Patchy Chorioretinal Atrophy Changes at the Posterior Pole After Ranibizumab for Myopic Choroidal Neovascularization

Mariacristina Parravano; Fabio Scarinci; Marta Gilardi; Lea Querques; Monica Varano; Francesco Oddone; Francesco Bandello; Giuseppe Querques

doi:10.1167/iovs.17-22633

Abstract

Purpose: To investigate the potential role of ranibizumab treatment on the development or enlargement of chorioretinal atrophy (CRA) at the posterior pole in eyes with myopic choroidal neovascularization (mCNV).

Methods: This observational case series included patients having high myopia spherical equivalent refractive error ≥ −6.00 diopters, axial length (AxL) ≥ 26.0 mm in both eyes, and mCNV treated with ranibizumab 0.5 mg in one eye, who were retrospectively enrolled. Areas of CRA in treated and fellow eyes were measured on fundus autofluorescence images at baseline, 12, and 24 months. The CRA hypoautofluorescent lesions were divided in two groups: perilesional atrophy, corresponding to area around the mCNV, and patchy extralesional atrophy, corresponding to CRA between the temporal vascular arcades.

Results: Thirty-six eyes of 18 patients were included. The mean perilesional CRA size significantly increased from baseline to 12 months (3.5 ± 10.6 mm², P = 0.02) and 24 months (4.4 ± 11.7 mm², P = 0.038) in the treated eye. In treated and not treated eyes, patchy extralesional CRA at the posterior pole increased significantly from baseline to 12 and 24 months follow-up. None of the fellow eyes developed mCNV. No significant relationship was found between the number of injections, AxL, age, and perilesional and patchy extralesional CRA in the treated and not treated eyes (P > 0.05).

Conclusions: In eyes with pathologic myopia and mCNV, intravitreal injections of ranibizumab should not be considered as a contributing risk factor worsening the natural course of CRA, even though the risk of the perilesional CRA enlargement should be taken into account.

The axial elongation and deformity of the eye, as well as the presence of myopic maculopathy and posterior staphyloma, are specific findings of pathologic myopia. These anatomic alterations of the globe can cause several complications that lead to visual impairment.^1–3 Pathologic myopia per se is a disease with a different clinical manifestation and progression, depending on the age of the onset and duration, as well as the mechanical stretching of the retina from axial elongation.⁴

Myopic maculopathy, including myopic choroidal neovascularization (mCNV) and chorioretinal atrophy (CRA) is the primary cause of vision loss associated with pathologic myopia and often affects patients during their most productive years.^5–7 Importantly, it has been found that the most common cause of CNV in patients younger than 50 years is pathologic myopia with a prevalence up to 40% in highly myopic patients.⁸ Although the long-term visual prognosis of mCNV is considered to be poor, with a high proportion of patients having a significant loss of visual acuity,^9,10 the use of intravitreal anti-VEGF therapy is considered the standard care of treatment. Of note, whereas several studies with 1-year follow-up have shown significant visual acuity improvement after anti-VEGF therapy,^11–15 in other reports with 2-year follow-up the overall outcomes seem to be less predictable, with conflicting results.^16–23 Several factors might influence the long-term visual prognosis after anti-VEGF treatment in myopic patients, including worsening of the CRA, as well as staphyloma and lacquer crack formation.⁶

The aim of this study is to explore if the anti-VEGF treatment could accelerate and worsen the development or enlargement of CRAs in eyes with mCNV treated with intravitreal injection of ranibizumab with follow-up at 2 years.

Methods

A retrospective chart review identified patients affected by pathologic myopia (myopic refractive error ≥6 diopters [D]), who were diagnosed with subfoveal, juxtafoveal, or extrafoveal mCNV at the Ophthalmology Department of Fondazione G.B. Bietti-IRCCS from January 1, 2008, through January 1, 2015. The local institutional review board approved this research protocol, and written informed consent was obtained from all patients.

The inclusion criteria were (1) high myopia, defined by a spherical equivalent (SE) refractive error equal or greater than 6.00 D and/or axial length (AxL) equal or superior to 26.0 mm in both eyes and the difference in AxL between the eyes no greater than 2 mm; (2) mCNV treated with ranibizumab 0.5 mg in one eye; (3) at least 2 years posttreatment follow-up; (4) fellow eye that never developed mCNV.

The exclusion criteria included myopic eyes with diffuse CRA and other ocular disorders such as glaucoma, diabetic retinopathy, or other retinal vascular diseases, or history of vitreoretinal surgery. Also, patients who received any treatments for myopic lesions, which might have worsened the natural course of myopic retinopathy, including laser photocoagulation, surgical treatment, and photodynamic therapy for mCNV were excluded.

At baseline, diagnosis of mCNV was based on a complete ophthalmological evaluation, which included best-corrected visual acuity (BCVA) measurement with Early Treatment Diabetic Retinopathy Study (ETDRS) charts, fundus examination, fundus autofluorescence, and fluorescein angiography (FA) (TRC-50X; Topcon Instrument Corp., Tokyo, Japan). Measurement of AxL was also recorded at baseline (IolMaster; Carl Zeiss Meditec AG, Jena, Germany).

Patients diagnosed with mCNV were treated with a single intravitreal injection of 0.5 mg/0.05 mL ranibizumab and re-treated according to predefined criteria.^24–26

Patients were evaluated to identify the need for retreatment with ranibizumab during the monthly follow-up. During follow-up, retreatment criteria were either a decrease of BCVA >5 ETDRS letters or presence of retinal hemorrhage or signs of mCNV activity on FA.

The number of ranibizumab intravitreal injections was evaluated at baseline, 12, and 24 months. The fellow nontreated eye was used as control.

Retinal fundus photography (FP), fundus autofluorescence (FAF), and FA were evaluated at baseline, 12, and 24 months to obtain a longitudinal analysis of the posterior pole, including optic disc, macular view, and upper and lower temporal arcade from both eyes.

Areas of CRA in treated and fellow eye were measured on FAF images at baseline and at 12 and 24 months. The measurements included the posterior pole area between the temporal vascular arcades.

A dedicated software (Draw Region, HRA and Measure Image, IMAGEnet; Topcon Medical Systems, Inc., Oakland, NJ, USA) was used to assess the extension of CRA in square millimeters, and all measurements were performed by two masked experienced investigators (MP and MG).

The hypoautofluorescent lesions, corresponding to CRA measured in the FAF image, were divided in two groups: perilesional atrophy, which corresponded to area around the mCNV, and patchy extralesional atrophy, which corresponded to areas between the temporal vascular arcades.

At baseline the peripapillary atrophy area shown on FAF was outlined. For patients in whom the CRA areas at the posterior pole merged with peripapillary atrophy over time, the peripapillary atrophy area at the baseline was subtracted from the whole CRA area measured at 1- and 2-year follow-ups.

All CRA areas that merged during the 2 years of follow-up were summed for the measurements and considered as one area.

The degree of CRA changes around the perilesional and patchy extralesional CRA was expressed as the difference between the CRA area at each follow-up time point and the CRA area at baseline.

Statistical Analysis

Statistical analysis was performed using analysis software (GraphPad Prism ver. 6.0; GraphPad Software, San Diego, CA, USA). Continuous data were described as mean ± standard deviation and categorical data as frequencies. Multivariate analysis of variance for repeated measures was used to compare the effect of the interaction between time and treatment over the follow-up between the groups. Post hoc between-group comparison was analyzed using the Mann-Whitney test. Linear regression analysis was used to explore the relationship between variables. A P value < 0.05 was considered statistically significant.

A bivariate correlation between variables has been performed by Pearson correlation coefficient or Spearman's ρ correlation coefficient in case of nonparametric distributions to explore the relationship between the growth of patchy atrophy at the posterior pole as a mean change in treated and untreated eyes in each individual patient over 2 years of follow-up.

Results

Patient Demographic Data

Among 132 screened patients, 18 met the inclusion criteria (12 females and 6 males, mean age 62.2 ± 16.7 years), and thus 36 eyes were analyzed. Mean AxL was 28.9 ± 2.3 mm in the treated and 28.4 ± 2.1 mm in the fellow eyes (P = 0.57).

Demographic and clinical data are shown in Table 1. During the study period (24 months) patients treated with ranibizumab received a mean of 2.6 ± 1.7 intravitreal injections (1.7 ± 1.8 [range, 1–4] in the first year and 0.9 ± 1.1 [range, 0–3] in the second year). None of the fellow eyes developed mCNV, and no eyes underwent cataract surgery during the study period.

Table 1

View Table

Main Demographics and Clinical Data

Characterization and Progression of Myopic Maculopathy

In the treated eye, mCNVs were classified as subfoveal in 27.7% (5/18) of eyes, juxtafoveal in 50% (9/18) of eyes, and extrafoveal in 22.2% (4/18) of eyes.

Perilesional CRA was present at baseline in 38.9% (7/18) of eyes; patchy extralesional CRA at the posterior pole was present in 72.2% (13/18) of treated eyes and in 61.1% (11/18) of fellow eyes.

The mean perilesional CRA size significantly increased from baseline (3.1 ± 10.2 mm²) to 12 months (3.5 ± 10.6 mm², P = 0.02) and 24 months (4.4 ± 11.7 mm², P = 0.038) during anti-VEGF treatment (Fig. 1).

Figure 1

View Original Download Slide

CRA changes in eyes with mCNV. Fundus color photograph and autofluorescence of patient 2 in the tables diagnosed with mCNV showing the enlargement of perilesional (arrow) as well as patchy extralesional (arrowhead) CRA from baseline (top left–top right) to 24 months follow-up (bottom left–bottom right).

Among those eyes with absence of perilesional CRA at baseline (61.1%, 11/18), 55.5% (10/18) did not develop atrophy during 24-months follow-up, while one eye showed the presence of perilesional CRA after 12 months (1.6 mm²) that enlarged after 24 months (3.3 mm²).

In the treated eyes, patchy extralesional CRA at the posterior pole increased significantly from baseline (3.9 ± 10.6 mm²) at 12 (6.4 ± 14.3 mm², P = 0.037) and 24 (8.3 ± 16.4 mm², P = 0.019) months of follow-up (Fig. 1); similarly, in the nontreated eyes patchy extralesional CRA at the posterior pole increased significantly from baseline (7.5 ± 11.6 mm²) at 12 (8.4 ± 12.4 mm², P = 0.035) and 24 (8.9 ± 12.9 mm², P = 0.006) months of follow-up without any difference between groups (P = 0.09) (Fig. 2).

Figure 2

View Original Download Slide

CRA changes in the fellow eyes with pathologic myopia without CNV. Fundus color photograph and autofluorescence of patient 2 (in the tables) with high myopia showing the enlargement of patchy (arrowhead) CRA in the fellow nontreated eye from baseline (top left–top right) to 24 months follow-up (bottom left–bottom right).

Development of new areas at 24 months did not significantly differ between treated and fellow eyes.

In the treated eyes, two patients showed posterior pole CRA merging with peripapillary atrophy over the 2 years of follow-up. However, as indicated in the method, because the value of the peripapillary atrophy area at the baseline was subtracted from the whole CRA area measured at 1- and 2-year follow-up, these changes did not influence the final measurements obtained.

Progression of CRA in both the treated and fellow eyes at 12 and 24 months is presented in detail in Tables 2, 3, and 4.

Table 2

View Table

Progression of Perilesional CRA and Number of Intravitreal Injections in the Treated Eyes at Baseline, 12, and 24 Months

Table 3

View Table

Progression of Patchy Extralesional CRA at the Posterior Pole in the Treated Eyes at Baseline, 12, and 24 Months

Table 4

View Table

Progression of Patchy Extralesional CRA at the Posterior Pole in the Fellow (Not Treated) Eyes at Baseline, 12, and 24 Months

A significant correlation of moderate strength was found between 2 years mean change of patchy atrophy at the posterior pole in treated and fellow eyes (Spearman's ρ correlation coefficient: R² 0.56, P = 0,016). This finding corroborates our results of a similar growth of patchy atrophy at the posterior pole in treated and untreated eyes; this seems not to be influenced by anti-VEGF treatment.

Within-group analysis revealed that the patients treated with ranibizumab experienced a stabilization of the mean BCVA from baseline, which was evident since the first follow-up visit (70.2 ± 9.8 vs. 68.4 ± 14.8 letters, P = 0.4), and maintained up to the last visit at 24 months (68.4 ± 14.8 vs. 66.05 ± 15.3 letters, P = 0.07). Six (33.3%) of 18 treated eyes showed an improvement of BCVA (range, 1–8 letters). Eleven (61.1%) out of 18 treated eyes experienced visual loss (range, 3–29 letters), with two eyes losing more than two lines because of the greater extension of perilesional CRA in the macular area.

BCVA in the fellow eyes remained stable during 24 months in most of the patients (64.7 ± 5.1 vs. 63.9 ± 5.8 letters, P = 0.07). Only one (5.5%) out of 18 fellow eyes experienced a visual loss of seven letters from the baseline because of the enlargement of CRA in the macula area.

No significant relationship was found between the number of injections and visual acuity change in the treated eyes and between the number of injections and perilesional CRA change at 24 months (R² 0.08, P = 0.2).

No significant relationship was found between AxL and age and patchy extralesional CRA in the treated and not treated eyes nor between AxL and age and perilesional CRA in the treated eye (data not shown).

Discussion

Our results showed that under anti-VEGF intravitreal injection with ranibizumab in highly myopic eyes with mCNV the perilesional size of CRA increased, whereas the treatment did not influence the development or enlargement of the patchy extralesional CRA areas at the posterior pole as compared to fellow eyes (not treated) over 2 years of follow-up.

Patchy extralesional CRA at the posterior pole increased significantly from baseline in both the treated and fellow (not treated) eyes at 12 and 24 months of follow-up without any difference between groups.

Chorioretinal atrophy represents the end stage of progressive photoreceptor and RPE cell death causing a dramatic loss of visual acuity, especially when the fovea and perifovea are involved. However, in addition to the well-known natural progression pattern of pathologic myopia, the prevalence of structural changes, including the development of new CRA areas and their enlargement, may be influenced by several factors such as age, AxL, the presence of staphyloma, and choroidal thickness.^5,7,27–29 Moreover, natural history of pathologic myopia is characterized by progression of CRA in eyes with mCNV either treated or untreated.³⁰

It has been shown that 40% of the highly myopic eyes have progression of myopic maculopathy over a mean follow-up of 12.7 years; eyes with tessellated fundus, lacquer cracks, and diffuse atrophy, as well as patchy atrophy, at the first visit progressed to the development of CNV, while eyes with CNV developed macular atrophy with time.⁶

Moreover, eyes with patchy atrophy and eyes with CNV showed a higher progression of the myopic maculopathy compared to the other myopic retinal findings, and in the presence of the patchy atrophy, the most frequent progression pattern was an enlargement of the area followed by fusion with other patchy atrophy originated from diffuse atrophy or patchy atrophy along the staphyloma.⁶

In our group of patients, only two eyes showed the fusion of the diffuse atrophy or patchy atrophy at the posterior pole with the peripapillary atrophy.

Of note, Hayashi et al.³¹ reported that 96.3% of untreated eyes with mCNV developed macular atrophy due to natural progression of the disease after 5 years of follow-up.

On the other hand, in line with our results, Calvo-Gonzalez et al.³² also found that after 2 years of treatment with intravitreal injection, 70.2% of the myopic eyes with mCNV developed atrophy around the regressed lesion. More recently, Oishi et al.³³ showed the development/enlargement of CRA in 72.7% of the eyes with mCNV treated with bevacizumab after 4 years of follow-up. However, since we used ranibizumab to treat the mCNV, we believe the results cannot be directly compared.

In a previous study,³⁴ we have found that in eyes with mCNV treated with either photodynamic therapy or ranibizumab the mean perilesional size of CRA increased at the final visit. Interestingly, the group treated with photodynamic therapy showed higher CRA values in comparison with the ranibizumab group (82.6% vs. 52.6%, respectively).

There is a little information on the possible effect and mechanism of anti-VEGF treatment in pathologic myopia, not only around the mCNV lesion but also at the posterior pole. Furthermore, studies have found that ranibizumab could have a stronger effect on the macular atrophy formation than bevacizumab in patients with AMD.^35,36

While anti-VEGF treatments are important to reduce and inhibit the disease activity in patients with mCNV, the VEGF inhibition might influence its expression in RPE cell,^37–39 which is fundamental for RPE cells and choriocapillaris integrity. This in turn would result in the enlargement of perilesional CRA, but not of patchy extralesional CRA at the posterior pole, as demonstrated in our study. The similar extension of patchy extralesional CRA, between treated and untreated eyes, suggests limited or no role of anti-VEGF treatments in the development and progression of atrophy and allows us to hypothesize that the enlargement of perilesional CRA simply represents the natural progression of atrophy and fibrosis related to mCNV.

In keeping with this possible effect of anti-VEGF treatment, McLeod et al.⁴⁰ found that choriocapillaris dropout in areas surrounding CNV may explain the higher growth of geographic atrophy close to CNV in AMD.

On the other hand, one could discuss the possibility that intravitreal injection in one eye may have an effect on the fellow eye, even though, to date, this concept remains uncertain. Indeed, especially in patients with diabetic macular edema, a compromised blood–retinal barrier caused by the disease could facilitate the anti-VEGF effect in both eyes.⁴¹ We believe that the effect of intravitreal treatment in the fellow eye is less likely to happen in patients with pathologic myopia, especially when the latter is not affected by any vascular changes. Finally, we cannot totally exclude that intravitreal ranibizumab may reach the fellow eye via the systemic circulation.

While the correlation between the number of injection and atrophy has been studied in several studies in patients with AMD, the results in patients with mCNV are still controversial.^{35,36,42–44} In patients with AMD, several studies concluded that there was no correlation between the number of injections and macular atrophy.^35,36,44,45

In our cohort of patients, the number of treatments did not influence CRA changes over time, even in eyes with mCNV. However, since we used a pro re nata regimen, we cannot extend this conclusion to other regimens of treatment, where the dose–response effect could be higher.

Limitations include the retrospective design of the study as well as the relatively small number of eyes. Future prospective, longitudinal studies with longer period of follow-up are needed to confirm our results.

In conclusion, we showed that in eyes with pathologic myopia and mCNV, intravitreal injections of ranibizumab should not be considered as a contributing risk factor to worsening of the natural course of CRA areas at the posterior pole, even though the risk of the perilesional CRA enlargement, which possibly represents the natural progression of atrophy and fibrosis related to mCNV, should be taken into account.

Acknowledgments

Supported by Italian Ministry of Health and Fondazione Roma. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Disclosure: M. Parravano, Allergan (S), Bayer (S); Novartis (S); F. Scarinci, None; M. Gilardi, None; L. Querques, Allergan (S); M. Varano, Allergan (S), Bayer (S); Novartis (S); F. Oddone, Allergan (S), Glaucoom (S), Omikron (S), Santen (S); F. Bandello, Allergan (S), Alimera (S), Bayer (S), Farmila-Thea (S), Novartis (S), Thrombogenics (S); G. Querques, Allergan (S), Alimera (S), Bayer (S), Novartis (S), Heidelberg (C), Zeiss (S), Sandoz (S), KHB (S)

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