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Sleep Medicine Reviews (2008) 12, 87–94

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GUEST EDITORIAL

Excessive daytime sleepiness: Population andetiology versus nosology

The present issue is remarkable for containingthree complementary reviews on the topics ofnarcolepsy and hypersomnia. In the first, Ohayon etal.,1 provide data on the prevalence of hypersom-nia disorders. In the second, Plazzi et al.2 reviewnocturnal sleep disturbances in human narcolepsy.In the third, Overeem et al.3 discuss the possibilityof an autoimmune mediation of hypocretin cell lossin narcolepsy. These three reviews reveal strikinggaps in our knowledge, and argue for increasedresearch efforts.

Starting from the epidemiological point of view,whereas population correlates of excessive daytimesleepiness (EDS) are reasonably well studied,4–7

little is known regarding the prevalence of hyper-somnia disorders.1,8 In population-based studies,the prevalence of severe daytime sleepiness,defined either as ‘‘feeling of excessive daytimesleepiness occurring often or very often’’, or ‘‘wheninterfering with daily activities’’, is 4–10%.1 Moststudies have also found decreased subjectivesleepiness from young to middle age and increasesfrom middle to old age, but no strong differencesacross sex. Interestingly, studies across Europe haveshown more daytime sleepiness in Northern Eur-opean countries.

EDS is often considered a mere reflection ofinsufficient sleep6,7 or sleep-disordered breathing(SDB).5,9–11 In fact, strong correlations betweensleepiness and neuropsychiatric disorders, mostnotably depression are also systematicallyfound4,12–15 and often underestimated. An addi-tional complication may be that SDB and depressionare also associated.16,17 These correlations extendto sleep paralysis, hypnagogic hallucinations, twosymptoms found in narcolepsy, with suggestionsthat sleepiness could be a partial mediator.18–21

These associations underscore the complexity ofthe clinical landscape in this clinical area. Similarly,

ee front matter & 2008 Elsevier Ltd. All rights reservmrv.2007.12.006

Ohayon et al. report that sleepiness associated withinsufficient sleep, as defined by ‘‘sleepiness thatcould be alleviated if the subject had the oppor-tunity to sleep more’’, can be found in �8% of thepopulation.1 Importantly however, in many casesinsomnia or depression was also reported. In onestudy where these diagnoses were excluded, theprevalence of ‘‘insufficient sleep’’ was found to beonly 1%.4

Whereas EDS has been explored in many samples,very few studies have studied prevalence andcorrelates of excessive sleep amounts. The mostcommonly cited study, from the National Instituteof Health Catchment area, suggests a prevalence of3% for excessive sleep.22 Ohayon et al. reported a0.3% prevalence for excessive sleep with daytimesleepiness but no evidence of depression orconfounding factors,4,23 a definition similar toInternational Classification of Sleep Disorders(ICSD-2)24 hypersomnia with long sleep time, a raredisorder originally described by Bedrich Roth.25

Hypersomnia in this context has the original mean-ing of ‘‘increased sleep’’ with sleepiness, whereasthe term is now commonly used to describe EDS ofprobable central origin, when not explained byinsufficient sleep, circadian abnormalities or otherproblems disrupting sleep at night (essentially adiagnosis of exclusion, see Table 1).

Problematically, epidemiological study resultsare often difficult to compare as they typicallyuse different designs and assessment tools. TheEpworth Sleepiness Scale (EES), a commonly usedinstrument, is notable for its variation acrosssamples, with 13–30% of various populations re-porting scores above 10 (indicative of sleepiness),5

raising the question of the validity of the scaleacross cultures. Furthermore, as noted by Ohayonet al.,1 few epidemiological studies address symp-tom duration, a key component in the ICSD-2

ed.

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Table 1 International classification of sleep disorders (ICSD2): diagnosis pertaining to commonly encounteredhypersomnias.

Condition Symptoms Diagnostic criteria

Narcolepsy withcataplexy

Complaint ofEDS, recurrentnaps, or lapsesinto sleep forat least 3months

A definite history ofcataplexy is present;cataplexy defined assudden and transientepisodes of loss ofmuscle tonetriggered by strongemotions (mostreliably laughing orjoking; bilateral andbrief; less than 2min;consciousnesspreserved)

No medical or mentaldisorder accounts forthe symptom

The diagnosis of narcolepsy should,whenever possible, be confirmed bynocturnal polysomnography (TST 46 h)followed by an MSLT(MSLp8min;X2SOREMPs).Alternatively,CSF hypocretin-1 may be measured andfound to be low (p110 pg/ml or 1/3 ofmean normal control values

Narcolepsywithoutcataplexy

Complaint ofEDS, recurrentnaps, or lapsesinto sleep forat least 3months.

Typical cataplexy isnot present althoughdoubtful or atypicalcataplexy-likeepisodes may bereported

No medical or mentaldisorder accounts forthe symptom

Supporting evidence is required,typically in the form of a positive MSLT,as described above for narcolepsy withcataplexy

Idiopathichypersomniawith long sleeptime

Complaint ofEDS for atleast 3 months

Prolonged nocturnalsleep time (X10 h),documented byinterviews,actigraphy or sleeplogs. Waking up in themorning or at the endof naps is almostalways laborious

No medical (mostnotably head trauma)or mental disorder ispresent that couldaccount for thesymptoms. Symptomsdo not meet thediagnostic criteria ofother sleep disorderscausing excessivesleepiness

PSG excludes other causes of sleepiness.It demonstrates a short-sleep latencyand a major sleep period that isprolonged to more than 10 h in duration.If an MSLT is performed, a mean sleeplatency of less than 8mins and no or oneSOREMPs

Idiopathichypersomniawithout longsleep time

Complaint ofEDS for atleast 3 months

Nocturnal sleep ofnormal habitualduration (46buto10 h). Needdocumentation byinterviews,actigraphy or sleeplogs

No medical or mentaldisorder accounts forthe symptom.Symptoms do notmeet the diagnosticcriteria of othersleep disorderscausing excessivesleepiness

PSG must be performed anddemonstrates a major sleep period ofnormal duration (46 buto10 h). Sleepefficiency is usually more than 85%. AnMSLT performed following a PSG mustshow: (1) MSL p8min; (2)o2SOREMPs

Recurrenthypersomnia(includesKleine–Levinsyndrome andmenstrual-relatedhypersomnia)

The patientexperiencesepisodes ofEDS lasting aminimum of 2days up to 4weeks

Episodes recur atleast once or twice ayear

The hypersomnia isnot associated withother medical ormental disorders,such as tumors of thecentral nervoussystem or bipolardisorder

The patient has normal alertness,cognitive functioning and behaviorbetween attacks

CSF: lumbar sac cerebrospinal fluid; EDS: excessive daytime sleepiness; MSLT: Multiple Sleep Latency Test; PSG:polysomnography; SOREMP: sleep-onset rapid eye movement period; TST: total sleep time.

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definition of disorders. Finally, large-scale studiesdo not use polysomnography and thus cannotexclude a contribution of SDB or periodic legmovements (PLMs). The lack of sleep data also

means that actual biological data, more likely to begenetically and pathophysiologically correlated,are not gathered. Illustrating this point, studieshave shown only modest correlations between

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subjective reports of EDS (e.g. ESS) and MultipleSleep Latency Tests (MSLT)-based assessment.7,26,27

These findings are in line with recent workindicating significant inter-individual variationsand a clear disconnection between actual physio-logical measurements of sleep debt and perfor-mance versus self-reports of sleepiness.10,28 Asobjective measures of sleepiness are known to bemore sensitive to sleep deprivation than subjectiveassessments, it is clear that subjective assess-ments, such as the EES, do not simply reflectchronic sleep deprivation, and may be moresensitive to psychiatric context (perhaps mostevident in subjects with depression). Similarly,recent studies have shown genetic correlationswith ferritin levels and PLMs,29,30 illustrating thevalue of physiological assessments for etiologicalresearch.

Moving from symptom association to actual ICSD-2 diagnosis for specific hypersomnia disorders isdifficult (Table 1), as much of the data describedabove suggest multi-factorial effects rather thanisolated, well-defined, homogeneous disease enti-ties. As will be discussed below, with a fewexceptions, hypersomnia diagnoses are subjectivelydefined, and agreed upon solely based on con-sensus. A careful exclusion of differentials isneeded to establish valid diagnosis, a problemaddressed by Ohayon et al. through the use of aneural network-based diagnostic system calledsleep EVAL. This system is unique as it has beenapplied to several hundred thousand subjectsacross multiple cultures, and allows for thesampling of truly representative control populationsamples, with exclusion of many differentialdiagnoses. A weakness of the system remains thelack of polysomnographic data.

As detailed in Table 1, of the disorders associatedwith central nervous system (CNS)-mediated hy-persomnia, only narcolepsy–cataplexy has a clearpathophysiological basis, hypocretin cell loss. Inthe present issue, Overeem et al.,3 review thepossibility of an autoimmune basis for hypocretincell destruction. The case for an autoimmune basisis strong based on genetic epidemiology (adoles-cence onset, increased risk in relatives of patients,and environmental influences)31 and a strong andcomplex HLA-DQB1 association.32 However, unlikeother autoimmune disorders, specific autoantibo-dies, for example directed against hypocretin cells,have never been found in spite of multipleattempts. In few cases, suggestive results wereobtained, but later not replicated. The possibilitythat the N-terminal end of the preprohypocretinpeptide could bind the DQB1*0602/DQA1*0102heterodimer for example was noted,33 but no proof

brought forward regarding a pathological role forthis observation. Indeed, antihypocretin antibodiesare not present in human narcolepsy sera,34,35 andwe were unable to find hypocretin-1 peptideautoreactive T-cell clones in narcolepsy (unpub-lished results). The lack of immunological findingsis actually surprising given that in other autoim-mune diseases, multiple autoantibodies are typi-cally found as a result of epitope spreading.36–38

Indeed, in these cases, the difficulty is rather todetermine whether the autoantibodies found arepathogenic or mere correlates of the disease.

Based on the above, Overeem et al.3 justifiablyconcluded that more research needs to be done,most notably the study of non-antibody-mediatedimmune responses (for example T-cell mediatedimmune responses), and the exploration of non-autoimmune mechanisms where HLA moleculescould be involved. Why are hypocretin cells lostand how is HLA involved are clearly the mostimportant questions to answer but also the mostdifficult to pursue. Indeed, only once mechanismsinvolved in cell destruction have been identified,will disease markers other than HLA be identified,for example in blood samples as opposed to CSF.These could then be applied to population studiesor used to design therapeutic interventions close todisease onset, prior to complete cell destruction.

More work also remains to be done in carefullydelineating the human narcolepsy phenotype, asillustrated by Plazzi et al.2 in his review ofnocturnal sleep disturbances. Narcolepsy is classi-cally characterized by cataplexy and EDS refreshedtemporarily by naps,39 although almost all knownassociated symptoms were already described asearly as the 1930s, most notably in the remarkablecase series by Daniels.40 More variably, sleepparalysis, hypnagogic hallucinations, PLMs, REMbehavior disorder, and difficulties maintaining sleepare also present.39,41–43 Interestingly, acute recentonset of narcolepsy is often associated withincreased sleep amounts and ill-defined muscleweakness feelings in the jaw (tongue protruding) orlegs (sometimes with difficulties walking), followedrapidly by the development of a more typicalpicture of EDS and isolated cataplexy triggered bytypical emotions such as laughing and joking.2

Sleep paralysis, hypnagogic hallucinations, andfinally disturbed nocturnal sleep manifestationsare often last to manifest.39,42 Once fully devel-oped, however, the disorder clearly is not a true‘‘hypersomnia’’, as multiple studies have shownthat total sleep time is not increased in patientsallowed to sleep at will.41,44 A key to understandingthese symptoms may thus be a more carefuldescription of the natural history of narcolepsy,

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as patients are increasingly diagnosed closer toonset.

In this issue, Plazzi et al.2 thoroughly reviewedthe complex and often disabling nocturnal sleepabnormalities found in typical narcolepsy–cata-plexy cases. These include: (1) an inability tomaintain sleep, reminiscent of the inability to stayawake for long periods of time experienced duringthe day, suggesting sleep-state instability,44 andobserved in all animal models of narcolepsy45; (2)REM sleep dissociation events such as sleepparalysis, hypnagogic hallucinations, nightmares/vivid dreaming, and REM behavior disorder39,43; (3)increased PLMs, although of slightly differentperiodicity when compared to those associatedwith restless leg syndrome (RLS) and generally of nofunctional consequence46; (4) not infrequently,sleep apnea,47 secondary to increased body weightin many patients; and (5) night-eating distur-bances. Plazzi et al.2 also emphasize the impor-tance of proper sleep hygiene in the treatment ofnarcolepsy, a very important and too often ignoredrecommendation.48

The importance of nighttime disturbances hastaken on importance with the increased realizationthat sodium oxybate (or gammahydroxybutyrate,GHB), a compound increasing slow-wave sleep, haspositive effects on daytime somnolence and cata-plexy.49 Whether or not the global improvementseen in these patients after GHB is due to the slow-wave sleep enhancing effect of the drug, withsubsequent reduction of sleep debt, is unknown andin need of further testing. Alternatively, complexeffects through GHB and GABA-B receptors may beinvolved.50

As hypocretin release increases with sleepdeprivation, we hypothesized that one of the majorfunction of the peptide may be to fight daytimesleepiness associated with moderate amounts ofsleep debt.45 This could explain why patients arerested just after a nap or nighttime sleep, butbecome sleepy only after a few hours of wakeful-ness. In this context, sodium oxybate may be ableto reduce sleep debt further, making daytimealertness less dependent on hypocretin. The in-ability to consolidate sleep in narcolepsy could thenbe the result of decreased sleep debt at sleep onsetor/and due to the engagement of compensatorywake-promoting systems, for example dopaminer-gic mechanisms.43 This would result in increasedalertness during the day (and a reduction of theinitial hypersomnia) but sleep fragmentary effectsat night (and possibly PLMs).46 The fact thatsleepiness does not usually improve after hypnoticadministration of drugs other than sodium oxybate,together with the observation that adequate wake-

maintenance during the day does not system-atically improve nighttime sleep, argue in favor ofthe second hypothesis. Similar compensatory me-chanisms may also be involved in the generation ofcataplexy, a symptom often appearing with somedelay after sleepiness.42,51 Indeed, hypocretin is apositive regulator of muscle tone,52 and its losscould explain why ill-defined muscle weakness issometimes first observed around disease onset.53

The progression into more typical cataplecticepisodes often occurs later and could be the resultof similar general compensatory mechanisms thatwould reestablish basal muscle tone, except underchallenging conditions. In favor of this hypothesis,Overeem et al.54 demonstrated transient loss ofmonosynaptic reflexes after laughing in healthyvolunteers that do not escalate into actual muscleweakness, possibly because of immediate compen-sation. In narcoleptic patients, these compensatorymechanisms may already be maximally engaged atbaseline, leading to breakthrough muscle weaknessafter positive emotions.

Another interesting relationship to explorefurther may be that of nocturnal REM sleepabnormalities and disturbed nocturnal sleep. In-deed, whereas REM sleep abnormalities and diffi-culties maintaining sleep are generally consideredindependent, it is worth noting that in the generalpopulation, sleep paralysis and hypnagogic halluci-nations are associated with sleep fragmentationand sleepiness (especially in the context ofneuropsychiatric associations).19 These symptomsmay therefore only be secondary to sleep fragmen-tation, explaining their poor specificity. Similarly,there is a need to better correlate increasedoccurrence of night-eating behaviors55 in narco-lepsy with nocturnal awakenings, as it is possiblethe symptom is simply a reflection of insomnia.Finally, nocturnal sleep studies in narcolepsy haveled to the increased realization that SDB is commonin the pathology, and can occasionally maskgenuine sleep maintenance difficulties, these beingonly revealed when CPAP therapy is applied.47

Continuing on to epidemiological studies, it isalso notable that cataplexy, as defined by suddenepisodes of muscle weakness triggered by emo-tions, is almost pathognomomic for narcolepsy–

cataplexy/hypocretin deficiency. Searching for thissymptom allows a reasonable prescreening of largesamples, followed by additional questioning (sleep-Eval)1 or interviews/polysomnography to gatheractual prevalence data.31 Remarkably, the preva-lence obtained for the condition, 0.02–0.05% hasbeen extremely consistent whatever the methodused, including across cultures and ethnic groups(Japan, Korea, China, France, Great Britain,

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USA).1,31,56 This is surprising considering differ-ences in DQB1*0602 carrier frequency (4–8% inIsraeli Jews, 12–15% in Japan and Korea, 25% inCaucasians and 28% in African Americans),32,56 butmay simply reflect small sample sizes in most ofthese studies and small methodological differ-ences.

The only two genuine prevalence outliers includetwo studies in Japan57,58 and one in Israel.59 BothJapanese studies found higher prevalence(0.16–0.18%), a surprising result considering thelower prevalence of DQB1*0602 in this country (8%carrier frequency). In one, however, only inter-views and no polysomnographic confirmation wereperformed. Further, in this study, up to a third ofthe adolescents screened reported ‘‘cataplexy’’57

without having narcolepsy, raising doubts on thelife-long prevalence of symptoms. In the secondJapanese study, systematic questionnaire-basedassessments were used, followed by clinical eva-luation and polysomnography, but 50% of the casesidentified were HLA-DQB1*0602/DR2 negative,58

suggesting diagnostic difficulties.Similarly, a study estimated an extremely low

prevalence of narcolepsy–cataplexy in Israel(0.002%), based on the observation that mostpatients in sleep clinics have sleep apnea, notnarcolepsy.59 This low prevalence was also sup-ported by the fact that patients with narcolepsyshould have been diagnosed when undergoingmandatory military service and by the remarkablylow DQB1*0602 carrier frequency in Israel (4–8% or3–5 fold lower than in the USA). In our ownnarcolepsy clinic however, we have seen a numberof Jewish patients including two from Israel,suggesting that the condition may be somewhatunderestimated. Ascertainment difficulties maythus have led to underestimation. In all cases,considering a prevalence of 0.01–0.05%, sampleshigher than 100,000 subjects in various ethnicgroups would be needed to statistically compareprevalence across ethnic groups and contrastprevalence values with DQB1*0602 frequency dif-ferences (ranging from 4% to 38%).

Prevalence-based values for other hypersomniadisorders are extremely difficult to conduct sincedefinitions involve polysomnography testing (Table1). Narcolepsy without cataplexy is diagnosed usingthe MSLT, and is likely etiologically heterogeneous,with approximately 10% of cases associated withdefinite hypocretin deficiency (p110 pg/ml) in ourcenter (30% in HLA positive subjects) (unpublisheddata). Only one study reported on the prevalenceof narcolepsy without cataplexy, through systema-tic case findings in Olsmed County, MN and found a0.02% prevalence,60 a value likely to be a gross

underestimate, as many patients without cataplexymay not be diagnosed. Recent studies in largesamples have found that an unexpectedly largenumber of subjects, most notably male, havemultiple sleep-onset rapid eye movement periods(SOREMPs) on the MSLT, often without a significantcomplaint of EDS (approximately 2.3% met criteriafor narcolepsy without cataplexy, without the 3-month duration criteria for sleepiness).61,62 Thesefindings raise the possibility that narcolepsy with-out cataplexy is under diagnosed. Alternatively, itmay be that narcolepsy without cataplexy is anartificial construct of no biological significance.Indeed, one of the major reasons for creating thisentity in the ICSD-2 was the problem of ‘‘uncalling’’previously diagnosed narcoleptic patients withoutcataplexy based on positive MSLT testing.

Prevalence studies for idiopathic hypersomnia, asdefined by ICSD-2 are also lacking, and even moredifficult to perform. As noted above, the traditionalidiopathic hypersomnia picture with prolongedsleep time, sleep drunkenness, severe subjectiveand objective sleepiness is rare and in need offurther prevalence studies, although it may bedifficult to separate this condition from depressionwith hypersomnia without clinical evaluation.8,13,63

The only population prevalence is that of Ohayon etal., reporting 0.3% of the population,1 a relativelyhigh value. Idiopathic hypersomnia without longsleep time is a practically defined disease entitywith unexplained EDS as defined by the MSLT.24

MSLT criteria include a mean sleep latency below8min, an abnormality found in up to 20% of thenormal population. Like narcolepsy without cata-plexy, this entity is thus not likely to be pathophy-siologically meaningful, and is only relevant to theclinical classification of patients to justify ther-apeutic interventions. The use of the ICSD-2 in thiscontext should thus be used for classificationpurposes, rather than for research.

The complex correlates of daytime sleepinessand excessive sleep are mirrored in the evaluationof the sleepy patient in clinical practice. Indeed,once hypocretin deficiency and rare instances ofidiopathic hypersomnia with prolonged sleep time8

or Kleine–Levin syndrome64,65 have been excluded,remaining cases are merely patients with EDSwithout (or in search of) a clear etiology. Whetheror not SOREMPs are observed during the MSLT hasnot been shown to have biological or therapeuticsignificance or to affect prognosis. Further, in myexperience, many such patients, whether withnarcolepsy without cataplexy or with idiopathichypersomnia, do not have a simple disorder, but aconstellation of problems of various importance,for example some degree of SDB, poor sleep

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hygiene, latent or patent neuropsychiatric sympto-matology (typically anxiety, depression, conversiondisorder).48 Sleepiness of central nervous origin inthis context may also be confounded by long sleeprequirements that cannot be satisfied. Similarly,the general concept of ‘‘insufficient sleep syn-drome’’ is but a caricature of reality, as are typical‘‘delayed sleep phase patients’’ as these twoconditions are often associated in adolescents.Complex shift work patients may have similarassociated problems, and are more likely to haveSOREMPs on the MSLT.61 An understanding of thesecomponents and the successive therapy of theseelements is typically more likely to lead to agenuine recovery than the promoting of a diagnos-tic category of narcolepsy without cataplexy oridopathic hypersomnia.

In summary, and as illustrated by the reviewsthat follow in this issue of Sleep Medicine Reviews,much remains to be done. Additional studies ofexcessive sleep and daytime sleepiness aiming atdefining symptoms clusters in population and theirlongitudinal evolution are needed. The true sig-nificance of multiple SOREMPs during MSLT alsoneeds further studies, most notably reliabilitystudies of repeat MSLTs. Similarly, population-basedprevalence studies of Kleine–Levin syndrome arelacking, in spite of recent findings suggesting ahigher prevalence than previously anticipated.65

Finally, a better understanding of the etiologicaloverlap of narcolepsy with and without cataplexy isneeded, as is a true prevalence of hypocretindeficiency in cases without cataplexy. Importantlyhowever, it is unlikely that further pathophysiolo-gical sub-typing will occur solely based on epide-miology and without the discovery of novelbiological or genetic markers. Such markers arealready available for narcolepsy and RLS, and thereis hope for additional discoveries through humangenetic, biochemistry and imaging studies. In theinterim, the study of the sleepy patients should beinformed by epidemiological correlates and theirmeaning, and therapies practically based on trialand error.

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ARTICLE IN PRESS

Guest Editorial94

64. Arnulf I, Zeitzer JM, File J, Farber N, Mignot E. Kleine–Levinsyndrome: a systematic review of 186 cases in theliterature. Brain 2005;128(Part 12):2763–76.

65. Arnulf I, Lin L, Gadoth N, File J, Lecendreux M, Franco P,et al. Kleine–Levin syndrome: a systematic study of 108patients. Ann Neurol, in press.

Emmanuel MignotStanford University Center for Narcolepsy,

Palo Alto, CA 94301, USAE-mail address: mignot@lelend.stanford.edu