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Karina Krajden Haratz, Yaakov Melcer, Zvi Leibovitz, Hagit Feit, Tally Kerman-Sagie, Dorit Lev, Shimon Ginath, Liat Gindes, Antonio Fernandes Moron, Gustavo Malinger With compliments of Georg Thieme Verlag

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Ultrasound Nomograms of the Fetal Optic Nerve Sheath Diameter

DOI http://dx.doi.org/10.1055/a0594-2053 For personal use only. No commercial use, no depositing in repositories.

Publisher and Copyright © 2018 by Georg Thieme Verlag KG Rüdigerstraße 14 70469 Stuttgart ISSN 0172-4614 Reprint with the permission by the publisher only

Original Article

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Ultrasound Nomograms of the Fetal Optic Nerve Sheath Diameter Ultraschall-Nomogramme des Durchmessers der fetalen Sehnervenscheide

Authors Karina Krajden Haratz1, 2*, Yaakov Melcer2, 3*, Zvi Leibovitz1, 4, Hagit Feit1, 2, Tally Kerman-Sagie1, 2, 5, Dorit Lev1, 2, 6, Shimon Ginath1, 2, Liat Gindes1, 2, Antonio Fernandes Moron7, Gustavo Malinger2, 8

Affiliations 1 Ultrasound in ObGyn Unit and Fetal Neurology Clinic, Department of Obstetrics and Gynecology, Wolfson Medical Center, Holon, Israel 2 Affiliated with the Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel 3 Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin, Israel 4 Ultrasound in ObGyn Unit, Bnai Zion Medical Center, Haifa, Israel 5 Pediatric Neurology Unit, Wolfson Medical Center, Holon, Israel 6 Genetics Institute, Wolfson Medical Center, Holon, Israel 7 Fetal Medicine Discipline, Department of Obstetrics, Federal University of Sao Paulo, Sao Paulo, Brazil 8 Division of Ultrasound in Obstetrics and Gynecology, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel Key words fetus, brain, optic nerve sheath diameter, ultrasound, septo-optic dysplasia received 27.07.2017 accepted 27.02.2018

Bibliography DOI https://doi.org/10.1055/a-0594-2053 Published online: June 7, 2018 Ultraschall in Med © Georg Thieme Verlag KG, Stuttgart · New York ISSN 0172-4614

Correspondence Karina Krajden Haratz MD Department of Obstetrics and Gynecology – Fetal Neurology Clinic, Edith Wolfson Medical Center, 2 Halochamim St. IL–58100 Holon, Israel Tel.: ++ 9 72/3/5 02 84 91 [email protected]

*

These authors contributed equally

Haratz KK et al. Ultrasound Nomograms of… Ultraschall in Med

ABSTR AC T

Objective To construct prenatal age-specific reference intervals for sonographic measurements of the optic nerve sheath diameter (ONSD) during gestation in normal fetuses. Materials and Methods Prospective cross-sectional study of fetuses assessed in antenatal ultrasound units between 2010 and 2014. The examination was based on a technique for the sonographic assessment of ONSD previously published by our group. The mean values and SDs of the ONSD were modeled as a function of the gestational week by curve estimation analysis based on the highest adjusted R2 coefficient. Repeatability tests were performed to assess intraobserver variability and interobserver agreement. Results During the study period 364 healthy fetuses were enrolled. The mean values for the ONSD varied from 0.6 mm at 15 – 16 weeks to 2.8 mm at 37 – 38 weeks. The ONSD grows in a linear fashion throughout gestation, with a quadratic equation providing an optimal fit to the data (adjusted R2 = 0.957). Conclusion Sonographic age-specific references for the fetal ONSD are presented. This data may assist in the decision-making process in fetuses with a suspected increase in intracranial pressure, or anomalies affecting the development of optic stalks, such as optic hypoplasia and septo-optic dysplasia. Z US A M M E N FA SS U N G

Ziel Bestimmung von pränatalen, altersbezogenen Referenzintervallen für sonografische Messungen des Durchmessers der Sehnervscheide („optic nerve sheath diameter“ = ONSD) bei normalen Feten über die gesamte Schwangerschaft. Material und Methoden Prospektive Querschnittsstudie an Feten, die zwischen 2010 und 2014 in Zentren für Pränataldiagnostik beurteilt wurden. Die Untersuchung basierte auf einer zuvor von unserer Gruppe publizierten Methode zur sonografischen Bewertung des ONSD. Die Mittelwerte und SDs des ONSD wurden als Funktion der Schwangerschaftswoche durch Kurvenschätzungsanalyse basierend auf dem höchsten bereinigten R2-Koeffizienten dargestellt. Für die Bewertung der Intraobserver-Variabilität und InterobserverÜbereinstimmung wurden Reproduzierbarkeitsteste durchgeführt. Ergebnisse Im Studienzeitraum wurden 364 gesunde Feten aufgenommen. Die Mittelwerte für den ONSD variierten von

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0,6 mm in der 15. –16. Woche bis 2,8 mm in der 37. –38. Woche. Der ONSD nimmt während der Schwangerschaft linear zu, wobei eine quadratische Gleichung eine optimale Anpassung an die Daten liefert (bereinigter R2 = 0,957). Schlussfolgerung Es wurden sonografische altersspezifische Referenzwerte für den fetalen ONSD vorgestellt. Diese Daten

Introduction

The optic nerve (cranial nerve II) is a paired nerve which develops as part of the central nervous system rather than a peripheral nerve. It is derived from an outpouching of the diencephalon during embryonic development and is covered with myelin produced by olygodendrocytes (rather than Schwann cells). It is also ensheathed within 3 layers of meninges and a thin layer of cerebrospinal fluid (CSF), assembling a structure called the “optic nerve complex” (ONC) [1]. The space between the optic nerve and the dural sheath is a trabeculated system and plays a role in the CSF dynamics between the perineural space and the intracranial subarachnoid space [2]. Assessment of the intraorbitary portions of the ONC by ultrasound allows an extracranial glimpse into the intracranial compartment. Ultrasound demonstrates ONC as a sharply defined homogeneous hypoechoic band extending posterior from the base of the bulb in adults, children and fetuses [3 – 8]. Modifications in the optic nerve sheath diameter (ONSD) may be secondary to thinning of the nerve component (hypoplasia) or due to pressure changes within the intracranial compartment which are transmitted directly to the ONC [9 – 11]. Sonographic measurement of the ONSD has proven to be a reliable and repeatable technique in children and adults, demonstrating a good relationship with intracranial pressure (ICP) values, particularly at higher thresholds [12]. Our group has previously published on the diagnostic use of ONSD measurement for the identification of increased ICP in fetuses with brain lesions. ONSD values above 2 standard deviations (SD) were associated with increased intracranial pressure [8]. Although prenatal diagnosis of increased fetal ICP or optic hypoplasia enables appropriate multidisciplinary counseling and on-time medical intervention, reference data on fetal ONSD are currently not available. This study aimed to establish ONSD nomograms in healthy fetuses and to assess the reproducibility of the measurements throughout gestation.

Materials and Methods

This prospective cross-sectional study assessed healthy patients who underwent routine ultrasound scans between December 2010 and June 2014 at prenatal diagnosis reference centers. Enrolled patients presented with singleton healthy fetuses from 15 to 38 gestational weeks, determined by the crown-rump length measured in the first trimester. The exclusion criteria were uncertain gestational age (GA), multiple gestations, presence of fetal malformations or genetic anomalies, maternal disease that

können bei Feten mit Verdacht auf intrakraniellen Druckanstieg oder bei Anomalien, die die Bildung der Augenstiele beeinträchtigen, wie z. B. optische Hypoplasie und septo-optische Dysplasie, zur Entscheidungsfindung beitragen.

could affect fetal development and fetal growth abnormalities. Fetuses with a difference of 7 or more days between gestational age calculated by the last menstrual period date and sonographic biometry were excluded as well. All participants received verbal explanation of the nature of the study, and provided informed consent to include the optic nerve assessment in their routine scans. The study was approved by Helsinki Committees in Wolfson Medical Center and Lis Maternity Hospital. Ultrasound scans were performed by two examiners (K. H. and G. M.) with expertise in prenatal diagnosis and fetal neurosonography. Either a 4 – 8 MHz convex abdominal transducer or a 5 – 9 MHz vaginal probe was used to perform fetal assessments (according to fetal presentation), attached to Voluson 730 Expert, E6 or E8 ultrasound devices (GE Medical systems, Milwaukee, WI). The technique for sonographic assessment of the optic nerve in its retrobulbar part (anterior visual tract) and for measurement of the ONSD has been previously described by our group [8]. The preferred plane for the examination of the fetal eye is an axial plane at the level of the lens, with the face positioned towards the transducer or at an angle of approximately 45 degrees from the midline. This plane provides a transverse view of the globe and the structures of the retrobulbar area in which the optic nerve sheath complex can be visualized. Since the optic nerve sheath moves along with eyeball movements, it may be visualized in the center or laterally in the retrobulbar space. The calipers were placed perpendicularly on the outer contours of the optic nerve complex and the distance from the optic disk depends on gestational age: 1.5 mm posterior to the papilla before 28 weeks and 2.0 mm after 28 weeks (▶ Fig. 1). Whenever possible, the ONSD was measured when the lens was centrally positioned, using maximum zoom. Images without the measurements were stored for offline interobserver and intraobserver analysis at another time.

Statistical analysis

Fetal measurements including GA and ONSD measurements were registered in a computerized database and analyzed using IBM SPSS statistics software (IBM Corporation Software Group, NY, USA). Descriptive parameters were expressed as mean ± standard deviation (SD).

First step

44 fetuses underwent measurement of both ONSDs (left and right) and this data was submitted for the first statistical analysis (two-tailed t-test) in order to ensure that measurement of one eye only would be representative for the construction of the nomograms. Once we found no differences between the right and

Haratz KK et al. Ultrasound Nomograms of… Ultraschall in Med

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▶ Table 1 Nomogram for the ONSD (mean ± 2SD) in normal fetuses.

▶ Fig. 1 Technique for measuring the ONSD on the left eye of a 33-week-old fetus. The measurement is performed 2 mm below the papilla.

left sides (p = 0.871), the other enrolled fetuses underwent unilateral measurement of the ONSD for study purposes.

Second step

The mean values and SDs of the ONSD were modeled as a function of the gestational week by curve estimation analysis based on the highest adjusted R2 coefficient. The reproducibility of the ONSD measurements (intra- and interobserver variability) was assessed analyzing a subgroup of 55 arbitrarily selected subjects. For intraobserver variability the ONSD was measured 2 times by a single observer and the mean of these 2 values was used for the estimation of the repeatability coefficient (1.96 ×√2 ×SD – where SD is calculated from the differences between each measurement and the mean of measurements). For interobserver variability the ONSD of each subject was measured once by a second observer. Agreement between measurements was assessed using Student’s paired t-test (p), intraclass correlation coefficients (ICC) and Bland-Altman plots. The 95 % limits of agreement method was used for detecting possible discordant observations [13].

Results

This study included 364 fetuses scanned between 15 and 38 gestational weeks which met the previously mentioned inclusion criteria. A linear growth function was observed between GA and ONSD (r = 0.978; p < 0.0001). The mean ONSD values varied between

Haratz KK et al. Ultrasound Nomograms of… Ultraschall in Med

GA (weeks)

Mean (mm)

+ 2SD

– 2SD

15

0.51

0.77

0..25

16

0.61

0.87

0..35

17

0.71

0.97

0.45

18

0.81

1.07

0.55

19

0.91

1.17

0.64

20

1.01

1.27

0.74

21

1.11

1.39

0.84

22

1.20

1.47

0.94

23

1.31

1.57

1.04

24

1.40

1.67

1.14

25

1.50

1.77

1.24

26

1.60

1.87

1.34

27

1.70

1.97

1.44

28

1.80

2.07

1.54

29

1.90

2.16

1.64

30

2.00

2.26

1.74

31

2.10

2.36

1.84

32

2.20

2.46

1.94

33

2.30

2.56

2.04

34

2.40

2.66

2.14

35

2.50

2.76

2.24

36

2.60

2.86

2.34

37

2.70

2.96

2.44

38

2.80

3.06

2.53

0.6 mm at 15 – 16 weeks and 2.8 mm at 37 – 38 weeks, following the formula: mean ONSD (mm) = 0.996*GA(weeks) – 0.9848. The adjusted R 2 -based analysis of curve estimation for the ONSD showed optimal fit using a second-degree polynomial equation (adjusted R2 0.957). The modeled mean values and SDs for the ONSD, according to gestational week, are provided in ▶ Table 1 and ▶ Fig. 2.

Reproducibility of the measurements – intra- and interobserver reliability For intraobserver variability the estimated repeatability coefficient for the ONSD was 0.12 mm and the absolute difference between measurements in a single subject did not differ by more than this limit on 95 % of occasions. Analysis of interobserver agreement using paired Student’s t-test showed that the assessments made by the two operators were similar (p = 0.30). The ICC was 0.92, showing a strong correlation between measurements (CI 0.85; 0.96). The mean of differences was 0.018 mm (95 % limits of agreement – 0.15; + 0.18) and the standard deviation was ± 0.08 mm in the Bland-Altman plot (▶ Fig. 3).

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▶ Fig. 2 Graph of the ONSD in mm, according to gestational age in weeks. Lines show mean ± 2SD, were modeled according to secondorder polynomial trends.

▶ Fig. 3 Bland-Altman plot showing interobserver agreement of ONSD measurements in a subgroup of 55 fetuses. The mean of differences and 95 % limits of agreement are indicated.

Discussion

Fetal ophthalmic sonography is a noninvasive, readily available, and cost-effective technique for the assessment of the ocular structures and the extracranial segment of the optic nerve. Insonation through the anechoic vitreous allows good depiction of the retrobulbar structures, and measurements of the ONSD in children and adults are highly reproducible [9, 12]. In contrast to imaging obtained by postnatal sonography with high-resolution probes, antenatal sonography of the ONC cannot differentiate the hypoechogenic optic nerve from the other components of the complex: the echogenic pia mater, the very thin subarachnoid space layer (0.1 mm) which appears hypoechogenic and is surrounded by the hyperechogenic dura mater [14]. Obstetric ophthalmic sonography depicts the whole ONC as a sharply defined homogeneous low-reflection band extending posteriorly from the base of the bulb. Measurements of the ONSD should be performed at a depth of 1.5 mm or 2 mm posterior to the papilla before and after 28 weeks, respectively [8]. This region was chosen for the measurement because of the greater amount of elastic

fibers in the connective matrix, which yields a strong distensibility capacity and sensibility to intracranial pressure changes [15]. The current study provides reference data for the fetal ONSD, which grows in a linear fashion between 15 and 38 gestational weeks. Measurements were highly reproducible in fetuses as well, and were similar to the postnatal findings. In the postnatal period, optic nerve sonography serves as an important tool for the noninvasive assessment of ICP especially in the emergency medicine and intensive care settings [11, 16]. Although correlations of the ONSD in infants with an open anterior fontanelle showed a less robust correlation with absolute ICP measurements, Padayachy et al. demonstrated good positive predictive values when the ICP was higher than 10 – 15 mmHg [17]. These findings support our previously published data on increased fetal ICP, and although acute fetal ventriculomegaly does not cause enlargement of the head circumference until it becomes severe with very high ICP levels, an enlarged fetal ONSD seems to be an early and sensitive marker for increased ICP long before any increase in head size or the development of papilledema [8]. Another possible and very important application of the present nomogram is in the prenatal diagnosis of optic nerve hypoplasia (ONH), a congenital malformation which is a leading cause of congenital blindness and visual impairment in the United States and Europe [18, 19]. Underdevelopment of the optic nerve in one or both eyes is the defining feature and it may appear isolated or associated with other findings, as in fetal alcohol spectrum disorder, septo-optic dysplasia or optic nerve hypoplasia syndrome. The latter is a common disease of child neurodevelopment associated with anatomic abnormalities and overall miswiring of the brain that results in visual impairment and profound systemic and functional morbidity. It may be associated to neuroradiographic abnormalities including hydrocephalus, white matter hypoplasia, cortical heterotopia, pachygyria, polymicrogyria, schizencephaly and arachnoid cysts. It is of interest that corpus callosum anomalies are more common than septal agenesis, which has been classically related to optic hypoplasia [18, 20]. The present data may possibly assist in the differential diagnosis between isolated septal agenesis and the so-called “septo-optic dysplasia” syndrome, as currently available imaging tools do not enable in utero differentiation [21]. Fetuses with isolated septal agenesis have an 18 % risk of having septo-optic dysplasia [22], and although optic nerve hypoplasia and endocrine anomalies will never be completely ruled out, measurements of the ON below – 2 SD may be of added value in this challenging counseling process. Technical factors should be taken into account when assessing the ONSD in fetuses. Recent observations in optic nerve sheath sonography emphasize the incidence of artifacts resulting in false ONSD measurements. These should be observed and avoided [23]. The transbulbar sound direction and the incidence of the ultrasound beam on the lamina cribrosa or the dura mater may produce acoustic shadows, giving the impression of a wider optic nerve sheath. The use of color Doppler for the identification of the central retinal artery may aid in the prevention of over-measurement of the shadow, thus decreasing the false-positive rates. This observation may be especially relevant in fetal optic sonographic assessment using probes with a frequency lower than 7.5 MHz [6, 24]. It should also be remembered that the optic

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nerve and the retrobulbar fat move according to ocular globe motion. Furthermore, the nerve transverse section is not spherical and its course may not run strictly straight, which may create meningeal sonographic shadows [25]. We do not propose that ONSD measurement should be incorporated into routine detailed anomaly scans. However, in selected cases that require targeted neuroscan, the integration of ONSD measurement into the antenatal assessment could be of additional value. In conclusion, measurement of the fetal ONSD is feasible and reproducible and we hereby provide reference ranges throughout the second and third trimesters of pregnancy. The present data may assist in the evaluation of fetuses with suspected anomalies affecting the ocular tract or related to increased intracranial pressure, allowing multidisciplinary counseling and proper management.

Conflict of Interest

The authors declare that they have no conflict of interest.

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