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Child's Nervous System
ISSN 0256-7040
Childs Nerv Syst
DOI 10.1007/s00381-019-04384-w
Not all ventriculomegaly is created equal:
diagnostic overview of fetal, neonatal and
pediatric ventriculomegaly
Smruti K.Patel, Jorge Zamorano-
Fernandez, Usha Nagaraj, Karin
S.Bierbrauer & Francesco T.Mangano
1 23
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FOCUS SESSION
Not all ventriculomegaly is created equal: diagnostic
overview of fetal, neonatal and pediatric ventriculomegaly
Smruti K. Patel
1
&Jorge Zamorano-Fernandez
2
&Usha Nagaraj
3
&Karin S. Bierbrauer
1,2
&Francesco T. Mangano
1,2
Received: 26 August 2019 / Accepted: 20 September 2019
#Springer-Verlag GmbH Germany, part of Springer Nature 2019
Abstract
Fetal ventriculomegaly refers to a condition in which there is enlargement of the ventricular spaces, typically on prenatal
ultrasound. It can be associated with other CNS or extra-CNS abnormalities, and this relationship is crucial to understand as it
affects overall neonatal outcome. Isolated ventriculomegaly has been described in the literature with variable clinical outcome.
Typically, outcome is based on the etiology and degree of ventriculomegaly. When associated with a pathologic condition,
ventriculomegaly can be a result of hydrocephalus. While initial diagnosis is usually made on prenatal ultrasound, fetal magnetic
resonance imaging is preferred to further elucidate any associated CNS malformations. In this paper, the authors aim to provide a
comprehensive review of the diagnosis, associated etiologies, prognosis, and treatment options related to fetal, neonatal, and
pediatric ventriculomegaly and hydrocephalus. In addition, preliminary data is provided from our institutional cohort of patients
with a prenatal diagnosis of ventriculomegaly followed through the perinatal period.
Keywords Fetal ventriculomegaly .Hydrocephalus .Fetus .Fetal magnetic resonance imaging .Myelomeningocele
Abbreviations
CNS Central nervous system
ICP Intracranial pressure
GA Gestational age
MRI Magnetic resonance imaging
CT Computed tomography
FeMRI Fetal magnetic resonance imaging
CSF Cerebrospinal fluid
CAS Congenital aqueductal stenosis
ETV Endoscopic third ventriculostomy
PHH Post-hemorrhagic hydrocephalus
VAD Ventricular access device
VSG Ventriculosubgaleal shunt
LP Lumbar puncture
ACC Agenesis of the corpus callosum
CC Corpus callosum
CIM Chiari I malformation
MPS Mucopolysaccharidoses
HPE Holoprosencephaly
VGM Vein of Galen malformation
MMC Myelomeningocele
CPC Choroid plexus cauterization
DTI Diffusion tensor imaging
Introduction
Ventriculomegaly, or dilatation of the ventricles of the brain, is
one of the most commonly diagnosed abnormalities of the
pediatric central nervous system (CNS) [1,2]. The incidence
of ventriculomegaly is 0.3 to 2.0 per 1000 pregnancies [3,4].
The diagnosis of fetal ventriculomegaly is typically made on
prenatal ultrasound and is defined by an atrial diameter of the
lateral ventricle that is >10mm[2]. Fetal ventriculomegaly
can be subclassified into mild (10–12 mm), moderate (12–15
mm), and severe (> 15 mm) [5,6]. While there is consensus
regarding the definition of severe ventriculomegaly, the termi-
nology for mild and moderate ventriculomegaly differs de-
pending on the classification used [7]. In general, although
*Francesco T. Mangano
Francesco.mangano@cchmc.org
1
Department of Neurosurgery, University of Cincinnati College of
Medicine, 3333 Burnet Avenue, MLC 2016,
Cincinnati, OH 45229-3026, USA
2
Division of Pediatric Neurosurgery, Cincinnati Children’s Hospital
Medical Center, 3333 Burnet Avenue, MLC 2016,
Cincinnati, OH 45229-3026, USA
3
Division of Radiology, Cincinnati Children’s Hospital Medical
Center, Cincinnati, OH, USA
Child's Nervous System
https://doi.org/10.1007/s00381-019-04384-w
Author's personal copy
ventriculomegaly implies enlarged ventricular size, it is not
synonymous with hydrocephalus which implies a pathologic
condition in which the dilatation of the ventricles is due
to increased intracranial pressure (ICP) [8]. Though fetal
ventriculomegaly can progress to postnatal hydrocepha-
lus, it can also be due to acquired or intrinsically de-
creased cerebral volume in the absence of intracranial
hypertension [9].
While ventriculomegaly can occur in isolation, it has been
shown to be linked to various other CNS anomalies such as
neural tube defects, posterior fossa malformations, agenesis of
the corpus callosum, and genetic syndromes [8]. It is para-
mount to recognize that ventriculomegaly is associated with
other CNS or extra-CNS structural malformations due to
the significant impact on overall outcome of the neonate
[9]. In some patients, these abnormalities are not iden-
tified until the postnatal period. In this review, we de-
scribe the various imaging tools used to evaluate and
diagnose ventriculomegaly and review the various etiol-
ogies related to the presence of ventriculomegaly. We
also provide some preliminary data from our institution-
al cohort of patients with pediatric ventriculomegaly that
have been followed from the prenatal assessment to the
postnatal period.
Radiologic assessment of ventriculomegaly
Prenatal ultrasonography
Ultrasound is the initial imaging study used to evaluate the
fetal anatomy typically performed routinely at 20 to 24 weeks
gestational age (GA) [10,11]. The general symmetry of the
fetal brain is assessed, and standard intracranial structures are
identified. During this survey, the lateral ventricles are exam-
ined, and it is important to keep in mind that, while the ultra-
sound images are viewed in two dimensions, the ventricles
must be thought of in three dimensions. The lateral ventricles
consist of five parts: the frontal horn, the body, the occipital
horn, the temporal horn, and the atrium. The atrium is the
convergence of the body, occipital, and temporal horns of
the lateral ventricles. It is also the easiest part of the
ventricular system to identify at this GA on fetal ultra-
sound. The atrium can be measured in the axial plane at
the level of the thalami [12]. Measurement calipers are
placed at the inner margins of the ventricular walls at
the level of the posterior margin of the choroid plexus.
At any gestational age, lateral ventricle size of 10 mm or
greater is considered enlarged [13]. The normal mean atrial
diameter is 7.6 ± 0.6 mm between 14 and 38 weeks GA [14].
In the setting of normal intracranial anatomy, the ventricular
system becomes even less prominent as GA advances, but the
10-mm threshold is still valid.
Fetal magnetic resonance imaging
Fetal magnetic resonance imaging (FeMRI) can be a very
valuable tool to complement ultrasonography findings.
Unlike ultrasound, it is not limited by the ability to penetrate
the surround fetal calvarium and maternal soft tissues, and
also demonstrates superior contrast resolution making the
study of choice in the evaluation of fetal neuroanatomy [14,
15]. Current guidelines list ventriculomegaly as one of several
CNS-related indications for further evaluation with FeMRI
[12]. Recently, a prospective, multicenter-cohort study
(MERIDIAN) showed that FeMRI improved diagnostic accu-
racy and allowed greater confidence in management of pa-
tients with fetal brain abnormalities [16]. A subgroup analysis
of patients with ventriculomegaly showed that information
provided by FeMRI influenced decision-making in approxi-
mately 25% of patients [17]. Similar to ultrasound imaging,
the atrial diameter of the lateral ventricles can be measured on
in the axial or coronal plane. On FeMRI, the average normal
values are between 6 and 7 mm, with the same threshold of
≥10 mm [18]. The coronal plane is typically favored
on FeMRI (different compared to the axial plane on
ultrasound) because atrial measurements at the level of
the choroid plexus are highly concordant with ultra-
sound for comparison purposes [19].
Postnatal imaging
Postnatal imaging typically consists of both ultrasound
and MRI and may even include computed tomography
(CT) in an acute setting. Like with fetal imaging, to our
knowledge, there is no clear standardized definition for
ventriculomegaly in the postnatal population, making it
difficult to formulate a true quantitative comparison be-
tween prenatal and postnatal studies. There are various
methods by which neonatal ventricles are assessed on
ultrasonography including: (1) ratio of the distance from
the falx to the lateral wall of the ventricle to the hemi-
spheric width, (2) ratio of ventricular diameter to the
diameter of the brain at the same level, (3) displacement
of the medial wall of the ventricle toward the midline,
and (4) frontal-occipital horn ratio (FOHR) [20–26].
Similarly, ventricular size is typically measured on neo-
natal MRI using ventricular/brain ratio or FOHR [26,
27]. It is also prudent to state that the standard defini-
tion of fetal ventriculomegaly cannot be applied to post-
natal imaging studies because neonatal imaging does not
give the ultrasonographer the same axial plane of view,
and even on postnatal MRI, an atrial diameter of ≥10 mm
cannot always be classified as enlarged [28]. A recent study
showed that atrial diameter and FOHR both correlate well
with normalized ventricular size after GA of 24 weeks and
can be reported in fetal studies to help provide continuity for
Childs Nerv Syst
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comparison with postnatal studies [29]. Diffusion tensor
imaging (DTI) and tractography have also emerged as
powerful tools in the identification of white matter ab-
normalities related to pediatric hydrocephalus on MRI
[30,31]. Longitudinal analysis of white matter changes
showed signs of recovery after treatment of congenital
hydrocephalus suggesting that DTI can serve a sensitive
imaging biomarker for underlying anatomical changes
and postsurgical developmental outcome [32]. The data
suggests that DTI may also have potential application in
fetal ventriculomegaly and a potential role in the im-
provement of decision-making for these patients [31].
Etiologies associated with ventriculomegaly
Isolated ventriculomegaly
The incidence of isolated mild and moderate postnatal
ventriculomegaly has a prevalence of 0.7%, while iso-
lated severe ventriculomegaly has a prevalence between
0.03 and 0.15% [4,33]. A systematic review and meta-
analysis of 20 studies [34] reported that the overall rate
of developmental delay in patients with mild to moder-
ate ventriculomegaly was 7.9%, which is comparable to
that seen in the general population. Thus, following an
appropriate postnatal workup, parents can be given re-
assurance regarding a normal neurodevelopmental out-
come in cases of isolated mild to moderate ventriculomegaly.
In contrast, a recent prospective, observational study of 263
cases of fetal ventriculomegaly evaluating 2-year postnatal
outcomes showed that the prognosis was poorest for babies
with severe ventriculomegaly and associated CNS defects at
both birth and 2 years of age. Only 23.5% of patients survived
beyond age 2 [35]. Furthermore, another systematic review
assessing the outcome of neonates with severe isolated
ventriculomegaly reported that 58.2% of surviving patients
had some form of disability, with more than two-thirds
exhibiting severe disability [36].
Congenital hydrocephalus
Congenital hydrocephalus is a serious condition that can arise
from multiple causes (Table 1). It comprises a diverse group of
conditions which result in impaired circulation and absorption
of cerebrospinal fluid (CSF), including complex syndromes.
A list of well-known genetic diseases and cytogenetic abnor-
malities associated with congenital hydrocephalus can be
found in Tables 2,3,and4[37]. The most frequent cytoge-
netic abnormalities in symptomatic hydrocephalus include
(mosaic) trisomy 9, 9p, 13, and 18 and (mosaic) triploidy
[38]. A significant number of in utero acquired infections are
also known to result in congenital hydrocephalus by causing
inflammation of the ependymal lining of the ventricles and the
subarachnoid space [39] or mechanical blockage of the CSF
circulation (Table 5)[40]. The phenotypical presentation of
patients with congenital hydrocephalus varies widely, and
the prognosis depends on the underlying cause of hydroceph-
alus, associated malformations, and the timing and success of
surgical treatment [41]. The degree of cognitive impairment
does not necessarily correlate with head circumference or se-
verity of hydrocephalus, and clinical decisions must be based
on the characteristics of each individualized patient.
Table 1 Primary etiologies of
congenital hydrocephalus or
ventriculomegaly
Neural tube defects Congenital CNS tumors
In-utero intracranial hemorrhage Syndromic craniosynostosis
In utero CNS infection Achondroplasia
In utero trauma Mucopolysaccharidosis
Isolated ventriculomegaly Cytogenetic anomalies/complex syndromes
Secondary to posterior fossa anomalies Isolated hydrocephalus
Dandy-Walker continuum
Blake’s pouch remnant
Rhombencephalosynapsis
Chiari I malformation
Aqueductal stenosis
X-linked hydrocephalus
Autosomal recessive hydrocephalus
Associated with CNS malformations
Hydranencephaly
Holoprosencephaly
Schizencephaly/Porenencephaly
Vein of Galen malformation
Congenital cysts
Agenesis of the corpus callosum
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Congenital aqueductal stenosis
Congenital aqueductal stenosis (CAS) is a form of ob-
structive hydrocephalus in which there is partial or com-
plete obstruction of flow through the cerebral aqueduct lead-
ing to enlargement of the lateral and third ventricles in the
setting of intracranial hypertension. CAS can be due to
genetic causes or acquired [42]. To date, there are only
four described genes known to cause congenital hydro-
cephalus as the main feature of this disease process, two
of which are X-linked (L1CAM and AP1S2) and two
autosomal recessive (CCDC88C and MPDZ) [43].
Ventriculomegaly in the setting of rhombencephalosynapsis
or dystroglycanopathy has also been shown to occur as a result
of congenital aqueductal stenosis [44]. Intrinsic acquired
forms of CAS include infection or intraventricular hemor-
rhage (IVH), whereas extrinsic acquired forms include tectal
plate or other periaqueductal lesions [44,45]. A recent insti-
tutional study showed that at mean 6-year follow-up, their
cohort of patients with CAS [regardless of type of treatment
intervention including shunting and endoscopic third
ventriculostomy (ETV)] showed high rates of epilepsy
(48.8%) and developmental delay (68%), as well as har-
bored diagnoses of cerebral palsy (9.8%) and attention-
deficit hyperactivity disorder (14.6%). Only one-third of
patients were neurologically normal [46].
Post-hemorrhagic hydrocephalus
Intraventricular hemorrhage is a common cause of post-
hemorrhagic hydrocephalus (PHH) primarily in premature or
very low birth weight infants. Perinatal IVH can lead to sig-
nificant neurologic disability and lifelong treatment for PHH.
Typically, the treatments of choice for PHH are early tempo-
rizing measures such as ventricular access devices (VAD) or
ventriculosubgaleal shunts (VSGS), followed by permanent
therapies such as shunting [47]. In a recent study comparing
180-day rates of conversion to permanent shunting between
VSGS and VADs, the rates were reported to be 63.5% and
74% respectively (p= 0.36) with an equivocal infection rate of
14% and 17%, respectively (p=0.71)[48]. Neonates
with PHH that require permanent CSF diversion are at
greatest risk for adverse neurodevelopmental outcome
and delayed growth compared with those not requiring
intervention [49].
Neural tube defects: myelomeningocele
Myelomeningocele (MMC) is the most common open neural
tube defect seen in clinical practice. The persistence of
an in-utero CSF leak at the level of the defect creates a
pressure gradient between the brain and the spine that
results in significant alterations in the development of
the brain (hindbrain herniation, small posterior fossa,
and distorted ventricular anatomy among others). This
can often lead to an alteration of CSF dynamics and
development of ventriculomegaly with progression to
either communicating and/or non-communicating hydro-
cephalus [50]. Most patients born with an unrepaired
MMC will not show clinic-radiological signs of hydro-
cephalus until the defect is surgically closed, but the
incidence of hydrocephalus in postnatally repaired
MMC patients has been reported to be as high as 80%
[51]. The severity of the disease is associated with the
level of the dysraphic defect, with higher incidence of
hydrocephalus for cervical and thoracic defects com-
pared to those located in the lower lumbosacral region
[52].
Prenatal repair of MMC before 26 weeks of GA has been
correlated with a decreased incidence of postnatal hydroceph-
alus and better outcomes related to motor function as shown in
the Management of Myelomeningocele Study (MOMS); it is
slowly becoming an increasing option for a select number of
patients diagnosed in utero [53]. Shunting remains the main
surgical option for treating MMC-related hydrocephalus.
Table 2 Recurrent cytogenetic abnormalities in congenital
hydrocephalus
a
Chromosome Cytogenetic abnormality
1 Terminal deletion 1p36
Trisomy 1q
Duplication 1q12-q25
2 Inversion (2)(p21q11)
Terminal deletion 2q
3 Interstitial deletion 3q
4 Deletion 4q21-27
5Trisomy5p
6 Ring chromosome 6
Terminal deletion 6p
Terminal deletions 6q
8 Interstitial deletion 8q12.2-q21.1
9 (Mosaic) trisomy 9
Tetrasomy 9p
11 Deletion 11q23-q25
13 Trisomy 13
14 Maternal uniparental disomy 14
18 Trisomy 18
20 Isochromosome 20q
22 Duplication distal 22q
XMonosomyX
Pentasomy X
All (Mosaic) triploidy
a
Adapted with permissions from: Verhagen JM et al. (2011) Congenital
hydrocephalus in clinical practice: a genetic diagnostic approach. Eur J
Med Genet 54: e542-547
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However, this specific population shows higher complications
rates, shunt failure-related mortality, and lower shunt survival
times than those with other etiologies. This is likely due to the
specific alterations in ventricular and cerebral anatomy and
shunting at an early age that causes a higher rate of proximal
obstruction [54]. Infection rates have also been reported to be
higher in MMC than for the general shunted population and
may be correlated with the specific needs of patients with
MMC (multiple abdominal surgeries, repeated bladder cathe-
terizations, etc.) [55]. To date, delayed or synchronous
shunting at the time of the postnatal MMC repair remain valid
options and have been reported to have comparable compli-
cation rates [56]. Controversy exists on the topic of avoidance
of shunting patients with MMC and ventriculomegaly when
clinically tolerated. The high complication rate must be bal-
anced with the deleterious effects of acutely and chronically
elevated ICP such as long-term neurodevelopmental and cog-
nitive delays. ETV with or without choroid plexus cauteriza-
tion (CPC) for the treatment of MMC-related hydrocephalus
has emerged as a valid option for a number of patients [57].
Limitations to this approach include age < 6 months old and
the predominant presence of a non-communicating compo-
nent that reduces the success rate of ETV [57].
Craniosynostosis and ventriculomegaly
Ventricular enlargement in the setting of non-syndromic cra-
niosynostosis appears to be a coincidental disorder which can
represent simple ventriculomegaly or shunt-dependent hydro-
cephalus [58,59]. However, diagnosis can be challenging in
these patients and may require invasive methods such as ICP
monitoring or lumbar puncture (LP), since both syndromic
and non-syndromic disorders may elevate ICP and show over-
lapping symptoms [58,60]. Ventriculomegaly is common in
syndromic craniosynostosis (Table 4) and has been reported in
30 to 70% of patients with Crouzon’s and Pfeiffer’ssyndrome
[58,60,61], and 40 to 90% of patients with Apert syndrome
[58,62–64]. While shunt-dependent hydrocephalus is com-
mon in Crouzon’s and Pfeiffer’s syndromes, in Apert syn-
drome, the majority of cases with ventriculomegaly do not
require shunting [58,61,63,64].
Agenesis of the corpus callosum
Agenesis of the corpus callosum (ACC) is one of the most
common congenital brain anomalies, with a prevalence rang-
ing from 1.8 per 10,000 in the general population [65]to
230–600 per 10,000 in children with neurodevelopmental dis-
abilities [66]. It can be isolated or associated with a vast num-
ber of complex disorders. Fetuses with ACC are at high risk of
chromosomal anomalies even when a standard karyotype is
negative [67]. Other disorders associated with progressive hy-
drocephalus may have concurrent ACC. The presence of
a reduced size of the corpus callosum (CC) can be a
sign of fetal hydrocephalus secondary to thinning of the
third ventricular roof. However, in isolated ACC, the
Table 3 Well-known genetic
disorders with congenital
hydrocephalus
a
Disorder Type Inheritance Gene Locus
X-linked hydrocephalus HSAS XL L1CAM Xq28
Hydrocephalus due to aqueduct stenosis XL L1CAM Xq28
Hydrocephalus due to aqueduct stenosis AR ? ?
MASA syndrome MASA XL L1CAM Xq28
X-linked spastic paraplegia SPG1 XL L1CAM Xq28
X-linked agenesis of the corpus callosum CCA XL L1CAM Xq28
X-linked mental retardation MRX59 XL AP1S2 Xp22
VACTERL-H XL FANCB Xp22
VACTERL-H AD PTEN 10p23.31
AR ? ?
Muscular dystrophy-dystroglycanopathy AR POMT1 9q34
AR POMT2 14q24
AR POMGNT1 1p34-p33
AR FKTN 9q31
AR FKRP 19q13
AR LARGE 22q12
Marden-Walker syndrome AR ? ?
Hydrolethalus AR HYLS1 11q24.2
a
Adapted with permissions from: Verhagen JM et al. (2011) Congenital hydrocephalus in clinical practice: a
genetic diagnostic approach. Eur J Med Genet 54: e542-547
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Table 4 Genetic disorders associated with congenital hydrocephalus
Disorder Key features
Achondroplasia Rhizomelic shortening of limbs, frontal bossing, trident hands
Acrodysostosis Peripheral dysostosis, growth failure, psychomotor retardation
Adams-Oliver syndrome Aplasia cutis, transverse limb defects, congenital heart defects
Alpha-mannosidosis Mental retardation, immune deficiency, hearing loss, dysostosis multiplex
Antley-Bixter syndrome Craniosynostosis, midface hypoplasia, radiohumeral synostosis, bowing femora
Apert syndrome Craniosynostosis, midface hypoplasia, syndactyly hand and feet
Asphyxiating thoracic dysplasia Short limbs, narrow thoracic cage, cloverleaf skull
Beare-Stevenson syndrome Craniosynostosis, cutis gyrata, acanthosis nigrans, anogenital anomalies
Beemer lethal malformation syndrome Congenital heart defects, dense bones, genital anomalies
Craniodiaphyseal dysplasia Craniofacial hyperostosis and sclerosis, progressive cranial nerve compression
Craniometaphyseal dysplasia Craniofacial hyperostosis and sclerosis, metaphyseal flaring
Cole-Carpenter syndrome Craniosynostosis, osseous fragility, ocular proptosis, micrognathia
Crouzon syndrome Craniosynostosis, midface hypoplasia, exophthalmos
Dyssegmental dysplasia, RD type Short-limbed dwarfism, narrow chest, decreased joint mobility
Ellis-van Creveld syndrome Short-limbed-dwarfism, short ribs, postaxial polydactyly, dysplastic nails/teeth
Fanconi anemia Radial ray defects, failure to thrive, microcephaly skin pigmentary changes
Greig cephalopolysyndactyly Pre-/postaxial polydactyly, cutaneous syndactyly, hypertelorism, macrocephaly
Metatropic dysplasia Short-limbed dwarfism, progressive joint enlargement, kyphoscoliosis
Osteogenesis imperfecta Osseous fragility, long bone deformity, blue sclerae, joint hypermobility
Osteopathia striata-cranial sclerosis Linear striations of long bone diametaphyses, sclerotic cranial base
Osteopetrosis Increased bone density, macrocephaly, hepatosplenomegaly, aplastic anemia
Otopalatodigital syndrome type II Bowing of long bones, absent fibula, omphalocele, hypospadias, cleft palate
Pfeiffer syndrome Craniosynostosis, partial syndactyly of hands and feet, broad thumbs
Shprintzen-Goldberg syndrome Craniosynostosis, marfanoid habitus, maxillary hypoplasia, exophthalmos
Tetraamelia Absence upper and lower limbs, lung hypoplasia, cleft lip/palate
Thanatophoric dysplasia Micromelic dwarfism, narrow thorax, severe platyspondyly, small iliac bones
Aicardi syndrome Corpus callosum agenesis, infantile spasms, lanular retinopathy
Bardet-Biedl syndrome Renal abnormalities, retinal dystrophy, postaxial polydactyly, short stature
De Hauwere syndrome Iris hypoplasia, hypertelorism, psychomotor retardation, sensorineural deafness
Joubert syndrome Cerebellar hypoplasia, retinal dystrophy, renal cysts, typical breathing pattern
Fraser syndrome Cryptophthalmos, cutaneous syndactyly, abnormal genitalia
Meckel-Gruber syndrome Polycystic kidneys, postaxial polydactyly, occipital encephalocele
Orofaciodigital syndrome type I Polycystic kidneys, oral cleft, lingual hamartomas, hypertelorism, brachydactyly
Plasminogen deficiency type I Ligneous conjunctivitis/gingivitis, upper respiratory tract infections
Sjögren-Larsson syndrome Congenital ichthyosis, macular degeneration, mental retardation, spasticity
Aase-Smith syndrome Dandy-Walker malformation, cleft palate, joint contractures
Alexander disease Megalencephaly, diffuse demyelination, seizures, psychomotor regression
Cardiofaciocutaneous syndrome Hyperkeratosis, high forehead with bitemporal constriction, cardiac anomalies
Chudley-McCullough syndrome Corpus callosum agenesis, sensorineural deafness, arachnoid cysts
Cockayne syndrome Failure to thrive, progressive leukodystrophy, microcephaly
Costello syndrome Mental retardation, short stature, coarse facies, loose skin, nasal papillomata
Cutis marmorata telangiectatica Livedo reticularis, telangiectasis, superficial ulcerations
Dystrophia myotonica Myotonia, muscular dystrophy, cataract, frontal balding, ECG abnormalities
Epidermal nevus syndrome Sebaceous nevi, hypopigmentation, seizures, mental retardation
Farber lipogranulomatosis Painful joint deformity, subcutaneous nodules, hoarseness
FG syndrome Mental retardation, large head, congenital hypotonia, constipation
Fryns syndrome Congenital diaphragmatic hernia, lung hypoplasia, distal limb hypoplasia
Gorlin syndrome Multiple basal cell carcinomas, jaw cysts, hyperkeratosis, rib anomalies
Hemifacial microsomia Facial asymmetry, external ear deformity, vertebral anomalies, microphthalmy
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colpocephalic morphology of the ventricles can be interpreted
as a mild increase in the ventricular volume on fetal and post-
natal neuroimaging. This ventriculomegaly, unless associated
with other pathologies, is non-progressive [68]. A significant
number of patients with ACC might be referred for fetal neu-
rosurgical consultation. Although the prognosis of isolated
ACC tends to be favorable, close post-natal follow-up of these
patients is advised to rule out its association with complex
syndromes with progressive hydrocephalus.
Chiari I malformation
Although hydrocephalus affects only a small number of patients
with Chiari type I malformation (CIM), the two entities have
been correlated. Association of ventriculomegaly and CIM has
been reported at around 10% in most clinical series, ranging
from6to25%[69,70]. Di Rocco et al. [71]proposedtwo
hypotheses regarding the pathogenesis of this relationship. The
first, simple hypothesis, states that a supratentorial hypertensive
Table 5 In utero acquired
infections associated with
congenital hydrocephalus
Infectious organism Key features of disease
Varicella virus Cicatricial skin lesions, limb hypoplasia, cataracts, chorioretinitis, structural
cerebral abnormalities
Parvovirus B19 Ocular anomalies, cleft lift, musculoskeletal anomalies, hepatitis,
cardiomyopathy, myositis
Herpes simplex virus Immunodeficiency, intracranial calcifications, encephalopathy
Human immunodeficiency
virus
Skin and mucosal lesions, microcephaly, chorioretinitis, pneumonitis, hepatitis
Treponema pallidum Dental and osseous abnormalities, hepatosplenomegaly, deafness, interstitial
keratitis, hemolytic anemia, pneumonitis
Toxoplasma gondii Microcephaly, chorioretinitis, intracranial calcifications
Rubella Cardiac defects, sensorineural hearing deficit, intracranial calcifications
Cytomegalovirus Microcephaly, intracranial calcifications, hemolytic anemia, hepatosplenomegaly
Zika virus Microcephaly, intracranial calcifications, arthrogryposis, chorioretinitis
Lympho cytic
choriomeningitis virus
Chorioretinitis, structural cerebral abnormalities, seizures
Tabl e 4 (continued)
Disorder Key features
Incontinentia pigmenti Skin pigmentary changes, nail dystrophy, dental and hair abnormalities
Ivemark syndrome Asplenia/polysplenia, abnormal situs, congenital heart defects, lung isomerism
Kartagener syndrome Chronic rhinosinusitis, otitis media with effusion, bronchiestasis, heterotaxy
Kabuki syndrome Eversion lower lateral eyelid, fetal fingerpads, brachydactlyly, joint laxity
Larsen syndrome Multiple congenital dislocations, talipes equinovares, prominent forehead
Loeys-Dietz syndrome type IA Arterial tortuosity and aneurysm, hypertelorism, bifid uvula, cleft palate
Mucopolysaccharidoses Mental retardation, hepatosplenomegaly, dysostosis multiplex, corneal clouding
Mulibrey nanism Growth failure, hypotonia, hepatomegaly, triangular face, high-pitched voice
Multiple sulfatase deficiency Rapid neurologic deterioration, hepatosplenomegaly, dysostosis multiplex
Myotubular myopathy I Generalized muscle weakness, neonatal respiratory distress, macrocephaly
Neurofibromatosis type I Café-au-lait spots, freckling, neurofibromas, optic glioma, Lisch nodules
Noonan syndrome Short stature, webbed neck, feeding difficulties, hypertelorism, low-set ears
Pena-Shokeir sydrome Fetal akinesia, intrauterine growth retardation, arthrogryposis, lung hypoplasia
Ritscher-Schinzel syndrome Dandy-Walker malformation, congenital heart defects, cleft palate, coloboma
Simpson-Golabi-Behmel syndrome Pre- and postnatal overgrowth, coarse facies, congenital heart defects
Smith-Lemli-Opitz syndrome Failure to thrive, microcephaly, ptosis, syndactyly second and third toes
Tuberous sclerosis Facial angiofibroma, mental retardation, epilepsy, cardiac rhabdomyoma
a
Adapted with permissions from: Verhagen JM et al. (2011) Congenital hydrocephalus in clinical practice: a genetic diagnostic approach. Eur J Med
Genet 54: e542-547
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hydrocephalus may cause CIM by exerting pressure from
above; the second, complex hypothesis, implies that the exis-
tence of congenital cranial base, posterior fossa, or
craniocervical junction abnormalities in the setting of CIM leads
to the development of secondary hydrocephalus. Nevertheless,
in most patients presenting with ventriculomegaly and CIM, the
pathogenesis depends on the combined action of those factors
and these findings can vary across subjects and different age
groups. Management of these patients can be challenging and
requires an understanding of the primary underlying pathogen-
esis at the time of the diagnosis [71].
Achondroplasia
Hydrocephalus in children with achondroplasia has been
reported in 15 to 50% of patients [72]. Increased pressure
in the dural venous sinuses due to impaired venous
drainage at the level of the jugular foramina and stenosis
at the foramen magnum is presumed to be the cause of
increased ICP in these children [72,73]. The underlying
cause of the condition can be due to mutations of the
FGFR3 gene leading to maldevelopment and growth of
the skull base, causing hydrocephalus [74]. Intellectual out-
come is excellent if detected early and treated [75]. The
decision for hydrocephalus intervention in an infant with
achondroplasia has significant consequences for the pa-
tient’s lifetime. The risk of shunt failure is very high in
this population and clear evidence that necessitates shunting
is warranted [76]. ETV has been reported to be successful
and has resulted in shunt-independent hydrocephalus in
some of these infants [77,78]. In a recent review [76],
the authors recommend a period of watchful observation
and follow-up, as a good outcome with normal cognition
is expected and to only consider treatment in infants with
Table 6 Mucopolysaccharidosis associated with ventriculomegaly or hydrocephalus
Type of MPS Enzyme deficiency Key features
I (Hurler, Hurler-Scheie, and
Scheie syndromes)
α-L-iduronidase Coarse facial features, macrocephaly, skeletal and articular anomalies,
corneal and retinal degeneration, hepatosplenomegaly, abdominal hernias
II (Hunter) Iduronate sulfatase Behavioral disturbances, mental retardation, hepatosplenomegaly,
obstructive airway disease, articular degeneration, pebbling of skin,
abdominal hernias
III (Sanfilippo syndrome) Heparan-N-sulfatase and others Facial dysmorphism, progressive dementia, behavioral disturbances,
seizures, progressive motor disease
VI (Maroteaux-Lamy syndrome) N-acetylgalactosamine 4-sulfatase Normal intellectual development, deafness, corneal clouding, dysostosis
multiplex, abdominal hernias
VII (sly syndrome) β-glucuronidase Intellectual disability, corneal degeneration, obstructive airway disease,
recurrent pneumoniae, carpal tunnel syndrome
Table 7 Cephalic disorders
associated with hydrocephalus Cephalic disorder Key features
Hydranencephaly Absence of cerebral hemispheres with preservation of brainstem,
thalami, basal ganglia, choroid plexus and posterior fossa
Midline malformations
Holoprosencephaly
Septo-optic dysplasia
Frontal-nasal dysplasia
Others
Incomplete separation of cerebral hemispheres and other midline
structures.
Optic nerve hypoplasia, septum-pellucidum hypoplasia,
hypothalamic-pituitary dysfunction hypertelorism, cleft lip
and palate, ethmoidal cephalocele, ACC, interhemispheric cyst
Porencephaly Cysts not lined by gray matter and often circumscribed to a vascular
territory, variable presentations
Lissencephaly Absent or minimal cortical sulcation, hypotonia, motor delay, muscular
dystrophy-like syndromes
Megalencephaly Excessive amount of cerebral tissue, uni or bilateral, macrocrania,
mental retardation, seizures
Schizencephaly Grey matter lined cleft extending from the ependymal to the pia matter,
presentation depending on size and location, motor and developmental
delay
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achondroplasia and progressive hydrocephalus. Using high-
pressure valve settings and anti-siphon devices is suggested
when shunting these patients at the initial procedure. In
cases of recurrent proximal shunt failures, a shunt that
drains the cortical subarachnoid space and ventricle to the
distal cavity with the splice proximal to the valve is rec-
ommended [76].
Mucopolysaccharidoses
The mucopolysaccharidoses (MPSs) are a group of inherited
lysosomal storage disorders resulting from a glycosaminoglycan
Table 8 Ty pes of
holoprosencephaly Type Key features
I Alobar Monoventricle, fused thalami, absent corpus callosum, absent
interhemispheric fissure, absent cavum septi pellucidi,
absence of third ventricle, middle and anterior cerebral
arteries replaced by tangled branches of internal carotid
and basilar vessels, severe facial malformations
II Semilobar Absence of septum pellucidum, monoventricle with partially
developed occipital and temporal horns, rudimentary falx
cerebri, incompletely formed interhem ispheric fissure,
partial or complete fusion of the thalami, absent olfactory
tracts and bulbs, agenesis or hypoplasia of the corpus
callosum, incomplete hippocampal formation
III Lobar Fusion of the frontal horns of the lateral ventricles, wide
communication of this fused segment with the third ventricle,
fusion of the fornices, absence of septum pellucidum,
normal or hypoplasia of the corpus callosum, anterior
cerebral artery malposition
IV Midline interhemispheric Vertically oriented sylvian fissures abnormally connected
across midline, cortical dysplasia, subcortical heterotopic
grey matter, dorsal cyst, hypoplasia or aplasia of the body
of corpus callosum, presence of interhemispheric fissure,
absent septum pellucidum,, separate frontal, occipital
lobes and olfactory lobes
Table 10 Primary etiologies associated with CCHMC Fetal Center
patient cohort
Fetal diagnosis Number of cases Percent
Spina bifida
Myelomeningocele 37 39%
Meningocele 2 2.1%
Myelocystocele 1 1%
Posterior fossa anomalies
Dandy-Walker continuum 4 4.2%
Blake’s Pouch remnant 3 3.1%
Posterior encephalocele 6 6.5%
Chiari 3 malformation 2 2.1%
Aqueductal stenosis 12 12.6%
Isolated agenesis of the corpus callosum 7 7.5%
Isolated ventriculomegaly 4 4.2%
In utero IVH 4 4.2%
Post ischemic ventriculomegaly 2 2.1%
Multiple congenital anomalies 3 3.1%
Other
Sphenoetmoidal encephalocele 1 1%
Syndromic 2 2.1%
Porencephaly/Schizencephaly 4 4.2%
Septo-optic dysplasia 1 1%
Table 9 Demographic data for patients seen in consultation at CCHMC
Fetal Center between December 2017 and July 2019
Prenatal characteristics Number of cases (n=95)Percent
Maternal age in years at diagnosis
16–21 15 15.7%
22–27 41 43.3%
28–32 25 26.3%
>33 14 14.7%
Fetus gender
Male 58 61%
Female 37 39%
Type of pregnancy
Singleton 89 93.7%
Multiple 6 6.3%
Gestational age in weeks at diagnosis
<21 7 7.4%
21–24 40 42.1%
25–28 16 16.8%
29–32 18 19%
>33 14 14.7%
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metabolism enzymatic deficiency [79]. Hydrocephalus associ-
ated with MPS is usually communicating and slowly progres-
sive (Table 6), with characteristics that are difficult to distinguish
from the primary disease [79]. Clear understanding of the fea-
tures of hydrocephalus in the setting of these diseases is critical
to improve the accuracy of patient selection and define appro-
priate timing and technique for surgical intervention [79]. Since
the use of bone marrow transplantation and chemotherapy has
increased survival for some of these syndromes, it is possible
that clinicians may see a rise in the number of older patients with
MPS and possible hydrocephalus.
Holoprosencephaly
Holoprosencephaly (HPE) is the most common malformation
of the embryonic forebrain (prosencephalon) consisting of
partial or complete failure of division of the prosencephalon
into two separate hemispheres and is often associated with
ventriculomegaly, occurring in approximately 1 in 10,000
births [80]. Different forms of septo-optic dysplasia and
fronto-nasal dysplasia within the holoprosencephaly spectrum
have been described in association with hydrocephalus
(Table 7). The heterogeneity of these patients creates chal-
lenges for neurosurgeons and individualized approaches are
necessary. There are four major HPE subtypes described
(Table 8). Despite the fact that overall mortality is high, a
small number of patients with milder forms will reach adult-
hood (mainly types III and IV). Children with alobar HPE and
those with a dorsal cyst are more likely to need surgical treat-
ment. For milder forms of the disease, the purpose of treating
hydrocephalus can be that of improving functional outcome.
For patients with severe disease, a palliative shunt may be
considered to avoid the development of macrocephaly; how-
ever, this benefit must be seriously weighed against the risks
related to chronic CSF diversion. These patients are at high
risk of over-drainage and development of subdural collec-
tions, which could be reduced with the use of adjustable
valves and anti-siphoning devices [81].
Hydranencephaly
Hydranencephaly is a rare condition characterized by the ab-
sence of cerebral hemispheres, with meninges and skull intact.
Cerebellum, thalamus, choroid plexus, brain stem, and re-
maining occipital and temporal lobes are typically preserved
[82]. This is a devastating condition with a high mortality rate
in the first 2 years, although some patients can reach adult-
hood [83]. Early diagnosis and surgery to avoid the problems
associated with progressive macrocephaly may improve the
care of these patients and the quality of life of their caregivers.
Table 11 Proportion of cases with in utero ventriculomegaly and post-natal outcomes stratified by primary etiology
Fetal diagnosis Number of cases (N=95)Number of cases with
in utero ventriculomegaly
Worsening Stability Improvement
Spina bifida
Myelomeningocele 37 29 (78.4%) 20 (54%) 16 (43%) 1 (3%)
Meningocele 2 0 2 (100%)
Myelocystocele 1 0 1 (100%)
Posterior fossa anomalies
Dandy-Walker continuum 4 3 (75%) 2 (50%) 2 (50%)
Blake’sPouchremnant 3 2(66%) 2(67%) 1(33%)
Posterior encephalocele 6 5 (83%) 4 (67%) 2 (33%)
Chiari 3 malformation 2 1 (50%) 2 (100%)
Aqueductal stenosis 12 12 (100%) 10 (83%) 2 (17%)
Isolated agenesis of the corpus callosum 7 7 (100%) 5 (71.4%) 2 (28.6%)
Isolated ventriculomegaly 4 4 (100%) 2 (50%) 2 (50%)
In utero IVH 4 4 (100%) 1 (25%) 2 (50%) 1 (25%)
Post ischemic ventriculomegaly 2 2 (100%) 2 (100%)
Multiple congenital anomalies 3 3 (100%) 3 (100%)
Other
Sphenoetmoidal encephalocele 1 0 1 (100%)
Syndromic 2 2 (100%) 1 (50%)
Porencephaly/Schizencephaly 4 4 (100%) 3 (75%)
Septo-optic dysplasia 1 1 (100%) 1 (100%)
1(50%)
1 (25%)
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Different approaches have been described when treatment for
these patients has been sought including shunting and ETV
with or without CPC [84].
Congenital encephalocele
Congenital encephaloceles are cystic congenital malformations
in which CNS structures, in communication with CSF spaces,
herniate through a skull defect at a site of local mesenchymal
disruption [85]. Hydrocephalus carries significant morbidity in
these children and has been associated with large posterior
encephaloceles and reported to be more likely to develop fol-
lowing repair than be present at birth. Although the location
does not seem to increase the incidence of hydrocephalus or
neurological deficit, the presence of neural tissue inside the
encephalocele has been described as the most influential factor
for hydrocephalus and poor neurological prognosis [86].
Shunting (at the same stage or after repair) remains the most
common treatment technique, although the use of ETV has
been reported [87]. Given the anatomical diversity found, treat-
ment indications and technique selection must be tailored to
each individualized case.
Vein of Galen malformations
Ventriculomegaly is a common feature in patients with Vein of
Galen malformations (VGMs) and can either represent loss of
white matter or true hydrocephalus [88]. Hydrocephalus is
thought to relate to increased intracranial venous pressure,
and also to direct compression of the cerebral aqueduct by
the VGM sac. A significant number of cases will respond to
a decrease in venous hypertension after endovascular treat-
ment, and external ventricular drains can be used as temporary
measures. In the remaining cases, shunting or ETV remain
potential tools, depending on the main pathophysiological
presentation and course of disease [89].
Fig. 1 This figure shows prenatal
(a,b, 29 weeks GA, singleton
pregnancy) and postnatal (c,d)
imaging studies from the same
patient. aAxial image from head
ultrasound at 29 weeks GA
showing triventricular
enlargement secondary to
aqueductal stenosis. bCoronal
T2-SSFSE fetal MR image at 29
weeks GA, singleton pregnancy,
showing severe bilateral
ventriculomegaly (right lateral
ventricle = 38 mm, left lateral
ventricle = 37 mm) and third
ventricular enlargement (measur-
ing 12 mm) secondary to
aqueductal stenosis. The septum
pellucidum is absent secondary to
perforation. A few subependymal
nodules are seen which were
confirmed to be grey matter
heterotopias on postnatal imag-
ing. cCoronal oblique image
from postnatal head ultrasound
that continues to show
triventricular enlargement, with
apparent persistent hydrocephalus
on T2-weighted coronal image
from subsequent MRI (d)ulti-
mately requiring surgical inter-
vention with ventriculoperitoneal
shunting in the first week of life
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Original data
As a supplement to this review, the authors retrospectively
reviewed their own institutional experience with the diagnoses
of fetal, congenital, and pediatric ventriculomegaly and hydro-
cephalus. This study was reviewed by the Cincinnati
Children’s Hospital Medical Center Institutional Review
Board (study ID 2019-0728). All maternal (seen in fetal con-
sultation) and patient charts available for review prior to
July 2019 were reviewed for various parameters; results can
be found in Tables 9,10,and11. Our preliminary data in-
cludes results from 95 patients diagnosed prenatally with
hydrocephalus/ventriculomegaly or related pathology follow-
ed after birth (Figs. 1,2,and3).
Discussion and future directions
Despite the great advances made with ETV with or with-
out CPC for the treatment of various hydrocephalic con-
ditions, ventriculoperitoneal shunting remains the most
widely used form of CSF diversion in the management
of pediatric hydrocephalus. Unfortunately, the complica-
tion rate remains high, mainly during the first year of
life. The anatomical heterogeneity and differences in
CSF hydrodynamics across these patients make
implementing a universal treatment strategy nearly im-
possible. In addition, no modern device has eliminated
the risk of malfunction or even demonstrated superiority
over others, and the use of both programmable and non-
programmable valves remain appropriate options [90].
Fig. 2 aAxial T2-weighted and bsagittal BFFE/FIESTA MRI demon-
strating massive enlargement of the lateral ventricles causing marked
stretching and thinning of the corpus callosum, inferior displacement of
the tentorium with compression of the brainstem and cerebellar hemi-
spheres secondary to congenital aqueductal stenosis. This patient
underwent ventriculoperitoneal shunting for treatment. cAxial and d
sagittal T2-weighted MRI showing complete agenesis of the corpus
callosum with associated colpocephaly. This patient did not require sur-
gical intervention. eCoronal and axial fT2-weighted MRI demonstrating
diffusely abnormal supratentorial brain with porencephalic cysts in bilat-
eral cerebral hemispheres. The cystic structure in the left middle cranial
fossa represents a segregated porencephalic cyst. This patient underwent
cystoperitoneal shunting due to progressive dilatation of the cyst. g
Sagittal and haxial T1-weighted imaging showing partial separation of
the frontal lobes with the anterior falx present with absent separation of
the posterior bodies of the lateral ventricle with dorsal cyst formation.
There is also a large CSF collection within the superior posterior fossa
that appears to be in communication with the ventricles compatible with
semilobar holoprosencephaly. Also noted on imaging is a small parietal
cephalocele. iAxial and jsagittal T2-FSE MR images demostrating
hydranencephaly treated with ventriculoperitoneal shunt and develop-
ment of subdural collections secondary to overshunting. kSagittal non-
contrast T1-weighted MRI of the brain and spine showing a 14 cm
cephalocele with moderately enlarged colpocphaly. This patient
underwentrepair of the cephalocele, withexternal ventricular drain place-
ment and delayed shunt placement.
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While the systematic use of anti-siphon devices does not
improve shunt survival in general,itcanbeusefulinthe
setting of over-drainage and slit-ventricle syndrome [91].
Similar to the lack of evidence regarding superiority of
utilizing a certain type of valve over another, there is no
consensus or clear association with shunt survival and
the cranial entry point [92] or intraventricular target
[93], or the use of neuroimaging and/or endoscopic/lap-
aroscopic techniques [94,95]. In addition, since the ini-
tial attempts in the early 1980s, in utero surgery for
hydrocephalus has not shown any clinical progress de-
spite the significant advances in fetal imaging and sur-
gery over the past two decades [96]. Current researchers
are working on developing animal models of fetal hydro-
cephalus that may allow for the design of future trials
[97].
It is clear that hydrocephalus is considered to be a multi-
factorial disease, caused by both genetic and environmental
factors. For some single-gene disorders, clinical genetic test-
ing is already available and can be a helpful prognostic tool.
Future and current research on gene therapy aims to focus on
developing therapies based on specific molecular mechanisms
[98]. The use of biomarkers as valuable diagnostic tools and
predictors of clinical course, as well as therapeutic efficacy, is
an evolving field [99].
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
References
1. Salomon LJ, Ouahba J, Delezoide AL, Vuillard E, Oury JF, Sebag
G, Garel C (2006) Third-trimester fetal MRI in isolated 10- to 12-
mm ventriculomegaly: is it worth it? BJOG 113:942–947
2. Cardoza JD, Goldstein RB, Filly RA (1988) Exclusion of fetal
ventriculomegaly with a single measurement: the width of the lat-
eral ventricular atrium. Radiology 169:711–714
3. Benacerraf BR, Birnholz JC (1987) The diagnosis of fetal hydro-
cephalus prior to 22 weeks. J Clin Ultrasound 15:531–536
4. Vergani P, Locatelli A, Strobelt N, Cavallone M, Ceruti P, Paterlini
G, Ghidini A (1998) Clinical outcome of mild fetal
ventriculomegaly. Am J Obstet Gynecol 178:218–222
5. Griffiths PD, Reeves MJ, Morris JE, Mason G, Russell SA, Paley
MN, Whitby EH (2010) A prospective study of fetuses with isolat-
ed ventriculomegaly investigated by antenatal sonography and in
utero MR imaging. AJNR Am J Neuroradiol 31:106–111
6. Farrell TA, Hertzberg BS, Kliewer MA, Harris L, Paine SS (1994)
Fetal lateral ventricles: reassessment of normal values for atrial
diameter at US. Radiology 193:409–411
7. Melchiorre K, Bhide A, Gika AD, Pilu G, Papageorghiou AT
(2009) Counseling in isolated mild fetal ventriculomegaly.
Ultrasound Obstet Gynecol 34:212–224
8. Pisapia JM, Sinha S, Zarnow DM, Johnson MP, Heuer GG (2017)
Fetal ventriculomegaly: diagnosis, treatment, and future directions.
Childs Nerv Syst 33:1113–1123
9. McKechnie L, Vasudevan C, Levene M (2012) Neonatal outcome
of congenital ventriculomegaly. Semin Fetal Neonatal Med 17:
301–307
10. Committee ISoUiOGE (2007) Sonographic examinationof the fetal
central nervous system: guidelines for performing the 'basic exam-
ination' and the 'fetal neurosonogram'. Ultrasound Obstet Gynecol
29:109–116
11. Gynecologists ACoOa (2009) ACOG Practice Bulletin No. 101:
ultrasonography in pregnancy. Obstet Gynecol 113:451–461
12. Kline-Fath BM, Bulas DI, Bahado-Singh R (2015) Fundamental
and advanced fetal imaging : ultrasound and MRI. Wolters
Kluwer Health, Philadelphia
Fig. 3 Flow chart of the current study cohort demonstrating that after review, ultimately, 95 patients were included in the study with fetal imaging
consistent with hydrocephalus and/or ventriculomegaly. Of those included, survival rate at 1 month was 88.4% (84/95)
Childs Nerv Syst
Author's personal copy
13. Lutz H, Buscarini E, World Health Organization (2011) Manual of
diagnostic ultrasound. World Health Organization, Geneva
14. Kline-Fath BM (2019) Ultrasound and MR imaging of the normal
fetal brain. Neuroimaging Clin N Am 29:339–356
15. Glenn OA, Barkovich AJ (2006) Magnetic resonance imaging of
the fetal brain and spine: an increasingly important tool in prenatal
diagnosis, part 1. AJNR Am J Neuroradiol 27:1604–1611
16. Griffiths PD, Bradburn M, Campbell MJ, Cooper CL, Graham R,
Jarvis D, Kilby MD, Mason G, Mooney C, Robson SC, Wailoo A,
group Mc (2017) Use of MRI in the diagnosis of fetal brain abnor-
malities in utero (MERIDIAN): a multicentre, prospective cohort
study. Lancet 389:538–546
17. Griffiths PD, Brackley K, Bradburn M, Connolly DJA, Gawne-
Cain ML, Griffiths DI, Kilby MD, Mandefield L, Mooney C,
Robson SC, Vollmer B, Mason G (2017) Anatomical subgroup
analysis of the MERIDIAN cohort: ventriculomegaly. Ultrasound
Obstet Gynecol 50:736–744
18. Twickler DM, Reichel T, McIntire DD, Magee KP, Ramus RM
(2002) Fetal central nervous system ventricle and cisterna magna
measurements by magnetic resonance imaging. Am J Obstet
Gynecol 187:927–931
19. Garel C, Alberti C (2006) Coronal measurement of the fetal lateral
ventricles: comparison between ultrasonography and magnetic res-
onance imaging. Ultrasound Obstet Gynecol 27:23–27
20. Soni JP, Singhania RU, Sharma A (1992) Measurement of ventric-
ular size in term and preterm infants. Indian Pediatr 29:55–59
21. Saliba E, Bertrand P, Gold F, Vaillant MC, Laugier J (1990) Area of
lateral ventricles measured on cranial ultrasonography in preterm
infants: reference range. Arch Dis Child 65:1029–1032
22. Fiske CE, Filly RA, Callen PW (1981) Sonographic measurement
of lateral ventricular width in early ventricular dilation. J Clin
Ultrasound 9:303–307
23. Davies MW, Swaminathan M, Chuang SL, Betheras FR (2000)
Reference ranges for the linear dimensions of the intracranial ven-
tricles in preterm neonates. Arch Dis Child Fetal Neonatal Ed 82:
F218–F223
24. Graziani L, Dave R, Desai H, Branca P, Waldroup L, Goldberg B
(1980) Ultrasound studies in preterm infants with hydrocephalus. J
Pediatr 97:624–630
25. O'Hayon BB, Drake JM, Ossip MG, Tuli S, Clarke M (1998)
Frontal and occipital horn ratio: a linear estimate of ventricular size
for multiple imaging modalities in pediatric hydrocephalus. Pediatr
Neurosurg 29:245–249
26. Kulkarni AV, Drake JM, Armstrong DC, Dirks PB (1999)
Measurement of ventricular size: reliability of the frontal and oc-
cipital horn ratio compared to subjective assessment. Pediatr
Neurosurg 31:65–70
27. McArdle CB, Richardson CJ, Nicholas DA, Mirfakhraee M,
Hayden CK, Amparo EG (1987) Developmental features of the
neonatal brain: MR imaging. Part II. Ventricular size and
extracerebral space. Radiology 162:230–234
28. Senapati GM, Levine D, Smith C, Estroff JA, Barnewolt CE,
Robertson RL, Poussaint TY, Mehta TS, Werdich XQ, Pier D,
Feldman HA, Robson CD (2010) Frequency and cause of disagree-
ments in imaging diagnosis in children with ventriculomegaly di-
agnosed prenatally. Ultrasound Obstet Gynecol 36:582–595
29. Pisapia JM, Rozycki M, Akbari H, Bakas S, Thawani JP,
Moldenhauer JS, Storm PB, Zarnow DM, Davatzikos C, Heuer
GG (2017) Correlations of atrial diameter and frontooccipital horn
ratio with ventricle size in fetal ventriculomegaly. J Neurosurg
Pediatr 19:300–306
30. Patel SK, Yuan W, Mangano FT (2017) Advanced neuroimaging
techniques in pediatric hydrocephalus. Pediatr Neurosurg 52:436–
445
31. Mangano FT, Stevenson CB, Nagaraj U, Conley A, Yuan W (2019)
Abnormal anisotropic diffusion properties in pediatric
myelomeningocele patients treated with fetal surgery: an initial
DTI study. Childs Nerv Syst
32. Mangano FT, Altaye M, McKinstry RC, Shimony JS, Powell SK,
Phillips JM, Barnard H, Limbrick DD, Holland SK, Jones BV,
Dodd J, Simpson S, Mercer D, Rajagopal A, Bidwell S, Yuan W
(2016) Diffusion tensor imaging study of pediatric patients with
congenital hydrocephalus: 1-year postsurgical outcomes. J
Neurosurg Pediatr 1–14
33. Pilu G, Falco P, Gabrielli S, Perolo A, Sandri F, Bovicelli L (1999)
The clinical significance of fetal isolated cerebral borderline
ventriculomegaly: report of 31 cases and review of the literature.
Ultrasound Obstet Gynecol 14:320–326
34. Pagani G, Thilaganathan B, Prefumo F (2014) Neurodevelopmental
outcome in isolated mild fetal ventriculomegaly: systematic review
and meta-analysis. Ultrasound Obstet Gynecol 44:254–260
35. Kumar M, Garg N, Hasija A, Pritam A, Shukla P, Vanamail P, Roy
Choudhury S (2018) Two-year postnatal outcome of 263 cases of
fetal ventriculomegaly. J Matern Fetal Neonatal Med 1–7
36. Carta S, Kaelin Agten A, Belcaro C, Bhide A (2018) Outcome of
fetuses with prenatal diagnosis of isolated severe bilateral
ventriculomegaly: systematic review and meta-analysis.
Ultrasound Obstet Gynecol 52:165–173
37. Verhagen JM, Schrander-Stumpel CT, Krapels IP, de Die-Smulders
CE, van Lint FH, Willekes C, Weber JW, Gavilanes AW, Macville
MV, Stegmann AP, Engelen JJ, Bakker J, Vos YJ, Frints SG (2011)
Congenital hydrocephalus in clinical practice: a genetic diagnostic
approach. Eur J Med Genet 54:e542–e547
38. Gorlin RJ, Cohen MM, Hennekam RCM (2001) Syndromes of the
head and neck. Oxford University Press, New York
39. Schrander-Stumpel C, Fryns JP (1998) Congenital hydrocephalus:
nosology and guidelines for clinical approach and genetic counsel-
ling. Eur J Pediatr 157:355–362
40. Hutson SL, Wheeler KM, McLone D, Frim D, Penn R, Swisher
CN, Heydemann PT, Boyer KM, Noble AG, Rabiah P, Withers S,
Montoya JG, Wroblewski K, Karrison T, Grigg ME, McLeod R
(2015) Patterns of hydrocephalus caused by congenital toxoplasma
gondii infection associate with parasite genetics. Clin Infect Dis 61:
1831–1834
41. Kulkarni AV, Shams I (2007) Quality of life in children with hy-
drocephalus: results from the Hospital for Sick Children, Toronto. J
Neurosurg 107:358–364
42. Levitsky DB, Mack LA, Nyberg DA, Shurtleff DB, Shields LA,
Nghiem HV, Cyr DR (1995) Fetal aqueductal stenosis diagnosed
sonographically: how grave is the prognosis? AJR Am J
Roentgenol 164:725–730
43. Shaheen R, Sebai MA, Patel N, Ewida N, Kurdi W, Altweijri I,
Sogaty S, Almardawi E, Seidahmed MZ, Alnemri A, Madirevula
S, Ibrahim N, Abdulwahab F, Hashem M, Al-Sheddi T, Alomar R,
Alobeid E, Sallout B, AlBaqawi B, AlAali W, Ajaji N, Lesmana H,
Hopkin RJ, Dupuis L, Mendoza-Londono R, Al Rukban H, Yoon
G, Faqeih E, Alkuraya FS (2017) The genetic landscape of familial
congenital hydrocephalus. Ann Neurol 81:890–897
44. Heaphy-Henault KJ, Guimaraes CV, Mehollin-Ray AR, Cassady
CI, Zhang W, Desai NK, Paldino MJ (2018) Congenital aqueductal
stenosis: findings at fetal MRI that accurately predict a postnatal
diagnosis. AJNR Am J Neuroradiol 39:942–948
45. Barkovich AJ, Newton TH (1989) MR of aqueductal stenosis: ev-
idence of a broad spectrum of tectal distortion. AJNR Am J
Neuroradiol 10:471–476
46. Tonetti DA, Richter B, Andrews E, Xu C, Emery SP, Greene S
(2018) Clinical outcomes of isolated congenital aqueductal steno-
sis. World Neurosurg 114:e976–e981
47. Mazzola CA, Choudhri AF, Auguste KI, Limbrick DD, Rogido M,
Mitchell L, Flannery AM, Force PHSRaE-BGT (2014) Pediatric
hydrocephalus: systematic literature review and evidence-based
Childs Nerv Syst
Author's personal copy
guidelines. Part 2: Management of posthemorrhagic hydrocephalus
in premature infants. J Neurosurg Pediatr 14(Suppl 1):8–23
48. Wellons JC, Shannon CN, Holubkov R, Riva-Cambrin J, Kulkarni
AV, Limbrick DD, Whitehead W, Browd S, Rozzelle C, Simon TD,
Tamber MS, Oakes WJ, Drake J, Luerssen TG, Kestle J, Network
HCR (2017) Shunting outcomes in posthemorrhagic hydrocepha-
lus: results of a Hydrocephalus Clinical Research Network prospec-
tive cohort study. J Neurosurg Pediatr 20:19–29
49. Dorner RA, Burton VJ, Allen MC, Robinson S, Soares BP (2018)
Preterm neuroimaging and neurodevelopmental outcome: a focus
on intraventricular hemorrhage, post-hemorrhagic hydrocephalus,
and associated brain injury. J Perinatol 38:1431–1443
50. Tamburrini G, Frassanito P, Iakovaki K, Pignotti F, Rendeli C,
Murolo D, Di Rocco C (2013) Myelomeningocele: the manage-
ment of the associated hydrocephalus. Childs Nerv Syst 29:1569–
1579
51. Elgamal EA (2012) Natural history of hydrocephalus in children
with spinal open neural tube defect. Surg Neurol Int 3:112
52. Rintoul NE, Sutton LN, Hubbard AM, Cohen B, Melchionni J,
Pasquariello PS, Adzick NS (2002) A new look at
myelomeningoceles: functional level, vertebral level, shunting,
and the implications for fetal intervention. Pediatrics 109:409–413
53. Adzick NS, Thom EA, Spong CY, Brock JW, Burrows PK, Johnson
MP, Howell LJ, Farrell JA, Dabrowiak ME, Sutton LN, Gupta N,
Tulipan NB, D'Alton ME, Farmer DL, Investigators M (2011) A
randomized trial of prenatal versus postnatal repair of
myelomeningocele. N Engl J Med 364:993–1004
54. Tuli S, Drake J, Lamberti-Pasculli M (2003) Long-term outcome of
hydrocephalus management in myelomeningoceles. Childs Nerv
Syst 19:286–291
55. Piatt JH (2010) Treatment of myelomeningocele: a review of out-
comes and continuing neurosurgical considerations among adults. J
Neurosurg Pediatr 6:515–525
56. Radmanesh F, Nejat F, El Khashab M, Ghodsi SM, Ardebili HE
(2009) Shunt complications in children with myelomeningocele:
effect of timing of shunt placement. Clinical article. J Neurosurg
Pediatr 3:516–520
57. Warf BC, Campbell JW (2008) Combined endoscopic third
ventriculostomy and choroid plexus cauterization as primary treat-
ment of hydrocephalus for infants with myelomeningocele: long-
term results of a prospective intent-to-treat study in 115 East
African infants. J Neurosurg Pediatr 2:310–316
58. Collmann H, Sörensen N, Krauss J (2005) Hydrocephalus in cra-
niosynostosis: a review. Childs Nerv Syst 21:902–912
59. Golabi M, Edwards MS, Ousterhout DK (1987) Craniosynostosis
and hydrocephalus. Neurosurgery 21:63–67
60. Cinalli G, Sainte-Rose C, Kollar EM, Zerah M, Brunelle F, Chumas
P, Arnaud E, Marchac D, Pierre-Kahn A, Renier D (1998)
Hydrocephalus and craniosynostosis. J Neurosurg 88:209–214
61. Noetzel MJ, Marsh JL, Palkes H, Gado M (1985) Hydrocephalus
and mental retardation in craniosynostosis. J Pediatr 107:885–892
62. Cohen MM, MacLean RE (2000) Craniosynostosis : diagnosis,
evaluation, and management. Oxford University Press, New York
63. Hanieh A, David DJ (1993) Apert's syndrome. Childs Nerv Syst 9:
289–291
64. Renier D, Arnaud E, Cinalli G, Sebag G, Zerah M, Marchac D
(1996) Prognosis for mental function in Apert's syndrome. J
Neurosurg 85:66–72
65. Glass HC, Shaw GM, Ma C, Sherr EH (2008) Agenesis of the
corpus callosum in California 1983-2003: a population-based study.
Am J Med Genet A 146A:2495–2500
66. Jeret JS, Serur D, Wisniewski K, Fisch C (1985) Frequency of
agenesis of the corpus callosum in the developmentally disabled
population as determined by computerized tomography. Pediatr
Neurosci 12:101–103
67. D'Antonio F, Pagani G, Familiari A, Khalil A, Sagies TL, Malinger
G, Leibovitz Z, Garel C, Moutard ML, Pilu G, Bhide A, Acharya G,
Leombroni M, Manzoli L, Papageorghiou A, Prefumo F (2016)
Outcomes associated with isolated agenesis of the corpus callosum:
a meta-analysis. Pediatrics 138
68. Imataka G, Nakagawa E, Kuwashima S, Watanabe H, Yamanouchi
H, Arisaka O (2006) Callosal agenesis followed postnatally after
prenatal diagnosis. Congenit Anom (Kyoto) 46:160–162
69. Elster AD, Chen MY (1992) Chiari I malformations: clinical and
radiologic reappraisal. Radiology 183:347–353
70. Park JK, Gleason PL, Madsen JR, Goumnerova LC, Scott RM
(1997) Presentation and management of Chiari I malformation in
children. Pediatr Neurosurg 26:190–196
71. Di Rocco C, Frassanito P, Massimi L, Peraio S (2011)
Hydrocephalus and Chiari type I malformation. Childs Nerv Syst
27:1653–1664
72. Steinbok P, Hall J, Flodmark O (1989) Hydrocephalus in achondro-
plasia: the possible role of intracranial venous hypertension. J
Neurosurg 71:42–48
73. Bosemani T, Orman G, Hergan B, Carson KA, Huisman TA, Poretti
A (2015) Achondroplasia in children: correlation of
ventriculomegaly, size of foramen magnum and jugular foramina,
and emissary vein enlargement. Childs Nerv Syst 31:129–133
74. King JA, Vachhrajani S, Drake JM, Rutka JT (2009) Neurosurgical
implications of achondroplasia. J Neurosurg Pediatr 4:297–306
75. Priestley BL, Lorber J (1981) Ventricular size and intelligence in
achondroplasia. Z Kinderchir 34:320–326
76. Rekate HL (2019) Pathogenesis of hydrocephalus in achondroplas-
tic dwarfs: a review and presentation of a case followed for 22
years. Childs Nerv Syst 35:1295–1301
77. Swift D, Nagy L, Robertson B (2012) Endoscopic third
ventriculostomy in hydrocephalus associated with achondroplasia.
J Neurosurg Pediatr 9:73–81
78. Etus V, Ceylan S (2005) The role of endoscopic third
ventriculostomy in the treatment of triventricular hydrocephalus
seen in children with achondroplasia. J Neurosurg 103:260–265
79. Dalla Corte A, de Souza CFM, Anés M, Giugliani R (2017)
Hydrocephalus and mucopolysaccharidoses: what do we know
and what do we not know? Childs Nerv Syst 33:1073–1080
80. Croen LA, Shaw GM, Lammer EJ (1996) Holoprosencephaly: ep-
idemiologic and clinical characteristics of a California population.
Am J Med Genet 64:465–472
81. Levey EB, Stashinko E, Clegg NJ, Delgado MR (2010)
Management of children with holoprosencephaly. Am J Med
Genet C: Semin Med Genet 154C:183–190
82. Khalid M, Khalid S, Zaheer S, Redhu N, Ekramullah (2012)
Hydranencephaly: a rare cause of an enlarging head size in an
infant. N Am J Med Sci 4:520–522
83. Merker B (2008) Life expectancy in hydranencephaly. Clin Neurol
Neurosurg 110:213–214
84. Pedrosa HAR, Lemos SP, Vieira C, Amaral LC, Malheiros JA,
Oliveira MM, Gomez RS, Giannetti AV (2017) Choroid plexus
cauterization on treatment of hydranencephaly and maximal hydro-
cephalus. Childs Nerv Syst 33:1509–1516
85. Youmans JR (1996) Neurological surgery : a comprehensive refer-
ence guide to the diagnosis and management of neurosurgicalprob-
lems. Saunders, Philadelphia
86. Da Silva SL, Jeelani Y, Dang H, Krieger MD, McComb JG (2015)
Risk factors for hydrocephalus and neurological deficit in children
born with an encephalocele. J Neurosurg Pediatr 15:392–398
87. Moorthy RK, Rajshekhar V (2002) Management of hydrocephalus
associated with occipital encephalocoele using endoscopic third
ventriculostomy: report of two cases. Surg Neurol 57:351–355 dis-
cussion 355
88. Gopalan V, Rennie A, Robertson F, Kanagarajah L, Toolis C, Bhate
S, Ganesan V (2018) Presentation, course, and outcome of
Childs Nerv Syst
Author's personal copy
postneonatal presentations of vein of Galen malformation: a large,
single-institution case series. Dev Med Child Neurol 60:424–429
89. Meila D, Grieb D, Melber K, Jacobs C, Maslehaty H, Petridis A, El
Habony R, Lanfermann H, Scholz M, Brassel F (2016)
Hydrocephalus in vein of Galen malformation: etiologies and ther-
apeutic management implications. Acta Neurochir 158:1279–1284
90. Kestle J, Drake J, Milner R, Sainte-Rose C, Cinalli G, Boop F, Piatt
J, Haines S, Schiff S, Cochrane D, Steinbok P, MacNeil N (2000)
Long-term follow-up data from the Shunt Design Trial. Pediatr
Neurosurg 33:230–236
91. Hoshide R, Meltzer H, Dalle-Ore C, Gonda D, Guillaume D, Chen
CC (2017) Impact of ventricular-peritoneal shunt valve design on
clinical outcome of pediatric patients with hydrocephalus: lessons
learned from randomized controlled trials. Surg Neurol Int 8:49
92. Kemp J, Flannery AM, Tamber MS, Duhaime AC, Force PHSRaE-
BGT (2014) Pediatric hydrocephalus: systematic literature review
and evidence-based guidelines. Part 9: effect of ventricular catheter
entry point and position. J Neurosurg Pediatr 14(Suppl 1):72–76
93. Whitehead WE, Riva-Cambrin J, Kulkarni AV, Wellons JC,
Rozzelle CJ, Tamber MS, Limbrick DD, Browd SR, Naftel RP,
Shannon CN, Simon TD, Holubkov R, Illner A, Cochrane DD,
Drake JM, Luerssen TG, Oakes WJ, Kestle JR, Network ftHCR
(2017) Ventricular catheter entry site and not catheter tip location
predicts shunt survival: a secondary analysis of 3 large pediatric
hydrocephalus studies. J Neurosurg Pediatr 19:157–167
94. Flannery AM, Duhaime AC, Tamber MS, Kemp J, ForcePHSRaE-
BGT (2014) Pediatric hydrocephalus: systematic literature review
and evidence-based guidelines. Part 3: endoscopic computer-
assisted electromagnetic navigation and ultrasonography as techni-
cal adjuvants for shunt placement. J Neurosurg Pediatr 14(Suppl 1):
24–29
95. Phan S, Liao J, Jia F, Maharaj M, Reddy R, Mobbs RJ, Rao PJ,
Phan K (2016) Laparotomy vs minimally invasive laparoscopic
ventriculoperitoneal shunt placement for hydrocephalus: a system-
atic review and meta-analysis. Clin Neurol Neurosurg 140:26–32
96. Glick PL, Harrison MR, Halks-Miller M, Adzick NS, Nakayama
DK, Anderson JH, Nyland TG, Villa R, Edwards MS (1984)
Correction of congenital hydrocephalus in utero II: efficacy of in
utero shunting. J Pediatr Surg 19:870–881
97. Duru S, Oria M, Arevalo S, Rodo C, Correa L, Vuletin F, Sanchez-
Margallo F, Peiro JL (2019) Comparative study of intracisternal
kaolin injection techniques to induce congenital hydrocephalus in
fetal lamb. Childs Nerv Syst 35:843–849
98. Yamasaki M, Kanemura Y (2015) Molecular biology of pediatric
hydrocephalus and hydrocephalus-related diseases. Neurol Med
Chir (Tokyo) 55:640–646
99. Limbrick DD, Castaneyra-Ruiz L, Han RH, Berger D, McAllister
JP, Morales DM (2017) Cerebrospinal Fluid Biomarkers of
Pediatric Hydrocephalus. Pediatr Neurosurg 52:426–435
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