PRENATAL DIAGNOSIS Prenat Diagn 2009; 29: 326–339. Published online 10 November 2008 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/pd.2146

REVIEW

Normal sonographic development of the central nervous system from the second trimester onwards using 2D, 3D and transvaginal sonography

Ana Monteagudo* and Ilan E. Timor-Tritsch Division of Obstetrical and Gynecological Ultrasound, Department of Obstetrics and Gynecology, Professor of Obstetrics and Gynecology, NYU School of Medicine, 530 First Avenue NB9N26, New York, NY 10016, USA

The developmental changes of the fetal central nervous system (CNS) during the second and third trimesters, specifically the brain, relate mostly to changes in size. However, other changes do occur in the fetal brain during the second and third trimester such as: the union of the cerebellar hemispheres, development of the corpus callosum (CC), and increasing complexity of the cerebral cortex. These changes follow a well-defined developmental timeline recognizable by sonography. The fetal neuroscan can be divided into a ‘basic scan’ which is performed transabdominally and a ‘targeted Exam or neurosonogram’ which uses a multiplanar approach, which preferably should be performed transvaginally. During the ‘basic scan’, several brain structures are imaged in addition to obtaining important biometric measurements. The ‘neurosonogram’ is a more extensive or detailed fetal study during which the emphasis is on the addition of coronal and sagittal planes. The easiest way to obtain these planes, if the fetus is in a cephalic presentation, is the transvaginal route. Three-dimensional (3D) sonography should, if possible, be performed transvaginally using the multiplanar approach. An added benefit of 3D sonography is the ability to display and render the volume in a variety of ways which may enhance the detection of pathology. Copyright  2008 John Wiley & Sons, Ltd.

KEY WORDS: neurosonography; transvaginal sonography

INTRODUCTION drawback of the transvaginal technique was that the axial plane could rarely be imaged and that serial sections had to be obtained one at a time. At present, volume scanning Sonography is the best and most used tool to docu- (3D sonography) allows us to scan transabdominally or ment, study and understand the anatomy, pathology and transvaginally, obtaining images in all three classic scan- developmental changes of the fetal central nervous sys- ning planes and thus giving us the ability to view the tem (CNS). Over the past 30 years, as the technology brain through serial sections in all three classic planes has evolved so has our understanding and our ability as well as in any other desired planes of our choice to image the fetal brain. When the first ultrasound (US) (Monteagudo et al., 2000). In addition, several post- machines were introduced, the bony skull was the first to processing features assist us in highlighting pathology be imaged; this enabled the development of nomograms that may not be otherwise obvious. Therefore, in current of fetal growth. Since at that time only transabdomi- obstetrical scanning, especially as it relates to the fetal nal probes were used, the fetal brain was studied using CNS, multiple technical approaches are simultaneously only or mostly the axial planes. One major draw back used (i.e. 2D and 3D transabdominal and transvaginal was that as the gestational age increased, the density sonography). (ossification) of the cranial bones increased; therefore, the hemisphere close to the transducer appeared blurred permitting to study mainly the hemisphere distal to the probe which was clearly imaged. The introduction of the THE FIRST TRIMESTER transvaginal probes allowed us to place the transducer in close proximity to the head and obtain coronal and sagit- tal views through the acoustic window provided by the A detailed description of the CNS in the first trimester is fontanels and sutures. This way both hemispheres could not the central topic of this review; however, before we be seen simultaneously (Monteagudo et al., 1991). The proceed several important issues about the development of the CNS necessary to set the stage for this review should be mentioned. *Correspondence to: Ana Monteagudo, Division of Obstetrical The first trimester ends at the 14th week of the and Gynecological Ultrasound, Department of Obstetrics and Gynecology, Professor of Obstetrics and Gynecology, NYU pregnancy. It is during this period of its development, School of Medicine, 530 First Avenue NB9N26, New York, NY that the CNS undergoes tremendous transformation. The 10016, USA. E-mail: [email protected] embryo starts as a flat disc that undergoes cranial,

Copyright  2008 John Wiley & Sons, Ltd. Received: 1 July 2008 Revised: 25 September 2008 Accepted: 25 September 2008 Published online: 10 November 2008 DEVELOPMENT OF THE CNS BEYOND THE FIRST TRIMESTER 327 lateral and caudal folding. This process is completed (BPD)] are performed. The three most clinically useful by approximately the 6th postmenstrual week. levels or sections at which the axial images are produced Using sonography, we can begin to examine the devel- are: transventricular, transthalamic and transcerebellar oping embryonic brain from the 7th postmenstrual week, (ISUOG Guidelines, 2007) (Figure 1). when the head becomes discernible from the rest of the body and the primitive embryonic can • The landmarks for the transventricular axial plane be imaged. The 8th postmenstrual week reveals the four from anterior-to-posterior are as follows: the CSP, convoluted sequential sonolucencies in the embryonic flanked in each side by the anterior horns (AHs) head that correspond to the telencephalon, diencephalon, of the ; caudally the PHs of the mesencephalon and . From approximately lateral ventricle, which contain the hyperechoic CPs. the 9th postmenstrual week, the fetal period begins and The walls of the ventricles are echogenic and are the falx cerebri and the choroid plexuses (CPs) in the clearly demarcated by the fluid contained within the lateral ventricles can be imaged; these are important ventricles. At this level, the lateral ventricles are landmark in the development of the CNS. measured at its widest part; at the level of the glomus. In this section, the CP is seen filling bilaterally the cavity of the ventricles. The calipers are placed SECOND AND THIRD TRIMESTER perpendicular to the axis of the ventricles touching DEVELOPMENTAL CHANGES OF THE FETAL the inner aspect. A measurement of up to 10 mm is BRAIN deemed normal (Almog et al., 2003) (Figure 1A). • Inferior to the transventricular plane, the transtha- The second trimester begins during the 14th week of lamic plane can be obtained. The landmarks from the pregnancy and extends through the 27th week of the anterior-to-posterior are: the frontal horns of the lat- gestation. During the second and the third trimesters, the eral ventricles, CSP, thalami and the hippocampal CNS slows its developmental pace. However, this period gyri (HG). It is at this level that most of the bio- is characterized by an unparalleled growth of the brain metric measurements of the head are obtained: BPD, volume; there is nearly a 40-fold increase in the weight head circumference (HC) and occipitofrontal diameter of the brain between the end of the embryonic period and (OFD) (Figure 1B). birth (O’Rahilly and Muller, 2008). In addition, some of • The transcerebellar axial plane is inferior to the the brain structures, which began their developmental transthalamic plane and is slightly tilted posteriorly to journey during the first trimester, continue to evolve or adequately image the posterior fossa. The landmarks change through the second and third trimester. Some from anterior-to-posterior are: frontal horns of the structures may not reach their full ‘mature state’ until lateral ventricles, CSP, thalami, , and the several months after the birth of the infant. Changes that cerebello-peduncular cistern [ (CM)]. occur in the fetal brain are: the union of the cerebellar A CM measuring greater than 10 mm is considered hemispheres, development of the corpus callosum (CC), abnormal; also considered abnormal is the lack of the cerebral cortex, which becomes thickly populated its visualization strongly suggesting a spinal defect by neuronal migration and more complex, the insula (Figure 1C). which becomes buried by the opercula. There is a backward projection of the occipital lobes and formation In contrast to the axial plane easily obtainable by of the posterior horns (PHs) of the lateral ventricles, transabdominal sonography, the coronal and sagittal development of gyri and sulci, and asymmetry of the planes are easier to obtain by transvaginal sonography; right and left hemispheres (O’Rahilly and Muller, 2008). that is, if the fetus is in cephalic presentation. However, Some of these changes can be imaged by US especially transabdominally the frontal suture can be used as an those that relate to the CC, cavum septi pellucidi (CSP), acoustic window to obtain the transfrontal view of the ventricular system, cerebellum, vermis, and finally the brain. This view can be use to image the median brain development of gyri and sulci. structures such as CC, CSP, and cerebellum (Visentin Before we go over the developmental changes that et al., 2001). This view can be routinely obtained during occur in the fetal brain during the second and third the screening anatomical scan; however, when a targeted trimesters of pregnancy, it is imperative to review the neuroscan is performed the transvaginal route provides anatomy of the brain using the multiplanar approach. better resolution especially if the fetus is in a cephalic The multiplanar approach (which in fact means scrolling presentation. or navigating within the acquired volume of the brain in When scanning transvaginally, the sections are the orthogonal planes) should always be used when brain obtained through the anterior fontanelle or one of the pathology is present or suspected. sutures of the skull; therefore, both hemispheres can be effectively imaged therefore compared to each other for symmetry. Although, a large number of coronal as SONOGRAPHIC NEURO-ANATOMY IN THE well as sagittal sections are technically possible, con- AXIAL, CORONAL AND SAGITTAL PLANES centrating only on four coronal and two sagittal sections will yield valuable and diagnostically necessary addi- The axial plane is the most frequently used plane in tional information to those obtained by the axial sections obstetrics, since this is the plane in which the biometric (Timor-Tritsch and Monteagudo, 1996; Monteagudo and measurements of the head [e.g. biparietal diameter Timor-Tritsch, 1997; ISUOG Guidelines, 2007). In the

Copyright  2008 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 326–339. DOI: 10.1002/pd 328 A. MONTEAGUDO AND I. E. TIMOR-TRITSCH

Figure 1—The three standard views of the fetal brain using the axial plane are demonstrated. (A) Transventricular plane is the plane in which the lateral ventricle is routinely measured. The anatomic structures seen are: cavum septi pellucidi (CSP), the anterior horn (AH), the posterior horn (PH) and the (CP). (B) Transthalamic plane is the plane in which most of the biometric measurements of the fetal head [i.e biparietal diameter (BPD) and head circumference (HC)] are performed. In this plane, in addition to the anterior horn, cavum septi pellucidi, the thalami (TH) and the hippocampal gyri (HG) are seen. (C) Transcerebellar plane is a plane that is tilted posterior. The anterior landmarks of the brain are similar to those seen in the transthalamic plane; but posteriorly the cerebellum (C) and the cisterna magna (CM) are seen majority of cases, the combination of these sections is anechoic triangular CSP, flanked on both sides by the sufficient to arrive at the diagnosis. anechoic frontal horns of the lateral ventricles. The most inferior structure evident is the caudate nuclei. Bilaterally, close to the bones of the cranium, the CORONAL SECTIONS indentations of the insula are apparent (Figure 2B). • Moving more posterior, the next plane is the mid- The four sections to be described here from anterior- coronal-2 or transthalamic plane. This is an important to-posterior are: the frontal-2 or transfrontal plane, view, since a significant number of pathologies can mid-coronal-1 or transcaudate plane, mid-coronal-2 or be identified by carefully studying this plane. The transthalamic plane and the occipital-1 and -2 or tran- structures from superior-to-inferior are similar to scerebellar plane (ISUOG Guidelines, 2007) (Timor- those viewed in the previous section but instead of Tritsch and Monteagudo, 1996) (Figure 2). the caudate nucleus (CN) the thalami are seen. The 3rd ventricle is situated in the midline between the • The landmarks for the frontal-2 or transfrontal plane thalami; if prominent it is usually a part of a generally are as follows: interhemispheric fissure (IHF), which dilated ventricular system (Figure 2C). equally divides the right and left hemispheres; the • The occipital-1 and -2 or transcerebellar plane is AHs of the lateral ventricles. The bony structures the most posterior plane. The structures seen from seen are the sphenoidal bone as well as the orbits superior-to-inferior are: the IHF, the occipital horns of (Figure 2A). the lateral ventricles, which on this plane are devoid • In the mid-coronal-1 or transcaudate plane moving of CPs seen on the previous planes and appear round, from superior-to-inferior, the structures seen are: the rendering this plane the owl’s face configuration. Infe- IHF, the hypo-echoic horizontal lines of the CC, the rior, below the tentorium, the contents of the posterior

Copyright  2008 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 326–339. DOI: 10.1002/pd DEVELOPMENT OF THE CNS BEYOND THE FIRST TRIMESTER 329

Figure 2—Using transvaginal sonography the fetal brain is scanned using four serial coronal planes. (A) Frontal-2 or transfontal plane; this is a very anterior plane that cuts through the orbits. The brain structures seen are the anterior lobe of the brain separated into two equal parts by the interhemispheric fissure (IHF). (B) Mid-coronal-1 or transcaudate plane is slightly posterior to the frontal-2 plane. The anatomic landmarks seen from top to bottom are: the interhemispheric fissure (IHF), the corpus callosum (CC), the cavum septi pellucidi (CSP), anterior horns (AH) and caudate nucleus (CN) to each side of the CSP and the insula (INS) just below the fetal cranium. (C) Mid-coronal-2 or transthalamic plane. Many of the anatomic landmarks seen on the mid-coronal-1 are seen in this plane as well. However, the thalami (TH) replace the candate nucleus. Occasionally, the can be seen as a slit-like anechoic structure between the thalami. (D) Occipital-1 and 2 or transcerebellar plane. In this posterior plane, the posterior horns (PH) of the lateral ventricles appear as rounded structures devoid of the choroid plexus. Below the posterior horn, the posterior fossa is seen containing the cerebellum (C) and the cisterna magna (CM)

fossa are seen: the cerebellum, the vermis and the hemorrhage), the quadrigeminal plate and cistern cerebello-peduncular cistern (CM) (Figure 2D). (frequent place of arachnoid cysts). Sectoring more posteriorly, the vermis of the cerebellum, the 4th ventricle and the CM can be seen (Figure 3B). SAGITTAL SECTIONS

The two clinically significant sagittal sections are the VOLUME OR MULTIPLANAR SONOGRAPHY: 3D median plane and the two left-and-right oblique-1 or ULTRASOUND parasagittal planes (Figure 3). Volume sonography is better known as 3D sonography; • The right-and left-oblique-1 or parasagittal planes it shortens the process of obtaining the serial sagittal reveal the anterior, posterior and at times the infe- and coronal sections (Monteagudo et al., 2000; Timor- rior horns of the lateral ventricle and are seen Tritsch et al., 2000a). There are differences between the as an inverted ‘C’ containing the echogenic CPs planes obtained by two-dimensional (2D) transvaginal (Figure 3A). or transabdominal sonography from 3D transvaginal • The median plane is one of the most important sonography. Using 2D US, all sections arise from a and diagnostically useful planes depicting all of the single point (the transducer tip) usually at the anterior midline structures, namely the CC, pericallosal artery fontanelle, and fan-out in a radial fashion; the planes (PCA) (using power Doppler evaluation), located are oblique to one another. However, when using 3D superior to and hugging the CC, the area of the transvaginal sonography the sections derived from the 3rd ventricle. The (TC) covering the volume are parallel to each other similar to those thalamus (locus of the germinal matrix prone to obtained by computed tomography (CT) or magnetic

Copyright  2008 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 326–339. DOI: 10.1002/pd 330 A. MONTEAGUDO AND I. E. TIMOR-TRITSCH

Figure 3—The sagittal plane is seen mostly when transvaginal sonography is used. (A) Oblique-1 or parasagittal plane is a very useful plane since the three components of the lateral ventricles can be seen: the anterior horn (AH), the posterior horn (PH) and the inferior horn (IH). In addition, the thalami and the choroid plexus are also evident in this section. (B) Median or mid-sagittal plane is an essential plane since the corpus callosum (CC) can be seen in its entirety. Below the corpus callosum the anechoic cavum septi pellucidi (CSP) is seen, as well as the area where the third ventricle (3V) is located between the two portions of the thalami; the tela choroidea (TC) is the choroid plexus of the third ventricle. Posteriorly the posterior fossa is seen, the most echogenic structure present is the vermis (V) of the cerebellum, the (4V) is an anechoic, triangular in shape and is located anterior to the vermis and the cisterna magna (CM) is the anechoic area between the back of the vermis and the cranium. Using color Doppler the pericallosal artery (PCA) is seen resonance imaging (MRI) (Figure 4). The images of the sections that are below the fontanelle and sutures have higher resolution than those that are more lateral or distal from the acquisition plane. Another difference between the 2D and 3D transvaginal sonography is that with 3D sonography a reconstructed axial plane (the C -plane) is possible; therefore, all three scanning planes can be simultaneously displayed on the screen (orthogonal planes) (Figure 5). The user can scroll to navigate in a continuous fashion through each plane at will.

HOW IS TRANSVAGINAL OR TRANSABDOMINAL 3D NEUROSONOGRAPHY DONE? Figure 4—Three dimensional rendered faces are used to demonstrate Acquisition, storage and display are the three basic steps the difference between the direction of the transvaginally generated 2D planes and those studied from a 3D volume of the brain.(A) When in performing a 3D US study. This section will review scanning using 2D US through the anterior fontanelled, the planes these basic steps. arise from a single point (fontanenlle) and fan-out laterally. The sectional planes are comparable to those obtained by neonatal trans- Step 1: Data acquisition: fontanelle imaging. (B) Successive planes obtained using 3D volume This first step (the data acquisition) is the most important scanning are parallel to each other similar to those obtained when step in the process of creating clinically diagnostic using a CT or an MRI images. Remember that poor quality 2D images will create poor quality 3D images! Therefore it is not grayscale 2D image. Once the brain is clearly seen on only worth, but also mandatory to optimize the the screen, several volumes should be captured; if the

Copyright  2008 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 326–339. DOI: 10.1002/pd DEVELOPMENT OF THE CNS BEYOND THE FIRST TRIMESTER 331

Figure 5—After a brain volume has been acquired, the three orthog- Figure 6—Tomographic display showing serial coronal sections from onal planes are displayed; in ‘box A’—the coronal section, in ‘box anterior (A) to posterior (P). The central picture is highlighted by the B’—the sagittal with the fetus facing the left side of the screen and box around it and the thicker white line. The marker dot is seen in in ‘box C’—the axial the midline on the corpus callosum. The slices between the interval is 3 mm. Arrows point to the occiput

volume is being captured transvaginally one should be in the sagittal plane and one in the coronal plane. The volume acquired in the sagittal plane enables a diagnostic view of the structures in the median plane. The one acquired in the coronal plane permits scrolling in the coronal plane. The ‘reconstructed’ plane; in this case the axial, may be of somewhat lower resolution; however, it still is instrumental in making clinically relevant observations. When the volumes are captured transabdominally, we obtain one in the axial plane at the level of the BPD and the second either in the coronal or sagittal depending on the fetal position. We display the orthogonal planes on the screen as follows: in box A, the coronal section of the head; in box B, the median sagittal with the fetal face facing the box A and box C, the axial section with the posterior fossa being superior on the screen (Figure 5). Figure 7—This figure shows a tomographic display of Sagittal sections. Similar to Figure 7, the central picture is highlighted by Step 2: Data Storage. the box around it and the thicker white line. The marker dot is in The volume data is stored in the computer as a volume the midline on the corpus callosum and the slice interval is 3 mm. of data points in a Cartesian system and can be reused However, the arrows point to the right and left side of the face; to display images using different technologies. therefore both right (R) and left (L) of the median sections are seen Step 3: Display There are multiple displays that may enhance certain planes similar to those seen by CT or MRI are possible features of the volume and assist in making the (Figures 6 and 7). clinical diagnosis. We have arranged the displays in The thick slice display in which the selected area of the order that we usually use them. the volume is collapsed into a 2D image can enhance edges, improve contrast detection and at times give Multiplanar imaging (orthogonal planes) is the first more depth to the image (Figure 8). Volume contrast type of display that we use. The three scanning planes imaging (VCI ) is another software application enabling (sagittal, coronal and axial) can simultaneously be dis- the display of a number of slices ‘collapsed’ into one played at right angles to each other on the US monitor. In 2D picture enhancing tissue borders. The thick slice and this display, it is possible to scroll or navigate in a con- the VCI are essentially the same. Thick slice rendering tinuous fashion through each plane at will. If the volume requires several steps: placing a rendering box on the was obtained either in a coronal or sagittal plane, the orthogonal planes, narrowing it to a minimum and axial plane generated is a reconstructed plane (Figure 5). displaying the rendered image, which represents the 2D The tomographic display is useful since it allows (thick slice) ‘image of many collapsed 2D images’. This visualization of multiple parallel slices at different process basically is an edge enhancement process. VCI spacing through a volume at the same time on the is essentially the same process, which is achieved by US screen; therefore, serial sections of any of the touching one of the control knobs. It represents the 2D

Copyright  2008 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 326–339. DOI: 10.1002/pd 332 A. MONTEAGUDO AND I. E. TIMOR-TRITSCH

Figure 10—In the inversion rendering a selected, fluid filled areas of the acquired volume (in this case: ventricles) can be seen, which were initially anechoic thus become echogenic. (A) A parasagittal view of the on-screen appearance of the ‘cast’ like fluid filled space of the lateral ventricle. (B) The ‘inverted’ image now demonstrates the two Figure 8—The thick slice display is demonstrated. The box shows ventricles parallel to each other. Between the two, the interventricular the selected area of the volume in all three planes which has been foramina connecting to the third ventricle can be appreciated ‘collapsed’ into a 2D image with enhanced edges, contrast and apparently more depth to the image (lower right image) with facial dysmorphism, such as is the case with alobar holoprosencephaly. (collapsed) image of a certain number of 2D slices. It The X-ray, maximum (‘bone’) or transparency mode is possible to control the slice thickness from 2–5-mm allows selective imaging of the fetal cranium (or bones), thick slices. as well as defining the sutures. In neurosonography, this 3D sonoangiography which enables selective imaging is probably the display that is least used. In contrast, of blood vessels after a 3D acquisition of a power when searching for anomalies of the bony skeleton this or color Doppler containing volume is very useful, is an invaluable tool. especially in agenesis of CC where absence of the PCA At this point, we will review the developmental aids in the diagnosis (Figure 9). changes of fetal brain that occur during the second and The inversion mode is one in which the selected fluid third trimesters of pregnancy. It is relevant to point filled areas of the acquired volume can be ‘inverted’ out that many of the developmental changes of the and therefore, the areas, which were initially anechoic brain follow a very specific and defined developmental become echogenic. The on-screen appearance is that of a timeline. Therefore, establishing the correct gestational cast representing the fluid filled space—in this case the age of the fetus is the key to the correct interpretation lateral ventricles. This is useful in cases of hydrocephaly of the anatomy seen. in which the ventricles are enlarged with cerebral spinal fluid (CSF) (Figure 10). Surface rendering is the most widely known display. The surface features can be seen and recognized resem- THE CORPUS CALLOSUM bling a photograph (e.g. the face) (Figures 1–4). This is useful since certain brain anomalies are associated The CC, the CSP and the cingulate gyrus are devel- opmentally very closely related. On the median section the CC is located between the cingulate gyrus, which is above it and the CSP, which is below it. The CC arises from the commissural plate and is a pathway of fibers that connect the cerebral hemispheres with each other. Initially, the CC is a compact mass of tissue, but as the pregnancy progresses it significantly lengthens in size. The CC develops in a front-to-back (or rostral- to-occipital) fashion creating a cover over the roof of the third ventricle; the underlying portion of the com- missural plate becomes thinned and forms the (O’Rahilly and Muller, 1992, 2001). The development of CSP is closely associated with that of the CC; there cannot be a CSP without a covering CC; however, a CC can be present in the absence of the CSP such as in septo-optic dysplasia (Figures 11 and 12). Transvaginal 2D and 3D sonography allows imaging Figure 9—The 3D sonoangiography display allows selective imaging of blood vessels after a 3D acquisition of a power or color Doppler of the CC relatively quickly and easily; however, containing volume has been acquired. Arrows represent the perical- this can also be done by transabdominal sonography. losal artery Sonographically, the CC is anechoic. When color or

Copyright  2008 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 326–339. DOI: 10.1002/pd DEVELOPMENT OF THE CNS BEYOND THE FIRST TRIMESTER 333

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Figure 11—This figure targets the corpus callosum in the median plane. (A) At 34 weeks, the corpus callosum is seen just below the cingulate gyrus. (B) The ‘anatomy’ of the corpus callosum is depicted at 22 weeks. CSP represents Cavum septi pellucid; CV represents Cavum vergae (C) At 16 weeks of gestation, the median section is normal for age. However, the corpus callosum, cavum septi pellucidi and cingulate gyrus are still absent due to their later appearance

Figure 12—The normal and pathological findings of the median section. (A) In the median plane, a normal appearing corpus callosum (CC) and cavum septi pellucidi (CSP). (B) In a coronal section, the cavum septi pellucidi (CSP) is seen below the corpus callosum. Note the thin walls of the CSP separating it bilaterally from the anterior horns (AH) of the lateral ventricles. (C) In this median section, the corpus callosum and the CSP are seen appearing normal. (D) The same fetus as in C; when scanned coronally the thin walls of the CSP that normally separate it from the anterior horns are not evident. This can be seen in cases of lobar holoprosencephaly as well as in septo-optic dysplasia. (E) In the median plane, the corpus callosum cannot be seen; instead a relatively large anechoic structure is seen. 3V represents third ventricle. (F) In the coronal plane, the upwardly displaced third ventricle is touching the lower most part of the falx power Doppler US is added, the pericallosal arteries translucent membranes of the septum pellucidum and (there are two of them: one on each hemisphere) can be the fornices. At times, a posterior portion is seen and is seen superior to the CC following their inner margin. called the cavum vergae (Figure 11B). We can begin to The CC has several parts: the rostrum (beak), genu image the CSP as early as the 15th postmenstrual week; (knee), corpus (trunk) and the splenium (tail) (Figures 11 however, it cannot be consistently imaged until the and 3B). It can be seen in its full developmental shape 16th–17th week of the pregnancy. As term approaches, from 18–20 weeks of the gestation. The CC continues to grow reaching its final adult-like appearance at around the CSP begins to narrow in an occipital-to-rostral fash- the 28th postmenstrual week. ion. In normal pregnancies, a CSP should be seen in all fetuses between 18th and 37th postmenstrual weeks. After the 38th postmenstrual week, it is only imaged in THE CAVUM SEPTI PELLUCIDI approximately 70% of the fetuses. It has been reported that as many as 50% of term neonates will have a CSP The CSP is a fluid filled space; its boundaries are present, but by the 3–6 months of life only 15% of superiorly the CC and laterally the two thin and infants will have a CSP. In adults, the CSP is totally

Copyright  2008 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 326–339. DOI: 10.1002/pd 334 A. MONTEAGUDO AND I. E. TIMOR-TRITSCH

Figure 13—In the axial section: (A) The sonographic appearance of the fornix is that of two hypo-echoic parallel with a central echogenic line. (B) The cavum septi pellucidi resembles a box-like structure located between the anterior horns of the lateral ventricles with a central anechoic core obliterated and appears as an echogenic line. The sono- THE VENTRICULAR SYSTEM graphic appearance of the CSP is that of a rectangular box-like structure located between the AHs of the lat- The ventricular system consists of the lateral ventricles, eral ventricles. This should not be confused with the two the third and fourth ventricle, and the interventricular hypo-echoic parallel columns of the fornix, which have foramina (Monro) which connects the lateral ventricles to the third ventricle, the (Sylvius) a central echogenic line and these are seen in a slightly which connects the third ventricle with the fourth ven- inferior section to the one in which the CSP is seen tricle, (Magendi) which connects the (Figure 13). The size of the CSP increases gradually fourth ventricle with subarachonoid space and cere- from the 18th postmenstrual week to 27th week and then bellomedullary cistern (CM) and the lateral apertures plateaus. The mean width of the CSP is 5.3 ± 1.7mm; (Luschka), which connect the fourth ventricle with the therefore a CSP greater than 10 mm is deemed to be subarachnoid space as well as the cistern of the great dilated. Lack of visualization of the CSP between 18 cerebral vein. and 37 weeks of gestation should raise the suspicion The lateral ventricles are positioned in a parallel man- ner within the cerebral hemispheres and have three horns that it is absent. Absence of CSP is a feature age- anterior, posterior and inferior, a body and a triangu- nesis of the CC, holoprosencephaly, septo-optic dys- lar atrium (Figures 3A and 14). The lateral ventricles plasia, schizencephaly, porencephaly/hydranencephaly, undergo significant changes in size and shape during the basilar encephaloceles and severe hydrocephaly. At this second and third trimesters of the pregnancy. Initially, time, it is virtually impossible to use US to differenti- late-first-trimester-to early-second trimester, the lateral ate between septo-optic dysplasia and lobar holoprosen- ventricles appear large due to the thin brain parenchyma cephaly. Some of the isolated lobar holoprosencephalies and consist mostly of an AH and inferior horn, but as the may carry a good prognosis. At this time there is contro- pregnancy progresses it gradually become more slender. The PHs of the lateral ventricle develop late in compar- versy in the literature about the significance of a dilated ison to the AH and inferior horns. The occipital lobes of CSP; however, it has been associated with chromosomal the brain grow by projecting backward which enables aneuploidy as well as congenital anomalies (Jou et al., the formation of the PHs of the lateral ventricles. At 1998; Falco et al., 2000; Sherer et al., 2004; Pilu et al., 12 weeks of gestation, the lateral ventricles are essen- 2005; ISUOG Guidelines, 2007; Callen et al., 2008). tially ‘C-shaped’ and no PHs are present; however, as

AB C

Figure 14—Using 2D transvaginal US the ‘three-horn view’ of lateral ventricles are seen in the oblique-1 or parasagittal section. (A) At 12 weeks, the lateral ventricles appear relatively large due to the thin brain parenchyma and consist mostly of an anterior and inferior horn. The choroid plexus appear relatively large and almost fills the entire ventricle. (B) By 15 weeks, the choroid plexus has ‘moved’ posteriorly leaving a relatively large anterior horn. (C) By the 20th week of gestation, due to growth of the fetal brain the lateral ventricles are slit-like

Copyright  2008 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 326–339. DOI: 10.1002/pd DEVELOPMENT OF THE CNS BEYOND THE FIRST TRIMESTER 335 pregnancy progresses the PHs grow and at the 18th week sonography is that of a single echogenic line between of gestation a clearly defined PH is seen (Figure 14). the thalami. However, during the third trimester the The width of the lateral ventricles, as measured in the cerebro-spinal fluid fills the cavity of the third ventricle axial transventricular plane, remains constant through- and the transabdominal appearance changes to two out the pregnancy with a normal measurement at less parallel lines separated by an anechoic area between the than 10 mm. Using 2D transvaginal sonography, the thalami. During the second trimester, the size of the third lateral ventricles can be imaged in the coronal and ventricle ranges from 1–2 mm. Its mean ventricular sagittal planes. In the coronal section, the normal sono- width after 32 weeks is 2.7 ± 0.4mm;3.6mm(two graphic appearance of the AHs of the lateral ventricles standard deviation above the mean) is the upper level before the 18th week is that of a ‘plump’ comma-like of normal (Sari et al., 2005). fluid filled structure flanking the CSP; after 18th week, The fourth ventricle is located posterior to the the width decreases eventually becoming ‘slit-like’. The and upper part of the medulla and anterior to the cere- three horns of the lateral ventricles can be visualized bellum. It has a characteristic diamond shape in cross- with 2D transvaginal sonography when an oblique sec- sections of the . Cerebro-spinal fluid enter- tion of the brain is obtained; this section is lateral to ing the fourth ventricle through the cerebral aqueduct the median section of the brain. When using 3D, a can exit to the subarachnoid space of the spinal cord ‘3-horn view’, is possible after the volume has been through two (Luschka) and a single, tilted so that a plane is generated to reveal all three median aperture (Magendie). When scanning transvagi- horns (Timor-Tritsch et al., 2000b) (Figure 15). nally in the median section, the fourth ventricle can be Dilation of the lateral ventricles can be a clue to clearly seen by its anechoic fluid filled contents. Only several pathologies such as spina bifida and agenesis of the median aperture is seen sonographically (on axial the CC. The size of the lateral ventricles is influenced by planes) and only at ages less than 15–16 postmenstrual fetal gender and in the absence of any other structural weeks. and karyotypical abnormalities, normal male fetuses are The CPs are an integral part of the ventricular system. more likely to have lateral ventricles measuring slightly They are made of multiple villi with rich blood supply, more than 10 mm when compared to normal female which provide a large surface area to produce the fetuses of the same gestational age (Signorelli et al., cerebro-spinal fluid filling the ventricular system. During 2004; Gaglioti et al., 2005). the first trimester the CP fills the entire lateral ventricle; The third ventricle can be imaged in the majority of but as the pregnancy progress, their size compared to fetuses during pregnancy. Early in the second trimester, that of the lateral ventricle decreases. Early in pregnancy the appearance of the third ventricle by transabdominal they are located in the AH of the lateral ventricles;

Figure 15—To display ‘three-horn views,’ when a brain volume has been obtained, the coronal plane has to be tilted to the right and subsequently to the left to see the entire ventricle. Using the tomographic display, the coronal section was tilted to the right and multiple parasagittal sections of the brain were displayed

Copyright  2008 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 326–339. DOI: 10.1002/pd 336 A. MONTEAGUDO AND I. E. TIMOR-TRITSCH

Figure 16—The posterior fossa. A and B are axial sections and C and D are median (Sagittal) sections (A) The upper surface of the cerebellum (C) and the midline vermis (V). (B) Posterior to the cerebellum the cisterna magna (CM) is seen containing the cisterna magna septa. (C) Median section demonstrates anteriorly the corpus callosum and in the posterior fossa, the echogenic vermis is clearly seen. The fourth ventricle (4V) appears as a triangular indentation in the anterior aspect of the vermis. (D) A magnified view of the vermis, fourth ventricle (4V), cisterna magna and the tentorium of the cerbellum (T) but as the CP ‘moves’ posteriorly and assume their and 17). It recently has been suggested that deviation final position within the atrium of the lateral ventricle, from its normal appearance (i.e. the lack of them) may the lateral ventricle appears relatively large. Therefore, be an early marker of abnormalities of the cerebellum, when scanning the fetal brain at 14–15 weeks the lateral vermis and brain stem, therefore in these cases a targeted ventricles appear prominent; this is most obvious in the scan of the posterior fossa using multiplanar imaging is axial as well as the parasagittal sections. Abnormalities suggested (Robinson and Goldstein, 2007). In pregnan- of the CP, such as thin or dangling choroids, are cies of less than 20 weeks, obtaining low axial section, associated with and/or hydrocephaly. that is too inferior, may falsely give the impression of a A separation of the CP from the median wall of the vermian defect (Figure 18). This is due to the fact that lateral ventricle of up to 3 mm is considered to be the development of the occurs from normal. However, if measured beyond 3 mm, a careful a superior (rostral) to an inferior (caudal) fashion and evaluation of the fetal brain is necessary. When isolated, a normal connection between the fourth ventricle and CP separation of more than 3 mm is seen during the cerebellomedullary cistern can be demonstrated until the second trimester; it is usually a transient finding and in development of the vermis is complete (Bromley et al., majority of the cases resolution occurs within 1 month; 1994; Babcook et al., 1996; Malinger et al., 2001; Ben- most infants will have no abnormalities (Bronsteen Amin et al., 2002) (Figure 18). et al., 2006).

THE CORTEX THE CEREBELLUM AND THE VERMIS The surface of the fetal brain at the beginning of the The posterior fossa includes the cerebellum, cerebellar second trimester is smooth and lacks gyri and sulci. vermis and cerebellomedullary cistern (CM). In the tran- As the pregnancy reaches the third trimester, there is a scerebellar plane, in addition to evaluating the size of the growth spurt of the fetal brain cortex. This growth spurt cerebellomedullary cistern, the cerebellar hemispheres results in the development of new gyri and sulci giving as well as the cerebellar vermis can be assessed. Within the brain its typical (convoluted) appearance (Chi et al., the cerebellomedullary cistern thin septa are commonly 1977; Dorovini-Zis and Dolman, 1977; Monteagudo seen; this is a common and normal finding (Figures 16 and Timor-Tritsch, 1997; Cohen-Sacher et al., 2006)

Copyright  2008 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 326–339. DOI: 10.1002/pd DEVELOPMENT OF THE CNS BEYOND THE FIRST TRIMESTER 337

Figure 17—Using the tomographic display, serial sections through the posterior fossa are seen. Note the rounded bilateral posterior horns (PH) of the lateral ventricle. Inferiorly the posterior fossa is imaged. C represents cerebellum

Figure 18—At 16 weeks, tomographic sections of the posterior fossa. (A) A most superior section; the marker dot (cyan) is seen over the vermis. (B) In approximately the midsection of the cerebellum, both the cerebellar hemispheres are evident connected by the echoic vermis (in cyan the marker dot is over the area of the vermis). (C) A most inferior section; a gap appears to be between the cerebellar hemispheres where the fourth ventricle connects with the cisterna magna. Although, it appears that the vermis is missing, at this gestational age this is a normal finding

(Figure 19). Sonographic identification of the sulci and most active sonographic period in respect to cortical gyri lags behind the anatomical evaluation as much development (Cohen-Sacher et al., 2006). As the gyri, as 4–6 weeks. The 28–30 weeks of gestation is the sulci and fissures appear and deepen, there is an increase

Copyright  2008 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 326–339. DOI: 10.1002/pd 338 A. MONTEAGUDO AND I. E. TIMOR-TRITSCH

Figure 19—Transvaginal US demonstrating the median plane (A) At 16 weeks of gestation, the surface of the median plane is relatively smooth, lacking any gyri and sulci. (B) At 34 weeks of gestation, the median plane of this fetus demonstrates many interlacing echoic lines which represent the sulci

Figure 20—The insula. (A) A transabdominal scan at the level of the thalami demonstrating the insula (arrow). (B) A transvaginal scan slightly posterior to the mid-coronal-2 or transthalamic plane demonstrating the insula in linear bright echoes at the surface of the brain. This CONCLUSIONS result from the echogenicity of the pia matter and the pia arachnoid complex (soft-brain coverings).This can The fetal brain compared to other organ systems con- best be imaged on a median section of the fetal brain. tinues to evolve and grow during the fetal period and Using transvaginal and transabdominal sonography, the beyond. The complexity of this development results in gestational age at which several sulci and fissures are a variety of malformations that at times appear very first sonographically apparent are: the callosal sulcus challenging to diagnose. However, we believe that the key to correctly diagnose these malformations lie in from the 14th postmenstrual week; the parieto-occipital understanding the embryology, remembering that ges- and calcarine fissures from 18 weeks; the cingulate tational age is crucial in the development of certain gyrus and cingulate sulcus from 24 to 26 weeks. structures and lastly being very familiar with the nor- The region of the insula and the lateral sulcus anatom- mal anatomy of the brain in all three scanning planes. ically appears as a linear groove at the 13th gestational Three-dimensional US generates volumes which can be week and by 18 gestational weeks it becomes macro- evaluated using a variety of planes and rendering modal- scopically identifiable. Sonographically, the area of the ities will become an indispensable tool to evaluate the insula and lateral sulcus first appears as a smooth inden- developing brain. tation on the lateral surface of the brain at around 17–18 weeks (Monteagudo and Timor-Tritsch, 1997; REFERENCES Toi et al., 2004; Cohen-Sacher et al., 2006; Afif et al., 2007). As the pregnancy progresses the shape of the ISUOG Guidelines. 2007. Sonographic examination of the fetal central insula relative to the deepening lateral sulcus (oper- nervous system: Guidelines for performing the ‘basic examination’ cularization) takes the shape of an obtuse angle and and the ‘fetal neurosonogram’. Ultrasound Obstet Gynecol 29: 1109–1116. eventually an acute angle (Toi et al., 2004) (Figure 20). Afif A, Bouvier R, Buenerd A, Trouillas J, Mertens P. 2007. As the growth spurt of the brain proceeds and opercu- Development of the human fetal insular cortex: Study of the larization advances, the insula is buried by the parietal gyrationfrom13to28gestationalweeks.Brain Struct Funct 212: 3-4335-346. (anterior) and temporal (posterior) opercula; this process Almog B, Gamzu R, Achiron R, Fainaru O, Zalel Y. 2003. Fetal is not complete until term (Govaert et al., 2004). lateral ventricular width: What should be its upper limit? A

Copyright  2008 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 326–339. DOI: 10.1002/pd DEVELOPMENT OF THE CNS BEYOND THE FIRST TRIMESTER 339

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Copyright  2008 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 326–339. DOI: 10.1002/pd