Original Paper
Ophthalmologica
Ophthalmologica 2015;233:2–7 DOI: 10.1159/000369397
Received: September 23, 2014 Accepted after revision: October 28, 2014 Published online: December 6, 2014
Intravitreal Ranibizumab for the Treatment of Choroidal Neovascularizations Associated with Pathologic Myopia: A Prospective Study Nataliya V. Pasyechnikova a Volodymyr O. Naumenko a Andrii R. Korol a Oleg S. Zadorozhnyy a Taras B. Kustryn a Paul B. Henrich b–d a
State Institution ‘The Filatov Institute of Eye Diseases and Tissue Therapy of the NAMS of Ukraine’, Odessa, Ukraine; b Winterthur Cantonal Hospital, Winterthur, c Department of Ophthalmology, University of Basel, Basel, and d Centro Ticinese di Chirurgia Ambulatoriale Avanti, Lugano, Switzerland
Abstract Purpose: It was the aim of this study to determine the efficacy of intravitreal ranibizumab as treatment of choroidal neovascularizations associated with pathologic myopia. Materials and Methods: In an uncontrolled, prospective time series cohort study, 65 eyes of 64 consecutive patients with choroidal neovascularization associated with pathologic myopia were treated with intravitreal ranibizumab and observed over 12 months. The change in best-corrected visual acuity (BCVA) at 6 and 12 months served as primary end point. Safety, central retinal thickness, neovascularization activity on fluorescein angiography and the number of ranibizumab injections were secondary end points. Results: BCVA improved significantly throughout the follow-up (p = 0.001). The mean BCVA was 0.2 at baseline (SD 0.13) and 0.4 at 12 months (SD 0.21). Improvement was strongest within the first 3 months (p = 0.0001). The mean central retinal thickness showed a reduction from 313 μm (SD 82) to 243.5 μm (SD 31; p = 0.0001). Conclusion: Intravitreal ranibizumab offers a safe and effective treatment for choroidal neovascularizations in pathologic myopia. © 2014 S. Karger AG, Basel
© 2014 S. Karger AG, Basel 0030–3755/14/2331–0002$39.50/0 E-Mail [email protected] www.karger.com/oph
Introduction
Choroidal neovascularization (CNV) is among the most threatening complications of pathologic myopia, and untreated myopic CNV has a poor visual prognosis. More than 95% of affected eyes will experience a drop in visual acuity to 20/200 or worse [1, 2]. The risk of developing a myopic CNV is 5–11%. Young and middle-aged patients are mostly affected. Patients affected by a myopic CNV in one eye have a chance of over 30% to develop CNV in the fellow eye within 8 years [3, 4]. Because of the poor natural history of myopic CNVs, a variety of different treatment approaches have been suggested. Thermal laser photocoagulation, transpupillary thermotherapy (TTT) and photodynamic therapy (PDT) with verteporfin have shown a short-term effect, but long-term efficacy and safety are disappointing [5–8]. The role of subretinal surgery in the treatment of myopic CNV remains controversial. Ranibizumab is the first inhibitor of vascular endothelial growth factor (VEGF)-A licensed for the treatment of visual impairment due to CNV. The clinical benefit of ranibizumab in adults with myopic CNV has been documented in a randomized, double-masked, active comparator-controlled, phase III trial [9]. In this trial, intravitreal ranibizumab was superior to intravenous verteporfin Paul B. Henrich, MD Department of Ophthalmology Winterthur Cantonal Hospital, Brauerstrasse 15 CH–8400 Winterthur (Switzerland) E-Mail bernhard.henrich @ ksw.ch
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Key Words Myopia · Macular degeneration · Anti-vascular endothelial growth factor
Materials and Methods Protocol The study was approved by the Filatov Institute of Eye Diseases and Tissue Therapy of the National Academy of Medical Sciences of Ukraine Institutional Review and Ethics Board before study commencement. All procedures were performed in accordance with the 1964 Declaration of Helsinki. Filatov Institute patients presenting to any of the coauthors with signs and symptoms consistent with CNV associated with pathologic myopia were eligible for the study. Inclusion criteria were: pathological myopia defined as a spherical equivalent of more than −6.0 diopters, a new onset of CNV associated with pathologic myopia (18 years, a medical history of pathologic myopia and an absence of signs of inflammation at baseline. Ocular exclusion criteria comprised: an indication of any origin of the CNV other than pathologic myopia, intraocular or periocular inflammation, known glaucoma or clinical suspicion of glaucoma upon presentation, ocular hypertension (intraocular pressure >24 mm Hg) and a complicated fundus observation by optic media opacity. Nonocular exclusion criteria were pregnancy, lactation and the inability to provide informed consent. The injection schedule followed a pro re nata (PRN) regimen and consisted of 2 fixed loading injections, one at baseline and the second 1 month later. As studies based on strict reinjection criteria have shown results superior to physician-based retreatment schedules [14], the indication for a third and further injections was based on the following reinjection criteria: visual acuity (loss of 1 line or more), development of new macular hemorrhage on fundus examination, evidence of late leakage on fluorescein angiography (FA) and the presence of any fluid or any increase in macular thickness of >50 μm on optical coherence tomography (OCT). These retreatment criteria are largely identical with the ones in the
Intravitreal Ranibizumab in Pathologic Myopia: A Prospective Study
PRONTO study [15], with the exception of OCT findings. PRONTO studied a cohort with exudative age-related macular degeneration and required an increase of at least 100 μm in central retinal thickness. As the sample of the current study involves patients with myopic CNV which tend to present with more subtle OCT changes, an increase in central retinal thickness of 50 μm was deemed more adequate. In the case of CNV activity on FA or OCT, additional monthly injections were performed until the absence of fluorescein leakage from the CNV and the absence of any fluid collections on OCT were observed. Eligible subjects were provided with a comprehensive explanation concerning their disease and the proposed study and treatment. Consent was obtained after a minimum of 24 h of time for consideration. All enrolled patients underwent baseline ophthalmological examination and investigations including measurements of Snellen best-corrected visual acuity (BCVA), intraocular pressure, pupillary, biomicroscopic and dilated fundus examination and OCT of the macular area, color fundus photography and FA. After consent was obtained for study entry, patients were transferred to another coinvestigator for injection. Intervention Ranibizumab (0.5 mg; Novartis AG, Basel, Switzerland) was delivered into the vitreous cavity via a pars plana transcleral injection. Sterile propracaine drops were instilled in the affected eye. The eye and surrounding periocular skin was prepped with 5% betadine solution. A lid speculum was placed and the anesthetized area disinfected with 5% betadine. A variable caliper was utilized to mark the pars plana, 4.0 mm from the limbus for phakic patients and 3.5 mm for pseudophakic patients. A 27-gauge needle was then introduced through the mark into the vitreous cavity, and ranibizumab was injected. The needle was retracted and the injection site covered with a sterile cotton-tipped applicator. A drop of topical ofloxacin was instilled in the conjunctival sac and the speculum removed. Patients were instructed to continue the ofloxacin drops 4 times a day for 5 days. Study Visits Patients were seen at baseline and underwent a comprehensive ophthalmological examination including OCT, color fundus photography and FA as noted above. BCVA measurements, intraocular pressure measurements, pupilary, biomicroscopic and dilated fundus examination were also performed. Subsequently, all patients were re-examined every month for 12 months. Follow-up examinations involved ophthalmological examination including BCVA measurements, intraocular pressure measurements and dilated fundus examination. OCT and color fundus photography were also repeated at each of these visits. FA was performed in case of a decreasing BCVA and/or an increase in macular edema. In addition to the study visits, a postoperative visit was performed 1 day following each intervention to rule out possible injection-related complications. Particular attention was paid to exclude elevated intraocular pressure, endophthalmitis, retinal tears, retinal detachments, vitreous hemorrhages, uveitis and corneal erosions. Any other complications encountered were also noted. Outcome Measures The primary outcome was a change in BCVA compared to baseline at 6 and 12 months. The secondary outcome was a change
Ophthalmologica 2015;233:2–7 DOI: 10.1159/000369397
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plus PDT, the standard licensed therapy available to patients with CNV based on pathologic myopia. Visual acuity improved from month 1 through month 3 of treatment. Improvements in vision and anatomic outcomes were sustained for up to 12 months. Compared to other trials using ranibizumab for age-dependent macular degeneration, relatively few ranibizumab injections were required during the course of the trial, with more than 60% of patients not needing to receive the drug from month 6 to month 11. Ranibizumab was generally well tolerated, with few patients experiencing serious ocular or nonocular adverse events [9]. Earlier case series have already reported good visual outcomes after intravitreal ranibizumab therapy without any serious ocular or systemic complications, and, at present, intravitreal ranibizumab is considered the first-line therapy for sub- and juxtafoveal myopic CNVs [10–13]. The purpose of this study was to determine the efficacy of the intravitreal injection of ranibizumab as a treatment for CNV associated with pathologic myopia.
0.45
0.50 0.45
0.35
0.40
0.30
0.35
0.25
0.30
BCVA
Mean BCVA
0.40
0.20 0.15
0.20 0.10
0.05
a
0.25 0.15
0.10 0
Mean Mean ± SE Mean ± 1.96 SE
0.05 Baseline
1
2
3 Months
6
12
b
0
Baseline
12 months
Fig. 1. Change in BCVA during the study. a Mean BCVA throughout the study. b Change in BCVA from baseline through month 12.
in central retinal thickness as per OCT from baseline to 6 and 12 months as well as safety, neovascularization activity on FA and the number of ranibizumab injections applied. Analysis Using a last observation carried forward strategy, baseline and final outcome measurements for the primary and secondary outcome variables were compared using a repeated measures ANOVA design with one between-subjects factor. The independent variable of group assignment was included for treatment effect. Any statistically significant baseline differences between groups were entered as covariates in the model. Baseline characteristics were compared to Student’s t test, χ2 and Fisher’s exact test as appropriate. All analyses were performed with Statistica for Windows version 10.0.
Table 1. Baseline patient characteristics
Patient characteristics
Hypertension Smoking Age, years Juxtafoveal CNV Subfoveal CNV
33.0 (21) 6 (4) 48.8 ± 14.2 19 (12) 81 (52)
Baseline measurements
BCVA 0.2 ± 0.13 Retinal thickness in the foveal area, μm 313.0 ± 82 Data are given as mean ± SD, or as percentages with number of patients in parentheses.
Study Visits Sixty-four patients (65 eyes) attended the 12-month follow-up examination. The mean patient age was 47.8 years, with a standard deviation (SD) of 14.2 years. Fifty-five patients (86.0%) were females. A past medical history of hypertension was found in 33.0% of patients (n = 21). All patients had a history of pathologic myopia with involvement of the macular area. All patients presented a predominantly classic CNV in the macular area. By localization with respect to the foveal area, 19% of CNVs were juxtafoveal (n = 12) and 81% subfoveal (n = 52). The median presenting visual acuity was equivalent to 0.2. The mean baseline cen4
Ophthalmologica 2015;233:2–7 DOI: 10.1159/000369397
tral retinal thickness was 313 μm. Clinical data at baseline are summarized in table 1. Compared to the baseline, BCVA had improved significantly at all later points in time (p = 0.001; fig. 1a). The mean baseline BCVA was 0.2 (SD 0.13). At 12 months, it was 0.4 (SD 0.21; fig. 1b). The greatest improvement in BCVA was seen within the first 3 months (p = 0.0001). Visual results over time are shown in table 2. The mean central retinal thickness analyzed by OCT showed a reduction from 313 μm (SD 82) to 243.5 μm (SD 31; p = 0.0001; fig. 2). There was a continuous decrease in mean OCT retinal thickness over time (table 2). Throughout the follow-up period, patients received an average number of 2 injections of ranibizumab. Pasyechnikova /Naumenko /Korol / Zadorozhnyy /Kustryn /Henrich
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Results
Table 2. Visual and anatomical results in patients treated with CNV associated with pathologic myopia
Results
Baseline
1 month
3 months
6 months
12 months
BCVA p value OCT CRT, μm p value CNV closure rate Injections
0.2 ± 0.13
0.3 ± 0.19 0.0001 286.5 ± 93 0.1
0.36 ± 0.24 0.0001 261.8 ± 55 0.0001 41/65 (63)
0.37 ± 0.20 0.001 250.2 ± 36 0.0001 57/65 (88)
0.4 ± 0.21 0.001 243.5 ± 31 0.0001 61/65 (94) 2.3 ± 0.9
313.0 ± 82
Intravitreal Ranibizumab in Pathologic Myopia: A Prospective Study
Ophthalmologica 2015;233:2–7 DOI: 10.1159/000369397
Mean retinal thickness in the fovea, μm
Treatment options for CNV associated with pathological myopia were traditionally unsatisfactory: laser photocoagulation of subfoveal CNVs is unrewarding with respect to the permanent control of CNV activity, apart from damaging the overlying neurosensory retina and resulting in compromised visual acuity. In a comparison of laser photocoagulation versus the natural history of myo-
pic CNV, laser-treated eyes showed superior BCVA at 2 years, but this difference turned out to be untraceable 5 years after treatment [16, 17]. Jalkh et al. [18] found that BCVA improved in only 11% of eyes with extrafoveal myopic CNV treated with laser photocoagulation, remained unchanged in 21% and worsened in 68%. Although TTT seems to stabilize myopic CNVs both clinically and angiographically, resulting in a significant decrease in lesion activity, this technique has not shown any significant change in BCVA over a 1-year observation period in myopic CNV [7]. Furthermore, adequate energy levels have not been clearly defined. PDT with verteporfin has been advocated as a safe and well-tolerated approach for patients with myopic CNV. Report No. 3 of the VIP study group is the largest study to analyze the efficacy and safety of PDT as treatment for subfoveal myopic CNV. At month 12, 72% of the verteporfin-treated patients compared to 44% of the placebotreated patients lost fewer than 8 letters, including 32 versus 15% improving by at least 5 letters. Eighty-six percent of the verteporfin-treated patients compared to 67% of the placebo-treated patients lost fewer than 15 letters. However, results at 2 years demonstrated no statistically significant difference between eyes treated with PDT and the control groups [6, 19]. Roughly a decade ago, intravitreal application of antiVEGF compounds emerged as a treatment option which not only preserved, but even improved, visual acuity in many patients suffering from different kinds of CNV, including myopic CNV. Several anti-VEGF compounds are available, with similar, albeit not identical, pharmacological properties [20]. Although the risk of complications like retinal detachment is somewhat higher in myopic than in emmetropic patients [21], the data from numerous articles demonstrate the safety and efficacy of intravitreal bevacizumab in eyes with myopic CNV. Arias et
350 300 250 200 150 100 50 0
Baseline
1
2
Months
3
6
Fig. 2. Change in the mean central retinal thickness during 12
months following treatment with ranibizumab for CNVs associated with pathologic myopia.
Complications No cases of endophthalmitis were noted. No patient demonstrated an intraocular pressure >20.0 mm Hg at any study visit. No cases of uveitis or recurrence of CNV were observed.
Discussion
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Data are given as mean ± SD, unless otherwise indicated. Figures in parentheses are percentages. p values determined by Student’s t test for paired data. OCT CRT = Central retinal thickness measured by OCT.
References
6
Despite a growing body of evidence, no consensus has been reached with regard to the injection protocol in pathologic CNV. As in the treatment of exudative agerelated macular degeneration, most authors advocate the use of a PRN regime, where injections are repeated based on predefined reinjection criteria. While an initial ‘upload’ with 3 monthly injections at the beginning of treatment is considered a standard treatment in exudative agerelated macular degeneration, a swifter treatment response has been observed in pathologic myopia so that most authors recommend a PRN regime immediately after the first injection [25, 26]. The results from the literature are in accordance with the findings from our current study. We could show that ranibizumab is a safe and efficacious treatment option in myopic CNV. The gain in visual acuity was swift and could be maintained throughout the study. Compared to other forms of CNV, the recurrence rate was low, and patients needed an average of only 2.3 injections for maintenance. The number of injections needed is also in accordance with the literature.
Conclusion
Our findings in this clinical study demonstrate the high degree of safety and efficacy of intravitreal ranibizumb treatment in patients with myopic CNV. Our results are in line with the literature in that intravitreal ranibizumab significantly increases BCVA while decreasing the central retinal thickness. The greatest improvement in BCVA was seen within the first 3 months. The patients maintained the improvement at a low average number of 2.3 injections.
1 Tano Y: Pathologic myopia: where are we now? Am J Ophthalmol 2002;134:645–660. 2 Yoshida T, Ohno-Matsui K, Yasuzumi K, Kojima A, Shimada N, Futagami S, Tokoro T, Mochizuki M: Myopic choroidal neovascularization: a 10-year follow-up. Ophthalmology 2003;110:1297–1305. 3 Grossniklaus HE, Green WR: Pathologic findings in pathologic myopia. Retina 1992; 12:127–133. 4 Ohno-Matsui K, Yoshida T, Futagami S, Yasuzumi K, Shimada N, Kojima A, Tokoro T, Mochizuki M: Patchy atrophy and lacquer cracks predispose to the development of choroidal neovascularisation in pathological myopia. Br J Ophthalmol 2003;87:570–573.
Ophthalmologica 2015;233:2–7 DOI: 10.1159/000369397
5 Baba T, Kubota-Taniai M, Kitahashi M, Okada K, Mitamura Y, Yamamoto S: Two-year comparison of photodynamic therapy and intravitreal bevacizumab for treatment of myopic choroidal neovascularisation. Br J Ophthalmol 2010;94:864–870. 6 Blinder KJ, Blumenkranz MS, Bressler NM, Bressler SB, Donato G, Lewis H, Lim JI, Menchini U, Miller JW, Mones JM, Potter MJ, Pournaras C, Reaves A, Rosenfeld P, Schachat AP, Schmidt-Erfurth U, Sickenberg M, Singerman LJ, Slakter JS, Strong HA, Virgili G, Williams GA: Verteporfin therapy of subfoveal choroidal neovascularization in pathologic myopia: 2-year results of a randomized clinical trial – VIP report No. 3. Ophthalmology 2003;110:667–673.
Pasyechnikova /Naumenko /Korol / Zadorozhnyy /Kustryn /Henrich
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al. [22] found that at the 6-month follow-up, the mean visual acuity improved by 8.4 letters after intravitreal bevacizumab. The visual acuity of 41% of patients improved by at least 1 line, while 17% of patients gained more than 6 lines. The mean central retinal thickness decreased by 79.6 μm on OCT measurements. Patients with myopic CNV received an average of 1.5 injections of bevacizumab at 6 months. Laud et al. [23] found a 1.5-line improvement in eyes with myopic CNV treated with intravitreal bevacizumab, with a mean follow-up of 7.3 months. In their 24-month study, Baba et al. [5] showed that intravitreal bevacizumab is more effective than PDT in eyes with myopic CNV. A number of publications showed favorable results of intravitreal ranibizumab for myopic CNV. Lai et al. [13] demonstrated a mean improvement of 3.0 lines at 12 months, while 75.0% of eyes showed an improvement of 2 or more lines; 93.8% of eyes demonstrated an angiographic CNV closure at 3 months, and 12.5% of patients had a recurrence of CNV and required retreatment for between 3 and 9 months. OCT showed a significant reduction in the mean central foveal thickness after treatment. Based on a prospective randomized clinical trial, which established a superiority of intravitreal ranibizumab over PDT, ranibizumab has recently received approval in the European Union as the first effective anti-VEGF treatment for myopic CNV. The study showed that around 40% of patients treated with ranibizumab, as opposed to 15% of Visudyne-treated patients, gained 15 or more letters of visual acuity at 3 months [24]. The mean visual acuity gain was approximately 14 ETDRS letters at 1 year at a median of 2.0 injections.
Intravitreal Ranibizumab in Pathologic Myopia: A Prospective Study
14 Finger RP, Wiedemann P, Blumhagen F, Pohl K, Holz FG: Treatment patterns, visual acuity and quality-of-life outcomes of the wave study – a noninterventional study of ranibizumab treatment for neovascular age-related macular degeneration in Germany. Acta Ophthalmol 2013;91:540–546. 15 Fung AE, Lalwani GA, Rosenfeld PJ, Dubovy SR, Michels S, Feuer WJ, Puliafito CA, Davis JL, Flynn HW Jr, Esquiabro M: An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol 2007; 143: 566–583. 16 Laser photocoagulation of subfoveal neovascular lesions of age-related macular degeneration. Updated findings from two clinical trials. Macular photocoagulation study group. Arch Ophthalmol 1993;111:1200–1209. 17 Secretan M, Kuhn D, Soubrane G, Coscas G: Long-term visual outcome of choroidal neovascularization in pathologic myopia: natural history and laser treatment. Eur J Ophthalmol 1997;7:307–316. 18 Jalkh AE, Weiter JJ, Trempe CL, Pruett RC, Schepens CL: Choroidal neovascularization in degenerative myopia: role of laser photocoagulation. Ophthalmic Surg 1987; 18: 721– 725. 19 Photodynamic therapy of subfoveal choroidal neovascularization in pathologic myopia with verteporfin. 1-year results of a randomized clinical trial – VIP report No. 1. Ophthalmology 2001;108:841–852.
20 Meyer CH, Holz FG: Preclinical aspects of anti-VEGF agents for the treatment of wet AMD: ranibizumab and bevacizumab. Eye 2011;25:661–672. 21 Meyer CH, Michels S, Rodrigues EB, Hager A, Mennel S, Schmidt JC, Helb HM, Farah ME: Incidence of rhegmatogenous retinal detachments after intravitreal antivascular endothelial factor injections. Acta Ophthalmol 2011; 89:70–75. 22 Arias L, Planas N, Prades S, Caminal JM, Rubio M, Pujol O, Roca G: Intravitreal bevacizumab (Avastin) for choroidal neovascularisation secondary to pathological myopia: 6-month results. Br J Ophthalmol 2008; 92: 1035–1039. 23 Laud K, Spaide RF, Freund KB, Slakter J, Klancnik JM Jr: Treatment of choroidal neovascularization in pathologic myopia with intravitreal bevacizumab. Retina 2006;26:960–963. 24 Wolf S, Balciuniene VJ, Laganovska G, Menchini U, Ohno-Matsui K, Sharma T, Wong TY, Silva R, Pilz S, Gekkieva M: RADIANCE: a randomized controlled study of ranibizumab in patients with choroidal neovascularization secondary to pathologic myopia. Ophthalmology 2014;121:682–692.e2. 25 Maier M: Diagnose und Therapie der pathologischen Myopie, ed 1. Bremen, UNI-MED, 2013. 26 Hefner L, Riese J, Gerding H: Three years follow-up results of ranibizumab treatment for choroidal neovascularization secondary to pathologic myopia. Klin Monbl Augenheilkd 2013;230:401–404.
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7 Ozdek S, Hondur A, Gurelik G, Hasanreisoglu B: Transpupillary thermotherapy for myopic choroidal neovascularization: 1-year follow-up: TTT for myopic CNV. Int Ophthalmol 2005;26:127–133. 8 Virgili G, Menchini F: Laser photocoagulation for choroidal neovascularisation in pathologic myopia. Cochrane Database Syst Rev 2005:Cd004765. 9 Deeks ED: Ranibizumab: a review of its use in myopic choroidal neovascularization. BioDrugs 2014;28:403–410. 10 Vadala M, Pece A, Cipolla S, Monteleone C, Fasolino G, Casuccio A, Cillino S: Is ranibizumab effective in stopping the loss of vision for choroidal neovascularisation in pathologic myopia? A long-term follow-up study. Br J Ophthalmol 2011;95:657–661. 11 Silva RM, Ruiz-Moreno JM, Rosa P, Carneiro A, Nascimento J, Rito LF, Cachulo ML, Carvalheira F, Murta JN: Intravitreal ranibizumab for myopic choroidal neovascularization: 12-month results. Retina 2010;30:407–412. 12 Lalloum F, Souied EH, Bastuji-Garin S, Puche N, Querques G, Glacet-Bernard A, Coscas G, Soubrane G, Leveziel N: Intravitreal ranibizumab for choroidal neovascularization complicating pathologic myopia. Retina 2010; 30: 399–406. 13 Lai TY, Chan WM, Liu DT, Lam DS: Intravitreal ranibizumab for the primary treatment of choroidal neovascularization secondary to pathologic myopia. Retina 2009;29:750–756.
Ophthalmologica
Ophthalmologica 2015;233:2–7 DOI: 10.1159/000369397
Received: September 23, 2014 Accepted after revision: October 28, 2014 Published online: December 6, 2014
Intravitreal Ranibizumab for the Treatment of Choroidal Neovascularizations Associated with Pathologic Myopia: A Prospective Study Nataliya V. Pasyechnikova a Volodymyr O. Naumenko a Andrii R. Korol a Oleg S. Zadorozhnyy a Taras B. Kustryn a Paul B. Henrich b–d a
State Institution ‘The Filatov Institute of Eye Diseases and Tissue Therapy of the NAMS of Ukraine’, Odessa, Ukraine; b Winterthur Cantonal Hospital, Winterthur, c Department of Ophthalmology, University of Basel, Basel, and d Centro Ticinese di Chirurgia Ambulatoriale Avanti, Lugano, Switzerland
Abstract Purpose: It was the aim of this study to determine the efficacy of intravitreal ranibizumab as treatment of choroidal neovascularizations associated with pathologic myopia. Materials and Methods: In an uncontrolled, prospective time series cohort study, 65 eyes of 64 consecutive patients with choroidal neovascularization associated with pathologic myopia were treated with intravitreal ranibizumab and observed over 12 months. The change in best-corrected visual acuity (BCVA) at 6 and 12 months served as primary end point. Safety, central retinal thickness, neovascularization activity on fluorescein angiography and the number of ranibizumab injections were secondary end points. Results: BCVA improved significantly throughout the follow-up (p = 0.001). The mean BCVA was 0.2 at baseline (SD 0.13) and 0.4 at 12 months (SD 0.21). Improvement was strongest within the first 3 months (p = 0.0001). The mean central retinal thickness showed a reduction from 313 μm (SD 82) to 243.5 μm (SD 31; p = 0.0001). Conclusion: Intravitreal ranibizumab offers a safe and effective treatment for choroidal neovascularizations in pathologic myopia. © 2014 S. Karger AG, Basel
© 2014 S. Karger AG, Basel 0030–3755/14/2331–0002$39.50/0 E-Mail [email protected] www.karger.com/oph
Introduction
Choroidal neovascularization (CNV) is among the most threatening complications of pathologic myopia, and untreated myopic CNV has a poor visual prognosis. More than 95% of affected eyes will experience a drop in visual acuity to 20/200 or worse [1, 2]. The risk of developing a myopic CNV is 5–11%. Young and middle-aged patients are mostly affected. Patients affected by a myopic CNV in one eye have a chance of over 30% to develop CNV in the fellow eye within 8 years [3, 4]. Because of the poor natural history of myopic CNVs, a variety of different treatment approaches have been suggested. Thermal laser photocoagulation, transpupillary thermotherapy (TTT) and photodynamic therapy (PDT) with verteporfin have shown a short-term effect, but long-term efficacy and safety are disappointing [5–8]. The role of subretinal surgery in the treatment of myopic CNV remains controversial. Ranibizumab is the first inhibitor of vascular endothelial growth factor (VEGF)-A licensed for the treatment of visual impairment due to CNV. The clinical benefit of ranibizumab in adults with myopic CNV has been documented in a randomized, double-masked, active comparator-controlled, phase III trial [9]. In this trial, intravitreal ranibizumab was superior to intravenous verteporfin Paul B. Henrich, MD Department of Ophthalmology Winterthur Cantonal Hospital, Brauerstrasse 15 CH–8400 Winterthur (Switzerland) E-Mail bernhard.henrich @ ksw.ch
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Key Words Myopia · Macular degeneration · Anti-vascular endothelial growth factor
Materials and Methods Protocol The study was approved by the Filatov Institute of Eye Diseases and Tissue Therapy of the National Academy of Medical Sciences of Ukraine Institutional Review and Ethics Board before study commencement. All procedures were performed in accordance with the 1964 Declaration of Helsinki. Filatov Institute patients presenting to any of the coauthors with signs and symptoms consistent with CNV associated with pathologic myopia were eligible for the study. Inclusion criteria were: pathological myopia defined as a spherical equivalent of more than −6.0 diopters, a new onset of CNV associated with pathologic myopia (18 years, a medical history of pathologic myopia and an absence of signs of inflammation at baseline. Ocular exclusion criteria comprised: an indication of any origin of the CNV other than pathologic myopia, intraocular or periocular inflammation, known glaucoma or clinical suspicion of glaucoma upon presentation, ocular hypertension (intraocular pressure >24 mm Hg) and a complicated fundus observation by optic media opacity. Nonocular exclusion criteria were pregnancy, lactation and the inability to provide informed consent. The injection schedule followed a pro re nata (PRN) regimen and consisted of 2 fixed loading injections, one at baseline and the second 1 month later. As studies based on strict reinjection criteria have shown results superior to physician-based retreatment schedules [14], the indication for a third and further injections was based on the following reinjection criteria: visual acuity (loss of 1 line or more), development of new macular hemorrhage on fundus examination, evidence of late leakage on fluorescein angiography (FA) and the presence of any fluid or any increase in macular thickness of >50 μm on optical coherence tomography (OCT). These retreatment criteria are largely identical with the ones in the
Intravitreal Ranibizumab in Pathologic Myopia: A Prospective Study
PRONTO study [15], with the exception of OCT findings. PRONTO studied a cohort with exudative age-related macular degeneration and required an increase of at least 100 μm in central retinal thickness. As the sample of the current study involves patients with myopic CNV which tend to present with more subtle OCT changes, an increase in central retinal thickness of 50 μm was deemed more adequate. In the case of CNV activity on FA or OCT, additional monthly injections were performed until the absence of fluorescein leakage from the CNV and the absence of any fluid collections on OCT were observed. Eligible subjects were provided with a comprehensive explanation concerning their disease and the proposed study and treatment. Consent was obtained after a minimum of 24 h of time for consideration. All enrolled patients underwent baseline ophthalmological examination and investigations including measurements of Snellen best-corrected visual acuity (BCVA), intraocular pressure, pupillary, biomicroscopic and dilated fundus examination and OCT of the macular area, color fundus photography and FA. After consent was obtained for study entry, patients were transferred to another coinvestigator for injection. Intervention Ranibizumab (0.5 mg; Novartis AG, Basel, Switzerland) was delivered into the vitreous cavity via a pars plana transcleral injection. Sterile propracaine drops were instilled in the affected eye. The eye and surrounding periocular skin was prepped with 5% betadine solution. A lid speculum was placed and the anesthetized area disinfected with 5% betadine. A variable caliper was utilized to mark the pars plana, 4.0 mm from the limbus for phakic patients and 3.5 mm for pseudophakic patients. A 27-gauge needle was then introduced through the mark into the vitreous cavity, and ranibizumab was injected. The needle was retracted and the injection site covered with a sterile cotton-tipped applicator. A drop of topical ofloxacin was instilled in the conjunctival sac and the speculum removed. Patients were instructed to continue the ofloxacin drops 4 times a day for 5 days. Study Visits Patients were seen at baseline and underwent a comprehensive ophthalmological examination including OCT, color fundus photography and FA as noted above. BCVA measurements, intraocular pressure measurements, pupilary, biomicroscopic and dilated fundus examination were also performed. Subsequently, all patients were re-examined every month for 12 months. Follow-up examinations involved ophthalmological examination including BCVA measurements, intraocular pressure measurements and dilated fundus examination. OCT and color fundus photography were also repeated at each of these visits. FA was performed in case of a decreasing BCVA and/or an increase in macular edema. In addition to the study visits, a postoperative visit was performed 1 day following each intervention to rule out possible injection-related complications. Particular attention was paid to exclude elevated intraocular pressure, endophthalmitis, retinal tears, retinal detachments, vitreous hemorrhages, uveitis and corneal erosions. Any other complications encountered were also noted. Outcome Measures The primary outcome was a change in BCVA compared to baseline at 6 and 12 months. The secondary outcome was a change
Ophthalmologica 2015;233:2–7 DOI: 10.1159/000369397
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plus PDT, the standard licensed therapy available to patients with CNV based on pathologic myopia. Visual acuity improved from month 1 through month 3 of treatment. Improvements in vision and anatomic outcomes were sustained for up to 12 months. Compared to other trials using ranibizumab for age-dependent macular degeneration, relatively few ranibizumab injections were required during the course of the trial, with more than 60% of patients not needing to receive the drug from month 6 to month 11. Ranibizumab was generally well tolerated, with few patients experiencing serious ocular or nonocular adverse events [9]. Earlier case series have already reported good visual outcomes after intravitreal ranibizumab therapy without any serious ocular or systemic complications, and, at present, intravitreal ranibizumab is considered the first-line therapy for sub- and juxtafoveal myopic CNVs [10–13]. The purpose of this study was to determine the efficacy of the intravitreal injection of ranibizumab as a treatment for CNV associated with pathologic myopia.
0.45
0.50 0.45
0.35
0.40
0.30
0.35
0.25
0.30
BCVA
Mean BCVA
0.40
0.20 0.15
0.20 0.10
0.05
a
0.25 0.15
0.10 0
Mean Mean ± SE Mean ± 1.96 SE
0.05 Baseline
1
2
3 Months
6
12
b
0
Baseline
12 months
Fig. 1. Change in BCVA during the study. a Mean BCVA throughout the study. b Change in BCVA from baseline through month 12.
in central retinal thickness as per OCT from baseline to 6 and 12 months as well as safety, neovascularization activity on FA and the number of ranibizumab injections applied. Analysis Using a last observation carried forward strategy, baseline and final outcome measurements for the primary and secondary outcome variables were compared using a repeated measures ANOVA design with one between-subjects factor. The independent variable of group assignment was included for treatment effect. Any statistically significant baseline differences between groups were entered as covariates in the model. Baseline characteristics were compared to Student’s t test, χ2 and Fisher’s exact test as appropriate. All analyses were performed with Statistica for Windows version 10.0.
Table 1. Baseline patient characteristics
Patient characteristics
Hypertension Smoking Age, years Juxtafoveal CNV Subfoveal CNV
33.0 (21) 6 (4) 48.8 ± 14.2 19 (12) 81 (52)
Baseline measurements
BCVA 0.2 ± 0.13 Retinal thickness in the foveal area, μm 313.0 ± 82 Data are given as mean ± SD, or as percentages with number of patients in parentheses.
Study Visits Sixty-four patients (65 eyes) attended the 12-month follow-up examination. The mean patient age was 47.8 years, with a standard deviation (SD) of 14.2 years. Fifty-five patients (86.0%) were females. A past medical history of hypertension was found in 33.0% of patients (n = 21). All patients had a history of pathologic myopia with involvement of the macular area. All patients presented a predominantly classic CNV in the macular area. By localization with respect to the foveal area, 19% of CNVs were juxtafoveal (n = 12) and 81% subfoveal (n = 52). The median presenting visual acuity was equivalent to 0.2. The mean baseline cen4
Ophthalmologica 2015;233:2–7 DOI: 10.1159/000369397
tral retinal thickness was 313 μm. Clinical data at baseline are summarized in table 1. Compared to the baseline, BCVA had improved significantly at all later points in time (p = 0.001; fig. 1a). The mean baseline BCVA was 0.2 (SD 0.13). At 12 months, it was 0.4 (SD 0.21; fig. 1b). The greatest improvement in BCVA was seen within the first 3 months (p = 0.0001). Visual results over time are shown in table 2. The mean central retinal thickness analyzed by OCT showed a reduction from 313 μm (SD 82) to 243.5 μm (SD 31; p = 0.0001; fig. 2). There was a continuous decrease in mean OCT retinal thickness over time (table 2). Throughout the follow-up period, patients received an average number of 2 injections of ranibizumab. Pasyechnikova /Naumenko /Korol / Zadorozhnyy /Kustryn /Henrich
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Results
Table 2. Visual and anatomical results in patients treated with CNV associated with pathologic myopia
Results
Baseline
1 month
3 months
6 months
12 months
BCVA p value OCT CRT, μm p value CNV closure rate Injections
0.2 ± 0.13
0.3 ± 0.19 0.0001 286.5 ± 93 0.1
0.36 ± 0.24 0.0001 261.8 ± 55 0.0001 41/65 (63)
0.37 ± 0.20 0.001 250.2 ± 36 0.0001 57/65 (88)
0.4 ± 0.21 0.001 243.5 ± 31 0.0001 61/65 (94) 2.3 ± 0.9
313.0 ± 82
Intravitreal Ranibizumab in Pathologic Myopia: A Prospective Study
Ophthalmologica 2015;233:2–7 DOI: 10.1159/000369397
Mean retinal thickness in the fovea, μm
Treatment options for CNV associated with pathological myopia were traditionally unsatisfactory: laser photocoagulation of subfoveal CNVs is unrewarding with respect to the permanent control of CNV activity, apart from damaging the overlying neurosensory retina and resulting in compromised visual acuity. In a comparison of laser photocoagulation versus the natural history of myo-
pic CNV, laser-treated eyes showed superior BCVA at 2 years, but this difference turned out to be untraceable 5 years after treatment [16, 17]. Jalkh et al. [18] found that BCVA improved in only 11% of eyes with extrafoveal myopic CNV treated with laser photocoagulation, remained unchanged in 21% and worsened in 68%. Although TTT seems to stabilize myopic CNVs both clinically and angiographically, resulting in a significant decrease in lesion activity, this technique has not shown any significant change in BCVA over a 1-year observation period in myopic CNV [7]. Furthermore, adequate energy levels have not been clearly defined. PDT with verteporfin has been advocated as a safe and well-tolerated approach for patients with myopic CNV. Report No. 3 of the VIP study group is the largest study to analyze the efficacy and safety of PDT as treatment for subfoveal myopic CNV. At month 12, 72% of the verteporfin-treated patients compared to 44% of the placebotreated patients lost fewer than 8 letters, including 32 versus 15% improving by at least 5 letters. Eighty-six percent of the verteporfin-treated patients compared to 67% of the placebo-treated patients lost fewer than 15 letters. However, results at 2 years demonstrated no statistically significant difference between eyes treated with PDT and the control groups [6, 19]. Roughly a decade ago, intravitreal application of antiVEGF compounds emerged as a treatment option which not only preserved, but even improved, visual acuity in many patients suffering from different kinds of CNV, including myopic CNV. Several anti-VEGF compounds are available, with similar, albeit not identical, pharmacological properties [20]. Although the risk of complications like retinal detachment is somewhat higher in myopic than in emmetropic patients [21], the data from numerous articles demonstrate the safety and efficacy of intravitreal bevacizumab in eyes with myopic CNV. Arias et
350 300 250 200 150 100 50 0
Baseline
1
2
Months
3
6
Fig. 2. Change in the mean central retinal thickness during 12
months following treatment with ranibizumab for CNVs associated with pathologic myopia.
Complications No cases of endophthalmitis were noted. No patient demonstrated an intraocular pressure >20.0 mm Hg at any study visit. No cases of uveitis or recurrence of CNV were observed.
Discussion
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Data are given as mean ± SD, unless otherwise indicated. Figures in parentheses are percentages. p values determined by Student’s t test for paired data. OCT CRT = Central retinal thickness measured by OCT.
References
6
Despite a growing body of evidence, no consensus has been reached with regard to the injection protocol in pathologic CNV. As in the treatment of exudative agerelated macular degeneration, most authors advocate the use of a PRN regime, where injections are repeated based on predefined reinjection criteria. While an initial ‘upload’ with 3 monthly injections at the beginning of treatment is considered a standard treatment in exudative agerelated macular degeneration, a swifter treatment response has been observed in pathologic myopia so that most authors recommend a PRN regime immediately after the first injection [25, 26]. The results from the literature are in accordance with the findings from our current study. We could show that ranibizumab is a safe and efficacious treatment option in myopic CNV. The gain in visual acuity was swift and could be maintained throughout the study. Compared to other forms of CNV, the recurrence rate was low, and patients needed an average of only 2.3 injections for maintenance. The number of injections needed is also in accordance with the literature.
Conclusion
Our findings in this clinical study demonstrate the high degree of safety and efficacy of intravitreal ranibizumb treatment in patients with myopic CNV. Our results are in line with the literature in that intravitreal ranibizumab significantly increases BCVA while decreasing the central retinal thickness. The greatest improvement in BCVA was seen within the first 3 months. The patients maintained the improvement at a low average number of 2.3 injections.
1 Tano Y: Pathologic myopia: where are we now? Am J Ophthalmol 2002;134:645–660. 2 Yoshida T, Ohno-Matsui K, Yasuzumi K, Kojima A, Shimada N, Futagami S, Tokoro T, Mochizuki M: Myopic choroidal neovascularization: a 10-year follow-up. Ophthalmology 2003;110:1297–1305. 3 Grossniklaus HE, Green WR: Pathologic findings in pathologic myopia. Retina 1992; 12:127–133. 4 Ohno-Matsui K, Yoshida T, Futagami S, Yasuzumi K, Shimada N, Kojima A, Tokoro T, Mochizuki M: Patchy atrophy and lacquer cracks predispose to the development of choroidal neovascularisation in pathological myopia. Br J Ophthalmol 2003;87:570–573.
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5 Baba T, Kubota-Taniai M, Kitahashi M, Okada K, Mitamura Y, Yamamoto S: Two-year comparison of photodynamic therapy and intravitreal bevacizumab for treatment of myopic choroidal neovascularisation. Br J Ophthalmol 2010;94:864–870. 6 Blinder KJ, Blumenkranz MS, Bressler NM, Bressler SB, Donato G, Lewis H, Lim JI, Menchini U, Miller JW, Mones JM, Potter MJ, Pournaras C, Reaves A, Rosenfeld P, Schachat AP, Schmidt-Erfurth U, Sickenberg M, Singerman LJ, Slakter JS, Strong HA, Virgili G, Williams GA: Verteporfin therapy of subfoveal choroidal neovascularization in pathologic myopia: 2-year results of a randomized clinical trial – VIP report No. 3. Ophthalmology 2003;110:667–673.
Pasyechnikova /Naumenko /Korol / Zadorozhnyy /Kustryn /Henrich
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al. [22] found that at the 6-month follow-up, the mean visual acuity improved by 8.4 letters after intravitreal bevacizumab. The visual acuity of 41% of patients improved by at least 1 line, while 17% of patients gained more than 6 lines. The mean central retinal thickness decreased by 79.6 μm on OCT measurements. Patients with myopic CNV received an average of 1.5 injections of bevacizumab at 6 months. Laud et al. [23] found a 1.5-line improvement in eyes with myopic CNV treated with intravitreal bevacizumab, with a mean follow-up of 7.3 months. In their 24-month study, Baba et al. [5] showed that intravitreal bevacizumab is more effective than PDT in eyes with myopic CNV. A number of publications showed favorable results of intravitreal ranibizumab for myopic CNV. Lai et al. [13] demonstrated a mean improvement of 3.0 lines at 12 months, while 75.0% of eyes showed an improvement of 2 or more lines; 93.8% of eyes demonstrated an angiographic CNV closure at 3 months, and 12.5% of patients had a recurrence of CNV and required retreatment for between 3 and 9 months. OCT showed a significant reduction in the mean central foveal thickness after treatment. Based on a prospective randomized clinical trial, which established a superiority of intravitreal ranibizumab over PDT, ranibizumab has recently received approval in the European Union as the first effective anti-VEGF treatment for myopic CNV. The study showed that around 40% of patients treated with ranibizumab, as opposed to 15% of Visudyne-treated patients, gained 15 or more letters of visual acuity at 3 months [24]. The mean visual acuity gain was approximately 14 ETDRS letters at 1 year at a median of 2.0 injections.
Intravitreal Ranibizumab in Pathologic Myopia: A Prospective Study
14 Finger RP, Wiedemann P, Blumhagen F, Pohl K, Holz FG: Treatment patterns, visual acuity and quality-of-life outcomes of the wave study – a noninterventional study of ranibizumab treatment for neovascular age-related macular degeneration in Germany. Acta Ophthalmol 2013;91:540–546. 15 Fung AE, Lalwani GA, Rosenfeld PJ, Dubovy SR, Michels S, Feuer WJ, Puliafito CA, Davis JL, Flynn HW Jr, Esquiabro M: An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol 2007; 143: 566–583. 16 Laser photocoagulation of subfoveal neovascular lesions of age-related macular degeneration. Updated findings from two clinical trials. Macular photocoagulation study group. Arch Ophthalmol 1993;111:1200–1209. 17 Secretan M, Kuhn D, Soubrane G, Coscas G: Long-term visual outcome of choroidal neovascularization in pathologic myopia: natural history and laser treatment. Eur J Ophthalmol 1997;7:307–316. 18 Jalkh AE, Weiter JJ, Trempe CL, Pruett RC, Schepens CL: Choroidal neovascularization in degenerative myopia: role of laser photocoagulation. Ophthalmic Surg 1987; 18: 721– 725. 19 Photodynamic therapy of subfoveal choroidal neovascularization in pathologic myopia with verteporfin. 1-year results of a randomized clinical trial – VIP report No. 1. Ophthalmology 2001;108:841–852.
20 Meyer CH, Holz FG: Preclinical aspects of anti-VEGF agents for the treatment of wet AMD: ranibizumab and bevacizumab. Eye 2011;25:661–672. 21 Meyer CH, Michels S, Rodrigues EB, Hager A, Mennel S, Schmidt JC, Helb HM, Farah ME: Incidence of rhegmatogenous retinal detachments after intravitreal antivascular endothelial factor injections. Acta Ophthalmol 2011; 89:70–75. 22 Arias L, Planas N, Prades S, Caminal JM, Rubio M, Pujol O, Roca G: Intravitreal bevacizumab (Avastin) for choroidal neovascularisation secondary to pathological myopia: 6-month results. Br J Ophthalmol 2008; 92: 1035–1039. 23 Laud K, Spaide RF, Freund KB, Slakter J, Klancnik JM Jr: Treatment of choroidal neovascularization in pathologic myopia with intravitreal bevacizumab. Retina 2006;26:960–963. 24 Wolf S, Balciuniene VJ, Laganovska G, Menchini U, Ohno-Matsui K, Sharma T, Wong TY, Silva R, Pilz S, Gekkieva M: RADIANCE: a randomized controlled study of ranibizumab in patients with choroidal neovascularization secondary to pathologic myopia. Ophthalmology 2014;121:682–692.e2. 25 Maier M: Diagnose und Therapie der pathologischen Myopie, ed 1. Bremen, UNI-MED, 2013. 26 Hefner L, Riese J, Gerding H: Three years follow-up results of ranibizumab treatment for choroidal neovascularization secondary to pathologic myopia. Klin Monbl Augenheilkd 2013;230:401–404.
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7 Ozdek S, Hondur A, Gurelik G, Hasanreisoglu B: Transpupillary thermotherapy for myopic choroidal neovascularization: 1-year follow-up: TTT for myopic CNV. Int Ophthalmol 2005;26:127–133. 8 Virgili G, Menchini F: Laser photocoagulation for choroidal neovascularisation in pathologic myopia. Cochrane Database Syst Rev 2005:Cd004765. 9 Deeks ED: Ranibizumab: a review of its use in myopic choroidal neovascularization. BioDrugs 2014;28:403–410. 10 Vadala M, Pece A, Cipolla S, Monteleone C, Fasolino G, Casuccio A, Cillino S: Is ranibizumab effective in stopping the loss of vision for choroidal neovascularisation in pathologic myopia? A long-term follow-up study. Br J Ophthalmol 2011;95:657–661. 11 Silva RM, Ruiz-Moreno JM, Rosa P, Carneiro A, Nascimento J, Rito LF, Cachulo ML, Carvalheira F, Murta JN: Intravitreal ranibizumab for myopic choroidal neovascularization: 12-month results. Retina 2010;30:407–412. 12 Lalloum F, Souied EH, Bastuji-Garin S, Puche N, Querques G, Glacet-Bernard A, Coscas G, Soubrane G, Leveziel N: Intravitreal ranibizumab for choroidal neovascularization complicating pathologic myopia. Retina 2010; 30: 399–406. 13 Lai TY, Chan WM, Liu DT, Lam DS: Intravitreal ranibizumab for the primary treatment of choroidal neovascularization secondary to pathologic myopia. Retina 2009;29:750–756.
