Abstract: Although excessive daytime sleepiness is most often simply the result of inadequate sleep, other causes must be considered as well. Common causes of daytime sleepiness include obstructive sleep apnea/hypopnea syndrome (OSAHS) and medication side effects. The differential diagnosis also includes narcolepsy and restless legs syndrome (RLS). In many cases, the answers to a few simple questions can provide the necessary clues to the diagnosis. Loud snoring is associated with OSAHS, while sudden muscle weakness triggered by intense emotion is consistent with narcolepsy. Referral for sleep evaluation is indicated to evaluate for OSAHS, narcolepsy, RLS, and idiopathic hypersomnia. Methods of measuring daytime sleepiness include the Multiple Sleep Latency Test and the Epworth Sleepiness Scale. (J Respir Dis. 2005;26(6):253-259)
Excessive daytime sleepiness is a major health problem in the United States. Several surveys indicate that approximately one third of Americans report daytime sleepiness that occurs at least a few days per month, and about 6% report daily symptoms.1-3 Daytime sleepiness can result in problems with vigilance, cognitive function, memory, concentration, and mood; it often leads to deterioration in school and/or job performance and productivity, social relationships, and driving skills.
The prevalence of driving while drowsy is high in the United States; 23% of persons surveyed in 1998 admitted to having dozed off behind the wheel of a car.3 It has been estimated that 15% to 20% of accidents may be related to sleepiness or fatigue, which causes about 1500 motor vehicle deaths per year.Therefore, an understanding of the causes and differential diagnosis of daytime sleepiness is important for all physicians.
In this article, I will discuss the determinants of sleepiness, the methods commonly used to measure sleepiness, the differential diagnosis, and a practical approach to the diagnosis, with emphasis on which patients need referral to a sleep center.
DETERMINANTS OF SLEEPINESS
Sleepiness in the midafternoon is normal; sleepiness is considered abnormal if it occurs at other times of the day or in situations in which alertness is warranted (meetings, lectures, driving). Sleepiness is a physiologic state that is similar to hunger or thirst. The subjective feeling of sleepiness can be reduced by motivation, excitement, exercise, and other competing needs.
As physiologic sleepiness worsens, it becomes more difficult to reduce its impact on overt behav-ior. Therefore, soporific behaviors (such as reading or watching television) unmask sleepiness but do not cause it. A truly alert person does not feel or appear to be sleepy when placed in a low-stimulus environment.
Quantity of sleep
A person's optimal sleep time is defined as the amount of time that allows him or her to maintain alertness throughout the day. For most persons, this is about 7 to 8 hours each night, although the optimal amount is variable.
Even 1 night of sleep deprivation, generally 4 hours of sleep or less, can lead to increased sleepiness on the following day, a situation that most persons have experienced.4 However, chronic sleep deprivation, usually less than 6 hours per night over consecutive nights, is a more common cause of daytime sleepiness. According to 2 surveys, approximately 15% of Americans sleep less than 6 hours per night on a regular basis.3,5
Quality of sleep
The quality and continuity of sleep are important determinants of sleepiness. Sleep disorders that are characterized by brief arousals, such as obstructive sleep apnea/hypopnea syndrome (OSAHS) and periodic limb movement disorder (PLMD), are chief examples of disorders that affect the quality of sleep. However, other conditions, such as asthma, congestive heart failure, gastroesophageal reflux disease, and various pain syndromes, can also contribute to daytime sleepiness by interfering with sleep.
A biphasic pattern of sleep tendency is observed in studies that test adults for physiologic sleepiness by asking them to sleep at 2-hour intervals in a low-stimulus environment, such as a darkened room.6 As expected, the shortest latencies to sleep occur during the early morning hours, 2 to 6 am. However, there are also shorter sleep latencies in the midafternoon, between 2 and 6 pm, which correspond to the time of day that many persons report increased sleepiness (and the time of the "siesta" that is prevalent in many cultures).
Drug side effects should always be investigated as a possible cause of sleepiness.7 Many medications can contribute to daytime sleepiness (Table 1).
The first-generation antihistamines, particularly those available over-the-counter (OTC), such as diphenhydramine, are among the most common causes of sleepiness. However, many patients do not think of these as medications, so they may not mention them when asked about medication use. Thus, it is important to ask patients specifically about the use of OTC antihistamines.Of thenewer, nonsedating antihistamines, only cetirizine has been associated with daytime sleepiness.
Many psychoactive medications cause daytime sleepiness. While the benzodiazepine sedative-hypnotics are generally taken at bedtime to help induce sleep, several of these agents are intermediate- or long-acting (temazepam and estazolam) and, therefore, they can cause residual sleepiness during the day. In addition, the anxiolytic benzodiazepines (such as diazepam and alprazolam) can cause sleepiness in some persons.
Several antidepressants, such as amitriptyline, trazodone, and paroxetine, have been associated with daytime sleepiness, as have barbiturates such as phenobarbital. Sedation is a common side effect of the traditional, older antipsychotic medications. Although sedation has been reported for most of the new-generation antipsychotics, it is much less common with these drugs.
In addition, antiepileptic drugs, such as phenytoin, carbamazepine, and valproic acid, have been reported to cause sedation. Newer antiepileptic agents, such as gabapentin and topiramate, can also have sedating effects, although at a lower rate than the other antiepileptic agents.
Narcotics can be associated with daytime sleepiness in some persons. Also, alcohol is a major cause of sleepiness.
There have been reports of sleepiness with antihypertensives, such as ß-blockers and centrally acting a-blockers (clonidine).7 However, with the exception of clonidine, no studies have shown objectively that these drugs increase sleepiness.
A normally functioning nervous system, particularly in the areas that control the wakefulness-sleep cycle (primarily the pons, hypothalamus, and basal forebrain), is critical to sleep regulation.8Abnormal function of the nervous system can cause daytime sleepiness, generally manifested as narcolepsy or idiopathic hypersomnolence.
Recent research has focused on the role of the neuropeptide hypocretinas a wake-promoting agent. Hypocretin-producing neurons in the hypothalamus project to much of the CNS and heavily innervate many areas of the brain associated with the sleep-wake cycle. A deficiency of hypocretin is now thought to be the major abnormality underlying the pathogenesis of narcolepsy.
MEASUREMENT OF DAYTIME SLEEPINESS
There are 2 common methods of measuring daytime sleepiness: the Multiple Sleep Latency Test (MSLT) and the Epworth Sleepiness Scale (ESS).
Multiple Sleep Latency Test
The MSLT measures the physiologic sleep tendency by measuring the time it takes to fall asleep when one begins a nap in the absence of alerting factors such as noise and light.9,10 During the test, which is generally performed on the day after a full sleep study, the patient is asked to fall asleep in bed, in a dark, quiet room, 4 or 5 times at 2-hour intervals during the day.
The latency to sleep for each nap is averaged to determine the daytime sleep latency. Generally, mean latencies of greater than 10 to 15 minutesare considered normal; a sleep latency of 5 minutes or less is considered severe or pathologic. In addition, there should be no rapid eye movement (REM) sleep during any of the nap opportunities.
The MSLT is a well-validated test of daytime sleepiness that can detect changes in sleepiness secondary to changes in sleep time,4 medications,11 and treatment.12 The main disadvantage of the MSLT is that it is laboratory-based and has to be performed by trained sleep personnel.
Given this requirement, the primary indication for the MSLT is to evaluate sleepiness in patients in whom sleep apnea is unlikely. In particular, the test is indicated for the evaluation of patients with suspected narcolepsy. Patients with narcolepsy generally show pathologic sleep latencies (less than 5 minutes) and have REM sleep during at least 2 of the 4 or 5 naps. In the absence of cataplexy, these findings on the MSLT are considered diagnostic of narcolepsy.
A modified version of the MSLT that is now frequently used in research studies--the Maintenance of Wakefulness Test (MWT)--measures a patient's ability to stay awake under soporific conditions rather than the time it takes to fall asleep.13,14 The MWT protocol is similar to that of the MSLT (4 naps, spaced 2 hours apart), except that the patient is instructed to stay awake while sitting upright in a low-stimulus environment.
The MWT is considered to be more clinically relevant because it reflects more closely the challenge patients face in soporific situations of everyday life. It is used frequently in research studies on the effectiveness of treatment strategies such as nasal continuous positive airway pressure in OSAHS10 and stimulants in narcolepsy.15 Regulatory agencies occasionally require a normal MWT result before allowing truck drivers or airline pilots who have a diagnosis of OSAHS to return to work.
Epworth Sleepiness Scale
The ESS was developed as an easy-to-use subjective scale that can measure daytime sleepiness without the requirement for in-laboratory testing.16-18 In answering the ESS, the patient rates his or her likelihood of dozing off in 8 situations ranging from highly soporific, such as watching television or reading, to those requiring attention, such as talking or attending a meeting (Table 2). Each situation is scored on a scale of 0 (will not doze off) to 3 (high likelihood of dozing off). The scores from each situation are added, which gives a final score between 0 and 24.
The major criticism of the ESS is that it does not correlate well with the MSLT. Traditionally, a score of 10 or above has been used to distinguish between persons with and without daytime sleepiness, although a recent article suggested that a cutoff of 12 may be a more reliable predictor of an increased tendency to fall asleep on the MSLT.19 A higher ESS score indicates a greater propensity to fall asleep19--but not necessarily a shorter sleep latency20--on the MSLT. Therefore, on initial evaluation, the ESS value may or may not indicate that the patient is truly sleepy, as measured objectively by the MSLT.
However, several studies show that higher ESS scores decrease with effective treatment of the primary sleep disorder.12,15,21,22 Therefore, the ESS can provide valuable information to the physician in determining whether the treatment plan has been effective for the patient. It should be noted that while the MWT, MSLT, and ESS all have their uses, there is little or no outcomes-based research that would allow clinicians to use any of them as a reliable predictor of risk for motor vehicle accidents or other future morbidity associated with sleepiness.
The differential diagnosis of excessive daytime sleepiness is presented in Table 3. Chronically insufficient sleep is probably the most common cause of sleepiness, given the prevalence of sleep deprivation in adults.2,3,5,23 However, this diagnosis is rarely made, because chronic sleep deprivation is not generally viewed as a medical problem.
The 2 major characteristics of chronically insufficient sleep are habitual sleep episodes that are shorter in duration than is expected for age (generally, 7 to 8 hours for adults) and longer than normal sleep episodes on weekends or vacations. Other diagnostic clues in the history include the patient's work schedule, number of jobs, family and other social obligations, and hours of television and Internet use.
Chronically insufficient sleep is a clinical diagnosis based on the patient's sleep and social history. However, many patients with other sleep disorders also have insufficient sleep. Therefore, it is important to consider other causes before deciding that insufficient sleep is the only cause of a patient's daytime sleepiness.
OSAHS is characterized by recurrent collapse of the upper airway during sleep; the episodes of collapse are associated with oxyhemoglobin desaturation and recurrent arousals.24 Patients generally present with a complaint of loud snoring that is bothersome to the bed partner, witnessed apneas, nocturnal gasping and choking, morning headaches, and nonrefreshing sleep.
Obesity is the most common finding on physical examination. Other common abnormalities associated with OSAHS include tonsillar hyperplasia, crowding of the oropharynx, lateral narrowing of the pharyngeal walls, an enlarged tongue, and retrognathia. OSAHS is diagnosed by polysomnography; therefore, referral to a sleep center is recommended.
Narcolepsy is a chronic neurologic condition characterized by both excessive daytime sleepiness and impaired regulation of REM sleep.25,26In addition to daytime sleepiness, narcoleptic patients often have cataplexy, hypnagogic hallucinations, and sleep paralysis.
Cataplexy, considered pathognomonic of this disorder, is sudden muscle weakness brought on by intense emotion, such as anger, or by laughter. The muscle weakness can affect any muscle group and manifest as falling, facial or head droop, or dropping objects.
Hypnagogic hallucinations (intense, dreamlike hallucinations at the beginning of the night soon after the patient falls asleep) and sleep paralysis (profound weakness of the skeletal muscles, generally occurring during awakenings) are not specific to narcolepsy; both have been reported by patients with severe OSAHS or idiopathic hypersomnia, and sleep paralysis can also occur as a sporadic parasomnia. Because a nocturnal sleep study and an MSLT are often required for the diagnosis of narcolepsy, especially in cases without cataplexy, referral to a sleep specialist is recommended.
The restless legs syndrome (RLS) is characterized by a feeling of motor restlessness or urge to move the legs that is relieved with leg movement and occurs while sitting or lying down, typically in the evening.27 RLS is often associated with recurrent leg kicking during sleep, the main feature of PLMD.
RLS may present as insomnia because the restlessness prevents the patient from falling asleep; however, daytime sleepiness can also be the presenting symptom if there are prominent leg movements during sleep. RLS is diagnosed clinically, requiring only the presence of the symptoms noted above, while PLMD is diagnosed by sleep study.
PLMD is characterized by repetitive, rhythmic limb movements during sleep, particularly during the first half of the night. The limb movements are generally associated with arousals from sleep.
Approximately 80% of patients with RLS have PLMD. However, most patients with PLMD that has been documented by sleep study do not have the characteristic features of RLS. PLMD is frequently seen in patients with OSAHS and narcolepsy. Whether the finding of PLMD on sleep study is clinically significant in the absence of an association with another sleep disorder is controversial.
Disorders of the sleep-wake cycle are often characterized by a misalignment between the patient's sleep cycle and the societal norm (generally a bedtime between 10 pm and midnight with awakening between 6 and 8 am).28 Most shift workers, particularly those with night shifts or frequently rotat- ing shifts, complain of excessive sleepiness because it is difficult to achieve normal sleep when the major sleep episode begins in the morning.29
Patients with delayed sleep phase syndrome tend to go to bed after midnight (bedtime is delayed relative to the societal norm) and, if allowed, will generally sleep uninterruptedly for 7 to 8 hours, awakening refreshed. The shifted sleep pattern becomes abnormal when the patient must awaken earlier than his or her optimal time, usually because of employment. The correspondingly shortened sleep time leads to insufficient sleep and excessive sleepiness.
Idiopathic hypersomnia is characterized by constant daytime sleepiness and frequent daytime sleep episodes lasting 1 hour or more that are generally not refreshing.26,30 The MSLT demonstrates moderate to severe shortening of the daytime sleep latency (less than 10 minutes), but there is generally no REM during any of the naps.
Idiopathic hypersomnia is difficult to diagnose, in part because there are no clear diagnostic criteria. It is usually diagnosed only after patients have had a full sleep evaluation--including a sleep log, polysomnography, and MSLT--and after ruling out other causes of daytime sleepiness, particular- ly chronically insufficient sleep, OSAHS, narcolepsy, and RLS.
APPROACH TO THE SLEEPY PATIENT
A systematic approach is important to the evaluation and treatment of patients who present with excessive daytime sleepiness. Those identified as possibly having OSAHS, RLS, or narcolepsy need prompt referral to a sleep center for proper evaluation and treatment. Other patients, particularly those who are not getting sufficient sleep or who are taking medications that are associated with sedation, can be treated initially by their primary care physicians.
Identification of these patients begins with asking whether they are excessively sleepy during the day. If the answer is yes, there are 6 simple follow-up questions to ask (Figure).
Do you snore? If the answer is yes and the snoring is loud, habitual, and/or bothersome, OSAHS is a likely possibility. However, it is important to remember that the absence of snoring does not rule out sleep apnea. Referral to a sleep center for a sleep study or to a clinician experienced with the problem is recommended for all patients with suspected OSAHS.
Do your legs feel restless when you relax, or do your legs kick at night? If the answer is yes, consider the possibility of RLS. Referral to a sleep specialist for a full evaluation and management is recommended.
Do you have weakness in any muscle when you experience sudden or strong emotion? This question attempts to identify cataplexy. If the patient has cataplexy or any of the other major symptoms or signs of narcolepsy, referral to a sleep center for a sleep study and MSLT is recommended.
What is your sleep schedule? If the patient's sleep schedule is outside the above-mentioned societal norm or if the patient works shifts, a sleep-wake cycle disorder must be considered. Referral to a sleep center is recommended.
What medications do you take? The physician should obtain a complete list of medications, including common OTC agents. If the patient is taking a medication associated with daytime sleepiness, the physician should make a therapeutic substitution if possible (and when appropriate).
How much sleep do you get? Do you sleep much longer on weekends or on a vacation? Most persons who are sleep-deprived attempt to make up for the lost sleep by "sleeping in" on weekends or during vacations. They often report less sleepiness after obtaining the additional sleep. Persons who are chronically sleep-deprived should be counseled regarding the importance of regular sleep and of obtaining at least 7 to 8 hours of sleep per night.
Since most persons must be up at a certain time in the morning, it is generally recommended that patients plan to add the extra needed sleep to the beginning of their sleep time. Most patients need to be advised that this will mean giving up certain enjoyable evening activities, such as late-night television and computer use. In addition, obtaining an extra hour or two of sleep on the weekends (when possible) is highly recommended.
In summary, patients who have symptoms consistent with a major sleep disorder, such as OSAHS or narcolepsy, should be referred to a sleep center. Patients who have symptoms consistent with drug effects or chronically insufficient sleep can be counseled initially by their primary care physicians. If a medication change or additional sleep does not improve the daytime sleepiness, referral to a sleep specialist is recommended.
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