Foveal Serous Retinal Detachment with Inferior Staphyloma: Long-Term Treatment Response to Anti-VEGF and Photodynamic Therapy

Abstract

Purpose

To evaluate the treatment response and long-term prognosis of foveal serous retinal detachment (SRD) associated with inferior staphyloma to anti-vascular endothelial growth factor (anti-VEGF) treatment and photodynamic therapy (PDT).

Methods

Nineteen treatment-naïve patients who underwent > 24 months follow-up were included. We analyzed the inter-visit changes in the foveal subretinal fluid (SRF) height after anti-VEGF treatment or PDT compared to no treatment and long-term prognosis of best-corrected visual acuity.

Results

At the last visit of patients who received the treatment, complete resolution was more significantly achieved in the CNV (choroidal neovascularization) group than in the CNV-free group (P = 0.028). In the CNV-free patients, visual acuity improved when complete resolution was achieved; otherwise, it generally decreased and after adjusting for confounding factors, analyses showed no statistically significant differences in inter-visit changes of foveal SRF height between the anti-VEGF treatment and no treatment cases (Absolute value, Rate, Subgroup categorized as ± 20% of change; P = 0.733, P = 0.916, P = 0.277; respectively). All three patients who underwent PDT did not show complete resolution or maintained improvement of the SRF.

Conclusion

Treatment with anti-VEGF and PDT do not seem to be effective for foveal SRD of CNV-free inferior staphyloma.

Introduction

Inferior staphyloma is a type of primary posterior staphyloma associated with myopia and classified as a type V staphyloma.¹ In rare cases of patients with inferior staphyloma, macular serous retinal detachment (SRD) can occur and deteriorate visual function.^2–5 However, little is known about the long-term prognosis or effective treatment strategies for macular SRD associated with inferior staphyloma.

Intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection was established as the standard treatment for choroidal neovascularization (CNV) secondary to age-related macular degeneration^6,7 and pathologic myopia,^8,9 and further has been applied in various medical situations involving subretinal or intraretinal fluids.^10–15 Recently, four case series about anti-VEGF trials for the treatment of SRD associated with inferior staphyloma were reported, and the results were contradictory.^16–19 In those reports, only 1, 2, 1, and 6 patients were enrolled; thus, it seems difficult to draw a confirmative conclusion. Besides, low fluence photodynamic therapy (PDT) did not show effective results in two patients.¹⁷

Herein, we evaluated whether anti-VEGF treatment and PDT were effective for foveal SRD associated with CNV-free inferior staphyloma and determine the long-term prognosis of the disease in a relatively large number of patients.

Methods

Treatment Protocols

In the administration of the anti-VEGF injection, bevacizumab (Avastin) 1.25 mg or ranibizumab (Lucentis) 0.5 mg was injected 3.0 or 3.5 mm posterior to the limbus through the pars plana using a 30-gauge needle in the operating room, using an aseptic technique.

PDT was performed using half-dose verteporfin (Visudyne; Novartis, Basel, Switzerland). For this, 3 mg/m² of verteporfin was infused over 10 minutes, and 15 minutes after beginning the infusion, the laser treatment was begun. Laser treatment with standard fluency of 50 J/cm² and a wavelength of 689 nm was applied to the affected area for 83 seconds.

Imaging Analysis

All OCT images, color fundus photographs, and FA and ICGA findings were reviewed by two independent examiners (J.L., J.W.J.) to determine the presence of accompanying CNV, and height of foveal SRD. The agreement between the two examiners was good. Discrepancies between examiners for categorical values and differences over 20% between the quantitatively measured values were resolved by open adjudication. If no consensus was reached, a final decision was made by the other senior examiner (S.H.B.) and the two closest values were averaged.

The height of the SRF was measured at the point of the subfovea, from the distance between the lower interface of the detached retina and the upper interface of the retinal pigment epithelium (RPE), manually using the OCT system’s built-in calipers.

Outcomes And Statistical Analysis

The changes in BCVA between the initial and final visit were evaluated according to whether complete SRF resolution and CNV were accompanied. Wilcoxon signed-rank test was used to determine the difference in BCVA between the initial and last visit. Fisher’s exact test was used to compare the proportions of complete SRF resolution at the last visit according to the presence of CNV. The anti-VEGF agents administered were bevacizumab (119) and ranibizumab (7); the two medications were not analyzed separately.

The main question of this study was whether anti-VEGF treatment was effective in foveal SRD of patients with CNV-free inferior staphyloma. We determined the inter-visit changes of SRF at every visit according to anti-VEGF treatment and observation without any treatment as the main variable. The SRF values within 12 months after PDT were excluded from the analysis. All included inter-visit duration was over 1 month, and it was analyzed under the assumption that every inter-visit change was independent. There were a total of 243 inter-visits among the 14 patients without CNV, with 88 being administered intravitreal anti-VEGF injection and 155 being observed without treatment. As for the retrospective nature of this study, the initial amount of foveal SRF, follow-up duration, inter-visit intervals, and number of visits and anti-VEGF injections were heterogenous among subjects. Therefore, the patients, follow-up duration between the former and latter visits, and the amount of foveal SRF at the former visit were statistically adjusted. To improve the validity of the conclusion, inter-visit changes in foveal SRF height were converted into various variables and analyzed. Absolute value change and rate of change in foveal SRF between the anti-VEGF treatment group and the no treatment (observation) group were analyzed by a linear mixed model with an unstructured covariance matrix. As classified into categorical groups, the criterion was defined as a change of ± 20% or more and changes of less than ± 20% were classified as stable. The chi-squared test and generalized linear mixed model with adjusting of confounding factors were used to analyze the difference in categorical classification of ± 20%. All statistical analyses were performed using SAS version 9.4 software (SAS Institute, Cary, NC, USA). A P-value < 0.05 was considered statistically significant.

Results

The study included 19 eyes from 19 enrolled patients (5 males, 14 females). The mean (± standard deviation) patient age was 62.47 (± 13.48) years, and the mean (± standard deviation) follow-up period was 4.81 ± 2.71 years. During the follow-up period, a total number of 126 anti-VEGF injections were administered (bevacizumab; 119, ranibizumab; 7).

Patients’ detailed diagnoses and received treatment are summarized in Fig. 1. Among the patients enrolled in the study, 5 patients were diagnosed with accompanying CNV and all patients were treated with anti-VEGF injection. Among the 14 patients without CNV, 11 patients received an anti-VEGF injection treatment and 3 patients also received PDT treatment. The remaining 2 CNV-free patients were followed up without any treatment. Among the 14 CNV-free patients, there was a total of 243 inter-visits, 88 (bevacizumab; 81, ranibizumab; 7) were administered intravitreal anti-VEGF injection, and 155 were observed without treatment.

Visual Prognosis

In the CNV-free group, visual acuities were improved in patients with complete resolution, while visual acuities showed decreased tendency in the patients without complete resolution (mean ± standard deviation, LogMAR, 0.48 ± 0.35 to 0.62 ± 0.28; P = 0.092, Wilcoxon signed-rank test) (Fig. 2A).

In the CNV group, despite treatment efforts, visual acuities decreased at the final visit compared to those at the first visit, showing marginal significance (mean ± standard deviation, LogMAR, 0.32 ± 0.13 to 0.67 ± 0.27; P = 0.068, Wilcoxon signed-rank test) (Fig. 2B).

Effectiveness Of Anti-vegf Treatment

The effect of anti-VEGF treatment was determined in the inter-visit changes of foveal SRF height between the cases of anti-VEGF versus observation (no treatment).

When the inter-visit change patterns of foveal SRF were divided into increase, stable (within ± 20%), and decrease, patterns were evaluated as 47 (30.3%), 67 (43.2%), 41 (26.5%) cases in cases of observation, and 19 (21.6%), 33 (37.5%), 36 (40.9%) cases in cases of anti-VEGF administration, respectively, with no significant differences (P = 0.243, chi-squared test) (Table 2).

After correction for confounding factors such as the foveal SRF height at the former visit and inter-visit duration, there was no difference in inter-visit SRF change between the observation cases and anti-VEGF cases for all variable types (Fig. 3, Tables 3 and 4). The estimated mean (95% confidence interval) of the absolute value of inter-visit SRF change was + 0.252 (-43.864,44.368) µm in the observation cases and − 11.845 (-71.003,47.314) µm in the anti-VEGF cases, and there was no significant difference between the two groups (P = 0.733, linear-mixed model with unstructured covariance matrix) (Fig. 3, Table 3). The estimated mean (95% confidence interval) of rate of inter-visit SRF change was + 13.738 (-73.363,100.839) % in the observation cases and + 6.270(-111.628,124.167) % in the anti-VEGF cases, and there was no significant difference between the two groups (P = 0.916, linear-mixed model with unstructured covariance matrix) (Table 3). Adjusted proportion of increase, stable (within ± 20%), and decrease cases of inter-visit SRF were 46.0%, 40.5%, and 13.3% in the observation cases and 47.2%, 33.6%, and 19.3% in the anti-VEGF injection cases, respectively, which was statistically not significant between the two groups (P = 0.277, generalized linear-mixed model) (Table 4).

As a result, the anti-VEGF injection did not significantly reduce SRF compared to observation (no treatment). In fact, in many cases, the SRF was increased despite anti-VEGF injection, and the SRF was decreased despite just observation. A representative case is displayed in Fig. 4.

Effectiveness Of Pdt

A total of 3 patients underwent half-dose PDT, and all patients underwent a single PDT session. After the PDT treatment, in three consecutive follow-up visits at 3-month intervals, complete resolution could not be reached at any time, and the decreased SRF was not maintained (Supplementary Fig. 1).

Discussion

Inferior staphyloma with foveal SRD is a rare medical condition. Therefore, there have been only studies of case reports or case series with a limited number of patients or follow-up duration. The amount of SRD, especially in cases without CNV, may fluctuate in general and may spontaneously disappear without any treatment. Previously, a spontaneous resolution case was reported in a patient with inferior staphyloma with foveal SRD, and one patient was also observed in our cohort. Therefore, when SRF decreases after treatment, it is difficult to determine whether it is caused by the treatment effect or is just a spontaneous decrease. In addition, it is difficult to construct a prospective study for these rare medical conditions, and the clinical data of a retrospective study are usually unrefined and heterogenous. Under these limitations, only conclusions based on relatively sufficient cases and sophisticated statistical methods would be reliable. We believe that our study could draw confirmative conclusions about the treatment effect of anti-VEGF, based on enrolling a relatively large number of patients and the anti-VEGF injections with a long-term follow-up duration of more than 2 years and a mean of 4.81 years.

Longstanding SRD can cause permanent damage to photoreceptors and visual deterioration.^20–22 In our cohort of CNV-free patients, visual acuity improved when complete resolution was achieved; otherwise, visual acuity generally decreased. Therefore, any treatment which leads to complete resolution of SRF would be needed for the prevention of permanent photoreceptor damage and to improve visual prognosis.

In this study, anti-VEGF does not seem to be effective on foveal SRD of the patients with CNV-free inferior staphyloma. The inter-visit changes of foveal SRF height in CNV-free patients were investigated between 88 anti-VEGF treatment cases and 155 observation cases, and the absolute value, rate, and subgroup categorized as ± 20% of inter-visit foveal SRF changes were analyzed. After adjusting for confounding factors such as SRF height at the former visit and inter-visit duration, analyses showed no statistical differences in inter-visit change of foveal SRF between the anti-VEGF treatment cases and the observation cases (P = 0.733, P = 0.916, P = 0.277; respectively).

Bevacizumab (anti-VEGF) has been shown to be effective in reducing neurosensory detachment by reducing the vascular permeability in various ocular diseases, such as choroid-retinal vascular diseases^10–12 and choroidal tumors.^13–15 Since intravitreal anti-VEGF injections have proven their effectiveness on SRF, there have been attempts to treat anti-VEGF intravitreal injections in such refractory SRD. Previously, four case series on anti-VEGF trials for the treatment of foveal SRD associated with inferior staphyloma were reported, and the results were contradictory.^16–19 Milani et al.¹⁶ reported that one patient did not benefit from two consecutive monthly injections of bevacizumab. Similarly, Donati et al.¹⁷ described two patients, one of whom was treated using three injections of bevacizumab monotherapy, while the other was treated using combined bevacizumab and photodynamic therapy. Treatment was unsuccessful in both patients. In comparison, Hirano et al.¹⁸ reported one case of SRD in inferior staphyloma that was refractory to ranibizumab treatment, but in which exudative changes resolved after two injections of aflibercept. Lee et al.¹⁹ conducted a study on six patients with foveal SRD associated with CNV-free inferior staphyloma and noted the reduction of foveal SRF and choroidal thickness, and complete resolution of SRF in 50% of patients treated with anti-VEGF. In those studies, only 1, 2, 1, and 6 patients were enrolled; thus, it seems difficult to draw a confirmative conclusion. In our study, the inter-visit change patterns of foveal SRF were 20% more decreased in 41 (26.5%) cases without any treatment. The decrease in SRF after anti-VEGF treatment in the preceding case series is thought to be likely due to chance.

Half-dose PDT has been established as the first-line of treatment for chronic central serous chorioretinopathy (CSC).²³ As a concept similar to reducing SRF in the CSC, half-dose PDT has been performed on SRF of CNV-free inferior staphyloma. In all three of our cases, complete resolution was not achieved, and reduced SRF was not maintained, which was similar to the results of previous studies.¹⁷ PDT is effective in diseases showing thick choroid, so-called pachychoroid spectrum diseases such as CSC or polypoidal choroidal vasculopathy,^23,24 however, SRF accompanying inferior staphyloma is a clinical manifestation with thin choroid and high myopia, which is thought to have a different pathophysiology from that of pachychoroid-related disease manifesting SRF.

Although rare, intravitreal injections can potentially cause serious complications such as endophthalmitis, and PDT could cause outer retinal atrophy. By not administering unproven, unnecessary treatments, ineffective medical expenses and possible complications can be reduced.

The disease entity of foveal SRD associated with inferior staphyloma appears to be similar to that of SRD with a dome shaped macula. Both diseases are accompanied by high myopia and posterior staphyloma, and no effective treatment has been determined. Dome shaped macula is characterized by a convex anterior protrusion (bowing towards the vitreous cavity) or posterior protrusion on both sides of the macula, whereas inferior staphyloma has a posterior protrusion only in the inferior part of the macula. The pathophysiology of both diseases remains controversial; however, both diseases are thought to accumulate foveal SRF by a similar mechanism related to anatomical change which is focal scleral thickening and abrupt change of choroidal thickness.^25,26 Firstly, the abrupt change of choroidal thickness of the margin of inferior staphyloma or dome shaped macula could damage overlying RPE and/or choriocapillaris resulting in dysfunction.^25,27 Secondly, scleral thickening and choroidal thinning of the margin of both diseased macula may block the outflow of choroidal fluid, leading to fluid collection.^28–30

There were some limitations in this study. Although foveal SRF with inferior staphyloma is a very rare pathological condition, a larger number of patients and a prospective design of study would have strengthened the credibility of the conclusion.

In conclusion, in the case of foveal SRD in CNV-free inferior staphyloma, treatment with anti-VEGF and PDT do not seem to be effective. Because complete resolution of SRF can prevent potentially permanent damage to photoreceptors and lead to a better visual prognosis, novel therapies would be needed.

Declarations

Data availability

All data generated or analysed during this study are included in this published article (and its Supplementary Information files). The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

 Acknowledgements

Author contributions

J.L. and S.H.B. conceived the design of the study. J.W.J., H.G.K., S.H.B. and J.L. collected the data. J.W.J, S.J., G.P., H.G.K. and J.L. analyzed and interpreted the data. J.W.J. and J.L. drafted the article. J.W.J., C.S.L., M.K., S.S.K., S.H.B. and J.L critically revised the article. J.W.J., C.S.L., M.K., S.S.K., S.H.B. and J.L approved the final version of the article to be published.

 Funding

This research was supported by grants for the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Korea government (MSIT) (grant number: 2019R1A2C2086729) and funded by the Ministry of Education (grant number: 2021R1I1A1A01045648). The funding organization had no role in the design or conduct of this research. no conflicting relationship exists for any author. 

Competing interests

The authors declare no competing interests.

References

1. Ohno-Matsui, K. & Jonas, J. B. Posterior staphyloma in pathologic myopia. Prog Retin Eye Res 70, 99-109. https://doi.org/10.1016/j.preteyeres.2018.12.001 (2019).
2. Tosti, G. Serous macular detachment and tilted disc syndrome. Ophthalmology 106, 1453-1455. https://doi.org/10.1016/S0161-6420(99)90472-4 (1999).
3. Leys, A. M. & Cohen, S. Y. Subretinal leakage in myopic eyes with a posterior staphyloma or tilted disk syndrome. Retina 22, 659-665. https://doi.org/10.1097/00006982-200210000-00025 (2002).
4. Theodossiadis, P. G., Grigoropoulos, V., Emfietzoglou, J. & Theodossiadis, G. P. Optical coherence tomography study of tilted optic disk associated with macular detachment. Graefes Arch Clin Exp Ophthalmol 244, 122-124. https://doi.org/10.1007/s00417-005-0018-3 (2006).
5. Nakanishi, H. et al. Macular complications on the border of an inferior staphyloma associated with tilted disc syndrome. Retina 28, 1493-1501. https://doi.org/10.1097/IAE.0b013e318183589c (2008).
6. Brown, D. M. et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 355, 1432-1444. https://doi.org/10.1056/NEJMoa062655 (2006).
7. Rosenfeld, P. J. et al. Ranibizumab for neovascular age-related macular degeneration. The New England Journal of Medicine 355, 1419-1431 (2006).
8. Ikuno, Y. et al. Intravitreal bevacizumab for choroidal neovascularization attributable to pathological myopia: one-year results. Am J Ophthalmol 147, 94-100 e101. https://doi.org/10.1016/j.ajo.2008.07.017 (2009).
9. Silva, R. M. et al. Intravitreal ranibizumab for myopic choroidal neovascularization: 12-month results. Retina 30, 407-412. https://doi.org/10.1097/IAE.0b013e3181c9691e (2010).
10. Arevalo, J. F. et al. Primary intravitreal bevacizumab for diffuse diabetic macular edema: the Pan-American Collaborative Retina Study Group at 24 months. Ophthalmology 116, 1488-1497, 1497 e1481. https://doi.org/10.1016/j.ophtha.2009.03.016 (2009).
11. Figueroa, M. S., Contreras, I., Noval, S. & Arruabarrena, C. Results of bevacizumab as the primary treatment for retinal vein occlusions. Br J Ophthalmol 94, 1052-1056. https://doi.org/10.1136/bjo.2009.173732 (2010).
12. Lim, S. J., Roh, M. I. & Kwon, O. W. Intravitreal bevacizumab injection for central serous chorioretinopathy. Retina 30, 100-106. https://doi.org/10.1097/IAE.0b013e3181bcf0b4 (2010).
13. Kwon, H. J., Kim, M., Lee, C. S. & Lee, S. C. Treatment of serous macular detachment associated with circumscribed choroidal hemangioma. Am J Ophthalmol 154, 137-145 e131. https://doi.org/10.1016/j.ajo.2012.01.007 (2012).
14. Fenicia, V. et al. Intravitreal bevacizumab in the successful management of choroidal metastases secondary to lung and breast cancer unresponsive to systemic therapy: a case series. Eye (Lond) 28, 888-891. https://doi.org/10.1038/eye.2014.96 (2014).
15. Song, J. H., Bae, J. H., Rho, M. I. & Lee, S. C. Intravitreal bevacizumab in the management of subretinal fluid associated with choroidal osteoma. Retina 30, 945-951. https://doi.org/10.1097/IAE.0b013e3181c720ca (2010).
16. Milani, P. et al. Bevacizumab for macular serous neuroretinal detachment in tilted disk syndrome. J Ophthalmol 2010, 970580. https://doi.org/10.1155/2010/970580 (2010).
17. Donati, M. C. et al. Treatment of macular serous neuroretinal detachment in tilted disk syndrome: report of 3 cases. Eur J Ophthalmol 23, 267-270. https://doi.org/10.5301/ejo.5000169 (2013).
18. Hirano, Y. et al. Resolution of exudative changes refractory to ranibizumab after aflibercept injections at the margin of inferior staphyloma in tilted disc syndrome. Ophthalmic Surg Lasers Imaging Retina 46, 384-386. https://doi.org/10.3928/23258160-20150323-16 (2015).
19. Lee, E. K. & Yu, H. G. Outcomes of Anti-vascular Endothelial Growth Factor Treatment for Foveal Serous Retinal Detachment Associated with Inferior Staphyloma. Korean J Ophthalmol 33, 228-237. https://doi.org/10.3341/kjo.2018.0125 (2019).
20. Loo, R. H. et al. Factors associated with reduced visual acuity during long-term follow-up of patients with idiopathic central serous chorioretinopathy. Retina 22, 19-24. https://doi.org/10.1097/00006982-200202000-00004 (2002).
21. Haga, F. et al. Long-term prognostic factors of chronic central serous chorioretinopathy after half-dose photodynamic therapy: A 3-year follow-up study. PLoS One 12, e0181479. https://doi.org/10.1371/journal.pone.0181479 (2017).
22. van Rijssen, T. J. et al. Correlation between redefined optical coherence tomography parameters and best-corrected visual acuity in non-resolving central serous chorioretinopathy treated with half-dose photodynamic therapy. PLoS ONE 13, e0202549-e0202549 (2018).
23. van Rijssen, T. J. et al. Central serous chorioretinopathy: Towards an evidence-based treatment guideline. Prog Retin Eye Res 73, 100770. https://doi.org/10.1016/j.preteyeres.2019.07.003 (2019).
24. Lim, T. H. et al. Comparison of Ranibizumab With or Without Verteporfin Photodynamic Therapy for Polypoidal Choroidal Vasculopathy: The EVEREST II Randomized Clinical Trial. JAMA Ophthalmology 138, 935-942 (2020).
25. Cohen, S. Y., Quentel, G., Guiberteau, B., Delahaye-Mazza, C. & Gaudric, A. Macular serous retinal detachment caused by subretinal leakage in tilted disc syndrome. Ophthalmology 105, 1831-1834. https://doi.org/10.1016/S0161-6420(98)91024-7 (1998).
26. Jain, M., Gopal, L. & Padhi, T. R. Dome-shaped maculopathy: a review. Eye (Lond) 35, 2458-2467. https://doi.org/10.1038/s41433-021-01518-w (2021).
27. Ohsugi, H., Ikuno, Y., Oshima, K., Yamauchi, T. & Tabuchi, H. Morphologic characteristics of macular complications of a dome-shaped macula determined by swept-source optical coherence tomography. Am J Ophthalmol 158, 162-170 e161. https://doi.org/10.1016/j.ajo.2014.02.054 (2014).
28. Yamagishi, T., Koizumi, H., Yamazaki, T. & Kinoshita, S. Choroidal thickness in inferior staphyloma associated with posterior serous retinal detachment. Retina 32, 1237-1242. https://doi.org/10.1097/IAE.0b013e318234cae6 (2012).
29. Maruko, I., Iida, T., Sugano, Y., Oyamada, H. & Sekiryu, T. Morphologic choroidal and scleral changes at the macula in tilted disc syndrome with staphyloma using optical coherence tomography. Invest Ophthalmol Vis Sci 52, 8763-8768. https://doi.org/10.1167/iovs.11-8195 (2011).
30. Deobhakta, A., Ross, A. H., Helal, J., Jr., Maia, A. & Freund, K. B. Localized choroidal thickness variation and pigment epithelial detachment in dome-shaped macula with subretinal fluid. Ophthalmic Surg Lasers Imaging Retina 46, 391-392. https://doi.org/10.3928/23258160-20150323-18 (2015).