Review Article
When Is Enlargement of the Subarachnoid
Spaces Not Benign? A Genetic Perspective
Alex R. Paciorkowski, MD* and Robert M. Greenstein, MD*†
Enlargement of the subarachnoid spaces is occasion-
ally encountered during neuroimaging of children.
This enlargement is generally regarded as a nonpatho-
logic process that resolves uneventfully. However,
there are several genetic disorders in which enlarge-
ment of the subarachnoid spaces can be an early sign,
or the feature of an associated syndrome, that may aid
in the underlying diagnosis. Recognizing subarachnoid
space enlargement in these circumstances requires an
understanding of the normal physiology of the sub-
arachnoid space at different time points in a child’s
neurodevelopment. This article reviews the events
shaping the subarachnoid space, both during normal
physiologic maturation and in specific genetic disor-
ders. © 2007 by Elsevier Inc. All rights reserved.
Paciorkowski AR and Greenstein RM. When is enlarge-
ment of the subarachnoid spaces not benign? A genetic
perspective. Pediatr Neurol 2007;37:1-7.
Introduction
Enlargement of the subarachnoid spaces is character-
ized radiologically by increased cerebrospinal fluid in the
subarachnoid spaces, usually bifrontal, with a widened
interhemispheric fissure and normal to slightly increased
ventricular size (Fig 1) [1]. It is an occasional finding in
the neuroimaging of children with macrocephaly [2]. The
overall incidence of enlargement of the subarachnoid
spaces is difficult to estimate. A retrospective review of 88
children with macrocephaly and no neurologic abnormal-
ities found that 77.5% had this finding on neuroimaging
[3], but to our knowledge, a larger prospective study has
not been performed.
Enlargement of the subarachnoid spaces is usually
benign and not associated with developmental delay or
From the *Department of Genetics and Developmental Biology,
Division of Human Genetics, University of Connecticut Health Center,
West Hartford, Connecticut and †Department of Pediatrics, University
of Connecticut Health Center, Farmington, Connecticut.
© 2007 by Elsevier Inc. All rights reserved.
doi:10.1016/j.pediatrneurol.2007.04.001 ● 0887-8994/07/$—see front matter
neurologic disease. There are, however, genetic conditions
that should be considered when a patient manifests en-
largement of the subarachnoid spaces (Table 1). These
include several of the mucopolysaccharidoses, achondro-
plasia, Sotos syndrome, and the inborn error of metabo-
lism glutaric aciduria type I. Enlargement of the subarach-
noid spaces, when seen in the context of one of these
disorders, may appear identical radiographically to the
benign form. Therefore, some knowledge of the physio-
logic development of the subarachnoid spaces is necessary
to evaluate the images appropriately. The purpose of this
review is to assist pediatricians, child neurologists, and
medical geneticists in distinguishing the isolated, benign
form of enlargement of the subarachnoid spaces from that
associated with genetic syndromes.
History of the Terminology
Multiple terms have been employed over the years to
describe dilatation of the subarachnoid spaces, making it
difficult to compare case series, and even more trouble-
some for the practitioner to decide what to do about such
dilatation from a patient-management standpoint. The
difficulty with nomenclature may be attributed in part to
improvements in imaging techniques, but also may reflect
the fact that debate exists in the medical community over
the significance of the finding of enlargement of the
subarachnoid spaces. In 1918, Dandy described infants
with increased intracranial pressure and dilatated sub-
arachnoid spaces, and stated skeptically that “no separate
subdivision has been made into internal and external
hydrocephalus. It is a question as to whether external
hydrocephalus ever really exists as a primary condition”
[4]. Nevertheless, “external hydrocephalus” remains a
synonym for enlargement of the subarachnoid spaces, and
appears in major textbooks on child neurology [5].
Communications should be addressed to:
Dr. Paciorkowski; Division of Human Genetics; University of
Connecticut Health Partners; 65 Kane St.; West Hartford, CT 06119.
E-mail: apaciorkowski@resident.uchc.edu
Received December 13, 2006; accepted April 13, 2007.
Paciorkowski and Greenstein: Enlargement of Subarachnoid Spaces 1

Figure 1. T2-weighted magnetic resonance image (TR/TE ⫽ 3500/
119.4 ms) of the brain of a 3-month-old boy with macrocephaly
demonstrates increased cerebrospinal fluid in the bifrontal subarachnoid
space (star), with a widened interhemispheric fissure (solid arrow) and
normal ventricular size (dashed arrow), i.e., findings characteristic of
enlargement of the subarachnoid spaces.
Barkovich [1] emphasized that “benign enlargement of
the subarachnoid spaces” was the appropriate term when
describing otherwise normal infants with macrocephaly
and the radiologic features under discussion here. The
conclusion that an infant with enlargement of the sub-
arachnoid spaces is “otherwise normal” should rest, how-
ever, on an understanding of the normal physiologic
development of cerebrospinal fluid circulation and the
subarachnoid spaces, coupled to serial clinical observa-
tions over time.
Macrocephaly has been traditionally defined as an
occipito-frontal head circumference greater than two stan-
dard deviations above the population mean, or above the
98th percentile [6]. Definitions of enlargement of the
subarachnoid spaces have included abnormally large head
size as a required feature, because this feature helps
distinguish it from cortical atrophy, which also results in
an increase in subarachnoid cerebrospinal fluid space [7].
Normal Development of the Subarachnoid Spaces
Cerebrospinal fluid not only serves to mechanically
support the brain, but also provides for the delivery of
nutrients, removal of metabolites, and circulation of neu-
rotransmitters from different areas of the central nervous
system [8]. The majority of cerebrospinal fluid is produced
in four choroid plexuses in the ventricles, and exits into the
2 PEDIATRIC NEUROLOGY Vol. 37 No. 1
basal cisterns, entering the subarachnoid space over the
surface of the cortex (Fig 2) [9]. The secretory epithelium
of the choroid plexus is formed by 6 weeks of gestation
[10]. It remains unclear when the onset of cerebrospinal
fluid production begins, but by 2 months of gestation,
circulation is established from the ventricles to the sub-
arachnoid space [5].
The subarachnoid space is formed by the separation of
the arachnoid membrane from the primitive dura mater,
and spreads from the ventral portion of the mes- and
rhombencephalon caudally to the spinal cord, and crani-
ally to the prosencephalon [11]. Cerebrospinal fluid is
absorbed into the cerebral venous system from the sub-
arachnoid space through herniations of the arachnoid
membrane into the dural venous sinuses [12,13]. These
microtubular invaginations of the subarachnoid space into
the lumen of the dural venous sinuses first form micro-
scopic arachnoid villi in utero [9]. This development
probably correlates with the decrease in size of the arachnoid
space after 32 weeks of gestation, as seen on fetal magnetic
resonance imaging studies [14]. Arachnoid villi can be found
in the fetus and newborn, and the granulations develop
between 6 and 18 months of age [15,16].
There appears to be a spectrum of functional maturity of
the arachnoid villi in infants, whereby absorption may not
keep pace with cerebrospinal fluid production for a period
of time. Indeed, it was shown that normal children under
the age of 2 years have slow cerebrospinal fluid flow over
the cerebral surface, as demonstrated by early ventricular
entry of radioisotope during cisternography [17]. Until the
sutures of the skull close, cerebrospinal fluid accumulates
preferentially in the subarachnoid space, leaving the ven-
tricles largely undilatated, because the bulk of cerebrospi-
nal fluid absorption occurs through the subarachnoid
channels that cover the cerebral hemispheres [18].
After 2 years of age, the capacity for cerebrospinal fluid
drainage can attain two to four times the normal rate of
production [5]. Further growth of the arachnoid villi and
granulations leads to the formation of macroscopic Pac-
chionian bodies, i.e., dilatations of the subarachnoid space
in the pedicle of the mature arachnoid villus that are
increasingly visible by 3 years of age [9]. This capacity for
cerebrospinal fluid absorption follows a progressive, but
variable, timeline (Fig 3), and it is therefore not surprising
that variability has been observed in the size of the
subarachnoid spaces in normal children [19]. This progres-
sive, but variable, enlargement appears to provide the
physiologic basis for benign enlargement of the subarach-
noid spaces.
Establishing the Diagnosis of Enlargement of the
Subarachnoid Spaces
The decision to obtain neuroimaging in a child with
macrocephaly is usually based on the presence of other
neurologic abnormalities, such as seizures, abnormal tone,
or developmental delay or regression. Rapidly increasing
Table 1. Genetic conditions associated with enlargement of the subarachnoid spaces

Condition Inheritance Other Clinical Findings Other Neuroimaging Findings Diagnostic Studies

MPS Enzyme studies for:

I (Hurler) AR Varying degrees of developmental Cribriform changes, increased ␣-l-iduronidase
arrest, coarse features, white matter signal,
hirsutism, hernias, dysostosis ventriculomegaly, cortical
multiplex atrophy
II (Hunter) X-linked Iduronate-2-sulfatase
III (Sanfilippo) AR IIIA: glucosamine-N-sulfatase
Types A-D IIIB: ␣-N-acetyl-glucosaminidase
IIIC: Acetyl-coenzyme A:
␣-glucosaminide-N-acetyltransferase
IIID: N-acetyl-glucosamine-6-sulfatase
Achondroplasia AD Rhizomelic dwarfism, Foramen magnum stenosis, Skeletal survey
characteristic radiographic cervicomedullary compression FGFR3 studies
findings
Sotos syndrome AD Skeletal overgrowth, characteristic Delayed maturation, abnormalities NSD1 sequence analysis, chromosome
facies, learning disability of corpus callosum, prominent analysis for 5q35 microdeletion
trigone, occipital horns,
ventriculomegaly
Glutaric aciduria AR Hypotonia, encephalopathy, Symmetric widening of the Sylvian Newborn screening, urine organic acid
type I stroke-like episodes fissures, failure of operculation, analysis, glutaryl-coenzyme
basal ganglia injury, striatal A-dehydrogenase deficiency in
necrosis fibroblasts or leukocytes

Abbreviations:
AD ⫽ Autosomal dominant
AR ⫽ Autosomal recessive
MPS ⫽ Mucopolysaccharidosis

head size (i.e., head circumference measurements that
cross at least two percentile lines on standard growth
curves over several months or shorter timeframe) is also
an indication for neuroimaging.
Figure 2. Circulation of cerebrospinal fluid in the brain. (Reprinted
from Neuroscience, Vol 129, Brown et al, ⬙Molecular mechanisms of
cerebrospinal fluid production,⬙ 957-70, 2004, with permission from
Elsevier.)
Cranial ultrasound is often performed on infants with an
open anterior fontanel because it is a quick procedure,
does not require sedation, and does not expose the patient
to ionizing radiation. The technique provides adequate
views of supratentorial anatomy, but is less useful in
visualizing the posterior fossa where important causes of
obstructive hydrocephalus may be present. The limited
diagnostic accuracy of anterior fontanel cranial ultrasound
can be improved somewhat through supplemental poste-
rior fontanel and mastoid windows [20], but the potential
for diagnostic error remains [21]. Computed tomography,
while offering a more thorough examination of neuroanat-
omy, carries with it the risk of ionizing radiation. This risk
for a 1-year-old child was estimated as a 0.07% increase in
the lifetime cancer mortality rate per computed tomogra-
phy of the head, with a cumulative increase if multiple
studies are performed [22,23]. For most cases of stable
macrocephaly (i.e., not exhibiting a rapid increase in head
circumference) with abnormal neurologic signs or altered
development, magnetic resonance imaging is the modality
of choice, because it maximizes the details of the brain
structures under examination, while minimizing the risk to
the patient, provided that sedation can be safely managed.
Although normal values for the frontal subarachnoid
space in infancy were published (0-4 mm) [24,25], many
neuroradiologists adopt a more qualitative approach that
may occasionally lead to over- or undercalling of the
phenomenon. Caution must be exercised in interpreting
enlargement of the subarachnoid spaces, because it can be

Paciorkowski and Greenstein: Enlargement of Subarachnoid Spaces 3


caused by many nongenetic factors. These include corti-
cotropin and steroid therapy, dehydration, malnutrition,
total parenteral nutrition, cancer chemotherapy [1], and
hypomagnesemia [26]. In addition, the presence of cere-
bral atrophy must be considered. In a study of patients
with enlargement of the subarachnoid spaces compared
with patients with cerebral atrophy, it was noted that in
cases of cerebral atrophy, the sulci were prominent
throughout the entire cerebrum, and the ventricles were
dilatated in proportion to the rest of the subarachnoid
spaces [7]. Occasionally, the differentiation of enlarge-
ment of the subarachnoid spaces from subdural hygroma
after head trauma may pose a diagnostic dilemma, because
subdural fluid collections can be difficult to distinguish
from subarachnoid fluid [27].
Clinical Signs and Symptoms of Enlargement of the
Subarachnoid Spaces
In many infants with enlargement of the subarachnoid
spaces, the head size is so alarming that neuroimaging is
obtained, despite a negative review of organ systems, a
normal neurologic examination, and a normal develop-
mental history. The child continues to meet normal devel-
opmental milestones, until head growth reaches a plateau
somewhere above the 95th percentile, and repeat imaging,
if obtained, is normal [28,29]. Occasionally, transient
gross motor delay is observed, and this delay is usually
attributed to the added head weight of the macrocephalic
infant [29,30]. Importantly, there is often a family history
of macrocephaly [30].
The variability of terms in the literature makes it
difficult to catalogue what, if any, neurologic signs other
than macrocephaly are associated with enlargement of the
subarachnoid spaces. Some reports included surprising
numbers of children with significant motor delay [31],
while others were probably describing children with cor-
tical atrophy, because they included microcephalic and
normocephalic children in their discussion of enlarged
subarachnoid spaces [32].
The infant with apparently benign enlargement of the
subarachnoid spaces must still be approached with suspi-
cion. The head circumferences of the parents and other
4 PEDIATRIC NEUROLOGY Vol. 37 No. 1
Figure 3. Timeline of development of cerebro-
spinal fluid circulation and the subarachnoid
space. The structures of cerebrospinal fluid
absorption mature in a progressive fashion, and
by 18-24 months of age, production is typically
equaled by absorption. CSF ⫽ cerebrospinal
fluid; mos ⫽ months; wks ⫽ weeks; yrs ⫽ years.
first-degree relatives should be obtained, and familial
macrocephaly (inherited in an autosomal dominant man-
ner) should be expected. The diagnosis of benign enlarge-
ment of the subarachnoid spaces requires following the
child for a period of years to confirm normal develop-
ment. Evidence of a neurodevelopmental plateau or
decline should be sought during serial evaluations.
Ultimately, the parents can be reassured that their child
should “grow into the increased head size,” and gener-
ally no long-term ill effects are anticipated. Table 2 lists
the cardinal features of benign enlargement of the
subarachnoid spaces that should be fulfilled for the
diagnosis to be applied.
The Mucopolysaccharidoses
The mucopolysaccharidoses are a diverse group of
lysosomal storage diseases, each caused by the deficiency
of a specific enzyme whose task in the lysosomal com-
partment is to degrade glycosaminoglycans [33]. The
treatment of mucopolysaccharidoses I, II, and VI was
affected dramatically by the introduction of peripheral
enzyme-replacement therapies [34-37], and patients with
many forms of mucopolysaccharidosis have undergone
bone marrow and stem-cell transplantation with increas-
ingly positive results [38-40]. Therefore, it is important to
diagnose these diseases in a timely fashion before signif-
icant, irreversible organ damage has occurred.
Table 2. Characteristics of benign enlargement of the
subarachnoid spaces of infancy that should be fulfilled for the
diagnosis to be accurately applied
History ● Family history of macrocephaly
Neurodevelopment ● Normal attainment of
developmental milestones at least
through 18-24 months of age
● No neurologic disease
Radiographic (magnetic ● Bifrontal enlargement of the
resonance imaging) subarachnoid space
● Widened interhemispheric fissure
● Normal or near-normal lateral
ventricles
● Resolution on repeated imaging
(if obtained) after 18-24 months
of age
 Pathology reports in patients with mucopolysaccharido-
ses have found thickening of the leptomeninges, with
increased deposition of glycosaminoglycans in the con-
nective tissue lining the brain [41,42]. This thickening
may lead to dysfunction of the arachnoid granulations that
carry out cerebrospinal fluid absorption [43]. Leptomen-
ingeal glycosaminoglycan deposition appeared to be more
prominent in mucopolysaccharidoses I and II than in III
[44]. Nevertheless, isolated enlargement of the subarach-
noid spaces is a feature observed in patients with muco-
polysaccharidoses IIIA and IIIB [45]. A recent study of 18
patients (age range, 6-20 years) with mild forms of
mucopolysaccharidosis I or II found that enlargement of
the subarachnoid spaces was also associated with moder-
ate to severe ventriculomegaly [43]. According to the
normal timeline of the development of cerebrospinal fluid
absorption, increased fluid in the subarachnoid spaces
should resolve by 24 months. Instead, there appears to be
a progression in patients with mucopolysaccharidosis from
enlargement of the subarachnoid spaces to ventriculo-
megaly and communicating hydrocephalus. We have en-
countered enlargement of the subarachnoid spaces in
patients with mucopolysaccharidoses who are under 2
years of age, and we suggest that enlargement of the
subarachnoid spaces may be an early finding in infants
with this family of lysosomal disease.
Achondroplasia
Achondroplasia is inherited in an autosomal dominant
fashion, but 90% of cases arise de novo [46]. Enlargement
of the subarachnoid spaces has long been observed in
patients with achondroplasia [47]. Enlargement of the
subarachnoid spaces may be part of a spectrum of findings
related to a small foramen magnum and resultant intracra-
nial venous hypertension [48]. By this mechanism, in-
creased pressure on the venous flow out of the cranium
results in congestion of the dural venous sinuses. This
congestion impedes cerebrospinal fluid absorption, lead-
ing to enlargement of the subarachnoid spaces in infancy,
and then to communicating hydrocephalus after the su-
tures fuse. It is not known whether there is a direct effect
of the causative FGFR3 mutation on the fine structure of
the arachnoid villi.
The finding of enlargement of the subarachnoid spaces
may be an important early sign in an infant with achon-
droplasia. Infants with a de novo mutation in FGFR3, and
therefore no family history of achondroplasia, often
present to the nongeneticist with macrocephaly and small
stature, and the outward manifestations of classic skeletal
dysplasia may not be detectable to the untrained eye.
The identification of enlargement of the subarachnoid
spaces in an infant who also has small stature, and in
particular shortness of the proximal limbs, should
therefore trigger a more thorough evaluation, including
a skeletal survey.
Sotos Syndrome
Sotos syndrome is characterized by pre- and postnatal
overgrowth, macrocephaly, hypotonia, learning disability,
and distinctive facial features that include frontal bossing,
high anterior hairline, downward-slanting palpebral fis-
sures, prominent mandible, and pointed chin [49]. More
than 80% of cases of Sotos syndrome are caused by
mutations in NSD1, with a further 10% attributable to
5q35 microdeletions [50-52]. Most cases of Sotos syn-
drome have been sporadic, but autosomal dominant inher-
itance has been described [53,54].
Up to 70% of imaged Sotos syndrome patients were found
to have enlargement of the subarachnoid spaces, with the
rather unsatisfying explanation that the finding may be a
secondary effect of accelerated growth of the skull, because
these children have a normal brain volume [55]. Another
possible explanation is related to other structural findings
consistent with delayed maturation of the central nervous
system, such as abnormalities of the corpus callosum, and
prominence of the trigone of the lateral ventricles [51,55,56].
It seems reasonable to postulate that because maturational
abnormalities are present in neuronal development, there may
be a coexistent delay in maturation of the arachnoid absorp-
tion of cerebrospinal fluid.
Glutaric Aciduria Type I
Glutaric aciduria type I is a rare inborn error in
the metabolism of lysine and tryptophan, caused by autoso-
mal recessive deficiency of the enzyme glutaryl-coenzyme
A-dehydrogenase [57]. Affected infants may develop mac-
rocephaly in the first weeks after birth, followed by acute
encephalopathy associated with an intercurrent febrile illness,
with the potential for the neurologic symptoms of seizures
and dystonia, and less commonly spastic quadriplegia and
choreoathetosis [57-59].
Patients with glutaric aciduria type I often have expan-
sion of the cerebrospinal fluid spaces anterior to the
temporal and frontal lobes, in a pattern that has been
variously labeled “external hydrocephalus” or “subdural
collections” [60,61]. The etiology of the enlargement of
the subarachnoid spaces in glutaric aciduria type I is not
clear. Although mitochondrial impairment from elevated
3-hydroxyglutaric acid levels was proposed as an etiology
for the striatal necrosis associated with the disease [62],
there is no evidence to attribute enlargement of the
subarachnoid spaces to this metabolic dysfunction.
Conclusion
Enlargement of the subarachnoid spaces has been consid-
ered a benign entity associated with developmentally normal
infants with macrocephaly. The literature on the topic is
complicated by varying terminology. We favor the use of the
term “benign enlargement of the subarachnoid spaces of
infancy” for those children with proven normal development.
Paciorkowski and Greenstein: Enlargement of Subarachnoid Spaces 5
Benign enlargement of the subarachnoid spaces appears to be
related to normal variations in cerebrospinal fluid absorptive
capacity, and the radiographic findings should follow an
expected time course to resolution by 18-24 months of age, as
the absorptive capacity of the arachnoid villi matures. There-
after, the child usually remains macrocephalic into adulthood.
There should be no significant developmental abnormalities
found after serial observations that include the time of
resolution of the physiologic imbalance in cerebrospinal fluid
absorption.
In the case of a child with enlargement of the subarach-
noid spaces who does not fit the expected normal pattern
of development, or in whom the finding does not resolve
after 18-24 months of age, further investigations may be
warranted. Several genetic conditions, i.e., certain muco-
polysaccharidoses, achondroplasia, Sotos syndrome, and
glutaric aciduria type I, can feature enlargement of the
subarachnoid spaces as either an early or an associated
finding on neuroimaging. In the case of the mucopolysac-
charidoses, enlargement of the subarachnoid spaces may
be a direct consequence of impairment of cerebrospinal
fluid absorption by the storage material. Enlargement of
the subarachnoid spaces may therefore be an important
clue to a correct early genetic diagnosis. This early
diagnosis is becoming increasingly important, because
therapeutic options exist for many forms of mucopolysac-
charidosis, and for glutaric aciduria type I.
The authors thank Ethan Foxman, MD, Department of Neuroradiology,
Hartford Hospital, Hartford, CT, for his review of selected neuroimages, and
Francis J. DiMario, Jr., MD, Division of Neurology, Department of Pediat-
rics, Connecticut Children’s Medical Center, Hartford, CT, for his review of
the manuscript.
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