Original Article

Neuroimaging Findings in 41 Low-Functioning

Children With Autism Spectrum Disorder:
A Single-Center Experience

Journal of Child Neurology

2014, Vol. 29(12) 1626-1631
The Author(s) 2013
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DOI: 10.1177/0883073813511856
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Alessandra Erbetta, MD1, Sara Bulgheroni, PsyD2,

Valeria Contarino, Eng1, Luisa Chiapparini, MD1,
Silvia Esposito, MD2, Chiara Vago, PsyD2, and Daria Riva, MD2

Abstract
The data on the rate of brain imaging abnormalities in autistic spectrum disorders are still inconsistent. A recent study on patients
with high-functioning autism found that approximately 90% of children had normal magnetic resonance imaging (MRI) scans
whereas an unexpected high rate of MRI abnormalities was reported in 77 nonsyndromic autistic children with or without intellectual disability. The aim of this study was to evaluate the prevalence of neuroradiologic findings in low-functioning autistic children compared to controls matched for age. Minor brain abnormalities were found in 44% of patients and 22% of controls. Our
main result is the high rate of mega cisterna magna in autistic patients. High rate of minor neuroradiologic abnormalities in lowfunctioning autistic patients could contribute to the research about the various endophenotypes and complete the clinical assessment of children with autistic spectrum disorder and intellectual disability.
Keywords
autism spectrum disorder, conventional magnetic resonance imaging (MRI), structural brain abnormalities, children
Received June 27, 2013. Received revised August 23, 2013; September 27, 2013. Accepted for publication September 30, 2013.

Neuropathologic studies report a wide range of brain abnormalities and suggest an underlying structural disorder in patients with
autism spectrum disorders.1,2 The first set of neuroimaging in
patients with autism demonstrated focal lesions or structural
abnormalities often incidental and unrelated to autism itself.3-7
For this reason, conventional magnetic resonance imaging (MRI)
was judged to be of little value in the clinical diagnosis according
to the guidelines of the American Academy of Neurology and
Child Neurology Society.8 However, this statement was based
on results obtained from small samples of patients and, more
importantly, included mostly insufficient MRI sequences. More
recently, Zeegers et al9 and Boddaert et al10 reported an unexpectedly high rate of MRI abnormalities in autistic patients using an
appropriate set of sequences. Zeegers et al9 studied patients with
language disorders and mental retardation in addition to autistic
spectrum disorders, whereas Boddaert et al10 enrolled 77 autistic
patients clinically heterogeneous with respect to intellectual
disability. Vasa et al11 disconfirmed these results studying exclusively high-functioning autistic patients and found that approximately 90% of children had normal MRI scans.
The aim of our study was to evaluate the prevalence of brain
abnormalities in a group including exclusively low-functioning
autistic patients compared with age-matched controls, using an
appropriate set of MR sequences.

Methods
From 93 children with autistic spectrum disorders, referred to our
developmental neurology unit from January 2008 to January 2012,
a group of 41 children with idiopathic autistic spectrum disorders
without associated seizures or other neurologic diseases were
selected. Patients with profound mental retardation, known infectious, metabolic or genetic diseases, and chromosomal abnormalities
and children with disintegrative disorder were excluded. Of the 41
patients (12 girls; 29 boys; age range 2-15.4 y, mean 7.2 y, standard deviation 3.4 y), 28 had a diagnosis of autism, and 13 of pervasive developmental disordernot otherwise specified.
In all cases, diagnosis was established according to the Diagnostic
and Statistical Manual of Mental Disorders (4th edition) diagnostic
criteria and confirmed by the Autism Diagnostic Observation ScheduleGeneric and the Autism Diagnostic InterviewRevised. The

Neuroradiology Division, Fondazione IRCCS Istituto Neurologico C.Besta,

via Celoria 11, 20133 Milano, Italy
2
Developmental Neurology Division, Fondazione IRCCS Istituto Neurologico
C.Besta, via Celoria 11, 20133 Milano, Italy
Corresponding Author:
Alessandra Erbetta, MD, Neuroradiology Division, Fondazione IRCCS Istituto
Neurologico C.Besta, Via Celoria 11, 20133 - Milano, Italy.
Email: aerbetta@istituto-besta.it

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Erbetta et al

1627

Table 1. Frequencies and Type of Magnetic Resonance Imaging Abnormalities in Patients and Controls.
Autistic spectrum disorders
(n 41)

Controls
(n 41)

w2, P value

23
4
5
1
2
3
2
3
1

32
3
0
0
1
4
2
0
0

w2 4.473, P .034
ns
w2 5.325, P .021
ns
ns
ns
ns
ns
ns

Normal
Dilated Virchow-Robin spaces
Mega cisterna magna
Choroid plexus cyst
Arachnoid cyst
Mild enlargement of the ventricles
Abnormal hippocampal shape
Abnormal signal intensities
Lipoma
Abbreviation: ns, non significant.

Autism Diagnostic InterviewRevised12 is a standardized, semistructured, investigator-based interview for parents or caregivers, whereas
the Autism Diagnostic Observation ScheduleGeneric13 is a semistructured autism diagnostic observation. These Diagnostic and Statistical Manual of Mental Disordersoriented instruments continue
to be recommended gold standards for diagnosis of autistic spectrum disorders14
All children were evaluated by a pediatric neurologist, a clinical
geneticist, and a child neuropsychologist. In addition, the recommended biological and medical screening for autistic spectrum disorders were performed, including high-resolution karyotyping, DNA
analysis of Fragile X syndrome, array-comparative genomic hybridization, and normal standard metabolic testing. The cognitive functioning was assessed using the Wechsler Intelligence Scales according to
their age, the Leiter Performance ScaleRevised for nonverbal children and the Griffiths Mental Developmental Scale for those with
chronologic or mental age under 4 years. The IQ/DQ ranged from
28 to 68 (mean 50, standard deviation 12).
The control group consisted of 41 normally developing children
(21 girls; 20 boys; age range 1.5-14 y; mean 7.1 y, standard deviation 3.4 y), with normal IQ, no signs of autistic behavior or other
psychiatric or neurologic disorders, and negative family history for
neurologic or psychiatric illness among their first-degree relatives.
They were recruited among inpatients with suspected spinal cord
abnormalities and included in the study if the brain and spine examination was normal. The controls over age 6 were examined without
sedation; they were recruited among the children of the medical and
technical staff involved in the study. The study was approved by the
Internal Ethics Committee of the Carlo Besta Neurological Institute.

Magnetic Resonance Imaging Acquisition

All the autistic patients were examined under propofol sedation (1 mg/
kg). The controls under age 6 were also examined under propofol
sedation.
Structural imaging included axial proton density/T2-weighted
images (long repetition time 3500 ms, echo time 17 ms/84 ms,
slice thickness 5 mm), coronal and sagittal turbo spin-echo T2weighted images (long repetition time 4100 ms, echo time 143
ms, slice thickness 5 mm), axial and coronal fluid-attenuated inversion recovery images (long repetition time 8200 ms, echo time 83
ms, inversion time 2500 ms, slice thickness 5 mm). Imaging was
independently assessed by 2 senior neuroradiologists (AE, LCblinded for the diagnosis). Special attention was paid to evaluate the

shape and size of the posterior fossa, morphology of the cerebellum

and corpus callosum, cortical malformations, and hippocampal shape.
Abnormal signal intensity in white and gray matter was also considered. The presence of arachnoid cysts and choroid plexus cysts was
evaluated. We considered also ventricles, subarachnoid spaces, and
Virchow-Robin spaces size. The thresholds of ventricular enlargement
was taken as 10 mm.15 The thresholds of Virchow-Robin space enlargement was taken as 3 mm.10 Scans were also inspected for ageappropriate myelination.16 Mega cisterna magna, abnormal shape of
hippocampus, and choroid plexus cyst were considered as minor
MRI abnormalities. Therefore, the scan was categorized as normal
only when also these minor MRI abnormalities were absent.

Statistical Analysis
Chi-square test was applied to study if the observed frequencies of
MRI abnormalities were influenced by diagnosis.
The interrater reliability analysis using the Kappa statistic was performed to determine consistency among raters. A meeting was held to
reach consensus when inconsistencies were found between the reports
of the 2 raters.
Further, t test for independent samples was used to compare clinical and demographic features of autistic children with normal or
abnormal MRIs. All statistic analyses were conducted using the
SPSS.10, and P values of .05 or lower were considered significant.

Results
The interrater reliability for the neuroradiologists was found to
be Kappa 0.77 (95% confidence interval 0.6, 0.84), which
is rated as substantial according to the categorization of Landis
and Koch.17
Table 1 provides the frequencies and type of MRI findings in
patients and controls. Minor MRI abnormalities were significantly more frequent in the autistic group compared to controls
(44% vs 22%); in particular, the mega cisterna magna was found
in 5 patients (12.2%) (Figure 1). In autistic children, dilated
Virchow-Robin spaces (9.8%) (Figure 2), mild ventricular enlargement (7.3%), and abnormal signal intensities (7.3%) (Figure 3)
were also found. One patient had a prominent choroid plexus
cysts whereas 2 had an arachnoid cyst located in the left temporal arachnoid space and in the right choroid fissure, respectively. Two patients showed abnormal hippocampal shape and

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Journal of Child Neurology 29(12)

Figure 1. Midline sagittal T1-weighted image (A) shows prominent extra-axial space dorsal to the cerebellar vermis with cerebrospinal fluid
equivalent signal characteristic consistent with mega cisterna magna. Note absence of abnormalities of the vermis and fourth ventricle. Coronal
fluid-attenuated inversion recovery image (B) shows normal cerebellar hemispheres.

Figure 2. Axial (A) and coronal (B) T2-weighted images show enlargement of Virchow-Robin spaces more prominent in the white matter of the
parietal lobes.

one had lipoma of the tuber cinereum. The myelination was age
appropriate in all the patients.
All abnormalities were isolated but in 3 cases; the patients
showed dilated Virchow-Robin spaces associated with mega
cisterna magna (2 cases) and lipoma (1 case).
In the control group, mega cisterna magna and abnormal
signal intensities were never observed. Dilated VirchowRobin spaces were observed in 3 subjects (7.3%) as well as
mild ventricular enlargement (7.3%). Abnormal hippocampal
shape was found in 2 (4.9%). Only 1 showed cavum septum
and cavum vergae.
Clinical and demographic characteristics (age, sex, IQ/GQ,
Autism Diagnostic InterviewRevised and Autism Diagnostic
Observation ScheduleGeneric scores) of autistic children having normal and abnormal MRI were not different (see Table 2).

Discussion
Our study examined the frequency of neuroradiologic findings
in a sample of exclusively low-functioning autistic patients
compared to controls matched for age. The study methods were
stringent in the use of the same MRI system, the same multisequence MR protocol, and the review of images by 2 experienced neuroradiologists. According to Boddaert et al,10 we
found an unexpectedly high incidence of brain abnormalities
(44%) in contrast with the generally accepted view that MRI
is close to normal in children with autistic spectrum disorders.11,18 The high rate of MR findings could be explained
by a methodologic improvement, including all the acquisitions
necessary to detect brain abnormalities, but it can also depend
on different clinical inclusion criteria. In fact, we included

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1629

Figure 3. Axial T2-weighted image (A) and coronal fluid attenuated inversion recovery image (B) show focal abnormal signal intensity in the
medial portion of the left thalamus of uncertain nature (white arrow).
Table 2. Clinical and Demographic Features of Autistic Children Related to Normal and Abnormal Magnetic Resonance Imagings (MRIs).a
Normal MRI (n 23)
Age
Sex
ADI-R total score, Mean (SD)
ADOS-G total score, Mean (SD)
Mean IQ/DG, Mean (SD)

7.3 + 3.5
15 M; 8 F
1.19 (0.44)
1.29 (0.37)
51 (12)

Abnormal MRI (n 18)

7.1
14
1.34
1.34
49

+ 3.5
M; 4 F
(0.39)
(0.43)
(13)

P value
t test, P .890
w2 0.770, P .380
t test, P .266
t test, P .696
t test, P .683

Abbreviations: ADI-R, Autism Diagnostic InterviewRevised; ADOS-G, Autism Diagnostic Observation ScheduleGeneric; F, female; M, male; SD, standard
deviation.
a
The mean ADI-R and ADOS-G scores were obtained by dividing the total score by the number of items from which the total is derived (ie, to account for
differences in the modules and diagnostic algorithm that differ by developmental and language level).

exclusively low-functioning autistic children, whereas Vasa

et al11 included exclusively high-functioning autistic patients
and considered as normal variants some MR findings that we
considered as minor MR abnormalities. Our main result is
the high rate of mega cisterna magna in autistic patients, that
is, an enlarged cisterna magna with a normal fourth ventricle
and cerebellar hemispheres and vermis.19 The normal size limit
is debated. The concept of mega cisterna magna was first introduced by Gonsette et al,20 who described an enlargement of the
cisterna magna on ventriculography. Mega cisterna magna is a
common condition, accounting for approximately 54% of
cystlike posterior fossa malformation.21 A computed tomography study of 3000 normal subjects found 11 cases with mega
cisterna magna.22 Boddaert et al10 considered this finding as
a normal variant, generally accepted to be present in normal
individuals.23 However, mega cisterna magna has been
reported in association with developmental delay and it is considered a marker of brain dysgenesis.24,25
White matter abnormalities were reported only in 2 cases. In
one case, these abnormalities were multiple and punctate
hyperintensities on T2/fluid-attenuated inversion recovery
sequences in the frontal lobes and they could have a vascular
origin. In the other one, the signal abnormality was located

anteriorly to the frontal horn of the right ventricle. An ependymal loss of uncertain nature could be postulated. White matter
abnormalities in a widely distributed network and in the temporal lobes have also been described by Boddaert et al10 and
by Zeegers et al9 in autistic patients and by Sotos-Ares
et al26 in mental retardation. The myelination was age appropriate in all our patients in contrast to that in Boddaert et al.10
In 1 case, a focal abnormal signal intensity was found in the
left medial thalamus. The medial thalamic nuclei are connected
to the fronto-orbital gyrus, which is part of the limbic circuit
involved in emotional regulation impaired in autistic patients.27
Dilated Virchow-Robin spaces were seen in 4 patients but
also in 3 controls. Similar results were found by Zeegers
et al9 in a mixed sample of autistic spectrum disorders, developmental delay, and language disorders. In addition, Taber
et al28 have also described a high rate of abnormal VirchowRobin spaces in patients with autistic spectrum disorders and
normal IQ. Although enlarged Virchow-Robin spaces can be
benign in some cases, the increased incidence reported in children with headaches, developmental delay, and psychiatric disorders suggests that they might indicate an underlying
pathologic state. Schick et al29 have suggested that in children
with migraine, the enlarged Virchow-Robin spaces can be

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Journal of Child Neurology 29(12)

caused by alterations in the serotonergic system, which is also

involved in autistic spectrum disorders.30
Arachnoid cysts were found in 2 patients (5%), respectively,
in the left middle fossa and in the right choroid fissure. In a
study of incidental findings in 225 healthy children, only 2 children were found with an arachnoid cyst (0.09%).23 This finding
can be associated with numerous neurologic disorders including developmental delay, impaired cognition, and attention
deficit disorder.31 However, we did not find the frequency of
arachnoid cysts significantly increased in autistic spectrum
disorders.
Ventricular enlargement was found in the same percentage
in autistic patients and in the normal group, such as abnormal
shape of the left hippocampus. In 2 patients and in 2 controls,
we found a round or pyramidal hippocampus and a vertical collateral sulcus interpreted as hippocampal malrotation or incomplete hippocampal inversion. This finding was reported in
18%-19% of the subjects in healthy populations and in patients
without epilepsy or developmental brain anomalies.32,33
In 1 autistic patient, a lipoma of the tuber cinereum was
recorded. Intracranial lipomas are rare, with a prevalence rate
of approximately 0.46%. Most intracranial lipomas are incidental findings without any associated pathologic conditions; however, they have been reported as associated with several
syndromes and congenital malformations.34
Main limitation of the present study is that autistic children
have only been compared to typically developing subjects, and
not to children with intellectual disability of homogenous
etiology.
In summary, we found an unexpectedly high incidence of
minor MRI abnormalities in low-functioning autistic children
as previously reported in other 3 studies.10,11,28 Our findings are
not diagnostic nor unique and specific of autism. The discussion
about whether MR scans are clinically relevant in the assessment
of infants and children with autistic spectrum disorders is an
ongoing issue. MR scans do not have direct additional value for
the diagnosis of autism currently based only on behavioural findings. However, in this study, all participants have mental retardation, for example, the 85% of autistic children, and MRI is
highly recommended in mental retardation/developmental delay
to exclude brain lesion, significant structural abnormalities, or
other neurodegenerative diseases.35,36 Moreover, some minor
abnormalities (eg, subcortical and white matter signal abnormalities, intracranial cysts, etc) might need radiologic follow-up and
eventually surgical intervention. This unexpectedly high rate of
MRI abnormalities, even if minor, can contribute to complete the
clinical assessment of autistic spectrum disorders, particularly if
associated with intellectual disability.
Author Contributions
AE assessed structural imaging and wrote the draft of the article. SB
carried out the statistical analysis, evaluated the patients, and contributed to revising the manuscript. LC assessed structural imaging. VC
collected the neuroradiologic examination results and contributed to
preparation of the tables. SE cared for the patients and contributed
to collect clinical data. CV was involved in the patient enrolment and

in diagnostic evaluation of patients. DR, the senior author, designed

and supervised the study and revised the manuscript.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.

Funding
The authors received no financial support for the research, authorship,
and/or publication of this article.

Ethical Approval
This study is part of a research line about brain developmental promoted
in the 2008-2010 period by the Neurological Institute C.Besta within
the Institute and automatically approved by the ethics committee.

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