Intravitreal Bevacizumab for Nonsubfoveal Choroidal Neovascularization Associated With Angioid Streaks MAURIZIO BATTAGLIA PARODI, PIERLUIGI IACONO, CARLO LA SPINA, LUIGI BERCHICCI, FABRIZIO SCOTTI, ANITA LEYS, UGO INTROINI, AND FRANCESCO BANDELLO PURPOSE:
To evaluate the effects of intravitreal bevacizumab injections in the treatment of nonsubfoveal choroidal neovascularization (CNV) associated with angioid streaks. DESIGN: Nonrandomized, interventional, prospective case series. METHODS: Fifteen patients (15 eyes) affected by juxtafoveal or extrafoveal CNV secondary to angioid streaks were enrolled in the study. All patients underwent a complete ophthalmologic examination, including best-corrected visual acuity (BCVA) measurement on Early Treatment Diabetic Retinopathy Study (ETDRS) chart, optical coherence tomography (OCT), and fluorescein angiography (FA). The protocol treatment included a first injection, followed by repeated injections over a 12-month follow-up period on the basis of the detection of new hemorrhage on biomicroscopic examination, any type of fluid on OCT, or presence of leakage on FA. Primary outcome measures: Mean changes in BCVA and proportion of eyes gaining at least 10 letters (2 ETDRS lines) at the end of the follow-up. Secondary outcomes: Mean changes of central macular thickness (CMT) and extension to the fovea. RESULTS: Mean BCVA did not change throughout the follow-up period, being 0.2 ± 0.2 logMAR at baseline and 0.2 ± 0.3 logMAR at the 12-month examination. A functional improvement of at least 2 ETDRS lines was achieved by 5 eyes (33%), with 3 eyes (20%) gaining 3 lines. Mean CMT at baseline was 215 ± 13 mm and 225 ± 85 mm at the 12-month examination. Two eyes (13.3%) showed CNV extension to the fovea. CONCLUSIONS: Intravitreal bevacizumab injection can be a beneficial approach for the management of nonsubfoveal CNV secondary to angioid streaks over a Accepted for publication Oct 23, 2013. From the Department of Ophthalmology, University Vita-Salute, Scientific Institute San Raffaele, Milan, Italy (M.B.P., C.L.S., L.B., U.I., F.B.); Fondazione G. B. Bietti per l’Oftalmologia, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), Rome, Italy (P.I.); Department of Ophthalmology, Humanitas Clinical and Research Center, Rozzano, Italy (F.S.); Department of Ophthalmology, Humanitas Gavazzeni, Bergamo, Italy (F.S.); and Department of Ophthalmology, University Hospitals, Leuven, Belgium (A.L.). Inquiries to Pierluigi Iacono, Fondazione G. B. Bietti per l’Oftalmologia, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), Via Livenza 3, 00198, Roma, Italy; e-mail: [email protected]
374
Ó
2014 BY
1-year follow-up. (Am J Ophthalmol 2014;157: 374–377. Ó 2014 by Elsevier Inc. All rights reserved.)
A
NGIOID STREAKS ARE IRREGULAR LINEAR BREAKS
or dehiscence in thickened and calcified Bruch membrane, radiating from the peripapillary area. Angioid streaks may present isolated or associated with various systemic diseases, including pseudoxanthoma elasticum, Paget disease, Ehlers-Danlos syndrome, and sickle cell disease.1 Choroidal neovascularization (CNV) is the most important vision-threatening complication of angioid streaks, occurring in at least 1 eye in 72%-86% of cases1–4 and involving the second eye in up to 71% of cases.2 Moreover, the disease generally affects a young population, so that by the age of 50 most patients have a visual acuity of 20/200 or worse in the better eye.1 The treatment of angioid streak–related CNV is still debated. Both laser photocoagulation and photodynamic therapy with verteporfin have provided unsatisfactory results owing to the high rate of recurrence, the development of atrophic changes, and the progressive CNV growth.2,3,5–9 The recent introduction of the anti– vascular endothelial growth factor (anti-VEGF) approach has raised new hopes for a more beneficial management. The results published up to now have been encouraging, generally reporting a visual acuity stability over the followup.4,10–17 However, no study has specifically focused on the outcomes of nonsubfoveal CNV secondary to angioid streaks. The aim of this investigation is to evaluate the effects of the treatment with intravitreal bevacizumab (IVB) for nonsubfoveal CNV associated with angioid streaks over a 1-year follow-up.
METHODS ALL PATIENTS AFFECTED BY JUXTAFOVEAL OR EXTRAFO-
veal CNV secondary to angioid streaks referred to the Department of Ophthalmology of San Raffaele Scientific Institute in Milan from October 2010 to October 2011 were prospectively enrolled in the study. The research was approved by the local institutional review board and adhered to the tenets of the Declaration of Helsinki.
ELSEVIER INC. ALL
RIGHTS RESERVED.
0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2013.10.015
Each patient was carefully informed about the purpose of the research and provided signed consent to all procedures. Inclusion criteria were: diagnosis of angioid streaks; evidence of naı¨ve CNV with juxtafoveal location (1-199 mm from the fovea center) or extrafoveal location (>199 mm from the fovea); best-corrected visual acuity (BCVA) of at least 1.2 logMAR (approximately corresponding to 20/320 Snellen equivalent). Exclusion criteria were: any other ocular disease that could compromise vision in the study eye; pregnancy; previous corticosteroid therapy (either local or oral administration); uncontrolled systemic hypertension; peripheral vascular disease; or history of thromboembolism or stroke. Each patient underwent an ophthalmologic examination, including measurement of BCVA using Early Treatment Diabetic Retinopathy Study (ETDRS) charts, slit-lamp biomicroscopy, fundus color photography, fluorescein angiography (FA), and optical coherence tomography (OCT). After a first IVB treatment (Avastin, 1.25 mg; Genentech Inc., San Francisco, California, USA; 1.25 mg), all patients were reevaluated monthly over the 12 months of follow-up. Further re-treatments were performed on the basis of the detection of new hemorrhage on biomicroscopic examination, any type of fluid on OCT, or presence of leakage on FA. Primary outcome measures were the mean change in BCVA and the proportion of eyes gaining at least 10 letters (2 ETDRS lines) at the end of the follow-up. Secondary outcomes included the central macular thickness (CMT) variations, the changes in CNV size, and the extension to the fovea over the follow-up. Wilcoxon signed rank nonparametric test for the significance of the difference between the distributions of 2 nonindependent samples involving repeated measures was used for statistical analyses. A 2-tailed P value < .05 was taken as statistically significant. All calculations were performed with SPSS 18 (IBM, Armonk, New York, USA).
RESULTS OVERALL, 15 PATIENTS (15 EYES) FULFILLING THE INCLUSION
and exclusion criteria were recruited for the study (Table). Mean age of the patients was 51.7 6 10 years. Five patients were female. One patient (6.6%) had a bioptic diagnosis of pseudoxanthoma elasticum. Eight patients (53.3%) showed juxtafoveal CNV, whereas 7 (46.7%) presented with extrafoveal CNV. Mean CNV duration on the basis of the symptoms was 2.1 6 1.1 months. Overall, the mean BCVA was 0.2 6 0.2 logMAR (approximately corresponding to 20/32 Snellen equivalent) at baseline and 0.2 6 0.3 logMAR at the 12-month examination (P ¼ .15). Neither the subgroup with extrafoveal CNV nor the one with juxtafoveal CNV presented VOL. 157, NO. 2
statistically significant mean BCVA changes throughout the follow-up period. In detail, a functional improvement of at least 2 lines was achieved by 5 eyes (33.3%), with 3 eyes (20.0%) gaining 3 ETDRS lines (all of them presenting with juxtafoveal lesions at baseline) and 2 eyes (13.3%) gaining 2 lines (1 eye with extrafoveal CNV and 1 eye with juxtafoveal CNV at baseline). Seven eyes (46.6%) (all with extrafoveal CNV) turned out to be stable, whereas 3 eyes (20.0%) (2 with juxtafoveal CNV, 1 with extrafoveal CNV) lost 1 ETDRS line. The mean CMT at baseline was 215 6 13 mm, changing to 225 6 85 mm at the 12-month examination (P ¼ .89). No statistically significant difference, either in the subgroup with extrafoveal CNV or in the subgroup with juxtafoveal CNV, was found. Two eyes (13.3%) originally presenting with juxtafoveal CNV at baseline showed extension toward the fovea. The mean number of IVB injections was 2.5 6 1 (range: 1-6) at the end of 12 months (2.3 6 2 injections in the subgroup with extrafoveal CNV and 2.5 6 1 injections in the subgroup with juxtafoveal CNV). No systemic or ocular side effects were registered over the whole 12-month follow-up.
DISCUSSION CNV CAN COMPLICATE ANGIOID STREAKS IN UP TO 80% OF
cases or more,1–4 bringing about a severe functional burden in a young population. Indeed, most of the patients reach a visual acuity value of 20/200 or worse in the better eye by the age of 50.4 Even though scant data are available regarding the natural history, most authors agree that untreated CNV leads to a poor visual outcome, with fast evolution toward a disciform scar.1,3,6 In particular, only a few retrospective studies evaluating the natural history are available. Three case series with a pooled number of 147 cases reported that visual acuity commonly drops to 20/200 or less around the fourth to the fifth decade of life.18–20 Thus, an effective treatment for this complication would be essential. Unfortunately, even though many treatment options have been suggested, including laser photocoagulation, photodynamic therapy, and surgical excision,2–17,21,22 currently there is no general consensus concerning the most appropriate treatment. Moreover, most of the studies have especially focused on the management of subfoveal CNV, whereas the treatment of nonsubfoveal CNV related to angioid streaks has received limited attention. Our study offers data regarding the clinical and anatomic outcomes of nonsubfoveal CNV associated with angioid streaks treated with IVB over a 1-year follow-up. Overall, the results can be considered reasonably satisfactory, showing that IVB treatment with monthly monitoring allows a substantial stabilization in eyes affected by
ANGIOID STREAKS: BEVACIZUMAB IN CHOROIDAL NEOVASCULARIZATION
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TABLE. Bevacizumab Treatment for Choroidal Neovascularization Associated With Angioid Streaks: Demographic Characteristics, Best-Corrected Visual Acuity, Central Macular Thickness, Number of Injections, and Foveal Distance Patient No.
Age
Sex
Baseline BCVA
Final BCVA
Baseline CMT
Final CMT
Number of Injections
Foveal Distance
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
79 57 55 47 46 46 44 41 40 41 48 58 59 55 60
F M M M F F M M M M F F M M M
0 0 0 0 0 0 0.1 0 0 0.3 0.6 0.1 0.2 1 0.5
0.1 0.1 0 0.1 0 0 0.1 0 0 0.1 0.4 0.1 0.1 0.4 0.2
200 214 217 214 207 215 230 199 230 220 238 234 235 240 225
225 102 210 237 220 220 228 197 199 225 230 199 225 299 233
4 3 1 2 2 1 6 4 1 1 3 3 2 2 3
186 256 232 57 244 205 177 289 315 297 121 115 144 62 85
BCVA ¼ best-corrected visual acuity; CMT ¼ central macular thickness. BCVA expressed as logMAR value, CMT and foveal distance expressed as mm.
nonsubfoveal CNV secondary to angioid streaks through a 12-month follow-up. Indeed, almost half of the patients obtained a stable visual function, whereas one third gained at least 2 ETDRS lines. More specifically, a BCVA variation could not be registered in the subgroup with extrafoveal CNV because of a ceiling effect attributable to the relatively excellent baseline acuity (almost 20/20) and the restricted number of eyes included in the study. Conversely, the subgroup presenting with juxtafoveal CNV did show a small improvement, from 0.2-0.1 logMAR (approximately from 20/32-20/25 Snellen equivalent). Mean CMT values turned out to be low at all time points, demonstrating once again that the exudative manifestations ascribable to angioid streak–related CNV are very limited. The number of injections over the follow-up corresponded to a mean value of 2.5, which compares well with the number of IVB injections necessary to control extrafoveal and juxtafoveal CNV in pathologic myopia and ocular trauma.23–25 Unfortunately, no other data regarding the management of nonsubfoveal CNV related to other disorders is available yet. We acknowledge that our investigation suffers from a number of limitations, including the absence of a control group, the restricted number of patients, the administration
of a treatment independently of a visual acuity deterioration, and the choice of a pro re nata treatment regimen requiring a monthly monitoring. However, angioid streaks is an infrequent disease, and even rarer is the detection of a CNV with nonsubfoveal location. Thus, it is highly unlikely that a randomized clinical trial for this condition could be designed in the near future. Moreover, bearing in mind the great burden related to visual acuity impairment in patients as young as those generally affected by CNV secondary to angioid streaks, we do not find it ethical to delay the treatment of even nonsubfoveal CNV. It is possible that a fixed-regimen scheduling of monthly injections, or treatment with ranibizumab, may achieve better results. Although the results of the recent investigations comparing the effects of bevacizumab vs ranibizumab in CNV secondary to age-related macular degeneration and pathologic myopia would not support a different outcome related to a specific drug,26,27 a comparative study regarding CNV associated with angioid streaks is not available. In the absence of data from a randomized clinical trial for the management of nonsubfoveal CNV secondary to angioid streaks, IVB can be regarded as a beneficial approach over a 1-year follow-up. Further studies are warranted to confirm our preliminary results.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST. F. Bandello is an advisory board member for Allergan, Novartis Pharmaceuticals Corporation, Farmila-Thea, Bayer Schering Pharma, Pfizer, Alcon, Bausch and Lomb, Genentech, Alimera Sciences, Sanofi Aventis, and Thrombogenics. The other authors have no proprietary/ financial interest. The authors indicate no funding support. Contributions of authors: conception and design (M.B.P., P.I., C.L.S.); analysis and interpretation (M.B.P., P.I., C.L.S., L.B., A.L., F.S.); writing the article (M.B.P., P.I., C.L.S., L.B., U.I., F.B.); critical revision of the article (M.B.P., C.L.S., P.I., F.B.); final approval of the article (M.B.P., P.I., C.L.S., F.B.); data collection (C.L.S., L.B., A.L., F.S., U.I.); provision of materials, patients, or resources (M.B.P., P.I., C.L.S., L.B., F.S., A.L., U.I., F.B.); statistical expertise (P.I., M.B.P., C.L.S., L.B., U.I.); literature search (L.B., F.S., U.I.).
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REFERENCES 1. Clarkson JG, Altman RD. Angioid streaks. Surv Ophthalmol 1982;26(5):235–246. 2. Lim JI, Bressler NM, Marsh MJ, Bressler SB. Laser treatment of choroidal neovascularization in patients with angioid streaks. Am J Ophthalmol 1993;116(4):414–423. 3. Pece A, Avanza P, Galli L, Brancato R. Laser photocoagulation of choroidal neovascularization in angioid streaks. Retina 1997;17(1):12–16. 4. Wiegand TW, Rogers AH, McCabe F, Reichel E, Duker JS. Intravitreal bevacizumab (Avastin) treatment of choroidal neovascularization in patients with angioid streaks. Br J Ophthalmol 2009;93(1):47–51. 5. Pece A, Avanza P, Zorgno F, Chizzoli A, Camesasca F, Brancato R. Laser treatment of macular subretinal neovascularization in angioid streaks. J Fr Ophtalmol 1989;12(10): 687–689. 6. Singerman LJ, Hatem G. Laser treatment of choroidal neovascular membranes in angioid streaks. Retina 1981; 1(2):75–83. 7. Menchini U, Virgili G, Introini U, et al. Outcome of choroidal neovascularization in angioid streaks after photodynamic therapy. Retina 2004;24(5):763–771. 8. Chung AK, Gauba V, Ghanchi FD. Photodynamic therapy (PDT) using verteporfin for juxtafoveal choroidal neovascularisation (CNV) in angioid streaks (AS) associated with pseudoxanthoma elasticum: 40 months results. Eye 2006; 20(5):629–631. 9. Browning AC, Chung AKK, Ghanchi F, et al; United Kingdom PDT Users Group. Verteporfin photodynamic therapy of choroidal neovascularization in angioid streaks: oneyear results of a prospective case series. Ophthalmology 2005; 112(7):1227–1231. 10. Finger RP, Charbel Issa P, Schmitz-Valckenberg S, Holz FG, Scholl HN. Long-term effectiveness of intravitreal bevacizumab for choroidal neovascularization secondary to angioid streaks in pseudoxanthoma elasticum. Retina 2011;31(7): 1268–1278. 11. Neri P, Salvolini S, Mariotti C, Mercanti L, Celani S, Giovannini A. Long-term control of choroidal neovascularisation secondary to angioid streaks treated with intravitreal bevacizumab (Avastin). Br J Ophthalmol 2009;93(2):155–158. 12. Sawa M, Gomi F, Tsujikawa M, Sakaguchi H, Tano Y. Longterm results of intravitreal bevacizumab injection for choroidal neovascularization secondary to angioid streaks. Am J Ophthalmol 2009;148(4):584–590.e2. 13. Gupta B, Elagouz M, Sivaprasad S. Intravitreal bevacizumab for choroidal neovascularisation secondary to causes other than age-related macular degeneration. Eye 2010;24(2):203–213.
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14. Mimoun G, Tilleul J, Leys A, Coscas G, Soubrane G, Souied EH. Intravitreal ranibizumab for choroidal neovascularization in angioid streaks. Am J Ophthalmol 2010;150(5): 692–700.e1. 15. El Matri L, Kort F, Bouraoui R, Karim B, Chebil A, Chaker N. Intravitreal bevacizumab for the treatment of choroidal neovascularization secondary to angioid streaks: one year of follow-up. Acta Ophthalmol 2011;89(7):641–646. 16. Shah M, Amoaku WMK. Intravitreal ranibizumab for the treatment of choroidal neovascularisation secondary to angioid streaks. Eye 2012;26(9):1194–1198. 17. Gliem M, Finger RP, Fimmers R, Brinkmann CK, Holz FG, Charbel Issa P. Treatment of choroidal neovascularization due to angioid streaks: a comprehensive review. Retina 2013;33(7):1300–1314. 18. Connor PJ Jr, Juergens JL, Perry HO, Hollenhorst RW, Edwards JE. Pseudoxanthoma elasticum and angioid streaks. A review of 106 cases. Am J Med 1961;30:537–543. 19. Gro¨nblad E. Color photographs of angioid streaks in the late stages. Acta Ophthalmol (Copenh) 1958;36(3):472–474. 20. Shilling JS, Blach RK. Prognosis and therapy of angioid streaks. Trans Ophthalmol Soc U K 1975;95(2):301–306. 21. Roth DB, Estafanous M, Lewis H. Macular translocation for subfoveal choroidal neovascularization in angioid streaks. Am J Ophthalmol 2001;131(3):390–392. 22. Tanaka M, Shimada H, Haruyama M, Lee Z, Nakajima M, Yuzawa M. Surgical removal of choroidal neovascularization in angioid streaks. Nihon Ganka Gakkai Zasshi 2003;107(8): 440–444. 23. Parodi MB, Iacono P, Papayannis A, Sheth S, Bandello F. Laser photocoagulation, photodynamic therapy, and intravitreal bevacizumab for the treatment of juxtafoveal choroidal neovascularization secondary to pathologic myopia. Arch Ophthalmol 2010;128(4):437–442. 24. Parodi MB, Iacono P, Papayannis A, Kontadakis S, Cascavilla ML, Bandello F. Intravitreal bevacizumab for extrafoveal choroidal neovascularisation secondary to pathologic myopia. Retina 2013;33(3):593–597. 25. De Benedetto U, Battaglia Parodi M, Knutsson KA, et al. Intravitreal bevacizumab for extrafoveal choroidal neovascularization after ocular trauma. J Ocul Pharmacol Ther 2012; 28(5):550–552. 26. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Martin DF, Maguire MG, Fine SL, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology 2012;119(7):1388–1398. 27. Iacono P, Parodi MB, Papayannis A, et al. Intravitreal ranibizumab versus bevacizumab for treatment of myopic choroidal neovascularization. Retina 2012;32(8):1539–1546.
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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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ANGIOID STREAKS: BEVACIZUMAB IN CHOROIDAL NEOVASCULARIZATION
377.e2
To evaluate the effects of intravitreal bevacizumab injections in the treatment of nonsubfoveal choroidal neovascularization (CNV) associated with angioid streaks. DESIGN: Nonrandomized, interventional, prospective case series. METHODS: Fifteen patients (15 eyes) affected by juxtafoveal or extrafoveal CNV secondary to angioid streaks were enrolled in the study. All patients underwent a complete ophthalmologic examination, including best-corrected visual acuity (BCVA) measurement on Early Treatment Diabetic Retinopathy Study (ETDRS) chart, optical coherence tomography (OCT), and fluorescein angiography (FA). The protocol treatment included a first injection, followed by repeated injections over a 12-month follow-up period on the basis of the detection of new hemorrhage on biomicroscopic examination, any type of fluid on OCT, or presence of leakage on FA. Primary outcome measures: Mean changes in BCVA and proportion of eyes gaining at least 10 letters (2 ETDRS lines) at the end of the follow-up. Secondary outcomes: Mean changes of central macular thickness (CMT) and extension to the fovea. RESULTS: Mean BCVA did not change throughout the follow-up period, being 0.2 ± 0.2 logMAR at baseline and 0.2 ± 0.3 logMAR at the 12-month examination. A functional improvement of at least 2 ETDRS lines was achieved by 5 eyes (33%), with 3 eyes (20%) gaining 3 lines. Mean CMT at baseline was 215 ± 13 mm and 225 ± 85 mm at the 12-month examination. Two eyes (13.3%) showed CNV extension to the fovea. CONCLUSIONS: Intravitreal bevacizumab injection can be a beneficial approach for the management of nonsubfoveal CNV secondary to angioid streaks over a Accepted for publication Oct 23, 2013. From the Department of Ophthalmology, University Vita-Salute, Scientific Institute San Raffaele, Milan, Italy (M.B.P., C.L.S., L.B., U.I., F.B.); Fondazione G. B. Bietti per l’Oftalmologia, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), Rome, Italy (P.I.); Department of Ophthalmology, Humanitas Clinical and Research Center, Rozzano, Italy (F.S.); Department of Ophthalmology, Humanitas Gavazzeni, Bergamo, Italy (F.S.); and Department of Ophthalmology, University Hospitals, Leuven, Belgium (A.L.). Inquiries to Pierluigi Iacono, Fondazione G. B. Bietti per l’Oftalmologia, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), Via Livenza 3, 00198, Roma, Italy; e-mail: [email protected]
374
Ó
2014 BY
1-year follow-up. (Am J Ophthalmol 2014;157: 374–377. Ó 2014 by Elsevier Inc. All rights reserved.)
A
NGIOID STREAKS ARE IRREGULAR LINEAR BREAKS
or dehiscence in thickened and calcified Bruch membrane, radiating from the peripapillary area. Angioid streaks may present isolated or associated with various systemic diseases, including pseudoxanthoma elasticum, Paget disease, Ehlers-Danlos syndrome, and sickle cell disease.1 Choroidal neovascularization (CNV) is the most important vision-threatening complication of angioid streaks, occurring in at least 1 eye in 72%-86% of cases1–4 and involving the second eye in up to 71% of cases.2 Moreover, the disease generally affects a young population, so that by the age of 50 most patients have a visual acuity of 20/200 or worse in the better eye.1 The treatment of angioid streak–related CNV is still debated. Both laser photocoagulation and photodynamic therapy with verteporfin have provided unsatisfactory results owing to the high rate of recurrence, the development of atrophic changes, and the progressive CNV growth.2,3,5–9 The recent introduction of the anti– vascular endothelial growth factor (anti-VEGF) approach has raised new hopes for a more beneficial management. The results published up to now have been encouraging, generally reporting a visual acuity stability over the followup.4,10–17 However, no study has specifically focused on the outcomes of nonsubfoveal CNV secondary to angioid streaks. The aim of this investigation is to evaluate the effects of the treatment with intravitreal bevacizumab (IVB) for nonsubfoveal CNV associated with angioid streaks over a 1-year follow-up.
METHODS ALL PATIENTS AFFECTED BY JUXTAFOVEAL OR EXTRAFO-
veal CNV secondary to angioid streaks referred to the Department of Ophthalmology of San Raffaele Scientific Institute in Milan from October 2010 to October 2011 were prospectively enrolled in the study. The research was approved by the local institutional review board and adhered to the tenets of the Declaration of Helsinki.
ELSEVIER INC. ALL
RIGHTS RESERVED.
0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2013.10.015
Each patient was carefully informed about the purpose of the research and provided signed consent to all procedures. Inclusion criteria were: diagnosis of angioid streaks; evidence of naı¨ve CNV with juxtafoveal location (1-199 mm from the fovea center) or extrafoveal location (>199 mm from the fovea); best-corrected visual acuity (BCVA) of at least 1.2 logMAR (approximately corresponding to 20/320 Snellen equivalent). Exclusion criteria were: any other ocular disease that could compromise vision in the study eye; pregnancy; previous corticosteroid therapy (either local or oral administration); uncontrolled systemic hypertension; peripheral vascular disease; or history of thromboembolism or stroke. Each patient underwent an ophthalmologic examination, including measurement of BCVA using Early Treatment Diabetic Retinopathy Study (ETDRS) charts, slit-lamp biomicroscopy, fundus color photography, fluorescein angiography (FA), and optical coherence tomography (OCT). After a first IVB treatment (Avastin, 1.25 mg; Genentech Inc., San Francisco, California, USA; 1.25 mg), all patients were reevaluated monthly over the 12 months of follow-up. Further re-treatments were performed on the basis of the detection of new hemorrhage on biomicroscopic examination, any type of fluid on OCT, or presence of leakage on FA. Primary outcome measures were the mean change in BCVA and the proportion of eyes gaining at least 10 letters (2 ETDRS lines) at the end of the follow-up. Secondary outcomes included the central macular thickness (CMT) variations, the changes in CNV size, and the extension to the fovea over the follow-up. Wilcoxon signed rank nonparametric test for the significance of the difference between the distributions of 2 nonindependent samples involving repeated measures was used for statistical analyses. A 2-tailed P value < .05 was taken as statistically significant. All calculations were performed with SPSS 18 (IBM, Armonk, New York, USA).
RESULTS OVERALL, 15 PATIENTS (15 EYES) FULFILLING THE INCLUSION
and exclusion criteria were recruited for the study (Table). Mean age of the patients was 51.7 6 10 years. Five patients were female. One patient (6.6%) had a bioptic diagnosis of pseudoxanthoma elasticum. Eight patients (53.3%) showed juxtafoveal CNV, whereas 7 (46.7%) presented with extrafoveal CNV. Mean CNV duration on the basis of the symptoms was 2.1 6 1.1 months. Overall, the mean BCVA was 0.2 6 0.2 logMAR (approximately corresponding to 20/32 Snellen equivalent) at baseline and 0.2 6 0.3 logMAR at the 12-month examination (P ¼ .15). Neither the subgroup with extrafoveal CNV nor the one with juxtafoveal CNV presented VOL. 157, NO. 2
statistically significant mean BCVA changes throughout the follow-up period. In detail, a functional improvement of at least 2 lines was achieved by 5 eyes (33.3%), with 3 eyes (20.0%) gaining 3 ETDRS lines (all of them presenting with juxtafoveal lesions at baseline) and 2 eyes (13.3%) gaining 2 lines (1 eye with extrafoveal CNV and 1 eye with juxtafoveal CNV at baseline). Seven eyes (46.6%) (all with extrafoveal CNV) turned out to be stable, whereas 3 eyes (20.0%) (2 with juxtafoveal CNV, 1 with extrafoveal CNV) lost 1 ETDRS line. The mean CMT at baseline was 215 6 13 mm, changing to 225 6 85 mm at the 12-month examination (P ¼ .89). No statistically significant difference, either in the subgroup with extrafoveal CNV or in the subgroup with juxtafoveal CNV, was found. Two eyes (13.3%) originally presenting with juxtafoveal CNV at baseline showed extension toward the fovea. The mean number of IVB injections was 2.5 6 1 (range: 1-6) at the end of 12 months (2.3 6 2 injections in the subgroup with extrafoveal CNV and 2.5 6 1 injections in the subgroup with juxtafoveal CNV). No systemic or ocular side effects were registered over the whole 12-month follow-up.
DISCUSSION CNV CAN COMPLICATE ANGIOID STREAKS IN UP TO 80% OF
cases or more,1–4 bringing about a severe functional burden in a young population. Indeed, most of the patients reach a visual acuity value of 20/200 or worse in the better eye by the age of 50.4 Even though scant data are available regarding the natural history, most authors agree that untreated CNV leads to a poor visual outcome, with fast evolution toward a disciform scar.1,3,6 In particular, only a few retrospective studies evaluating the natural history are available. Three case series with a pooled number of 147 cases reported that visual acuity commonly drops to 20/200 or less around the fourth to the fifth decade of life.18–20 Thus, an effective treatment for this complication would be essential. Unfortunately, even though many treatment options have been suggested, including laser photocoagulation, photodynamic therapy, and surgical excision,2–17,21,22 currently there is no general consensus concerning the most appropriate treatment. Moreover, most of the studies have especially focused on the management of subfoveal CNV, whereas the treatment of nonsubfoveal CNV related to angioid streaks has received limited attention. Our study offers data regarding the clinical and anatomic outcomes of nonsubfoveal CNV associated with angioid streaks treated with IVB over a 1-year follow-up. Overall, the results can be considered reasonably satisfactory, showing that IVB treatment with monthly monitoring allows a substantial stabilization in eyes affected by
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TABLE. Bevacizumab Treatment for Choroidal Neovascularization Associated With Angioid Streaks: Demographic Characteristics, Best-Corrected Visual Acuity, Central Macular Thickness, Number of Injections, and Foveal Distance Patient No.
Age
Sex
Baseline BCVA
Final BCVA
Baseline CMT
Final CMT
Number of Injections
Foveal Distance
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
79 57 55 47 46 46 44 41 40 41 48 58 59 55 60
F M M M F F M M M M F F M M M
0 0 0 0 0 0 0.1 0 0 0.3 0.6 0.1 0.2 1 0.5
0.1 0.1 0 0.1 0 0 0.1 0 0 0.1 0.4 0.1 0.1 0.4 0.2
200 214 217 214 207 215 230 199 230 220 238 234 235 240 225
225 102 210 237 220 220 228 197 199 225 230 199 225 299 233
4 3 1 2 2 1 6 4 1 1 3 3 2 2 3
186 256 232 57 244 205 177 289 315 297 121 115 144 62 85
BCVA ¼ best-corrected visual acuity; CMT ¼ central macular thickness. BCVA expressed as logMAR value, CMT and foveal distance expressed as mm.
nonsubfoveal CNV secondary to angioid streaks through a 12-month follow-up. Indeed, almost half of the patients obtained a stable visual function, whereas one third gained at least 2 ETDRS lines. More specifically, a BCVA variation could not be registered in the subgroup with extrafoveal CNV because of a ceiling effect attributable to the relatively excellent baseline acuity (almost 20/20) and the restricted number of eyes included in the study. Conversely, the subgroup presenting with juxtafoveal CNV did show a small improvement, from 0.2-0.1 logMAR (approximately from 20/32-20/25 Snellen equivalent). Mean CMT values turned out to be low at all time points, demonstrating once again that the exudative manifestations ascribable to angioid streak–related CNV are very limited. The number of injections over the follow-up corresponded to a mean value of 2.5, which compares well with the number of IVB injections necessary to control extrafoveal and juxtafoveal CNV in pathologic myopia and ocular trauma.23–25 Unfortunately, no other data regarding the management of nonsubfoveal CNV related to other disorders is available yet. We acknowledge that our investigation suffers from a number of limitations, including the absence of a control group, the restricted number of patients, the administration
of a treatment independently of a visual acuity deterioration, and the choice of a pro re nata treatment regimen requiring a monthly monitoring. However, angioid streaks is an infrequent disease, and even rarer is the detection of a CNV with nonsubfoveal location. Thus, it is highly unlikely that a randomized clinical trial for this condition could be designed in the near future. Moreover, bearing in mind the great burden related to visual acuity impairment in patients as young as those generally affected by CNV secondary to angioid streaks, we do not find it ethical to delay the treatment of even nonsubfoveal CNV. It is possible that a fixed-regimen scheduling of monthly injections, or treatment with ranibizumab, may achieve better results. Although the results of the recent investigations comparing the effects of bevacizumab vs ranibizumab in CNV secondary to age-related macular degeneration and pathologic myopia would not support a different outcome related to a specific drug,26,27 a comparative study regarding CNV associated with angioid streaks is not available. In the absence of data from a randomized clinical trial for the management of nonsubfoveal CNV secondary to angioid streaks, IVB can be regarded as a beneficial approach over a 1-year follow-up. Further studies are warranted to confirm our preliminary results.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST. F. Bandello is an advisory board member for Allergan, Novartis Pharmaceuticals Corporation, Farmila-Thea, Bayer Schering Pharma, Pfizer, Alcon, Bausch and Lomb, Genentech, Alimera Sciences, Sanofi Aventis, and Thrombogenics. The other authors have no proprietary/ financial interest. The authors indicate no funding support. Contributions of authors: conception and design (M.B.P., P.I., C.L.S.); analysis and interpretation (M.B.P., P.I., C.L.S., L.B., A.L., F.S.); writing the article (M.B.P., P.I., C.L.S., L.B., U.I., F.B.); critical revision of the article (M.B.P., C.L.S., P.I., F.B.); final approval of the article (M.B.P., P.I., C.L.S., F.B.); data collection (C.L.S., L.B., A.L., F.S., U.I.); provision of materials, patients, or resources (M.B.P., P.I., C.L.S., L.B., F.S., A.L., U.I., F.B.); statistical expertise (P.I., M.B.P., C.L.S., L.B., U.I.); literature search (L.B., F.S., U.I.).
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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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