SUBFOVEAL CHOROIDAL THICKNESS IN IDIOPATHIC CHOROIDAL NEOVASCULARIZATION AND TREATMENT OUTCOMES AFTER INTRAVITREAL BEVACIZUMAB THERAPY HYESUN KIM, MD, KAHYUN LEE, MD, CHRISTOPHER SEUNGKYU LEE, MD, SUK HO BYEON, MD, PHD, SUNG CHUL LEE, MD, PHD Purpose: To determine subfoveal choroidal thickness in idiopathic choroidal neovascularization (CNV) and evaluate visual and anatomical outcomes in patients with idiopathic CNV after intravitreal bevacizumab. Methods: Retrospective observation case series. Seventeen eyes of 17 patients with idiopathic CNV were treated with a single intravitreal bevacizumab injection, followed by additional doses based on optical coherence tomography findings, including intraretinal fluid, subretinal fluid, or pigment epithelial detachment. We analyzed best-corrected visual acuity, central subfield thickness, and subfoveal choroidal thickness at presentation and final visit. Seventeen unaffected fellow eyes and 17 healthy eyes constituted the control group for subfoveal choroidal thickness. Results: The subfoveal choroidal thickness was significantly thinner in eyes with idiopathic CNV (237.59 ± 53.84 mm) than in the unaffected fellow eyes (281.71 ± 59.01 mm, P = 0.001) or normal control eyes (290.38 ± 58.94 mm, P = 0.028). Mean logarithm of the minimum angle of resolution best-corrected visual acuity improved from 0.46 initially to 0.26 after treatment (P = 0.024). Mean central subfield thickness decreased from 387.88 ± 97.52 mm at baseline to 261.41 ± 31.18 mm after treatment (P , 0.001). Conclusion: Subfoveal choroidal thickness is reduced and may be associated with the pathophysiology of idiopathic CNV. Intravitreal bevacizumab resulted in significant visual and anatomical improvement in patients with idiopathic CNV. RETINA 35:481–486, 2015
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the pathophysiology of idiopathic CNV,3,4 but the exact mechanism of idiopathic CNV is still uncertain. The visual outcome of idiopathic CNV is generally more favorable than CNV associated with AMD because of its tendency for spontaneous regression.5 In a previous study with 87 months of follow-up, approximately 95% of patients with idiopathic CNV had stable or significantly improved visual acuity.5 However, severe visual loss can occur in 5% to 37% of untreated patients with idiopathic CNV.5–7 Various treatments for idiopathic CNV have been reported, such as photodynamic therapy or intravitreal anti-vascular endothelial growth factor (VEGF) therapy. However, the treatment of idiopathic CNV is still not well established.8–10 The choroid, which is one of the most highly vascularized tissues of the body, plays a significant
horoidal neovascularization (CNV) occurs under various ophthalmic or systemic conditions, such as myopia, angioid streak, trauma, infection, or agerelated macular degeneration (AMD). Idiopathic CNV is diagnosed when the cause of CNV is undetermined and accounts for approximately 17% of patients with CNV.1–3 Focal choroiditis or compensation of choroidal vessels has been thought to be involved in From the Department of Ophthalmology, The Institute of Vision Research, Yonsei University College of Medicine, Seoul, South Korea. H. Kim and K. Lee contributed equally to this study. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Christopher Seungkyu Lee, MD, Department of Ophthalmology, Severance Hospital, Yonsei University College of Medicine, 134 Sinchon-dong, Seodaemun-gu, Seoul 120-752, South Korea; e-mail: [email protected]
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role in various macular diseases, including AMD, polypoidal choroid vasculopathy, and central serous chorioretinopathy.11–19 The positive correlation of ocular perfusion pressure with subfoveal choroidal thickness suggests that subfoveal choroidal thickness may reflect the status of subfoveal ocular perfusion.20 A study using enhanced depth imaging OCT in eyes with CNV associated with AMD, whose key pathophysiologic factors include choroidal ischemia and hypoxia, demonstrated a reduction in subfoveal choroidal thickness.15,21 However, a recent study reported that AMD, neither in its nonexudative form nor exudative form, was significantly associated with a marked thinning or thickening of the choroid in the foveal and parafoveal region after adjusting for age and refractive error.22 In this study, we evaluated subfoveal choroidal thickness in eyes with idiopathic CNV compared with that in unaffected fellow eyes and normal eyes of healthy subjects. In addition, we analyzed visual and anatomical outcomes in patients with idiopathic CNV after intravitreal bevacizumab therapy.
Methods This retrospective observational study was approved by the Institutional Review Board of Yonsei University, Seoul, South Korea. We reviewed the charts of 20 patients who received intravitreal bevacizumab (1.25 mg/0.05 mL Avastin; Genentech, Inc, San Francisco, CA) for idiopathic CNV between January 2007 and March 2012, who were followed up for more than 2 months in the Department of Ophthalmology, Severance Hospital. Eight eyes were followed for more than 12 months after their first injection. All patients were younger than 50 years and showed active CNV by ophthalmoscopy, slit-lamp biomicroscopy, fluorescein angiography, indocyanine green angiography, and OCT. Active CNV was defined as evidence of leakage within the lesion on fluorescein angiography and indocyanine green angiography, and the presence of intraretinal fluid, subretinal fluid, or pigment epithelial detachment, based on Spectralis OCT (version 1.5.12.0; Heidelberg Engineering, Heidelberg, Germany). We excluded patients with CNV because of pathological myopia (refractive error $ −6 diopter [D] or axial eye length $26 mm), angioid streaks, evidence of uveitis or choroiditis, trauma, and those with findings suggestive of AMD, such as drusen. We also excluded patients who had undergone prior treatment of idiopathic CNV, such as intravitreal antiVEGF injection, surgery, laser photocoagulation, or photodynamic therapy.
Best-corrected visual acuity (BCVA) and OCT were obtained in all patients at every visit. The BCVA was converted to logarithm of the minimum angle of resolution (logMAR) equivalents for statistical analysis. Retinal thickness, defined as the distance between the vitreoretinal interface and the basement membrane of the retinal pigment epithelium–Bruch membrane complex, was measured with OCT. The central subfield thickness was defined as the mean retinal thickness of the 1-mm center, as described in the Early Treatment Diabetic Retinopathy Study.23 Choroidal thickness was measured by enhanced depth imaging OCT, which was performed by positioning the objective lens of the Spectralis OCT scanner close enough to invert the image, as described in previous methods.24–26 In this study, an upright image of the retina and choroid was obtained using EDI option. A horizontal scan and a vertical scan across the foveal 5 · 30° area for each eye were obtained with good quality after 100 scans were averaged for each section. The subfoveal choroidal thickness was defined as the vertical distance from the hyperreflective line of Bruch membrane at the fovea to the outermost hyperreflective line of the chorioscleral interface, and it was measured using the calipers provided by the Heidelberg Spectralis OCT software. The measurement of both horizontal and vertical images was performed by two independent observers (H.K. and K.L.) who were masked to the clinical information and then were averaged. The subfoveal choroidal thickness in affected eyes in patients with idiopathic CNV was measured at baseline and at each visit after intravitreal injections. For comparison, we also measured the subfoveal choroidal thickness in unaffected fellow eyes and 17 eyes of normal healthy controls (Figure 1). After the first injection of bevacizumab, patients received additional intravitreal bevacizumab injections if OCT showed persistent or increased intraretinal or subretinal fluid or expanding pigment epithelial detachment. Statistical Analysis Mean values were compared by Wilcoxon signedrank test with SPSS software (version 18.0; SPSS, Inc, Chicago, IL). Data were expressed as mean ± SD. P values less than 0.05 were considered significant. Results A total of 17 eyes from 17 patients were included in this study, which included 7 men and 10 women. The mean age was 31.59 ± 9.56 years (range, 15–49 years), and the mean refractive error was −2.71 ± 2.42 D
CHOROID THICKNESS IN IDIOPATHIC CNV KIM ET AL
Fig. 1. Enhanced depth imaging optical coherence tomography (EDIOCT) images in the affected eye of a patient from the idiopathic CNV group (left). Also shown is an EDI-OCT image of an unaffected eye from the fellow eye group (right). Subfoveal choroidal thickness (white arrow) is defined as the vertical distance from the hyperreflective line of the Bruch membrane to the outermost hyperreflective line.
(range, −5.50 to +0.25 D). The mean number of injections was 2.94 ± 2.84 (range, 1–13), and the mean follow-up period was 10.35 ± 10.62 months (range, 2–38 months). Among the 17 eyes, we identified subfoveal idiopathic CNV in 14 eyes (82%), juxtafoveal idiopathic CNV in 3 eyes (18%) (Table 1). The mean subfoveal choroidal thickness at baseline in affected eyes was 237.59 ± 53.84 mm. This was significantly less than the mean subfoveal choroidal thickness of 281.71 ± 59.01 mm in unaffected eyes
Table 1. Demographics and Clinical Characteristics of Patients With Idiopathic CNV Characteristics Mean age ± SD, years Men:women Refractive error ± SD, D Location of CNV Subfoveal Juxtafoveal Number of injections Follow-up period ± SD, months
Numbers 31.59 ± 9.56 (range, 15 to 49) 7:10 −2.71 ± 2.42 (range, −5.50 to +0.25) 14 eyes (82.4%) 3 eyes (17.6%) 2.94 ± 2.84 (range, 1 to 13) 10.35 ± 10.62 (range, 2 to 38)
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(P = 0.001). When compared with a normal control group, matched by age and spherical equivalent, the mean subfoveal choroidal thickness in affected eyes was also reduced significantly compared with the mean subfoveal choroidal thickness of 290.38 ± 58.94 mm in normal control eyes (P = 0.028) (Figure 2). The mean logMAR BCVA after intravitreal injection of bevacizumab also improved significantly to 0.26 ± 0.31 from a baseline logMAR BCVA of 0.46 ± 0.36 (P = 0.024). Sixteen of 17 eyes (94%) showed improvement or no change in BCVA after injection. Thirteen eyes (76%) had a final BCVA of 20/40 or better, and all eyes had a final BCVA of 20/200 or better. After bevacizumab treatment, fluorescein angiography was performed in 5 of 17 eyes, and all fluorescein angiographies show decreased fluorescein leakages. The central subfield thickness was significantly reduced to 261.41 ± 31.18 mm from an initial central subfield thickness of 387.88 ± 97.52 mm in bevacizumab-treated eyes (P , 0.001). However, the subfoveal choroidal thickness after bevacizumab injection did not differ significantly from the initial subfoveal choroidal thickness (P = 0.149) (Figure 3). No significant ocular or systemic adverse effects occurred after the injection of intravitreal bevacizumab during the follow-up period. Discussion This study showed that, at baseline, subfoveal choroidal thickness was reduced in eyes with idiopathic CNV compared with unaffected fellow eyes or age-matched normal eyes. To the best of our knowledge, reduced choroidal thickness has not previously been reported in patients with idiopathic CNV. Previous studies have suggested the existence of reduced choroidal perfusion and ischemia in eyes with CNV. Fluorescein angiography and indocyanine green angiography have shown choroidal filling delay in eyes with AMD or myopic CNV,21,27 and choroidal arterial perfusion is also known to be significantly decreased in the eyes with CNV.28 Choroidal thickness has been described as reduced in eyes with typical AMD, myopic CNV, and retinal angiomatous proliferation.14,29,30 Reduced subfoveal choroidal thickness was thought to be related to reduced volume of choroidal vasculature. Thinning of the choroid may be associated with decreased oxygenation and a reduced supply of metabolites to the retinal pigment epithelium and outer retina, which contributes to the development of CNV.24 Choroidal ischemia may also be involved in the pathogenesis of idiopathic CNV. The subfoveal choroidal thickness in unaffected fellow eyes with idiopathic CNV was not significantly
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Fig. 2. Comparison of mean subfoveal choroidal thickness (CT) among eyes of idiopathic CNV, unaffected fellow eyes, and normal control eyes. The mean subfoveal CT of affected eyes (237.59 ± 53.84 mm) was significantly reduced compared with unaffected fellow eyes (281.71 ± 59.01 mm, P = 0.001) and normal control eyes (290.38 ± 58.94 mm, P = 0.028). *P = 0.001, **P = 0.028.
different from that of normal eyes (P = 0.586). In contrast, the choroid of unaffected eyes of patients with other choroidal vascular diseases, such as myopic CNV and typical AMD, appears to exhibit comparable thickness to the affected fellow eyes despite the absence of disease. Bilateral reduction in choroidal thickness may support the presumptive involvement of systemic factors (e.g., aging or systemic hypertension) or common characteristics of both eyes (e.g., myopia).31,32 The change in choroidal thickness only in affected eyes of patients with idiopathic CNV suggests that local factors in affected eyes, not systemic factors, may play a significant role in the pathophysiology of idiopathic CNV. The effect of intravitreal anti-VEGF therapy on choroidal thickness in eyes with CNV is not clear. Koizumi et al reported that in 40 patients with neovascular AMD, including typical AMD, polypoidal choroidal vasculopathy, and retinal angiomatous proliferation, mean subfoveal choroidal thickness Fig. 3. Changes in the mean central subfield thickness (CST) (left) and mean subfoveal choroidal thickness (CT) (right) in eyes with idiopathic CNV after intravitreal bevacizumab therapy. The mean CST in eyes with idiopathic CNV was significantly reduced after bevacizumab therapy (261.41 ± 31.18 mm) compared with baseline CST (387.88 ± 97.52 mm, P , 0.001). However, the mean subfoveal CT (237.59 ± 53.84 mm) did not change after bevacizumab therapy (244.29 ± 42.69 mm, P = 0.149). *P , 0.001.
decreased from 228 mm at baseline to 213 mm at 12 months.17 However, Ellabban et al33 reported no significant change in choroidal thickness of eyes with wet AMD, polypoidal choroidal vasculopathy, or myopic CNV at 1 month after intravitreal ranibizumab treatment or at final examination (mean follow-up of 8.9 ± 3.9 months). In this study, the final subfoveal choroidal thickness after intravitreal anti-VEGF injections was not significantly different from the baseline choroidal thickness in eyes with idiopathic CNV (mean follow-up of 10.35 ± 10.62 months). However, it may not mean that choroidal vasculature itself did not change morphologically because current enhanced depth imaging OCT cannot adequately detect changes in choroidal microvasculature. To date, it remains unclear whether intravitreal anti-VEGF therapy provides a vasoconstrictive effect in the choroidal vasculature, similar to that reportedly seen in retinal vasculature.34,35 Future research on the change in choroidal vasculature, using higher resolution imaging
CHOROID THICKNESS IN IDIOPATHIC CNV KIM ET AL
techniques, may help to determine the mechanism of anti-VEGF therapy on idiopathic CNV. After intravitreal anti-VEGF therapy, patients with idiopathic CNV in this study showed a good visual prognosis, which is similar to findings in previous studies.8,10,36,37 Central subfield thickness was reduced significantly. The mean number of injections per eye was 2.94 during a mean follow-up of 10.35 months. Furthermore, all lesions were in the quiescent stage of CNV at last follow-up, with no intraretinal or subretinal fluid by OCT imaging. No significant ocular or systemic adverse effects occurred after intravitreal bevacizumab therapy during the follow-up period. The treatment of idiopathic CNV is still not well established, but this study suggests that intravitreal administration of an anti-VEGF drug for idiopathic CNV is safe and effective. Relatively short follow-up times may have affected the evaluation of final BCVA, central subfield thickness, or subfoveal choroidal thickness in this study. The small number of patients and the retrospective nature of this study are important limitations. However, we noted a clear trend toward reduced subfoveal choroidal thickness in eyes with idiopathic CNV. A clear understanding of the clinical efficacy of anti-VEGF agents will require further prospective randomized-controlled clinical trials with longer follow-up and larger patient cohorts. In conclusion, reduced choroidal thickness was observed in eyes with idiopathic CNV, which may be involved in the pathogenesis of this condition. Intravitreal anti-VEGF administration resulted in significant anatomical and visual benefits for patients along with an excellent safety profile. Key words: bevacizumab, central subfield thickness, enhanced depth imaging optical coherence tomography, idiopathic choroidal neovascularization, subfoveal choroidal thickness. Acknowledgments Design and conduct of the study (H.K., K.L., C.S.L.); collection of data (H.K., K.L.); management, analysis, and interpretation of data (H.K., K.L., C.S.L., S.H.B., S.C.L.); and preparation, review, and approval of the manuscript (H.K., K.L., C.S.L.). References 1. Cleasby GW. Idiopathic focal subretinal neovascularization. Am J Ophthalmol 1976;81:590–599. 2. Green WR, Wilson DJ. Choroidal neovascularization. Ophthalmology 1986;93:1169–1176. 3. Cohen SY, Laroche A, Leguen Y, et al. Etiology of choroidal neovascularization in young patients. Ophthalmology 1996; 103:1241–1244.
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4. Inagaki M, Harada T, Kiribuchi T, et al. Subfoveal choroidal neovascularization in uveitis. Ophthalmologica 1996;210:229–233. 5. Ho AC, Yannuzzi LA, Pisicano K, DeRosa J. The natural history of idiopathic subfoveal choroidal neovascularization. Ophthalmology 1995;102:782–789. 6. Lindblom B, Andersson T. The prognosis of idiopathic choroidal neovascularization in persons younger than 50 years of age. Ophthalmology 1998;105:1816–1820. 7. Group MPS. Krypton laser photocoagulation for idiopathic neovascular lesions. Results of a randomized clinical trial. Macular Photocoagulation Study Group. Arch Ophthalmol 1990;108:832–837. 8. Wang F, Wang W, Yu S, et al. Functional recovery after intravitreal bevacizumab treatments for idiopathic choroidal neovascularization in young adults. Retina 2012;32:679–686. 9. Inoue M, Kadonosono K, Watanabe Y, et al. Results of 1-year follow-up examinations after intravitreal bevacizumab administration for idiopathic choroidal neovascularization. Retina 2010;30:733–738. 10. Zhang H, Liu Z, Sun P, Gu F. Intravitreal bevacizumab for treatment of subfoveal idiopathic choroidal neovascularization: results of a 1-year prospective trial. Am J Ophthalmol 2012; 153:300–306.e301. 11. Regatieri CV, Branchini L, Fujimoto JG, Duker JS. Choroidal imaging using spectral-domain optical coherence tomography. Retina 2012;32:865–876. 12. Branchini L, Regatieri CV, Flores-Moreno I, et al. Reproducibility of choroidal thickness measurements across three spectral domain optical coherence tomography systems. Ophthalmology 2012;119:119–123. 13. Kuroda SIY, Yasuno Y, Nakai K, et al. Choroidal thickness in central serous chorioretinopathy. Retina 2013;33:302–308. 14. Jirarattanasopa P, Ooto S, Nakata I, et al. Choroidal thickness, vascular hyperpermeability, and complement factor H in agerelated macular degeneration and polypoidal choroidal vasculopathy. Invest Ophthalmol Vis Sci 2012;53:3663–3672. 15. Kim S, Oh J, Kwon S, et al. Comparison of choroidal thickness among patients with healthy eyes, early age-related maculopathy, neovascular age-related macular degeneration, central serous chorioretinopathy, and polypoidal choroidal vasculopathy. Retina 2011;31:1904–1911. 16. Yamazaki T, Koizumi H, Yamagishi T, Kinoshita S. Subfoveal choroidal thickness after ranibizumab therapy for neovascular age-related macular degeneration: 12-month results. Ophthalmology 2012;119:1621–1627. 17. Maruko I, Iida T, Sugano Y, et al. Subfoveal choroidal thickness after treatment of central serous chorioretinopathy. Ophthalmology 2010;117:1792–1799. 18. Maruko I, Iida T, Sugano Y, et al. Subfoveal retinal and choroidal thickness after verteporfin photodynamic therapy for polypoidal choroidal vasculopathy. Am J Ophthalmol 2011; 151:594–603.e591. 19. Imamura Y, Fujiwara T, Margolis R, Spaide RF. Enhanced depth imaging optical coherence tomography of the choroid in central serous chorioretinopathy. Retina 2009;29:1469–1473. 20. Kim M, Kim SS, Kwon HJ, et al. Association between choroidal thickness and ocular perfusion pressure in young, healthy subjects: enhanced depth imaging optical coherence tomography study. Invest Ophthalmol Vis Sci 2012;53:7710–7717. 21. Sasahara MTA, Musashi K. Polypoidal choroidal vasculopathy with choroidal vascular hyperpermeability. Am J Ophthalmol 2006;142:601–607. 22. Jonas JB, Forster TM, Steinmetz P, et al. Choroidal thickness in age-related macular degeneration. Retina 2014;34:1149–1155.
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23. Early Treatment Diabetic Retinopathy Study design and baseline patient characteristics. ETDRS report number 7. Ophthalmology 1991;98:741–756. 24. Margolis R, Spaide RF. A pilot study of enhanced depth imaging optical coherence tomography of the choroid in normal eyes. Am J Ophthalmol 2009;147:811–815. 25. Spaide RF, Koizumi H, Pozzoni MC, Pozonni MC. Enhanced depth imaging spectral-domain optical coherence tomography. Am J Ophthalmol 2008;146:496–500. 26. Chung SE, Kang SW, Lee JH, Kim YT. Choroidal thickness in polypoidal choroidal vasculopathy and exudative age-related macular degeneration. Ophthalmology 2011;118:840–845. 27. Wakabayashi T, Ikuno Y. Choroidal filling delay in choroidal neovascularisation due to pathological myopia. Br J Ophthalmol 2010;94:611–615. 28. Mori K, Gehlbach PL, Ito YN, Yoneya S. Decreased arterial dye-filling and venous dilation in the macular choroid associated with age-related macular degeneration. Retina 2005;25:430–437. 29. Ikuno Y, Jo Y, Hamasaki T, Tano Y. Ocular risk factors for choroidal neovascularization in pathologic myopia. Invest Ophthalmol Vis Sci 2010;51:3721–3725. 30. Kim JR, Kang SW, Kim SJ, Ha HS. Thinner choroid and greater drusen extent in retinal angiomatous proliferation than in typical exudative age-related macular degeneration. Am J Ophthalmol 2013;155:743–749.e742.
31. Cheung CM, Loh BK, Li X, et al. Choroidal thickness and risk characteristics of eyes with myopic choroidal neovascularization. Acta Ophthalmol 2013;91:e580–e581. 32. Farinha CL, Baltar AS, Nunes SG, et al. Choroidal thickness after treatment for myopic choroidal neovascularization. Eur J Ophthalmol 2013;23:887–898. 33. Ellabban AA, Tsujikawa A, Ogino K, et al. Choroidal thickness after intravitreal ranibizumab injections for choroidal neovascularization. Clin Ophthalmol 2012;6: 837–844. 34. Papadopoulou DN, Mendrinos E, Mangioris G, et al. Intravitreal ranibizumab may induce retinal arteriolar vasoconstriction in patients with neovascular age-related macular degeneration. Ophthalmology 2009;116:1755–1761. 35. Sacu S, Pemp B, Weigert G, et al. Response of retinal vessels and retrobulbar hemodynamics to intravitreal anti-VEGF treatment in eyes with branch retinal vein occlusion. Invest Ophthalmol Vis Sci 2011;52:3046–3050. 36. Kang HM, Koh HJ. Intravitreal anti-vascular endothelial growth factor therapy versus photodynamic therapy for idiopathic choroidal neovascularization. Am J Ophthalmol 2013; 155:713–719. 37. Hsing YE, Lee LR. Anti-VEGF treatment for subfoveal idiopathic (type II) choroidal neovascular membranes. Clin Exp Optom 2012;95:544–547.
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the pathophysiology of idiopathic CNV,3,4 but the exact mechanism of idiopathic CNV is still uncertain. The visual outcome of idiopathic CNV is generally more favorable than CNV associated with AMD because of its tendency for spontaneous regression.5 In a previous study with 87 months of follow-up, approximately 95% of patients with idiopathic CNV had stable or significantly improved visual acuity.5 However, severe visual loss can occur in 5% to 37% of untreated patients with idiopathic CNV.5–7 Various treatments for idiopathic CNV have been reported, such as photodynamic therapy or intravitreal anti-vascular endothelial growth factor (VEGF) therapy. However, the treatment of idiopathic CNV is still not well established.8–10 The choroid, which is one of the most highly vascularized tissues of the body, plays a significant
horoidal neovascularization (CNV) occurs under various ophthalmic or systemic conditions, such as myopia, angioid streak, trauma, infection, or agerelated macular degeneration (AMD). Idiopathic CNV is diagnosed when the cause of CNV is undetermined and accounts for approximately 17% of patients with CNV.1–3 Focal choroiditis or compensation of choroidal vessels has been thought to be involved in From the Department of Ophthalmology, The Institute of Vision Research, Yonsei University College of Medicine, Seoul, South Korea. H. Kim and K. Lee contributed equally to this study. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Christopher Seungkyu Lee, MD, Department of Ophthalmology, Severance Hospital, Yonsei University College of Medicine, 134 Sinchon-dong, Seodaemun-gu, Seoul 120-752, South Korea; e-mail: [email protected]
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role in various macular diseases, including AMD, polypoidal choroid vasculopathy, and central serous chorioretinopathy.11–19 The positive correlation of ocular perfusion pressure with subfoveal choroidal thickness suggests that subfoveal choroidal thickness may reflect the status of subfoveal ocular perfusion.20 A study using enhanced depth imaging OCT in eyes with CNV associated with AMD, whose key pathophysiologic factors include choroidal ischemia and hypoxia, demonstrated a reduction in subfoveal choroidal thickness.15,21 However, a recent study reported that AMD, neither in its nonexudative form nor exudative form, was significantly associated with a marked thinning or thickening of the choroid in the foveal and parafoveal region after adjusting for age and refractive error.22 In this study, we evaluated subfoveal choroidal thickness in eyes with idiopathic CNV compared with that in unaffected fellow eyes and normal eyes of healthy subjects. In addition, we analyzed visual and anatomical outcomes in patients with idiopathic CNV after intravitreal bevacizumab therapy.
Methods This retrospective observational study was approved by the Institutional Review Board of Yonsei University, Seoul, South Korea. We reviewed the charts of 20 patients who received intravitreal bevacizumab (1.25 mg/0.05 mL Avastin; Genentech, Inc, San Francisco, CA) for idiopathic CNV between January 2007 and March 2012, who were followed up for more than 2 months in the Department of Ophthalmology, Severance Hospital. Eight eyes were followed for more than 12 months after their first injection. All patients were younger than 50 years and showed active CNV by ophthalmoscopy, slit-lamp biomicroscopy, fluorescein angiography, indocyanine green angiography, and OCT. Active CNV was defined as evidence of leakage within the lesion on fluorescein angiography and indocyanine green angiography, and the presence of intraretinal fluid, subretinal fluid, or pigment epithelial detachment, based on Spectralis OCT (version 1.5.12.0; Heidelberg Engineering, Heidelberg, Germany). We excluded patients with CNV because of pathological myopia (refractive error $ −6 diopter [D] or axial eye length $26 mm), angioid streaks, evidence of uveitis or choroiditis, trauma, and those with findings suggestive of AMD, such as drusen. We also excluded patients who had undergone prior treatment of idiopathic CNV, such as intravitreal antiVEGF injection, surgery, laser photocoagulation, or photodynamic therapy.
Best-corrected visual acuity (BCVA) and OCT were obtained in all patients at every visit. The BCVA was converted to logarithm of the minimum angle of resolution (logMAR) equivalents for statistical analysis. Retinal thickness, defined as the distance between the vitreoretinal interface and the basement membrane of the retinal pigment epithelium–Bruch membrane complex, was measured with OCT. The central subfield thickness was defined as the mean retinal thickness of the 1-mm center, as described in the Early Treatment Diabetic Retinopathy Study.23 Choroidal thickness was measured by enhanced depth imaging OCT, which was performed by positioning the objective lens of the Spectralis OCT scanner close enough to invert the image, as described in previous methods.24–26 In this study, an upright image of the retina and choroid was obtained using EDI option. A horizontal scan and a vertical scan across the foveal 5 · 30° area for each eye were obtained with good quality after 100 scans were averaged for each section. The subfoveal choroidal thickness was defined as the vertical distance from the hyperreflective line of Bruch membrane at the fovea to the outermost hyperreflective line of the chorioscleral interface, and it was measured using the calipers provided by the Heidelberg Spectralis OCT software. The measurement of both horizontal and vertical images was performed by two independent observers (H.K. and K.L.) who were masked to the clinical information and then were averaged. The subfoveal choroidal thickness in affected eyes in patients with idiopathic CNV was measured at baseline and at each visit after intravitreal injections. For comparison, we also measured the subfoveal choroidal thickness in unaffected fellow eyes and 17 eyes of normal healthy controls (Figure 1). After the first injection of bevacizumab, patients received additional intravitreal bevacizumab injections if OCT showed persistent or increased intraretinal or subretinal fluid or expanding pigment epithelial detachment. Statistical Analysis Mean values were compared by Wilcoxon signedrank test with SPSS software (version 18.0; SPSS, Inc, Chicago, IL). Data were expressed as mean ± SD. P values less than 0.05 were considered significant. Results A total of 17 eyes from 17 patients were included in this study, which included 7 men and 10 women. The mean age was 31.59 ± 9.56 years (range, 15–49 years), and the mean refractive error was −2.71 ± 2.42 D
CHOROID THICKNESS IN IDIOPATHIC CNV KIM ET AL
Fig. 1. Enhanced depth imaging optical coherence tomography (EDIOCT) images in the affected eye of a patient from the idiopathic CNV group (left). Also shown is an EDI-OCT image of an unaffected eye from the fellow eye group (right). Subfoveal choroidal thickness (white arrow) is defined as the vertical distance from the hyperreflective line of the Bruch membrane to the outermost hyperreflective line.
(range, −5.50 to +0.25 D). The mean number of injections was 2.94 ± 2.84 (range, 1–13), and the mean follow-up period was 10.35 ± 10.62 months (range, 2–38 months). Among the 17 eyes, we identified subfoveal idiopathic CNV in 14 eyes (82%), juxtafoveal idiopathic CNV in 3 eyes (18%) (Table 1). The mean subfoveal choroidal thickness at baseline in affected eyes was 237.59 ± 53.84 mm. This was significantly less than the mean subfoveal choroidal thickness of 281.71 ± 59.01 mm in unaffected eyes
Table 1. Demographics and Clinical Characteristics of Patients With Idiopathic CNV Characteristics Mean age ± SD, years Men:women Refractive error ± SD, D Location of CNV Subfoveal Juxtafoveal Number of injections Follow-up period ± SD, months
Numbers 31.59 ± 9.56 (range, 15 to 49) 7:10 −2.71 ± 2.42 (range, −5.50 to +0.25) 14 eyes (82.4%) 3 eyes (17.6%) 2.94 ± 2.84 (range, 1 to 13) 10.35 ± 10.62 (range, 2 to 38)
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(P = 0.001). When compared with a normal control group, matched by age and spherical equivalent, the mean subfoveal choroidal thickness in affected eyes was also reduced significantly compared with the mean subfoveal choroidal thickness of 290.38 ± 58.94 mm in normal control eyes (P = 0.028) (Figure 2). The mean logMAR BCVA after intravitreal injection of bevacizumab also improved significantly to 0.26 ± 0.31 from a baseline logMAR BCVA of 0.46 ± 0.36 (P = 0.024). Sixteen of 17 eyes (94%) showed improvement or no change in BCVA after injection. Thirteen eyes (76%) had a final BCVA of 20/40 or better, and all eyes had a final BCVA of 20/200 or better. After bevacizumab treatment, fluorescein angiography was performed in 5 of 17 eyes, and all fluorescein angiographies show decreased fluorescein leakages. The central subfield thickness was significantly reduced to 261.41 ± 31.18 mm from an initial central subfield thickness of 387.88 ± 97.52 mm in bevacizumab-treated eyes (P , 0.001). However, the subfoveal choroidal thickness after bevacizumab injection did not differ significantly from the initial subfoveal choroidal thickness (P = 0.149) (Figure 3). No significant ocular or systemic adverse effects occurred after the injection of intravitreal bevacizumab during the follow-up period. Discussion This study showed that, at baseline, subfoveal choroidal thickness was reduced in eyes with idiopathic CNV compared with unaffected fellow eyes or age-matched normal eyes. To the best of our knowledge, reduced choroidal thickness has not previously been reported in patients with idiopathic CNV. Previous studies have suggested the existence of reduced choroidal perfusion and ischemia in eyes with CNV. Fluorescein angiography and indocyanine green angiography have shown choroidal filling delay in eyes with AMD or myopic CNV,21,27 and choroidal arterial perfusion is also known to be significantly decreased in the eyes with CNV.28 Choroidal thickness has been described as reduced in eyes with typical AMD, myopic CNV, and retinal angiomatous proliferation.14,29,30 Reduced subfoveal choroidal thickness was thought to be related to reduced volume of choroidal vasculature. Thinning of the choroid may be associated with decreased oxygenation and a reduced supply of metabolites to the retinal pigment epithelium and outer retina, which contributes to the development of CNV.24 Choroidal ischemia may also be involved in the pathogenesis of idiopathic CNV. The subfoveal choroidal thickness in unaffected fellow eyes with idiopathic CNV was not significantly
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Fig. 2. Comparison of mean subfoveal choroidal thickness (CT) among eyes of idiopathic CNV, unaffected fellow eyes, and normal control eyes. The mean subfoveal CT of affected eyes (237.59 ± 53.84 mm) was significantly reduced compared with unaffected fellow eyes (281.71 ± 59.01 mm, P = 0.001) and normal control eyes (290.38 ± 58.94 mm, P = 0.028). *P = 0.001, **P = 0.028.
different from that of normal eyes (P = 0.586). In contrast, the choroid of unaffected eyes of patients with other choroidal vascular diseases, such as myopic CNV and typical AMD, appears to exhibit comparable thickness to the affected fellow eyes despite the absence of disease. Bilateral reduction in choroidal thickness may support the presumptive involvement of systemic factors (e.g., aging or systemic hypertension) or common characteristics of both eyes (e.g., myopia).31,32 The change in choroidal thickness only in affected eyes of patients with idiopathic CNV suggests that local factors in affected eyes, not systemic factors, may play a significant role in the pathophysiology of idiopathic CNV. The effect of intravitreal anti-VEGF therapy on choroidal thickness in eyes with CNV is not clear. Koizumi et al reported that in 40 patients with neovascular AMD, including typical AMD, polypoidal choroidal vasculopathy, and retinal angiomatous proliferation, mean subfoveal choroidal thickness Fig. 3. Changes in the mean central subfield thickness (CST) (left) and mean subfoveal choroidal thickness (CT) (right) in eyes with idiopathic CNV after intravitreal bevacizumab therapy. The mean CST in eyes with idiopathic CNV was significantly reduced after bevacizumab therapy (261.41 ± 31.18 mm) compared with baseline CST (387.88 ± 97.52 mm, P , 0.001). However, the mean subfoveal CT (237.59 ± 53.84 mm) did not change after bevacizumab therapy (244.29 ± 42.69 mm, P = 0.149). *P , 0.001.
decreased from 228 mm at baseline to 213 mm at 12 months.17 However, Ellabban et al33 reported no significant change in choroidal thickness of eyes with wet AMD, polypoidal choroidal vasculopathy, or myopic CNV at 1 month after intravitreal ranibizumab treatment or at final examination (mean follow-up of 8.9 ± 3.9 months). In this study, the final subfoveal choroidal thickness after intravitreal anti-VEGF injections was not significantly different from the baseline choroidal thickness in eyes with idiopathic CNV (mean follow-up of 10.35 ± 10.62 months). However, it may not mean that choroidal vasculature itself did not change morphologically because current enhanced depth imaging OCT cannot adequately detect changes in choroidal microvasculature. To date, it remains unclear whether intravitreal anti-VEGF therapy provides a vasoconstrictive effect in the choroidal vasculature, similar to that reportedly seen in retinal vasculature.34,35 Future research on the change in choroidal vasculature, using higher resolution imaging
CHOROID THICKNESS IN IDIOPATHIC CNV KIM ET AL
techniques, may help to determine the mechanism of anti-VEGF therapy on idiopathic CNV. After intravitreal anti-VEGF therapy, patients with idiopathic CNV in this study showed a good visual prognosis, which is similar to findings in previous studies.8,10,36,37 Central subfield thickness was reduced significantly. The mean number of injections per eye was 2.94 during a mean follow-up of 10.35 months. Furthermore, all lesions were in the quiescent stage of CNV at last follow-up, with no intraretinal or subretinal fluid by OCT imaging. No significant ocular or systemic adverse effects occurred after intravitreal bevacizumab therapy during the follow-up period. The treatment of idiopathic CNV is still not well established, but this study suggests that intravitreal administration of an anti-VEGF drug for idiopathic CNV is safe and effective. Relatively short follow-up times may have affected the evaluation of final BCVA, central subfield thickness, or subfoveal choroidal thickness in this study. The small number of patients and the retrospective nature of this study are important limitations. However, we noted a clear trend toward reduced subfoveal choroidal thickness in eyes with idiopathic CNV. A clear understanding of the clinical efficacy of anti-VEGF agents will require further prospective randomized-controlled clinical trials with longer follow-up and larger patient cohorts. In conclusion, reduced choroidal thickness was observed in eyes with idiopathic CNV, which may be involved in the pathogenesis of this condition. Intravitreal anti-VEGF administration resulted in significant anatomical and visual benefits for patients along with an excellent safety profile. Key words: bevacizumab, central subfield thickness, enhanced depth imaging optical coherence tomography, idiopathic choroidal neovascularization, subfoveal choroidal thickness. Acknowledgments Design and conduct of the study (H.K., K.L., C.S.L.); collection of data (H.K., K.L.); management, analysis, and interpretation of data (H.K., K.L., C.S.L., S.H.B., S.C.L.); and preparation, review, and approval of the manuscript (H.K., K.L., C.S.L.). References 1. Cleasby GW. Idiopathic focal subretinal neovascularization. Am J Ophthalmol 1976;81:590–599. 2. Green WR, Wilson DJ. Choroidal neovascularization. Ophthalmology 1986;93:1169–1176. 3. Cohen SY, Laroche A, Leguen Y, et al. Etiology of choroidal neovascularization in young patients. Ophthalmology 1996; 103:1241–1244.
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