Prenatal Hydrocephalus: Prenatal Diagnosis

Paladini, Dario; Birnbaum, Roee

doi:10.1007/978-3-319-27250-4_47

Dario Paladini⁴ &
Roee Birnbaum⁴

1581 Accesses

Abstract

This chapter comprises three parts: (1) embryology of the central nervous system, (2) normal ultrasound appearance of the brain from the embryonic period to term of pregnancy, and (3) ultrasound prenatal diagnosis of primary and secondary ventriculomegaly/hydrocephalus. In particular, the first part of the chapter represents a thorough description of the early development of the brain in the human fetus, including an interesting sono-anatomic correlation since when the embryonic brain can be explored with ultrasound, i.e., from the 7th gestational week. The second part is meant to illustrate to non-experts in fetal neurology how ultrasound is able to follow the dramatic changes in the brain appearance and anatomy due to the various phases of cerebral development (from the normally lissencephalic brain of the 2nd trimester to the 3rd trimester process of neuronal proliferation and migration). The last part describes in details the diagnostic criteria to establish in the fetus a diagnosis of primary (aqueductal stenosis) versus secondary ventriculomegaly, the latter related to a wide range of genetic and developmental disorders.

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Prenatal Hydrocephalus: Prenatal Diagnosis

Prenatal Hydrocephalus

The Dilemma of Prenatal Hydrocephalus: Grading and Classification of Fetal Hydrocephalus

Keywords

Introduction

In a reference book on pediatric hydrocephalus, the chapter dealing with fetal hydrocephalus has to take into consideration the fact that most of the readers will not be fetal medicine experts but professionals involved in the diagnosis and treatment of hydrocephalus in the neonatal and pediatric patient. Hence, we need to convey in this premise a series of key concepts in order to facilitate the interpretation of the whole chapter sections.

A Premise: The Fetus and the Cerebrospinal Fluid Circulation

1.
Embryology and brain developmental changes. It is well-known that the human central nervous system (CNS) undergoes dramatic changes across all ages, from birth to death. However, the extent of the architectural and anatomical modifications occurring from the embryonic to the neonatal age is outstanding. This concept has important diagnostic consequences for the accuracy of prenatal diagnosis. As an example, some anomalies such as holoprosencephaly (Fig.1a) can be detected as early as 10 weeks of pregnancy; on the other hand, migration and proliferation abnormalities such as cortical malformations or microcephaly can be diagnosed only in the 3rd trimester of pregnancy in the majority of cases (Fig. 1b, c).
2.
Cerebrospinal fluid circulation. Another field in which the uncertainties are frustratingly numerous is the issue of cerebrospinal fluid (CSF) production, circulation, and reabsorption. In fact, this very crucial topic is still but unresolved. In some studies, it has been demonstrated that the Pacchioni granules are scant and barely functional in the fetus (Mack et al. 2009). At the same time, we have still to understand why in the fetal Blake’s pouch cyst, at a time when neither the Magendie nor the Luschka foramina are patent (<26 weeks), and, hence, there is apparently no communication whatsoever between the ventricular system and the subarachnoid spaces, there is no ventriculomegaly (Paladini et al. 2012).
3.
Association with other genetic or developmental abnormalities. In the fetus, the risk of association with severe genetic and phenotypic conditions is much higher than in the newborn or child. This is due to the fact that severely affected fetuses may die spontaneously in utero or, more often, undergo termination of pregnancy, at least in those countries in which this option is available by law.
4.
CNS imaging in the fetus. The size of the fetal brain is such that imaging – no matter if ultrasound or MR – cannot provide the extent of information that postnatal MRI can. However, detailed ultrasound imaging can be carried out from the earliest weeks of pregnancy, allowing to visualize the various steps of the CNS development almost from the beginning. It should be considered here that the small size of the fetal brain and the occurrence of fetal movements represent a major drawback limiting the accuracy of MRI evaluation before 24–25 weeks of pregnancy. Hence, before that period ultrasound information are often much more reliable that MRI ones, whereas in the 3rd trimester the two techniques – ultrasound and MRI – become complementary, evenly contributing to a thorough evaluation of fetal CNS anatomy (Paladini et al. 2014).

To provide an idea of the dramatic changes in the appearance of the brain during prenatal life, it suffices to follow the development of the choroid plexuses (CPs) from the late embryonic stage, at 9–10 weeks onward, assisting at their progressive reduction in comparison with the growing fetal brain (Fig. 2). The ventricular system is obviously deeply involved in these changes.
5.
Epidemiology of CNS abnormalities in the fetus. For any expert dealing with the differential diagnosis of congenital anomalies, one of the first steps is to consider the prevalence of the various conditions in prenatal life. Professionals dealing with the postnatal patient, widely defined, from neonate to pediatric age, deal with a completely different epidemiological scenario, due to the abovementioned high termination and mortality rates of affected fetuses.

The Developing Human Brain: From Embryology to Sonoembryology

In this first part of the chapter, we summarize the current knowledge on the development of the human brain adding a sonoembryologic anatomic correlation part from when high-frequency ultrasound may effectively show the developing brain structure.

Introduction

The embryonic period, defined as the first 8 weeks following fertilization, is characterized by a continuum of morphological changes of both the external and internal anatomical features, whereas the fetal period is characterized by elaboration of existing structures (O’Rahilly and Muller 2005). Conveniently, in obstetric practice, pregnancy dating begins on the first day of the last menstrual period (LMP) and counted in gestational (menstrual) weeks (GW). Since ovulation and fertilization are commonly considered close events, and menses commence presumably 14 days prior to ovulation, in the first fortnight of gestation (the 2 weeks prior to the embryonic period), the embryo has not yet formed. Hence, the embryological term “8 weeks’ embryo” is commonly referred to by the obstetrician as “10 gestational weeks.”

One of the most commonly used staging system of the developing human brain, called the “Carnegie stages,” was first introduced by Streeter in the 1940s and later modified by O’Rahilly and Muller in 1987 (1987). According to the Carnegie system, embryonal brain development is subdivided into 23 morphologically distinct stages of both the internal and external characteristic. For each stage, an approximate embryonic length and postfertilization age are described and should solely be used as guidelines, since variability exists between the morphological stage and the mere length or age of the embryo (O’Rahilly and Muller 2010). Key features of the developing human brain based on both the Carnegie staging system and the work published by Bayer and Altman (2008) in their comprehensive atlas on human central nervous system development represent the bases for the following text. The objective of this text is to provide an overview of the human brain development, from the fetal medicine specialist’s point of view, highlighting the developmental dynamics of brain structures commonly imaged on neurosonography throughout pregnancy, in both normally and abnormally developed brain, with a specific insight into fetal ventriculomegaly and hydrocephalus.

Early Organization

Nervous system development is termed neurulation. The first morphologic sign of the primary neurulation appears in stage 8 of the Carnegie system (approximately 23 days postfertilization, 5 GW) when the epiblast layer is being transformed, as a result of inductive influence, into a thickened neuroectoderm, giving rise to the neural plate. In the following stages, the edges of the plate create two parallel longitudinal neural folds, bending medially over the developing neural groove. At stage 9 (approximately 26 days postfertilization, 5.5 GW), despite the fact that the neural tube has not yet closed, the three primary divisions of the future brain are distinguishable: prosencephalon (forebrain), mesencephalon (midbrain), and rhombencephalon (hindbrain), cranial to caudal, respectively. Also, at this stage, the first flexure of the neural tube appears at the level of the mesencephalon. It has been suggested that both longitudinal and transverse patterns of gene expression contribute to the formation of a grid-like array of cells’ primordia in a process termed regionalization (Rubenstein et al. 1998). At this stage, the rhombencephalon is subdivided into four rhombomeres (i.e., transverse subdivisions of the neural folds and groove at the level of the rhombencephalon) termed A–D, cranial to caudal, respectively. Rhombomere D represents the level where the first somite pair appears in the mesoderm (Müller and O’Rahilly 2003), indicating the future cerebrospinal junction (Fig. 3). The two neural folds begin to fuse at the level of the rhombencephalon when five somitic pairs are present (stage 10, approximately 29 postfertilizational days, 6 GW). From this point, fusion will continue in a bidirectional pattern, both caudally and cranially. This is followed by the appearance of a second fusion point at the cranial most end of the neural plate, at the level of the prosencephalon, called the “terminal lip,” by means of a unidirectional fusion. The gradually closing gap between the two unfused folds is termed the anterior neuropore, whereas the open region between the two neural folds at the caudal end is termed the posterior neuropore. Closure of the terminal lip of the anterior neuropore gives rise to the floor of the telencephalon, representing the area of the future lamina terminalis and its commissural plate. As fusion progresses, a farther neuromeric subdivision of the brain is distinguished: the prosencephalon gives rise to the telencephalon and the diencephalon (rostral to caudal, respectively); the mesencephalon enlarges, becomes a more tubular structure, and further subdivides into mesencephalic neuromas (M1, M2); the rhombencephalon will further subdivide into eight different rhombomeres (Fig. 4a).

During 6–7 GW, the neuropores close, beginning with the cranial neuropore at stage 11, followed by the caudal neuropore at stage 12 (approximately 6.5 GW). This represents the end of the primary neurulation and the beginning of the secondary. Also during this period, the pontine flexure appears as a bulge in the ventral surface of the rhombencephalon (Fig. 4b). From this point onward, ultrasound may document the further steps of the secondary neurulation (Fig. 4c). Once the neural tube closure completes, its lumen disconnects from the amniotic cavity, giving rise to the future ventricular system of the brain. By stage 15 of development (7 GW), the five precursors of the brain and spinal cord can be distinguished (commonly termed the brain vesicles): telencephalon (future hemispheres and part of basal nuclei), diencephalon (future thalamus and its subdivisions and part of the basal nuclei), mesencephalon (future midbrain), metencephalon (future cerebellum and pons), and myelencephalon (future medulla oblongata). It should be noted that, bridging between the mesencephalon and the rostral part of the metencephalon (i.e., rhombomere 1), a new neuromere is distinguished at stage 13 (approximately 6.5 GW), termed the isthmus rhombencephali (Fig. 4b, c). The cerebellum, as discussed later, will evolve from both the isthmus and the rostral part of the metencephalon.

The use of three-dimensional multiplanar sonographic reconstruction imaging provides a reliable demonstration of the main brain subdivisions (Fig. 5). In this way, the embryonic brain development may be followed closely. Figure 6 shows a plane to plane correlation between an 8- and a 10-GW-old fetus. Note that by 10 GW (i.e., the end of embryonic period), both the brain’s five subdivisions and the early ventricular system are clearly demonstrated.

Brain Hemispheres

The two brain hemispheres emerge bilaterally from the telencephalon, in an “outpouching” fashion, on both sides of the neural tube (beginning at stage 14, approximately 6.5 GW). As development proceeds, the two telencephalic vesicles begin to follow their frontal and occipital growth poles, and by stage 22 (approximately 9.5 GW), the temporal pole starts to develop, too. The growing hemispheres approach each other at the midline, dorsal to the roof of the diencephalon and mesencephalon, progressively enclosing deeper brain structures (Fig. 6). It is worth mentioning that by the end of the embryonic period (10 GW), the two hemispheres cover most of the diencephalon, separated in the midline by the longitudinal fissure, which, at this stage, ends at the roof of the 3rd ventricle. Another important note is that at 10 GW the surface of the hemispheres is smooth with only the beginning of the insular indentation, bordered by the growing anterior and temporal growth poles. As development continues, this indentation will become the Sylvian fissure. At 12 GW, the brain hemispheres have gained their midline separation represented by the echogenic falx and their three growth poles giving the hemispheres their characteristic C shape configuration (Fig. 7). The insular cortex will get progressively buried under the folds of the developing surrounding cortex from frontal, temporal, and frontoparietal areas, in a process called operculization (see text and images below in section on “Cortical Development”).

The Ventricular System and Choroid Plexus

As mentioned in the previous section, the ventricular system first appears when the neural tube closes and its lumen disconnects from the amniotic cavity. At this point, the fluid trapped within this cavity is an “embryological CSF” derived from the lining neuroepithelium, until the later appearance of the choroid plexuses. It has been suggested that this early CSF has a major role in early brain growth and morphogenesis (Gato and Desmond 2009). As development continues, the ventricular system will fold and shape, guided by the development of the surrounding brain structures, while maintaining its luminal continuity. During early stages of development, including the beginning of the fetal period, the walls of the growing hemispheres, designated to become the future neocortex, are relatively thin, and as a result, the lumen of the ventricular system is prominent, most notably in the lateral ventricles. The different segments of the developing ventricular system are termed according to their anatomic relations with the surrounding structure; the lateral ventricles of the telencephalic vesicles are connected to the 3rd ventricle of the diencephalon and telencephalon medium (the midline segment of the telencephalon) through the interventricular foramina of Monro. The lumen of the mesencephalon, i.e., the future aqueduct of Sylvius, together with the lumen of the isthmus rhombencephali, termed the isthmal canal, tunnels between the 3rd and the 4th ventricle of the rhombencephalon. The progressive development of the ventricular system can be seen in Figs. 8 and 9.

The ventricular lumen continues from the 4th ventricle to the central canal of the spinal cord, and the CSF circulates out from the ventricular system into the subarachnoid space, from where it is eventually absorbed back into the venous system of the brain. It has been suggested that the middle (Magendie) and the two lateral (Luschka) foramina, located in the roof and lateral recesses of the 4th ventricle, develop at approximately 8 and 26 GW, respectively (Brocklehurst 1969). However, a final confirmation on the timing of opening of the foramina is still lacking (for further discussion see section on “Rhombencephalon”). As for all the other brain structures, the ventricular system changes dramatically during gestation. These changes are illustrated in the next section on sonographic anatomy of the ventricular system and choroid plexus.

The choroid plexus (CP) consists of an outer epithelial layer, derived from the neuroepithelium, which surrounds a core of capillaries and connective tissue derived from mesenchymal cells commonly referred as the tela choroidea . The CP creates a papillary structure, invaginating the ventricular lumen, functioning as an interface between the blood and the cerebrospinal fluid (CSF) secreted by its cells. The first to appear is the CP located in the roof of the 4th ventricle at stage 19 (approximately 44 postfertilizational days, 8 GW). It is followed by the formation of the CP of the lateral ventricles that becomes continuous with the CP located at the roof of the 3rd ventricle by passing through the IVF, 1 and 2 weeks later, respectively. Between 9 and 17 GW, the CP is considerably large with respect to the ventricle, whereas after that period it progressively regresses, so that beyond 29 GW the CP is fairly small compared with the ventricular lumen (Fig. 2) (Lun et al. 2015; Mortazavi et al. 2014; Strazielle and Ghersi-Egea 2000). On ultrasound, the CPs appear as hyperechoic structures inside the anechoic ventricles. At 9 GW the CPs are well visualized both in the fourth and lateral ventricles (Figs. 8 and 10).

Cortical Development

The neocortex develops from the dorsolateral walls of the telencephalic vesicles. The earliest sign of cortex formation is the emergence of the cortical plate (CoP) , the layer where the first wave of postmitotic neurons migrated to and accumulates in. The CoP first appears at the most lateral part of the rostral telencephalon at approximately 9 GW (50 postfertilizational days), and in about 1 week it spreads throughout the hemispheres, moving in a rostro-lateral to dorso-caudal direction. The initiation of migration and the appearance of the cortical plate establish a new, transient laminar configuration to the cerebral wall. The following zones are distinguished, inner-to-outer (ventricle to subarachnoid space): ventricular zone, subventricular zone, intermediate zone (IZ) , subplate (SP) , CoP, and marginal zone (MZ) . The IZ is a heterogeneous zone, containing both radially and tangentially migrating neurons and neural axons, and it contains neither precursors nor post-migratory cells. The white matter of the brain evolves within, and eventually replaces, this layer (Bystron et al. 2008). The SP contains heterogeneous cellularity associated with an abundant hydrophilic extracellular matrix that reaches its maximus thickness by 26–27 GW and gradually regresses thereafter (Pugash et al. 2012). The MZ, the future layer 1 of the six-layered cortex, contains cells that have mostly migrated tangentially and involve in the arrest of migration of radially migrating neurons (Rakic and Zecevic 2003).

Neuronal migratory activity peaks between 12 and 20 GW and is completed gradually through the 3rd trimester of pregnancy. During this period of peak migratory activity, the cortical plate thickens and expands radially, maintaining a smooth surface until approximately mid-gestation. The progressive accumulation of new neurons in the cortical plate sets the ground for the final process in cortical maturation, establishment of cortical connections between various brain regions, commonly termed neuronal differentiation and connectivity formation. It is through this period, beginning after 22 GW and culminating in the 3rd trimester, that the brain’s surface area increases considerably, as reflected by the sequential formation of sulci and gyri, and the progressive appearance of the characteristic six-layered cortex, while neuronal migration gradually subsides. The sonographic description of this gradual process is presented in the section below on Cortical development – normal gyration and sulcation.

Rhombencephalon

As mentioned previously, the cerebellum develops from the isthmus rhombencephali and the metencephalon. At stage 18 (approximately 44 postfertilizational days), the primordium of the cerebellar hemispheres (the flocculus) can be distinguished as two bilateral swellings at the level of the metencephalon, protruding both internally (i.e., facing the lumen) and externally. The dorsal surface of the rhombencephalon, caudal to the level of the developing cerebellum, i.e., the roof of the 4th ventricle, is formed by a thin layer called the medullary velum. The transition point between the thin “roof” and the developing “wall” of the rhombencephalon is termed the rhombic lip, an area that will markedly contribute to the formation of the cerebellar hemispheres. As the pontine flexure deepens (stage 21, approximately 9 GW), the two developing cerebellar hemispheres grow laterally, creating the two lateral recesses of the 4th ventricle, which give the rhombencephalon its diamond-shaped appearance on the dorsal view. At this stage, the hemispheres are connected in the midline only by the rostral part of the medullary velum. This section of the medullary velum is commonly termed the anterior membranous area (AMA). Bordering between the anterior and the more caudal, posterior membranous area (PMA) of the medullary velum is a transverse invaginating fold, called the plica choroidea, arching over the 4th ventricle (perpendicular to the long axis of the neural tube) indicating the budding site of the future choroid plexus of the 4th ventricle (Fig. 11). The fusion of the two cerebellar hemispheres begins with the fusion of the two floccular regions, at the midline nodule, forming the flocculonodular lobe, i.e., the archicerebellum (distinguished at the end of embryonic period, approximately 10 GW). From the end of the embryonic period, the growth of the cerebellar hemispheres will lead to their fusion, initiating the vermian formation from the anterior membranous area. This will lead to the eversion of the evolving cerebellar hemispheres on top of the floccule, and to lengthening of the vermis in a caudal direction, over the nodule, replacing the anterior membranous area (Fig. 12). As evident in Fig. 13, the two cerebellar hemispheres are still not fully fused, and the vermis is yet barely evident. The progressive growth caudal of the cerebellar vermis and its relationships with the other structures of the posterior fossa from 12 to 30 GW are shown in Fig. 12.

As briefly mentioned earlier, the midline foramen of Magendie is thought to develop at approximately 8 GW (Brocklehurst 1969). It has been suggested by Blake (1900) and later supported by Wilson (1937) that the formation of the Magendie begins as a temporary dorsal outpouching of the PMA into the developing cisterna magna, which since this description has been named Blake’s pouch. At around 10 weeks, it is believed that this digit-like evagination eventually opens, connecting the 4th ventricle to the subarachnoid space. The appearance of the lateral foramina of Luschka seems to take place later in pregnancy, according to some authors at about 26 GW (Brocklehurst 1969).

Corpus Callosum and Cavum Septi Pellucidi

As mentioned earlier, closure of the anterior neuropore of the neural tube gives rise to the embryonic lamina terminalis, the rostro-medial part of the telencephalon. Within the lamina terminalis, the commissural plate (ComP) seems to provide the infrastructure for the commissures of the brain. The largest commissure of the brain, the corpus callosum (CC) is composed of axons destined to connect corresponding cortical areas of the two cerebral hemispheres. The CC develops bidirectionally from a budding area representing the anterior part of the body, both posteriorly giving rise to the body and splenium and anteriorly giving rise to the genu and eventually the rostrum (Kier and Truwit 1996). By 12 GW the first fibers of the CC can be recognized in pathological specimens. At about 15 GW, the anterior most part of the body is developed, roofing over the anterior section of the 3rd ventricle. From this gestational age, the corpus callosum will grow rapidly so that by midpregnancy its complete structure is visible on the midsagittal view of the fetal brain (Fig. 14). The development of the cavum septi pellucidi (CSP), assumed to develop by necrosis within the commissural plate, takes place at the same time as that of the corpus callosum. The CSP begins to develop at approximately 15 GW, and its caudal continuation, the cavum vergae, is visualized on the sagittal and coronal vies of the brain (Fig. 14).

Normal Two- and Three-Dimensional Ultrasound Anatomy of the Brain and the Ventricular System in the Fetus

1.
Ultrasound equipment, techniques, and scanning approach. There are two different levels of approach to the sonographic examination of the fetal brain: screening and diagnosis. The former is meant to be carried out in low-risk pregnant women and relies on the visualization of two basic sonographic axial planes – transventricular and trans-cerebellar (ISUOG 2007) (Fig. 15) – which will be illustrated in the dedicated section below. The latter approach – the diagnostic one – is required when a suspicion of CNS anomaly is raised at screening ultrasound and the patient is then referred for expert sonography. In this case, the task of the fetal medicine expert is to carry out a thorough sonographic evaluation of the fetal brain, the so-called neurosonography (ISUOG 2007; Monteagudo and Timor-Tritsch 2009; Timor-Tritsch and Monteagudo 1996). The different objectives of the two types of examinations dictate the scanning approach – transabdominal for screening and transvaginal for detailed neurosonography – unless a breech position of the fetus makes the transvaginal approach not feasible. For the readership not used to fetal ultrasound, it should be noted that transabdominal approach relies on the employment of lower emission frequency transducers which, in turn, increase the depth of insonation at the expense of the resolution. On the contrary, if the fetus is in vertex presentation, using transvaginal transducers warrants much higher resolution and, doing so, allows also subtle abnormal findings (e.g., subependymal heterotopias) to be detected. Another important concept regards the employment of three-dimensional ultrasound. These techniques allow not only to store whole volume dataset of fetal brains for future reassessment but enhance, at the same time, the accuracy of the evaluation, due to the possibility of multiplanar image correlation. Finally, color Doppler, or preferably, the more sensitive and less angle-dependent power Doppler, is used for detailed assessment of the fetal brain circulation, both in 2D and in 3D.
2.
The scanning windows and the scanning concept. One of the challenges we encounter in exploring the fetal brain with ultrasound is represented by the calvarial bones, the mineralization of which hampers ultrasound waves’ penetration. This is why we are bound to use the fontanelles and the still unsealed cranial sutures as ports of access to explore the fetal brain with ultrasound. In particular, the anterior and posterior fontanelles and the coronal suture are used in transvaginal ultrasound, whereas the coronal, mastoid, and parieto-occipital areas are employed in transabdominal ultrasound (Fig. 16). Considering what has been expressed above, especially about the restrictions imposed by the calvarial ossification to ultrasound beam penetration, it becomes clear why with transabdominal ultrasound mainly axial views can be obtained, with limited exceptions. These are also simpler to obtain for screening purposes. On the other hand, transvaginal neurosonography uses the fontanelles to literally penetrate with the tip of the transducer just beyond the bones allowing most of the brain to be seen. This approach leads to a series of images of the brain that can be oriented with a fanlike movement of the transducer on the coronal and the sagittal planes (Fig. 17).
3.
Normal anatomy
- Key landmark appearance by gestational age . In fetal CNS imaging, the operator should be aware of a series of developmental steps not to incur in basic diagnostic mistakes. As an example, the cavum septi pellucidi appears at about 15–16 gestational weeks to disappear after 34–35 weeks, becoming the septum pellucidum. Along the same lines, a developed cingulate gyrus cannot be visualized with ultrasound before 28 weeks of gestation.
- Twelve to 14 gestational weeks:
  - Figure 18 shows a cross-sectional anatomy of a 12 GW brain on the axial plane view. The brain’s subdivisions are distinguished, along with the following structures:
  - Butterfly-shape CPs of the lateral ventricles
  - Midline
  - Developing thalami (diencephalon) and midbrain (mesencephalon)
  - Aqueduct of Sylvius
  - Cerebellum
  - Fourth ventricle
- Nineteen to 22 gestational weeks:
  - Figures 19 and 20 show brain structures normally observed on the axial view at 20–22 GW. The main features include the following:
  - Cerebral cortex visible
  - Cavum septi pellucidi and corpus callosum
  - Insula visible
  - Vermis and cerebellum visible with cisterna magna
  - Initial evidence of calcarine and parieto-occipital fissures
- Twenty-seven to 28 gestational weeks (Figs. 21 and 22):
  - Operculization of insula
  - Deepening of calcarine and parieto-occipital fissures
  - Beginning of the cingulate gyrus
- > 30 gestational weeks (Figs. 21 and 22):
  - Cingulate gyrus evident
  - Convexity sulci visible
  - Further opercolization of insula
4.
Characterization of the ventricular system

The appearance of the ventricular system in prenatal life is completely different from what is considered normalcy after birth. This is why there is a need to illustrate the differential features in detail.

Lateral ventricles . As a result of the progressive development of the anterior and temporal hemispheric poles, the corresponding anterior and temporal horns of the lateral ventricles evolve (Fig. 23). At approximately 11–12 GW, the posterior (occipital) horn begins to evaginate posteriorly. This gives rise to the following subdivisions of each lateral ventricle: the anterior horns, central part (body), and atrium, commonly termed the trigone (representing a triangular spatial junction between the anterior areas and the posterior and inferior, temporal horns). From the sonographic point of view, the ventricular system is best studied using the multiplanar approach, aimed at both measuring and examining the appearance of the entire ventricular lumen, its ependymal continuity, and the surrounding brain parenchyma. The CPs appear as echogenic structures located within the ventricular lumen. The part located at the atrium of the lateral ventricle is called the glomus of the CP, and from there it continues both anteriorly (toward the anterior horn and IVF) and inferiorly (toward the temporal horn), giving the CP its C-shape appearance (Fig. 24). As mentioned earlier, along development, the CPs become progressively small compared with the growing brain structures (Fig. 23). Under normal conditions, the CPs of the 3rd and 4th ventricles are not routinely visualized during the routine midpregnancy scan due to the small size of both the CP and the surrounding ventricular lumen.

By tilting the US transducer laterally, in a fanlike movement (Fig. 17), on a parasagittal plane, the entire lateral ventricle can be examined (Fig. 24). Furthermore this plane allows the assessment of the temporal horns and their surrounding brain parenchyma. A coronal, posterior view of the occipital lobes allows to compare the size of the occipital horns of the ventricles (Fig. 25). The same plane can also be employed to assess the gyration process, evaluating the calcarine fissure.

The two anterior horns of the lateral ventricles are part of a more complex structure termed the anterior complex, observed in the frontal coronal plane. As demonstrated in Fig. 26, the anterior complex represents a unique configuration of integrated structures: the anterior horns laterally, the floor of which is formed by the head of the caudate nucleus bilaterally, and the medial walls by the septum pellucidum. Roofing over the cavum septi pellucidi (CSP) is a transverse section of the corpus callosum, and bordering ventrally are the two columns of the fornix, approaching each other at the midline, roofing over the area of the slit-like 3rd ventricle.

Third ventricle. A cross section of the 3rd ventricle can be seen on axial scans from the embryonic period, until the end of pregnancy (Hertzberg et al. 1997; Sari et al. 2005). On this plane, it appears as a small, round structure between the two thalami. A dated article describes the 3rd ventricle’s width to be 1 mm wide in the second and 1.9 mm in the 3rd trimester (from 29 weeks onward), respectively (Hertzberg et al. 1997). Although additional ultrasound studies describing the aspect of the 3rd ventricle in the fetus have not been published, we believe that it can be visualized on the midsagittal view of the fetal brain, at least from the 2nd trimester onward. It shows the well-known triangular shape, with the apex reaching down to the hypothalamic area and the massa intermedia connecting the two thalami (Fig. 27).

The aqueduct of Sylvius . The Sylvian aqueduct is clearly visible during the embryonic and early fetal periods, until 12–13 weeks (Figs. 8 and 9). After this period, its lumen becomes virtual and can only be detected when partially obstructed or on MRI, when carried out in the second half of pregnancy. On rare occasions, the aqueduct can be seen on an axial plane passing through the midbrain, anterior to the tectum, and on the midsagittal view (Fig. 27).

Fourth ventricle. The 4th ventricle derives from the rhomboid-shaped lumen of the rhombencephalon. It is visible from the embryonic period until late in pregnancy (Figs. 6 and 9). Nevertheless, under normal conditions, as the brain develops beyond early fetal life, the sonographic appearance of the 4th ventricle is no longer rhomboid, and only the midline area, i.e., the fastigium, is visualized (Fig. 12).
5.
Cortical development – normal gyration and sulcation

Using the three-dimensional multiplanar approach, normal cortical development with respect to the sequential appearance of fissures, sulci, and gyri can be assessed. At early stages, sulci appear as small “V”-shape indentations on the surface of the brain. As cortical development proceeds, the sulci become bright echogenic lines protruding internally from the surface (representing two segments of cortex facing each other as the sulci get deeper). Figures 21, 22, and 28 show the sequential development of the cerebral cortex during gestation. As mentioned earlier in the embryology section, at 18–20 GW, the brain is almost completely smooth with only the following major fissures observed on US: the interhemispheric fissure (IHF), Sylvian fissure (also called the lateral fissure), and the callosal sulcus . The parieto-occipital fissure begins to appear at this developmental age. At 22 GW the beginning of the calcarine fissure is observed. At 26 GW, the cingulate sulcus and gyrus begin to appear, along with further deepening of the previously mentioned convolutions and a gradual closure of the Sylvian fissure. The olfactory sulci begin to appear at 26–28 GW and are confidently seen at 30 GW. Operculization of the insular cortex can be visualized both on the parasagittal and coronal views. On the former, the Sylvian fissure has an echogenic V-shape appearance, progressively closing from occipital to temporal direction (Fig. 22) (Cohen-Sacher et al. 2006; Monteagudo and Timor-Tritsch 1997; Toi et al. 2004).
6.
Screening for CNS lesions in the fetus. Having demonstrated the normal sonographic anatomy in the former heading, we move here to illustrate how prenatal screening for CNS lesions is carried out. Since routine obstetric scans are carried out in most countries at 11–13, 18–22, and 28–32 gestational weeks, these are the timings in which a basic assessment of the fetal brain is carried out. At the end of the 1st trimester, only the most obvious and severe anomalies are detected, such as holoprosencephaly, anencephaly/exencephaly, and cephalocele (Fig. 29). The 2nd trimester, at 19–21 gestational weeks, is the time where screening ultrasound for all major anomalies detectable in utero is carried out. This is based on two axial scanning views, the transventricular and trans-cerebellar views (ISUOG 2007) (Fig. 15). The former represents an axial view of the fetal head and brain passing through the occipital horns of the lateral ventricles (Fig. 19). On this view, the atrial width at the level of the glomus of the choroid plexus is measured, wall to wall (positioning the calipers IN to IN), in order to detect ventriculomegaly. In the fetus, ventriculomegaly is rated moderate if the atrial width is 10–15 mm and severe if it exceeds 15 mm (Fig. 19). Some authors also differentiate mild (10–12 mm) from moderate (13–15) ventriculomegaly, considering that feto–neonatal outcome may vary significantly in the two categories.

On the very same scanning plane, i.e., the transventricular view, also the cavum septi pellucidi is checked – according to most national and international guidelines (Fig. 19). This is recommended in order to reach an indirect diagnosis of agenesis of corpus callosum, being the CSP absent in all cases of complete agenesis and in a third of partial ones.

The other scanning view which has to be visualized during screening ultrasound in pregnancy is the trans-cerebellar one (Fig. 20). The visualization of this plane is recommended in order to diagnose abnormalities of the posterior fossa, mainly cystic vermian anomalies, such as Dandy-Walker malformation or vermian hypoplasia (Figs. 20 and 30).

Most of the anomalies are detected in the 2nd trimester of pregnancies thanks to the two scanning views described above. However, the brain is one of the organs whose development continues in the 3rd trimester of pregnancies, especially with neuronal migration and gyration. Hence, there are several malformations of the CNS that are late-onset, i.e., that can be detected only in the 3rd trimester of pregnancy because their signs are virtually absent or non-recognizable earlier. A partial list of these conditions is shown in Table 1.
7.
Diagnosis of CNS lesions in the fetus. Fetal neurosonography. The above–described screening views are part of the 2nd trimester anomaly scan, the routine sonographic assessment of midpregnancy, the main objective of which is to screen for all congenital anomalies, including cerebral ones. Once the suspicion of a CNS anomaly is raised, the patient is referred to an expert. The experts perform then the diagnostic procedure which is called fetal neurosonography, i.e., a scan performed by an expert who is able to thoroughly assess the cerebral anatomy on ultrasound. The two main features of the fetal neurosonography are (1) that it includes not only axial planes, but sagittal and coronal ones, and (2) that, if the fetal presentation allows, the examination is performed transvaginally. In this way, higher emission frequency transducers allow a much higher spatial resolution than conventional transabdominal probes.

Normal anatomy of the fetal brain has already been described in the heading above. Hereafter, the reader will find a description of all pathologic conditions possibly associated with ventriculomegaly in the fetus. As already outlined in other parts of this chapter, a definite diagnosis of primary, obstructive hydrocephalus cannot be made with certainty in the fetus in most cases.

Table 1 Late-onset anomalies of the fetal brain

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Ventriculomegaly and Hydrocephalus

Hydrocephalus is the correct term for pathologic dilatation of the brain’s ventricular system from increased pressure, usually due to obstruction. Ventriculomegaly is the appropriate term when dilatation is due to other causes, such as brain dysgenesis or atrophy. Because ventricular pressure cannot be measured prenatally, the two terms are sometimes used synonymously when applied to the fetus. Most commonly, the term “ventriculomegaly” is used when the ventricles are mildly enlarged, and “hydrocephalus” is used when they measure >15 mm (Fig. 31). Considering also that in the fetus the Sylvian aqueduct cannot be visualized for most of the pregnancy, then the most common cause of obstructive hydrocephalus, i.e., aqueductal stenosis, cannot be diagnosed with certainty.

As already mentioned, the lateral ventricle is measured at the level of the atrium. The atrium of the lateral ventricle is the portion where the body, posterior horn, and temporal (inferior) horn converge. Atrial diameter remains stable between 15 and 40 weeks of gestation (Cardoza et al. 1988). A number of studies have assessed the normal size of the fetal atria. Most of these studies are in agreement with the original study by Cardoza et al. (1988), who found that in the 2nd trimester the mean ± SD measurement is 7.6 ± 0.6 mm and suggested a threshold of abnormality of 10 mm, corresponding to about four SD above the mean. In a pooled analysis of nine studies containing 8216 cases, Almog et al. (2003) showed no significant change in width between 20 and 40 weeks of gestation.

VM is defined as an atrial diameter ≥ 10 mm (ISUOG 2007). VM is generally considered mild if the atrial diameter is between 10 and 15 mm and severe if >15 mm, although some authors use the categories of mild (10–12 mm), moderate (13–15 mm), and severe (≥16 mm) (Bromley et al. 1991) (Fig. 31).

Ventriculomegaly is considered “isolated” when the fetus has no other anomalies, except those that are a direct result of the ventricular enlargement. By definition this is a provisional diagnosis of exclusion. Many cases that appear isolated prenatally are ultimately found to have other abnormalities, particularly when ventriculomegaly exceeds 15 mm. We will illustrate these abnormalities in the second part of this chapter.

Isolated Mild Ventriculomegaly

Isolated mild VM (atrial width 10–12 mm; Fig. 31b) represents a relatively common condition, complicating 1% of all pregnancies. It is a benign finding in most cases, but it may associated with a wide range of completely different etiologies, from infections to chromosomal anomalies, from cerebral clastic conditions to migration abnormalities. As such, considering also its common occurrence, the diagnostic management of mild VM (called until recently borderline VM) and the prenatal counseling for it have been the topic of several articles. Recently, an elegant meta-analysis (Melchiorre et al. 2009) summarized the pertinent literature. As far as the diagnostic management is concerned, should the suspicion of mild ventriculomegaly be raised at midtrimester screening ultrasound, this should undergo transvaginal neurosonography, fetal echocardiography, and detailed anatomic assessment in order to exclude or diagnose concurrent malformations. The employment of MRI as an adjunctive diagnostic procedure is controversial. On one hand, the literature seem to demonstrate that when MRI is performed in case of apparently isolated mild ventriculomegaly, it detects 5–9% of significant CNS abnormalities that have a significant impact on the prognosis (Ouahba et al. 2006; Salomon et al. 2006). However, with the exception of cortical malformations, which may be a challenging diagnosis on ultrasound, the anomalies detected at MRI and not at ultrasound in these studies include malformations that should have been diagnosed at transvaginal neurosonography, such as vermian hypoplasia or partial agenesis of the corpus callosum. Therefore, the evidence is such that the decision to perform an MRI in case of apparently isolated mild ventriculomegaly depends on the experience of the expert performing fetal ultrasound and on the local resource allocation. However, should an MRI deemed advisable, this should be carried out not before 28 gestational weeks, to be able to evaluate cortical development. Another issue is the infectious disease workup . All the infections that are known to be teratogenic for the fetus – rubella, CMV, and toxoplasmosis – may be responsible for mild ventriculomegaly. In most of the cases in which these infections reach the feus, there will be other CNS and/or non-CNS signs of infection in addition to ventriculomegaly. However, 0–5% of foetuses with mild ventriculomegaly will eventually result infected with CMV. Therefore, it is a general recommendation that maternal serology should be checked for CMV and Toxoplasma gondii. Next comes karyotyping : older articles report an association rate for mild ventriculomegaly up to 10%. However, the currently available early screening tests for aneuploidies (combined test [nuchal translucency + biochemistry] and cell-free DNA in maternal blood) ensure a 90–99.5% detection rate for Down syndrome, respectively. Therefore, the prevalence of trisomy 21 among 2nd trimester fetuses with VM will highly depend on the extent of the population coverage with those screening tests. In most developed countries, the overwhelming majority of the pregnant population undergoes one or the other test, according to their moral and religious background. Therefore, currently the prevalence of fetuses with Down syndrome in the 2nd trimester of pregnancy has significantly decreased, due to termination of pregnancy. Consequently, the risk of association of mild ventriculomegaly with aneuploidy has dropped and is now considered to be around 2–3%. Considering the relative incidence of Down syndrome and mild ventriculomegaly in the fetus, the likelihood ratio for Down syndrome has been estimated to be 9. Hence, investigation for aneuploidy in the presence of this finding may therefore be appropriate, depending on the prior risk (Van den Hof et al. 2005).

The last issue regards the neurological outcome of fetuses with a diagnosis of mild ventriculomegaly. Several studies have addressed the issue of neurodevelopmental delay, with controversial data. However, pooled data seem to lead to consider a figure of 10% (confidence interval, 6.1–18.1%) as a reliable estimate for this risk (Melchiorre et al. 2009).

Factors that have been found to be irrelevant for the outcome include gestational age at diagnosis, gender, laterality (uni- or bilateral), and asymmetry.

In utero progression from mild to severe ventriculomegaly occurs in about 16% of the cases, and in this subset of fetuses, the prognosis deteriorates, with an incidence of adverse outcome of 44%.

Severe Ventriculomegaly

In the fetus, a diagnosis of severe ventriculomegaly is made when the atrial width is >15 mm (Fig. 31d). In general, severe ventriculomegaly is bilateral, though some degree of asymmetry may be seen. However, in selected cases, unilateral severe ventriculomegaly can be found. Again, a wide range of conditions may represent the ultimate cause of the ventriculomegaly. In bilateral ventriculomegaly, aqueductal stenosis or severe developmental malformations may be present. In unilateral severe ventriculomegaly, the etiology is more often acquired, considering that the pathogenesis of the ventriculomegaly is in this case obstruction of the foramen of Monro. This may be due to hemorrhage, tumor, or arachnoid cysts which all have a mass effect on the foramen of Monro.

Severe ventriculomegaly may or may not be accompanied by macrocephaly (i.e., head circumference greater than two standard deviations above the mean). In general, macrocephaly is detected from the 26–28 weeks of gestation onward, with only a limited number of cases showing macrocephaly in the 2nd trimester of pregnancy.

When severe ventriculomegaly is detected, a first diagnostic effort to make regards the distinction of primary obstructive ventriculomegaly (i.e., hydrocephalus) from ventriculomegaly secondary to other CNS severe malformations, such as diencephalosynapsis or Dandy-Walker malformation. This distinction has important prognostic significance because severe neurodevelopmental delay is expected in the overwhelming majority of secondary hydrocephalus, while the outcome may be better in case of obstructive hydrocephalus due to aqueductal stenosis. In most industrialized countries, with obvious differences due to religious and moral background, couples who receive such a diagnosis for their fetus tend to opt for termination of pregnancy, especially in case of severe ventriculomegaly associated with other major cerebral malformations. This is why the spectrum of diseases that can be seen in the fetus is completely different from that seen after birth.

Aqueductal Stenosis in the Fetus

From what has been said so far, it becomes clear how a clear-cut diagnosis of aqueductal stenosis cannot be made in prenatal life. However, there are some signs and hints that may lead to suspect such a diagnosis; in any case, the final diagnosis will only be confirmed by postnatal MRI.

The sonographic and MR signs that seem to indicate the likely presence of aqueductal stenosis are as follows (Emery et al. 2005) (Figs. 32 and 33):

1.
Severe ventriculomegaly (atrial width >15 mm)
2.
Symmetrical parenchymal thinning
3.
Dangling choroid plexuses
4.
Dilated 3rd ventricle (>2 mm)
5.
Normal posterior fossa
6.
Loss of peri-cerebral spaces (on MRI)
7.
No evidence of an aqueduct distal to the 3rd ventricle (on MRI)

The authors who proposed these criteria were apparently able to correctly diagnose six out of six cases of aqueductal stenosis in fetuses (Emery et al. 2005). However, to the best of our knowledge, this is the only article appeared so far in which a prospective diagnosis of aqueductal stenosis was reported to be feasible in the fetus. With this exception, most authors have considered such a diagnosis an exclusion diagnosis: when no other CNS abnormalities are seen in association with (severe) ventriculomegaly, the underlying occurrence of aqueductal stenosis is hypothesized. It should be noted that a significant amount of information can be gathered only from the end of the 2nd trimester onward, both on neurosonography and MRI. This is due to the fact that the brain changes completely appearance in the 3rd trimester due to migration and gyrification. Hence, all migration-related abnormalities – and these may also be associated with ventriculomegaly – represent late-onset malformations that can be diagnosed not before the end of the 2nd trimester in most cases. In fact, fetal brain MRI provides much better results if performed >26 weeks of gestation (Paladini et al. 2014). Considering that most cases of ventriculomegaly are diagnosed in the 2nd trimester, it can be easily understood how the diagnosis of aqueductal stenosis is a putative one. In the 3rd trimester, an associated malformation will be discovered in a significant number of cases of ventriculomegaly, reducing the number of case in which a diagnosis of aqueductal stenosis is maintained until delivery. Final confirmation will be provided by postnatal MRI.

Hydranencephaly

Hydranencephaly is characterized by a complete or almost complete absence of the cerebral cortex, with the normal brain tissue being replaced by a large fluid collection covered by leptomeninges and dura. The presence of the falx and of the cranial nerves demonstrates that the hemispheres have developed but have subsequently been destroyed. The most accepted hypothesis for explaining such a huge destructive process is an early vascular disruption process involving both carotid arteries. This process may be triggered by maternal (severe hypoxia, abdominal trauma) or fetal (CMV infection, coagulation deficits, twin-to-twin transfusion syndrome, especially when one fetus dies in utero) conditions (Figs. 34 and 35).

Ventriculomegaly and Associated Genetic Conditions

In this heading, we summarize a limited number of severe genetic conditions that: (1) feature hydrocephalus/ventriculomegaly as one of the main signs and (2) can be – and have been – diagnosed in the fetus.

Walker-Warburg syndrome (WWS). WWS is a dystroglycanopathy, being due to an abnormal O-glycosylation of alpha-dystroglycan. This condition shows genetic heterogeneity, and, hence, a direct molecular diagnosis is not feasible in all cases, especially prenatally; only fetuses of families with known mutations can undergo CVS for diagnostic purposes. However, in families at risk, the detection of ventriculomegaly and/or associated CNS and eye anomalies, such as cataract (Fig. 36), may lead to the diagnosis in the 2nd trimester. The classic cobblestone lissencephaly develops often only in the 3rd trimester and can therefore be diagnosed only >27–28 gestational weeks in most cases on transvaginal neurosonography and MRI.

WWS represents the most severe form of congenital muscular dystrophy, leading almost invariably to death by the age of 3–4 years.
L1 syndrome (MASA – CRASH). L1 syndrome is a mild to severe congenital X-linked developmental disorder characterized by hydrocephalus of varying degrees of severity, intellectual deficit, spasticity of the legs, and adducted thumbs. The syndrome represents a spectrum of disorders including: X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS), MASA syndrome, X-linked complicated hereditary spastic paraplegia type 1, and X-linked complicated corpus callosum agenesis. L1 syndrome is caused by mutations in the L1CAM gene (Xq28) encoding the L1 cell adhesion molecule that is expressed mainly in the developing nervous system. Prenatal diagnosis through chorionic villous sampling or amniocentesis can be performed in pregnant female carriers if an L1CAM disease-causing mutation has been identified in a family member. In this case, the known mutation can be searched in the fetal DNA. The acronyms MASA (Mental retardation, Aphasia, Shuffling gait, Adducted thumbs) and CRASH (Corpus callosum hypoplasia, Retardation, Adducted thumbs, Spasticity, Hydrocephalus) had been used in the past to identify conditions that eventually were included in the L1 syndrome, sharing the same mutations of the L1CAM gene on Xq28.

On prenatal ultrasound, the most common lesion is agenesis of the corpus callosum, while ventriculomegaly is less common (Fig. 37). On some occasions, the adducted thumbs may be displayed with three-dimensional ultrasound.

In families with positive history, both hydrocephalus and more often – at least in the fetus – corpus callosum agenesis (partial or complete) can be diagnosed from mid-gestation. Alternatively, as mentioned, the L1 gene can be analyzed on fetal DNA samples. In Fig. 37a, a case of prenatal diagnosis of L1 syndrome is shown. In this case, there was partial agenesis of the corpus callosum but not hydrocephaly in all affected members of the family including two fetuses.
Megalencephaly, polymicrogyria, polydactyly, hydrocephalus (MMPH) syndrome. All the CNS abnormalities present in this genetic condition – megalencephaly (and macrocrania), polymicrogyria, and ventriculomegaly – can be detected in the fetus (De Keersmaecker et al. 2013). MRI is needed to characterize the cortical malformation, but neurosonography can effectively detect megalencephaly and ventriculomegaly. All these are late-onset abnormalities and can, therefore, be diagnosed only in the 3rd trimester. The only feature which might be recognized as early as the 1st trimester is the postaxial polydactyly.

Ventriculomegaly Secondary to Other CNS Malformations

This represents an extensive chapter in fetal neurology. In fact, the spectrum of possible cerebral malformations that can be associated with ventriculomegaly is rather wide. We will try to approach this topic systematically, dealing with the various groups of developmental anomalies that may be responsible for ventriculomegaly. From the diagnostic standpoint, the extent of ventriculomegaly (bi-, tri-, or tetraventricular) may suggest where the obstruction is. As an example, Dandy-Walker malformation is associated with tetraventricular hydrocephalus, whereas hemorrhage or aqueductal stenosis may determine triventricular hydrocephalus. However, again this concept has to be adjusted taking also gestational age at diagnosis into account; in fact, in Dandy-Walker malformation, the onset of ventriculomegaly is between the end of the 2nd and the beginning of 3rd trimester of pregnancy, with the lateral ventricles being unremarkable up to 22–25 weeks of gestation in a significant percentage of cases.

Holoprosencephaly. This malformation is one of the first to be determined in the cerebral organogenesis, occurring at 28–40 days of development. The term “holoprosencephaly” refers to a group of complex abnormalities of the forebrain deriving from a failed cleavage of the prosencephalon that yields an incomplete division of the cerebral hemispheres and of the telencephalon from the diencephalon. Three main subtypes (alobar, semilobar, and lobar) have been recognized, but this anomaly represents a spectrum of malformations, so intermediate forms may occur. A robust genetic base has been found in several cases, with trisomy 13 being the most common occurrence. However, the etiology comprises microdeletions, duplications, single-gene mutations, and environmental factors (retinoic acid or alcohol exposure, rubella, CMV infections, nonchromosomal syndromic conditions [Smith-Lemli-Opitz syndrome], etc.) which have been found in several cases.

The diagnosis can be made very early in pregnancy, because the absence of the falx and the fused cerebral hemispheres are evident from the 1st trimester of pregnancy (Figs.1a and 38). The distinctive feature is the single ventricle. The amount of cerebrospinal fluid is only slightly increased. The cerebrospinal fluid increases later in pregnancy, but this event is seldom seen because in developed countries the overwhelming majority of women opt for termination of pregnancy. In the rare instance of late diagnosis or if the couple elects to continue the pregnancy, single-ventricle ventriculomegaly may ensue (Fig. 38c). A long series of midline facial anomalies may be associated (Fig. 39). The most frequent facial anomalies are usually classified into the following types: cyclopia, with a single midline orbit or absent eyes; arhinia, with or without a proboscis; ethmocephaly, with evident ocular hypotelorism and a proboscis located between the eyes; cebocephaly, with less pronounced ocular hypotelorism and a nose with a single nostril; and a median cleft lip and palate, with premaxillary agenesis (Fig. 39).

Prenatal management includes amniocentesis for karyotyping and, if possible, cGH-Array, considering the wide range of microdeletions, duplications, and single-gene disorders that may be responsible for holoprosencephaly. Brain MRI has a limited role, considering the fact that, due to the severity of the prognosis, most couple opt for termination of pregnancy.
Agenesis of the corpus callosum. The formation of the CC starts with the development of the genu; the body and splenium develop at a later stage. Due to this developmental sequence, in case of partial agenesis of the corpus callosum, usually the posterior portion is affected. On the other hand, if the CC is missing due to clastic events, such as CMV infection or tumors, any part of the commissure can be involved.

The etiology of ACC is very heterogeneous. Identified causes are chromosomal, monogenic, and teratogenic. Chromosomal abnormalities are present in 20% of cases, especially trisomies 18 and 13. However, >100 syndromes involving ACC have been reported in the literature.

A pathogenetic classification of ACC takes into account the presence/absence of the so-called Probst bundles. Probst bundles are the misrouted callosal axons that run parallel to the interhemispheric fissure and do not cross the midline. ACC can then be basically classified into four categories: (1) ACC may be the result of earlier forebrain abnormalities blocking its development, e.g., holoprosencephaly or frontal cephalocele; (2) ACC without Probst bundles, wherein this group includes those cases in which the overall neuronal population is decreased and, therefore, the Probst bundles cannot form, and it includes conditions such as cobblestone lissencephaly and Walker-Warburg syndrome; (3) ACC with Probst bundles, which is the typical and more common subtype of ACC; and (4) clastic ACC (Barkovich et al. 2009).

The suspicion of corpus callosum agenesis is raised commonly at the midtrimester scan due to non-visualization of the cavum septi pellucidi on the transventricular view (see above) and colpocephaly. Then, neurosonography is carried out, and the direct signs of ACC are detected. These include non-visualization of the CC on the midsagittal view of the fetal brain (Fig. 40a), abnormal shape of the frontal horns, and cranial displacement of the 3rd ventricle on the coronal view (Fig. 40b). An associated interhemispheric cyst may or may not be present (Fig. 40a, d). As far as secondary ventriculomegaly and colpocephaly, we have demonstrated that the teardrop dilatation of the occipital horns is often evident from 20 weeks but with near-normal atrial width; the atria becomes abnormally enlarged only by the end of the 2nd trimester in most cases, usually >24 gestational weeks (Paladini et al. 2013), with the degree of ventriculomegaly that may vary significantly. However, if severe ventriculomegaly is found in association with ACC, then the occurrence of other CNS malformations and/or syndromic conditions should be carefully evaluated (Fig. 41).

Associated CNS malformations are found relatively often, the most common of which are Dandy-Walker malformation (Fig. 40b), cortical malformations, and heterotopias.
Prenatal management includes also in this case amniocentesis for karyotyping and, if possible, cGH-Array. In case of ACC, the latter is of overwhelming importance, considering that, on one hand, truly isolated ACC is associated with a good prognosis in the majority of cases (Mangione et al. 2011) while, on the other, several cases result eventually associated with microdeletions, duplications, and single-gene disorders (such as the L1 syndrome; see above). ACC represents one of the main indication to perform fetal brain MRI, because of the association, among other CNS defects, with gyration abnormalities that may escape, especially if involving the convexity of the hemispheres, sonographic diagnosis. As underlined in the dedicated section, fetal CNS MRI is recommended to be carried out >25 gestational weeks, ideally at 28–30 weeks, when its diagnostic performance is optimal, in comparison with earlier gestational ages (Paladini et al. 2014).
Dandy-Walker malformation (DWM). This anomaly represents the more obvious cystic malformation of the cerebellar vermis. In the fetus, the anatomic criteria to diagnose DWM are (1) complete or partial agenesis of the vermis, (2) cystic dilatation of the 4th ventricle that fills the posterior fossa and extends into the cisterna magna, (3) enlarged posterior fossa with upward displacement of the tentorium, and (4) upward rotation of the partial agenetic vermis (Barkovich and Kjos 1989).

The diagnosis of DWM and other cystic abnormalities of the posterior fossa cannot be made in the 1st trimester of pregnancy, due to the fact that the cerebellar vermis is still physiologically incomplete at that gestational age (see “Early Organization” subheading). In fact, the only evidence we have of posterior fossa and vermian abnormalities at 12–13 weeks of gestation is represented by a cystic posterior fossa (Fig. 42; Volpe et al. 2015). However, until now, the early sonographic differentiation of benign (e.g., Blake’s pouch cyst) and less benign (DWM, vermian hypoplasia) conditions is impossible at that gestational age. From 16 weeks onward, there is the possibility to make a putative diagnosis; at 20–22 weeks, the differential diagnosis among the various conditions (DWM, vermian hypoplasia, Blake’s pouch cyst, mega cisterna magna) can be reliably made in most of the cases (Figs. 43 and 44). The sonographic criteria for a differential diagnosis among the various entities are reported in Table 2 (Paladini et al. 2012; Paladini and Volpe 2006). As evident, obstructive ventriculomegaly may complicate some of these malformations. By definition, being the obstruction at the level of the 4th ventricle, in all these cases ventriculomegaly is tetraventricular (Fig. 43b).

DWM may be associated with chromosomal anomalies (mainly trisomy 18 and 13), other CNS, and extra-CNS malformations. Therefore, prenatal management includes also in this case amniocentesis for karyotyping and, if possible, cGH-Array. Prenatal MRI is rarely needed to confirm a diagnosis of DWM. However, in some cases in which there is a diagnostic doubt about vermian hypoplasia and Blake’s pouch cyst, it may help, provided that it is carried out in the 3rd trimester, when the performance of MRI in the characterization of fetal CNS anomalies is highest (Paladini et al. 2014).
Blake’s pouch cyst (BPC or persistence). This entity has been described in the pediatric literature only 20 years ago (Tortori-Donati et al. 1996). Several years have passed before the same entity was recognized in the fetus (Paladini et al. 2012). In prenatal life, the diagnostic triad to diagnose BPC is (Fig. 45) (1) vermis has normal size; (2) there is anticlockwise rotation of variable degree; and (3) there is a cystic structure in communication with the 4th ventricle, which occupies the posterior fossa. In most cases, the cyst wall and the differential echogenicity of the cyst content (anechoic) versus the cisterna magna fluid (hypoechoic) is also evident. Interestingly, there is a striking difference among the two populations: in neonates and infants, BPC seems almost invariably associated with obstructive hydrocephalus (Tortori-Donati et al. 1996), whereas this is not happening in fetuses with such a diagnosis. Our perception is that after birth, only those cases resulting in obstructive hydrocephalus are referred and, hence, recognized as having a BPC, whereas the overwhelming majority in which there is an uncomplicated, asymptomatic BPC remain undiagnosed – at least before prenatal diagnosis was described. An interesting concept regards the patency of the Magendie and Luschka foramina and the timing of their opening. In fact, BPC may regress or disappear in the fetus at about 26 weeks of gestation (Paladini et al. 2012; Pinto et al. 2016), and this is the time of gestation when the Luschka foramina have been described to open (Brocklehurst 1969). We may speculate that if the BPC persists until birth, it can represent an unstable steady state which may be altered for whatever insult responsible for an increase in CSF production, such as inflammation or hemorrhage. In this case, the BPC might become responsible for obstructive hydrocephalus. In the remaining majority of cases, BPC remains silent and unknown if not for those cases with a prenatal diagnosis (Paladini et al. 2012; Pinto et al. 2016).
Rhomboencephalosynapsis (RES). In this rare pathological entity, the cerebellar vermis is completely absent, and there is fusion of the two cerebellar hemispheres on the midline. Kinking of the brainstem is often found in association. On prenatal ultrasound, the complete absence of the midline vermis is relatively easy to recognize (Fig. 46). In particular, at ultrasound, the cerebellar hemispheres are hypoechoic, while the vermis is hyperechoic, which leads to an easy differentiation between the two anatomical structures on an axial scan (Fig. 46c). At the same time, the absence of the vermis determines a pathological reduction in the transverse cerebellar diameter, which represents one of the basic measurements in obstetric screening ultrasound (Fig. 46c). On transvaginal neurosonography, the employment of higher-frequency transducers leads to a clearer demonstration of the anomaly (Fig. 46b). In case of RES, the occurrence of severe hydrocephalus is common and early onset and leads to referral also in those cases in which the actual infratentorial anomaly has not yet been recognized (Fig. 46c).

In the fetus, RES should be differentiated from cerebellar hypoplasia. In the former, the vermis is absent, and, often, the cerebellum shows a triangular shape; in the latter (cerebellar hypoplasia), the sonographic appearance of the cerebellum is not modified, but the whole organ is significantly hypoplastic.
Diencephalosynapsis . This is an extremely rare anomaly, in which there is failure of diencephalic cleavage; in particular, it is characterized by partial or complete fusion of the thalami associated with third-ventricle atresia (Cagneaux et al. 2013). In most cases, this condition is associated with severe cerebellar hypoplasia or, in some cases, RES. This is due to the fact that the mechanism behind the failed diencephalic cleavage extends to the mesencephalon, leading to mesencephalosynapsis. In this case, by definition, there is obstructive triventricular hydrocephalus, which is early onset and associated, in several cases, with early-onset macrocephaly. At ultrasound, the striking features are represented by cerebellar hypoplasia and early-onset severe ventriculomegaly (Fig. 47). Even if the cerebellar anomaly is overlooked at screening, the latter always triggers referral to experts because of the severity of the ventricular enlargement.
Malformations of cortical development . This covers a wide spectrum of developmental and genetic anomalies. In pregnancy, the two main features are that they are late-onset anomalies, because they are in general virtually unrecognizable in the 2nd trimester of pregnancy, and that mild ventriculomegaly may be associated. It is thought that in this type of malformation, ventriculomegaly represents a passive filling of volumes that are not filled with neurons.

Table 2 Sonographic criteria for a differential diagnosis of posterior fossa cystic abnormalities in the fetus

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Ventriculomegaly Secondary to Acquired CNS Lesions

Ventriculomegaly – as well as obstructive hydrocephalus – may also develop as a complication of brain insults occurred during gestation. There are two pathogenetic mechanisms that may lead to ventriculomegaly in acquired lesions: either obstruction of the ventricular system (e.g., hemorrhage, tumors) or destruction of brain parenchyma close to the ventricular system followed by cavitation and filling with CSF (e.g., porencephaly, schizencephaly). Space-occupying lesions, such as arachnoid cysts, tumors, but also hemorrhage, and all those conditions associated with significant distortion of the brain anatomy are those in which fetal MRI is more helpful in reaching the final diagnosis, in comparison with neurosonography (Paladini et al. 2014). In this study, 773 cases of fetal brain malformations underwent neurosonography, and an MRI was requested as second diagnostic step in 126 (16.3%). In this subgroup of cases, MRI provided additional clinically relevant information in three of seven space-occupying lesion undergoing both neurosonography and MRI. This finding demonstrates that when the degree of brain anatomy distortion is high, MRI performs better than neurosonography, especially if MRI is performed in the 3rd trimester.

Cerebral hemorrhage . This event may occur spontaneously or be due to underlying causes that make the vessels bleed. The most common etiology is fetomaternal alloimmune thrombocytopenia (FMAIT), which is the prenatal counterpart of the neonatal alloimmune thrombocytopenia. FMAIT is due to the maternal production of antibodies against paternal antigens (usually HPA-1a, less frequently HPA-1b – Paladini et al. 2005) present on fetal platelets that are not recognized by the maternal immune system. Maternal exposure to these antigens during pregnancy can lead to the production of various classes of immunoglobulins: the IgG antibodies are small enough to cross the placental barrier and enter the fetal circulation, causing severe thrombocytopenia. Unlike hemolytic disease of the newborn, FMAIT can also occur in the first pregnancy, if there is parental incompatibility. The importance of recognizing this etiology of fetal cerebral hemorrhage lies in the fact that it can be effectively treated, if disclosed prior to the hemorrhagic episode, with intravenous immunoglobulins and intrauterine transfusion of compatible platelets. More rarely, cerebral hemorrhage may be due to vascular malformations (e.g., vein of Galen aneurysm) or infection (e.g., CMV).

The severity of the hemorrhage is classified into four grades (Garel 2004): Grade 1 (Fig. 48a), the hemorrhage is limited to the germinal matrix; Grade 2, the hemorrhage diffuses from the matrix into the ventricle, which fills up with blood without distension; Grade 3 (Fig. 48b–d), the hemorrhage distends the ventricles; and Grade 4 (Fig. 48e), there is extension of the hemorrhage to the parenchyma. In this case, when the necrotic areas clear up, they fill with CSF becoming porencephalic cysts (Fig. 48f). These are in communication with the ventricular system through disrupture of the ependymal lining. In Grades 2–4, the obstruction of the Sylvian aqueduct by debris and clots may lead to obstructive bi- or triventricular hydrocephalus (Fig. 48b–d). On rare occasions, posthemorrhagic membranes may obstruct selectively of one of the Monro foramina leading to progressive and severe unilateral ventriculomegaly (Fig. 49). Sonographic follow-up should be warranted, in order to assess the progression of the hemorrhage and the onset of complications. In fact, both progression of the same bleeding and recurrent bleedings have been documented, and these events are unpredictable. This is why in case of fetal cerebral hemorrhage, scans should be arranged at 3–4 days’ intervals for the first week after the initial diagnosis and then biweekly. Only in this way, it will be possible to keep track of the progression of the lesion. The final prognosis will depend on the cause, the extent, and the location of the hemorrhage.

Hemorrhages from CMV infection have a typical parenchymal location, because they are probably due to vasculitis which may lead to local endothelial necrosis everywhere in the brain. Most common locations are parietal and cerebellar.
Arachnoid cyst. Also arachnoid cysts are late-onset lesions in most of the cases. They can be responsible for parenchymal compression but also for compression on the ventricular system which leads to obstructive hydrocephalus (Fig. 50). Those located on the quadrigeminal plate or in the posterior fossa are more likely to obstruct the ventricular system leading to hydrocephalus. However, in rarer instances, arachnoid cysts may be found in severe syndromic conditions, such as Seckel syndrome. In this case, the arachnoid cysts are associated with other severe CNS malformations, such as ACC or gyration abnormalities, microcephaly, short limbs, and a typical facial appearance which is named bird-headed dwarfism (Fig. 51; Napolitano et al. 2009).
Cerebral arteriovenous malformations (including the vein of Galen). Also these lesions are in most of the cases appearing only in the 3rd trimester, with a limited number of them being diagnosed at the 20-week anomaly scan (Fig. 52). Even though the vein of Galen aneurysmal malformations account for <1% of all intracranial arteriovenous malformation, they represent the most common arteriovenous malformations detected prenatally. VGAM results from an arteriovenous connection between the primitive choroidal vessels and the median prosencephalic vein of Markowski, occurring between the 6th and 11th weeks of gestation. This leads to abnormal flow, preventing involution of the embryonic vein and subsequent development of the aneurysmatic dilatation of the vein of Galen. Prenatal diagnosis is usually made during the 3rd trimester, with color Doppler ultrasonography demonstrating turbulent arterial and venous flow within a hypoechogenic structure located in the midline of the posterior part of the 3rd ventricle (Deloison et al. 2012). On transvaginal neurosonography, the whole architecture of the vascular malformation can be studied with three-dimensional color/power Doppler (Figs. 52 and 53); at the same time, associated anomalies, such as ventriculomegaly, hemorrhage, or parenchymal necrosis, can be diagnosed, in order to make a prognostic evaluation (Fig. 54). MRI represents a must in this assessment, because it is able to detect better than ultrasound ischemic necrotic lesions also in the initial stage, unlike ultrasound. In fact, the perinatal mortality for this anomaly is high. Causes of death are cardiac decompensation from high-output cardiac failure (due to the arteriovenous fistula) and secondary brain lesions, including hemorrhage, necrosis, etc. A study reporting the largest number of fetal cases of VGAM which is going to be published shortly has shown that the most important poor prognostic signs are represented by severe tricuspid regurgitation and an aneurysmal volume ≥ 20 ml. In this setting, ventriculomegaly may be caused by obstruction or hemorrhage. In the former instance, it can regress after endovascular treatment of the VGAM; if due to hemorrhage, it obviously requires a surgical approach for treatment.
Tumors. Also cerebral tumors represent late-onset lesions in most cases. It is quite rare to see brain tumors arising in the 2nd trimester (Fig. 55). In most cases, they appear in the 3rd trimester and, if malignant or locally invasive, progress rapidly, with secondary obstructive ventriculomegaly, parenchymal destruction, and macrocrania (Fig. 56). In this case, the prognosis is dictated by histology of the tumor and its location (Vassallo et al. 2012).
Schizencephaly is characterized by the presence of abnormal clefts in the areas of the cerebral mantle that separate the lateral ventricles from the subarachnoid spaces. Clefts are lined by dysplastic gray matter, so that a loss of substance due to acquired causes, such as encephaloclastic porencephaly, can be ruled out. Schizencephaly can be uni- or bilateral, symmetric or asymmetric. Up to 50% of cases are bilateral; when bilateral, 60% are “open lipped” on both sides. Of the two types of schizencephaly, “closed-lip” schizencephaly shows very thin clefts (fused clefts), while open-lip schizencephaly has clefts filled with CSF and is often associated with ventriculomegaly. Schizencephaly is a malformation secondary to abnormal postmigrational development and is thought to be related to a vascular disruption process; in fact, in a significant proportion of cases, other non-CNS anomalies possibly related to a vascular insult have been found (e.g., gastroschisis, bowel atresia).

On ultrasound, only the open-lipped form of schizencephaly can be diagnosed. The diagnosis is made when a CSF-filled cleft of one or both cerebral hemispheres that extends from the subarachnoid spaces to the lateral ventricles is found (Figs. 57 and 58). The lateral ventricles are often dilated and clearly visible on the transventricular plane. Schizencephaly involves more commonly the Sylvian fissure, and in this case it is often associated with septo-optic dysplasia. In the fetus, the most difficult differential diagnosis is with a large porencephalic cyst of the Sylvian fissure (Fig. 59). The aspect and the shape of the cystic lesion might in some cases lead to the correct diagnosis: schizencephaly is wedge-shaped or triangular, whereas poroencephalic cysts tend to be rounder.

On ultrasound, the diagnosis of schizencephaly is very simple: there is a huge collection of CSF filling virtually the whole cranial cavity, with no recognizable cortex. The falx is usually present, though it may be eccentrically positioned; the thalami, basal ganglia, brainstem, and cerebellum may be normal, because the vascular insult usually involves the telencephalic portion of the brain (Figs. 57 and 58). In most cases, there is significant macrocrania.
Porencephaly. The term “porencephaly” includes every type of lesion with cavitary character, that is, a fluid-filled area within the brain that usually communicates with the ventricles and, on very rare occasions, with subarachnoid spaces or both. It involves destruction of previously developed brain tissue, with subsequent cavity formation. It may be isolated or associated with ventriculomegaly. It is usually classified in two subtypes: type I is due to parenchymal damage followed by liquefaction/reabsorption (encephaloclastic porencephaly), resulting from an insult (ischemia, hemorrhage, etc.); type II (schizencephalic porencephaly) is completely cystic with a smooth wall. It is the less frequent type.

On ultrasound, porencephaly appears as a unilateral cystic lesion, usually communicating with the ipsilateral ventricle and/or the subarachnoid space. Due to destruction of brain tissue, it does not cause any mass effect. If the cyst is the result of a former parenchymal hemorrhage, debris from the clot liquefaction can be seen along the walls of the cyst (Fig. 48f). The final prognosis will obviously depend on the underlying etiology, the extent, and the site of the parenchymal destruction.

Ventriculomegaly Secondary to Open Spinal Dysraphisms

The prenatal sonographic approach to the examination of the normal and abnormal fetal spine has been thoroughly reported in another textbook (Paladini 2008). The reader interested in this type of defect and its evidence in the fetus may refer to that publication. Here, we report a brief summary of the basic and advanced evaluation of the fetal spine, in relation to the diagnosis of spinal dysraphisms, the related Chiari II malformation, and ventriculomegaly.

Until a few decades ago, the prenatal detection rate of spina bifida was relatively low and was based mainly on serum screening (alpha-fetoprotein). The low detection rate for spina bifida on screening ultrasound was due to the fact that it is often difficult or impossible to obtain a diagnostic view of the fetal spine because the fetus often lies with its back along the uterine wall and this makes a detailed assessment of the fetal spine challenging or impossible. Only after the recognition that indirect endocranial signs were present in >97% of cases of open spina bifida did the detection rates increased significantly (Bahlmann et al. 2015; Nicolaides et al. 1986). The indirect signs of spina bifida are those related to the Chiari II malformation. This malformation is characterized by a small posterior fossa associated with downward displacement of a dysmorphic vermis, the brainstem, and the 4th ventricle into the foramen magnum or even into the cervical spinal canal. The ultrasound diagnosis of the Chiari II malformation is based upon the recognition of a series of signs including (Fig. 60): obliteration of the cisterna magna; dysmorphic and dysplastic cerebellum featuring an abnormal anterior curvature (banana sign); frontal scalloping, which is responsible for the lemon sign; and moderate-to-severe ventriculomegaly. The frontal bossing (lemon sign) develops early, is inconstantly present (50% of the cases), and is lost in most cases by 22–24 weeks. On the contrary, obliteration of the cisterna magna and the cerebellar banana sign are the most sensitive features, with the percentage of false positives being <3% (Bahlmann et al. 2015). These signs can be found from 16 weeks of gestation until term. Ventriculomegaly is a relatively late-onset sign, and its features will be described separately below; it is found in 57% of the cases. Sonographic assessment of the fetal spine is rather difficult even today, being strongly dependent upon the fetal life. Direct sonographic recognition of the spinal defect requires systematic examination of each neural arch, from the cervical to the sacral ones, in the axial and midsagittal planes. In particular, the midsagittal plane can be used for an adequate evaluation of the cranio-caudal extension of the defect and to assess the dimensions of the myelomeningocele (Fig. 61). On axial views, it is possible to detect the interruption of the cutaneous contour at the level of the affected vertebrae, which will therefore show a “C” or “U” configuration, due to the absence of the dorsal arches (Fig. 61b). The coronal planes will demonstrate splaying of the lateral processes (Fig. 61c). The three aspects just mentioned can advantageously be demonstrated on the same panel of images using the multiplanar display allowed by three-dimensional ultrasound (Fig. 61a–c). It should be underlined that the direct recognition of the defect is not always so straightforward; in a significant number of cases, the spinal lesion is missed on initial evaluation – especially in case of myelocele or small sacral defects (Fig. 62) – and is diagnosed only because the operator has detected the previously described indirect signs at the level of the fetal head. Fortunately, even small lesions of the spine are associated with these secondary cerebral abnormalities, provided that the spinal defect is an open one. In particular, it has been demonstrated that indirect cranial signs are associated with open spinal defects in more than 97% of the cases (Bahlmann et al. 2015). Conversely, closed spinal dysraphisms are never associated with cranial signs and can only be recognized on direct inspection of the spine and only in few instances. In some cases, open spina bifida is complicated by the presence of severe abnormalities of the affected segment. In particular, the lumbosacral tract of the spine may be severely distorted, showing acute posterior convexity (Fig. 63). It should be underlined that it is possible, by two- and three-dimensional ultrasound, to recognize the level and the extent of the spinal defect very accurately, and this information is important because the level of the spinal lesion dictates to a certain extent motor and the neurofunctional outcome of fetuses with OSD; and these data can be advantageously employed during prenatal counseling sessions, when the neurosurgeon will need this piece of information to fine-tuning his/her consultation.

Associated anomalies include talipes, pyelectasis, and/or bladder distension with the latter representing signs of neurofunctional damage. The risk of chromosomal anomalies is significant (8–16%) (Kennedy et al. 1998; Sepulveda et al. 2004).

In fetuses with open spina bifida, ventriculomegaly represents a relatively late-onset sign. It appears in the late 2nd trimester in most cases (70%) and worsens thereafter (80–90%) (Fig. 64). In spina bifida, the dilated ventricles have a peculiar shape: they show a pointed frontal horn, which is rather typical. On a transventricular plane, the lateral wall of the frontal horn is therefore parallel with the frontal bone, which shows a flattened outline, consistent with the so-called lemon sign (Fig. 64). This sign, which describes the frontal scalloping, is present in roughly 50% of fetuses with spina bifida, develops early, and is lost in most cases by 24 weeks (Nicolaides et al. 1986).

In any case, a thorough assessment of the fetal brain should be warranted in fetuses with open spina bifida, because ventriculomegaly may also be related to associated CNS malformations (Fig. 65). In fact, both midline anomalies as agenesis of the corpus callosum and migration defects or also aqueductal stenosis (Fig. 66) may be associated with neural tube defects.

Conclusion

In conclusion, we have shown that the diagnosis of “hydrocephalus” cannot be made with certainty in the fetus. In prenatal life, the most used term is ventriculomegaly because this is the sign that can easily be detected and characterized, less so to ascertain whether it is due to obstruction (hydrocephalus) or not. Another concept that we have illustrated in these pages is that in prenatal life the epidemiology of CNS abnormalities is completely different in comparison with neonatal and, above all, pediatric populations. This is due to the fact that termination of pregnancy (in the countries where this option is allowed by law) and spontaneous fetal or early neonatal demise have a deep impact on the prevalence of the various pathologic conditions after birth. In the fetus, the association of ventriculomegaly with other severe CNS and extra-CNS malformations is therefore much more common that in postnatal life.

A final notation regards the issue of the normal and abnormal mechanisms of CSF circulation. In postnatal life, this mechanism is still unclear and in fact various theories have been put forward. In the fetus, the uncertainty is even more pronounced, because of the limited possibility to explore instrumentally the physiology of the CSF circulation, considering also that the Pacchioni granules, that, according to one of the most accredited theories, are considered the main clearance pathway for the CSF, are absent, until almost at the end of gestation. At the same time, with the exception of the lateral ventricles, it is rather challenging if not impossible to evaluate sonographically the Sylvian aqueduct in the fetus. This is why the literature addressing the prenatal counterpart of hydrocephalus is very scant, as mentioned in this chapter.

The take-home message for non-fetal medicine experts is that in prenatal life the overwhelming majority of cases of ventriculomegaly are secondary to other more severe congenital anomalies of the CNS in the context of chromosomal, nonchromosomal, or field developmental abnormalities.

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Fetal Medicine and Surgery Unit, G. Gaslini Children’s Hospital, Genoa, Italy
Dario Paladini & Roee Birnbaum

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Pediatric Neurosurgery, Santobono Pausilipon Children’s Hospital, Naples, Italy
Giuseppe Cinalli
Division of Pediatric Neurosurgery, Acıbadem University, School of Medicine, Istanbul, Turkey
M. Memet Özek
Pediatric Neurosurgery, Hôpital Necker-Enfants Malades Université René Descartes-Paris V, Paris, France
Christian Sainte-Rose

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Paladini, D., Birnbaum, R. (2019). Prenatal Hydrocephalus: Prenatal Diagnosis. In: Cinalli, G., Özek, M., Sainte-Rose, C. (eds) Pediatric Hydrocephalus. Springer, Cham. https://doi.org/10.1007/978-3-319-27250-4_47

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DOI: https://doi.org/10.1007/978-3-319-27250-4_47
Published: 24 April 2019
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Prenatal Hydrocephalus: Prenatal Diagnosis

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Keywords

Introduction

A Premise: The Fetus and the Cerebrospinal Fluid Circulation

The Developing Human Brain: From Embryology to Sonoembryology

Introduction

Early Organization

Brain Hemispheres

The Ventricular System and Choroid Plexus

Cortical Development

Rhombencephalon

Corpus Callosum and Cavum Septi Pellucidi

Normal Two- and Three-Dimensional Ultrasound Anatomy of the Brain and the Ventricular System in the Fetus

Ventriculomegaly and Hydrocephalus

Isolated Mild Ventriculomegaly

Severe Ventriculomegaly

Aqueductal Stenosis in the Fetus

Hydranencephaly

Ventriculomegaly and Associated Genetic Conditions

Ventriculomegaly Secondary to Other CNS Malformations

Ventriculomegaly Secondary to Acquired CNS Lesions

Ventriculomegaly Secondary to Open Spinal Dysraphisms

Conclusion

References

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