- Email: [email protected]
Neurocognitive assessment and sleep analysis in children with sleep-disordered breathing
Clinical Neurophysiology 122 (2011) 311–319
Contents lists available at ScienceDirect
Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Neurocognitive assessment and sleep analysis in children with sleep-disordered breathing Silvia Miano, Maria Chiara Paolino, Antonella Urbano, Pasquale Parisi, Anna Claudia Massolo, Rosa Castaldo, Maria Pia Villa * Department of Paediatrics, Sleep Disease Centre, La Sapienza University of Rome – Sant’Andrea Hospital, Rome, Italy
a r t i c l e
i n f o
Article history: Accepted 24 June 2010 Available online 15 July 2010 Keywords: Children Sleep breathing disorder Intelligent quotient Attention deficit hyperactive disorder Cyclic alternating pattern analysis
a b s t r a c t Objective: To assess possible correlations between intelligence quotient (IQ) and attention deficit hyperactive disorder (ADHD) rating scale values and sleep (including cyclic alternating patterns analysis) and respiratory parameters in children with sleep-disordered breathing (SDB). Methods: Thirteen children who satisfied the criteria for primary snoring and 31 children for obstructive sleep apnea syndrome (OSAS) underwent polysomnography in a standard laboratory setting and a neurocognitive assessment. Sixty normal controls recruited from two schools underwent the neurocognitive assessment. Results: The IQ estimates of controls were higher and the ADHD rating scale scores lower than those of children with SDB. Children with OSAS had a higher REM sleep latency and arousal index as well as a lower N3 and A mean duration than children who snored. In our sample of children with SDB, the percentage of wakefulness after sleep onset, of N1, of A2, of arousal and A2 index correlated positively with global intelligence. Total and hyperactivity scores correlated positively with the A2 index. Regression analysis mostly confirmed the correlations between neurocognitive measures and sleep parameters and further demonstrated a negative correlation between the hyperactivity rating score and oxygen saturation during the night. Conclusions: Our results support the hypothesis that arousal is a defensive mechanism that may preserve cognitive function by counteracting the respiratory events, at the expense of sleep maintenance and NREM sleep instability. Significance: We believe that our study makes an interesting contribution to research on the relationship between sleep fragmentation and cognitive function. Ó 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Children with sleep-disordered breathing (SDB) are affected by diurnal neurobehavioural problems, such as attention deficit and hyperactive disorder (ADHD), learning problems, behavioural disorders and hypersomnolence (Chervin et al., 2005; Gozal, 2008). Although a significant improvement in diurnal neurobehavioural disorders following adenotonsillectomy has been demonstrated (Owens-Stively et al., 1997; Montgomery-Downs et al., 2005; Mitchell and Kelly, 2006; Gozal, 2008), the relationship between SDB severity and cognitive deficits is usually weak (Decary et al., 2000; Friedman et al., 2003), and a ‘‘learning debt” may develop as a consequence of SDB (Gozal and Pope, 2001).
* Corresponding author. Address: Paediatric Clinic, Sant’Andrea Hospital, Via Grottarossa 1035/1039 – 00189 Rome, Italy. Tel.: +39 0633775855; fax: +39 0633775941. E-mail address: [email protected] (M.P. Villa).
Findings from previous studies suggest that intermittent hypoxia during sleep, respiratory events and sleep fragmentation are the main causative factors of the diurnal neurocognitive consequences of obstructive sleep apnea syndrome (OSAS) (Chervin et al., 2004; Kheirandish and Gozal, 2006). A large cohort study demonstrated that the degree of hypoxemia correlates preferentially with deficits in executive function (Kheirandish and Gozal, 2006), whereas the magnitude of sleep fragmentation, as expressed by the number of arousals during sleep in response to respiratory events, appears to account for changes in attention and memory deficits (O’Brien and Gozal, 2004; O’Brien et al., 2004a,b; Kennedy et al., 2004; Kheirandish-Gozal et al., 2010). The neurocognitive phenotype of paediatric OSAS may reflect a dysfunction in the prefrontal cortex, which controls executive functions and contains the brain areas that mature last, and might thus be susceptible to OSA-mediated injury (Beebe and Gozal, 2002). In addition, several studies have reported reduced intelligence quotient (IQ) scores in children with OSAS, the majority of whom exhibits a lower normal or borderline performance (Blunden et al., 2000; O’Brien et al., 2004a).
1388-2457/$36.00 Ó 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2010.06.019
312
S. Miano et al. / Clinical Neurophysiology 122 (2011) 311–319
The same PFC regions generate slow oscillations during NREM sleep (Terzano et al., 2001), which are the main components of the A1 subtypes of the so-called cyclic alternating pattern (CAP) and map over the frontal and prefrontal regions of the scalp (Ferri et al., 2005). The few data available on CAP in paediatric SDB are somewhat contradictory (Guilleminault et al., 2005; Lopes and Guilleminault, 2006; Kheirandish-Gozal et al., 2007; Miano et al. 2009a). In one study, children with SDB had a lower CAP rate, particularly during slow-wave sleep, with no clear increase in the number of arousals if compared with normal controls (Kheirandish-Gozal et al., 2007). By contrast, Lopes and Guilleminault (2006) found an increased CAP rate in children who snored, as well as in sleepwalking children with SBD (Guilleminault et al., 2005). Moreover, a positive correlation between the increased CAP rate and behavioural complaints was found in children who habitually snored (Lopes and Guilleminault, 2006). We also reported a higher CAP rate during slow-wave sleep and an increased A2 index in children with OSAS compared with normal controls (Miano et al., 2009a,b), and a lower CAP rate and lower A1 index during slowwave sleep in children with OSAS and EEG abnormalities compared with those without EEG abnormalities (Miano et al., 2009b). However, not only have these subtle changes in sleep architecture not yet been fully understood, but few studies have investigated the correlation between CAP values and neurocognitive dysfunction. The true significance of NREM sleep alterations thus remains speculative. The aim of our study was to measure IQ by means of a standardized test and to measure ADHD symptoms by means of a standardized questionnaire in a large group of children with SDB (primary snoring and obstructive sleep apnea syndrome) and to compare these data with the children’s polysomnographic parameters (including sleep stages, CAP and EEG arousal analysis). 2. Materials and methods 2.1. Subjects We consecutively enrolled children undergoing a diagnostic assessment for OSAS in our Paediatric Sleep Centre (Rome, Italy) because of habitual snoring, apnea or restless sleep, as witnessed by their parents. The diagnosis of OSAS was confirmed by means of a laboratory polysomnography (PSG) revealing an obstructive apnea/hypopnea index (AHI) > 1, according to the criteria of the American Academy of Sleep Medicine (AASM, 2005). Primary snoring was diagnosed in children with habitual snoring, an AHI <1 and microphone-detected snoring. Children were enrolled between February 2009 and June 2009. Patients with a history of epilepsy, EEG abnormalities, previous treatment for OSAS (including tonsillectomy and adenoidectomy), acute or chronic cardiorespiratory or neuromuscular diseases, dysmorphism, major craniofacial abnormalities or chromosomal syndromes were excluded. A detailed personal and family history was obtained for all the participants and a clinical examination performed. The participants’ parents completed the Brouillette questionnaire on symptoms of OSAS (Brouillette et al., 1984). The questionnaire comprised questions on sleep, breathing during sleep, medical diagnoses and previous surgery. Likelihood ratios for OSAS scores were: a score < 1 predicted no OSAS; a score from 1 to 3.5 was considered to be inconclusive; a score >3.5 predicted the presence of OSAS. 2.2. Cognitive assessment The ADHD Rating Scale, adapted for the Italian population, was filled out by the parents of participants (Marzocchi and Cornoldi, 2000; DuPaul et al., 2001). It consists of 18 items, divided into
two subgroups of nine questions that investigate inattention and hyperactivity symptoms. Intelligence (IQ) estimates were obtained using the Wechsler Intelligence Scale for Children – Third Edition Revised (WISC-R, 1973; Rubini and Padovani, 1986). The WISC-R has been translated into Italian, uses Italian-based norms (Termine et al., 2005), and has demonstrated a level of reliability that is equal to the English version (Grimaldi and Lisi, 1983). Administration of the WISC-R, which is validated for children between the ages of 6 and 16 years, usually requires 75–80 min. The test comprises 10 core subtests and two supplemental tests. These subtests generate a full scale score (Total Intelligence Quotient, T-IQ), and two composite scores known as indexes: the Verbal Intelligence quotient (V-IQ) and the Performance Intelligence Quotient (P-IQ). The IQ testing was performed on the morning before the sleep study. A Wechsler score <70 was considered to indicate mental retardation, while a Wechsler score <85 was considered to indicate borderline intellectual functioning, according to the Statistical Manual of Mental Disorders, Fourth Edition axis II diagnosis (1994). Sixty normal age- and sex-matched controls (22 males, mean years of age 9.1 ± 2.4 S.D.) were recruited. The control children came from two schools that were in the same urban area as the subjects with SDB, were of Caucasian origin and middle socioeconomic status. The IQ estimates were obtained using the WISC-R, which was administered in the morning at school. The parents of the control children were also asked to fill out the ADHD-rating scales. The control subjects were recruited between January 2006 and December 2006. Inclusion criteria were: normal healthy prepubertal children who were attending local schools and had normal sleep habits; these criteria were confirmed by means of interviews with both the parents and child. None of the controls was obese or had any serious physical, neurological or psychiatric disorder. No history of major sleep problems was reported, and none was taking medication at the time of testing. The local ethics committee approved the study protocol and all children’s parents gave their informed consent to the procedures. 2.3. Polysomnography and sleep stage scoring All the patients underwent a full-night PSG in our Sleep Centre after one adaptation night. Standard overnight PSG recordings were obtained using a Grass Heritage polygraph. The variables recorded included at least a 6channel electroencephalogram (bilateral frontal, central temporal and occipital monopolar montages referred to the controlateral mastoid); electro-oculogram (electrodes placed 1 cm above the right outer cantus and 1 cm below the left outer cantus and referred to A1), submental electromyogram and electrocardiogram (1 derivation). Sleep was subdivided into 30-s epochs, and sleep stages were scored according to the standard criteria of the AASM (Iber et al., 2007). The following sleep parameters were measured: sleep latency, defined as the time between light out and the first epoch of any sleep stage in minutes; total sleep time, defined as the time from sleep onset to the end of the final sleep; sleep period time, defined as total sleep time minus time awake after sleep onset; sleep efficiency, defined as the percentage ratio between total sleep time and total recording time (from lights out clock time to lights on clock time); wakefulness after sleep onset, defined as the time spent awake between sleep onset and the end of sleep; lastly, the number of stage shifts per hour of sleep. The percentage of total sleep time in each stage was measured as follows: percentage of stage N1, stage N2, stage N3, and stage R (REM sleep).
313
S. Miano et al. / Clinical Neurophysiology 122 (2011) 311–319
2.4. CAP scoring
2.6. Sleep respiration analysis
CAP was scored according to the criteria by Terzano et al. (2001). CAP is periodic EEG activity in NREM sleep characterized by repeated spontaneous sequences of transient events (phase A) that clearly break away from the background rhythm of the ongoing sleep stage, with an abrupt frequency/amplitude variation, and recur at intervals that last up to 1 min. The return to the background activity identifies the interval that separates the repetitive elements (phase B). CAP A phases have been subdivided into three different subtypes:
Central, obstructive and mixed apnea events were counted according to the criteria established by the AASM (AASM, 2005; Iber et al., 2007). Obstructive apnea was scored when there was a >90% drop in the signal amplitude of airflow for >90% of the entire event, compared with the pre-event baseline amplitude, with continued chest wall and abdominal movement, for a duration of at least two breaths. Central apnea was defined as the absence of airflow, with the cessation of respiratory effort, lasting more than 20 s or lasting at least two missed breaths (or the duration of two baseline breaths), associated with an arousal, an awakening or a >3% desaturation; central apnea occurring after gross body movements or after sighs was not considered as a pathological finding. Mixed apnea was defined as apnea that usually began as central and ended in obstruction, according to changes in the chest, abdominal and flow traces. An event could be scored as hypopnea if there was a >50% drop in airflow signal amplitude compared with the pre-event baseline amplitude for at least 90% of the duration of the event; the event had to last at least two missed breaths and be associated with an arousal, awakening or a >3% desaturation. Chest and abdomen movements were measured by strain gauges. Oronasal airflow was recorded by means of a thermocouple and nasal pressure. Arterial oxygen saturation was monitored with a pulse oximeter. The apnea/ hypopnea index (AHI) was defined as the average number of apneas, hypopneas and respiratory event-related arousals per hour of sleep. All recordings started at the patients’ usual bedtime and continued until spontaneous awakening. All recordings were scored visually by one of the investigators (SM), who was blinded to the subject’s group, age and sex.
1. A1 – A phases with synchronized EEG patterns (intermittent alpha rhythm in stage 1; sequences of K complexes or delta bursts in the other NREM stages), associated with mild or trivial polygraphic variations; 2. A2 – A phases with desynchronized EEG patterns preceded by or mixed with slow high-voltage waves (K complexes with alpha and beta activities, k-alpha, arousals with slow-wave synchronization), associated with a moderate increase in muscle tone and/or cardiorespiratory rate; 3. A3 – A phases with desynchronized EEG patterns alone (transient activation phases or arousals) or exceeding 2/3 of the phase A length, associated with a remarkable enhancement in muscle tone and/or cardiorespiratory rate. The following CAP parameters were measured: CAP time (sum of the length of all CAP sequences, in minutes); in NREM sleep CAP rate of total NREM sleep time occupied by CAP sequences; number and mean duration of CAP cycles (phase A + phase B); number and mean duration of CAP sequences, number, mean duration and percentage of A phases (including phase A subtypes); A1, A2 and A3 index (number of A1, A2 or A3 phases of NREM sleep per hour, and of stages N1 and N2 and N3 per hour of sleep); number and mean duration of B phases. All these variables were detected visually and their parameters measured by means of the Hypnolab 1.0 sleep analysis software (SWS Soft, Italy). Owing to its complex and time-consuming nature, we only performed the CAP analysis in a subgroup of children (those enrolled in the first 2 months of the study, in February and March 2009). 2.5. Arousal analysis Arousals were detected visually according to the criteria reported in the recent manual for the scoring of sleep and associated events by the AASM (Iber et al., 2007).
2.7. Statistical analysis Data are expressed as mean ± SD. The Mann–Whitney U or v2 test was chosen, when appropriate, to compare data. The Spearman rank correlation coefficient was used to assess the relationships between the PSG parameters and behavioural/cognitive measures. A multiple linear regression analysis (stepwise method) was performed to explore any correlations between sleep and respiratory parameters, arousal index and CAP parameters (independent variables), and IQ measures and ADHD scores (dependent variables). Differences and correlations were considered as statistically significant when p < 0.05. The statistical analysis was performed using a commercial software package (SPSS, version 11; SPSS; Chicago, IL).
Table 1 Anthropometric and clinical characteristics of all subjects, as well as verbal intelligence quotient (V-IQ), performance (P-IQ) and total IQ (T-IQ) scores, attention deficit, hyperactive disorder (ADHD) rating scales scores of normal controls, children with primary snoring (PS) and with obstructive sleep apnea syndrome (OSAS).
Mean Age (years) Body mass index (kg/m2) Duration of disease (years) Brouillette score T-IQ V-IQ P-IQ Hyperactive rating scale Inattention rating scale Total ADHD rating scale
9.8 18.3 – – 115.5 118.2 109.7 1.8 1.5 3.3
(c) OSAS (n = 31)
(b) PS (n = 13)
(a) Controls (n = 60) SD 2.4 1.8 – – 10.8 11.7 11.8 1.3 1.7 2.5
Kruskall–Wallis
Mann–Whitney p<
Mean
SD
Mean
SD
p<
a vs b
a vs c
b vs c
8.6 18.2 3.9 0.8 94.8 91.1 100.5 9.5 6.8 16.3
1.9 3.6 3.1 2.3 8.9 12.2 9.9 6.3 6.5 11.6
9.1 19.6 4.1 0.7 98.2 96.5 101.0 9.1 8.5 17.6
2.3 3.6 2.9 2.2 12.4 14.4 14.8 6.5 6.4 11.4
NS NS – – 0.001 0.001 0.005 0.001 0.001 0.001
– – 0.001 0.001 0.05 0.001 0.005 0.001
– – 0.001 0.001 0.005 0.001 0.001 0.001
NS NS NS NS NS NS NS NS
314
S. Miano et al. / Clinical Neurophysiology 122 (2011) 311–319
Table 2 Respiratory and sleep parameter values in children with primary snoring (PS) and with obstructive sleep apnea syndrome (OSAS). RP (n = 13) Mean Apnea/hypopnea-respiratory related arousal index/h (n/h) Overnight oxygen saturation (%) Minimal overnight oxygen saturation Mean sleep oxygen desaturations (%) Oxygen desaturation index (n/h) Sleep period time (min) Total sleep time (min) Sleep latency (min) REM latency (min) Stage shifts (n/h) Sleep efficiency (%) Wakefulness after sleep onset (min) Wakefulness after sleep onset (%) N1 (%) N2 (%) N3 (%) R (%) Arousal index (n/h)
0.5
OSAS (n = 31) SD 0.3
Mean 8.2
Mann– Whitney SD 9.9
Table 3 Cyclic alternating patterns (CAP) parameter values and arousal index in the subgroup of children with primary snoring (PS) and with obstructive sleep apnea syndrome (OSAS) enrolled in February and March 2009. PS (n = 10)
p<
Mean
0.001
97.2 95.4
1.2 2.8
96.9 90.9
1.7 4.5
NS 0.005
96.1
2.1
93.6
2.6
0.005
0.1 397.4 419.6 25.2 110.7 10.2 85.9 43.9
0.3 58.5 56.5 21.0 51.5 2.9 12.5 57.5
2.1 395.7 423.8 25.9 146.3 10.4 87.0 34.2
3.5 46.5 44.1 15.9 54.0 2.9 7.6 32.5
0.001 NS NS NS 0.05 NS NS NS
5.3 8.6 31.7 35.5 18.8 9.8
4.9 3.6 6.8 5.1 4.2 3.7
6.4 9.3 34.3 30.1 19.3 14.9
6.5 4.1 9.7 7.4 5.9 7.9
NS NS NS 0.05 NS 0.05
3.1. Clinical and anthropometric parameters, ADHD rating scale scores and WISC-R scale IQ estimates (Table 1) In total, 13 children met the criteria for primary snoring (8 males, mean age in years: 8.6 ± 1.9 S.D.) while 31 children met the criteria for OSAS (18 males, mean age in years: 9.1 ± 2.3 S.D.); all the subjects were of Caucasian origin and of middle socioeconomic status. No differences were found between snorers and children with OSAS in disease duration, Brouillette scores, V-IQ, P-IQ, T-IQ or ADHD rating scale scores. The IQ estimates of normal controls were significantly higher and the hyperactive and ADHD rating scale scores lower than those of both groups of children with SDB. 3.2. Sleep architecture and respiratory parameters (Table 2) No significant differences emerged in sleep macrostructure if we exclude the fact that children with OSAS had a higher REM sleep latency and a lower N3 percentage than snorers.
SD
Mean
Mann– Whitney SD
p<
CAP rate (%) In N1 In N2 In N3
39.2 28.8 17.7 60.9
13.6 11.3 10.5 21.5
41.5 33.0 26.4 67.0
15.4 18.4 25.3 23.2
NS NS NS NS
A1% A2% A3%
80.9 9.8 9.2
7.9 5.1 3.0
76.7 12.6 11.0
9.5 7.6 4.1
NS NS NS
A1 index (n/h) In N1 In N2 In N3
47.7 7.6 26.0 90.4
20.1 4.5 15.5 33.7
52.2 6.8 26.1 113.1
26.1 5.2 14.9 34.4
NS NS NS NS
A2 index (n/h) In N1 In N2 In N3
4.9 14.6 5.1 3.8
1.9 6.2 3.1 1.5
7.4 17.2 5.4 8.7
3.9 13.3 3.1 7.8
NS NS NS NS
A3 index (n/h) In N1 In N2 In N3
3.4 32.6 3.4 1.5
1.3 11.9 1.9 0.7
4.7 41.8 2.9 1.7
3.6 20.8 1.8 1.2
NS NS NS NS
8.6 7.4 11.8 16.3 19.8 291.8
1.2 1.1 3.1 3.1 3.3 106.1
7.1 6.0 9.2 13.2 19.9 326.3
0.8 1.2 1.2 2.1 3.8 140.4
10.6
3.8
14.9
5.4
A mean duration (min) A1 mean duration (min) A2 mean duration (min) A3 mean duration (min) B mean duration (min) Sequences mean duration (min) Arousal index (n/h)
3. Results
OSAS (n = 11)
0.005 0.05 0.05 0.05 NS NS 0.05
3.4. Correlation analyses ADHD scores correlated negatively with IQ measures in all the subjects, while the percentage of wakefulness after sleep onset, of N1, of A2 and of the arousal and A2 indexes correlated positively with global intelligence in children with SDB. Total and hyperactivity scores correlated positively with the A2 index in N3. Table 4 shows the correlation coefficients between measures yielded by the neurocognitive assessment in all the subjects with SDB and in normal controls. Table 5 shows the correlation coefficients yielded by the sleep and respiratory parameters (including the arousal index) and neurocognitive assessment in all the subjects with SDB. Table 6 shows the correlation coefficients between the measures yielded by the CAP parameters, sleep respiratory parameters and neurocognitive assessment in the subgroups of children with
3.3. Results of sleep parameters and CAP analysis (Table 3) The subgroup of children who underwent CAP analysis comprised 23 children. Children with OSAS (13 subjects, 8 males; mean age in years 9.1 ± 3.1 S.D.) had a lower percentage of N3 (27.3 ± 8.7 vs 35.6 ± 5.4, p < 0.05), of minimal overnight oxygen saturation (90.5 ± 3.6 vs 95.8 ± 2.9, p < 0.05) and of mean desaturation (93.9 ± 1.5 vs 96.6 ± 2.0, p < 0.05) as well as a higher AHI (9.9 ± 8.2 vs 0.5 ± 0.3, p < 0.01) and ODI (1.9 ± 2.0 vs 0.2 ± 0.4) than snorers (10 subjects, 8 males, mean age in years 8.6 ± 2.3 S.D.). Children with OSAS had a lower A phase mean duration, a lower mean duration of each A phase subtype and a higher arousal index higher than children who snored. No differences were found in disease duration, Brouillette scores, V-IQ, P-IQ, T-IQ or ADHD rating scale scores.
Table 4 Significant correlations (Spearman coefficient) between ADHD (attention deficit hyperactivity disorder) rating scale scores and Total Intelligence Quotient, (T-IQ), Verbal Intelligence Quotient (V-IQ), and Performance Intelligence Quotient (P-IT) scores in all the children investigated (normal controls and subjects with sleepdisordered breathing). T-IQ
V-IQ
P-IQ
q= Hyperactive rating scale Inattention rating scale Total ADHD rating scale *
p < 0.05. p < 0.001. °° p = 0.07. °
0.432° 0.362° 0.464°
0.495° 0.419° 0.521°
0.161°° 0.202*
315
S. Miano et al. / Clinical Neurophysiology 122 (2011) 311–319
Table 5 Significant correlations (Spearman coefficient) between sleep parameters (including arousal index) and respiratory parameters and neurocognitive assessment (Total Intelligence Quotient, T-IQ, Verbal Intelligence Quotient, V-IQ, and Performance Intelligence Quotient, P-IT; attention deficit hyperactivity disorder – ADHD – rating scales) in all the children with sleep-disordered breathing. Apnea/hypopnearespiratory related arousals (n/h)
Overnight oxygen saturation (%)
Minimal overnight oxygen saturation (%)
Mean oxygen desaturations (%)
Oxygen desaturation index (n/h)
T-IQ
P-IQ
Hyperactive rating scale
Total ADHD rating scale
0.344*
0.295*
q= Brouillette score Wakefulness after sleep onset% First REM latency (min) N1% Arousal index * **
0.32*
0.36*
0.35* 0.31*
0.42**
0.34*
0.447**
p < 0.05. p < 0.005.
SDB enrolled in February and March 2009. Only significant values are reported in Tables 4–6. Fig. 1 shows a sequence of apnea and hypopnea and the occurrence of phase A (after the events) and phase B of CAP (in concomitance with the respiratory events). 3.5. Regression analysis Stepwise linear multiple-regression analysis identified the percentage of wakefulness after sleep onset as the only variable that was significantly correlated positively with the T-IQ and P-IQ, while minimal overnight oxygen saturation was the only variable that correlated negatively with the hyperactive rating scale in all the children with SDB (see Table 7). In children who underwent the CAP analysis, stepwise linear multiple-regression analysis identified the percentage of A2 as the only variable that was positively correlated with the T-IQ and P-IQ, while the A2 index in N3 and in N1, the percentage of A1 and the apnea/hypopnea index were the only variables that correlated positively with the hyperactive rating scale. Overnight oxygen saturation and the apnea/hypopnea index were the only variables that correlated negatively with the hyperactive rating scale. The CAP rate in N2 was the only variable that correlated positively with the total ADHD rating scores (see Table 7).
4. Discussion This study represents, to our knowledge, the first report of a correlation among sleep architecture (including cyclic alternating pattern analysis), sleep respiratory parameters and neurocognitive measures in school-age children with SDB. We found a significant reduction in total, verbal and performance-IQ scores in children affected by both primary snoring and OSAS, compared with normal controls, although the mean IQ estimates remained in the normal range. The lack of difference in the IQ scores between children who snore and those with OSAS confirms previous reports regarding the significant impact of primary snoring on neurocognitive functioning and the lack of correspondence between the severity of SDB and the degree of neurocognitive deficits (Gozal, 2008). The same result was observed in the ADHD rating scale mean scores, which were higher in both groups of SDB subjects than in normal controls, though with no difference between children who snore and those with OSAS. Moreover, cognitive scores did not correlate significantly with sleep respiratory values in children with SDB. The values yielded by the IQ testing and ADHD-rating scales correlated with sleep architecture, CAP analysis and arousal index, thereby confirming the hypothesis that sleep fragmentation and
Table 6 Significant correlations (Spearman coefficient) between cyclic alternating pattern parameters, sleep respiratory parameters and neurocognitive assessment (Total Intelligence Quotient, T-IQ, Verbal Intelligence Quotient, V-IQ, and Performance Intelligence Quotient, P-IT; attention deficit hyperactivity disorder – ADHD-rating scales) in the subgroups of children with sleep-disordered breathing enrolled in February and March 2009. Apnea/hypopnearespiratory related arousals (n/h)
Overnight oxygen saturation (%)
Minimal overnight oxygen saturation (%)
Mean oxygen desaturations (%)
Oxygen desaturation index (n/h)
T-IQ
P-IQ
0.444* 0.445*
0.544* 0.501*
Hyperactive rating scale
Total ADHD rating scale
q= A1 index in N3 A2% A2 index A2 index in N3 A mean duration A1 mean duration A2 mean duration A3 mean duration CAP rate% in N3 * ** °
p < 0.05. p < 0.005. p < 0.001.
0.483* 0.485* 0.541° 0.447*
0.440* 0.662** 0.548° 0.594** 0.481*
0.498* 0.456*
0.590** 0.529*
0.434* 0.533*
0.448*
316
S. Miano et al. / Clinical Neurophysiology 122 (2011) 311–319
Fig. 1. Example of polysomnography illustrating the presence of phases A2, A3 and B in concomitance with a sequence of obstructive apneas; 60-s epochs, 300 lV.
respiratory events during sleep may be involved in the neurocognitive deficits of paediatric SDB. The correlations between CAP measures and neurocognitive function support the hypothesis that sleep disruption, even without respiratory compromise, may be detrimental to neurocognitive function, which represents an alternative means of understanding sleep disruption (Blunden and Beebe, 2006). Sleep respiratory values and CAP parameters were also correlated. Lastly, when we compared the values yielded by the IQ tests and the ADHD rating scale scores in all the subjects investigated, including normal controls, we found a negative correlation between the IQ scores and the overall ADHD rating scale
scores. Although we did not explore the executive functions with specific tests, our results confirm the close relationship between global intelligence and neurobehavioural disorders expressed by diurnal symptoms of inattention and hyperactivity (Tillman et al., 2009). Previous reports suggesting that persistent ADHD may have a negative effect on global intelligence (Biederman et al., 2009) are confirmed by the significant correlation we found between IQ measures and ADHD scores in our sample. This result indicates that the persistence of ADHD symptoms due to SDB may have a negative impact on overall intelligence. Interestingly, one study reported that the attention/alertness level in OSAS patients of ‘‘normal”
Table 7 Stepwise multiple linear regression analysis. Dependent variables
Significant variables
All subjects with sleep-disordered breathing T-IQ Wakefulness after sleep onset % P-IQ Wakefulness after sleep onset % Hyperactive rating scale Minimal overnight oxygen saturation % All subjects with sleep-disordered breathing who underwent CAP analysis T-IQ A2% P-IQ A2% Hyperactive rating scale A2 index in N3 Apnea/hypopnea index (events/hour) A1% Overnight oxygen saturation % A2 index in N1 Total ADHD rating scale
CAP rate % in N2
R2
Standardized beta coefficients
p
0.259 0.217 0.224
1.109 1.169 0.787
0.019 0.033 0.030
0.290 0.488 0.798
1.049 1.569 1.405 0.398 0.756 1.782 0.210
0.012 0.001 0.001 0.006 0.001 0.012 0.022
0.279
0.319
0.014
T-IQ: total intelligent quotient, P-IQ: performance intelligent quotient; CAP: cyclic alternating pattern; ADHD: attention deficit hyperactive disorder. Models 1 and 2 (T-IQ and P-IQ) excluded variables: apnea/hypopnea-respiratory related arousal index/h, overnight oxygen saturation %, minimal overnight oxygen saturation %, mean sleep oxygen desaturations %, oxygen desaturation index n/h, stage shifts n/h, sleep efficiency %, N1%, N2%, N3%, R%, Arousal index (n/h). Model 3 (Hyperactive rating scale) excluded variables: apnea/hypopnea-respiratory related arousal index/h, overnight oxygen saturation %, mean sleep oxygen desaturations, oxygen desaturation index, stage shifts n/h, sleep efficiency %, N1%, N2%, N3%, R%, Arousal index (n/h), wakefulness after sleep onset %. Models 4–5 (T-IQ and P-IQ) excluded variables: apnea/hypopnea-respiratory related arousal index/h, overnight oxygen saturation %, minimal overnight oxygen saturation %, mean sleep oxygen desaturations %, oxygen desaturation index n/h, CAP rate % in NREM sleep and in N1 in N2, in N3, A1%, A3%, A1, A2, A3 indexes (n/h) in NREM sleep and in N1 in N2, in N3, A, A1, A2, A3 mean duration (min), B mean duration (min), sequences mean duration (min), arousal index (n/h). Model 6 (hyperactive rating scale) excluded variables: minimal overnight oxygen saturation %, mean sleep oxygen desaturations %, oxygen desaturation index n/h, CAP rate % in NREM sleep and in N1, in N2, in N3, A2%, A3%, A1, A3 indexes (n/h) in NREM sleep and in N1, in N2, in N3, A2 index in NREM sleep and in N2, A, A1, A2, A3 mean duration (min), B mean duration (min), sequences mean duration (min), arousal index (n/h). Model 7 (total ADHD rating scale) excluded variables: apnea/hypopnea-respiratory related arousal index/h, overnight oxygen saturation %, minimal overnight oxygen saturation %, mean sleep oxygen desaturations %, oxygen desaturation index n/h, CAP rate % in NREM sleep and in N1, in N3, A1%, A2%, A3%, A1, A2, A3 indexes (n/h) in NREM sleep and in N1 in N2, in N3, A, A1, A2, A3 mean duration (min), B mean duration (min), sequences mean duration (min), arousal index (n/h).
S. Miano et al. / Clinical Neurophysiology 122 (2011) 311–319
intelligence was lower than in normal controls, while patients with a high intelligence level did not show attention deficits (Alchanatis et al., 2005). Surprisingly, we found a positive correlation between the IQ scores and the percentage of wakefulness after sleep onset in children with SDB. This result, which was confirmed by regression analysis, cannot be applied to the normal controls because they did not undergo a PSG; we could not consequently glean any information about the relationship between cognitive function and sleep fragmentation in our group of normal controls, though we presume the result would be different in a normal group of children. Indeed, data in the literature clearly demonstrate that sleep disruption is associated with a wide range of behavioural, cognitive and mood impairments (O’Brien, 2009). Furthermore, treatment of sleep disruption, by improving sleep hygiene or treating specific sleep disorders, is often associated with improvements in daytime performance (O’Brien, 2009). Interestingly, one longitudinal study that assessed sleep duration by means of 24-h actigraphic recording in a large community-sample of 7-year-old children showed that IQ and ADHD scores did not differ according to sleep duration (Nixon et al., 2008), while another study that assessed sleep duration by means of a longer actigraphic recording showed that longer habitual sleep duration in healthy school-age participants was associated with a better performance in IQ tests (Gruber et al., 2010). Our findings are apparently in disagreement with the assumption that fragmented sleep might lead to important cognitive problems, as widely hypothesized in paediatric SDB (Chervin et al., 2004; O’Brien et al., 2004a,b; Kheirandish-Gozal et al., 2007). It should, however, be borne in mind that previous studies focused on the behavioural consequences of sleep fragmentation and on the relationship with executive functions (O’Brien et al., 2004a,b), rather than on a possible correlation between sleep architecture and global intelligence in paediatric SDB. We hypothesize that sleep fragmentation may exert a protective role on the brain by counteracting the negative effects of intermittent hypoxia during sleep in paediatric SDB. This hypothesis is supported by animal models showing that hypoxia causes cerebral damage in the prefrontal cortex and hippocampus, and that such damage might be irreversible (Row et al., 2004; Kheirandish et al., 2005). This result is indirectly confirmed by the correlations found between the CAP rate and IQ values in children with SDB: global and performance intelligence correlated positively with the A2 percentage and A2 index. CAP A phases have been subdivided into a 3-stage hierarchy of arousal strength from A1 to A3 (Terzano et al., 2001). Considering that the A2 subtype is defined as the A phase with mixed synchronized and desynchronized EEG patterns, our result seems to lend further support to the afore-mentioned hypothesis, i.e. that arousal mechanisms counteract the respiratory events to preserve cognitive functions at the expense of sleep maintenance and NREM sleep instability. We cannot demonstrate that one variable is correlated with another by a causative factor, nor can we prove the hypothesis that children with a higher overall intelligence have a better capacity to arouse from sleep, although the results of the regression analysis support our hypothesis. A neuroimaging study in children with SDB is warranted to address this issue. Moreover, future studies with a long-term follow-up are warranted to compare the CAP analysis in normal healthy children with that in children with SDB. Although we found few correlations between the ADHD rating scale score and sleep parameters, the total and hyperactivity scores did correlate positively with the A2 index, particularly during sleep stage N3. A positive correlation between the increased CAP rate and behavioural complaints (difficulties at school, hyperactivity, inattention, aggressiveness and irritability) has been reported in children who habitually snore (Lopes and Guilleminault, 2006).
317
In a previous study, we found a lower CAP rate and A1 index in ADHD children without SDB than in normal controls (Miano et al., 2006). In the present study, we did not compare the CAP rate with that of normal controls, although the correlation between the A2 index and ADHD rating scale scores supports the hypothesis that ADHD symptoms in children with SDB are related to sleep fragmentation, particularly during slow-wave sleep (Miano et al., 2006). The regression analysis yielded similar results (positive correlation between hyperactive rating scale and A2 index in N3 and A1 percentage, and between total ADHD rating scale and the CAP rate in N2). Slow-wave activity plays a critical role in both developmental and learning-induced plasticity and is the main component of CAP A1 subtypes, which mapped over the prefrontal cortex and controls executive functions (Ferri et al., 2005; Bruni and Ferri, 2009). We believe that an NREM instability, as expressed by the occurrence of A2 during N3, and by the A1 percentage, may alter this brain function in children with SDB. One interesting pathogenetic model for paediatric OSAS linked NREM sleep instability to alterations in growth hormone secretion during sleep, which may in turn have an impact on neurocognitive deficits (Bruni and Ferri 2009; Gozal et al., 2009). Interestingly, in a previous study the close relationship between attention level and arousal was expressed in terms of the sleep pressure score (O’Brien et al., 2004a,b). The authors reported that the sleep pressure score is a numerical factor derived from spontaneous and respiratory arousals and is associated with deficits in neurobehavioural daytime functions, regardless of the severity of the paediatric SDB (O’Brien et al., 2004a,b). Another study reported changes in microarousals (mainly expressed by delta and theta activity) associated with an improvement in attention levels in children with OSAS following adenotonsillectomy (Chervin et al., 2004). Moreover, the regression analysis in our sample demonstrated that the hyperactivity rating score is negatively correlated with mean and minimal oxygen saturation. This result lends support to our hypothesis that sleep fragmentation due to respiratory events has a neurobehavioural diurnal effect. Although the regression analysis confirmed the results of correlation between neurocognitive measures and sleep parameters, the values of the R2 coefficient of determination limit the strength of these results, so further investigations to confirm our findings are needed. We compared the sleep architecture and respiratory parameters in children who snore with those of OSAS children: as expected, we found a higher AHI and ODI, and a lower mean overnight oxygen saturation, minimal oxygen saturation and mean desaturation in children with OSAS. We also detected some differences in sleep parameters: a lower N3 percentage, a higher REM sleep latency, a higher arousal index and a lower A mean duration in children with OSAS than in snorers. The differences in sleep architecture confirm the findings of a previous study on sleep in paediatric SDB assessed by means of the new AASM criteria (Miano et al., 2010). By contrast, there were no differences in the CAP rate, though OSAS children had a lower mean A phase duration. Although we found differences in sleep quality between snoring and OSAS children, such as a higher arousal index in those with OSAS, the correlation and regression analysis demonstrated that the underlying arousal mechanisms may be the same in both groups of children with SDB. In addition, the comparison between the CAP rates and respiratory parameter values revealed that AHI correlated negatively with the A mean duration and A2 percentage, while it correlated positively with the A2 index and arousal index. These findings may indicate that the occurrence of respiratory events (apnea, hypopnea, respiratory events related arousal) may increase the occurrence of A phases and arousals, reducing their duration (as indirectly expressed by the negative correlation with the A2
318
S. Miano et al. / Clinical Neurophysiology 122 (2011) 311–319
percentage). We also found a positive correlation between the CAP rate during N3 and mean overnight oxygen saturation, which further suggests that the increase in NREM sleep instability is a response designed to counteract respiratory events and desaturations. It has previously been demonstrated that all CAP-related respiratory events arise in close temporal connection with phase B, while effective breathing is always restored during phase A (especially A2 and A3 subtypes) in adults with OSAS (Terzano et al., 1996). The absence of a significant correlation between respiratory events and the A1 phases may be due to the fact that the A1 subtypes, which are characterized by a lower degree of arousability than the other CAP A subtypes (Terzano et al., 2001), might be unable to counteract the effects of sleep respiratory events, their function mainly being related to the building-up and maintenance of sleep, thus preserving cognitive functions (Ferri et al., 2005). Moreover, we found few correlations between the A3 subtypes and respiratory parameters. This finding may be due to the peculiarity of the paediatric age range, in which the A2 phase occurs more frequently as an expression of arousal than the A3 phase (Bruni et al., 2002). This phenomenon has previously been reported in children with SDB, though not expressed within the CAP context: the EEG pattern of arousal activation following an upper airway occlusion may occur in a burst of delta waves or a K complex (which may be the first part of an A2 event) instead of the classical cortical arousal (Moreira et al., 2005). In conclusion, despite the limited number of subjects with SBD investigated, we believe that our study makes an interesting contribution to research on the relationship between sleep fragmentation and cognitive function. Arousal is an important defensive mechanism against sleep-disordered breathing that leads to sleep fragmentation. Many studies have suggested that children with OSAS have an altered sleep microstructure, which is characterised by a significantly enhanced number of movements, EEG arousals, periodic leg movements and increasing NREM instability (Mograss et al., 1994; Scholle and Zwacka, 2001; Moreira et al., 2005; Lopes and Guilleminault, 2006; Miano et al., 2009a). Our results strongly support this hypothesis, and show that, among the SDB children we studied, those with a high level of arousal seem to have a higher degree of protection against the cognitive consequences of sleep respiratory problems; in other words, the higher the arousability, the higher the IQ, the latter also being accompanied, however, by higher diurnal hyperactive and inattentive levels. We may conclude that, on a hypothetical scale of cognitive processes, the attempt to preserve global intelligence in children with SDB has a diurnal cost due to sleep deprivation. Conflict of interest statement None of the authors have any conflict of interest, financial support or off-label and investigational use to disclose. References Alchanatis M, Zias N, Deligiorgis N, Amfilochiou A, Dionellis G, Orphanidou D. Sleep apnea-related cognitive deficits and intelligence: an implication of cognitive reserve theory. J Sleep Res 2005;14:69–75. Beebe DW, Gozal D. Obstructive sleep apnea and the prefrontal cortex: towards a comprehensive model linking nocturnal upper airway obstruction to daytime cognitive and behavioural deficits. J Sleep Res 2002;11:1–16. Biederman J, Petty CR, Ball SW, Fried R, Doyle AE, Cohen D, et al. Are cognitive deficits in attention deficit/hyperactivity disorder related to the course of the disorder? A prospective controlled follow-up study of grown up boys with persistent and remitting course. Psychiatry Res 2009;170: 177–82. Blunden SL, Beebe DW. The contribution of intermittent hypoxia, sleep debt and sleep disruption to daytime performance deficits in children: consideration of respiratory and non-respiratory sleep disorders. Sleep Med Rev 2006;10: 109–18.
Blunden S, Lushington K, Kennedy D, Martin J, Dawson D. Behavior and neurocognitive performance in children aged 5–10 years who snore compared to controls. J Clin Exp Neuropsychol 2000;22:554–68. Brouillette R, Hanson D, David R, Klemka L, Szatkowski A, Fernbach S, et al. A diagnostic approach to suspected obstructive sleep apnea in children. J Pediatr 1984;105:10–4. Bruni O, Ferri R. Neurocognitive deficits in paediatric obstructive sleep apnea: a multifaceted pathogenetic model. Sleep Med 2009;10:161–3. Bruni O, Ferri R, Miano S, Verrillo E, Vittori E, Della Marca G, et al. Sleep cyclic alternating pattern in normal school-age children. Clin Neurophysiol 2002;113:1806–14. Chervin RD, Burns JW, Subotic NS, Roussi C, Thelen B, Ruzicka DL. Correlates of respiratory cycle-related EEG changes in children with sleep-disordered breathing. Sleep 2004;27:116–21. Chervin RD, Ruzicka DL, Archbold KH, Dillon JE. Snoring predicts hyperactivity four years later. Sleep 2005;28:885–90. Decary A, Rouleau I, Montplaisir J. Cognitive deficits associated with sleep apnea syndrome: a proposed neuropsychological test battery. Sleep 2000;23: 369–81. DuPaul GJ, McGoey KE, Eckert TL, VanBrakle J. Preschool children with attentiondeficit/hyperactivity disorder: impairments in behavioral, social, and school functioning. J Am Acad Child Adolesc Psychiatry 2001;40:508–15. Ferri R, Bruni O, Miano S, Terzano MG. Topographic mapping of the spectral components of the cyclic alternating pattern (CAP). Sleep Med 2005;6:29–36. Friedman BC, Hendeles-Amitai A, Kozminsky E, Leiberman A, Friger M, Tarasiuk A, et al. Adenotonsillectomy improves neurocognitive function in children with obstructive sleep apnea syndrome. Sleep 2003;26:999–1005. Gozal D. Obstructive sleep apnea in children: implications for the developing central nervous system. Semin Pediatr Neurol 2008;15:100–6. Gozal D, Pope Jr DW. Snoring during early childhood and academic performance at ages thirteen to fourteen years. Paediatrics 2001;107:1394–9. Gozal D, Sans CO, McLaughlin CV, Serpero LD, Witcher LA, Kheirandish-Gozal L. Plasma IGF 1 levels and cognitive dysfunction in children with obstructive sleep apnea. Sleep Med 2009;10:167–73. Grimaldi A, Lisi F. Wecshler intelligence scale for children: a test of the reliability of the Italian version. Bollettino di Psicologia Applicata 1983;166:41–5. Gruber R, Laviolette R, Deluca P, Monson E, Cornish K, Carrier J. Short sleep duration is associated with poor performance on IQ measures in healthy school-age children. Sleep Med 2010;11:289–94. Guilleminault C, Lee JH, Chan A, Lopes MC, Huang YS, da Rosa A. Non-REM-sleep instability in recurrent sleepwalking in pre-pubertal children. Sleep Med 2005;6:515–21. Iber C, Ancoli-Israel S, Chesson AL, Quan SF. The AASM manual for the scoring of sleep and associated events: rules, terminology, and technical specifications. Westchester, IL: American Academy of Sleep Medicine; 2007. International Classification of Sleep Disorders – ICSD. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005. Kennedy JD, Blunden S, Hirte C, Parsons DW, Martin AJ, Crowe E, et al. Reduced neurocognition in children who snore. Pediatr Pulmonol 2004;37:330–7. Kheirandish L, Gozal D. Neurocognitive dysfunction in children with sleep disorders. Dev Sci 2006;9:388–99. Kheirandish L, Gozal D, Pequignot JM, Pequignot J, Row BW. Intermittent hypoxia during development induces long-term alterations in spatial working memory, monoamines, and dendritic branching in rat frontal cortex. Pediatr Res 2005;58:594–9. Kheirandish-Gozal L, Miano S, Bruni O, Ferri R, Pagani J, Villa MP. Reduced NREM sleep instability in children with sleep disordered breathing. Sleep 2007;30:450–7. Kheirandish-Gozal L, de Jong MR, Spruyt K, Chamuleau SA, Gozal D. Obstructive sleep apnoea is associated with impaired pictorial memory task acquisition and retention in children. Eur Respir J 2010 [Epub ahead of print]. Lopes MC, Guilleminault C. Chronic snoring and sleep in children: a demonstration of sleep disruption. Paediatrics 2006;118:e741–6. Marzocchi GM, Cornoldi C. Una scala di facile uso per la rilevazione dei comportamenti problematici dei bambini con deficit di attenzione e iperattività. Psicologia Clinica dello Sviluppo 2000;4:43–64. Miano S, Donfrancesco R, Bruni O, Ferri R, Galiffa S, Pagani J, et al. NREM sleep instability is reduced in children with attention-deficit/hyperactivity disorder. Sleep 2006;29:797–803. Miano S, Rizzoli A, Evangelisti M, Bruni O, Ferri R, Villa MP. NREM sleep instability changes following rapid maxillary expansion in children with obstructive apnea sleep syndrome. Sleep Med 2009a;10:471–8. Miano S, Paolino MC, Peraita-Adrados R, Montesano M, Barberi S, Villa MP. Prevalence of EEG paroxysmal activity in a population of children with obstructive sleep apnea syndrome. Sleep 2009b;32:522–9. Miano S, Paolino MC, Castaldo R, Villa MP. Visual scoring of sleep: a comparison between the Rechtschaffen and Kales criteria and the American Academy of Sleep Medicine criteria in a paediatric population with obstructive sleep apnea syndrome. Clin Neurophysiol 2010;121:39–42. Mitchell RB, Kelly J. Long-term changes in behavior after adenotonsillectomy for obstructive sleep apnea syndrome in children. Otolaryngol Head Neck Surg 2006;134:374–8. Mograss MA, Ducharme FM, Brouillette RT. Movement/arousals: description, classification, and relationship to sleep apnea in children. Am J Respir Crit Care Med 1994;150:1690–6. Montgomery-Downs HE, Crabtree VM, Gozal D. Cognition, sleep and respiration in atrisk children treated for obstructive sleep apnoea. Eur Respir J 2005;25:336–42.
S. Miano et al. / Clinical Neurophysiology 122 (2011) 311–319 Moreira GA, Tufik S, Nery LE, Lutz J, Verfaille K, Luan X, et al. Acoustic arousal responses in children with obstructive sleep apnea. Pediatr Pulmonol 2005;40:300–5. Nixon GM, Thompson JM, Han DY, Becroft DM, Clark PM, Robinson E, et al. Short sleep duration in middle childhood: risk factors and consequences. Sleep 2008;31:71–8. O’Brien LM. The neurocognitive effects of sleep disruption in children and adolescents. Child Adolesc Psychiatr Clin N Am 2009;18:813–23. O’Brien LM, Gozal D. Sleep in children with attention deficit/hyperactivity disorder. Minerva Pediatr 2004;56:585–601. O’Brien LM, Mervis CB, Holbrook CR, Bruner JL, Smith NH, McNally N, et al. Neurobehavioral correlates of sleep-disordered breathing in children. J Sleep Res 2004a;13:165–72. O’Brien LM, Tauman R, Gozal D. Sleep pressure correlates of cognitive and behavioral morbidity in snoring children. Sleep 2004b;15(27):279–82. Owens-Stively J, Frank N, Smith A, Hagino O, Spirito A, Arrigan M, et al. Child temperament, parenting discipline style, and daytime behavior in childhood sleep disorders. J Dev Behav Pediatr 1997;18:314–21. Row BW, Kheirandish L, Li RC, Guo SZ, Brittian KR, Hardy M, et al. Platelet-activating factor receptor-deficient mice are protected from experimental sleep apneainduced learning deficits. J Neurochem 2004;89:189–96.
319
Rubini V, Padovani F. WISC-R Scala di Intelligenza Wechsler per bambini riveduta. Organizzazioni Speciali. Florence; 1986 [in Italian]. Scholle S, Zwacka G. Arousals and obstructive sleep apnea syndrome in children. Clin Neurophysiol 2001;112:984–91. Statistical Manual of Mental Disorders. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington: American Psychiatric Association; 1994. Termine C, Balottin U, Nicoli F, Zopello M, Lanzi G. Verbal performance intelligence quotient discrepancies on the Wecshler scales: are they still useful? Literature review and clinical implications. Minerva Psichiatrica 2005;46:209–19. Terzano MG, Parrino L, Boselli M, Spaggiari MC, Di Giovanni G. Polysomnographic analysis of arousal responses in obstructive sleep apnea syndrome by means of the cyclic alternating pattern. J Clin Neurophysiol 1996;13:145–55. Terzano MG, Parrino L, Smerieri A, Chervin R, Chokroverty S, Guilleminault C, et al. Atlas, rules, and recording techniques for the scoring of cyclic alternating pattern (CAP) in human sleep. Sleep Med 2001;2:537–53. Tillman CM, Bohlin G, Sørensen L, Lundervold AJ. Intellectual deficits in children with ADHD beyond central executive and non-executive functions. Arch Clin Neuropsychol 2009;24:769–82. Wechsler D. Wechsler intelligence scale for children-revised. New York: The Psychological Corporation; 1973.
Contents lists available at ScienceDirect
Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Neurocognitive assessment and sleep analysis in children with sleep-disordered breathing Silvia Miano, Maria Chiara Paolino, Antonella Urbano, Pasquale Parisi, Anna Claudia Massolo, Rosa Castaldo, Maria Pia Villa * Department of Paediatrics, Sleep Disease Centre, La Sapienza University of Rome – Sant’Andrea Hospital, Rome, Italy
a r t i c l e
i n f o
Article history: Accepted 24 June 2010 Available online 15 July 2010 Keywords: Children Sleep breathing disorder Intelligent quotient Attention deficit hyperactive disorder Cyclic alternating pattern analysis
a b s t r a c t Objective: To assess possible correlations between intelligence quotient (IQ) and attention deficit hyperactive disorder (ADHD) rating scale values and sleep (including cyclic alternating patterns analysis) and respiratory parameters in children with sleep-disordered breathing (SDB). Methods: Thirteen children who satisfied the criteria for primary snoring and 31 children for obstructive sleep apnea syndrome (OSAS) underwent polysomnography in a standard laboratory setting and a neurocognitive assessment. Sixty normal controls recruited from two schools underwent the neurocognitive assessment. Results: The IQ estimates of controls were higher and the ADHD rating scale scores lower than those of children with SDB. Children with OSAS had a higher REM sleep latency and arousal index as well as a lower N3 and A mean duration than children who snored. In our sample of children with SDB, the percentage of wakefulness after sleep onset, of N1, of A2, of arousal and A2 index correlated positively with global intelligence. Total and hyperactivity scores correlated positively with the A2 index. Regression analysis mostly confirmed the correlations between neurocognitive measures and sleep parameters and further demonstrated a negative correlation between the hyperactivity rating score and oxygen saturation during the night. Conclusions: Our results support the hypothesis that arousal is a defensive mechanism that may preserve cognitive function by counteracting the respiratory events, at the expense of sleep maintenance and NREM sleep instability. Significance: We believe that our study makes an interesting contribution to research on the relationship between sleep fragmentation and cognitive function. Ó 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Children with sleep-disordered breathing (SDB) are affected by diurnal neurobehavioural problems, such as attention deficit and hyperactive disorder (ADHD), learning problems, behavioural disorders and hypersomnolence (Chervin et al., 2005; Gozal, 2008). Although a significant improvement in diurnal neurobehavioural disorders following adenotonsillectomy has been demonstrated (Owens-Stively et al., 1997; Montgomery-Downs et al., 2005; Mitchell and Kelly, 2006; Gozal, 2008), the relationship between SDB severity and cognitive deficits is usually weak (Decary et al., 2000; Friedman et al., 2003), and a ‘‘learning debt” may develop as a consequence of SDB (Gozal and Pope, 2001).
* Corresponding author. Address: Paediatric Clinic, Sant’Andrea Hospital, Via Grottarossa 1035/1039 – 00189 Rome, Italy. Tel.: +39 0633775855; fax: +39 0633775941. E-mail address: [email protected] (M.P. Villa).
Findings from previous studies suggest that intermittent hypoxia during sleep, respiratory events and sleep fragmentation are the main causative factors of the diurnal neurocognitive consequences of obstructive sleep apnea syndrome (OSAS) (Chervin et al., 2004; Kheirandish and Gozal, 2006). A large cohort study demonstrated that the degree of hypoxemia correlates preferentially with deficits in executive function (Kheirandish and Gozal, 2006), whereas the magnitude of sleep fragmentation, as expressed by the number of arousals during sleep in response to respiratory events, appears to account for changes in attention and memory deficits (O’Brien and Gozal, 2004; O’Brien et al., 2004a,b; Kennedy et al., 2004; Kheirandish-Gozal et al., 2010). The neurocognitive phenotype of paediatric OSAS may reflect a dysfunction in the prefrontal cortex, which controls executive functions and contains the brain areas that mature last, and might thus be susceptible to OSA-mediated injury (Beebe and Gozal, 2002). In addition, several studies have reported reduced intelligence quotient (IQ) scores in children with OSAS, the majority of whom exhibits a lower normal or borderline performance (Blunden et al., 2000; O’Brien et al., 2004a).
1388-2457/$36.00 Ó 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2010.06.019
312
S. Miano et al. / Clinical Neurophysiology 122 (2011) 311–319
The same PFC regions generate slow oscillations during NREM sleep (Terzano et al., 2001), which are the main components of the A1 subtypes of the so-called cyclic alternating pattern (CAP) and map over the frontal and prefrontal regions of the scalp (Ferri et al., 2005). The few data available on CAP in paediatric SDB are somewhat contradictory (Guilleminault et al., 2005; Lopes and Guilleminault, 2006; Kheirandish-Gozal et al., 2007; Miano et al. 2009a). In one study, children with SDB had a lower CAP rate, particularly during slow-wave sleep, with no clear increase in the number of arousals if compared with normal controls (Kheirandish-Gozal et al., 2007). By contrast, Lopes and Guilleminault (2006) found an increased CAP rate in children who snored, as well as in sleepwalking children with SBD (Guilleminault et al., 2005). Moreover, a positive correlation between the increased CAP rate and behavioural complaints was found in children who habitually snored (Lopes and Guilleminault, 2006). We also reported a higher CAP rate during slow-wave sleep and an increased A2 index in children with OSAS compared with normal controls (Miano et al., 2009a,b), and a lower CAP rate and lower A1 index during slowwave sleep in children with OSAS and EEG abnormalities compared with those without EEG abnormalities (Miano et al., 2009b). However, not only have these subtle changes in sleep architecture not yet been fully understood, but few studies have investigated the correlation between CAP values and neurocognitive dysfunction. The true significance of NREM sleep alterations thus remains speculative. The aim of our study was to measure IQ by means of a standardized test and to measure ADHD symptoms by means of a standardized questionnaire in a large group of children with SDB (primary snoring and obstructive sleep apnea syndrome) and to compare these data with the children’s polysomnographic parameters (including sleep stages, CAP and EEG arousal analysis). 2. Materials and methods 2.1. Subjects We consecutively enrolled children undergoing a diagnostic assessment for OSAS in our Paediatric Sleep Centre (Rome, Italy) because of habitual snoring, apnea or restless sleep, as witnessed by their parents. The diagnosis of OSAS was confirmed by means of a laboratory polysomnography (PSG) revealing an obstructive apnea/hypopnea index (AHI) > 1, according to the criteria of the American Academy of Sleep Medicine (AASM, 2005). Primary snoring was diagnosed in children with habitual snoring, an AHI <1 and microphone-detected snoring. Children were enrolled between February 2009 and June 2009. Patients with a history of epilepsy, EEG abnormalities, previous treatment for OSAS (including tonsillectomy and adenoidectomy), acute or chronic cardiorespiratory or neuromuscular diseases, dysmorphism, major craniofacial abnormalities or chromosomal syndromes were excluded. A detailed personal and family history was obtained for all the participants and a clinical examination performed. The participants’ parents completed the Brouillette questionnaire on symptoms of OSAS (Brouillette et al., 1984). The questionnaire comprised questions on sleep, breathing during sleep, medical diagnoses and previous surgery. Likelihood ratios for OSAS scores were: a score < 1 predicted no OSAS; a score from 1 to 3.5 was considered to be inconclusive; a score >3.5 predicted the presence of OSAS. 2.2. Cognitive assessment The ADHD Rating Scale, adapted for the Italian population, was filled out by the parents of participants (Marzocchi and Cornoldi, 2000; DuPaul et al., 2001). It consists of 18 items, divided into
two subgroups of nine questions that investigate inattention and hyperactivity symptoms. Intelligence (IQ) estimates were obtained using the Wechsler Intelligence Scale for Children – Third Edition Revised (WISC-R, 1973; Rubini and Padovani, 1986). The WISC-R has been translated into Italian, uses Italian-based norms (Termine et al., 2005), and has demonstrated a level of reliability that is equal to the English version (Grimaldi and Lisi, 1983). Administration of the WISC-R, which is validated for children between the ages of 6 and 16 years, usually requires 75–80 min. The test comprises 10 core subtests and two supplemental tests. These subtests generate a full scale score (Total Intelligence Quotient, T-IQ), and two composite scores known as indexes: the Verbal Intelligence quotient (V-IQ) and the Performance Intelligence Quotient (P-IQ). The IQ testing was performed on the morning before the sleep study. A Wechsler score <70 was considered to indicate mental retardation, while a Wechsler score <85 was considered to indicate borderline intellectual functioning, according to the Statistical Manual of Mental Disorders, Fourth Edition axis II diagnosis (1994). Sixty normal age- and sex-matched controls (22 males, mean years of age 9.1 ± 2.4 S.D.) were recruited. The control children came from two schools that were in the same urban area as the subjects with SDB, were of Caucasian origin and middle socioeconomic status. The IQ estimates were obtained using the WISC-R, which was administered in the morning at school. The parents of the control children were also asked to fill out the ADHD-rating scales. The control subjects were recruited between January 2006 and December 2006. Inclusion criteria were: normal healthy prepubertal children who were attending local schools and had normal sleep habits; these criteria were confirmed by means of interviews with both the parents and child. None of the controls was obese or had any serious physical, neurological or psychiatric disorder. No history of major sleep problems was reported, and none was taking medication at the time of testing. The local ethics committee approved the study protocol and all children’s parents gave their informed consent to the procedures. 2.3. Polysomnography and sleep stage scoring All the patients underwent a full-night PSG in our Sleep Centre after one adaptation night. Standard overnight PSG recordings were obtained using a Grass Heritage polygraph. The variables recorded included at least a 6channel electroencephalogram (bilateral frontal, central temporal and occipital monopolar montages referred to the controlateral mastoid); electro-oculogram (electrodes placed 1 cm above the right outer cantus and 1 cm below the left outer cantus and referred to A1), submental electromyogram and electrocardiogram (1 derivation). Sleep was subdivided into 30-s epochs, and sleep stages were scored according to the standard criteria of the AASM (Iber et al., 2007). The following sleep parameters were measured: sleep latency, defined as the time between light out and the first epoch of any sleep stage in minutes; total sleep time, defined as the time from sleep onset to the end of the final sleep; sleep period time, defined as total sleep time minus time awake after sleep onset; sleep efficiency, defined as the percentage ratio between total sleep time and total recording time (from lights out clock time to lights on clock time); wakefulness after sleep onset, defined as the time spent awake between sleep onset and the end of sleep; lastly, the number of stage shifts per hour of sleep. The percentage of total sleep time in each stage was measured as follows: percentage of stage N1, stage N2, stage N3, and stage R (REM sleep).
313
S. Miano et al. / Clinical Neurophysiology 122 (2011) 311–319
2.4. CAP scoring
2.6. Sleep respiration analysis
CAP was scored according to the criteria by Terzano et al. (2001). CAP is periodic EEG activity in NREM sleep characterized by repeated spontaneous sequences of transient events (phase A) that clearly break away from the background rhythm of the ongoing sleep stage, with an abrupt frequency/amplitude variation, and recur at intervals that last up to 1 min. The return to the background activity identifies the interval that separates the repetitive elements (phase B). CAP A phases have been subdivided into three different subtypes:
Central, obstructive and mixed apnea events were counted according to the criteria established by the AASM (AASM, 2005; Iber et al., 2007). Obstructive apnea was scored when there was a >90% drop in the signal amplitude of airflow for >90% of the entire event, compared with the pre-event baseline amplitude, with continued chest wall and abdominal movement, for a duration of at least two breaths. Central apnea was defined as the absence of airflow, with the cessation of respiratory effort, lasting more than 20 s or lasting at least two missed breaths (or the duration of two baseline breaths), associated with an arousal, an awakening or a >3% desaturation; central apnea occurring after gross body movements or after sighs was not considered as a pathological finding. Mixed apnea was defined as apnea that usually began as central and ended in obstruction, according to changes in the chest, abdominal and flow traces. An event could be scored as hypopnea if there was a >50% drop in airflow signal amplitude compared with the pre-event baseline amplitude for at least 90% of the duration of the event; the event had to last at least two missed breaths and be associated with an arousal, awakening or a >3% desaturation. Chest and abdomen movements were measured by strain gauges. Oronasal airflow was recorded by means of a thermocouple and nasal pressure. Arterial oxygen saturation was monitored with a pulse oximeter. The apnea/ hypopnea index (AHI) was defined as the average number of apneas, hypopneas and respiratory event-related arousals per hour of sleep. All recordings started at the patients’ usual bedtime and continued until spontaneous awakening. All recordings were scored visually by one of the investigators (SM), who was blinded to the subject’s group, age and sex.
1. A1 – A phases with synchronized EEG patterns (intermittent alpha rhythm in stage 1; sequences of K complexes or delta bursts in the other NREM stages), associated with mild or trivial polygraphic variations; 2. A2 – A phases with desynchronized EEG patterns preceded by or mixed with slow high-voltage waves (K complexes with alpha and beta activities, k-alpha, arousals with slow-wave synchronization), associated with a moderate increase in muscle tone and/or cardiorespiratory rate; 3. A3 – A phases with desynchronized EEG patterns alone (transient activation phases or arousals) or exceeding 2/3 of the phase A length, associated with a remarkable enhancement in muscle tone and/or cardiorespiratory rate. The following CAP parameters were measured: CAP time (sum of the length of all CAP sequences, in minutes); in NREM sleep CAP rate of total NREM sleep time occupied by CAP sequences; number and mean duration of CAP cycles (phase A + phase B); number and mean duration of CAP sequences, number, mean duration and percentage of A phases (including phase A subtypes); A1, A2 and A3 index (number of A1, A2 or A3 phases of NREM sleep per hour, and of stages N1 and N2 and N3 per hour of sleep); number and mean duration of B phases. All these variables were detected visually and their parameters measured by means of the Hypnolab 1.0 sleep analysis software (SWS Soft, Italy). Owing to its complex and time-consuming nature, we only performed the CAP analysis in a subgroup of children (those enrolled in the first 2 months of the study, in February and March 2009). 2.5. Arousal analysis Arousals were detected visually according to the criteria reported in the recent manual for the scoring of sleep and associated events by the AASM (Iber et al., 2007).
2.7. Statistical analysis Data are expressed as mean ± SD. The Mann–Whitney U or v2 test was chosen, when appropriate, to compare data. The Spearman rank correlation coefficient was used to assess the relationships between the PSG parameters and behavioural/cognitive measures. A multiple linear regression analysis (stepwise method) was performed to explore any correlations between sleep and respiratory parameters, arousal index and CAP parameters (independent variables), and IQ measures and ADHD scores (dependent variables). Differences and correlations were considered as statistically significant when p < 0.05. The statistical analysis was performed using a commercial software package (SPSS, version 11; SPSS; Chicago, IL).
Table 1 Anthropometric and clinical characteristics of all subjects, as well as verbal intelligence quotient (V-IQ), performance (P-IQ) and total IQ (T-IQ) scores, attention deficit, hyperactive disorder (ADHD) rating scales scores of normal controls, children with primary snoring (PS) and with obstructive sleep apnea syndrome (OSAS).
Mean Age (years) Body mass index (kg/m2) Duration of disease (years) Brouillette score T-IQ V-IQ P-IQ Hyperactive rating scale Inattention rating scale Total ADHD rating scale
9.8 18.3 – – 115.5 118.2 109.7 1.8 1.5 3.3
(c) OSAS (n = 31)
(b) PS (n = 13)
(a) Controls (n = 60) SD 2.4 1.8 – – 10.8 11.7 11.8 1.3 1.7 2.5
Kruskall–Wallis
Mann–Whitney p<
Mean
SD
Mean
SD
p<
a vs b
a vs c
b vs c
8.6 18.2 3.9 0.8 94.8 91.1 100.5 9.5 6.8 16.3
1.9 3.6 3.1 2.3 8.9 12.2 9.9 6.3 6.5 11.6
9.1 19.6 4.1 0.7 98.2 96.5 101.0 9.1 8.5 17.6
2.3 3.6 2.9 2.2 12.4 14.4 14.8 6.5 6.4 11.4
NS NS – – 0.001 0.001 0.005 0.001 0.001 0.001
– – 0.001 0.001 0.05 0.001 0.005 0.001
– – 0.001 0.001 0.005 0.001 0.001 0.001
NS NS NS NS NS NS NS NS
314
S. Miano et al. / Clinical Neurophysiology 122 (2011) 311–319
Table 2 Respiratory and sleep parameter values in children with primary snoring (PS) and with obstructive sleep apnea syndrome (OSAS). RP (n = 13) Mean Apnea/hypopnea-respiratory related arousal index/h (n/h) Overnight oxygen saturation (%) Minimal overnight oxygen saturation Mean sleep oxygen desaturations (%) Oxygen desaturation index (n/h) Sleep period time (min) Total sleep time (min) Sleep latency (min) REM latency (min) Stage shifts (n/h) Sleep efficiency (%) Wakefulness after sleep onset (min) Wakefulness after sleep onset (%) N1 (%) N2 (%) N3 (%) R (%) Arousal index (n/h)
0.5
OSAS (n = 31) SD 0.3
Mean 8.2
Mann– Whitney SD 9.9
Table 3 Cyclic alternating patterns (CAP) parameter values and arousal index in the subgroup of children with primary snoring (PS) and with obstructive sleep apnea syndrome (OSAS) enrolled in February and March 2009. PS (n = 10)
p<
Mean
0.001
97.2 95.4
1.2 2.8
96.9 90.9
1.7 4.5
NS 0.005
96.1
2.1
93.6
2.6
0.005
0.1 397.4 419.6 25.2 110.7 10.2 85.9 43.9
0.3 58.5 56.5 21.0 51.5 2.9 12.5 57.5
2.1 395.7 423.8 25.9 146.3 10.4 87.0 34.2
3.5 46.5 44.1 15.9 54.0 2.9 7.6 32.5
0.001 NS NS NS 0.05 NS NS NS
5.3 8.6 31.7 35.5 18.8 9.8
4.9 3.6 6.8 5.1 4.2 3.7
6.4 9.3 34.3 30.1 19.3 14.9
6.5 4.1 9.7 7.4 5.9 7.9
NS NS NS 0.05 NS 0.05
3.1. Clinical and anthropometric parameters, ADHD rating scale scores and WISC-R scale IQ estimates (Table 1) In total, 13 children met the criteria for primary snoring (8 males, mean age in years: 8.6 ± 1.9 S.D.) while 31 children met the criteria for OSAS (18 males, mean age in years: 9.1 ± 2.3 S.D.); all the subjects were of Caucasian origin and of middle socioeconomic status. No differences were found between snorers and children with OSAS in disease duration, Brouillette scores, V-IQ, P-IQ, T-IQ or ADHD rating scale scores. The IQ estimates of normal controls were significantly higher and the hyperactive and ADHD rating scale scores lower than those of both groups of children with SDB. 3.2. Sleep architecture and respiratory parameters (Table 2) No significant differences emerged in sleep macrostructure if we exclude the fact that children with OSAS had a higher REM sleep latency and a lower N3 percentage than snorers.
SD
Mean
Mann– Whitney SD
p<
CAP rate (%) In N1 In N2 In N3
39.2 28.8 17.7 60.9
13.6 11.3 10.5 21.5
41.5 33.0 26.4 67.0
15.4 18.4 25.3 23.2
NS NS NS NS
A1% A2% A3%
80.9 9.8 9.2
7.9 5.1 3.0
76.7 12.6 11.0
9.5 7.6 4.1
NS NS NS
A1 index (n/h) In N1 In N2 In N3
47.7 7.6 26.0 90.4
20.1 4.5 15.5 33.7
52.2 6.8 26.1 113.1
26.1 5.2 14.9 34.4
NS NS NS NS
A2 index (n/h) In N1 In N2 In N3
4.9 14.6 5.1 3.8
1.9 6.2 3.1 1.5
7.4 17.2 5.4 8.7
3.9 13.3 3.1 7.8
NS NS NS NS
A3 index (n/h) In N1 In N2 In N3
3.4 32.6 3.4 1.5
1.3 11.9 1.9 0.7
4.7 41.8 2.9 1.7
3.6 20.8 1.8 1.2
NS NS NS NS
8.6 7.4 11.8 16.3 19.8 291.8
1.2 1.1 3.1 3.1 3.3 106.1
7.1 6.0 9.2 13.2 19.9 326.3
0.8 1.2 1.2 2.1 3.8 140.4
10.6
3.8
14.9
5.4
A mean duration (min) A1 mean duration (min) A2 mean duration (min) A3 mean duration (min) B mean duration (min) Sequences mean duration (min) Arousal index (n/h)
3. Results
OSAS (n = 11)
0.005 0.05 0.05 0.05 NS NS 0.05
3.4. Correlation analyses ADHD scores correlated negatively with IQ measures in all the subjects, while the percentage of wakefulness after sleep onset, of N1, of A2 and of the arousal and A2 indexes correlated positively with global intelligence in children with SDB. Total and hyperactivity scores correlated positively with the A2 index in N3. Table 4 shows the correlation coefficients between measures yielded by the neurocognitive assessment in all the subjects with SDB and in normal controls. Table 5 shows the correlation coefficients yielded by the sleep and respiratory parameters (including the arousal index) and neurocognitive assessment in all the subjects with SDB. Table 6 shows the correlation coefficients between the measures yielded by the CAP parameters, sleep respiratory parameters and neurocognitive assessment in the subgroups of children with
3.3. Results of sleep parameters and CAP analysis (Table 3) The subgroup of children who underwent CAP analysis comprised 23 children. Children with OSAS (13 subjects, 8 males; mean age in years 9.1 ± 3.1 S.D.) had a lower percentage of N3 (27.3 ± 8.7 vs 35.6 ± 5.4, p < 0.05), of minimal overnight oxygen saturation (90.5 ± 3.6 vs 95.8 ± 2.9, p < 0.05) and of mean desaturation (93.9 ± 1.5 vs 96.6 ± 2.0, p < 0.05) as well as a higher AHI (9.9 ± 8.2 vs 0.5 ± 0.3, p < 0.01) and ODI (1.9 ± 2.0 vs 0.2 ± 0.4) than snorers (10 subjects, 8 males, mean age in years 8.6 ± 2.3 S.D.). Children with OSAS had a lower A phase mean duration, a lower mean duration of each A phase subtype and a higher arousal index higher than children who snored. No differences were found in disease duration, Brouillette scores, V-IQ, P-IQ, T-IQ or ADHD rating scale scores.
Table 4 Significant correlations (Spearman coefficient) between ADHD (attention deficit hyperactivity disorder) rating scale scores and Total Intelligence Quotient, (T-IQ), Verbal Intelligence Quotient (V-IQ), and Performance Intelligence Quotient (P-IT) scores in all the children investigated (normal controls and subjects with sleepdisordered breathing). T-IQ
V-IQ
P-IQ
q= Hyperactive rating scale Inattention rating scale Total ADHD rating scale *
p < 0.05. p < 0.001. °° p = 0.07. °
0.432° 0.362° 0.464°
0.495° 0.419° 0.521°
0.161°° 0.202*
315
S. Miano et al. / Clinical Neurophysiology 122 (2011) 311–319
Table 5 Significant correlations (Spearman coefficient) between sleep parameters (including arousal index) and respiratory parameters and neurocognitive assessment (Total Intelligence Quotient, T-IQ, Verbal Intelligence Quotient, V-IQ, and Performance Intelligence Quotient, P-IT; attention deficit hyperactivity disorder – ADHD – rating scales) in all the children with sleep-disordered breathing. Apnea/hypopnearespiratory related arousals (n/h)
Overnight oxygen saturation (%)
Minimal overnight oxygen saturation (%)
Mean oxygen desaturations (%)
Oxygen desaturation index (n/h)
T-IQ
P-IQ
Hyperactive rating scale
Total ADHD rating scale
0.344*
0.295*
q= Brouillette score Wakefulness after sleep onset% First REM latency (min) N1% Arousal index * **
0.32*
0.36*
0.35* 0.31*
0.42**
0.34*
0.447**
p < 0.05. p < 0.005.
SDB enrolled in February and March 2009. Only significant values are reported in Tables 4–6. Fig. 1 shows a sequence of apnea and hypopnea and the occurrence of phase A (after the events) and phase B of CAP (in concomitance with the respiratory events). 3.5. Regression analysis Stepwise linear multiple-regression analysis identified the percentage of wakefulness after sleep onset as the only variable that was significantly correlated positively with the T-IQ and P-IQ, while minimal overnight oxygen saturation was the only variable that correlated negatively with the hyperactive rating scale in all the children with SDB (see Table 7). In children who underwent the CAP analysis, stepwise linear multiple-regression analysis identified the percentage of A2 as the only variable that was positively correlated with the T-IQ and P-IQ, while the A2 index in N3 and in N1, the percentage of A1 and the apnea/hypopnea index were the only variables that correlated positively with the hyperactive rating scale. Overnight oxygen saturation and the apnea/hypopnea index were the only variables that correlated negatively with the hyperactive rating scale. The CAP rate in N2 was the only variable that correlated positively with the total ADHD rating scores (see Table 7).
4. Discussion This study represents, to our knowledge, the first report of a correlation among sleep architecture (including cyclic alternating pattern analysis), sleep respiratory parameters and neurocognitive measures in school-age children with SDB. We found a significant reduction in total, verbal and performance-IQ scores in children affected by both primary snoring and OSAS, compared with normal controls, although the mean IQ estimates remained in the normal range. The lack of difference in the IQ scores between children who snore and those with OSAS confirms previous reports regarding the significant impact of primary snoring on neurocognitive functioning and the lack of correspondence between the severity of SDB and the degree of neurocognitive deficits (Gozal, 2008). The same result was observed in the ADHD rating scale mean scores, which were higher in both groups of SDB subjects than in normal controls, though with no difference between children who snore and those with OSAS. Moreover, cognitive scores did not correlate significantly with sleep respiratory values in children with SDB. The values yielded by the IQ testing and ADHD-rating scales correlated with sleep architecture, CAP analysis and arousal index, thereby confirming the hypothesis that sleep fragmentation and
Table 6 Significant correlations (Spearman coefficient) between cyclic alternating pattern parameters, sleep respiratory parameters and neurocognitive assessment (Total Intelligence Quotient, T-IQ, Verbal Intelligence Quotient, V-IQ, and Performance Intelligence Quotient, P-IT; attention deficit hyperactivity disorder – ADHD-rating scales) in the subgroups of children with sleep-disordered breathing enrolled in February and March 2009. Apnea/hypopnearespiratory related arousals (n/h)
Overnight oxygen saturation (%)
Minimal overnight oxygen saturation (%)
Mean oxygen desaturations (%)
Oxygen desaturation index (n/h)
T-IQ
P-IQ
0.444* 0.445*
0.544* 0.501*
Hyperactive rating scale
Total ADHD rating scale
q= A1 index in N3 A2% A2 index A2 index in N3 A mean duration A1 mean duration A2 mean duration A3 mean duration CAP rate% in N3 * ** °
p < 0.05. p < 0.005. p < 0.001.
0.483* 0.485* 0.541° 0.447*
0.440* 0.662** 0.548° 0.594** 0.481*
0.498* 0.456*
0.590** 0.529*
0.434* 0.533*
0.448*
316
S. Miano et al. / Clinical Neurophysiology 122 (2011) 311–319
Fig. 1. Example of polysomnography illustrating the presence of phases A2, A3 and B in concomitance with a sequence of obstructive apneas; 60-s epochs, 300 lV.
respiratory events during sleep may be involved in the neurocognitive deficits of paediatric SDB. The correlations between CAP measures and neurocognitive function support the hypothesis that sleep disruption, even without respiratory compromise, may be detrimental to neurocognitive function, which represents an alternative means of understanding sleep disruption (Blunden and Beebe, 2006). Sleep respiratory values and CAP parameters were also correlated. Lastly, when we compared the values yielded by the IQ tests and the ADHD rating scale scores in all the subjects investigated, including normal controls, we found a negative correlation between the IQ scores and the overall ADHD rating scale
scores. Although we did not explore the executive functions with specific tests, our results confirm the close relationship between global intelligence and neurobehavioural disorders expressed by diurnal symptoms of inattention and hyperactivity (Tillman et al., 2009). Previous reports suggesting that persistent ADHD may have a negative effect on global intelligence (Biederman et al., 2009) are confirmed by the significant correlation we found between IQ measures and ADHD scores in our sample. This result indicates that the persistence of ADHD symptoms due to SDB may have a negative impact on overall intelligence. Interestingly, one study reported that the attention/alertness level in OSAS patients of ‘‘normal”
Table 7 Stepwise multiple linear regression analysis. Dependent variables
Significant variables
All subjects with sleep-disordered breathing T-IQ Wakefulness after sleep onset % P-IQ Wakefulness after sleep onset % Hyperactive rating scale Minimal overnight oxygen saturation % All subjects with sleep-disordered breathing who underwent CAP analysis T-IQ A2% P-IQ A2% Hyperactive rating scale A2 index in N3 Apnea/hypopnea index (events/hour) A1% Overnight oxygen saturation % A2 index in N1 Total ADHD rating scale
CAP rate % in N2
R2
Standardized beta coefficients
p
0.259 0.217 0.224
1.109 1.169 0.787
0.019 0.033 0.030
0.290 0.488 0.798
1.049 1.569 1.405 0.398 0.756 1.782 0.210
0.012 0.001 0.001 0.006 0.001 0.012 0.022
0.279
0.319
0.014
T-IQ: total intelligent quotient, P-IQ: performance intelligent quotient; CAP: cyclic alternating pattern; ADHD: attention deficit hyperactive disorder. Models 1 and 2 (T-IQ and P-IQ) excluded variables: apnea/hypopnea-respiratory related arousal index/h, overnight oxygen saturation %, minimal overnight oxygen saturation %, mean sleep oxygen desaturations %, oxygen desaturation index n/h, stage shifts n/h, sleep efficiency %, N1%, N2%, N3%, R%, Arousal index (n/h). Model 3 (Hyperactive rating scale) excluded variables: apnea/hypopnea-respiratory related arousal index/h, overnight oxygen saturation %, mean sleep oxygen desaturations, oxygen desaturation index, stage shifts n/h, sleep efficiency %, N1%, N2%, N3%, R%, Arousal index (n/h), wakefulness after sleep onset %. Models 4–5 (T-IQ and P-IQ) excluded variables: apnea/hypopnea-respiratory related arousal index/h, overnight oxygen saturation %, minimal overnight oxygen saturation %, mean sleep oxygen desaturations %, oxygen desaturation index n/h, CAP rate % in NREM sleep and in N1 in N2, in N3, A1%, A3%, A1, A2, A3 indexes (n/h) in NREM sleep and in N1 in N2, in N3, A, A1, A2, A3 mean duration (min), B mean duration (min), sequences mean duration (min), arousal index (n/h). Model 6 (hyperactive rating scale) excluded variables: minimal overnight oxygen saturation %, mean sleep oxygen desaturations %, oxygen desaturation index n/h, CAP rate % in NREM sleep and in N1, in N2, in N3, A2%, A3%, A1, A3 indexes (n/h) in NREM sleep and in N1, in N2, in N3, A2 index in NREM sleep and in N2, A, A1, A2, A3 mean duration (min), B mean duration (min), sequences mean duration (min), arousal index (n/h). Model 7 (total ADHD rating scale) excluded variables: apnea/hypopnea-respiratory related arousal index/h, overnight oxygen saturation %, minimal overnight oxygen saturation %, mean sleep oxygen desaturations %, oxygen desaturation index n/h, CAP rate % in NREM sleep and in N1, in N3, A1%, A2%, A3%, A1, A2, A3 indexes (n/h) in NREM sleep and in N1 in N2, in N3, A, A1, A2, A3 mean duration (min), B mean duration (min), sequences mean duration (min), arousal index (n/h).
S. Miano et al. / Clinical Neurophysiology 122 (2011) 311–319
intelligence was lower than in normal controls, while patients with a high intelligence level did not show attention deficits (Alchanatis et al., 2005). Surprisingly, we found a positive correlation between the IQ scores and the percentage of wakefulness after sleep onset in children with SDB. This result, which was confirmed by regression analysis, cannot be applied to the normal controls because they did not undergo a PSG; we could not consequently glean any information about the relationship between cognitive function and sleep fragmentation in our group of normal controls, though we presume the result would be different in a normal group of children. Indeed, data in the literature clearly demonstrate that sleep disruption is associated with a wide range of behavioural, cognitive and mood impairments (O’Brien, 2009). Furthermore, treatment of sleep disruption, by improving sleep hygiene or treating specific sleep disorders, is often associated with improvements in daytime performance (O’Brien, 2009). Interestingly, one longitudinal study that assessed sleep duration by means of 24-h actigraphic recording in a large community-sample of 7-year-old children showed that IQ and ADHD scores did not differ according to sleep duration (Nixon et al., 2008), while another study that assessed sleep duration by means of a longer actigraphic recording showed that longer habitual sleep duration in healthy school-age participants was associated with a better performance in IQ tests (Gruber et al., 2010). Our findings are apparently in disagreement with the assumption that fragmented sleep might lead to important cognitive problems, as widely hypothesized in paediatric SDB (Chervin et al., 2004; O’Brien et al., 2004a,b; Kheirandish-Gozal et al., 2007). It should, however, be borne in mind that previous studies focused on the behavioural consequences of sleep fragmentation and on the relationship with executive functions (O’Brien et al., 2004a,b), rather than on a possible correlation between sleep architecture and global intelligence in paediatric SDB. We hypothesize that sleep fragmentation may exert a protective role on the brain by counteracting the negative effects of intermittent hypoxia during sleep in paediatric SDB. This hypothesis is supported by animal models showing that hypoxia causes cerebral damage in the prefrontal cortex and hippocampus, and that such damage might be irreversible (Row et al., 2004; Kheirandish et al., 2005). This result is indirectly confirmed by the correlations found between the CAP rate and IQ values in children with SDB: global and performance intelligence correlated positively with the A2 percentage and A2 index. CAP A phases have been subdivided into a 3-stage hierarchy of arousal strength from A1 to A3 (Terzano et al., 2001). Considering that the A2 subtype is defined as the A phase with mixed synchronized and desynchronized EEG patterns, our result seems to lend further support to the afore-mentioned hypothesis, i.e. that arousal mechanisms counteract the respiratory events to preserve cognitive functions at the expense of sleep maintenance and NREM sleep instability. We cannot demonstrate that one variable is correlated with another by a causative factor, nor can we prove the hypothesis that children with a higher overall intelligence have a better capacity to arouse from sleep, although the results of the regression analysis support our hypothesis. A neuroimaging study in children with SDB is warranted to address this issue. Moreover, future studies with a long-term follow-up are warranted to compare the CAP analysis in normal healthy children with that in children with SDB. Although we found few correlations between the ADHD rating scale score and sleep parameters, the total and hyperactivity scores did correlate positively with the A2 index, particularly during sleep stage N3. A positive correlation between the increased CAP rate and behavioural complaints (difficulties at school, hyperactivity, inattention, aggressiveness and irritability) has been reported in children who habitually snore (Lopes and Guilleminault, 2006).
317
In a previous study, we found a lower CAP rate and A1 index in ADHD children without SDB than in normal controls (Miano et al., 2006). In the present study, we did not compare the CAP rate with that of normal controls, although the correlation between the A2 index and ADHD rating scale scores supports the hypothesis that ADHD symptoms in children with SDB are related to sleep fragmentation, particularly during slow-wave sleep (Miano et al., 2006). The regression analysis yielded similar results (positive correlation between hyperactive rating scale and A2 index in N3 and A1 percentage, and between total ADHD rating scale and the CAP rate in N2). Slow-wave activity plays a critical role in both developmental and learning-induced plasticity and is the main component of CAP A1 subtypes, which mapped over the prefrontal cortex and controls executive functions (Ferri et al., 2005; Bruni and Ferri, 2009). We believe that an NREM instability, as expressed by the occurrence of A2 during N3, and by the A1 percentage, may alter this brain function in children with SDB. One interesting pathogenetic model for paediatric OSAS linked NREM sleep instability to alterations in growth hormone secretion during sleep, which may in turn have an impact on neurocognitive deficits (Bruni and Ferri 2009; Gozal et al., 2009). Interestingly, in a previous study the close relationship between attention level and arousal was expressed in terms of the sleep pressure score (O’Brien et al., 2004a,b). The authors reported that the sleep pressure score is a numerical factor derived from spontaneous and respiratory arousals and is associated with deficits in neurobehavioural daytime functions, regardless of the severity of the paediatric SDB (O’Brien et al., 2004a,b). Another study reported changes in microarousals (mainly expressed by delta and theta activity) associated with an improvement in attention levels in children with OSAS following adenotonsillectomy (Chervin et al., 2004). Moreover, the regression analysis in our sample demonstrated that the hyperactivity rating score is negatively correlated with mean and minimal oxygen saturation. This result lends support to our hypothesis that sleep fragmentation due to respiratory events has a neurobehavioural diurnal effect. Although the regression analysis confirmed the results of correlation between neurocognitive measures and sleep parameters, the values of the R2 coefficient of determination limit the strength of these results, so further investigations to confirm our findings are needed. We compared the sleep architecture and respiratory parameters in children who snore with those of OSAS children: as expected, we found a higher AHI and ODI, and a lower mean overnight oxygen saturation, minimal oxygen saturation and mean desaturation in children with OSAS. We also detected some differences in sleep parameters: a lower N3 percentage, a higher REM sleep latency, a higher arousal index and a lower A mean duration in children with OSAS than in snorers. The differences in sleep architecture confirm the findings of a previous study on sleep in paediatric SDB assessed by means of the new AASM criteria (Miano et al., 2010). By contrast, there were no differences in the CAP rate, though OSAS children had a lower mean A phase duration. Although we found differences in sleep quality between snoring and OSAS children, such as a higher arousal index in those with OSAS, the correlation and regression analysis demonstrated that the underlying arousal mechanisms may be the same in both groups of children with SDB. In addition, the comparison between the CAP rates and respiratory parameter values revealed that AHI correlated negatively with the A mean duration and A2 percentage, while it correlated positively with the A2 index and arousal index. These findings may indicate that the occurrence of respiratory events (apnea, hypopnea, respiratory events related arousal) may increase the occurrence of A phases and arousals, reducing their duration (as indirectly expressed by the negative correlation with the A2
318
S. Miano et al. / Clinical Neurophysiology 122 (2011) 311–319
percentage). We also found a positive correlation between the CAP rate during N3 and mean overnight oxygen saturation, which further suggests that the increase in NREM sleep instability is a response designed to counteract respiratory events and desaturations. It has previously been demonstrated that all CAP-related respiratory events arise in close temporal connection with phase B, while effective breathing is always restored during phase A (especially A2 and A3 subtypes) in adults with OSAS (Terzano et al., 1996). The absence of a significant correlation between respiratory events and the A1 phases may be due to the fact that the A1 subtypes, which are characterized by a lower degree of arousability than the other CAP A subtypes (Terzano et al., 2001), might be unable to counteract the effects of sleep respiratory events, their function mainly being related to the building-up and maintenance of sleep, thus preserving cognitive functions (Ferri et al., 2005). Moreover, we found few correlations between the A3 subtypes and respiratory parameters. This finding may be due to the peculiarity of the paediatric age range, in which the A2 phase occurs more frequently as an expression of arousal than the A3 phase (Bruni et al., 2002). This phenomenon has previously been reported in children with SDB, though not expressed within the CAP context: the EEG pattern of arousal activation following an upper airway occlusion may occur in a burst of delta waves or a K complex (which may be the first part of an A2 event) instead of the classical cortical arousal (Moreira et al., 2005). In conclusion, despite the limited number of subjects with SBD investigated, we believe that our study makes an interesting contribution to research on the relationship between sleep fragmentation and cognitive function. Arousal is an important defensive mechanism against sleep-disordered breathing that leads to sleep fragmentation. Many studies have suggested that children with OSAS have an altered sleep microstructure, which is characterised by a significantly enhanced number of movements, EEG arousals, periodic leg movements and increasing NREM instability (Mograss et al., 1994; Scholle and Zwacka, 2001; Moreira et al., 2005; Lopes and Guilleminault, 2006; Miano et al., 2009a). Our results strongly support this hypothesis, and show that, among the SDB children we studied, those with a high level of arousal seem to have a higher degree of protection against the cognitive consequences of sleep respiratory problems; in other words, the higher the arousability, the higher the IQ, the latter also being accompanied, however, by higher diurnal hyperactive and inattentive levels. We may conclude that, on a hypothetical scale of cognitive processes, the attempt to preserve global intelligence in children with SDB has a diurnal cost due to sleep deprivation. Conflict of interest statement None of the authors have any conflict of interest, financial support or off-label and investigational use to disclose. References Alchanatis M, Zias N, Deligiorgis N, Amfilochiou A, Dionellis G, Orphanidou D. Sleep apnea-related cognitive deficits and intelligence: an implication of cognitive reserve theory. J Sleep Res 2005;14:69–75. Beebe DW, Gozal D. Obstructive sleep apnea and the prefrontal cortex: towards a comprehensive model linking nocturnal upper airway obstruction to daytime cognitive and behavioural deficits. J Sleep Res 2002;11:1–16. Biederman J, Petty CR, Ball SW, Fried R, Doyle AE, Cohen D, et al. Are cognitive deficits in attention deficit/hyperactivity disorder related to the course of the disorder? A prospective controlled follow-up study of grown up boys with persistent and remitting course. Psychiatry Res 2009;170: 177–82. Blunden SL, Beebe DW. The contribution of intermittent hypoxia, sleep debt and sleep disruption to daytime performance deficits in children: consideration of respiratory and non-respiratory sleep disorders. Sleep Med Rev 2006;10: 109–18.
Blunden S, Lushington K, Kennedy D, Martin J, Dawson D. Behavior and neurocognitive performance in children aged 5–10 years who snore compared to controls. J Clin Exp Neuropsychol 2000;22:554–68. Brouillette R, Hanson D, David R, Klemka L, Szatkowski A, Fernbach S, et al. A diagnostic approach to suspected obstructive sleep apnea in children. J Pediatr 1984;105:10–4. Bruni O, Ferri R. Neurocognitive deficits in paediatric obstructive sleep apnea: a multifaceted pathogenetic model. Sleep Med 2009;10:161–3. Bruni O, Ferri R, Miano S, Verrillo E, Vittori E, Della Marca G, et al. Sleep cyclic alternating pattern in normal school-age children. Clin Neurophysiol 2002;113:1806–14. Chervin RD, Burns JW, Subotic NS, Roussi C, Thelen B, Ruzicka DL. Correlates of respiratory cycle-related EEG changes in children with sleep-disordered breathing. Sleep 2004;27:116–21. Chervin RD, Ruzicka DL, Archbold KH, Dillon JE. Snoring predicts hyperactivity four years later. Sleep 2005;28:885–90. Decary A, Rouleau I, Montplaisir J. Cognitive deficits associated with sleep apnea syndrome: a proposed neuropsychological test battery. Sleep 2000;23: 369–81. DuPaul GJ, McGoey KE, Eckert TL, VanBrakle J. Preschool children with attentiondeficit/hyperactivity disorder: impairments in behavioral, social, and school functioning. J Am Acad Child Adolesc Psychiatry 2001;40:508–15. Ferri R, Bruni O, Miano S, Terzano MG. Topographic mapping of the spectral components of the cyclic alternating pattern (CAP). Sleep Med 2005;6:29–36. Friedman BC, Hendeles-Amitai A, Kozminsky E, Leiberman A, Friger M, Tarasiuk A, et al. Adenotonsillectomy improves neurocognitive function in children with obstructive sleep apnea syndrome. Sleep 2003;26:999–1005. Gozal D. Obstructive sleep apnea in children: implications for the developing central nervous system. Semin Pediatr Neurol 2008;15:100–6. Gozal D, Pope Jr DW. Snoring during early childhood and academic performance at ages thirteen to fourteen years. Paediatrics 2001;107:1394–9. Gozal D, Sans CO, McLaughlin CV, Serpero LD, Witcher LA, Kheirandish-Gozal L. Plasma IGF 1 levels and cognitive dysfunction in children with obstructive sleep apnea. Sleep Med 2009;10:167–73. Grimaldi A, Lisi F. Wecshler intelligence scale for children: a test of the reliability of the Italian version. Bollettino di Psicologia Applicata 1983;166:41–5. Gruber R, Laviolette R, Deluca P, Monson E, Cornish K, Carrier J. Short sleep duration is associated with poor performance on IQ measures in healthy school-age children. Sleep Med 2010;11:289–94. Guilleminault C, Lee JH, Chan A, Lopes MC, Huang YS, da Rosa A. Non-REM-sleep instability in recurrent sleepwalking in pre-pubertal children. Sleep Med 2005;6:515–21. Iber C, Ancoli-Israel S, Chesson AL, Quan SF. The AASM manual for the scoring of sleep and associated events: rules, terminology, and technical specifications. Westchester, IL: American Academy of Sleep Medicine; 2007. International Classification of Sleep Disorders – ICSD. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005. Kennedy JD, Blunden S, Hirte C, Parsons DW, Martin AJ, Crowe E, et al. Reduced neurocognition in children who snore. Pediatr Pulmonol 2004;37:330–7. Kheirandish L, Gozal D. Neurocognitive dysfunction in children with sleep disorders. Dev Sci 2006;9:388–99. Kheirandish L, Gozal D, Pequignot JM, Pequignot J, Row BW. Intermittent hypoxia during development induces long-term alterations in spatial working memory, monoamines, and dendritic branching in rat frontal cortex. Pediatr Res 2005;58:594–9. Kheirandish-Gozal L, Miano S, Bruni O, Ferri R, Pagani J, Villa MP. Reduced NREM sleep instability in children with sleep disordered breathing. Sleep 2007;30:450–7. Kheirandish-Gozal L, de Jong MR, Spruyt K, Chamuleau SA, Gozal D. Obstructive sleep apnoea is associated with impaired pictorial memory task acquisition and retention in children. Eur Respir J 2010 [Epub ahead of print]. Lopes MC, Guilleminault C. Chronic snoring and sleep in children: a demonstration of sleep disruption. Paediatrics 2006;118:e741–6. Marzocchi GM, Cornoldi C. Una scala di facile uso per la rilevazione dei comportamenti problematici dei bambini con deficit di attenzione e iperattività. Psicologia Clinica dello Sviluppo 2000;4:43–64. Miano S, Donfrancesco R, Bruni O, Ferri R, Galiffa S, Pagani J, et al. NREM sleep instability is reduced in children with attention-deficit/hyperactivity disorder. Sleep 2006;29:797–803. Miano S, Rizzoli A, Evangelisti M, Bruni O, Ferri R, Villa MP. NREM sleep instability changes following rapid maxillary expansion in children with obstructive apnea sleep syndrome. Sleep Med 2009a;10:471–8. Miano S, Paolino MC, Peraita-Adrados R, Montesano M, Barberi S, Villa MP. Prevalence of EEG paroxysmal activity in a population of children with obstructive sleep apnea syndrome. Sleep 2009b;32:522–9. Miano S, Paolino MC, Castaldo R, Villa MP. Visual scoring of sleep: a comparison between the Rechtschaffen and Kales criteria and the American Academy of Sleep Medicine criteria in a paediatric population with obstructive sleep apnea syndrome. Clin Neurophysiol 2010;121:39–42. Mitchell RB, Kelly J. Long-term changes in behavior after adenotonsillectomy for obstructive sleep apnea syndrome in children. Otolaryngol Head Neck Surg 2006;134:374–8. Mograss MA, Ducharme FM, Brouillette RT. Movement/arousals: description, classification, and relationship to sleep apnea in children. Am J Respir Crit Care Med 1994;150:1690–6. Montgomery-Downs HE, Crabtree VM, Gozal D. Cognition, sleep and respiration in atrisk children treated for obstructive sleep apnoea. Eur Respir J 2005;25:336–42.
S. Miano et al. / Clinical Neurophysiology 122 (2011) 311–319 Moreira GA, Tufik S, Nery LE, Lutz J, Verfaille K, Luan X, et al. Acoustic arousal responses in children with obstructive sleep apnea. Pediatr Pulmonol 2005;40:300–5. Nixon GM, Thompson JM, Han DY, Becroft DM, Clark PM, Robinson E, et al. Short sleep duration in middle childhood: risk factors and consequences. Sleep 2008;31:71–8. O’Brien LM. The neurocognitive effects of sleep disruption in children and adolescents. Child Adolesc Psychiatr Clin N Am 2009;18:813–23. O’Brien LM, Gozal D. Sleep in children with attention deficit/hyperactivity disorder. Minerva Pediatr 2004;56:585–601. O’Brien LM, Mervis CB, Holbrook CR, Bruner JL, Smith NH, McNally N, et al. Neurobehavioral correlates of sleep-disordered breathing in children. J Sleep Res 2004a;13:165–72. O’Brien LM, Tauman R, Gozal D. Sleep pressure correlates of cognitive and behavioral morbidity in snoring children. Sleep 2004b;15(27):279–82. Owens-Stively J, Frank N, Smith A, Hagino O, Spirito A, Arrigan M, et al. Child temperament, parenting discipline style, and daytime behavior in childhood sleep disorders. J Dev Behav Pediatr 1997;18:314–21. Row BW, Kheirandish L, Li RC, Guo SZ, Brittian KR, Hardy M, et al. Platelet-activating factor receptor-deficient mice are protected from experimental sleep apneainduced learning deficits. J Neurochem 2004;89:189–96.
319
Rubini V, Padovani F. WISC-R Scala di Intelligenza Wechsler per bambini riveduta. Organizzazioni Speciali. Florence; 1986 [in Italian]. Scholle S, Zwacka G. Arousals and obstructive sleep apnea syndrome in children. Clin Neurophysiol 2001;112:984–91. Statistical Manual of Mental Disorders. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington: American Psychiatric Association; 1994. Termine C, Balottin U, Nicoli F, Zopello M, Lanzi G. Verbal performance intelligence quotient discrepancies on the Wecshler scales: are they still useful? Literature review and clinical implications. Minerva Psichiatrica 2005;46:209–19. Terzano MG, Parrino L, Boselli M, Spaggiari MC, Di Giovanni G. Polysomnographic analysis of arousal responses in obstructive sleep apnea syndrome by means of the cyclic alternating pattern. J Clin Neurophysiol 1996;13:145–55. Terzano MG, Parrino L, Smerieri A, Chervin R, Chokroverty S, Guilleminault C, et al. Atlas, rules, and recording techniques for the scoring of cyclic alternating pattern (CAP) in human sleep. Sleep Med 2001;2:537–53. Tillman CM, Bohlin G, Sørensen L, Lundervold AJ. Intellectual deficits in children with ADHD beyond central executive and non-executive functions. Arch Clin Neuropsychol 2009;24:769–82. Wechsler D. Wechsler intelligence scale for children-revised. New York: The Psychological Corporation; 1973.