The Fetal vermis, pons and brainstem: normal

http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, 2013; 26(8): 757–762 ! 2013 Informa UK Ltd. DOI: 10.3109/14767058.2012.755508

The Fetal vermis, pons and brainstem: normal longitudinal development as shown by dedicated neurosonography

1

Department of Obstetrics and Gynecology, 2Pediatric Neurology Unit, 3Genetics Institute, Edith Wolfson Medical Center, Holon and Sackler School of Medicine, Tel-Aviv University, Holon, Israel, and 4Department of Obstetrics and Gynecology, Helen Schneider Hospital for Women, Rabin Medical Center, Petach Tikva and Sackler School of Medicine, Tel Aviv University, Holon, Israel

Abstract

Keywords

Objective: To describe the normal appearance and the growth of the fetal vermis, pons and midline brainstem by ultrasound from 18 weeks of gestation to term in order to produce developmental nomograms. Methods: Serial ultrasound examinations of the fetal brain were performed in 21 fetuses between 18 and 39 weeks of gestation every two weeks. A total of 173 examinations were done, 8.2 5.2 examinations per fetus. A mid-sagittal plain of the brain was obtained either by transvaginal or transabdominal sonography. Antero-posterior, cranio-caudal diameters, and surface area of the pons and the vermis were measured. The surface area of the brain stem was also measured. Nomograms were produced according to Royston and Wright. Results: The pons, vermis and brain stem grow in a linear fashion throughout pregnancy. The growth pattern correlates well with gestational age, biparietal diameter, head circumference and the cerebellar transverse diameter. Conclusions: We have provided nomograms for assessment of the fetal brainstem. The present information supplies tools for the accurate identification of fetal mid-hindbrain anomalies providing a solid basis for a multidisciplinary approach, management and counseling of these conditions.

Fetal, hindbrain, midbrain, prenatal diagnosis, ultrasound

Introduction Ultrasound assessment of the fetal brain is of paramount importance in prenatal diagnosis [1]. While significant progress has been made in recent years in understanding development and malformations of the forebrain and the cerebellum, much less attention has been given to the brainstem [2]. The brainstem, which is a distinct subdivision of the brain, includes: the midbrain (mesencephalon), pons and medulla oblongata [3]. The pons contains neurons of the pontine nuclei, transverse fibers extending from the pontine nuclei and longitudinal bundles of the pyramidal tracts. In mammals, a correlation exists between the developmental stage of the cerebral hemispheres, the protuberance from the ventral part side of the pons and the cerebellum. Ascending the

Address for correspondence: Gustavo Malinger, MD, Department of Obstetrics and Gynecology, Edith Wolfson Medical Center, HaLohamim 62, Holon 58100, Israel. Tel: þ972-3-5028491. Fax: þ972-3-503-6408. E-mail: [email protected]

History Received 23 June 2012 Revised 1 November 2012 Accepted 30 November 2012 Published online 12 January 2013

mammalian evolutional scale, the ventral part increases in size [4]. In recent years, it has become evident that although anomalies of infratentorial structures are frequently present in patients with cortical malformations they can also be isolated in patients with mental retardation [5–7]. These structures can be visualized both by fetal MRI and ultrasound. The development of the vermis has been studied in depth [8–10] but there are few studies describing normal fetal biometric data of the pons [11,12] and no studies regarding the fetal development of the midbrain. The possibility to study the normal appearance of the fetal midbrain and pons in conjunction with the vermis will probably lead the way to prenatal diagnosis of malformations secondary to early patterning defects in which the size and ratios between the midbrain and pons are usually altered. The purpose of the present study is to describe the normal appearance and the growth of the fetal vermis, pons and midline brainstem by ultrasound from 18 weeks of gestation to term in order to produce developmental nomograms.

20 13

J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Tel Aviv University on 04/11/15 For personal use only.

Shimon Ginath1, Tally Lerman-Sagie2, Karina Haratz Krajden1, Dorit Lev3, Bina Cohen-Sacher4, Jacob Bar1, Gustavo Malinger1


758

S. Ginath et al.

J Matern Fetal Neonatal Med, 2013; 26(8): 757–762

Figure 1. (a) Illustration of the midsagittal midbrain/hindbrain showing the midbrain tegmentum (1), basal pons (2), pontine tegmentum (3), 4th ventricle (4), vermis (5) and medulla (6). (b) High magnification of transvaginal ultrasound in the midsagittal plane at 32 weeks of gestation demonstrating the same structures.

Methods The study was conducted at the Fetal Neurology Clinic of the Edith Wolfson Medical Center, Holon, Israel, and was part of a larger one that described prospectively the development of the fetal cortex [13]. The study protocol was approved by the institutional review board. Pregnant women volunteering to take part in the study were informed about the scope of the study and asked to sign a consent form. Exclusion criteria were multiple pregnancies, past or present history of fetal brain malformations or neurological disorders and placenta previa. Gestational age (GA) was established by the first day of the last menstrual period and was confirmed by at least one ultrasound scan performed before 15 weeks of gestation. Serial ultrasound examinations were performed by a single examiner (GM) every two weeks from the 18th week of pregnancy until term, using transabdominal 6–8-MHz and 5–13-MHz transducers and/or a transvaginal 5–8-MHz transducer (Logiq 9, General Electric, Milwaukee, WI). In each examination fetal biometry was assessed and estimated fetal weight was calculated based on the biparietal diameter (BPD), head circumference (HC), abdominal circumference and femur length. A detailed examination of the brain was performed, using either a transabdominal and/or transvaginal approach depending on fetal presentation. A midsagittal view was used to measure vermis diameters and area, basal pons diameters and area and midline brainstem area, as depicted in Figure 1. The cerebellar vermis was depicted as an echogenic midline structure interposed between the fourth ventricle and the cisterna magna. The anteroposterior (AP) length was defined as the maximal distance between the most anterior part of the central lobule and the most posterior part of the tuber. The cranio-caudal (CC) length was defined as the maximal distance between the most cranial part of the culmen and the most caudal part of the uvula. The surface area of the vermis was also measured in this plane using the same electronic caliper (Figure 1) [8].

The basilar pons was measured at its AP length and CC length [11]. The AP length was defined as the maximal distance between the most anterior part and the most posterior part of the basilar pons. The CC length was defined as the maximal distance between the most cranial part and the most caudal part of the basilar pons. The surface area of the pons was also measured in this plane using the same electronic caliper (Figure 1). The brainstem area was measured without including the basal pons between the following borders; cranially the lower part of the third ventricle, caudally the lower part of the medulla at the level of the most caudal part of the uvula, dorsally the fourth ventricle and ventrally the basilar pons (Figure 1). The studied structures were measured directly from a magnified scan using an incorporated electronic caliper with 0.1 mm resolution. All measurements were performed at least twice during the examination and the mean of each measurement was used for calculations. Data was collected on an Excel spreadsheet (Microsoft, Redmond, WA) and analyzed using the software SPSS for Windows, version 20.0 (SPSS Inc., Chicago, IL, USA). The data is presented using adjusted regression models that were calculated following Pearson correlation coefficient (all tests applied were two-tailed). p Value50.05 was considered statistically significant. Dispersion charts and reference intervals were constructed based on the method proposed by Royston and Wright [14]. Ninety-five percent confidence intervals were calculated to evaluate the precision of the 5th and 95th centiles.

Results Twenty-one women volunteered to participate in the study. A total of 173 measurements were performed in 21 fetuses by serial examinations between 19 and 39 weeks of gestation, 8.2 5.2 examinations per fetus.

Figure 2. (a) Mean of CC length of cerebellar vermis and respective 5th and 95th centiles according to GA. (b) Mean of AP length of cerebellar vermis and respective 5th and 95th centiles according to GA. (c) Mean of cerebellar vermis surface area and respective 5th and 95th centiles according to GA. (d) Mean of CC length of basilar pons and respective 5th and 95th centiles according to GA. (e) Mean of AP length of basilar pons and respective 5th and 95th centiles according to GA. (f) Mean of basilar pons surface area and respective 5th and 95th centiles according to GA. (g) Mean of brainstem surface area and respective 5th and 95th centiles according to GA.


DOI: 10.3109/14767058.2012.755508

Normal sonographic development of fetal brainstem 759


760

S. Ginath et al.

GA was 19 weeks 4 d 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. The remaining women delivered at term and all newborns were healthy as determined from chart review and telephone interviews. 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 GA and no fetal malformations were detected in any of the patients. The midsagittal AP and CC diameters of the cerebellar vermis increased in a linear fashion, from 8.8 and 9.2 mm at 19–20 weeks’ gestation to 23 and 26 mm at term, respectively. The vermian surface area increased from 0.7 to 4.6 cm2 at the same period (Table 1, Figure 2). The midsagittal AP and CC diameters of the basilar pons increased in a linear fashion, from 5 and 4 mm at 19–20 weeks’ gestation to 13 and 9 mm at term, respectively, an increase of 2.3-fold over 20 weeks of gestation. The basilar pons surface area increased from 0.22 to 1.51 cm2 at the same period (Table 1, Figure 2). The midsagittal brain stem surface area increased from 1.26 to 5.0 cm2, an increase of 3.9-fold over 20 weeks of gestation (Table 1, Figure 2).

Discussion Recent advances in developmental biology, molecular genetics and neuroimaging lead to significant improvement in comprehension of developmental disorders of the embryonic mid- and hind-brain. Malformations of these structures can occur as the only recognized malformation in individuals with mental retardation or autism, or more frequently can be associated with other brain anomalies (i.e. lissencephaly, cobblestone malformations, commissural anomalies and disorders of primary cilia function) and/or extra-CNS malformations (i.e. ocular, renal, hepatic, and limb bud anomalies related to many ciliopathies) [15–18]. Imaging of the cerebellum and cisterna magna has become an important part of the structural survey of the fetus by ultrasound. However, the structures within the midbrainhindbrain are not routinely studied since they are small and difficult to visualize using standard axial planes. Even in children and adults, until recently, it was difficult to recognize subtle distortions in their structure by MRI [7]. Currently fetal brain imaging either using MRI or dedicated neurosonography provide good visualization of the fetal posterior fossa including the cerebellar vermis and the main structures of the brain stem [8,9,19]. Shadowing can occur when attempting to insonate the brain through the facial or occipital bones or when the examination is not done in the midline; therefore the examinations should be performed through the acoustic window provided by either the anterior fontanel, sagittal suture or posterior fontanel. Although the number and complexity of the recognized malformations of the cerebellum and brainstem has been constantly increasing, accurate prenatal assessment of the fetal brainstem-cerebellum still remains restricted to a few centers and frequently relies on MRI studies. Data on normal


sonographic morphology, developmental patterns throughout gestation and biometric parameters are scarce and no former longitudinal sonographic developmental study of this nature has ever been published. The current study brings new quantitative and qualitative data for the sonographic evaluation of the abovementioned structures, and provides an overview of their patterns of coordinated anatomical development throughout gestation. We used Royston and Wright’s method [14] to calculate the reference intervals for various brainstem measurements according to GA. Our findings show that the vermis, pons and brainstem grow in a linear fashion throughout pregnancy and correlate well with GA, BPD, HC and TCD. The pons and vermis surface area also show a linear correlation with GA. Only few previous imaging studies have addressed the fetal brainstem by either sonography or MRI and all of them were cross-sectional. Using the trans fontanel approach, Achiron et al. [11] studied by ultrasound the fetal pons and cerebellum of 293 healthy fetuses of low-risk pregnancies between 19 and 34 weeks. The AP diameter of the pons and the CC diameter of the vermis in a midsagittal plane showed a linear correlation with GA. The mean vermis–pons ratio was 1.5 and did not change throughout the pregnancy. Tilea et al. [12] performed fetal brain MRIs in 589 normal subjects (26–40 weeks). The nomograms of the AP diameter of the pons were in good agreement with previous published US data. Hatta et al. [4] performed a morphometric histological study on 28 normal human fetal brains, ranging from 13 to 28 weeks of gestation. The development of the ventral (basilar) part of the pons was depicted as faster and more prominent compared to the dorsal part, at the level of the motor trigeminal nucleus. This difference was due to paramount cellular differences between the two different parts and the presence of the pontine nuclei at the basilar pons. The pons, the major part of the brainstem, owes its name to the bridge-like appearance in the ventral view. Its main function is to be a communication and conduction center between the spinal cord, cerebellar and cerebral cortex, apart from sheltering ten cranial nerve nuclei and important centers that control integrative functions (cardiovascular system, respiratory and pain sensitivity control, alertness, awareness and consciousness) [3]. The protuberance on the ventral part of the pons is called the basilar pons and it is one of the most characteristic structures of the developing human brainstem, being a model for the study of long distance neuronal migration. It contains the pontine nuclei, which provide the cerebellar hemispheres with the majority of their fiber afferents, and receive their main input from the cerebral cortex [20]. From 18 weeks onward, the basilar pons is highly cellular, with multiple nervous fibers, particularly belonging to the corticospinal motor pathway. The axonal fasciculi mingle with the nuclei at the ventral pons and with the inferior olives at the spinal bulb level, creating the multiple layers that probably explain the hyperechogenic sonographic appearance of this anatomic structure [8]. The genetics and embryology of mid-hindbrain development are still being elucidated, and different classification systems of the disorders have been published, many

18–19 20–21 22–23 24–25 26–27 28–29 30–31 32–33 34–35 36–37 38–39 r p

21 16 20 17 19 19 14 15 19 9 4

GA Patients (weeks) (n)

8.4 10.0 11.3 14.6 15.6 16.4 19.1 19.6 20.6 22.0 24.3

9.2 12.2 13.4 15.7 17.3 18.5 20.3 22.3 22.1 24.7 26.5 0.957 50.0001

11.3 14.0 15.1 17.3 18.6 22.2 22.8 23.5 25.4 27.1 28.2

7.8 8.3 11.2 13.3 13.7 16.1 16.5 18.3 18.6 20.5 18.8

8.8 10.0 12.6 14.7 16.2 18.6 19.1 20.2 22.0 24.7 22.7 0.937 50.0001

50% 10.6 13.2 15.5 16.9 18.7 20.6 22.8 22.4 23.6 26.0 25.8

95%

5%

95%

5%

50%

Sagittal AP (mm)

Sagittal CC (mm)

Vermis 2

0.61 0.80 1.07 1.32 1.9 1.73 2.59 2.84 3.12 3.71 4.30

5% 0.65 1.06 1.25 1.63 2.20 2.48 3.12 3.27 3.81 4.00 4.64 0.968 50.0001

50% 0.80 1.34 1.56 1.87 2.50 2.97 3.52 3.90 4.38 4.78 5.02

95%

Sagittal Surface area (cm )

Table 1. Reference intervals for the cerebellar vermis, basilar pons, and the brain stem.

4.5 4.8 5.8 7.4 6.4 9.3 10.0 11.2 11.5 12.1 12.5

5% 5.5 6.7 7.1 8.6 9.1 10.1 12.3 13.1 13.5 13.7 13.4 0.907 50.0001

50% 6.8 8.4 9.3 10.9 10.9 14.1 13.9 15.7 15.1 14.4 14.0

95%

Sagittal CC (mm)

3.4 4.3 3.6 5.4 4.7 5.8 6.7 7.9 7.6 6.8 9.3

5% 4.2 5.2 5.2 6.3 5.9 7.6 7.9 8.9 8.6 8.9 9.4 0.856 50.0001

50% 4.7 6.7 6.5 8.0 7.7 9.5 9.9 10.5 10.3 10.1 10.1

95%

Sagittal AP (mm)

Pons 2

0.13 0.22 0.30 0.41 0.40 0.50 0.62 0.75 0.92 1.00 1.20

5%

0.22 0.30 0.40 0.48 0.69 0.69 0.83 0.99 1.11 1.28 1.51 0.943 50.0001

50%

0.28 0.39 0.56 0.54 0.86 0.78 0.98 1.23 1.37 1.35 1.67

95%

Sagittal surface area (cm )


1.08 1.51 1.66 1.89 2.62 2.85 3.15 3.59 3.59 5.04 4.76

5%

1.26 1.75 2.14 2.34 3.09 3.74 4.00 4.36 4.72 5.26 5.02 0.951 50.0001

50%

1.66 1.98 2.57 2.92 3.61 4.40 4.58 5.08 5.56 5.59 5.57

95%

Sagittal surface area (cm2)

Brainstem

DOI: 10.3109/14767058.2012.755508

Normal sonographic development of fetal brainstem 761


762

S. Ginath et al.

of them being based on the developmental mechanisms either of the forebrain and the mid-hindbrain [2,21]. The so-called ‘‘regionalization of the brain’’ process starts with the formation of patterning centers that secrete signaling molecules such as the fibroblast growth factors which are important signaling molecules at both the anterior forebrain and the midbrain-hindbrain junction [7]. Considering that AP and dorsoventral patterning share many genes and gene products with the developmental processes of the cerebrum, it is very important to remember that the supratentorial compartment or other organs may also be affected when an infratentorial structure is found abnormal. Moreover, in many of these disorders, the supratentorial malformation is the first to be discovered, and the infratentorial malformation needs to be searched for and then depicted. The nomograms developed in the present study can assist physicians in the diagnosis and differential diagnosis of challenging fetal conditions with involvement of the brainstem and cerebellum. Midbrain-hindbrain malformations have been described in multiple syndromes that can be diagnosed in utero. Our study has several limitations: (a) High quality images of the brainstem structures, particularly of the midbrain may be difficult to obtain particularly when the fetus is in breech presentation and in obese patients. (b) We did not perform inter and intra observer examinations. However, each measurement was performed at least twice during the examination by the same experienced physician (GM) and the mean of each measurement was used for calculations. In conclusion, this is the first longitudinal sonographic study on the development of the fetal brainstem, ventral pons and cerebellar vermis. We have described the patterns of morphometric development and provided nomograms. The present information supplies tools for the accurate identification of fetal mid-hindbrain anomalies providing a solid basis for a multidisciplinary approach, management and counseling of these conditions.


2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

14. 15.

16.

17.

18.

Declaration of interest The authors report no declarations of interest.

19. 20.

References 1. International Society of Ultrasound in Obstetric, Gynecology Education Course. Sonographic examination of the fetal central

21.

nervous system: guidelines for performing the ’basic examination’ and the ’fetal neurosonogram’. Ultrasound Obstet Gynecol 2007;29:109–16. Parisi MA, Dobyns WB. Human malformations of the midbrain and hindbrain: review and proposed classification scheme. Mol Genet Metab 2003;80:36–53. Smith LH, DeMyer WE. Anatomy of the brainstem. Semin Pediatr Neurol 2003;10:235–40. Hatta T, Satow F, Hatta J, et al. Development of the pons in human fetuses. Congenit Anom (Kyoto) 2007;47:63–7. Adamsbaum C, Moutard ML, Andre C, et al. MRI of the fetal posterior fossa. Pediatr Radiol 2005;35:124–40. Malinger G, Lev D, Lerman-Sagie T. The fetal cerebellum. Pitfalls in diagnosis and management. Prenat Diagn 2009;29:372–80. Barkovich AJ. Developmental disorders of the midbrain and hindbrain. Front Neuroanat 2012;6:7 (1–10). Malinger G, Ginath S, Lerman-Sagie T, et al. The fetal cerebellar vermis: normal development as shown by transvaginal ultrasound. Prenat Diagn 2001;21:687–92. Zalel Y, Seidman DS, Brand N, et al. The development of the fetal vermis: an in-utero sonographic evaluation. Ultrasound Obstet Gynecol 2002;19:136–9. Garel C. Posterior fossa malformations: main features and limits in prenatal diagnosis. Pediatr Radiol 2010;40:1038–45. Achiron R, Kivilevitch Z, Lipitz S, et al. Development of the human fetal pons: in utero ultrasonographic study. Ultrasound Obstet Gynecol 2004;24:506–10. Tilea B, Alberti C, Adamsbaum C, et al. Cerebral biometry in fetal magnetic resonance imaging: new reference data. Ultrasound Obstet Gynecol 2009;33:173–81. Cohen-Sacher B, Lerman-Sagie T, Lev D, Malinger G. Sonographic developmental milestones of the fetal cerebral cortex: a longitudinal study. Ultrasound Obstet Gynecol 2006;27:494–502. Royston P, Wright EM. How to construct ’normal ranges’ for fetal variables. Ultrasound Obstet Gynecol 1998;11:30–8. Valente EM, Salpietro DC, Brancati F, et al. Description, nomenclature, and mapping of a novel cerebello-renal syndrome with the molar tooth malformation. Am J Hum Genet 2003;73:663–70. Courchesne E, Redcay E, Morgan JT, Kennedy DP. Autism at the beginning: microstructural and growth abnormalities underlying the cognitive and behavioral phenotype of autism. Dev Psychopathol 2005;17:577–97. Poirier K, Keays DA, Francis F, et al. Large spectrum of lissencephaly and pachygyria phenotypes resulting from de novo missense mutations in tubulin alpha 1A (TUBA1A). Hum Mutat 2007;28:1055–64. Lancaster MA, Gopal DJ, Kim J, et al. Defective Wnt-dependent cerebellar midline fusion in a mouse model of Joubert syndrome. Nat Med 2011;17:726–31. Blazer S, Berant M, Sujov PO, et al. Prenatal sonographic diagnosis of vermal agenesis. Prenat Diagn 1997;17:907–11. Brodal P, Bjaalie JG. Organization of the pontine nuclei. Neurosci Res 1992;13:83–118. Barkovich AJ, Millen KJ, Dobyns WB. A developmental and genetic classification for midbrain-hindbrain malformations. Brain 2009;132:3199–230.