2D Visualization and Measurement of the Fetal Optic Chiasm. Improving The

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Ultrasound Obstet Gynecol 2016; 48: 733–738 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.15862

Two-dimensional visualization and measurement of the fetal optic chiasm: improving counseling for antenatal diagnosis of agenesis of the septum pellucidum

F. VINALS*,˜ P. RUIZ*†, F. CORREA‡ and P. GONC¸ ALVES PEREIRA§ *Centro AGB Ultrasonografıa,´ Clınica´ Sanatorio Aleman´ and Facultad de Medicina, Universidad de Concepcion,´ Concepcion,´ Chile; †Hospital Costa del Sol, Marbella, Spain; ‡Fetal and Neonatal Ultrasound Department, Hospital Fernando Fonseca, Lisbon, Portugal; §Neuroradiology Department, Hospital Lusıadas,´ Lisbon, Portugal

KEYWORDS: agenesis; fetal neurosonography; optic chiasm; septo-optic dysplasia; septum pellucidum

ABSTRACT INTRODUCTION

Objective To develop an objective method for visualizing Absence of the septum pellucidum (SP) is considered and measuring the fetal optic chiasm (OC) using to be a rare congenital brain malformation1. Over transvaginal two-dimensional (2D) ultrasound in the recent years, identification rates of this condition have coronal plane and to report measurements in fetuses with increased owing to progress in prenatal and neonatal agenesis of the septum pellucidum (SP). diagnosis2. Counseling of these patients represents one of the challenges of fetal medicine, as it can be isolated Methods This was a prospective cross-sectional study or associated with a wide range of brain defects3,4. of 115 morphologically normal fetuses in low-risk Some of these associated anomalies, such as open pregnancies, between 21 and 30 weeks’ gestation. The lip schizencephaly, severe holoprosencephaly, complete OC was measured in a coronal plane at the level of the agenesis of the corpus callosum and ventriculomegaly, third ventricle and was seen as a horizontally aligned can be diagnosed easily with sonography3. Others, such dumbbell-shaped structure of moderate echogenicity. In as septo-optic dysplasia, can be difficult to identify by fetal addition, OC measurements from eight fetuses with imaging. This condition presents a highly heterogeneous agenesis of the SP and complete follow-up were compared phenotype and is defined by the variable association of with the reference range. hypoplasia of the visual connecting pathways, agenesis Results OC measurements were obtained in 110/115 nor- of the SP and/or pituitary endocrine impairment. A wide mal fetuses and showed that OC increases linearly with spectrum of neurological abnormalities associated with gestational age. Our method of measurement demon- septo-optic dysplasia has been reported5,6. strated good intraobserver repeatability and excellent Septo-optic dysplasia is usually diagnosed postnatally. interobserver reproducibility. Among the eight fetuses The magnetic resonance imaging (MRI) criteria for with agenesis of the SP, five had normal OC measure- postnatal diagnosis are direct evaluation of the optic ments and five had normal vision postnatally. Pregnancy nerves and the optic chiasm (OC)7–9. The latter is continued to term in all cases and the follow-up period visualized through the coronal plane. Since agenesis of varied from 6 months to 7 years. the SP is highly indicative of septo-optic dysplasia during Conclusion Our study demonstrates that it is possible to fetal life3, it would be very helpful to evaluate the OC in visualize and measure the OC directly on a 2D ultrasound such cases. Although a normal-sized OC does not rule out coronal plane. In fetuses with agenesis of the SP, the septo-optic dysplasia, a hypoplastic OC associated with morphology and width of the OC visual pathway could absence of the SP gives cause to suspect it7. prove a relevant tool for assessing its development. It To date, few prenatal studies have carried out would also help in the difficult task of providing antenatal evaluations that have been focused exclusively on counseling when faced with the diagnosis of agenesis of the posterior optic tracts using three-dimensional (3D) the SP. Copyright © 2016 ISUOG. Published by John ultrasound10. The aim of this study was to develop an Wiley & Sons Ltd. objective method for visualizing and measuring the OC on

Correspondence to: Dr F. Vinals,˜ Centro AGB Ultrasonografıa,´ Clınica´ Sanatorio Aleman,´ Facultad de Medicina, Universidad de Concepcion,´ Junge 75-A, Concepcion,´ Chile (e-mail: [email protected]) Accepted: 8 January 2016

Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd. ORIGINAL PAPER 734 Vinals˜ et al. a two-dimensional (2D) pre-established coronal plane and OC. Measurement of the OC was also compared with to document the normal range of OC width throughout that on coronal MRI, whenever this was available. gestation. Additionally, the study sought to assess the value of analyzing the measurements of a series of fetuses Statistical analysis affected by agenesis of the SP. Analysis was performed using measurements of central tendency, dispersion and position for quantitative SUBJECTS AND METHODS variables, and frequency distribution for qualitative This was a prospective cross-sectional study of 115 variables. Centile ranges were calculated and tabulated morphologically normal vertex fetuses in low-risk for consecutive GA values and regression fitness with GA pregnancies undergoing routine ultrasound examination was determined. Linear regression analysis was performed at 21–30 weeks’ gestation. All cases underwent 2D to determine the association of outcome variables with transvaginal neurosonography, performed by a single respect to GA, describing the value of coefficient of trained sonographer using a Voluson E8 BT13 ultrasound determination. The level of statistical significance was machine (GE Healthcare Ultrasound, Milwaukee, WI, set at P < 0.05. USA) equipped with an RIC 5–9D vaginal probe. Multiple Agreement between the measurements of the two raters pregnancies and fetuses with congenital malformations, and between the two consecutive assessments performed abnormal karyotype or growth restriction were excluded by the expert assessor were analyzed using the intraclass from the study. All patients gave informed consent for correlation coefficient (ICC). They were then described participation in the study. Gestational age (GA) was using a Bland–Altman plot. Intraobserver variation was determined from measurement of the fetal crown–rump calculated from 30 cases, with 1 week’s GA difference length at 11–13 weeks’ gestation. Fractions of weeks were between measurements, while interobserver repeatability rounded up to the nearest week, with fractions of ≤ 4 days was assessed in 110 patients. Data were analyzed using assigned to the earlier week and ≥ 5 days to the later week. the SPSS statistical software v.15 (SPSS Inc., Chicago, IL, On the coronal approach through the anterior USA) and 3.1 Epidat (EpiData Association, Denmark). fontanelle, the OC was identified as a horizontally aligned dumbbell-shaped structure of moderate echogenicity RESULTS located in the midline, situated centrally within the suprasellar cistern at the level of the anteroinferior Measurements of fetal OC width could be obtained in wall of the third ventricle, below the optic recess11,12 110/115 (95.7%) normal fetuses from 21–30 weeks’ (Figure 1). Transvaginal fetal neurosonography was gestation. Measurements of fetal OC width were fitted carried out according to the method of Timor-Tritsch adequately with a linear regression model as follows: and Monteagudo13; the coronal plane used in our OC width (mm) = 0.078 + (0.275 × GA), where GA is the study corresponds to the mid-coronal-2 plane used gestational age closest to the nearest week. The rate of in their description. Visualizing the pulsation of the increase of OC was 0.275 mm/week (Figure 3). supracavernous segment of the internal carotid artery GA explained 32.4% of parameter variability (r = 0.33) immediately below the borders of the OC and the anterior and there was evidence of increased variability with cerebral artery, which passes cranially to the OC, provided increasing GA (P < 0.001). Table 1 shows the mean and clear anatomical reference points to help define the 3rd,5th,95th and 97th centiles for OC width measurement lateral and superior boundaries of the fetal OC (Figure 1). at 21–30 weeks in our cohort of fetuses. Mean OC width The width of the OC was measured by an experienced increased throughout gestation, from 6.0 mm at 21 weeks sonographer in a coronal plane with the calipers touching to 8.2 mm at 29 weeks. the inner edge of the slightly echogenic chiasma wall The ICCs were 0.784 (95% CI, 0.45–0.91) for (Figure 2). A 3-s videoclip was stored digitally at this level. intraobserver and 0.917 (95% CI, 0.88–0.94) for inter- All measurements were repeated by a second sonographer, observer measurements. The mean difference in OC blinded to the first measurements, using the cineloop saved width measurement was 0.28 mm (95% CI, −0.11 to on the ultrasound machine. 0.67 mm) for intraobserver repeatability and 0.0082 mm All fetuses defined as having ‘absence of the cavum (95% CI, −0.079 to 0.095 mm) for interobserver repeata- septi pellucidi’ or ‘agenesis of the SP’ were selected bility, and the respective SDs were 0.84 and 0.46. retrospectively from our single-center database. After The Bland–Altman plot for interobserver variability excluding cases with anomalies such as holoprosen- showed that the difference between the OC measure- cephaly, callosal agenesis, ischemic hemorrhagic lesions ments obtained by the two observers was close to and severe ventriculomegaly, eight patients who had the mean (Figure 4). been examined by ultrasound between June 2009 and We were able to obtain complete follow-up for all eight June 2015 with complete follow-up were included in cases with agenesis of the SP (Table 2). The OC measure- the study. Postnatal ophthalmological examination was ment for these cases was carried out retrospectively by available in all cases. Digital videoclips and 3D volume an experienced operator, but in three cases it had also datasets from coronal transvaginal neurosonography been measured during transvaginal neurosonography, performed as described above were used to measure the following the same technique described above. Two

Figure 1 Transvaginal neurosonographic images in a normal 29-week fetus. (a) Coronal view through anterior fontanelle showing optic chiasm (arrows) and cavum septi pellucidi ( ) delimited laterally by the leaves of the septum pellucidum. (b) Same view showing supracavernous segment of internal carotid artery (large arrowhead) and anterior cerebral artery (small arrowhead).

10.0

9.0

8.0

7.0

Optic chiasm width (mm) 6.0

5.0 20 22 24 26 28 30 Gestational age (weeks)

Figure 3 Reference range for fetal optic chiasm width at 21–30 Figure 2 Transvaginal coronal ultrasound image showing weeks’ gestation, calculated by linear regression. Median, 5th and measurement of normal optic chiasm width in a 26-week fetus. 95th centiles are shown (r = 0.33).

3.0 Table 1 Reference range for fetal optic chiasm (OC) width between 2.4 21 and 29 weeks’ gestation 1.8 1.2 OC width (mm) 0.6 3rd 5th 50th 95th 97th GA (weeks) n centile centile centile centile centile 0.0 –0.6 21 4 5.6 5.66.06.36.3 –1.2 22 15 5.6 5.66.07.57.5 23 27 5.4 5.48 6.47.74 7.9 –1.8 24 23 5.7 5.74 6.57.96 8.0 –2.4 25 25 5.5 5.56 6.89.010.0 Difference between two observers (mm) –3.0 26 7 5.7 5.77.08.18.1 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 27 3 6.8 6.87.08.18.1 Mean of two measurements (mm) 28 2 7.1 7.17.85 8.68.6 29 3 6.9 6.98.28.78.7 Figure 4 Bland–Altman plot for interobserver variability of measurements of fetal optic chiasm width, showing differences At 30 weeks’ gestation, only one fetus was assessed; OC width was between pairs of measurements plotted against the mean value. 10 mm. GA, gestational age. , mean difference; , 95% limits of agreement.

Table 2 Summary of eight fetuses with agenesis of the septum pellucidum (ASP), measurement of the optic chiasm (OC) and complete follow-up

GA OC width OC-width Fetal Ultrasound Age at time Postnatal Case (weeks) (mm) centile sex diagnosis of writing MRI Outcome

1 28/31* 7.7/8.2* Normal F ASP 5 yr 11 mo No Normal vision 2 27 8.5 Normal F ASP 5 yr 11 mo No Normal vision 3 24/30* 7.8/8.8* Normal F ASP 2 yr 3 mo No Normal vision 4 33 10.6 Normal F ASP 4 yr 7 mo No Normal vision 5255.1< 3rd F ASP, severe FGR 2 yr 7 mo Yes Normal vision 6295.1< 3rd F ASP, bilateral 2 yr Yes Nystagmus, poor vision, schizencephaly epilepsy, psychomotor delay 7 28 6.5 Normal M ASP, unilateral 7 yr Yes Bilateral optic nerve schizencephaly hypoplasia, epilepsy 8294.3< 3rd F ASP, unilateral 6 mo Yes Nystagmus, right-sided schizencephaly, deafness, psychomotor polymicrogyria delay, epilepsy

*Two OC measurements were obtained at different gestational ages (GA). F, female; FGR, fetal growth restriction; M, male; mo, months; MRI, magnetic resonance imaging; yr, years.

11.0 DISCUSSION The OC is a commissure formed by converging optic 10.0 nerves anteriorly and diverging optic tracts posteriorly. Its development begins between the fourth and sixth weeks 9.0 of gestation, forming a later structure with meeting and partial decussation of the optic nerves. Subsequently, the 8.0 optic tracts grow backwards from the OC, terminating in the diencephalon and midbrain. The OC is in direct contact with cerebrospinal fluid anteriorly within the 7.0 subarachnoid space and posteriorly within the third ventricle, features that can be identified easily on postnatal Optic chiasm width (mm) 6.0 MRI11,12. The floor of the third ventricle is located above the OC and below it lies the body of the sphenoid bone, 14 5.0 typically above the sella turcica , although the relative position of the chiasm over the sella turcica is variable. 20 22 24 26 28 30 32 In 12% of the population, the chiasm is above the Gestational age (weeks) tuberculum sellae (i.e. ‘prefixed’); in 79% it is above the diaphragma sellae; and in only 4% of cases it lies above Figure 5 Optic chiasm width in eight cases of agenesis of the 11 septum pellucidum plotted against normal reference range at the dorsum sellae (i.e. ‘postfixed’) . However, in MRI 21–30 weeks’ gestation, calculated by linear regression (r = 0.33). studies, these differences in position are not mentioned Median, 5th and 95th centiles of normal range are shown. ,Case as impacting on measurement of the width of the OC 1 (two different measurements at 28 and 31 weeks); ,Case2; , coronally15–18. Case 3 (two different measurements at 24 and 30 weeks); ,Case The OC is an important landmark for interpreting MRI 4; ,Case5; ,Case6; ,Case7; , Case 8. The optic chiasm 16 width in Cases 5, 6 and 8 is below the limits of the confidence examinations of adults’ and children’s brains .Asmall interval according to the linear regression curve. chiasm can be an indicator of several disorders, the most common of which is septo-optic dysplasia. The diagnosis of postnatal atrophy or enlargement of the chiasm has patients were assessed at different stages of gestation, with mainly been made by qualitative interpretation on MRI; OC measurements taken 3 weeks apart in one case and few studies have published normal range values of OC 6 weeks apart in the other (Figure 5). The OC width was area and width on coronal MRI images. Wagner et al.16 below the 3rd centile in three fetuses; two were affected reported that, in adults, the width of the OC on MRI by schizencephaly (Figure 6) and one had severe growth ranged between 10.3 mm and 18.3 mm. According to this restriction (Figure 7). In the remaining cases of agenesis same study, coronal images provide the most accurate OC of the SP, the width of the OC was within the normal measurements16, and coronal images of the brain are a range for GA (Figure 8). Follow-up of these cases ranged standard sequence for imaging the chiasm and sella. There between 2 and 7 years. In four cases, vision was normal, may be some variation between studies due to section but in one case, in which OC had been normal in size differences, but the study by Wagner et al.16 postulates but schizencephaly was detected prenatally, vision was that errors can be minimized by using the section impaired. with the largest chiasm measurement. Measuring OC

Figure 6 (a,b) Small abnormally shaped optic chiasm (arrow) on two-dimensional ultrasound in a 28-week fetus with unilateral schizencephaly ( ) and agenesis of septum pellucidum. (c) Coronal T2 fetal magnetic resonance image at 30 weeks conﬁrming abnormal shape of chiasm (arrow).

Figure 7 (a,b) Optic chiasm (arrow) in a 25-week fetus with agenesis of septum pellucidum ( ) and severe growth restriction. Chiasm width was < 3rd centile. At 55 months of age, development and vision were normal.

Figure 8 Normal appearance (a) and size (b) of optic chiasm (arrow) in a 30-week fetus with agenesis of septum pellucidum ( ). At 51 months of age, development and vision were normal.

Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2016; 48: 733–738. 738 Vinals˜ et al. width is justified by the fact that postnatal MRI studies range for OC width, measured using 2D transvaginal found that chiasm height was so small that its measure- neurosonography, which provides evidence that this ment led to significant intraobserver and interobserver dimension of the OC increases linearly with GA. We errors16. have reported OC measurements and clinical follow-up Bault et al.10 described the visualization and devel- in a series of fetuses with agenesis of the SP. Finally, we opment of the fetal optic tract using 3D ultrasound, believe that our study provides a novel parameter that mainly transabdominal axial acquisition. Our ultrasound could be useful in assessing and counseling patients with technique showed good intraobserver repeatability and signs of fetal septo-optic dysplasia. excellent interobserver reproducibility. 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