Neurocognitive outcomes in sleep-disordered breathing

Abstract

Snoring is present in 18% to 20% of infants, 7% to 13% of children 2 to 8 years old, and 3% to 5% of older children.1.National Sleep Disorders Research Plan. National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), U.S. Department of Health and Human Services. NIH Publication No. 03-5209, July, 2003. Available at: http://www.nhlbi.nih.gov/health/prof/sleep/res_plan/index.html.Google Scholar Sleep-disordered breathing (SDB) comprises a spectrum of severity of upper airway resistance (UAR) ranging from mild increases associated only with snoring to progressively higher resistance levels associated with increasingly severe obstructive sleep apnea (OSA). OSA is characterized by repetitive partial or complete collapse of the pharyngeal airway during sleep and intermittent hypercarbic hypoxia (IHH). OSA is also characterized by recurrent transient arousals from sleep, but respiratory effort-related arousals can also occur at levels of increased UAR insufficient to reach threshold diagnostic criteria for OSA.2.Douglas N.J. Upper airway resistance syndrome is not a distinct syndrome.Am J Resp Crit Care Med. 2000; 161: 1412-1416Crossref PubMed Scopus (75) Google Scholar The frequent sleep arousals and resulting sleep fragmentation lead to functional sleep deprivation and waking hypersomnolence. Adenotonsillar hypertrophy is a major contributor to SDB in children, but other factors such as obesity, craniofacial genetics, and neural control mechanisms of upper airway patency are other likely important contributors.1.National Sleep Disorders Research Plan. National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), U.S. Department of Health and Human Services. NIH Publication No. 03-5209, July, 2003. Available at: http://www.nhlbi.nih.gov/health/prof/sleep/res_plan/index.html.Google ScholarCardiovascular disease is known to be a long-term consequence of untreated SDB, but diminished neurocognitive performance appears to be another important consequence.3.Quan S.F. Gersh B.J. Cardiovascular consequences of sleep-disordered breathing: past, present, and future.Circulation. 2004; 109: 951-957Crossref PubMed Scopus (201) Google Scholar, 4.Gottlieb D.J. Chase C. Vezina R.M. Heeren T.C. Corwin M.J. Auerbach S.H. et al.Sleep-disordered breathing symptoms are associated with poorer cognitive function in 5-year-old children.J Pediatr. 2004; 145: 458-464Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar, 5.Gozal D. O'Brien L. Row B.W. Consequences of snoring and sleep disordered breathing in children.Pediatr Pulmonol. 2004; 26: 166-168Crossref Scopus (37) Google Scholar, 6.Blunden S. Lushington K. Kennedy D. Cognitive and behavioural performance in children with sleep-related obstructive breathing disorders.Sleep Med Rev. 2001; 5: 447-461Abstract Full Text PDF PubMed Scopus (75) Google Scholar Neurodevelopmental sequelae have been attributed to IHH and sleep fragmentation, which in combination impair normal sleep restorative processes and perhaps further induce inflammatory and other chemical and structural central nervous system cellular injury.7.Tauman R. Ivanenko A. O'Brien L.M. Gozal D. Plasma c-reactive protein levels among children with sleep disordered breathing.Pediatrics. 2004; 113 (Available at:): e564-e569http://www.pediatrics.org/cgi/content/full/113/6/e564Crossref PubMed Scopus (243) Google Scholar, 8.Beebe D.W. Gozal D. Obstructive sleep apnea and the prefrontal cortex: towards a comprehensive model linking nocturnal upper airway obstruction to daytime cognitive and behavioral deficits.J Sleep Res. 2002; 11: 1-16Crossref PubMed Scopus (669) Google Scholar The neuropsychologic deficits in adults with SDB include impaired coordination of fine visuomotor control and defects of sustained attention and concentration.9.Kim H.C. Young T. Matthews C.G. Weber S.M. Woodard A.R. Palta M. Sleep-disordered breathing and neuropsychological deficits. A population-based study.Am J Respir Crit Med. 1997; 156: 1813-1819Crossref PubMed Scopus (246) Google Scholar High resolution magnetic resonance imaging studies of the brain in OSA have identified evidence of gray matter volume loss in a severity-dependent fashion, affecting multiple sites including frontal and parietal cortex, temporal lobe, anterior cingulate, hippocampus, and cerebellum.10.Macey P.M. Henderson L.A. Macey K.E. Alger J.R. Frysinger R.C. Woo M.A. et al.Brain morphology associated with obstructive sleep apnea.Am J Respir Crit Care Med. 2002; 166: 1382-1387Crossref PubMed Scopus (448) Google Scholar These findings are consistent with early-onset neural deficits including executive cognitive dysfunction.The neurobehavioral morbidities observed in children with SDB include learning and cognitive deficits, and behavioral problems associated with inattention and hyperactivity.5.Gozal D. O'Brien L. Row B.W. Consequences of snoring and sleep disordered breathing in children.Pediatr Pulmonol. 2004; 26: 166-168Crossref Scopus (37) Google Scholar, 6.Blunden S. Lushington K. Kennedy D. Cognitive and behavioural performance in children with sleep-related obstructive breathing disorders.Sleep Med Rev. 2001; 5: 447-461Abstract Full Text PDF PubMed Scopus (75) Google Scholar, 8.Beebe D.W. Gozal D. Obstructive sleep apnea and the prefrontal cortex: towards a comprehensive model linking nocturnal upper airway obstruction to daytime cognitive and behavioral deficits.J Sleep Res. 2002; 11: 1-16Crossref PubMed Scopus (669) Google Scholar In this issue of The Journal a new study is reported that adds to our knowledge regarding the adverse neurobehavioral consequences of lesser degrees of SDB.4.Gottlieb D.J. Chase C. Vezina R.M. Heeren T.C. Corwin M.J. Auerbach S.H. et al.Sleep-disordered breathing symptoms are associated with poorer cognitive function in 5-year-old children.J Pediatr. 2004; 145: 458-464Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar Using a broad range of neurocognitive tests in a population-derived sample of 5-year-old children, 30% had symptoms of SDB (frequent snoring, loud or noisy breathing during sleep, witnessed sleep apnea). Having SDB symptoms was associated with impaired behavioral control and diminished executive function, memory, and general intellectual ability. It is particularly noteworthy that these adverse findings persisted even after excluding the 8 children meeting their arbitrary threshold criterion for OSA of an apnea-hypopnea index (AHI) of ≥4. These neurocognitive impairments are thus associated with milder degrees of increased UAR associated only with “benign” snoring (AHI <1) or with borderline OSA (AHI 1-3.9).The main strengths of this study include use of a population-based rather than a referral-based cohort, and use of a state-of-the-art battery of neurocognitive tests yielding a comprehensive assessment of executive function. The high percent of successful polysomnograms (PSG) allows clear separation of children with SDB symptoms, and increased UAR too mild to meet minimum PSG criteria for OSA, from children who do meet minimum diagnostic criteria for OSA.There are several potential limitations. We do not know the generalizability of these data to children from families with lower income or education levels, differing race/ethnicity, or different sleep patterns. Increased body mass index (BMI) is associated with increased UAR, but in the absence of BMI data we do not know the extent to which BMI affected the results. Because there may have been differential study enrollment of children having SDB symptoms, this observed frequency of SDB symptoms may be significantly higher than other children from the Infant Care Practice cohort or other cohorts. The 95th percentile for AHI might therefore be <4 in a randomly selected subset of subjects undergoing PSG compared with this nonrandom cohort. We do not know when the SDB symptoms began or how long they had been at this level of severity, or the extent to which adenotonsillar hypertrophy was the primary contributor to increased UAR. Because witnessed sleep apnea likely has a greater sensitivity and specificity for OSA (and IHH), would the relationship between SDB symptoms and neurocognitive outcome be the same if the symptomatic group were limited to those with snoring and noisy breathing? Finally, we do not know to what extent AHI as defined in this study approximates AHI as defined and measured in other studies.AHI is the standard metric used to quantify severity of OSA, but it does not correlate well with clinical symptoms including hypersomnolence.11.Tauman R. O'Brien L.M. Holbrook C.R. Gozal D. Sleep pressure score: a new index of sleep disruption in snoring children.Sleep. 2004; 27: 274-278PubMed Google Scholar Similarly, these data suggest that AHI may not be very useful in defining the minimum threshold severity of SDB at which cognitive dysfunction begins in children. Additional studies are needed to confirm whether other metrics such as a sleep pressure numerical factor derived from the PSG may be more useful in quantifying disturbances in sleep homeostasis associated with deficits in neurobehavioral function.12.O'Brien L.M. Tauman R. Gozal D. Sleep pressure correlates of cognitive and behavioral morbidity in snoring children.Sleep. 2004; 27: 279-282Crossref PubMed Scopus (78) Google ScholarWhat causes poorer neurocognitive function in children with SDB symptoms?Do the SDB symptoms and neurocognitive impairment have a common underlying cause or are the SDB symptoms causal? Intermittent hypoxia has been shown experimentally to result in impaired learning and memory, but we do not know the extent to which IHH was present in these children with SDB symptoms but not OSA.13.Row B.W. Kheirandish L. Neville J.J. Gozal D. Impaired spatial learning and hyperactivity in developing rats exposed to intermittent hypoxia.Pediatr Res. 2002; 52: 449-453Crossref PubMed Scopus (197) Google ScholarTerm infants with multiple central and obstructive apneas and intermittent hypoxia during early infancy in the Collaborative Home Infant Monitoring Evaluation (CHIME) have lower adjusted means for mental development at 1 year of age as reported by our group in the current issue.14.Hunt C.E. Baird T. Tinsley L. Corwin M. Palmer P. Ramanathan R. et al.Collaborative Home Infant Monitoring Evaluation (CHIME) Study GroupCardiorespiratory events detected by home memory monitoring and one year neurodevelopmental outcome.J Pediatr. 2004; 145: 465-471Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar Longitudinal studies assessing cognitive performance using a comprehensive test battery are needed to determine to what extent mental performance limitations such as those observed in the CHIME study are of clinical significance as children approach school age, and to what extent, if any, such children later manifest SDB symptoms.14.Hunt C.E. Baird T. Tinsley L. Corwin M. Palmer P. Ramanathan R. et al.Collaborative Home Infant Monitoring Evaluation (CHIME) Study GroupCardiorespiratory events detected by home memory monitoring and one year neurodevelopmental outcome.J Pediatr. 2004; 145: 465-471Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar Longitudinal studies are also needed to determine the extent to which children with SDB at school age had antecedent SDB symptoms and neurocognitive impairments evident in infancy or during the preschool years.Assessments of school performance will be important as school-age children with SDB symptoms progress through the early school years. Will neurocognitive performance improve if adenotonsillar hypertrophy diminishes later, for example, or will these children have persisting increased UAR, SDB symptoms, and persisting or even progressive neurocognitive limitations? Assuming that neurocognitive dysfunction is at least in part caused by IHH and/or sleep fragmentation, no data are available in adults to indicate whether the neurocognitive impairments are reversible with intervention. If not reversible with treatment initiated as adults, we do not know at what earlier age treatment would need to be initiated to prevent or reverse neurocognitive impairment. The neuroimaging data in adults do not distinguish hypoxic/ischemic changes or other pathophysiologic changes associated with OSA from volume changes that existed earlier and perhaps contributed to the onset of OSA and its symptoms.10.Macey P.M. Henderson L.A. Macey K.E. Alger J.R. Frysinger R.C. Woo M.A. et al.Brain morphology associated with obstructive sleep apnea.Am J Respir Crit Care Med. 2002; 166: 1382-1387Crossref PubMed Scopus (448) Google ScholarChildren may be uniquely vulnerable to SDB symptoms and their consequences, especially if such symptoms begin during infancy or early childhood. Central nervous system maturation is a continuing process from infancy to later childhood and even adolescence; areas still developing are probably more vulnerable to injury.8.Beebe D.W. Gozal D. Obstructive sleep apnea and the prefrontal cortex: towards a comprehensive model linking nocturnal upper airway obstruction to daytime cognitive and behavioral deficits.J Sleep Res. 2002; 11: 1-16Crossref PubMed Scopus (669) Google Scholar Early neurocognitive deficits associated with SDB and its symptoms in infants and children may have substantially greater potential for injuries in the prefrontal cortex, therefore, because prefrontal cortical development does not finish until later. Future studies will need to determine how and when to intervene to prevent persisting cognitive impairment. Because AHI may not be a useful metric for identifying children with SDB symptoms at risk for neurocognitive dysfunction, alternatives may be needed that better quantify sleep fragmentation and awake hypersomnolence, in addition to apnea, hypopnea, and IHH.Previous studies of SDB-related neurocognitive function in children have used snoring and noisy breathing as a surrogate for OSA. These new data, however, indicate that SDB symptoms without OSA are nevertheless associated with poorer neurocognitive performance. These provocative findings need to be confirmed in other cohorts and their longer-term significance established, but they do suggest substantial gaps in our knowledge. If increased UAR associated with snoring or noisy breathing does indeed represent a causal risk factor for impaired school performance in children, future studies will need to determine what clinical metric best quantifies this risk. The remaining but complex challenge will be to define at what age, and by what means, intervention will be required to prevent long-term neurocognitive dysfunction. Snoring is present in 18% to 20% of infants, 7% to 13% of children 2 to 8 years old, and 3% to 5% of older children.1.National Sleep Disorders Research Plan. National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), U.S. Department of Health and Human Services. NIH Publication No. 03-5209, July, 2003. Available at: http://www.nhlbi.nih.gov/health/prof/sleep/res_plan/index.html.Google Scholar Sleep-disordered breathing (SDB) comprises a spectrum of severity of upper airway resistance (UAR) ranging from mild increases associated only with snoring to progressively higher resistance levels associated with increasingly severe obstructive sleep apnea (OSA). OSA is characterized by repetitive partial or complete collapse of the pharyngeal airway during sleep and intermittent hypercarbic hypoxia (IHH). OSA is also characterized by recurrent transient arousals from sleep, but respiratory effort-related arousals can also occur at levels of increased UAR insufficient to reach threshold diagnostic criteria for OSA.2.Douglas N.J. Upper airway resistance syndrome is not a distinct syndrome.Am J Resp Crit Care Med. 2000; 161: 1412-1416Crossref PubMed Scopus (75) Google Scholar The frequent sleep arousals and resulting sleep fragmentation lead to functional sleep deprivation and waking hypersomnolence. Adenotonsillar hypertrophy is a major contributor to SDB in children, but other factors such as obesity, craniofacial genetics, and neural control mechanisms of upper airway patency are other likely important contributors.1.National Sleep Disorders Research Plan. National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), U.S. Department of Health and Human Services. NIH Publication No. 03-5209, July, 2003. Available at: http://www.nhlbi.nih.gov/health/prof/sleep/res_plan/index.html.Google Scholar Cardiovascular disease is known to be a long-term consequence of untreated SDB, but diminished neurocognitive performance appears to be another important consequence.3.Quan S.F. Gersh B.J. Cardiovascular consequences of sleep-disordered breathing: past, present, and future.Circulation. 2004; 109: 951-957Crossref PubMed Scopus (201) Google Scholar, 4.Gottlieb D.J. Chase C. Vezina R.M. Heeren T.C. Corwin M.J. Auerbach S.H. et al.Sleep-disordered breathing symptoms are associated with poorer cognitive function in 5-year-old children.J Pediatr. 2004; 145: 458-464Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar, 5.Gozal D. O'Brien L. Row B.W. Consequences of snoring and sleep disordered breathing in children.Pediatr Pulmonol. 2004; 26: 166-168Crossref Scopus (37) Google Scholar, 6.Blunden S. Lushington K. Kennedy D. Cognitive and behavioural performance in children with sleep-related obstructive breathing disorders.Sleep Med Rev. 2001; 5: 447-461Abstract Full Text PDF PubMed Scopus (75) Google Scholar Neurodevelopmental sequelae have been attributed to IHH and sleep fragmentation, which in combination impair normal sleep restorative processes and perhaps further induce inflammatory and other chemical and structural central nervous system cellular injury.7.Tauman R. Ivanenko A. O'Brien L.M. Gozal D. Plasma c-reactive protein levels among children with sleep disordered breathing.Pediatrics. 2004; 113 (Available at:): e564-e569http://www.pediatrics.org/cgi/content/full/113/6/e564Crossref PubMed Scopus (243) Google Scholar, 8.Beebe D.W. Gozal D. Obstructive sleep apnea and the prefrontal cortex: towards a comprehensive model linking nocturnal upper airway obstruction to daytime cognitive and behavioral deficits.J Sleep Res. 2002; 11: 1-16Crossref PubMed Scopus (669) Google Scholar The neuropsychologic deficits in adults with SDB include impaired coordination of fine visuomotor control and defects of sustained attention and concentration.9.Kim H.C. Young T. Matthews C.G. Weber S.M. Woodard A.R. Palta M. Sleep-disordered breathing and neuropsychological deficits. A population-based study.Am J Respir Crit Med. 1997; 156: 1813-1819Crossref PubMed Scopus (246) Google Scholar High resolution magnetic resonance imaging studies of the brain in OSA have identified evidence of gray matter volume loss in a severity-dependent fashion, affecting multiple sites including frontal and parietal cortex, temporal lobe, anterior cingulate, hippocampus, and cerebellum.10.Macey P.M. Henderson L.A. Macey K.E. Alger J.R. Frysinger R.C. Woo M.A. et al.Brain morphology associated with obstructive sleep apnea.Am J Respir Crit Care Med. 2002; 166: 1382-1387Crossref PubMed Scopus (448) Google Scholar These findings are consistent with early-onset neural deficits including executive cognitive dysfunction. The neurobehavioral morbidities observed in children with SDB include learning and cognitive deficits, and behavioral problems associated with inattention and hyperactivity.5.Gozal D. O'Brien L. Row B.W. Consequences of snoring and sleep disordered breathing in children.Pediatr Pulmonol. 2004; 26: 166-168Crossref Scopus (37) Google Scholar, 6.Blunden S. Lushington K. Kennedy D. Cognitive and behavioural performance in children with sleep-related obstructive breathing disorders.Sleep Med Rev. 2001; 5: 447-461Abstract Full Text PDF PubMed Scopus (75) Google Scholar, 8.Beebe D.W. Gozal D. Obstructive sleep apnea and the prefrontal cortex: towards a comprehensive model linking nocturnal upper airway obstruction to daytime cognitive and behavioral deficits.J Sleep Res. 2002; 11: 1-16Crossref PubMed Scopus (669) Google Scholar In this issue of The Journal a new study is reported that adds to our knowledge regarding the adverse neurobehavioral consequences of lesser degrees of SDB.4.Gottlieb D.J. Chase C. Vezina R.M. Heeren T.C. Corwin M.J. Auerbach S.H. et al.Sleep-disordered breathing symptoms are associated with poorer cognitive function in 5-year-old children.J Pediatr. 2004; 145: 458-464Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar Using a broad range of neurocognitive tests in a population-derived sample of 5-year-old children, 30% had symptoms of SDB (frequent snoring, loud or noisy breathing during sleep, witnessed sleep apnea). Having SDB symptoms was associated with impaired behavioral control and diminished executive function, memory, and general intellectual ability. It is particularly noteworthy that these adverse findings persisted even after excluding the 8 children meeting their arbitrary threshold criterion for OSA of an apnea-hypopnea index (AHI) of ≥4. These neurocognitive impairments are thus associated with milder degrees of increased UAR associated only with “benign” snoring (AHI <1) or with borderline OSA (AHI 1-3.9). The main strengths of this study include use of a population-based rather than a referral-based cohort, and use of a state-of-the-art battery of neurocognitive tests yielding a comprehensive assessment of executive function. The high percent of successful polysomnograms (PSG) allows clear separation of children with SDB symptoms, and increased UAR too mild to meet minimum PSG criteria for OSA, from children who do meet minimum diagnostic criteria for OSA. There are several potential limitations. We do not know the generalizability of these data to children from families with lower income or education levels, differing race/ethnicity, or different sleep patterns. Increased body mass index (BMI) is associated with increased UAR, but in the absence of BMI data we do not know the extent to which BMI affected the results. Because there may have been differential study enrollment of children having SDB symptoms, this observed frequency of SDB symptoms may be significantly higher than other children from the Infant Care Practice cohort or other cohorts. The 95th percentile for AHI might therefore be <4 in a randomly selected subset of subjects undergoing PSG compared with this nonrandom cohort. We do not know when the SDB symptoms began or how long they had been at this level of severity, or the extent to which adenotonsillar hypertrophy was the primary contributor to increased UAR. Because witnessed sleep apnea likely has a greater sensitivity and specificity for OSA (and IHH), would the relationship between SDB symptoms and neurocognitive outcome be the same if the symptomatic group were limited to those with snoring and noisy breathing? Finally, we do not know to what extent AHI as defined in this study approximates AHI as defined and measured in other studies. AHI is the standard metric used to quantify severity of OSA, but it does not correlate well with clinical symptoms including hypersomnolence.11.Tauman R. O'Brien L.M. Holbrook C.R. Gozal D. Sleep pressure score: a new index of sleep disruption in snoring children.Sleep. 2004; 27: 274-278PubMed Google Scholar Similarly, these data suggest that AHI may not be very useful in defining the minimum threshold severity of SDB at which cognitive dysfunction begins in children. Additional studies are needed to confirm whether other metrics such as a sleep pressure numerical factor derived from the PSG may be more useful in quantifying disturbances in sleep homeostasis associated with deficits in neurobehavioral function.12.O'Brien L.M. Tauman R. Gozal D. Sleep pressure correlates of cognitive and behavioral morbidity in snoring children.Sleep. 2004; 27: 279-282Crossref PubMed Scopus (78) Google Scholar What causes poorer neurocognitive function in children with SDB symptoms?Do the SDB symptoms and neurocognitive impairment have a common underlying cause or are the SDB symptoms causal? Intermittent hypoxia has been shown experimentally to result in impaired learning and memory, but we do not know the extent to which IHH was present in these children with SDB symptoms but not OSA.13.Row B.W. Kheirandish L. Neville J.J. Gozal D. Impaired spatial learning and hyperactivity in developing rats exposed to intermittent hypoxia.Pediatr Res. 2002; 52: 449-453Crossref PubMed Scopus (197) Google ScholarTerm infants with multiple central and obstructive apneas and intermittent hypoxia during early infancy in the Collaborative Home Infant Monitoring Evaluation (CHIME) have lower adjusted means for mental development at 1 year of age as reported by our group in the current issue.14.Hunt C.E. Baird T. Tinsley L. Corwin M. Palmer P. Ramanathan R. et al.Collaborative Home Infant Monitoring Evaluation (CHIME) Study GroupCardiorespiratory events detected by home memory monitoring and one year neurodevelopmental outcome.J Pediatr. 2004; 145: 465-471Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar Longitudinal studies assessing cognitive performance using a comprehensive test battery are needed to determine to what extent mental performance limitations such as those observed in the CHIME study are of clinical significance as children approach school age, and to what extent, if any, such children later manifest SDB symptoms.14.Hunt C.E. Baird T. Tinsley L. Corwin M. Palmer P. Ramanathan R. et al.Collaborative Home Infant Monitoring Evaluation (CHIME) Study GroupCardiorespiratory events detected by home memory monitoring and one year neurodevelopmental outcome.J Pediatr. 2004; 145: 465-471Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar Longitudinal studies are also needed to determine the extent to which children with SDB at school age had antecedent SDB symptoms and neurocognitive impairments evident in infancy or during the preschool years.Assessments of school performance will be important as school-age children with SDB symptoms progress through the early school years. Will neurocognitive performance improve if adenotonsillar hypertrophy diminishes later, for example, or will these children have persisting increased UAR, SDB symptoms, and persisting or even progressive neurocognitive limitations? Assuming that neurocognitive dysfunction is at least in part caused by IHH and/or sleep fragmentation, no data are available in adults to indicate whether the neurocognitive impairments are reversible with intervention. If not reversible with treatment initiated as adults, we do not know at what earlier age treatment would need to be initiated to prevent or reverse neurocognitive impairment. The neuroimaging data in adults do not distinguish hypoxic/ischemic changes or other pathophysiologic changes associated with OSA from volume changes that existed earlier and perhaps contributed to the onset of OSA and its symptoms.10.Macey P.M. Henderson L.A. Macey K.E. Alger J.R. Frysinger R.C. Woo M.A. et al.Brain morphology associated with obstructive sleep apnea.Am J Respir Crit Care Med. 2002; 166: 1382-1387Crossref PubMed Scopus (448) Google ScholarChildren may be uniquely vulnerable to SDB symptoms and their consequences, especially if such symptoms begin during infancy or early childhood. Central nervous system maturation is a continuing process from infancy to later childhood and even adolescence; areas still developing are probably more vulnerable to injury.8.Beebe D.W. Gozal D. Obstructive sleep apnea and the prefrontal cortex: towards a comprehensive model linking nocturnal upper airway obstruction to daytime cognitive and behavioral deficits.J Sleep Res. 2002; 11: 1-16Crossref PubMed Scopus (669) Google Scholar Early neurocognitive deficits associated with SDB and its symptoms in infants and children may have substantially greater potential for injuries in the prefrontal cortex, therefore, because prefrontal cortical development does not finish until later. Future studies will need to determine how and when to intervene to prevent persisting cognitive impairment. Because AHI may not be a useful metric for identifying children with SDB symptoms at risk for neurocognitive dysfunction, alternatives may be needed that better quantify sleep fragmentation and awake hypersomnolence, in addition to apnea, hypopnea, and IHH.Previous studies of SDB-related neurocognitive function in children have used snoring and noisy breathing as a surrogate for OSA. These new data, however, indicate that SDB symptoms without OSA are nevertheless associated with poorer neurocognitive performance. These provocative findings need to be confirmed in other cohorts and their longer-term significance established, but they do suggest substantial gaps in our knowledge. If increased UAR associated with snoring or noisy breathing does indeed represent a causal risk factor for impaired school performance in children, future studies will need to determine what clinical metric best quantifies this risk. The remaining but complex challenge will be to define at what age, and by what means, intervention will be required to prevent long-term neurocognitive dysfunction. Do the SDB symptoms and neurocognitive impairment have a common underlying cause or are the SDB symptoms causal? Intermittent hypoxia has been shown experimentally to result in impaired learning and memory, but we do not know the extent to which IHH was present in these children with SDB symptoms but not OSA.13.Row B.W. Kheirandish L. Neville J.J. Gozal D. Impaired spatial learning and hyperactivity in developing rats exposed to intermittent hypoxia.Pediatr Res. 2002; 52: 449-453Crossref PubMed Scopus (197) Google Scholar Term infants with multiple central and obstructive apneas and intermittent hypoxia during early infancy in the Collaborative Home Infant Monitoring Evaluation (CHIME) have lower adjusted means for mental development at 1 year of age as reported by our group in the current issue.14.Hunt C.E. Baird T. Tinsley L. Corwin M. Palmer P. Ramanathan R. et al.Collaborative Home Infant Monitoring Evaluation (CHIME) Study GroupCardiorespiratory events detected by home memory monitoring and one year neurodevelopmental outcome.J Pediatr. 2004; 145: 465-471Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar Longitudinal studies assessing cognitive performance using a comprehensive test battery are needed to determine to what extent mental performance limitations such as those observed in the CHIME study are of clinical significance as children approach school age, and to what extent, if any, such children later manifest SDB symptoms.14.Hunt C.E. Baird T. Tinsley L. Corwin M. Palmer P. Ramanathan R. et al.Collaborative Home Infant Monitoring Evaluation (CHIME) Study GroupCardiorespiratory events detected by home memory monitoring and one year neurodevelopmental outcome.J Pediatr. 2004; 145: 465-471Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar Longitudinal studies are also needed to determine the extent to which children with SDB at school age had antecedent SDB symptoms and neurocognitive impairments evident in infancy or during the preschool years. Assessments of school performance will be important as school-age children with SDB symptoms progress through the early school years. Will neurocognitive performance improve if adenotonsillar hypertrophy diminishes later, for example, or will these children have persisting increased UAR, SDB symptoms, and persisting or even progressive neurocognitive limitations? Assuming that neurocognitive dysfunction is at least in part caused by IHH and/or sleep fragmentation, no data are available in adults to indicate whether the neurocognitive impairments are reversible with intervention. If not reversible with treatment initiated as adults, we do not know at what earlier age treatment would need to be initiated to prevent or reverse neurocognitive impairment. The neuroimaging data in adults do not distinguish hypoxic/ischemic changes or other pathophysiologic changes associated with OSA from volume changes that existed earlier and perhaps contributed to the onset of OSA and its symptoms.10.Macey P.M. Henderson L.A. Macey K.E. Alger J.R. Frysinger R.C. Woo M.A. et al.Brain morphology associated with obstructive sleep apnea.Am J Respir Crit Care Med. 2002; 166: 1382-1387Crossref PubMed Scopus (448) Google Scholar Children may be uniquely vulnerable to SDB symptoms and their consequences, especially if such symptoms begin during infancy or early childhood. Central nervous system maturation is a continuing process from infancy to later childhood and even adolescence; areas still developing are probably more vulnerable to injury.8.Beebe D.W. Gozal D. Obstructive sleep apnea and the prefrontal cortex: towards a comprehensive model linking nocturnal upper airway obstruction to daytime cognitive and behavioral deficits.J Sleep Res. 2002; 11: 1-16Crossref PubMed Scopus (669) Google Scholar Early neurocognitive deficits associated with SDB and its symptoms in infants and children may have substantially greater potential for injuries in the prefrontal cortex, therefore, because prefrontal cortical development does not finish until later. Future studies will need to determine how and when to intervene to prevent persisting cognitive impairment. Because AHI may not be a useful metric for identifying children with SDB symptoms at risk for neurocognitive dysfunction, alternatives may be needed that better quantify sleep fragmentation and awake hypersomnolence, in addition to apnea, hypopnea, and IHH. Previous studies of SDB-related neurocognitive function in children have used snoring and noisy breathing as a surrogate for OSA. These new data, however, indicate that SDB symptoms without OSA are nevertheless associated with poorer neurocognitive performance. These provocative findings need to be confirmed in other cohorts and their longer-term significance established, but they do suggest substantial gaps in our knowledge. If increased UAR associated with snoring or noisy breathing does indeed represent a causal risk factor for impaired school performance in children, future studies will need to determine what clinical metric best quantifies this risk. The remaining but complex challenge will be to define at what age, and by what means, intervention will be required to prevent long-term neurocognitive dysfunction.