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J. Sleep Res.

(2011) 20, 338347 Sleep in children


doi: 10.1111/j.1365-2869.2010.00882.x

Sleep in children with autism with and without autistic regression


FLAVIA GIANNOTTI, FLAVIA CORTESI, ANTONELLA CERQUIGLINI,
C R I S T I N A V A G N O N I and D O N A T E L L A V A L E N T E
Center of Pediatric Sleep Disorders, Department of Developmental Neurology and Psychiatry, University of Rome La Sapienza, Italy

Accepted in revised form 25 June 2010; received 24 January 2010

SUMMARY The purpose of the present investigation was to characterize and compare traditional
sleep architecture and non-rapid eye movement (NREM) sleep microstructure in a well-
dened cohort of children with regressive and non-regressive autism, and in typically
developing children (TD). We hypothesized that children with regressive autism would
demonstrate a greater degree of sleep disruption either at a macrostructural or
microstructural level and a more problematic sleep as reported by parents. Twenty-two
children with non-regressive autism, 18 with regressive autism without comorbid
pathologies and 12 with TD, aged 510 years, underwent standard overnight multi-
channel polysomnographic evaluation. Parents completed a structured questionnaire
(Childrens Sleep Habits QuestionnaireCSHQ). The initial hypothesis, that regressed
children have more disrupted sleep, was supported by our ndings that they scored
signicantly higher on CSHQ, particularly on bedtime resistance, sleep onset delay,
sleep duration and night wakings CSHQ subdomains than non-regressed peers, and
both scored more than typically developing controls. Regressive subjects had
signicantly less ecient sleep, less total sleep time, prolonged sleep latency, prolonged
REM latency and more time awake after sleep onset than non-regressive children and
the TD group. Regressive children showed lower cyclic alternating pattern (CAP) rates
and A1 index in light sleep than non-regressive and TD children. Our ndings suggest
that, even though no particular dierences in sleep architecture were found between the
two groups of children with autism, those who experienced regression showed more
sleep disorders and a disruption of sleep either from a macro- or from a microstructural
viewpoint.
keywords autism, autistic regression, polysomnography, sleep, sleep architecture

disorder not otherwise specied. Other rare, very severe


INTRODUCTION
disorders that are included in the autism spectrum disorders
Autism spectrum disorders (ASD) are characterized by varying are Rett syndrome and childhood disintegrative disorder
degrees of impairment in communication skills, social interac- (American Psychiatric Association, 2000). The precise neuro-
tions and restricted, repetitive and stereotyped patterns of biological causes of autism and other ASD have yet to be
behaviour, ranging from a severe form, called autism, to a found, but some in cases genetic abnormalities have been
milder form, Asperger syndrome. If a child has symptoms of identied. In about one-third of children, autism becomes
either of these disorders, but does not meet the specic criteria apparent after a period of apparently normal or only relatively
for either, the diagnosis is called pervasive developmental delayed development, with as a loss of previously acquired
abilities (Davidovitch et al., 2000; Goldberg et al., 2003). The
Correspondence: Flavia Giannotti MD, Center of Pediatric Sleep main clinical features of this phenomenon, which has been
Disorders, Department of Developmental Neurology and Psychiatry,
University of Rome La Sapienza, Via dei Sabelli 108, 00185 Rome,
dened as autistic regression, is the loss of spoken language,
Italy. Tel.: +390644712219; fax: +39064957857; e-mail: avia.gian but social interests and other communicative skills are often
notti@uniroma1.it also aected. Regression typically takes place between 1 and

338  2010 European Sleep Research Society


Sleep in autism 339

3 years of age, with a peak around 24 months. Estimates of the autism and severe mental retardation, Miano et al. (2007)
prevalence of this regressive pattern range between 15% and found reduced total sleep time and duration associated with
40% of children with autism (Davidovitch et al., 2000; shorter REM latency. In contrast, Malow et al. (2006), in a
Goldberg et al., 2003; Lord et al., 2004; Ozono et al., 2005; polysomnography (PSG) study on a group of selected children
Rice, 2007; Richler et al., 2006). Even though the mechanisms with autism without mental retardation, found lower sleep
underlying regression are still unknown, it has been postulated eciency, prolonged sleep latency, decreased REM sleep and
that anatomical remodelling of the brain with synaptic growth increased NREM Stages 34 and reported higher prevalence of
and pruning during the second year of life is impaired in sleep problems compared to children with autism without sleep
autism due to a gene-based mechanism (Carper and Cour- problems and typically developing (TD) children.
chesne, 2005), resulting in a variable behavioural phenotype. Moreover, the microanalysis of the sleep electroencephalo-
The core decits of autism and their underlying neurophys- gram (EEG) structure have led to the identication of the
iology and neurochemistry may predispose children with ASD cyclic alternating pattern (CAP) that provides a further
to intrinsic stressors that threaten sleep. According to available approach to the classication of sleep and amplies the
studies, sleep problems are endemic in children with ASD and existing rules by Rechtschaen and Kales (1968), representing
have been reported clinically in an estimated 4080% (Hering a marker of instability of the sleep process. CAP consists in a
et al., 1999; Honomichl et al., 2002; : Liu et al., 2006; Polimeni prolonged oscillation of the arousal level between two
et al., 2005; Schreck and Mulick, 2000; Wiggs, 2001). The reciprocal functional states termed phase A (greater arousal
main clinical manifestations are resistance to go to bed at an level; cluster of EEG transient) and phase B (lesser arousal
appropriate time, diculty in initiating sleep, frequent and level, interval between the successive clusters) and is considered
prolonged night-time awakenings or early morning awaken- one of the elementary structures in the organization of NREM
ings, irregularity in sleep wake pattern and poor sleep routines sleep Terzano et al., 1985, 1988; Terzano and Parrino, 2000).
(Giannotti et al., 2006; Krakowiak et al., 2008; Takase et al., Using CAP analysis, Miano et al. (2007) found peculiarities in
1998; Williams et al., 2004). sleep microstructure in children with autism characterized by a
In one of our previous studies, we found that over 50% of low CAP rate associated with a low A1 index and a slight
children with autism had at least one sleep problem (Giannotti increase of A2 and A3 subtypes, indicative of subtle alteration
et al., 2006), with a peak age of onset during the second year of of the arousal level of uctuations during NREM sleep.
life, similar to what is known for autistic regression. The The conicting data on sleep architecture in ASD might be
remarkable temporal overlap between peak age of onset of due to the heterogeneity in age, IQ and comorbidity with other
sleep problems and that of regression might be coincidental, physical and psychological disorders, as well as the inclusion of
but could also be interpreted as the expression of a biologically mixed diagnostic group in the same cohort that characterizes
determined substrate which inuences a particular develop- the majority of the studies conducted. This emphasizes the
mental trajectory in critical phase of development. Addition- need for patients selection process based on more stringent
ally, in a more recent questionnaire-based study, we found that diagnostic criteria.
regressed children showed more disrupted sleep wake patterns To the best of our knowledge, no studies specically
than non-regressed children (Giannotti et al., 2008). More investigated sleep architecture of children with autism who
recently Wiggins et al. (2009), evaluating the phenomenon of displayed regression. As a part of a larger study examining
autistic regression using population-based data, reported that sleep wake patterns in ASD, the purpose of the present
regressed children showed more sleeping diculties than did investigation was to characterize and compare traditional sleep
children with an ASD without documented regression. architecture and NREM sleep microstructure in a well-dened
Although conicting in some aspects, polysomnographic cohort of children with regressive and non-regressive autism,
studies have conrmed sleep disruption in children with ASD and in TD children. We hypothesized that children with
quite consistently (Diomedi et al., 1999; Elia et al., 2000; regressive autism would demonstrate a greater degree of sleep
Limoges et al., 2005; Malow et al., 2006; Miano et al., 2007, disruption either at a macrostructural or microstructural level
2008). In particular, a study on sleep architecture in autism and more problematic sleep as reported by parents. Further-
found normal rapid eye movement (REM) sleep percentage more, to avoid potential comorbid conditions and to enhance
and increased REM density (Elia et al., 2000), whereas a patient compliance with the PSG study, we excluded subjects
signicant reduction of REM sleep, an increase of undieren- with moderate to profound mental retardation.
tiated sleep and increased number of awakenings with a clear
abundance of spindle activity not only during Stage 2 non-
REM (NREM) sleep but also during slow wave sleep (SWS) METHODS
and REM sleep was reported by Diomedi et al. (1999). Other
Participants
investigators found longer sleep latency, more frequent awak-
enings, lower sleep eciency, increased duration of Stage 1 Participants were recruited from referrals to the developmental
NREM sleep and decreased SWS as well as decreased density disabilities speciality clinic of the Department of Developmen-
of spindle activity in a group of high functioning adults with tal Neuropsychiatry over a 24-month period. Inclusion criteria
autism (Limoges et al., 2005). In a study on children with were: (1) clinical diagnosis of autistic disorder according to the

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340 F. Giannotti et al.

Diagnostic and Statistical Manual of Mental Disorders, 4th probes the intensity of the loss, the age when the loss was rst
edition, Text Revision (DSM-IV TR) criteria (American apparent, the duration of the loss and the association with
Psychiatric Association, 2000), conrmed by the Autistic physical illness. In order to be eligible for a loss of language
Diagnostic InterviewRevised 3rd edition (ADI-R) (Rutter skills, it must be established that the child has attained
et al., 2003), and the Autism Diagnostic Observation Sche- sucient language skills, such as the communicative use of at
duleGeneric (ADOS-G) (Lord et al., 2000); (2) age between 5 least ve words on a daily basis. Children were classied as
and 10 years; (3) non-verbal IQ > 50 assessed by the Leiter regressed if they received a score of 1 on question 11 (loss of
International Performance Scale with revised norms (Roid and at least ve words) and or 2 on question 20 (loss of general
Miller, 1997); and (4) absence of other serious neurological, skills) and or 2 on question 25 (probable or denite loss of
psychiatric, bipolar disorder or medical conditions. social interest and engagement). The loss of skills had to have
For all patients a detailed history was taken and full physical taken place before 36 months of age and lasted at least
and neurological examinations were performed. The absence 3 months (Lord et al., 1994).
of associated pathologies was ascertained by a diagnostic The presence of sleep disturbances was not a selection
protocol, which included high-resolution banding karyotype, criterion. However, children with breathing disturbances
brain magnetic resonance imaging and neurometabolic screen- during sleep were excluded clinically by investigating the
ing. Multi-modal evoked responses and prolonged awake and presence at least one of the following criteria: parental report
sleep EEG were also performed to exclude the most frequently of snoring heavy or loud breathing, snoring more than half the
associated conditions such as epilepsy, phenylketonuria, fragile time, snoring loudly, trouble breathing, sleeping with open
X syndrome or other chromosomal disorders, tuberous scle- mouth, congested nose at night, stopping breathing at night,
rosis, visual hearing or motor impairment and other structural shaking sleeping child to breathe, awakening with a snoring
alterations of the central nervous system. No subjects with sound, physical examination investigating tonsillar hypertro-
autism were obese and the parents did not report snoring at the phy and being overweight.
time of the study. All subjects had a normal haematological The nal sample consisted of three groups of children: one
screening, were free of any infections, inammatory or allergic with non-regressive autism [22 subjects, male sex 75%, mean
reactions for at least 2 months prior to blood samplings and age 5.5 years, standard deviation (SD) 2.1], one with regressive
were drug-free for at least 6 months prior to the beginning and autism (18 subjects, male sex 80%, mean age 5.10 years, SD
throughout the study. In order to exclude the associated 3.9) and one with TD (12 subjects, male sex 75%, mean age
behaviours and psychiatric comorbidity seen frequently in 5.8 years, SD 2.4).
autistic disorder, parents, who were largely mothers, com- Informed written consent was obtained from the parents
pleted the Child Behavior Checklist (CBCL) (Achenbach and of all participants to the study. The study was approved by
Rescorla, 2000) during the initial screening. Children reporting the Ethic Review Board of Rome University School of
a T-score 70 on any of the syndrome scales and three Medicine.
composite scores were not included in this study.
A non-convenience TD cohort was selected based on age
Measures
and gender recruited from area schools and recreation centres,
then screened for the absence of neurodevelopmental dis- The ADI-R is a semi-structured standardized parent interview
orders, including ASD, using the ADOS-G and the absence of designed to assess the presence and severity of symptoms of
psychopathology on the basis of internalizing problems, autism. An ADI-R diagnosis of autism is conferred on the
externalizing problems and total problems CBCL composite basis of an algorithm that distinguishes reliably children with
scores. autism from those with other developmental delays or typical
According to inclusion criteria, a total of 42 subjects with development. A diagnosis of autism was assigned with scores
autism, selected from 130 patients with autism, and 12 TD of 8 (7 if non-verbal), 10 and 3 for communication, social and
children were recruited for the study. Of the 78 children with behaviour, respectively.
autism excluded, 19 suer from epilepsy, 25 showed EEG The ADOS-G is a semi-structured observational play-based
abnormalities, 2 had tuberous sclerosis, 3 had fragile X instrument, which discriminates between the narrower deni-
syndrome, 7 showed severe mental retardation and 22 showed tion of autism and the broader PDD-NOS on the basis of
psychiatric comorbidity. severity. Because not all children with autism were verbally
Children with autism were classied further according to uent Module 1 or Module 2 were used, while Module 3 was
whether or not their parent had reported a history of loss of used for TD children. Diagnostic algorithm scores for
skills (autistic regression) on the ADI-R. The occurrence of reciprocal social interaction and communication are calculated
regression is explored in two independent sections of the ADI- with cuto values for Autism and Autistic Spectrum Disor-
R: language skill loss and general skill loss. The denition of ders. Items are scored from 0 (typical for age or not autistic in
loss within the ADI-R is twofold: it requires that any loss be quality) to 3 (unquestionably abnormal and autistic in
coded only if the skill was established initially for at least quality). Items are summed into a social communication
3 months, and the loss of skill must last at least 3 months. For algorithm score that provides ranges for ASDs (711 points)
the specic features of the skill that were lost, each section and autistic disorder (12 points).

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Sleep in autism 341

The CBCL is a parentally completed questionnaire validated synchronized video monitoring and a sensitive intercom were
in children aged 1.518 years, used to provide normative also used. Analogue electrophysiological signal was digitized
values for domains of daytime behaviour in children. This using a commercially available PSG system (Embla N7000
measure was chosen because is applicable for TD children or and Somnologica Software; Medcare Flaga hf., Reykjavik,
with neurodevelopmental problems. The age-appropriate Iceland) and video recording were acquired synchronously to
module (1.55 years or 618 years) was completed by parents. the EEG data. The data were digitized with a sampling rate of
A T-score of 70 and above (at least 2 SD above the mean for 256 Hz. Then, sleep signals with duration of 30 s were stored
the general population) is generally considered to be clinically on hard disk in European data format (Kemp et al., 1992). The
signicant, and was used as the criterion for clinical signif- measured EEG signals were rst acquired with a wide-band
icance in the present study. analogue lter (0.001)70 Hz) and then digitally band-pass
Participants current level of non-verbal cognitive functioning ltered at 0.1)50 Hz.
was evaluated using the Leiter International Performance Scale
with revised norms (Roid and Miller, 1997) for individuals
Procedures
between 2 years and 20 years of age. TD children were admin-
istered individually one of the following standardized measures All parents completed the CSHQ, and in order to obtain a
of intellectual functioning. The Wechsler intelligence sca- measure of the childs habitual bedtime and wake time sleep
lesthe Wechsler Preschool and Primary Scale of Intelligence, diaries were collected for 1 week prior to the laboratory PSGs.
3rd edition (WPPSIIII) (Wechsler, 2008) and the Wechsler Parents were invited to record the diary for the previous 24 h
Intelligence Scale for Children, 3rd edition (WISCIII) (Wechs- each morning after the child awakened.
ler, 2006)are standardized intelligence tests designed for indi- All children underwent PSG multi-channel polysomnogra-
viduals across the lifespan. In order to compare non-verbal phy for two consecutive nights in the laboratory in order to
IQ more eectively, we considered WPSSI Performance IQ avoid the rst-night eect. No sedation or sleep deprivation
and WISC Perceptual Reasoning Index for TD children. was used to induce sleep. Children were instructed to avoid
The Childrens Sleep Habits Questionnaire (CSHQ) (Owens products containing caeine during the week prior to the PSG
et al., 2000) is a parent-completed questionnaire used in a large study. All recordings started at the patients usual bedtime and
number of studies to examine sleep behaviour in children. This continued until spontaneous awakening. To alleviate separa-
instrument has shown good psychometric properties and is tion anxiety, the parent slept in a bed next to their child.
clinically useful for screening of sleep problems in TD children
at these young ages as well as in children with diverse
Analysis of polysomnographic recordings
neurodevelopmental diagnoses. It includes items relating to a
number of key sleep domains grouped conceptually into eight Sleep macrostructure. Sleep was subdivided into 30-s epochs
subscales reecting: (1) bedtime resistance; (2) sleep onset and sleep stages were scored according to the standard
delay; (3) sleep duration; (4) sleep anxiety; (5) night wakings; criteria by Rechtschaen and Kales (1968), following the
(6) parasomnias; (7) sleep disordered breathing; and (8) recommendation made by Scholle and Schafer (1999). The
daytime sleepiness. In the present study CSHQ showed following conventional sleep parameters were evaluated: time
adequate internal consistency in clinical and control groups in bed (TIB); total sleep time (TST): the time from sleep onset
(Cronbachs alpha of 0.80 and 0.85, respectively). The alpha to the end of the nal sleep epoch minus time awake; sleep
coecients for CHSQ subscales ranged from 0.70 (night eciency (SE%): the percentage ratio between total sleep
wakings) to 0.91 (sleep disordered breathing) across all groups. time and time in bed (TST TIB 100); sleep latency (SL):
The sleep diary is a standardized weekly form that asks the the start of three consecutive epochs Stage 1 or the rst epoch
parent to note the specic sleep-related events on a daily basis: of any deeper sleep stage in minutes; REM latency: time from
times of sleep onset, awakenings from sleep, subsequent sleep onset to the rst stage REM epoch; wake after sleep
returns to sleep, bedtime and waking times and times of day onset (WASO) expressed in minutesnumber of stage
naps. shifts h (SS h); number of awakenings h (AWN h); per-
centage of TST spent in stage WASO (W%) and in sleep
stage 1 (NREM 1%), Stage 2 (NREM 2%), SWS% and
Video-polysomnography
Stage REM (REM%).
An overnight attended PSG for each participant was per- Periodic leg movements during sleep (PLMS) were detected
formed in the sleep laboratory. following the recent criteria established by the American
EEG recordings and electrode placement were performed Academy of Sleep Medicine (AASM) (Iber et al., 2007). PLMS
according the 1020 International System and the PSG were dened as a sequence of four or more limb movements of
montage included at least 11 EEG channels (Fp1, Fp2, C3, 0.55.0 s in duration that were separated by more than 5 s and
C4, Cz, P3, P4, T3, T4, O1, O2) referenced to contralateral less than 90 s and the amplitude of which was greater than or
mastoid, left and right electroculogram (EOG), chin electro- equal to 25% of toe dorsiexion during calibration. The
myogram (EMG), left and right tibialis anterior EMG and PLMS index was calculated by dividing the number of PLMS
electrocardiogram (ECG), one derivation. Infrared EEG- by the total number of hours of sleep (AASM, 2005). To avoid

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342 F. Giannotti et al.

the rst-night eect, only the results from the second night
Statistical analysis
were included in the analyses.
All data were coded and computerized with statistical analysis
Sleep microstructure. CAP was scored according to the performed using statistica version 6 package for Windows
currently accepted criteria (Bruni et al., 2002, 2005; Terzano (StatSoft Inc., Tulsa, OK, USA). Descriptive statistics (means,
et al., 2001), as shown in Table 1. SD) were calculated for all continuous variables and frequen-
A CAP is formed by electrocortical events indicated by cies were generated for non-continuous variables. Unpaired
periodic EEG activity occurring during NREM sleep and Students t-test or Pearsons chi-square test were used to test
characterized by transitory events that recur at regular for group dierences as appropriate. Multivariate statistics
intervals in the range of seconds during NREM sleep. These [analysis of covariance (ancova)] included health status
events are clearly distinct from the background EEG rhythm (regressed, non-regressed, TD), as between-subjects factor
as abrupt frequency shifts or amplitude changes. were performed on PSG variables, controlling for age. We
The following CAP parameters were evaluated: CAP rate conducted post hoc multiple pairwise comparisons using the
(percentage of total NREM sleep time occupied by CAP Schee tests to control for overall Type 1 error and to
sequences); percentage and duration of each A phase subtype; determine which group comparisons were signicant across
A1 index (number of phase A1 per hour of NREM sleep and variables.
of Stage 1, Stage 2 and SWS sleep stages; A2 index (number of Because distributions were positively skewed for most
phase A2 per hour of NREM sleep and of Stage 1, Stage 2 and variables, a log-transform was applied to variables whose
SWS sleep stages; A3 index (number of phase A3 per hour of skewness statistics was greater than twice the standard error
NREM sleep and of Stage 1, Stage 2 and SWS sleep stages; (these included all but the following: Stage 2, Stage 4 and
duration of B phases; and number and duration of CAP SWS). Group dierences were also compared by eect size,
sequences. All these variables were analysed by means of the measured by eta-squared (g2), a measure of contrast between
Hypnolab version 1.2 sleep software analysis (SWS Soft, groups independent of sample size (Olejnik and Algina,
Troina, Italy). All the recordings were scored visually. For the 2003). The P level was set at <0.05 for statistical
purposes of the current research, all recordings were rescored signicance.
by three expert scorers (F.G., F.C., C.V.) blinded to subject
identity and health status. A randomly chosen primary scorer
RESULTS
identied CAP events, on the basis of predened criteria. A
second scorer reviewed this initial scoring. When there was a The nal sample consisted of three groups of children: one
discrepancy for any event, a third scorer reviewed the with non-regressive autism (22 subjects, male sex 75%, mean
questionable event and the majority score was used. Sleep age 5.5 years, SD 2.1), one with regressive autism (18
parameters derived were tabulated for statistical analysis. Of subjects, male sex 80%, mean age 5.10 years, SD 3.9) and
the total participants who met inclusion criteria, two were one with TD (12 subjects, male sex 75%, mean age 5.8 years
excluded from the analysis because of electrode artefact or SD 2.4).
equipment malfunction. Among the children with ASD group, 25 had a mild mental
retardation and 15 other subjects showed borderline intellec-
tual functioning. All TD children showed normal intellectual
Table 1 Cyclic alternating pattern (CAP) scoring criteria functioning.
Transient events Regressed and non-regressed children did not dier in their
abrupt EEG shiftslow or fastfrom the sleep Leiter-R Brief IQ [61.35, SD 20.30 versus 66.12, SD 24.05; not
electroencephalogram (EEG) background activity signicant (NS)]. In the regressive group the average age at
duration of events: lasting more than 2 and less than 60 s which parents reported the main loss of skills was 20 months
Phase A
(range 1230 months; SD 4.86).
A1 synchronized EEG patterns (intermittent alpha rhythms and
sequence of vertex sharp waves in Stage 1; sequence of two or Among children with regression, language loss was noted in
more K-complexes in Stage 2 and delta bursts in slow wave 74%, social skills losses were noted in 17% of records and
sleep (SWS) general losses were noted in 9%.
A2 desynchronized EEG patterns preceded by slow high voltages Scores for CSHQ variables and from the sleep diary are
waves (K complexes with alpha or beta rhythms)
presented in Table 2. Analysis of sleep diaries showed that
A3 desynchronized EEG patterns alone
Phase B children in the regressed group woke more frequently during
EEG background activity according to each sleep stage the night than non-regressed, and the average time they spent
CAP cycle awake during the night was signicantly longer. Several
Each cycle consists of a phase A and a phase B lasting between children in the regressed group were awake for periods of
2 and 60 s
1 h or more and slept for a signicantly shorter length of time
CAP sequence
Two or more CAP cycles beginning with a phase A and ending (P < 0.001). Furthermore, children in the regressed group
with a phase B were found to have signicantly longer sleep latency than
children in the non-regressed group. Lights were turned o for

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Sleep in autism 343

Table 2 Sleep variables and Childrenss Sleep Habits Questionnaire (CSHQ) subscales scores children with autism (non-regressed and regressed)
and typically developing children

Non-regressed Regressed TD

Sleep variables Mean (SD) (n = 22) Mean (SD) (n = 18) Mean (SD) (n = 12) F-value for group eect P

Bedtime (hh:mm) 22.15 (1.07) 23.30 (1.12) 21.30 (0.50) 100.42 <0.001abc
Rise time (hh:mm) 07.20 (1.26) 7.00 (1.24) 7.15 (0.26) 5.41 <0.01bc
Sleep length (min) 530 (86) 430 (95) 580 (46) 88.90 <0.001abc
Sleep latency (min) 31.23 (30.56) 40.51 (28.88) 12.59 (5.08) 42.86 <0.05a <0.001bc
CSHQ subdomains scores
Bedtime resistance 10.10 (3.42) 13.8 (3.00) 7.20 (2.10) 102.01 <0.001abc
Sleep onset delay 1.70 (0.92) 2.40 (0.9) 1.00 (0.29) 70.14 <0.001abc
Sleep duration 4.73 (2.35) 6.50 (2.40) 3.10 (0.20) 75.38 <0.001abc
Sleep anxiety 4.90 (2.10) 4.70 (2.89) 4.68 (0.99) 0.44 NS
Night-wakings 4.40 (1.76) 6.90 (1.77) 3.10 (0.57) 93.91 <0.001abc
Parasomnias 8.10 (1.73) 8.20 (2.50) 7.90 (1.10) 0.98 NS
Sleep disordered breathing 3.31 (0.88) 3.30 (0.99) 3.20 (0.89) 0.91 NS
Daytime sleepiness 10.10 (2.51) 10.20 (3.90) 9.92 (2.90) 0.90 NS

One-way analysis of covariance for continuous variables controlled for age. NS, not signicant. aNon-regressed versus regressed; bnon-regressed
versus typically developing (TD); cregressed versus TD.

sleep signicantly later and children in the regressed group fell


Sleep macrostructure
asleep at a signicantly later time. Moreover, regressed
children woke up about 20 min earlier than non-regressed ancovas were conducted to assess between-group dierences in
children. Post hoc contrast analyses showed that regressed sleep architecture (Table 3).
children had signicantly higher CSHQ total scores than non- These analyses revealed a signicant group main eect for
regressed autistic children, and both groups scored more than almost all sleep variables. The eect size was modest to large,
typically developing controls (respectively, 55.6 versus 48.6 with g2 of 0.77 for decreased of slow wave sleep, indicating that
versus 39, one-way ancova, F(2.25) = 85.78; P < 0.001). autism itself accounted for 77% of the overall variance of this
Regressed children showed signicantly higher scores on variable. Sleep eciency, total sleep time, sleep latency and
bedtime resistance, sleep onset delay, sleep duration and night stage NREM Stage 2 had a less prominent but still sizeable
wakings CSHQ subdomains than non-regressed children and, eect. Within-group post hoc analyses indicated that children
as expected, both more than TD children, while no signicant with regressive autism had signicantly less ecient sleep,
dierences were found for sleep anxiety, parasomnias, sleep- decreased total sleep time, prolonged sleep latency, prolonged
iness and sleep disordered breathing CSHQ subdomains across REM latency and more percentage of time awake after sleep
all groups. onset than the children with non-regressive autism and TD

Table 3 Polysomnographic macrostuctural data in children with autism (non-regressed and regressed) and typically developing children

Non-regressed Regressed TD

Mean (SD) (n = 22) Mean (SD) (n = 18) Mean (SD) (n = 12) F P g2 Post hoc

TST (min) 525.20 (52.73) 451.30 (58.30) 610.20 (66.38) 29.10 <0.001 0.48 a,b,c
SE (%) 84.18 (6.95) 74.55 (8.56) 94.70 (2.77) 28.70 <0.001 0.46 a,b,c
SL (min) 35.25 (18.77) 53.10 (24.60) 20.40 (5.47) 15.94 <0.05 0.35 a,b,c
WASO (%) 9.55 (5.43) 15.90 (9.31) 2.10 (2.75) 17.56 <0.001 0.38 a,b,c
AWN h 1.98 (1.51) 3.34 (2.35) 0.36 (0.19) 7.30 <0.01 0.18 b,c
REM L (min) 154.02 (97.74) 198.91 (101.51) 99.65 (21.21) 10.05 <0.01 0.22 b,c
Stage 1% 9.12 (4.74) 8.96 (9.57) 7.25 (1.08) 1.05 NS 0.02 NS
Stage 2% 47.65 (5.47) 54.50 (8.02) 41.30 (2.38) 15.91 <0.001 0.40 c
SWS% 19.35 (4.93) 12.89 (3.11) 26.67 (2.03) 15.55 <0.001 0.77 c
REM (%) 14.70 (6.56) 7.75 (5.62) 22.68 (1.60) 5.05 <0.01 0.18 c
SS h 10.42 (4.43) 10.13 (6.98) 8.55 (3.07) 4.14 <0.5 0.08 NS

One-way analysis of covariance controlled for age. TST, total sleep time; SL, sleep latency; SWS, slow wave sleep; REM L, rapid eye movement
(REM) latency; SS h, stage shifts per hour; AWN h, awakenings per hour; SD, standard deviation; SE, sleep efciency; WASO, wake after
sleep onset; g2 is the effect size; anon-regressed versus regressed; bnon-regressed versus typically developing (TD); cregressed versus TD; NS, not
signicant.

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344 F. Giannotti et al.

groups. Moreover, children with autism and developmental was found in light sleep as well as an increased A2 and A3
regression showed a statistically signicant lower time in REM index in children with autism and regression.
and in NREM SWS and higher in NREM 2 sleep compared to
TD children. Also stage shifts were slightly increased (without
DISCUSSION
statistical signicance) in both groups with autism. All children
had a periodic leg movement index (PLMI) with values <5 To the best of our knowledge, this study represents the rst
(non-regressive autism 1.4 1.2; regressive autism 1.5 0.9; attempt to evaluate sleep architecture in subgroups of children
TD 1.2 0.8; NS). with narrowly dened autism without other coexistent pathol-
ogies. Consistent with our hypothesis, this study has suggested
that a history of autistic regression is associated strongly with
Sleep microstructure
disrupted sleep. The ndings we present reinforce the idea of a
CAP analysis results (Table 4) revealed that both groups with marked alteration of sleep pattern in children with regressive
autism had lower total A1 percentages and increased A2 and autism. Notwithstanding that the type of sleep alterations did
A3 percentages than TD children. not dier from those reported by children with non-regressive
It is to be noted that in this case the eect size was modest to autism, consisting mainly in decreased total sleep time,
large, which means that autism itself accounted for 80% (low prolonged sleep latency, prolonged REM latency, less per-
A1 percentage), 58% (increased A2 percentage) and 55% centage time in REM, less percentage time in SWS, more time
(increased A3 percentages) of the overall (eect+error) in NREM 2 sleep and more WASO in both groups, regressed
variance. These ndings were statistically signicantly more children showed a more severe sleep alteration.
evident in children with regression. Post hoc comparison Data from previous PSG studies in children with autism
analyses showed that children with regressive autism had a are controversial. In particular, Aihara and Hashimoto
lower total CAP rates and lower CAP rates during Stages 1 (1986), reporting a similar amount of REM sleep in children
and 2 sleep than TD children and signicantly reduced CAP with autism and normal controls, observed an abnormal
rates during Stage 2 sleep than children with non-regressive presence of spindling-like activity during REM and the
autism. This latter group showed a lower CAP rate than TD presence of rapid eye movements during light sleep, suggest-
children only during Stage 2. In particular, a lower A1 index ing a defect of maturational process in these children. Elia

Table 4 Polysomnographic microstructural data in children with autism (non-regressed and regressed) and typically developing children

Non-regressed Regressed TD

Mean (SD) (n = 22) Mean (SD) (n = 18) Mean (SD) (n = 12) F P g2 Post hoc

Total CAP rate (%) 31.28 (5.20) 27.12 (4.60) 34.45 (5.40) 3.25 <0.5 0.10 c
In S1 (%) 17.68 (14.13) 12.24 (11.27) 22.67 (1.50) 3.15 <0.5 0.11 c
In S2 (%) 18.28 (5.90) 14.22 (8.10) 25.34 (5.34) 8.15 <0.01 0.25 a,b,c
In SWS (%) 40.55 (13.74) 42.34 (15.53) 45.88 (2.90) 1.05 NS 0.03 NS
A1 (%) 55.20 (4.33) 45.65 (3.17) 72.53 (2.04) 102.03 <0.001 0.80 a,b,c
A2 (%) 24.24 (2.87) 27.97 (1.21) 14.07 (0.82) 52.92 <0.01 0.58 a,b,c
A3 (%) 20.46 (5.10) 26.38 (3.31) 13.50 (1.78) 30.19 <0.001 0.55 a,b,c
A1 duration (s) 5.10 (0.25) 5.00 (0.30) 6.18 (0.38) 25.26 <0.01 0.45 b,c
A2 duration (s) 6.15 (0.80) 5.92 (1.21) 8.45 (0.88) 30.00 <0.01 0.56 b,c
A3 duration (s) 14.65 (2.20) 15.60 (1.71) 16.41 (1.02) 4.05 <0.05 0.15 c
A1 index 25.56 (8.45) 21.45 (8.20) 30.87 (8.01) 4.25 <0.01 0.30 c
In S1 18.30 (12.57) 10.55 (8.96) 21.28 (8.49) 3.18 <0.5 0.10 c
In S2 25.14 (8.10) 17.22 (8.04) 30.88 (12.25) 8.05 <0.01 0.40 c
In SWS 62.27 (22.97) 61.45 (25.42) 62.71 (4.55) 0.25 NS 0.01 NS
A2 index 5.22 (2.22) 5.81 (2.16) 4.58 (0.74) 0.88 NS 0.04 NS
In S1 4.22 (3.05) 14.45 (3.17) 3.28 (2.97) 27.28 <0.01 0.45 b,c
In S2 14.56 (9.89) 12.45 (6.69) 8.44 (2.78) 4.05 <0.5 0.11 b,c
In SWS 3.75 (2.38) 2.35 (3.56) 5.38 (1.31) 4.00 <0.05 0.10 c
A3 index 4.90 (2.45) 5.45 (3.04) 4.00 (0.44) 1.05 NS 0.05 NS
In S1 17.08 (6.90) 19.24 (10.04) 11.32 (9.37) 3.89 <0.5 0.14 c
In S2 6.72 (3.78) 7.88 (4.37) 6.72 (0.85) 0.95 NS 0.02 NS
In SWS 4.79 (2.24) 5.09 (2.22) 2.96 (0.51) 6.05 <0.01 0.18 b,c
B duration (s) 22.16 (2.86) 21.88 (2.46) 23.95 (0.77) 4.05 <0.01 0.14 c
Sequence duration (s) 168.58 (36.43) 159.55 (30.20) 182.98 (31.35) 1.98 NS 0.04 NS
No. of sequences 46.34 (10.36) 48.45 (9.60) 37.25 (3.29) 17.95 <0.01 0.44 b,c

CAP, cyclic alternating pattern; S1, Stage 1; S2, Stage 2; SWS, slow wave sleep; g2, effect size; anon-regressed versus regressed, bnon-regressed
versus typically developing (TD); cregressed versus TD; NS, not signicant.

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Sleep in autism 345

et al. (2000) reported a reduced total sleep time, a normal of A2 and A3 subtypes in children with autism and develop-
percentage of sleep NREM stages and REM sleep and a mental regression. It has been reported widely that A1
decreased latency to rst REM period. Diomedi et al. (1999) subtypes are indicative of neuronal mechanism for NREM
found an increased number of interspersed wakefulness and sleep maintenance while subtypes A2 and A3 are the expres-
awakenings, increased undierentiated sleep, reduced REM sion of NREM sleep disruption (Terzano and Parrino, 2000).
sleep, fragmentation of REM period due to frequent intru- In the build-up to and maintenance of deep sleep, activation
sion of NREM sleep, increased REM density and more events are composed basically of subtypes A1, which could
latency to the rst REM sleep episode. Consistent with play an important role in protecting sleep continuity from light
results of the latter study we found reduced REM sleep, but sleep to deep sleep. However, in contrast to that reported by
also a prolonged latency to rst REM episode, mainly in Miano et al. (2007), who found the low A1 percentage in SWS,
regressed children with autism. Conversely, Miano et al. we found it only during light sleep. It must be noted that in this
(2007) did not nd any dierence in percentage of NREM study Miano et al. (2007) also included children with severe
stages and REM sleep, but only a shorter sleep time and rst mental retardation, who represent more than half of their
REM latency compared to controls in a sample of children patients, while in our study we excluded children with an IQ
with autism and mental retardation. lower than 50. As already stated, SWS represents a crucial
The literature commonly emphasized the importance of a component of the hypothesized synaptic downscaling during
relationship between REM sleep and intellectual functioning: sleep, probably important for the cognitive processing (Ferini-
the greater the level of mental retardation, the lower the Strambi et al., 2004; Ferri et al., 2008); thus, as stated by
amount of REM sleep (Castaldo and Krynicki, 1973; Espie Miano et al. (2007) the reduction of A1 in SWS in their sample
et al., 1998). However, many studies suggested that sleep might be related to the degree of mental retardation. In
patterns of children with autism dier from other develop- agreement with this hypothesis, a more recent study (Miano
mental disabilities (Krakowiak et al., 2008; Richdale and et al., 2008) found a reduction of A1 in SWS in subjects with
Prior, 1995). In the study by Diomedi et al. (1999), which Down syndrome and fragile X syndrome, conrming that this
compared sleep patterns of dierent developmental disabilities, alteration might be related to the level of mental retardation.
children with autism showed less REM sleep and more Moreover, another dierence between our study and that of
undierentiated sleep even though the level of mental retar- Miano et al. (2007) regards the childrens age, which we have
dation was consistent across groups. Similarly, in the current kept within a narrow range in consideration of the age-
study regressed children showed more disrupted sleep patterns dependency of CAP parameters (Bruni et al., 2002, 2005).
than those without regression, even though the level of mental The low CAP rate with a attention decit hyperactive
retardation did not dier signicantly between the groups. On disorder (ADHD) lower amount of A1 during light sleep
the basis of our ndings, it is quite plausible that children with found in our study has already been described in children with
autism, mainly those who displayed regression, suer from an (Miano et al., 2006), and it might therefore not be considered a
intrinsic sleep problem that could be related to an underlying specic feature but an expression of a dysregulation of arousal
pathophysiology of this disorder. Several neurotransmitter level of uctuations during NREM sleep, particularly evident
systems, including gamma aminobutyric acid, serotonin and in, but not exclusive to, children with autism and regression.
melatonin, implicated in promoting sleep and establishing a Some limitations of the study should be taken into account.
regular sleep wake cycle, are aected by autism, and their Even though we did not include children with respiratory
aberration in autism may be responsible for a component of disturbances, habitual snoring or with obesity, we are not
the prevalent sleep alterations (Levitt et al., 2004). Develop- able to exclude polysomnographically the presence of sleep
mental abnormalities of serotonin synthesis have been dem- breathing disorders, as we did not record respiratory param-
onstrated in children with autism consisting in increased level eters in order to improve PSG compliance. Moreover, even
of synthesis capacity and asymmetry of serotonin production though we did not include children with moderate and severe
(Chandana et al., 2005; Chugani et al., 1999). As already mental retardation, our sample also included patients aected
reported by Elia et al. (2000), the reduction of total sleep time by mild mental retardation, thus we cannot state whether the
might be a consequence of dysfunction of the brainstem alteration of sleep macro- and microstructure are characteristic
aminergic pathways. A failure in the development of the of autism or related to mental retardation. Finally, it may be
circadian sleep wake cycle due to failure to entrain to the argued that the high rate of children reporting sleep problems
day night cycle has been suggested (Segawa and Nomura, in our sample might be responsible for the PSG sleep alteration
2006). This failure implicates involvement of 5 HT neurones we found. In a recent PSG study on a group of selected
among ascending brainstem monoaminergic neurones that children with autism without mental retardation, Malow et al.
modulate the development of the circadian sleep wake cycle (2006) found a lower sleep eciency, prolonged sleep latency,
(Tordjman et al., 2005). decreased REM sleep and increased SWS only in children with
Sleep microstructural analysis results complement those of autism reporting sleep problems compared to children with
macrostructural analysis, conrming sleep alterations. Parti- autism without sleep problems and TD children.
cularly, in agreement with Miano et al. (2007) we found a low Taken together, our ndings suggest that, even though no
CAP rate associated with a low A1 index and a slight increase particular dierences in sleep architecture were found between

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346 F. Giannotti et al.

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