Autism Spectrum Disorders in Survivors of Extreme Prematurity

Article (PDF Available)inClinics in perinatology 36(4):791-805, vi · December 2009with99 Reads
DOI: 10.1016/j.clp.2009.07.010 · Source: PubMed
Recent studies in survivors of extreme prematurity point to an increased prevalence of a previously underrecognized atypical social-behavioral profile strongly suggestive of an autism spectrum disorder. Prospective studies that incorporate early autism screening and autism diagnostic testing are needed to better delineate the sensitivity and specificity of early signs of autism in ex-premature children. Advances in neonatal MRI techniques capable of quantitative structural and functional measurements will also provide important insights into the effects of prematurity itself, and prematurity-related brain injury on the genesis of autism spectrum disorders in this population. Available evidence linking prematurity and autism spectrum disorders is reviewed in this article.

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Available from: Catherine Limperopoulos, Jul 07, 2016
Autism Spectrum
Disorders in Survivors
of Extreme Prematurity
Catherine Limperopoulos, PhD
The impact of extreme prematurity on the neurodevelopmental outcome in survivors is
Advances in perinatal and neonatal care have resulted in dramatic
increases in survival of premature infants, most strikingly among the smallest and
Unfortunately, this decrease in mortality has not been accompanied by
a similar decrease in long-term neurodevelopmental morbidity among survivors.
Ex-premature infants are at substantial risk for significant and costly lifelong disabil-
Of particular concern is the risk for significant higher-order neurodevelop-
mental impairment in ex-premature children reaching school age. In some studies,
up to 50% of ex-preterm infants experience difficulties in executive functioning,
learning, and behavior, often requiring special educational support.
These chil-
dren are at increased risk for attentional difficulties, hyperactivity,
and communication dysfunction,
and for psychiatric disorders in adolescence
Failure to cope with the demands of adulthood is more prevalent
among survivors of prematurity, with lower educational and income attainment, and
difficulties establishing a family.
Converging lines of evidence point to a significantly increased risk among extremely
premature infants for subsequent development of cognitive, learning, behavioral, and
Dr. Limperopoulos is supported by the Canada Research Chairs Program, Canada Research Chair
in Brain and Development. This work was supported in part by the LifeBridge Fund and the
Trust Family Foundation.
Department of Neurology and Neurosurgery, School of Physical and Occupational Therapy,
McGill University, 2300 Tupper Street, Montreal, Quebec, H3H 1P3, Canada
Department of Pediatrics, School of Physical and Occupational Therapy, McGill University,
2300 Tupper Street, Montreal, Quebec, H3H 1P3, Canada
Fetal-Neonatal Neurology Research Group, Department of Neurology, Children’s Hospital
Boston, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA
Pediatric Neurology, Montreal Children’s Hospital, 2300 Tupper Street A-334, Montreal,
Quebec H3H 1P3, Canada
* Pediatric Neurology, Montreal Children’s Hospital, 2300 Tupper Street A-334, Montreal,
Quebec H3H 1P3, Canada.
E-mail address:
Prematurity Autism spectrum disorders Brain
MRI Outcome
Clin Perinatol 36 (2009) 791–805
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psychoaffective disturbances. Recent reports also suggest an increase in atypical
social-behavioral functioning in this population that is strongly suggestive of autism
spectrum disorders (ASD). These recent data have triggered a vigorous and highly
charged debate, given the potential implications for this growing population of prema-
turity survivors, their caretakers, and society at large. This article reviews available
evidence for prematurity and ASD, examines the potential role of early life neuroana-
tomic antecedents for these behavior patterns in survivors of extreme preterm birth,
and explores future directions in this emerging area of research.
ASD are a heterogeneous group of behaviorally defined, neurodevelopmental disor-
ders characterized by impaired development in communication, social interaction,
and behavior.
There are three broad categories (ie, autism, Asperger syndrome,
and pervasive developmental disorder not otherwise specified), each with a wide
range of effects but shared core symptoms. At the lower-functioning end of the autism
spectrum, individuals have impaired reciprocal social interaction, abnormal develop-
ment and use of language, and repetitive and ritualized behaviors. Conversely, those
with Asperger syndrome are higher-functioning with normal intelligence but abnormal-
ities in social interaction. When a child has autistic symptoms that do not fit another
ASD diagnosis, pervasive developmental disorder not otherwise specified may be
The earliest behavioral signs of ASD emerge between 1 and 2 years of age, and
include impaired social attention, language development, and emotional reactivity.
Given the importance of early detection and intervention for children with ASD, the
American Academy of Pediatrics has recently published guidelines endorsing
autism-specific screening for all children at age 18 months.
Early screening tools
for ASD, such as the Modified Checklist for Autism in Toddlers (M-CHAT), incorporate
items that capture these early signs of ASD. These screening tests identify children
who warrant formal testing for the diagnosis of ASD, which is usually made between
2 and 4 years of age.
ASDs are increasingly recognized as a major public health issue in childhood and
Although ASD was once considered a rare disorder, the Centers for
Disease Control and Prevention recently estimated its prevalence at around 1 in
The personal and familial impact of these conditions is often catastrophic. Like-
wise, the economic cost of ASD to society is enormous, with an estimated annual cost
as high as $35 billion per year and an individual lifetime cost of $3.2 million.
potential contribution from increasing survivors of extreme prematurity to this growing
population of children with ASD is explored herein.
Etiology of ASD
Although a broad range of etiologies has been implicated in the development of ASD,
prevailing consensus favors a multifactorial pathogenesis. A growing body of evidence
supports the presence of abnormal fetal brain development in ASD. Many researchers
adhere to a triple-hit hypothesis for the development of ASD.
In this paradigm, ASD
develops in individuals with (1) an underlying biologic vulnerability who experience (2)
varying degrees of exogenous stressors (3) during a critical period of brain develop-
The notion that the underlying predisposition to ASD is caused by a single
gene defect has been refuted, and current understanding is that the risk of developing
ASD is modified by multiple susceptibility and protective genes.
The putative genetic
factors implicated in ASD form part of a vast and complex area of research that is
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beyond the scope of this article. Rather, this article explores the other two arms of this
triple-hit paradigm, namely the potential role of insults to the immature brain during
a critical period of brain development in prematurely born infants. Early life insults
may play a role in the development of ASD. Clinical data support the notion of
a vulnerability period during the second and third trimester of gestation for subsequent
development of ASD and are summarized later.
Prematurity-related Risk Factors and ASD
To date, population-based studies have consistently identified prematurity and low
birth weight
as important perinatal risk factors for the development of ASD. A
recent large population-based study of adults born at very low gestational age
compared with term-born adults described a significant increased risk for ASD, with
a relative risk of 7.3 among those born at 28 to 30 weeks gestation, increasing to nearly
10 in those born at 23 to 27 weeks gestational age.
These data suggest that the inci-
dence of ASD among survivors of preterm birth is inversely related to gestational age.
Obstetric complications and intrapartum hypoxia (eg, bleeding during pregnancy,
maternal hypotension, cesarean delivery, fetal distress, low Apgar score)
and a history of neonatal intensive care
have also been reported to increase the
risk of autism. Parental infertility and advanced maternal and paternal age at birth
are additional risk factors that have been associated with ASD.
a higher prevalence of ASD has recently been linked with in vitro fertilization compared
with the general population.
Available evidence suggests that pregnancy, delivery, and neonatal complications
increase the risk for ASD through independent etiologic pathways that likely interact
with a genetic predisposition, thereby interfering with brain maturation at critical points
in development.
It is important to note that, to date, population-based studies
generally reflect a population born preterm over two decades ago, and the prevalence
of ASD among ex-premature infants born in the modern era remains unknown. Given
that the greatest advances in survival are among the most premature and critically ill
infants, the need to better define the risk of ASD in these new survivors of extreme
preterm birth is of unquestionable importance. Moreover, given the established risk
of preterm birth associated with in vitro fertilization,
the complex relationship
between in vitro fertilization, prematurity, and ASD needs further definition. Taken
together, large population-based studies are needed to allow for a more precise
and detailed assessment of exposures and potential confounders for a more conclu-
sive investigation of prematurity-related risk factors and ASD.
Prematurity and Evidence for Social-behavioral Dysfunction
Current understanding of the behavioral and psychosocial health of survivors of very
preterm birth indicates that these children are at increased risk for social-behavioral
dysfunction. Most notably, low birth weight and gestational age have been identified
as important perinatal risk factors for disturbances in social interaction, communica-
tion, and behavior
and later psychoaffective disorders in adulthood.
childhood and adolescence, very low birth weight children exhibit greater internalizing
and externalizing behavior problems than their peers, and attentional difficulties and
A high prevalence of difficulties with social integration, such
as excessive shyness, withdrawn behavior, and more difficulties in establishing social
contacts, and antisocial behaviors has also been described.
Noteworthy is the
fact that preterm adolescents are far more likely to experience psychiatric symptoms
Autism Spectrum Disorders 793
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(46%) than controls (13%), particularly attention deficit, anxiety symptoms, and
relational problems.
More recent literature has underscored significant concerns about the ability of
these children to cope with the demands of adulthood, including lower levels of
educational attainment and income, and difficulties with establishing a family.
From a social-behavioral perspective, extremely low birth weight adults are reported
to have an overall lower level of social competence characterized by significantly high-
er shyness, behavioral inhibition, lower extraversion and higher neuroticism, impaired
interpersonal relationships, and overall lower sociability and emotional well-being than
their normal birth weight counterparts.
The personality profile of adults born
very preterm is increasingly characterized by behavioral inhibition and negative affec-
tivity, and decreased positive affectivity, collectively, placing them at risk for mental
health problems, such as anxiety and depression.
Interestingly, despite
increased recognition of psychosocial impairments among prematurity survivors, to
date these problems remain clinically underdiagnosed.
Converging evidence points to an increased risk among extremely premature
infants for significant future psychiatric and emotional problems. Despite increasing
reports of atypical social-behavioral functioning among survivors of extreme preterm
birth, little is currently known about the true prevalence of ASD in this vulnerable
Prematurity and ASD: What is the Evidence?
The potential role of ASD in the spectrum of social-behavioral dysfunction described in
this population has been underexplored. Anecdotal experience in the clinical follow-up
of ex-preterm infants in recent years has suggested that a subgroup of infants born
very preterm exhibit noticeably atypical social behavioral characteristics, many of
which are similar to those typically documented in young children with ASD. Until
recently, however, studies linking very low birth weight and ASD have been few and
limited largely to small subgroups of higher functioning adolescents and young adults
with Asperger disorder,
or those with severe retinopathy of prematurity.
that have reported an association between ASD and prematurity are summarized in
Table 1. Msall
using a parental questionnaire reported a higher prevalence of autism
in a cohort of extremely preterm infants (<1251 g) with unfavorable vision status
(ie, severe retinopathy of prematurity) (8.5%) versus those with favorable vision status
(0.8%) at 8 years of age. Indredavik and colleagues
have reported increased
scores on the Autism Spectrum Screening Questionnaire and an increased prevalence
of Asperger syndrome–like symptoms (assessed by interview) in very low birth weight
adolescents. The authors speculated that very low birth weight adolescents exhibit
a milder form of ASD, and experience particular deficits with encoding and interpreting
subtle cues of social relations,
which likely implicates cognitive and emotional mech-
anisms and impaired brain connectivity (described later).
The recent availability of validated screening instruments for detection of early signs
of ASD
has facilitated the early screening of infants to prompt appropriate referrals
for specialized autism diagnostic testing.
Stimulated by observations of autism-
like behavioral profiles in clinical follow-up of very premature infants, together with
the greater availability of ASD screening tools for toddlers, the author and others
have recently begun to explore the potential relationship of ADS and survivors of
extreme preterm birth. The author’s group published the first study that examined
the relationship between early signs of autism in young toddlers with a history of
extreme prematurity.
They performed initial screening for early autistic features
using the M-CHAT in a consecutive series of 91 ex-preterm infants born less than
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Tabl e 1
Rates of ASD in follow-up studies of infants born preterm
Author Year
Characteristics ASD Measure Age at Follow-up Rates of ASD
Msall et al
2004 24 <1250 g Preterm and severe
14–15 y 7 (8.5%) severe ROP
1 (0.8%) favorable
vision status
et al
2005 104 <1500 g Preterm and SGA ASSQ 14–15 y 4 symptoms of
1 ASD (2%)
et al
2007 86 <32 wk GA Preterm with CBH
Preterm with SPI
Preterm controls
SCQ (subset)
1–5 years 13 (37%) M-CHAT
5 (33%) SCQ
et al
2008 91 <1500 g
<31 wk GA
Preterm M-CHAT 18–24 mo 23 (25%)
Kuban et al
2009 988 <28 wk GA Preterm M-CHAT 24 mo 212 (22%)
Limperopoulos et al
42 <32 wk GA Preterm with CBH ADOS
6–9 y 12 (28%)
Abbreviations: ADOS, autism diagnostic observation schedule; ASSQ, autism spectrum screening questionnaire; CBH, cerebellar hemorrhagic injury; DSM-IV, Diag-
nostic and Statistical Manual of Mental Disorders, 4th edition; GA, gestational age; M-CHAT, Modified Checklist for Autism in Toddlers; ROP, retinopathy of prema-
turity; SCQ, Social Communication Questionnaire; SGA, small for gestational age; SPI, supratentorial parenchymal injury.
Autism Spectrum Disorders 795
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or equal to 1500 g prospectively recruited at birth. They reported that an alarming 25%
of ex-preterm infants (mean of 21 months corrected age) tested positive on these
autism screening instruments. Abnormal M-CHAT scores correlated highly with inter-
nalizing behavioral problems on the Child Behavior Checklist and socialization and
communication deficits on the Vineland Adaptive Behavior Scale. Importantly, with
the exception of three children, the cohort was otherwise not affected by significant
visual, auditory, and motor (eg, cerebral palsy) impairments. Perinatal risk factors
associated with a positive autism screening included lower birth weight, chorioamnio-
nitis, acute intrapartum hemorrhage, male gender, and illness severity on admission.
Kuban and colleagues
in a subsequent study also examined the prevalence of
a positive screen for ASD using the M-CHAT in a large multicenter study of preterm
infants born less than 28 weeks of gestation, and reported more than 21% screened
positive for ASD. The authors also examined the impact of sensorimotor and cognitive
impairments on a false-positive screening. Major motor (eg, cerebral palsy), cognitive
(eg, mental retardation), and significant visual and hearing impairments accounted for
more than 50% of the positive M-CHAT screens in their cohort. For example, children
with major visual or hearing impairments were eight times more likely to screen posi-
tive. Among the subgroup of children who were free of motor, cognitive, visual, and
hearing impairments, 10% screened positive, nearly double the expected rate. Note-
worthy is the fact that cognitive impairment is frequently present in children with ASD;
adjusting for this variable likely underestimates the true prevalence.
A third study to report an association between prematurity and ASD by the author’s
group examined the developmental consequences in a subgroup of ex-preterm
infants with cerebellar hemorrhagic injury,
a form of brain injury increasingly recog-
nized among survivors of extreme preterm birth.
Children underwent formal
neurologic examinations and a battery of standardized developmental, functional,
and behavioral evaluations, and autism screening questionnaires at a mean age 32
months. Results indicated that children with isolated cerebellar injury versus preterm
age-matched controls demonstrated significantly greater motor disabilities, language
delays, and cognitive deficits. Notably, 37% of infants with cerebellar injury tested
positive for early signs of autism using the M-CHAT. The author speculates that cere-
bellar hemorrhagic injury in preterm infants was associated with a high prevalence of
pervasive neurodevelopmental disabilities and may play a critical and underrecog-
nized role in social, affective, and behavioral dysfunction (discussed later).
Collectively, these initial data strongly suggested that early autistic behaviors seem
to be an underappreciated feature in survivors of extreme prematurity, and that these
behaviors might be increased by injury and growth failure (see later) to the premature
cerebellum. These provocative preliminary findings clearly require confirmation using
definitive autism diagnostic tests. One important limitation of the studies summarized
previously is that the cut-off scores of screening measures are typically designed to
maximize the identification of children at greatest risk, and consequently may compro-
mise both false-positive and false-negative results. Furthermore, the extent to which
these initial positive screen rates are transient or indicative of a milder form of ASD
that is specific to extreme preterm survivors or merely reflective of future social-
emotional impairments is unclear. Long-term studies are urgently needed to examine
the sensitivity and specificity of the M-CHAT, and determine the true prevalence of
ADS in infants born preterm.
To date, formal follow-up evaluations using the Autism Diagnostic Observation
Schedule and Diagnostic and Statistical Manual of Mental Disorders, 4th edition
criteria in the author’s cohort of ex-preterm children with isolated cerebellar hemor-
rhagic injury who tested positive on initial screening using the M-CHAT (described
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previously) are revealing that approximately 30% of children meet diagnostic criteria
for ASD (Limperopoulos, 2009). The relationship between perinatal risk factors and
topography of cerebellar injury is currently under investigation. Ongoing research is
needed to better elucidate the prevalence, mechanisms, and neural basis of autism
spectrum features in ex-preterm children.
Neuroimaging and neuropathologic studies in ASD have shown a heterogeneous array
of anatomic findings in the cerebrum and cerebellum.
Although a comprehensive
review of this literature is beyond the scope of this article, the potential relationship
between altered brain development in ASD and the role of prematurity itself and
prematurity-related brain injury is explored.
One of the most striking observations in autism research to date is the lack of neuro-
imaging studies that have focused on early neuroanatomic development at the age of
clinical onset of autism.
Conversely, studies have focused largely on subjects
a decade or more after the onset of the disorder, and primarily on higher-functioning
autistic individuals. Consequently, there is a glaring lack of early neuroimaging data
from around the time of autism diagnosis (ie, between 2 and 4 years of age).
over, because ASDs are typically diagnosed around age 2 or later, no studies have
reported the pre-existing neuroimaging findings in children subsequently diagnosed
with ASD. Existing data largely reflect neuroanatomic changes years after the onset
of autism, delineating the end result of the pathology of autism rather than the struc-
tural changes taking place before or during the emergence of ASD symptoms.
neuroanatomic antecedents of ASD remain essentially unknown at the present time.
Longitudinal neural anatomic studies before the emergence of ASD features are
urgently needed.
Neuroimaging, Prematurity, and ASD
Evidence for neuroimaging abnormalities and ASD in survivors of preterm birth is
currently limited to a handful of reports, which are summarized next.
Impaired connectivity
Skranes and colleagues
demonstrated that very low birth weight adolescents with
symptoms of Asperger disorder all had white matter reduction and ventricular enlarge-
ment on MRI. Moreover, higher scores on the Autism Spectrum Screening Question-
naire were significantly correlated with impaired connectivity characterized by
reduced fractional anisotropy values on diffusion tensor imaging in the external
capsule and superior fascicle on the left side. The authors speculate that the low frac-
tional anisotropy values may be associated with damage to the immature developing
white matter that has long-term consequences on microstructure and connectivity.
This damage in turn leads to poor connectivity in commissural and association tracts
and impairs the abilities that demand cooperation between different brain regions.
Specifically, the external capsule contains fibers that connect the temporal and fontal
These findings corroborate neuroimaging studies reporting white matter
abnormalities in the frontal, superior temporal cortex, and temporoparietal junction,
and neuropathology reports of smaller frontal and temporal cortical minicolumns in
individuals with autism.
Impaired cerebellar growth and development
Using advanced three-dimensional volumetric MRI studies in premature infants, the
author’s group has demonstrated a particularly rapid growth period for the immature
Autism Spectrum Disorders 797
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cerebellum during the third trimester of gestation, a growth rate that far exceeds that
of the cerebral hemispheres.
In late gestation, proliferation and migration of the cere-
bellar granule cells are particularly prominent events,
and such insults as hemor-
rhage and hypoxia-ischemia may injure these immature granule cells, with
secondary effects on other cell populations
ultimately impairing cerebellar growth
and development.
Impaired growth and development of the cerebellum in premature infants may be
grouped into two broad categories, based on early neonatal MRI studies.
The first category of cerebellar growth impairment observed in preterm infants is
evidence of direct cerebellar injury during the neonatal period. Cerebrovascular
(often hemorrhagic) injury is an important and previously underrecognized form of
injury to the immature cerebellum, particularly in the extremely low gestational
age infant. Although the pathogenesis for this type of injury remains unknown, it
is likely related to impaired cerebral autoregulation and vascular fragility of the cere-
bellar germinal matrices.
The author’s group has shown that ex-preterm infants
with isolated cerebellar hemorrhagic injury were significantly more likely to score
positive on initial autism screening compared with those infants without cerebellar
Moreover, the presence of associated supratentorial injury (eg, periventric-
ular leukomalacia, periventricular hemorrhagic infarction) did not further increase the
risk for testing positive on early autism screening in these infants. It is noteworthy
that socialization difficulties and a positive autism screening were almost exclusively
associated with injury to the vermis (Fig. 1). Recent findings also suggest that
unilateral cerebellar hemorrhagic injury is associated with region-specific contralat-
eral cerebral gray and white matter volume reductions in the sensorimotor, premo-
tor, dorsolateral prefrontal, and mid-temporal cortices, suggesting trophic
withdrawal (ie, cerebellocerebral crossed diaschisis [Limperopoulos, 2009]). The
potential role of such remote contralateral cerebellocerebral growth failure in the
subsequent development of cognitive, affective, and behavioral impairment,
including ASD, remains unknown.
The second category of cerebellar growth impairment is present in the absence of
direct injury to the cerebellum detected by MRI. Using quantitative MRI studies, the
author and others
have also shown an increased risk for impaired cerebellar
growth in ex-premature infants. Such cerebellar growth impairment is already detect-
able by quantitative MRI as early as term gestational age equivalent.
Whether this
growth impairment is caused by cellular injury below the current resolution of MRI,
loss of maternal-placental growth factors, or environmental factors injurious to the
immature cerebellum remains unknown.
Importantly, decreased total cerebellar
volume at term equivalent in the absence of direct cerebellar injury is associated
with higher M-CHAT scores in toddlers born preterm, controlling for total brain volume
and gestational age (Limperopoulos, 2009) (Fig. 2). These data support the notion that
impaired development of the cerebellum (in the absence of direct cerebellar injury) in
the preterm infant may be associated with long-term atypical socioaffective develop-
ment in this vulnerable population. Taken together, these data suggest that both direct
and indirect mechanisms of cerebellar injury seem to stunt cerebellar growth and
development in the preterm infant. Likewise, these findings provide important insights
into the highly integrated anatomic and functional interactions between the immature
cerebrum and cerebellum, and suggest significant remote trophic effects between
these structures during development. It is also reasonable to suggest that early life
impairment of cerebellar growth plays a central but previously underrecognized role
in the long-term cognitive, behavioral, and social deficits associated with brain injury
among premature infants.
The full extent of the role of cerebellar injury, however, in
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the genesis of social behavioral deficits among premature infants remains to be
Neuropathology and Autism
Neuropathologic studies have highlighted evidence of cellular abnormalities and
processes that may underlie the neuropathologic substrates of autism. Although
Fig. 1. Relationship between cerebellar injury topography and early signs of ASD. (A)
Example of a normal cerebellum. (B) Unilateral right cerebellar injury without injury to
the vermis. (C) Unilateral cerebellar and vermis hemorrhagic injury. (D) Extensive (near
complete) bilateral cerebellar-vermis injury.
M-CHAT scores
Cerebellar volume (cc)
Fig. 2. Relationship between cerebellar volume at term equivalent and M-CHAT scores at
follow-up testing between 18 and 24 months corrected age. Higher M-CHAT scores were
associated with lower total cerebellar volume at term.
Autism Spectrum Disorders 799
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neuroanatomic descriptions from cases of autism are limited, a variety of findings has
been described in autopsy studies
supporting these cellular and growth
abnormalities in the cerebellar, frontal, and temporal cortices. Noteworthy is the fact
that 80% of these have demonstrated well-defined cerebellar anatomic abnormali-
Importantly, there are no autopsy reports from autistic children around the
typical age at diagnosis (ie, 2–4 years). The most commonly described neuropatho-
logic findings in the cerebellum of autistic individuals include glial activation with
gliosis, and neuronal degeneration most prominently among the Purkinje neurons.
Available data on the role of the cerebellum and ASD in preterm infants are in harmony
with an accumulating experience in older subjects reflecting the relationship between
the cerebellum and socioaffective development. Although traditional understanding of
the cerebellum’s role has been that of a center for motor control,
in recent years this
traditional view has been challenged by increasing recognition that the cerebellum has
an important role in ‘‘higher functions,’’ such as cognition, learning, affect, and
behavior. Central to this development has been the description of a distinct ‘‘cere-
bellar cognitive affective disorder’’
in older children
and adults
cerebellar injury, particularly to the posterior lobe. The cerebellar cognitive affective
syndrome is characterized by a constellation of impairments in executive, visual
spatial, linguistic, and affective function. Relevant to survivors of extreme preterm birth
is an earlier description of an apparent ‘‘developmental’’ form of cerebellar cognitive
affective syndrome.
Central to the cerebellar cognitive affective disorder is
emotional dysregulation, which is usually evident with impaired behavioral modulation
and flattening or disinhibition of affect.
In addition, obsessive-compulsive traits may
be prominent, and behavioral stereotypies and disturbed interpersonal relations that
meet criteria for autism.
In studies, the features of this developmental cerebellar
cognitive affective syndrome show clear overlap with the features of early autism.
Of particular note is the fact that these behavioral changes in the cerebellar cognitive
affective syndrome are most prominent when the vermis and paravermian regions of
the cerebellum are injured, as is the case in a cohort of ex-premature children in which
injury to the vermis is strongly associated with early signs of ASD.
The relationship
between regional cerebellar volumes and ADS in ex-preterm children with cerebellar
injury diagnosed with ASD at school age is currently underway.
Clearly, the most pervasive long-term neurodevelopmental sequelae among survivors
of extreme prematurity are those in the areas of cognitive, behavioral, and affective
function. Although clinical experience and initial screening tests point to a significant
prevalence of autistic-like behaviors in these children, the true nature and severity of
these behaviors need further definition. Likewise, the precise mechanisms underlying
the development of these autism-like behaviors among ex-premature children are
unclear. The precise structure-function relationships between these observations
are not yet known. Ongoing research is needed to provide new insight into the true
prevalence of diagnosed ASD, and the association between prematurity itself, and
the effects of prematurity-related brain injury, and the development of ASD among
survivors of extreme prematurity. Importantly, delineation of these relationships
provides clinicians with the understanding needed for informed prognostic counseling
of future parents of premature infants and for anticipatory guidance, and for the
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development of more timely and cost-effective models for early intervention and better
allocation of resources.
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Autism Spectrum Disorders 805
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    • "yed cortical folding , and reduced volumes of the cerebral cortex , thalamus , basal ganglia and hippocam - pus compared with their term - born peers [ Ajayi - Obe et al . , 2000 ; Inder , et al . , 2005 , 2003 ; Miller et al . , 2002 ; Peterson et al . , 2003 ] . Lesions and delayed growth of the cerebellum have also been reported in VP infants [ Limperopoulos et al . , 2005 ; Volpe , 2009b ] . However , few studies have examined the link between neonatal brain alterations and ASD in VP children . One study reported that cerebellar hemorrhage on neonatal MRI was associated with positive screens for ASD on the Modified Checklist for Autism in Toddlers ( M - CHAT ) at preschool age [ Limperopoulos et al . , 2007 ] ."
    [Show abstract] [Hide abstract] ABSTRACT: Very preterm (VP) survivors are at increased risk of autism spectrum disorder (ASD) compared with term-born children. This study explored whether neonatal magnetic resonance (MR) brain features differed in VP children with and without ASD at 7 years. One hundred and seventy-two VP children (<30 weeks' gestation or <1250 g birth weight) underwent structural brain MR scans at term equivalent age (TEA; 40 weeks' gestation ±2 weeks) and were assessed for ASD at 7 years of age. The presence and severity of white matter, cortical gray matter, deep nuclear gray matter, and cerebellar abnormalities were assessed, and total and regional brain volumes were measured. ASD was diagnosed using a standardized parent report diagnostic interview and confirmed via an independent assessment. Eight VP children (4.7%) were diagnosed with ASD. Children with ASD had more cystic lesions in the cortical white matter at TEA compared with those without ASD (odds ratio [OR] 8.7, 95% confidence interval [CI] 1.5, 51.3, P = 0.02). There was also some evidence for smaller cerebellar volumes in children with ASD compared with those without ASD (OR = 0.82, CI = 0.66, 1.00, P = 0.06). Overall, the results suggest that VP children with ASD have different brain structure in the neonatal period compared with those who do not have ASD. Autism Res 2015. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.
    Article · Oct 2015
    • "Indeed, among children born weighing < 2000 g, the prevalence of autism spectrum disorder is 5%—a value approximately five times higher than that seen in the general population (PintoMartin et al., 2011). It has been argued, however, that the " autistic phenotype " of preterm children represents a milder form of the disorder seen in full-term children (Indredavik, Vik, Skranes, & Brubakk, 2008 ) and reflects the effects of brain injuries and altered neurodevelopment associated with very premature birth (Johnson & Marlow, 2011; Limperopoulos, 2009). In particular, Movsas et al. (2013) have shown that in low-birth-weight children the risk of screening positive for, or being diagnosed with, an autism spectrum disorder is related to white matter injury but not to isolated germinal matrix/intraventricular hemorrhage (another common type of brain injury affecting premature infants; Volpe, 1995). "
    [Show abstract] [Hide abstract] ABSTRACT: Biological motion perception can be assessed using a variety of tasks. In the present study, 8- to 11-year-old children born prematurely at very low birth weight (<1500 g) and matched, full-term controls completed tasks that required the extraction of local motion cues, the ability to perceptually group these cues to extract information about body structure, and the ability to carry out higher order processes required for action recognition and person identification. Preterm children exhibited difficulties in all 4 aspects of biological motion perception. However, intercorrelations between test scores were weak in both full-term and preterm children-a finding that supports the view that these processes are relatively independent. Preterm children also displayed more autistic-like traits than full-term peers. In preterm (but not full-term) children, these traits were negatively correlated with performance in the task requiring structure-from-motion processing, r(30) = -.36, p < .05), but positively correlated with the ability to extract identity, r(30) = .45, p < .05). These findings extend previous reports of vulnerability in systems involved in processing dynamic cues in preterm children and suggest that a core deficit in social perception/cognition may contribute to the development of the social and behavioral difficulties even in members of this population who are functioning within the normal range intellectually. The results could inform the development of screening, diagnostic, and intervention tools.
    Full-text · Article · Aug 2014
    • "Disrupted cerebellar development has been associated with significant deficits in cognition, communication, and socialbehavioral function in premature babies, apart from those expected consequences of cerebellar dysfunction, such as ataxia, spasticity and dystonia [6, 7]. Moreover, cerebellar growth impairment seems to have a role in the genesis of spectrum autism disorders among preterm newborns, being this association currently under investigation [16]. "
    [Show abstract] [Hide abstract] ABSTRACT: Objectives: Recent studies realized with magnetic resonance imaging (MRI) showed impaired cerebellar growth in follow-up of preterm infants. Cerebellar injury may contribute to impaired motor, cognitive, language and behavioral dysfunction seen among this group. This study was designed to evaluate cerebellar growth in premature babies by ultrasound, a bedside imaging method, and to detect variables that could influence impaired cerebellar growth. Material and methods: Postnatal cerebellar growth, measured by transverse cerebellar diameter (TCD), was prospectively assessed in 88 consecutive preterm infants born ≤ 32 weeks of gestational age (GA). TCD was obtained via mastoid fontanelle (MF) ultrasound on a weekly basis, since the first week of life until 40 weeks postmenstrual age (p.m.a.). Variables that could influence cerebellar growth, such as GA, intrauterine growth restriction (IUGR), periventricular leukomalacia (PVL), peri-intraventricular hemorrhage (IVH), and posterior fossa hemorrhage (PFH) were evaluated. Results: TCD could be measured by MF ultrasound in all patients. Cerebellar growth occurred linearly with postnatal age. At 40th p.m.a. week, TCD was smaller in IUGR group compared with no IUGR infants but their weekly cerebellar growth was similar. At term-equivalent age, cerebellar size was influenced by PFH, PVL and IVH severity. Conclusion: TCD measured by MF ultrasound has demonstrated to be a bedside method for measuring the cerebellum in preterm babies. Impaired cerebellar growth seemed to be influenced by other brain lesions in these patients. We suggest that cerebellum should be studied in preterm infants born ≤ 32 weeks gestation, at term equivalent age, using MF ultrasound.
    Full-text · Article · Jun 2014
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September 19, 2016
Universidade do Vale do Sapucaí
interesting and indispensable article for the understanding of the biological mechanisms involved in autism

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