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Chapter 4
VENTRICULOMEGALY
Gianluigi Pilu ● Gustavo Malinger ● Selim Buyukkurt
KEY POINTS
1. Ventriculomegaly is not a diagnosis. It is a sign.
The search for all underlying causes should be
immediately undertaken.
2. Ventriculomegaly is frequently associated with a
large number of intra- and extracranial chromosomal
as well as nonchromosomal anomalies.
3. For measuring the lateral ventricle it is recommended
to use an axial view of the brain and to place the
clipers at the level of the parieto-occipital fissure that
is usually well demonstrated from 20 weeks’ gestation.
4. Congenital ventriculomegaly has a increased
recurrence rate and after the birth of an affected
infant a targeted neurscan is recommended in a
subsequent pregnancy.
Ventriculomegaly, a term commonly employed to indicate
the enlargement of the lateral cerebral ventricles, is found
in ~1% of fetuses at midgestation and is the most common
abnormal fetal cerebral diagnosis.
Although the enlargement of the lateral ventricles
encompasses a wide spectrum of severity, at present a
width of the atrium <10 mm is considered normal, 10 to
15 mm indicates mild ventriculomegaly, and >15 mm represents severe ventriculomegaly. This categorization has
prognostic implications. Fetuses with normal ventricles
have an exceedingly low risk of cerebral anomalies. Fetuses
with mild ventriculomegaly in the majority of cases are
normal at birth but have an increased risk of an abnormal
outcome. Fetuses with severe ventriculomegaly have a very
high probability of an abnormal outcome.
Enlargement of the cerebral lateral ventricles is not an
anomaly per se. The clinical significance of this finding is
that it signals to the possibility of associated anomalies of the
brain or other organs. The final prognosis depends more on
such anomalies than on the degree of ventricular dilation.
Fetuses with mild ventriculomegaly in particular have
an increased risk of chromosomal aberrations.
MILD LATERAL CEREBRAL
VENTRICULOMEGALY
Synonyms
Mild hydrocephaly, borderline ventriculomegaly
Definition and Diagnosis
The widely accepted definition of mild cerebral lateral
ventriculomegaly is an atrial width of 10 to 15 mm on the
transverse plane ( Figure 4–1 )
Prevalence
Seen in 1% of fetuses 4
Pathogenesis and Pathology
In many cases, it probably represents a normal variant. In
other cases, mild enlargement of the lateral ventricles may
be the only obvious epiphenomenon of heterogeneous
cerebral anomalies.
Differential Diagnosis
Isolated mild ventriculomegaly should be differentiated
from more complex abnormalities of the fetal brain that
frequently have a different prognosis (eg, agenesis of the
corpus callosum and cortical malformations). Several
reports suggest that magnetic resonance imaging (MRI)
may be a useful adjunct to sonography, particularly in late
gestation.
5 , 6
Implications for Targeted Examination
The main problem in cases that are referred with mild
dilatation of the lateral ventricles is to exclude other neural
and extraneural malformations. We recommend careful
multiplanar examination of the fetal brain, performed
if possible with a high-resolution vaginal probe, and a
detailed evaluation of the spine. Both lateral ventricles
should be visualized and assessed, as this condition can be
1–3
172
Chapter 4 Ventriculomegaly
AB
Figure 4 –1.
choroid plexuses.
Mild (A) and severe (B) ventriculomegaly in midtrimester fetuses. Atrial width is 10 and 16 mm, respectively. Arrows indicate the dangling
unilateral ( Figure 4–2 ). A stepwise ultrasound (US) evalu-
ation of the fetal brain should be performed in order to
exclude associated anomalies ( Figure 4–3 ). Although the
use of MRI has also been advocated,
5 , 6
we believe that when
following the protocol suggested in Figure 4–3 , the role of
fetal MRI remains limited to those cases in which technical issues impairs US visualization. A detailed evaluation of
the entire fetal anatomy, including fetal echocardiography,
should also be performed. These examinations may be
incomplete or limited during the third trimester.
Implications for Sonographic Screening
In all standard sonographic examinations, a view of the
lateral ventricles should be obtained, and at least one of
the atria should be visualized and assessed. A qualitative
evaluation is acceptable, and the presence of the choroid plexus filling the cavity of the atrium, being closely
apposed to both the medial and lateral walls of the ventricle, is indicative of normalcy. A quantitative approach,
however, is favored, and a measurement <10 mm is considered normal between 15 and 40 weeks.
7
Congenital
A
Figure 4 –2. (A) Unilateral ventriculomegaly. The calcarine fissure ( arrows ) is significantly less pronounced in the ventriculomegalic hemisphere than
in the controlateral one. (B) Bilateral ventriculomegaly. The calcarine fissure is not seen in this image, even though it was obtained at 21 weeks. A delayed
cortical maturation is frequently encountered with ventriculomegaly. The clinical significance of such finding is uncertain. Both of these fetuses had a
completely normal outcome and normal neurologic development at long-term follow-up.
B
Chapter 4 Ventriculomegaly
173
Infratentorial structures normal?
NO
ONTD DWM
CH
Insults? MCD?
YES
Corpus callosum/cavum septi pellucidi
normal?
NO
HPE ACC
YES
ASP
YES
Infection Hemorrage
Normal or large
Normal/macrocephaly
Figure 4 –3. Flowchart for the investigation of fetuses with mild bilateral ventriculomegaly. Ventriculomegaly may be present with any congenital or
acquired brain anomaly. Isolated mild ventriculomegaly may be diagnosed only after exclusion of these central nervous system anomalies. ONTD, open
neural tube defects ( Chapter 5 ); DWC, Dandy-Walker complex ( Chapter 8 ); HPE, holoprosencephaly ( Chapter 6 ); ACC, agenesis of the corpus callosum
( Chapter 6 ); MCD, malformations of cortical development ( Chapter 7 ); IVH, intraventricular hemorrhage ( Chapter 12 ); HC, head circumference.
Tu m or
NO
Probably isolated ventriculomegaly
Measure head circomference
Lissencephaly
Small
Microcephaly/trisomy 21
174
Chapter 4 Ventriculomegaly
4
3
2
A
Figure 4 –4. Pitfalls in the measurement of the lateral ventricle. (A) Axial plane. The correct measurement of the lateral ventricular width (LVW) is
numbered 1. The measurements depicted as 2 and 3 are wrong; 2 is positioned in the occipital horn, and 3 measures not only the ventricles but also
part of the brain parenchyma. (B) This image shows a common error in measuring the proximal lateral ventricle. The proximal ventricle is difficult to
visualize in a true axial plane, and the operator tilted the transducer to reach access to show the proximal ventricle. This plane shows a poorly visualized
ventricle in an oblique plane, and measurement 4 overestimates the LVW.
ventriculomegaly may develop late in gestation, and a
normal midtrimester exam does not exclude this condition. The correct measurement of the lateral ventricles is
important to avoid false-positive diagnoses of ventriculomegaly. Common errors in measurement include placing
the calipers in the brain parenchyma instead of at the inner
border of the ventricular wall, measuring the ventricle not
perpendicular to their walls, measuring the occipital horn,
or measuring the lateral ventricle not in a truly axial plane.
A specific approach has been described that proposes
placing the calipers at the level of the parietooccipital
fissure, an easily recognizable landmark beginning
around 20 weeks’ gestation
8
( Figure 4–4 ).
B
Obstetric Management
Mild lateral cerebral ventriculomegaly is frequently associated with neural and extraneural anomalies; therefore, a
careful evaluation of the fetal anatomy should be carried
out using expert US examination and, if possible, transvaginalneurosonography. Where available, fetal MRI may be
indicated, although there is no consensus on the optimal
time for this examination. The likelihood ratio for trisomy
21 is about 9, and invasive testing for chromosomal analysis should be offered. Maternal serum cytomegalovirus
(CMV) and Toxoplasma studies should be considered.
Follow-up sonograms and/or MRI in the third trimester
should be considered.
2
Prognosis
Fetal mild cerebral ventriculomegaly is an elusive entity.
It is frequently seen without consequences. However,
most of the available studies are consistent in indicating
an increased risk of abnormal outcomes.
2 , 3
The likelihood
of trisomy 21 is increased 9-fold over the general population. 2 Despite careful antenatal assessment, anomalies
will be present at birth in ~13% of cases.
2
Most of these
anomalies are mild and of little consequence, but developmental malformations of the cerebrum, including progressive hypertensive hydrocephaly, cystic brain lesions, and
abnormal cortical development, have been documented
in up to 4% of cases.
2
The rate of neurodevelopmental
delay in infants with a prenatal diagnosis of isolated mild
ventriculomegaly is ~11%, and it is unclear whether this
is increased or not over the general population. The most
important prognostic factor is the association with other
abnormalities undetected at the time of the first diagnosis
(~13% of cases) and progression of the ventricular dilation
(~16% of cases).
2
SEVERE CEREBRAL LATERAL
VENTRICULOMEGALY
Synonym
Hydrocephaly
Definition and diagnosis
Overt enlargement of the lateral ventricles (atrial width
>15 mm) in the absence of other sonographically demonstrable central nervous system anomalies
Prevalence
The incidence of hydrocephaly, a condition that overlaps
with severe ventriculomegaly, ranges between 0.3 and 1.5
in 1000 births in different series. 9 In many fetuses, associated anomalies are present, but isolated ventriculomegaly
accounts for 10% to 60% of cases in different series. 10 – 12
2 , 3
Chapter 4 Ventriculomegaly
175
Pathogenesis
In the majority of cases, cerebral lateral ventriculomegaly
is the consequence of associated cerebral abnormalities.
Isolated severe ventriculomegaly is usually the consequence of an obstruction along the normal pathway of the
cerebrospinal fluid. When this is associated with intracranial hypertension, the term obstructive hydrocephaly is
commonly used.
10
Etiology
Congenital severe ventriculomegaly is a heterogeneous
disease for which genetic, infectious, teratogenetic,
and neoplastic causes have been implicated. X-linked
hydrocephaly accounts for ~5% of all cases. This condition
is caused by mutations in the gene at Xq28 encoding for
L1, a neural cell adhesion molecule ( L1CAM ). Mutations
in this gene are also responsible for other syndromes with
clinical overlap; these are frequently referred to as the
X-linked hydrocephaly spectrum, or L1 spectrum, and
include MASA (mental retardation, aphasias, shuffling
gait, and adducted thumbs), complicated X-linked spastic
paraplegia (SP 1), X-linked mental retardation–clasped
thumb (MR-CT) syndrome, and some forms of X-linked
agenesis of the corpus callosum.
pattern of inheritance is probably responsible for most
other cases of congenital hydrocephaly.
13 – 16
A multifactorial
14
Infections implicated in the determination of congenital ventriculomegaly
include toxoplasmosis, syphilis, CMV, mumps, and influenza virus.
Pathology
Severe lateral ventriculomegaly ( Figures 4–1 and 4–5 ) can
result from different pathologic entities. In our experience,
fetuses with this finding usually have other neural and
extraneural malformations. Even those with presumably
isolated ventricular dilation were found in the majority of
cases to have complex abnormalities. In a large series, only
10% of fetuses with severe ventricular dilation were found
not to have associated malformations.
12
Only a small proportion of fetuses are found to have isolated obstructive
hydrocephaly, either aqueductal stenosis or communicating hydrocephaly. In these cases, the degree of ventricular
enlargement is variable. Knowledge about the pathogenesis of congenital ventriculomegaly is largely incomplete.
Thinning of the cortex, macrocrania, and symptoms of
intracranial hypertension are frequently found. Studies
performed in experimental animals and based on biopsies
of brain tissue obtained in children at the time of shunting
seem to demonstrate the following sequence of events:
Initially, there is disruption of the ependymal lining, followed by edema of the white matter and proliferation of
astrocytes and fibrosis of the cortex.
Recurrence Risk
Apart from X-linked hydrocephaly (recurrence risk 50%
of males), isolated congenital ventriculomegaly is mostly
multifactorially determined. Couples with a previously
affected child have a recurrence risk of 4%.
17
Associated Anomalies
Extracranial abnormalities occur in 30% to 60% of cases. 10
Chromosomal aberrations are found in 11% of cases (6% of
fetuses with ventriculomegaly as the only antenatal finding, 25% of cases with multiple anomalies).
18
The X-linked
hydrocephaly spectrum is frequently associated with
abduction of the thumbs, abnormal facies, and absence or
dehiscence of the septum pellucidum ( Figure 4–5 ).
, 12
19
Diagnosis
Overt lateral cerebral ventriculomegaly is defined as a
measurement >15 mm ( Figures 4–2 and 4–3 ).
3 , 20
A
Figure 4 –5. Severe ventriculomegaly in a fetus with X-linked hydrocephaly. (A) Axial plane. (B) Coronal plane. (C) Three-dimensional ultrasonogra-
phy reconstruction of the body surface shows the adducted thumb ( arrow ).
BC
176
Chapter 4 Ventriculomegaly
Differential Diagnosis
The main problem is distinguishing isolated ventriculomegaly from more complex abnormalities of the fetal
brain that frequently have a different prognosis, including intracranial hemorrhage,
Walker-Warburg syndrome,
spectrum.
19
Identifying such conditions is usually a major
21
cortical malformations, 22
23
or X-linked hydrocephaly
challenge. When severe isolated ventriculomegaly is identified, genetic analysis for X-linked hydrocephaly should
be offered. Ventriculomegaly may be associated with
cortical malformations, and the diagnosis of these conditions is often difficult or impossible. In particular, it has
been recently demonstrated that ventriculomegalic brains
have delayed cortical maturation ( Figure 4–2 ); it is unclear
whether this has an impact on the final outcome or not.
24
Several authors have suggested that MRI can be helpful in
the assessment of ventriculomegalic fetuses, particularly in
advanced gestation.
5 , 6
Implications for Targeted Examinations
For patients at risk for fetal cerebral ventriculomegaly
(eg, because of a previously affected child or because of
TORCH [toxoplasmosis, other infections, rubella, CMV,
herpes simplex virus] infection), we recommend careful
multiplanar examination of the fetal brain, performed if
possible with a high-resolution vaginal probe, including
visualization and assessment of both lateral ventricles.
It has been our experience, and it has been reported in
a handful of cases, that ventriculomegaly may develop
only in late gestation or after birth, particularly with the
X-linked hydrocephaly spectrum.
14
The patients at risk
should be informed that a normal midtrimester sonogram
does not rule out this condition. Couples with a previously
affected child should receive genetic counseling, because
sometimes a generic diagnosis of congenital hydrocephaly
may hinder a more complex anomaly with significant
genetic implications. For example, patients at risk for
X-linked hydrocephaly spectrum should be offered DNA
analysis, as the recurrence rate is high, and midtrimestersonography is frequently unsuccessful.
13
Implications for Sonographic Screening
In all standard sonographic examinations, a view of the
lateral ventricles should be obtained, and at least one of the
atria should be visualized and assessed. A qualitative evaluation is acceptable, and the presence of the choroid plexus
filling the cavity of the atrium, being closely apposed to
both the medial and lateral walls of the ventricle, is indicative of normalcy. A quantitative approach, however, is
favored, and a measurement <10 mm is considered normal
between 15 and 40 weeks.
7
Congenital ventriculomegaly
may develop late in gestation, and a normal midtrimester
exam does not exclude this condition.
Prognosis
In a review, isolated ventriculomegaly diagnosed in utero
was associated with a postnatal survival rate of 70%, and
59% of the survivors had a normal developmental quotient
at follow-up.
11
In most, though not all cases with isolated
progressive ventriculomegaly, intracranial hypertension
develops after birth, and a shunting procedure is necessary.
In a large pediatric series (excluding cases with X-linked
hydrocephaly and congenital infections), the survival rate
was 62% at 10 years, and 50% of survivors had a low developmental quotient (<60). Only 29% of infants attending
school reached a normal academic level. Macrocrania at
birth, ventricular size, and age at surgery had no influence
on the outcome.
carries a severe prognosis, being usually associated with
severe neurologic deficits and premature death.
Obstetric Management
25
The X-linked hydrocephaly spectrum
13 , 15 , 16
A search for associated congenital anomalies, including
fetal karyotyping and a workup for congenital infections
associated with hydrocephaly (ie, toxoplasmosis, CMV,
and rubella), is indicated. Before viability, the option of
pregnancy termination should be offered to the parents.
Little data exist to support any specific management plan
in continuing pregnancies. There is no evidence that anticipation of delivery is beneficial. Most infants with ventriculomegaly do not have macrocrania; therefore, a trial
of labor is indicated in the vertex presentation. Cesarean
section should be reserved for standard obstetrical indications. Whether cephalocentesis should be offered in cases
with macrocrania to overcome cephalopelvic disproportion is debated. In one series cephalocentesis resulted in
perinatal mortality in >90% of cases.
26
Careful aspiration
with fine needles guided with high-resolution US equipment, trying to limit as much as possible damage to brain
parenchyma and cerebral vessels, may cause much less
harm than these rather old data indicate.
Intrauterine treatment consisting of the implantation
of a ventricular-amniotic shunt for the relief of intracranial
pressure during gestation has been attempted.Although
preliminary experience in animal models was encouraging, the clinical application of these procedures remains
undetermined. In a group of 39 treated fetuses, the perinatal mortality rate was 18%, and 66% of the survivors were
affected by moderate to severe handicaps.
new fetal endoscopic technique may provide a different
approach to the problem in the future.
27
However, the
28
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Counseling in isolated mild fetal ventriculomegaly. Ultrasound
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cerebral ventriculomegaly: Clinical course and outcome. Radiology.
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6. Salomon LJ, Ouahba J, Delezoide AL, et al. Third-trimester fetal
MRI in isolated 10- to 12-mm ventriculomegaly: Is it worth it?
BJOG. 2006;113(8):942–947.
7. ISUOG. Sonographic examination of the fetal central nervous system: Guidelines for performing the basic examination and the fetal
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8. Guibaud L. Fetal cerebral ventricular measurement and ventriculomegaly: Time for procedure standardization. Ultrasound Obstet
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Neurology. Amsterdam: Elsevier; 1977:139–171.
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11. Gupta JK, Bryce FC, Lilford RJ. Management of apparently isolated
fetal ventriculomegaly. Obstet Gynecol Surv. 1994;49(10):716–721.
12. Nyberg DA, Mack LA, Hirsch J, Pagon RO, Shepard TH. Fetal
hydrocephalus: sonographic detection and clinical significance of
associated anomalies. Radiology. 1987;163(1):187–191.
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14. Schrander-Stumpel C, Fryns JP. Congenital hydrocephalus: Nosology
and guidelines for clinical approach and genetic counselling. Eur J
Pediatr. 1998;157(5):355–362.
15. Schrander-Stumpel C, Howeler C, Jones M, et al. Spectrum of
X-linked hydrocephalus (HSAS), MASA syndrome, and complicated spastic paraplegia (SPG1): Clinical review with six additional
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16. Varadi V, Csecsei K, Szeifert GT, Toth Z, Papp Z. Prenatal diagnosis of X linked hydrocephalus without aqueductal stenosis. J Med
Genet. 1987;24(4):207–209.
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risk for congenital hydrocephalus (ventriculomegaly): A prospective
study. Am J Med Genet. 1988;29(2):305–310.
18. Schwanitz G, Schuler H, Gembruch U, Zerres K. Chromosomal
findings in fetuses with ultrasonographically diagnosed ventriculomegaly. Ann Genet. 1993;36(3):150–153.
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Chapter 5
ANOMALIES OF DORSAL INDUCTION
Ana Monteagudo ● Ilan E. Timor-Tritsch
KEY POINTS
1. Failure of closure of the neural tube during
neurulation results in neural tube defects.
Neurulation, both primary and secondary, are
completed by approximately 32 post-ovulatory days.
2. Not all cases of neural tube defects are open lesions.
Approximately 20% of spina bifida and 80% of
MSAFP is normal and the diagnosis is made at the
time of the ultrasound examination.
3. Approximately 80 to 90% of children with Chiari II
will develop hydrocephaly.
4. During the second and third trimesters the “classic”
sonographic findings that aid in the diagnosis
of spina bifida are the lemon and banana signs.
Recently, three additional findings have been
described: pointed lateral ventricles, beaked tectum,
and interhemispheric cyst. In the first trimester, the
newly proposed “intracranial translucency” may
become an early sign of open spina bifida.
Anomalies of dorsal induction are those that result from
failure or abnormal closure of the neural tube. Essentially
these anomalies are better known as neural tube defects
(NTDs). NTDs result from failure of the neural tube to
close during primary neurulation. They are characterized
by the presence of a cerebral, spinal, or combined cerebral/
spinal defect or dysraphia.
The normal appearance of the fetal central nervous
system (CNS) results from primary neurulation or dorsal
induction; this in turn results in the formation of the brain
and spinal cord exclusive of those segments caudal to the
lumbar area. During primary neurulation, fusion of the
neural fold occurs first in the dorsal region of the lower
medulla at approximately 22 days after conception. Fusion
does not proceed continuously in a caudal to rostral fashion as previously believed (the “zipper” theory).
two fusion sites, and closure occurs bidirectional with the
anterior neuropore closing before the rostral neuropore.
1
There are
2 , 3
Secondary neurulation, or caudal neural tube formation,
occurs approximately between 26 and 32 postovulatory
days and results in the formation of the lower sacral and
coccygeal segments.
4
It is during secondary neurulation
that canalization occurs (see Chapter 1 ). Table 5–1 lists the
defects that arise as a result of abnormal primary neurulation in decreasing order of severity.
In the United States, all pregnant women are routinely
offered screening with maternal serum alpha-fetoprotein
(MSAFP) for neural tube defects at 15 to 18 postmenstrual
weeks. MSAFP is one of the components of the quad
screen (alpha-fetoprotein, human chorionic gonadotropin,
estriol, and inhibin-A), which is commonly used at present
for screening of Down syndrome and open NTDs. Among
low-risk women, MSAFP screening results in the detection
of 80% to 90% of cases of fetal open NTDs.
5
Limb et al
published a study on the changes in prenatal detection
and birth status of anencephaly between 1972 and 1990
in the Malformations Surveillance program of Brigham
and Women’s Hospital in Boston. In the 1970s, half of the
infants with anencephaly were born alive at an average
gestational age of 35.6 weeks, and few were diagnosed
prenatally; between 1988 and 1990, however, all affected
fetuses were diagnosed either by prenatal ultrasonography
or as a result of MSAFP, and the average age at delivery
was 18 weeks.
MSAFP levels are expressed as multiples of the median
(MoMs). An abnormal value is one that exceeds 2.5 MoMs.
Elevated MSAFP levels are associated with NTDs, as well
as a variety of other conditions ( Table 5–2 ). In a retrospective study of 773 cases with elevated MSAFP, Reichler et al
evaluated the percentage of fetal anomalies detected. They
found that there was a progressive increase in the incidence of fetal anomalies as a direct function of the level of
the MSAFP ( Figure 5–1 ).
NTDs can be categori zed as open or closed, depending
on whether or not they are covered by skin
8
( Table 5–3 ).
In an open NTD, the neural tissue is exposed or covered
only by the thinnest of membranes; therefore, the lesion is
directly in contact with the amniotic fluid. In these cases,
the alpha-fetoprotein (AFP) molecule freely diffuses across
the lesion, which results in an abnormally increased level
in the amniotic fluid, hence in the maternal serum. Not all
cases of NTDs are open lesions. For example, whereas all
anencephaly are open defects, only 80% of spina bifida and
18% of cephaloceles are open NTDs.
8
In a closed neural
tube lesion, the defect is covered by skin or a thick membrane. In these cases, AFP cannot freely diffuse across
the lesion into the amniotic fluid; therefore, the MSAFP
6
7