Medical Care
Current knowledge of molecular events in the pathogenesis of choroidal neovascularization (CNV) has allowed CNV to be targeted with very specific antiangiogenic factors. Targeting VEGF allows a two-hit strategy: antiangiogenesis and antipermeability. VEGF is 50,000 times more potent than histamine in inducing vascular permeability. An important component of decreased vision is the accumulation of subretinal fluid secondary to increased vascular permeability. [5]
The major limitation of anti-VEGF treatment is the injection burden. Most patients require multiple injections. Therefore, a number of different protocols are looking at combining photodynamic therapy (PDT), corticosteroids, and anti-VEGF drugs. [6, 7, 8, 9, 10] PDT has fallen out of favor since randomized clinical trials have shown no added benefit to anti-VEGF monotherapy. [32] Recently the angiopoietin-Tie2 pathway has been implicated in the pathogenesis of CNV. Increased levels of Angiopoietin-2 (Ang-2) have been shown to be elevated in eyes with CNV secondary to exudative AMD. Targeting Ang-2 may provide added benefits in these patients. [33]
Currently, the treatment of choice for CNV secondary to exudative AMD is intravitreal anti-VEGF therapy. A reduced biological response to both intravitreal ranibizumab and bevacizumab has been reported by several authors. [34, 35, 36, 37, 38, 39] A distinction between tachyphylaxis and drug tolerance should be made. [40] Tachyphylaxis refers to the loss of drug effectiveness following repetitive use during a short period of time. In general, drug effectiveness is restored after a short drug holiday. In contrast, drug tolerance develops slowly over time. Increasing the drug dosage or shortening the dosing interval improves its effectiveness. A drug holiday does not restore its effectiveness. [40]
Several mechanisms have been proposed to explain these phenomena. VEGF blockade may lead to an increase in other angiogenic signaling pathways as a compensatory mechanism. [41] Up-regulation of VEGF production by macrophages within CNV has also been proposed. [36] Anti-bevacizumab and anti-ranibizumab auto-antibodies have been documented in the systemic circulation of patients undergoing chronic anti-VEGF therapy for exudative AMD. These auto-antibodies may neutralize the effect of anti-VEGF agents. [36] } CNV lesion composition might change with time with more mature and therefore less VEGF sensitive vessels. [36, 41]
A retrospective case series reported that tachyphylaxis occurred in 5 of the 59 patients treated with intravitreal bevacizumab. [36] In this study, the median time to develop tachyphylaxis with intravitreal bevacizumab was 100 weeks, with a median number of 8 intravitreal injections. Another retrospective case series identified tachyphylaxis in 2% of patients being treated with ranibizumab. [34]
Several strategies, including drug holidays, increasing the drug dosage, combination therapy, and switching from one anti-VEGF drug to another anti-VEGF agent, have been advocated to counteract these phenomena. [36, 37, 39, 40] Gasperini and colleagues showed that in 81% of cases, the switch from ranibizumab to bevacizumab and vice versa was at least somewhat effective in further reducing subretinal fluid. [37]
Several other antiangiogenic compounds are currently in different stages of development. [42] These agents include genetic therapy with vectors carrying anti-angiogenics, [43] si (small interference) RNA-VEGF, various PDGF inhibitors, angiopoietin inhibitors, and combretastatin A4.
Pegaptanib sodium [11]
Pegaptanib sodium is an aptamer against VEGF165, the isoform identified with pathological angiogenesis. An aptamer is an oligonucleotide that acts like a high affinity antibody to VEGF, neutralizing it before it can contact its receptor.
Pegaptanib sodium is given as an intravitreal injection every 6 weeks.
Overall, pegaptanib sodium was able to decrease visual loss when compared to placebo in a similar fashion to that of PDT therapy with verteporfin. Only 6% of eyes were reported to have an improvement in visual acuity of three or more lines after 12 months of follow-up. Unlike therapy with verteporfin, all eyes with exudative ARMD benefited from treatment regardless of lesion composition. In addition, the trials using pegaptanib sodium included eyes with larger lesions than those eyes in the trials using verteporfin. [44]
Complications associated with the intravitreal injection of pegaptanib sodium are few but include retinal detachment and endophthalmitis.
Ranibizumab
Ranibizumab is a recombinant monoclonal antibody Fab fragment that neutralizes all active forms of VEGF-A.
Ranibizumab is delivered as a monthly intravitreal injection.
The US Food and Drug Administration approved the use of ranibizumab for the treatment of all angiographic subtypes of subfoveal neovascular ARMD.
Intravitreal ranibizumab is the first treatment that significantly improves visual acuity in up to 40% of eyes. [45] An extension study of patients who completed one of three different randomized clinical trials of ranibizumab for exudative age-related macular degeneration showed that intravitreal injections of ranibizumab were well tolerated for more than 4 years. However, less frequent follow-up led to fewer injections, which in turn led to a loss of the initial gains in visual acuity. [46] Several studies have shown that in regular clinical practice, most patients with exudative age-related macular degeneration are undertreated and as a result the visual outcomes are compromised. [47, 48, 49, 50, 51, 52] Recently the port delivery system (PDS), a refillable surgically implanted drug delivery system of ranibizumab, has been shown to reduce the treatment burden in patients with exudative age-related macular degeneration. [53] The ranibizumab PDS continuously delivers 100 mg/mL of ranibizumab into the vitreous cavity. It can be refllled repeatedly in an office setting. In a randomized clinical trial comparing the ranibizumab PDS with monthly intravitreal injections of 0.5 mg of ranibizumab in eyes with neovascular age-related macular degeneration, the ranibizumab PDS was found to be non-inferior and equivalent to monthly ranibizumab.
Although infrequent, complications associated with ranibizumab intravitreal injections include endophthalmitis and severe uveitis.
Bevacizumab
Bevacizumab is a humanized, recombinant monoclonal immunoglobulin G (IgG) antibody that binds and inhibits all VEGF isoforms and is currently approved for systemic use in metastatic colorectal cancer and non–small cell lung cancer.
Off-label use of intravitreal bevacizumab for CNV secondary to ARMD was first reported in 2005. Most of the reports of bevacizumab are uncontrolled, open-label case series that have suggested functional and anatomical efficacy, short-term safety, and low cost.
Results from several studies suggest that bevacizumab may be useful in the treatment of CNV secondary to multiple etiologies including myopia, [54] angioid streaks, [55] inflammatory conditions, [56, 57] and ARMD. [58, 59]
A retrospective study reported findings in 180 patients with choroidal neovascularization secondary to age-related macular degeneration who were injected with either 1.5 mg or 2.5 mg and were followed for a minimum of 24 months. [60] An average of five injections using a PRN protocol demonstrated improvement or stability in vision. No statistically significant differences between doses were noted.
Aflibercept
The VIEW 1 and VIEW 2, two similarly designed double-masked, randomized multicenter clinical trials, demonstrated that intravitreal aflibercept dosed monthly or every 2 months after a loading dose of three monthly doses was noninferior to monthly ranibizumab. [61] The FDA has approved aflibercept for the treatment of all angiographic subtypes of subfoveal neovascular ARMD.
Brolucizumab
Brolucizumab (RTH258, ESBA 1008) is the newest anti-VEGF agent to gain FDA approval. It is the smallest, with a molecular weight of 26 kDa. It is a humanized single-chain antibody fragment against all VEGF isoforms. Recent clinical trials demonstrated that brolucizumab compared favorably to aflibercept in the management of CNV due to exudative age-related macular degeneration. [62] A 2020 report suggests that brolucizumab may be associated with a higher risk of developing retinal vasculitis and intraocular inflammation. [63]
Faricimab
Faricimab is a bispecific antibody that inhibits both VEGF and Ang-2. Clinical trials have shown that in eyes with neovascular AMD, faricimab was non-inferior to aflibercept. Furthermore ≥ 80% of eyes were able to be treated every 12 weeks without sacrificing effectivity. [64]
Surgical Care
The Macular Photocoagulation Study (MPS) proved the efficacy of laser photocoagulation in the treatment of CNV secondary to ARMD, POHS, and idiopathic causes.
The goal is to completely obliterate CNV.
Partial treatment of CNV is not beneficial when compared with observation. Extrapolate these results to other conditions that are complicated by CNV on a case-by-case basis. Many patients and their physicians choose not to elect immediate loss of several lines of vision in an attempt to have a very modest visual improvement in 18 months. Extrapolation of MPS results to CNV secondary to myopia probably is not indicated in juxtafoveal CNV. Cases of enlargement of laser scars through the fovea with subsequent visual loss have been reported.
PDT uses light-activated drugs and nonthermal light to achieve selective destruction of CNV with minimal effects on the surrounding normal tissues. Randomized clinical trials have shown that PDT with verteporfin is effective in reducing visual loss in certain eyes with CNV secondary to ARMD. In eyes with at least some classic CNV, treatment with verteporfin reduced visual loss. Subgroup analysis revealed that eyes with a classic component of greater than 50% fared much better than those eyes with a classic component of less than 50%. In eyes with a classic component of less than 50%, no difference existed in visual loss between the eyes treated with placebo and the eyes treated with verteporfin. [65] Another study reported that therapy with verteporfin for occult CNV secondary to ARMD was effective in slowing the progression of visual loss. However, such benefit was only seen after the second year of follow-up. Subgroup analysis revealed that eyes with a visual acuity of 20/50 or worse or eyes with lesions smaller than four disc areas in size had a better outcome. Further analysis of the data revealed that lesion size rather than lesion composition is a strong predictor of visual benefit following PDT with verteporfin. [66] Despite all the encouraging initial results, PDT provides marginal benefit. Most eyes will continue losing vision, though at a slower rate, and only 15% of eyes will manifest some visual improvement. PDT in combination with intravitreal triamcinolone, bevacizumab, or ranibizumab may have better visual outcomes than PDT alone in patients with ARMD.
High-speed ICG confocal angiography guided laser photocoagulation of feeder vessels is reportedly beneficial in selected patients with exudative ARMD but remains unproven.
Uncontrolled studies have recommended surgical excision of subfoveal CNV via pars plana vitrectomy. The goal is to remove CNV but to leave the underlying RPE and choriocapillaris intact. Surgical excision of type 2 CNV would be more beneficial than type 1 CNV. Pilot studies resulted in substantial numbers of patients with worse vision, many with unchanged vision, and a small number with apparent improved vision. The current rhetoric is that stabilization may occur with surgery. [67] The Submacular Surgery Trial (SST), a randomized multicenter prospective trial sponsored by the National Eye Institute (NEI), confirmed that submacular surgery in eyes with CNV secondary to ARMD generally does not have a good visual outcome. [68] In addition, with CNV secondary to idiopathic causes and POHS, submacular surgery offers a modest benefit in eyes with a baseline visual acuity of 20/100 or worse.
Two surgical methods to translocate the fovea have been developed to treat subfoveal CNV. The previously subfoveal CNV is now juxtafoveal or extrafoveal; then, standard laser photocoagulation or PDT can be performed without damaging the fovea. Caution is warranted because high rates of retinal detachment, proliferative vitreoretinopathy (PVR), macular holes, recurrent CNV, cystoid macular edema (CME), and hemorrhage have been reported.
Low-dose radiation therapy has been effective in inhibiting neovascularization in different tissues. A randomized clinical trial reported better visual outcomes in eyes with exudative ARMD receiving radiation therapy of 24 Gy given in 6 fractions of 4 Gy each compared with observation. [69] However, other trials do not support radiation therapy as a treatment alternative in eyes with CNV secondary to ARMD. Long-term effects are unknown, and radiation retinopathy is definitely a concern.
Consultations
Diagnosis and treatment are often difficult. Consider referring to a retinal specialist who is experienced with these conditions.
Complications
After 5 years of follow-up, the MPS reported that 55% of patients with exudative ARMD, 33% of patients with POHS, and 34% of patients with idiopathic CNV had a recurrent or persistent CNV after laser photocoagulation. [23] These recurrences, regardless of etiology, tended to be toward the foveal side and were associated with visual loss. In most cases, photocoagulation of these recurrent CNV is indicated. Laser treatment of peripapillary CNV may be complicated by thermal damage to the papillomacular bundle.
Surgical excision of CNV may be complicated by retinal detachment, postvitrectomy cataract, choroidal hemorrhage, epimacular membrane, and macular hole. CNV recurrence following excision occurred in up to 44% of cases. How to effectively manage these recurrences is unclear.
Prevention
The Age-Related Eye Disease Study (AREDS) has shown that eyes with a high risk of developing CNV secondary to age-related macular degeneration benefit from antioxidants and zinc. The recommended daily dosages are 500 mg of vitamin C, 400 IU of vitamin E, 15 mg of beta carotene, 80 mg of zinc oxide, and 2 mg of cupric oxide. [70] Smokers should not take the AREDS formulation because beta carotene has been associated with an increased risk of developing pulmonary neoplasia.
Long-Term Monitoring
Two weeks following laser photocoagulation, the patient should be observed and undergo fluorescein angiography. Pay special attention to the borders, especially the foveal border, of the laser treatment zone to detect any persistence. If no leakage is detected, the patient should have another fluorescein angiogram 4 weeks later or if there are new changes on the Amsler grid. If no leakage is detected again, another angiogram should possibly be obtained 4 weeks to 6 weeks later.
Clinical examination cannot replace FA during the first 18 months after laser treatment, because most persistent and recurrent leakage occurs during this period.
