Pathological myopia is more common in Asian populations.

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1 REVIEW ARTICLE Management of Choroidal Neovascularization Secondary to Pathological Myopia: The Era of Changes Mary Ho, MRCS,* David T.L. Liu, FRCOphth, FRCS,*Þ Alvin L. Young, MMedSc (Hons), FRCS (Irel),*Þ and Dennis S.C. Lam, MD, FRCOphth*Þ Abstract: Choroidal neovascularization (CNV) secondary to pathological myopia is an important cause of significant visual impairment in young adults. High myopia is particularly prevalent in Asian population. New scientific contributions have been made to the understanding of high myopia and myopic CNV. Treatment for myopic CNV has previously relied on photodynamic therapy, laser photocoagulation, and submacular surgery. The treatment outcomes from these modalities are, however, controversial. The introduction of antiangiogenic agents including bevacizumab and ranibizumab has brought the treatment of myopic CNV into a new era. The purpose of this review was to provide an overview of the natural history of myopic CNV, the prognostic factors, and the various treatment options including laser photocoagulation and photodynamic therapy, with particular attention on antiangiogenic agents. Key Words: pathological myopia, choroidal neovascularization, review, myopic CNV (Asia-Pac J Ophthalmol 2014;3: 94Y103) Pathological myopia is more common in Asian populations. 1Y3 The prevalence of pathological myopia was reported to be 9% to 12% 1,2 in Asian population compared with 2% to 4% in white people. 3Y6 Overall, pathological myopia is a common cause of visual impairment worldwide. 7,8 Its pathogenesis is associated with progressive and excessive elongation of the eyeball. 7,8 In highly myopic eyes, the collagen fibers has less crosslinking, 9,10 and the choroidal thickness is thinner compared with the normal eyes. 11,12 The various degenerative changes affecting the sclera, choroid, and retina may lead to visual loss. In younger adults, a rapid visual acuity (VA) loss is more commonly associated with the development of choroidal neovascularization (CNV). If left untreated, it can result in a poor visual outcome for the majority of patients. Recently, antiangiogenic agents with or without combination with photodynamic therapy (PDT) have shown promising results in the treatment of myopic CNV (mcnv). This article emphasizes the clinical features of CNV secondary to pathological myopia and the recent treatment modalities available. From the *Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, People s Republic of China; and Dennis Lam and Partners Eye Center, Central Building, Central, Hong Kong, People s Republic of China. Received for publication July 5, 2013; accepted September 26, The authors have no funding or conflicts of interest to declare. Reprints: Dr David T.L. Liu, FRCOphth, FRCS, Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Chinese University of Hong Kong, 4/F, Hong Kong Eye Hospital, Argyle Street, Kowloon, Hong Kong, People s Republic of China. david_tlliu@yahoo.com. Copyright * 2014 by Asia Pacific Academy of Ophthalmology ISSN: DOI: /APO Our literature searches aimed at a comprehensive review of the current literature. The literature searches from 1975 to May 2013 were performed with following keywords, pathological myopia, choroidal neovascularization, myopia, myopic maculopathy, andtreatment using search engines PubMed, EMBASE, MEDLINE, and the Cochrane Library. Meta-analysis, populationbased cohort studies, case-controlled trials, and case series were reviewed, whereas case reports, commentaries, abstracts, or personal observations were excluded. VITREORETINAL DEGENERATIONS ASSOCIATED WITH PATHOLOGICAL MYOPIA Pathological myopia is also known as degenerative or progressive myopia and is characterized by marked fundus myopic changes. High myopia is usually defined as myopia of j6.00 diopters or more. Pathological myopia is associated with varying degrees of vitreoretinal degeneration including posterior staphyloma, diffuse or patchy chorioretinal atrophy, retinal pigment epithelial atrophy, lacquer cracks, Fuchs spots, spontaneous subretinal hemorrhages, and macular CNV. 9,13 Patchy atrophy and lacquer cracks were reported to be associated with higher risk of the development of CNV. 14 Lacquer cracks are formed by rupture in the Bruch s membrane, often associated with subretinal hemorrhages, rendering it difficult to differentiate clinically from CNV. CHORIDAL NEOVASCULARIZATION IN PATHOLOGICAL MYOPIA Prevalence of Myopic Choroidal Neovascularization The prevalence of myopia is higher in Chinese population. It is reported to be 4.2% in Chinese population, 1 among whom 72.7% are reported to experience myopic maculopathy. A risk factor for the development of maculopathy was higher myopic degree reported to be more than j10 diopter. 1 Macular CNV constitutes one of the most sight-threatening complications of pathological myopia 15,16 especially in young adults. Pathological myopia serves as the most common cause for CNV development in young patients younger than 50 years. 17 The commonest histopathological findings in pathological myopia include myopic configuration of the optic nerve head and posterior staphyloma, 13 whereas subretinal neovascularization could appear in up to 5% to 11% of highly myopic eyes. 9,13,14 Choroidal neovascularization in pathological myopia may show a self-limiting course with self regression, resulting in an atrophic, nonexudative scar. 15 Without treatment, mcnv carries poor prognosis, with more than 40% developed loss of more than 2 lines of vision, whereas 60% may experience profound visual loss. 16 Clinical Features of Myopic Choroidal Neovascularization The clinical picture of mcnv is less aggressive than agerelated macular degeneration (AMD)Yrelated CNV. Typical 94 Asia-Pacific Journal of Ophthalmology & Volume 3, Number 2, March/April 2014

2 Asia-Pacific Journal of Ophthalmology & Volume 3, Number 2, March/April 2014 CNV Secondary to Pathological Myopia mcnv is small in size, with grayish subretinal membrane, which is less than 1 disc diameter in size. 16 Most mcnv is subfoveal or juxtafoveal, with minimal subretinal fluid or exudates. 16 Choroidal neovascularization was observed to have bilateral involvement in 16% of cases. 18 Choroidal neovascularization was classically growing between the retinal pigment epithelium and neurosensory retina (type 2 CNV). Surface area of CNV was reported to be larger in age group older than 55 years old. 18 Pathological myopia is associated with clinical features including posterior pole staphyloma, pigmentary changes, lacquer cracks, and chorioretinal atrophic lesions. These features render the identification of new onset mcnv difficult by simple fundus examination. Retinal hemorrhages are also commonly seen with recent lacquer cracks associated with pathological myopia. Fluorescein angiography (FA) and optical coherence tomography (OCT) scans are important tools that facilitate the diagnosis of recent mcnv. Fluorescein Angiographic Findings of Myopic Choroidal Neovascularization Myopic CNV is described to have the classic pattern of leakage on FA. 16,19 Median size of the lesion was reported to be 1840 Hm to 1900 Hm. 19 Myopic CNV usually presents as classic CNV; it is reported in one series to constitute 83.3% of all cases of mcnv. Occult CNV is responsible for approximately 14% of mcnv. 19 Lesion size is usually smaller when compared with ARMD-related CNV; minority (6%) of cases would present as size larger than 3 disc areas. Common features are described as classic angiographic pattern with transit-phase hyperfluorescence followed by late-phase minor leakage. Thus, FA is an important tool that facilitates the diagnosis of recent mcnv by showing the CNV network on early frames as well as staining and leakage at late frames. 20 Optical Coherence Tomographic Findings of Myopic Choroidal Neovascularization Optical coherence tomography produces high resolution cross-sectional images of the retina and is helpful in providing detailed description of the morphological changes of mcnv. Spectral-domain OCT is currently an important diagnostic tool for mcnv, showing a hyperreflective lesion located beneath the neurosensory retina. Associated features such as retinal thickening, retinal cysts, or subretinal accumulation of fluids could be shown. 21,22 Correlation and agreement on diagnosis between FA and OCT were only fair. When CNV was identified, leakage of dye on late frames of FA was observed in 82% of eyes, whereas exudative signs such as intraretinal cysts or subretinal fluid are not a must in OCT scans. Exudative signs are only observed by spectral-domain OCT in 48.6% of eyes. 18 Indocyanine Green Angiographic Findings of Myopic Choroidal Neovascularization Indocyanine green has its role especially in doubtful cases, when retinal hemorrhages masked typical angiographic findings. 18 Indocyanine green is blocked by retinal pigment epithelium and blood but allows clear differentiation of CNV membranes. 23Y26 Indocyanine green could provide supplementary information to FA; it may locate the site for CNV even with the presence of subretinal blood. It could also serve as a guide for the type of CNV formation and feeder vessel identification. 14,26 The information provided by FA could be limited especially when there is subretinal blood or in cases with small CNV lesions. 27 Genetic Factor Associated With Myopic Choroidal Neovascularization So far, no genetic factor for AMD has been associated with mcnv. 14,19 The morphological size of CNV lesions was reported to be larger in older patients. Some hypothesized that the pathophysiological features of mcnv differ in old patients. Natural History of Myopic Choroidal Neovascularization Without Treatment Myopic CNV shows a slight female predominance of 67%; it may show a possible relationship between estrogen and the expression of mcnv. 19 Myopic CNV has a younger presenting age of less than 50 years. 19 Concerning the natural progression of mcnv, studies on the natural history of CNV have conflicting results. 15,16,28Y33 Some studies showed favorable outcome with observation alone, 15 whereas the majority showed a poor prognosis. The natural history of 55 highly myopic eyes with Fuch s spot was followed up for 36Y180 months. 34 In 63% of eyes, VA stabilized or improved without treatment during the follow-up. A limitation of the study was that 23% of the eyes did not show angiographic evidence of CNV. Avila et al 15 followed up 70 eyes with mcnv for a mean of 3.4 years, and 96% of the CNV regressed or remained stable. In contrast, Tabandeh et al 29 reported the natural outcome of 22 patients with mcnv aged 50 years or older; 73% had a final VA of 20/200 or worse during a 4-year period of follow-up. Secretan et al 28 followed up the natural history of 50 eyes with extrafoveal (11%) or juxtafoveal (89%) CNVs associated with pathological myopia. By 5 years of follow-up, all lesions extended to subfoveal, and the mean VA was 20/160. Yoshida et al 32 conducted a study looking into the long-term outcome of 27 eyes with a minimum follow-up of 10 years. At 10 years, 93.3% of the eyes had a VA of 20/200 or worse. This study confirms poor long-term prognosis of mcnv without treatment. Several studies have provided clue into the prognostic factors determining visual outcome in mcnv. 31,33,35 Hayashi et al 33 demonstrated that younger patients, smaller CNV size, and better initial VA were related to better visual outcomes. In another retrospective review of 76 eyes with mcnv by Yoshida et al, young age is also shown to be a good predictive factor. Seventy-three eyes were divided into 2 groups for analysis: older than 40 years and younger than 40 years. For the older age group, there was a significant worsening of logmar during the follow-up period of 3 years. Kojima et al 35 reported that chorioretinal atrophy was the main culprit for visual loss in mcnv; regression analysis showed older age and larger CNV size were factors associated with the chorioretinal atrophy. To conclude, active intervention should be implemented for patients with mcnv because the natural course of mcnv by observation is unsatisfactory with poor visual outcomes. Management of Choroidal Neovascularization in Pathological Myopia Myopic CNV carries poor natural history with progression loss of vision experienced in a large proportion of patients. Certain procedures including thermal laser photocoagulation, 36 PDTwith visudyne, 37 transpupillary thermotherapy, submacular surgery, and combined treatments have been introduced. The use of intravitreal antiyvascular endothelial growth factor (anti- VEGF) has brought the treatment of CNV, including mcnv, into a new era. * 2014 Asia Pacific Academy of Ophthalmology 95

3 Ho et al Asia-Pacific Journal of Ophthalmology & Volume 3, Number 2, March/April 2014 Direct Thermal Laser Photocoagulation Laser treatment was adopted for juxtafoveal and extrafoveal mcnv for many years, with limited benefit. 28,38Y41 Jalkh et al, 38 in a study of 19 eyes treated with laser photocoagulation for extrafoveal choroidal new vessels, found that laser caused regression of choroidal new vessels, leaving a dry, atrophic photocoagulation scar. However, the laser scars showed spontaneous progressive enlargement and worsened VA in 68% of eyes. Steidl and Pruett 39 in another study showed that laser photocoagulation for mcnv lead to complete closure of myopic choroidal new vessels but VA deterioration was observed in all the studied eyes at the end of the follow-up. Secretan et al 28 in a study of the natural progression of mcnv found that laser photocoagulation could have beneficial effect in the treatment of the disease in 2 years but the benefit was not shown at 5 years. Ruiz-Moreno and Montero 42 in a retrospective series of 23 eyes experiencing juxtafoveal CNV treated with laser photocoagulation showed that laser photocoagulation can improve best corrected VA (BCVA) initially between 2 and 24 months. The improvement fades with time and is no longer significant after the third year. Photocoagulation scar expansion was described by Brancato et al 43 ; 97% of cases was found to have scar expansion in the first year after laser treatment, with a mean increase of 103% in size. The expansion of laser scar could be responsible for the visual loss. To conclude, laser photocoagulation, once considered as the only treatment, 15,28,38Y41 is of limited benefit in mcnv. 38 It is not considered as a primary or alternative treatment in subfoveal or juxtafoveal lesions. Surgical Treatment of Choroidal Neovascularization Surgical treatments have been evaluated before PDT treatment and intravitreal anti-vegf. Surgical treatments included submacular surgery for CNV, macular translocation surgery, limited macular translocation (LMT) and macular translocation with 360-degree retinotomy (MT360). Submacular surgery has been evaluated for mcnv in several studies with differing outcomes. 44Y49 These were small case series and had conflicting results. Bottoni et al 47 reported 45% of cases with 2 lines of improvement after CNV removal in 16 months of follow-up. Similarly, Uemura et al 47 reported 65% with stable VA or visual gain after removal of subfoveal mcnv. However, similar improvement was not observed in another case series by Ruiz-Moreno and de la Vega. 49 Two techniques for macular translocation have been described: the limited macular translocation and MT360. These techniques were reported in the last decade with controversial results. 50Y53 Limited macular translocation has the advantage of being less invasive compared with MT360. Glacet-Bernard et al, 50 Hamelin et al, 51 and Ichibe et al 54 reported favorable results in small series of patients who underwent LMT. However, Fujii et al 55 in a similar study design revealed less favorable result. This technique is technically demanding, and at the same time, CNV recurrences and progressive atrophy could limit the visual prognosis. 55 Macular translocation with 360-degree retinotomy is technically more demanding than LMT. The fovea is more likely to be translocated to a healthier area, which reduces the risk for CNV recurrence. Surgical steps were well described by Fujikado et al. 52,56 Simultaneous or sequential muscle surgeries are performed to counter-rotate the globe to avoid postoperative diplopia. 52 Fujikado et al 52 reported the result of 11 patients who underwent this procedure; 6-month follow-up showed good result, with 64% of the eyes having a final VA of 20/50 or better. Yamada et al 53 reported good results of 5 eyes with mcnv treated with MT360. They proposed that MT360 could be considered for selected cases of mcnv with foveal fibrosis or high activity of CNV in which the sole treatment by PDT or anti-vegf may not be enough. However, complications after this high-risk procedure include retinal detachment, proliferative vitreoretinopathy, postoperative diplopia, recurrent CNV, severe hypotony, and foveal atrophy. 57 Photodynamic Therapy With Verteporfin Lipoproteins are recognized as major blood carriers of many hydrophobic prophyrins including photosensitizers in the PDT. The selectivity and efficacy of PDT is the result of preferential binding of verteporfin to CNV endothelial low-density lipoprotein receptors. 58 In contrast to laser photocoagulation, PDT causes nonselective necrotic damage to the area where laser is applied. Photodynamic therapy is useful in treating subfoveal CNV because it can spare the damage to the neurosensory retina, retinal pigment epithelium, and optic nerve. 59,60 The basis of PDT is the initiation of photochemistry at target sites. The 2 main steps include the intravenous injection of photosensitizer and subsequent light irradiation at a specific wavelength that is appropriate for absorption by the sensitizer. 61 Diode laser activation generates reactive oxygen species, which occlude abnormal CNV with selective choriocapillary endothelial damage. 59 The Verteporfin in Photodynamic Therapy (VIP) study of patients with subfoveal CNV caused by pathological myopia reported that PDT with verteporfin stabilize VA for 1 year. 19 At 1 year, 72% of the verteporfin-treated patients compared with 44% of the placebo-treated patients lost fewer than 8 letters. Among them, 32% of the PDT-treated group versus 15% of the placebo treatment group improved at least 5 letters. Eighty-six percent of the verteporfin-treated patients compared with 67% of the placebo-treated patients lost fewer than 15 letters. The visual outcome after PDT was significantly better than placebo at 3 and 12 months, but 57% of eyes still had persistent leakage at 12 months. However, the long-term efficacy was not statistically significant according to a 2-year report. 37 Despite the gain of 3 or more lines in 12% of the treated eyes, 26% lost 3 or more lines in a 2-year period. The primary outcome of the 2-year report was the proportion of eyes with fewer than 8 letters of VA loss at the 24-month examination. Thirty-six percent of verteporfintreated patients versus 51% of placebo-treated patients lost at least 8 letters (P = 0.11). Although the primary outcome was not statistically significantly better for the PDT group at 2 years, the distribution of change in VA at the 24-month examination was in favor of the PDT group. A larger proportion of the treatment group gained at least 5 letters than the placebo-treated group (40% vs 13%) as well as improvement in at least 15 letters (12% vs 0%) in the 2-year period. Patients enrolled in the 24-month examination of the VIP trial and met the criteria for inclusion of the VIP extension at 3-month follow-up visits for an additional 36 months, up to a total of 60 months. The results of the first 12 months of this extension study showed that verteporfin-treated patients with subfoveal CNV maintained stable VA from 24 to 36 months after therapy was initiated. Patient with vision improvement maintained this improved vision, and few patients required treatment during the extension. 62 The extended study suggested a beneficial effect of PDT in the long term * 2014 Asia Pacific Academy of Ophthalmology

4 Asia-Pacific Journal of Ophthalmology & Volume 3, Number 2, March/April 2014 CNV Secondary to Pathological Myopia Many other studies reported favorable outcomes for PDT in the treatment of mcnv. 63Y71 In a 24-month follow-up study for verteporfin PDT treatment, Lam et al 66 showed that 63.6% of the eyes had stable or improved BCVA at 24 months and 27.3% of them had a moderate gain in vision (improved by Q3 lines). The visual results were comparable with that of the VIP study, but the average accumulative PDT treatments required in 12 and 24 months were 1.7 and 2.3, respectively, which are significantly less than 3.4 and 5.1 treatment in VIP study. The study showed that younger age group had more favorable visual outcome than older counterparts. The mean logmar BCVA of the younger age group at 24 months was 0.41, which was significantly better than the older age group with Pece et al, 67 in a follow-up study of 31 months of 62 eyes, found improvement by more than 1 snellen lines in 13% of patients and stabilization of vision in 55% of patients receiving PDT in mcnv. In this study, younger age of younger than 55 years was a good prognostic factor of visual outcome. Similarly, Ruiz-Moreno et al, 68 through a 4-year follow-up of PDT-treated mcnv, showed that 46% of eyes had visual improvement and 26% maintained stable VA. Coutinho et al 72 showed similar promising result by PDT treatment throughout a 5-year follow-up period. Throughout the 5-year follow-up period, the mean change in BCVA of 43 eyes experiencing mcnv improved to 0.70 logmar from 0.78 logmar. Final BCVA was improved in 53.5% of the eyes, and remained stable in 11.6% of the eyes. A certain proportion of patients (20.9%) were registered to experience moderate loss of vision 3 or more lines at 5 years. In fact, younger age and a better initial VA were the only related predictive factors for the final VA outcome. 72 Many other case series studies reported similar results across ethnicity, 65Y67,73Y75 showing VA gain in the first 6 to 12 months, which may not be maintained in the long term. Photodynamic therapy treatment brings favorable outcome regardless of the site of mcnv; several studies with inclusion of juxtafoveal CNV secondary to pathological myopia showed similar improvement of VA by PDT treatment. 68,76,77 Virgili et al 69 in a series of 100 eyes of nonsubfoveal CNV revealed good visual outcome using PDT as treatment. During the firstyear follow-up, 20% to 25% reached visual gain of at least 3 lines, whereas only a small proportion (5%Y10%) experienced visual loss in the first year. From the current evidence, PDT treatment is better than observation in mcnv in the short term of up to 2 years. The long-term results of PDT treatment alone in mcnv is not well established; there are only a few studies with a follow-up of up to 5 years. 68,78,79 Giansanti et al 79 reported a large series of 43 patients receiving PDT as treatment for mcnv. The mean number of PDT applications was 4.2. In the first 2 years, the mean number of PDT application was 3.5. The VA did not change much after 1 year but tended to be worse at 2 years with borderline significance. The drop in VA was even more obvious from 3 years onward. The author observed a phenomenon showing that VA tended to improve earlier in those with worse vision to present with but progressively deteriorate with time from 2 years and beyond. The progressive deterioration could be caused by chorioretinal atrophy formation, as chorioretinal atrophy was observed in 83% of the patients at the 5-year follow-up visit. Hayashi et al 78 reported that BCVA in eyes with subfoveal CNV decreased significantly at 4 years after PDT compared with the BCVA at baseline. In contrast to a series of Giansanti et al, Ruiz-Moreno et al 68 and Coutinho et al 72 reported VA stabilization in 72% and 65% of the cases, respectively. Despite the contradicting observations, it is obvious that a certain proportion of mcnv eye developed chorioretinal atrophy after PDT application. Photodynamic therapy is known to be associated with decreased potential in multifocal electroretinogram after application. 80 It is reported that PDT could cause chorioretinal atrophy in eyes with polypoidal choroidal vasculopathy. 81 The damage to the retina by PDT in highly myopic eyes with thinner retina and choroid may be worse and cause more profound chorioretinal atrophy. The occurrence of chorioretinal atrophy could be the main reason hindering repeated PDT applications in mcnv. Hayashi et al 78 reported that the incidence of chorioretinal atrophy was more frequent in PDT-treated eyes than in untreated ones at 1-year follow-up. They also reported that the size of atrophy was significantly larger in PDT-treated patients than in untreated ones. Krebs et al 65 and Parodi et al 82 reported retinal pigment epithelial atrophy being observed in 40% and 54% after PDT application, respectively. Krebs et al did not find any relationship between the number of retreatments and the incidence of retinal atrophy. So far, no evidence can confidently conclude that the chorioretinal atrophy is directly related to PDT application. Chorioretinal atrophy developed in a majority of patients in the long-term natural history of mcnv. Hayashi et al 78 reported a 10-year follow-up of mcnv; chorioretinal atrophy developed in 74.1% of the eyes at 3 years and up to 96.3% at 5 years after the onset of CNV. 83 Whether PDT application could alter this natural progress or worsen the atrophy process is not yet known. To date, evidence regarding the longterm outcome by sole treatment of PDT in mcnv is still lacking; future trials are suggested to solve the puzzle. Treatment of Myopic Choroidal Neovascularization With Antiangiogenic Drugs Use of Bevacizumab Systemic infusion of bevacizumab was reported in 2005 by Michels et al 84 with enrollment of 9 patients experiencing ARMDrelated CNV. Treatment was given by infusion of bevacizumab (5 mg/kg), without severe systemic adverse events identified. All cases showed angiographic reduction or absence of leakage from CNV. At the same time, Nguyen et al 85 showed beneficial results of systemic bevacizumab in the treatment of mcnv. A few case series showed improvement in functional and anatomical outcome in mcnv after intravitreal injection of bevacizumb in short follow-up periods. 86Y88 Yamamoto et al 86 showed good visual outcome in 11 cases of classic CNV secondary to pathological myopia after a single injection of 1.25-mg bevacizumab with 1-month follow-up. The improvement was certain irrespective of previous treatment by PDT. Sakaguchi et al 87 reported the off-label use of intravitreal 1-mg bevacizumab in subfoveal CNV of 8 cases, showing promising result in shortterm follow-up. Similar result was reported by Laud et al 88 in the off-label use of bevacizumab in the treatment of mcnv. The effectiveness of intravitreal bevacizumab was compared with PDT treatment. Parodi et al 89 performed a prospective randomized controlled trial (RCT) of 54 patients divided into 3 groups receiving PDT, laser therapy, or intravitreal bevacizumab treatment. Bevacizumab 1.25 mg was given at baseline, and retreatment was performed if persistent intraretinal or subretinal fluid was found. The mean BCVA in the PDT group decreased from 0.52 logmar at baseline to 0.72 logmar at 2-year. In contrast, the bevacizumab group provided good visual outcome with the BCVA increasing from 0.6 logmar at baseline to 0.42 logmar at 2 years. This study showed best functional outcome by bevacizumab injection compared with laser therapy and PDT * 2014 Asia Pacific Academy of Ophthalmology 97

5 Ho et al Asia-Pacific Journal of Ophthalmology & Volume 3, Number 2, March/April 2014 in groups of patient mainly experiencing subfoveal mcnv. 89 Many prospective and retrospective studies evaluating the efficacy of intravitreal bevacizumab injection have been published in recent years. 90Y95 Among these studies, some showed that the acquired visual gain by bevacizumab injection in 1 year was not maintained at 2 years 96,97 To summarize, current evidence for bevacizumab use in mcnv mainly came from prospective or retrospective case series. Larger randomized trials or multicentric clinical trials are necessary to validate the long-term efficacy of bevacizumab use in mcnv. Treatment With Ranibizumab Intravitreal ranbizumab has been used off-label in the treatment of mcnv and shows good short-term result. Silva et al 98 was the first to report the short-term result of a single intravitreal ranibizumab (IVR) injection followed with pro re nata (PRN) injection. Twenty-six eyes were recruited, with 42% receiving previous PDT treatment; at 1 month, 31% of the eyes had an improvement in VA of 3 or more lines. The promising result was maintained to 3 months, where 65% of the eyes and all eyes had stabilized or improved by 1 or more lines. These short-term results echo the findings in case series using intravitreal bevacizumab. 87,93,99,100 Silva et al 101 subsequently performed a multicenter series of 34 eyes with follow-up period of 1 year in IVR treatment in mcnv. The 1-year result was promising; 65% of the cases had improvement of at least 1 line, with a mean of 3.6 treatments given. The 2 cohorts included cases with previous PDT treatments; history of previous PDT treatments does not seem to affect the final visual outcome. Effect of IVR with 3-month loading dose was evaluated in a study conducted by Lai et al. 102 Lai et al recruited 16 patients with mcnv who is treatment naive into the study and who subsequently received 3 monthly loading dose of IVR; additional doses were performed in persistent or recurrent cases. The mean improvement at 12 months was 3.0 lines; 75% of the eyes had improvement of at least 2 lines [Early Treatment Diabetic Retinopathy Study (ETDRS)]. Of the eyes, 93.8% had angiographic closure at 3 months. This study showed that IVR with 3 initial loading doses seemed to be an effective primary treatment for mcnv. The additional beneficial effect by a loading dose of IVR needs to be evaluated; good visual outcomes were reported by a few case series with a single injection of ranibizumab followed by PRN injection. 103Y106 Mones et al 103 showed good visual outcome in a 1-year follow-up of 23 cases receiving a single injection of ranibizumab followed by as-needed basis. The mean injection was 1.52 during 12 months, and 69% of the patient improved with at least 1 line. Although the proportion of patients with moderate-to-good visual outcome (gaining at least 2 lines) were superior in the study of Lai et al 102 with 3 loading doses, whether the difference is statistically significant requires a larger randomized study to tell. Lalloum et al, 104 Calvo-Gonzalez et al, 105 and Vadala et al 106 showed similar results in their prospective studies with a single nonloading dose and a significant BCVA improvement from baseline. Regarding the long-term result of mcnv by ranibizumab treatment, Franqueira et al 107 performed a study with 3 years of follow-up. The study included 40 eyes, of which 15 had previous PDT. Twenty-five percent gained more than 3 lines (15 letters ETDRS) at 12 months, 30% at 24 months and 35% at 36 months. Mean visual improvement was from 55.4 ETDRS letters at baseline to 59.7 letters at 12 months. The mean number of injections was 4.1 at the first year. These studies proved IVR to be an effective and safe therapeutic procedure to treat mcnv, with a high proportion of patients gaining or stabilizing BCVA at a 3-year follow-up. The REPAIR study was a phase II, prospective multicenter study for IVR treatment outcome for mcnv. 108 The 12-month result showed a mean change in BCVA score on the ETDRS letters by 13.8 letters. Overall, 86% of the patients showed improvement in mean BCVA score, with 24 patients (36.9%) achieving a BCVA gain of 15 or more letters in the study eye. Anatomically, the mean reduction in central macular thickness was 135 Hm from baseline at 12 months after initiation of treatment, which is quite significant. This is a large prospective up-to-date study of the treatment of mcnv, guiding treatment by primary ranibizumab. However, a control arm is lacking in the REPAIR study. 108 This limitation could be better addressed in current ongoing trials such as the phase III RADIANCE study comparing ranibizumab and verteporfin-pdt (clinicaltrials.gov identifier NCT ). Treatment Outcome of Juxtafoveal Myopic Choroidal Neovascularization The natural history of juxtafoveal CNV is not well-known. 109 Majority of studies targeting on treatments, namely, PDT, bevacizumab, or ranibizumab included both patients with subfoveal mcnv and patients with juxtafoveal mcnv. In study by Parodi et al, 89 with a certain proportion of juxtafoveal CNV included, the outcome by PDT treatment seems to be suboptimal. The mean best-corrected VA in the PDT group decreased from 0.52 log- MAR at baseline to 0.72 logmar at the end of the study. In contrast, treatment by intravitreal bevacizumab was successful in stabilizing VA in juxtafoveal CNV. Currently, no particular treatment has a special indication for nonsubfoveal CNV. Comparison Between Photodynamic Therapy and Antiangiogenics Currently, 2 randomized studies are available, which directly compared the effect of PDT with antiangiogenics. In the study of Parodi et al, patients were randomized into 3 arms (laser therapy, intravitreal bevacizumab, or PDT) and followed up for 2 years. Intravitreal bevacizumab (IVB) was shown to have the best outcome among the 3 groups with mean best-corrected VA increasing from 0.6 logmar at baseline to 0.42 logmar at the end of study. Ruiz-Moreno et al, 110 in a randomized design of 55 eyes divided into receiving a 3-month induction of either ranibizumab or PDT treatment, directly compared these 2 modalities. At 12 months, the average number of letters read in the PDT group was 52.5 versus 64.2 in the IVB group. The ratio of eyes gaining 10 or more letters in the IVB group was 52% versus 14% in the PDT group. This suggested IVB to be a useful procedure to treat mcnv as a first-line therapy. In addition, PDT is suspected to increase the risk of chorioretinal atrophy in eyes with mcnv and reduce visual improvement. 61 Similar results of the superiority of antiangiogenics compared with PDT were shown in a few prospective or retrospective case series. 61,64,111 Yoon et al in a retrospective series of 142 eyes compared treatment with anti-vegf (ranibizumab or bevacizumab) and treatment by PDT or a combination therapy of both. The anti-vegf group was shown to have the best outcome at 1 year. In the anti-vegf group, 39.7% of patients improved from baseline by 15 or more letters compared with 17.7% in the PDT group and 21.4% in the combination group. Hayashi et al 61 in a prospective series of 44 eyes proved that 98 * 2014 Asia Pacific Academy of Ophthalmology

6 Asia-Pacific Journal of Ophthalmology & Volume 3, Number 2, March/April 2014 CNV Secondary to Pathological Myopia TABLE 1. Comparative Studies of PDT and Anti-VEGF Therapy for mcnv Study Year Study Design Follow-up, mo Arms of Intervention (No. of Cases) Baseline Median VA Final Median VA Parodi et al RCT 24 IVB (1+ PRN) (18) 0.6 logmar 0.42 logmar Significant improvement PDT (18) 0.52 logmar 0.72 logmar Decreased VA Ruiz-Moreno 2011 RCT 12 IVB(3+ PRN) (27) V 64.2 letters 52% gained 10 letters et al 110 PDT (28) V 52.8 letters 14% gained 10 letters Hayashi et al Non-RCT 12 IVB (1+ PRN) (43) 0.68 logmar 0.45 logmar 48.8% gained 90.2 logmar PDT (42) 0.61 logmar 0.54 logmar 27.3% gained 90.2 logmar Baba et al Non-RCT 24 IVB (1+ PRN) (12) 0.77 logmar 0.78 logmar No significant change PDT (12) 0.75 logmar 0.50 logmar Significant improvement Yoon et al Non-RCT 12 IVB (1+ PRN) (63) 0.57 logmar 0.34 logmar Significant improvement PDT (51) 0.54 logmar 0.6 logmar Deteriorated IVB (1+ PRN) logmar 0.49 logmar Better, but not significant PDT (28) El Matri et al Non-RCT 12 IVB (1+ PRN) (40) 0.9 logmar 0.6 logmar 70% gained 93 lines PDT (40) 0.88 logmar 0.9 logmar 22.5% gained 93 lines 2012 Non-RCT Not available IVB (18) 20/80 20/80 P = 0.32, no change Dethorey et al 121 PDT (27) 20/200 20/63 P = 0.04, significant improvement Matsuo et al Non-RCT 6 IVB (1+ PRN) (22) j0.29 logmar P = 0.021, significant change PDT (20) j0.10 logmar No significant change Result IVB-treated patients had significantly better BCVA than PDTtreated and control eyes at 1 year. Ikuno et al 64 showed better outcome in BCVA values at 12 and 24 months in the IVB group than in the PDT group. The study was performed in women 50 years or older with a 24-month follow-up; the difference, however, was not statistically significant. To conclude, despite the presence of 2 randomized trials comparing intravitreal anti-vegf and PDT as well as numerous prospective or retrospective series (Table 1), optimal treatment for mcnv is still unclear today because of a lack of large-scale randomized clinical trials. Treatment effect by bevacizumab or ranibizumab was found to be similar. Gharbiya et al 112 performed a randomized trial with 32 patients divided into 1:1 ratio receiving either IVR or IVB. Asneeded injections were given after the first injection in either group. No statistical difference was found in ETDRS BCVA, foveal center thickness, or fluorescein angiographic findings at a 6-month period between the 2 drugs. Predictive Factors Associated With Treatment Outcomes Younger patients with mcnv have been described to have better VA outcome when comparing with older patients regardless of treatment procedures. Young age is a good prognostic factor determining the visual outcome in mcnv. 31Y33 Photodynamic therapy treatment was reported to have diminished effect in older patients. 63,64,113 Young patients were found to attain better visual outcome after bevacizumab injection 90,94 Ruiz-Moreno et al 90 and Gharbiya et al 94 found better VA outcomes in patients younger than 50 years. Again, similar result was found in cross-sectional studies looking into the predictive factors for mcnv outcome. Age younger than 50 years was found to acquire better final vision than the older group. A cutoff at 50 years old may be arbitrary, and the natural progression of myopic maculopathy may also be responsible for the lower VA outcomes in older patients. So far, no evidence supports that previous PDT treatment would alter the outcome by subsequent anti-vegf or limit visual recovery. Ruiz-Moreno et al 90 found that previous PDT treatment did not have a significant difference in visual outcome comparing with treatment-naive eyes, which was subsequently treated with bevacizumab in a series of 107 eyes. Similar results were supported by Silva et al, 101 and Franqueira et al, 107 both showing no significant difference in visual outcome, in patients treated with and without previous PDT. Another area of debate would be the necessity of a loading dose of anti-vegf; Lai et al 102 reported good recovery of VA in eyes receiving 3 loading doses of anti-vegf. Seventyfive percent of the eyes had improvement of 2 or more lines, with angiographic closure occurring at 3 months in 93.8% of the eyes. Three non-rct studies 114Y117 compared 3 monthly injections and a single injection at initial stage. The 3 studies with 1-year follow-up observed a total of 63 eyes with 3 monthly injections followed by PRN treatment and 139 eyes with a single injection followed by PRN. 118 Eyes in the 3+ PRN group gained more vision than eyes in the 1+ PRN group. However, the early visual benefit seems to shrink over time. The 2 dosing regimens did not show significant difference in reducing central retinal thickness at months 3, 6, and 12. Overall, eyes in the 3+ PRN group received 1.37 more injections than the 1+ PRN group in 1-year period. To conclude, treatment regimens with a loading dose of 3 injections may show a better early visual gain; the intermediate-term to long-term results were apparently the same with initial one single injection followed by PRN injections. CONCLUSIONS AND FUTURE PERSPECTIVES Current evidence from small-scale RCT and prospective studies supports antiangiogenic agents including bevacizumab and ranibizumab as primary treatments for mcnv. To date, the best treatment for mcnv is still unknown. The benefit of 3 loading doses of intravitreal anti-vegf and the additional benefit of a combination therapy still need to be defined. Promising investigations in guiding treatment in mcnv are still * 2014 Asia Pacific Academy of Ophthalmology 99

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9 Ho et al Asia-Pacific Journal of Ophthalmology & Volume 3, Number 2, March/April Schnurrbusch UE, Jochmann C, Wiedemann P, et al. Quantitative assessment of the long-term effect of photodynamic therapy in patients with pathologic myopia. Graefes Arch Clin Exp Ophthalmol. 2005;243:829Y Pece A, Vadala M, Isola V, et al. Photodynamic therapy with verteporfin for juxtafoveal choroidal neovascularization in pathologic myopia: a long-term follow-up study. Am J Ophthalmol. 2007;143:449Y Lam DS, Liu DT, Fan DS, et al. Photodynamic therapy with verteporfin for juxtafoveal choroidal neovascularization secondary to pathologic myopia-1-year results of a prospective series. Eye (Lond). 2005;19:834Y Hayashi K, Ohno-Matsui K, Shimada N, et al. Long-term results of photodynamic therapy for choroidal neovascularization in Japanese patients with pathologic myopia. Am J Ophthalmol. 2011;151:137Y147.e Giansanti F, Virgili G, Donati MC, et al. 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