- Email: [email protected]
Fundus Autofluorescence Changes After Ranibizumab Treatment for Subfoveal Choroidal Neovascularization Secondary to Pathologic Myopia
Fundus Autofluorescence Changes After Ranibizumab Treatment for Subfoveal Choroidal Neovascularization Secondary to Pathologic Myopia MAURIZIO BATTAGLIA PARODI, PIERLUIGI IACONO, RICCARDO SACCONI, LORENZO IULIANO, AND FRANCESCO BANDELLO PURPOSE:
To describe fundus autofluorescence (FAF) patterns of myopic choroidal neovascularization (CNV) treated with intravitreal ranibizumab and their correlation with visual acuity. DESIGN: Prospective interventional case series. METHODS: Twenty-seven eyes (27 patients) affected by myopic CNV were enrolled from January 2011 to January 2013. All patients underwent a complete ophthalmologic examination, including best-corrected visual acuity (BCVA) determination and fundus autofluorescence (FAF). The patients underwent ranibizumab injections following a pro re nata treatment regimen. The main outcome measure was the identification of the FAF patterns of myopic CNV over a 12-month followup. The secondary outcome was the correlation of the FAF patterns with the BCVA. RESULTS: At baseline 17 eyes (63%) showed a hyperautofluorescent pattern and 10 eyes (37%) a patchy pattern. BCVA changed from 0.48 ± 0.23 (logMAR) to 0.30 ± 0.32 at the 12-month examination (P [ .027) in the hyper-FAF subgroup. In the subgroup showing the patchy pattern, the BCVA declined slightly from 0.51 ± 0.27 to 0.56 ± 0.37 (P [ .53). The 14 eyes preserving the hyper-FAF pattern during the follow-up had a final BCVA of 0.20 ± 0.17, whereas the 9 eyes maintaining the patchy pattern showed a final BCVA of 0.60 ± 0.37 (P [ .002). The atrophic area of the retinal pigment epithelium assessed on the basis of FAF increased from 1.27 ± 2.80 mm2 to 1.83 ± 3.74 mm2 at the 12-month examination (P [ .016). The mean atrophic area increased by 0.37 mm2 in the hyper-FAF subgroup and by 0.90 mm2 in the patchy FAF subgroup. CONCLUSIONS: Two main patterns were identified on FAF in myopic CNV and were related to the prognostic evolution, the hyperautofluorescent CNV being associ-
Accepted for publication Apr 21, 2015. From the Department of Ophthalmology (M.B.P., R.S., L.I., F.B.), University Vita-Salute, Scientific Institute San Raffaele, Milano, Italy; and Fondazione G. B. Bietti per l’Oftalmologia (P.I.), IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), Rome, Italy. Inquiries to Pierluigi Iacono, Fondazione G. B. Bietti per l’Oftalmologia, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), Via Livenza 3, Rome, Italy; e-mail: [email protected] 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2015.04.030
Ó
2015 BY
ated with a greater visual gain and fewer atrophic changes over a 12-month follow-up. (Am J Ophthalmol 2015;-:-–-. Ó 2015 by Elsevier Inc. All rights reserved.)
T
HE FUNDUS AUTOFLUORESCENCE (FAF) OF EYES
affected by pathologic myopia may be very complex owing to the various alterations typical of the condition.1–3 The FAF pattern of choroidal neovascularization (CNV) associated with pathologic myopia has seldom been investigated.4,5 Generally speaking, the FAF of myopic CNV is most frequently characterized by a hyperautofluorescence signal,5 probably owing to the double retinal pigment epithelium (RPE) layer enveloping the type 2 CNV typical of pathologic myopia.6 In addition, the progressive atrophic changes, related both to the natural history of the myopic CNV and to treatments, can lead to an increased deterioration of the RPE.4,5,7,8 Nonetheless, no study has specifically focused on the correlation between the FAF response and anti– vascular endothelial growth factor (VEGF) treatment of myopic CNV. The aim of the present study is to describe the FAF changes of subfoveal myopic CNV treated with intravitreal ranibizumab and its relationship with the visual outcomes.
METHODS THE STUDY IS A PROSPECTIVE INTERVENTIONAL CASE SE-
ries. Patients consecutively referred to the Ophthalmology Department of the Vita-Salute University in Milan from January 2011 to January 2013 for subfoveal CNV secondary to pathologic myopia were prospectively recruited. Each patient was carefully informed about the purpose of the research and provided signed consent. The research adhered to the tenets of the Declaration of Helsinki and the institutional review board of Ospedale San Raffaele approved the study. The inclusion criteria were as follows: spherical equivalent refractive error of 6.0 diopters or more (an eye that
ELSEVIER INC. ALL
RIGHTS RESERVED.
1
TABLE 1. Fundus Autofluorescence in Myopic Choroidal Neovascularization: Best-Corrected Visual Acuity Changes According to the Baseline Fundus Autofluorescence Pattern in 27 Eyes Treated With Intravitreal Ranibizumab
Total Hyper-FAF, 17 eyes (63%) Patchy FAF, 10 eyes (37%)
Baseline BCVA (logMAR)
Final BCVA (logMAR)
0.49 0.48 0.51
0.40 0.30 0.56
BCVA ¼ best-corrected visual acuity; Hyper-FAF ¼ hyperfundus autofluorescence; Patchy FAF ¼ patchy fundus autofluorescence.
had a spherical equivalent under 6.0 diopters was eligible if there were chorioretinal abnormalities consistent with pathologic myopia, such as lacquer cracks, chorioretinal atrophy, and posterior staphyloma, and if the axial length of the eye was at least 26.5 mm); naı¨ve subfoveal CNV with active dye leakage on fluorescein angiography (FA); and baseline best-corrected visual acuity (BCVA) between 20/400 and 20/32. The exclusion criteria included intraocular surgery of any kind within 6 months of the day of injection; any ocular disease able to confound a proper clinical examination, including vitreoretinal traction and myopic foveoschisis; ocular hypertension or glaucoma; uncontrolled systemic hypertension; peripheral vascular disease; a history of thromboembolism, ischemic heart disease, or stroke; and pregnancy. Each patient underwent a complete monthly ophthalmologic examination, including BCVA assessment on ETDRS charts, slit-lamp examination, tonometry, dilated fundus evaluation, fluorescein angiography, spectraldomain optical coherence tomography (SD OCT), and FAF. FAF was obtained using a confocal scanning laser ophthalmoscope (Heidelberg Retinal Angiograph 2; Heidelberg Engineering, Heidelberg, Germany), with an excitation wavelength of 488 nm and a barrier filter of 500 nm. A series of 50–90 images were averaged to obtain a highquality picture. The FAF patterns of the CNV were divided into 2 main categories. The hyper-FAF pattern was characterized by an increased FAF signal corresponding to the area of the CNV, as identified on FA. The patchy FAF pattern was characterized by a variable combination of increased and decreased signals over the CNV area, as outlined by FA. In cases of CNV associated with retinal/subretinal hemorrhage, only the unmasked area of the CNV could be assessed by means of FAF. Areas of low FAF signal corresponding to atrophic changes in the RPE were measured using the instrument’s image analysis software. Different types of atrophy were distinguished: enlargements of pre-existing atrophies and newly developed atrophies. BCVA was assessed on EDTRS 2
TABLE 2. Baseline Fundus Autofluorescence in Myopic Choroidal Neovascularization: Atrophic Changes in the Retinal Pigment Epithelium Over the Follow-up in 27 Eyes Treated With Intravitreal Ranibizumab Baseline Fundus Autofluorescence Pattern
Hyper-FAF Patchy FAF
Number of Patients (%)
Baseline Mean Atrophy Area (mm2)
Final Mean Atrophy Area (mm2)
17/27 (63%) 10/27 (37%)
1.33 1.16
1.70 2.06
Hyper-FAF ¼ hyper-fundus autofluorescence; Patchy FAF ¼ patchy fundus autofluorescence.
charts by an examiner unaware of the purpose of the study. Two examiners well trained in FAF evaluation and masked to the purpose of the investigation (R.S. and P.I.) provided an independent appraisal of the FAF images. FA and OCT examinations were carried out by means of HRT and SD OCT, respectively (Spectralis; Heidelberg Engineering). The study protocol required an initial ranibizumab injection and a subsequent monthly follow-up with pro re nata treatment regimen over a 12-month follow-up. Additional treatments were performed on the basis of the detection of leakage on FA and/or fluid on SD OCT. The primary outcome measure was the identification of the FAF patterns of myopic CNV over a 12-month follow-up. The secondary outcomes included the correlation between each FAF pattern and the BCVA changes over the follow-up, and the correlation with the number of injections for each FAF pattern. Statistical analyses were performed using SPSS Statistics Version 20 (IBM, Armonk, New York, USA). The Gaussian distribution of continuous variables was verified with the Kolmogorov-Smirnov test. Subgroup comparison of the mean BCVA, central foveal thickness (CFT), RPE atrophic area, and number of injections was performed using Student t test. Pearson correlation analysis examined the correlation between the number of injections and RPE atrophic area changes. In all analyses, P values <.05 were considered statistically significant.
RESULTS TWENTY-SEVEN PATIENTS WITH SUBFOVEAL MYOPIC CNV
(27 eyes) were recruited for the study. The mean age was 58.30 6 15.7 years. Fourteen patients were female and 13 male. In 8 eyes (30%) the CNV was associated with retinal/ subretinal hemorrhage along its border. At baseline the mean BCVA was 0.49 6 0.24 logMAR (approximately corresponding to 20/60 Snellen equivalent), whereas the mean CFT was 359 6 106 mm. At the end of the followup the mean BCVA was 0.40 6 0.21 logMAR overall
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FIGURE 1. Hyperautofluorescent pattern on fundus autofluorescence of subfoveal choroidal neovascularization secondary to pathologic myopia. (Top right) Fluorescein angiography of a subject with subfoveal choroidal neovascularization associated with hemorrhage on the nasal side. (Top left) Fundus autofluorescence of the same subject displaying a hyperautofluorescent lesion in correspondence with the choroidal neovascularization as imaged on fluorescein angiography. (Bottom) Optical coherence tomography of the same subject with little intraretinal fluid.
(approximately corresponding to 20/50 Snellen equivalent) and the mean CFT was 346 6 92 mm. The main clinical data are listed in Tables 1 and 2. Overall, the FAF pattern of the CNV at baseline turned out to be hyperautofluorescent in 17 eyes (63%), whereas 10 eyes (37%) showed a patchy pattern (Figures 1, 2, and 3). BCVA changed from 0.48 6 0.23 at baseline to 0.30 6 0.32 at the 12-month examination (P ¼ .027) in the subgroup with CNV with hyper-FAF pattern at baseline. On the other hand, BCVA slightly declined from 0.51 6 0.27 at baseline to 0.56 6 0.37 at the end of the followup (P ¼ .53) in the subgroup showing a CNV patchy pattern. At the end of the follow-up 3 eyes starting with hyper-FAF of the CNV at baseline changed to a patchy pattern, whereas a single eye with patchy pattern at baseline changed to the hyper-FAF pattern. Overall, considering separately the 14 eyes starting and completing the follow-up with a hyper-FAF pattern of the CNV, final BCVA was 0.20 6 0.17, whereas in the 9 eyes starting and completing the follow-up with a patchy pattern, final BCVA was 0.60 6 0.37 (P ¼ .002). The mean number of injections was 2.78 6 1.28 (2.82 and VOL. -, NO. -
2.70, in the hyper-FAF and patchy-FAF CNV subgroups, respectively, with no statistically significant difference; P ¼ .76). The analyses of the FAF variations also included the assessment of atrophic changes at the RPE level. RPE atrophy was registered in 19 out of 27 eyes (70%) at baseline and in 25 out of 27 eyes (92.5%) at the end of the 12month follow-up. In particular, 15 out of 27 eyes (55.5%) showed an enlargement of the RPE atrophy and 7 eyes (26%) revealed the development of new atrophic areas, whereas 5 eyes (18.5%) showed no change (3 eyes with stable pre-existing RPE atrophy and 2 with no atrophy). RPE atrophy measured on the basis of FAF changes was 1.27 6 2.80 mm2 at baseline and 1.83 6 3.74 mm2 at the end of the follow-up (P ¼ .016). Examining the correlation between the CNV FAF pattern and the development of atrophic changes, we found that the mean atrophic area increased by 0.37 mm2 (P ¼ .146) in hyper-FAF CNV and by 0.90 mm2 (P ¼ .004) in patchy FAF CNV. Moreover, 9 of the eyes with hyper-FAF CNV (9/17, 53%) and 7 of the eyes with patchy FAF CNV (7/10,
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FIGURE 2. Patchy fundus autofluorescence of subfoveal choroidal neovascularization secondary to pathologic myopia. (Top right) Fluorescein angiography of a subject affected by subfoveal choroidal neovascularization associated with small hemorrhage on the nasal side. (Top left) Fundus autofluorescence of the same subject showing a patchy autofluorescent area related to the choroidal neovascularization, as visualized on fluorescein angiography, bordered by a pigmentary band. (Bottom) Optical coherence tomography of the same subject showing subretinal fluid.
70%) displayed an enlargement of the originally present atrophy, with no statistically significant difference in the proportion between the 2 subgroups (P ¼ .64). Similarly, no statistically significant difference (P ¼ .79) was found comparing the figures of eyes developing new atrophic areas (17% [3/17 eyes] in the hyper-FAF CNV and 30% [3/10 eyes] in the patchy FAF CNV) at the end of the followup. No correlation was found between the number of injections and the area of atrophy. We tried to correlate the FAF response of the CNV with the corresponding FA and OCT findings, but no clear relationship was found, particularly between dye leakage and FAF patterns, or between outer retinal layers status and FAF signal.
DISCUSSION FAF ABNORMALITIES TYPICAL OF PATHOLOGIC MYOPIA ARE
very complex, including both hyper-FAF lesions, such as pigment clumping and stretch lines, and hypo-FAF lesions, including RPE atrophy, lacquer cracks, and retinal/subretinal hemorrhages.1–3 Myopic CNV has rarely been 4
investigated using FAF, but this technique might provide information useful in the prognosis.4,5 The results of the present study indicate that CNV related to pathologic myopia displays 2 main patterns: a hyper-FAF pattern, detectable in about two thirds of cases, and a patchy pattern, imaged in the remaining third. The FAF pattern seems to have a prognostic value, because the eyes showing a hyper-FAF CNV respond better to the intravitreal ranibizumab treatment, and achieve a greater visual acuity improvement, than eyes displaying a patchy FAF pattern. Moreover, at the end of the 12-month follow-up all the eyes with a patchy FAF pattern had a statistically lower visual acuity than eyes maintaining a hyper-FAF response. The reasons underlying the development of the different FAF patterns of myopic CNV remain a matter of debate. Myopic CNV is generally a type 2 CNV, located between the sensory retina and the RPE and coated by a double RPE layer.6 The hyper-FAF pattern may thus correspond to a healthier and more efficient RPE, metabolically supporting the photoreceptors to attain better functional activity. On the other hand, a hypo-FAF response may relate to an impaired RPE characterized by defective metabolic activity, leading to a photoreceptor dysfunction.
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FIGURE 3. Hyperautofluorescence of subfoveal choroidal neovascularization secondary to pathologic myopia. (Top right) Fluorescein angiography of a subject with subfoveal choroidal neovascularization. (Top left) Corresponding fundus autofluorescence with slightly hyperautofluorescent pattern of the choroidal neovascularization outlined on fluorescein angiography. It should be noted that the central hypofluorescent lesion represents a small atrophic area. (Bottom) Optical coherence tomography of the same subject with limited intraretinal fluid.
Moreover, FAF examination also highlighted the progressive atrophic changes in the RPE, detectable on FAF in 70% of cases at baseline in the present case series, and tending to increase even over a short-term follow-up of 12 months, reaching a figure of 92.5%, with 26% of eyes developing new atrophic areas. The mean area of the atrophy increased by 44% over the follow-up, and eyes with patchy FAF CNV were more prone to develop atrophic changes. It is well known that atrophy is a common feature in the natural course of pathologic myopia. Nevertheless, we believe that the RPE changes we registered are to be considered secondary to the treatment because the natural evolution of atrophic changes takes several years.9–11 Only limited data are currently available regarding the development of RPE atrophy after anti-VEGF treatment for CNV. Atrophic changes to RPE frequently occur in eyes affected by CNV secondary to age-related macular degeneration (AMD) treated with anti-VEGF.12–14 A study analyzing the development of atrophy after antiVEGF injection in myopic eyes revealed the development or enlargement of an atrophy in 41% of eyes over a 1-year follow-up.15 However, the study protocol included an assessment based on color photographs and the manual
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measurement of the atrophic changes by means of earlyphase fluorescein angiography.15 The causes of the development of atrophic changes in the RPE after anti-VEGF treatment are purely theoretical. Anti-VEGF molecules may exert a harmful effect on RPE and choriocapillaris. An experimental study has shown that mice lacking the soluble forms of VEGF developed choroidal and RPE loss, mimicking atrophic AMD.16 Moreover, the neutralization of VEGF in cultured RPE led to increased cell death, and VEGF neutralization in vivo resulted in damage to the RPE-choroid complex, including vacuolization, loss of association with photoreceptor outer segments, and decreased choriocapillaris fenestrations.17 We acknowledge that the present study has a number of limitations, including the reduced number of patients, the short-term follow-up, and the subjective classification of the FAF patterns of the CNV. An additional shortcoming is the absence of a control group providing a more precise appraisal of the anti-VEGF effects. In view of this, the present research should be regarded as the basis for further analyses on the changes related to the anti-VEGF treatment in myopic CNV.
FUNDUS AUTOFLUORESCENCE IN CHOROIDAL NEOVASCULARIZATION
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In essence, the present study reveals that the FAF pattern of myopic CNV is correlated with the prognostic evolution, hyperautofluorescent CNV showing greater visual gain and fewer atrophic changes over a 12-month
follow-up. Atrophic changes in the RPE occur in the majority of cases. Further studies are warranted to confirm our data and to call attention to the undesired effect of anti-VEGF therapy.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST. Financial Disclosures: F. Bandello is an advisory board member for Allergan (USA), Novartis Pharmaceuticals Corporation (Switzerland), Farmila-Thea (France), Bayer Schering Pharma (Germany), Pfizer, Alcon, Bausch and Lomb (USA), Genentech (USA), Alimera Sciences (USA), Sanofi-Aventis (FRANCE), Thrombogenics (USA), Hoffmann-La Roche (Switzerland), and Novagali Pharma (France). P. Iacono is consultant for Novartis Pharmaceutical Corporation (Switzerland). Funding/Support: The research for this paper was partially supported by Ministry of Health and Fondazione Roma (Rome, Italy). All authors attest that they meet the current ICMJE requirements to qualify as authors.
REFERENCES 1. Moriyama M, Ohno-Matsui K, Shimada N, et al. Correlation between visual prognosis and fundus autofluorescence and optical coherence tomographic findings in highly myopic eyes with submacular hemorrhage and without choroidal neovascularization. Retina 2011;31(1):74–80. 2. Ohno-Matsui K. Proposed classification of posterior staphylomas based on analyses of eye shape by three-dimensional magnetic resonance imaging and wide-field fundus imaging. Ophthalmology 2014;121(9):1798–1809. 3. Shinohara K, Moriyama M, Shimada N, et al. Myopic stretch lines: linear lesions in fundus of eyes with pathologic myopia that differ from lacquer cracks. Retina 2014;34(3):461–469. 4. Sawa M, Gomi F, Tsujikawa M, et al. Abnormal fundus autofluorescence patterns in myopic choroidal neovascularisation. Br J Ophthalmol 2008;92(9):1236–1240. 5. Parodi MB, Iacono P, Ravalico G. Fundus autofluorescence in subfoveal choroidal neovascularisation secondary to pathological myopia. Br J Ophthalmol 2009;93(6):771–774. 6. Grossniklaus HE, Gass JDM. Clinicopathologic correlations of surgically excised type 1 and type 2 submacular choroidal neovascular membranes. Am J Ophthalmol 1998;126(1): 59–69. 7. Parodi MB, Da Pozzo S, Ravalico G. Retinal pigment epithelium changes after photodynamic therapy for choroidal neovascularization in pathological myopia. Acta Ophthalmol Scand 2007;85(1):50–54. 8. Farinha CL, Baltar AS, Nunes SG, et al. Progression of myopic maculopathy after treatment of choroidal neovascularization. Ophthalmologica 2014;231(4):211–220.
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9. Vongphanit J, Mitchell P, Wang JJ. Prevalence and progression of myopic retinopathy in an older population. Ophthalmology 2002;109(4):704–711. 10. Yoshida T, Ohno-Matsui K, Ohtake Y, et al. Long-term visual prognosis of choroidal neovascularization in high myopia. Ophthalmology 2002;109(4):712–719. 11. Yoshida T, Ohno-Matsui K, Yasazumi K, et al. Myopic choroidal neovascularization: a 10 year follow-up. Ophthalmology 2003;110(7):1297–1305. 12. McBain VA, Kumari R, Townend J, Lois N. Geographic atrophy in retinal angiomatous proliferation. Retina 2011;31(6): 1043–1052. 13. Lois N, McBain V, Abdelkader E, Scott NW, Kumari R. 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. 14. Grunwald JE, Daniel E, Huang J, et al. Risk of geographic atrophy in the comparison of age-related macular degeneration treatments trials. Ophthalmology 2014;121(1):150–161. 15. Oishi A, Yamashiro K, Tsujikawa A, et al. Long-term effect of intravitreal injection of anti-VEGF agent for visual acuity and chorioretinal atrophy progression in myopic choroidal neovascularization. Graefes Arch Clin Exp Ophthalmol 2013; 251(1):1–7. 16. Saint-Geniez M, Kurihara T, Sekiyama E, et al. An essential role for RPE-derived soluble VEGF in the maintenance of the choriocapillaris. Proc Natl Acad Sci U S A 2009;106(44): 18751–18756. 17. Ford KM, Saint-Geniez M, Walshe T, et al. Expression and role of VEGF in the adult retinal pigment epithelium. Invest Ophthalmol Vis Sci 2011;52(13):9478–9487.
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Biosketch Maurizio Battaglia Parodi received his medical degree from the University of Genoa and completed his residency in Ophthalmology at the University of Trieste. He is a medical retina specialist and is currently working at the Department of Ophthalmology at University Vita-Salute in Scientific Institute San Raffaele in Milan.
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Biosketch Pierluigi Iacono achieved the medical degree from the University of Trieste and completed the residency program in Ophthalmology at the same University. He is a medical retina specialist with special interests in age-related macular degeneration, and myopia. Dr Iacono has currently an appointment at Fondazione GB Bietti in Rome.
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To describe fundus autofluorescence (FAF) patterns of myopic choroidal neovascularization (CNV) treated with intravitreal ranibizumab and their correlation with visual acuity. DESIGN: Prospective interventional case series. METHODS: Twenty-seven eyes (27 patients) affected by myopic CNV were enrolled from January 2011 to January 2013. All patients underwent a complete ophthalmologic examination, including best-corrected visual acuity (BCVA) determination and fundus autofluorescence (FAF). The patients underwent ranibizumab injections following a pro re nata treatment regimen. The main outcome measure was the identification of the FAF patterns of myopic CNV over a 12-month followup. The secondary outcome was the correlation of the FAF patterns with the BCVA. RESULTS: At baseline 17 eyes (63%) showed a hyperautofluorescent pattern and 10 eyes (37%) a patchy pattern. BCVA changed from 0.48 ± 0.23 (logMAR) to 0.30 ± 0.32 at the 12-month examination (P [ .027) in the hyper-FAF subgroup. In the subgroup showing the patchy pattern, the BCVA declined slightly from 0.51 ± 0.27 to 0.56 ± 0.37 (P [ .53). The 14 eyes preserving the hyper-FAF pattern during the follow-up had a final BCVA of 0.20 ± 0.17, whereas the 9 eyes maintaining the patchy pattern showed a final BCVA of 0.60 ± 0.37 (P [ .002). The atrophic area of the retinal pigment epithelium assessed on the basis of FAF increased from 1.27 ± 2.80 mm2 to 1.83 ± 3.74 mm2 at the 12-month examination (P [ .016). The mean atrophic area increased by 0.37 mm2 in the hyper-FAF subgroup and by 0.90 mm2 in the patchy FAF subgroup. CONCLUSIONS: Two main patterns were identified on FAF in myopic CNV and were related to the prognostic evolution, the hyperautofluorescent CNV being associ-
Accepted for publication Apr 21, 2015. From the Department of Ophthalmology (M.B.P., R.S., L.I., F.B.), University Vita-Salute, Scientific Institute San Raffaele, Milano, Italy; and Fondazione G. B. Bietti per l’Oftalmologia (P.I.), IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), Rome, Italy. Inquiries to Pierluigi Iacono, Fondazione G. B. Bietti per l’Oftalmologia, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), Via Livenza 3, Rome, Italy; e-mail: [email protected] 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2015.04.030
Ó
2015 BY
ated with a greater visual gain and fewer atrophic changes over a 12-month follow-up. (Am J Ophthalmol 2015;-:-–-. Ó 2015 by Elsevier Inc. All rights reserved.)
T
HE FUNDUS AUTOFLUORESCENCE (FAF) OF EYES
affected by pathologic myopia may be very complex owing to the various alterations typical of the condition.1–3 The FAF pattern of choroidal neovascularization (CNV) associated with pathologic myopia has seldom been investigated.4,5 Generally speaking, the FAF of myopic CNV is most frequently characterized by a hyperautofluorescence signal,5 probably owing to the double retinal pigment epithelium (RPE) layer enveloping the type 2 CNV typical of pathologic myopia.6 In addition, the progressive atrophic changes, related both to the natural history of the myopic CNV and to treatments, can lead to an increased deterioration of the RPE.4,5,7,8 Nonetheless, no study has specifically focused on the correlation between the FAF response and anti– vascular endothelial growth factor (VEGF) treatment of myopic CNV. The aim of the present study is to describe the FAF changes of subfoveal myopic CNV treated with intravitreal ranibizumab and its relationship with the visual outcomes.
METHODS THE STUDY IS A PROSPECTIVE INTERVENTIONAL CASE SE-
ries. Patients consecutively referred to the Ophthalmology Department of the Vita-Salute University in Milan from January 2011 to January 2013 for subfoveal CNV secondary to pathologic myopia were prospectively recruited. Each patient was carefully informed about the purpose of the research and provided signed consent. The research adhered to the tenets of the Declaration of Helsinki and the institutional review board of Ospedale San Raffaele approved the study. The inclusion criteria were as follows: spherical equivalent refractive error of 6.0 diopters or more (an eye that
ELSEVIER INC. ALL
RIGHTS RESERVED.
1
TABLE 1. Fundus Autofluorescence in Myopic Choroidal Neovascularization: Best-Corrected Visual Acuity Changes According to the Baseline Fundus Autofluorescence Pattern in 27 Eyes Treated With Intravitreal Ranibizumab
Total Hyper-FAF, 17 eyes (63%) Patchy FAF, 10 eyes (37%)
Baseline BCVA (logMAR)
Final BCVA (logMAR)
0.49 0.48 0.51
0.40 0.30 0.56
BCVA ¼ best-corrected visual acuity; Hyper-FAF ¼ hyperfundus autofluorescence; Patchy FAF ¼ patchy fundus autofluorescence.
had a spherical equivalent under 6.0 diopters was eligible if there were chorioretinal abnormalities consistent with pathologic myopia, such as lacquer cracks, chorioretinal atrophy, and posterior staphyloma, and if the axial length of the eye was at least 26.5 mm); naı¨ve subfoveal CNV with active dye leakage on fluorescein angiography (FA); and baseline best-corrected visual acuity (BCVA) between 20/400 and 20/32. The exclusion criteria included intraocular surgery of any kind within 6 months of the day of injection; any ocular disease able to confound a proper clinical examination, including vitreoretinal traction and myopic foveoschisis; ocular hypertension or glaucoma; uncontrolled systemic hypertension; peripheral vascular disease; a history of thromboembolism, ischemic heart disease, or stroke; and pregnancy. Each patient underwent a complete monthly ophthalmologic examination, including BCVA assessment on ETDRS charts, slit-lamp examination, tonometry, dilated fundus evaluation, fluorescein angiography, spectraldomain optical coherence tomography (SD OCT), and FAF. FAF was obtained using a confocal scanning laser ophthalmoscope (Heidelberg Retinal Angiograph 2; Heidelberg Engineering, Heidelberg, Germany), with an excitation wavelength of 488 nm and a barrier filter of 500 nm. A series of 50–90 images were averaged to obtain a highquality picture. The FAF patterns of the CNV were divided into 2 main categories. The hyper-FAF pattern was characterized by an increased FAF signal corresponding to the area of the CNV, as identified on FA. The patchy FAF pattern was characterized by a variable combination of increased and decreased signals over the CNV area, as outlined by FA. In cases of CNV associated with retinal/subretinal hemorrhage, only the unmasked area of the CNV could be assessed by means of FAF. Areas of low FAF signal corresponding to atrophic changes in the RPE were measured using the instrument’s image analysis software. Different types of atrophy were distinguished: enlargements of pre-existing atrophies and newly developed atrophies. BCVA was assessed on EDTRS 2
TABLE 2. Baseline Fundus Autofluorescence in Myopic Choroidal Neovascularization: Atrophic Changes in the Retinal Pigment Epithelium Over the Follow-up in 27 Eyes Treated With Intravitreal Ranibizumab Baseline Fundus Autofluorescence Pattern
Hyper-FAF Patchy FAF
Number of Patients (%)
Baseline Mean Atrophy Area (mm2)
Final Mean Atrophy Area (mm2)
17/27 (63%) 10/27 (37%)
1.33 1.16
1.70 2.06
Hyper-FAF ¼ hyper-fundus autofluorescence; Patchy FAF ¼ patchy fundus autofluorescence.
charts by an examiner unaware of the purpose of the study. Two examiners well trained in FAF evaluation and masked to the purpose of the investigation (R.S. and P.I.) provided an independent appraisal of the FAF images. FA and OCT examinations were carried out by means of HRT and SD OCT, respectively (Spectralis; Heidelberg Engineering). The study protocol required an initial ranibizumab injection and a subsequent monthly follow-up with pro re nata treatment regimen over a 12-month follow-up. Additional treatments were performed on the basis of the detection of leakage on FA and/or fluid on SD OCT. The primary outcome measure was the identification of the FAF patterns of myopic CNV over a 12-month follow-up. The secondary outcomes included the correlation between each FAF pattern and the BCVA changes over the follow-up, and the correlation with the number of injections for each FAF pattern. Statistical analyses were performed using SPSS Statistics Version 20 (IBM, Armonk, New York, USA). The Gaussian distribution of continuous variables was verified with the Kolmogorov-Smirnov test. Subgroup comparison of the mean BCVA, central foveal thickness (CFT), RPE atrophic area, and number of injections was performed using Student t test. Pearson correlation analysis examined the correlation between the number of injections and RPE atrophic area changes. In all analyses, P values <.05 were considered statistically significant.
RESULTS TWENTY-SEVEN PATIENTS WITH SUBFOVEAL MYOPIC CNV
(27 eyes) were recruited for the study. The mean age was 58.30 6 15.7 years. Fourteen patients were female and 13 male. In 8 eyes (30%) the CNV was associated with retinal/ subretinal hemorrhage along its border. At baseline the mean BCVA was 0.49 6 0.24 logMAR (approximately corresponding to 20/60 Snellen equivalent), whereas the mean CFT was 359 6 106 mm. At the end of the followup the mean BCVA was 0.40 6 0.21 logMAR overall
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FIGURE 1. Hyperautofluorescent pattern on fundus autofluorescence of subfoveal choroidal neovascularization secondary to pathologic myopia. (Top right) Fluorescein angiography of a subject with subfoveal choroidal neovascularization associated with hemorrhage on the nasal side. (Top left) Fundus autofluorescence of the same subject displaying a hyperautofluorescent lesion in correspondence with the choroidal neovascularization as imaged on fluorescein angiography. (Bottom) Optical coherence tomography of the same subject with little intraretinal fluid.
(approximately corresponding to 20/50 Snellen equivalent) and the mean CFT was 346 6 92 mm. The main clinical data are listed in Tables 1 and 2. Overall, the FAF pattern of the CNV at baseline turned out to be hyperautofluorescent in 17 eyes (63%), whereas 10 eyes (37%) showed a patchy pattern (Figures 1, 2, and 3). BCVA changed from 0.48 6 0.23 at baseline to 0.30 6 0.32 at the 12-month examination (P ¼ .027) in the subgroup with CNV with hyper-FAF pattern at baseline. On the other hand, BCVA slightly declined from 0.51 6 0.27 at baseline to 0.56 6 0.37 at the end of the followup (P ¼ .53) in the subgroup showing a CNV patchy pattern. At the end of the follow-up 3 eyes starting with hyper-FAF of the CNV at baseline changed to a patchy pattern, whereas a single eye with patchy pattern at baseline changed to the hyper-FAF pattern. Overall, considering separately the 14 eyes starting and completing the follow-up with a hyper-FAF pattern of the CNV, final BCVA was 0.20 6 0.17, whereas in the 9 eyes starting and completing the follow-up with a patchy pattern, final BCVA was 0.60 6 0.37 (P ¼ .002). The mean number of injections was 2.78 6 1.28 (2.82 and VOL. -, NO. -
2.70, in the hyper-FAF and patchy-FAF CNV subgroups, respectively, with no statistically significant difference; P ¼ .76). The analyses of the FAF variations also included the assessment of atrophic changes at the RPE level. RPE atrophy was registered in 19 out of 27 eyes (70%) at baseline and in 25 out of 27 eyes (92.5%) at the end of the 12month follow-up. In particular, 15 out of 27 eyes (55.5%) showed an enlargement of the RPE atrophy and 7 eyes (26%) revealed the development of new atrophic areas, whereas 5 eyes (18.5%) showed no change (3 eyes with stable pre-existing RPE atrophy and 2 with no atrophy). RPE atrophy measured on the basis of FAF changes was 1.27 6 2.80 mm2 at baseline and 1.83 6 3.74 mm2 at the end of the follow-up (P ¼ .016). Examining the correlation between the CNV FAF pattern and the development of atrophic changes, we found that the mean atrophic area increased by 0.37 mm2 (P ¼ .146) in hyper-FAF CNV and by 0.90 mm2 (P ¼ .004) in patchy FAF CNV. Moreover, 9 of the eyes with hyper-FAF CNV (9/17, 53%) and 7 of the eyes with patchy FAF CNV (7/10,
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FIGURE 2. Patchy fundus autofluorescence of subfoveal choroidal neovascularization secondary to pathologic myopia. (Top right) Fluorescein angiography of a subject affected by subfoveal choroidal neovascularization associated with small hemorrhage on the nasal side. (Top left) Fundus autofluorescence of the same subject showing a patchy autofluorescent area related to the choroidal neovascularization, as visualized on fluorescein angiography, bordered by a pigmentary band. (Bottom) Optical coherence tomography of the same subject showing subretinal fluid.
70%) displayed an enlargement of the originally present atrophy, with no statistically significant difference in the proportion between the 2 subgroups (P ¼ .64). Similarly, no statistically significant difference (P ¼ .79) was found comparing the figures of eyes developing new atrophic areas (17% [3/17 eyes] in the hyper-FAF CNV and 30% [3/10 eyes] in the patchy FAF CNV) at the end of the followup. No correlation was found between the number of injections and the area of atrophy. We tried to correlate the FAF response of the CNV with the corresponding FA and OCT findings, but no clear relationship was found, particularly between dye leakage and FAF patterns, or between outer retinal layers status and FAF signal.
DISCUSSION FAF ABNORMALITIES TYPICAL OF PATHOLOGIC MYOPIA ARE
very complex, including both hyper-FAF lesions, such as pigment clumping and stretch lines, and hypo-FAF lesions, including RPE atrophy, lacquer cracks, and retinal/subretinal hemorrhages.1–3 Myopic CNV has rarely been 4
investigated using FAF, but this technique might provide information useful in the prognosis.4,5 The results of the present study indicate that CNV related to pathologic myopia displays 2 main patterns: a hyper-FAF pattern, detectable in about two thirds of cases, and a patchy pattern, imaged in the remaining third. The FAF pattern seems to have a prognostic value, because the eyes showing a hyper-FAF CNV respond better to the intravitreal ranibizumab treatment, and achieve a greater visual acuity improvement, than eyes displaying a patchy FAF pattern. Moreover, at the end of the 12-month follow-up all the eyes with a patchy FAF pattern had a statistically lower visual acuity than eyes maintaining a hyper-FAF response. The reasons underlying the development of the different FAF patterns of myopic CNV remain a matter of debate. Myopic CNV is generally a type 2 CNV, located between the sensory retina and the RPE and coated by a double RPE layer.6 The hyper-FAF pattern may thus correspond to a healthier and more efficient RPE, metabolically supporting the photoreceptors to attain better functional activity. On the other hand, a hypo-FAF response may relate to an impaired RPE characterized by defective metabolic activity, leading to a photoreceptor dysfunction.
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FIGURE 3. Hyperautofluorescence of subfoveal choroidal neovascularization secondary to pathologic myopia. (Top right) Fluorescein angiography of a subject with subfoveal choroidal neovascularization. (Top left) Corresponding fundus autofluorescence with slightly hyperautofluorescent pattern of the choroidal neovascularization outlined on fluorescein angiography. It should be noted that the central hypofluorescent lesion represents a small atrophic area. (Bottom) Optical coherence tomography of the same subject with limited intraretinal fluid.
Moreover, FAF examination also highlighted the progressive atrophic changes in the RPE, detectable on FAF in 70% of cases at baseline in the present case series, and tending to increase even over a short-term follow-up of 12 months, reaching a figure of 92.5%, with 26% of eyes developing new atrophic areas. The mean area of the atrophy increased by 44% over the follow-up, and eyes with patchy FAF CNV were more prone to develop atrophic changes. It is well known that atrophy is a common feature in the natural course of pathologic myopia. Nevertheless, we believe that the RPE changes we registered are to be considered secondary to the treatment because the natural evolution of atrophic changes takes several years.9–11 Only limited data are currently available regarding the development of RPE atrophy after anti-VEGF treatment for CNV. Atrophic changes to RPE frequently occur in eyes affected by CNV secondary to age-related macular degeneration (AMD) treated with anti-VEGF.12–14 A study analyzing the development of atrophy after antiVEGF injection in myopic eyes revealed the development or enlargement of an atrophy in 41% of eyes over a 1-year follow-up.15 However, the study protocol included an assessment based on color photographs and the manual
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measurement of the atrophic changes by means of earlyphase fluorescein angiography.15 The causes of the development of atrophic changes in the RPE after anti-VEGF treatment are purely theoretical. Anti-VEGF molecules may exert a harmful effect on RPE and choriocapillaris. An experimental study has shown that mice lacking the soluble forms of VEGF developed choroidal and RPE loss, mimicking atrophic AMD.16 Moreover, the neutralization of VEGF in cultured RPE led to increased cell death, and VEGF neutralization in vivo resulted in damage to the RPE-choroid complex, including vacuolization, loss of association with photoreceptor outer segments, and decreased choriocapillaris fenestrations.17 We acknowledge that the present study has a number of limitations, including the reduced number of patients, the short-term follow-up, and the subjective classification of the FAF patterns of the CNV. An additional shortcoming is the absence of a control group providing a more precise appraisal of the anti-VEGF effects. In view of this, the present research should be regarded as the basis for further analyses on the changes related to the anti-VEGF treatment in myopic CNV.
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In essence, the present study reveals that the FAF pattern of myopic CNV is correlated with the prognostic evolution, hyperautofluorescent CNV showing greater visual gain and fewer atrophic changes over a 12-month
follow-up. Atrophic changes in the RPE occur in the majority of cases. Further studies are warranted to confirm our data and to call attention to the undesired effect of anti-VEGF therapy.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST. Financial Disclosures: F. Bandello is an advisory board member for Allergan (USA), Novartis Pharmaceuticals Corporation (Switzerland), Farmila-Thea (France), Bayer Schering Pharma (Germany), Pfizer, Alcon, Bausch and Lomb (USA), Genentech (USA), Alimera Sciences (USA), Sanofi-Aventis (FRANCE), Thrombogenics (USA), Hoffmann-La Roche (Switzerland), and Novagali Pharma (France). P. Iacono is consultant for Novartis Pharmaceutical Corporation (Switzerland). Funding/Support: The research for this paper was partially supported by Ministry of Health and Fondazione Roma (Rome, Italy). All authors attest that they meet the current ICMJE requirements to qualify as authors.
REFERENCES 1. Moriyama M, Ohno-Matsui K, Shimada N, et al. Correlation between visual prognosis and fundus autofluorescence and optical coherence tomographic findings in highly myopic eyes with submacular hemorrhage and without choroidal neovascularization. Retina 2011;31(1):74–80. 2. Ohno-Matsui K. Proposed classification of posterior staphylomas based on analyses of eye shape by three-dimensional magnetic resonance imaging and wide-field fundus imaging. Ophthalmology 2014;121(9):1798–1809. 3. Shinohara K, Moriyama M, Shimada N, et al. Myopic stretch lines: linear lesions in fundus of eyes with pathologic myopia that differ from lacquer cracks. Retina 2014;34(3):461–469. 4. Sawa M, Gomi F, Tsujikawa M, et al. Abnormal fundus autofluorescence patterns in myopic choroidal neovascularisation. Br J Ophthalmol 2008;92(9):1236–1240. 5. Parodi MB, Iacono P, Ravalico G. Fundus autofluorescence in subfoveal choroidal neovascularisation secondary to pathological myopia. Br J Ophthalmol 2009;93(6):771–774. 6. Grossniklaus HE, Gass JDM. Clinicopathologic correlations of surgically excised type 1 and type 2 submacular choroidal neovascular membranes. Am J Ophthalmol 1998;126(1): 59–69. 7. Parodi MB, Da Pozzo S, Ravalico G. Retinal pigment epithelium changes after photodynamic therapy for choroidal neovascularization in pathological myopia. Acta Ophthalmol Scand 2007;85(1):50–54. 8. Farinha CL, Baltar AS, Nunes SG, et al. Progression of myopic maculopathy after treatment of choroidal neovascularization. Ophthalmologica 2014;231(4):211–220.
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9. Vongphanit J, Mitchell P, Wang JJ. Prevalence and progression of myopic retinopathy in an older population. Ophthalmology 2002;109(4):704–711. 10. Yoshida T, Ohno-Matsui K, Ohtake Y, et al. Long-term visual prognosis of choroidal neovascularization in high myopia. Ophthalmology 2002;109(4):712–719. 11. Yoshida T, Ohno-Matsui K, Yasazumi K, et al. Myopic choroidal neovascularization: a 10 year follow-up. Ophthalmology 2003;110(7):1297–1305. 12. McBain VA, Kumari R, Townend J, Lois N. Geographic atrophy in retinal angiomatous proliferation. Retina 2011;31(6): 1043–1052. 13. Lois N, McBain V, Abdelkader E, Scott NW, Kumari R. 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. 14. Grunwald JE, Daniel E, Huang J, et al. Risk of geographic atrophy in the comparison of age-related macular degeneration treatments trials. Ophthalmology 2014;121(1):150–161. 15. Oishi A, Yamashiro K, Tsujikawa A, et al. Long-term effect of intravitreal injection of anti-VEGF agent for visual acuity and chorioretinal atrophy progression in myopic choroidal neovascularization. Graefes Arch Clin Exp Ophthalmol 2013; 251(1):1–7. 16. Saint-Geniez M, Kurihara T, Sekiyama E, et al. An essential role for RPE-derived soluble VEGF in the maintenance of the choriocapillaris. Proc Natl Acad Sci U S A 2009;106(44): 18751–18756. 17. Ford KM, Saint-Geniez M, Walshe T, et al. Expression and role of VEGF in the adult retinal pigment epithelium. Invest Ophthalmol Vis Sci 2011;52(13):9478–9487.
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Biosketch Maurizio Battaglia Parodi received his medical degree from the University of Genoa and completed his residency in Ophthalmology at the University of Trieste. He is a medical retina specialist and is currently working at the Department of Ophthalmology at University Vita-Salute in Scientific Institute San Raffaele in Milan.
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Biosketch Pierluigi Iacono achieved the medical degree from the University of Trieste and completed the residency program in Ophthalmology at the same University. He is a medical retina specialist with special interests in age-related macular degeneration, and myopia. Dr Iacono has currently an appointment at Fondazione GB Bietti in Rome.
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