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230
Chapter 6 Anomalies of Ventral Induction
Ventricle
ABC
Figure 6–3. Multiplanar sonography of alobar holoprosencephaly in the midtrimester. (A) Median plane demonstrating the single ventricular cavity,
which has a rim of cortex anteriorly and amply communicates posteriorly with a dorsal sac. (B) Axial scan at the level of the thalamus, demonstrating
the crescent-shaped single ventricle and the absence of the midline in the anterior cortex. (C) In a slightly craniad axial plane than the previous one,
the communication between the ventricular cavity and the dorsal sac is demonstrated. (Reproduced, with permission, from the Visual Encyclopedia of
Ultrasound in Obstetrics and Gynecology, International Society of Ultrasound in Obstetrics and Gynecology, 2010, www.isuog.org .)
Timor-Tritsch et al
22
Dorsal sac
used three-dimensional (3D)
inversion rendering in the first as well as the early second
trimester as an aid to diagnose holoprosencephaly. It was
possible to discern between alobar and semilobar holoprosencephaly ( Figure 6–6 ).
The ultrasonic findings of semilobar holoprosencephaly are very similar to the ones described for the alobar
type. The diagnosis of the semilobar variety is suggested by
Ventricle
Thalami
Ventricle
Dorsal sac
the presence of well-developed occipital horns. Although
lobar holoprosencephaly is amenable to antenatal identification, a specific diagnosis is difficult. The typical case will
present with absence of the septum pellucidum and slightly
enlarged and dysmorphic lateral ventricles ( Figure 6–7 ).
The major problem resides in the differential diagnosis
between lobar holoprosencephaly, agenesis of the septum
pellucidum, and other hydrocephalic conditions associated
Hyppocampal
Dorsal sac
Ventricle
Thalami
A
Figure 6–4.
is variable. ( A ) In some cases, it forms a thin rim at the base of the ventricles (pancake). ( B ) In other cases, it is partially enfolded on top of the
ventricular cavity. ( C ) In still other cases, the ventricle is completely covered, and there is no dorsal sac; frequently, these cases are pathologically
diagnosed as belonging to the semilobar variety. (Reproduced, with permission, from the Visual Encyclopedia of Ultrasound in Obstetrics and
Gynecology, International Society of Ultrasound in Obstetrics and Gynecology, 2010, www.isuog.org .)
In alobal holoprosencephaly, a dorsal sac is frequently seen on top of the ventricular cavity; the degree of development of the cortex
ridge
Ventricle
Thalami
B
Dorsal sac
Ventricle
Thalami
C
Chapter 6 Anomalies of Ventral Induction
231
Ventricle
A
Figure 6–5. Alobar holoprosencephaly in a fetus at 13 postmenstrual weeks. The most striking findings, the absence of the midline echo and the pres-
ence of a single rudimentary ventricular cavity, are well demonstrated in a vaginal scan. (Reproduced, with permission, from Tutschek B, PiluG. Virtual
reality ultrasound imaging of the normal and abnormal fetal central nervous system. Ultrasound Obstet Gynecol. 2009;34(3):259–267.)
Thalami
Ventricle
Choroid plexuses
B
with secondary disruption of the septum pellucidum.
Failure to demonstrate a well-developed corpus callosum,
poorly formed frontal horns, and incomplete separation
of the inferior frontal lobes favor the diagnosis of lobar
holoprosencephaly.
9 , 16 , 23 , 24
Recently, it has been suggested
that color Doppler may be useful for a specific diagnosis.
In lobar holoprosencephaly, the frontal horns are fused,
and the anterior cerebral arteries run along the surface of
the brain instead of coursing within the interhemispheric
fissure. This sign has been defined as the serpent crawling
under the skull.
23
The middle interhemispheric variant of
holoprosencephaly is intermediate between the lobar and
alobar variety. When compared with the alobar variety, the
frontal lobes are more differentiated than usual with recognizable frontal horns. Posteriorly, however, there is one
single large and undifferentiated ventricular cavity with a
hypoplastic diencephalon ( Figure 6–8 ).
A specific diagnosis of holotelencephaly is difficult.
We have always found this condition with severe obstructive ventricular dilation, as well as well-formed but fused
Cortex
Ventricle
Thalami
C
anomalies has always allowed a clear distinction between
these two entities, it goes without saying that, from a
practical perspective, a diagnostic error would be anyhow
uneventful, given the very poor prognosis of both conditions. Lobar holoprosencephaly must be distinguished
from simple hydrocephaly with secondary disruption of
the septum pellucidum.
12
A midcoronal scan of the fetal
head is the most important view to differentiate among
these two conditions, because it allows identification of
findings that are typical of lobar holoprosencephaly: the
flat roof of the frontal horns and the possible presence of
the fused fornices. Distinction between lobar holoprosencephaly and the absence of the septum pellucidum,
isolated or associated with septo-optic dysplasia, is a much
greater challenge, and the experience is limited. We have
always found lobar holoprosencephaly associated with significant derangements of the anatomy of the hemispheres.
The presence of well-formed and separated frontal horns
and corpus callosum favors the diagnosis of absence of the
septum pellucidum.
12
frontal horns because of the absence of the septum pellucidum. In all our cases, as well as in some cases of the lobar
type, the fornices are fused and are seen in the midline as
a thick fasicle running from the anterior to the posterior
commissure.
16
In a midcoronal scan, the abnormal fornices
result in a peculiar image: a small, round structure is seen
in the midportion of the third ventricle ( Figure 6–9 ). Fetal
magnetic resonance imaging (MRI) may have a role in the
elucidation of particularly difficult cases of lobar types or
some of the nonclassical forms, such as the middle interhemispheric variant.
13 , 25
Implications for Sonographic Diagnosis
In many cases, expert vaginal sonography can diagnose
alobar and possibly semilobar forms during the first
trimester.
18 , 21
The lobar variety is probably difficult to iden-
tify prior to 16 to 18 weeks.
Implications for Sonographic Screening
Alobar and semilobar holoprosencephalies are associated
with profound distortion of intracranial architecture
that should always be detected with a standard sono-
Differential Diagnosis
Alobar holoprosencephaly with a large ventricular cavity and/or dorsal sac has an appearance similar to that
of hydranencephaly. Although in our experience demonstration of the remains of the frontal cortex and/or facial
graphic examination performed in the midtrimester.
Findings associated with the lobar variety may be subtle.
The cavum septi pellucidi, however, is always absent,
with central fusion of the frontal horns. Identification
of the absence of the septum pellucidum is not always
26
easy.
232
Chapter 6 Anomalies of Ventral Induction
A
B
C
D
Figure 6–6. Pictorial table showing three-dimensional inversion rendering of the fluid in the ventricles of fetuses with holoprosencephaly in lateral,
frontal, and superior views. (A) 9 weeks 2 days; (B) 10 weeks 2 days; (C) 13 weeks 5 days; (D) 14 weeks 5 days. (Reproduced, with permission, from
Timor-Tritsch IE, Monteagudo A, Santos R. Three dimensional inversion rendering in the first and early second trimester fetal brain: Its use in holoprosencephaly. Ultrasound Obstet Gynecol. 2008;32:744–750.)
Chapter 6 Anomalies of Ventral Induction
233
A
C
Figure 6–7. Lobar holoprosencephaly. ( A ) The cavum septi pellucidi is absent, and the lateral ventricles appear significantly dysmorphic and fused
from the level of the frontal horns to the bodies. ( B ) In the sagittal plane, the corpus callosum is not clearly visible, and only an irregular ridge of tissue
is seen bridging between the hemispheres posteriorly ( arrow ). ( C–E ) Coronal sections are most useful for the diagnosis in that they demonstrate inferior
fusion of the frontal lobes, poorly developed fused frontal horns, and communication between the bodies of the lateral ventricles. (Reproduced, with
permission, from the Visual Encyclopedia of Ultrasound in Obstetrics and Gynecology, International Society of Ultrasound in Obstetrics and Gynecology,
2010, www.isuog.org .)
Prognosis
Alobar holoprosencephaly is lethal, although cases with
long survival rates have been described. Semilobar holoprosencephaly is not necesserily lethal, but it is associated
Thalami
Frontal horns
D
with extremely severe neurologic compromise. When these
conditions are identified in utero, termination of pregnancy could be offered prior to viability. A conservative
management is recommended in continuing pregnancies.
B
E
Single ventricle
Frontal horns
A
Figure 6–8. Middle interhemispheric variant of holoprosencephaly in the axial ( A ), anterior coronal ( B ), and midcoronal plane ( C ). The frontal horns
are well developed, and there is a partial formation of the interhemispheric fissure. However, the midcoronal plane reveals a common ventricular cavity
with hypoplastic undivided thalami.
B
C
Thalami
234
Chapter 6 Anomalies of Ventral Induction
Fornices
FH
3v
3v
A
Figure 6–9. The appearance of a well-developed frontal cortex and ventricular system associated with obstructive dilation favors the diagnosis of
holotelencephaly. The fornices ( arrow ) are fused and form a thick fascicle running in the floor of the ventricular cavity. (Reproduced, with permission,
from Pilu G, Ambrosetto P, Sandri F, et al. Intraventricular fused fornices: A specific sign of fetal lobar holoprosencephaly. Ultrasound Obstet Gynecol.
1994;4[1]:65–67.)
The prognosis of lobar holoprosencephaly is uncertain.
The available clinical data are limited. It has been reported
that affected individuals may have a normal life span, but
mental retardation and neurologic sequelae are common.
B
C
the right and left side of the brain. The corpus callosum starts its development relatively late in pregnancy,
at around 10 weeks, and continues growing well after
delivery.
Fornices
Dysplasia of the aqueduct of Sylvius is presumably present
in many cases, leading to obstructive hydrocephaly. The
only available antenatal series includes five infants who
were followed up after birth, and all had very abnormal
developmental quotients. This series may be biased by the
inclusion of fetuses with severe hydrocephaly and other
associated anomalies.
24
Obstetric Management
Fetal karyotype is mandatory when holoprosencephaly is
discovered by ultrasound (US). Termination of pregnancy
Epidemiology
The incidence varies in different studies, depending on
the population investigated and the method of ascertainment. Estimates of 0.3% to 0.7% in the general popula-
27
and 2% to 3% in the developmentally disabled are
tion
usually quoted.
patients assessed by US at 15 to 17 postmenstrual weeks
and reassessed at 22 to 25 postmenstrual weeks, we found
only one case of agenesis of the corpus callosum out of
2835 examinations (personal observation).
28
In our own experience with low-risk
can be offered to parents with previable fetuses. Because
alobar and semilobar holoprosencephalies are associated
with a dismal prognosis, in the presence of severe hydrocephaly, US-guided cephalocentesis could be considered to
avoid the risk of dystocia.
Etiology
The etiology is heterogeneous. Various teratogens have
also been implicated as a possible cause of agenesis of
the corpus callosum, including alcohol and maternal
phenylketonuria. Genetic factors are probably pre-
DISORDERS OF PROSENCEPHALIC
MIDLINE DEVELOPMENT
dominant. Autosomal dominant, autosomal recessive,
and sex-linked transmission have all been documented.
Chromosomal anomalies, including autosomal trisomies
Agenesis of the corpus callosum
Definition
Agenesis of the corpus callosum is complete or partial
absence of the corpus callosum. The corpus callosum
is the largest commissure connecting the hemispheres
and is composed of axonal tracts connecting between
and other rearrangements, are increasingly reported.
Agenesis of the corpus callosum may also be associated with mendelian syndromes. Causative genes have
not been found to date.
that congenital callosal pathologies may also develop
after prenatal insults such as infections
processes.
31
29
It is important to remember
30
or ischemic
Chapter 6 Anomalies of Ventral Induction
Figure 6–10. Complete agenesis of the corpus callosum. ( A ) Pathology in a midtrimester fetus. ( B,C ) Magnetic resonance imaging (MRI) at 32 post-
menstrual weeks. Apart from the absence of the corpus callosum, a number of abnormal findings can be appreciated, including the enlarged interhemispheric fissure due to the separation of the hemispheres, the comma-shaped frontal horns, and the radiate array of sulci around the roof of the third
ventricles. (Reproduced, with permission, from the Visual Encyclopedia of Ultrasound in Obstetrics and Gynecology, International Society of Ultrasound
in Obstetrics and Gynecology, 2010, www.isuog.org .)
235
Embryology/Pathology
The corpus callosum is a broad plate of dense myelinated
fibers, located deep in the longitudinal fissure, that reciprocally interconnect regions of the cortex in all lobes with
corresponding regions of the opposite hemispheres. It
derives from the massa commissuralis, an embryologic
structure formed by the fusion of the lateral margins
of the groove that separates the primitive telencephalic
vesicles. Formation of the corpus callosum is a late event
in cerebral ontogenesis. Callosal fibers may be identified
close to the lamina terminalis during the 10th gestational
week, but the corpus callosum itself develops some weeks
later. Histologic studies have shown the presence of callosal fibers crossing the midline at 13 weeks, but recent
studies based on diffusion tensor MRI were able to demonstrate the presence of a clearly defined midline corpus
callosum only at around 15 weeks; by this time only the
anterior portions (rostrum, genu, and part of the body) are
32
present.
identified only 3 to 5 weeks later. The corpus callosum
is in close anatomical and embryologic relationship with
the underlyng septum pellucidum. Although there is no
a priori evidence to suggest that the development of the
In the same study, the corpus callosum was fully
septum pellucidum cannot proceed independently of the
corpus callosum, most observers claim that there can be no
septum pellucidum without a corpus callosum.
Agenesis of the corpus callosum may be either
complete ( Figure 6–10 ) or partial ( Figure 6–11 ). When
partial, the caudad portion (splenium and body) is most
commonly missing to varying degrees ( Figure 6–12 ), but
some degree of anterior agenesis or dysmorphism may
be present.
Complete agenesis of the corpus callosum is typically
associated with significant distortion of the intracranial
architecture. The lateral ventricles tend to be larger than
normal, particularly at the level of the atria and occipital
horns. It has been postulated that the absence of the posterior portion of the corpus callosum results in distortion
of the array of white matter tracts in the occipital lobes,
leading to caudad expansion of the ventricles.
33
Such ventricular enlargement tends to be stable and is not usually
associated with intracranial hypertension. The frontal
horns are usually normal in size but are more separated
than usual from the midline. The third ventricle is often
superiorly elongated, reaching the area normally occupied
by the corpus callosum. At times, it may be found to communicate with a large interhemispheric cyst. On other
Figure 6–11. Partial agenesis of the cor-
pus callosum. ( A ) Pathology in a midtrimester
fetus. ( B ) MRI at 32 postmenstrual weeks. The
corpus callosum does not arch over the entire
area of the third ventricle but is interrupted
about halfway. (Reproduced, with permission,
from the Visual Encyclopedia of Ultrasound in
Obstetrics and Gynecology, International Society
of Ultrasound in Obstetrics and Gynecology,
2010, www.isuog.org .)
236
Chapter 6 Anomalies of Ventral Induction
IHF
IHF
Frontal
horn
3v
AB
Figure 6–12. Sonography of fetal agenesis of the corpus callosum. ( A ) In the axial plane, the interhemispheric fissure (IHF) appears wider than usual
without evidence of the cavum septi pellucidi. ( B ) In the coronal and sagittal plane, no corpus callosum and cavum septi pellucidi can be seen above the
third ventricle (3v). (Reproduced, with permission, from the Visual Encyclopedia of Ultrasound in Obstetrics and Gynecology, International Society of
Ultrasound in Obstetrics and Gynecology, 2010, www.isuog.org .)
occasions, a lipoma may be found at or above the position
usually occupied by the corpus callosum. Absence of the
corpus callosum also results in abnormal induction of
medial cerebral convolutions determining during the third
trimester a radiate arrangement of cerebral sulci around
the roof of the third ventricle, extending through the zone
normally occupied by the cingulate gyrus. The modification of the arterial vascular supply in infants with agenesis
of the corpus callosum has been investigated in depth with
both angiography and sonography and they are relevant
for antenatal diagnosis. Under normal conditions, the callosal arteries, branches of the anterior cerebral arteries,
run along the superior surface of the corpus callosum,
describing a semicircular loop. When the corpus callosum
is absent, such a loop is lost, and branches of the anterior
cerebral artery are seen ascending linearly with a radiate
arrangement.
34
Hypoplasia of the corpus callosum refers to a corpus
callosum that has a normal length but is thinner than
normal.
Lateral
ventricle
C
depicted using the standard axial planes, but coronal and
particularly sagittal. In fetuses in the vertex presentation,
the transvaginal approach is preferred;
36
in the breech
presentation, we recommend a transfundal approach.
Recently, the use of 3D multiplanar technique has been
proposed.
37
The anatomy of agenesis of the corpus callosum
is variable. Definitive diagnosis depends on showing
absence of the complex formed by the corpus callosum
and cavum septum pellucidum. This should include multiplanar imaging to demonstrate the corpus callosum in
both sagittal and coronal planes ( Figure 6–13 ). Vaginal
sonography is particularly helpful in vertex fetuses to
obtain these views.
There are a number of other indirect clues to
complete agenesis of the corpus callosum on standard
transverve views. Failure to visualize the cavum septum
pellucidum, which under normal conditions is seen without difficulty beyond 18 postmenstrual weeks, should
raise the suspicion of agenesis of the corpus callosum.
Other findings include
Diagnosis
Development of the corpus callosum is a late event, completed only by 18 weeks; therefore, an early diagnosis of
its absence is difficult if not impossible. In one antenatal
series, 10 of 15 affected fetuses were found to have an
unremarkable intracranial sonogram at 16 to 22 postmenstrual weeks’ gestation.
complete agenesis of the corpus callosum can be realiably
diagnosed as early as 18 to 20 postmenstrual weeks. Our
earliest diagnosis was made in a pregnant patient at specific risk at 16 weeks. The demonstration of the normal
corpus callosum is possible with US, starting from around
18 to 20 postmenstrual weeks of gestation, but requires
some degree of technical skill, as this structure is not
35
However, in expert hands
●
Ventriculomegaly, typically mild. Prenatal studies
suggest that agenesis of the corpus callosum is
found in 3% of all fetuses with ventriculomegaly
and in almost 10% of those with mild ventriculo-
38 – 40
megaly.
●
Disproportionate enlargement of the occipital horns
(also referred to as colpocephaly) with a sharp
anterior horn. This usually results in the typical
teardrop configuration of the lateral ventricles
( Figure 6–13 ).
●
Upward displacement of the third ventricle, which
can be identified by demonstrating that this structure reaches superiorly the level of lateral ventri-
34
cles
( Figure 6–14 ).
34
Chapter 6 Anomalies of Ventral Induction
IHF
Lateral
A
ventricle
B
237
Figure 6–13. Ventriculomegaly with tear-shaped lateral ventricles is a very typical finding of agenesis of the corpus callosum. (A) fetal sonogram;
(B) postnatal computed tomography (CT). The IHF is typically enlarged. (Reproduced, with permission, from Pilu G, Sandri F, Perolo A, et al.
Sonography of fetal agenesis of the corpus callosum: A survey of 35 cases. Ultrasound Obstet Gynecol. 1993;3[5]:318–329.)
●
Abnormal midline lesions occur frequently, including
cysts ( Figure 6–15 )
41
and lipomas ( Figure 6–16 ).
34 , 42
anterior cerebral artery are seen ascending linearly
with a radiate arrangement
34
( Figure 6–17 ).
Lipomas appear as brightly echogenic lesions. A
lipoma in the anterior midline is associated with
agenesis of the corpus callosum in 50% of cases.
42
is worth noting, however, that lipomas usually are
not demonstrable in the second trimester and tend
to appear only in late gestation.
●
Absence of the pericallosal arteries, branches of
34
the anterior cerebral arteries that normally run
along the superior surface of the corpus callosum
in a semicircular loop. When the corpus callosum
is absent, such a loop is lost, and branches of the
It
Partial agenesis of the corpus callosum has been
described antenatally.
34 , 43
The cerebral findings associated
with it are usually more subtle than with the complete
form. Ventriculomegaly and the teardrop sign are usually
absent. The cavum septi pellucidi, although shorter, is
present. In many cases, the diagnosis is only possible by
demonstrating in a midsagittal plane that the corpus callosum is shorter than normal ( Figure 6–18 ).
In addition to conventional US, 3D US may prove useful
in evaluating fetuses with suspected agenesis of the corpus
Falx
3v
3v
3v
Thalami
A
B
C
Figure 6–14. In this fetus with complete agenesis of the corpus callosum, the third ventricle is enlarged and superiorly displaced, coming into direct
contact with the falx cerebri. (Reproduced, with permission, from the Visual Encyclopedia of Ultrasound in Obstetrics and Gynecology, International
Society of Ultrasound in Obstetrics and Gynecology, 2010, www.isuog.org .)
238
Figure 6–15. Agenesis of the corpus callosum with interhemispheric cysts. (Reproduced, with permission, from the Visual Encyclopedia of Ultrasound
in Obstetrics and Gynecology, International Society of Ultrasound in Obstetrics and Gynecology, 2010, www.isuog.org .)
Chapter 6 Anomalies of Ventral Induction
callosum by allowing the reconstruction of a sagittal plane
even in cases where this is not easily accessible.
37 , 44
The role
of MRI in the diagnosis and assessment of agenesis of the
corpus callosum is controversial. Some authors have found
it to be more informative than US.
45 – 47
In our experience,
US provides a more detailed visualization of the corpus callosum than fetal MRI and enables better measurements of
callosal length and thickness. We do agree, however, that
MRI may be more informative regarding the presence of
associated anomalies, and cortical malformations in par-
45 , 46
ticular.
To our knowledge, hypoplasia of the corpus callosum
has rarely been diagnosed in utero. In our own experience,
we have recognized this condition in a handful of cases,
but only in third trimester fetuses that had other CNS
malformations.
Differential Diagnosis
Agenesis of the corpus callosum must be distinguished
from other causes of ventriculomegaly.
corpus callosum with an interhemispheric cyst must be
differentiated from other intracranial fluid-filled lesions,
such as arachnoid cyst, porencephaly, or an aneurysm of
the vein of Galen.
45
Agenesis of the
Implications for Sonographic Diagnosis
In expert hands, complete agenesis of the corpus callosum can be demonstrated at midgestation. Our earliest
diagnosis was made at 16 weeks. The lesion can be suspected in axial planes, but usually multiplanar imaging
is required to diagnose the condition. Coronal views are
AB C D
Figure 6–16. Agenesis of the corpus callosum with lipomas. In some cases, there is lateral extension of the midline lipomatous process to
involve the choroid plexuses of the lateral ventricle. ( A–C ) Prenatal ultrasound. ( D ) Postnatal CT.
Chapter 6 Anomalies of Ventral Induction
239
pericallosal artery
ACA
a
3v
ACA
b
3v
pericallosal artery
3v
ACA
c
Figure 6–17. Color Doppler of the cerebral circulation in the midsagittal plane. ( A ) In normal fetuses, the anterior cerebral artery (ACA) forms the
pericallosal artery that runs over the corpus callosum. ( B ) Complete agenesis of the corpus callosum. The ACA ascends vertically without forming the
loop of the pericallosal artery. ( C ) Partial agenesis of the corpus callosum. The loop of the pericallosal artery is present but shortened. 3v, third ventricle.
(Reproduced, with permission, from Atlas of Obstetric Ultrasound, 2009. The Global Library of Women’s Medicine. www.glowm.com .)
helpful, but sagittal views are more important in that
they allow recognition of at least some cases of partial
agenesis. It is uncertain whether all cases of partial agenesis can be diagnosed in early gestation. It is important to
stress that complete or partial absence of the corpus callosum is usually the consequence of a malformative process, but it may also derive from intrauterine-acquired
insults. In these cases, diagnosis prior to the destructive
event is impossible. Other anomalies of the corpus callosum, such as hypoplasia, usually are not identified
antenatally.
Implications for Sonographic Screening
Prenatal diagnosis of agenesis of the corpus callosum
is difficult. In low-risk fetuses, which are usually examined only with axial sections,
suspected in the presence of abnormal findings, including mostly ventriculomegaly and failure to visualize the
cavum septi pellucidi. In one large series, the diagnosis could never be made in early gestation in low-risk
patients.
high-risk cases, the findings in axial planes were found to
be elusive.
35
In another series including both low- and
34
We do expect, therefore, that the diagnostic
48
the condition should be
3v
BA
C
Figure 6–18. Partial agenesis of the corpus callosum. ( A ) In the axial plane, the cavum septi pellucidi ( arrow ) is present. ( B ) In the coronal plane,
the corpus callosum ( arrow ) is seen bridging between the two hemispheres, although it appears thinner than usual. ( C ) Only in the sagittal plane is the
anomaly clearly demonstrated. The cavum septi pellucidi/corpus callosum complex ( arrow ) is present but is much smaller than normal; it does form
a complete arch over the third ventricle (3v), but only reaches about midway. (Reproduced, with permission, from Tutschek B, Pilu G: Virtual reality
ultrasound imaging of the normal and abnormal fetal central nervous system. Ultrasound Obstet Gynecol. 2009;34(3):259–267.)