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Three-Dimensional Sonographic Evaluations of Embryonic Brain Development Mi Suk Kim, MD, Philippe Jeanty, MD, PhD, Cheryl Turner, RDMS, Bernard Benoit, MD

Objective. The purpose of this presentation is to show 3-dimensional development of the ventricles of the brain in early pregnancy, from 6 to 13 weeks, and to provide a reference for early diagnosis of central nervous system anomalies such as hydrocephalus and holoprosencephaly. Methods. From March 2007 to August 2007, 46 patients were included. All patients had routine first-trimester 2- and 3-dimensional sonographic examinations at the same time. All cases were examined with a Voluson 730 Expert or Voluson E8 ultrasound scanner (GE Healthcare, Milwaukee, WI) using a 4- to 8- or 6- to 12-MHz transvaginal probe. Volumes were reviewed and analyzed with GE 4DView release 6 software. After the inversion-rendering mode was selected, volumes were dissected by the MagicCut function to show the ventricles. Results. A total of 34 volumes from 7 to 12 complete gestational weeks were successfully dissected. Those before 7 and after 12 weeks could not be dissected properly. The crownrump length ranged from 12.7 to 68 mm. Twelve representative images of the rendered volumes in chronologic order are shown. The brain volume dissections of 2 fetuses with ventriculomegaly and alobar holoprosencephaly are shown for comparison. Conclusions. Early human brain ventricular structures could be evaluated in vivo with 3-dimensional sonography. This presentation shows the timeline of brain development and provides reference images to compare possible anomalies of development. Key words: brain embryology; first-trimester sonography; holoprosencephaly; inversion rendering; ventricle development; ventriculomegaly.

Abbreviations CRL, crown-rump length; 3D, 3-dimensional; 2D, 2dimensional

Received September 6, 2007, from Inner Visions Women’s Ultrasound, Nashville, Tennessee USA (P.J., C.T.); Department of Obstetrics and Gynecology, Flushing Hospital Medical Center, Flushing, New York USA (M.S.K.); and Department of Obstetrics and Gynecology, Princess Grace Hospital, Monaco (B.B.). Revision requested September 25, 2007. Revised manuscript accepted for publication October 3, 2007. Address correspondence to Mi Suk Kim, MD, Department of Obstetrics and Gynecology, Flushing Hospital Medical Center, 4500 Parsons Blvd, Flushing, NY 11355 USA. E-mail: [email protected] Video online at www.jultrasoundmed.org

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he human brain develops initially from a simple tube to a complex, highly developed structure. Morphologic changes of the brain configuration are particularly rapid in the first trimester. Although there have been efforts to investigate early human brain development with sonography,1–3 recent advances in technology allow performance of more precise 3-dimensional (3D) fetal brain volume scans.4 Three-dimensional evaluations of the fetal brain previously had been limited to second- and third-trimester scans, with only 1 study related to 3D imaging of embryonic brain development.5 The objective of this presentation is to show 3D development of the ventricles of the brain in early pregnancy, from 6 to 13 weeks, and to provide a reference for early diagnosis of central nervous system anomalies such as hydrocephalus and holoprosencephaly.

© 2008 by the American Institute of Ultrasound in Medicine • J Ultrasound Med 2008; 27:119–124 • 0278-4297/08/$3.50

3D Sonographic Evaluations of Embryonic Brain Development

Materials and Methods A total of 46 patients from 1 clinic (Inner Visions Women’s Ultrasound) were included in this study from March 2007 to August 2007. All patients had routine first-trimester 2-dimensional (2D) and 3D sonographic examinations at the same time. The gestational age ranged from 6 to 13 weeks, and all cases were singleton pregnancies. Three-dimensional sonography was performed routinely as the patients were scanned. Not all first-trimester patients were included; only those patients who had the appropriate age without abnormal findings and for whom we had a 3D volume were included. All images were reviewed and dissected retrospectively. The gestational age was calculated by the crownrump length (CRL), which was measured by 2D sonography. During routine first-trimester 2D and 3D examinations, volumes of the embryonic and fetal brain were acquired. All cases were examined with a Voluson 730 Expert or Voluson E8 ultrasound scanner (GE Healthcare, Milwaukee, WI) using a 4to 8- or 6- to 12-MHz transvaginal probe. Although the acquisition time was a few seconds, it took about 30 to 45 seconds to configure and acquire the volume. This included reconfiguring the transFigure 1. Plane A, Sagittal section of the brain with the fetus facing the bottom right. Plane B, Axial section of the brain. Plane C, Coronal section. The rendered volume appears in the bottom right box. This is from an embryo at 8 weeks 2 days with a CRL of 18 mm. The reference dots on the left of plane A are 5 mm apart.

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ducer to the 3D surface acquisition mode on the first-trimester setting and obtaining the volume. Volumes were reviewed and analyzed retrospectively with GE 4DView release 6 software. Volumes were acquired in random axis views. However, the volume was reoriented to display the brain as follows: in plane A, a sagittal section of the brain had the face of the embryo to the right side in box A; the axial section of the brain was displayed in box B at the top right of the monitor; and the coronal section was displayed in box C, at the bottom left side of the monitor. The rendered volume appeared in the bottom right box of the multiplanar display (Figure 1). Acquisition of 3D volumes had been in practice for several years, so this was part of our routine scanning. The dissection required great attention to detail. First, simple 8-week embryonic brains were dissected, progressing then to the earlier and later stages of the investigated range. When all volumes had been dissected a first time, the initial volumes were reopened and dissected a second time on the basis of the experience acquired over the first dissection. The images presented are based only on the second dissections. Several types of rendering were tried before settling on the final one, which is shown in Video 1. It was impossible to get the inversion-rendered images before 7 weeks because there was not enough fluid in the neural tube for our transducer to detect and after 12 weeks because the choroid plexus filled too much of the cavity to isolate the ventricle in healthy embryos. Two extra cases, 1 with hydrocephalus and 1 with holoprosencephaly, were added for comparison. The embryo’s brain develops from the neural tube to vesicles and then later to ventricles. To visualize these vesicles and cavities, the inversion-rendering mode was selected. The surface was displayed in a mixture of gradient light and a smooth-surface mode. All volumes were dissected by the MagicCut function to show the ventricles. A back-and-forth movement of the threshold was used to highlight the various structures, and multiple rotations were performed to isolate structures at the periphery of the ventricles. A demonstration of the technique is shown in Video 1. Editing and reconstruction of 3D volumes were performed by 1 author (M.S.K.). J Ultrasound Med 2008; 27:119–124

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Results From the 46 patients enrolled, 34 volumes could be edited. The age distribution included is shown in Table 1. The CRL ranged from 12.7 to 68 mm. We attempted to include 6-week embryonic images, but it was impossible to isolate the ventricles in the brain volume before 7 gestational weeks. The earliest gestational age at which we could get the brain volume was 7 weeks 4 days, corresponding to a CRL of 13.6 mm. Dissections became progressively more difficult after 12 weeks as the choroid plexuses enlarged and contacted the roof of the lateral ventricle, decreasing the fluid interface. By 13 weeks, we were no longer able to dissect the ventricles. Twelve representative images of the rendered volumes are shown in Figure 2. For a better understanding of the sequential development of the brain, the images are arranged chronologically. Three video clips of the rotation of the model, at 7 weeks 4 days, 9 weeks 4 days, and 11 weeks 5 days, are shown in Videos 2–4. The brain volumes of 2 additional fetuses with central nervous system malformations were also dissected to show the anomalies. One was a fetus at 10 weeks 2 days with hydrocephalus who had translocation between chromosomes 1 and 17 (Figure 3 and Video 5). The other was a fetus at 12 weeks 4 days with alobar holoprosencephaly who had trisomy 13 (Figure 4 and Video 6). In these 2 cases, the ventricular cavities were more prominent than in healthy fetuses, and they were easier to render and dissect.

Discussion Knowledge of the 3D structure of the developing brain in early pregnancy has been limited in the past because of the limitations of the anatomic approaches. Earlier attempts to clarify the developing brain with 3D sonography were limited by the resolution of the image.5 Because of recent improvements in resolution, volume acquisition, dissection, and rendering techniques, there have been several studies evaluating 3D structures of the fetal brain. However, most of them were performed in second- and third-trimester fetuses.6–8 J Ultrasound Med 2008; 27:119–124

Table 1. Distribution of Cases by Gestational Age Gestational Age, wk

6 7 8 9 10 11 12 13 Total

Cases

2 7 9 9 3 6 9 1 46

Cases With Images Acquired

0 6 9 9 2 6 2 0 34

A total of 34 cases were successfully dissected. It was impossible to get volumes before 7 and after 12 complete gestational weeks. Two brain volumes could not be acquired, 1 at 7 weeks and 1 at 10 weeks, because of inadequate acquisition during the examinations.

Three-dimensional imaging can be performed without difficulty. During the first trimester, the embryo’s movements are minimal. The small size makes it possible to get 3D images within a short time. Editing and reconstruction can be performed at any time after the examination. Three-dimensional sonographic studies of the fetal brain require a good 2D image to obtain a good volume of the brain.4 However, the axis of acquisition of the brain is not critical in the first trimester, in contrast to the second and third trimesters. There is little imaging in the literature or the Web that describes human brain development. Most references are to lower animals such as mice and chicks. Development of the lateral ventricles and, in particular, their posterior extension are more pronounced in humans than in mice, as can be seen in the illustrations. The 2 pathologic cases clearly show how different anomalies can readily be recognized from the normal references. In the cases of holoprosencephaly and ventriculomegaly, 3D imaging made the diagnoses easier and rendered the concepts of the anomalies vividly. These reference images should allow more confident diagnoses and reduce the need for repeated or additional examinations. During the sixth gestational week, 3 primary brain vesicles form: the forebrain or prosencephalon, the midbrain or mesencephalon, and the hindbrain or rhombencephalon. During the seventh gestational week, 5 secondary brain 121


vesicles form from the 3 primary brain vesicles: the telencephalon, diencephalon, mesencephalon, metencephalon, and myelencephalon. Adult derivatives of the 5 secondary brain vesicle cavities are the lateral ventricles, third ventricles, aqueduct, upper part of the fourth ventricle, and lower part of the fourth ventricle from the telencephalon to the myelencephalon (Figure 5).9 The structures on the diagram can be used to recognize the landmarks in the rendered image. Care

must be taken, though, that only the fluid-filled portion of the ventricles is visible in the rendered image. The actual ventricle is larger as it encompasses the choroid plexus. In conclusion, early human brain ventricular structures could be evaluated in vivo with 3D sonography. This image presentation shows the timeline of brain development and provides reference images to compare possible anomalies of development.

Figure 2. Twelve representative volumes arranged by gestational age. The first and fourth columns are strict sagittal sections obtained with volume contrast imaging, with section 1 to 2 mm thick. The second and fifth columns are strict right lateral views of the dissected ventricular system, and the third and sixth columns are anteroinferior views (≈45° from the longitudinal axis of the metencephalon). The white bars used for length reference on the left edges of the images in the first and fourth columns are 10 mm long. The reference dots on the left of each 3D rendering are 5 mm apart. The ages of the embryos are 7 weeks 4 days (CRL, 13.6 mm) and 7 weeks 6 days (CRL, 14.6 mm) in the first row, 8 weeks 1 day (CRL, 16.5 mm) and 8 weeks 3 days (CRL, 19.1mm) in the second row, 8 weeks 6 days (CRL, 22.5 mm) and 9 weeks 2 days (CRL, 25.3 mm) in the third row, 9 weeks 4 days (CRL, 28.1 mm) and 9 weeks 6 days (CRL, 30 mm) in the fourth row, 10 weeks 6 days (CRL, 39.1 mm) and 11 weeks 1 day (CRL, 42.2 mm) in the fifth row, and 11 weeks 5 days (CRL, 49.2 mm) and 12 weeks (CRL, 53.3 mm) in the sixth row.

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Figure 3. Images from a fetus at 10 weeks 2 days with ventriculomegaly showing enlargement of all ventricular cavities. Compared with the images of a healthy fetus at 10 weeks 6 days, which is shown in the bottom row, the 3D images show the entire lateral ventricle because the choroid plexuses do not touch the ventricular wall. There was a translocation between chromosomes 1 and 17 (with monosomy of the telomeric region of the short arm of chromosome 1 and trisomy of the telomeric region of the long arm of chromosome 17). The white bars used for length reference on the left edges of the images in the first column are 10 mm long.

Figure 4. Images from a fetus at 12 weeks 4 days with alobar holoprosencephaly who had trisomy 13 confirmed by chorionic villus sampling. The images show the fused thalami and fused hemispheres. In the healthy fetuses shown in Figure 2, we could see the separation of the prosencephalon from the embryo at 7 weeks 4 days. The white bars used for length reference on the left edges of the images in the first column are 10 mm long.

Figure 5. During the seventh gestational week, 5 secondary brain vesicles form: the telencephalon, diencephalon, mesencephalon, metencephalon and myelencephalon. The drawing on the left shows the anatomic landmarks in an embryonic brain at 7 weeks. On the right, the comparable landmarks are identifiable in an inversion-rendered image of an embryonic brain at 7 weeks 6 days. The adult derivatives of each vesicle are the lateral ventricles, third ventricles, aqueduct, upper part of the fourth ventricle, and lower part of the fourth ventricle from the telencephalon to the myelencephalon.


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