Chapter 2

Excessive daytime sleepiness in OSA

A. 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 cause of 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 population. 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. Iranzo Neurology Service, Hospital Clinic de Barcelona, C/Villarroel 170, Barcelona 08036, Spain, Email airanzo@clinic.ub.es

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

akefulness and sleep are integral aspects of all diurnal organisms. Sleepiness is a normal phenomenon that occurs when individuals experience a physiological tendency to fall asleep according to homeostatic influences, the circadian cycle and the length of time from the last period of sleep. In normal people, sleepiness is maximal between 02:00 h and 06:00 h with a second minor 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 a activity (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 Parkinson disease and hypocretinergic dysfunction in narcolepsy with cataplexy) may lead to several sleep disturbances including hypersomnia. Medications that promote dopaminergic activity at small doses (e.g. levodopa, dopaminergic agonists), histamine receptor antagonists and benzodiazepines may induce sleepiness, whereas drugs with monoaminergic activity, such as methylphenidate and modafinil act as central nervous system stimulants inducing persistent wakefulness. Also, diseases associated with recurrent episodes of upper airway collapse during sleep may be associated with hypersomnia. 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 inability to stay awake and alert during the major waking episodes of the day, resulting in undesirable lapses into drowsiness or sleep. In other words, EDS can be defined as a condition that is associated 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 is more 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 of automatic behaviour, in which subjects have no memory of some of the events that they have performed through the day. EDS can be dangerous in individuals who drive, fly or work with some technologies. In children, EDS may be manifested as restless, inattention and hyperactivity to stay alert. Duration of chronic EDS is arbitrarily defined as occurring for o3 months [1]. In most cases, EDS is a chronic symptom and, when acute or subacute, a causative factor should be sought (e.g. depression, systemic infection, head trauma, brain structural lesions including tumours and stroke, etc.). The fact that EDS is a subjective feature which depends on the patient perception and his/her ability to recognise a tendency to fall asleep is reflected by the finding that some subjects with true pathologic EDS have little or no warning of sleep. In contrast, patients with primary insomnia may be tired and have an intense desire to fall asleep during the day but are unable to do so. In most of the cases at sleep centres, EDS is generally the direct result of sleep loss from either reduced sleep quantity or fragmented sleep resulting in decreased sleep quality. The causes of EDS are variable, ranging from insufficient night-time sleep, fragmented sleep, circadian rhythm disturbances causing a mismatch in the sleepwake pattern, use of sedative medications and neuronal 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. EDS is a symptom associated with several sleep disorders including obstructive sleep apnoea syndrome (OSAS) and narcolepsy, and neurological or general clinical conditions such as Parkinsons disease, 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 occurs when an individual persistently fails to obtain the amount of sleep required to maintain a normal level of alertness and wakefulness. This is the explanation of why normal healthy people, when inquired, may self-record high scores on scales that evaluate the presence of EDS and also show reduced 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 OSAS patients report this symptom. The presence of EDS is a prerequisite for the diagnosis of some sleep conditions like narcolepsy but not in others such as in OSAS. In some disorders, chronic EDS may represent the main and most disabling complaint. It also can be the first to occur, such as in narcolepsy, depression or Parkinsons disease. However, it is worth mentioning that there is a great variability 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 consultation is difficulty maintaining sleep, but detailed questioning reveals experience of EDS for years. Contrary to popular belief, EDS is not linked to restless legs syndrome and periodic leg movements in sleep. EDS can be present, though, in subjects with these two conditions when they cause insufficient nocturnal sleep time. Physicophysiological insomnia is not associated with EDS.

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

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 such as OSAS. This may be to several factors including: 1) patients do not complain about it; 2) patients do not recognise that EDS is present; 3) patients recognise that EDS is present but interpret that this does not interfere with their quality of life; and 4) physicians do not inquire about this symptom. Epidemiological studies have shown impressive data regarding the prevalence of EDS in the general population. However, it should be noted that in these studies the definition of EDS may vary from study to study [4]. Studies in the USA report rates of EDS varying from 0.3% to 16.3%. These differences in prevalence are probably explained by the different definitions of EDS used by the different authors. The Cardiovascular Health study found a 20% prevalence of individuals reporting being usually sleepy in the daytime in a sample of .4,500 people aged o65 yrs [5]. In another study, EDS was reported in 1721% of school-aged children and adolescents [6]. According to the National Sleep Foundation 2005 Sleep in America Poll, 27% of males 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 a subjective feature which depends on patient ability to distinguish normal from abnormal. Individuals may deny experiencing EDS but report important tiredness, poor memory and concentration, lack of energy, weakness or fatigue during the day. In contrast, individuals suffering from true fatigue may falsely report experiencing EDS [13]. There are two possible clinical presentations of EDS which usually coexist in the same patient, if they are not really the same phenomenon. Both types of EDS may impact upon the patients quality 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 it but 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 this undesirable sensation. Patients, however, fall asleep and take frequent short naps at inappropriate times and/or settings, especially when situations are not stimulating, such as watching television and reading. Some subjects are unable even to stay awake in active situations like eating or talking. This type of EDS is non-specific for OSAS since it is the main feature of other conditions in which EDS is common, such as narcolepsy, idiopathic hypersomnia, depression and nocturnal sleep deprivation.

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These sleep episodes in patients with OSAS are typically short (515 min) but they may last for 1 or 2 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 active situations, 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 or they are merely an extreme manifestation of severe hypersomnia. They have been classically described in patients with narcolepsy and more recently in Parkinsons disease, particularly in those patients under dopaminergic therapy replacement. They also occur in a few patients with severe OSAS. It is possible that patients with sudden onset of sleep episodes of any aetiology, including some cases with OSAS, are not aware that they are sleepy simply because of the amnesia associated with falling asleep or because they have long habituated to the sensation of chronic and severe hypersomnia and are not aware that they are sleepy during the day. It is possible that increased drowsiness precedes sudden onset of sleep episodes, perhaps because patients become habituated to a state of chronic drowsiness. It is our experience that the few patients that have fallen asleep during a clinical interview suffered from severe OSAS only and not other classic conditions traditionally linked to severe EDS, such as narcolepsy or idiopathic hypersomnia. In children and adolescents, EDS may be manifested as restless, inattention and hyperactive to stay alert. 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 a decreased activity [7].
EXCESSIVE DAYTIME SLEEPINESS

Evaluation and measurement of EDS

The evaluation of EDS is problematic for at least two reasons. First, the description of the symptom may be misleading or not recognised by the patient. Secondly, the physiologic state of somnolence is not easily measured from the available subjective and objective methodological tools. Clinical history is the most important tool. Sleepiness scales and objective tests can also be used 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 collateral history from a bed partner, relatives, friends or caregivers when available. Clinical history is the most important tool for evaluating the occurrence and characteristics of EDS. Details of patients typical night sleep time and sleepwake schedule are always required along with the observation of other symptoms, such as the presence of waking with choking sensation in the throat, witnessed apnoeas and snoring. EDS and these features are the classical symptoms of OSAS. The degree and relevance of EDS should always be evaluated clinically, and special emphasis should be paid to driving performance. Clinically, it is crucial to distinguish EDS from fatigue, lack of energy, asthenia, poor concentration and tiredness. Once one is sure that the patient has EDS which interferes with his quality 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 other symptoms, 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 and reflect the patients own opinion on the severity of his/her EDS. They are used to supplement the history and to follow the effects of treatment. Currently, the following two sleep questionnaires are routinely 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 sleepiness at a specific moment and is often administrated just before the trials of the multiple sleep latency test to 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 seven descriptions ranging from felling active and vital; alert wide awake to almost in reverie; sleep onset soon; lost struggle to remain awake. The SSS is fast and easy to use. However, there are no reference 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. The ESS was developed in 1991 as a trait to measure the tendency to fall asleep in several specific situations. It is a subjective tool of how sleepiness interferes with an individuals common daily activities. 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 the likelihood of their falling asleep in a four-point scale (05never doze to 35high probability). Scores from 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. The scale shows acceptable testretest reliability. Studies have shown little or no correlation between ESS scores 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 several limitations. For example, it asks subjects to picture themselves in situations which they may actually experience rarely or never (e.g. driving, going to the theatre). Semantic issues may also lead to confusion. Circadian variations in alertness are not captured with this scale. The eight situations are equally weighted, despite obvious differences in significance (e.g. driving versus going to the theatre). Finally, there may be individual variation scores over time. Generally, the ESS is more reliable when scores are abnormally high or very low. Many sleepy subjects may score in the normal range because they do not actually fall asleep, despite being drowsy, either because of effective compensatory measures 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 or tendency to fall asleep. The MSLT is considered by most specialists to be the standard objective measurement for EDS. It is also the most widely Table 2. Stanford Sleepiness Scale used and most extenFeeling active; alert; wide awake sively published objecFunctioning at a high level, but not at peak; able to concentrate tive measure of EDS. Relaxed; awake; not full alertness; responsive The MSLT is intended A little foggy; clearly not at a peak; let down to measure physiological Fogginess; beginning to lose interest in remaining awake; slowed down sleep tendency under Sleepiness; prefer to be lying down; fighting sleep; woozy standardised conditions Almost in reverie; sleep onset soon; lost struggle to remain awake in the absence of external

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alerting factors. The test is based on the premise Sitting and reading that the degree of sleepiWatching TV ness is reflected by the Sitting inactive in a public place (e.g. theatre or a meeting) sleep latency. The sleep As a passenger in a car for an hour without a break latency is defined as the Lying down to rest in the afternoon when circumstances permit interval between the start Sitting and talking to someone of the test when the lights Sitting quietly after lunch without alcohol are turned off and the In a car, while stopped for a few minutes in traffic sleep onset. The MSLT was 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-h intervals across the day. Within a few years, researchers began using the MSLT to measure sleepiness in several sleep disorders, including OSAS, narcolepsy and insomnia [1013].
Table 3. Situations included in the Epworth Sleepiness Scale

EXCESSIVE DAYTIME SLEEPINESS

The test is performed the day after an overnight polysomnogram to evaluate the occurrence of a cause 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 nap opportunities performed at 2-h intervals across a patients major usual period of wakefulness. The first nap opportunity begins 1.53 h after termination of an overnight polysomnographic recording. The patient should be offered a light breakfast o1 h before the first nap, and a light lunch after termination of the second nap opportunity. Alcohol is not allowed. The test environment should be quiet and free of noises, such as ambulance sirens, elevators, construction and toilets. Room temperature should be set based on the patients comfort level. Sleep rooms should be quite and dark during test sessions. The patient is dressed in street clothes during each opportunity removing his or her shoes and loosening constricting clothes. Patients and sleep technologists mobile telephones must be switched off. The patient must abstain from drinking caffeinated beverages between naps. Tobacco use and vigorous and stimulating activities should be stopped o30 min before each nap opportunity. Patients should be in bed 5 min before each nap opportunity with the lights on. 30 s before each nap test, the patient is encouraged to assume a comfortable position for falling asleep. 5 s before the start of each nap opportunity, the patient is
Table 4. Mean sleep latencies (MSLs) in the Multiple Sleep Latency Test (MSLT) and Maintenance of
Wakefulness test (MWT)

MSLT

MWT 40-min version

MWT 20-min version

Normal MSL .10 min MSL of 810 min is considered the twilight zone MSL in controls was 10.54.6 and 12.84.6 min in two different studies 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 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 Normal MSL is considered .10 min MSL 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 a comfortable position, keep your eyes closed and try to fall asleep. The technologists then turn the lights off signalling lights out and the start of the test. Between naps the patient should be out of bed and prevented from sleeping. The conventional recording MSLT montage includes bilateral central and occipital leads, left and right electro-oculograms, submental electromyography and electrocardiogram. The sleep latency is defined 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 a 30-s epoch. Sleep onset is defined as the first epoch containing more than 15 s of cumulative sleep in 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 taken as the time from the first epoch of sleep to the beginning of the first epoch of REM sleep. Sleep onset 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 nap opportunity is scored as a sleep latency of 20 min. The mean sleep latency (MSL) is the arithmetic mean of sleep latencies for all four or five nap opportunities. The MSLT report should include the start 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 sleep latency of the polysomnogram performed the previous night should be reviewed before the report of a MSLT. It is recommended that 2 weeks prior to the MSLT session, an adequate sleepwake schedule should 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 of o6 h. This is crucial since SOREMPs and short MSL on the MSLT can be easily seen in shift workers, 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 life of the drug and long-lasting metabolite, and patients had a regular sleepwake schedule during the previous week. Conditions that may affect the validity of the MSLT include: 1) insufficient sleep the night or week before the MSLT; 2) performance of the MSLT at a time different than the patient usual time of wakefulness; 3) excessive noise or temperature extremes; 4) use of medications that could alter sleep 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 of methodological issues arise when attempting to determine normal and pathological ranges for the MSLT values. Precise normative ranges for MSL are not well defined. It has not been established whether a single pathologic cut-off should be used for all patients groups and ages. Although MSLT is a validated measure, there is no large systematically collected normative data. Many factors may influence the MSL, such as motivation, age, external stimuli, medication, previous sleep quality and sleep time, medical disorders and psychological factors. Identification of normative values is limited by the large standard deviation in MSLs on the MSLT, as well as floor and ceiling effects which suggests that values are not normally distributed. Thus, there is a significant 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 presence or severity of EDS. Assessment should involve integration of the clinical history, objective tests results and some other medical information. Overall, adult control subjects usually have a MSL values in the 1020 min range and MSL values between 5 and 10 min are described as being in the diagnostic grey area of uncertain origin. In patients with OSAS the MSL is 7.26.0 min. For the diagnosis 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 below this 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 to sleep deprivation or underdiagnosed conditions linked to EDS). Thus, it can be stated that the MSLT does not discriminate well between clinical populations and control populations. Although more than one SOREMP is seen in most cases with narcolepsy, this feature can also be seen in subjects with OSAS, normal subjects and shift workers, and after acute withdrawal of REMsuppressing drugs (e.g. antidepressants) causing REM sleep rebound. The diagnostic sensitivity of the MSLT for the diagnosis of narcolepsy has been estimated around 60%, while the diagnostic specificity when two or more SOREMPs are present is around 95%. If the presence of two or more SOREMPs is combined with a MSL of ,5 min, then the diagnostic specificity for narcolepsy rises to 97%. The majority of narcoleptics show a MSL of ,8 min. The MSL 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 two SOREMPs 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 has been 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 without cataplexy and idiopathic hypersomnia. The MSLT is not routinely indicated for the evaluation or diagnosis of OSAS or assessment of response to treatment of OSAS. However, the MSLT should be indicated in OSAS patients that continue to experience EDS despite correct treatment of the underlying condition (surgery, continuous positive airway pressure (CPAP), etc.). In this particular case, the MSLT and the previous overnight polysomnogram can be both performed with the CPAP that the patient uses habitually at his/her home. MSLT is not the best measure of treatment 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 to sleep under soporific conditions, rather than a tendency to fall asleep.

EXCESSIVE DAYTIME SLEEPINESS

The MWT
This is a variant of the MSLT in which, rather than attempt to sleep, the patient is asked to remain awake as long as possible. It assesses the ability to resist the urge to fall asleep during soporific circumstances and provides an objective measure of wake tendency. It is not a diagnostic test for the degree of sleepiness but a test of the ability to remain awake. It is used to assess the efficacy of a treatment 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. It is 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 awake when his or her ability to remain awake constitutes a public or personal safety use. The MWT is more subject to motivational factors than the MSLT [1013]. Four nap opportunities are performed at 2-h intervals after an overnight polysomnogram. The patient is positioned sitting up in bed, with the back and head supported by a bed rest pillow or cushion or at a 4590u angle with respect to the legs. The patient is asked to try to remain awake with the eyes open, but is not allowed to use extraordinary measures such as walking, singing or talking. The latency to the first three consecutive 30-s epochs of sleep (or to the first epoch of sleep as in the MSLT) is measured for each trial and the MSL is calculated. The patient is awakened when sleep onset is scored. Two variants of the test have been described: in the first, a trial is terminated 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 the 20 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 in the 40 min version, and 11 in the 20 min version. The MSL in the MWT does not correlate with total 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 are presented. 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 the same variable (the mean sleep latency), one would expect the results to be correlated even if not similar in magnitude. However, this is not true. Only low correlations have been found between MSLT and MWT results in the same subjects. Such low correlation indicates that the relationship accounts for only 1025% of the total variance. Only weak correlations have been found between the MSL in the MSLT and both SSS and ESS scores. Weak correlation has also been found between the MSLT and treatment responses among patients with OSAS. The lack of substantial correlations between these tests implies that judgements of sleepiness may be test-specific features, indicating that there is more than a single component to EDS. Thereby, it can be speculated that subjective and 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 during daytime. Type and characteristics of EDS in OSAS do not completely differ from that seen in other entities clearly linked to hypersomnia such as narcolepsy with and without cataplexy, idiopathic hypersomnia and atypical depression. There is a great variability in the clinical presentation of EDS in OSAS. Like in some other disorders associated with EDS, OSAS patients usually report that they fall asleep under boring situations or during periods of physical inactivity like resting or sitting. Typically, patients with OSAS who nap for a short duration (515 min) do not feel refreshed upon awakening and do not recall dreaming. A common complaint of poor memory may be simply the consequence of a chronic state of drowsiness. At presentation or during followup visits, some untreated patients with true OSAS falsely report not experiencing EDS. This is because 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 MSLT Clinical indications 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 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 EDS who want to return to work or driving In research trials to test the efficacy of a new drug or therapeutic strategy for EDS

MWT

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 in subjective sleep scales and objective tools. This may reflect the limitation of subjective sleep scales and objective tests or other unknown biological, social or psychological factors. It is possible that nonsleepy patients may have an innate increased sleep threshold or greater level of activation. In one study, only 15% of males and 22% of females with OSAS, as defined as an apnoea/hypopnoea index (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 of energy 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 job performance, lack of motivation, compromised performance in social function, cognitive impairment, poor attention and lack of concentration [14]. EDS in OSAS also results in a high rate of accidents in traffic and work. Patients with OSAS are involved in traffic accidents 27-times more often than the general population [16]. Paediatric OSA has different clinical features and requires different management strategies from OSA 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 adult OSA from the epidemiological, physiopathological and clinical points of view. This is why the normal values for AHI and the definitions of an apnoeic event and OSA are different between children and adults [18]. In children, an obstructive apnoeic event is defined as the absence of airflow with continued chest and abdominal movements for at least two breaths or 5 s [19]. The abnormal diagnostic for children is AHI .1 event?h-1, and OSAS has been classified in children as mild (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 between 1 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 identify the true significance of OSAS in children [22].

EXCESSIVE DAYTIME SLEEPINESS

What is the cause of EDS in OSAS?

Since obstructive sleep apnoea fragments sleep, due to an increased number of arousals, and sleep fragmentation reduces sleep quality and sleep quantity, it has long believed that obstructive sleep apnoea is the sole cause of EDS in subject with OSAS. This is supported by the fact that many OSAS patients 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 occurrence of .60 obstructive apnoeic episodes per h seen during baseline nocturnal polysomnographic recordings, whereas others report residual EDS despite adequate therapy with CPAP. In patients with OSAS, the obstructive apnoeic episodes are linked to various features, such as arousals that break the sleep continuity, reduced deep-sleep percentage, increased light-sleep percentage, snoring, hypoxaemia and autonomic activation. All of these features have been investigated to assess if they are the primary cause of EDS in subjects with OSAS [15]. Studies have shown 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 with moderate OSA [26]. It has been shown that there are no consistent correlations between the number of arousals and subjective scales score [27] and objective measures of the MSLT [25]. After adequate treatment with CPAP, the amount of deep sleep is not correlated with the MSL in MSLT, posttreatment [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 data may point towards methodological limitations of polysomnography, such as the night-to-night variation 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 known that subjective sleep scales and objective tools are not perfect methods for measuring such complex symptom as EDS. In summary, the mechanisms of EDS in OSAS are probably very complex and multifactorial 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 in subjects with OSAS. This is probably due to different aspects, including biological and psychological factors and limitation of the available tools. Measures of objective sleepiness quantify EDS during a single day whereas ESS quantifies EDS in the recent past. The MSLT and the MWT may not adequately reveal diurnal impairment in sleepy patients and may not be comparable since they evaluate different aspects of EDS. Overall, neither objective nor subjective measures of alertness currently 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 feel sleepier on ESSS than OSAS patients who had not accidents. MSL in patients who had accidents was 7.8 min and it was 8.0 min in those who had no car crashes [30]. There is no significant association 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 the ESS 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 and 1.0 standard deviations less than the normal control mean. This indicates that the routine use of MSLT to assess EDS in OSAS may not always contribute significantly in diagnosis or evaluating response to treatment for OSAS. The MSLT has shown reduced MSL values in subjects with severe OSAS but not in those with higher AHI [24, 32]. The MSL in OSAS is much higher than that is seen in patients with narcolepsy. SOREMPs can be seen in subjects with OSAS, especially in male subjects 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 to the 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 severe OSA [26]. In the MWT 40-min protocol, the MSL in normal controls was 345.5 min, and 23.210.2 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, and 11.05.6 min in OSAS patients, which is more than two standard deviations from the normal control value [38].

Effect of treatment of EDS in OSAS

After adequate CPAP therapy, many patients report an important decrease or resolution of their previous EDS [39]. Most of the studies have shown significant increases in MSL on the MSLT with CPAP [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 therapy does not improve subjective and objective measures of EDS [40]. In subjects with EDS that experience improvement of EDS with CPAP, the MSL on the MSLT increases about 1 or 2 min but does not normalise [10]. Some studies have found no significant improvement in MSL on MSLT when comparing CPAP with placebo [41]. Using the 40-min protocol of the MWT, it has been shown that there is a statistically significant improvement 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. When these patients are evaluated and inadequate CPAP therapy (e.g. wrong pressures, poor humidification, 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 to experience disabling persistent EDS [34, 42]. In these patients, the underlying cause of residual EDS remains unclear, although it is speculated that chronic hypoxaemia, related to years of untreated 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% versus 14%, respectively), suggesting the possibility that the post-CPAP sleepiness is not only a specific condition but also a situation commonly seen in the general population which is not abnormal [43]. This is in line with one study involving 502 OSAS patients using CPAP for .3 h?night-1 showing that the prevalence of residual EDS (defined by an EES score .10) was 12%. After excluding cases of conditions linked to EDS, such as depression and narcolepsy, the prevalence of residual sleepiness of unknown origin was 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 more likely to experience no improvement in EDS after adequate CPAP therapy [44]. Thus, it has been speculated 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 the physician 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 modafinil and armodafinil have shown to improve subjective and objective vigilance measures and quality of life. Modafinil (100400 mg) is licensed to be indicated for post-CPAP sleepiness and it has been shown to improve objective measures of sleepiness in the MWT and MSLT and subjective measures using the ESS [45]. Armodafinil is the R-isomer of modafinil and has recently received US 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 the AHI, sleep architecture and do not reverse the underlying pathophysiology of OSAS. In other words, these medications treat the symptom (EDS) but not its origin.

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Statement of Interest
None declared.

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