Abstract
While choroidal neovascularization (CNV) is typically associated with age-related macular degeneration (AMD), other ocular pathologies such as pathologic myopia, inflammatory diseases, angioid streaks, central serous chorioretinopathy, and trauma may also cause CNV. CNV lesions in these diseases are typically smaller and associated with better prognoses than those in AMD; however, these diseases affect younger individuals and can be a significant burden for the patients and the society. Although there is little randomized trial-based evidence due to the small number of patients with each individual disease, antivascular endothelial growth factor therapy is generally accepted as the first-choice treatment. Additional treatments such as steroid or photodynamic therapy may be beneficial in some cases. An appropriate diagnosis is essential for the optimal management of these conditions. This chapter deals with CNV secondary to diseases other than AMD and reviews its epidemiology, pathogenesis, and treatment options.
Keywords
Myopic CNV, Inflammatory CNV, Pseudoxanthoma elasticum, Central serous chorioretinopathy, Traumatic CNV, Idiopathic CNV, Photodynamic therapy, Anti-VEGF therapy
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.
Diagnosis
CNV caused by inflammatory diseases is generally Gass type 2 and shows a classic FA pattern. Some abnormalities such as anterior chamber/vitreous cells, vitreous opacity, retinal vasculitis, or chorioretinal atrophy can generally be seen in the affected eye or the fellow eye. It is important to examine both eyes even if the fellow eye is asymptomatic ( Fig. 8.4 ). In addition to the routine examinations, late-phase indocyanine-green angiography reveals multiple hypofluorescent spots in PIC ( Fig. 8.4 ) and MEWDS and is of diagnostic value. Abnormal findings such as drusen-like material, vitreous cells, choroidal hyperreflectivity, and chorioretinal atrophy can be seen on OCT. Presence of photopsia or enlargement of the blind spot can help in the diagnosis, since these symptoms are relatively rare in CNV associated with other diseases. Serum examinations to evaluate the titers of antitoxoplasma or antihistoplasma antibodies may help in confirming the diagnosis of toxoplasmosis or POHS, respectively.
Treatment
There is little information on visual prognosis in inflammatory CNV. About half of the patients with posterior uveitis retain visual acuity >20/40 unless they have CNV. However, once CNV develops, severe vision loss can occur.
Laser, Surgery, and PDT
Laser photocoagulation and surgical treatment are applied, and they can be beneficial in some cases; however, it should be noted that these procedures will cause further inflammation. Hence, these techniques are rarely used nowadays. The effect of PDT is also uncertain, although there are some favorable reports regarding the effects of PDT on POHS, PIC, and toxoplasmosis.
Immunosuppression
Considering that inflammation is the primary cause of CNV in this group of patients, immunosuppressive agents can be a reasonable treatment option. Sub-Tenon’s injection of corticosteroids is often used despite the lack of established evidence. Oral administration of steroid or immunosuppressive drugs is also an option. Steroids can be administered independently or in combination with other treatments such as PDT. A randomized study showed that PDT combined with systemic steroids can achieve better visual outcomes with fewer treatment sessions than PDT alone, although the sample size was relatively small. However, it should be noted that the use of corticosteroids increases the incidence of cataract and glaucoma. In case of oral administration, systemic complications should also be monitored.
Antibiotics
In case of active retinochoroiditis with infectious disease, antibiotics or antiviral agents should be considered.
Anti-VEGF Therapy
The use of anti-VEGF agents is becoming increasingly common in inflammatory CNV as well as in other diseases. Considering that inflammatory CNV typically is Gass type 2 and shows a classic pattern on FA, and that anti-VEGF therapy is superior to PDT for predominantly classic CNV in AMD (Brown et al . ), it should be a reasonable choice for the treatment of inflammatory CNV despite the lack of robust evidence. One injection followed by disease activity-based retreatment is generally applied but the retreatment criteria vary among the studies and the optimal treatment strategy is yet to be established. Another problem is that anti-VEGF agents for inflammatory CNV are off-label in most countries.
Angioid Streaks
Epidemiology
Angioid streaks (AS) are named after the characteristic fundus appearance—vessel-like irregular lines radiating from the optic disc ( Fig. 8.5 ). This disease can be an ocular presentation of systemic diseases such as pseudoxanthoma elasticum (PXE), Paget disease, beta-thalassemia, sickle-cell hemoglobinopathy, or congenital dyserythropoietic anemia. Among them, PXE is the most common cause of AS, while other causes are very rare. Conversely, patients with PXE almost always have AS. AS-associated CNV was found in 5% of patients younger than 50 years. Patients with AS can be asymptomatic unless they develop CNV; however, development of CNV and the subsequent vision loss has the strongest impact on the quality of life in patients with PXE.
Pathogenesis
Abnormal deposition of calcium and the consequent breaks in the Bruch’s membrane is the primary feature of the disease. The abnormal calcification of connective tissue in PXE is induced by mutations in ABCC6 . This calcification may affect the skin and cardiovascular system as well. The characteristic vessel-like appearance is the consequence of the cracks in the Bruch’s membrane. These cracks can develop spontaneously or as a result of trauma. Sometimes, even a minor trauma may cause the crack. These cracks impair the physiologic barrier to CNV development.
Diagnosis
In patients with a typical fundus appearance, it is not difficult to make a diagnosis of AS ( Fig. 8.5 ). Patients with PXE also show characteristic findings referred to as Peau d’orange; this change precedes the development of AS. Reticular pigmentary changes of the macula, deposition of crystalline bodies on the midperipheral retina, and the presence of optic disc drusen are common in PXE and may help in the diagnosis. In case of uncertain fundus appearance, a skin biopsy would be useful. CNV in PXE is usually Gass type 2 and shows a classic appearance on FA. Occasionally, occult CNV and polypoidal choroidal vasculopathy may develop, with better prognosis compared to that of classic CNV. The lesions are bilateral in many cases. On spectral domain OCT, calcification of the Bruch’s membrane is visible as increased reflectivity. Disruption and undulation of the Bruch’s membrane are other OCT features frequently seen in patients with PXE. Fundus autofluorescence is also useful to depict RPE atrophy associated with the AS.
Accumulation of subretinal fluid, independent of CNV, sometimes occurs in patients with PXE, resembling the appearance of chronic central serous chorioretinopathy (CSC). The fluid accumulation is probably due to impairment of the RPE pump function and/or increased hydrophobicity of the Bruch’s membrane. It is important to confirm the presence of CNV before the treatment, since such fluid accumulation does not respond to anti-VEGF therapy.
Breaks in the Bruch’s membrane can be induced by high myopia or ocular trauma, but they can be easily differentiated from AS on their appearance and the patient’s clinical history. In high myopia, the breaks are called lacquer cracks and present a thinner, linear appearance at the posterior pole, not radiating from the optic disc. Traumatic rupture of the Bruch’s membrane generally shows a larger single lesion.
Treatment
Visual prognosis of AS-associated CNV is poor unless treated. Laser photocoagulation, surgery, and PDT were used for treatment, but they can induce further impairment of the Bruch’s membrane/choroid, and the result was not satisfactory. In spite of the off-label use in many countries and the requirement for continuous multiple injections in some cases, anti-VEGF therapy became popular since around 2006, and more recent studies confirmed the efficacy up to 4 years of follow-up. The required number of injections were 6.5–8.4 in about 28 months. Current evidence indicates that anti-VEGF therapy is the best option to treat CNV secondary to AS.
Of note, PXE is the most common cause of AS and is sometimes associated with cardiovascular disease. Hence, interdisciplinary cooperation is important for the management of patients with AS/PXE.
Central Serous Chorioretinopathy
Epidemiology
CNV may be associated with chronic CSC. Diagnosis of CSC-associated CNV is not easy for several reasons discussed later. Although CNV had been supposed to be a rare complication of CSC, partly due to the diagnostic difficulty, recent reports employing multimodal imaging techniques suggested that 9–15% of patients with chronic CSC develop CNV.
Pathogenesis
Again, in this case, the exact mechanism is unknown. Choroidal congestion and choroidal vascular hyperpermeability are considered the main pathologies of CSC. Decompensation of the RPE may develop secondary to fluid accumulation in the choroid. The chronic damage to RPE and Bruch’s membrane can be a cause of CNV. Alternatively, decreased blood flow and hypoperfusion in the choriocapillaris has been reported in CNV, and such ischemic stimuli might be another mechanism of CNV development.
Recently, a new clinical entity—pachychoroid pigment epitheliopathy—has been proposed as a forme fruste of CSC. The authors argue that impairment of the RPE can occur under the above choroidal abnormality even without the symptoms of CSC. CNV may occur in patients with pachychoroid pigment epitheliopathy and is called pachychoroid neovasculopathy. It is yet to be established whether the condition should be dealt with as a clinical entity distinct from CSC-associated CNV.
Diagnosis
Diagnosis of CSC-associated CNV is sometimes challenging. In the first place, distinguishing between CSC and AMD is not always easy. Small type I CNV may be overlooked and diagnosed as CSC. In addition, certain cases of AMD show choroidal vascular hyperpermeability, which is a common feature of CSC. This is particularly true for a subtype of AMD called polypoidal choroidal vasculopathy. It is not clear whether these cases of CNV develop independently or secondary to known or asymptomatic CSC. In such instances, the abovementioned pachychoroid neovasculopathy would be a matter of discussion.
CSC-associated CNV can be Gass type 1 or 2 and can show classic, occult, or PCV patterns ( Fig. 8.6 ). It is not always easy to determine the presence of CNV because funduscopic and angiographic findings are already modified by preexisting CSC and the CNV is generally less active. En face OCT and OCT angiography would be helpful for the identification of CNV in these cases.
