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Elsevier Editorial System(tm) for Clinical Neurophysiology Manuscript Draft Manuscript Number: Title: Sleep cyclic alternating pattern analysis in infants with apparent life-threatening events: a daytime polysomnographic study Article Type: Full Length Article Section/Category: Sleep Keywords: arousal, apparent life-threatening event, child development, clinical neurophysiology Corresponding Author: Prof. Maria P. Villa, MD Corresponding Author's Institution: University of Rome First Author: Silvia Miano Order of Authors: Silvia Miano; Rosa Castaldo; Raffaele Ferri; Rosa Peraita-Adrados; Maria Chiara Paolino; Marilisa Montesano; Maria P. Villa, MD Suggested Reviewers: Opposed Reviewers:
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Sleep cyclic alternating pattern analysis in infants with apparent life-threatening events: a
daytime polysomnographic study
Abstract
Objective
Non-REM sleep is characterized by a physiologic oscillating pattern that exhibits different levels of
arousal, coded as cyclic alternating pattern. The aim of this study was to analyze the development of
cyclic alternating pattern parameters in a group of infants with apparent life-threatening events.
Methods
A total of 26 infants with apparent life-threatening events (14 females, mean age 3.4 months, 2.37
S.D.) were studied while they slept in the morning between feedings, by means of a 3-hour video-
electroencephalographic-polygraphic recording. Sleep was visually scored using standard criteria.
The control group was composed of 36 healthy infants (16 females, mean age 3.2 months, 2.17
S.D.).
Results
Children with apparent life-threatening events showed an increased frequency of periodic breathing,
gastroesofageal reflux and of other risk conditions. They presented also an increased obstructive
apnoea/hypopnea index. A full NREM sleep development was found in a significantly smaller
percentage of patients, and they showed a significant reduction of the percentage of REM sleep, of
cyclic alternating pattern A1 subtypes, an increased percentage of A2 and A3 subtypes and
increased index of A2, A3 subtypes and arousal, compared to normal controls. Cyclic alternating
pattern rate showed a significant positive correlation with age, only in controls.
Conclusions
Our results show a higher level of arousal and an increased non-REM sleep discontinuity in babies
with ALTE, compared to controls.
Significance
Abstract
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The enhanced mechanism of arousal might counteract life-threatening events and represent an
important neurophysiologic distinction from future victims of sudden infant death syndrome who
also experience similar events.
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Sleep cyclic alternating pattern analysis in infants with apparent life-threatening events: a
daytime polysomnographic study
Running head: Sleep cyclic alternating pattern in apparent life-threatening events
Silvia Miano, MD1; Rosa Castaldo MD
1; Raffaele Ferri, MD
2; Rosa Peraita-Adrados, MD
3 ; Maria
Chiara Paolino MD1; Marilisa Montesano MD
1; and Maria Pia Villa, MD
1
1Department of Pediatrics, Sleep Disease Centre, University of Rome La Sapienza-S.Andrea
Hospital, Rome, Italy; 2Department of Neurology I.C, Sleep Research Center, Oasi Institute for
Research on Mental Retardation and Brain Aging (IRCCS), Troina, Italy; 3Sleep and Epilepsy Unit-
Clinical Neurophysiology Department, University Hospital Gregorio Marañón, Madrid, Spain;
Correspondence and reprint requests to:
Prof. Maria Pia Villa
Paediatric Clinic, Sant’Andrea Hospital
Via Grottarossa 1035/1039 - 00189 Rome, Italy
Tel: +39/0633775855
Fax: +39/0633775941
e-mail: [email protected]
None of the authors have any conflict of interest, financial support or off-label and investigational
use to disclose.
*Manuscript
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Abstract
Objective
Non-REM sleep is characterized by a physiologic oscillating pattern that exhibits different levels of
arousal, coded as cyclic alternating pattern. The aim of this study was to analyze the development of
cyclic alternating pattern parameters in a group of infants with apparent life-threatening events.
Methods
A total of 26 infants with apparent life-threatening events (14 females, mean age 3.4 months, 2.37
S.D.) were studied while they slept in the morning between feedings, by means of a 3-hour video-
electroencephalographic-polygraphic recording. Sleep was visually scored using standard criteria.
The control group was composed of 36 healthy infants (16 females, mean age 3.2 months, 2.17
S.D.).
Results
Children with apparent life-threatening events showed an increased frequency of periodic breathing,
gastroesofageal reflux and of other risk conditions. They presented also an increased obstructive
apnoea/hypopnea index. A full NREM sleep development was found in a significantly smaller
percentage of patients, and they showed a significant reduction of the percentage of REM sleep, of
cyclic alternating pattern A1 subtypes, an increased percentage of A2 and A3 subtypes and
increased index of A2, A3 subtypes and arousal, compared to normal controls. Cyclic alternating
pattern rate showed a significant positive correlation with age, only in controls.
Conclusions
Our results show a higher level of arousal and an increased non-REM sleep discontinuity in babies
with ALTE, compared to controls.
Significance
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The enhanced mechanism of arousal might counteract life-threatening events and represent an
important neurophysiologic distinction from future victims of sudden infant death syndrome who
also experience similar events.
Highlights
1. Add new information about sleep arousal in infants with apparent life threatening events
2. Add new information about sleep continuity studied by menas of cyclic alternating pattern
analysis in infants with apparent life threatening events
3. Add new information about sleep maturation in in infants with apparent life threatening
events
Keywords: arousal, apparent life-threatening event, child development, clinical neurophysiology
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Introduction
The development of arousal mechanisms is strongly influenced by maturation of sleep patterns.
Arousal is considered to be a transient intrusion of wakefulness into sleep, which counteracts many
endogenous or exogenous stimuli (Grigg-Damberger et al., 2007), reflecting a progressive
activation of various structures, from subcortical to cortical areas (Moruzzi and Magoun 1949;
McNamara et al., 1998; Rees et al., 1995). Cyclic alternating pattern (CAP) is a a physiologic
NREM sleep oscillating mechanism, composed by the occurrence of three main EEG patterns,
according to the prevalence of EEG synchrony (subtype A1), prevalence of EEG desynchronization
(subtype A3), or a combination of both (subtype A2), reflecting different levels of arousal (Terzano
et al., 2001). We recently provided normative data on CAP analysis in infants aged 1–16 months,
studied when they slept during the morning, and we found that CAP events begin to occur when the
tracé alternant disappears (Miano et al., 2009; Miano et al., 2010). CAP rate increases during the
first year of life, following the degree of maturation of the thalamocortical pathways (Miano et al.,
2010).
Failure to arouse from sleep is suspected to play a key role in sudden infant death syndrome (SIDS),
because an insufficient capacity to arouse might lower the ability of infants to cope with exposure to
noxious conditions during sleep (Newman et al., 1989; Kahn et al., 2002). Sleep of infants who
subsequently died of SIDS has been shown to be characterized by fewer body movements and
awakenings from sleep, especially at the end of the night when most deaths occur (Kahn et al.,
2002), and by a reduction in cortical arousals associated with an increase in subcortical activation
(Kato et al., 2003). It has been hypothesized that the elevated levels of subcortical activation
observed in infants with SIDS might be caused by an increase of activity and by a reduced plasticity
of the central noradrenaline system (Sawaguchi et al., 2002), or by a deficiency of brainstem
serotoninergic activity (Duncan et al, 2010).
Infants with an apparent life-threatening event (ALTE) are referred to emergency room because of a
sudden unexpected incident, i.e., an acute and unexpected change in behaviour stressful for the
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caregiver and that was interpreted to be a ―life threatening‖ event and it was necessary a more or
less vigorous stimuli to reverse the episode. The initial episode may occur during sleep,
wakefulness, or feeding and is most commonly described as a combination of several of the
following symptoms and signs: apnoea, color change (cyanotic or pallid, occasionally
erythematous), marked change in muscle tone (limpness, rarely rigidity), choking, or gagging
(Kahn, 2004). Since these infants are at risk for SIDS, an arousal dysfunction for ALTE has been
hypothesized. An abnormal cardiovascular autonomic control with a decreased arousability during
REM sleep (Harrington et al., 2002), a deficiency of sleep autonomic activation in response to
hypoxic events, (Dunne et al., 1992), and an increase of sleep periodic breathing due to weak feed-
back control (Milerad et al., 1989), have been reported in infants with ALTE, using different ways
to score arousal (such as the direct observation of movements, nap-recording or full-night
recording, scoring of cortical arousals or subcortical activations). Recently, a study has been
published analyzing accurately cortical and subcortical arousals and their changes during the first
year of life in a relatively large sample of infants with ALTE, studied during night sleep (Franco et
al., 2011). The authors found fewer subcortical activations and cortical arousals in NREM sleep in
infants with ALTE compared to normal controls, while infants with ALTE and smoking mothers
showed more subcortical activations in REM sleep, similarly to infants future victims of SIDS
(Franco et al., 2011).
The aim of this study was to analyze cortical arousals and CAP parameters in a group of infants
with ALTE, studied when they slept in the morning, in order to compare the results with those
already obtained in the group of normal healthy infants (Miano et al., 2009; 2010), to add
information on the maturation of arousals together with the maturation of NREM sleep continuity in
infants with ALTE.
Methods
Participants
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We consecutively enrolled infants who were undergoing their first diagnostic assessment for an
episode of ALTE at the Department of Pediatrics, University of Rome La Sapienza, Sant’Andrea
Hospital (Rome, Italy), from January 2009 to December 2009. In detail, we studied infants who
had experienced, from their birth to the first birthday, the sudden occurrence of 1 or more of the
following symptoms that frightened the caregiver enough to seek for medical attention: breathing
irregularity (apnoea, laboured or shallow breathing, choking, gagging), colour change (cyanosis or
pallor), altered muscle tone or alertness (hypotonia, hypertonia, clonic movements,
unresponsiveness). ALTE was diagnosed following international criteria for infant sleep apnea
(American Academy of Sleep Medicine, 2005).
The control group was composed of 36 healthy infants (16 females), born at term,. Normal babies
from 1 to 4 months of life underwent a 3-hour video-polysomnographic recording at the Sleep Unit
of the Clinical Neurophysiology Department of the University Hospital Gregorio Marañón in
Madrid, Spain (Miano et al., 2009); whereas normal babies from 5 to 16 month of life underwent a
3-h video-polysomnographic recording at the Pediatric Sleep Unit of Sant’Andrea Hospital in
Rome, Italy (Miano et al., 2010). None of these subjects had family history of sudden infant death
syndrome or of having had apparent life-threatening events; they did not sleep prone at home, as
reported by parents.
All patients underwent a clinical examination; peripheral blood glucose, ammonia concentrations,
and electrolytes were measured, and renal and liver function tests, urinalysis, and chest radiography
were performed. When there was a history of gastroesofageal reflux (GER), an abdominal
ultrasonography was obtained.
Before the sleep study, clinical evaluation of these infants did not reveal any abnormality. All
infants were studied while they slept in the morning. They underwent a 3-hour video-EEG-
polysomnographic recording at the Sleep Unit of the Pediatric Department of ―Sapienza‖
University, Sant’Andrea Hospital in Rome, Italy. The recordings were performed in a quiet dark
room, with temperature ranging between 20 and 23° C. All children slept in the morning between
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feeds in supine position, without restraints. Recording started at around 11:00 and lasted for about 3
hours; no infant had a pacifier during the recording. The polysomnographic study included the
following parameters: EEG (three or six channels according to compliance, frontal, central, and
occipital, with reference to the contralateral mastoid); electro-oculogram (electrodes placed 1 cm
above the right outer canthus and 1 cm below the left outer canthus with reference to A1);
electromyogram of the submentalis muscle; and electrocardiogram (one lead). The respiratory
pattern during sleep was assessed using oral and nasal airflow (thermistor), thoracic and abdominal
respiratory effort (strain gauge), and oxygen saturation (pulse oximetry). Data were collected on a
computerized sleep system (Grass Heritage polygraph) using a sampling frequency of 256 Hz. The
recordings were subdivided into 30-s epochs.
Analysis of Sleep Architecture
Based on the polygraphic recordings, sleep stages and sleep apnoeas were scored according to
standard definitions (Guilleminault et al., 1975; Guilleminault and Souquet, 1979; Kelly and
Shannon, 1979). One of the authors (SM) scored all the recordings (sleep staging and sleep
respiratory analysis).
According to the age of the subject and to the recommendations of Anders’s et al., (1971), Curzi
Dascalova and Mirmiran (1996) and the Pediatric Task Force (Grigg-Damberger et al., 2007), sleep
was scored as quiet sleep (QS), active sleep (AS), and indeterminate sleep (IS), in infants aged ≤2
months post-term. QS is composed by two EEG patterns: TA and high voltage slow activity (HVS).
TA is an EEG pattern in which 3- to 8-second bursts of moderate to high voltage 0.53.0 Hz slow
waves, intermixed with 24 Hz sharply contoured waveforms, alternate with 4- to 8-second
intervals of attenuated mixed frequency EEG activity. In contrast, HVS consists of continuous
moderately rhythmic 50150 μV, 0.54 Hz slow activity.
Guilleminault and Souquet (1979) and the Pediatric Task Force (Grigg-Damberger et al., 2007)
further recommended that stages 1, 2, and slow-wave sleep should be scored by 4 to 4.5 months
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post-term, usually by 5 to 6 months. SWS in an infant or child can be called stage NREM 3 and be
scored when 20% or more of an epoch consists of waves of 0.52 Hz frequencies and peak-to-peak
amplitude of >75 μV in the frontal derivations. In patients with fully developed sleep patterns,
standard criteria for sleep stages were used (Iber et al., 2007).
Apnoeas were scored when they lasted 3 s or longer. They were classified as central apnoea when
flat tracings were obtained simultaneously from the strain gauges and the nasal thermistor. Periodic
breathing was defined as the succession of more than two central apnoeas separated from each other
by less than 20 s. Obstructive apnoeas were defined as continuous deflections from the strain
gauges, with a flat tracing recorded from the oro-nasal thermistor. Mixed apnoea was defined as a
central apnoea directly followed by an obstructive episode and was scored together with the
obstructive episodes. For the purposes of this study, we considered 3 main respiratory parameters:
mean peripheral blood oxygen saturation (SaO2, expressed as a percentage), obstructive
apnoea/hypopnea index, and presence of periodic breathing (Iber et al., 2007).
Analysis of arousals
Arousals were detected according to the consensus on arousal scoring in healthy infants under 6
months of age by the International Pediatric Work Group on Arousal (IPWGA, 2005) and to the
AASM criteria for older children. An arousal was scored with the occurrence of an abrupt change in
the electroencephalogram background frequency of at least 1 Hz, for a minimum of 3 s. EEG
arousals in young infants may provoke an abrupt diffuse decrease in EEG amplitude called a
―decremental response‖ and this was also scored as an arousal.
Rules for Scoring CAP in babies in the first year of life
CAP was visually scored by one of the investigators (SM), without knowledge of the subject’s age
or sex, and the sleep parameters derived were tabulated for subsequent statistical analysis. All of
variables were visually detected and their parameters measured by means of the Hypnolab 1.0 sleep
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software analysis (SWS Soft, Italy). In order to adapt CAP scoring for the age of the subjects
included in this study, in agreement with the previous normative studies (Miano et al., 2009; 2010),
we made some modifications of the rules for identifying the different CAP A phase subtypes in
children. EEG arousals in young children often include rhythms slower than those seen in adults,
usually represented by frequencies in the range of theta and other faster rhythms. In infants an
arousal can include also frequencies ranging in the delta band, according to the definition of an
arousal in this age range: an arousal is defined as an abrupt change in electroencephalogram
background frequency of at least 1 Hz, even into the delta band (IPWGA, 2005). Therefore, we also
modified the CAP scoring criteria and considered these EEG frequencies as components potentially
characterizing the A3 and, partially, the A2 subtypes of CAP.
CAP can not be scored in a recording if it is not possible to recognize K complexes, delta bursts
and/or spindles. Spindles are usually first present in term infants by 8 to 8 weeks postnatal age,
while K complexes first appear 5 months post-term and slow wave activity (SWA) of slow wave
sleep (SWS) is first seen as early as 2 to 3 months post-term and is usually present 4 to 4.5 months
post-term. Therefore, we analyzed tracings and scored CAP only when at least rudimentary spindles
appeared and slow wave activity emerged from HVS.
Taking this into account, we modified the CAP-subtype scoring criteria for infants as follows:
Subtype A1 A phases in which slow EEG synchrony is the predominant activity, mostly
composed by high-voltage delta bursts. Phasic activities initiating a phase A must be one-
third higher than the background voltage (calculated during the 2 seconds before the onset
and 2 seconds after the offset of a phase A). Compared to the background EEG delta
rhythms of quiet sleep, delta bursts tend to be lower in frequency.
Subtype A2 A phases that contain a mixture of slow and fast EEG activities, including
bursts of theta rhythms, associated or not with EMG activation, delta wave bursts followed
by theta, and other faster rhythms. Fast EEG activities generally represent 20% to 50% of
the entire phase A2. Subtype A2 can be linked with a moderate increase of muscle tone,
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cardiorespiratory rate, or both. As stated before, in our recordings, we found several phasic
events represented mainly by bursts of high-voltage delta activity.
Subtype A3 A phases in which the EEG activity is predominantly fast low-voltage
rhythms with more than 50% of a phase A occupied by fast EEG activities, including EEG
arousals, polyphasic bursts, and high-voltage delta waves with an amplitude one-third
higher, or more, than the background activity, followed by theta, and other faster rhythms.
All A3 phases are very often associated with remarkable enhancement of muscle tone,
cardiorespiratory rate, or both. It is not common to find A3 CAP subtypes without EMG
activation infants. As stated by the IPWG (2005), EEG arousals in young infants may
provoke an abrupt diffuse decrease in EEG amplitude called a ―decremental response‖ and
we also scored this transient event as A3.
We detected A phases if they appeared at least in the anterior channels (F3-C3, F4-C4), meanwhile
the events scored as A phases rarely appeared simultaneously in the anterior and posterior regions,
especially for the A1 phases.
The following CAP parameters were derived: CAP time (temporal sum of all CAP sequences) in
quiet sleep; CAP rate (percentage of total quiet sleep time occupied by CAP sequences); number
and duration of CAP cycles; number and duration of CAP sequences; number, duration, and
percentage of A phases (including the phase A subtypes); A1 index (number of A1 phases per hour
of quite sleep or NREM sleep); A2 index (number of A2 phases per hour of quite sleep or NREM
sleep); A3 index (number of A3 phases per hour of quite sleep or NREM sleep); and number and
duration of B phases.
Statistical analysis
For the statistical analysis of the differences in age, breathing parameters, sleep architecture and
CAP parameters found in the groups of children included in this study (normal healthy infants and
with ALTE) the nonparametric Mann-Whitney test for independent data-sets, was used. The
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differences in frequency of detection in the 2 groups of subjects of parameters with the
characteristics of a binomial variable were analyzed by means of the Chi-square test. Finally, some
specific, hypothesis-driven correlations were tested by means of the Spearman rank correlation
coefficient.
Differences and correlations were considered statistically significant at p <0.05. The commercially
available software STATISTICA (data analysis software system), version 6, StatSoft, Inc. (2001)
was used for all statistical tests.
Results
A total of 26 infants with ALTE were studied (14 females, mean age 3.4 months, 2.37 S.D.) with a
mean gestational age of 40.6±1.8 weeks, and mean birth weight of 3.3±0.26 Kilograms; and a total
of 36 controls (16 females, mean age 3.2 months, 2.17 S.D.). Age and gender composition were not
significantly different between the two groups of subjects.
There was no family history of SIDS or ALTE in our sample except for one baby; they did not sleep
prone at home as reported by their parents; smoking during pregnancy was reported in one mother
and 17 out of 26 babies were breast feeding.
Table 1 reports the comparison between the two groups (ALTE and controls) involving the
variables with a binomial distribution while table 2 shows, in detail, the comparison between age,
sleep respiratory parameters, sleep architecture, and sleep microstructure (CAP and arousals).
Regarding clinical features, infants with ALTE showed an increased frequency of periodic
breathing, GER and of other different conditions, such as suspected seizures, paradoxical breathing,
low birth weight, dystocic delivery, transitory increase of blood lactic acid and ammonemia). The
clinical examination showed a normal psychomotor development, no electroclinical seizures were
documented and a mild GER was only detected in 18 cases by ultrasonography. So far, these infants
fit the diagnosis criteria of idiopathic ALTE. The frequency of immature sleep EEG patterns (TA
HVS/no CAP or HVS/spindles) was similar in the two groups while the full NREM sleep
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development was found in a significantly smaller percentage of ALTE patients, compared to
controls.
Beside the increased frequency of periodic breathing, patients with ALTE presented also an
increased obstructive apnoea/hypopnea index, even if their mean SaO2 was not different from that
of controls.
Sleep architecture of ALTE subjects was also very similar to that of normal controls with a
significant reduction only of the percentage of REM sleep.
Based on the results of nap-recordings all subjects with ALTE were asked to undergo periodic nap
recordings in the sleep laboratory (at least every 3 months) until one year of age or until the
normalization of sleep patterns, whereas half of the patients were also asked to undergo home–
monitoring for apnoea, based on the immaturity of sleep breathing patterns and on the occurrence of
sleep apnoeas (even if home apnoea monitor may alter sleep microstructure because of repeated
alarms).
Regarding CAP, it should be noticed that it was scored only in subjects with a sufficiently mature
sleep pattern (excluding those with the pattern indicated as TA HVS/no CAP). However, several
differences were found, with somewhat high statistical significance level, involving the percentage
of CAP A1 subtypes, which was decreased in ALTE subjects, and the percentage of CAP A2 and
CAP A3 subtypes and CAP A2 and A3 subtypes index which were increased in the same group.
Accordingly, also the arousal index was significantly higher in ALTE subjects than in controls,
showing a 1.5-fold increase.
Table 3 reports the results of the comparison between age, sleep respiratory parameters, sleep
architecture, and sleep microstructure (CAP and arousals) obtained in the 2 subgroups of ALTE
children identified on the basis of the presence or absence of periodic breathing. Children with
periodic breathing only showed an increased apnoea/hypopnea index, compared with those without.
However, it should be noted that the low number of subjects without periodic breathing made the
statistical comparison of CAP parameters not applicable because of the exclusion of those with
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immature EEG pattern. However, the count of arousals (also possible in the cases with immature
EEG pattern) did not yield a significant difference between the two groups.
Finally, CAP rate showed a significant positive correlation with age only in controls while no
correlation was found between these two parameters in ALTE subjects. Similarly, arousal index
showed a significant negative correlation with age only in controls (fig. 1).
Figures 2, 3, 4, are examples respectively of A1, A2, A3 CAP subtypes during NREM sleep.
Discussion
This is the first analysis of CAP parameters in infants with ALTE, studied when they slept in the
morning. We found many differences between infants with ALTE and normal healthy babies: the
former had a reduction of the percentage of CAP A1 subtypes, while the percentage of CAP A3
subtype and CAP A2, A3 and arousal indexes were increased in the same group. In contrast we
found only few differences in sleep architecture, as babies with ALTE showed a lower percentage
of REM sleep, and a lower frequency of full mature NREM sleep patterns, compared to normal
controls. Furthermore, normal controls showed a significant increase of CAP rate and a decrease of
arousal index with age, while the infants with ALTE did not show any correlation of CAP rate or
arousal index with age. Our results indicate an increased level of arousal in our sample of babies
with ALTE, persisting with age. The increased level of arousal in our infants with ALTE is not only
merely related to the findings of a higher arousal index, but also to the increase of CAP A2 and
CAP A3 subtypes. Interestingly the percentage of CAP A1 was decreased in the same group and
this finding deserves some explanations. At the beginning of our life the arousal may be also
expressed by slow wave activity, but slow wave activity are also expression of the maturation of the
thalamocortical pathways (Miano et al., 2010; Ferri et al., 2005). The appearance of slow waves and
sleep spindles in infants promote the formation of thalamocortical networks and probably lead to
the appearance of the phasic events that we were able to recognize as CAP A1 subtypes. A1
subtypes may reflect sleep defense, which ensures the maintenance, or even deepening, of sleep,
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rather than an effect of arousal (Hirshkowitz, 2002, Halász et al, 2004). On the other hand, A2 and
A3 are the expression of maintenance of arousability (Terzano et al., 2001, Halász et al, 2004). We
are not able to state if the decrease of A1 subtypes in this age range is an expression of a reduction
of the ―anti-arousal‖ A1 subtypes (Hirshkowitz, 2002), or the ―arousal‖ A1 subtype, since in babies
arousals are expressed also by delta burst (Miano et al., 2009; 2010).
Our results are apparently in contrast with a recent study showing fewer cortical arousals during
night sleep in infant with ALTE. This reduction persists over 9 months of age, in particular during
NREM sleep (Franco et al., 2011). This discrepancy might be explained by the different
methodologies used (morning versus night sleep recording), to the high frequency of respiratory
events (obstructive sleep apnea and periodic breathing), and to the low frequency of smoking
mothers found in our sample of infants with ALTE, leading to an increase of total arousals
(respiratory and spontaneous arousals) compared to Franco et al. study (2011). The same authors
(Franco et al. 2011) found an alteration of arousability mostly during NREM sleep, and in infants
with ALTE and smoking mothers. Our results partially confirm these data, since we found a low
percentage of A1 sybtypes in our group of infants with ALTE. Both studies support the idea that
babies with ALTE show an immaturity of sleep EEG patterns, in particular during NREM sleep. On
the contrary, the increase of cortical arousal found in our study, can be a common defense
mechanism to counteract respiratory events, contributing to NREM sleep discontinuity, such as we
have already reported in school-aged children (Miano et al., 2011). A full-night sleep recording
with multiple EEG channels to assess other EEG characteristics (focal or multifocal interictal and/or
ictal paroxysmal activity, background asymmetries, etc) and to analyze and better define cortical
arousal and CAP in babies with ALTE is warranted, since the study by Franco et al. (2011)
analyzed arousal using only two EEG channels. Moreover, the analysis of sleep during daytime is a
significant limit of our study, and recently the AASM stated that nap polysomonographic recording
is not recommended for the evaluation of paediatric sleep respiratory disorders (Nisha Aurora et al,
2001).
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Anyway, our findings seem to be completely in contrast with those found in future victims of SIDS
who showed a decrease in cortical arousal and an increase in subcortical activations, which may be
a defective survival mechanisms (Kahn et al., 1992; 2003). On the contrary, since our babies with
ALTE were not future victims of SIDS, we can suppose that they expressed a successful answer to
counteract threatening events (such as episodes of apnea, periodic breathing, gastroesophageal
reflux, or seizures), at least during daytime-sleep
Finally, we can hypothesize that infants with ALTE have an alteration of the maturation of
thalamocortical pathways, and this is also confirmed by the higher frequency of immature NREM
sleep EEG found in infants with ALTE, compared to controls. At this point, we are not able to say if
this is a feature of infants at risk for ALTE or if the attempt to counteract the threatening events
increases the level of arousal, leading to a disruption of slow-wave sleep maturation.
Furthermore we did not analyze subcortical (autonomic) activations and heart rate variability that
will be part of future studies.
Beside the increased obstructive apnoea/hypopnea index, the lack of differences between the infants
with ALTE and sleep periodic breathing compared to those without, may be explained by the small
size of the sample analyzed and, therefore, this does not allow any statistical analysis regarding
CAP parameters. Since CAP rate and CAP A1 percentage are increased in infants with ALTE and
sleep periodic breathing, we are only able to speculate that in these babies the occurrence of A1
subtypes may also be an attempt to counteract sleep respiratory events, confirming a weak feed-
back control (Milerad et al., 1989).
As already reported in the literature, also our group of infants with ALTE showed a higher
frequency of periodic breathing, gastroesofageal reflux and of other different conditions, (such as
paroxysmal events, abnormal movements, paradoxical breathing, low birth weight, dystocic
delivery, increased lactic acid and ammonemia), and increased apnoea/hypopnea index, compared
to controls (Kahn et al., 2003).
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Our results may add new information about the survival mechanisms in babies with ALTE, at least
during morning daytime-sleep. Our babies showed a higher level of arousal and an increased
NREM sleep discontinuity as expressed by CAP analysis, compared to controls, which seem to be
an opposite mechanism to arouse, if compared with that reported in future victims of SIDS: a higher
level of cortical arousal instead of subcortical activations (as indirectly expressed by the occurrence
of A1 subtypes).
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Table 1. Comparison between gender composition, clinical features, and sleep EEG pattern found
in the 2 groups of children included in this study.
ALTE (n=26) Controls (n=36) Chi-square test
n % n % Chi p<
Sex, females 14 53.8 16 44.4 0.53 NS
Clinical findings
Born at term 25 96.2 36 100.0 1.41 NS
Periodic breathing 20 76.9 0 0.0 40.88 0.00001
Gastroesofageal reflux 18 69.2 0 0.0 35.12 0.00001
Other conditions 6 23.1 0 0.0 9.20 0.0024
Sleep EEG pattern
TA HVS/no CAP 12 46.2 9 25.0 3.02 NS
HVS/spindles 6 23.1 5 13.9 0.87 NS
Full NREM sleep development 8 30.8 22 61.1 5.57 0.02
TA = Tracè alternant; HVS = High-voltage slow waves; NS = not significant.
Other conditions: suspected seizures (one subject, the seizures were not confirmed at follow up), paradoxical
breathing (one subject), low birth weight and perinatal distress (2 subjects who had also gastroesophageal reflux,
with normal psychomotor development), dystocic delivery (one subject, who had also gastroesophageal reflux,
normal psychomotor development), increased lactic acid and ammonemia (one subject, who had also
gastroesophageal reflux)
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Table 2. Comparison between age, sleep respiratory parameters, sleep architecture, and sleep
microstructure (CAP and arousals) obtained in the 2 groups of children included in this study.
ALTE (n=26;
n=14 for CAP)
Controls (n=36;
n=27 for CAP)
Mann-Whitney test
mean S.D. mean S.D. U p<
Age, years 3.4 2.37 3.2 2.17 467.5 NS
Respiratory parameters
Mean SaO2, % 96.8 1.85 97.0 1.11 434.5 NS
Obstructive apnoea/hypopnea index 3.0 5.31 0.0 0.14 142.5 0.000003
Sleep architecture
Time in bed, min 151.3 91.71 126.1 28.66 454.5 NS
Sleep period time, min 121.8 87.66 104.2 32.93 442.5 NS
Total sleep time, min 97.8 70.65 79.9 24.46 456.5 NS
Sleep latency, min 19.2 22.78 18.4 19.20 458.5 NS
REM sleep latency, min 23.8 29.68 10.8 17.29 337.0 NS
Sleep efficiency,% 64.3 18.52 64.1 16.33 464.0 NS
Wakefulness after sleep onset, % 16.3 17.88 22.4 13.72 336.5 NS
REM sleep, % 23.8 14.96 31.1 12.13 331.0 0.05
Sleep microstructure
CAP rate, % 19.0 12.36 14.0 8.50 148.5 NS
CAP time, min 7.3 4.97 8.2 7.46 177.0 NS
CAP A1 subtypes, % 38.6 24.82 83.2 13.81 26.0 0.000007
CAP A2 subtypes, % 14.1 8.28 11.8 10.69 155.5 NS
CAP A3 subtypes, % 15.1 19.16 5.0 4.93 103.0 0.018
CAP A duration, s 7.4 2.76 7.7 1.30 138.5 NS
CAP A1 subtype index, n/hour 17.0 13.28 19.8 14.13 173.5 NS
CAP A2 subtype index, n/hour 16.9 12.81 3.4 3.59 80.0 0.003
CAP A3 subtype index, n/hour 14.1 12.41 1.2 1.45 76.5 0.002
CAP B phase duration, s 25.0 5.93 22.1 3.99 131.0 NS
Arousal index, n/hour 18.6 7.36 12.1 3.53 202.0 0.00015
NS = not significant.
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Table 3. Comparison between age, sleep respiratory parameters, sleep architecture, and sleep
microstructure (CAP and arousals) obtained in the 2 subgroups of ALTE children identified on
the basis of the presence or absence of periodic breathing.
Periodic breathing
(n=20;
n=11 for CAP)
Nonperiodic
breathing (n=6;
n=3 for CAP)
Mann-Whitney test
mean S.D. mean S.D. U p<
Age, years 3.5 2.50 3.0 2.03 55.0 NS
Respiratory parameters
Mean SaO2, % 96.7 1.52 97.2 2.84 38.5 NS
Obstructive apnoea/hypopnea
index 3.8 5.85 0.4 0.55 27.5 0.05
Sleep architecture
Time in bed, min 156.7 100.02 133.3 59.44 58.0 NS
Sleep period time, min 123.8 96.05 115.2 57.43 53.0 NS
Total sleep time, min 105.0 77.37 73.6 35.95 49.0 NS
Sleep latency, min 20.4 22.22 15.4 26.38 41.0 NS
REM sleep latency, min 16.9 21.50 46.7 42.79 35.0 NS
Sleep efficiency,% 66.5 19.18 56.9 15.27 42.0 NS
Wakefulness after sleep onset, % 12.1 12.29 30.4 26.73 36.5 NS
REM sleep, % 26.3 15.90 15.6 7.28 28.0 NS
Sleep microstructure
CAP rate, % 19.1 12.78 18.6 13.27 NA
CAP time, min 7.7 5.48 5.9 2.51 NA
CAP A1 subtypes, % 41.9 26.80 26.2 11.08 NA
CAP A2 subtypes, % 13.6 8.94 15.8 6.33 NA
CAP A3 subtypes, % 11.7 10.61 27.7 39.00 NA
CAP A duration, s 7.4 2.89 7.3 2.84 NA
CAP A1 subtype index, n/hour 17.1 13.35 16.6 15.95 NA
CAP A2 subtype index, n/hour 16.4 12.26 18.9 17.56 NA
CAP A2 subtype index, n/hour 11.7 10.88 22.9 16.17 NA
CAP B phase duration, s 23.8 5.32 29.5 7.02 NA
Arousal index, n/hour 19.2 7.67 16.7 6.48 48.0 NS
NS = not significant; NA = not applicable.
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Figure legends
Figure 1. Correlation analysis between age and CAP rate (top panel) or arousal index (bottom
panel) in both groups of subjects included in this study.
Figure 2. Cyclic alternating pattern (CAP) Subtype A1—Slow electroencephalographic (EEG)
synchrony is the predominant activity, mostly composed by high-voltage delta bursts,
associated with regular respiratory pattern. Epoch 30 seconds, amplitude 200 µV.
Figure 3: CAP Subtype A2—Mixture of slow and fast EEG activities, including bursts of theta
rhythms, and other faster rhythms superimposed, associated or not with EMG activation,
associated with central apnea. Epoch 30 seconds, amplitude 200 µV.
Figure 4: CAP Subtype A3—EEG activity with predominant fast low-voltage rhythms; more than
50% of phase A is occupied by fast EEG activities, including EEG arousals, polyphasic bursts,
and high-voltage delta waves with an amplitude one-third higher, or more, than the background
activity, followed by theta and other faster rhythms, associated with central apnea. Epoch 30
seconds, amplitude 200 µV
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