Assessment of sleepiness in children

Assessment of Sleepiness in Children Timothy F. Hoban and Ronald D. Chorvin Excessive sleepiness is a common but under-recognized problem in children. This article examines the clinical and laboratory evaluation of sleepiness in children, including the use of polysomnography, the multiple sleep latency test, and other varieties of neurophysiologic testing. Where applicable, technical aspects of laboratory testing are reviewed. Alternative laboratory and neurobehavioral techniques used to investigate daytime sleepiness are also briefly covered. Copyright 9 2001 by W.B. Saunders Company

XCESSIVE DAYTIME sleepiness represents a common but often under-recognized symptom in children, one that may accompany a variety of intrinsic and extrinsic sleep disorders. The precise frequency with which excessive sleepiness affects children is unknown, in contrast to an estimated prevalence of 4% to 5% in the adult population. 1 Several questionnaire-based studies have suggested that sleepiness in school-aged children and adolescents is relatively common, with as many as 17% to 21% of subjects reporting frequent sleepiness in these surveys. 2'3 A survey of an entire junior high school revealed that 18% of students sampled complained of falling asleep in school despite receiving 7 to 10 hours of sleep nightly.4 The fact that sleepiness in children is under-recognized is additionally underscored by examining the frequent and well-recognized delays in diagnosis often encountered by patients with narcolepsy. In one large series of 400 narcoleptic patients, 59% of subjects reported onset of symptoms before 15 years of age, whereas only 4% were accurately diagnosed by that age. 5 When excessive daytime sleepiness is suspected in a child, the diagnostic evaluation may be lengthy, complex, and costly. Brief, widely used, and inexpensive questionnaires, such as the Stanford Sleepiness Scale 6 and the Epworth Sleepiness Scale, 7 are not well suited to younger children. Rating scales more recently designed for children have been validated only in specific contexts. 8 Objective modes of assessment, such as polysom-

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From the Departments of Pediatrics and Neurology, The University of Michigan, The Michael S. Aldrich Sleep Disorders Center, University of Michigan Health System, Ann Arbor, MI. Address reprint requests to Timothy F. Hoban, MD, Department of Pediatrics, University of Michigan, L3227 Women's Hospital, 200 East Hospital Dr, Ann Arbor, MI 48109-0203. Copyright 9 2001 by W.B. Saunders Company 1071-9091/01/0804-0005535.00/0 doi:l O.lO53/spen.2001.29043 216

nography and multiple sleep latency testing, are frequently used, but have their own limitations with respect to time, cost, and the lack of wellestablished pediatric norms to aid in interpretation. This article examines the complexities of assessment for sleepiness in children. The authors briefly review the clinical evaluation of the sleepy child and the relationship between the maturational changes of sleep during childhood and the conditions that cause hypersomnolence. The primary laboratory techniques that are reviewed include nocturnal polysomnography, the multiple sleep latency test, and human leukocyte antigen (HLA) haplotyping. Alternative physiologic and neurobehavioral methods used to investigate daytime sleepiness also are covered. CLINICAL ASSESSMENT

The clinical manifestations of sleepiness in children are extraordinarily variable and often differ substantially from those exhibited by adults. Overt somnolence sometimes occurs only intermittently, often during sedentary activities, such as reading, watching television, or riding in an automobile. Sleepy children may not always "act sleepy" and may instead exhibit inattention, hyperactivity, or behavioral problems as the principal clinical manifestations of their sleepiness. This mode of presentation appears particularly common in preadolescent children. Adolescents, in the authors' experience, are more likely to present in an "adult" fashion, with pervasive fatigue or somnolence representing a primary and easily recognizable complaint. A thorough clinical history is of paramount importance in the initial evaluation of a child with excessive sleepiness. A detailed review of the child's wake/sleep schedule, and symptoms exhibited during both wakefulness and sleep is important in two respects. First, this process allows for precise examination of the child's sleep habits, sleep influences, and estimation of sleep quantity,

Seminars in Pediatric Neurology, Vol 8, No 4 (December), 2001: pp 216-228

ASSESSMENT OF SLEEPINESS IN CHILDREN

which may then be compared with expected norms for age. 9"1~ For example, the presence of daily napping changes from being a normal event for many 3-year-olds to being highly unusual for most 7-year-olds. Conversely, 7 hours of nighttime sleep is not uncommon in the adolescent population but would be considered significantly insufficient sleep for most preadolescents. Hence, it is imperative that children's sleep habits and sleep length be interpreted within the context of their age and overall level of development. Second, the clinical history frequently provides enough information to suggest either a provisional diagnosis or at least the mode of testing most likely to disclose a specific diagnosis. History-taking should include detailed screening for symptoms of sleep-disordered breathing, periodic limb movement disorder, symptoms associated with narcolepsy, and for medical conditions having the potential to cause excessive daytime somnolence. 1! Review of the child's daytime and bedtime behavior, evening and nighttime activities, and typical sleep schedule often permits the identification of circadian rhythm disorders and behavioral sleep disorders underlying daytime sleepiness. In addition to the clinical history, a detailed sleep diary recording at least 2 weeks of the child's wake/sleep schedule should be obtained for most patients to confirm the history provided by the child or parents and to permit more effective screening for insufficient sleep and for subtle clues in the child's sleep schedule or pattern of arousals. Physical examination is often entirely normal in children with excessive sleepiness, although overt somnolence, hyperactivity, or other behavioral disturbances are occasionally evident. It should be emphasized that the absence of obvious somnolence in no way diminishes the possibility of a significant sleep disorder in any given child. Conversely, the presence of overt sonmolence inappropriate for a youngster's age is strongly suggestive of either acute sleep deprivation or of an underlying chronic sleep disorder of significant severity. Other potentially significant findings on examination include the presence of mouth breathing, "adenoid facies," and obesity in some youngsters with obstructive sleep apnea hypoventilation syndrome, muscle weakness and myotonia in some with myotonic dystrophy, slowed deep tendon reflexes in hypothyroid youngsters, and the distinctive pattern of obesity, hypotonia, and small

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hand/foot size, which accompanies Prader-Willi syndrome. OBJECTIVE MEASUREMENT OF SLEEP

Nocturnal Polysomnography Nocturnal polysomnography (PSG) is a diagnostic tool that continuously records multiple physiologic parameters during nighttime sleep, including electroencephalography (EEG), electrooculography (EOG), electromyography (EMG), electrocardiography (ECG), respiratory effort and airflow, gas exchange ( 0 2 and usually CO2), and sometimes esophageal pressure. The PSG permits objective evaluation of sleep onset, sleep duration, and sleep architecture, which may reflect sleepiness in some cases. The PSG also can assess for obstructive sleep apnea hypoventilation syndrome, upper airway resistance syndrome, periodic limb movement disorder, and other sleep disorders that cause daytime somnolence. In general, PSG is indicated for most children who exhibit inappropriate daytime sleepiness and when no definite diagnosis can be established by clinical evaluation alone. A PSG is necessary before a multiple sleep latency test (MSLT), both to document sufficient sleep before the test for sleepiness and to identify nocturnal sleep disturbances that cause sleepiness. ~2 Advance preparation for the polysonmogram is quite important, particularly for younger children. Pertinent aspects of the procedure itself should be reviewed with the parents and usually with the child at a level appropriate for age. Any potentially stressful aspects of the test, such as esophageal pressure (Pes) monitoring, should be discussed with the family in advance. Medications having the potential to disrupt nighttime sleep, such as stimulants and antidepressants, should be discontinued for 2 weeks before the study, if possible. ~2 Under select circumstances, a urine toxicology screen should be obtained to ensure that the study is not influenced by prescription medication, illicit drugs, or alcohol. If possible, the study should be scheduled to accommodate the youngster's typical bedtime and rising time. TECHNICAL ASPECTS OF POLYSOMNOGRAPHY

The interested reader is referred to other sources for detailed technical specifications regarding

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polysomnography. 13'14 The EEG monitoring typically uses at least one central channel (C3-A2 or C4-A1), which augments the demonstration of vertex sharp waves, K-complexes, and sleep spindles for scoring purposes. ~5 Most laboratories also use one or two occipital EEG leads (O1-A2 or O2-A1) to capture alpha activity during wakefulness and arousals. Electrodes are placed using the international 10-20 system 16 and secured with collodion. Bilateral electrooculograms (EOGs) allow detection of the slow, rolling eye movements of light sleep and the rapid saccades characteristic of rapid eye movement (REM) sleep. 17 Electrodes are placed near the outer canthus of each eye: one just superior to the right outer canthus and the left just inferior to the left outer canthus. ~8 This oblique placement allows improved detection of both vertical as well as horizontal eye movements. Surface EMG permits detection of REM sleepassociated muscle atonia and muscular contraction or movement that may accompany arousals, periodic limb movements, or bruxism. The EMG is traditionally recorded using any two of three electrodes affixed beneath the chin, overlying the mentalis and submentalis muscles. 13 Many laboratories also use leads over the anterior tibialis muscles to detect periodic leg movements, and some laboratories record over the masseter muscles when bruxism is suspected. Respiratory monitoring during polysomnography assesses airflow, chest and abdominal movement, and some aspects of gas exchange during nighttime sleep. Oral and nasal airflow is measured semiquantitatively using thermisters or thermocouples. Recordings of nasal pressure are more sensitive to decrements in airflow, but lack of published pediatric experience and normative data limit more widespread use of this technique. Strain gauges attached to belts are most often used to monitor chest and abdominal excursion, although these

may be supplanted by intercostal EMG leads or less often by pletbysmography. 19 Pes monitoring can be performed during pediatric studies when upper airway resistance syndrome--increased respiratory effort leading to arousals in the absence of apneas or hypopneas--is within the differential diagnoses. A thin, water-filled esophageal catheter connected to a transducer can be used without major impact on sleep quality or architecture. 2~ Continuous pulse oximetry is standard during pediatric polysomnograms, and many laboratories additionally use end-tidal or transcutaneous monitoring of CO 2 to improve the sensitivity of the study for the detection of hypoventilation. EKG monitoring facilitates detection of both minor findings, such as sinus arrhythmia, and more pathologic disturbances, such as heart block. INTERPRETATION OF POLYSOMNOGRAPHIC FINDINGS

Scoring of sleep stages and arousals is usually performed manually in 30-second epochs using standard criteria. 21 A limited amount of normative data derived from healthy children 22-26 are available to provide guidance in interpretation. In practice, many centers score respiratory events, such as apneas and hypopneas according to adult criteria, 18 which typically require a duration exceeding 10 seconds for an event to be scored. However, it has been convincingly argued that young children may exhibit clinically significant symptoms of sleepdisordered breathing even in the absence of apnea and hypopnea scored and interpreted using adult criteria. 27'28 Therefore alternative pediatric norms for scoring and interpretation have been proposed (Table 1), although no single set of pediatric standards has as yet achieved universal acceptance. Similarly, interpretation of Pes tracings for children is also limited by the lack of well-accepted norms. APes nadir value of - 10 cm H20 has been

Table 1. Proposed Normal Polysomnographic Values for Children -> Age 1 Year RosenT M Defined minimum duration for an obstructive apnea Obstructive Apnea Index Desaturation Index (>4%) SpO2 Nadir CO2 Norms

Data from Marcus et a127 and Rosen. 104

Two breath cycles <1 -<1.5 ->92% ETCO2 -> 50 mm Hg should comprise -< 9% TST Peak ETCO 2 < 55

Marcus et a127 Any length -<1 -<1.4 ->92% ETCO2 > 45 mm Hg should comprise -< 60% TST Peak ETCO 2 -< 53

ASSESSMENT OF SLEEPINESS IN CHILDREN

proposed as the limit of normal for children over the age of 2 years, and a variety of specific respiratory patterns has been described in children with upper airway resistance syndrome. 29 Pediatric norms for periodic limb movements are also not well established, although 5 periodic limb movements per hour has been proposed as the upper limit of normal for children. 3~ The polysomnogram of a child who presents with a complaint of excessive sleepiness is most easily interpreted in the event that the study confirms both disruption of nighttime sleep and a specific cause, such as obstructive sleep apnea. However, on many occasions, the nocturnal study reveals only subtle and nonspecific findings; this is often the case in children with narcolepsy, chronic sleep deprivation, and idiopathic hypersomnolence. Nevertheless, the noctumal study may still provide useful clues to diagnosis when interpreted within the broader context of the child's overall clinical presentation. Specific patterns of nocturnal sleep disruption have been reported in both adults and children with narcolepsy. Studies of adult patients have disclosed consistent disruptions in the architecture of nighttime sleep, including reduced sleep efficiency, increased stage 1 sleep, and decreased stage 2 sleep compared with controls. 31 Some investigators have identified reductions or abnormal distribution of slow-wave sleep, 32 whereas others have found shortened latency to both sleep onset and REM sleep. 33 Data regarding polysomnographic findings for children with narcolepsy are somewhat more limited but generally correlate well with the adult data. Dahl et al5 reported findings in 16 children whose symptoms of narcolepsy began before the age of 13 years. Nocturnal polysomnograms revealed that 9 of the 16 patients demonstrated sleep efficiency below 90% and that sleep was often fragmented by movements and brief, unexplained arousals. Young et a134described findings in eight narcoleptics aged 15 years or younger, reporting decreased sleep efficiency, increased stage 1 sleep, and increased wake time compared with normals. This report also identified a high frequency of periodic limb movements, which affected 5 of the 8 children studied and yielded and average periodic limb movement index of 49.0 for the pediatric group as a whole. Four preadolescent narcoleptics described by Kotagal et a135 also showed reduced sleep

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efficiency and increase stage 1 percentage, although only 1 child in this group exhibited periodic limb movements. Information regarding polysomnographic findings in children with hypersomnolence not due to narcolepsy or sleep-disordered breathing is extremely limited. Data on idiopathic hypersomnolence are available only for the adult population. Bassetti and Aldrich 36 reported short sleep latency with normal respiration and REM sleep on nocturnal sleep studies. Sleep-onset REM has been reported in some children with Prader-Willi syndrome, 37 whereas hypoventilation and additional varieties of sleep-disordered breathing have been found in others. 38'6~ Polysomnographic studies on adolescents with Kleine-Levin syndrome have revealed reduced sleep efficiency, fragmented sleep, decreased slow wave sleep, and reduced latencies to stage 1 and REM sleep. 39'6~ LIMITATIONS OF POLYSOMNOGRAPHY IN CHILDREN

The lack of widely accepted normative values sometimes limit the use of polysomnography in children. Furthermore, the extent to which findings must exceed normal values, before adverse outcomes appear, remains unknown. Some children demonstrate a "first-night effect," in which sleep may be disrupted to a variable degree during acclimation to the unfamiliar environment of the sleep laboratory. The polysomnogram offers only a "snapshot" of one night of sleep and may not reflect typical occurrences. Night-to-night variability in the manifestations of pediatric sleep disorders remains largely unstudied. Finally, the polysornnogram is an expensive, lengthy, and labor-intensive examination. Some children tolerate this test less well than others. However, no other diagnostic test offers comparable sensitivity in the study of nighttime sleep disruption in children.

Multiple Sleep Latency Testing The multiple sleep latency test (MSLT) is a diagnostic tool first developed at Stanford University in the 1970s4~ and based on a simple, straightforward premise: that individuals who are sleepy will tend to fall asleep more quickly than those who are not. The test assesses daytime sleep tendency, in a structured series of daytime nap oppor-

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Table 2. Pediatric Norms for the Multiple Sleep Latency Test (MSLT) Tanner Stage

Mean Sleep Latency (minutes)

Standard Deviation

Stage I Stage II Stage III Stage IV Stage V Older adolescents

19.0 18.5 16.1 15.8 16.6 15.7

1.6 1.9 3.8 3.4 2.1 3.4

Data averaged from tests performed on 3 successive days of recording. Adapted and reprinted with permission. 47

tunities, through recordings of EEG, EOG, and EMG. Mean latency to sleep onset is calculated and the presence of any REM sleep periods noted. The MSLT is often considered a "gold standard" for the objective measurement of daytime sleepiness in both children and adults. Normative data for children exist (Table 2), but the test is generally not administered in children younger than 6 or 7 years of age, for whom some degree of daytime napping may still be normal. 15 An MSLT may be useful when a child is suspected to have excessive daytime sleepiness, but no specific cause is confirmed by clinical history, examination, and PSG. Published MSLT guidelines do not specifically address children, but do support judicious use of this study in evaluations for sleep-disordered breathing, circadian rhythm disorders, narcolepsy, and other disorders of excessive somnolence. 41 The test also may be useful to assess the severity of sleepiness or the response to treatment. A full-night polysomnogram must be performed during the night preceding the MSLT to ensure correct interpretation of the daytime study. 41 As for PSG, all stimulating or sedating medications that might affect sleep should be discontinued, when possible, 2 weeks before the study. A detailed sleep log of the child's sleep and wakefulness during the prior 2 weeks should be reviewed to verify that neither recent sleep deprivation nor aberrant sleep phase have influenced results of the study. 42 TECHNICAL ASPECTS OF THE MSLT

Detailed technical specifications for the MSLT are available to the interested reader. 43'44 The MSLT typically begins 1.5 to 3 hours following

morningtime awakening and consists of 4 to 5 opportunities for sleep under soporific circumstances, typically at intervals of 2 hours. The test should be performed in a dark, quiet environment. Consumption of caffeinated beverages before and during the study should be prohibited. Polygraphic recording during each nap includes referential EEG with central (C3 or C4) and occipital (O1 or 02) electrodes. Leads are also placed in either an oblique or horizontal plane near the outer canthus of each eye for the electrooculogram. Chin EMG also is recorded. Optional additions can include EKG, and respiratory monitoring if sleepdisordered breathing might disrupt sleep onset. Each nap opportunity during the MSLT follows a prescribed hook-up and calibration procedure as outlined in Table 3. Just before lights out, the child is encouraged to relax, close the eyes, and try to fall asleep. If sleep is attained during the first 20 minutes of recording, monitoring is continued for an additional 15 minutes following the first epoch of unequivocal stage 1 sleep. If no sleep is attained during the first 20 minutes of the study, the session is truncated at that point. Between sessions, the child should be permitted to engage in quiet activities only because moderate physical activity between MSLT naps has been reported to affect sleep latency results. 45 Staging of sleep and wakefulness for each nap opportunity on the MSLT is performed using 30second epochs and standard scoring criteria. 21 For each of the five sessions, latency from lights-out to the first epoch scored as sleep is calculated, with a designated latency of 20 minutes assigned to each session where no sleep is obtained. Finally, the mean sleep latency across all nap opportunities is calculated and the number of sleep-onset REM periods (SOREMPs) tallied. INTERPRETING MSLT FINDINGS

Average sleep latencies usually exceed 10 minutes for normal adults, whereas those with excessive sleepiness typically demonstrate average sleep latencies of 8 minutes o r l e s s . 46 These guidelines cannot be applied to children, who normally have substantially longer sleep latencies. For example, average sleep latency in preadolescents is 19 minutes, 47 compared with an average sleep latency of 10 minutes in young adults. 46 A reduction of sleep latency by two standard deviations from the preadolescent normal value would still be well within

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Table 3. Recommended Protocol for the Multiple Sleep Latency Test (MSLT) Measure

Time Before testing 15 minutes 10 minutes

Sleep latency REM latency

5 minutes 45 seconds 30 seconds 5 seconds Following lights out { 0 minutes + xl minutes + x 3 minutes X1 + 15 minutes + 20 minutes

Procedure

Suspend vigorous physical activity Prepare for bed Remove shoes Loosen constrictive clothing In bed, hooked up Calibration series

Introspective sleepiness measure (age-appropriate) Assume comfortable position for falling asleep "Please lie quietly, keep your eyes closed, and try to fall asleep" Lights out First epoch of sleep First epoch of REM sleep End the test for clinical MSLT If no sleep to this point, end the test

Adapted and reprinted with permission, az

the normal range for adults. Mean sleep latencies for children are outlined in Table 2, grouped by Tanner stage of sexual development. Until outcome-based and age-specific standards become available, interpretation of pediatric MSLTs must be guided primarily by comparison to values expected among normal children of similar age and Tanner stage. In addition to mean sleep latency, the tendency to have sleep-onset REM periods (SOREMPs)--important in evaluations for narcolepsy---is also assessed during an MSLT, Premature occurrence of REM sleep in patients with narcolepsy was first reported in 1960, 48 and the presence of narcolepsy is often confirmed by the combination of an MSLT mean sleep latency less than 5 minutes and appearance of REM sleep during two or more naps. However, these criteria have recently been called into question following reports of multiple SOREMPs in as many as one quarter of adults with severe obstructive sleep apnea49'5~ and reports of occasional SOREMPs in adults with idiopathic hypersomnolence and chronic sleep insufficiency.51,36 Estimates suggest that an MSLT mean sleep latency below 5 minutes in combination with two or more SOREMPs result in a sensitivity of 70% and specificity of 97% for the diagnosis of adult narcolepsy. 52 Analogous data are not available for the pediatric age group, but MSLT abnormalities have been described for narcoleptic children. The largest pediatric case series reported MSLT findings in 51 preadolescent children; all subjects demonstrated

mean sleep latencies below 5 minutes (average 1.5 minutes) and all demonstrated at least 2 SOREMPs. 53 Although smaller series of narcoleptic children also have exhibited multiple SOREMPs and similarly low sleep latencies, 5'34 several notable exceptions have been identified. These include reports of youngsters who have convincing symptoms of narcolepsy with cataplexy, but exhibit mean sleep latencies of 9 to 10 minutes. 35 One girl's narcolepsy developed during the course of a longitudinal study that followed the children of narcoleptic parents. 54 During a 2-year period, this child's mean sleep latency dropped from 11.8 minutes (average 18.4 for Tanner stage 2) to 5.8 minutes (average 15.8 for Tanner stage 4) with the simultaneous development of multiple SOREMPs. These cases highlight the limited applicability of adult MSLT standards in children. Data on MSLT results for sleepy children without narcolepsy were generated mainly in experimental sleep deprivation paradigms. As part of the Stanford Summer Sleep Camp project, the effects of one night's sleep loss were measured in 12 subjects whose ages ranged from 11.7 to 14.6 years.42 This sleep deprivation reduced the mean sleep latency from 16.8 minutes to 1.2 minutes. Mean sleep latency improved to 13.1 minutes on the first recovery day and 17.6 minutes on the second. Randazzo et a155 assessed the effects of partial sleep restriction for seven children between the ages of 10 and 14 years. For the children restricted to 5 hours in bed (mean sleep time 287 minutes), daytime sleep latency averaged 14.4

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minutes, in comparison to 23.5 minutes for a control group, which averaged 553.7 minutes of nighttime sleep. Carskadon et a156 reported the MSLT effects of advancing school start times by 65 minutes--with consequent reduction of average school-night sleep time by 19 minutes--among students who transitioned from 9 th to 10th grade. Mean sleep latency for the group declined from 11.4 minutes to 8.5 minutes. In addition, 16% of the 10th grade participants exhibited at least two SOREMPs during their MSLTs, which suggests that SOREMPs may result from insufficient nighttime sleep. Studies of adults have also reported a correlation between sleepiness, as measured by the mean sleep latency, and the tendency to have two or more SOREMPs. 57'5s These data suggest that in some cases SOREMPs may reflect sleepiness rather than narcolepsy. MSLT findings for preadolescent children with obstructive sleep apnea were recently described by Gozal et al. 59 Using a modified MSLT protocol with nap opportunities lasting 30 minutes, children with obstructive sleep apnea (mean apnea index 15.1) were found to have significantly shorter mean sleep latency (20.0 _+ 7.1 min) compared with normal controls and youngsters with primary snoring (23.7 + 3.0 and 23.7 __+ 3.1 minutes, respectively). Less than 15% of the 54 children with sleep apnea demonstrated mean sleep latency of less than 10 minutes using this modified protocol, again underscoring the limited applicability of adult standards for pediatric studies. Limited MSLT data exist for children with Prader-Willi syndrome. This genetic disorder, characterized by hypotonia, cognitive delays, and obesity, is frequently complicated by excessive sleepiness with or without sleep-disordered breathing. In one survey of 7 Prader-Willi patients under age 21 years, 6 exhibited mean sleep latency below 10 minutes and 3 had values below 5 minutes. 6~ Although SOREMPs were observed in all but one patient, mean sleep latency was not correlated with body weight or disordered breathing rate during noctumal sleep. Data on MSLT findings among children with idiopathic hypersomnolence and other causes of hypersomnolence are not available. Comparison of MSLT findings for adults with idiopathic hypersomnolence (IHS) to those with narcolepsy has revealed a slightly higher mean sleep latency (4.3 minutes vs. 2.2 to 2.8 minutes) and less frequent

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SOREMPs (4% vs. 49% to 50%) among those with IHS. 36 ADVANTAGES AND LIMITATIONS OF THE MSLT

The primary strength of the multiple sleep latency test is that it represents a standardized, wellvalidated, objective measure of sleep tendency, which can be easily administered to children beyond the age of 6 to 7 years. 15 The MSLT is also useful in documenting response to treatment, although reports do exist in which subjectively effective treatment of hypersomnolence failed to appreciably impact MSLT results. 61 Limited evidence suggests that the Maintenance of Wakefulness Test (MWT, described below) may be a more sensitive measure of treatment efficacy than the MSLT. 41'62'63 but this tool has not been widely used or validated in children. Another potential limitation to the use of the MSLT in children is the test's sensitivity to extraneous influences, such as environmental disturbances, medication effects, and recent disruptions of sleep length, quality, or schedule. Some children may demonstrate a "last nap" effect, in which the excitement or anticipation of completing the study and going home may temporarily override sleepiness that might otherwise be evident. The test may also be influenced by the child's mood, level of activity, and ability to comprehend and cooperate with the instructions of the test. Children with hyperactive behavior in association with nocturnal sleep disturbance may not be able to cooperate with instructions to lie quietly and try to sleep. As a consequence, failure of an MSLT to confirm clinically suspected sleepiness should rarely be taken as evidence that sleepiness is not a significant problem for a patient. Positive MSLT results are probably more reliable. Like PSG, an MSLT is a time-consuming, laborintensive, and expensive test. Many children believed to have excessive sleepiness are evaluated by PSG without an MSLT. However, in appropriate age groups, the MSLT is an option that allows some objective assessment for excessive sleepiness and sometimes helps to establish a diagnosis of narcolepsy. Results must be interpreted carefully in the clinical context, with recognition of what biological and technical factors can influence results.

ASSESSMENT OF SLEEPINESS IN CHILDREN

The Maintenance of Wakefulness Test The MWT differs from the MSLT in that it is designed to assess the ability to remain awake rather than sleep tendency. First described in 1982, the MWT resembles the MSLT in its use of four to five nap opportunities at 2-hour intervals and use of EEG, EMG, and EOG monitoring. 64 The MWT varies from the MSLT in that patients are instructed to try to stay awake as they sit in a comfortable chair within a darkened room. Latency to sleep onset is calculated for each nap opportunity of 20 (less commonly 40) minutes. 65 Mean sleep latency on the MWT for normal adults is 18 minutes, whereas adults with narcolepsy average 6 to 10 minutes. 1'66 MWT results correlate only weakly with MSLT findings. 67 The paucity of data regarding the use of the MWT in children tends to limit its usefulness in the pediatric age group.

Biological Markers Associated With Sleepiness Within the last 20 years, several biologic markers associated with narcolepsy have been identified, including certain human leukocyte antigen (HLA) haplotypes and absence of hypocretin in cerebrospinal fluid. The association between the HLA DR2 allele and human narcolepsy was first reported in the early 1980s. Although the association was initially believed to be quite close, cases of DR2-negative narcolepsy were subsequently identified and it was discovered that the frequency of association varied to some extent by ethnicity. 68 As improved HLA typing techniques have come to allow detailed examination of subtypes for the DR2 and DQ1 antigens, attention has focused most closely on the DQB 1"0602 allele, which has demonstrated consistently strong association with narcolepsy across a variety of ethnic groups. In several large series of narcoleptic patients, the frequency of DQBI*0602 appeared highest in those individuals with concurrent cataplexy, ranging from 76.1% and 90.1%. 68"69 In patients without definite cataplexy, the frequency of association varied between 40.9% and 57.1% compared with carrier rates of 12% to 38% for DQBI*0602 in the general population. 7~ In the single series of pediatric patients for which DQBI*0602 results have been reported, all of the 12 prepubertal narcoleptic tested were positive for the allele. 53

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It appears that the presence of DQB 1"0602 is neither necessary nor sufficient for the development of narcolepsy. 68 Absence of the trait in a specific patient may tend to diminish but not exclude the likelihood of associated narcolepsy because as few as 10% of individuals with narcolepsy-cataplexy are thought to be DQBI*0602negative. Presence of the allele provides little assistance in establishing a diagnosis of narcolepsy, due to a significant carrier frequency for this trait in healthy and asymptomatic individuals. During the last several years, deficiencies of hypocretin (orexin), an excitatory neuropeptide found in neurons of the lateral hypothalamus, have been identified reliably in a small number of individuals with narcolepsy. Following the initial identification of genetic mutations affecting the hypocretin receptor-2 gene in canine narcolepsy, 71 limited investigation into the role of hypocretin in human narcolepsy has been completed. In one series of 9 adult narcoleptics positive for HLA DR2 and DQBI*0602, 7 (78%) demonstrated absence of detectable levels of hypocretin-1 in cerebrospinal fluid. 72 Low hypocretin-1 levels have also been reported in the cerebrospinal fluid of a DQB l*0602-negative adult with autosomal-dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN), a familial variety of symptomatic narcolepsy. 73 Data on use of this assay in children have not been published yet, and further investigation is required to better determine the overall use of hypocretin-1 assays in the assessment of sleepy children.

Other Varieties of Physiologic Monitoring Pupillometry uses an infrared video-recording system to gauge sleepiness on the basis of changes in pupillary size or stability in a dark environment. Formal study of this method was prompted by clinical observations that supported the premise that pupillary size and stability are inversely related to degree of sleepiness. 65 Pupillary changes are influenced by autonomic activity, which in turn, correlates with level of alertness. 74 Research that has assessed the correlation between daytime somnolence and pupillary size or reactivity has yielded largely inconclusive results, although some reports have suggested that pupillary size indeed diminishes with increasing sleepiness. 1"75"76Some studies have suggested that pupillary instability or oscillation may represent a

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more sensitive indicator of sleepiness, as this measure has been found to exhibit both circadian v a r i a t i o n 77 and characteristic abnormalities in some narcoleptic patients. 7s The role of pupillography for the assessment of sleepiness in children is largely unstudied and no well-established pediatric norms exist. The potential usefulness of this tool in the assessment of sleepy children is reduced by the level of patient cooperation necessary and by the limited availability of required equipment. Spectral analysis allows quantitative study of EEG frequency data obtained during either wakefulness or sleep. Using the fast Fourier transform technique, amplitude or power data are compiled for the EEG frequency bands being studied, most typically alpha (8 to 13 Hz), beta (13 to 20 Hz), theta (4 to 8 Hz), and delta (0 to 4 Hz). Spectral analysis for the assessment of sleepiness has been undertaken exclusively in the adult population and remains primarily a research tool at present. Analysis of EEG spectra for medicationfree narcoleptics during the MSLT has identified increased delta amplitude and decreased alpha amplitude during narcoleptic stage 2 and REM naps compared with normal naps containing stage 1 sleep. 79 Normalization of excessive frontal-central delta slowing detected by spectral analysis in adults with OSA, has been reported after treatment. so Visual and auditory evoked potentials have occasionally been used in the assessment of sleepiness. Long-latency potentials, such as the P300, are considered to be useful in the study of attentional and cognitive problems and also have been applied in a limited fashion to the investigation of sleepiness. 8~ Prolongation of P300 latency has been reported in individuals with OSA and idiopathic hypersomnolence, although variable results have been reported for narcoleptics. 81-s3 No pediatric data have been reported for this measure. Actigraphy has been used to a limited extent in the assessment of many sleep disorders. A portable wristwatch-like monitoring unit logs the frequency of physical movements for periods of days to weeks. The raw data are uploaded later into a computer for more detailed analysis, which usually includes estimation of nighttime sleep periods from reduction in movement. Actigraphic and polysonmographic results correlate in adults, s4'85 but actigraphy does not distinguish reliably be-

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tween daytime naps and sedentary awake activities in young adults, s6 Actigraphy also may fail to identify sleep accurately in patients with insomnia and other sleep disorders. Actigraphy has no demonstrated application in the assessment of childhood sleepiness, but has been used in the study of motor activity in children with attention deficit hyperactivity disorder (ADHD). s7 The technique nevertheless may be extremely useful in children if there is a compelling need to longitudinally verify the length, duration, and degree of disruption for nighttime sleep more objectively than can be accomplished via the clinical history and sleep diary. The procedure is also ambulatory, inexpensive, and can be easily used at any age from infancy through adolescence.

Other Laboratory Measures Judicious use of other laboratory tests should be considered for sleepy youngsters with atypical clinical features or potential underlying medical causes. Laboratory screening for anemia or thyroid disease is appropriate for select children. Genetic testing for such conditions as Prader-Willi syndrome or myotonic dystrophy should be considered for youngsters who demonstrate appropriate physical and neurologic findings. More detailed diagnostic testing should be considered in youngsters with strikingly atypical clinical presentations, such as extremely young age of onset, severe cataplexy, or associated neurologic abnormalities. These unusual findings have been reported as part of "symptomatic narcolepsy," which can result from conditions, such as diencephalic tumors and Niemann-Pick disease type CJ 2 NEUROBEHAVIORAL MEASURES OF SLEEPINESS IN CHILDREN

Sleep Questionnaires Sleep questionnaires, such as the Stanford Sleepiness Scale (SSS), 6 and Epworth Sleepiness Scale (ESS), 7 arguably represent the most widely administered neurobehavioral tools used for the assessment of sleepiness in adults. Questionnairebased assessments are attractive because of negligible cost, ease of administration, and suitability for longitudinal use in assessment of treatment effects. However, offsetting these advantages are concerns that results correlate only poorly with objective measures of sleepiness. The ESS, for

ASSESSMENT OF SLEEPINESS IN CHILDREN

example, does not correlate well with the MWT in adult narcoleptics 88 and correlates weakly if at all with the MSLT. 7'89'9~ ESS scores ----10 demonstrate poor sensitivity and specificity as a predictor of reduced mean sleep latency. 91 The optimal role of questionnaire-based sleepiness assessment has been the subject of debate. 92'93 Neither the Stanford nor Epworth sleepiness scales are well suited for use in young children, and neither has been validated in older children. As a result, sleep questionnaires designed specifically for use in children have been developed in the hope of providing appropriate, cost-effective screening tools that are sensitive to the broad range of behavioral symptoms that may accompany daytime sleepiness. The Children's Sleep Habits Questionnaire (CSHQ) is one such instrument, designed for use in school-aged children between 4 and 10 years of age. 94 The tool consists of a retrospective 45-item parental survey and covers a number of key sleeprelated behaviors; each item is rated on a 3-point scale that describes frequency of the behavior. Daytime sleepiness is one of the specific domains assessed, through questions about morningtime waking problems, visible tiredness, and symptoms during sedentary activity. The CSHQ has been validated by comparison of results from a sleep clinic population to those from a community cohort. The instrument demonstrated adequate internal consistency and test-retest reliability. It has been used in studies of sleep-related behavior in children, 95'96 but correlation with objective measures, such as the MSLT, has not been assessed. The Pediatric Sleep Questionnaire was developed as a clinical research tool to assist in the identification of children with sleep disorders. 8 A 22-item scale for sleep-related breathing disorders and related symptoms was developed and then validated. This scale includes a 4-item subscale for daytime sleepiness, and a 6-item scale for inattentive and hyperactive behavior often seen in sleepy children. The sleep-related breathing disorders scale was validated by comparison of a group of children (ages 2 through 18 years) with polysomnographically proven sleep-related breathing disorders to a control group drawn from a general pediatrics clinic. All scales described in the initial validation study 8 demonstrated reliable internal consistency and test-

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retest stability, and identified the presence of sleep-related breathing disorders with adequate sensitivity and specificity for use in clinical research. However, the authors cautioned against reliance on this instrument in clinical settings until further data become available, including comparisons to MSLT results. A subscale for periodic leg movements during sleep recently showed moderate ability to predict the finding on PSG, 97 but sections of the Pediatric Sleep Questionnaire that concern other potential causes of excessive sleepiness await validation.

Neuropsychiatric Testing Standardized neuropsychiatric testing and neurobehavioral assessments represent valuable adjunctive tools for the assessment of sleepy children, although formal research in this area has been scant. Use of these measures reflects recognition that daytime manifestations of sleepiness include a wide variety of neurobehavioral symptoms, including inattention, hyperactivity, or other alterations of mood and behavior. As succinctly and appropriately elucidated by Stores, "sleepiness can take the form of an increase rather than reduction of activity" in children. 98 The degree to which standard measures of memory, intelligence, and attention in children are affected by the presence of sleepiness remains poorly understood. Modest changes in memory have been demonstrated on the Wide Range Assessment of Memory and Learning99 in morbidity obese adolescents with sleep-disordered breathing 1~176 and in 5- to 10-year-old snoring children, lm who additionally showed lower intelligence scores (Weschler Preschool and Primary Scale of Intelligence--Revised (WPPSI-R) 1~ and the Wechsler Intelligence Scale for Children--Third Edition (WISC-III). 1~176 Continuous performance testing has been advocated as a promising assessment for childhood sleepiness ~5 but has not yet been formally validated. CONCLUSION

Assessment of sleepiness in children provides substantial challenges to the clinicians and researchers involved with pediatric sleep disorders. Increased recognition of the high overall prevalence of childhood sleepiness, and of complex effects on attention and behavior, has increased

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p e d i a t r i c referrals f o r f o r m a l c l i n i c a l a n d l a b o r a tory a s s e s s m e n t . E f f e c t i v e c l i n i c a l e v a l u a t i o n o f s l e e p i n e s s i n c h i l d r e n relies p r i m a r i l y o n a d e t a i l e d sleep h i s t o r y , s o m e t i m e s d e p e n d s o n n o c t u r n a l polysomnography, and occasionally requires an

M S L T . I n t h e future, e v a l u a t i o n o f h y p e r s o m n o l e n c e will i m p r o v e w i t h b e t t e r a g e - a p p r o p r i a t e n o r m a t i v e d a t a for e x i s t i n g tests a n d d e v e l o p m e n t o f a c c u r a t e , c o s t - e f f e c t i v e , a n d " c h i l d - f r i e n d l y " alternatives.

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