Chapter 15: PRENATAL DIAGNOSIS OF CEREBROSPINAL ANOMALIES

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 15-1). 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 15-2).^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 15-3 and 15-4).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 15-5).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 15-6). 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 15-7).⁹

In coronal planes, 1, 2, or 3 lines parallel lines are visualized, depending upon the orientation of the sound beam (Figure 15-8).

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 15-9) 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 15-9 and 15-10).^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.^{15,16, and 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 15-1).

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 15-11).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 15-12). 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.^{23,24,25, and 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 15-13). 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 15-14).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.^{30,31, and 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 15-4).

Fetal cephaloceles should be suspected when a paracranial mass is seen on sonography (Figure 15-15). 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 15-16) 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 15-17). 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 15-18). 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 15-19).^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 15-20).

Diagnosis of partial ACC has also been reported, but the sonographic findings are even more elusive than with the complete form (Figure 15-21).^41,43 The cavum septi pellucidi are usually present and the axial sections may be completely unremarkable. Identification of partial ACC requires a median section demonstrating that the posterior portion of the corpus callosum is absent. This results in the corpus callosum forming an incomplete arch over the area of the fourth ventricle. The incomplete corpus callosum also tends to be thinner and to form an angle that is more open posteriorly than usual.

Agenesis of the corpus callosum, be it complete or partial, is frequently part of a syndrome or is associated with multiple malformations (Table 15-2). As an isolated finding, ACC is usually associated with normal to borderline intellectual development.^41,44 However, long-term studies have reported a progressive decrease in intellectual capacity throughout the years, and most infants tend to have significant difficulties in school.⁴⁵ Agenesis of the corpus callosum has also been linked to psychosis.⁴⁶

Absence of the septum pellucidum is present with holoprosencephaly and agenesis of the corpus callosum. It may also occur with other intracranial anomalies, such as de Morsier syndrome or septooptic dysplasia, cortical abnormalities, and schizencephaly, or it may also be present as an isolated finding (Figure 15-22).^{37,47,48, and 49} The differential diagnosis is frequently difficult. Pediatric data suggest, however, that the prognosis is often severe, with more than 90% of cases demonstrating mental retardation and/or severe neurologic abnormalities.⁴⁹

The term Dandy-Walker syndrome or malformation was originally introduced to indicate the association of (1) ventriculomegaly of variable degree; (2) a fourth ventricle that is posteriorly open, causing superior displacement a large cisterna magna; and (3) a defect in the cerebellar vermis through which the cyst communicates with the fourth ventricle. In these cases, the axial plane demonstrates a large cisterna magna and a median V-shaped defect of the cerebellum that extends into the fourth ventricle. In the median plane, which is the most important one for the diagnosis, the cisterma magna extends superiorly, displacing the cerebellar vermis (which is frequently hypoplastic) and elevating above its normal position the tentorium cerebelli and the torcular herophili (Figure 15-23). The presence of ventriculomegaly is not essential to make the diagnosis because in many cases it has been found to develop only years after birth. Dandy-Walker malformation is frequently associated with other neural defects, mostly with other midline anomalies, such as agenesis of the corpus callosum and holoprosencephaly. Other deformities include encephaloceles, polycystic kidneys, cardiovascular defects, and facial clefting. Table 15-3 lists the most frequent associations. Even if isolated, it has been generally considered to have a poor prognosis. However, recent experience with magnetic resonance (MR) in infants suggests that those cases in which the vermis appears hypoplastic have a subnormal intelligence in 85% of cases versus only 15% of those in which the vermis appears intact.^50,51 In the original study, the cerebellar vermis was considered normal if it was possible with MR to document in the median plane 3 main anatomic landmarks: the fastigium point that corresponds to the posterior apex of the fourth ventricle and the 2 main fissures. A similar approach has also been suggested for antenatal studies. Both MR and multiplanar, possibly transvaginal, ultrasonography can be used. It is expected, however, that the small size of the vermis and the difficulty in obtaining an exact median plane will represent at times major limiting factors, particularly in early gestation.

Dandy-Walker malformation is exceedingly rare, with an estimated incidence of about 1:30,000 births, and is found in 4% to 12% of all cases of infantile hydrocephalus. However, minor variations of this condition are rather frequently encountered, as it is attested by an increasing number of reports, both in the prenatal and pediatric literature. The term Dandy-Walker complex (or continuum) is used to indicate this spectrum of abnormal findings that share in common an enlargement of the cisterna magna and/or the impression of a V-shaped cleft in the cerebellar vermis in the axial plane.^50,52,53

The Dandy-Walker complex is very frequently a part of multiple anomalies or syndromes (see Table 15-3), and it is always difficult to predict the outcome for a given fetus. When other anomalies are excluded, however, careful evaluation of the posterior fossa anatomy may orient the prognosis. If the cisterna magna depth is 10 mm and the cerebellar vermis appears intact and in its normal position, the condition is usually referred to as megacisterna magna (Figure 15-24). Although this is a risk factor for associated malformations including aneuploidies (trisomy 18 in particular)^54,55 most isolated cases are of no consequence.^8,33,52,56 If there is the impression of a V-shaped cleft in the cerebellum in the axial plane and the median plane reveals a vermis that is intact, the diagnosis is most likely a Blake pouch cyst (Figure 15-25), and the prognosis is usually good.^33,57 Conversely, a hypoplastic superiorly rotated vermis is the landmark of vermian hypoplasia (Figure 15-26), previously referred to as Dandy-Walker variant, a condition that is frequently associated with other intracranial anaomalies and carries a very high risk of abnormal neurodevelopment.^{50,51, and 52} Distinction between an intact and a hypoplastic vermis is far from simple. Under normal conditions, in the median plane it is usually possible with either sonography or MR to demonstrate the fastigium of the fourth ventricle and the 2 main fissures from about midgestation.^{50,51, and 52} With hypoplasia of the vermis these landmarks cannot be identified. Nomograms of the normal size of the vermis throughout gestation are also available (Table 15-4).⁵⁸

In our own experience, isolated megacisterna magna and Blake pouch cyst represent the bulk of the posterior fossa anomalies that are diagnosed antenatally.⁸ Although the available data are limited and the neurologic risk cannot be predicted precisely, it would seem that prognosis is usually good.

The greatest diagnostic challenge is probably represented by Joubert syndrome, an anomaly with autosomal recesive transmission that is featured by absence or hypoplasia of the vermis, which, however, is not rotated. In a pregnancy at specific risk, the condition can be suspected when a communication is seen between the fourth ventricle and a cisterna magna of normal size in the transverse plane.⁵⁹ In the absence of the vermis, the 2 hemispheres impinge on the midline, and therefore the median plane is of little use, although at times it may demonstrate a fourth ventricle of slightly irregular shape.⁵⁹ In the absence of a positive familial history, however, this finding has a very low predictive value and most cases that we have seen were found to be normal at birth.

Caution is warranted while making the diagnosis of a minor variety of the Dandy-Walker continuum. Development of the cerebellar vermis is incomplete prior to 20 weeks' gestation and this frequently creates an artifact mimicking a vermian defect.⁶⁰

In general, meticulous scanning with a multiplanar approach is recommended in cases with a suspicion of a posterior fossa anomaly. The poor correlation that has been demonstrated in several studies between antenatal diagnosis and autopsy finding is probably related to the use of only axial planes, which can be extremely misleading. In the axial plane, entities that are clinically different, such as Dandy-Walker malformation, vermian hypoplasia, and Blake pouch cyst, cannot be clearly differentiated.

As the diagnosis of midline anomalies depends upon section planes of the fetal head that are sometimes difficult to obtain, we have found that three-dimensional ultrasound is frequently of considerable help. Multiplanar slicing of a volume obtained from axial scans usually provide images of diagnostic quality.⁸

Many congenital anomalies of the brain are not the consequence of an embryogenetic malformative process, but are due to a destructive process. The pathophysiology is frequently unclear and the conditions remains idiopathic. A link with obstetric complications of a different nature is, however, frequently found.

Intracranial hemorrhage (ICH) is usually found at the level of the lateral ventricles, although it can occur in other anatomical locations. It is a frequent complication that occurs in premature infants. Although rarely, it may occur antenatally, as a consequence of coagulopathy, trauma, or other yet unexplained factors. The sonographic appearance of an intracranial hemorrage is extremely variable depending upon the severity and the time since it occurred (Figure 15-27).⁶¹ Blood accumulated into the ventricles appears initially as an echogenic collection. With time the blood clot retracts and demonstrates an anechoic core, and is frequently associated with ventricular dilatation (grade 3 hemorrhage). Large hemorrhagic collections may be complicated by infarct and destruction of the surrounding white matter (grade 4 hemorrhage).

The prognosis is severe. In a review of the literature, perinatal death occurred in about 50% of cases, and 50% of survivors had neurologic compromise at long-term follow-up. There was a correlation between the outcome and the grade of the hemorrhage. The prognosis was more favorable with grade 1 and 2 hemorrhages (hemorrhage limited to the germinal matrix or lateral ventricles without ventriculomegaly), that at times may have even resolved in utero, and was usually severe with grade 3 and 4 lesions (intraventricular hemorrage associated with severe ventriculomegaly and white matter destruction, respectively).⁶¹

Congenital porencephaly is defined as the presence of cystic cavities within the brain matter (Figure 15-28). The cavities usually communicate with either the ventricular system, the subarachnoid space, or both.⁶² Loss of cerebral tissue may derive from a morphogenetic disorder (true porencephaly or schizencephaly). More frequently, it is the consequence of an intrauterine disruption (pseudoporencephaly or encephaloclastic porencephaly). The developmental form is typically bilateral and symmetrical, and is frequently associated with microcephaly. In pseudoporencephaly a unilateral lesion is usually found. In both cases, there is a wide variability in the size of the lesion.⁶² Cerebrospinal fluid turnover is often impaired and hydrocephalus is present. Hydranencephaly can be regarded as an extreme form of pseudoporencephaly. Most of the cerebral hemispheres are replaced by fluid. The brain stem and rhomboencephalic structures are usually spared. The head may be small, of normal size, or extremely enlarged. The etiology is heterogeneous. Congenital infections including toxoplasmosis and cytomegalovirus (CMV), and intrauterine strangulation or occlusion of the internal carotid arteries have been reported. Accurate antenatal diagnosis of both schizencephaly and porencephaly has been reported. It should be stressed, however, that porencephaly is a disruption that usually occurs only in the third trimester.

The outcome of infants with congenital destructive process of the brain is dictated by the size and location of the lesion. Extensive porencephaly, particularly if associated with hydrocephalus or microcephaly, and hydranencephaly have a uniformly poor outcome.⁶²

Periventricular leukomalacia is a degenerative disorder of the white matter that is most frequently encountered in premature infants and is often associated with a severe prognosis. The cystic variety of this condition has been described recently in the fetus. The diagnosis is made by demonstrating multiple small cysts close to the upper corner of the lateral ventricles.⁶³

Intrauterine infection in general is one of the major causes of congenital brain lesions, and CMV in particular is one of the leading causes of brain damage in children. Fetuses with CMV infection affecting the brain may present with a wide range of intracranial abnormalities. The most frequent findings, in our experience, include echogenic bowel and abnormal intracranial anatomy. The cerebral findings are pleomorphic and may include periventricular and intraparenchymal echogenicity, ventriculomegaly, cerebellar hypoplasia, microcephaly, and cortical abnormalities.⁶⁴

Although the experience thus far is limited, it would seem that ultrasonography plays a limited role in the prenatal diagnosis of CMV infection. In our experience, while examining a pregnant patient with a recent infection, the positive predictive value of abnormal sonographic findings predict a symptomatic CMV infection in about only one-third of cases.⁶⁵

The association between decreased head size and reduction of both brain mass and total cell number in microcephalic infants is well established. However, the threshold of abnormalcy is uncertain. Some authors suggest employing a head circumference below –2 standard deviations from the mean as diagnostic criterion. Others prefer to consider head circumference below –3 standard deviations as abnormal. The incidence of microcephaly obviously varies in different surveys, depending upon the definition used to identify the lesion.

Microcephaly should not be considered as a single clinical entity, but rather as a symptom of many etiologic disturbances, including both environmental and genetic factors (Table 15-5). Microcephaly is featured by a typical disproportion in size between the skull and the face. The forehead is sloping. The brain is small, with the cerebral hemispheres affected to a greater extent than the diencephalic and rhomboencephalic structures. Abnormal convolutional patterns, including macrogyria, microgyria, and agyria, are frequently found. The ventricles may be enlarged. Microcephaly is frequently found in cases of porencephaly, lissencephaly, and holoprosencephaly.

Many difficulties arise in attempting to identify fetal microcephaly. The utility of head measurements alone may be hampered by incorrect dating or intrauterine growth retardation. Furthermore, the natural history of fetal microcephaly is largely unknown. A progressive development of the lesion interfering with early recognition has been described. A comparison of biometric parameters such as the head circumference:abdominal circumference ratio and the femur length:biparietal diameter ratio has been suggested. Nevertheless, both false-positive and false-negative diagnoses occur frequently.⁶⁶ It is clear that the predictive value of sonographic biometry has significant limitations. A qualitative evaluation of the intracranial structures is a very useful adjunct to biometry because many cases of microcephaly are associated with morphologic derangement, particularly with ventriculomegaly, schizencephaly, and disorders of ventral induction. Demonstration of a sloping forehead also increases the index of suspicion (Figure 15-29).⁶⁷

The final outcome of microcephaly is uncertain. Infants with a small head have a much increased risk of neurologic compromise and there is a correlation with the size of the head. When the head circumference is extremely small, 4 standard deviations or more below the mean, and/or there are associated abnormalities the prognosis tend to be severe.

Megalencephaly, that is, an abnormally large brain, is usually found in individuals of normal and even superior intelligence, but it may be associated with mental retardation and neurologic impairment.⁶⁸ Megalencephaly is also part of congenital anomalies and syndromes such as Beckwith-Wiedemann syndrome, achondroplasia, neurofibromatosis, and tuberous sclerosis. Obstetric and pediatric sonographers are frequently challenged by the problem of megalencephaly, a condition that should be suspected in the presence of abnormally large head measurements without evidence of hydrocephalus or intracranial masses. In such cases, examination of the parents may be of help, as asymptomatic megalencephaly is frequently familial.

Fetal intracranial tumors are rare. The incidence has been estimated at 0.34 per million live births. There are several classifications of congenital brain tumors (Table 15-6). In a review of 48 cases diagnosed antenatally,⁶⁹ teratomas accounted for 62% of cases. Neuroepithelial tumors were present in 15%, lipomas in 10%, and craniopharyngiomas in 6%. The origin of tumors diagnosed in utero is frequently difficult to ascertain, given the large dimensions of the mass. Most of the lesions are, however, supratentorial, in contrast to the more frequent infratentorial location of brain tumors occurring in older children.

Fetal intracranial tumors are frequently associated with macrocephaly, ventricular enlargement, intracranial calcifications, and hemorrhage. Ventriculomegaly is most frequently the cause of obstruction to cerebrospinal fluid circulation. However, overproduction of fluid may occur with teratomas and choroid plexus papillomas. Polyhydramnios is present in 40% of cases. In most cases, the mechanism is probably related to failure of swallowing, whether this is neurologically induced or is the consequence of mechanical obstruction to the pharynx. Hydrops has also been reported, most frequently as a consequence of arteriovenous shunting within the large tumoral mass, causing high-output cardiac failure. Facial dysmorphism is frequent with large tumors. There is a well-established association between interhemispheric lipomas and agenesis of the corpus callosum. No associations between fetal and neonatal tumors with chromosomal aberrations have been described.

A brain tumor is suspected when mass-occupying lesions, cystic areas, or solid areas are seen within the fetal head (Figure 15-30). Ultrasonography does not allow a specific diagnosis of the histologic variety. Fetal teratomas, astrocytomas, and craniopharyngiomas have a similar appearance, which is a complex mass distorting the brain architecture, possibly associated with macrocephaly, ventriculomegaly, and intracranial calcifications. Intracranial lipomas have well-defined echogenic areas that are usually located in the midline, in the position normally occupied by the corpus callosum, and/or within the bodies of lateral ventricles. Eventually, choroid plexus papillomas appear as large choroid plexuses, most frequently in association with ventriculomegaly and subarachnoid space enlargement.⁶⁹

The natural history of fetal brain tumors is uncertain. The available data suggest, however, that even very severe lesions may develop rapidly in late gestation. In fact, several cases have been reported in which midtrimester sonograms were unremarkable. Teratomas may be associated with increased maternal serum and amniotic fluid AFP.

The differential diagnosis of brain tumors includes other space-occupying intracranial lesions. At times, it may be particularly challenging to distinguish between a tumor and fresh intraparenchymal hemorrhage. Cerebral hemorrhages usually lack the mass effect that is found with tumors. Serial sonograms (in 2 to 3 weeks) are helpful for a specific diagnosis, as the most severe intracranial hemorrhages are expected to result in cavitation, ventriculomegaly, and blood clot formation. Antenatal MRI may also be helpful, particularly using T1 weighted sequences that are specific for blood collections.

The prognosis of congenital tumors is poor. A review of 48 cases found an overall mortality rate of 77%.⁶⁹ No clear data are available with regard to the degree of neurological impairment in survivors, but this is expected to be high as well. The histologic type of the specific tumor is certainly a major factor. In a postnatal series, the 1-year survival rate of teratomas was only 7%, compared with 44% of astrocytomas and 50% of choroid plexus papillomas. There are many limitations to the antenatal diagnosis of the specific tumor type. However, large, complex masses that are associated with distorted intracranial anatomy (usually teratomas, astrocytomas, or craniopharyngiomas) were found to have an overall survival rate of only 14%. On the other hand, intracranial lipomas, which have a specific ultrasound appearance, were associated with a survival rate of 100% and no developmental handicap.⁶⁹

The neuronal cells that form the gray matter originate internally to the brain, on the surface of the lateral ventricles, and only later migrate along radially aligned glial cells to the surface of the brain. The migration occurs in different waves that last for several weeks. Most of the process takes place between 8 and 16 weeks' gestation, but continues up to 25 weeks. Once the neuronal cells have reached their destination on the surface of the brain, they undergo a process of maturation and differentiation, grow axons and dendrites, and develop synapses with other neurons, giving rise to a well-ordered, 6-layer cortex. Migration abnormalities are characterized by the incomplete formation of cortical layers, with abnormal locations of neurons that have failed to reach their final destination. In general, the cortex is thickened by a large, disorganized layer of neurons. Conversely, the white matter underneath the cortex is thinned by failure of production of axons by the disorganized neuronal cells. Macroscopically, the main finding is an alteration in the convolutional pattern of the brain, which may be associated with modifications in brain mass and size of the ventricles.

Failure of neuron migration includes a broad spectrum of anomalies: absence to severe reduction of convolutions (lissencephaly), increased number of small convolutions (polymycrogyria), unilateral megalencephaly, schizencephaly, and gray matter heterotopias. The migrational process may be arrested by environmental factors (ischemia, teratogens), but a genetic predisposition is clearly present at least for some anomalies.

Postnatally, the technique of choice for the diagnosis of this condition is MR, which allows a clear discrimination between white and gray matter. Sonographic detection of typical macroscopic abnormalities of brain anatomy (clefts in the cortex, gyral anomalies, etc) can provide important clues for their prenatal detection, although usually only in late gestation.⁷⁰

Vascular anomalies of the fetal brain are rare, and only a handful of cases have been described thus far. The majority of reports concentrates on the vein of Galen vascular malformations.

The term aneurysm of the vein of Galen indicates a spectrum of arteriovenous malformations, ranging from a single, large aneurysmal dilatation of the vein of Galen to multiple communications between the vein and the carotid and vertebrobasilar systems.⁷¹ Three types are described: (1) arteriovenous fistula, (2) arteriovenous malformation with ectasia of the vein of Galen, and (3) varix of the vein of Galen. The arteriovenous fistula is frequently manifested in the fetal or neonatal period with high-output heart failure due to cardiac overload. Both the ectasia and the varix tend to present later in life with bleeding episodes and are not associated with cardiac failure. Arteriovenous fistulae associated with a varix are not part of the definition when they are located elsewhere in the brain.

Prenatally, the typical finding is an elongated anechoic area at the level of the cistern of the vein of Galen, with color and pulsed Doppler evidence of turbulent venous and/or blood arterial flow (Figure 15-31).⁷² The cerebral architecture may be intact, or it may be distorted because of the concomitance of ventriculomegaly, porencephaly, and/or brain edema, which is inferred by increased echogenicity of the cortex. The dural sinuses and neck vessels are frequently enlarged, and signs of cardiac overload may be present, including cardiomegaly, epatosplenomegaly, soft tissue edema, polyhydramnios, and hydrops. Color Doppler sonography may help in identifying the origin of the vessels feeding the lesion, an observation that may have practical implications for assessing the prognosis. MR has also been used in these cases.

Although vein of Galen aneurysms may become symptomatic in the elderly, they are more frequently seen in the neonatal period. The common clinical features in the neonate are cardiomegaly with congestive heart failure, and increased intracranial pressure with hydrocephaly or cranial bruit. Focal neurological deficit, seizure, and hemorrhages are less commonly found. The available experience with prenatal diagnosis suggests a mortality rate in the range of 50%, and normal development in about 50% of survivors.^62,72,73 The outcome was strongly dependent upon the antenatal evidence of other intracranial abnomalities (hydrocephalus, brain edema, porencephaly) and/or hydrops. In the presence of any of these findings, the prognosis was always poor. In general, cases with a normal postnatal development had isolated vascular lesions, without cerebral or cardiovascular compromise in utero, and were treated after birth using angiographic embolization.⁷³

Intracranial arachnoid cysts are accumulations of clear cerebrospinal-like fluid between the dura and the brain substance. The histologic diagnosis is not always available and the term is frequently used to indicate any intracranial cyst located in the subarachnoid space.

Arachnoid cysts have been found anywhere in the central nervous system including the spinal canal. The most frequent locations are the surface of the cerebral hemispheres in the sites of the major fissures (sylvian, rolandic, and interhemispheric), the region of sella turcica, the anterior fossa, and the middle fossa. Less frequently, they are seen in the posterior fossa. Most of the cases diagnosed antenatally involve supratentorial cysts in the midline, sylvian fissure, and ambient cistern. Arachnoid cysts may be primary (congenital) or secondary (acquired). Congenital types are believed to be formed by maldevelopment of the leptomeninges and do not freely communicate with the subarachnoid space. Acquired types are formed as the result of hemorrhage, trauma, and infection, and often communicate with subarachnoid space. Arachnoid cysts have the potential to grow as the result of either some communication with the subarachnoid space from a ball valve mechanism or cerebrospinal fluid production by a choroid plexus-like tissue contained within the cyst wall. Large arachnoid cysts can cause obstructive ventriculomegaly by compressing the foramen of Monro, the aqueduct posteriorly, or blocking the basal cisterns. Hydrocephalus and macrocephaly are the most common presentations in the neonatal period. Arachnoid cysts have been reported very rarely in association with other anomalies. The list includes trisomy 18, tetralogy of Fallot, sacrococcygeal tumor, and neurofibromatosis.

Ultrasound examination of arachnoid cysts demonstrates a well-defined anechoic lesion with adjacent mass effect, occasionally associated with hydrocephalus (Figure 15-32). The overall majority of arachnoid cysts diagnosed in utero thus far have been recognized only in the third trimester. In a few cases, unremarkable sonograms had been obtained in the midtrimester. It is therefore likely that most of these lesions develop only in late gestation. Differentiating fetal arachnoid cysts from other intracranial fluid collections may be difficult at times. However, in the largest available series, multiplanar brain imaging and vaginal sonography of vertex fetuses were found to be extremely effective.⁶² Porencephalic cysts are located inside the brain substance, whereas arachnoid cysts lie between the skull and brain surface. Furthermore, the majority of congenital porencephalic cysts communicate with the lateral ventricles. In schizencephaly, the fluid-filled collection connects the lateral ventricles to the subarachnoid space.

A posterior fossa arachnoid cyst is distinguished from the Dandy-Walker complex by demonstrating the integrity of the cerebellar vermis. Another useful clue is the demonstration that arachnoid cysts tend to be laterally positioned and result in an asymmetric posterior fossa.

In many cases, arachnoid cysts are asymptomatic, but they may cause epilepsy, mild motor or sensory abnormalities, or hydrocephalus. Hydrocephalus and macrocephaly are the most common presentations in the neonatal period.

The neurosurgical series generally suggest a good prognosis, with absence of symptoms in more than 70% of cases. The location of the cyst has influence on the final outcome. In one series, the temporal cysts were found to have the best outcome, with more than 90% of patients recovering completely or with only slight deficits, and there were no deaths. The other locations were associated with a significantly lower success rate. In particular, posterior fossa arachnoid cysts had the worst outcomes.^74,75

Glioependymal cysts are thought to derive from displaced neuroectodermal tissue and have the same sonographic appearance of arachnoid cysts.⁷⁶ Differentiation between these 2 entities is usually possible only on the basis of histologic examination. The diagnosis of a gliopendymal cysts should, however, be favored when the cyst is in the midline and is associated with agenesis of the corpus callosum. The distinction may not be clinically relevant, as it is uncertain whether the prognostic implications are different.

Choroid plexus cysts appear as round sonolucent areas in the context of the choroid plexus of lateral ventricles (Figure 15-33). They have been described with increasing frequency over the last years. Survey of low-risk pregnant patients indicates that the frequency of this finding in the midtrimester is in the range of 1%. However, the real incidence is probably dependent upon the resolution of the ultrasound equipment, the attention of the operator, and the definition of choroid plexus cyst that is employed. On average, the incidence in most studies is in the range of 1%. However, figures as high as 3.6% have been reported.^77,78

Choroid plexus cysts may be unilateral or bilateral, and occasionaly are multiple. They are typically found at the level of the atrium of lateral ventricles, less frequently within the bodies. When examined with high-resolution ultrasound equipment, the choroid plexus of lateral ventricle often appears slightly inhomogeneous. Choroid plexus cysts should measure at least 2 mm in diameter. Large cysts up to 14 mm may be seen, and usually contain internal septations.

The diagnosis of a choroid plexus cyst is readily made in the majority of cases by noting the typical location within the atria of lateral ventricles, with a normal appearance of the surrounding fetal brain. The only problem that can be encountered at times is differentiating a large choroid plexus cyst slightly distending the cavity of a ventricle from primary ventriculomegaly. In such cases, the most important clue is the demonstration that choroid plexus cysts have a thick echogenic wall and tend to have internal septations. In dubious cases, a follow-up scan may be useful as most choroid plexus cysts usually rapidly decrease in size and even disappear with advancing gestation. A localized intraventricular bleed may result in a blood clot resembling an abnormality of the choroid plexus. However, the clot is less regular than a choroid plexus cyst and the surrounding ventricle is usually enlarged.

Fetal choroid plexus cysts are benign findings that are, however, associated with an increased likelihood of trisomy 18. The available data do not indicate an association with other chromosomal aberrations, including trisomy 21.^79,80 In 80% to 90% of fetuses with trisomy 18, anatomic deformities will be detected by ultrasound.⁵⁵ On the basis of these data a prudent approach is to perform a thorough sonographic examination of the fetus when a choroid plexus cyst is identified. This examination should include evaluation of the hands and feet, and a thorough examination of the fetal heart. If an additional ultrasound abnormality is identified, chromosomal analysis should be offered to the patient. Otherwise, the patient may be counselled with the figures suggested by Snijders and coworkers,⁸⁰ which is that the risk of trisomy 18 is increased 1.5 times over the baseline. Additional reassurance can be obtained by correlating ultrasound findings with serum biochemical markers.

From time to time, suggestions have been made that the risk of aneuploidy is related to the size of the cyst, whether it is unilateral or bilateral, whether it is persistent or disapperars. From the available literature, no evidence supports any of these suggestions. Small cyst, unilateral cyst, and transient cyst have all been documented in association with aneuploidies.

Isolated choroid plexus cysts do not modify standard obstetrical management. As no deleterious effect on the fetus has been thus far reported with this finding, there is no need in our opinion for follow-up scans. A handful of very large cysts of the choroid plexuses causing intracranial hypertension has been described in the neurosurgical literature, but these represent probably a separate clinical entity.⁸¹

Modern ultrasound equipment yields a unique potential for the evaluation of the normal and abnormal fetal central nervous system. A large number of congenital anomalies can be consistently recognized. Transvaginal sonography is extending antenatal diagnosis to very early gestation MR and can be used to improve the accuracy of the diagnosis in seleceted cases.

Nevertheless, there are many limits to the prenatal diagnosis of CNS anomalies. Some studies of low-risk patients undergoing basic examinations have reported sensitivities in excess of 80%.^25,82 However, these results probably greatly overestimate the diagnostic potential of the technique. These surveys had invariably very short follow-up and almost all only included open neural tube defects, whose recognition was probably facilitated by systematic screening with maternal serum AFP. Pitfalls of prenatal ultrasonography are well documented and occur for a number of reasons. One of the most important limitations is related to continuing brain development in the second half of gestation and into the neonatal period, which limits the detection of anomalies such as microcephaly and cortical malformations. Furthermore, some cerebral lesions are not due to faulty embryological development but represent the consequence of acquired prenatal, perinatal, and postnatal insults. Even in expert hands some types of anomalies may be difficult or impossible to diagnose in utero, in a proportion that is yet impossible to determine with precision.⁸³

On the other hand, prenatal counseling and development of a practical obstetric management plan are frequently difficult under these circumstances. Some cerebral anomalies have outcomes that can be predicted with reasonable precision. This is certainly the case with catastrophic lesions such as anencephaly and severe holoprosencephaly, as well as with anomalies that are invariably detected at birth, such as spina bifida. There is, however, a large number of conditions that can be accurately identified in utero and yet have an unclear natural history. Agenesis of the corpus callosum, mild ventriculomegaly, and minor variations of the Dandy-Walker continuum are remarkable examples of this scenario.

Highlighted References