Skip to main content

Advertisement

SpringerLink
Log in

Three-dimensional pattern of extraretinal neovascular development in retinopathy of prematurity

  • Retinal Disorders
  • Published:
Graefe's Archive for Clinical and Experimental Ophthalmology Aims and scope Submit manuscript

Abstract

Background

The application of three-dimensional (3D) visualization techniques to evaluate the earliest visible onset of abnormal retinal vascular development in preterm infants with retinopathy of prematurity (ROP), using bedside non-contact optical coherence tomography (OCT) imaging to characterize morphology and sequential structural changes of abnormal extraretinal neovascularization.

Methods

Thirty-one preterm infants undergoing routine ROP screening with written informed consent for research imaging were enrolled in this prospective observational study. We imaged the macula and temporal periphery of preterm infants using a handheld OCT system (Envisu 2300 or handheld swept-source research system). The scans obtained were segmented and, using enhanced ray casting, were converted to 3D volumes to which color filter was applied.

Results

Using colorized 3D visualization, we defined extraretinal neovascular structures as buds, bridging networks, and placoid lesions. We could longitudinally follow progression and regression of extraretinal neovascularization in stage 3 ROP after treatment in one infant over 12 weeks and document the appearance of early buds, and formation of florid neovascularization. From stages 2 to 3 ROP, we observed progression from sessile buds to a complex plaque that corresponded to stage 3 ROP on clinical examination. We demonstrated regression of neovascular complexes to small pre-retinal tufts after treatment with anti-VEGF.

Conclusions

The extension of OCT processing to include surface flattening and colorization that further improved structural analysis rendered better understanding of extraretinal tissue. Our ability to image similar areas in the same infant over multiple visits enabled us to study the evolution of these structural components and follow pathological vascular events longitudinally in development and regression after treatment. These methods can be applied to further study which are likely contribute to our understanding of the pathophysiology of neovascularization in ROP.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Gilbert C, Foster A (2001) Childhood blindness in the context of VISION 2020--the right to sight. Bull World Health Organ 79:227–232

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Hartnett ME (2010) The effects of oxygen stresses on the development of features of severe retinopathy of prematurity: knowledge from the 50/10 OIR model. Doc Ophthalmol 120:25–39. https://doi.org/10.1007/s10633-009-9181-x

    Article  PubMed  Google Scholar 

  3. Mann IC (1928) The develpoment of the human eye. Cambridge University Press, London

    Google Scholar 

  4. Hartnett ME (2015) Pathophysiology and mechanisms of severe retinopathy of prematurity. Ophthalmology 122:200–210. https://doi.org/10.1016/j.ophtha.2014.07.050

    Article  PubMed  Google Scholar 

  5. Hartnett ME (2017) Advances in understanding and management of retinopathy of prematurity. Surv Ophthalmol 62:257–276. https://doi.org/10.1016/j.survophthal.2016.12.004

    Article  PubMed  Google Scholar 

  6. Lutty GA, McLeod DS, Bhutto I, Wiegand SJ (2011) Effect of VEGF trap on normal retinal vascular development and oxygen-induced retinopathy in the dog. Invest Ophthalmol Vis Sci 52:4039–4047. https://doi.org/10.1167/iovs.10-6798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lutty GA, Chan-Ling T, Phelps DL, Adamis AP, Berns KI, Chan CK, Cole CH, D'Amore PA, Das A, Deng WT, Dobson V, Flynn JT, Friedlander M, Fulton A, Good WV, Grant MB, Hansen R, Hauswirth WW, Hardy RJ, Hinton DR, Hughes S, McLeod DS, Palmer EA, Patz A, Penn JS, Raisler BJ, Repka MX, Saint-Geniez M, Shaw LC, Shima DT, Smith BT, Smith LE, Tahija SG, Tasman W, Trese MT (2006) Proceedings of the third international symposium on retinopathy of prematurity: an update on ROP from the lab to the nursery (November 2003, Anaheim, California). Mol Vis 12:532–580

    PubMed  Google Scholar 

  8. Foos RY (1987) Retinopathy of prematurity. Pathologic correlation of clinical stages. Retina 7:260–276

    Article  CAS  PubMed  Google Scholar 

  9. Foos RY, Kopelow SM (1973) Development of retinal vasculature in paranatal infants. Surv Ophthalmol 18:117–127

    Google Scholar 

  10. Ashton N, Cook C (1954) Direct observation of the effect of oxygen on developing vessels: preliminary report. Br J Ophthalmol 38:433–440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ashton N (1954) Pathological basis of retrolental fibroplasia. Br J Ophthalmol 38:385–396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Schmidt-Erfurth U, Leitgeb RA, Michels S, Povazay B, Sacu S, Hermann B, Ahlers C, Sattmann H, Scholda C, Fercher AF, Drexler W (2005) Three-dimensional ultrahigh-resolution optical coherence tomography of macular diseases. Invest Ophthalmol Vis Sci 46:3393–3402. https://doi.org/10.1167/iovs.05-0370

    Article  PubMed  Google Scholar 

  13. Maldonado RS, Izatt JA, Sarin N, Wallace DK, Freedman S, Cotten CM, Toth CA (2010) Optimizing hand-held spectral domain optical coherence tomography imaging for neonates, infants, and children. Invest Ophthalmol Vis Sci 51:2678–2685. https://doi.org/10.1167/iovs.09-4403

    Article  PubMed  PubMed Central  Google Scholar 

  14. Maldonado RS, Yuan E, Tran-Viet D, Rothman AL, Tong AY, Wallace DK, Freedman SF, Toth CA (2014) Three-dimensional assessment of vascular and perivascular characteristics in subjects with retinopathy of prematurity. Ophthalmology 121:1289–1296. https://doi.org/10.1016/j.ophtha.2013.12.004

    Article  PubMed  PubMed Central  Google Scholar 

  15. Chavala SH, Farsiu S, Maldonado R, Wallace DK, Freedman SF, Toth CA (2009) Insights into advanced retinopathy of prematurity using handheld spectral domain optical coherence tomography imaging. Ophthalmology 116:2448–2456. https://doi.org/10.1016/j.ophtha.2009.06.003

    Article  PubMed  PubMed Central  Google Scholar 

  16. Viehland C, Keller B, Carrasco-Zevallos OM, Nankivil D, Shen L, Mangalesh S, Viet d T, Kuo AN, Toth CA, Izatt JA (2016) Enhanced volumetric visualization for real time 4D intraoperative ophthalmic swept-source OCT. Biomed Opt Express 7:1815–1829. https://doi.org/10.1364/boe.7.001815

    Article  PubMed  PubMed Central  Google Scholar 

  17. Bleicher ID, Jackson-Atogi M, Viehland C, Gabr H, Izatt JA, Toth CA (2018) Depth-Based, Motion-Stabilized Colorization of Microscope-Integrated Optical Coherence Tomography Volumes for Microscope-Independent Microsurgery. Translational Vision Science and Technology In Press

  18. Hughes S, Yang H, Chan-Ling T (2000) Vascularization of the human fetal retina: roles of vasculogenesis and angiogenesis. Invest Ophthalmol Vis Sci 41:1217–1228

    CAS  PubMed  Google Scholar 

  19. Smith LE, Hard AL, Hellström A (2013) The biology of retinopathy of prematurity: How Knowledge of Pathogenesis Guides Treatment. Clin Perinatol 40:201–214. https://doi.org/10.1016/j.clp.2013.02.002

    Article  PubMed  PubMed Central  Google Scholar 

  20. Hartnett ME, Penn JS (2012) Mechanisms and management of retinopathy of prematurity. N Engl J Med 367:2515–2526. https://doi.org/10.1056/NEJMra1208129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lepore D, Quinn GE, Molle F, Baldascino A, Orazi L, Sammartino M, Purcaro V, Giannantonio C, Papacci P, Romagnoli C (2014) Intravitreal bevacizumab versus laser treatment in type 1 retinopathy of prematurity: report on fluorescein angiographic findings. Ophthalmology 121:2212–2219. https://doi.org/10.1016/j.ophtha.2014.05.015

    Article  PubMed  Google Scholar 

  22. Purcaro V, Baldascino A, Papacci P, Giannantonio C, Molisso A, Molle F, Lepore D, Romagnoli C (2012) Fluorescein angiography and retinal vascular development in premature infants. J Matern Fetal Neonatal Med 25(Suppl 3):53–56. https://doi.org/10.3109/14767058.2012.712313

    Article  PubMed  Google Scholar 

  23. Garoon I, Epstein G, Segall M, Rabb MF, LaFranco F, Quirk TC 3rd (1980) Vascular tufts in retrolental fibroplasia. Ophthalmology 87:1128–1132

    Article  CAS  PubMed  Google Scholar 

  24. Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, Abramsson A, Jeltsch M, Mitchell C, Alitalo K, Shima D, Betsholtz C (2003) VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol 161:1163–1177. https://doi.org/10.1083/jcb.200302047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kushner BJ, Essner D, Cohen IJ, Flynn JT (1977) Retrolental Fibroplasia. II Pathologic correlation. Arch Ophthalmol 95:29–38

    Article  CAS  PubMed  Google Scholar 

  26. Wallace DK, Kylstra JA, Greenman DB, Freedman SF (1998) Significance of isolated neovascular tufts ("popcorn") in retinopathy of prematurity. J Aapos 2:52–56

    Article  CAS  PubMed  Google Scholar 

  27. Chen X, Mangalesh S, Dandridge A, Tran-Viet D, Wallace DK, Freedman SF, Toth CA (2018) Spectral-domain OCT findings of retinal vascular-avascular junction in infants with retinopathy of prematurity. Ophthalmology Retina. https://doi.org/10.1016/j.oret.2018.02.001

  28. Lepore D, Molle F, Pagliara MM, Baldascino A, Angora C, Sammartino M, Quinn GE (2011) Atlas of fluorescein angiographic findings in eyes undergoing laser for retinopathy of prematurity. Ophthalmology 118:168–175. https://doi.org/10.1016/j.ophtha.2010.04.021

    Article  PubMed  Google Scholar 

  29. Cunningham S, Fleck BW, Elton RA, McIntosh N (1995) Transcutaneous oxygen levels in retinopathy of prematurity. Lancet 346:1464–1465

    Article  CAS  PubMed  Google Scholar 

  30. Penn JS, Tolman BL, Lowery LA, Koutz CA (1992) Oxygen-induced retinopathy in the rat: hemorrhages and dysplasias may lead to retinal detachment. Curr Eye Res 11:939–953

    Article  CAS  PubMed  Google Scholar 

  31. Simmons AB, Bretz CA, Wang H, Kunz E, Hajj K, Kennedy C, Yang Z, Suwanmanee T, Kafri T, Hartnett ME (2018) Gene therapy knockdown of VEGFR2 in retinal endothelial cells to treat retinopathy. Angiogenesis. https://doi.org/10.1007/s10456-018-9618-5

  32. Becker S, Wang H, Simmons AB, Suwanmanee T, Stoddard GJ, Kafri T, Hartnett ME (2018) Targeted knockdown of overexpressed VEGFA or VEGF164 in Muller cells maintains retinal function by triggering different signaling mechanisms. Sci Rep 8:2003. https://doi.org/10.1038/s41598-018-20278-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. McCloskey M, Wang H, Jiang Y, Smith GW, Strange J, Hartnett ME (2013) Anti-VEGF antibody leads to later atypical intravitreous neovascularization and activation of angiogenic pathways in a rat model of retinopathy of prematurity. Invest Ophthalmol Vis Sci 54:2020–2026. https://doi.org/10.1167/iovs.13-11625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wang H, Yang Z, Jiang Y, Flannery J, Hammond S, Kafri T, Vemuri SK, Jones B, Hartnett ME (2014) Quantitative analyses of retinal vascular area and density after different methods to reduce VEGF in a rat model of retinopathy of prematurity. Invest Ophthalmol Vis Sci 55:737–744. https://doi.org/10.1167/iovs.13-13429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Du Tran-Viet and Alexandria Dandridge (Duke University Eye Center), for data acquisition, Dr. Neeru Sarin, MBBS (Duke University Eye Center), and Dr. C Michael Cotten (Department of Neonatology, Duke University Medical Center) for recruiting infants for the study. We also thank Colin A. Bretz, PhD (Moran Eye Center, Utah) for preparing, staining, and imaging the retinal flat-mount of the rat OIR model.

Funding

Bayer global ophthalmology awards program (GOAP) fellowship project award, K23EY028227 and RPB career development award (XC); The Hartwell Foundation (CAT); The Andrew Family Charitable Foundation (CAT); Grants P30 EY001583, RO1 EY025009 and R01 EY015130 and R01 EY017011 from the National Eye Institute (NEI); Rockefeller Writing Residency (CAT); and an Unrestricted Grant from Research to Prevent Blindness, Inc., New York, NY, to the Department of Ophthalmology & Visual Sciences, University of Utah. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NEI, or NIH. The sponsors or funding organizations had no role in the design or conduct of this research.

Author information

Authors and Affiliations

  1. Department of Ophthalmology, Duke University School of Medicine, 2351 Erwin Road-Suite 1002 AERI, Durham, NC, 27710, USA

    Shwetha Mangalesh, Isaac D. Bleicher, Xi Chen, Joseph A. Izatt, Sharon F. Freedman & Cynthia A. Toth

  2. Department of Biomedical Engineering, Duke University, Durham, NC, 27708, USA

    Christian Viehland, Francesco LaRocca, Joseph A. Izatt & Cynthia A. Toth

  3. Department of Pediatrics, Duke University School of Medicine, Erwin Rd, Durham, NC, 27710, USA

    Sharon F. Freedman

  4. Department of Ophthalmology, Moran Eye Center, University of Utah, Salt Lake City, UT, USA

    M. Elizabeth Hartnett

Authors
  1. Shwetha Mangalesh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Isaac D. Bleicher
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xi Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christian Viehland
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Francesco LaRocca
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Joseph A. Izatt
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sharon F. Freedman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M. Elizabeth Hartnett
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Cynthia A. Toth
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cynthia A. Toth.

Ethics declarations

This study was conducted under two study protocols and was approved by the Duke University Medical Center institutional review board and adhered to the tenets of the Declaration of Helsinki.

Conflict of interest

Dr. Toth receives royalties through her university from Alcon. Dr. Izatt has a patent and receives royalties from Leica Microsystems. No other authors have financial disclosures. No authors have a proprietary interest in the current study.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Written informed consent was obtained from all individual participants (parent/guardian) included in the study.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(DOCX 2666 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mangalesh, S., Bleicher, I.D., Chen, X. et al. Three-dimensional pattern of extraretinal neovascular development in retinopathy of prematurity. Graefes Arch Clin Exp Ophthalmol 257, 677–688 (2019). https://doi.org/10.1007/s00417-019-04274-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00417-019-04274-6

Keywords

Search

Navigation