Introduction

The fetal brain develops during the course of pregnancy, from its primitive three-vesicle stage into a complex structure with an array of sulci and gyri resembling the adult brain by the end of gestation [Nadich et al., 1994]. Fetal brain development is characterized by well-defined, genetically programmed, morphological and maturational changes, including neuronal migration, sulcation, and myelination that can be studied by ultrasound, starting from gestational week 6–7 until delivery [Ertl-Wagner et al., 2002]. Fetal magnetic resonance imaging (MRI) enables good demonstration of anatomy, particularly of cortical development and diagnosis of diverse anomalies, starting at around 18–20 weeks of pregnancy.

Sonography is the most important imaging method for prenatal malformation screening. It is noninvasive, widely available, and safe for both mother and child. The ultrasonographic approach to the evaluation of the fetal brain is based on the transabdominal visualization of three different axial planes: the transventricular, the transthalamic, and the transcerebellar (Figure 29-1). The use of these three planes enables good visualization of the lateral ventricles but is not sufficient for depiction of malformations of the cortex and of midline brain structures, mainly the corpus callosum, the third ventricle, and the cerebellar vermis [Malinger et al., 2007]. The use of a more comprehensive, multiplanar approach, in which coronal and sagittal planes are added to the classical axial planes, and addition of a transvaginal or transfundal approach overcome these limitations [Malinger et al., 1993] (Figure 29-2 and Figure 29-3).

Fig. 29-1 Ultrasound: axial sections of the fetal brain at 16 weeks of gestation.

A, Transventricular plane. B, Transthalamic plane. C, Transcerebellar plane. CP, choroid plexus; LV, lateral ventricle; 1, thalamus; 2, aqueduct of Sylvius; 3, middle cerebellar peduncles; 4, cerebellum; 5, cavum septi pellucidi.

Fig. 29-2 Ultrasound: coronal sections of the fetal brain at 25 weeks of gestation.

A, Transfrontal plane. B, Transcaudate plane. C, Transthalamic plane. D, Transcerebellar planes. 1, superior sagittal sinus; 2, interhemispheric fissure; 3, lateral ventricle; 4, genu of the corpus callosum; 5, head of the caudate; 6, anterior fontanel; 7, corpus callosum; 8, cavum septi pellucidi; 9, periventricular vascular hyperechogenicities; 10, sylvian fissure; 11, thalamus; 12, hippocampus; 13, cerebellum.

Fig. 29-3 Ultrasound: sagittal sections of the fetal brain at 25 weeks of gestation.

A, Midsagittal plane. B, Parasagittal plane. C, caudate; CP, choroid plexus; O, orbit; T, thalamus; 1, genu of the corpus callosum; 2, body of the corpus callosum; 3, splenium of the corpus callosum; 4, cavum septi pellucidi; 5, cavum interpositi; 6, choroid plexus of the third ventricle; 7, basal cistern; 8, pons; 9, fourth ventricle; 10, vermis; 11, cisterna magna; 12, anterior horn of the lateral ventricle; 13, occipital horn of the lateral ventricle; 14, temporal horn of the lateral ventricle; 15, periventricular vascular hyperechogenicities; 16, caudothalamic groove.

Fetal MRI is used primarily to confirm and characterize brain abnormalities detected by routine prenatal sonography. More than 25 years after its introduction into fetal imaging, MRI is considered a valuable complementary tool in the imaging of structural anomalies of the fetal brain [Guibaud, 2009; Sonigo et al., 1998].

Implementation of fast and ultrafast sequences has allowed reduction of acquisition time, which has subsequently decreased artifacts resulting from fetal movement and allowed one to obtain good-quality images. Fetal MRI has higher contrast resolution than prenatal sonography and may allow better differentiation of normal from abnormal tissue.

Fetal MRI is performed primarily using ultrafast MRI techniques known as single-shot, fast spin-echo (SS-FSE) or half-Fourier acquired single-shot turbo spin-echo (HASTE). Using these rapid-pulse sequences, a single T2-weighted image can be acquired in less than 1 second, reducing the likelihood of fetal motion during image acquisition [Brugger et al., 2006; Glenn and Barkovich, 2006]. When the fetal brain is being evaluated, images are obtained with a section thickness of 3 mm with no gap, in axial, sagittal, and coronal planes. Good orthogonal planes may not always be obtainable.

T1-weighted imaging and fast multiplanar gradient recalled-echo techniques, such as FMPSPGR (fast multiplanar spoiled gradient recalled acquisition in the steady state), are primarily used to detect hemorrhage or calcification [Glenn and Barkovich, 2006].

With the recent application of advanced MRI techniques, an opportunity to investigate the developing brain is available beyond the qualitative morphologic evaluation [Limperopoulos and Clouchoux, 2009; Glenn, 2009]. Diffusion-weighted imaging (DWI) and diffusion tensor imaging (DTI) are used to evaluate maturation-dependent microstructural changes associated with brain growth and development of cerebral white matter. DWI provides quantitative information about water motion and tissue microstructure, and provides additional applications for destructive brain processes. DTI allows the visualization and quantification of white-matter fiber direction. Advanced postprocessing techniques, such as the formation of high-resolution three-dimensional structural images, can be used to study morphometry [Glenn, 2009]. MR spectroscopy can be applied in the third trimester for the study of cerebral metabolism in vivo, since metabolites such as N-acetyl aspartate, creatine, and choline can be detected [Limperopoulos and Clouchoux, 2009].

The dynamic stages of fetal brain development can be imaged accurately with ultrasound and fetal MRI. An understanding of embryologic aspects of brain development and their correlative appearance on ultrasound and MRI is critical in order to be able to diagnose structural brain defects prenatally.

Prenatal Assessment of Normal Brain Development in the First Trimester

Brain development in the embryonic phase is only assessed by ultrasound. Blaas and Eik-Nes [2009] describe the milestones of normal brain development between 7 and 12 weeks’ gestation based on longitudinal two-dimensional and three-dimensional ultrasound studies. Cortical development starts at about 7 weeks’ gestation and other brain structures develop synchronously with the cortex, including the commissures and the cerebellum. At 7–8 weeks, the lateral ventricles are seen as separated, small, round hypoechogenic brain cavities, and the future third ventricle runs posteriorly. The curved tube-like mesencephalic cavity (future sylvian aqueduct) lies anteriorly, and the broad and shallow rhombencephalic cavity is in the cranial pole of the embryo (Figure 29-4).

Fig. 29-4 High-resolution transvaginal ultrasound (12 MHz probe).

A. Axial plane at 8 weeks of gestation. B, Sagittal plane at 8 weeks of gestation. C, Axial plane at 13 weeks of gestation. 1, telencephalic supraventricle; 2, aqueduct; 3, rhombencephalon; 4, tectum; 5, rhomboencephalon choroid plexus; 6, upper medulla; 7, pontine flexure; 8, eye; 9, cortical rim; 10, lateral ventricle choroid plexus; 11, third ventricle; 12, fourth ventricle.

By the end of the first trimester (weeks 10–12), the cortex is about 1–2 mm thick and the crescent hemispheres fill the anterior part of the head and conceal the diencephalic cavity. The lateral ventricles are large and filled by the echogenic choroid plexuses. The insula appears as a slight depression on the lateral surface of the hemispheres. The diencephalon lies between the hemispheres, and the mesencephalon gradually moves towards the center of the head. The width of the third ventricle narrows. The corpus callosum is not yet visible. The cerebellar hemispheres seem to meet in the midline [Blaas and Eik-Nes, 2009].

Major structural defects, particularly malformations of dorsal induction and prosencephalic development that are usually severe or lethal, can be identified in first-trimester studies. Examples of these anomalies include acrania, anencephaly, craniorachischisis, iniencephaly, holoprosencephaly, and encephalocele.

Prenatal Assessment of Normal Development of the Cortex

Initially, the brain surface is smooth. Gyration can be observed by the second month of intrauterine life. It continues to the end of the pregnancy and even later after birth. The primary sulci appear as shallow grooves on the surface of the brain that become progressively more deeply infolded and then develop side branches, designated secondary sulci. Gyration proceeds with the formation of other side branches of the secondary sulci, referred to as tertiary sulci [Nadich et al., 1994]. The major fissures and sulci develop in predictable patterns, starting at about 16 weeks [Dorovini-Zis and Dolman, 1997], and therefore the timing of their appearance is a reliable estimate of gestational age. Anatomical changes precede ultrasound and MRI detection by about 2 weeks [Levine and Barnes, 1999] (Table 29-1).

Several studies [Toi et al., 2004; Cohen-Sacher et al., 2006] have assessed the development of the fetal cortex by ultrasound. Major sulci can be discerned, starting at about 18–19 weeks’ gestation. At 18–20 weeks, the brain surface is almost completely smooth, with only the major fissures present. The callosal sulcus is observed between 18 and 20 weeks. Between 22 and 26 weeks, the calcarine fissure, the cingulate sulcus, and the central sulcus gradually appear. The most active period of cortical development, as demonstrated by ultrasound, is between 28 and 30 weeks. During this time, most sulci become detectable. After 32 weeks, all structures, other than the insular and olfactory sulci, are present. During the last 4 weeks of pregnancy, the sulci over the convexity are best demonstrated using sagittal planes [Cohen-Sacher et al., 2006] (see Table 29-1). Early sulci are easier to evaluate by ultrasound than later-developing complex secondary and tertiary patterns [Malinger et al., 2006].

MRI after about 20 weeks of gestation provides excellent information unimpeded by calvarial calcification. Similar to ultrasound, it shows age-related predictable patterns of development, but, in addition, brain parenchyma and myelination can be evaluated [Garel et al., 2001].

Brain MRI can depict the walls of the ventricles, which are critical to normal brain development. They are lined by the ventricular zone (germinal matrix), which is very thick earlier in gestation, and appears as a smooth band of dark T2 signal and bright T1 signal lining the lateral ventricles. The cerebral mantle is seen on fetal MRI until about 28 weeks of gestation in a multilayered pattern [Kostovic and Vasung, 2009]. When viewed from the ventricular margin to the pial surface of the brain, five layers can be demonstrated (Figure 29-5).

Fig. 29-5 Magnetic resonance imaging at 23 weeks demonstrates five layers.

1, Ventricular zone – the innermost layer of the cerebral mantle, lining the lateral ventricles; it appears dark on T2-weighted images (short single arrow). 2, Periventricular fiber-rich zone – this is located just superficial to the ventricular zone and is a thin area of increased T2 (two arrows). 3, Subventricular and intermediate zones – the subventricular zone and intermediate zone (site of the fetal white matter) lie superficial to the periventricular zone and appear as a fairly homogeneous band of slightly hypointense T2 (three arrows). 4, Subplate zone – this appears as a band of hyperintense T2 (four arrows). 5, Cortical plate – the developing cortex appears dark on T2-weighted images, and is similar in signal intensity to the germinal matrix (long single arrow).

The development of the cortex can be visualized from midpregnancy. On MRI, gyration starts with the appearance of a shallow indentation of the fetal brain in the temporal regions at the 18th gestational week. At the same time, the anterior cingular fissure and the parieto-occipital fissure occur. The central sulcus begins to be visible at 24 weeks’ gestation. Fissures then become deeper and tighter, and gyri bulge into the subarachnoid space. Until the 35th gestational week, all primary and most of the secondary sulci are present, with secondary sulci appearing from the 24th gestational week, and tertiary after the 28th gestational week [Garel et al., 2001; Prayer et al., 2006] (see Table 29-1; Figure 29-6).

Fig. 29-6 Magnetic resonance imaging: axial images at different weeks of gestation.

Normal development of sulcation and normal “closure” of the insula are demonstrated.

The development of the sylvian fissure is one of the major brain maturational processes occurring in fetal life, and abnormalities in this process are frequent in children with developmental delay. The appearance and shape of the sylvian fissure can be evaluated both by ultrasound and MRI [Lerman-Sagie and Malinger, 2008; Garel et al., 2001; Chen et al., 1995]. It is observed in all fetuses at 22–23 weeks’ gestation as a shallow depression at the surface of the brain, and the insula is wide open at this time. The temporal lobe folds over to engulf the insula, and the progressive closure begins posteriorly and extends anteriorly. By 33 weeks’ gestation, insular sulci are recognizable and the surface of the Sylvian fissure becomes more and more indented [Garel et al., 2001; Quarello et al., 2008].

Prenatal Assessment of Normal Development of the Corpus Callosum

The corpus callosum develops between gestational weeks 8 and 20 as axons from the developing cerebral hemispheres navigate to and through the hemispheres and interhemispheric fissure. The corpus callosum is difficult to visualize by ultrasound during the performance of routine transabdominal evaluations using axial planes. For a complete demonstration of this structure, it is necessary to obtain sagittal planes through the anterior or posterior fontanels or the sagittal suture with the transvaginal or transfundal approach. Coronal planes are useful for studying the relationship between the corpus callosum and neighboring structures. The completely formed corpus callosum may be depicted using high-resolution transducers by 18–20 weeks of gestation, as an arched hypoechogenic structure delimited by the more echogenic callosal sulcus cranially and the anechogenic cavum septi pelucidi caudally. At this age, its shape is already very similar to that of the mature corpus callosum, and the genu, body, and splenium can be well demonstrated (see Figures 29-2 and 29-3). The corpus callosum develops in a linear pattern during pregnancy, its length progressively increasing from 20 mm at 20 weeks to 40 mm close to term. Nomograms of callosal growth during pregnancy, including length and thickness, can be used to assess normal development [Malinger et al., 1993].

The corpus callosum can be depicted by MRI on midline sagittal T2 images by gestational week 20 as a band of low signal intensity superior to the fornix (Figure 29-7). It can also be seen on coronal T2 images. It has fairly uniform thickness [Toi et al., 2009].

Fig. 29-7 Magnetic resonance imaging: midsagittal image of normal corpus callosum.

Note the very sharp posterior border (splenium) relative to the indistinct anterior corpus (genu).

Prenatal Assessment of Normal Development of the Posterior Fossa

Both ultrasound [Malinger et al., 2001] and MRI [Glenn, 2009; Adamsbaum et al., 2005] can evaluate the development of the fetal cerebellum.

The ultrasonographic evaluation should include multiplanar images of the cerebellum. The axial plane is useful for determining the transcerebellar diameter, cisterna magna size, and the cerebellar peduncle’s thickness. The coronal plane enables differentiation between the cerebellar hemispheres and the vermis. The midsagittal plane is the most important plane to be investigated, since it allows depiction of the vermian lobules, fissures, and shape of the fastigium; measurements of the vermian diameter and surface; and calculation of the ratio between the superior and inferior parts. This plane also permits evaluation of the size and shape of the pons, cisterna magna, and tentorium [Malinger et al., 2001].

The cerebellar vermis can be detected in the midsagittal plane as early as 18 weeks of gestation. The midsagittal anterior–posterior diameters increase in a linear fashion, from nearly 10 mm at 20–21 weeks’ gestation to 24 mm at term.

The cerebellar vermis measurements and calculations (midsagittal anterior–posterior and craniocaudal diameters, circumference, and surface area) correlate linearly with gestational age, biparietal diameter, head circumference, and transverse cerebellar diameter.

The primary fissure is observed between 27 and 30 weeks of pregnancy. Some degree of differentiation between lobules is possible, starting from 30–32 weeks of gestation.

The fourth ventricle is uniformly observed as a triangular structure anterocaudal to the vermis. The inferior lobe of the vermis and the nodulus separate the fourth ventricle and the cistern magna [Malinger et al., 2001].

MRI is highly accurate in illustrating the morphologic MRI biometry of cerebellar development [Adamsbaum et al., 2005; Triulzi et al., 2005]. The cerebellar vermis is best assessed by MRI on direct midline sagittal images and on coronal images; the measurements should be compared with established norms. The cerebellar hemispheres are best assessed on nonoblique axial and coronal views.

Fetal MRI shows gestational age-specific changes in signal intensity in the normal development and maturation of the cerebellar hemispheres and brainstem [Huisman et al., 2002]. The cerebellar cortex, dentate nucleus, tectum, dorsal pons, and medulla are T1-hyperintense and T2-hypointense. The changes in signal intensity in the brainstem and cerebellum are not encountered until 20–23 weeks of gestation. By 26–27 weeks of gestation, a three-layered pattern is noted in the cerebellar hemispheres, corresponding to the cerebellar cortex, cerebellar white matter, and dentate nucleus. Fetal brain MRI can show the fissures of the cerebellum, depending on the gestational age. The primary fissure is identified on sagittal images at 22 weeks but the cerebellar surface is smooth. From 24 to 29 weeks, foliation of the vermis and posterior lobes of the cerebellum is seen on sagittal images. The cerebellar surface is smooth, with the appearance of some indentations corresponding to the horizontal and secondary fissures on axial images. The convoluted pattern of the cerebellum is well identified from 30 weeks on and is always seen beyond 33 weeks. [Fogliarini et al., 2005a].

Posterior fossa anatomy is sufficiently well defined in order to diagnose most cerebellar abnormalities prenatally; however, there may be many pitfalls in the differentiation of normal and abnormal cerebellar development [Malinger et al., 2009; Limperopoulos et al., 2008].

Prenatal Diagnosis of Ventriculomegaly

Assessment of the width of the atria of the lateral cerebral ventricles is recommended as part of the routine anomaly scan. Enlargement of the fetal lateral ventricles is the most common indication for referral for dedicated neurosonography and MRI, since it may be a sign of a possible brain anomaly.

The lateral ventricle should be measured by ultrasound in the axial plane, at the level of the frontal horns and cavum septi pellucidi, with the calipers positioned at the level of the internal margin of the medial and lateral wall of the atria, at the level of the glomus of the choroid plexus, on an axis perpendicular to the long axis of the lateral ventricle [ISUOG guidelines, 2007].

Ventriculomegaly is defined as a lateral ventricular width equal to or larger than 10 mm [ISUOG guidelines, 2007]. Fetal ventriculomegaly may be classified as mild when the lateral ventricular width is between 10 and 15 mm, and severe when larger than 15 mm; it may be unilateral or bilateral (Figure 29-8).

Fig. 29-8 Ultrasound: ventriculomegaly.

A, Mild at 34 weeks of gestation. B, Severe at 22 weeks of gestation. Note that the choroid plexus (CP) of the proximal ventricle has moved into the distal ventricle due to disruption of the septi pellucidi (*).

Ventriculomegaly is defined as isolated if there is no sonographic evidence of associated malformations or markers of aneuploidy at the time of the initial presentation. Isolated mild ventriculomegaly represents a diagnostic and counseling difficulty, as it can be an apparently benign finding, but can also be associated with chromosomal abnormalities, congenital infection, cerebral vascular accidents or hemorrhage, and other fetal cerebral and extracerebral abnormalities; it may also have implications regarding long-term neurodevelopmental outcome [Melchiorre et al., 2009]. Therefore, upon confirmation of ventriculomegal, a complete search for associated central nervous system and non-central nervous system anomalies should be attempted, including a study of the brain in a multiplanar approach with particular attention to the shape of the ventricles, periventricular white matter, sulcation, corpus callosum, and posterior fossa [Malinger et al., 2006]. The investigation should also include screening for in utero infection, amniocentesis, and fetal echocardiography. Many studies have indicated that MRI may add important information to that obtained by ultrasound imaging [Ouahba et al., 2006]. Information relevant enough to modify obstetric management can be obtained in 6–9 percent of cases, including cortical malformations, absence of the septum pellucidum, partial agenesis of the corpus callosum, and agenesis of the cerebellar vermis [Salomon et al., 2006; Valsky et al., 2004].

Follow-up examinations at 3–4-week intervals are indicated to assess progressive enlargement of ventricles or to diagnose associated pathologies not previously detected [Ouahba et al., 2006].

When mild ventriculomegaly is isolated, the outcome is usually good [Ouahba et al., 2006; Melchiorre et al., 2009]. However, the risk for abnormal outcome increases when there are associated anomalies, the ventriculomegaly is asymmetric, the atrial width is greater than 12 mm, or there is a progressive increase of the lateral ventricular width [Pilu et al., 1999; Sadan et al., 2007; Falip et al., 2007]. A false-negative diagnosis of associated anomalies is possible in up to 12.8 percent of cases [Melchiorre et al., 2009].

The outcome of severe ventriculomegaly depends mainly on the presence of associated pathologies. When associated pathologies are diagnosed, the prognosis is usually very poor. Even when isolated, the risk of perinatal death or severe neurologic sequelae is in the range of 50 percent of survivors [Kennelly et al., 2009].

Prenatal Diagnosis of Abnormalities of the Corpus Callosum

Developmental abnormalities of the corpus callosum include agenesis, hypogenesis (or partial agenesis), dysgenesis, hypoplasia, and secondary destruction [Glenn and Barkovich, 2006]. Agenesis of the corpus callosum (ACC) can be detected prenatally by routine sonography, for which the important signs include absence of the cavum septum pellucidum, colpocephaly, high-riding third ventricle, widening of the interhemispheric fissure, and radiating medial hemispheric sulci. Ultrasound can also depict an abnormally thick corpus callosum, which usually signifies a poor prognosis [Lerman-Sagie et al., 2009].

Fetal MRI is clinically helpful in suspected cases of ACC because it can confirm the absence of the corpus callosum and diagnose associated anomalies. Since the corpus callosum is not myelinated in utero, it can often be very difficult to distinguish on sagittal images, so agenesis of the corpus callosum can often be concluded from an altered shape of the lateral ventricles with straight anterior horns and colpocephalic posterior horns (Figure 29-9).

Fig. 29-9 Magnetic resonance imaging: complete agenesis of the corpus callosum.

A, Coronal image at 26 weeks, with multicystic dysplasia of the interhemispheric meninges and overriding third ventricle. B, Axial image of a different fetus at 30 weeks demonstrates colpocephaly with parallel ventricles.

ACC is rarely isolated. Additional abnormalities occur frequently (93 percent). The most common findings are sulcation and posterior fossa abnormalities. Abnormal sulcal morphology can be detected as early as 19 gestational weeks. The gyral abnormalities include polymicrogyria, lissencephaly, pachygyria, schizencephaly, and other nonclassified abnormalities [Tang et al., 2009].

Interestingly, in 10 percent of fetuses with ACC, there may be evidence of destructive changes in the brain parenchyma, suggesting either an acquired etiology or a genetic/metabolic abnormality [Prasad et al., 2009].

Prenatal Diagnosis of Malformations of Cortical Development

Although the migration process terminates around the end of the first half of pregnancy, malformations of cortical development are seldom diagnosed in utero, possibly because the time of appearance of significant morphological changes is beyond the recommended time of the anatomic scan (19–23 weeks), and because ultrasound evaluation of the brain is often limited to visualization of the lateral ventricles and cerebellum [Malinger et al., 2004].

Abnormal sulcation landmarks can be observed as early as the 22nd week of gestation in fetuses suffering from Miller–Dicker and Walker–Warburg lissencephaly [Fong et al., 2004]. In patients with migration disorders, the ultrasound usually demonstrates one of the following patterns: delayed or premature appearance of sulcation; a thin and irregular cortical mantle; wide abnormal overdeveloped gyri; wide opening of isolated sulci, nodular bulging into the lateral ventricles, cortical clefts, and intraparenchymal echogenic nodules [Malinger et al., 2007; Malinger et al., 2006] (Figure 29-10).

Fig. 29-10 Ultrasound findings in fetuses with malformations of cortical development.

Transvaginal parasagittal views. A, Ultrasound at 16 weeks of gestation shows the presence of an abnormal gyrus (arrowhead) and brain tissue bulging into the lateral ventricle (arrow). B, Ultrasound at 25 weeks of gestation shows thin cortical mantle with irregular surface (arrow) consistent with cobblestone lissencephaly. Transvaginal frontal coronal views. C, Ultrasound at 34 weeks of gestation shows lack of normal sulcation in a fetus with type 1 lissencephaly. D, Ultrasound at 26 weeks of gestation in a fetus with tuberous sclerosis presenting with multiple cardiac rhabdomyomata and discrete parenchymal nodules (arrows).

A definitive diagnosis is hard to reach prenatally; ultrasound can identify abnormal migration but cannot definitively differentiate between different pathologies.

MRI may identify cortical malformations more accurately, particularly late in pregnancy. The imaging signs suggestive of abnormal sulcation are mild ventriculomegaly associated with delayed cortical development, dysgenesis of the sylvian fissure, delayed sulcal appearance, callosal abnormality, cortical thickening, heterotopias, absence or abnormal appearance of fissure, irregular, abnormal, asymmetric gyri, and noncontinuous cortex in schizencephaly [Guibaud et al., 2008; Fong et al., 2004].

Chen et al. [1995] defined abnormal patterns of operculization and divided them into five types. Further studies [Quarello et al., 2008] have proven that, when the operculum is unformed or abnormally formed, the prognosis is usually poor and an underlying malformation of cortical development may be detected. When the operculum is underdeveloped for gestational age, it is usually associated with an abnormal head circumference or other brain anomalies. When it is an isolated finding, it may represent a metabolic disease, chromosomal anomaly, or benign delayed maturation of the operculum, usually associated with macrocephaly and enlargement of the subarachnoid spaces.

Prenatal Diagnosis of Lissencephaly Type I

Fetuses with lissencephaly type 1 or Miller–Dieker syndrome can be diagnosed after 27–30 weeks’ gestation when most of the primary sulci are already present, either by detailed neurosonography or MRI, by demonstration of dysgenesis of the sylvian fissure, delayed sulcal appearance, callosal abnormality, and cortical thickening [Saltzman et al., 1991; Greco et al., 1991] (see Figure 29-10C and Figure 29-11). Sometimes, zones of normal cortex and zones of pachygyric or agyric cortex alternate. The bilateral opercular dysplasia is responsible for a figure-eight-shaped brain [Fong et al., 2004].

Fig. 29-11 Magnetic resonance imaging: lissencephaly type 1 at 33 weeks of gestation.

A, Axial ultrasound with agyria and thick cortex (arrow). B, Parasagittal MRI confirming thick featureless cortex (arrow). C, Axial MRI demonstrating “figure of eight” configuration.

Mild ventriculomegaly and delayed sulcal development are the earliest signs and can be diagnosed by 23 weeks’ gestation in fetuses at risk [Malinger et al., 2004]. Fetuses with Miller–Dieker syndrome have abnormal parieto-occipital and sylvian fissures by the time of the second-trimester ultrasound examination [Malinger et al., 2004]. Fluorescence in situ hybridization (FISH) or mutation analysis for 17p13.3 abnormalities helps confirm the diagnosis.

Prenatal Diagnosis of Cobblestone Complex/Lissencephaly Type 2

The prenatal diagnosis of Walker–Warburg syndrome has been reported in families at risk [Crowe et al., 1985; Rodgers et al., 1994]. An early diagnosis in the first trimester may be made if there is a cephalocele [Crowe et al., 1985]. Other findings suggestive of lissencephaly type 2 are early enlargement of the lateral ventricles, abnormal vermis, retinal detachment [Farrell et al., 1987], cataract, and abnormal sulcation [Monteagudo et al., 2001].

The presence of abnormal sulcation may only be demonstrated during the third trimester. MRI can better visualize the posterior fossa and gyration [Gasser et al., 1998; Kojima et al., 2002], and can demonstrate a kinked brainstem and bifid pons [Strigini et al., 2009; Mitchell et al., 2000] (see Figure 29-10B and Figure 29-12).

Fig. 29-12 Magnetic resonance imaging: lissencephaly type 2/Walker–Warburg syndrome.

A and B, Sagittal and coronal images at 34 weeks demonstrate pathognomonic “z”-shaped (kinked) brainstem with severe ventricular dilatation and abnormal sulcation. C. Coronal postnatal MRI confirming a typical cobblestone cortex. Note abnormal white matter.

(Courtesy of Dr. Chen Hoffman.)

Prenatal Diagnosis of Periventricular Nodular Heterotopia

Periventricular nodular heterotopia should be considered when ultrasound depicts an irregular lateral ventricular wall with indentations of periventricular tissue and a signal similar to that of the cortex (see Figure 29-10A). The sonographic diagnosis is difficult, particularly when the lateral ventricle width is normal. MRI demonstrates multiple small nodular subependymal foci of low signal intensity, isointense to the germinal matrix, similar to that of the gray matter, located in the margins of the lateral ventricles (Figure 29-13). They cannot be distinguished reliably from the subependymal nodules seen in tuberous sclerosis; therefore, it is important to search for other manifestations of tuberous sclerosis, such as cortical hamartomas (which are hypointense compared with normal unmyelinated white matter) and cardiac rhabdomyomas [Glenn and Barkovich, 2006] A mega cisterna magna, which can be seen in females with filamin A mutations, may be the initial abnormality and, in association with periventricular nodules, may suggest the prenatal diagnosis of periventricular nodular heterotopia [Mitchell et al., 2000; Bargallo et al., 2002].

Fig. 29-13 Magnetic resonance imaging: periventricular heterotopias at 25 weeks of gestation.

A and B, Parasagittal and axial images demonstrate multiple hypointense, subependymal nodules bulging into ventricles.

Heterotopia may be not recognized when the nodules are small or subcortical. Large nodules may be confused with tumoral or hemorrhagic masses [Onyeije et al., 1998].

Prenatal Diagnosis of Polymicrogyria

The cortical changes of polymicrogyria take place late in pregnancy and appear as localized and/or generalized absence of normal sulcation with multiple abnormal infoldings of the affected cortex [Glenn and Barkovich, 2006]. It is more apparent on MRI than ultrasound. In young fetuses (24 weeks), the identification of the cortical malformation is quite difficult and the manifestations in both ultrasound and MRI are subtle. They include presence of sulci that are not as expected, according to the gestational age; an irregular surface of the brain; and absence of the normal signal of the cortical ribbon (Figure 29-14). Late in pregnancy, the MRI features are similar to what is known in the postnatal period: packed and serrated microgyri, irregular cortex–white-matter junction, and an aberrant and asymmetrical sulcal pattern [Fogliarini et al., 2005a]. The most frequent MRI presentation diagnosed in utero demonstrates mild ventricular dilatation associated with numerous sulci in the perisylvian area, with irregular cortex–white-matter junction and a prominent subarachnoid space overlying the cortical malformation. Since the MRI pattern of polymicrogyria changes with increasing gestational age, it is important to follow young fetuses and repeat the ultrasound and MRI examinations in order to confirm the diagnosis.

Fig. 29-14 Magnetic resonance imaging: bilateral frontal polymicrogyria.

A, Fetal MRI at 28 weeks demonstrates subtle irregularity of the frontal cortex with subtle abnormal operculum bilaterally. B, Postnatal axial T2 MRI demonstrates diffuse, mildly thickened, irregular, frontal cortex extending into the insula.

Prenatal Diagnosis of Schizencephaly

Prenatal ultrasound enables diagnosis of schizencephaly, although prenatal MRI is more specific in detection of the gray matter lining the defect, communication with the ventricle, and other associated structural abnormalities [Oh et al., 2005]. The prenatal diagnosis of schizencephaly depends on the extent of cleft separation; closed-lip and open-lip variants with a very small gap remain undiagnosed. The prenatal diagnosis of schizencephaly has been described as early as 21 weeks. Fetuses are usually diagnosed after a routine ultrasound examination demonstrates enlarged lateral ventricles, fluid-filled cavities, or absence of the cavum septum pellucidum [Malinger et al., 2007]. Neurosonography demonstrates bilateral or unilateral open-lip wedge-shaped defects, usually in the parietotemporal regions, frequently accompanied by absence of the cavum septum pellucidum. Fetal MRI shows schizencephalic clefts extending from the pial surface to the ventricle lined with gray matter, which is seen as a low-signal-intensity line covering the edge of the remaining brain parenchyma (Figure 29-15). This finding allows differentiation of the defect from porencephaly [Oh et al., 2005; Denis et al., 2001].

Fig. 29-15 Magnetic resonance imaging: open-lip schizencephaly.

Wide gray matter-lined cavity connecting the ventricle with the extra-axial space.

Prenatal Diagnosis of Posterior Fossa Anomalies

Infratentorial anomalies are usually diagnosed in utero when associated with an enlarged cisterna magna, with or without an abnormal fourth ventricle. The suspicion of abnormal cerebellar development is usually raised following the visualization of a small cerebellum or a large communication between the fourth ventricle and the cisterna magna, using the transcerebellar axial plane [Malinger et al., 2006]. Severe anomalies, such as Arnold–Chiari malformation type 2, Dandy–Walker malformation [Oh et al., 2005; Denis et al., 2001], and cerebellar hypoplasia, are usually detected during routine second-trimester ultrasound examinations. However, prenatal diagnosis of isolated cerebellar and/or vermian anomalies may be difficult because of the complexity of normal development of these structures.

A systematic approach to the posterior fossa is recommended in order to enable differentiation between normal and abnormal development [Guibaud and des Portes, 2006; Adamsbaum et al., 2005]. Understanding the anatomy is vital to avoid misdiagnosis and to characterize the abnormalities accurately. Confirmation of the diagnosis necessitates the visualization of the cerebellum in the coronal planes, and a true midline sagittal picture of the vermis, brainstem, and fourth ventricle. Particular care should be taken in order to differentiate between the vermis and the cerebellar hemisphere in cases of suspected vermian agenesis or hypoplasia. Visualization of the normal triangular shape of the fourth ventricle, and of the primary vermian fissure, facilitates exclusion of vermian pathologies [Denis et al., 2001]. Vermian agenesis may also be part of the molar tooth-associated syndromes.

The in utero diagnosis of the pontocerebellar hypoplasias [Klein et al., 2003] necessitates measurements of the pons circumference in addition to the cerebellar dimensions.

In cases of diagnostic uncertainties, a follow-up examination is pertinent, since a false positive diagnosis of vermian agenesis may be made before 24 weeks of pregnancy, due to delayed closure of the fourth ventricle owing to a persistent Blake pouch cyst [Robinson and Goldstein, 2007], and cerebellar hypoplasia may be missed early in pregnancy because the arrest of growth occurs later [Malinger et al., 2009].

A dysplastic cerebellum, which refers to disorganized development, such as an abnormal folial pattern or the presence of heterotopic nodules of gray matter, is rarely diagnosed in utero, even by MRI, since it does not produce signal abnormalities [Tilea et al., 2007]. However, in most cases of posterior fossa anomalies, there is good agreement between fetal MRI and fetopathological results.

Prenatal Diagnosis of Dandy–Walker Malformation

Prenatal diagnosis of Dandy–Walker malformation is usually possible during the second trimester; midsagittal planes enable visualization of the abnormal vermis, the communication between the fourth ventricle and the enlarged cisterna magna, and the elevated torcula (Figure 29-16C). It should not be confused with partial vermian agenesis, in which there is a large communication between the fourth ventricle and the cisterna magna without elevation of the torcula (Figure 29-16B and Figure 29-17C). Dandy–Walker malformation may be associated with other central nervous system anomalies, such as callosal dysgenesis, occipital encephalocele, polymicrogyria, or heterotopias, so these should be sought. Hydrocephalus may only develop late in pregnancy or postnatally.

Fig. 29-16 Ultrasound of cerebellar pathologies, midsagittal planes.

A, Ultrasound of normal vermis at 23 weeks of gestation; the arrow indicates the primary fissure. B, Ultrasound at 22 weeks of gestation; fetus with a small vermis and large fourth ventricle (arrow). C, Ultrasound at 22 weeks of a fetus with classical Dandy–Walker malformation; the arrow shows the elevated tentorium.

Fig. 29-17 Magnetic resonance imaging of various cerebellar pathologies.

A, Mega cisterna magna, 31 weeks. B, Joubert’s syndrome, 32 weeks. C, Partial vermian agenesis, 24 weeks. D, Rotation of a normal vermis in a fetus with persistent Blake’s pouch; the arrow shows the apparently large fourth ventricle, 24 weeks.

The prognosis following a prenatal diagnosis of Dandy–Walker malformation is variable; however, the presence of a normally lobulated vermis and the absence of associated brain anomalies are associated with a more favorable outcome [Bolduc and Limperopoulos, 2009].

Prenatal Diagnosis of Rhombencephalosynapsis

Ultrasound diagnosis of rhombencephalosynapsis is generally suspected after 22 weeks of gestation, and usually the abnormality is suggested by ventriculomegaly [Pasquier et al., 2009]. The diagnosis is raised, following demonstration of a small transcerebellar diameter. Ultrasound and MRI both demonstrate a hypoplastic, single-lobed cerebellum with fused cerebellar hemispheres, no vermis, and transverse folia (Figure 29-18). Associated cerebral abnormalities are usually found and include additional midline defects, such as aqueductal stenosis leading to hydrocephalus, holoprosencephaly, corpus callosum dysgenesis, and septo-optic dysplasia. Extracranial anomalies include segmentation and fusion anomalies of the spine, musculoskeletal anomalies, and cardiovascular, respiratory, and urinary tract defects. Rhombencephalosynapsis may be frequently associated with VACTERL-H (vertebral anomalies, anal atresia, cardiac defects, tracheoesophageal fistula, esophageal atresia, renal anomalies, hydrocephalus) syndrome [Pasquier et al., 2009].

Fig. 29-18 Magnetic resonance imaging: rhombencephalosynapsis.

A, Axial view at 31 weeks demonstrates small continuous folia of the cerebellum, “diamond-shaped.” B, Sagittal view shows lack of the normal primary fissure and fastigium.

It is important to emphasize that coronal and axial planes are superior for diagnosis of rhombencephalosynapsis, since a midline sagittal cut through the cerebellum can be mistaken for a vermis. A narrow diamond-shaped fourth ventricle and a fused horseshoe-shaped dentate nucleus are the features seen on axial MRI planes. Sagittal views, when carefully interpreted, can demonstrate the lack of visualization of the primary vermian fissure and lack of a normal fastigial point of the fourth ventricle [McAuliffe et al., 2008].