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Ultrasound Obstet Gynecol 2006; 27: 494–502 Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/uog.2757

Sonographic developmental milestones of the fetal cerebral cortex: a longitudinal study B. COHEN-SACHER*, T. LERMAN-SAGIE†, D. LEV‡ and G. MALINGER* *Department of Obstetrics and Gynecology, Fetal Neurology Clinic, †Pediatric Neurology Unit and ‡Genetics Institute, The Edith Wolfson Medical Center, Holon and Sackler School of Medicine, Tel Aviv University, Tel-Aviv, Israel

K E Y W O R D S: fetal anatomy; fetal brain; fetal cortex; ultrasound

ABSTRACT Objective To identify sonographic landmarks of normal fetal cortical development. Methods Serial ultrasound examinations were performed every 2 weeks from 18 weeks of gestation until term. In each session a detailed examination of the fetal brain was performed and the appearance of the main sulci and gyri was recorded. Results Twenty-two pregnant women volunteered to participate in the study. The fetal cortex followed an orderly pattern of development. By the time of the first ultrasound examination, at 18 weeks, the major fissures were present. The first sulci could be demonstrated as early as 18 weeks. Main landmarks, represented by the parietooccipital fissure and the cingulate and calcarine sulci, were present between 22–24 weeks. The central sulcus was present in all cases by 28 weeks. By 30–32 weeks most of the main sulci could be demonstrated. Conclusions Prenatal sonographic examinations can accurately demonstrate structures of the fetal cortex. Comparison of our results with those of both magnetic resonance imaging and other sonographic studies shows similarities in the order of appearance of the sulci and gyri, with only minor differences in the exact gestational age at which they are detected. Accurate knowledge of the ultrasound appearance of the fetal cortex at different stages of gestation is important in order to be able to diagnose in-utero malformations of cortical development. Copyright  2006 ISUOG. Published by John Wiley & Sons, Ltd.

INTRODUCTION The fetal cortex undergoes significant development during the course of pregnancy; from a completely smooth

surface at 22 weeks, it develops into a complex array of sulci and gyri resembling the adult brain by the end of gestation1,2 . Some congenital brain malformations, like migration disorders, may only affect the cortex, other brain structures remaining normal. Migration disorders are caused by the failure of postmitotic neurons to migrate from the ventricular zone to the cortical plate, resulting in a wide spectrum of cortical malformations3 . The use of ultrasound to depict the fetal brain enables demonstration of cortical development and diagnosis of its aberrations. However, most information on the development of the fetal cortex is obtained from descriptive anatomical studies1,4 , fetal magnetic resonance imaging (MRI)5 – 9 , or neonatal sonography2,10 – 14 . Very little information is available regarding the sonographic appearance of the fetal cortex in utero15 – 18 and no longitudinal study of fetal brain development has been carried out. The aim of this study was to determine normal fetal cortical development as observed by serial ultrasound examinations from 18 weeks of gestation to term.

METHODS The study took place at the Fetal Neurology Clinic of the Edith Wolfson Medical Center, Holon, Israel. The study protocol was approved by the Helsinki Committee of our institution. Pregnant women volunteering to take part in the study were required to sign a consent form. Exclusion criteria were multiple pregnancies, past or present history of fetal brain malformations or neurological conditions and placenta previa. Gestational age was established by the first day of the last menstrual period and was confirmed by at least one ultrasound scan performed before 15 weeks’ gestation. Serial ultrasound examinations were performed every 2 weeks from the 18th week of pregnancy until

Correspondence to: Dr G. Malinger, Department of Obstetrics and Gynecology, The Edith Wolfson Medical Center, P.O. Box 5, Holon 58100, Israel (e-mail: [email protected]) Accepted: 16 December 2005

Copyright  2006 ISUOG. Published by John Wiley & Sons, Ltd.

ORIGINAL PAPER

Development of the fetal cortex


0 0 5 0 25 68 94 100 100 100 100 0 0 5 25 18 58 83 93 100 100 100 0 0 0 0 31 61 88 100 100 100 100 0 0 0 0 6 22 71 93 100 100 100 0 0 0 0 0 11 65 100 100 100 100 0 0 0 5 0 45 83 100 100 100 100 0 0 5 10 12 60 83 100 100 100 100 0 0 0 10 6 58 94 100 100 91 88 0 0 0 5 19 63 94 100 100 91 88 0 0 0 5 11 60 100 100 100 100 100 0 0 0 5 5 60 100 100 100 100 100 GA, gestational age; inf., inferior; sec., secondary; sup., superior; temp., temporal.

0 0 0 10 55 90 100 100 100 100 100

Fetuses in which sulcus or fissure was seen (%)

0 33 53 76 89 95 94 100 100 100 100 0 33 84 81 94 100 100 100 100 100 100 95 100 100 100 100 100 100 100 100 100 100 95 100 100 100 100 100 100 100 100 100 100 55 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 18 20 22 24 26 28 30 32 34 36 38

Twenty-two women volunteered to participate in the study. Gestational age was 18 weeks ±3 days at the time of the first examination. Three women did not complete the study: two elected to leave the study at 24 and 26 weeks, and the third delivered prematurely at 29 weeks of pregnancy due to spontaneous labor. Seventy-one percent of the examinations were performed using the transvaginal approach and the remaining 29% were transabdominal. Fetal biometric measurements were within normal ranges for gestational age and no fetal malformations were detected in any of the patients. Table 1 shows the percentage of fetuses in each gestational week in which each sulcus or gyrus was demonstrated. Figure 1 shows the presence, detectability or absence of sulci and gyri at each gestational age. As expected, the brain at 18 and 20 weeks was almost

InterParieto- HippoPostPreSup. Inf. Sup. Inf. Sec. Sec. GA hemispheric Sylvian occipital campal Callosal Calcarine Cingulate Central central central temp. temp. frontal frontal cingulate Insular occipital Olfactory Marginal fissure sulcus fissure sulcus sulcus sulcus sulcus sulcus sulcus sulcus sulcus sulci sulci sulci sulcus sulcus (weeks) fissure fissure fissure

RESULTS

Table 1 Sonographic demonstration of sulci and fissures at different gestational ages

term. In each examination, fetal measurements were obtained, including biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC) and femur length (FL). An estimation of fetal weight was calculated using these parameters. A detailed examination of the brain was performed, using a transabdominal approach as well as a transvaginal one in cases of vertex presentation19 – 20 . The lateral ventricle width, transverse cerebellar width, vermis diameters and area, brain stem area, and corpus callosum length were measured. The appearance of the main fissures, sulci and gyri were demonstrated by axial, coronal, and sagittal views. The presence of the interhemispheric, Sylvian, parietooccipital, and hippocampal fissures and callosal, calcarine, cingulate, central, pre- and postcentral, superior and inferior temporal, superior and inferior frontal, secondary cingulate, insular, secondary occipital, olfactory and marginal sulci were studied in each of the fetuses and in all of the examinations. A positive demonstration of the studied structure was noted only when the specific structure was visualized in both hemispheres. In order to present and analyze our data we used a method similar to the one described by Garel9 . At a given gestational age we considered a particular structure to be present when it was observed in more than 75% of the fetuses, detectable if it was observed in 25–75% of the examinations, and absent when it was observed in less than 25% of the examinations. The sonographic examinations were performed using transabdominal 6–8-MHz and 5–13-MHz transducers and/or a transvaginal 5–8-MHz transducer (Logiq 9, General Electric, Milwaukee, WI, USA). The examinations were recorded using a video recorder and digital images were stored within the patient file. An ultrasound scan to rule out fetal malformations was conducted at 14–16 and 24 weeks of gestation. The newborns were examined by an experienced neonatologist to rule out the presence of any gross malformation. Telephone follow-up interviews were conducted 12–24 months after delivery to ensure normal development.

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496 Insular sulci Secondary cingulate sulci Inferior frontal sulcus Superior frontal sulcus Inferior temporal sulcus Superior temporal sulcus Precentral sulcus Postcentral sulcus Marginal sulcus Secondary occipital sulci Olfactory sulcus Central sulcus Cingulate sulcus Calcarine fissure Parieto-occipital fissure Hippocampal fissure Callosal sulcus Sylvian fissure Interhemispheric fissure Gestational age (weeks)

18

20

22

24

26

28

30

32

34

36

38

Figure 1 Detectability of sulci and gyri according to gestational age. We considered a particular structure to be present when it was seen in more than 75% of the fetuses ( ) detectable if it was observed in 25–75% of the examinations ( ) and absent when it was not observed in at least 25% of the examinations ( ).

Figure 2 Ultrasound images showing coronal planes at 18 and 22 gestational weeks. Callosal sulcus (1), Sylvian fissure (2), hippocampal fissure (3). W, weeks.

completely smooth, with only the major fissures present (Figure 2). The callosal sulcus was observed in almost all the patients (95%) at 18 weeks and in all the patients at 20 weeks (Figure 2). The period between 22 and 26 weeks is characterized by the gradual appearance of the calcarine fissure and the cingulate sulcus, followed shortly after by the central sulcus (Figure 3). The most active period of cortical development as demonstrated by ultrasound is between 28 and 30 weeks. During this time, most sulci become detectable (Figures 4 and 5). After 32 weeks, all structures other than the insular and olfactory sulci were present in 100% of the patients


(Figures 4 and 5). The olfactory sulcus was detected for the first time at 22 weeks but was detectable in more than 25% of the fetuses at 24 weeks (Figure 6). During the last 4 weeks of pregnancy, the convexity sulci were best demonstrated using sagittal planes (Figure 7); during this period the temporal sulci were difficult to visualize due to impaired lateral resolution of the ultrasound. It was not always possible to demonstrate a specific sulcus on both hemispheres in the same ultrasound image; in these cases we recorded each hemisphere in separate images (Figure 8). We found that when a particular structure was present in more than 75% of the fetuses for the first time,



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Figure 3 Ultrasound images showing sagittal planes at 24 and 28 gestational weeks. Note that the section at 24 weeks is close to the midline and at 28 weeks, periventricular. Cingulate sulcus (1), parieto-occipital fissure (2), calcarine sulcus (3), precentral sulcus (4), central sulcus (5), postcentral sulcus (6), marginal sulcus (7), Sylvian fissure (8). W, weeks.

Figure 4 Ultrasound images of midsagittal planes showing the development of the medial sulci. W, weeks.



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Figure 5 Ultrasound images of coronal planes at the level of the posterior horns of the lateral ventricles showing the development of the occipital sulci. W, weeks.

Figure 6 Ultrasound images of coronal planes at the level of the anterior horns of the lateral ventricles showing the normal appearance of the olfactory sulci (arrows). The cingulate sulci can also be seen (arrowheads). W, weeks.




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Figure 7 Ultrasound images of serial sagittal planes at 36 weeks showing fully developed sulci characteristic of the fetal brain near term.

Figure 8 Ultrasound images showing coronal planes at the level of the frontal lobes at 30 weeks of gestation showing the superior frontal horns (arrows) separately in each hemisphere ((a) right and (b) left).



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Table 2 Chronology of sulcation in the present sonographic study and in neuropathological and magnetic resonance imaging (MRI) studies GA of sulcation (weeks)

Structure Interhemispheric fissure Sylvian fissure Parieto-occipital fissure Hippocampal fissure Callosal sulcus Calcarine fissure Cingulate sulcus Central sulcus Postcentral sulcus Precentral sulcus Superior temporal sulcus Inferior temporal sulcus Superior frontal sulcus Inferior frontal sulcus Secondary cingulate sulci Insular sulci Secondary occipital sulci Olfactory sulcus Marginal

Neuropathological appearance (Chi et al.4 )

Detectable in 25–75% of brains by MRI (Garel9 )

10 14 16

24–25

14 16 18 20 25 24 23 30 25 28 32 34–35 34 16

22–23 22–23 24–25 27 26 26 30 24–25 26 31 33 32

Detectable in 25–75% of brains, our study

18

22–23

20 20 26 28 28 28 28 28 28 30 30 26 24 26

Present in > 75% of brains by MRI (Garel9 )

Present in > 75% of brains, our study

22–23 29 22–23 22–23 22–23 24–25 24–25 27 28 27 27 33 29 29 33 34 34

18 18 20 18 18 22 24 28 30 30 30 30 30 30 32 32 30 30 30

27

GA, gestational age.

Table 3 Comparison between previous sonographic studies in newborns and fetuses and our study of gestational age of detection of specific structures GA of detection of specific structures (weeks)

Structure

Interhemispheric fissure Sylvian fissure Parieto-occipital fissure Hippocampal fissure Callosal sulcus Calcarine fissure Cingulate sulcus Central sulcus Postcentral sulcus Precentral sulcus Superior temporal sulcus Inferior temporal sulcus Superior frontal sulcus Inferior frontal sulcus Secondary cingulate sulci Insular sulci Secondary occipital sulci Olfactory sulcus Marginal

Newborns: detectable in at least 25% of examinees* (Huang and Yeh11 )

Fetuses: (Monteagudo et al.17 )

Fetuses: first appearance of sulci/detected in all examinees (Toi et al.18 )

24

18 18

18/20

18

24–25 24–25

14 18 26

18/22 23/24

20 20 26 28 28 28 28 28 28 30 30 26 24 26

26–27

30–31

30–31 32–33

Fetuses: detectable in 25–75% of brains (our study)

Fetuses: present in > 75% of brains (our study)

18 18 20 18 18 22 24 28 30 30 30 30 30 30 32 32 30 30 30

*Examinations were not performed prior to 24 weeks of pregnancy. GA, gestational age.

the same structure would be expected to be present in all the fetuses in the next examination 2 weeks later. The only exceptions to this observation were the cingulate and olfactory sulci (Table 1).


The neonatal examination was normal in all patients. Follow-up telephone interviews with the parents of children aged 12–24 months confirmed that all the children were developing normally.



DISCUSSION The development of the fetal cortex has been studied anatomically1,4 and by MRI5 – 9 . Most sonographic studies have examined neonates born at different gestational ages in order to demonstrate the normal cortical structure at that particular gestational age10 – 14 . Sonographic studies of normal fetal cortical development have been published15 – 18 but there is no sonographic study focusing on the normal longitudinal development of cortical sulci and gyri in utero. Droulle et al.15 were the first to describe the use of transabdominal ultrasound for the assessment of the normal development of the Sylvian fissure. The same group16 studied 70 fetuses and 30 newborns and compared the sonographic findings with anatomical specimens; they were able to visualize some of the main sulci and found a 2–4 week delay between the appearance of the first infoldings of the brain in the anatomical specimens and their corresponding visualization by ultrasound. Monteagudo and Timor-Tritsch17 retrospectively reviewed transvaginal scans of 337 fetal brains, between 14 and 40 weeks’ gestation. Their study was limited to only a few structures. The callosal sulcus could be identified as early as 14 weeks with the lateral sulcus, parieto-occipital fissure and calcarine fissure identified at 18 weeks. The cingulate gyrus and sulcus were first identified at 26 weeks, with secondary branches appearing at 30–40 weeks. Toi et al.18 recently reported their experience with fetal sulcal development. In this study, 50 fetuses between 16 and 30 weeks’ gestation were examined by ultrasound using standard transabdominal axial planes in order to record their cortical development. The parieto-occipital fissure first appeared at 18.5 weeks and was visible in all fetuses at 20.5 weeks. The calcarine sulcus was identified first at 18.5 weeks and was always visible by 21.9 weeks. The cingulate sulcus was first identified at 23.2 weeks and always seen after 24.3 weeks. In a sonographic study by Slagle et al.10 serial examinations were performed on preterm infants until 40 weeks’ postconceptional age. The purpose of the study was to define the normal pattern of cingulate sulcal development. The cingulate sulcus was first identified at a mean of 26 weeks’ gestation with its branches appearing at 30–34 weeks. It is important to mention that according to Slagle et al., maturation of the cortex as a whole (and the cingulate sulcus in particular) was similar pre- and postnatally, and that brain insults resulted in delays in postnatal maturation of the cingulate sulcus. Garel9 published a study with normal fetal brain MRI from 22–38 weeks; as mentioned previously, the same criteria for present, detectable and absent sulci were applied in both this and the present study. Table 2 summarizes the time of appearance of some sulci and gyri examined in this study, compared with the anatomical findings of Chi et al.4 and the MRI study of Garel9 . The appearance of the sulci and gyri, as


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demonstrated by sonographic imaging and MRI, was not always synchronous with their recognition in anatomical studies2,6,7,12 . The difference between sonography and MRI was less pronounced, usually 1–2 weeks apart, with some structures demonstrated earlier by MRI and others earlier by ultrasound. In Table 3 we compare our findings with those of other sonographic studies. Although the cingulate sulcus was observed 4–6 weeks earlier in our study compared with that in other sonographic studies, the development of the other cortical structures resembled that of the other studies, with any differences being within a 1–2 week margin. This is remarkable bearing in mind that although all these studies used ultrasound, the study methods were completely different: Toi et al.18 prospectively studied fetuses in utero; Monteagudo and Timor-Tritsch17 studied them retrospectively; while Huang and Yeh11 examined newborns. Knowledge of the developmental milestones of the fetal cortex is important in order to accurately diagnose in-utero malformations of cortical development. At present there are only a few case reports describing prenatal diagnosis of cortical malformations, mainly of the lissencephaly group21 – 25 . In most of the articles the exact diagnosis was only established after the end of the pregnancy and the earliest sonographic findings were nonspecific, such as hydrocephalus and polyhydramnios. Fong et al.25 retrospectively studied prenatal sonographic examinations of seven newborns identified with Miller–Dieker syndrome. Three of them were diagnosed during pregnancy; the other four were diagnosed after birth. In this retrospective analysis, knowledge of the normal cortical features for each gestational age enabled diagnosis of the cortical malformations in all seven fetuses after 23 weeks. A relatively simple method for the in-utero diagnosis of lissencephaly has been proposed18,25 . However, a disadvantage of this method is that it enables identification of only the more severe forms of cortical malformations26 . Some studies claim that when compared to MRI, sonography is less accurate in the demonstration of cortical malformations. However, MRI is not readily available in most countries, it is expensive, and sedation of the fetus is usually required. Whether MRI is truly superior to ultrasonography in the imaging of the fetal brain remains a matter of debate. In our paper published in 200227 , we compared the diagnosis of brain abnormalities by dedicated fetal neurosonography to that of MRI and concluded that there was no convincing evidence supporting the assumption that MRI was superior to ultrasound in diagnoses of common brain anomalies. The present study proves that the in-utero development of sulci and gyri can be demonstrated by ultrasound just as well as by MRI, in some cases the cortical structures even being depicted sooner by sonography. The knowledge of normal cortical developmental milestones will enable sonographers to demonstrate abnormal development and diagnose cortical malformations in utero.


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