Skip to main content
Top
Published in: Documenta Ophthalmologica 2/2020

01-10-2020 | Macular Degeneration | Original Research Article

Changes in cone-driven functions after intravitreal aflibercept injections in patients with age-related macular degeneration

Authors: Tomoharu Nishimura, Shigeki Machida, Yuji Hara

Published in: Documenta Ophthalmologica | Issue 2/2020

Login to get access

Abstract

Purpose

To determine the changes in the cone-driven functions in patients with age-related macular degeneration (AMD) treated with intravitreal aflibercept.

Methods

We studied 44 eyes of 44 patients diagnosed with AMD whose mean age was 75 years. The contralateral unaffected eyes served as controls. All patients were initially treated with 3 consecutive monthly intravitreal aflibercept injections and thereafter with bimonthly injections for 12 months. Full-field cone electroretinograms (cone ERGs) were recorded at the baseline and at 3, 6, and 12 months after beginning the intravitreal aflibercept injections. The cone ERGs were elicited by red stimuli on a blue background. The focal macular ERGs (fmERGs) were elicited by 15 degrees white stimulus spot centered on the fovea. The amplitudes of the a- and b-waves, photopic negative response (PhNR), and sum of the oscillatory potentials (ΣOPs, sum of OP1–3 amplitudes) were analyzed. In addition, the implicit times of the a- and b-waves were also analyzed.

Results

The amplitudes and implicit times of all components of the fmERGs were significantly improved compared to the baseline at 3 months after beginning the intravitreal aflibercept injections (P < 0.0005–0.05). The amplitudes of the a-waves and PhNRs were further increased during the maintenance phase (P < 0.005–0.01). On the other hand, the amplitudes of the full-field a-waves and PhNR of the cone ERGs were significantly reduced at 6 and 12 months compared to the baseline.

Conclusions

The macular function improved continuously during the maintenance phase of the intravitreal aflibercept injections. In contrast, the cone-driven functions of the more peripheral retina decreased with repeated injections suggesting adverse effects of the intravitreal aflibercept injections on the function of the more peripheral normal retina.
Literature
1.
go back to reference Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY, MARINA Study Group (2006) Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 355:1419–1431CrossRef Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY, MARINA Study Group (2006) Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 355:1419–1431CrossRef
2.
go back to reference Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T, ANCHOR Study Group (2009) Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study. Ophthalmology 116:57–65CrossRef Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T, ANCHOR Study Group (2009) Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study. Ophthalmology 116:57–65CrossRef
3.
go back to reference Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, Brown DM, Chong V, Nguyen QD, Ho AC, Ogura Y, Simader C, Jaffe GJ, Slakter JS, Yancopoulos GD, Stahl N, Vitti R, Berliner AJ, Soo Y, Anderesi M, Sowade O, Zeitz O, Norenberg C, Sandbrink R, Heier JS (2014) Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies. Ophthalmology 121:193–201CrossRef Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, Brown DM, Chong V, Nguyen QD, Ho AC, Ogura Y, Simader C, Jaffe GJ, Slakter JS, Yancopoulos GD, Stahl N, Vitti R, Berliner AJ, Soo Y, Anderesi M, Sowade O, Zeitz O, Norenberg C, Sandbrink R, Heier JS (2014) Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies. Ophthalmology 121:193–201CrossRef
4.
go back to reference Ogura Y, Terasaki H, Gomi F, Yuzawa M, Iida T, Honda M, Nishijo K, Sowade O, Komori T, Schmidt-Erfurth U, Simader C, Chong V, VIEW 2 Investigators (2015) Efficacy and safety of intravitreal aflibercept injection in wet age-related macular degeneration: outcomes in the Japanese subgroup of the VIEW 2 study. Br J Ophthalmol 99:92–97CrossRef Ogura Y, Terasaki H, Gomi F, Yuzawa M, Iida T, Honda M, Nishijo K, Sowade O, Komori T, Schmidt-Erfurth U, Simader C, Chong V, VIEW 2 Investigators (2015) Efficacy and safety of intravitreal aflibercept injection in wet age-related macular degeneration: outcomes in the Japanese subgroup of the VIEW 2 study. Br J Ophthalmol 99:92–97CrossRef
5.
go back to reference Papadopoulos N, Martin J, Ruan Q, Rafique A, Rosconi MP, Shi E, Pyles EA, Yancopoulos GD, Stahl N, Wiegand SJ (2012) Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis 15:171–185CrossRef Papadopoulos N, Martin J, Ruan Q, Rafique A, Rosconi MP, Shi E, Pyles EA, Yancopoulos GD, Stahl N, Wiegand SJ (2012) Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis 15:171–185CrossRef
6.
go back to reference Lee WK, Iida T, Ogura Y, Chen SJ, Wong TY, Mitchell P, Cheung GCM, Zhang Z, Leal S, Ishibashi T, Investigators PLANET (2018) Efficacy and safety of intravitreal aflibercept for polypoidal choroidal vasculopathy in the PLANET study: a randomized clinical trial. JAMA Ophthalmol 136:786–793CrossRef Lee WK, Iida T, Ogura Y, Chen SJ, Wong TY, Mitchell P, Cheung GCM, Zhang Z, Leal S, Ishibashi T, Investigators PLANET (2018) Efficacy and safety of intravitreal aflibercept for polypoidal choroidal vasculopathy in the PLANET study: a randomized clinical trial. JAMA Ophthalmol 136:786–793CrossRef
7.
go back to reference Maruko I, Iida T, Saito M, Nagayama D, Saito K (2007) Clinical characteristics of exudative age-related macular degeneration in Japanese patients. Am J Ophthalmol 144:15–22CrossRef Maruko I, Iida T, Saito M, Nagayama D, Saito K (2007) Clinical characteristics of exudative age-related macular degeneration in Japanese patients. Am J Ophthalmol 144:15–22CrossRef
8.
go back to reference Liu Y, Wen F, Huang S, Luo G, Yan H, Sun Z, Wu D (2007) Subtype lesions of neovascular age-related macular degeneration in Chinese patients. Graefes Arch Clin Exp Ophthalmol 245:1441–1445CrossRef Liu Y, Wen F, Huang S, Luo G, Yan H, Sun Z, Wu D (2007) Subtype lesions of neovascular age-related macular degeneration in Chinese patients. Graefes Arch Clin Exp Ophthalmol 245:1441–1445CrossRef
9.
go back to reference Miyake Y, Yanagida K, Kondo K, Ota I (1981) Subjective scotometry and recording of local electroretinogram and visual evoked response. System with television monitor of the fundus. Jpn J Ophthalmol 25:439–448 Miyake Y, Yanagida K, Kondo K, Ota I (1981) Subjective scotometry and recording of local electroretinogram and visual evoked response. System with television monitor of the fundus. Jpn J Ophthalmol 25:439–448
10.
go back to reference Miyake Y (2006) Electrodiagnosis of retinal diseases. Springer, Tokyo Miyake Y (2006) Electrodiagnosis of retinal diseases. Springer, Tokyo
11.
go back to reference Takayama K, Kaneko H, Ueno S, Maruko R, Piao CH, Yasuda S, Kawano K, Ito Y, Terasaki H (2017) Evaluation of short-term outcomes of intravitreal aflibercept injections for age-related macular degeneration using focal macular electroretinography. Retina 37:553–560CrossRef Takayama K, Kaneko H, Ueno S, Maruko R, Piao CH, Yasuda S, Kawano K, Ito Y, Terasaki H (2017) Evaluation of short-term outcomes of intravitreal aflibercept injections for age-related macular degeneration using focal macular electroretinography. Retina 37:553–560CrossRef
12.
go back to reference Nishimura T, Machida S, Harada T, Kurosaka D (2012) Retinal ganglion cell function after repeated intravitreal injections of ranibizumab in patients with age-related macular degeneration. Clin Ophthalmol 6:1073–1082PubMedPubMedCentral Nishimura T, Machida S, Harada T, Kurosaka D (2012) Retinal ganglion cell function after repeated intravitreal injections of ranibizumab in patients with age-related macular degeneration. Clin Ophthalmol 6:1073–1082PubMedPubMedCentral
13.
go back to reference Storkebaum E, Lambrechts D, Carmeliet P (2004) VEGF: once regarded as a specific angiogenic factor, now implicated in neuroprotection. Bioessays 26:943–954CrossRef Storkebaum E, Lambrechts D, Carmeliet P (2004) VEGF: once regarded as a specific angiogenic factor, now implicated in neuroprotection. Bioessays 26:943–954CrossRef
14.
go back to reference Nishijima K, Ng YS, Zhong L, Bradley J, Schubert W, Jo N, Akita J, Samuelsson SJ, Robinson GS, Adamis AP, Shima DT (2007) Vascular endothelial growth factor-A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury. Am J Pathol 171:53–67CrossRef Nishijima K, Ng YS, Zhong L, Bradley J, Schubert W, Jo N, Akita J, Samuelsson SJ, Robinson GS, Adamis AP, Shima DT (2007) Vascular endothelial growth factor-A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury. Am J Pathol 171:53–67CrossRef
15.
go back to reference Julien S, Biesemeier A, Taubitz T, Schraermeyer U (2014) Different effects of intravitreally injected ranibizumab and aflibercept on retinal and choroidal tissues of monkey eyes. Br J Ophthalmol 98:813–825CrossRef Julien S, Biesemeier A, Taubitz T, Schraermeyer U (2014) Different effects of intravitreally injected ranibizumab and aflibercept on retinal and choroidal tissues of monkey eyes. Br J Ophthalmol 98:813–825CrossRef
16.
go back to reference Koizumi H, Kano M, Yamamoto A, Saito M, Maruko I, Sekiryu T, Okada AA, Iida T (2016) Subfoveal choroidal thickness during aflibercept therapy for neovascular age-related macular degeneration: twelve-month results. Ophthalmology 123:617–624CrossRef Koizumi H, Kano M, Yamamoto A, Saito M, Maruko I, Sekiryu T, Okada AA, Iida T (2016) Subfoveal choroidal thickness during aflibercept therapy for neovascular age-related macular degeneration: twelve-month results. Ophthalmology 123:617–624CrossRef
17.
go back to reference Strauss O (2005) The retinal pigment epithelium in visual function. Physiol Rev 85:845–881CrossRef Strauss O (2005) The retinal pigment epithelium in visual function. Physiol Rev 85:845–881CrossRef
18.
go back to reference Oshima Y, Kimoto K, Yoshida N, Fujisawa K, Sonoda S, Kubota T, Murata T, Sakamoto T, Yoshida S, Sonoda KH, Ishibashi T (2017) One-year outcomes following intravitreal aflibercept for polypoidal choroidal vasculopathy in Japanese patients: the APOLLO study. Ophthalmologica 238:163–171CrossRef Oshima Y, Kimoto K, Yoshida N, Fujisawa K, Sonoda S, Kubota T, Murata T, Sakamoto T, Yoshida S, Sonoda KH, Ishibashi T (2017) One-year outcomes following intravitreal aflibercept for polypoidal choroidal vasculopathy in Japanese patients: the APOLLO study. Ophthalmologica 238:163–171CrossRef
19.
go back to reference Yamamoto A, Okada AA, Kano M, Koizumi H, Saito M, Maruko I, Sekiryu T, Iida T (2015) One-year results of intravitreal aflibercept for polypoidal choroidal vasculopathy. Ophthalmology 122:1866–1872CrossRef Yamamoto A, Okada AA, Kano M, Koizumi H, Saito M, Maruko I, Sekiryu T, Iida T (2015) One-year results of intravitreal aflibercept for polypoidal choroidal vasculopathy. Ophthalmology 122:1866–1872CrossRef
20.
go back to reference Lee JE, Shin JP, Kim HW, Chang W, Kim YC, Lee SJ, Chung IY, Lee JE, VAULT Study Group (2017) Efficacy of fixed-dosing aflibercept for treating polypoidal choroidal vasculopathy: 1-year results of the VAULT study. Graefes Arch Clin Exp Ophthalmol 255:493–502CrossRef Lee JE, Shin JP, Kim HW, Chang W, Kim YC, Lee SJ, Chung IY, Lee JE, VAULT Study Group (2017) Efficacy of fixed-dosing aflibercept for treating polypoidal choroidal vasculopathy: 1-year results of the VAULT study. Graefes Arch Clin Exp Ophthalmol 255:493–502CrossRef
21.
go back to reference Berg K, Pedersen TR, Sandvik L, Bragadóttir R (2015) Comparison of ranibizumab and bevacizumab for neovascular age-related macular degeneration according to LUCAS treat-and-extend protocol. Ophthalmology 122:146–152CrossRef Berg K, Pedersen TR, Sandvik L, Bragadóttir R (2015) Comparison of ranibizumab and bevacizumab for neovascular age-related macular degeneration according to LUCAS treat-and-extend protocol. Ophthalmology 122:146–152CrossRef
22.
go back to reference Morimoto M, Matsumoto H, Mimura K, Akiyama H (2017) Two-year results of a treat-and-extend regimen with aflibercept for polypoidal choroidal vasculopathy. Graefes Arch Clin Exp Ophthalmol 255:1891–1897CrossRef Morimoto M, Matsumoto H, Mimura K, Akiyama H (2017) Two-year results of a treat-and-extend regimen with aflibercept for polypoidal choroidal vasculopathy. Graefes Arch Clin Exp Ophthalmol 255:1891–1897CrossRef
23.
go back to reference Adrean SD, Chaili S, Ramkumar H, Pirouz A, Grant S (2018) Consistent long-term therapy of neovascular age-related macular degeneration managed by 50 or more anti-VEGF Injections using a treat-extend-stop protocol. Ophthalmology 125:1047–1053CrossRef Adrean SD, Chaili S, Ramkumar H, Pirouz A, Grant S (2018) Consistent long-term therapy of neovascular age-related macular degeneration managed by 50 or more anti-VEGF Injections using a treat-extend-stop protocol. Ophthalmology 125:1047–1053CrossRef
24.
go back to reference Niwa Y, Kakinoki M, Sawada T, Wang X, Ohji M (2015) Ranibizumab and aflibercept: intraocular pharmacokinetics and their effects on aqueous VEGF level in vitrectomized and nonvitrectomized macaque eyes. Invest Ophthalmol Vis Sci 56:6501–6505CrossRef Niwa Y, Kakinoki M, Sawada T, Wang X, Ohji M (2015) Ranibizumab and aflibercept: intraocular pharmacokinetics and their effects on aqueous VEGF level in vitrectomized and nonvitrectomized macaque eyes. Invest Ophthalmol Vis Sci 56:6501–6505CrossRef
25.
go back to reference Miyake Y (1988) Studies on local macular ERG. Acta Soc Ophthalmol Jpn 92:1419–1449 Miyake Y (1988) Studies on local macular ERG. Acta Soc Ophthalmol Jpn 92:1419–1449
26.
go back to reference Machida S, Toba Y, Ohtaki A, Gotoh Y, Kaneko M, Kurosaka D (2008) Photopic negative response of focal electroretinogram in glaucomatous eyes. Invest Ophthalmol Vis Sci 49:5636–5644CrossRef Machida S, Toba Y, Ohtaki A, Gotoh Y, Kaneko M, Kurosaka D (2008) Photopic negative response of focal electroretinogram in glaucomatous eyes. Invest Ophthalmol Vis Sci 49:5636–5644CrossRef
27.
go back to reference Nishimura T, Machida S, Hashizume K, Kurosaka D (2015) Structures affecting recovery of macular function in patients with age-related macular degeneration after intravitreal ranibizumab. Graefes Arch Clin Exp Ophthalmol 253:1201–1209CrossRef Nishimura T, Machida S, Hashizume K, Kurosaka D (2015) Structures affecting recovery of macular function in patients with age-related macular degeneration after intravitreal ranibizumab. Graefes Arch Clin Exp Ophthalmol 253:1201–1209CrossRef
28.
go back to reference Stewart MW, Rosenfeld PJ (2008) Predicted biological activity of intravitreal VEGF Trap. Br J Ophthalmol 92:667–668CrossRef Stewart MW, Rosenfeld PJ (2008) Predicted biological activity of intravitreal VEGF Trap. Br J Ophthalmol 92:667–668CrossRef
29.
go back to reference Koh A, Lee WK, Chen LJ, Chen SJ, Hashad Y, Kim H, Lai TY, Pilz S, Ruamviboonsuk P, Tokaji E, Weisberger A, Lim TH (2012) EVEREST study: efficacy and safety of verteporfin photodynamic therapy in combination with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy. Retina 32:1453–1464CrossRef Koh A, Lee WK, Chen LJ, Chen SJ, Hashad Y, Kim H, Lai TY, Pilz S, Ruamviboonsuk P, Tokaji E, Weisberger A, Lim TH (2012) EVEREST study: efficacy and safety of verteporfin photodynamic therapy in combination with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy. Retina 32:1453–1464CrossRef
30.
go back to reference Curcio CA, Sloan KR, Kalina RE, Hendrickson AE (1990) Human photoreceptor topography. J Comp Neurol 292:497–523CrossRef Curcio CA, Sloan KR, Kalina RE, Hendrickson AE (1990) Human photoreceptor topography. J Comp Neurol 292:497–523CrossRef
31.
go back to reference Rangaswamy NV, Frishman LJ, Dorotheo EU, Schiffman JS, Bahrani HM, Tang RA (2004) Photopic ERGs in patients with optic neuropathies: comparison with primate ERGs after pharmacologic blockade of inner retina. Invest Ophthalmol Vis Sci 45:3827–3837CrossRef Rangaswamy NV, Frishman LJ, Dorotheo EU, Schiffman JS, Bahrani HM, Tang RA (2004) Photopic ERGs in patients with optic neuropathies: comparison with primate ERGs after pharmacologic blockade of inner retina. Invest Ophthalmol Vis Sci 45:3827–3837CrossRef
32.
go back to reference Pedersen KB, Møller F, Sjølie AK, Andréasson S (2010) Electrophysiological assessment of retinal function during 6 months of bevacizumab treatment in neovascular age-related macular degeneration. Retina 30:1025–1033CrossRef Pedersen KB, Møller F, Sjølie AK, Andréasson S (2010) Electrophysiological assessment of retinal function during 6 months of bevacizumab treatment in neovascular age-related macular degeneration. Retina 30:1025–1033CrossRef
33.
go back to reference Lamb TD, Pugh EN Jr (2006) Phototransduction, dark adaptation, and rhodopsin regeneration the proctor lecture. Invest Ophthalmol Vis Sci 47:5137–5152CrossRef Lamb TD, Pugh EN Jr (2006) Phototransduction, dark adaptation, and rhodopsin regeneration the proctor lecture. Invest Ophthalmol Vis Sci 47:5137–5152CrossRef
34.
go back to reference Machida S, Gotoh Y, Toba Y, Ohtaki A, Kaneko M, Kurosaka D (2008) Correlation between photopic negative response and retinal nerve fiber layer thickness and optic disc topography in glaucomatous eyes. Invest Ophthalmol Vis Sci 49:2201–2207CrossRef Machida S, Gotoh Y, Toba Y, Ohtaki A, Kaneko M, Kurosaka D (2008) Correlation between photopic negative response and retinal nerve fiber layer thickness and optic disc topography in glaucomatous eyes. Invest Ophthalmol Vis Sci 49:2201–2207CrossRef
35.
go back to reference Frishman L, Sustar M, Kremers J, McAnany JJ, Sarossy M, Tzekov R, Viswanathan S (2018) ISCEV extended protocol for the photopic negative response (PhNR) of the full-field electroretinogram. Doc Ophthalmol 136:207–211CrossRef Frishman L, Sustar M, Kremers J, McAnany JJ, Sarossy M, Tzekov R, Viswanathan S (2018) ISCEV extended protocol for the photopic negative response (PhNR) of the full-field electroretinogram. Doc Ophthalmol 136:207–211CrossRef
Metadata
Title
Changes in cone-driven functions after intravitreal aflibercept injections in patients with age-related macular degeneration
Authors
Tomoharu Nishimura
Shigeki Machida
Yuji Hara
Publication date
01-10-2020
Publisher
Springer Berlin Heidelberg
Published in
Documenta Ophthalmologica / Issue 2/2020
Print ISSN: 0012-4486
Electronic ISSN: 1573-2622
DOI
https://doi.org/10.1007/s10633-020-09758-z

Other articles of this Issue 2/2020

Documenta Ophthalmologica 2/2020 Go to the issue