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Choroidal Neovascularization Secondary to Diseases Other than Age-Related Macular Degeneration
Introduction
Choroidal neovascularization (CNV) is an ocular pathology represented by newly formed blood vessels extending above the Bruch’s membrane. Classically, CNV was histopathologically divided into subretinal pigment epithelium (RPE, Gass type 1) and subretinal (Gass type 2). Later, neovascularization with intraretinal origin (type 3, also called retinal angiomatous proliferation) was proposed as another subtype of CNV. While CNV is a principal feature of wet age-related macular degeneration (AMD), it is not exclusive to AMD and can develop secondary to many other disorders. This chapter deals with CNV secondary to diseases other than AMD and reviews its epidemiology, pathogenesis, and treatment options.
Pathologic Myopia
Epidemiology
Pathologic myopia refers to degenerative changes in the sclera, choroid, and RPE induced by abnormal elongation of axial length in eyes with high myopia. Myopic CNV (mCNV) develops in approximately 10% of patients with high myopia and is a major cause of vision loss associated with high myopia.
High myopia is the major cause of CNV other than AMD. A study showed that 60% of cases of CNV developing in patients aged younger than 50 years are due to pathologic myopia. Considering that the prevalence of high myopia is increasing worldwide, especially in Asian countries, the number of patients with mCNV is also likely to increase in the near future.
Pathogenesis
The exact pathogenesis of mCNV is unknown, but elongation of axial length and the changes associated with it should be the principal cause. Disruption of the stretched Bruch’s membrane is suggested as one of the mechanisms. In fact, the presence of lacquer cracks, which represent breaks in the Bruch’s membrane, is associated with the development of mCNV. Another hypothesis proposes the change in chorioidal circulation due to the stretching of the Bruch’s membrane and choroid as a cause of mCNV. Inflammatory mechanisms may also be involved in the process. Several genetic variants contribute to the susceptibility to mCNV.
Diagnosis
mCNV is typically type 2 CNV and shows small grayish tissue on funduscopy and slit-lamp biomicroscopy ( Fig. 8.1 ). Fluorescein angiography (FA) generally shows classic CNV pattern, characterized by well circumscribed hyperfluorescence in the early phase and active leakage in the late phase. Subretinal hemorrhage is commonly seen, but prominent pigment epithelium detachment is rare. mCNV is observed as an area of high-to-moderate reflectivity above the RPE on optical coherence tomography (OCT). In chronic cases, a fibrous scar develops and shows a more pigmented and solid appearance on fundus examinations. These lesions often accompany chorioretinal atrophy, which may induce further vision loss ( Fig. 8.2 ). At this chronic stage, hyperfluorescent staining of the fibrous tissue with minimal leakage is observed on FA. A well circumscribed, hyperreflective material is observed beneath the retina on OCT.
It is important to differentiate mCNV from simple hemorrhage without the presence of mCNV. The prognosis of this type of hemorrhage is good and does not require specific treatment. Fluorescein and indocyanine-green angiography is useful to confirm the presence of CNV in these cases.
Another condition that should be differentiated from mCNV is inflammatory CNV, which often affects myopic patients. Slit lamp biomicroscopy and angiography can help detect signs of inflammation. In addition, the distinction between mCNV and AMD is not straightforward. mCNV lesions are typically smaller compared to those in AMD–CNV; however, some cases of mCNV show large lesions accompanying massive exudative changes. In fact, mCNV generally develops in patients in the age range of 50–70 years, indicating that age is a significant factor for the development of this disease. Although CNV is typically diagnosed on the basis of spherical equivalent values of −6.0 to −8.0 D and/or an axial length of 26.5 mm, it should be noted that these criteria are arbitrary.
Treatment
Visual prognosis in mCNV is poor unless treated. It is reported that visual acuity declines to <20/200 in 89% of the cases in 5 years and in 96% of the cases in 10 years.
Laser Photocoagulation
The first widely applied treatment for mCNV, particularly for extrafoveal lesions, was laser photocoagulation. However, this treatment is associated with a high recurrence rate and more importantly, it induces chorioretinal atrophy, which impairs long-term visual outcome. A systematic review concluded that there is no clear benefit of this treatment.
Surgical Treatment
Surgical removal of mCNV with or without macular translocation was tried before the era of photodynamic therapy (PDT) and antivascular endothelial growth factor (anti-VEGF) therapy. This treatment can be beneficial for selected patients. However, it is associated with severe complications such as retinal detachment, proliferative vitreoretinopathy, macular hole, hemorrhage, atrophic scar formation, and rotational diplopia. Nowadays, surgical treatment is rarely performed because of the difficulty of the procedure and the aforementioned complications.
Photodynamic Therapy
In the 2000s, PDT was approved for the treatment of mCNV. A randomized trial showed that PDT was effective in stabilizing vision in patients with mCNV ; although the effect did not persist over a 24-month follow-up. The long-term visual outcome in patients receiving PDT seems better than that in untreated patients. However, in spite of the fact that PDT is theoretically a selective treatment of CNV, there is a concern about its adverse effects on the choroid. In addition, the choroid in myopic eyes is already atrophic and would be highly susceptible to any kind of injury. The development of chorioretinal atrophy after the treatment may eventually cause visual impairment. Because of all these factors, this treatment is not commonly performed now.
Anti-VEGF Therapy
Intravitreal injections of anti-VEGF agents such as bevacizumab and ranibizumab have become the first-line treatments for mCNV. Recently, a randomized trial, RADIANCE, showed ranibizumab to be superior to PDT in the treatment of mCNV. The definition of high myopia in the study was spherical equivalence greater than −6.0 D or axial length longer than 26 mm. The study consisted of three arms: two loading injections followed by visual-acuity-based retreatment and the remaining followed by OCT-based retreatment and PDT. The former two groups showed 13.8 and 14.4 letters visual gain at month 12 with medians of 4.0 and 2.0 injections, respectively. Meanwhile, the visual gain in PDT arm was 9.3 letters. Overall, the treatment halts disease progression in mCNV with fewer injections compared to those required for AMD-associated CNV. The effect of bevacizumab seems to be almost the same as that of ranibizumab, in spite of the limited evidence. The efficacy of another anti-VEGF agent, aflibercept, has also been proved in a randomized MYRROR study. In this study, the definition of high myopia was spherical equivalence greater than −6.0 D or axial length longer than 26.5 mm. Patients were randomized to aflibercept or sham group, and the aflibercept group received one injection followed by as-needed treatment. The control group also received aflibercept after week 24. While the aflibercept arm gained 12.1 letters of vision at week 24, the sham group lost 2.0 letters. Although the sham group started aflibercept, thereafter, the final gain of vision was 3.9 letters at week 48 compared to 13.5 letters in aflibercept group. Median numbers of injections were 3.0 in both groups. The result showed the efficacy of aflibercept on mCNV and also highlighted the importance of early detection and intervention for the disease.
Thus, there’s no doubt about the efficacy of anti-VEGF therapy; however, the optimal treatment protocol is still controversial. Even the abovementioned representative trials use different inclusion and retreatment criteria as well as different drugs. There is no randomized study comparing one, two, and three injections for the loading phase or different retreatment criteria. Nevertheless, current recommendation is one initial injection followed by as-needed retreatment. More intensive treatment can be applied case by case. Although the long-term visual outcome might be impaired by the development of chorioretinal atrophy in some cases, anti-VEGF therapy is still superior to PDT.
Inflammatory Diseases
Epidemiology
Inflammatory diseases comprise the second most common cause of CNV in young patients. The incidence of CNV is reported to be approximately 2–5% in patients with posterior uveitis/panuveitis. Multiple evanescent white dot syndrome (MEWDS), punctate inner choroidopathy (PIC), multifocal choroiditis (MFC, also known as MFC with panuveitis), and serpiginous choroiditis are the common causes. The incidence of CNV is relatively high in PIC ( Figs. 8.3 and 8.4 ) and Vogt–Koyanagi–Harada disease. Presumed ocular histoplasmosis syndrome (POHS) is another example of an inflammatory disorder that may cause CNV.
Pathogenesis
The exact pathogenesis of inflammation-associated CNV is not known. Upregulation of proangiogenic factors such as VEGF in case of active inflammation would play a significant role in the etiology. Ischemia due to vasculitis can also induce VEGF upregulation. In case of infectious uveitis such as POHS or toxoplasmosis, immune reaction to the pathogen is likely to be involved in the breakdown of the Bruch’s membrane. It should be remembered that even AMD is partly considered an immunopathological disease.
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