Inner retinal layer change in glaucoma patients receiving anti-VEGF for neovascular age related macular degeneration

  • Rafidah Saleh
  • Aashraya Karpe
  • Martin S. Zinkernagel
  • Marion R. Munk
Medical Ophthalmology
First Online:
Received:
Revised:
Accepted:

Abstract

Purpose

The purpose was to evaluate the effects of long-term anti-VEGF treatment on the retinal nerve fiber layer (RNFL) and retinal ganglion cell layer (RGCL) thickness for patients with neovascular AMD and glaucoma.

Methods

Medical records of respective patients who had received more than 15 anti-VEGF injections were reviewed. Initial and latest SD-OCT macular scans were segmented and changes of the RNFL and RGCL thickness at the four outer ETDRS quadrants were evaluated. Secondary outcome measures included changes of visual field parameters seen in automated perimetry.

Results

Sixteen patients were included (mean age 78 ± 6 years). The mean total number of anti-VEGF injections was 39 ± 16. The mean treatment duration was 6.1 ± 2.1 years. The mean IOP decreased from 18 ± 5 mmHg at baseline to 15 ± 5 mmHg at the last visit (p = 0.026). The mean RNFL thickness volume of the outer ETDRS quadrants (0.98 ± 0.18 mm3 to 0.97 ± 0.18 mm3 p = 0.61) and its average thickness (37.9 ± 7.3 μm to 37.2 ± 7.4 μm, p = 0.6) did not significantly change. However, the average RGCL thickness decreased significantly from 0.86 ± 0.12 mm3 to 0.79 ± 0.11 mm3 (p = 0.01), and from 27.7 ± 4.2 to 25.9 ± 3.7 μm (p = 0.01). Number of injections correlated with the RGCL change (r2 = 0.36, p = 0.01). The mean sensitivity, mean defect and absolute scotomata did not significantly change with p-values of 0.28, 0.21 and 0.07, respectively.

Conclusion

Patients under long term treatment with anti-VEGF and concurrent glaucoma show significant decrease in macular RGLC volume. However, this decrease is comparable to reported RGCL decrease in patients under anti-VEGF treatment without underlying glaucoma and suggests that glaucoma patients may not be at a higher risk for losing macular RNFL and RGCL, at least if adequate control of intraocular pressure is maintained.

Keywords

Retinal nerve fiber layer thickness Ganglion cell layer thickness Anti-VEGF Wet AMD Glaucoma Exudative age-related macular degeneration Intraocular pressure Ocular hypertension Visual fields Retinal layer segmentation 
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Notes

Compliance with ethical standards

Funding

No funding was received for this research. Martin S Zinkernagel is a stock holder and a consultant for Novartis and a consultant for Bayer. Marion R Munk is a consultant for Novartis and Bayer and received travel grants from Bayer. The remaining authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.

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. For this type of study formal consent is not required.

Financial support

None.

Conflict of interest

The authors have no conflict of interest to report.

Supplementary material

417_2017_3590_MOESM1_ESM.docx (17 kb)
Supplemental Table 1 (DOCX 16 kb)
417_2017_3590_Fig4_ESM.gif (13 kb)
Supplemental Fig. 1

Scatter blot of average retinal nerve fiber layer (RNFL) thickness of the ETDRS outer rings in patients with glaucoma and neovascular age-related macular degeneration under long-term anti-VEGF treatment at baseline (BL) and last follow-up visit (FU). No significant changes were noted over time. (GIF 13 kb)

417_2017_3590_MOESM2_ESM.tif (307 kb)
High resolution image (TIF 306 kb)
417_2017_3590_Fig5_ESM.gif (14 kb)
Supplemental Fig. 2

Scatter blot of average the retinal ganglion cell layer (RGCL) thickness of the ETDRS outer rings in patients with glaucoma and neovascular age-related macular degeneration under long-term anti-VEGF treatment at baseline (BL) and last follow-up visit (FU).at baseline (BL) and last follow-up visit (FU). Significant decrease of RGCL thickness was noted over time. (GIF 14 kb)

417_2017_3590_MOESM3_ESM.tif (313 kb)
High resolution image (TIF 312 kb)

References

  1. 1.
    Bressler SB, Almukhtar T, Bhorade A, Bressler NM, Glassman AR, Huang SS, Jampol LM, Kim JE, Melia M, Diabetic Retinopathy Clinical Research Network Investigators (2015) Repeated intravitreous ranibizumab injections for diabetic macular edema and the risk of sustained elevation of intraocular pressure or the need for ocular hypotensive treatment. JAMA Ophthalmol 133:589–597. doi: 10.1001/jamaophthalmol.2015.186 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Schmidt-Erfurth U, Eldem B, Guymer R, Korobelnik JF, Schlingemann RO, Axer-Siegel R, Wiedemann P, Simader C, Gekkieva M, Weichselberger A, EXCITE Study Group (2011) Efficacy and safety of monthly versus quarterly ranibizumab treatment in neovascular age-related macular degeneration: the EXCITE study. Ophthalmology 118:831–839. doi: 10.1016/j.ophtha.2010.09.004 CrossRefPubMedGoogle Scholar
  3. 3.
    Holz FG, Amoaku W, Donate J, Guymer RH, Kellner U, Schlingemann RO, Weichselberger A, Staurenghi G, SUSTAIN Study Group (2011) Safety and efficacy of a flexible dosing regimen of ranibizumab in neovascular age-related macular degeneration: the SUSTAIN study. Ophthalmology 118:663–671. doi: 10.1016/j.ophtha.2010.12.019 CrossRefPubMedGoogle Scholar
  4. 4.
    Good TJ, Kimura AE, Mandava N, Kahook MY (2011) Sustained elevation of intraocular pressure after intravitreal injections of anti-VEGF agents. Br J Ophthalmol 95:1111–1114. doi: 10.1136/bjo.2010.180729 CrossRefPubMedGoogle Scholar
  5. 5.
    Kim JE, Mantravadi AV, Hur EY, Covert DJ (2008) Short-term intraocular pressure changes immediately after intravitreal injections of anti-vascular endothelial growth factor agents. Am J Ophthalmol 146:930–934 e931. doi: 10.1016/j.ajo.2008.07.007
  6. 6.
    Dedania VS, Bakri SJ (2015) Sustained elevation of intraocular pressure after intravitreal anti-VEGF agents: what is the evidence? Retina 35:841–858. doi: 10.1097/IAE.0000000000000520 CrossRefPubMedGoogle Scholar
  7. 7.
    Quigley HA (1999) Neuronal death in glaucoma. Prog Retin Eye Res 18:39–57CrossRefPubMedGoogle Scholar
  8. 8.
    Sommer A, Katz J, Quigley HA, Miller NR, Robin AL, Richter RC, Witt KA (1991) Clinically detectable nerve fiber atrophy precedes the onset of glaucomatous field loss. Arch Ophthalmol 109:77–83CrossRefPubMedGoogle Scholar
  9. 9.
    Quigley HA, Dunkelberger GR, Green WR (1989) Retinal ganglion cell atrophy correlated with automated perimetry in human eyes with glaucoma. Am J Ophthalmol 107:453–464. doi: 10.1016/0002-9394(89)90488-1 CrossRefPubMedGoogle Scholar
  10. 10.
    Airaksinen PJ, Drance SM, Douglas GR, Mawson DK, Nieminen H (1984) Diffuse and localized nerve fiber loss in glaucoma. Am J Ophthalmol 98:566–571CrossRefPubMedGoogle Scholar
  11. 11.
    Zeimer R, Asrani S, Zou S, Quigley H, Jampel H (1998) Quantitative detection of glaucomatous damage at the posterior pole by retinal thickness mapping: a pilot study. Ophthalmology 10:224–231CrossRefGoogle Scholar
  12. 12.
    Chiu SJ, Li XT, Nicholas P, Toth CA, Izatt JA, Farsiu S (2010) Automatic segmentation of seven retinal layers in SDOCT images congruent with expert manual segmentation. Opt Express 18:19413–19428. doi: 10.1364/OE.18.019413 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Ishikawa H, Stein DM, Wollstein G, Beaton S, Fujimoto JG, Schuman JS (2005) Macular segmentation with optical coherence tomography. Invest Ophthalmol Vis Sci 46:2012–2017. doi: 10.1167/iovs.04-0335 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Demirel S, Batioglu F, Ozmert E, Erenler F (2015) The effect of multiple injections of ranibizumab on retinal nerve fiber layer thickness in patients with age-related macular degeneration. Curr Eye Res 40:87–92. doi: 10.3109/02713683.2014.917190 CrossRefPubMedGoogle Scholar
  15. 15.
    Horsley MB, Mandava N, Maycotte MA, Kahook MY (2010) Retinal nerve fiber layer thickness in patients receiving chronic anti-vascular endothelial growth factor therapy. Am J Ophthalmol 150:558–561 e551. doi: 10.1016/j.ajo.2010.04.029
  16. 16.
    Rimayanti U, Kiuchi Y, Yamane K, Latief MA, Mochizuki H, Hirata J, Akita T, Tanaka J (2014) Inner retinal layer comparisons of eyes with exudative age-related macular degeneration and eyes with age-related macular degeneration and glaucoma. Graefes Arch Clin Exp Ophthalmol 252:563–570. doi: 10.1007/s00417-013-2496-z CrossRefPubMedGoogle Scholar
  17. 17.
    Menke MN, Zinkernagel MS, Ebneter A, Wolf S (2014) Functional and anatomical outcome of eyes with neovascular age-related macular degeneration treated with intravitreal ranibizumab following an exit strategy regimen. Br J Ophthalmol 98:1197–1200. doi: 10.1136/bjophthalmol-2013-304775 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Freund KB, Korobelnik JF, Devenyi R, Framme C, Galic J, Herbert E, Hoerauf H, Lanzetta P, Michels S, Mitchell P, Mones J, Regillo C, Tadayoni R, Talks J, Wolf S (2015) Treat-and-extend regimens with anti-VEGF agents in retinal diseases: a literature review and consensus recommendations. Retina 35:1489–1506. doi: 10.1097/IAE.0000000000000627 CrossRefPubMedGoogle Scholar
  19. 19.
    Katayama BY, Bonini-Filho MA, Messias AM, Paula JS, Martin LF, Costa R, Jorge R (2014) Comparison of acetazolamide, brimonidine, and anterior chamber paracentesis for ocular hypertension control after initial intravitreal bevacizumab injection: a randomized clinical trial. J Glaucoma 23:461–463. doi: 10.1097/IJG.0b013e3182948476 CrossRefPubMedGoogle Scholar
  20. 20.
    Griffith JF, Goldberg JL (2015) Prevalence of comorbid retinal disease in patients with glaucoma at an academic medical center. Clin Ophthalmol 9:1275–1284. doi: 10.2147/OPTH.S85851 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Shin HJ, Shin KC, Chung H, Kim HC (2014) Change of retinal nerve fiber layer thickness in variousretinal diseases treated with multiple intravitreal antivascular endothelial growth factor. Invest Ophthalmol Vis Sci 55:2403–2411. doi: 10.1167/iovs.13-13769 CrossRefPubMedGoogle Scholar
  22. 22.
    Zucchiatti I, Parodi MB, Pierro L, Cicinelli MV, Gagliardi M, Castellino N, Bandello F (2015) Macular ganglion cell complex and retinal nerve fiber layer comparison in different stages of age-related macular degeneration. Am J Ophthalmol 160:602–607 e601. doi: 10.1016/j.ajo.2015.05.030
  23. 23.
    Lee EK, Yu HG (2015) Ganglion cell-inner plexiform layer and peripapillary retinal nerve fiber layer thicknesses in age-related macular degeneration. Invest Ophthalmol Vis Sci 56:3976–3983. doi: 10.1167/iovs.15-17013 CrossRefPubMedGoogle Scholar
  24. 24.
    Beck M, Munk MR, Ebneter A, Wolf S, Zinkernagel MS (2016) Retinal ganglion cell layer change in patients treated with anti-vascular endothelial growth factor for neovascular age-related macular degeneration. Am J Ophthalmol 167:10–17. doi: 10.1016/j.ajo.2016.04.003 CrossRefPubMedGoogle Scholar
  25. 25.
    Harwerth RS, Wheat JL, Rangaswamy NV (2008) Age-related losses of retinal ganglion cells and axons. Invest Ophthalmol Vis Sci 49:4437–4443. doi: 10.1167/iovs.08-1753 CrossRefPubMedGoogle Scholar
  26. 26.
    Curcio CA, Medeiros NE, Millican CL (1996) Photoreceptor loss in age-related macular degeneration. Invest Ophthalmol Vis Sci 37:1236–1249PubMedGoogle Scholar
  27. 27.
    Garas A, Papp A, Hollo G (2013) Influence of age-related macular degeneration on macular thickness measurement made with fourier-domain optical coherence tomography. J Glaucoma 22:195–200. doi: 10.1097/IJG.0b013e31824083e6 CrossRefPubMedGoogle Scholar
  28. 28.
    Martinez-de-la-Casa JM, Ruiz-Calvo A, Saenz-Frances F, Reche-Frutos J, Calvo-Gonzalez C, Donate-Lopez J, Garcia-Feijoo J (2012) Retinal nerve fiber layer thickness changes in patients with age-related macular degeneration treated with intravitreal ranibizumab. Invest Ophthalmol Vis Sci 53:6214–6218. doi: 10.1167/iovs.12-9875 CrossRefPubMedGoogle Scholar
  29. 29.
    Yuda K, Inoue Y, Tomidokoro A, Tamaki Y, Yanagi Y (2010) Nerve fiber layer thickness in exudative age-related macular degeneration in Japanese patients. Graefes Arch Clin Exp Ophthalmol 248:353–359. doi: 10.1007/s00417-009-1222-3 CrossRefPubMedGoogle Scholar
  30. 30.
    Dunaief JL, Dentchev T, Ying GS, Milam AH (2002) The role of apoptosis in age-related macular degeneration. Arch Ophthalmol 120:1435–1442CrossRefPubMedGoogle Scholar
  31. 31.
    Shin HY, Park HY, Jung KI, Park CK (2013) Comparative study of macular ganglion cell-inner plexiform layer and peripapillary retinal nerve fiber layer measurement: structure-function analysis. Invest Ophthalmol Vis Sci 54:7344–7353. doi: 10.1167/iovs.13-12667 CrossRefPubMedGoogle Scholar
  32. 32.
    Tan O, Chopra V, Lu AT, Schuman JS, Ishikawa H, Wollstein G, Varma R, Huang D (2009) Detection of macular ganglion cell loss in glaucoma by Fourier-domain optical coherence tomography. Ophthalmology 116:2305–2314 e2301–2302. doi: 10.1016/j.ophtha.2009.05.025
  33. 33.
    Kim NR, Lee ES, Seong GJ, Kim JH, An HG, Kim CY (2010) Structure–function relationship and diagnostic value of macular ganglion cell complex measurement using Fourier-domain OCT in glaucoma. Invest Ophthalmol Vis Sci 51:4646–4651. doi: 10.1167/10.1167/iovs.09-5053 CrossRefPubMedGoogle Scholar
  34. 34.
    Girkin CA, McGwin G Jr, Sinai MJ, Sekhar GC, Fingeret M, Wollstein G, Varma R, Greenfield D, Liebmann J, Araie M, Tomita G, Maeda N, Garway-Heath DF (2011) Variation in optic nerve and macular structure with age and race with spectral-domain optical coherence tomography. Ophthalmology 118:2403–2408. doi: 10.1016/j.ophtha.2011.06.013 CrossRefPubMedGoogle Scholar
  35. 35.
    Budenz DL, Anderson DR, Varma R, Schuman J, Cantor L, Savell J, Greenfield DS, Patella VM, Quigley HA, Tielsch J (2007) Determinants of normal retinal nerve fiber layer thickness measured by Stratus OCT. Ophthalmology 114:1046–1052. doi: 10.1016/j.ophtha.2006.08.046 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Patel PJ, Chen FK, da Cruz L, Tufail A (2009) Segmentation error in Stratus optical coherence tomography for neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci 50:399–404. doi: 10.1167/iovs.08-1697 CrossRefPubMedGoogle Scholar
  37. 37.
    Lee HJ, Kim MS, Jo YJ, Kim JY (2015) Ganglion cell-inner plexiform layer thickness in retinal diseases: repeatability study of spectral-domain optical coherence tomography. Am J Ophthalmol 160:283–289 e281. doi: 10.1016/j.ajo.2015.05.015

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Rafidah Saleh
    • 1
  • Aashraya Karpe
    • 1
  • Martin S. Zinkernagel
    • 1
    • 2
    • 3
  • Marion R. Munk
    • 1
    • 3
  1. 1.Department of Ophthalmology, Inselspital, Bern University Hospital, and University of BernBernSwitzerland
  2. 2.Department of Clinical ResearchUniversity Hospital BernBernSwitzerland
  3. 3.Bern Photographic Reading Center, Department of Ophthalmology, Inselspital, Bern University Hospital, and University of BernBernSwitzerland

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