Scholarly article on topic 'Retention of good visual acuity in eyes with neovascular age-related macular degeneration and chronic refractory subfoveal subretinal fluid'

Retention of good visual acuity in eyes with neovascular age-related macular degeneration and chronic refractory subfoveal subretinal fluid Academic research paper on "Clinical medicine"

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Saudi Journal of Ophthalmology
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{"Neovascular age-related macular degeneration" / "Subretinal fluid" / "Anti-VEGF therapy" / "Optical coherence tomography"}

Abstract of research paper on Clinical medicine, author of scientific article — Kavita V. Bhavsar, K. Bailey Freund

Abstract Purpose To describe the clinical characteristics of a subset of eyes with neovascular age-related macular degeneration (NVAMD) receiving intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy which retain good visual acuity despite chronic, persistent subfoveal subretinal fluid (SRF). Design Retrospective, observational case series. Methods Study eyes were identified from a consecutive series of 186 patients treated with anti-VEGF therapy seen for regular follow-up over a 3-month period. The clinical histories of 10 eyes of 9 patients with NVAMD, chronic subfoveal SRF despite continuous anti-VEGF therapy, and good long-term visual acuity of 20/40 or greater were reviewed. Demographic factors, baseline and final visual acuity, neovascular lesion type, duration of persistent fluid, baseline and final subfoveal choroidal thickness, presence of geographic atrophy, and number of anti-VEGF injections were analyzed. Results The mean age of patients was 78years (range 55–91). The mean duration of persistent fluid was 5.2years (range 1.3–11.0). Long-term visual acuities remained stable at 20/40 or better in all eyes. All eyes had type 1 (sub-retinal pigment epithelial) neovascularization. Average baseline subfoveal choroidal thickness was 285.3μm and the average follow-up subfoveal choroidal thickness was 239.7μm. No eyes had the presence of geographic atrophy. The mean number of injections was 36.5 (range 17–66). Conclusion Some eyes with type 1 neovascularization associated with chronic persistent subfoveal subretinal fluid despite continuous intravitreal anti-VEGF therapy may maintain good long-term visual outcomes. We hypothesize that type 1 neovascularization and greater subfoveal choroidal thickness may exert a protective effect on photoreceptor integrity. Further studies are necessary to assess long-term visual prognosis and predictive factors in patients with type 1 neovascularization leading to persistent subretinal fluid that is recalcitrant to anti-VEGF treatment.

Academic research paper on topic "Retention of good visual acuity in eyes with neovascular age-related macular degeneration and chronic refractory subfoveal subretinal fluid"

Saudi Journal of Ophthalmology (2014) 28, 129-133

Original Article

Retention of good visual acuity in eyes with neovascular c«^

age-related macular degeneration and chronic refractory subfoveal subretinal fluid

Kavita V. Bhavsar, MD; K. Bailey Freund, MD *

Abstract

Purpose: To describe the clinical characteristics of a subset of eyes with neovascular age-related macular degeneration (NVAMD) receiving intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy which retain good visual acuity despite chronic, persistent subfoveal subretinal fluid (SRF). Design: Retrospective, observational case series.

Methods: Study eyes were identified from a consecutive series of 186 patients treated with anti-VEGF therapy seen for regular follow-up over a 3-month period. The clinical histories of 10 eyes of 9 patients with NVAMD, chronic subfoveal SRF despite continuous anti-VEGF therapy, and good long-term visual acuity of 20/40 or greater were reviewed. Demographic factors, baseline and final visual acuity, neovascular lesion type, duration of persistent fluid, baseline and final subfoveal choroidal thickness, presence of geographic atrophy, and number of anti-VEGF injections were analyzed.

Results: The mean age of patients was 78 years (range 55-91). The mean duration of persistent fluid was 5.2 years (range 1.311.0). Long-term visual acuities remained stable at 20/40 or better in all eyes. All eyes had type 1 (sub-retinal pigment epithelial) neovascularization. Average baseline subfoveal choroidal thickness was 285.3 im and the average follow-up subfoveal choroidal thickness was 239.7 im. No eyes had the presence of geographic atrophy. The mean number of injections was 36.5 (range 17-66). Conclusion: Some eyes with type 1 neovascularization associated with chronic persistent subfoveal subretinal fluid despite continuous intravitreal anti-VEGF therapy may maintain good long-term visual outcomes. We hypothesize that type 1 neovascularization and greater subfoveal choroidal thickness may exert a protective effect on photoreceptor integrity. Further studies are necessary to assess long-term visual prognosis and predictive factors in patients with type 1 neovascularization leading to persistent subretinal fluid that is recalcitrant to anti-VEGF treatment.

Keywords: Neovascular age-related macular degeneration, Subretinal fluid, Anti-VEGF therapy, Optical coherence tomography

2014 Saudi Ophthalmological Society, King Saud University. Production and hosting by Elsevier B.V. All rights reserved.

http://dx.doi.org/10.1016/jj.sjopt.2014.03.001

Introduction

Neovascular age-related macular degeneration (AMD) is characterized by the formation of an abnormal complex of

vascular tissue which leads to visually significant complications such as hemorrhage or exudation.1 The pathologic mechanisms underlying the formation of choroidal neovascularization (CNV) are incompletely understood. The advent of

Received 24 December 2013; received in revised form 19 February 2014; accepted 4 March 2014; available online 12 March 2014. Vitreous Retina Macula Consultants of New York, New York, NY, United States

LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear and Throat Hospital, New York, NY, United States Department of Ophthalmology, New York University Langone Medical Center, New York, NY, United States Department of Ophthalmology, Columbia University, New York, NY, United States

* Corresponding author. Address: Vitreous Retina Macula Consultants of New York, 460 Park Avenue, New York, NY 10022, United States. Tel.: +1 212 861 9797; fax: +1 212 628 0698. e-mail address: kbfnyf@aol.com (K.B. Freund).

r- i : Peer review under responsibility

of Saudi Ophthalmological Society, King Saud University

Production and hosting by Elsevier

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optical coherence tomography (OCT) has revolutionized the classification of CNV which was previously defined by fluorescein angiography alone.2 Vascular endothelial growth factor A (VEGF-A) is a diffusible cytokine implicated in inducing angiogenesis and increased vascular permeability in the setting of neovascular AMD.3,4 Blockade of VEGF-A has become an effective treatment for the management of CNV secondary to AMD.5-10 The employment of anti-VEGF therapy has improved long term visual outcomes by reducing the risk of fluid accumulation and hemorrhage.11

However, in a small subset of patients, successful resolution of anatomic features such as the presence of sub or intra-retinal fluid may be difficult.12 Current clinical practice advocates treatment with anti-VEGF to achieve complete or near complete resolution of foveal threatening fluid to minimize risk of structural damage to retinal photoreceptors. However, the relationships between morphologic features and visual prognosis after intravitreal anti-VEGF treatment are complex and not well characterized.13,14 Integrity of retinal photoreceptor cells may be dependent on a combination of factors that interact to modify the retinal pigment epithelium and photoreceptor layer.

The purpose of this study is to assess the clinical characteristics of eyes with neovascular AMD receiving continuous intravitreal anti-VEGF therapy that retain good visual acuity despite chronic, persistent, subfoveal subretinal fluid (SRF).

Methods

This study design was approved by Western institutional review board (Olympia, WA, USA). It complied with the Health Insurance Portability and Accountability Act of 1996 and followed the tenets of the Declaration of Helsinki.

Study eyes were identified from a consecutive series of 186 NVAMD patients treated with intravitreal anti-VEGF therapy seen for regular follow-up visits over a 3-month period by a single physician (KBF). All patients had active choroidal neovascularization documented by SD-OCT and fluorescein angiography (Topcon, Tokyo, Japan) prior to the initiation of intravitreal anti-VEGF therapy. To be included in this study, eyes were required to have chronic subfoveal subretinal fluid (defined as fluid present at >80% of all follow-up visits for >1 year) secondary to NVAMD despite continuous anti-VEGF therapy, and good long-term visual acuity of 20/40 or better. All patients had undergone a complete ophthalmic examination including a slit-lamp examination, dilated fundus biomicroscopy, and eye-tracked imaging with Spectralis SD-OCT (Heidelberg Engineering, Vista, California, USA) at each

office visit. Eyes with concomitant retinal disease including diabetic retinopathy, pathologic myopia, angioid streaks, and retinal vascular occlusions were excluded. A retrospective chart review was performed to obtain data on demographics and treatment history (photodynamic therapy, number and type of anti-VEGF injections).

Spectralis SD-OCT was used to obtain measurements of subfoveal choroidal thickness. Choroidal thickness was manually measured beneath the foveal center from the posterior edge of the retinal pigment epithelium to the choroid/sclera junction using a linear measuring tool built-into the review software. SD-OCT scans were also qualitatively assessed for integrity of the ellipsoid zone and external limiting membrane, presence of cystoid macular edema, location of subretinal fluid, and characterization of choroidal neovascularization subtype (1 - sub-RPE, 2 - subretinal, 3 - intraretinal/retinal angiomatous proliferation or mixed) in all patients.

Results

From the 186 consecutive NVAMD patients seen over 3 months, a total of 9 (4.8%) patients (10 eyes) with chronic subretinal fluid were identified for this study (Table 1). The mean patient age was 78 years (range 55-91). Of these subjects, 3 were male and 6 were female. All patients were white. In addition to neovascular AMD, the only other ocular comorbidity shared by these patients was the presence of nuclear sclerotic cataracts. 5 eyes of 4 patients had nuclear sclerotic cataracts and the remaining 5 eyes of 5 patients had undergone uncomplicated cataract surgery with posterior chamber intraocular lens placement.

SD-OCT data showed the presence of vascularized pigment epithelial detachment (PED) consistent with type 1 neovascularization in all eyes and baseline fluorescein angiography was consistent with type 1 neovascularization in all eyes (Fig. 1A-D). All 10 eyes had subfoveal subretinal fluid, and 1 eye also had an additional area of subretinal fluid located temporal to the fovea. The mean duration of persistent subretinal fluid was 5.2 years (range 1.3-11.0). Only 1 eye had or developed cystoid macular edema detected by SD-OCT. At least partial preservation of the foveal ellipsoid zone and external limiting membrane was identified in all patients. No eyes had or developed the presence of foveal or non-foveal geographic atrophy over the follow-up period.

Reliable measurements of choroidal thickness were attained in all cases. Mean baseline subfoveal choroidal thickness was measured to be 285.3 im (range 100-573 im) and the mean follow-up subfoveal choroidal thickness was

Table 1. Patient demographics and clinical characteristics.

Age Duration of subretinal Baseline best Follow-up best Baseline choroidal Choroidal

fluid (Years) corrected corrected thickness (|im) neovascularization

visual acuity visual acuity subtype (1, 2, 3)

Patient 1 85 5.0 20/30 20/40 100 1

Patient 2 87 9.5 20/25 20/25 289 1

Patient 3 81 4.9 20/25 20/25 231 1

Patient 4 91 11.0 20/30 20/30 174 1

Patient 5 79 1.5 20/30 20/25 326 1

Patient 6 84 7.0 20/30 20/30 427 1

Patient 7 68 1.3 20/60 20/25 258 1

Patient 8 55 2.5 20/30 20/30 573 1

Patient 9 (OD) 75 4.9 20/30 20/25 238 1

Patient 9 (OS) 75 4.9 20/40 20/30 237 1

Figure 1. Retinal imaging of patient 1 at presentation and follow-up. (A) Color photograph of patient 1 at presentation reveals an elevated vascularized pigment epithelial detachment and drusen. (B) Fundus autofluorescence image of patient 1 at 5-year follow-up reveals no geographic atrophy. (C) Spectral domain optical coherence tomography shows subfoveal subretinal fluid over a vascularized pigment epithelial detachment at (i) presentation and (ii) 5-year follow-up. (D) Baseline fluorescein angiography confirms the presence of active type 1 neovascularization prior to treatment.

239.7 im (range 83-470 im). Data for normal age-matched choroidal thickness were obtained from another study which measured choroidal thickness in 42 eyes of 42 healthy subjects.14 These subjects had no history of retinal or choroidal pathology, and patients with myopic refractive error of greater than 6.0 diopters were excluded. The average subfoveal choroidal thickness in this group of healthy patients was measured to be 256.8 ± 75.8 im (Fig. 2).

All eyes were being treated with intravitreal anti-VEGF therapy in order to control their disease (Table 2). Eyes had received a mean of 36.5 injections (range 17-66) of either bevacizumab (intra-vitreal 1.25 mg/0.05 ml), ranibizumab (in-tra-vitreal 0.5 mg/0.05 ml), or aflibercept (2.0 mg/0.05 ml). Only a single eye had received verteporfin photodynamic

Figure 2. Average subfoveal choroidal thickness in healthy, normal eyes compared to enrolled study subjects.

therapy (PDT) prior to the initation of intravitreal therapy, with a total of 5 treatment sessions, including one session of combined PDT and intra-vitreal triamcinolone acetonide. At the most recent follow-up, 7 eyes were receiving intravitreal monthly aflibercept and the remaining 3 eyes were receiving monthly intravitreal ranibizumab. Criteria for retreatment included persistent subretinal or intraretinal fluid by OCT with or without the presence of clinically identified hemorrhage.

Discussion

This study illustrates that good long-term visual outcomes are possible in certain eyes with persistent subretinal fluid secondary to type 1 neovascularization in the setting of NVAMD. While morphologic features detected by SD-OCT are typically used to guide intravitreal anti-VEGF therapy, their relationship to visual prognosis may be complex and incompletely characterized.

Jaffe et al. investigated the association of macular morphology with visual acuity in eyes with neovascular AMD treated with intravitreal ranibizumab or bevacizumab for 1 year.15 The results of their study indicated that residual intraretinal fluid in the macula, mainly intraretinal fluid involving the fovea, had a significant negative effect on visual acuity, whereas subretinal or sub-retinal pigment epithelial (RPE) fluid was not found to have a significant negative effect on visual function. Previous studies have also reported that cystoid macular edema has an adverse impact on visual acuity when associated with subfoveal CNV.16 The etiology of this specific negative effect of intraretinal fluid (not subretinal or sub-RPE

Table 2. Treatment Histories of Study Subjects.

Total # of anti-VEGF injections % Bevacizumab % Ranibizumab % Aflibercept Total # PDT Total # of PDT + IVK

Patient 1 66.0 - 72.7 27.3 - -

Patient 2 65.0 3.0 95.4 1.5 - -

Patient 3 55.0 - 65.5 34.6 - -

Patient 4 64.0 - 96.9 3.1 4 1

Patient 5 17.0 - 88.2 11.8 - -

Patient 6 17.0 - 5.9 94.1 - -

Patient 7 21.0 - 19.1 71.4 - -

Patient 8 26.0 - 11.5 88.5 - -

Patient 9 (OD) 17.0 - - 100.0 - -

Patient 9 (OS) 17.0 - - 100.0 - -

fluid) is unclear at present. In some cases, intraretinal fluid may simply be a manifestation of irreversible photoreceptor damage, rather than its cause. Our study further supports the possibility that persistent subretinal fluid may not always have a progressive impact on visual outcomes. Moreover, one subject in this study had intraretinal fluid inferior to the fovea in addition to the presence of subretinal fluid and was able to maintain a visual acuity of 20/25 at 5 year follow-up.

A cone-specific, RPE-independent, pigment regeneration pathway may explain the relative integrity of photoreceptor function despite chronic subretinal fluid accumulation. In primate and human models, an intraretinal visual cycle has been proposed to play an important role in preserving cone function in pathologic states that selectively impair the established RPE visual cycle.17 Following photolysis, chromophore molecules may bypass an RPE dependent process, instead undergoing recycling in the Müller cells of the retina. Subsequently, the molecules are supplied to cones in order to complete the cycle of pigment regeneration. Persistent subretinal fluid may mechanically inhibit the RPE dependent pathway, but could allow or even theoretically augment the intraretinal pathway through diffusion of necessary substrates to Müller cells.

It is pertinent to note that the average subfoveal choroidal thickness in our study subjects was greater than expected for patients with macular degeneration on long-term intravitreal anti-VEGF therapy. Branchini et al. found mean subfoveal choroidal thickness to be 171.8 im in 22 patients with neovascular AMD treated with anti-VEGF therapy for one year.18 Risk of geographic atrophy and resultant poor visual prognosis is a significant concern in NVAMD patients with chronic anti-VEGF treatment due its potential atrophic effects on the choroid, RPE, and photoreceptor layer.19 Increased choroidal thickness may provide greater nourishment to the outer retina and facilitate enhanced function of retinal photoreceptor cells.20,21 This may help explain the lack of geographic atrophy in all studied eyes.

Interestingly, all subjects also had type 1 neovascularization. We hypothesize that the sub-RPE neovascular complex may deliver nutrients to the outer retina without invading the subretinal space and damaging adjacent delicate structures, such as the photoreceptor layer. Type 1 neovascularization could theoretically be protective against geographic atrophy. Future investigations need to be performed to elucidate the relationship between anatomic neovascular subtypes, risk of geographic atrophy, and visual prognosis.

Further large scale, prospective studies could also address the limitations present in our study. First, due to the rarity of cases, the sample size of our study was limited to only 10

eyes of 9 patients. Future dedicated investigations of choroidal thickness might include matched control eyes. Additionally, measurements of 500-^m intervals up to 2500 im temporal and nasal to the fovea should be obtained, and all measurements should be performed by 2 independent observers. These measurements can then be compared using paired t-test in order to verify statistical significance. Another limitation of our study is that there was not a standard protocol for initiation of therapy or the timing and number of injections or PDT treatments.

In this investigation, patients with type 1 neovascularization causing persistent subretinal fluid refractory to anti-VEGF therapy were able to achieve good long-term visual outcomes. Increased subfoveal choroidal thickness and type 1 neovascularization may exert a protective effect on photoreceptor integrity and may result in better visual outcomes.

Financial interest disclosure

K. Bailey Freund - Genentech, Inc.: Consultant, Honoraria; Heidelberg Engineering: Consultant, Honoraria; Regeneron Pharmaceuticals, Inc.: Consultant, Honoraria; Bayer, Inc.: Consultant, Honoraria.

None of the authors have a proprietary interest.

Conflict of interest

The authors declared that there is no conflict of interest.

References

1. Gass JD. Stereoscopic atlas of macular diseases: diagnosis and treatment. 3rd ed. CV Mosby: St Louis; 1987.

2. Freund KB, Zweifel SA, Engelbert M. Do we need a new classification for choroidal neovascularization in age-related macular degeneration? Retina 2010;30(9):1333-49.

3. Lu M, Adamis AP. Molecular biology of choroidal neovascularization, Ophthalmol Clin North Am 2006;19:323-34.

4. Adamis AP, Shima DT. The role of vascular endothelial growth factor in ocular health and disease. Retina 2005;25:111-8.

5. Regillo CD, Brown DM, Abraham P, et al. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER study year 1. Am J Ophthalmol 2008;145:239248.

6. Brown DM, Michels M, Kaiser PK, et al. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study. Ophthalmology 2009;116(1):57-65.

7. Rofagha S, Bhisitkul RB, Boyer DS, et al. Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP). Ophthalmology 2013;120(11):2292-9.

8. CATT Research Group; Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011;364:1897-1908.

9. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419-31.

10. Lalwani GA, Rosenfeld PJ, Fung AE, et al. A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO study. Am J Ophthalmol 2009;148(43-58):e1.

11. Scott AW, Bressler SB. Long-term follow-up of vascular endothelial growth factor inhibitor therapy for neovascular age-related macular degeneration. Curr Opin Ophthalmol 2013;24(3):190-6.

12. Binder S. Loss of reactivity in intravitreal anti-VEGF therapy: tachyphylaxis or tolerance? Br J Ophthalmol 2012;96(1):1-2.

13. Brown DM, Tuomi L, Shapiro H. Anatomical measures as predictors of visual outcomes in ranibizumab-treated eyes with neovascular age-related macular degeneration. Retina 2013;33(1):23-34.

14. Branchini L, Adhi M, Regatieri CV, et al. Analysis of choroidal morphology and vasculature in healthy eyes using spectral-domain optical coherence tomography. Ophthalmology 2013;120(9):1901-8.

15. Jaffe GJ, Martin DF, Toth CA, et al. Macular morphology and visual acuity in the comparison of age-related macular degeneration treatments trials. Macular morphology and visual acuity in the

comparison of age-related macular degeneration treatments trials. Ophthalmology 2013;120(9):1860-70.

16. Ting TD, Oh M, CoxTA, et al. Decreased visual acuity associated with cystoid macular edema in neovascular age-related macular degeneration. Arch Ophthalmol 2002;120:731-7.

17. Wang JS, Kefalov VJ. The cone-specific visual cycle. Prog Retin Eye Res 2011;30(2):115-28.

18. Branchini L, Regatieri C, Adhi M, et al. Effect of intravitreous antivascular endothelial growth factor therapy on choroidal thickness in neovascular age-related macular degeneration using spectral-domain optical coherence tomography. JAMA Ophthalmol 2013;131 (5):693-4.

19. Lois N, Mcbain V, Abdelkader E, et al. Retinal pigment epithelial atrophy in patients with exudative age related macular degeneration undergoing anti-vascular endothelial growth factor therapy. Retina 2013;33(1):13-22.

20. Fitzgerald ME, Tolley E, Frase S, et al. Functional and morphological assessment of age-related changes in the choroid and outer retina in pigeons. Vis Neurosci 2001;18(2):299-317.

21. Linsenmeier RA, Padnick-Silver L. Metabolic dependence of photoreceptors on the choroid in the normal and detached retina. Invest Ophthalmol Vis Sci 2000;41 (10):3117-23.