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Chapter 2

Excessive daytime

sleepiness in OSAA. Iranzo

Summary

Chronic excessive daytime sleepiness (EDS) is a disabling condition

associated with an increased and exaggerated tendency to fall asleep,

leading to reduced quality of life and other problems. A common causeof EDS is obstructive sleep apnoea syndrome (OSAS).

Evaluating EDS is problematic as somnolence is not easily measured

with the available subjective and objective tools.

The Multiple Sleep Latency Test (MSLT) is the standard objective

measure, evaluating the tendency to fall asleep without external

alerting factors; however, it discriminates poorly between patients with

EDS-linked sleep disorders (except narcolepsy) and normal popula-

tion. Weak correlations have been found between the MSLT and

subjective sleep scales (Stanford/Epworth Sleepiness Scales) and

between the MSLT and treatment responses with CPAP. The weak

correlation, suggests that these measures may be evaluating different

aspects of a complex phenomenon.

It is assumed, but not demonstrated, that the OSA severity correlates

with the degree of sleepiness. Measures of EDS are not associated with

the apnoea/hypopnoea and arousal indices, hypoxaemia or slow-wave

sleep, suggesting a lack of understanding of either sleep disturbance in

OSA or MSLT measures. The mechanisms of EDS in OSAS remain to

be elucidated.

Keywords: Epworth sleepiness scale, excessive daytime sleepiness,

maintenance of wakefulness test, obstructive sleep apnoea, multiple

sleep latency test, Stanford Sleepiness Scale

Correspondence: A. IranzoNeurology Service, Hospital Clinic deBarcelona, C/Villarroel 170,Barcelona 08036, Spain, Email

[email protected]

Eur Respir Mon 2010. 50, 1730.Printed in UK all rights reserved.Copyright ERS 2010.European Respiratory Monograph;ISSN: 1025-448x.DOI: 10.1183/1025448x.00006710

Wakefulness and sleep are integral aspects of all diurnal organisms. Sleepiness is a normalphenomenon that occurs when individuals experience a physiological tendency to fall asleepaccording to homeostatic influences, the circadian cycle and the length of time from the last periodof sleep. In normal people, sleepiness is maximal between 02:00 h and 06:00 h with a secondminor peak between 12:00 h and 14:00 h. From the electrophysiological point of view, sleepiness(or the loss of wakefulness) is defined by the disappearance of the electroencephalographic aactivity (812 Hz) seen in the occipital leads [13].

Several brain structures modulate the sleepwake cycle, such as the hypothalamus, the thalamus,the brainstem, the limbic system and the cortex. These structures send and receive information

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from most of the major neurotransmitters which modulate the sleepwake cycle, namely melatonin,hypocretin, histamine, acetylcholine, c-aminobutyric acid (GABA), serotonin, noradrenaline,dopamine and adenosine. Abnormalities in these brain structures (e.g. hypothalamic tumours,brainstem strokes) and neurotransmitters systems (e.g. dopaminergic deficiency in Parkinsondisease and hypocretinergic dysfunction in narcolepsy with cataplexy) may lead to several sleepdisturbances including hypersomnia. Medications that promote dopaminergic activity at smalldoses (e.g.levodopa, dopaminergic agonists), histamine receptor antagonists and benzodiazepines

may induce sleepiness, whereas drugs with monoaminergic activity, such as methylphenidate andmodafinil act as central nervous system stimulants inducing persistent wakefulness. Also, diseasesassociated with recurrent episodes of upper airway collapse during sleep may be associated withhypersomnia.

Sleepiness can be excessive when it interferes with daytime activities, such as work, school,driving and family or social events. Excessive daytime sleepiness (EDS) is defined as the inabilityto stay awake and alert during the major waking episodes of the day, resulting in undesirablelapses into drowsiness or sleep. In other words, EDS can be defined as a condition that isassociated with an increased and exaggerated tendency to fall asleep under normal circumstances.This occurs when individuals fall asleep in situations where they are expected to be awake and

alert. EDS and hypersomnia are medical terms which are often used interchangeably. EDS ismore likely to occur in boring monotonous situations that do not require active participation,such as watching television and reading a book. When very severe, EDS may result in episodes ofautomatic behaviour, in which subjects have no memory of some of the events that they haveperformed through the day. EDS can be dangerous in individuals who drive, fly or work withsome technologies. In children, EDS may be manifested as restless, inattention and hyperactivityto stay alert. Duration of chronic EDS is arbitrarily defined as occurring for o3 months [1]. Inmost cases, EDS is a chronic symptom and, when acute or subacute, a causative factor should besought (e.g.depression, systemic infection, head trauma, brain structural lesions including tumoursand stroke, etc.). The fact that EDS is a subjective feature which depends on the patient percep-

tion and his/her ability to recognise a tendency to fall asleep is reflected by the finding that somesubjects with true pathologic EDS have little or no warning of sleep. In contrast, patients withprimary insomnia may be tired and have an intense desire to fall asleep during the day but are unableto do so.

In most of the cases at sleep centres, EDS is generally the direct result of sleep loss from eitherreduced sleep quantity or fragmented sleep resulting in decreased sleep quality. The causes of EDSare variable, ranging from insufficient night-time sleep, fragmented sleep, circadian rhythmdisturbances causing a mismatch in the sleepwake pattern, use of sedative medications andneuronal degeneration within the brain structures that modulate the sleepwake rhythm, such as

in narcolepsy and cataplexy where hypocretin neurons located in the hypothalamus are lost. EDSis a symptom associated with several sleep disorders including obstructive sleep apnoea syndrome(OSAS) and narcolepsy, and neurological or general clinical conditions such as Parkinsonsdisease, hepatic failure and hypothyroidism (table 1). Situations linked to broken sleep,insufficient sleep, sleep restriction, poor sleep hygiene and shift work are associated with EDS.The commonest cause of EDS is behaviourally induced insufficient sleep syndrome that occurswhen an individual persistently fails to obtain the amount of sleep required to maintain a normallevel of alertness and wakefulness. This is the explanation of why normal healthy people, wheninquired, may self-record high scores on scales that evaluate the presence of EDS and also showreduced mean sleep latency (a polysomnographic objective measure of EDS) when undergoing a

multiple sleep latency test. The second most common cause of EDS is OSAS, although not all OSASpatients report this symptom. The presence of EDS is a prerequisite for the diagnosis of some sleepconditions like narcolepsy but not in others such as in OSAS. In some disorders, chronic EDS mayrepresent the main and most disabling complaint. It also can be the first to occur, such as innarcolepsy, depression or Parkinsons disease. However, it is worth mentioning that there is a greatvariability in the clinical presentation of EDS, ranging from mild to severe. Interestingly, in some

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patients with true EDS,the cause of consultationis difficulty maintainingsleep, but detailed ques-tioning reveals experi-ence of EDS for years.Contrary to popular be-

lief, EDS is not linkedto restless legs syndromeand periodic leg move-ments in sleep. EDS canbe present, though, insubjects with these twoconditions when theycause insufficient noctur-nal sleep time. Physico-physiological insomnia isnot associated with EDS.

In adults, EDS may cause or exacerbate mood disturbance, cognitive disturbance, loss of productivity,motor vehicle accidents, occupational and familial problems and reduced quality of life.

EDS is often unidentified in the general population and even in some specific sleep disorders suchas OSAS. This may be to several factors including: 1) patients do not complain about it; 2) patientsdo not recognise that EDS is present; 3) patients recognise that EDS is present but interpret thatthis does not interfere with their quality of life; and 4) physicians do not inquire about thissymptom. Epidemiological studies have shown impressive data regarding the prevalence of EDS inthe general population. However, it should be noted that in these studies the definition of EDSmay vary from study to study [4]. Studies in the USA report rates of EDS varying from 0.3% to16.3%. These differences in prevalence are probably explained by the different definitions of EDSused by the different authors. The Cardiovascular Health study found a 20% prevalence ofindividuals reporting being usually sleepy in the daytime in a sample of .4,500 people agedo65 yrs [5]. In another study, EDS was reported in 1721% of school-aged children andadolescents [6]. According to the National Sleep Foundation 2005 Sleep in America Poll, 27% ofmales and 31% of females reported daytime sleepiness on at least 3 days per week [1].

Clinical presentation of EDS

Chronic EDS is a pathological state that may be ignored by affected patients simply because it is asubjective feature which depends on patient ability to distinguish normal from abnormal.Individuals may deny experiencing EDS but report important tiredness, poor memory andconcentration, lack of energy, weakness or fatigue during the day. In contrast, individuals sufferingfrom true fatigue may falsely report experiencing EDS [13].

There are two possible clinical presentations of EDS which usually coexist in the same patient, ifthey are not really the same phenomenon. Both types of EDS may impact upon the patientsquality of life causing social, professional and familial problems and leading to automobile crashes.One is a state of hypersomnia that is perceived by the patient allowing him/her to fight against itbut leading to unavoidable napping. Patients experience a constant pressure for falling asleep and

difficulty with remaining awake. They perceive that they are sleepy and fight against thisundesirable sensation. Patients, however, fall asleep and take frequent short naps at inappropriatetimes and/or settings, especially when situations are not stimulating, such as watching television andreading. Some subjects are unable even to stay awake in active situations like eating or talking. Thistype of EDS is non-specific for OSAS since it is the main feature of other conditions in which EDS iscommon, such as narcolepsy, idiopathic hypersomnia, depression and nocturnal sleep deprivation.

Table 1. Causes of excessive daytime sleepiness

Obstructive sleep apnoea syndrome

Other sleep-related breathing disorders

Narcolepsy with cataplexy

Narcolepsy without cataplexy

Narcolepsy due to a medical condition (e.g. stroke)

Recurrent hypersomnia (e.g. KleineLevin syndrome)

Idiopathic hypersomnia with long sleep time

Idiopathic hypersomnia without long sleep time

Behaviourally induced insufficient sleep syndrome

Hypersomnia due to a medical condition (e.g. infections, metabolic

disturbances, endocrinopathies, Parkinson disease, myotonic dystrophy)

Hypersomnia due to drug or substance

Circadian rhythm disorders

Shift work sleep disorder

Depression

Chronic fatigue syndrome

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These sleep episodes in patients with OSAS are typically short (515 min) but they may last for 1 or2 h. They are sometimes associated with vivid dreams but less often than in narcolepsy.

The other presentation of EDS is much less common and consists of sudden onset of sleep episodes.These episodes are abrupt, brief, unexpected and have been reported to occur during activesituations, like driving, eating, talking, having a shower, walking, being on the telephone and writing.It is unclear whether these episodes, classically termed sleep attacks, constitute a unique entity orthey are merely an extreme manifestation of severe hypersomnia. They have been classicallydescribed in patients with narcolepsy and more recently in Parkinsons disease, particularly in thosepatients under dopaminergic therapy replacement. They also occur in a few patients with severeOSAS. It is possible that patients with sudden onset of sleep episodes of any aetiology, includingsome cases with OSAS, are not aware that they are sleepy simply because of the amnesia associatedwith falling asleep or because they have long habituated to the sensation of chronic and severehypersomnia and are not aware that they are sleepy during the day. It is possible that increaseddrowsiness precedes sudden onset of sleep episodes, perhaps because patients become habituated toa state of chronic drowsiness. It is our experience that the few patients that have fallen asleep during aclinical interview suffered from severe OSAS only and not other classic conditions traditionallylinked to severe EDS, such as narcolepsy or idiopathic hypersomnia.

In children and adolescents, EDS may be manifested as restless, inattention and hyperactive to stayalert. As a result, children and adolescents with EDS may exhibit emotional lability, aggression,impulsivity, hyperactivity, no creativity, reduced frustration tolerance, mood disturbances,difficulties in learning, memory and academic performance, and social and conduct problems.Overall, in contrast to adults, EDS in children can take the form of an increased rather than adecreased activity [7].

Evaluation and measurement of EDS

The evaluation of EDS is problematic for at least two reasons. First, the description of thesymptom may be misleading or not recognised by the patient. Secondly, the physiologic state ofsomnolence is not easily measured from the available subjective and objective methodologicaltools. Clinical history is the most important tool. Sleepiness scales and objective tests can also beused in some cases. Pupillometry and performance vigilance tests, including driving stimulators,are other tools that evaluate EDS but are not routinely used in the clinical practice.

Clinical history

The elucidation of EDS starts with a careful history from the patient, supplemented by collateralhistory from a bed partner, relatives, friends or caregivers when available. Clinical history is the mostimportant tool for evaluating the occurrence and characteristics of EDS. Details of patients typicalnight sleep time and sleepwake schedule are always required along with the observation of othersymptoms, such as the presence of waking with choking sensation in the throat, witnessed apnoeasand snoring. EDS and these features are the classical symptoms of OSAS. The degree and relevance ofEDS should always be evaluated clinically, and special emphasis should be paid to drivingperformance. Clinically, it is crucial to distinguish EDS from fatigue, lack of energy, asthenia, poorconcentration and tiredness. Once one is sure that the patient has EDS which interferes with hisquality of life, clinical history should be focused then to elucidate the cause of this symptom [13].

Subjective sleepiness scales

Subjective sleep scales require individuals to rate their own degree of sleepiness. To do this well,subjects must have insight into their symptom and the capacity to dissociate sleepiness from othersymptoms, such as tiredness. They consist of standardised questions designed to quantify EDS by

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subjective means. The scales should be fast, simple, easy to understand, cheap to administer andreflect the patients own opinion on the severity of his/her EDS. They are used to supplement thehistory and to follow the effects of treatment. Currently, the following two sleep questionnaires areroutinely used in clinical practice [2, 3, 8, 9].

The Stanford Sleepiness Scale

The Stanford Sleepiness Scale (SSS) (table 2) was developed in 1972. This scale measures sleepinessat a specific moment and is often administrated just before the trials of the multiple sleep latency testto assess whether the patients perception correlates with the objective variables (sleep latency onset).This scale asks subjects to rate their degree of sleepiness at a single moment of time from sevendescriptions ranging from felling active and vital; alert wide awake to almost in reverie; sleeponset soon; lost struggle to remain awake. The SSS is fast and easy to use. However, there are noreference values and it has not been validated with other physiologic measures [8].

The Epworth Sleepiness Scale

The Epworth Sleepiness Scale (ESS) (table 3) is the commonest scale used to assess sleepiness. TheESS was developed in 1991 as a trait to measure the tendency to fall asleep in several specificsituations. It is a subjective tool of how sleepiness interferes with an individuals common dailyactivities. It consists of a simple self-administered questionnaire asking patients to rate the likelihood(from 0 to 3) of dozing or falling asleep in eight situations. For each situation, patients estimate thelikelihood of their falling asleep in a four-point scale (05never doze to 35high probability). Scoresfrom each of the eight situations yield a total scoring ranging from 0 to 24. The higher the ESS score,the greater the sleepiness. The upper limit of normality is generally accepted as 1012 points. Thescale shows acceptable testretest reliability. Studies have shown little or no correlation between ESSscores and the multiple sleep latency results, suggesting that the two tests measure different aspects of

sleepiness which remain to be elucidated. Although useful in clinical practice, this test has severallimitations. For example, it asks subjects to picture themselves in situations which they may actuallyexperience rarely or never (e.g. driving, going to the theatre). Semantic issues may also lead toconfusion. Circadian variations in alertness are not captured with this scale. The eight situations areequally weighted, despite obvious differences in significance (e.g.drivingversusgoing to the theatre).Finally, there may be individual variation scores over time. Generally, the ESS is more reliable whenscores are abnormally high or very low. Many sleepy subjects may score in the normal range becausethey do not actually fall asleep, despite being drowsy, either because of effective compensatorymeasures or lack of opportunity [9].

Objective measures of sleepiness

The Multiple Sleep Latency Test

The Multiple Sleep Latency Test (MSLT) (table 4) is a validated objective measure of the ability ortendency to fall asleep. The MSLT is considered by most specialists to be the standard objectivemeasurement for EDS. Itis also the most widelyused and most exten-sively published objec-

tive measure of EDS.The MSLT is intendedto measure physiologicalsleep tendency understandardised conditionsin the absence of external

Table 2. Stanford Sleepiness Scale

Feeling active; alert; wide awake

Functioning at a high level, but not at peak; able to concentrateRelaxed; awake; not full alertness; responsive

A little foggy; clearly not at a peak; let down

Fogginess; beginning to lose interest in remaining awake; slowed down

Sleepiness; prefer to be lying down; fighting sleep; woozy

Almost in reverie; sleep onset soon; lost struggle to remain awake

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alerting factors. The testis based on the premisethat the degree of sleepi-ness is reflected by thesleep latency. The sleeplatency is defined as theinterval between the start

of the test when the lightsare turned off and thesleep onset. The MSLTwas originally developed

in 1977 to measure sleepiness in young normal subjects involved in sleep deprivation experiments.Following two night of sleep deprivation, six young healthy volunteers had opportunities to nap at 2-hintervals across the day. Within a few years, researchers began using the MSLT to measure sleepiness inseveral sleep disorders, including OSAS, narcolepsy and insomnia [1013].

The test is performed the day after an overnight polysomnogram to evaluate the occurrence of acause of EDS (e.g.sleep-disordered breathing), and to document an adequate quantity and quality

of sleep on the night preceding the MSLT. The standard clinical MSLT consists of four or five napopportunities performed at 2-h intervals across a patients major usual period of wakefulness. Thefirst nap opportunity begins 1.53 h after termination of an overnight polysomnographicrecording. The patient should be offered a light breakfast o1 h before the first nap, and a lightlunch after termination of the second nap opportunity. Alcohol is not allowed. The testenvironment should be quiet and free of noises, such as ambulance sirens, elevators, constructionand toilets. Room temperature should be set based on the patients comfort level. Sleep roomsshould be quite and dark during test sessions. The patient is dressed in street clothes during eachopportunity removing his or her shoes and loosening constricting clothes. Patients and sleeptechnologists mobile telephones must be switched off. The patient must abstain from drinking

caffeinated beverages between naps. Tobacco use and vigorous and stimulating activities should bestoppedo30 min before each nap opportunity. Patients should be in bed 5 min before each napopportunity with the lights on. 30 s before each nap test, the patient is encouraged to assume acomfortable position for falling asleep. 5 s before the start of each nap opportunity, the patient is

Table 3. Situations included in the Epworth Sleepiness Scale

Sitting and reading

Watching TV

Sitting inactive in a public place (e.g. theatre or a meeting)

As a passenger in a car for an hour without a break

Lying down to rest in the afternoon when circumstances permit

Sitting and talking to someone

Sitting quietly after lunch without alcohol

In a car, while stopped for a few minutes in traffic

Table 4. Mean sleep latencies (MSLs) in the Multiple Sleep Latency Test (MSLT) and Maintenance ofWakefulness test (MWT)

MSLT Normal MSL .10 min

MSL of 810 min is considered the twilight zone

MSL in controls was 10.5

4.6 and 12.8

4.6 min in two differentstudies

MSL in narcoleptics with cataplexy was 3.12.9 min

MSL in OSAS was 7.26.0 min and 6.84.2 min in two different

studies

MSL in OSAS treated with CPAP was 11.65.3 min

MWT 40-min version MSL in controls was 34.05.5 min and 35.27.9 in two different

studies

MSL in OSAS was 23.210.2 min and 26.39.9 min in two

different studies

MSL in OSAS treated with CPAP is 26.310.0 min

MWT 20-min version Normal MSL is considered .10 minMSL in controls is 18.83.3 min

MSL in OSAS is 11.05.6 min

MSL in narcolepsy is 3 min

OSAS: obstructive sleep apnoea syndrome; CPAP: continuous positive airway pressure.

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given the same set of instructions from the sleep technologists: please lie quietly, assume acomfortable position, keep your eyes closed and try to fall asleep. The technologists then turn thelights off signalling lights out and the start of the test. Between naps the patient should be out ofbed and prevented from sleeping.

The conventional recording MSLT montage includes bilateral central and occipital leads, left andright electro-oculograms, submental electromyography and electrocardiogram. The sleep latency isdefined as the interval between the start of the test when the lights are turned off and sleep onset.

Sleep onset is determined by the time from lights out to the first epoch of any stage of sleep in a30-s epoch. Sleep onset is defined as the first epoch containing more than 15 s of cumulative sleepin a 30-s epoch. The patient is permitted to sleep for 15 min after the first epoch scored as sleep.This is to assess sleep continuity and the early occurrence of REM sleep. REM sleep latency is takenas the time from the first epoch of sleep to the beginning of the first epoch of REM sleep. Sleeponset REM periods (SOREMPs) are defined as episodes .15 s of REM sleep within a 30-s epoch.A nap session is terminated after 20 min if no sleep occurs. The absence of sleep during a napopportunity is scored as a sleep latency of 20 min. The mean sleep latency (MSL) is the arithmeticmean of sleep latencies for all four or five nap opportunities. The MSLT report should include thestart and end times of each nap opportunity, latency from lights out to the first epoch of sleep,

mean sleep latency and number of SOREMPs. The total sleep time, sleep efficiency and REM sleeplatency of the polysomnogram performed the previous night should be reviewed before the reportof a MSLT.

It is recommended that 2 weeks prior to the MSLT session, an adequate sleepwake scheduleshould be documented by sleep log or actigraphy. Drugs that influence sleep (e.g.benzodiazepines,antidepressants, sodium oxybate, stimulants) must be withdrawn before the test. For being useful,the MSLT must be preceded by nocturnal polysomnography showing sufficient total sleep time ofo6 h. This is crucial since SOREMPs and short MSL on the MSLT can be easily seen in shiftworkers, sleep-deprived people and those taking antidepressants. Polysomnography and MSLT

should be conducted when central nervous system drugs (e.g. central nervous stimulants,sedatives, sodium oxibate and antidepressants) are discontinued for at least five-times the half lifeof the drug and long-lasting metabolite, and patients had a regular sleepwake schedule during theprevious week.

Conditions that may affect the validity of the MSLT include: 1) insufficient sleep the night or weekbefore the MSLT; 2) performance of the MSLT at a time different than the patient usual time ofwakefulness; 3) excessive noise or temperature extremes; 4) use of medications that could altersleep architecture, such as antidepressants, wake promoting agents and benzodiazepines; and 5)stimulating or upsetting events between nap opportunities.

An important question raised here is whether sleep latency is a true measure of EDS. A number ofmethodological issues arise when attempting to determine normal and pathological ranges for theMSLT values. Precise normative ranges for MSL are not well defined. It has not been establishedwhether a single pathologic cut-off should be used for all patients groups and ages. AlthoughMSLT is a validated measure, there is no large systematically collected normative data. Manyfactors may influence the MSL, such as motivation, age, external stimuli, medication, previoussleep quality and sleep time, medical disorders and psychological factors. Identification ofnormative values is limited by the large standard deviation in MSLs on the MSLT, as well as floorand ceiling effects which suggests that values are not normally distributed. Thus, there is asignificant overlap between MSL among healthy controls and populations with EDS. Based on

evidence currently available, the MSL should not be the sole criterion for determining the presenceor severity of EDS. Assessment should involve integration of the clinical history, objective testsresults and some other medical information. Overall, adult control subjects usually have a MSLvalues in the 1020 min range and MSL values between 5 and 10 min are described as being in thediagnostic grey area of uncertain origin. In patients with OSAS the MSL is 7.26.0 min. For thediagnosis of narcolepsy, the MSL should be ,8 min. This liberal cut-off of 8 min for the diagnosis

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of narcolepsy was chosen because 90% of the patients with this condition have a MSL value belowthis level. About 16% patients with narcolepsy have MSL scores above the 5 min cut-off, and,16% of normal controls in the general population have MSL scores ,5 min (mainly due tosleep deprivation or underdiagnosed conditions linked to EDS). Thus, it can be stated that theMSLT does not discriminate well between clinical populations and control populations. Althoughmore than one SOREMP is seen in most cases with narcolepsy, this feature can also be seen insubjects with OSAS, normal subjects and shift workers, and after acute withdrawal of REM-

suppressing drugs (e.g. antidepressants) causing REM sleep rebound.The diagnostic sensitivity of the MSLT for the diagnosis of narcolepsy has been estimated around60%, while the diagnostic specificity when two or more SOREMPs are present is around 95%. Ifthe presence of two or more SOREMPs is combined with a MSL of,5 min, then the diagnosticspecificity for narcolepsy rises to 97%. The majority of narcoleptics show a MSL of ,8 min. TheMSL in healthy controls was 10.54.6 whereas it was 3.12.9 min in narcoleptics. However,about 10% of the patients with narcolepsy exhibit a MSL of .8 min and/or less than twoSOREMPs in the MSLT. Detection of two or more SOREMPs in the MSLT is highly specific (0.93)and sensitive (0.78) for the diagnosis of narcolepsy. High-test reliability (0.97) of the MSLT hasbeen demonstrated in normal healthy subjects. The intrarater reliability coefficient for MSL score

is also high (0.87).

The MSLT is recommended for the diagnosis of narcolepsy with cataplexy, narcolepsy withoutcataplexy and idiopathic hypersomnia. The MSLT is not routinely indicated for the evaluation ordiagnosis of OSAS or assessment of response to treatment of OSAS. However, the MSLT should beindicated in OSAS patients that continue to experience EDS despite correct treatment of theunderlying condition (surgery, continuous positive airway pressure (CPAP), etc.). In thisparticular case, the MSLT and the previous overnight polysomnogram can be both performed withthe CPAP that the patient uses habitually at his/her home. MSLT is not the best measure oftreatment response in cases with EDS. The Maintenance of Wakefulness Test (MWT) is a better

measure since this method evaluates the ability to stay awake when a subject is instructed not tosleep under soporific conditions, rather than a tendency to fall asleep.

The MWT

This is a variant of the MSLT in which, rather than attempt to sleep, the patient is asked to remainawake as long as possible. It assesses the ability to resist the urge to fall asleep during soporificcircumstances and provides an objective measure of wake tendency. It is not a diagnostic test forthe degree of sleepiness but a test of the ability to remain awake. It is used to assess the efficacy of atreatment once the diagnosis has been reached previously. Thus, it is performed when the patient

is taking a stimulant, CPAP or any medication or therapeutical strategy tested to improve EDS. Itis also used to assess the patient fitness to drive and to fly, or ability to return to work and,obviously, to quantify the extent of EDS. This is to assess an individuals ability to remain awakewhen his or her ability to remain awake constitutes a public or personal safety use. The MWT ismore subject to motivational factors than the MSLT [1013].

Four nap opportunities are performed at 2-h intervals after an overnight polysomnogram. Thepatient is positioned sitting up in bed, with the back and head supported by a bed rest pillow orcushion or at a 4590uangle with respect to the legs. The patient is asked to try to remain awakewith the eyes open, but is not allowed to use extraordinary measures such as walking, singing ortalking. The latency to the first three consecutive 30-s epochs of sleep (or to the first epoch of sleepas in the MSLT) is measured for each trial and the MSL is calculated. The patient is awakenedwhen sleep onset is scored. Two variants of the test have been described: in the first, a trial isterminated after 20 min; and in the second each trial can last up to 40 min.

In controls, the MSL for the test, based on 40 min is 3234 min, whereas it is 1819 min for the20 min version. For this 20 min version a MSL ,11 min is suggestive for the presence of EDS.

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In narcoleptics the MSL is 3.1 min in the 20 min version. In subjects with OSAS, the MSL is 23 inthe 40 min version, and 11 in the 20 min version. The MSL in the MWT does not correlate withtotal sleep time of the previous night, suggesting that sleep deprivation does not affect the results.

In table 5 the clinical indications of the MSLT and MWT followed in our sleep centre arepresented.

The crucial question here is whether there is an agreement between the subjective (SSS and ESS)

and objective (MSLT and MWT) measures of EDS. Because the MSLT and MWT measure thesame variable (the mean sleep latency), one would expect the results to be correlated even if notsimilar in magnitude. However, this is not true. Only low correlations have been found betweenMSLT and MWT results in the same subjects. Such low correlation indicates that the relationshipaccounts for only 1025% of the total variance. Only weak correlations have been found betweenthe MSL in the MSLT and both SSS and ESS scores. Weak correlation has also been found betweenthe MSLT and treatment responses among patients with OSAS. The lack of substantial correlationsbetween these tests implies that judgements of sleepiness may be test-specific features, indicatingthat there is more than a single component to EDS. Thereby, it can be speculated that subjectiveand objective measures of EDS are evaluating different aspects of a complex phenomenon as EDS.

EDS in patients with OSAS

Clinical presentation of EDS in OSAS

Nocturnal symptoms in OSAS (snoring, gasping) are more specific than those appearing duringdaytime. Type and characteristics of EDS in OSAS do not completely differ from that seen in otherentities clearly linked to hypersomnia such as narcolepsy with and without cataplexy, idiopathichypersomnia and atypical depression. There is a great variability in the clinical presentation ofEDS in OSAS. Like in some other disorders associated with EDS, OSAS patients usually report thatthey fall asleep under boring situations or during periods of physical inactivity like resting orsitting. Typically, patients with OSAS who nap for a short duration (515 min) do not feelrefreshed upon awakening and do not recall dreaming. A common complaint of poor memorymay be simply the consequence of a chronic state of drowsiness. At presentation or during follow-up visits, some untreated patients with true OSAS falsely report not experiencing EDS. This isbecause of a false perception of chronic habituated hypersomnia or because they aim to obtain

Table 5. Clinical indications of the Multiple Sleep Latency Test (MSLT) and Maintenance of Wakefulness Test

(MWT) followed in our sleep centre

Test Clinical indications

MSLT Suspected narcolepsy with cataplexy

Suspected narcolepsy without cataplexy

Suspected idiopathic hypersomnia

To verify in selected cases the presence or absence of EDS

In selected cases of residual sleepiness in OSAS patients treated with CPAP to

verify this condition and rule out comorbidities (e.g. narcolepsy); in these

cases, patients undergo polysomnography and MSLT using their own CPAP

MWT To assess an individuals ability to remain awake when his or her inability to

remain awake constitutes a personal or public safety issue. Particularly,

to assess response to treatment (CPAP, stimulants) in patients with previous EDSwho want to return to work or driving

In research trials to test the efficacy of a new drug or therapeutic strategy for EDS

EDS: excessive daytime sleepiness; OSAS: obstructive sleep apnoea syndrome; CPAP: continuous positive

airway pressure.

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some benefit (e.g.not losing the driving license, apply for a job). In contrast, for unknown causes,some other patients with true severe OSAS deny the presence of sleepiness and this is reflected insubjective sleep scales and objective tools. This may reflect the limitation of subjective sleep scalesand objective tests or other unknown biological, social or psychological factors. It is possible thatnonsleepy patients may have an innate increased sleep threshold or greater level of activation. Inone study, only 15% of males and 22% of females with OSAS, as defined as an apnoea/hypopnoeaindex (AHI) .5, reported EDS on the three subjective measures used [14]. Interestingly, patients

with OSAS who deny the occurrence of EDS may report daytime complaints, such as lack ofenergy or short memory, which can be the subjective perception of unrecognised EDS [2, 3, 15].

The consequences of EDS in subjects with OSAS are impaired quality of life, poor jobperformance, lack of motivation, compromised performance in social function, cognitiveimpairment, poor attention and lack of concentration [14]. EDS in OSAS also results in a high rateof accidents in traffic and work. Patients with OSAS are involved in traffic accidents 27-timesmore often than the general population [16].

Paediatric OSA has different clinical features and requires different management strategies fromOSA in adults. The condition can be very difficult to diagnose by only clinical history in children

[17] and requires polysomnography measuring the AHI. Peditaric OSA is different from adultOSA from the epidemiological, physiopathological and clinical points of view. This is why thenormal values for AHI and the definitions of an apnoeic event and OSA are different betweenchildren and adults [18]. In children, an obstructive apnoeic event is defined as the absence ofairflow with continued chest and abdominal movements for at least two breaths or 5 s [19]. Theabnormal diagnostic for children is AHI .1 event?h-1, and OSAS has been classified in children asmild (1.AHI,5 events?h-1), moderate (5.AHI,9 events?h-1) and severe (AHI.10 events?h-1)[20]. Proposed criteria for paediatric OSA that requires treatment is: 1) obstructive AHI.2 events?h-1 of sleep, 2) nadir SpO2 lower than 90%, and 3) EDS [21]. When using strict criteria,EDS is reported to affect 13% of all children [22]. In a study using polysomnography involving

children aged between 5 and 12 yrs, the prevalence of mild obstructive sleep apnoea (AHI between1 and 4) was 25%, and the prevalence of moderate sleep-disordered breathing (AHI .4) was 1.2%[23]. There is some evidence, though, that polysomnographic parameters are unlikely to identifythe true significance of OSAS in children [22].

What is the cause of EDS in OSAS?

Since obstructive sleep apnoea fragments sleep, due to an increased number of arousals, and sleepfragmentation reduces sleep quality and sleep quantity, it has long believed that obstructive sleepapnoea is the sole cause of EDS in subject with OSAS. This is supported by the fact that many OSASpatients under correct adequate therapy with nasal CPAP report the disappearance of EDS. However,the situation is much more complex; some patients deny the presence of EDS despite the occurrenceof .60 obstructive apnoeic episodes per h seen during baseline nocturnal polysomnographicrecordings, whereas others report residual EDS despite adequate therapy with CPAP.

In patients with OSAS, the obstructive apnoeic episodes are linked to various features, such asarousals that break the sleep continuity, reduced deep-sleep percentage, increased light-sleeppercentage, snoring, hypoxaemia and autonomic activation. All of these features have beeninvestigated to assess if they are the primary cause of EDS in subjects with OSAS [15]. Studies haveshown that none of these factors, however, explain per se the occurrence of EDS in OSAS.Although the severity of OSAS is classified into mild, moderate and severe according to the AHI

value, this measure is not associated with EDS when this symptom is evaluated with the MSLT [24,25]. Severe OSAS patients may report themselves to be more alert on the ESS than patients withmoderate OSA [26]. It has been shown that there are no consistent correlations between the numberof arousals and subjective scales score [27] and objective measures of the MSLT [25]. After adequatetreatment with CPAP, the amount of deep sleep is not correlated with the MSL in MSLT, post-treatment [28]. No change in the MSLT is observed when OSAS patients are treated with CPAP,

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irrespective of the absence or presence of nocturnal hypoxaemia [29]. Taken together, available datamay point towards methodological limitations of polysomnography, such as the night-to-nightvariation of the sleep parameters (number of arousals, number of apnoeas, severity of hypoxaemia,etc.) and visual scoring problems when scoring a polysomnogram. On the other hand, it is knownthat subjective sleep scales and objective tools are not perfect methods for measuring such complexsymptom as EDS. In summary, the mechanisms of EDS in OSAS are probably very complex andmultifactorial and still remain to be elucidated.

Evaluation of EDS in subjects with OSAS

Available data indicate weak or no correlation between objective and subjective measures of EDS insubjects with OSAS. This is probably due to different aspects, including biological and psychologicalfactors and limitation of the available tools. Measures of objective sleepiness quantify EDS during asingle day whereas ESS quantifies EDS in the recent past. The MSLT and the MWT may notadequately reveal diurnal impairment in sleepy patients and may not be comparable since theyevaluate different aspects of EDS. Overall, neither objective nor subjective measures of alertnesscurrently characterise the phenomenon of EDS in OSAS with comparable accuracy [15].

The MSLT in OSAS

OSAS patients who had car accidents did not have shorter MSL on their MSLT, and did not feelsleepier on ESSS than OSAS patients who had not accidents. MSL in patients who had accidentswas 7.8 min and it was 8.0 min in those who had no car crashes [30]. There is no significantassociation between the ESS scores and the MSL on MSLT in OSAS subjects. From this finding,one can conclude that the objectively documented MSL and subjectively scored sleepiness on theESS may well represent different facets of sleepiness [31].

When OSAS patients are compared with controls, there is a significant overlap in MSL, but the

overall results showed 7.26.0 min in patients and 12.84.1 min in controls, which is 1.5 and1.0 standard deviations less than the normal control mean. This indicates that the routine use ofMSLT to assess EDS in OSAS may not always contribute significantly in diagnosis or evaluatingresponse to treatment for OSAS. The MSLT has shown reduced MSL values in subjects with severeOSAS but not in those with higher AHI [24, 32]. The MSL in OSAS is much higher than that isseen in patients with narcolepsy. SOREMPs can be seen in subjects with OSAS, especially in malesubjects with severe EDS and short nocturnal latency to REM sleep [33]. It should be noted,though, that OSAS and narcolepsy may coexist in patients reporting EDS [34].

The use of MSLT in children with OSAS has shown that: 1) the reduction of the MSL is similar tothe restriction of sleep of 4 h; 2) severity of OSAS is related to the MSL; and 3) treatment of OSAS

results in normalisation of MSL [35, 36].

The MWT in OSAS

In a study, no difference was seen in MSL on MWT between patients with moderate and severeOSA [26]. In the MWT 40-min protocol, the MSL in normal controls was 345.5 min, and23.210.2 min in OSAS patients, almost two standard deviations from the normal control values[37]. In the MWT 20-min protocol, the MSL in normal controls was 18.83.3 min, and11.05.6 min in OSAS patients, which is more than two standard deviations from the normalcontrol value [38].

Effect of treatment of EDS in OSAS

After adequate CPAP therapy, many patients report an important decrease or resolution of theirprevious EDS [39]. Most of the studies have shown significant increases in MSL on the MSLT withCPAP [10]. Patients with OSAS who have EDS may benefit more with CPAP than those without EDS.

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MSL on MSLT, though, does not always improve after CPAP. In patients without EDS, CPAP therapydoes not improve subjective and objective measures of EDS [40]. In subjects with EDS that experienceimprovement of EDS with CPAP, the MSL on the MSLT increases about 1 or 2 min but does notnormalise [10]. Some studies have found no significant improvement in MSL on MSLT whencomparing CPAP with placebo [41].

Using the 40-min protocol of the MWT, it has been shown that there is a statistically significantimprovement in OSA patients after treatment with CPAP (18.89.9 min at baseline versus

26.310 min with CPAP therapy) [10].

Some patients report residual daytime sleepiness despite adequate treatment with CPAP. Whenthese patients are evaluated and inadequate CPAP therapy (e.g. wrong pressures, poorhumidification, rhinitis, mask leaks), insufficient night-time sleep and coexistent causes of EDS(narcolepsy, depression,etc.) are ruled out, there is still a subgroup of individuals who continue toexperience disabling persistent EDS [34, 42]. In these patients, the underlying cause of residualEDS remains unclear, although it is speculated that chronic hypoxaemia, related to years ofuntreated sleep apnoea, could result in neuronal brain injury resulting in EDS of central origin.One study showed that the prevalence of EDS (defined by an ESS .10) was not different between

572 patients on CPAP and 525 control subjects (16% versus14%, respectively), suggesting thepossibility that the post-CPAP sleepiness is not only a specific condition but also a situationcommonly seen in the general population which is not abnormal [43]. This is in line with onestudy involving 502 OSAS patients using CPAP for .3 h?night-1 showing that the prevalence ofresidual EDS (defined by an EES score .10) was 12%. After excluding cases of conditions linkedto EDS, such as depression and narcolepsy, the prevalence of residual sleepiness of unknown originwas 6%. Residual EDS was linked to an important somnolence before the initiation of CPAP.Thus, it seems that those OSAS patients who are sleepy at presentation are those who are morelikely to experience no improvement in EDS after adequate CPAP therapy [44]. Thus, it has beenspeculated that post-CPAP sleepiness may not be a pathological situation, leading to suggest that

the use of medications promoting wakefulness may not be indicated in this situation [43].However, it should be noted that these patients are still socially impaired and may ask thephysician for means to eliminate his/her EDS to improve their quality of life.

In patients with residual sleepiness despite the correct use of CPAP, stimulants such as modafiniland armodafinil have shown to improve subjective and objective vigilance measures and quality oflife. Modafinil (100400 mg) is licensed to be indicated for post-CPAP sleepiness and it has beenshown to improve objective measures of sleepiness in the MWT and MSLT and subjectivemeasures using the ESS [45]. Armodafinil is the R-isomer of modafinil and has recently receivedUS Food and Drug Administration approval for the treatment of residual sleepiness after CPAP.Like modafinil, armodafinil (150250 mg) modestly improves objective and subjective measures

of EDS [45, 46]. It should be noted that neither modafinil nor armodafinil have an effect on theAHI, sleep architecture and do not reverse the underlying pathophysiology of OSAS. In otherwords, these medications treat the symptom (EDS) but not its origin.

Statement of Interest

None declared.

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