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Review Article

Anti-Vascular Endothelial Growth Factor Therapy for Myopic Choroidal Neovascularization

Ng, Danny S.C. MPH, FRCSEd*; Lai, Timothy Y.Y. MD, FRCSEd, FRCOphth*, †; Cheung, Chui Ming Gemmy FRCOphth‡, §; Ohno-Matsui, Kyoko MD, PhD

Author Information
Asia-Pacific Journal of Ophthalmology: November 2017 - Volume 6 - Issue 6 - p 554-560
doi: 10.22608/APO.2017308
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Abstract

Myopia has become an increasingly important public health issue worldwide and Asians in urban populations are well known for having some of the highest prevalence of myopia in the world.1 Mild to moderate myopia often does not result in major sight-threatening sequelae.2 However, evidence from epidemiology studies suggests that eyes with high myopia are at greater risk of developing pathologic myopia.3,4 Epidemiological studies have used various cut-offs to define pathologic myopia, such as refractive error of less than -6.0 diopters (D) or less than -8.0 D and axial length greater than 26.5 mm.5 Others have considered defining pathologic myopia by the appearance of characteristic structural deformities in the posterior segment that could lead to visual impairment; nonetheless, there is yet to be a standardized definition of pathologic myopia based on substantial scientific evidence.5 Choroidal neovascularization (CNV) is one of the most visual threatening complications in eyes with pathologic myopia, which has been estimated to develop in 4% to 11% of eyes.6,7 A predominance of myopic CNV in females (67%) may reflect estrogen receptor expression in the CNV, along with the external influence of estrogen.8,9 Approximately 30% of patients with myopic CNV will be affected in the fellow eye within 8 years after disease onset in the first eye.10 It is also one of the most common causes of CNV in young individuals, accounting for 62% of CNV in patients younger than 50 years in 1 study.11 Most of these patients are employed as part of the workforce and therefore treatment to prevent visual loss in patients with myopic CNV is of particular importance from a socioeconomic standpoint.7 This review aims to summarize the clinical features, diagnosis, and use of anti-vascular endothelial growth factor (VEGF) therapy for the treatment of myopic CNV.

PATHOGENESIS AND RISK FACTORS OF MYOPIC CNV

Several theories and risk factors have been proposed for the pathogenesis of myopic CNV.12 The mechanical theory posits that the formation of myopic CNV, predisposed by lacquer crack formation, is due to progressive and excessive axial elongation of the eyeball causing mechanical stretch and release of proangiogenic factors. It has been shown that patchy atrophy and lacquer crack formation are important risk factors for the development of myopic CNV.10 The heredodegenerative theory proposes genetic factors leading to myopia with progression to myopic CNV. The hemodynamic theory suggests that myopic CNV develops from impaired choroidal circulation with choroidal thinning associated with choroidal ischemia. However, myopic CNV has occurred in eyes with shallow posterior staphyloma and relatively well preserved circulation, which implies a less significant role of hemodynamic factors in the pathogenesis of myopic CNV.12

CLINICAL FEATURES OF MYOPIC CNV

Patients who develop myopic CNV may experience metamorphopsia, scotoma, or a decrease in central vision. On fundus examination, myopic CNV typically appears as a small, flat, greyish subretinal membrane situated between the neurosensory retina and retinal pigment epithelium (Fig. 1).13,14 In contrast to CNV secondary to age-related macular degeneration (AMD), the amount of subretinal fluid, exudate, or hemorrhage caused by myopic CNV is typically much smaller. Distinguishing myopic CNV on fundoscopic examination can often be difficult in the presence of fundus tessellation, pigment hyperplasia, and patchy chorioretinal atrophy (CRA) because these coexisting features in pathologic myopia may camouflage the appearance of small CNV and hemorrhage. The minimal amount of exudation is postulated to be due to the attenuated and reduced choroidal blood circulation in eyes with pathologic myopia.15 In older patients, however, myopic CNV might have some overlapping features with CNV secondary to neovascular AMD.16 These eyes often have larger lesions and more exudative changes and may eventually lead to the formation of disciform scars.

FIGURE 1.
FIGURE 1.:
The color fundus photo of an active myopic choroidal neovascularization (arrow) of the left eye which appeared as a small, roundish patch of hemorrhage at the macula. This eye had concurrent features of pathologic myopia including tessellation, diffuse chorioretinal atrophy, posterior staphyloma, and peripapillary atrophy.

DIAGNOSTIC CHARACTERISTICS ON FLUORESCEIN ANGIOGRAPHY

Over 80% of active myopic CNV have a classic pattern of leakage on fluorescein angiography (FA), with transit phase hyperfluorescence followed by minor leakage in late phases (Fig. 2).8 Late leakage can be subtle but is sometimes the only sign of myopic CNV activity. Fluorescein angiography is particularly useful to differentiate myopic CNV from simple myopic macular hemorrhage due to lacquer crack formation because the latter will not show FA leakage. In cases with thick macular hemorrhage, leakage from myopic CNV might be concealed by the overlying hemorrhage blocking fluorescence, and the underlying myopic CNV might not be seen as a distinct hyperfluorescent lesion. Fluorescein angiography is also useful for determining the location of myopic CNV in relation to the fovea and for the measurement of CNV size. Distinguishing the location and size of myopic CNV are important clues for the prognosis and response to treatment.17

FIGURE 2.
FIGURE 2.:
FA of the right eye with new onset myopic choroidal neovascularization. A, Early phase FA revealed a well demarcated hyperfluorescence with blockage corresponding to the site of adjacent hemorrhage that appeared on the fundus photo. B, The leakage intensified throughout the late FA phase, which obscured the border of the CNV. Blockage of fluorescence by blood was still evident along the temporal border of the lesion.

As most myopic CNV are type 2 lesions, FA can usually provide adequate information in the majority of cases. However, indocyanine green angiography (ICGA) can sometimes be a useful adjunctive investigation that can provide additional information in selected cases, particularly where masking from blood might obscure visualization of the CNV on FA. Macular hemorrhage secondary to lacquer crack formation without CNV can be distinguished from myopic CNV on ICGA findings (Fig. 3). Abnormal vasculature or a hyperfluorescence on ICGA may indicate the presence of CNV when information from FA is limited due to masking by blood. No abnormalities of the choroidal vasculature will be seen on ICGA in submacular hemorrhage without CNV.18 Additionally, ICGA can be used to detect and characterize lacquer cracks, which appear as linear hypofluorescent streaks in late phase ICGA.19

FIGURE 3.
FIGURE 3.:
Simple myopic macular hemorrhage without choroidal neovascularization in the right eye. A, Fundus photo showed a patch of hemorrhage (arrow) at the macula. B, Late phase fluorescein angiography saw blockage (arrow) without obvious leakage. C, Indocyanine green angiography revealed a lacquer crack (arrow) without the appearance of abnormal neovascular network.

DIAGNOSTIC CHARACTERISTICS ON OPTICAL COHERENCE TOMOGRAPHY

On spectral domain optical coherence tomography (SD-OCT), a hyperreflective dome-shaped elevation above the retinal pigment epithelium (RPE) band may represent the myopic CNV, which is typically a type 2 CNV (Fig. 4). The contour of the RPE monolayer in eyes with myopic CNV can also be elevated. Spectral domain OCT can also reveal exudative features of myopic CNV, including intra- or subretinal fluid. Because of the typically minimal amount of exudation associated with myopic CNV, the presence of subretinal or intraretinal fluid on SD-OCT may not be a sensitive and reliable imaging marker for new onset or recurrent myopic CNV.20-23 Leveziel et al22 compared the use of FA with SD-OCT in 90 eyes and reported that the diagnosis of myopic CNV was made by FA alone in 60% of cases, by SD-OCT alone in 28.9%, and by both SD-OCT and FA in 11.1% of cases. Using FA as the reference standard, another study showed that at baseline, FA and SD-OCT findings agreed only in 76% of eyes with subfoveal myopic CNV with a low kappa value of 0.23-24 Hence, FA is still generally considered the current gold standard for diagnosing active myopic CNV. Spectral domain OCT can provide complementary imaging information and performing both imaging modalities will enhance the diagnostic accuracy of myopic CNV. Furthermore, SD-OCT is particularly useful in detecting other causes of visual impairment related to myopic traction maculopathy, including foveoschisis and macular hole.12 Because of its noninvasive nature, SD-OCT is indicated in monitoring for treatment response and prognostic factors related to vision outcomes.

FIGURE 4.
FIGURE 4.:
SD-OCT scans of myopic CNV. A, Intra- and subretinal fluid (arrow) associated with an active myopic CNV. B, After treatment with intravitreal anti-VEGF injection, there was complete resolution of both intra- and subretinal fluid. The lesion became more compact and the boundary between the lesion and retina became apparent. The anterior border of the CNV lesion also demonstrated increased hyperreflectivity (arrow).

Optical coherence tomography angiography (OCTA) is a noninvasive imaging technique that generates 3-dimensional microvascular angiograms in vivo without the need for injection of exogenous dyes.25 It enables rapid, noninvasive visualization of the retinal and choroidal vasculature by mapping erythrocyte movement over time and by comparing sequential OCT B-scans at a given cross-section (Fig. 5).26,27 Miyata et al28 reported that OCTA was able to detect over 90% of treatment-naive myopic CNV and it may help in distinguishing submacular hemorrhage secondary to lacquer crack formation without CNV. Further studies will establish the reliability of OCTA as a potential technology that may replace FA in the future as a noninvasive exam for myopic CNV diagnosis, follow-up, and monitoring of treatment response.28-30

FIGURE 5.
FIGURE 5.:
OCTA of a 54-year-old patient with myopic CNV of the left eye. A, B-scan OCT shows the green segmentation lines were aligned with the dome-shaped hyperreflective lesion (arrow) of the CNV anteriorly and the concave RPE posteriorly. B, En face view of OCTA revealed the myopic CNV network (arrow) in the corresponding outer retina layer.

DIFFERENTIAL DIAGNOSIS OF MYOPIC CNV

Occasionally, it is challenging to determine whether an eye has submacular hemorrhage related to lacquer crack or whether an underlying myopic CNV is masked by blood. It is recommended that these eyes be monitored closely, and repeat FA should be considered when the blood resolves. Multimodal imaging is important to help differentiate myopic CNV from other conditions. Punctate inner choriodopathy (PIC) is an inflammatory disorder of unknown etiology and CNV can also develop, resulting in vision loss. As PIC often occurs in individuals with moderate or high myopia, the main differentiating factor lies in the characteristic small, white-yellow lesions located at the level of the RPE.31 Multifocal choroiditis (MFC) is another inflammatory disorder of unknown origin similar to PIC. The presence of multiple lesions, panuveitis, and bilaterality can help distinguish MFC from myopic CNV. As the clinical and FA features are very similar to myopic CNV, suggestive SD-OCT findings of MFC not present in myopic CNV have been proposed, including the presence of sub-RPE material, choroidal hyperreflectivity below the lesions, and overlying vitreous cells.32 In older patients aged 50 years or more, neovascular AMD can also be a differential diagnosis. Idiopathic CNV is a diagnosis of exclusion and occurs more commonly in younger patients.33 These patients usually have unilateral CNV, and they seem to have a low risk of developing CNV in their fellow eyes.33 Although idiopathic CNV can occur in patients with high myopia, by definition, any CNV in an eye of more than -6 D would be considered myopic CNV rather than idiopathic CNV.11

NATURAL HISTORY OF MYOPIC CNV

Natural history studies revealed that the long-term visual prognosis of myopic subfoveal CNV without treatment was generally poor.13,14,16,34-37 Yoshida et al38 evaluated the natural history of patients with minimum follow-up of 10 years. It was found that 70.4% of eyes had a baseline visual acuity better than 20/200, whereas 55.5% of eyes still retained visual acuity of better than 20/200 after 3 years. However, 96.3% of eyes had visual acuity of 20/200 or worse within 5 to 10 years after the onset of myopic CNV.38 Choroidal neovascularization in pathological myopia tends to have a progressive enlargement with fibrotic evolution, and chorioretinal atrophy subsequently develops around the myopic CNV, which results in poor long-term visual outcome.16,38

Several studies have identified prognostic factors in patients with myopic CNV.16,37,39 Patients older than 40 years at onset, larger CNV size, and poor presenting visual acuity had worse visual prognosis. Knowledge of the natural history of myopic CNV is important for clinicians to decide on active treatment for myopic CNV that may improve the prognosis of patients.

RANDOMIZED CONTROLLED TRIALS OF ANTI-VEGF TREATMENT FOR MYOPIC CNV

Over the past few decades, a number of treatment options, including thermal laser photocoagulation, verteporfin photodynamic therapy (vPDT), and submacular surgery, for myopic CNV have been proposed with variable success rates.40 A number of retrospective and prospective uncontrolled case series have also reported improvement in visual acuity with the use of bevacizumab and ranibizumab for myopic CNV.41-44 Subsequently, 2 large clinical trials, the RADIANCE and MYRROR studies, also reported favorable outcomes and intravitreal anti-VEGF therapy is now the current first-line therapy for treatment of myopic CNV (Table 1).41,45,46 Favorable results from these studies have also led to approval of ranibizumab and aflibercept by various health authorities for the treatment of myopic CNV.

TABLE 1
TABLE 1:
Summary of Phase 3, Multicenter, Randomized Controlled Trials on Intravitreal Anti-VEGF for Treating CNV Secondary to Pathologic Myopia

RADIANCE is a phase 3, randomized, double-masked, multicenter study that compared the efficacy and safety of 2 different dosing regimens of ranibizumab (guided by visual stabilization or disease activity) compared with vPDT for the treatment of myopic CNV.45 Patients in the ranibizumab arms were treated with a pro re nata (PRN) approach after a single (disease activity group) or 2 ranibizumab injections (visual stabilization group). At the primary endpoint at 3 months, results demonstrated that both ranibizumab regimens were superior to vPDT in terms of mean best-corrected visual acuity (BCVA) change from baseline to month 3, with BCVA gains of 10.5 and 10.6 letters in the ranibizumab groups compared with 2.2 letters in the vPDT group. From month 3 to 11, eyes in the vPDT group could be treated with ranibizumab, vPDT, or both. This group of patients gained 9.3 letters by month 12 after commencing ranibizumab therapy, but the gain was lesser compared with eyes treated with ranibizumab from the outset (gains of 13.8 and 14.4 letters). This indicated that, though eyes previously treated with vPDT may still gain vision after switching to ranibizumab, the improvement may not be as good as those treated initially with ranibizumab.

The efficacy and safety of aflibercept were evaluated in a phase 3, multicenter, randomized, double-masked, sham-controlled trial known as the MYRROR study.46 Patients were randomized to a single initial 2 mg dose of intravitreal aflibercept or sham injections. Additional aflibercept injections were given in case of CNV persistence or recurrence at monthly visits through week 44. Patients in the sham group were allowed to switch to aflibercept injections at week 24. At the primary endpoint at week 24, patients in the aflibercept group gained a mean of 12.1 letters, whereas the sham group lost 2.0 letters. At week 48, patients in the sham group gained only 3.9 letters despite switching to aflibercept at week 24, whereas patients in the aflibercept group had a cumulative gain of 13.5 letters compared with baseline. Similar to the RADIANCE study, the number of intravitreal injections in this study was low. Over the study period of 48 weeks, patients received a median of 3 aflibercept injections.

More recently, the results from another large scale randomized controlled clinical trial—the BRILLIANCE study, which evaluated the use of ranibizumab versus vPDT for myopic CNV among Asian patients—were reported.47 The design of the BRILLANCE study was identical to the RADIANCE study and 457 patients with myopic CNV were randomized in a 2:2:1 ratio to ranibizumab 0.5 mg guided by visual acuity stabilization (182 patients), ranibizumab 0.5 mg by disease activity (184 patients), and vPDT (91 patients). At the primary endpoint at 3 months, it was shown that the ranibizumab groups guided by visual acuity stabilization and disease activity had gains of 9.5 and 9.8 letters at month 3, respectively, and the visual improvements were statistically superior compared with a gain of 4.5 letters in the vPDT group (both P < 0.001). At 6 months, ranibizumab guided by disease activity was statistically noninferior to ranibizumab guided by visual acuity stabilization with gains of 10.4 and 10.7 letters, respectively. At 12 months, the groups with ranibizumab guided by visual acuity stabilization and disease activity gained 12.0 and 13.1 letters, respectively, whereas eyes that received vPDT followed by switching to ranibizumab had a gain of 10.3 letters. In terms of number of ranibizumab injections, the number was low with 3.9 and 4.6 injections over 12 months for the ranibizumab groups guided by disease activity and visual acuity stabilization, respectively.

MONITORING FOR MYOPIC CNV RECURRENCE AND RETREATMENT WITH ANTI-VEGF

The RADIANCE, MYRROR, and BRILLIANCE studies all adopted a PRN treatment approach after the initial injections for retreatment. During reassessment, visual acuity, symptomatology, and SD-OCT findings are useful to determine if retreatment is needed. In cases where SD-OCT appears “dry” but is accompanied with visual loss, FA should be considered because fluorescein leakage may be a more sensitive indicator of residual activity in eyes with myopic CNV. When a treated lesion shows cessation of disease activity, the lesion generally becomes more compact. Other features suggestive of lack of activity include less internal reflectivity than the lesion surface, sharp boundary between the lesion and retina, and lack of associated intra- or subretinal fluid. When the lesion becomes active, any of these parameters may change. Figure 4 illustrates an active and an inactive CNV after intravitreal anti-VEGF therapy. Recently, subretinal hyper-reflective exudation imaged by SD-OCT in myopic CNV patients has been suggested in monitoring response to anti-VEGF agents by both qualitative (regression) and quantitative (thickness) assessments. The typical type 2 CNV in pathologic myopia grows under the RPE and penetrates the Bruch membrane to extend into the subretinal space, which may facilitate the deposition of these hyperreflective lesions into the subretinal space.47 The presence of a subretinal hyperreflective exudation on SD-OCT could help in deciding whether to perform FA and opting for retreatment. Nevertheless, multimodal imaging is necessary to distinguish it from other causes of hyperreflective subretinal lesions, such as hemorrhage and fibrosis. The subretinal hyperreflective exudation correlates to the fundus photography observation of a subtle yellowish material deposit and autofluorescence imaging showing it as an isoautofluorescent lesion.

SAFETY OF INTRAVITREAL ANTI-VEGF THERAPY FOR MYOPIC CNV

The RADIANCE, MYRROR, and BRILLIANCE studies all did not identify any new safety signals in the use of anti-VEGF agents for myopic CNV.44-46 In particular, there was no increased risk of retinal detachment, which might be a particular concern in highly myopic eyes receiving repeated intravitreal injections. Rare cases of macular detachment and macular hole formation have been reported after intravitreal bevacizumab injections.48 Progressive CRA around the CNV is the main cause of poor vision in patients with myopic CNV; however, these complications may also be part of the natural history of pathologic myopia and long-term studies are required to determine if these are sequelae of repeated anti-VEGF injections.12 A recent study by Ohno-Matsui et al49 found that eyes with previous intravitreal anti-VEGF therapy seemed to have reduced risk of Bruch membrane rupture in myopic CNV, which in turn was associated with a smaller area of macular atrophy.

PROGNOSTIC FACTORS OF ANTI-VEGF THERAPY FOR MYOPIC CNV

Baseline visual acuity, size of the CNV, location of CNV, development and progression of CRA, subfoveal choroidal thickness, and the number of recurrent episodes have been shown to be important prognostic factors of visual outcome in myopic CNV.17,44,49-52 Other factors, such as duration of symptoms, refractive error, axial length, and lens status, have been described.53 Furthermore, prior vPDT has also been suggested to limit visual prognosis.52 Progressive CRA around subfoveal myopic CNV was observed in 80% of untreated eyes and was the main cause of poor vision in patients with myopic CNV.38 A study on the longterm outcomes of intravitreal bevacizumab for myopic CNV also showed that 73% of eyes developed new or enlargement of CRA after a follow-up of at least 4 years.54

RECOMMENDATIONS FOR MANAGEMENT OF MYOPIC CNV WITH ANTI-VEGF AGENTS

Fluorescein angiography is indicated to confirm the diagnosis of myopic CNV before starting anti-VEGF treatment. Spectral domain OCT is also very useful for assessing myopic CNV and for documenting any coexisting macular changes, such as myopic traction maculopathy. Recent clinical trials, including the RADIANCE, MYRROR, and BRILLIANCE studies, all adopted a PRN treatment approach after the initial injections for retreatment. Although a 3-month loading phase is often practiced when using anti-VEGF therapy for neovascular AMD, evidence from a recent systematic review of clinical trials supports the use of a single intravitreal anti-VEGF followed by PRN dosing, suggesting that a loading phase is not always necessary in myopic CNV.55 Nonetheless, subgroup analysis from the RADIANCE study showed that eyes with larger CNV lesion area might require more anti-VEGF injections.56 Both clinical trial data and experience in real-world clinic settings have shown that anti-VEGF is highly efficacious in myopic CNV. However, after initial resolution, recurrence of myopic CNV can often occur. In a retrospective observational case series of 103 eyes with myopic CNV, recurrence was reported in 23.3% of eyes and most (72.7%) occurred within the first year of follow-up.50 Long-term visual outcomes might be limited by the development of progressive CRA even if the myopic CNV remains indolent. Future clinical trails should consider evaluating treatment that can aim to prevent or slow the progressive degenerative changes in the outer retina, RPE, choriocapillaris, and choroid associated with pathologic myopia.

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Keywords:

anti-vascular endothelial growth factor therapy; myopic choroidal neovascularization

© 2017 by Asia Pacific Academy of Ophthalmology