category, Sleep-Modified Disorders, is something of a "catch-all" category, but it generally includes the nu-merous disorders which are known to bechanged, either for better or worse, during thesleeping state, but which appear not to havesignificant effects on, or be accompanied bychanges in, sleep itself.
PRIMARY SLEEP DISORDERS
It is becoming increasingly evident to manyphysicians and researchers that primary insom-
TABLE ICLINICAL DISORDERS OF SLEEP
Primary Sleep DisordersInsomniaNarcolepsyChronic HypersomniaKleine-Levin SyndromePickwickian SyndromeSleep ParalysisNightmares
Secolldary Sleep DisordersSchizophreniaDepressionChronic AlcoholismPostpartum Emotional DisturbancesChronic Renal InsufficiencyNutritional DisordersThyroid DysfunctionNeurological Disorders
Sleep-Modified DisordersCardiovascular DisordersRespiratory DisordersEpilepsiesNeuromuscular Disorders
DISORDERS OF SLEEP-KARACAN. ET AL.
nia is a distinct disease entity, and is to be dis-tinguished from an inability to sleep which isassociated with some other chronic physical ormental disturbance. Although recent evidenceindicates that some form of psychological dis-turbance probably accompanies primary insom-nia or the related "poor sleep" syndrome,14.17there is also good evidence of a physiologicalbasis for the insomniac's often rather vaguecomplaint of inability to sleep. Sleep laboratorystudies have shown that these patients exhibitEEG signs of disturbances in sleep induction,sleep maintenance, and/or sleep quality.16,18-20Furthermore, Monroe16 has reported that hissample of "poor sleepers" exhibited heightenedphysiological activation (heart rate, peripheralvasoconstriction, and rectal temperature) bothbefore and during sleep. Our own concentratedstudy of insomniacs has impressed us with sev-eral facts. The first is that within any some-what random sample of insomniacs there is astriking degree of heterogeneity, both in termsof the patients' complaints and in terms oft;~e EEG signs of sleep disturbance. This hasled us to speculate that there are at least severalsubtypes of insomnia which further researchwill allow us to describe according to EEGcharacteristics. Another finding is that a par-ticular patient may show an abnormally highdegree of variability in his EEG sleep patternsfrom one night to the next. This suggests thatat least part of the insomniac's problem may behis inability to rely on a night's sleep properlypreparing him for the next day. A third findinghas been that some patients who may not exhib-it any quantitative EEG sleep disturbances,nevertheless exhibit certain qualitative EEGsleep disturbances, such as an intermingling ofalpha and delta activity. These qualitativechanges could conceivably be the basis for theircomplaints of inadequate sleep. Our prelim-inary irr.pression is that pharmacologic treat-ment is often ineffective in such patients.
Narcolepsy is one of the most dramatic ofthe primary sleep disorders. The modem diag-nostic criteria, elucidated by Voss and Daly in1957,21 delineate the narcoleptic tetrad as con-sisting of sleep attacks, cataplexy, sleep paraly-sis, and hypnagogic hallucinations. AU patientsdo not exhibit all four elements of the tetrad,
but most do exhibit sleep attacks. As withinsomnia, there is some indication that psycho-logical factors may play a role in narcolepsy,but in this case it would appear to be the roleof a precipitator22 rather than of a chronic dis-turbance. 23,24 From sleep laboratory studies itappears that most narcoleptics who exhibitsleep attacks and at least one of the auxiliarysymptoms in the tetrad, suffer from a distur-bance of the REM sleep system. This is sug-gested by the finding that both daytime andnocturnal sleep in these patients are frequentlycharacterized by a REM period very near theonset of sleep.25-30 Such sleep-onset REM pe-riods are rarely observed in normal subjects.Furthermore, the auxiliary symptoms of sleepparalysis, cataplexy, and hypnagogic hallucina-tions appear to be exaggerated and dissociatedforms of REM sleep.26,27,29.32 On the otherhand. narcoleptics who suffer only from sleepattacks seem to have a primary disturbanceof the NREM sleep system, for their sleep at-tacks are generally indistinguishable from typi-cal NREM sleep periods, and the patientsrarely exhibit the sleep-onset REM periodscharacteristic of the first type of narcoleptic. 26.29
A further distinction between these two typesof narcoleptics is the quality of their nocturnalsleep. Patients with several of the narcolepticsymptoms show numerous and long awaken-ings, decreased sleep time, frequent body move-ments, and decreased slow-wave sleep.25.3o,33.36Patients with only sleep attacks seem to sleepquite normally at night.25,34 Although it is gen-erally agreed among sleep researchers that nar-coleptics with auxiliary symptoms do sufferfrom a REM sleep disturbance, there is somecontroversy about whether or not all narcolep-tics suffer from a NREM sleep disturbance.Some evidence 29,37,38 suggests that this is thecase, but the issue remains to be resolved.
A distinct clinical disorder of chronic hy-persomnia has only recently been recognized,and this has been largely due to the studiesby Roth and Rechtschaffen and their col-leagues.23 ,:19,40 The principal complaints areextended nocturnal sleep periods and/or nu-merous and lengthy daytime sleep periods. Al-though nocturnal sleep appears to be undis-turbed, a frequent complaint is postdormital
confusion, or "sleep drunkenness." Daytimesleep attacks are generally longer and less com-pelling than those of the narcoleptic. Sleeplaboratory studies of samples of these patientsrevealed that their nocturnal sleep was essen-tially normal, though somewhat longer than isusually observed in the sleep laboratory. Theextended sleep consisted of a continuation ofthe expected pattern of REM and NREM sleep.Daytime sleep attacks were characterized byalternations between stages I and 2 sleep andwakefulness, although the recording times andprocedures may have biased against the appear-ance of REM and slow-wave sleep. Two epi-sodes of postdormital confusion were recorded,and seemed to consist of a mixture of stage Isleep and wakefulness. Perhaps the mostintriguing finding was that hypersomniacs ex-hibited higher heart and respiration rates thanthe investigators had recorded in various othertypes of normal and abnormal sleepers. Therewas even the suggestion that the severity of thehypersomnia was related to the degree of ele-vation of these physiological responses.
The Kleine-Levin syndrome is a rare dis-order consisting primarily of periodic hyper-somnia and excessive eating.41,4~ Among re-searchers there is currently some debate aboutwhether this is indeed a distinct clinical en-tity,4:1.4;; and, what is even more important,whether these patients really sleep excessively.In one series of patients the daytime sleep dur-ing exacerbations was described as natural;4G ina second study it was light and unstable, butessentially normal;47 and in two other studiesthere was no evidence of sleep spindles.4;;,48Since the presence of sleep spindles is requiredby current sleep EEG scoring methods to de-termine the presence of sleep, this latter resultwould indicate that the patients may in fact notbe asleep during their exacerbations. However,the few results from studies of nighttime sleepin these patients indicate that they do sufferfrom some sleep abnormality. During anexacerbation, one patient's nocturnal sleep waslight and unstable, with decreased amounts ofREM and stage 4 sleep.47 This and one otherpatient49 were studied between exacerbations,and although deep sleep had attained normallevels, REM sleep continued to be depressed.
The systems disturbed in this syndrome-sleep,alimentary, and sexual-support the currentnotion that the disorder stems from some dys-function in hypothalamic or diencephalicareas, 4~,4G.48,;;0.;;r. although some authors main-tain that psychological factors interact with thisorganic defect to produce the characteristicsymptom com...