Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Peripheral Vascular Abnormalities Detected by Fluorescein Angiography in Contralateral Eyes of Patients With Persistent Fetal Vasculature

Qiujing Huang, MD; Yu Xu, MD, PhD; Qi Zhang, MD; Jiao Lyu, MD, PhD; Shuangshuang Chen, MD; Peiquan Zhao, MD

Abstract

BACKGROUND AND OBJECTIVE:

To describe peripheral retinal vascular abnormalities in the contralateral eyes of patients with unilateral persistent fetal vasculature (PFV).

PATIENTS AND METHODS:

Retrospective medical record review of fluorescein angiography (FA) findings of patients with unilateral PFV. Width of the temporal peripheral avascular retina in contralateral eyes was measured in disc diameters (DD). Vascular abnormalities were described.

RESULTS:

In 45 included patients, mean width of temporal peripheral avascular areas in contralateral eyes was 1.87 ± 0.71 DD. Forty-three patients (95.6%) had temporal peripheral avascular areas of 1 DD or greater in contralateral eyes, with 16 having temporal peripheral avascular areas of 2 DD or greater. Vessel shunts, vascular tortuosity and dilatation, circumferential vessels, and abnormal capillary beds in the peripheral retina were observed in 23 (51.1%) contralateral eyes of patients with unilateral PFV.

CONCLUSION:

PFV patients should undergo careful evaluations of both eyes, preferably with FA, to identify vascular changes that are not visible clinically.

[Ophthalmic Surg Lasers Imaging Retina. 2020;51:506–511.]

Abstract

BACKGROUND AND OBJECTIVE:

To describe peripheral retinal vascular abnormalities in the contralateral eyes of patients with unilateral persistent fetal vasculature (PFV).

PATIENTS AND METHODS:

Retrospective medical record review of fluorescein angiography (FA) findings of patients with unilateral PFV. Width of the temporal peripheral avascular retina in contralateral eyes was measured in disc diameters (DD). Vascular abnormalities were described.

RESULTS:

In 45 included patients, mean width of temporal peripheral avascular areas in contralateral eyes was 1.87 ± 0.71 DD. Forty-three patients (95.6%) had temporal peripheral avascular areas of 1 DD or greater in contralateral eyes, with 16 having temporal peripheral avascular areas of 2 DD or greater. Vessel shunts, vascular tortuosity and dilatation, circumferential vessels, and abnormal capillary beds in the peripheral retina were observed in 23 (51.1%) contralateral eyes of patients with unilateral PFV.

CONCLUSION:

PFV patients should undergo careful evaluations of both eyes, preferably with FA, to identify vascular changes that are not visible clinically.

[Ophthalmic Surg Lasers Imaging Retina. 2020;51:506–511.]

Introduction

Persistent fetal vasculature (PFV), previously termed persistent hyperplastic primary vitreous (PHPV) by Algernon Reese in the 1940s, is one of the most common congenital malformations affecting the eye.1 The hyaloid artery fails to regress in newborn eyes with PFV, resulting in vascular remnants and anatomic abnormalities, including persistent pupillary membranes and posterior tunica vasculosa lentis.2 More than 50% of PFV patients are considered to have unilateral disease;3 however, unilaterality has generally been established by indirect ophthalmoscopy and fundus photography in the past.

Recently, fluorescein angiography (FA) using a wide-field imaging system has been more widely adopted; however, only limited research has been conducted to identify fluorescein angiographic findings in contralateral eyes of patients with unilateral PFV. In this study, we aimed to use this newer technology to identify vascular abnormalities in the contralateral eye of patients diagnosed with unilateral PFV.

Patients and Methods

Study Design

This retrospective study was conducted at a tertiary-level pediatric ophthalmology center at Xin Hua Hospital, affiliated to Shanghai Jiao Tong University School of Medicine. Consecutive patients who were diagnosed with unilateral PFV and who underwent FA examinations from August 2014 to January 2019 were included. Complete medical records were reviewed, and patients who were followed for fewer than 6 months were excluded. Additional exclusion criteria for this study were as follows: patients with a family history of ocular diseases; patients with a history of prematurity; patients with clinically bilateral involvement; patients with systemic symptoms.

This study was conducted with Institutional Review Board approval and adhered to the tenets of the Declaration of Helsinki. The legal guardian of each patient signed a consent form before all examinations and treatments.

Fluorescein Angiography and Description

FA was performed by one experienced doctor (QZ) in all patients using the RetCam3 system (Natus Medical Incorporated, Pleasanton, CA), with a standard pediatric dose (7.7 mg/kg body weight) of intravenous fluorescein sodium (Fluorescite; Alcon, Fort Worth, TX) under general anesthesia. For patients with complications of PFV requiring intraocular surgery, including cataracts or retinal detachment, FA was conducted after surgery and only in the contralateral eye to avoid infection. For patients undergoing noninvasive procedures such as an examination under anesthesia (EUA) or laser indirect ophthalmoscopy (LIO), FA was conducted before or after those procedures in both eyes. During FA, scleral indentation was utilized to image the ora serrata region if necessary; however, those photos were not used for measuring the width of peripheral avascular retina to avoid measuring deviations caused by ocular deformation (See video below).

The primary outcome of the study was the width of the temporal avascular area between the edge of the vessels and the ora serrata. The secondary outcome was the presence of any peripheral vascular abnormalities in the contralateral eyes of patients with unilateral PFV based on FA images. The width from the retinal vessel termini to the ora serrata temporally was measured and divided by disc diameters (DD) using the “straight tool” of ImageJ 1.52a (Wayne Rasband, National Institutes of Health, Bethesda, MD) on MacBook (Apple, Cupertino, CA). If vascular termini were visible but the ora serrata was not, the width of the peripheral avascular retina was measured from the vessel termini to the edge of the image, thus underestimating the actual width.4,5

Statistical Analysis and Photo Editing

All analyses were performed using the Statistical Package for the Social Science software version 22 (SPSS Inc., Chicago, IL). Kolmogorov-Smirnov tests were used to analyze the distribution of samples. Independent t-tests and analysis of variance tests were performed to compare means between groups. A P value of less than .05 was considered statistically significant. Brightness and contrast of FA images were enhanced by Microsoft PowerPoint for Mac Version 16.37 (Microsoft Corporation, Redmond, WA), and figure formats were converted to TIFF files by Photo Image Editor Pixelstyle Version 3.6.5 (EffectMatrix Inc., Little Neck, NY).

Results

Forty-five patients (34 males) were included in this retrospective study. The mean age at FA performance was 17.31 ± 16.86 months (range: 1 to 74 months). PFV affected the right eye in 25 patients and the left eye in 20 patients. Eleven patients had anterior PFV, two patients had posterior PFV, and 32 patients had combined PFV. Five patients had FA performed in both eyes, and 40 patients had FA performed only in the contralateral eye.

Temporal Peripheral Avascular Area in Contralateral Eyes

The mean width of the temporal peripheral avascular area in contralateral eyes was 1.87 ± 0.71 DD, with a median of 1.80 DD. Sixteen patients (35.6%) had temporal peripheral avascular areas of 2 DD or greater in the contralateral eye; 27 patients (60%) had avascular areas less than 2 DD but equal to or greater than 1 DD, and two patients (4.4%) had avascular areas less than 1 DD (Figure 1). The ora serrata was not visible in the FA images of 37 patients (82.2%); accordingly, the width of the peripheral avascular retina was measured from the vessel termini to the edge of the image in these patients, as mentioned above. There were no statistical differences in the mean widths of the peripheral avascular areas in different types of PFV.

Fluorescein angiogram photos showing temporal peripheral avascular areas in the contralateral eyes of three patients with unilateral persistent fetal vasculature. (A) The temporal peripheral avascular area was less than 1 disc diameter (DD) in patient A (0.56 DD). (B) The avascular area was less than 2 DD but greater than 1 DD in patient B (1.4 DD). (C) The avascular area was greater than 2 DD in patient C (2.4 DD).

Figure 1.

Fluorescein angiogram photos showing temporal peripheral avascular areas in the contralateral eyes of three patients with unilateral persistent fetal vasculature. (A) The temporal peripheral avascular area was less than 1 disc diameter (DD) in patient A (0.56 DD). (B) The avascular area was less than 2 DD but greater than 1 DD in patient B (1.4 DD). (C) The avascular area was greater than 2 DD in patient C (2.4 DD).

Peripheral Vascular Abnormalities in Contralateral Eyes

Vessel shunts, vascular tortuosity and dilatation, circumferential vessels, and abnormal capillary beds in the peripheral retina were observed in 23 (51.1%) contralateral eyes of patients with PFV (Figure 2). Among these patients, seven had anterior PFV, one had posterior PFV, and 15 had combined PFV.

(A–F) Fluorescein angiograms demonstrating vascular abnormalities in the contralateral eyes of five patients with unilateral persistent fetal vasculature (E and F are from the same patient). Vessel shunts along vascular-avascular junctions (arrows); vascular dilatation and staining (open arrows); vascular tortuosity (open arrowhead); circumferential vessels with radial branches (closed arrowheads); and abnormal lacy or feathery capillary beds (observed most clearly in the boxed areas).

Figure 2.

(A–F) Fluorescein angiograms demonstrating vascular abnormalities in the contralateral eyes of five patients with unilateral persistent fetal vasculature (E and F are from the same patient). Vessel shunts along vascular-avascular junctions (arrows); vascular dilatation and staining (open arrows); vascular tortuosity (open arrowhead); circumferential vessels with radial branches (closed arrowheads); and abnormal lacy or feathery capillary beds (observed most clearly in the boxed areas).

All patients with abnormal contralateral eyes were managed by observation. During the follow-up period (mean: 28.97 ± 14.84 months, range: 6 to 61 months), peripheral avascular areas and vascular anomalies remained stable, according to fundus photos obtained by RetCam.

Symmetry of Angiographic Patterns in Both Eyes

In one patient, we observed abnormal vascular shunting and hyperfluorescence in the temporal retina in both his PFV eye and his contralateral eye. In another patient, we observed similar hook-like vascular patterns in both eyes (Figure 3).

Fluorescein angiogram (FA) photos of patients with persistent fetal vasculature (PFV). (A) FA photos from a 9-month-old boy with PFV in his right eye and (A, B) abnormal vessel shunts along the vascular-avascular junctions (arrows) and hyperfluorescence in the temporal retina observed in both eyes. (C) FA photos from an 11-month-old boy with PFV in his right eye and (C, D) abnormal hook-like vascular patterns and vessel shunts (arrows) observed in both eyes.

Figure 3.

Fluorescein angiogram (FA) photos of patients with persistent fetal vasculature (PFV). (A) FA photos from a 9-month-old boy with PFV in his right eye and (A, B) abnormal vessel shunts along the vascular-avascular junctions (arrows) and hyperfluorescence in the temporal retina observed in both eyes. (C) FA photos from an 11-month-old boy with PFV in his right eye and (C, D) abnormal hook-like vascular patterns and vessel shunts (arrows) observed in both eyes.

Discussion

In this study, we used FA to observe retinal vascular features in the contralateral eyes of patients with unilateral PFV and measured the width of the temporal peripheral retinal avascular area. We found that more than 90% of patients had a temporal peripheral avascular retina of 1 DD or greater in the contralateral eye, and approximately 40% of patients had a temporal peripheral avascular retina of 2 DD or greater. In addition, 42% of patients with PFV had vascular abnormalities in the contralateral eyes, including vessel shunts, vascular tortuosity and dilatation, circumferential vessels, and abnormal capillary beds.

To our knowledge, limited research has previously been conducted to investigate the fluorescein angiographic findings in the contralateral eyes of patients with PFV,6 and the present study had the largest sample size of these related studies. FA images have, however, recently been used to show nonperfused peripheral retinas in the contralateral eyes of patients with Coats' disease.5,7 Although Coats' disease has generally been considered to be more frequently unilateral, those study findings may suggest otherwise. Similarly, the present study suggests that PFV may be also be a bilateral disease with asymmetry in presentation.

Incomplete peripheral vascularization is common in some pediatric retinal diseases, especially familial exudative vitreoretinopathy (FEVR) and retinopathy of prematurity (ROP). Additionally, incomplete peripheral vascularization has been observed even in healthy adults. Using ophthalmoscopy, Rutnin and Schepens showed that it is typical for the peripheral fundus to have approximately 0.5 DD of peripheral retinal nonperfusion.8 Asdourian and Goldberg reported approximately 1 DD of nonperfusion in young healthy adults.9 Blair et al. used FA to evaluate the length of retinal nonperfusion in 33 pediatric eyes with clinically normal-appearing periphery, and found it to be 1.5 DD or less, with a mean of 0.9 DD temporally.4 Those 33 patients had ocular diseases either only in the contralateral eye or, if in the study eye, to a degree judged by the authors not likely to affect peripheral retinal vascular development. Among those patients, four had PFV in the contralateral eye.4 Blair et al. concluded that 2 DD or greater of nonperfusion, or 3 standard deviations above normal, should be considered abnormal and a sign of peripheral nonperfusion.4

In our study, 35.6% of patients had peripheral temporal avascular retina of greater than or equal to 2 DD; however, no complications related to these avascular retinas were observed during follow-up. Accordingly, we would not yet consider the peripheral avascular areas to be abnormal in these patients. There is evidence, however, that peripheral avascular retinas are associated with an increased risk of retinal breaks and extraretinal fibrovascular proliferation in children with ROP and FEVR, as well as longer axial lengths and lattice degeneration leading to retinal detachment in adults.10–12 This study's patients will undergo long-term follow-up to monitor for the development of retinal holes, fibrovascular proliferation, and retinal detachment and to determine if ocular function is affected.

In this study, vascular abnormalities, including vessel shunts, vascular tortuosity and dilatation, circumferential vessels, and abnormal capillary beds, were identified in the contralateral eyes of patients with unilateral PFV. These findings are reminiscent of ROP, a neovascular retinal disorder resulting from delayed or abnormal retinal vessel growth in premature infants,13,14 with similar peripheral vascular patterns noted in ROP patients after bevacizumab (Avastin; Genentech, South San Francisco, CA) treatment.13,14 The present study's findings indicate that abnormal retinal vessel growth may also occur in the contralateral eyes of patients with PFV. Based on these findings, FA is highly recommended during EUAs, not only for children with bilateral diseases like FEVR or incontinentia pigmenti (IP), but also in children with presumed unilateral diseases such as Coats' disease or PFV. We also suggest modifications to the terminology used to describe PFV, with the clinically affected eye being referred to as “abnormal” or in the “clinical stage” and the contralateral eye being referred to as “subnormal” or in the “subclinical stage.”

The underlying mechanisms for the peripheral avascular retina and the abnormal vasculature in our cases is unknown. In truth, the exact regulatory mechanisms responsible for PFV even remain poorly understood. Several gene knockout (KO)/transgenic mouse models have been shown to manifest features of PFV, including the βA3/A1-crystallin model, Ephrin-A5 KO model, Lama1 KO model, Collagen type XVIII and type XV KO models, Atoh7 mutant mice, Frizzled 5 KO model, and Bax and Bak KO models.15

In addition, a case series has been reported regarding the phenotypic overlap between FEVR and PFV associated with the Frizzled 4 mutation.16 Abnormal retinal vasculature has also been observed in some gene KO mouse models. It is possible that the gene mutations that result in the cellular defects associated with PFV may also be involved in the formation of abnormal retinal vasculogenesis and angiogenesis.

The limitations of this study included its retrospective nature, referral bias, admission bias, small sample size, and the lack of a control group. Larger sample sizes and longer follow-up periods are needed to corroborate our findings and to observe long-term complications in these patients.

In conclusion, vascular abnormalities are more common in the contralateral eyes of patients with unilateral PFV than previously reported. Patients with PFV should undergo careful evaluations of both eyes, preferably with fluorescein angiography, to identify vascular changes not visible clinically.

References

  1. Reese AB, Payne F. Persistence and Hyperplasia of the Primary Vitreous: Tunica Vasculosa Lentis or Retrolental Fibroplasia. Trans Am Ophthalmol Soc. 1945;43:163–192. http://www.ncbi.nlm.nih.gov/pubmed/16693375 PMID:16693375
  2. Goldberg MF. Persistent fetal vasculature (PFV): an integrated interpretation of signs and symptoms associated with persistent hyperplastic primary vitreous (PHPV). LIV Edward Jackson Memorial Lecture. Am J Ophthalmol. 1997;124(5):587–626. doi:10.1016/S0002-9394(14)70899-2 [CrossRef] PMID:9372715
  3. Haddad R, Font RL, Reeser F. Persistent hyperplastic primary vitreous. A clinicopathologic study of 62 cases and review of the literature. Surv Ophthalmol. 1978;23(2):123–134. doi:10.1016/0039-6257(78)90091-7 [CrossRef] PMID:100893
  4. Blair MP, Shapiro MJ, Hartnett ME. Fluorescein angiography to estimate normal peripheral retinal nonperfusion in children. J AAPOS. 2012;16(3):234–237. doi:10.1016/j.jaapos.2011.12.157 [CrossRef] PMID:22681939
  5. Blair MP, Ulrich JN, Elizabeth Hartnett M, Shapiro MJ. Peripheral retinal nonperfusion in fellow eyes in coats disease. Retina. 2013;33(8):1694–1699. doi:10.1097/IAE.0b013e318285cb86 [CrossRef] PMID:23974953
  6. Jeng-Miller KW, Joseph A, Baumal CR. Fluorescein Angiography in Persistent Fetal Vasculature. Ophthalmology. 2017;124(4):455. doi:10.1016/j.ophtha.2016.09.033 [CrossRef] PMID:28335935
  7. Jung EH, Kim JH, Kim SJ, Yu YS. Fluorescein Angiographic Abnormalities in the Contralateral Eye with Normal Fundus in Children with Unilateral Coats' Disease. Korean J Ophthalmol. 2018;32(1):65–69. doi:10.3341/kjo.2016.0092 [CrossRef] PMID:29376220
  8. Rutnin U, Schepens CL. Fundus appearance in normal eyes. II. The standard peripheral fundus and developmental variations. Am J Ophthalmol. 1967;64(5):840–852. doi:10.1016/0002-9394(67)92225-8 [CrossRef] PMID:6054194
  9. Asdourian GK, Goldberg MF. The angiographic pattern of the peripheral retinal vasculature. Arch Ophthalmol. 1979;97(12):2316–2318. doi:10.1001/archopht.1979.01020020532003 [CrossRef] PMID:518382
  10. Chen S-N, Hwang J-F, Wu W-C. Peripheral Retinal Vascular Patterns in Patients with Rhegmatogenous Retinal Detachment in Taiwan. PLoS One. 2016;11(2):e0149176. doi:10.1371/journal.pone.0149176 [CrossRef] PMID:26909812
  11. Yamane T, Yokoi T, Nakayama Y, Nishina S, Azuma N. Surgical outcomes of progressive tractional retinal detachment associated with familial exudative vitreoretinopathy. Am J Ophthalmol. 2014;158(5):1049–1055. doi:10.1016/j.ajo.2014.08.009 [CrossRef] PMID:25127701
  12. Chen SN, Hwang JF, Lin CJ. Clinical characteristics and surgical management of familial exudative vitreoretinopathy-associated rhegmatogenous retinal detachment. Retina. 2012;32(2):220–225. doi:10.1097/IAE.0b013e31821c3ec5 [CrossRef] PMID:22277905
  13. Mansukhani SA, Hutchinson AK, Neustein R, Schertzer J, Allen JC, Hubbard GB. Fluorescein Angiography in Retinopathy of Prematurity: Comparison of Infants Treated with Bevacizumab to Those with Spontaneous Regression. Ophthalmol Retina. 2019;3(5):436–443. doi:10.1016/j.oret.2019.01.016 [CrossRef] PMID:31044736
  14. Vural A, Ekinci DY, Onur IU, Hergünsel GO, Yiğit FU. Comparison of fluorescein angiographic findings in type 1 and type 2 retinopathy of prematurity with intravitreal bevacizumab monotherapy and spontaneous regression. Int Ophthalmol. 2019;39(10):2267–2274. doi:10.1007/s10792-018-01064-7 [CrossRef] PMID:30604251
  15. Hegde S, Srivastava O. Different gene knockout/transgenic mouse models manifesting persistent fetal vasculature: are integrins to blame for this pathological condition?Life Sci. 2017;171:30–38. doi:10.1016/j.lfs.2016.12.019 [CrossRef] PMID:28039002
  16. Robitaille JM, Wallace K, Zheng B, et al. Phenotypic overlap of familial exudative vitreoretinopathy (FEVR) with persistent fetal vasculature (PFV) caused by FZD4 mutations in two distinct pedigrees. Ophthalmic Genet. 2009;30(1):23–30. doi:10.1080/13816810802464312 [CrossRef] PMID:19172507
Authors

From the Department of Ophthalmology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Presented in part as a poster at the 11th Joint Meeting of Japan-China-Korea Ophthalmologists in Fukuoka, Japan, December 1-2, 2018.

Supported by Science and Technology Commission of Shanghai Municipality, Shanghai Sailing Program grant 19YF1432500 (QH); National Natural Science Foundation of China (NSFC) grant 81900908 (QH); Science and Technology Commission of Shanghai Municipality grant 18PJ1407500 (YX); NSFC grant 81800837 (JL); Science and Technology Commission of Shanghai Municipality grant 17411952900 (PZ); and NSFC grant 81770964 (PZ).

Drs. Huang and Xu contributed equally to this manuscript as co-first authors.

The authors report no relevant financial disclosures.

Address correspondence to Peiquan Zhao, MD, Department of Ophthalmology, Xin Hua Hospital, Floor 11, No. 19 Building, 1665 Kongjiang Road, Shanghai, China 200092; email: zhaopeiquan@xinhuamed.com.cn.

Received: March 19, 2020
Accepted: July 09, 2020

10.3928/23258160-20200831-05

Sign up to receive

Journal E-contents