Wet Age-Related Macular Degeneration (AMD)

Samuel Hobbs; Koushik Tripathy; Kristine Pierce

Wet Age-Related Macular Degeneration (AMD)

Author: Samuel D. Hobbs Author: Koushik Tripathy Editor: Kristine Pierce Updated: 8/11/2024 8:49:26 PM

Introduction

The retina is a layer of neurosensory tissue in the eye that converts light into neural signals, which the brain interprets as images. The macula is the part of the retina with the highest concentration of cones essential for central vision.[1] Wet age-related macular degeneration (AMD), also known as exudative or neovascular AMD, primarily affects the macula and is the most common cause of central visual impairment and blindness among older individuals in developed countries.[2]

Vascular endothelial growth factor (VEGF) drives the development of choroidal neovascularization (CNV), where new vessels grow under or through the retinal pigment epithelium (RPE), often through breaks in the Bruch membrane. (see Image. Peripapillary Choroidal Neovascular Membrane).[3] Regular administration of intravitreal anti-VEGF medications may prevent blindness in most patients with wet AMD.[4] In the absence of such treatment, patients experience severe, irreversible vision loss.[5]

Etiology

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Etiology

AMD is a multifactorial disease, and numerous risk factors have been identified. The possible risk factors include the following:

Older age
Elevated total serum cholesterol
Micronutrient deficiency
Smoking
Family history
Hypertension
Cardiovascular disease
Exposure to visible light [6][7]

A genetic predisposition to AMD is evident, as at least 34 genetic loci and 52 gene variants are associated with the disease.[8] Many findings indicate that inflammation plays a key role in the pathogenesis of wet AMD. Most notably, polymorphisms of complement factor H, which normally inhibits the alternative complement pathway, are among the best-known mutations in AMD, suggesting the important role of complement activation in its development.[9][10]

Epidemiology

In 2015, AMD was the third most common cause of moderate-to-severe visual impairment worldwide. The global prevalence of AMD among individuals aged 45 to 85 was 8.7%, with a prevalence of 0.4% for advanced AMD.[11] Early AMD is more common among individuals of European ancestry compared to Asians, and AMD of any stage is less common in individuals of African origin.[12] The global prevalence of any AMD stage is predicted to increase from 196 million people in 2020 to 288 million by 2040.[11]

Approximately 10% to 15% of patients with AMD develop neovascular disease.[13] In the absence of anti-VEGF therapy, around 79% to 90% of affected eyes eventually become legally blind due to complications from neovascularization.[14]]

Pathophysiology

AMD is differentiated from early or dry AMD by the presence of CNV, where new blood vessels from the choroid penetrate through the Bruch membrane and proliferate either between the Bruch membrane and the RPE or in the subretinal space.[15] Various factors contribute to the development of CNV and vision loss in patients with wet AMD.[16] These factors include the following:

VEGF accumulation, particularly the VEGF-165 isoform
Growth of new blood vessels with the proliferation of fibrous tissue
Leakage of fluid, proteins, and lipids from the new vessels
Hemorrhage from the fragile new vessels
Fibrovascular scar formation, with the death of the neurosensory retina and vision loss

Histopathology

Dr. John Donald MacIntyre Gass classified CNVs into 2 types based on their anatomic histopathological location:

Type 1 CNV is located below the RPE. This type is typically observed in AMD and correlates with occult CNV in fluorescein angiography.[17]
Type 2 CNV is subretinal, occurring between the retina and the RPE. This type is typically noted with CNVs secondary to presumed ocular histoplasmosis syndrome.[18] Classic CNV in wet AMD is a type 2 CNV.

Type 3 neovascularization (retinal angiomatous proliferation or RAP) starts intraretinally and then reaches the subretinal or sub-RPE area.[19][20] The origin of neovascularization may vary and may not start in the choroid itself. Thus, according to the Consensus Nomenclature for Reporting Neovascular Age-Related Macular Degeneration, these subtypes are currently included under the broad term macular neovascularization (MNV).

MNV is further classified into 3 types based on multimodal imaging characteristics, including optical coherence tomography (OCT), OCT angiography, fluorescein angiography, and indocyanine green angiography (ICGA).

In type 1 MNV, the neovascularization process starts at the choriocapillaris and grows into and within the sub-RPE space, leading to different types of pigment epithelial detachment (PED) (see Image. Retinal Pigment Epithelial Detachment). Polypoidal choroidal vasculopathy (PCV) is a subtype of type 1 MNV.
Type 2 MNV originates in the choroid and passes through the Bruch membrane and RPE to reach the subretinal space, where it proliferates.
In type 3 MNV, the new vessel starts from the retinal circulation, typically in the deep retinal capillary plexus, and then grows toward the outer retina.[21]

History and Physical

Patients with wet AMD typically report visual distortion or blurring of central vision, particularly affecting their near vision. Some may experience metamorphopsia, micropsia, or scotoma, whereas others might report no symptoms or only vague vision complaints.[22]

Upon examination, patients often show decreased best-corrected visual acuity. An Amsler grid test may reveal areas of central or paracentral scotoma or visual distortion (see Image. Amsler Grid). The ophthalmic examination of the front part of the eye usually shows normal results. Age-related cataracts or pseudophakia may be noted. AMD-related CNV has several different appearances on the dilated funduscopic examination (see Image. Age-Related Macular Degeneration on Funduscopy).[23] These features may include the following:

A gray-green membrane deep into the retina, often associated with an overlying neurosensory retinal detachment.
Presence of blood, lipid, or subretinal fluid.
RPE detachment appears clinically as dome-shaped, sharply demarcated elevations of the RPE, which may also be serous, fibrovascular, drusenoid, or hemorrhagic.[24] A notch in serous PED may indicate the location of occult CNV membranes.[25]
Massive subretinal hemorrhage with central vision loss or, less commonly, breakthrough vitreous hemorrhage with peripheral vision loss (see Image. Intraocular Hemorrhage on Funduscopy).
RPE tear or rip.[26]
Disciform scars may be present, appearing as white or yellow subretinal membranes with or without RPE hyperplasia and pigmentation.

The use of blood thinners and hematological disorders should be ruled out in patients with massive subretinal hemorrhage (the size of at least 4 disc areas).

Evaluation

Accurate diagnosis of wet AMD relies on various ocular imaging techniques that assess retinal and choroidal changes. These modalities provide critical information for detecting and characterizing disease features and guiding treatment decisions. The ocular investigations recommended for evaluating wet AMD include the following:

Optical Coherence Tomography

OCT is a noninvasive imaging modality that can capture detailed images of the retina and surrounding structures.[27] OCT uses low-coherence light beams directed towards the target tissue. The reflected light is combined with a reference beam and measured to create an interference pattern. This modality is used to reconstruct an axial A-scan. Multiple A-scans may be used to reconstruct a cross-sectional B-scan. Raster scans and three-dimensional images may be produced from there. Features of wet AMD on macula OCT include the following:[28]

Subretinal and intraretinal fluid
Serous retinal PED, which is observed as a homogenously hyporeflective space between the dome-shaped RPE and the Bruch membrane
Fibrovascular PED (FVPED), which shows layers of moderate hyperreflectivity between the RPE and the Bruch membrane separated by hyporeflective clefts (see Image. Fibrovascular Retinal Pigment Epithelial Detachment)
Hemorrhagic PED, which appears as a large, dome-shaped, hyperreflective lesion between the RPE and the Bruch membrane with attenuation of deeper structures
RPE tears manifesting as areas of discontinuity in a large PED. The RPE edge may be observed curled under the PED [29]
Disciform scarring with subretinal hyperreflective material and loss of the ellipsoid zone [30]

Optical Coherence Tomography Angiography

OCT angiography (OCTA) is a newer technology that creates images of the retinal circulation by obtaining sequential B-scans from a single area, and decorrelation signals are generated to show only areas with movement, such as flow-through vessels.[31] OCTA may facilitate the earlier diagnosis of CNV, potentially identifying lesions before they are visible on conventional OCT or fluorescein angiography.[32]

Fundus Fluorescein Angiography

Fundus fluorescein angiography (FFA) should be considered early in diagnosing wet AMD to minimize diagnostic errors.[33] OCT, the most frequent imaging modality used to make retreatment decisions in wet AMD, is 85% sensitive yet only 48% specific for diagnosing active wet AMD.[34] Thus, treatment decisions made solely on OCT findings may result in overtreatment.[35][36]

FFA has traditionally been used to classify CNVs as either classic or occult. This classification is particularly useful for treatment decisions, as photodynamic therapy (PDT) with verteporfin is often more effective for classic CNV, which comprises at least 50% of the lesion area, compared to occult CNV or minimally classic CNV, which occupies less than 50% of the lesion area. [37] Classic CNV is marked by well-defined hyperfluorescence in early imaging phases, with leakage observed in the mid and late phases. Occult CNV is identified by FVPED showing stippled hyperfluorescent dots with or without leakage or by late leakage of an undetermined source, often appearing as speckled hyperfluorescence with subretinal dye pooling.

Common FFA patterns in wet AMD may include the following:

RAP (type 3 MNV), which is characterized by anastomosis between retinal and choroidal vessels and shows early hyperfluorescence, intraretinal hemorrhage, and vessels diving at right angles from the retina to the area of CNV (see Image. Retinal Angiomatous Proliferation)
Serous PED, which may present with early, bright hyperfluorescence that is uniform in appearance and demonstrates little to no leakage
Hemorrhagic PED, which is characterized by the blocking of underlying choroidal fluorescence
Drusenoid PED, with only faint fluorescence and lack of late staining or leakage
Speckled hyperfluorescence [38]
Loculated fluid with fluorescein dye pooling anterior to the area of CNV
RPE tears, which manifest as early hyperfluorescence with late staining of the choroid and sclera without leakage [39]
Disciform scars, which may show staining or blocking if RPE hyperplasia is present

Indocyanine Green Angiography

ICGA is a dye that is helpful in imaging choroidal circulation, as it is highly protein-bound and less likely to leak from choroidal vessel fenestrations (see Image. Polypoidal Choroidal Vasculopathy).[40] ICGA is particularly effective in delineating occult CNV, which may manifest as:

A hot spot or area of early to mid-phase hyperfluorescence
A plaque or area of late hyperfluorescence
An area of poorly defined fluorescence [41]

ICGA may be used to identify feeder vessels in CNV that may be treated with laser photocoagulation. This modality also better compares CNV subtypes, allowing for earlier diagnosis and determination of patient prognosis.[42] ICGA is very helpful in identifying idiopathic PCV, a close differential diagnosis of wet AMD. ICGA features of PCV include early focal subretinal hypercyanescence (polyps) within 6 min, pulsatile polyps, hypocyanescent halo around the polyp, and a branching vascular network.[43] ICGA features of RAP include hot spots in the mid or late phase and retinochoroidal or retinal-retinal anastomoses, such as hairpin-like loops connecting a retinal arteriole and venule.[44]

Treatment / Management

Intravitreal Anti-VEGF Therapy

The mainstay of therapy for wet AMD is intravitreal anti-VEGF treatment. Currently used agents prevent visual loss and may also improve vision in some cases.[45]

Pegaptanib sodium: Pegaptanib sodium is the first intravitreal anti-VEGF agent approved by the Food and Drug Administration (FDA) for wet AMD treatment. This agent is a specific VEGF-165 antagonist, and it gained approval on December 17, 2004.[46] However, pegaptanib sodium has largely been replaced by bevacizumab, ranibizumab, and aflibercept due to improved results in various trials.[47][48] The VISION study compared intravitreal pegaptanib with sham intravitreal injections in wet AMD and determined its efficacy in preventing vision loss.[49](A1)

Ranibizumab: Ranibizumab is a recombinant humanized antibody fragment that binds all isoforms of VEGF-A. The FDA approved ranibizumab for wet AMD on June 30, 2006. The MARINA and ANCHOR studies evaluated ranibizumab in minimally classic (occult) and classic CNV, respectively.[50] The ANCHOR trial showed superior efficacy of ranibizumab compared to PDT in classic CNV.[51](A1)

Bevacizumab: Bevacizumab is approved by the FDA for metastatic colorectal carcinoma but is used off-label for AMD treatment.[52] Bevacizumab is noninferior to ranibizumab for this purpose, as evidenced by multiple studies, including CATT, IVAN, GEFAL, LUCAS, BRAMD, and MANTA.[53][54][55][56][57][58] However, some studies have suggested a higher risk of serious systemic events with bevacizumab compared to ranibizumab, which may need further investigation.[59] (A1)

Aflibercept: Aflibercept acts as a VEGF receptor decoy, effectively trapping all VEGF isoforms. This drug works against VEGF-A, VEGF-B, and the placental growth factor. Aflibercept is given every 2 months after the initial 3 monthly loading doses, and this dosing is as effective as monthly ranibizumab dosing.[60] The FDA approved aflibercept for wet AMD on November 18, 2011. VIEW 1 and VIEW 2 evaluated the role of fixed-dose aflibercept (initial 3 monthly injections or loading dose followed by intravitreal injection every 2 months) in wet AMD.[61](A1)

The FDA approved a high-dose aflibercept (8 mg/0.07 mL) formulation in August 2023 after it was shown to have efficacy and safety with extended dosing intervals without new safety signals (see Image. Intravitreal Aflibercept Injection Result).[62] The CLEAR-IT 2 study evaluated the as-needed protocol, with the initial 3 monthly injections followed by intravitreal injections as needed, using monthly evaluations with macula OCT.[63](A1)

Ranibizumab-nuna: Ranibizumab-nuna is also also called SB11. This drug is the first ranibizumab biosimilar agent to be approved by the FDA (approved on September 7, 2021) for patients with wet AMD.[64] Ranibizumab-eqrn is another ranibizumab biosimilar approved by the FDA for use in patients with wet AMD (approved on August 2, 2022).[65]

Brolucizumab: Brolucizumab (ESBA 1008 or RTH 258) is a low-molecular-weight VEGF antagonist that allows for a higher molar concentration of medication with each injection. The FDA approved this drug on October 8, 2019 for use in wet AMD. The drug was found to be noninferior to aflibercept every 12 weeks.[66] Despite early success with brolucizumab, concerns exist regarding reports of severe intraocular inflammation and vasculitis following administration.[67] HAWK and HARRIER trials evaluated brolucizumab's safety and efficacy in wet AMD.[68](A1)

Aflibercept-jbvf and aflibercept-yszy: Aflibercept-jbvf and aflibercept-yszy are aflibercept biosimilars approved by the FDA in May 2024. These agents are the first interchangeable biosimilars to aflibercept 2 mg.[69](A1)

Faricimab-svoa: Faricimab-svoa is an antibody with an affinity for VEGF and angiopoietin-2, an additional factor that may drive inflammation and contribute to CNV development. Early reports regarding faricimab are promising, with extended dosing intervals of 16 weeks shown to be noninferior to ranibizumab every 4 weeks.[70] The FDA approved faricimab for use in wet AMD on January 28, 2022. TENAYA and LUCERNE demonstrated noninferiority of faricimab compared to aflibercept in wet AMD.[71] AVENUE and STAIRWAY trials compared faricimab with ranibizumab in wet AMD.[72][73](A1)

Treatment regimens: Anti-VEGF agents are administered according to various regimens:

Most anti-VEGF drugs are approved for fixed dosage with the following possible schedules:
- Monthly or every 28 days (ranibizumab 0.5 mg)
- Bimonthly after the initial 3 monthly (every 28 days) injections (aflibercept 2 mg)
- Every 8 to 12 weeks (brolucizumab 6 mg) after the initial 3 monthly (every 25-31 days) doses
- Up to every 16 weeks (faricimab 6 mg) after a loading dose of 4 monthly (every 28±7 days) injections
A pro re nata (PRN, or as needed) schedule where a patient receives injections only when the disease appears active, such as in subretinal or intraretinal fluid on OCT, retinal hemorrhage, or leakage on fluorescein angiography.[74]
A treat-and-extend (TAE) protocol, where injection frequency is slowly extended as long as disease activity remains controlled.[75][76]
A treat-extend-stop protocol, where the patient receives an anti-VEGF agent every month for at least 3 months until the OCT confirms dry macula. If the fovea remains dry, as per the TAE protocol, the interval between injections can increase by 1 to 2 weeks until a 12-week interval is reached. The injections are stopped in patients with at least 7 injections and dry macula at the third 12-week visit. Monthly evaluations are performed to monitor for CNV recurrence in approximately 30% of patients.[77]
A treat-extend-pause-and-monitor protocol initially follows a TAE regimen.[78] Injections were paused in stable patients who had reached 12-weekly injections and started a PRN protocol. The patient was contacted 6 weeks after the last injection (18 weeks from the previous visit). If stable, no injection was given, and the patient was scheduled for a follow-up evaluation 12 weeks later.

(A1)

Although monthly injections are more effective compared to PRN regimens, evidence comparing PRN to TAE regimens remains inconclusive. Endophthalmitis is more likely with monthly injections, and patients receive more injections with monthly and TAE dosing compared to PRN. However, PRN regimens require more frequent clinic visits compared to TAE dosing.[79](A1)

Long-term data suggest that PRN dosing may result in slightly worse visual outcomes compared to monthly injections after a year. This difference may be clinically insignificant after a year but may become crucial after several years of treatment. Ultimately, the clinician and patient should work together to choose the best treatment option.

Intravitreal anti-VEGF agents come with several risks. Common adverse events include subconjunctival hemorrhage and discomfort during or after the procedure, often due to the iodine-based antiseptic used to clean the ocular surface. Floaters may be caused by bubbles in the syringe or the medication itself. Serious adverse events rarely occur and can include vitreous hemorrhage or endophthalmitis.[80]

Several studies have also explored potential systemic adverse events related to intravitreal anti-VEGF administration, including the risk of myocardial infarction, stroke, nonocular hemorrhage, and thromboembolic events. Current evidence does not suggest an increase in systemic morbidity or mortality from the intravitreal administration of anti-VEGF agents. [81] However, this theoretical risk is still important to discuss with patients, especially those deemed to be at higher risk. (A1)

Emerging Therapies

Several emerging therapies for wet AMD are currently under investigation. These treatments aim to improve existing options by exploring new mechanisms, delivery systems, and formulations to enhance efficacy and reduce treatment burden.

Abicipar pegol: Abicipar pegol is a nonmonoclonal antibody developed with designed ankyrin repeat protein technology, with VEGF-binding affinity similar to aflibercept.[82] Similar to brolucizumab, its use may be limited due to higher reported rates of intraocular inflammation.[83] Abicipar pegol was not approved by the FDA, citing an unfavorable risk-benefit ratio. Studies evaluating the role of abicipar pegol in wet AMD include CEDAR, SEQUOIA, CYPRESS, BAMBOO, MAPLE, and REACH.[84][85](A1)

Conbercept: Conbercept is a VEGF decoy protein similar to aflibercept that appears to have increased binding capacity to VEGF with an extended intraocular half-life, and FDA studies are underway.[86] In addition, several sustained-release delivery devices are being developed to help decrease the burden of frequent intravitreal injections and reduce the potential for undertreatment.[87]

Ranibizumab port delivery system: The ranibizumab port delivery system (PDS) was approved by the FDA on October 22, 2021 and requires refill exchanges every 24 weeks. This agent was shown to be noninferior to monthly ranibizumab. However, the PDS had a higher risk of adverse events compared to ranibizumab monthly injections, with higher rates of endophthalmitis, retinal detachments, vitreous hemorrhages, conjunctival erosions, and conjunctival retractions.[88] A voluntary recall for the implant was initiated in October 2022 due to concerns about septum dislodgement with repeated refill exchanges and failure of internal safety standards.[89](A1)

Other agents being evaluated for wet AMD include the following:

OPT-302, which targets VEGF-C and VEGF-D
KSI-301, which targets VEGF-A
Agents that counter platelet-derived growth factor (PDGF), including rinucumab, pegpleranib, X-82, DE-120, and CLS-AX
Gene therapy, which utilizes various vectors, including adeno-associated virus (AAV), to produce anti-VEGF agents such as VEGF receptor, ranibizumab, aflibercept, endostatin, and angiostatin
Anti-tissue factor agents
Sustained release devices, including devices for delivering drugs such as ranibizumab and sunitinib (the latter targets VEGF-A and PDGF)

Topical medications being evaluated for wet AMD treatment include the following:

Agents targeting VEGF-A and PDGF, such as pazopanib, regorafenib, and PAN-90806
Squalamine targets VEGF, PDGF, and basic fibroblast growth factor
LHA510 targets tyrosine kinase

Oral medications evaluated for managing wet AMD include X-82, a tyrosine kinase inhibitor blocking VEGF and PDGF receptors, and AKST4290, which targets CCR3, the receptor for eotaxin.[90]

Other Treatments

Before the widespread use of anti-VEGF therapy, several other treatment modalities were employed for wet AMD. These modalities are now less important due to the effectiveness and ongoing advancements of anti-VEGF treatments.

Laser photocoagulation is beneficial for foveal-sparing CNV lesions, although failure to adequately cover the entire lesion can lead to treatment failure and vision loss.[91] Laser photocoagulation destroys the overlying retinal tissue. Thus, this treatment should not be used for fovea-involving lesions, which are more likely to be visually devastating for patients.(A1)

PDT is another treatment for CNV where the photosensitizing drug verteporfin is injected intravenously, and a low-intensity laser light treats the CNV tissue through a photochemical reaction that damages vascular endothelial cells, causing thrombosis.[92] Despite the lower intensity laser used in PDT, many patients still lose some vision after treatment. Anti-VEGF therapy has largely supplanted both laser photocoagulation and PDT in treating wet AMD.

Submacular surgery for patients with wet AMD has shown no benefit in patients with subfoveal CNV. This procedure also comes with the risk of cataract progression and retinal detachment.[93] Other surgical approaches for patients with CNV and vision loss include macular translocation surgery and mechanical displacement of subretinal hemorrhage with gas. Evidence is insufficient to recommend macular translocation unless the patient has severe, bilateral disease unresponsive to anti-VEGF therapy.[94](A1)

Pneumatic displacement of submacular hemorrhage, using intravitreal air or gas injection with face-down positioning, may improve a patient's visual acuity.[95] Even in these patients, anti-VEGF therapy may be sufficient without surgical intervention.[96] Other approaches to managing massive submacular hemorrhage include intravitreal or subretinal tissue plasminogen activator, intravitreal gas, intravitreal anti-VEGF agents, pars plana vitrectomy, subretinal air injection, and various combinations of therapies.[97] Subretinal injections of agents typically need pars plana vitrectomy. (B2)

Radiation therapy has been considered for CNV in wet AMD, but studies have not found a clear benefit from this modality. Radiation therapy combined with intravitreal ranibizumab is inferior to the as-needed use of ranibizumab monotherapy.[98] Evidence currently does not support the use of radiation therapy in wet AMD.(A1)

An exciting new avenue of treatment for wet AMD is gene therapy. RGX-314 is an AAV8 vector expressing an anti-VEGF-A fragment antigen-binding chain similar to ranibizumab. Subretinal delivery of the medication is generally safe and well-tolerated.[99] Phase 2 and 3 trials are underway to test the safety and efficacy of subretinal and suprachoroidal delivery of RGX-314.

Differential Diagnosis

The differential diagnosis for CNV due to wet AMD should include other potential causes of CNV. Other conditions that must be considered include the following:

Degenerative	Wet AMD Pathological myopia Angioid streak [100]
Inflammatory	Presumed ocular histoplasmosis syndrome Punctate inner choroidopathy Serpiginous choroiditis Serpiginous-like choroiditis Multifocal choroiditis Sympathetic ophthalmia Vogt-Koyanagi-Harada syndrome Ocular tuberculosis [101][102] Toxocariasis Toxoplasmosis Rubella
Trauma	Choroidal rupture Laser burns Iatrogenic (after vitreoretinal surgery)
Inherited retinal disorders	Best vitelliform macular dystrophy Fundus flavimaculatus
Optic nerve disorders	Optic disc drusen
Tumors	Choroidal osteoma [103] Choroidal hemangioma Choroidal nevus Choroidal metastasis Combined hamartoma of the retina and retinal pigment epithelium (CHRRPE)
Idiopathic

Breakthrough vitreous hemorrhage can also occur in wet AMD, and diagnosis may be challenging if the view is obscured during a dilated retinal examination. In such cases, evaluating the fellow eye or obtaining a detailed history can help establish the diagnosis. Other potential causes of vitreous hemorrhage include the following:

Proliferative diabetic retinopathy
Retinal tear or retinal detachment
Hemorrhagic posterior vitreous detachment
Neovascularization from other causes, such as vein occlusions, radiation retinopathy, or sickle cell retinopathy

PCV, a subtype of wet AMD more common in patients with Asian ancestry, is characterized by orangish-red, bulb-like subretinal polyps associated with adjacent subretinal hemorrhage or exudates. ICGA is crucial for diagnosing PCV, and recurrent disease is more common among PCV patients compared to those with wet AMD. Patients with PCV may benefit more from PDT compared to those with wet AMD.[104]

Peripheral exudative hemorrhagic chorioretinopathy is a disease affecting older individuals characterized by peripheral subretinal or sub-RPE hemorrhage or exudates that may sometimes reach the posterior pole.[105] Many such patients are hypertensive and on blood-thinning agents. This entity may be a variant of PCV, and around 60% of patients may show polyps on ICGA.[106] Treatment options include anti-VEGF agents, laser, PDT, pars plana vitrectomy, and cryotherapy. Peripheral exudative hemorrhagic chorioretinopathy may simulate choroidal melanoma.[107]

RAP should be kept in mind in patients with intraretinal hemorrhage near the fovea without evidence of diabetic retinopathy or macular branch retinal venous occlusion. This variant of wet AMD typically starts at the deep capillary plexus and then grows outward. The features include retinal-retinal anastomosis and retinal-choroidal anastomosis. The stages of RAP include stage 1 (intraretinal new vessels), stage 2 (subretinal new vessels), and stage 3 (choroidal or sub-RPE new vessels). Stage 3 is characterized by retinal-choroidal anastomosis and vascularized PEDs.[108] Treatment is similar to types 1 and 2 MNV.

Prognosis

If left untreated for 2 to 3 years, around 50% to 60% of eyes with wet AMD and subfoveal CNV lose 6 or more lines of vision, compared to 20% to 30% of eyes with any submacular CNV.[109][110][111] Classic CNV is associated with poorer visual outcomes compared to occult or minimally classic CNV, and up to 50% of the patients without classic lesions on initial presentation may develop classic CNV within 1 year after diagnosis.[112][113]

Eyes with large subretinal hemorrhages that involve the fovea often have poor visual outcomes. However, some eyes have surprisingly good visual recovery, suggesting that prompt treatment, such as intravitreal anti-VEGF medications or surgery, is still beneficial.[114] RPE tears involving the fovea also generally result in poor visual acuity and an elevated risk of vision loss from an RPE tear in the fellow eye.[115]

Complications

Untreated wet AMD leads to irreversible vision loss in most patients. However, vision loss can still occur even with treatment. Patients with vision loss from AMD often report a diminished quality of life.[116] These individuals report significantly more emotional distress, poorer health, and less independence in daily activities compared to those with other chronic illnesses.[117]

Deterrence and Patient Education

All patients with macular drusen should be educated on the importance of regular Amsler grid use to check for metamorphopsias or scotomas that may indicate conversion from dry to wet AMD. Any change in near or distance vision may also indicate developing CNV, prompting patients to contact their ophthalmologist immediately.

Patients may also benefit from lifestyle modifications, including eating a well-balanced diet with plenty of micronutrients, wearing sunglasses to avoid excessive visible light exposure, and participating in regular exercise. Patients should regularly visit their primary care physician and control underlying systemic disorders. Selected patients should also be encouraged to use Age-Related Eye Disease Study (AREDS) or AREDS2 ingredients regularly. These vitamins have been shown to prevent progression to advanced AMD in patients with an intermediate or advanced disease in 1 eye.[118][119]

Patients already with severe vision loss may benefit from visual rehabilitation and referral to a low-vision clinic where they can obtain educational resources to help them function with their limited vision. Several low-vision tools may be offered, including handheld magnifiers, closed-circuit television viewers, and accessibility applications on standard electronic devices, such as smartphones and tablets. Patients should be informed about the availability of large-print periodicals, audiobooks, and other resources offered by their local library and the Library of Congress. These individuals may also benefit from a referral to social services to help preserve their independence as much as possible.

Enhancing Healthcare Team Outcomes

Patients with wet AMD are typically evaluated by an interprofessional healthcare team, which may include a retina specialist. Primary care providers, optometrists, and general ophthalmologists play a crucial role in recognizing the signs and symptoms of worsening wet AMD and referring patients to a retina specialist or other clinicians trained in treating wet AMD and administering intravitreal injections. Expeditious diagnosis and treatment are crucial for preventing irreversible vision loss. Pharmacists can provide the team and the patient with information on the drugs used, including potential interactions and adverse events, and verify proper dosing. Interprofessional teamwork is vital for achieving the best patient outcomes in wet AMD.

Although retina specialists are traditionally responsible for administering intravitreal anti-VEGF agents, there is a shortage of these specialists, particularly in rural areas. The growing aging population in developed countries has prompted more comprehensive ophthalmologists to learn how to evaluate and treat wet AMD. Despite this trend, comprehensive ophthalmologists should understand that caring for patients with wet AMD requires complex decision-making based on individual vitreoretinal pathology. Consultation or co-management with a retina specialist is recommended.

Patients with advanced AMD should be considered for early referral for low-vision services. Vision impairment in patients with wet AMD can prevent them from performing activities of daily living, and several aids are available to allow patients to read and perform other tasks.[120][121]

Media

(Click Image to Enlarge)

<p>Intravitreal Aflibercept Injection Result

Intravitreal Aflibercept Injection Result. Optical coherence tomography image of an eye before (top) and 4 weeks after (bottom) intravitreal aflibercept injection. A significant reduction is observed in the subretinal fluid (hyporeflective area under the retina) after injection.

Contributed by SD Hobbs, MD

(Click Image to Enlarge)

Amsler Grid. This image shows the Amsler grid, as observed by a normal eye (left) and one with wet age-related macular degeneration (right), demonstrating distortion and a paracentral scotoma. All patients with macular drusen should be educated on the importance of regular use of the Amsler grid to detect new-onset distortion or scotomas that may indicate conversion from dry to wet ARMD.

Contributed by SD Hobbs, MD

(Click Image to Enlarge)

<p>Age-Related Macular Degeneration on Funduscopy

Age-Related Macular Degeneration on Funduscopy. This fundus photo of a left eye demonstrates drusen with a submacular hemorrhage, a complication of wet (exudative or neovascular) age-related macular degeneration.

Contributed by SD Hobbs, MD

(Click Image to Enlarge)

<p>Retinal Pigment Epithelial Detachment

Retinal Pigment Epithelial Detachment. This optical coherence tomography image shows neovascular age-related macular degeneration with subretinal fluid, retinal pigment epithelial detachment, and subretinal hyperreflective material.

M Musa, OD

(Click Image to Enlarge)

<p>Fibrovascular Retinal Pigment Epithelial Detachment

Fibrovascular Retinal Pigment Epithelial Detachment. This optical coherence tomography image shows wet age-related macular degeneration with fibrovascular retinal pigment epithelial detachment and intraretinal fluid.

M Musa, OD

(Click Image to Enlarge)

Intraocular Hemorrhage on Funduscopy. This image illustrates a hemorrhagic choroidal neovascular membrane observed on funduscopy.

Contributed by U Shukla, MS, DNB, FVRS, MNAMS, PhD

(Click Image to Enlarge)

<p>Peripapillary Choroidal Neovascular Membrane

Peripapillary Choroidal Neovascular Membrane. This optical coherence tomography image shows a peripapillary choroidal neovascular membrane with subretinal hyperreflective material and fluid. SRM, subretinal fluid; SHRM, subretinal hyperreflective material.

M Musa, OD

(Click Image to Enlarge)

Retinal Angiomatous Proliferation. These images from funduscopy (left) and fundus fluorescein angiography (middle and right) show retinal angiomatous proliferation features.

Contributed by S Muraleedharan, MS; Aravind Eye Hospital

(Click Image to Enlarge)

Polypoidal Choroidal Vasculopathy. These images show features of a left eye with polypoidal choroidal vasculopathy through fluorescein angiography (A) and indocyanine green angiography (B).

Contributed by S Muraleedharan, MS; Aravind Eye Hospital

References

[1]

Stewart EEM, Valsecchi M, Schütz AC. A review of interactions between peripheral and foveal vision. Journal of vision. 2020 Nov 2:20(12):2. doi: 10.1167/jov.20.12.2. Epub [PubMed PMID: 33141171]

[2]

Friedman DS, O'Colmain BJ, Muñoz B, Tomany SC, McCarty C, de Jong PT, Nemesure B, Mitchell P, Kempen J, Eye Diseases Prevalence Research Group. Prevalence of age-related macular degeneration in the United States. Archives of ophthalmology (Chicago, Ill. : 1960). 2004 Apr:122(4):564-72 [PubMed PMID: 15078675]

[3]

Spraul CW, Lang GE, Grossniklaus HE, Lang GK. Histologic and morphometric analysis of the choroid, Bruch's membrane, and retinal pigment epithelium in postmortem eyes with age-related macular degeneration and histologic examination of surgically excised choroidal neovascular membranes. Survey of ophthalmology. 1999 Oct:44 Suppl 1():S10-32 [PubMed PMID: 10548114]

Level 3 (low-level) evidence

[4]

Ba J, Peng RS, Xu D, Li YH, Shi H, Wang Q, Yu J. Intravitreal anti-VEGF injections for treating wet age-related macular degeneration: a systematic review and meta-analysis. Drug design, development and therapy. 2015:9():5397-405. doi: 10.2147/DDDT.S86269. Epub 2015 Sep 28 [PubMed PMID: 26451092]

Level 1 (high-level) evidence

[5]

Chew EY, Clemons TE, Agrón E, Sperduto RD, Sangiovanni JP, Davis MD, Ferris FL 3rd, Age-Related Eye Disease Study Research Group. Ten-year follow-up of age-related macular degeneration in the age-related eye disease study: AREDS report no. 36. JAMA ophthalmology. 2014 Mar:132(3):272-7. doi: 10.1001/jamaophthalmol.2013.6636. Epub [PubMed PMID: 24385141]

Level 1 (high-level) evidence

[6]

Tomany SC, Wang JJ, Van Leeuwen R, Klein R, Mitchell P, Vingerling JR, Klein BE, Smith W, De Jong PT. Risk factors for incident age-related macular degeneration: pooled findings from 3 continents. Ophthalmology. 2004 Jul:111(7):1280-7 [PubMed PMID: 15234127]

Level 2 (mid-level) evidence

[7]

Katsi VK, Marketou ME, Vrachatis DA, Manolis AJ, Nihoyannopoulos P, Tousoulis D, Vardas PE, Kallikazaros I. Essential hypertension in the pathogenesis of age-related macular degeneration: a review of the current evidence. Journal of hypertension. 2015 Dec:33(12):2382-8. doi: 10.1097/HJH.0000000000000766. Epub [PubMed PMID: 26536087]

[8]

Black JR, Clark SJ. Age-related macular degeneration: genome-wide association studies to translation. Genetics in medicine : official journal of the American College of Medical Genetics. 2016 Apr:18(4):283-9. doi: 10.1038/gim.2015.70. Epub 2015 May 28 [PubMed PMID: 26020418]

[9]

Kauppinen A, Paterno JJ, Blasiak J, Salminen A, Kaarniranta K. Inflammation and its role in age-related macular degeneration. Cellular and molecular life sciences : CMLS. 2016 May:73(9):1765-86. doi: 10.1007/s00018-016-2147-8. Epub 2016 Feb 6 [PubMed PMID: 26852158]

[10]

Schultz DW, Klein ML, Humpert AJ, Luzier CW, Persun V, Schain M, Mahan A, Runckel C, Cassera M, Vittal V, Doyle TM, Martin TM, Weleber RG, Francis PJ, Acott TS. Analysis of the ARMD1 locus: evidence that a mutation in HEMICENTIN-1 is associated with age-related macular degeneration in a large family. Human molecular genetics. 2003 Dec 15:12(24):3315-23 [PubMed PMID: 14570714]

[11]

Wong WL, Su X, Li X, Cheung CM, Klein R, Cheng CY, Wong TY. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. The Lancet. Global health. 2014 Feb:2(2):e106-16. doi: 10.1016/S2214-109X(13)70145-1. Epub 2014 Jan 3 [PubMed PMID: 25104651]

Level 1 (high-level) evidence

[12]

Jonas JB, Cheung CMG, Panda-Jonas S. Updates on the Epidemiology of Age-Related Macular Degeneration. Asia-Pacific journal of ophthalmology (Philadelphia, Pa.). 2017 Nov-Dec:6(6):493-497. doi: 10.22608/APO.2017251. Epub 2017 Sep 14 [PubMed PMID: 28906084]

[13]

Gehrs KM, Anderson DH, Johnson LV, Hageman GS. Age-related macular degeneration--emerging pathogenetic and therapeutic concepts. Annals of medicine. 2006:38(7):450-71 [PubMed PMID: 17101537]

[14]

Ferris FL 3rd, Fine SL, Hyman L. Age-related macular degeneration and blindness due to neovascular maculopathy. Archives of ophthalmology (Chicago, Ill. : 1960). 1984 Nov:102(11):1640-2 [PubMed PMID: 6208888]

[15]

Green WR, Enger C. Age-related macular degeneration histopathologic studies. The 1992 Lorenz E. Zimmerman Lecture. Ophthalmology. 1993 Oct:100(10):1519-35 [PubMed PMID: 7692366]

[16]

Ambati J, Ambati BK, Yoo SH, Ianchulev S, Adamis AP. Age-related macular degeneration: etiology, pathogenesis, and therapeutic strategies. Survey of ophthalmology. 2003 May-Jun:48(3):257-93 [PubMed PMID: 12745003]

Level 3 (low-level) evidence

[17]

Shaimov TB, Panova IE, Shaimov RB, Shaimovа VA, Shai Mova TA, Fomin AV, Shaimov TB, Panova IE, Shaimov RB, Shaimova VA, Shaimova TA, Fomin AV. [Optical coherence tomography angiography in the diagnosis of neovascular age-related macular degeneration]. Vestnik oftalmologii. 2015 Sep-Oct:131(5):4-13. doi: 10.17116/oftalma201513154-12. Epub [PubMed PMID: 26845866]

[18]

Gass JD. Biomicroscopic and histopathologic considerations regarding the feasibility of surgical excision of subfoveal neovascular membranes. American journal of ophthalmology. 1994 Sep 15:118(3):285-98 [PubMed PMID: 7521987]

Level 3 (low-level) evidence

[19]

Freund KB, Ho IV, Barbazetto IA, Koizumi H, Laud K, Ferrara D, Matsumoto Y, Sorenson JA, Yannuzzi L. Type 3 neovascularization: the expanded spectrum of retinal angiomatous proliferation. Retina (Philadelphia, Pa.). 2008 Feb:28(2):201-11. doi: 10.1097/IAE.0b013e3181669504. Epub [PubMed PMID: 18301024]

Level 3 (low-level) evidence

[20]

Yannuzzi LA, Freund KB, Takahashi BS. Review of retinal angiomatous proliferation or type 3 neovascularization. Retina (Philadelphia, Pa.). 2008 Mar:28(3):375-84. doi: 10.1097/IAE.0b013e3181619c55. Epub [PubMed PMID: 18327130]

[21]

Spaide RF, Jaffe GJ, Sarraf D, Freund KB, Sadda SR, Staurenghi G, Waheed NK, Chakravarthy U, Rosenfeld PJ, Holz FG, Souied EH, Cohen SY, Querques G, Ohno-Matsui K, Boyer D, Gaudric A, Blodi B, Baumal CR, Li X, Coscas GJ, Brucker A, Singerman L, Luthert P, Schmitz-Valckenberg S, Schmidt-Erfurth U, Grossniklaus HE, Wilson DJ, Guymer R, Yannuzzi LA, Chew EY, Csaky K, Monés JM, Pauleikhoff D, Tadayoni R, Fujimoto J. Consensus Nomenclature for Reporting Neovascular Age-Related Macular Degeneration Data: Consensus on Neovascular Age-Related Macular Degeneration Nomenclature Study Group. Ophthalmology. 2020 May:127(5):616-636. doi: 10.1016/j.ophtha.2019.11.004. Epub 2019 Nov 14 [PubMed PMID: 31864668]

Level 3 (low-level) evidence

[22]

Fine AM, Elman MJ, Ebert JE, Prestia PA, Starr JS, Fine SL. Earliest symptoms caused by neovascular membranes in the macula. Archives of ophthalmology (Chicago, Ill. : 1960). 1986 Apr:104(4):513-4 [PubMed PMID: 2420316]

[23]

Bressler NM, Bressler SB, Gragoudas ES. Clinical characteristics of choroidal neovascular membranes. Archives of ophthalmology (Chicago, Ill. : 1960). 1987 Feb:105(2):209-13 [PubMed PMID: 2434067]

[24]

Zayit-Soudry S, Moroz I, Loewenstein A. Retinal pigment epithelial detachment. Survey of ophthalmology. 2007 May-Jun:52(3):227-43 [PubMed PMID: 17472800]

Level 3 (low-level) evidence

[25]

Gass JD. Serous retinal pigment epithelial detachment with a notch. A sign of occult choroidal neovascularization. Retina (Philadelphia, Pa.). 1984 Fall-Winter:4(4):205-20 [PubMed PMID: 6085179]

Level 3 (low-level) evidence

[26]

Tripathy K, Chawla R, Kumar V, Sharma YR, Venkatesh P. A 56-year-old male with unilateral painless diminution of vision. Oman journal of ophthalmology. 2016 May-Aug:9(2):119. doi: 10.4103/0974-620X.184534. Epub [PubMed PMID: 27433043]

[27]

Drexler W, Fujimoto JG. State-of-the-art retinal optical coherence tomography. Progress in retinal and eye research. 2008 Jan:27(1):45-88 [PubMed PMID: 18036865]

Level 3 (low-level) evidence

[28]

Spaide RF. Enhanced depth imaging optical coherence tomography of retinal pigment epithelial detachment in age-related macular degeneration. American journal of ophthalmology. 2009 Apr:147(4):644-52. doi: 10.1016/j.ajo.2008.10.005. Epub 2009 Jan 18 [PubMed PMID: 19152869]

Level 3 (low-level) evidence

[29]

Chang LK, Sarraf D. Tears of the retinal pigment epithelium: an old problem in a new era. Retina (Philadelphia, Pa.). 2007 Jun:27(5):523-34 [PubMed PMID: 17558312]

[30]

Landa G, Su E, Garcia PM, Seiple WH, Rosen RB. Inner segment-outer segment junctional layer integrity and corresponding retinal sensitivity in dry and wet forms of age-related macular degeneration. Retina (Philadelphia, Pa.). 2011 Feb:31(2):364-70. doi: 10.1097/IAE.0b013e3181e91132. Epub [PubMed PMID: 21221051]

[31]

Jia Y, Tan O, Tokayer J, Potsaid B, Wang Y, Liu JJ, Kraus MF, Subhash H, Fujimoto JG, Hornegger J, Huang D. Split-spectrum amplitude-decorrelation angiography with optical coherence tomography. Optics express. 2012 Feb 13:20(4):4710-25. doi: 10.1364/OE.20.004710. Epub [PubMed PMID: 22418228]

[32]

Ma J, Desai R, Nesper P, Gill M, Fawzi A, Skondra D. Optical Coherence Tomographic Angiography Imaging in Age-Related Macular Degeneration. Ophthalmology and eye diseases. 2017:9():1179172116686075. doi: 10.1177/1179172116686075. Epub 2017 Mar 20 [PubMed PMID: 28579843]

[33]

Ruia S, Tripathy K. Fluorescein Angiography. StatPearls. 2024 Jan:(): [PubMed PMID: 35015403]

[34]

Castillo MM, Mowatt G, Elders A, Lois N, Fraser C, Hernández R, Amoaku W, Burr JM, Lotery A, Ramsay CR, Azuara-Blanco A. Optical coherence tomography for the monitoring of neovascular age-related macular degeneration: a systematic review. Ophthalmology. 2015 Feb:122(2):399-406. doi: 10.1016/j.ophtha.2014.07.055. Epub 2014 Oct 22 [PubMed PMID: 25444343]

Level 1 (high-level) evidence

[35]

Schachat AP, Thompson JT. Optical coherence tomography, fluorescein angiography, and the management of neovascular age-related macular degeneration. Ophthalmology. 2015 Feb:122(2):222-3. doi: 10.1016/j.ophtha.2014.09.015. Epub [PubMed PMID: 25618425]

[36]

Barbazetto I, Burdan A, Bressler NM, Bressler SB, Haynes L, Kapetanios AD, Lukas J, Olsen K, Potter M, Reaves A, Rosenfeld P, Schachat AP, Strong HA, Wenkstern A, Treatment of Age-Related Macular Degeneration with Photodynamic Therapy Study Group, Verteporfin in Photodynamic Therapy Study Group. Photodynamic therapy of subfoveal choroidal neovascularization with verteporfin: fluorescein angiographic guidelines for evaluation and treatment--TAP and VIP report No. 2. Archives of ophthalmology (Chicago, Ill. : 1960). 2003 Sep:121(9):1253-68 [PubMed PMID: 12963608]

[37]

. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials--TAP report. Treatment of age-related macular degeneration with photodynamic therapy (TAP) Study Group. Archives of ophthalmology (Chicago, Ill. : 1960). 1999 Oct:117(10):1329-45 [PubMed PMID: 10532441]

Level 1 (high-level) evidence

[38]

Dyer DS, Brant AM, Schachat AP, Bressler SB, Bressler NM. Angiographic features and outcome of questionable recurrent choroidal neovascularization. American journal of ophthalmology. 1995 Oct:120(4):497-505 [PubMed PMID: 7573308]

[39]

Chuang EL, Bird AC. The pathogenesis of tears of the retinal pigment epithelium. American journal of ophthalmology. 1988 Mar 15:105(3):285-90 [PubMed PMID: 2449819]

[40]

Muraleedharan S, Tripathy K. Indocyanine Green (ICG) Angiography. StatPearls. 2024 Jan:(): [PubMed PMID: 35593804]

[41]

Regillo CD, Benson WE, Maguire JI, Annesley WH Jr. Indocyanine green angiography and occult choroidal neovascularization. Ophthalmology. 1994 Feb:101(2):280-8 [PubMed PMID: 7509471]

Level 2 (mid-level) evidence

[42]

Bottoni F, Massacesi A, Cigada M, Viola F, Musicco I, Staurenghi G. Treatment of retinal angiomatous proliferation in age-related macular degeneration: a series of 104 cases of retinal angiomatous proliferation. Archives of ophthalmology (Chicago, Ill. : 1960). 2005 Dec:123(12):1644-50 [PubMed PMID: 16344434]

Level 2 (mid-level) evidence

[43]

Koh A, Lee WK, Chen LJ, Chen SJ, Hashad Y, Kim H, Lai TY, Pilz S, Ruamviboonsuk P, Tokaji E, Weisberger A, Lim TH. EVEREST study: efficacy and safety of verteporfin photodynamic therapy in combination with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy. Retina (Philadelphia, Pa.). 2012 Sep:32(8):1453-64 [PubMed PMID: 22426346]

Level 1 (high-level) evidence

[44]

Saito M, Iida T, Kano M, Itagaki K. Angiographic results of retinal-retinal anastomosis and retinal-choroidal anastomosis after treatments in eyes with retinal angiomatous proliferation. Clinical ophthalmology (Auckland, N.Z.). 2012:6():1385-91. doi: 10.2147/OPTH.S36333. Epub 2012 Aug 28 [PubMed PMID: 22969283]

[45]

Kaiser SM, Arepalli S, Ehlers JP. Current and Future Anti-VEGF Agents for Neovascular Age-Related Macular Degeneration. Journal of experimental pharmacology. 2021:13():905-912. doi: 10.2147/JEP.S259298. Epub 2021 Sep 29 [PubMed PMID: 34616189]

[46]

VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N.) Clinical Trial Group, D'Amico DJ, Masonson HN, Patel M, Adamis AP, Cunningham ET Jr, Guyer DR, Katz B. Pegaptanib sodium for neovascular age-related macular degeneration: two-year safety results of the two prospective, multicenter, controlled clinical trials. Ophthalmology. 2006 Jun:113(6):992-1001.e6 [PubMed PMID: 16647134]

Level 1 (high-level) evidence

[47]

CATT Research Group, Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. The New England journal of medicine. 2011 May 19:364(20):1897-908. doi: 10.1056/NEJMoa1102673. Epub 2011 Apr 28 [PubMed PMID: 21526923]

Level 1 (high-level) evidence

[48]

Heier JS, Brown DM, Chong V, Korobelnik JF, Kaiser PK, Nguyen QD, Kirchhof B, Ho A, Ogura Y, Yancopoulos GD, Stahl N, Vitti R, Berliner AJ, Soo Y, Anderesi M, Groetzbach G, Sommerauer B, Sandbrink R, Simader C, Schmidt-Erfurth U, VIEW 1 and VIEW 2 Study Groups. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012 Dec:119(12):2537-48. doi: 10.1016/j.ophtha.2012.09.006. Epub 2012 Oct 17 [PubMed PMID: 23084240]

Level 1 (high-level) evidence

[49]

Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR, VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for neovascular age-related macular degeneration. The New England journal of medicine. 2004 Dec 30:351(27):2805-16 [PubMed PMID: 15625332]

Level 1 (high-level) evidence

[50]

Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY, MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. The New England journal of medicine. 2006 Oct 5:355(14):1419-31 [PubMed PMID: 17021318]

Level 1 (high-level) evidence

[51]

Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, Sy JP, Schneider S, ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. The New England journal of medicine. 2006 Oct 5:355(14):1432-44 [PubMed PMID: 17021319]

Level 1 (high-level) evidence

[52]

Kumar A, Tripathy K, Chawla R. Intraocular use of bevacizumab in India: An issue resolved? The National medical journal of India. 2017 Nov-Dec:30(6):345-347. doi: 10.4103/0970-258X.239079. Epub [PubMed PMID: 30117450]

[53]

Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Martin DF, Maguire MG, Fine SL, Ying GS, Jaffe GJ, Grunwald JE, Toth C, Redford M, Ferris FL 3rd. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012 Jul:119(7):1388-98. doi: 10.1016/j.ophtha.2012.03.053. Epub 2012 May 1 [PubMed PMID: 22555112]

Level 1 (high-level) evidence

[54]

IVAN Study Investigators, Chakravarthy U, Harding SP, Rogers CA, Downes SM, Lotery AJ, Wordsworth S, Reeves BC. Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial. Ophthalmology. 2012 Jul:119(7):1399-411. doi: 10.1016/j.ophtha.2012.04.015. Epub 2012 May 11 [PubMed PMID: 22578446]

Level 1 (high-level) evidence

[55]

Kodjikian L, Souied EH, Mimoun G, Mauget-Faÿsse M, Behar-Cohen F, Decullier E, Huot L, Aulagner G, GEFAL Study Group. Ranibizumab versus Bevacizumab for Neovascular Age-related Macular Degeneration: Results from the GEFAL Noninferiority Randomized Trial. Ophthalmology. 2013 Nov:120(11):2300-9. doi: 10.1016/j.ophtha.2013.06.020. Epub 2013 Aug 2 [PubMed PMID: 23916488]

Level 1 (high-level) evidence

[56]

Berg K, Pedersen TR, Sandvik L, Bragadóttir R. Comparison of ranibizumab and bevacizumab for neovascular age-related macular degeneration according to LUCAS treat-and-extend protocol. Ophthalmology. 2015 Jan:122(1):146-52. doi: 10.1016/j.ophtha.2014.07.041. Epub 2014 Sep 13 [PubMed PMID: 25227499]

Level 1 (high-level) evidence

[57]

Schauwvlieghe AM, Dijkman G, Hooymans JM, Verbraak FD, Hoyng CB, Dijkgraaf MG, Peto T, Vingerling JR, Schlingemann RO. Comparing the Effectiveness of Bevacizumab to Ranibizumab in Patients with Exudative Age-Related Macular Degeneration. The BRAMD Study. PloS one. 2016:11(5):e0153052. doi: 10.1371/journal.pone.0153052. Epub 2016 May 20 [PubMed PMID: 27203434]

[58]

Krebs I, Schmetterer L, Boltz A, Told R, Vécsei-Marlovits V, Egger S, Schönherr U, Haas A, Ansari-Shahrezaei S, Binder S, MANTA Research Group. A randomised double-masked trial comparing the visual outcome after treatment with ranibizumab or bevacizumab in patients with neovascular age-related macular degeneration. The British journal of ophthalmology. 2013 Mar:97(3):266-71. doi: 10.1136/bjophthalmol-2012-302391. Epub 2013 Jan 3 [PubMed PMID: 23292928]

Level 1 (high-level) evidence

[59]

Wu B, Wu H, Liu X, Lin H, Li J. Ranibizumab versus bevacizumab for ophthalmic diseases related to neovascularisation: a meta-analysis of randomised controlled trials. PloS one. 2014:9(7):e101253. doi: 10.1371/journal.pone.0101253. Epub 2014 Jul 1 [PubMed PMID: 24983855]

Level 1 (high-level) evidence

[60]

Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, Brown DM, Chong V, Nguyen QD, Ho AC, Ogura Y, Simader C, Jaffe GJ, Slakter JS, Yancopoulos GD, Stahl N, Vitti R, Berliner AJ, Soo Y, Anderesi M, Sowade O, Zeitz O, Norenberg C, Sandbrink R, Heier JS. Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies. Ophthalmology. 2014 Jan:121(1):193-201. doi: 10.1016/j.ophtha.2013.08.011. Epub 2013 Sep 29 [PubMed PMID: 24084500]

Level 1 (high-level) evidence

[61]

Dixon JA, Oliver SC, Olson JL, Mandava N. VEGF Trap-Eye for the treatment of neovascular age-related macular degeneration. Expert opinion on investigational drugs. 2009 Oct:18(10):1573-80. doi: 10.1517/13543780903201684. Epub [PubMed PMID: 19694600]

Level 3 (low-level) evidence

[62]

Lanzetta P, Korobelnik JF, Heier JS, Leal S, Holz FG, Clark WL, Eichenbaum D, Iida T, Xiaodong S, Berliner AJ, Schulze A, Schmelter T, Schmidt-Ott U, Zhang X, Vitti R, Chu KW, Reed K, Rao R, Bhore R, Cheng Y, Sun W, Hirshberg B, Yancopoulos GD, Wong TY, PULSAR Investigators. Intravitreal aflibercept 8 mg in neovascular age-related macular degeneration (PULSAR): 48-week results from a randomised, double-masked, non-inferiority, phase 3 trial. Lancet (London, England). 2024 Mar 23:403(10432):1141-1152. doi: 10.1016/S0140-6736(24)00063-1. Epub 2024 Mar 7 [PubMed PMID: 38461841]

Level 1 (high-level) evidence

[63]

Heier JS, Boyer D, Nguyen QD, Marcus D, Roth DB, Yancopoulos G, Stahl N, Ingerman A, Vitti R, Berliner AJ, Yang K, Brown DM, CLEAR-IT 2 Investigators. The 1-year results of CLEAR-IT 2, a phase 2 study of vascular endothelial growth factor trap-eye dosed as-needed after 12-week fixed dosing. Ophthalmology. 2011 Jun:118(6):1098-106. doi: 10.1016/j.ophtha.2011.03.020. Epub [PubMed PMID: 21640258]

Level 1 (high-level) evidence

[64]

Kim E, Han J, Chae Y, Park H, Kim S, Kim S, Lee J, Kim BC. Evaluation of the Structural, Physicochemical, and Biological Characteristics of SB11, as Lucentis(®) (Ranibizumab) Biosimilar. Ophthalmology and therapy. 2022 Apr:11(2):639-652. doi: 10.1007/s40123-022-00453-7. Epub 2022 Jan 27 [PubMed PMID: 35084693]

[65]

Sharma A, Kondo M, Iwahashi C, Parachuri N, Kumar N, Bandello F, Loewenstein A, Kuppermann BD. Approved biosimilar ranibizumab-a global update. Eye (London, England). 2023 Feb:37(2):200-202. doi: 10.1038/s41433-022-02246-5. Epub 2022 Sep 16 [PubMed PMID: 36114290]

[66]

Dugel PU, Koh A, Ogura Y, Jaffe GJ, Schmidt-Erfurth U, Brown DM, Gomes AV, Warburton J, Weichselberger A, Holz FG, HAWK and HARRIER Study Investigators. HAWK and HARRIER: Phase 3, Multicenter, Randomized, Double-Masked Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration. Ophthalmology. 2020 Jan:127(1):72-84. doi: 10.1016/j.ophtha.2019.04.017. Epub 2019 Apr 12 [PubMed PMID: 30986442]

Level 1 (high-level) evidence

[67]

Baumal CR, Spaide RF, Vajzovic L, Freund KB, Walter SD, John V, Rich R, Chaudhry N, Lakhanpal RR, Oellers PR, Leveque TK, Rutledge BK, Chittum M, Bacci T, Enriquez AB, Sund NJ, Subong ENP, Albini TA. Retinal Vasculitis and Intraocular Inflammation after Intravitreal Injection of Brolucizumab. Ophthalmology. 2020 Oct:127(10):1345-1359. doi: 10.1016/j.ophtha.2020.04.017. Epub 2020 Apr 25 [PubMed PMID: 32344075]

[68]

Dugel PU, Singh RP, Koh A, Ogura Y, Weissgerber G, Gedif K, Jaffe GJ, Tadayoni R, Schmidt-Erfurth U, Holz FG. HAWK and HARRIER: Ninety-Six-Week Outcomes from the Phase 3 Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration. Ophthalmology. 2021 Jan:128(1):89-99. doi: 10.1016/j.ophtha.2020.06.028. Epub 2020 Jun 20 [PubMed PMID: 32574761]

[69]

Woo SJ, Bradvica M, Vajas A, Sagong M, Ernest J, Studnicka J, Veith M, Wylegala E, Patel S, Yun C, Orski M, Astakhov S, Tóth-Molnár E, Csutak A, Enyedi L, Kim T, Oh I, Jang H, Sadda SR. Efficacy and Safety of the Aflibercept Biosimilar SB15 in Neovascular Age-Related Macular Degeneration: A Phase 3 Randomized Clinical Trial. JAMA ophthalmology. 2023 Jul 1:141(7):668-676. doi: 10.1001/jamaophthalmol.2023.2260. Epub [PubMed PMID: 37289448]

Level 1 (high-level) evidence

[70]

Nicolò M, Ferro Desideri L, Vagge A, Traverso CE. Faricimab: an investigational agent targeting the Tie-2/angiopoietin pathway and VEGF-A for the treatment of retinal diseases. Expert opinion on investigational drugs. 2021 Mar:30(3):193-200. doi: 10.1080/13543784.2021.1879791. Epub 2021 Feb 4 [PubMed PMID: 33471572]

Level 3 (low-level) evidence

[71]

Heier JS, Khanani AM, Quezada Ruiz C, Basu K, Ferrone PJ, Brittain C, Figueroa MS, Lin H, Holz FG, Patel V, Lai TYY, Silverman D, Regillo C, Swaminathan B, Viola F, Cheung CMG, Wong TY, TENAYA and LUCERNE Investigators. Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials. Lancet (London, England). 2022 Feb 19:399(10326):729-740. doi: 10.1016/S0140-6736(22)00010-1. Epub 2022 Jan 24 [PubMed PMID: 35085502]

Level 1 (high-level) evidence

[72]

Sahni J, Dugel PU, Patel SS, Chittum ME, Berger B, Del Valle Rubido M, Sadikhov S, Szczesny P, Schwab D, Nogoceke E, Weikert R, Fauser S. Safety and Efficacy of Different Doses and Regimens of Faricimab vs Ranibizumab in Neovascular Age-Related Macular Degeneration: The AVENUE Phase 2 Randomized Clinical Trial. JAMA ophthalmology. 2020 Sep 1:138(9):955-963. doi: 10.1001/jamaophthalmol.2020.2685. Epub [PubMed PMID: 32729888]

Level 1 (high-level) evidence

[73]

Khanani AM, Patel SS, Ferrone PJ, Osborne A, Sahni J, Grzeschik S, Basu K, Ehrlich JS, Haskova Z, Dugel PU. Efficacy of Every Four Monthly and Quarterly Dosing of Faricimab vs Ranibizumab in Neovascular Age-Related Macular Degeneration: The STAIRWAY Phase 2 Randomized Clinical Trial. JAMA ophthalmology. 2020 Sep 1:138(9):964-972. doi: 10.1001/jamaophthalmol.2020.2699. Epub [PubMed PMID: 32729897]

Level 1 (high-level) evidence

[74]

Lalwani GA, Rosenfeld PJ, Fung AE, Dubovy SR, Michels S, Feuer W, Davis JL, Flynn HW Jr, Esquiabro M. A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO Study. American journal of ophthalmology. 2009 Jul:148(1):43-58.e1. doi: 10.1016/j.ajo.2009.01.024. Epub 2009 Apr 18 [PubMed PMID: 19376495]

[75]

Augsburger M, Sarra GM, Imesch P. Treat and extend versus pro re nata regimens of ranibizumab and aflibercept in neovascular age-related macular degeneration: a comparative study. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 2019 Sep:257(9):1889-1895. doi: 10.1007/s00417-019-04404-0. Epub 2019 Jun 29 [PubMed PMID: 31256237]

Level 2 (mid-level) evidence

[76]

Kertes PJ, Galic IJ, Greve M, Williams G, Baker J, Lahaie M, Sheidow T. Efficacy of a Treat-and-Extend Regimen With Ranibizumab in Patients With Neovascular Age-Related Macular Disease: A Randomized Clinical Trial. JAMA ophthalmology. 2020 Mar 1:138(3):244-250. doi: 10.1001/jamaophthalmol.2019.5540. Epub [PubMed PMID: 31917441]

Level 1 (high-level) evidence

[77]

Adrean SD, Chaili S, Grant S, Pirouz A. Recurrence Rate of Choroidal Neovascularization in Neovascular Age-Related Macular Degeneration Managed with a Treat-Extend-Stop Protocol. Ophthalmology. Retina. 2018 Mar:2(3):225-230. doi: 10.1016/j.oret.2017.07.009. Epub 2017 Sep 28 [PubMed PMID: 31047590]

[78]

Cao X, Sanchez JC, Dinabandhu A, Guo C, Patel TP, Yang Z, Hu MW, Chen L, Wang Y, Malik D, Jee K, Daoud YJ, Handa JT, Zhang H, Qian J, Montaner S, Sodhi A. Aqueous proteins help predict the response of patients with neovascular age-related macular degeneration to anti-VEGF therapy. The Journal of clinical investigation. 2022 Jan 18:132(2):. doi: 10.1172/JCI144469. Epub [PubMed PMID: 34874918]

Level 2 (mid-level) evidence

[79]

Li E, Donati S, Lindsley KB, Krzystolik MG, Virgili G. Treatment regimens for administration of anti-vascular endothelial growth factor agents for neovascular age-related macular degeneration. The Cochrane database of systematic reviews. 2020 May 5:5(5):CD012208. doi: 10.1002/14651858.CD012208.pub2. Epub 2020 May 5 [PubMed PMID: 32374423]

Level 1 (high-level) evidence

[80]

Bakri SJ, Thorne JE, Ho AC, Ehlers JP, Schoenberger SD, Yeh S, Kim SJ. Safety and Efficacy of Anti-Vascular Endothelial Growth Factor Therapies for Neovascular Age-Related Macular Degeneration: A Report by the American Academy of Ophthalmology. Ophthalmology. 2019 Jan:126(1):55-63. doi: 10.1016/j.ophtha.2018.07.028. Epub 2018 Aug 2 [PubMed PMID: 30077616]

[81]

Moja L, Lucenteforte E, Kwag KH, Bertele V, Campomori A, Chakravarthy U, D'Amico R, Dickersin K, Kodjikian L, Lindsley K, Loke Y, Maguire M, Martin DF, Mugelli A, Mühlbauer B, Püntmann I, Reeves B, Rogers C, Schmucker C, Subramanian ML, Virgili G. Systemic safety of bevacizumab versus ranibizumab for neovascular age-related macular degeneration. The Cochrane database of systematic reviews. 2014 Sep 15:9(9):CD011230. doi: 10.1002/14651858.CD011230.pub2. Epub 2014 Sep 15 [PubMed PMID: 25220133]

Level 1 (high-level) evidence

[82]

Sharma A, Kumar N, Kuppermann BD, Bandello F. Abicipar pegol: the non-monoclonal antibody anti-VEGF. Eye (London, England). 2020 May:34(5):797-801. doi: 10.1038/s41433-019-0607-8. Epub 2019 Sep 30 [PubMed PMID: 31570812]

[83]

Kunimoto D, Yoon YH, Wykoff CC, Chang A, Khurana RN, Maturi RK, Agostini H, Souied E, Chow DR, Lotery AJ, Ohji M, Bandello F, Belfort R Jr, Li XY, Jiao J, Le G, Schmidt W, Hashad Y, CEDAR and SEQUOIA Study Groups. Efficacy and Safety of Abicipar in Neovascular Age-Related Macular Degeneration: 52-Week Results of Phase 3 Randomized Controlled Study. Ophthalmology. 2020 Oct:127(10):1331-1344. doi: 10.1016/j.ophtha.2020.03.035. Epub 2020 Apr 9 [PubMed PMID: 32471729]

Level 1 (high-level) evidence

[84]

Khurana RN, Kunimoto D, Yoon YH, Wykoff CC, Chang A, Maturi RK, Agostini H, Souied E, Chow DR, Lotery AJ, Ohji M, Bandello F, Belfort R Jr, Li XY, Jiao J, Le G, Kim K, Schmidt W, Hashad Y, CEDAR and SEQUOIA Study Groups. Two-Year Results of the Phase 3 Randomized Controlled Study of Abicipar in Neovascular Age-Related Macular Degeneration. Ophthalmology. 2021 Jul:128(7):1027-1038. doi: 10.1016/j.ophtha.2020.11.017. Epub 2020 Nov 19 [PubMed PMID: 33221326]

Level 1 (high-level) evidence

[85]

Kunimoto D, Ohji M, Maturi RK, Sekiryu T, Wang Y, Pan G, Li XY, Schneider S, BAMBOO and CYPRESS Study Groups. Evaluation of Abicipar Pegol (an Anti-VEGF DARPin Therapeutic) in Patients With Neovascular Age-Related Macular Degeneration: Studies in Japan and the United States. Ophthalmic surgery, lasers & imaging retina. 2019 Feb 1:50(2):e10-e22. doi: 10.3928/23258160-20190129-13. Epub [PubMed PMID: 30768224]

[86]

Ferro Desideri L, Traverso CE, Nicolò M. An update on conbercept to treat wet age-related macular degeneration. Drugs of today (Barcelona, Spain : 1998). 2020 May:56(5):311-320. doi: 10.1358/dot.2020.56.5.3137164. Epub [PubMed PMID: 32406878]

[87]

Chen ER, Kaiser PK. Therapeutic Potential of the Ranibizumab Port Delivery System in the Treatment of AMD: Evidence to Date. Clinical ophthalmology (Auckland, N.Z.). 2020:14():1349-1355. doi: 10.2147/OPTH.S194234. Epub 2020 May 19 [PubMed PMID: 32546942]

[88]

Holekamp NM, Campochiaro PA, Chang MA, Miller D, Pieramici D, Adamis AP, Brittain C, Evans E, Kaufman D, Maass KF, Patel S, Ranade S, Singh N, Barteselli G, Regillo C, all Archway Investigators. Archway Randomized Phase 3 Trial of the Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration. Ophthalmology. 2022 Mar:129(3):295-307. doi: 10.1016/j.ophtha.2021.09.016. Epub 2021 Sep 29 [PubMed PMID: 34597713]

Level 1 (high-level) evidence

[89]

Sharma A, Khanani AM, Parachuri N, Kumar N, Bandello F, Kuppermann BD. Port delivery system with ranibizumab (Susvimo) recall- What does it mean to the retina specialists. International journal of retina and vitreous. 2023 Jan 30:9(1):6. doi: 10.1186/s40942-023-00446-z. Epub 2023 Jan 30 [PubMed PMID: 36717931]

[90]

Arepalli S, Kaiser PK. Pipeline therapies for neovascular age related macular degeneration. International journal of retina and vitreous. 2021 Oct 1:7(1):55. doi: 10.1186/s40942-021-00325-5. Epub 2021 Oct 1 [PubMed PMID: 34598731]

[91]

. The influence of treatment extent on the visual acuity of eyes treated with Krypton laser for juxtafoveal choroidal neovascularization. Macular Photocoagulation Study Group. Archives of ophthalmology (Chicago, Ill. : 1960). 1995 Feb:113(2):190-4 [PubMed PMID: 7532395]

Level 1 (high-level) evidence

[92]

Schmidt-Erfurth U, Miller JW, Sickenberg M, Laqua H, Barbazetto I, Gragoudas ES, Zografos L, Piguet B, Pournaras CJ, Donati G, Lane AM, Birngruber R, van den Berg H, Strong HA, Manjuris U, Gray T, Fsadni M, Bressler NM. Photodynamic therapy with verteporfin for choroidal neovascularization caused by age-related macular degeneration: results of retreatments in a phase 1 and 2 study. Archives of ophthalmology (Chicago, Ill. : 1960). 1999 Sep:117(9):1177-87 [PubMed PMID: 10496389]

[93]

Giansanti F, Eandi CM, Virgili G. Submacular surgery for choroidal neovascularisation secondary to age-related macular degeneration. The Cochrane database of systematic reviews. 2009 Apr 15:(2):CD006931. doi: 10.1002/14651858.CD006931.pub2. Epub 2009 Apr 15 [PubMed PMID: 19370663]

Level 1 (high-level) evidence

[94]

van Romunde SH, Polito A, Bertazzi L, Guerriero M, Pertile G. Long-Term Results of Full Macular Translocation for Choroidal Neovascularization in Age-Related Macular Degeneration. Ophthalmology. 2015 Jul:122(7):1366-74. doi: 10.1016/j.ophtha.2015.03.012. Epub 2015 Apr 14 [PubMed PMID: 25881514]

[95]

Martel JN, Mahmoud TH. Subretinal pneumatic displacement of subretinal hemorrhage. JAMA ophthalmology. 2013 Dec:131(12):1632-5. doi: 10.1001/jamaophthalmol.2013.5464. Epub [PubMed PMID: 24337559]

[96]

Shienbaum G, Garcia Filho CA, Flynn HW Jr, Nunes RP, Smiddy WE, Rosenfeld PJ. Management of submacular hemorrhage secondary to neovascular age-related macular degeneration with anti-vascular endothelial growth factor monotherapy. American journal of ophthalmology. 2013 Jun:155(6):1009-13. doi: 10.1016/j.ajo.2013.01.012. Epub 2013 Mar 7 [PubMed PMID: 23465269]

Level 2 (mid-level) evidence

[97]

Kishikova L, Saad AAA, Vaideanu-Collins D, Isac M, Hamada D, El-Haig WM. Comparison between different techniques for treatment of submacular haemorrhage due to Age-Related Macular Degeneration. European journal of ophthalmology. 2021 Sep:31(5):2621-2624. doi: 10.1177/1120672120959551. Epub 2020 Sep 29 [PubMed PMID: 32993349]

[98]

Evans JR, Igwe C, Jackson TL, Chong V. Radiotherapy for neovascular age-related macular degeneration. The Cochrane database of systematic reviews. 2020 Aug 26:8(8):CD004004. doi: 10.1002/14651858.CD004004.pub4. Epub 2020 Aug 26 [PubMed PMID: 32844399]

Level 1 (high-level) evidence

[99]

Liu Y, Fortmann SD, Shen J, Wielechowski E, Tretiakova A, Yoo S, Kozarsky K, Wang J, Wilson JM, Campochiaro PA. AAV8-antiVEGFfab Ocular Gene Transfer for Neovascular Age-Related Macular Degeneration. Molecular therapy : the journal of the American Society of Gene Therapy. 2018 Feb 7:26(2):542-549. doi: 10.1016/j.ymthe.2017.12.002. Epub 2017 Dec 8 [PubMed PMID: 29292162]

[100]

Tripathy K, Quint JM. Angioid Streaks. StatPearls. 2024 Jan:(): [PubMed PMID: 30844178]

[101]

Tripathy K. Choroidal neovascular membrane in intraocular tuberculosis. GMS ophthalmology cases. 2017:7():Doc24. doi: 10.3205/oc000075. Epub 2017 Sep 1 [PubMed PMID: 28944155]

Level 3 (low-level) evidence

[102]

Tripathy K, Chawla R, Sharma YR. Intravitreal Bevacizumab for Choroidal Neovascular Membrane at the Edge of a Healed Choroidal Tuberculoma. Ocular immunology and inflammation. 2018:26(2):239-241. doi: 10.1080/09273948.2016.1206205. Epub 2016 Aug 19 [PubMed PMID: 27541084]

[103]

Wadekar B, Tripathy K, Chawla R, Venkatesh P, Sharma YR, Vohra R. An 18-year-old female with unilateral painless vision loss. Oman journal of ophthalmology. 2016 Sep-Dec:9(3):193 [PubMed PMID: 27843243]

[104]

Chi SC, Kang YN, Huang YM. Systematic review with network meta-analysis of antivascular endothelial growth factor use in managing polypoidal choroidal vasculopathy. Scientific reports. 2021 Feb 2:11(1):2735. doi: 10.1038/s41598-021-82316-y. Epub 2021 Feb 2 [PubMed PMID: 33531615]

Level 1 (high-level) evidence

[105]

Arda H, Haritoglou C. [PEHCR-Peripheral exudative hemorrhagic chorioretinopathy: Diagnosis and treatment]. Die Ophthalmologie. 2022 Aug:119(8):868-871. doi: 10.1007/s00347-022-01658-8. Epub 2022 May 31 [PubMed PMID: 35925329]

[106]

Vandefonteyne S, Caujolle JP, Rosier L, Conrath J, Quentel G, Tadayoni R, Maschi C, Le Mer Y, Dot C, Aknin I, Thariat J, Baillif S. Diagnosis and treatment of peripheral exudative haemorrhagic chorioretinopathy. The British journal of ophthalmology. 2020 Jun:104(6):874-878. doi: 10.1136/bjophthalmol-2018-313307. Epub 2019 Oct 23 [PubMed PMID: 31645320]

[107]

Shields CL, Salazar PF, Mashayekhi A, Shields JA. Peripheral exudative hemorrhagic chorioretinopathy simulating choroidal melanoma in 173 eyes. Ophthalmology. 2009 Mar:116(3):529-35. doi: 10.1016/j.ophtha.2008.10.015. Epub 2009 Jan 20 [PubMed PMID: 19157563]

Level 2 (mid-level) evidence

[108]

Yannuzzi LA, Negrão S, Iida T, Carvalho C, Rodriguez-Coleman H, Slakter J, Freund KB, Sorenson J, Orlock D, Borodoker N. Retinal angiomatous proliferation in age–related macular degeneration. 2001. Retina (Philadelphia, Pa.). 2012 Feb:32 Suppl 1():416-34 [PubMed PMID: 22451953]

[109]

Bressler NM, Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials-tap report 2. Archives of ophthalmology (Chicago, Ill. : 1960). 2001 Feb:119(2):198-207 [PubMed PMID: 11176980]

Level 1 (high-level) evidence

[110]

. Laser photocoagulation of subfoveal neovascular lesions in age-related macular degeneration. Results of a randomized clinical trial. Macular Photocoagulation Study Group. Archives of ophthalmology (Chicago, Ill. : 1960). 1991 Sep:109(9):1220-31 [PubMed PMID: 1718250]

Level 1 (high-level) evidence

[111]

. Laser photocoagulation of subfoveal neovascular lesions of age-related macular degeneration. Updated findings from two clinical trials. Macular Photocoagulation Study Group. Archives of ophthalmology (Chicago, Ill. : 1960). 1993 Sep:111(9):1200-9 [PubMed PMID: 7689827]

Level 1 (high-level) evidence

[112]

Bressler NM, Frost LA, Bressler SB, Murphy RP, Fine SL. Natural course of poorly defined choroidal neovascularization associated with macular degeneration. Archives of ophthalmology (Chicago, Ill. : 1960). 1988 Nov:106(11):1537-42 [PubMed PMID: 2461191]

[113]

Bressler SB, Pieramici DJ, Koester JM, Bressler NM. Natural history of minimally classic subfoveal choroidal neovascular lesions in the treatment of age-related macular degeneration with photodynamic therapy (TAP) investigation: outcomes potentially relevant to management--TAP report No. 6. Archives of ophthalmology (Chicago, Ill. : 1960). 2004 Mar:122(3):325-9 [PubMed PMID: 15006843]

[114]

Hanscom TA, Diddie KR. Early surgical drainage of macular subretinal hemorrhage. Archives of ophthalmology (Chicago, Ill. : 1960). 1987 Dec:105(12):1722-3 [PubMed PMID: 3689195]

Level 3 (low-level) evidence

[115]

Schoeppner G, Chuang EL, Bird AC. The risk of fellow eye visual loss with unilateral retinal pigment epithelial tears. American journal of ophthalmology. 1989 Dec 15:108(6):683-5 [PubMed PMID: 2596548]

[116]

Mangione CM, Gutierrez PR, Lowe G, Orav EJ, Seddon JM. Influence of age-related maculopathy on visual functioning and health-related quality of life. American journal of ophthalmology. 1999 Jul:128(1):45-53 [PubMed PMID: 10482093]

Level 2 (mid-level) evidence

[117]

Williams RA, Brody BL, Thomas RG, Kaplan RM, Brown SI. The psychosocial impact of macular degeneration. Archives of ophthalmology (Chicago, Ill. : 1960). 1998 Apr:116(4):514-20 [PubMed PMID: 9565052]

[118]

Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Archives of ophthalmology (Chicago, Ill. : 1960). 2001 Oct:119(10):1417-36 [PubMed PMID: 11594942]

Level 1 (high-level) evidence

[119]

Age-Related Eye Disease Study 2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA. 2013 May 15:309(19):2005-15. doi: 10.1001/jama.2013.4997. Epub [PubMed PMID: 23644932]

Level 1 (high-level) evidence

[120]

Margrain TH. Helping blind and partially sighted people to read: the effectiveness of low vision aids. The British journal of ophthalmology. 2000 Aug:84(8):919-21 [PubMed PMID: 10906105]

[121]

Shuttleworth GN, Dunlop A, Collins JK, James CR. How effective is an integrated approach to low vision rehabilitation? Two year follow up results from south Devon. The British journal of ophthalmology. 1995 Aug:79(8):719-23 [PubMed PMID: 7547780]