I. Introduction
CNV Wenzhou Medical University Affiliated Optometry Hospital Cataract Specialist Zhao Yun’e as the killer, culprit complication of vision loss in myopic patients. There are various definitions of myopic CNV, often described as pathological myopia (PM) subretinal neovascularization, PM Fuchs’ spots or Forster-Fuchs’ spots or PM discoid degeneration. Although myopic CNV was previously thought to occur only in PM, it is increasingly recognized that myopic CNV can occur in any degree of myopia, even in those without typical myopic fundus changes.
Therefore, in clinical practice, CNV can be attributed to myopia based on refractive status, with the exception of other diseases associated with CNV. Several effective therapeutic measures have been developed for myopic CNV, especially anti-VEGF therapy, and this review reviews the pathogenesis, epidemiological features, natural course, and treatment progress of myopic CNV.
II. Pathogenesis of myopic CNV
There are several hypotheses about the pathogenesis of myopic CNV: the mechanical hypothesis is based on the idea that the longer the eye axis, the greater the mechanical pull on the retina, which leads to an imbalance of pro-angiogenic and anti-angiogenic factors and eventually CNV; the appearance of lacquer cracks is the cause of myopic CNV, which supports the mechanical hypothesis.
The genetic degeneration hypothesis suggests that myopic refractive errors are genetically determined, and some studies have shown that single nucleotide polymorphisms in several genes (e.g., pigment epithelium-derived factor) are associated with the development and progression of myopic CNV.
The hemodynamic hypothesis, on the other hand, suggests that the development of myopic CNV is associated with alterations in the choroidal circulation, such as delayed choroidal filling and choroidal thinning. However, myopic CNV can occur even if the choroidal circulation is preserved and posterior scleral chylomalacia is mild, implying that the role of hemodynamics in the development of myopic CNV is not significant.
III. Diagnosis of myopic CNV
Typical myopic CNV is small, flat, gray membrane-like under slit lamp, with pigmentation visible at the edges if it is chronic or recurrent. Symptoms may include decreased visual acuity, central dark spots, or distorted vision.
The standard tests for the diagnosis of myopic CNV include fundus examination, fluoroscopic angiography (FA), optical coherence tomography (OCT), FA, OCT combined with fundus color photography and clinical examination are the basic tests for the diagnosis of myopic CNV. FA can detect the presence, type, size and activity of myopic CNV and help to exclude other diseases. Most myopic CNVs are typical CNVs on FA, with well-defined hyperfluorescence in the early stages and fluorescein leakage in the late stages.
On OCT, myopic CNV is a continuous hyperreflective signal over the pigment epithelium (sometimes called type 2 CNV) with a small amount of subretinal fluid. Fundus autofluorescence can show accumulation of lipofuscin in the retinal pigment epithelium and can be used as part of the basic diagnostic measures of myopic CNV, follow-up examinations, and to help evaluate and diagnose the progression of myopic CNV and the accompanying map-like atrophy.
The differential diagnosis of myopic CNV is detailed in Table 1. myopic tractional maculopathy, anterior retinal membrane, vitreous macular tractional, and myopic total/laminar macular fissure are PM complications that must be clarified by OCT/FA. In particular, retinal hemorrhage, macular exudative changes with dome-like macula or posterior scleral chylomalacia in the presence of paint crack formation must be clarified and identified by OCT/FA (Figure 1). If there is more hemorrhage, indocyanine green contrast (ICGA) can be performed to clarify the presence or absence of lacrimation and CNV.
Table 1 Coexisting lesions of myopic CNV and their differential diagnosis
Other degenerative changes associated with myopia
Differential diagnosis of CNV
Myopic detrusor macular lesion (macular cleft)
Neovascular AMD
Macular cleft
Myopic macular hemorrhage due to lacquer cleavage formation
Retinal fissure/detachment
Punctate inner choroidal lesions (often with myopia)
Dome like macula
Multifocal chorioretinitis
Grapevine
Idiopathic CNV
Atrophic changes (patchy atrophy, vascular patterned changes, diffuse atrophy)
Idiopathic CNV is myopic CNV
Figure 1 Differential diagnosis of myopic CNV: A and B hemorrhage due to lacquer-like cracks; C for dome-like macula with placoid retinal detachment, and D and E for macular fluid due to grapheme.
OCT alone cannot distinguish retinal hemorrhage pathology due to myopic CNV or lacquer crack, and retinal hemorrhage caused by lacquer crack without CNV does not require anti-VEGF therapy. In addition, myopic CNV needs to be differentiated from multifocal chorioretinitis, punctate inner chorioretinopathy, and age-related macular degeneration (AMD). Keep in mind that myopic CNV is different from AMD-CNV, especially in younger patients. Myopic CNV is mainly a typical type 2 CNV, smaller than AMD-CNV, with less subretinal fluid accumulation, and often without vitreous warts at the onset.
IV. Epidemiology of myopic CNV
A recent systematic survey showed that the prevalence of PM is 1% to 3%, while CNV occurs in 5% to 11% of PM. Although several surveys have provided epidemiological features of myopic CNV, their conclusions need to be treated with caution given their different definitions of myopia, PM, and myopic CNV. In addition further investigation studies on different populations are still needed.
V. The natural course of myopic CNV
The characteristics of PM such as lacquer crackles, patchy atrophy, choroidal capillary/choroidal thinning, and CNV in the contralateral eye all imply a higher risk of developing myopic CNV. A retrospective study of 73 PM patients found that 17 (23%) developed binocular myopic CNV. in addition, another study found that when one eye developed myopic CNV, 35% of the contralateral eye developed myopic CNV within 8 years.
Figure 2 shows the 3 stages of myopic CNV, all of which are associated with vision loss; initially it causes direct damage to photoreceptor cells, resulting in vision loss; as the CNV atrophies and regresses, a fibrous pigment film, sometimes called a Fuchs’ or Forster-Fuchs’ spot, may form; and eventually the degenerating CNV atrophy will develop around it, which as a major complication of late myopic CNV can cause long-term/permanent low vision. It should also be noted that CNV can be present even in the absence of degenerative changes or leopard-like fundus.
Figure 2 Active myopic CNV, A is color fundus photograph, B is FA, C is OCT image; D is fibrous pigment scar (Fuchs’ spot) and E is choroidal retinal atrophy after fading of myopic CNV.
Factors associated with poor visual prognosis: neovascular OCT localized subcentrally (rather than paracentrically or extracentrally), age >40 years, CNV lesions >400 μm, and low baseline best-corrected visual acuity (BCVA). Long-term studies have demonstrated significant visual acuity loss in all patients, and a 10-year observation of 25 patients with myopic CNV found that 89% had visual acuity <0.1 at 5 years and 96% had visual acuity <0.1 at 10 years.
VI. Treatment of myopic CNV
Laser photocoagulation, vetiporfin photodynamic therapy (vPDT), surgical resection or macular transposition were used for CNV treatment before the introduction of vitreous cavity injection of anti-VEGF, and the following treatment strategies for myopic CNV will be summarized.
VII. Laser photocoagulation
Despite limited evidence, laser photocoagulation is still widely used to treat myopic CNV outside the central macular sulcus. laser scar enlargement and atrophy can cause retinal tissue damage, and laser treatment cannot achieve long-term visual acuity maintenance and has a high recurrence rate.
vPDT
vPDT is a recognized and proven measure available for the treatment of subcentral recess myopic CNV. In the 12-month treatment in the Vetiporfin Photodynamic Therapy Study (VIP trial), vPDT was better tolerated and more effective compared with placebo. vPDT essentially achieved lesion stabilization but no significant improvement in visual acuity, and 12 short-term studies (<12 months) and 6 long-term studies (≥36 months) also supported this finding.
Although it is possible that the trials were under-identified due to differences in testing criteria, the 2-year follow-up results of the VIP study found that visual acuity did not differ from placebo after vPDT treatment. vPDT’s main limitation is that some patients develop long-term/permanent choroidal retinal atrophy resulting in vision loss. Because atrophy is also an important feature of myopic CNV, further studies are needed to determine whether vPDT accelerates atrophy or whether atrophy is simply a natural regression of the disease.
VIII. Anti-VEGF therapy
Ranibizumab
Currently, ranibizumab is the only legally available anti-VEGF agent for the treatment of myopic CNV, and clinical phase II (REPAIR) and clinical phase III (RADIANCE) studies have supported the effectiveness of ranibizumab for the treatment of myopic CNV. In addition, in several small, retrospective, slightly lower level of evidence studies confirming the efficacy and safety of raizumab for the treatment of myopic CNV for 12 months, the improvement in BCVA can be maintained up to 36 months post-treatment.
The 12-month-long RAIDANCE trial compared vitreous cavity injection of ranibizumab with vPDT to assess the safety and efficacy of two ranibizumab on-demand (PRN) regimens. On-demand treatment was given according to visual acuity stability criteria (no treatment if there was no change in BCVA compared to the previous two months) and disease activity criteria (no treatment if there was no interretinal or subretinal fluid or vision loss due to PM-related active leakage).
The results of the RAIDANCE study showed that both PRN dosing regimens significantly improved BCVA (10.5, 10.6) compared with vPDT (2.2 letters improvement) at 3 months. at 12 months, BCVA improved by 13.8 letters (4 injections) and 14.4 letters (2 injections) for the razumab PRN regimen, respectively, and in the vPDT treatment group 9.3 letters (vPDT treatment can be changed to ranibizumab treatment at 3 months after vPDT treatment, with a mean of 2 injections at 9 months).
In other words, even with prior vPDT treatment, BCVA could still improve after treatment with ranibizumab, presumably because early application of ranibizumab for myopic CNV could prevent irreversible retinal damage or vPDT treatment could cause retinal damage, because patients in the vPDT group did not improve their BCVA as much as starting ranibizumab treatment even with later ranibizumab treatment The study group had a higher number of retinal structures. The effect of structural changes in the retina was significant in all study groups, with a significant reduction in the proportion of CNV leakage and interretinal edema.
RADIANCE suggested that other quality of life related parameters such as Visual Function Questionnaire-25 (VFQ-25), visual acuity, mental health, and independent self-care scores were also significantly improved with razumab treatment compared to vPDT and were sustained up to 12 months, data shared by K Ohno-Matsui et al. at the 2013 ARVO Annual Meeting.
RAIDANCE also confirmed the results of REPAIR (65 people) study. the REPAIRE trial gave patients a single injection of ranibizumab followed by monthly dosing according to the PRN regimen, and after 12 months of treatment, the BCVA improved by 13.8 letters after a mean of 3 injections. As shown by the data of RADIANCE, REPAIR, the safety of razumab myopic CNV treatment was similar to AMD-CNV, retinal vein occlusion, and diabetic macular edema, and no other safety issues were identified.
IX. More importantly, no complications were found for retinal detachment, which is a complication of greater concern for high myopia.
1, bevacizumab (Avastin)
Bevacizumab is not approved for intraocular use, and the evidence for its safety and effectiveness is more limited. There are currently more questions about its safety, particularly the increased risk of cardiovascular events (stroke, etc.) and the risk of infection from re-dispensing for vitreous cavity injections compared to ranibizumab. Nevertheless, many ophthalmologists also use bevacizumab, and there are several retrospective/prospective studies confirming visual acuity improvements of 4 to 18 letters at 12 months.
However, these studies have small sample sizes and low levels of evidence. In addition, when comparing the results of different studies it is important to note that there are differences in design and study populations between studies. Recent data showing that initial visual acuity improvements are not maintained for 5 years and are accompanied by retinal thinning (V Sarao’s presentation at the 2013 ARVO Annual Meeting) suggests that just like vPDT, it is not known whether chorioretinal atrophy is associated with treatment.
A study of 92 patients (68 bevacizumab, 24 ranibizumab) treated with a 4-year follow-up found better long-term results, with 9.4 letters of visual acuity improvement at 12 months and 7 letters at 4 months (mean of 4.9 injections). The variable response of myopic CNV to anti-VEGF may be due to the size of the CNV at baseline and the polymorphism of the VEGF gene. Therefore, further studies with large samples are needed to clarify the long-term effects of anti-VEGF therapy and the prognostic correlates of treatment outcomes.
There are no large prospective, randomized clinical trials of bevacizumab for myopic CNV, so the optimal dose to be administered cannot be determined. A study comparing the effects of bevacizumab and ranibizumab in the treatment of myopic CNV showed that both improved BCVA comparably, but the number of injections of bevacizumab was significantly higher than that of ranibizumab (4.7:2.6). Therefore, further studies are needed to investigate the advantages and disadvantages of the two and whether bevacizumab treatment increases the burden on patients.
2. Abciximab
Regarding the safety of abciximab for myopic CNV, a phase III, multicenter, randomized, blank-controlled, 12-month MYRROR trial is underway with 121 Asian patients treated with abciximab for PRN according to visual acuity and anatomical criteria. Data at a median of 6 months showed a 12.1 letter improvement in BCVA in the abciximab-treated group compared to a 2 letter decrease in the blank control group, and recent 12-month observations suggest that improvements in BCVA can be sustained up to 12 months.
X. Treatment recommendations for myopic CNV
Based on the above evidence, we propose a recommended protocol for the diagnosis and treatment of clinical myopic CNV, as shown in Figure 3.
Figure 3 Myopic CNV treatment route: * Ranibizumab is the only legal anti-VEGF agent available for myopic CNV treatment so far; # Initiate a single injection; & Detect disease activity by clinical examination, OCT or FA, and further examination if there are signs of vision loss, blurred vision, distortion or lesion activity.
XI. Evaluation and diagnosis
Patients with myopia with vision loss, central dark spot and/or visual distortion should be referred to a retinal specialist and should be referred early and promptly given that active myopic CNV can cause severe vision loss. Some myopic CNV will spontaneously atrophy back leading to choroidal retinal atrophy, thus missing the opportunity to treat active CNV.
Slit lamp examination and FA/OCT imaging can diagnose myopic CNV and differentiate it from other causes of CNV and other diseases of vision loss associated with PM, and individual cases require ICGA for definitive diagnosis.
XII. Initial treatment plan
Given the effectiveness of anti-VEGF therapy compared to other measures, a single intravitreal injection of anti-VEGF therapy is recommended once myopic CNV is diagnosed. Although other agents have been evaluated in trials, ranibizumab is currently the only anti-VEGF agent legally available for the treatment of myopic CNV. Although small studies have initiated PRN therapy after 3 loading doses for myopic CNV, RADIANCE and REPAIR support the initiation of PRN after a single injection.
Anti-VEGF therapy is also available for myopic CNV that has relapsed after prior vPDT treatment, and the results of the RADIANCE study suggest that BCVA may still improve after switching therapeutic measures. Because CNV-related chorioretinal atrophy can develop and affect central vision, extracentral CNV should also be treated immediately. First-line anti-VEGF therapy may also be given at this time, but vPDT may be considered if contraindicated or if anti-VEGF agents are not available.
XIII. Follow up
After initiation of anti-VEGF injections, monthly examinations should be performed for the first 2 months, and FA and/or OCT examinations should be performed as appropriate to assess disease activity, and fundus autofluorescence may also provide favorable information for assessing CNV progression. Disease activity is defined as decreased visual acuity, new or progressive visual symptoms (visual distortion) or signs of CNV activity (interretinal, subretinal fluid or active leakage) on FA/OCT.
The REPAIR and RADIANCE studies, which used OCT/FA leakage and/or BCVA decline with CNV activity as criteria for PRN, have demonstrated the validity of the reinjection criteria for this regimen. Another re-treatment criterion was visual stability, and again the RADIANCE results showed this criterion to be equally valid, but with similar results as the standard visual acuity based on morphologic structural changes, except that more treatments were required.
If the lesion is stable after the first injection, it will be reviewed monthly for the next two months and every three months for the first year. For some people quarterly reviews may result in under-treatment, so it is important to stress to the patient the importance of seeing a retinal specialist for any loss of vision and reappearance of visual distortion. If there are signs of lesion activity, more frequent testing and review should be performed, and after 1 year, the periodicity of review may be negotiated with the patient, but any loss of vision must be reviewed.
During the follow-up period, the treating physician should also check for the presence of other lesions such as myopic tractional maculopathy (macular splitting), macular fissures, retinal fissures, and foraminal retinal detachment, which can also cause vision loss and require additional therapeutic interventions. This is especially true for myopic retractive maculopathy, as the CNV membrane can contract acutely after anti-VEGF treatment to aggravate existing retinal splits. PM patients with myopic CNV should be aware of the symptoms of this type of disease.
It is clear that myopic CNV requires very few anti-VEGF injections compared to AMD-CNV, and the results of RADIANCE suggest that the PRN regimen, in which patients receive an average of 3.5 injections in the first 12 months, actually does not require injections in 60% of patients who are reinjected between 6 and 12 months.
XIV. Conclusion
Anti-VEGF significantly improves visual acuity and quality of life in patients with myopic CNV. In particular, there is now a large body of favorable evidence confirming the effectiveness of ranibizumab in the treatment of myopic CNV, although other drugs such as abciximab have been studied. Because this myopic CNV diagnosis and treatment protocol is based on existing knowledge and experience, further studies are needed to determine the optimal treatment measures, frequency of administration, timing of injections and follow-up.