Wet Age-Related Macular Degeneration (AMD)

Samuel Hobbs; Koushik Tripathy; Kristine Pierce

Wet Age-Related Macular Degeneration (AMD)

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Continuing Education Activity

Wet (exudative or neovascular) age-related macular degeneration is the most common cause of visual impairment among older patients in developed countries. Approximately 10% of patients with age-related macular degeneration develop choroidal neovascularization, which is the hallmark of wet age-related macular degeneration. Vascular endothelial growth factor plays a critical role in the development of choroidal neovascularization, leading to complications such as bleeding under the retina, retinal pigment epithelium detachment or atrophy, hard exudate deposition, or subretinal or subretinal pigment epithelium fluid accumulation with associated vision loss.

Wet age-related macular degeneration diagnosis relies on clinical examination and imaging techniques. Fundus examination may show retinal hemorrhages or exudates, whereas optical coherence tomography offers detailed images of retinal structure and fluid. Fluorescein angiography helps confirm neovascularization by visualizing dye leakage from retinal blood vessels.

Anti-vascular endothelial growth factor therapy is the primary treatment, with intravitreal injections of agents such as ranibizumab or aflibercept reducing abnormal blood vessel growth and fluid leakage. Depending on the case, laser photocoagulation and photodynamic therapy may also be used. Regular monitoring is crucial for assessing treatment effectiveness and making the necessary adjustments.

This activity for healthcare professionals is designed to enhance learners' competence in evaluating and managing wet age-related macular degeneration. Participants gain a deeper understanding of the condition's risk factors, pathogenesis, clinical presentation, and recommended evaluation and management strategies. Emphasis is placed on the role of the interprofessional team in improving patient care. Enhanced proficiency enables learners to work effectively and confidently within an interprofessional team caring for patients with wet age-related macular degeneration.

Objectives:

Determine the risk factors for developing wet age-related macular degeneration.
Identify the typical presentation of a patient with wet age-related macular degeneration.
Implement current evidence-based treatment options for wet age-related macular degeneration.
Collaborate with the interprofessional team to educate, treat, and monitor patients with wet age-related macular degeneration and improve patient outcomes.

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

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]

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]

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]

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]

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]

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]

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]

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]

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.

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]

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.

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]

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]

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.

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]

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.

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.

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]

(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

Details

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