Central nervous system (CNS) malformations are some of the most common congenital abnormalities. Neural tube defects are the CNS malformations most frequently encountered at birth and amount to about 1 to 2 cases per 1000 births. The incidence of intracranial abnormalities with an intact neural tube is uncertain as probably most of these escape detection at birth and only become manifest in later life. Long-term follow-up studies suggest, however, that the incidence may be as high as 1 in 100 births.¹

The CNS was probably the first major organ system to be investigated in utero by diagnostic ultrasonography. Since then, the investigation of the fetal neural axis has steadily remained a central issue of antenatal sonography. There are a number of reasons for such an interest. Central nervous system anomalies are frequent and often have a severe prognosis. In many cases they have a genetic background, and as a consequence of this there are a large number of couples at specific risk that demand antenatal diagnosis. Modern high-resolution ultrasound equipment yields a unique potential in evaluating normal and abnormal anatomy of the fetal neural axis from very early stages of development. Yet identification of selected anomalies remains a challenge in many cases.

In recent years, fetal magnetic resonance imaging (MRI) has emerged as a promising new technique that may add, in selected cases, important information,^2,3 although the real advantage over ultrasonography remains less defined.^4,5 In this chapter, the sonographic investigation of the fetal brain and the identification of CNS anomalies is reviewed.

Transvaginal high-frequency high-resolution probes reveal fine details of the developing cerebrum (Figure 18-1). Starting from 7 weeks, menstrual age, the primary cerebral vescicles can be identified with transvaginal sonography as fluid-filled areas. From 11 weeks’ gestation, the brightly echogenic choroid plexuses filling the large lateral ventricles are the most prominent intracranial structures. In the second trimester, a detailed sonographic examination of the already well-developed cerebral structures is feasible, allowing the detection of most anomalies. However, the results of an obstetric sonogram greatly depend upon the level of expertise of the sonographer and the time dedicated to the scan. In evaluating the fetal brain, a distinction must be made between a basic examination (frequently referred to as a level 1 scan or standard scan) and a fetal neurosonogram (or level 2 examination). The basic scan is fundamentally a screening exam for low-risk patients, and there is a general consensus that it is conveniently carried out by 2 or 3 axial views of the head, demonstrating the lateral ventricles, basal ganglia, and posterior fossa (Figure 18-2).^6,7 Measurement of the biparietal diameter, head circumference, and internal diameter of the atrium is recommended. Some also advocate measurement of the transverse cerebellar diameter and/or cisterna magna depth.

A fetal neurosonogram is a diagnostic exam, usually performed in a patient at increased risk of fetal anomalies, and may include coronal and sagittal views of the head that are more difficult to obtain, but have the advantage to better delineate subtle details of intracranial anatomy, particularly by using a vaginal probe in vertex fetuses (Figures 18-3 and 18-4).⁷ Three-dimensional ultrasound is a useful adjunct to the bidimensional examination in that it allows visualization of scanning planes that are difficult or impossible to obtain directly (Figure 18-5).⁸

The examination of the fetal spine requires expert and meticulous scanning, and the results are heavily dependent upon the fetal position. Sonography demonstrates the ossification centers of the vertebrae (1 inside the body, 1 at the junction of the lamina and pedicle on each side) that appear brightly echogenic. Three types of scanning planes can be used to evaluate the integrity of the spine.

In transverse planes, the vertebrae have different anatomic configurations (Figure 18-6). Fetal thoracic and lumbar vertebrae have a triangular shape, with the ossification centers surrounding the neural canal. The first cervical vertebrae are quadrangular in shape, and sacral vertebrae are flat. Examination of the spine is a dynamic process. While using the axial approach, the ultrasound transducer is swept along the entire length of the spine.

In sagittal planes, the ossification centers of the vertebral body and posterior arches form 2 parallel lines that converge in the sacrum. When the fetus is prone, a true sagittal section can also be obtained, directing the ultrasound beam across the unossified spinous process. This allows visualization of the neural tube, and of the neural cord within it. In the second and third trimester of gestation, the conus medullaris is usually found at the level of L2-L3 (Figure 18-7).⁹

In coronal planes, 1, 2, or 3 lines parallel lines are visualized, depending upon the orientation of the sound beam (Figure 18-8).

Integrity of the neural canal is inferred by the regular disposition of the ossification centers of the spine and the presence of soft tissue covering the spine. If a true sagittal section can be obtained, visualizing the conus medullaris in its normal location further strengthens the diagnosis of normalcy.

In the basic examination, a longitudinal view of the spine should always be demonstrated. However, a detailed evaluation is complex, and usually requires an experienced examiner.¹⁰

Enlargement of the lateral cerebral ventricles (Figure 18-9) can be regarded as a nonspecific marker of abnormal brain development, and is encountered with many different cerebral anomalies. Evaluation of the integrity of the cerebral lateral ventricles is therefore of particular importance while screening for fetal brain anomalies. Although many different approaches to the evaluation of the integrity of lateral ventricles have been proposed, measurement of the internal width of the atrium of the lateral ventricle at the level of the glomus of the choroid plexus is currently favored (Figures 18-9 and 18-10).^7,11 Under normal conditions the measurement is less than 10 mm, while a value of more than 15 mm indicates severe ventriculomegaly, which almost always is associated with an intracranial malformation at birth. The outcome of these fetuses is variable and depends largely upon the underlying etiology of the ventricular dilatation. The available studies suggest that fetuses with isolated severe ventriculomegaly have an increased risk of perinatal death and a probability of severe neurologic sequelae in the range of 50% of survivors.¹² An intermediate value of the atrial width, 10 to 15 mm, is commonly referred to as mild ventriculomegaly and is associated with a much increased probability of cerebral and extracerebral malformations, aneuploidies, and infections, and therefore should be carefully evaluated by a center with examiners who have experience in fetal neurosonology. Fetuses with isolated mild ventriculomegaly usually have a good outcome and the ventricles typically return to normal size throughout gestation. However, these infants run an increased risk of neurologic compromise, and some fetal cases can develop severe cerebral anomalies during later pregnancy or after birth, including hydrocephalus, white matter injury, and cortical plate abnormalities.¹³ The risk is particularly increased when the atrial width is greater than 12 mm, when the dilatation affects both lateral ventricles, and in females.¹³ It has been suggested that the term mild ventriculomegaly should be limited only to cases with atrial measurements of 10 to 12 mm, while values of 13.1 to 15 mm should be referred to as moderate ventriculomegaly, as they tend to have, in general, a worse outcome.¹⁴

Congenital hydrocephalus may have genetic ramifications. However, antenatal ultrasonography is unreliable for predicting the recurrence of isolated ventriculomegaly, and particularly of the X-linked variety, because enlargement of the lateral ventricles often develops late in gestation or after birth. DNA analysis for the X-linked variety is now available and should be considered, although the exact sensitivity remains uncertain.^15-17

The average incidence of neural tube defects is 1 to 2 in 1000 births, with a peak of 7 in 1000 in South Wales.¹ The multifactorial etiology of these anomalies is well established, and the birth of an affected child carries an increased risk to future offspring (Table 18-1).

Anencephaly is characterized by the absence of the cranial vault and telencephalon. Necrotic remnants of the brain stem and rhomboencephalic structures are covered by a vascular membrane. Associated malformations are common and include spina bifida, cleft lip palate, club foot, and omphalocele. Polyhydramnios is frequently found. The diagnosis is easy in the second and third trimester, and relies upon the demonstration of the absence of the cranial vault. Although the fetal head can be positively identified by vaginal sonography as early as the seventh week of gestation, the diagnosis may be difficult in the first trimester. Anencephaly is considered to be the final stage of acrania, as a consequence of disruption of abnormal brain tissue unprotected by the calvarium.¹⁸ A cephalic pole, albeit overtly abnormal, is therefore usually present in early gestation, and may be difficult to identify prior to 11 weeks’ gestation (Figure 18-11).¹⁹

Spina bifida is commonly subdivided into open and closed forms.²⁰ Open spina bifida is predominant at birth and is a full-thickness defect of the skin, with underlying soft tissues and vertebral arches exposing the neural canal. The defect may vary considerably in size. The lumbar, thoracolumbar, or sacrolumbar areas are most frequently affected. Leakage of cerebrospinal fluid through the defect causes an increased concentration of α-fetoprotein (AFP) in the amniotic fluid and maternal serum.¹⁰ Closed spina bifida is characterized by a vertebral defect that is covered by skin. The skin overlying the defect is rarely intact, and it is usually pigmented, dimpled, or associated with hypertrichosis. A subcutaneous mass, a meningocele or lipoma, may be present. Maternal serum and amniotic fluid AFP are usually within normal limits.²¹

Open spina bifida can be identified sonographically by demonstrating the defect of the neural tube that is constantly associated with separation of the posterior processes of the vertebra, and absence of posterior soft tissues. Most frequently, a cyst formed by the fusion of the malformed cord and meninges (myelomeningocele) is found. In a minority of cases the neural canal is open posteriorly without a covering membrane (myelocele) (Figure 18-12). Prenatal recognition has been reported as early as the first trimester.²² However, in everyday practice, the diagnosis remains difficult, even at midgestation, and always requires meticulous scanning. The experience of the operator, the quality of the equipment, and the amount of time dedicated to the scan continue to represent critical factors. The accuracy of referral centers is close to 100%.¹⁰ The sensitivity of routine nontargeted examinations at midgestation is extremely variable in different studies, and is probably about 40% when sonography is the only method and about 80% when sonography is used in conjunction with maternal serum AFP screening.^23-26 Examination of the fetal head can assist the sonologist, because open spina bifida is consistently associated with an easily recognizable cranial lesion.^27,28 Leakage of cerebrospinal fluid leads to displacement of the cerebellar vermis, fourth ventricle, and medulla oblongata through the foramen magnum inside the upper cervical canal (Chiari type II or Arnold-Chiari malformation). Sonographically this results in small head measurement at midgestation, obliteration of the cisterna magna, small size and abnormal shape of the cerebellum that is impacted deep into the posterior fossa (banana sign), and scalloping of the frontal bones (lemon sign) (Figure 18-13). Hydrocephalus of variable degrees is present in virtually all cases of spina bifida aperta at birth, but in less than 70% of cases in the midtrimester.^27,28

Closed spina bifida is associated with normal intracranial anatomy and normal AFP, and is therefore usually unpredictable, with the possible exception of cases associated with demonstrable subcutaneous lesions, such as meningoceles or, more frequently, lipomas (Figure 18-14).²¹

Anencephaly is invariably fatal. The outcome for infants with open spina bifida is dictated by the site and extension of the lesion. The mortality remains high in the long term, and many of the survivors will suffer from significant disabilities such as lower limb paralysis or dysfunction and incontinence.²⁹ Recently, attempts have been made at intrauterine repair of spina bifida, and it has been suggested that these operations may reduce the morbidity of the affected infants. It has been suggested that elective cesarean section may be beneficial to the infants, reducing the rate of neurologic complications and particularly the level of motor paralysis.³⁰ These results, however, remain a matter of debate.^30-32

The outcome of closed spina bifida is difficult to predict. These infants usually do not develop Arnold-Chiari malformation and hydrocephalus. Those with subcutaneous masses particularly, however, may suffer from neurologic sequelae of variable entity that are usually the consequence of tethering or compression of the spinal cord.³³

The term cephalocele indicates a protrusion of intracranial contents through a bony defect of the skull. In most cases, the lesion arises from the midline occipital area, and less frequently through the parietal or frontal bones. Encephaloceles are characterized by the presence of brain tissue inside the lesion. When only meninges protrude, the term “cranial meningocele” should be used. Cephaloceles often cause impaired cerebrospinal fluid circulation and hydrocephalus. Massive encephaloceles may be associated with microcephaly. Cephaloceles are frequently associated with other anomalies and/or are part of a syndrome (Table 18-4).

Fetal cephaloceles should be suspected when a paracranial mass is seen on sonography (Figure 18-15). The diagnosis of encephalocele is easy, as the presence of brain tissue inside the sac is striking on the sonogram.^34,35 Differentiation of a cranial meningocele from soft tissue edema or a cystic hygroma of the neck may be difficult. Demonstration of the bony defect in the skull would allow a proper diagnosis, but cranial meningoceles are often associated with extremely small (a few millimeters) defects that are not generally detectable using antenatal sonography. Indirect clues can assist the diagnosis. Cranial cephaloceles are very often associated with ventriculomegaly. Cystic hygromas arise from the region of the neck, have multiple internal septations and a thick wall, and are often associated with generalized soft tissue edema and hydrops.

The pediatric literature suggests that the outcome of cephaloceles is mainly related to the presence or absence of brain tissue inside the lesion. The largest available antenatal series, however, reports a dismal prognosis for both varieties.^34,35

Midline cerebral anomalies include a group of brain defects that encompass a wide spectrum of severity and are typically associated with craniofacial malformations.

The holoprosencephalies are complex abnormalities of the forebrain that share in common an incomplete separation of the cerebral hemispheres and formation of diencephalic structures.³⁶ The most widely accepted classification of these disorders (Figure 18-16) recognizes 4 major varieties: the alobar, semilobar, and lobar types, plus the more recently described middle interhemispheric variant. In the alobar variety, the most pronounced type, the interhemispheric fissure and the falx cerebrii are totally absent, there is a single primitive ventricle (holoventricle), the thalami are fused on the midline, and there is absence of the third ventricle, neurohypophysis, olfactory bulbs, and tracts. In semilobar holoprosencephaly, the 2 cerebral hemispheres are partially separated posteriorly, but there is still a single ventricular cavity. In both the alobar and semilobar forms, the roof of the ventricular cavity, the thela choroidea, normally enfolded within the brain, may balloon out between the cerebral convexity and the skull to form a cyst of variable size—the dorsal sac. Alobar and semilobar holoprosencephaly are often associated with microcephaly, and less frequently with macrocephaly, which is invariably due to internal obstructive hydrocephalus. In the lobar variety, the interhemispheric fissure is well developed posteriorly and anteriorly, but there is still a variable degree of fusion of the cyngulate gyrus and of the lateral ventricles, and absence of the septum pellucidum. In the middle interhemspheric variant of holoprosencephaly, fusion occurs mostly at the level of the bodies of lateral ventricles, while the frontal horns and posterior horns are relatively well developed.³⁷

Alobar and semilobar holoprosencephaly are typically and almost constantly associated with facial anomalies that can be regarded as the consequence of hypoplasia of the midfacial structures. The malformations span between cyclopia and severe hypotelorism with median cleft lip–palate. The nose can be absent, replaced by a proboscis, or be extremely flattened.³⁶ Conversely, facial anomalies are rarely encountered in the lobar form and middle interhemispheric variant.

Holoprosencephaly at birth is exceedingly rare. This anomaly has a high intrauterine fatality rate and is infrequently encountered in prenatal studies. The etiology is heterogeneous. In most cases, the anomaly is isolated and sporadic. In other cases, chromosomal abnormalities have been found (trisomy 13 and polyploidy) and/or anatomic abnormalities are found.

Prenatal diagnosis of alobar holoprosencephaly depends upon the demonstration of a single rudimentary cerebral ventricle that may protrude posteriorly through the incompletely enfolded cortex to form a dorsal sac (Figure 18-17). Additional findings include the presence of typical facial anomalies. Similar findings are expected with the semilobar type. The middle interhemispheric variant of alobar holoprosencephaly is characterized by relatively well-formed frontal horns that are fused on the midline without intervening septum pellucidum, and communicate posteriorly with a single rudimentary cavity (Figure 18-18). Recognition of the lobar variety has also been reported, although the differentiation from other cerebral anomalies such as the simple agenesis of the septum pellucidum is always difficult. This condition may be suspected in axial views, mainly because of an absent septum pellucidum with ventriculomegaly. However, the coronal scan is most informative because it demonstrates the flat, squared roof of the frontal horns, as well as an ample inferior communication with the inferior third ventricle. The presence of fused fornices, which appear as a linear structure running within the third ventricle from the anterior to the posterior commissure, is a frequent and very specific finding with this condition (Figure 18-19).^38,39

The invariably poor prognosis for infants affected by alobar and semilobar holoprosencephaly is well established. Thus far, cases diagnosed in utero with lobar holoprosencephaly also had extremely poor neurologic development.^38,40

Agenesis of the corpus callosum (ACC) is an anomaly of uncertain prevalence and clinical significance. Estimates of 0.3% to 0.7% in the general population and 2% to 3% in the developmentally disabled are usually quoted. The etiology is heterogeneous. Genetic factors are probably predominant. The high frequency of associated malformations and chromosomal aberrations suggest that ACC is often part of a widespread developmental disturbance.

Agenesis of the corpus callosum may be either complete or partial. In the latter case, also referred to as dysgenesis of the corpus callosum, the caudad portion (splenium and body) is missing to varying degrees.

The diagnosis of agenesis of the corpus callosum is possible from midgestation⁴¹ but is a challenge even for expert sonologists.⁴² With complete agenesis of the corpus callosum there is no septum pellucidum, the 2 hemispheres tend to be more separated than usual in the central part of the brain, and there are typical modifications in the morphology of the lateral ventricle. In the coronal section, the frontal horns are more distant than usual and have a “comma” shape, while in the transverse plane the lateral ventricle has a “teardrop” shape that is due to the combination of the posterior enlargement of the atria and occipital horn with frontal horns that have a normal size but are more separated than usual. In routine examinations an increased atrial width with a typical “teardrop configuration” of the lateral ventricles and/or failure to visualize the cavum septum pellucidum should alert the possibility of fetal ACC. Once a suspicion has been formulated, a direct diagnosis is possible by demonstrating the absence of the corpus callosum by coronal and sagittal scans (Figure 18-20).