Anti-VEGF drugs, specifically bevacizumab (Avas-tin; Genentech, South San Francisco, CA), have been successfully employed alone1–4 or in combination with other therapeutic agents5–7 to treat retinopathy of prematurity (ROP).
Optical coherence tomography (OCT), a noninvasive technique that enables cross-sectional retinal imaging, and more recently, high-resolution spectral-domain optical coherence tomography (SD-OCT) have been used to study the macula in patients with ROP.8–15
Significant advances have been made in the use of SD-OCT, namely in the understanding of central retinal development and anatomy.16,17 In the preterm infant population, the use of this technique imposes additional challenges. Adequate testing techniques and devices must be made available.18,19 More importantly, distinguishing normal retinal developmental changes20 from those arising from pathologies or therapeutic interventions remains a key goal.
Current ROP management techniques yield healthy-looking and vascularized retinas in individuals with ROP. The present goal is to detect the factors that are responsible for achieving good vision in these eyes. The identification of fine retinal characteristics using SD-OCT may play a key role in achieving this goal. The identification of prognostic factors will also aid in the selection of treatment options.
This study reports the results of our work using SD-OCT to study the macula in preterm infants treated with Avastin for ROP.
Patients and Methods
Twenty eyes of 11 patients who were treated with Avastin for ROP between 2007 and 2011 were included in the study. Most of the patients had been treated for type 1 ROP with a single intravitreal injection of Avastin. Other premature patients were referred due to progression of the disease despite laser treatment or due to stage 4A ROP requiring further treatment that included Avastin and/or vitreoretinal surgery.
The use of bevacizumab in our patients with ROP was discussed and approved by members of the National Neonatal Network. In all cases, written informed consent was obtained from the patients’ guardians before injections were administered.
Imaging was performed under sedation during routine follow-up examinations with a portable SD-OCT device (iVue with iStand; Optovue, Fremont, CA). This Optovue OCT does not have approval from the U.S. Food and Drug Administration. For the purposes of this study, images obtained with this device were comparable to others we have obtained with a newer SD-OCT, the Envisu 2300 (Bioptigen; Research Triangle Park, NC). In our experience, the Bioptigen OCT expands the potentials of pediatric OCT and also has FDA approval.
Both eyes of all infants were dilated by the instillation of one drop of phenylephrine hydrochloride 2.5% and tropicamide 1%. Following pupillary dilation, a clinical examination, including indirect ophthalmoscopy with a 28 D lens, was performed. After acquiring the OCT images, a series of retinal photographs were obtained using the RetCam imaging system (Clarity Medical Systems, Pleasanton, CA). All images were obtained by one of the authors.
Images from 20 eyes of 10 non-premature children with a mean age of 9 years (range: 5 to 16 years) with normal ophthalmoscopic findings and 20/20 vision were also examined.
All of the SD-OCT images were analyzed with the integrated software provided in the iVue system, and the following macular measurements were performed: presence of foveal contour (FC), retina map, central foveal thickness (CFT), parafoveal thickness (PT), and perifoveal thickness (PPT). The total, inner retinal (IRL), and outer retinal (ORL) layers were studied. A foveal-parafoveal index (F/P index) was calculated to quantify the foveal depth by dividing the CFT by the PT (the lower the value, the deeper the foveal pit). The following retinal layer measurements were performed for all images: nerve fiber layer (NFL), ganglion cell layer (GCL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), external limiting membrane (ELM), inner to outer segment (IS/OS), outer segment to retinal pigment epithelium (OS/RPE), and RPE. The OCT images were further analyzed using cross-line and three-dimensional reconstructions for foveal developmental signs and foveal avascular zone characteristics.
Twelve eyes of seven patients were treated with a single intravitreal injection of Avastin for type 1 ROP. Five eyes of four patients received Avastin after laser treatment, and three eyes of two patients underwent micro-incision vitrectomy for stage 4A retinal detachments. The outcome after treatment was favorable in all eyes.
The mean gestational age was 25 weeks, the mean birth weight was 722.5 g, and the mean chronological age at the time of OCT was 28.9 months (range: 4 to 50 months) (Table 1).
Demographic and Clinical Descriptions of Study Group
Fundus examination in all patients using indirect ophthalmoscopy and RetCam images revealed an unexceptional-looking posterior pole and macula to our routine examiners. A more detailed review of the Ret-Cam images by more expert readers revealed the presence of some macular changes, especially related to foveal reflex characteristics, but none were exclusive nor directly correlated with one particular underlying retinal structure. The SD-OCT images taken in each case were the only way of determining the macular architecture in these infants. Additionally, one patient exhibited a small decrease in the temporal vascular arcade angle and three eyes showed pallor of the optic disc at the time of treatment.
Table 2 depicts the measurements of the retinal areas in different groups of patients according to their retinal configuration. Of the 20 eyes treated with Avastin for ROP, the mean CFT was 245.1 ± 31.8 µm, and the mean PT was 262.7 ± 38.4 µm, with an F/P index of 0.94 ± 0.07. Thirteen eyes (of seven patients) of the 20 eyes (65%) developed an FC (foveal pit) with a mean CFT of 253.8 ± 23.2 µm, PF of 280.8 ± 27 µm, and F/P index of 0.9 ± 0.1. Of these eyes, 46% had zone I ROP. Seven eyes (35%) of four patients did not develop an FC. In this group, the mean CF was 228.86 ± 38.4 µm, and the mean PT was 229.14 ± 33.46 µm, resulting in an F/P index of 1.0 ± 0.04. All of these eyes had zone I ROP. The presence (or absence) of an FC was bilateral.
Macular Metrics of Study Population
In the group of non-premature children, an FC was noted in all cases. These patients presented a mean CF of 245.4 ± 15.3 µm, PT of 307.9 ± 11.1 µm, and F/P index of 0.79 ± 0.03.
Compared with non-premature children, the group of treated patients with FC development showed an increased CFT, a reduced PT and PPT, and a shallow foveal pit (mean F/P index: 0.9 vs 0.79). The thickness reduction in the PT and PPT in these patients was due to a thinner IRL at those points. The thickness of the ORL at the fovea, parafovea, and perifovea does not differ from these measurements in non-premature children. A higher F/P index was explained by an increase in the CFT (secondary to the presence of an IRL at the fovea) and a thinner IRL at the parafovea and perifovea (Table 2).
The morphological analysis of the retina in the group of treated patients with an FC showed that all retinal layers were present at the macula with persistence of retinal layers over the fovea (INL and IPL). The following signs of macular development were also noted: OS elongation, IS/OS and external limiting membrane presence, and thickening of the ONL at the fovea (Figure 1).
Example of a case with foveal contour development (13 eyes in seven patients). OCT and RetCam (Clarity Medical Systems, Pleasanton, CA) images of the left eye of patient 5 at 28 months after Avastin (bevacizumab; Genentech, South San Francisco, CA) treatment (birth weight: 720 g; gestational age: 24 weeks; zone I ROP). All retinal layers were present. Persistence of retinal layers (inner nuclear, inner plexiform) over the fovea (red bracket). Signs of macular development: outer segment elongation, inner segment/outer segment and external limiting membrane presence (blue arrows), and thickening of the outer nuclear layer at the fovea (orange bracket).
Patients without FC development (ie, with no foveal pit) presented a mean F/P index of 1. These patients showed a reduced CFT, PT, and PPT compared with treated ROP patients with FC development and with non-premature children (Table 2). The retinal thickness reduction at all three points was due to a thinner ORL and IRL. The greatest thickness reduction was in the IRL at the PT and PPT.
Image analysis of these patients revealed that although there was retinal layer persistence, not all retinal layers were present. The FL was absent except in patients with good visual acuity, and differentiation between the GCL and IPL was difficult. The following signs of macular development were also noted: OS elongation, the presence of the IS/OS and external limiting membrane, and thickening of the ONL. These morphological characteristics enable the recognition of the foveal area in the absence of a foveal pit (Figure 2).
Example of a patient with no foveal contour development (35% of treated eyes). OCT and RetCam (Clarity Medical Systems, Pleasanton, CA) images of the left eye of patient 2 at 38 months after Avastin (bevacizumab; Genentech, South San Francisco, CA) treatment (birth weight: 650 g; gestational age: 24 weeks; zone I ROP). Not all retinal layers are present (nerve fiber layer absent). It is difficult to differentiate between the ganglion cell layer and inner plexiform layer.
The absence of FC development was associated with a lower gestational age and zone I disease. Preterm infants with no foveal pit were all zone I cases and had a mean gestational age of 24.5 weeks. Patients with a foveal pit had a mean gestational age of 25.6 weeks (25 weeks when the disease was located in zone I and 26 weeks when located in zone II) (Table 3).
Foveal Pattern and Visual Acuity of Study Population
When an FC was present, vision tended to be better. In patients without an FC, two of the five eyes with measurable VA had better than 20/400 vision compared with 10 of 11 eyes with an FC (Table 3).
Morphological analysis of the retina in the group of patients with no FC revealed differences between patients with good vision and those with poor vision. In the two eyes with good VA, the foveal site revealed the persistence of distinct retinal layers, maturation signs, a reduced or nonexistent FAZ, and a CFT that was maintained compared with that of treated preterm infants with FC development. In eyes that presented with poor visual acuity, the foveal location could also be identified using signs of maturation. There were persistent retinal layers present, but these IRLs could not be clearly identified. FAZ was reduced or nonexistent and the CFT was decreased compared with treated preterm infants with FC development (Figure 3).
OCT and RetCam (Clarity Medical Systems, Pleasanton, CA) images of the retina in a patient with no foveal contour and good vision (A) compared with those of a patient with poor vision (B). In the left eye of patient 3 (A), treated with Avastin (bevacizumab; Genentech, South San Francisco, CA), laser, and micro-incision vitrectomy surgery, the morphological analysis show persistence of distinct retinal layers and the central foveal thickness (CFT) is maintained. In the left eye of patient 4 (B), treated with Avastin and laser, retinal layers cannot be clearly individualized, and there is a decreased CFT. The foveal location (asterisk) can be determined using signs of foveal maturation: outer segment elongation, inner segment/outer segment and external limiting membrane presence, and thickening of the outer nuclear layer (double arrow).
This study shows that the use of Avastin for the treatment of advanced ROP can result in different macular configurations, as revealed by SD-OCT. Despite a normal-looking retinal fundus in ophthalmoscopy and RetCam images, two distinct macular configurations showing the presence or absence of an FC could be observed in these patients.
Patients with FC development represented 65% of the eyes in our study. An increased CFT and a shallow foveal pit (evidenced by a higher F/P index) were observed in preterm infants. The failure of the migration of the inner retinal layers explains this increased central foveal thickness. Previous reports have also shown this condition13,21–23 in preterm infants who did not receive Avastin. In this study, the thickness measurements of the ORL at the fovea, parafovea, and perifovea in preterm children do not differ from those in non-premature children.
In the group of patients treated with Avastin who did not develop an FC, the presence of foveal maturation signs14 allowed for the location of the macula. The absence of the foveal pit was accompanied by a decrease in the retinal thickness at all measured points, and the layer analysis notably showed that not all of the retinal layers were present.
The absence of an FC was encountered in the smallest preterm infants, and all were zone I cases. An explanation for this result could be that changes secondary to ROP in a very immature retina can stop foveal pit development. There is evidence to suggest that it is not due to the Avastin. These features and associations were seen in the absence of Avastin in previous studies.13,20,22
In this study, the absence of an FC appears to correlate with poor vision. While two of the five eyes with measurable VA had better than 20/400 vision when the foveal pit was absent, 10 of the 11 eyes with a foveal pit had better than 20/400 VA. The term “fovea plana” has been used to identify retinas without a foveal pit.24 An absent foveal depression had previously not been shown to negatively influence visual function.8,24 Although the majority of eyes without an FC in this study had poor vision, a distinct retinal anatomy could be observed in the eyes that presented with good vision without an FC; specifically, the foveal site revealed the persistence of distinct retinal layers, maturation signs, a reduced or nonexistent FAZ, and a maintained CFT.
The clinical identification of this particular retinal configuration using SD-OCT may be predictive of better visual acuity.
Current ROP management techniques allow for healthy-looking and possibly fully vascularized retinas for individuals with ROP. The current goal of ophthalmologists is to identify the factors that are responsible for achieving good vision in the presence of ROP. Identification of these factors will thus inform therapeutic decisions, and SD-OCT studies may play a key role in this process.
- Mintz-Hittner HA, Kennedy KAChuang AZ; BEAT-ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med. 2011;364:603–615. doi:10.1056/NEJMoa1007374 [CrossRef]
- Dorta P, Kychenthal A. Treatment of type 1 retinopathy of prematurity with intravitreal bevacizumab (Avastin). Retina. 2010;30:S24–31. doi:10.1097/IAE.0b013e3181ca1457 [CrossRef]
- Travassos A, Teixeira S, Ferreira P, et al. Intravitreal bevacizumab in aggressive posterior retinopathy of prematurity. Ophthalmic Surg Lasers Imaging. 2007;38:233–237.
- Martínez-Castellanos MA, Schwartz S, Hernández-Rojas ML, et al. Long-term effect of antiangiogenic therapy for retinopathy of prematurity up to 5 years of follow-up. Retina. 2013;33:329–338. doi:10.1097/IAE.0b013e318275394a [CrossRef]
- Kychenthal A, Dorta P. Vitrectomy after intravitreal bevacizumab (Avastin) for retinal detachment in retinopathy of prematurity. Retina. 2010;30:S32–36. doi:10.1097/IAE.0b013e3181ca146b [CrossRef]
- Nazari H, Modarres M, Parvaresh MM, Ghasemi Falavarjani K. Intravitreal bevacizumab in combination with laser therapy for the treatment of severe retinopathy of prematurity (ROP) associated with vitreous or retinal hemorrhage. Graefes Arch Clin Exp Opthamol. 2010;248:1713–1718. doi:10.1007/s00417-010-1430-x [CrossRef]
- Axer-Siegel R, Snir M, Ron Y, et al. Intravitreal bevacizumab as supplemental treatment or monotherapy for severe retinopathy of prematurity. Retina. 2011;31:1239–1247. doi:10.1097/IAE.0b013e31820d4000 [CrossRef]
- Joshi MM, Trese MT, Capone A Jr, . Optical coherence tomography findings in stage 4A retinopathy of prematurity: a theory for visual variability. Opthamology. 2006;113:657–660. doi:10.1016/j.ophtha.2006.01.007 [CrossRef]
- Recchia FM, Recchia CC. Foveal dysplasia evident by optical coherence tomography in patients with a history of retinopathy of prematurity. Retina. 2007;27:1221–1226. doi:10.1097/IAE.0b013e318068de2e [CrossRef]
- Wu WC, Lin RI, Shih CP, et al. Visual acuity, optical components, and macular abnormalities in patients with a history of retinopathy of prematurity. Ophthalmology. 2012;119:1907–1916. doi:10.1016/j.ophtha.2012.02.040 [CrossRef]
- Muni RH, Kohly RP, Charonis AC, Lee TC. Retinoschisis detected with handheld spectral-domain optical coherence tomography in neonates with advanced retinopathy of prematurity. Arch Ophthalmol. 2010;128:57–62. doi:10.1001/archophthalmol.2009.361 [CrossRef]
- Maldonado RS, O’Connell R, Ascher SB, et al. Spectral-domain optical coherence tomographic assessment of severity of cystoids macular edema in retinopathy of prematurity. Arch Opthamol. 2012;130:569–578.
- Wang J, Spencer R, Leffler JN, Birch EE. Critical period for foveal fine structure in children with regressed retinopathy of prematurity. Retina. 2012;32:330–339. doi:10.1097/IAE.0b013e318219e685 [CrossRef]
- Vinekar A, Avadhani K, Sivakumar M, et al. Understanding clinically undetected macular changes in early retinopathy of prematurity on spectral domain optical coherence tomography. Invest Ophthalmol Vis Sci. 2011;52:5183–5188. doi:10.1167/iovs.10-7155 [CrossRef]
- Lee AC, Maldonado RS, Sarin N, et al. Macular features from spectral-domain optical coherence tomography as an adjunct to indirect ophthalmoscopy in retinopathy of prematurity. Retina. 2011;31:1470–1482. doi:10.1097/IAE.0b013e31821dfa6d [CrossRef]
- Vajzovic L, Hendrickson AE, O’Connell RV, et al. Maturation of the human fovea: correlation of spectral-domain optical coherence tomography findings with histology. Am J Ophthalmol. 2012;154:779–789. doi:10.1016/j.ajo.2012.05.004 [CrossRef]
- Hendrickson A, Possin D, Vajzovic L, Toth CA. Histologic development of the human fovea from midgestation to maturity. Am J Ophthalmol. 2012;154:767–778. doi:10.1016/j.ajo.2012.05.007 [CrossRef]
- Vinekar A, Sivakumar M, Shetty R, et al. A novel technique using spectral-domain optical coherence tomography (Spectralis, SD-OCT+HRA) to image supine non-anaesthetized infants: utility demonstrated in aggressive posterior retinopathy of prematurity. Eye (Lond). 2010;24:379–382. doi:10.1038/eye.2009.313 [CrossRef]
- Maldonado RS, Izatt JA, Sarin N, et al. Optimizing hand-held spectral domain optical coherence tomography imaging for neonates, infants, and children. Invest Ophthalmol Vis Sci. 2010; 51:2678–2685. doi:10.1167/iovs.09-4403 [CrossRef]
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- Yanni SE, Wang J, Chan M, et al. Foveal avascular zone and foveal pit formation after preterm birth. Br J Ophthalmol. 2012;96:961–966. doi:10.1136/bjophthalmol-2012-301612 [CrossRef]
- Ecsedy M, Szamosi A, Karkó C, et al. A comparison of macular structure imaged by optical coherence tomography in preterm and full-term children. Invest Ophthalmol Vis Sci. 2007;48:5207–5211. doi:10.1167/iovs.06-1199 [CrossRef]
- Akerblom H, Larsson E, Eriksson U, Holmström G. Central macular thickness is correlated with gestational age at birth in prematurely born children. Br J Ophthalmol. 2011;95:799–803. doi:10.1136/bjo.2010.184747 [CrossRef]
- Marmor MF, Choi SS, Zawadzki RJ, Werner JS. Visual insignificance of the foveal pit: reassessment of foveal hypoplasia as fovea plana. Arch Ophthalmol. 2008;126:907–913. doi:10.1001/archopht.126.7.907 [CrossRef]
Demographic and Clinical Descriptions of Study Group
|Patient No.||Eye||Zone||Avastin||Laser||MIV||BW (g)||GA (wks)||Age at SD-OCT (mos)||Sex|
Macular Metrics of Study Population
|Treated (n = 20)||No ROP (n = 20)||Treated ROP, Foveal Pit Present (n = 13)||Treated ROP, Foveal Pit Absent (n = 7)|
|CFT (µm)||245.1 ± 0.1||245.4 ± 15.4||253.8 ± 23.2||228.86 ± 38.4|
|PT (µm)||262.7 ± 38.4||308.0 ± 11.2||280.8 ± 27.0||229.14 ± 33.4|
|PPT (µm)||251.42 ± 33.3||286.3 ± 10.8||266.3 ± 29.6||223.85 ± 19.3|
|F/P index||0.94 ± 0.07||0.79 ± 0.03||0.9 ± 0.1||1.0 ± 0.04|
|IFT (µm)||83.25 ± 14.1||79.4 ± 8.5||87.2 ± 11.6||75.86 ± 15.43|
|IPT (µm)||105.6 ± 18.52||131.8 ± 5.3||115.0 ± 12.4||88.1 ± 14.99|
|IPPT (µm)||98.43 ± 16.88||119.9 ± 7.1||106.4 ± 14.3||83.71 ± 10.1|
|OFT (µm)||161.85 ± 19.73||166.0 ± 9.5||166.6 ± 14.6||153.0 ± 24.42|
|OPT (µm)||157.6 ± 19.67||176.2 ± 8.3||165.8 ± 16.0||142.46 ± 16.71|
|OPPT (µm)||153.04 ± 17.91||168.7 ± 7.4||160.1 ± 16.6||139.88 ± 11.6|
Foveal Pattern and Visual Acuity of Study Population
|Zone and FC||Eyes (n)||GA (mos)||F/P Index||Weeks After Avastin||VA|
|Zone I, FC (−)||7||24.5 ± 2.18||0.99||34 ± 2||20/436|
|Zone I, FC (+)||6||25.0 ± 0.8||0.92||35 ± 1||20/286|
|Zone II, FC (+)||7||26.0 ± 0.1||0.89||39 ± 3||20/194|