Article

OCTA Findings in Pediatric Patients With X-Linked Retinoschisis

Imaging reveals hyporeflective cysts and loss in the foveal avascular zone.

By Nimesh A. Patel, MD; Camila V. Ventura, MD, PhD; Linda A. Cernichiaro-Espinosa, MD; Nicolas A. Yannuzzi, MD; João Rafael de Oliveira Dias, MD, PhD; Kenneth C. Fan, MD, MBA; Marco A. Zarbin, MD, PhD; Ninel Z. Gregori, MD; Harry W. Flynn Jr., MD ; Audina M. Berrocal, MD

X-linked retinoschisis (XLRS) was first described by Joseph Haas in 1898.1 It is a congenital retinal dystrophy caused by a mutation in the retinoschisin (RS1) gene, located on Xp22.1, which encodes for retinoschisin protein that functions in cellular adhesion.2 The most characteristic clinical finding is foveal schisis cavities with a spoke-wheel pattern in the neurosensory retina with or without peripheral schisis (Figure 1).1,3,4 Spectral-domain optical coherence tomography (SD-OCT) findings in XLRS include foveal cystoid spaces with splitting of the inner nuclear layer (INL) and outer plexiform layer (OPL).5

Optical coherence tomography angiography (OCTA) is a noninvasive imaging tool that generates angiographic images by detecting the movement of red blood cells in the capillaries without the administration of fluorescein.6-9 Despite its widespread use in adult clinical practice, OCTA is utilized less in pediatric retinal imaging due to challenges in image acquisition. Previous studies have reported using OCTA in the pediatric population to describe the posterior pole in cases of epiretinal membrane, Coats disease, and retinopathy of prematurity.10,11

Studies have suggested vascular changes in conjunction with XLRS, including peripheral dendritic vessels, angioma, and vasoproliferative tumor.12-14 Also, a study of a small series of OCTA in XLRS reported perifoveal telangiectasias.10,15 The aim of this study is to determine if there are vascular changes in XLRS; to determine feasibility of obtaining imaging in this population; and to provide data to support the utility, or lack of utility, of OCTA imaging in XLRS.

Figure 1. Fundus photo of right eye, showing foveal schisis in a stellate pattern.

MATERIALS AND METHODS

This cross-sectional, nonconsecutive case series included patients under 18 years of age from the Bascom Palmer Eye Institute (BPEI) diagnosed with XLRS who underwent OCT and OCTA imaging using the AngioVueHD device (Optovue, Inc.) from January 2016 to June 2017. This study was approved by the institutional review board of University of Miami Miller School of Medicine (protocol number 20160487) and was conducted at the BPEI. Eyes of patients were selected for inclusion if 2 authors agreed that images were of high enough quality for analysis.

A trained pediatric ophthalmology photographer used the AngioVueHD device to obtain full-thickness internal limiting membrane to Bruch’s membrane OCTA images and SD-OCT images of the macula. Two observers performed segmentation of the images manually, and the SD-OCT and OCTA images were analyzed. The age, visual acuity, and biomicroscopy findings description were collected from the medical records.

Full-thickness 8 mm x 8 mm OCTA images were recorded. The 8 mm x 8 mm image size was chosen due to a reduction in motion artifact in comparison to 3 mm x 3 mm images. For patient 3, 3 mm x 3 mm images were recorded (Figure 2), which allowed for the best demonstration of the characteristics studied. The OCTA images were manually segmented into the superficial plexus at the retinal nerve fiber layer/ganglion cell layer, deep inner retinal vascular plexuses, at inner plexiform layer/inner nuclear layer and inner nuclear layer/outer plexiform layer borders, and outer retina.

Figure 2. Spectral-domain optical coherence tomography of the left eye of patient 1. Horizontal section (A) shows thick hyaloid with tenting of the inner limiting membrane and hyporeflective cavities in the ganglion cell layer and inner nuclear layer. Vertical section (B) demonstrates cysts in the inner nuclear layer, outer plexiform layer, and outer nuclear layer. Note the disposition of the cysts at the inferior junction of the outer plexiform layer and outer nuclear layer.

RESULTS

Eleven eyes from 6 male patients were included. Owing to the history of retinal detachment and subsequent media opacity on the left eye of one patient (patient 4), image acquisition was not possible. The mean age at examination was 10.0 years old (SD 3.0; range 7.0-15.0 years). The mean logMAR visual acuity was 0.46 (SD 0.19; range 0.18-0.70). All eyes had both macular and peripheral schisis. One patient (patient 2) had a previous vitreous hemorrhage in the right eye that resolved without surgery. All eyes were being treated with dorzolamide 2% drops, once or twice a day.

Imaging findings with SD-OCT of the fovea (Figure 1) showed cystic maculopathy in all included eyes. Cysts were found in the inner nuclear layer in all eyes, outer plexiform layer in 4/11 (36%) eyes, outer nuclear layer in 5 (45%) eyes, and ganglion cell layer in 1 (9%) eye. In all 11 eyes there was distortion of the vessel architecture in the superficial capillary plexus. In 9 eyes, there was no appreciable foveal avascular. In all cases, there were avascular cystic cavities surrounded by vessels in a petaloid-like shape in the deep retinal plexus. There were no telangiectatic vessels or aneurysmal dilations identified. The choriocapillaris was within normal limits in 11/11 eyes (Table 1).

Table 1: SD-OCT and OCTA Findings Distributed by Patient
PATIENT AGE/SEX BCVA PERIPHERAL SCHISIS SD-OCT FINDINGS FOVEAL AVASCULAR ZONE IN THE SUPERFICIAL LAYER “PETALOID-LIKE” SHAPE ON OCTA (YES/NO)
(LogMAR) (Yes/no) (Yes/no) Deep retina Outer retina
1 9/M OD 0.70 Yes Thick hyaloid with tenting of the ILM. Cysts in GCL, INL, OPL, ONL No Yes Yes
OS 0.70 Yes Thick hyaloid with tenting of the ILM. Cysts in INL, OPL, and ONL No Yes Yes
2 7/M OD 0.60 Yes Cysts in INL, ONL No Yes Yes (mild)
OS 0.18 Yes Cysts in INL, OPL, ONL OS: Yes Yes Yes (mild)
3 15/M OD 0.54 Yes Cysts in INL, OPL Small Yes No
OS 0.48 Yes Cysts in INL, ONL No Yes No
4 12/M OD 0.40 Yes Cysts in INL No Yes No
5 8/M OD 0.18 Yes Cysts in INL Small Yes No
OS 0.30 Yes Cysts in INL No Yes Yes (mild)
6 9/M OD 0.60 Yes Cysts in INL No Yes No
OS 0.40 Yes Cysts in INL No Yes NA
GCL, GANGLION CELL LAYER; ILM, INNER LIMITING MEMBRANE; INL, INNER NUCLEAR LAYER; ONL, OUTER NUCLEAR LAYER; OPL, OUTER PLEXIFORM LAYER.

DISCUSSION

In this study, the OCT and OCTA characteristics in XLRS were examined. In prior OCT studies of XLRS, there have been inconsistencies regarding the specific retinal layer in which the schisis occurs. Histopathologic studies observed schisis in the nerve fiber layer.16,17 However, further studies using SD-OCT have shown schisis in the outer retinal layers as Gregori et al5 reported a case series in which the splitting was primarily in the inner nuclear layer and in the outer plexiform layer. This is similar to the results in the current study, where cystic changes were found in the level of the ganglion cell layer in 1 eye (9%), in the inner nuclear layer in 11 eyes (100%), in the outer plexiform layer in 4 eyes (36%), and in the outer nuclear layer in 5 eyes (45%).

Related

Given that XLRS is caused by defective cellular adhesion, vascular changes may not be expected. However, there have been studies that reported peripheral vascular abnormalities.12 Using OCTA of the macula, Stanga et al10 and Stringa et al15 described perifoveal telangiectasias and micovascular changes. In a recent study using swept-source OCTA in an older patient population, it was found that there were mild changes in the superficial capillary plexus, with flow loss in 11%, and no changes in the choriocapillaris and choroid.18 In the current study, there were linear vessels that surround the cystic cavities in petaloid pattern; however, there were no telangiectatic vessels, nor aneurysmal dilations noted.

In the superficial plexus, there were abnormalities in architecture of the vessels, and in some cases, there was lack of an appreciable foveal avascular zone. It is possible that the variations were due to structural changes caused by the underlying avascular cysts.

This study demonstrates that there are challenges to OCTA imaging in the pediatric population. Eye movement during imaging is more frequent and can lead to motion artifact. For focus on the foveal region, 3 mm x 3 mm images would be preferred, as seen in Figure 3, yet patient cooperation did not allow for this in all cases. Further studies using eye-tracking technology and postacquisition processing algorithms may reduce artifacts and improve quality. Additionally, there have been some investigations using handheld OCTA devices, which may be used with the patient under anesthesia.19

Figure 3. Optical coherence tomography angiography image 3 mm x 3 mm from the right eye of patient 3. A small distorted foveal avascular zone in the superficial retina (A). Cystic cavities are delineated by hyperreflective vessels in petaloid pattern the deep retina (B).

A limitation in this study specific to OCTA imaging XLRS is that the inner nuclear layer and outer nuclear layer cystic spaces can disrupt standard segmentation algorithms. Thus, manual nonlinear segmentation is necessary to delineate the superficial and deep plexus and may be time consuming and have a component of subjectivity.

In summary, OCTA images of pediatric patients with XLRS revealed alterations of the foveal avascular zone in the superficial plexus, distortion of vessel architecture, and avascular cystic cavities. There were no telangiectasias vessels, nor aneurysmal dilations noted. RP

Nimesh A. Patel, MD; Camila V. Ventura, MD, PhD; Linda A. Cernichiaro-Espinosa, MD; Nicolas A. Yannuzzi, MD; João Rafael de Oliveira Dias, MD, PhD; Ninel Gregori, MD; Harry W. Flynn Jr., MD; and Audina M. Berrocal, MD, are with the department of ophthalmology at the Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, Miami, Florida. Kenneth C. Fan, MD, MBA, is an ophthalmology resident at the Bascom Palmer Eye Institute. Catherin I. Negron, BA, MBA, is a clinical research coordinator at Bascom Palmer Eye Institute. Financial support was provided by NIH core grant P30EY014801, Department of Defense grant #W81XWH-12-1-0048. None of the authors have any potential conflicts of interest to disclose. All participants in the study had informed consent from the guardian. Reach Dr. Patel at nap46@med.miami.edu.

REFERENCES

  1. Tantri A, Vrabec TR, Cu-Unjieng A, Frost A, Annesley WH Jr, Donoso LA. X-linked retinoschisis: a clinical and molecular genetic review. Surv Ophthalmol. 2004;49(2):214-230.
  2. Iordanous Y, Sheidow TG. Vitrectomy for x-linked retinoschisis: a case report and review of the literature. Can J Ophthalmol. 2013;48:e71-e74.
  3. Fong DS, Frederick AR, Blumenkranz MS, Walton DS. Exudative retinal detachment in X-linked retinoschisis. Ophthalmic Surg Lasers. 1998;29:332-335.
  4. Molday RS, Kellner U, Weber BHF. X-linked juvenile retinoschisis: clinical diagnosis, genetic analysis, and molecular mechanisms. Prog Retin Eye Res. 2012;31(3):195-212.
  5. Gregori NZ, Berrocal AM, Gregori G, et al. Macular spectral-domain optical coherence tomography in patients with X linked retinoschisis. Br J Ophthalmol. 2009;93(3):373-378.
  6. Makita S, Hong Y, Yamanari M, Yatagai T, Yasuno Y. Optical coherence angiography. Opt Express. 2006;14(17):7821-7840.
  7. Savastano MC, Lumbroso B, Rispoli M. In vivo characterization of retinal vascularization morphology using optical coherence tomography angiography. Retina. 2015;35(11):2196-2203.
  8. Jia Y, Bailey ST, Hwang TS, et al. Quantitative optical coherence tomography angiography of vascular abnormalities in the living human eye. Proc Natl Acad Sci U S A. 2015;112(18):E2395-E2402.
  9. Ishibazawa A, Nagaoka T, Takahashi A, et al. Optical coherence tomography angiography in diabetic retinopathy: a prospective pilot study. AM J Ophthalmol. 2015;160(1):35-44.
  10. Stanga PE, Papayannis A, Tsamis E et al. Swept-source optical coherence tomography angiography of paediatric macular diseases. Dev Ophthalmol. 2016;56:166-173.
  11. Nonobe N, Keneko H, Ito Y, et al. Optical coherence tomography angiography of the foveal avascular zone in children with a history of treatment requiring retinopathy of prematurity retina. Retina. 2019;39(1):111-117.
  12. De Laey JJ, Heintz B, Pollet L. Retinal angioma and juvenile sex-linked retinoschisis. Ophthalmic Paediatr Genet. 1992;13(2):73-76.
  13. Patel NA, Laura D, Tran KD, Chang S, Barile G, Berrocal AM. Retinal vasoproliferative tumor in a case of X-linked retinoschisis. Am J Ophthalmol Case Rep. 2018;9:48-50.
  14. Green JL Jr, Jampol L. Vascular opacification and leakage in X-linked (juvenile retinoschisis). Br J Ophthalmol. 1979;63(5):368-373.
  15. Stringa F, Tsamis E, Papayannis A, et al. Segmented swept source optical coherence tomography angiography assessment of the perifoveal vasculature in patients with X-linked juvenile retinoschisis: a serial case report. Int Med Case Rep J. 2017;10:329-335.
  16. Yanoff M, Kertesz Rahn E, Zimmerman LE. Histopathology of juvenile retinoschisis. Arch Ophthalmol. 1968;79(1):49-53.
  17. Manschot WA. Pathology of hereditary juvenile retinoschisis. Arch Ophthalmol. 1972;88(2):131-138.
  18. Han IC, Whitmore SS, Critser DB, et al. Wide-field swept-source OCT and angiography in X-linked retinoschisis. Ophthalmol Retina. 2019;3(2):178-185.
  19. Campbell JP, Nudleman E, Yang J, et al. Handheld optical coherence tomography angiography and ultra-wide-field optical coherence tomography in retinopathy of prematurity. JAMA Ophthalmol. 2017;135(9):977-981.