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Sleep-associated respiratory disorders and their psychobehavioral consequences in children
Handbook of Clinical Neurology, Vol. 98 (3rd series) Sleep Disorders, Part 1 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved
Chapter 32
Sleep-associated respiratory disorders and their psychobehavioral consequences in children 1 2
HAWLEY E. MONTGOMERY-DOWNS 1 AND DAVID GOZAL 2 * Departments of Psychology and Pediatrics, West Virginia University, Morgantown, WV, USA
Department of Pediatrics, Comer Children’s Hospital, The University of Chicago, Chicago, IL, USA
SLEEP DISTURBANCES IN CHILDREN Pediatric sleep continues to gain significant recognition due to both increasing evidence of a high prevalence of sleep disorders among children, and by virtue of the potential somatic and psychobehavioral effects of disrupted sleep during early development. Obstructive sleep apnea (OSA) is by far the most frequently diagnosed pediatric sleep disorder, affecting at least 1–3% of children, while symptoms consistent with risk for sleep-disordered breathing (SDB) have been reported in 6–27% of children (Brouillette et al., 1984; Ali et al., 1993; Gislason and Benediktsdottir, 1995; Hulcrantz et al., 1995; Archbold et al., 2002; Young et al., 2002; Montgomery-Downs et al., 2003). Children with SDB experience more frequent pulmonary hypertension (Shiomi et al., 1993), systemic hypertension, and other cardiovascular disturbances such as left ventricular hypertrophy (Marcus et al., 1998; Amin et al., 2002, 2005; O’Brien and Gozal, 2005), deficient somatic growth (Everett et al., 1987), and comorbid chronic illnesses (Rona et al., 1998; Archbold et al., 2002). In addition, pediatric OSA is associated with poor quality of life (Rosen et al., 2002; Crabtree et al., 2004; Mitchell and Kelly, 2005; Stewart et al., 2005), depressed mood (Crabtree et al., 2004; Mitchell and Kelly, 2006), and increased health care utilization (Reuveni et al., 2002; Tarasiuk et al., 2004). For the majority of children with mild to moderate SDB, psychobehavioral comorbidities are understood to be the most crucial consequence. Studies on these specific costs have focused on the daytime effects of
sleep restriction and sleep-related breathing disorders (e.g., snoring and OSA), which are also associated with both intermittent hypoxia and sleep fragmentation. The consequences of disrupted sleep specific to the effects of sleep-associated respiratory disorders will form the specific focus of this review.
Sleepiness The predominant manifestation of sleeplessness or sleep disturbance is “sleepiness” and thus it is important first to address what is meant by this sometimes ambiguous term. Originally described by Carskadon and Dement (1977), one objective technique used to quantify sleepiness is the Multiple Sleep Latency Test (MSLT). This simple method involves a series of 20–30-minute polysomnographically recorded daytime nap opportunities in a sleep-promoting environment (i.e., darkened and quiet room, comfortable bed and temperature). Under such standardized circumstances, the shorter the latency to sleep onset during these nap opportunities, the higher the degree of sleepiness. Such assessment is expensive, labor-intensive, and difficult with children so rare studies have objectively measured daytime sleepiness in children, though it has been found that compared to control children, those with attention deficit hyperactivity disorder (ADHD) have greater daytime sleepiness (Golan et al., 2004). Like studies with adults, for sleepiness measured by MSLT with children there seems to be a limited relationship with subjective report (Chervin et al., 2006a). However, it is important to note that
*Correspondence to: David Gozal, M.D., Herbert T. Abelson Distinguished Professor and Chair, Department of Pediatrics, Physician-in-Chief, Comer Children’s Hospital, The University of Chicago, 5721 S. Maryland Avenue, MC 8000, Suite K-160, Chicago, IL 60637, USA. Tel: (773) 702-3360, Fax: (773) 702-4523, E-mail: [email protected]
490 H.E. MONTGOMERY-DOWNS AND D. GOZAL behavioral sleepiness may display differently in chilbehavioral problems (Lavigne et al., 1999), and the dren than it does in adults. The manifestations of reciprocal of this observation holds true as well, since sleepiness in children will be discussed throughout this improvements in sleep are associated with improvereview. ment in daytime behavior (Minde et al., 1994; Ali et al., 1996; Chervin et al., 2006a). Thus, sleep and behavior exhibit dynamic interacBEHAVIORAL CONSEQUENCES tions that may either interfere with each other or synerOF SLEEP DISTURBANCE gistically enhance each other in children. In order to When sleep fragmentation is experimentally induced in understand further the potential impact of SDB on healthy adults using auditory stimuli to elicit arousals cognitive and behavioral functioning it is necessary to throughout the night, performance detriments are understand that hypoxia is unlikely to occur in isolaclearly apparent the following day (Stepansky et al., tion. Rather, SDB is typified by the co-occurrence of 1984, 1987; Chugh et al., 1996). In this context, cogniintermittent hypoxia and brief arousals that cause fragtive functions requiring concentration and motor mented architecture. Therefore, a short review of the dexterity are preferentially affected by sleep fragmeneffects of sleep restriction on higher-level functioning tation and often confusion and disorientation also in children is appropriate. occur, and have led to the term “sleep drunkenness.” Aggressive outbursts, irritability, anxiety, and depresSleep restriction sion are all known manifestations of excessive daytime Acute sleep restriction for one night in children has sleepiness in adults, and appear to be fully reversed been shown to increase inattentive behavior the followonce sleep is allowed and recovery occurs (for review, ing day, although without changes in hyperactive or see Roth and Roehrs, 1996). impulsive behaviors (Fallone et al., 2001). Extended Similar to adult findings, Sadeh and colleagues sleep restriction for 7 nights led to increased parent(2000) reported a high prevalence of sleep fragmentareported oppositional and inattentive behaviors tion in children but the effects of sleep fragmentation (Fallone et al., 2000) and teacher-reported academic on daytime functioning have yet to be examined in problems and attention problems (Fallone et al., detail among pediatric populations. It is known that 2005). Notwithstanding such observations, total sleep infants, toddlers, and school-age children who are time does not appear to be the major determinant of reported by their parents to be poor sleepers display daytime behavior problems in children. Rather, disrupincreased incidence and severity of behavioral issues tion of the sleep process instead of total amount of compared to children without reported sleep problems sleep may be the key factor underlying behavioral (Zuckerman et al., 1987; Ali et al., 1993, 1994; Minde alterations that are vulnerable to sleep disruption et al., 1993; Chervin et al., 1997; Stein et al., 2001). (Stores, 1996). Thus, an association between neuroThese observations have been confirmed by objective behavioral disturbances and the fragmentation by assessments, in which the degree of sleep disturbance multiple arousals observed in OSA or in periodic limb and the severity of behavioral changes are strongly movement disorder of sleep would be expected. To associated in most studies (Guilleminault et al., 1981; corroborate this supposition, a study from our laboraAli et al., 1996; Aronen et al., 2000; Chervin et al., tory found significant relationships between arousals 2000; Chervin and Archbold, 2001; O’Brien et al., associated with periodic limb movements during sleep 2003). However, work by Chervin and colleagues and ADHD (Crabtree et al., 2003). Thus, an associative (2006a) showed that, although adenotonsillectomy and possibly causal link appears to be present between improved neurobehavioral and parent report measures fragmented sleep and hyperactive behaviors. of hyperactivity to the extent that children no longer Developmental changes during adolescence also differed from controls (who did not change), neither afford an opportunity to examine the effects of sleep baseline SDB measures nor improvement predicted restriction. It has been clear for some time that both the degree of improvement on any outcome measure homeostatic influences (e.g., the time elapsed since the other than sleepiness. previous sleep period and circadian clock regulatory sysNevertheless, 36% of young children with global tems), and individual differences (e.g., motivation to fall reports of sleep problems presented with significant asleep and psychological tension or anxiety) affect daybehavioral problems (Smedje et al., 2001) and daytime time sleepiness in this age group. Extensive work by hyperactivity, and anxiety and depressive symptoms Carskadon and colleagues has shown that pubertal have been associated with prolonged sleep latency development is associated with increased daytime sleep(Smedje et al., 2001; Stein et al., 2001). Preschool chiliness, such that postpubertal adolescents require more dren with shorter total sleep time exhibited more
SLEEP-ASSOCIATED RESPIRATORY DISORDERS IN CHILDREN 491 sleep to retain prepubertal levels of alertness (Carskadon looking” and slow to respond to questions, yet it took et al., 1980; Carskadon and Dement, 1987). a century before Osler’s observations on neurocognitive The Carskadon lab has established that there is a decrements in pediatric OSA were investigated using biological shift in the homeostatic drive during adolesobjective methodology. Of particular emphasis is the fact cence, inhibiting later-stage pubertal adolescents’ ability that OSA in children is radically distinct from the OSA to obtain sleep early in the night (Jenni et al., 2005). that occurs in adults, and such differences are particuDespite the physiological evidence, school start times larly striking in relation to racial and gender distriin the USA and many countries around the world are bution, clinical manifestations, and treatment (Carroll organized so that secondary school students have to and McLoughlin, 1992; Rosen et al., 1992). wake up earlier than primary school students, an In children, OSA is frequently diagnosed in associaarrangement that appears in paradox with the biological tion with adenotonsillar hypertrophy, and is common in preferences for later bed and wake-up times during the children with craniofacial abnormalities and neurologimore advanced stages of puberty (Carskadon et al., cal disorders affecting upper-airway patency during 1993; Jenni et al., 2005; Taylor et al., 2005). The resultsleep. In early reports, Guilleminault et al. (1976) suging sleepiness has been repeatedly shown to have an gested that removal of the enlarged adenotonsillar impact on students’ learning and behavior and, in distissue would lead to complete resolution of clinical tricts where school start times are delayed for secondary symptoms and cure of OSA. However, although students, improvements can be dramatic (for review, see enlarged tonsils and adenoids are by far the most Carskadon et al., 2004; Millman, 2005). An awareness important contributor to the pathophysiology of OSA of increased adolescent risk-taking behaviors in associain children, children with OSA also demonstrate the tion with inadequate sleep has also emerged (O’Brien presence of increased upper-airway collapsibility and Mindell, 2005). (Isono et al., 1998; Gozal and Burnside, 2004). Thus, In addition to these experimental and naturalistic adenotonsillar hypertrophy alone is usually not suffiexamples of the effects of sleep restriction on daytime cient to cause OSA; in fact, some children with sleepiness in children and adolescents, sleep disorders “kissing tonsils” will not have OSA, while others with may contribute to sleep that is inadequate, fragmented, relatively small adenotonsillar tissue will manifest or both and have been shown repeatedly to have an severe OSA and may not be cured after adenotonsiladverse impact on daytime functioning, while early lectomy (Suen et al., 1995; Lipton and Gozal, 2003). treatment often reverses these effects. Among these, Emphasis has also been placed on the importance of OSA is the most frequently diagnosed disorder and a multispecialty approach to clinical assessment and has received the greatest attention from research treatment of pediatric OSA, including sleep medicine laboratories around the world. specialists, maxillofacial and otolaryngologist surgeons, and orthodontists, particularly for patients with craniofacial abnormalities (Guilleminault and Abad, Sleep-disordered breathing 2004). Clearly, OSA is a complicated disorder, but addOSA is a more severe form of SDB, and is a relatively ing to this is the emerging perspective that OSA is only common disorder among both adults and children, with one end of a spectrum disorder. up to 3% of young children affected (Brouillette et al., The primary symptom of OSA is habitual snoring, 1984; Ali et al., 1993; Gislason and Benediktsdottir, a symptom that may affect up to 27% of children, with a 1995; Hulcrantz et al., 1995; Young et al., 2002; median revolving around 10–12% (Teculescu et al., 1992; Montgomery-Downs et al., 2003). OSA is characterAli et al., 1993; Gislason and Benediktsdottir, 1995; ized by repeated events of partial or complete upperHulcrantz et al., 1995; Owen et al., 1996; Ferreira et al., airway obstruction during sleep. These upper-airway 2000; O’Brien et al., 2003; Montgomery-Downs et al., changes induce disruption of normal alveolar ventila2003). Prevalence rates of snoring similar to those of tion and sleep structure, and lead to blood gas abnormpreschool and early school-age children have also been alities and sleep fragmentation (American Thoracic reported among infants. Indeed, habitual snoring was Society, 1995) (Figures 32.1 and 32.2). found in 5% of 2–4-month-olds (Kelmanson, 2000) and Despite the fact that OSA and its associated mani6–12-month-olds (Gislason and Benediktsdottir, 1995), festations were first described over 130 years ago with higher rates in infants aged 1–8 months (16–26%) (McKenzie, 1880; Osler, 1892), it was not until 1976 (Mitchell and Thompson, 2003). We have found habitual that Guilleminault et al. reported OSA as a clinically snoring in 1–9% of infants and toddlers (2–24 months of relevant entity in children. Furthermore, Osler (1892) age) (Montgomery-Downs and Gozal, 2006a). This relareported that children with “loud and snorting” respiratively high frequency of habitual snoring usually decreases tions with “prolonged pauses” were often “stupid in 9–14-year-olds to around 3–5% (Corbo et al., 2001).
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Fig. 32.1. Illustrative 1-minute example of a partial upper-airway obstruction (hypopnea), with repeated reductions (OH) of oronasal airflow in the presence of respiratory efforts, and with associated oxyhemoglobin desaturation, and sleep arousal (circles). These events occurred during rapid eye movement sleep (R). EEG, electroencephalogram; ECG, electrocardiogram; Chin EMG, chin electromyogram; Snore, sound channel; Flow, airflow; Abd, abdominal respiratory effort; SaO2, oxyhemoglobin saturation.
It needs to be stressed that the presence of snoring should not be viewed as a normal feature of sleeping children, because it indicates that increased upperairway resistance is present. A substantial percentage of snoring children may have primary snoring (i.e., habitual snoring without obvious visually recognizable disruptions in sleep architecture, alveolar ventilation, and oxygenation) but despite the traditional view of primary snoring as a benign condition, our laboratory has reported that primary snoring may in fact be associated with a higher risk for neurobehavioral deficits, albeit less severe than the deficits found in children with OSA (O’Brien et al., 2003). Of note, daytime sleepiness, behavioral hyperactivity, learning problems, and restless sleep are all significantly more common in habitual snorers (Ali et al., 1993; Blunden et al., 2000; Ferreira et al., 2000; Blunden et al., 2001; Chervin et al., 2002; O’Brien et al., 2003). Another report from our lab indicates that infants with higher snore-related arousal indices had lower
scores on a standardized mental development assessment. Because neither apneas nor hypopneas were present in these otherwise normal, healthy children, these findings constitute further evidence that snoring is not just an innocent noise during sleep in infants, but may in fact represent the lower end of the disease spectrum associated with SDB (Montgomery-Downs and Gozal, 2006b). We still do not know enough about the natural history of snoring and snore-induced arousals in infancy or early childhood to disregard any snoring. Zucconi and colleagues (1993) found that, among 18–24-month-olds evaluated for nightly snoring and referred for surgical treatment, the parents of >50% reported that the habitual snoring had developed during the child’s first year of life, and 16% reported an onset in the first month of life. The consequences of snoring and OSA with their associated hypoxemia and sleep fragmentation in children reveal complex pathophysiological mechanisms (Bass et al., 2004). If left untreated or treated late,
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Fig. 32.2. Overnight hypnogram of an 8-year-old child with mild to moderate obstructive sleep apnea illustrating the clustering of respiratory events during rapid eye movement (REM) sleep periods (circles). PLM, periodic limb movement; A/H, apnea/ hypopnea; SaO2, oxyhemoglobin saturation.
pediatric OSA may lead to significant morbidity affecting multiple target organs and systems, and such injurious consequences may, under certain circumstances, be partially irreversible despite appropriate therapy.
PSYCHOBEHAVIORAL CONSEQUENCES OF SLEEP DISRUPTION IN SDB Behavior Both habitual snoring and OSA are associated with behavioral problems, particularly hyperactivity and ADHD (Ali et al., 1993, 1996; Chervin and Archbold, 2001). Hyperactive and inattentive behaviors occur frequently in children with OSA (Guilleminault et al., 1981; Carroll and McLoughlin, 1992; Gozal, 1998; Blunden et al., 2000) and with habitual snoring (Weissbluth et al., 1983; Ali et al., 1993; Chervin et al., 1997, 2002; Blunden et al., 2000; Chervin and Archbold, 2001; O’Brien et al., 2003). Furthermore, approximately 30% of all children with frequent, loud
snoring or OSA manifest parentally reported hyperactivity and inattentive symptoms (Ali et al., 1993), with improvements noted following surgical treatment of SDB (Ali et al., 1996; Dagan-Friedman et al., 2002; Chervin et al., 2006b; Mitchell and Kelly, 2006). Interestingly, although children with ADHD appear to exhibit more sleep disturbances than normal children (Berry et al., 1986; Trommer et al., 1988), we found that, despite parental reports of sleep disturbances in >70% of children with ADHD, only 20% of these children had sleep disturbances when assessed by objective polysomnographic criteria (O’Brien et al., 2003). In this study, SDB was not more likely to occur among children with true ADHD (i.e., diagnoses following the stringent criteria recommended by the Academy of Pediatrics and the Academy of Psychiatry), yet SDB was significantly more prevalent among children with parent-reported hyperactive behaviors that do not fulfill strict ADHD criteria, suggesting that the subtle disruptions of sleep elicited by the presence of SDB may be associated with significant behavioral effects.
494 H.E. MONTGOMERY-DOWNS AND D. GOZAL In contrast, Chervin and colleagues (2006b) found that via disruption of PFC-dependent processes (Beebe and children diagnosed with ADHD and reported by their Gozal, 2002) and this is also the foundation for a proparents to be hyperactive improved following adenoposed heuristic model for interpreting the prolific and tonsillectomy, but that severity of sleep measures dynamic research on both animal models and humans did not predict either baseline or improvement post(Beebe, 2005). The individual processes that make up surgery. As mentioned earlier, sleep fragmentation neurocognitive processes will be described separately associated with periodic limb jerks is more frequent below. in children with ADHD, thus supporting the notion that restless sleep is indeed more common in ADHD Attention patients. The ability to remain focused on a task and respond appropriately to extraneous stimuli in the environment Neurocognition plays an important role in learning, and consequently In adult patients, substantial cumulative evidence indiin social and academic development. Using acute sleep cates that neurocognitive deficits emanate from sleep restriction and sleep deprivation, Carskadon and coldisruption induced by SDB. These may include deficits leagues (1981a, b) have shown that, despite increased in attention, concentration, memory, and verbal and sleep propensity, as measured by the MSLT, no impairnonverbal intelligence (Greenberg et al., 1987; Bedard ments could be found on auditory attention, visual suset al., 1991; Naegele et al., 1995; Kim et al., 1997; tained attention, or inhibition (Fallone et al., 2001). Engleman and Joffe, 1999; Lee et al., 1999). Sleep depThese laboratory findings contradict parental and rivation exerts profound effects on cognitive function self-reports of impaired attention following acute sleep in adults, with complex tasks being more susceptible restriction. For example, children with early school to such deprivation when compared to more simple start times have reported more difficulty than their or automatic tasks (Harrison and Horne, 1998). Arnedt later-starting peers when asked to rate their level of and colleagues (2005) found that postcall performance attention and concentration abilities during school impairment during a heavy call rotation is comparable hours (Epstein et al., 1998). Sadeh and colleagues to impairment from blood alcohol concentration (2002) found no correlations between sleep schedules 0.04–0.05 g% (per 100 ml of blood) during a light call or duration and neurobehavioral functioning, and rotation, as measured by sustained attention, vigilance, Meijer and colleagues (2000) found no significant relaand simulated driving tasks. Further, adult patients tionships between subjective sleep variables such as with OSA exhibit a wide range of neurocognitive defitime in bed, quality of sleep, feeling rested, and difficits, particularly those underlying executive functionculty getting up in the morning, and performance on ing (i.e., the brain processes mediating the planning, a task of selective attention. Thus, the cumulative eviinitiation, and self-regulation of goal-oriented behadence would suggest that sleep deprivation rather than viors) (Lezak, 1995). While the literature is not as restriction is associated with more important effects on extensive in children, similar deficits in neurocognitive attention. function emerge as a result of sleep disruption. However, inattentive behavior has been reported in In the context of SDB, the magnitude and probabilchildren with OSA (Guilleminault et al., 1981, 1982) ity of neurocognitive dysfunction in children with OSA and with habitual snoring (Ali et al., 1993; Chervin are more profound than those associated with primary et al., 1997, 2002). Furthermore, a dose–response in snoring (Shiomi et al., 1993; Blunden et al., 2000; the scores obtained using attention-impulsivity scales O’Brien et al., 2003). Furthermore, hypoxemia is in the presence of OSA in children has been suggested closely correlated with deficits in executive function, (Owens-Stively et al., 1997). Blunden and colleagues whereas sleepiness is preferentially associated with (2000) also reported that children with mild SDB attention loss (Bedard et al., 1991; Naegele et al., demonstrated diminished selective and sustained atten1995). The frequently reported deficits in executive tion compared with control children. Studies from our performance in adults with SDB may emanate from laboratory further buttress the concept that children hypoxemia-induced frontal lobe dysfunction (Beebe with primary snoring (O’Brien et al., 2003) as well as and Gozal, 2002). Several groups of investigators have those with OSA (O’Brien et al., 2004a, b) are at higher posited that sleep disturbances are associated with dysrisk for deficits in attention compared to control chilfunction of the prefrontal cortex (PFC) in adults, and dren when measured on parental report scales, and that the same principles should be applicable to children such deficits are substantially improved following ade(Dahl, 1996). We have introduced a theoretical model, notonsillectomy (Guilleminault et al., 1982; Ali et al., whereby sleep apnea induces daytime cognitive deficits 1996; Owens et al., 2000; Chervin et al., 2006b).
SLEEP-ASSOCIATED RESPIRATORY DISORDERS IN CHILDREN
Memory Following acute sleep restriction, no deficits are usually apparent in word memory tasks (Carskadon et al., 1981a), yet such deficits emerge following 38 hours of sleep deprivation in a sample of similar-aged children (Carskadon et al., 1981b). Performance of a verbal memory task was unaffected by acute sleep restriction (Randazzo et al., 1998a) and 3 nights of restricted sleep in children aged 10–14 years did not suggest the presence of any deficits on a workingmemory task (Randazzo et al., 1998b). However, in children with OSA, memory performance on standardized psychometric tests is significantly affected compared with control children (Rhodes et al., 1995; Blunden et al., 2000), with children with higher respiratory disturbance indices showing greater memory deficits (Rhodes et al., 1995). These findings are not consistently reported; neither Owens-Stively and colleagues (1997) nor O’Brien and colleagues (2004a, b) found any differences in memory performance in children with varying degrees of OSA severity when compared to control children. The limited number of studies in this area and the contradictory results emphasize the need for further investigation.
Intelligence Children’s general cognitive ability appears to be unaffected by acute sleep restriction but is impaired on abstract problem-solving tests and verbal fluency (Randazzo et al., 1998a, b). Acute sleep restriction (Carskadon et al., 1981a), sleep restriction for 3 nights (Randazzo et al., 1998b), and total sleep deprivation for 38 hours (Carskadon et al., 1981b) did not lead to significant decrements on computational accuracy, although computational speed declines after total sleep deprivation. Thus, cognitive functions that require verbal creativity and abstract thinking may be more sensitive to sleep restriction in children than their visual/ imagery counterparts. In children with OSA, several studies have documented significantly reduced IQ scores (obtained from the Wechsler Intelligence Scale for Children – WISC-III) compared with control children (Rhodes et al., 1995; Blunden et al., 2000; Beebe et al., 2004). In these studies, the probability for lower normal or borderline range performance was much higher in children with SDB. We have documented significantly impaired General Conceptual Ability scores (a measure of IQ obtained from the Differential Ability Scales: DAS) in school-age (O’Brien et al., 2004a) and preschoolage (Montgomery-Downs et al., 2005) children with OSA when compared with control children. However, Ali and colleagues (1996) failed to detect any
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differences in the short-form version of the WISC-III. Interestingly, Lewin and colleagues (2002) found an inverse relationship between the severity of OSA and verbal ability (obtained from DAS). These investigators suggested that only severe OSA is a risk factor for disruption of verbal abilities. However, this issue merits further investigation because in our extensive study the majority of children had an apnea–hypopnea index between 5 and 10, i.e., not severe OSA, and despite relatively modest level of SDB severity, the verbal abilities and overall language scores were adversely affected (O’Brien et al., 2004a). In a study of preschoolers with OSA who were prospectively screened through parental questionnaires, we were further able to show complete reversibility of cognitive deficits following timely treatment (Montgomery-Downs et al., 2005). Thus, these studies suggest that early SDB diagnosis and intervention may lead to overall favorable outcomes (Friedman et al., 2003).
Learning and school performance School problems have been reported in multiple case series of children with OSA, and such findings may underscore more extensive behavioral disturbances such as restlessness, aggressive behavior, excessive daytime sleepiness, and poor test performances (Guilleminault et al., 1981; Weissbluth et al., 1983; Ali et al., 1993, 1996; Rhodes et al., 1995; Chervin et al., 1997; Owens et al., 1998; Chervin and Archbold, 2001). Improvements in behavior emerge following treatment for OSA in children (Stradling et al., 1990; Ali et al., 1996; Gozal, 1998), suggesting that at least some of the deficits may be reversible. Epidemiological surveys in which the total amount of sleep is assessed with questionnaires have indicated that children with later, irregular bedtimes, short sleep duration, and increased daytime sleepiness have lower academic achievements than other children (Kahn et al., 1989; Wolfson and Carskadon, 1998), although such findings have not been consistent (Eliasson et al., 2002). Lower school performance has also been described in children with OSA (Guilleminault et al., 1981, 1982, 1996; Stradling et al., 1990; Carroll and McLoughlin, 1992; Richards and Ferdman, 2000) and the reciprocal has also been shown to be true, i.e., children with poor academic performance are more likely to have sleep disturbances such as snoring and breathing difficulties (Weissbluth et al., 1983; Gozal, 1998). Indeed, we found a six- to ninefold increase in the expected incidence of OSA among first-grade children who ranked in the lowest 10th percentile of their class (Gozal, 1998), and significant improvements emerged in school grades after those children with OSA were
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effectively treated. Since the optimal intellectual ability and academic performance for these children were unknown, we cannot exclude the possibility that longterm residual deficits may be present after treatment. To examine this possibility further, we investigated the history of snoring during early childhood in two groups of 13–14-year-old children who were matched for age, gender, race, school attended, and socioeconomic status, but whose performance was either in the upper or lower quartile of their class, and found that children who snored frequently and loudly during early childhood were at greater risk for lower academic performance in later years, well after snoring had resolved (Gozal and Pope, 2001). These findings suggest that, even if the major portion of OSA-induced learning deficits is reversible, there may be long-lasting residual deficits in learning capability. The latter could represent either a “learning debt,” i.e., the decreased learning capacity during OSA may have led to such a delay in learned skills that recuperation is only possible with additional teaching assistance, or may suggest that OSA may have irreversibly altered the performance characteristics of the neuronal circuitry responsible for learning particular skills. In summary, sleep disturbance in children, whether due to poor sleep habits, developmental changes, or SDB, is accompanied by marked and obvious behavioral and neurocognitive deficits. Both sleep fragmentation and intermittent hypoxia contribute to elicit neurobehavioral morbidity in pediatric SDB. While the long-term outcome for children with untreated SDB is currently unknown, reversibility of neurobehavioral morbidities following treatment has been reported. These findings have been extended to those children with snoring, now considered the end of the SDB spectrum disorder. Increased awareness by physicians and parents and early identification and treatment of conditions leading to altered sleep and nocturnal oxygenation should lead to improved psychobehavioral outcomes in pediatric sleep-related respiratory disorders.
ACKNOWLEDGMENTS This work was supported by grants from the National Institutes of Health (HL65270 and HL69932), The Children’s Foundation Endowment for Sleep Research, and The Commonwealth of Kentucky Research Challenge Trust Fund.
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Chapter 32
Sleep-associated respiratory disorders and their psychobehavioral consequences in children 1 2
HAWLEY E. MONTGOMERY-DOWNS 1 AND DAVID GOZAL 2 * Departments of Psychology and Pediatrics, West Virginia University, Morgantown, WV, USA
Department of Pediatrics, Comer Children’s Hospital, The University of Chicago, Chicago, IL, USA
SLEEP DISTURBANCES IN CHILDREN Pediatric sleep continues to gain significant recognition due to both increasing evidence of a high prevalence of sleep disorders among children, and by virtue of the potential somatic and psychobehavioral effects of disrupted sleep during early development. Obstructive sleep apnea (OSA) is by far the most frequently diagnosed pediatric sleep disorder, affecting at least 1–3% of children, while symptoms consistent with risk for sleep-disordered breathing (SDB) have been reported in 6–27% of children (Brouillette et al., 1984; Ali et al., 1993; Gislason and Benediktsdottir, 1995; Hulcrantz et al., 1995; Archbold et al., 2002; Young et al., 2002; Montgomery-Downs et al., 2003). Children with SDB experience more frequent pulmonary hypertension (Shiomi et al., 1993), systemic hypertension, and other cardiovascular disturbances such as left ventricular hypertrophy (Marcus et al., 1998; Amin et al., 2002, 2005; O’Brien and Gozal, 2005), deficient somatic growth (Everett et al., 1987), and comorbid chronic illnesses (Rona et al., 1998; Archbold et al., 2002). In addition, pediatric OSA is associated with poor quality of life (Rosen et al., 2002; Crabtree et al., 2004; Mitchell and Kelly, 2005; Stewart et al., 2005), depressed mood (Crabtree et al., 2004; Mitchell and Kelly, 2006), and increased health care utilization (Reuveni et al., 2002; Tarasiuk et al., 2004). For the majority of children with mild to moderate SDB, psychobehavioral comorbidities are understood to be the most crucial consequence. Studies on these specific costs have focused on the daytime effects of
sleep restriction and sleep-related breathing disorders (e.g., snoring and OSA), which are also associated with both intermittent hypoxia and sleep fragmentation. The consequences of disrupted sleep specific to the effects of sleep-associated respiratory disorders will form the specific focus of this review.
Sleepiness The predominant manifestation of sleeplessness or sleep disturbance is “sleepiness” and thus it is important first to address what is meant by this sometimes ambiguous term. Originally described by Carskadon and Dement (1977), one objective technique used to quantify sleepiness is the Multiple Sleep Latency Test (MSLT). This simple method involves a series of 20–30-minute polysomnographically recorded daytime nap opportunities in a sleep-promoting environment (i.e., darkened and quiet room, comfortable bed and temperature). Under such standardized circumstances, the shorter the latency to sleep onset during these nap opportunities, the higher the degree of sleepiness. Such assessment is expensive, labor-intensive, and difficult with children so rare studies have objectively measured daytime sleepiness in children, though it has been found that compared to control children, those with attention deficit hyperactivity disorder (ADHD) have greater daytime sleepiness (Golan et al., 2004). Like studies with adults, for sleepiness measured by MSLT with children there seems to be a limited relationship with subjective report (Chervin et al., 2006a). However, it is important to note that
*Correspondence to: David Gozal, M.D., Herbert T. Abelson Distinguished Professor and Chair, Department of Pediatrics, Physician-in-Chief, Comer Children’s Hospital, The University of Chicago, 5721 S. Maryland Avenue, MC 8000, Suite K-160, Chicago, IL 60637, USA. Tel: (773) 702-3360, Fax: (773) 702-4523, E-mail: [email protected]
490 H.E. MONTGOMERY-DOWNS AND D. GOZAL behavioral sleepiness may display differently in chilbehavioral problems (Lavigne et al., 1999), and the dren than it does in adults. The manifestations of reciprocal of this observation holds true as well, since sleepiness in children will be discussed throughout this improvements in sleep are associated with improvereview. ment in daytime behavior (Minde et al., 1994; Ali et al., 1996; Chervin et al., 2006a). Thus, sleep and behavior exhibit dynamic interacBEHAVIORAL CONSEQUENCES tions that may either interfere with each other or synerOF SLEEP DISTURBANCE gistically enhance each other in children. In order to When sleep fragmentation is experimentally induced in understand further the potential impact of SDB on healthy adults using auditory stimuli to elicit arousals cognitive and behavioral functioning it is necessary to throughout the night, performance detriments are understand that hypoxia is unlikely to occur in isolaclearly apparent the following day (Stepansky et al., tion. Rather, SDB is typified by the co-occurrence of 1984, 1987; Chugh et al., 1996). In this context, cogniintermittent hypoxia and brief arousals that cause fragtive functions requiring concentration and motor mented architecture. Therefore, a short review of the dexterity are preferentially affected by sleep fragmeneffects of sleep restriction on higher-level functioning tation and often confusion and disorientation also in children is appropriate. occur, and have led to the term “sleep drunkenness.” Aggressive outbursts, irritability, anxiety, and depresSleep restriction sion are all known manifestations of excessive daytime Acute sleep restriction for one night in children has sleepiness in adults, and appear to be fully reversed been shown to increase inattentive behavior the followonce sleep is allowed and recovery occurs (for review, ing day, although without changes in hyperactive or see Roth and Roehrs, 1996). impulsive behaviors (Fallone et al., 2001). Extended Similar to adult findings, Sadeh and colleagues sleep restriction for 7 nights led to increased parent(2000) reported a high prevalence of sleep fragmentareported oppositional and inattentive behaviors tion in children but the effects of sleep fragmentation (Fallone et al., 2000) and teacher-reported academic on daytime functioning have yet to be examined in problems and attention problems (Fallone et al., detail among pediatric populations. It is known that 2005). Notwithstanding such observations, total sleep infants, toddlers, and school-age children who are time does not appear to be the major determinant of reported by their parents to be poor sleepers display daytime behavior problems in children. Rather, disrupincreased incidence and severity of behavioral issues tion of the sleep process instead of total amount of compared to children without reported sleep problems sleep may be the key factor underlying behavioral (Zuckerman et al., 1987; Ali et al., 1993, 1994; Minde alterations that are vulnerable to sleep disruption et al., 1993; Chervin et al., 1997; Stein et al., 2001). (Stores, 1996). Thus, an association between neuroThese observations have been confirmed by objective behavioral disturbances and the fragmentation by assessments, in which the degree of sleep disturbance multiple arousals observed in OSA or in periodic limb and the severity of behavioral changes are strongly movement disorder of sleep would be expected. To associated in most studies (Guilleminault et al., 1981; corroborate this supposition, a study from our laboraAli et al., 1996; Aronen et al., 2000; Chervin et al., tory found significant relationships between arousals 2000; Chervin and Archbold, 2001; O’Brien et al., associated with periodic limb movements during sleep 2003). However, work by Chervin and colleagues and ADHD (Crabtree et al., 2003). Thus, an associative (2006a) showed that, although adenotonsillectomy and possibly causal link appears to be present between improved neurobehavioral and parent report measures fragmented sleep and hyperactive behaviors. of hyperactivity to the extent that children no longer Developmental changes during adolescence also differed from controls (who did not change), neither afford an opportunity to examine the effects of sleep baseline SDB measures nor improvement predicted restriction. It has been clear for some time that both the degree of improvement on any outcome measure homeostatic influences (e.g., the time elapsed since the other than sleepiness. previous sleep period and circadian clock regulatory sysNevertheless, 36% of young children with global tems), and individual differences (e.g., motivation to fall reports of sleep problems presented with significant asleep and psychological tension or anxiety) affect daybehavioral problems (Smedje et al., 2001) and daytime time sleepiness in this age group. Extensive work by hyperactivity, and anxiety and depressive symptoms Carskadon and colleagues has shown that pubertal have been associated with prolonged sleep latency development is associated with increased daytime sleep(Smedje et al., 2001; Stein et al., 2001). Preschool chiliness, such that postpubertal adolescents require more dren with shorter total sleep time exhibited more
SLEEP-ASSOCIATED RESPIRATORY DISORDERS IN CHILDREN 491 sleep to retain prepubertal levels of alertness (Carskadon looking” and slow to respond to questions, yet it took et al., 1980; Carskadon and Dement, 1987). a century before Osler’s observations on neurocognitive The Carskadon lab has established that there is a decrements in pediatric OSA were investigated using biological shift in the homeostatic drive during adolesobjective methodology. Of particular emphasis is the fact cence, inhibiting later-stage pubertal adolescents’ ability that OSA in children is radically distinct from the OSA to obtain sleep early in the night (Jenni et al., 2005). that occurs in adults, and such differences are particuDespite the physiological evidence, school start times larly striking in relation to racial and gender distriin the USA and many countries around the world are bution, clinical manifestations, and treatment (Carroll organized so that secondary school students have to and McLoughlin, 1992; Rosen et al., 1992). wake up earlier than primary school students, an In children, OSA is frequently diagnosed in associaarrangement that appears in paradox with the biological tion with adenotonsillar hypertrophy, and is common in preferences for later bed and wake-up times during the children with craniofacial abnormalities and neurologimore advanced stages of puberty (Carskadon et al., cal disorders affecting upper-airway patency during 1993; Jenni et al., 2005; Taylor et al., 2005). The resultsleep. In early reports, Guilleminault et al. (1976) suging sleepiness has been repeatedly shown to have an gested that removal of the enlarged adenotonsillar impact on students’ learning and behavior and, in distissue would lead to complete resolution of clinical tricts where school start times are delayed for secondary symptoms and cure of OSA. However, although students, improvements can be dramatic (for review, see enlarged tonsils and adenoids are by far the most Carskadon et al., 2004; Millman, 2005). An awareness important contributor to the pathophysiology of OSA of increased adolescent risk-taking behaviors in associain children, children with OSA also demonstrate the tion with inadequate sleep has also emerged (O’Brien presence of increased upper-airway collapsibility and Mindell, 2005). (Isono et al., 1998; Gozal and Burnside, 2004). Thus, In addition to these experimental and naturalistic adenotonsillar hypertrophy alone is usually not suffiexamples of the effects of sleep restriction on daytime cient to cause OSA; in fact, some children with sleepiness in children and adolescents, sleep disorders “kissing tonsils” will not have OSA, while others with may contribute to sleep that is inadequate, fragmented, relatively small adenotonsillar tissue will manifest or both and have been shown repeatedly to have an severe OSA and may not be cured after adenotonsiladverse impact on daytime functioning, while early lectomy (Suen et al., 1995; Lipton and Gozal, 2003). treatment often reverses these effects. Among these, Emphasis has also been placed on the importance of OSA is the most frequently diagnosed disorder and a multispecialty approach to clinical assessment and has received the greatest attention from research treatment of pediatric OSA, including sleep medicine laboratories around the world. specialists, maxillofacial and otolaryngologist surgeons, and orthodontists, particularly for patients with craniofacial abnormalities (Guilleminault and Abad, Sleep-disordered breathing 2004). Clearly, OSA is a complicated disorder, but addOSA is a more severe form of SDB, and is a relatively ing to this is the emerging perspective that OSA is only common disorder among both adults and children, with one end of a spectrum disorder. up to 3% of young children affected (Brouillette et al., The primary symptom of OSA is habitual snoring, 1984; Ali et al., 1993; Gislason and Benediktsdottir, a symptom that may affect up to 27% of children, with a 1995; Hulcrantz et al., 1995; Young et al., 2002; median revolving around 10–12% (Teculescu et al., 1992; Montgomery-Downs et al., 2003). OSA is characterAli et al., 1993; Gislason and Benediktsdottir, 1995; ized by repeated events of partial or complete upperHulcrantz et al., 1995; Owen et al., 1996; Ferreira et al., airway obstruction during sleep. These upper-airway 2000; O’Brien et al., 2003; Montgomery-Downs et al., changes induce disruption of normal alveolar ventila2003). Prevalence rates of snoring similar to those of tion and sleep structure, and lead to blood gas abnormpreschool and early school-age children have also been alities and sleep fragmentation (American Thoracic reported among infants. Indeed, habitual snoring was Society, 1995) (Figures 32.1 and 32.2). found in 5% of 2–4-month-olds (Kelmanson, 2000) and Despite the fact that OSA and its associated mani6–12-month-olds (Gislason and Benediktsdottir, 1995), festations were first described over 130 years ago with higher rates in infants aged 1–8 months (16–26%) (McKenzie, 1880; Osler, 1892), it was not until 1976 (Mitchell and Thompson, 2003). We have found habitual that Guilleminault et al. reported OSA as a clinically snoring in 1–9% of infants and toddlers (2–24 months of relevant entity in children. Furthermore, Osler (1892) age) (Montgomery-Downs and Gozal, 2006a). This relareported that children with “loud and snorting” respiratively high frequency of habitual snoring usually decreases tions with “prolonged pauses” were often “stupid in 9–14-year-olds to around 3–5% (Corbo et al., 2001).
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Fig. 32.1. Illustrative 1-minute example of a partial upper-airway obstruction (hypopnea), with repeated reductions (OH) of oronasal airflow in the presence of respiratory efforts, and with associated oxyhemoglobin desaturation, and sleep arousal (circles). These events occurred during rapid eye movement sleep (R). EEG, electroencephalogram; ECG, electrocardiogram; Chin EMG, chin electromyogram; Snore, sound channel; Flow, airflow; Abd, abdominal respiratory effort; SaO2, oxyhemoglobin saturation.
It needs to be stressed that the presence of snoring should not be viewed as a normal feature of sleeping children, because it indicates that increased upperairway resistance is present. A substantial percentage of snoring children may have primary snoring (i.e., habitual snoring without obvious visually recognizable disruptions in sleep architecture, alveolar ventilation, and oxygenation) but despite the traditional view of primary snoring as a benign condition, our laboratory has reported that primary snoring may in fact be associated with a higher risk for neurobehavioral deficits, albeit less severe than the deficits found in children with OSA (O’Brien et al., 2003). Of note, daytime sleepiness, behavioral hyperactivity, learning problems, and restless sleep are all significantly more common in habitual snorers (Ali et al., 1993; Blunden et al., 2000; Ferreira et al., 2000; Blunden et al., 2001; Chervin et al., 2002; O’Brien et al., 2003). Another report from our lab indicates that infants with higher snore-related arousal indices had lower
scores on a standardized mental development assessment. Because neither apneas nor hypopneas were present in these otherwise normal, healthy children, these findings constitute further evidence that snoring is not just an innocent noise during sleep in infants, but may in fact represent the lower end of the disease spectrum associated with SDB (Montgomery-Downs and Gozal, 2006b). We still do not know enough about the natural history of snoring and snore-induced arousals in infancy or early childhood to disregard any snoring. Zucconi and colleagues (1993) found that, among 18–24-month-olds evaluated for nightly snoring and referred for surgical treatment, the parents of >50% reported that the habitual snoring had developed during the child’s first year of life, and 16% reported an onset in the first month of life. The consequences of snoring and OSA with their associated hypoxemia and sleep fragmentation in children reveal complex pathophysiological mechanisms (Bass et al., 2004). If left untreated or treated late,
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Fig. 32.2. Overnight hypnogram of an 8-year-old child with mild to moderate obstructive sleep apnea illustrating the clustering of respiratory events during rapid eye movement (REM) sleep periods (circles). PLM, periodic limb movement; A/H, apnea/ hypopnea; SaO2, oxyhemoglobin saturation.
pediatric OSA may lead to significant morbidity affecting multiple target organs and systems, and such injurious consequences may, under certain circumstances, be partially irreversible despite appropriate therapy.
PSYCHOBEHAVIORAL CONSEQUENCES OF SLEEP DISRUPTION IN SDB Behavior Both habitual snoring and OSA are associated with behavioral problems, particularly hyperactivity and ADHD (Ali et al., 1993, 1996; Chervin and Archbold, 2001). Hyperactive and inattentive behaviors occur frequently in children with OSA (Guilleminault et al., 1981; Carroll and McLoughlin, 1992; Gozal, 1998; Blunden et al., 2000) and with habitual snoring (Weissbluth et al., 1983; Ali et al., 1993; Chervin et al., 1997, 2002; Blunden et al., 2000; Chervin and Archbold, 2001; O’Brien et al., 2003). Furthermore, approximately 30% of all children with frequent, loud
snoring or OSA manifest parentally reported hyperactivity and inattentive symptoms (Ali et al., 1993), with improvements noted following surgical treatment of SDB (Ali et al., 1996; Dagan-Friedman et al., 2002; Chervin et al., 2006b; Mitchell and Kelly, 2006). Interestingly, although children with ADHD appear to exhibit more sleep disturbances than normal children (Berry et al., 1986; Trommer et al., 1988), we found that, despite parental reports of sleep disturbances in >70% of children with ADHD, only 20% of these children had sleep disturbances when assessed by objective polysomnographic criteria (O’Brien et al., 2003). In this study, SDB was not more likely to occur among children with true ADHD (i.e., diagnoses following the stringent criteria recommended by the Academy of Pediatrics and the Academy of Psychiatry), yet SDB was significantly more prevalent among children with parent-reported hyperactive behaviors that do not fulfill strict ADHD criteria, suggesting that the subtle disruptions of sleep elicited by the presence of SDB may be associated with significant behavioral effects.
494 H.E. MONTGOMERY-DOWNS AND D. GOZAL In contrast, Chervin and colleagues (2006b) found that via disruption of PFC-dependent processes (Beebe and children diagnosed with ADHD and reported by their Gozal, 2002) and this is also the foundation for a proparents to be hyperactive improved following adenoposed heuristic model for interpreting the prolific and tonsillectomy, but that severity of sleep measures dynamic research on both animal models and humans did not predict either baseline or improvement post(Beebe, 2005). The individual processes that make up surgery. As mentioned earlier, sleep fragmentation neurocognitive processes will be described separately associated with periodic limb jerks is more frequent below. in children with ADHD, thus supporting the notion that restless sleep is indeed more common in ADHD Attention patients. The ability to remain focused on a task and respond appropriately to extraneous stimuli in the environment Neurocognition plays an important role in learning, and consequently In adult patients, substantial cumulative evidence indiin social and academic development. Using acute sleep cates that neurocognitive deficits emanate from sleep restriction and sleep deprivation, Carskadon and coldisruption induced by SDB. These may include deficits leagues (1981a, b) have shown that, despite increased in attention, concentration, memory, and verbal and sleep propensity, as measured by the MSLT, no impairnonverbal intelligence (Greenberg et al., 1987; Bedard ments could be found on auditory attention, visual suset al., 1991; Naegele et al., 1995; Kim et al., 1997; tained attention, or inhibition (Fallone et al., 2001). Engleman and Joffe, 1999; Lee et al., 1999). Sleep depThese laboratory findings contradict parental and rivation exerts profound effects on cognitive function self-reports of impaired attention following acute sleep in adults, with complex tasks being more susceptible restriction. For example, children with early school to such deprivation when compared to more simple start times have reported more difficulty than their or automatic tasks (Harrison and Horne, 1998). Arnedt later-starting peers when asked to rate their level of and colleagues (2005) found that postcall performance attention and concentration abilities during school impairment during a heavy call rotation is comparable hours (Epstein et al., 1998). Sadeh and colleagues to impairment from blood alcohol concentration (2002) found no correlations between sleep schedules 0.04–0.05 g% (per 100 ml of blood) during a light call or duration and neurobehavioral functioning, and rotation, as measured by sustained attention, vigilance, Meijer and colleagues (2000) found no significant relaand simulated driving tasks. Further, adult patients tionships between subjective sleep variables such as with OSA exhibit a wide range of neurocognitive defitime in bed, quality of sleep, feeling rested, and difficits, particularly those underlying executive functionculty getting up in the morning, and performance on ing (i.e., the brain processes mediating the planning, a task of selective attention. Thus, the cumulative eviinitiation, and self-regulation of goal-oriented behadence would suggest that sleep deprivation rather than viors) (Lezak, 1995). While the literature is not as restriction is associated with more important effects on extensive in children, similar deficits in neurocognitive attention. function emerge as a result of sleep disruption. However, inattentive behavior has been reported in In the context of SDB, the magnitude and probabilchildren with OSA (Guilleminault et al., 1981, 1982) ity of neurocognitive dysfunction in children with OSA and with habitual snoring (Ali et al., 1993; Chervin are more profound than those associated with primary et al., 1997, 2002). Furthermore, a dose–response in snoring (Shiomi et al., 1993; Blunden et al., 2000; the scores obtained using attention-impulsivity scales O’Brien et al., 2003). Furthermore, hypoxemia is in the presence of OSA in children has been suggested closely correlated with deficits in executive function, (Owens-Stively et al., 1997). Blunden and colleagues whereas sleepiness is preferentially associated with (2000) also reported that children with mild SDB attention loss (Bedard et al., 1991; Naegele et al., demonstrated diminished selective and sustained atten1995). The frequently reported deficits in executive tion compared with control children. Studies from our performance in adults with SDB may emanate from laboratory further buttress the concept that children hypoxemia-induced frontal lobe dysfunction (Beebe with primary snoring (O’Brien et al., 2003) as well as and Gozal, 2002). Several groups of investigators have those with OSA (O’Brien et al., 2004a, b) are at higher posited that sleep disturbances are associated with dysrisk for deficits in attention compared to control chilfunction of the prefrontal cortex (PFC) in adults, and dren when measured on parental report scales, and that the same principles should be applicable to children such deficits are substantially improved following ade(Dahl, 1996). We have introduced a theoretical model, notonsillectomy (Guilleminault et al., 1982; Ali et al., whereby sleep apnea induces daytime cognitive deficits 1996; Owens et al., 2000; Chervin et al., 2006b).
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Memory Following acute sleep restriction, no deficits are usually apparent in word memory tasks (Carskadon et al., 1981a), yet such deficits emerge following 38 hours of sleep deprivation in a sample of similar-aged children (Carskadon et al., 1981b). Performance of a verbal memory task was unaffected by acute sleep restriction (Randazzo et al., 1998a) and 3 nights of restricted sleep in children aged 10–14 years did not suggest the presence of any deficits on a workingmemory task (Randazzo et al., 1998b). However, in children with OSA, memory performance on standardized psychometric tests is significantly affected compared with control children (Rhodes et al., 1995; Blunden et al., 2000), with children with higher respiratory disturbance indices showing greater memory deficits (Rhodes et al., 1995). These findings are not consistently reported; neither Owens-Stively and colleagues (1997) nor O’Brien and colleagues (2004a, b) found any differences in memory performance in children with varying degrees of OSA severity when compared to control children. The limited number of studies in this area and the contradictory results emphasize the need for further investigation.
Intelligence Children’s general cognitive ability appears to be unaffected by acute sleep restriction but is impaired on abstract problem-solving tests and verbal fluency (Randazzo et al., 1998a, b). Acute sleep restriction (Carskadon et al., 1981a), sleep restriction for 3 nights (Randazzo et al., 1998b), and total sleep deprivation for 38 hours (Carskadon et al., 1981b) did not lead to significant decrements on computational accuracy, although computational speed declines after total sleep deprivation. Thus, cognitive functions that require verbal creativity and abstract thinking may be more sensitive to sleep restriction in children than their visual/ imagery counterparts. In children with OSA, several studies have documented significantly reduced IQ scores (obtained from the Wechsler Intelligence Scale for Children – WISC-III) compared with control children (Rhodes et al., 1995; Blunden et al., 2000; Beebe et al., 2004). In these studies, the probability for lower normal or borderline range performance was much higher in children with SDB. We have documented significantly impaired General Conceptual Ability scores (a measure of IQ obtained from the Differential Ability Scales: DAS) in school-age (O’Brien et al., 2004a) and preschoolage (Montgomery-Downs et al., 2005) children with OSA when compared with control children. However, Ali and colleagues (1996) failed to detect any
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differences in the short-form version of the WISC-III. Interestingly, Lewin and colleagues (2002) found an inverse relationship between the severity of OSA and verbal ability (obtained from DAS). These investigators suggested that only severe OSA is a risk factor for disruption of verbal abilities. However, this issue merits further investigation because in our extensive study the majority of children had an apnea–hypopnea index between 5 and 10, i.e., not severe OSA, and despite relatively modest level of SDB severity, the verbal abilities and overall language scores were adversely affected (O’Brien et al., 2004a). In a study of preschoolers with OSA who were prospectively screened through parental questionnaires, we were further able to show complete reversibility of cognitive deficits following timely treatment (Montgomery-Downs et al., 2005). Thus, these studies suggest that early SDB diagnosis and intervention may lead to overall favorable outcomes (Friedman et al., 2003).
Learning and school performance School problems have been reported in multiple case series of children with OSA, and such findings may underscore more extensive behavioral disturbances such as restlessness, aggressive behavior, excessive daytime sleepiness, and poor test performances (Guilleminault et al., 1981; Weissbluth et al., 1983; Ali et al., 1993, 1996; Rhodes et al., 1995; Chervin et al., 1997; Owens et al., 1998; Chervin and Archbold, 2001). Improvements in behavior emerge following treatment for OSA in children (Stradling et al., 1990; Ali et al., 1996; Gozal, 1998), suggesting that at least some of the deficits may be reversible. Epidemiological surveys in which the total amount of sleep is assessed with questionnaires have indicated that children with later, irregular bedtimes, short sleep duration, and increased daytime sleepiness have lower academic achievements than other children (Kahn et al., 1989; Wolfson and Carskadon, 1998), although such findings have not been consistent (Eliasson et al., 2002). Lower school performance has also been described in children with OSA (Guilleminault et al., 1981, 1982, 1996; Stradling et al., 1990; Carroll and McLoughlin, 1992; Richards and Ferdman, 2000) and the reciprocal has also been shown to be true, i.e., children with poor academic performance are more likely to have sleep disturbances such as snoring and breathing difficulties (Weissbluth et al., 1983; Gozal, 1998). Indeed, we found a six- to ninefold increase in the expected incidence of OSA among first-grade children who ranked in the lowest 10th percentile of their class (Gozal, 1998), and significant improvements emerged in school grades after those children with OSA were
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effectively treated. Since the optimal intellectual ability and academic performance for these children were unknown, we cannot exclude the possibility that longterm residual deficits may be present after treatment. To examine this possibility further, we investigated the history of snoring during early childhood in two groups of 13–14-year-old children who were matched for age, gender, race, school attended, and socioeconomic status, but whose performance was either in the upper or lower quartile of their class, and found that children who snored frequently and loudly during early childhood were at greater risk for lower academic performance in later years, well after snoring had resolved (Gozal and Pope, 2001). These findings suggest that, even if the major portion of OSA-induced learning deficits is reversible, there may be long-lasting residual deficits in learning capability. The latter could represent either a “learning debt,” i.e., the decreased learning capacity during OSA may have led to such a delay in learned skills that recuperation is only possible with additional teaching assistance, or may suggest that OSA may have irreversibly altered the performance characteristics of the neuronal circuitry responsible for learning particular skills. In summary, sleep disturbance in children, whether due to poor sleep habits, developmental changes, or SDB, is accompanied by marked and obvious behavioral and neurocognitive deficits. Both sleep fragmentation and intermittent hypoxia contribute to elicit neurobehavioral morbidity in pediatric SDB. While the long-term outcome for children with untreated SDB is currently unknown, reversibility of neurobehavioral morbidities following treatment has been reported. These findings have been extended to those children with snoring, now considered the end of the SDB spectrum disorder. Increased awareness by physicians and parents and early identification and treatment of conditions leading to altered sleep and nocturnal oxygenation should lead to improved psychobehavioral outcomes in pediatric sleep-related respiratory disorders.
ACKNOWLEDGMENTS This work was supported by grants from the National Institutes of Health (HL65270 and HL69932), The Children’s Foundation Endowment for Sleep Research, and The Commonwealth of Kentucky Research Challenge Trust Fund.
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