Wet Age-Related Macular Degeneration (AMD)

Samuel Hobbs; Kristine Pierce

Wet Age-Related Macular Degeneration (AMD)

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Continuing Education Activity

Wet (exudative or neovascular) age-related macular degeneration (AMD) is the most common cause of visual impairment among older patients in developed countries. Approximately 10% of patients with AMD will develop choroidal neovascularization (CNV), which is the hallmark of wet AMD. Vascular endothelial growth factor (VEGF) is one of the key factors in the development of CNV, which may lead to bleeding under the retina, detachment or atrophy of the retinal pigment epithelium (RPE), deposition of hard exudates, or sub-retinal or sub-RPE fluid accumulation with associated vision loss. This activity describes the clinical presentation, evaluation, management of the disease, and the role of an interprofessional team approach in improving care for patients with this condition.

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.
Interpret the typical imaging findings associated with choroidal neovascularization and management of wet age-related macular degeneration.
Collaborate with the interprofessional team to improve care and outcomes in patients with wet age-related macular degeneration.

Introduction

The retina is a layer of neurosensory tissue in the eye that converts light into neural signals that 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 via breaks in the Bruch membrane.[3] Regular administration of intravitreal anti-VEGF medications may prevent blindness in most of these patients.[4] Without such treatment, patients with wet AMD experience severe, irreversible vision loss.[5]

Etiology

AMD is a multifactorial disease, and numerous risk factors have been identified. The possible risk factors are as follows:[6][7]

older age
elevated total serum cholesterol
micronutrient deficiency
smoking
family history
hypertension
cardiovascular disease
visible light exposure

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 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 globally. The global prevalence of AMD among those aged 45 to 85 years was 8.7%, with a prevalence of 0.4% for advanced AMD.[11] Early AMD is more common among those of European ancestry than Asians, and AMD of any stage is less common in individuals of African origin.[12] The global prevalence of any stage of AMD 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-vascular endothelial growth factor therapy, between 79% to 90% of affected eyes will 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 retinal pigment epithelium 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:[16]

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 based into 2 types on anatomic histopathological location:[17]

Type 1 CNV is located below the retinal pigment epithelium (RPE). Type 1 CNV is usually seen with AMD and correlates with occult CNV in fluorescein angiography.[18]
Type 2 CNV is subretinal (between the retina and the retinal pigment epithelium, RPE). This is usually noted with CNVs secondary to presumed ocular histoplasmosis syndrome.[17] Classic CNV in wet AMD is a type 2 CNV.[18]

Type 3 neovascularization (retinal angiomatous proliferation) starts intraretinally and then reaches the subretinal or sub-RPE area.[19][20] As the area of origin of the neovascularization may vary and might not start at the choroid itself, these subtypes are currently included under the broad term macular neovascularization (MNV) as per the Consensus Nomenclature for Reporting Neovascular Age-Related Macular Degeneration.[21]

MNV is further classified into type 1, type 2, or type 3 according to multimodal imaging characteristics that include optical coherence tomography (OCT), OCT angiography, fluorescein angiography, and indocyanine green angiography.[21] 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 detachments.[21] Polypoidal choroidal vasculopathy is a subtype of type 1 MNV.[21] Type 2 MNV originates in the choroid and passes through the Bruch's membrane and RPE to reach the subretinal space, where it proliferates.[21] In type 3 MNV, the new vessel starts from the retinal circulation, typically in the deep retinal capillary plexus, and then grows towards the outer retina.[21]

History and Physical

Patients with wet age-related macular degeneration (AMD) typically report visual distortion or blurring of central vision, especially their near vision. Other patients report metamorphopsia, micropsia, or scotoma, although some may report no symptoms or only vague vision complaints.[22]

On examination, patients frequently have decreased best-corrected visual acuity, and Amsler grid evaluation may reveal areas of central, paracentral scotoma, or visual distortion. Ophthalmic examination of the anterior segment of the eye is usually normal. Age-related cataracts or pseudophakia may be noted. AMD-related choroidal neovascularization has several different appearances on the dilated funduscopic exam.[23] These may include the following:

A gray-green membrane deep into the retina, which is usually associated with an overlying neurosensory retinal detachment
Presence of blood, lipid, or subretinal fluid;
Retinal pigment epithelium (RPE) detachment appear clinically as dome-shaped, sharply demarcated elevations of the RPE. (These may also be serous, fibrovascular, drusenoid, or hemorrhagic.[24] A notch in serous PED may denote the location of occult choroidal neovascular membranes.);[25]
Massive subretinal hemorrhage with central vision loss or, less commonly, breakthrough vitreous hemorrhage with peripheral vision loss;
RPE tear or RPE rip;[26] and
Disciform scars may be present, which may appear as white or yellow subretinal membranes with or without RPE hyperplasia and pigmentation.

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

Evaluation

The ocular investigations of patients with wet age-related macular degeneration (AMD) include the following:

Optical Coherence Tomography

Optical coherence tomograpy (OCT) computerized tompgraphy is a noninvasive imaging modality that can capture detailed images of the retina and surrounding structures.[27] It uses low-coherence light beams directed toward the target tissue, and the reflected light is combined with a reference beam and measured to create an interference pattern. This is used to reconstruct an axial A-scan. Multiple A-scans can be used to reconstruct a cross-sectional B-scan. From there, raster scans and 3-dimensional images can be produced. Features of Wet AMD on OCT macula include the following[28]:

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

OCT 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 only show areas with movement (ie, flow-through vessels).[31] OCTA may be useful in the earlier diagnosis of choroidal neovascularization (CNV), even before such lesions can be detected by conventional OCT or fluorescein angiography imaging.[32]

Fundus Fluorescein Angiography

Fundus fluorescein angiography (FFA) should be considered early in diagnosing wet AMD to prevent an error in diagnosis.[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 been traditionally used to place CNVs into either classic or occult classifications. This classification has been particularly useful for treatment decisions using photodynamic therapy with verteporfin, which may work better in classic or predominantly classic (classic CNV occupying at least 50% of the size of the lesion) CNV rather than occult CNV or minimally classic CNV (less than 50% area of lesion occupied by classic CNV).[37] Classic CNV is characterized by well-demarcated areas of hyperfluorescence present in early phases of imaging with mid and late leakage. Occult CNV is characterized by either an FVPED that demonstrates stippled hyperfluorescent dots with pooling, with or without leakage, or late leakage of an undetermined source, often presenting as speckled hyperfluorescence with subretinal pooling of dye in the late phase.

Common FFA patterns in wet AMD can include the following:

Retinal angiomatous proliferation (RAP, type 3 macular neovascularization), 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;
Serous PED, which can 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 pooling of fluorescein dye anterior to the area of CNV;
RPE tears, which manifest as early hyperfluorescence with late staining of the choroid and sclera without leakage;[39] and
Disciform scars, which may show staining or blocking if there is RPE hyperplasia.

Indocyanine Green Angiography (ICGA)

Indocyanine green angiography (ICGA) is a dye that is useful for imaging the choroidal circulation as it is highly protein-bound and less likely to leak from the fenestrations in choroidal vessels.[40] ICGA is especially helpful in delineating occult CNV, which may manifest as either 1) a hot spot or area of early- to mid-phase hyperfluorescence, 2) a plaque or area of late hyperfluorescence, or 3) an area of poorly-defined fluorescence.[41] ICGA may be used to identify feeder vessels in CNV that may be treated with laser photocoagulation. It may also better compare subtypes of CNV, allowing for earlier diagnosis and determination of patient prognosis.[42] ICGA is very helpful in identifying idiopathic polypoidal choroidal vasculopathy (PCV) which is a close differential diagnosis of wet AMD. ICGA features of PCV include early focal subretinal hypercyanescence (polyps) within 6 minutes, pulsatile polyps, hypocyanescent halo around the polyp, and a branching vascular network.[43] The ICGA features of retinal angiomatous proliferation include hot spots in the mid or late phase, retinochoroidal, and retinal-retinal (hairpin-like loop directly connecting a retinal arteriole and venule) anastomosis.[44]

Treatment / Management

The mainstay of therapy for wet age-related macular degeneration (AMD) is intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents which not only prevent visual loss but may also improve vision in some cases.[45]

Intravitreal Anti-VEGF Therapy

Pegaptanib sodium, a VEGF(165)-specific antagonist was the first Food and Drug Administration (FDA) approved (17 December 2004) intravitreal anti-VEGF agent for wet AMD.[46] However, this has since been replaced by bevacizumab, ranibizumab, and aflibercept due to improved results in various trials.[47][48][49] The VISION study compared intravitreal pegaptanib with sham intravitreal injections in wet AMD and determined its efficacy in preventing vision loss.[50]

Ranibizumab is a recombinant humanized antibody fragment that binds all isoforms of VEGF-A. The FDA approved ranibizumab for wet AMD on 30 June 2006. The MARINA[51] and ANCHOR[48] studies evaluated ranibizumab in minimally classic (occult) and classic choroidal neovascularization (CNV), respectively. The ANCHOR trial showed superior efficacy of ranibizumab compared to photodynamic therapy (PDT) in classic CNV.[48]

Bevacizumab, approved by the FDA for metastatic colorectal carcinoma, is used off-label for AMD treatment.[52] It is non-inferior to ranibizumab for this purpose, as seen in multiple studies including CATT,[53] IVAN,[54] GEFAL,[55] LUCAS,[56] BRAMD,[57] and MANTA.[47][58] However, some studies have suggested a higher risk of serious systemic events with bevacizumab compared to ranibizumab, a fact that might need further study.[59]

Aflibercept acts as a VEGF receptor decoy, effectively trapping all VEGF isoforms. It works against VEGF-A, VEGF-B, and the placental growth factor. Given every 2 months (after the initial 3 loading doses given every month), aflibercept dosing is as effective as monthly ranibizumab dosing.[60] The FDA approved aflibercept for wet AMD on 18 November 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][49][61]

The CLEAR-IT 2 study evaluated the as-needed protocol (initial 3 injections given monthly, followed by intravitreal injection as needed with monthly evaluation using optical coherence tomograpy (OCT) macula.[62]

Ranibizumab-nuna (also called SB11) was the first ranibizumab biosimilar agent to be approved by the FDA on 7 September 2021 for patients with wet AMD.[63]

Ranibizumab-eqrn is another ranibizumab biosimilar that was approved by FDA for use in patients with wet AMD on 2 August 2022.[64] Biosimilars of aflibercept are currently under development.

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. It was approved by the FDA on 8 October 2019 for use in wet AMD. It was found to be non-inferior to aflibercept with every 12-week dosage.[65] Despite early success with brolucizumab, concerns exist regarding reports of severe intraocular inflammation and vasculitis following administration.[66] HAWK and HARRIER trials evaluated brolucizumab's safety and efficacy in wet AMD.[67]

Faricimab-svoa is an antibody with affinity for VEGF and angiopoietin-2 (Ang-2), an additional factor that may drive inflammation and contribute to CNV development. Early reports of faricimab are promising, with extended dosing intervals of 16 weeks shown to be non-inferior to ranibizumab every 4 weeks.[68] Faricimab was FDA approved for use in wet AMD on 28 January 2022. TENAYA and LUCERNE demonstrated noninferiority of faricimab compared to aflibercept in wet AMD.[69] AVENUE[70] and STAIRWAY[71] trials compared faricimab with ranibizumab in wet AMD.

Various regimens for using anti-VEGF agents include the following:

Most anti-VEGF drugs are approved for fixed dosage schedules of:
- 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; or
- 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 the presence of subretinal/intraretinal fluid on OCT, retinal hemorrhage, or leakage on FA)[72].
A treat-and-extend (TAE) protocol, where injection frequency is slowly extended as long as disease activity remains controlled.[73][74][73]
A treat extend stop[75] 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 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 a minimum of 7 injections and dry macula at the 3rd, 12-week visit. The patient will then be evaluated monthly to detect recurrence of CNV, which was seen in around 30% of patients.[75]
A treat, extend, pause, and monitor (TEP/M)[76] protocol, which follows a TAE regimen initially. Injections were paused in stable patients who had reached every 12 weekly injections and a PRN protocol was started. The patient was called after 6 weeks (after 18 weeks of the last injection) and if the patient was stable, the patient did not receive an injection and was called after 12 weeks for evaluation (monitoring phase).

Although monthly injections are more effective than PRN regimens, there is inconclusive evidence comparing PRN versus treat-and-extend regimens. Endophthalmitis is likely more common with monthly injections, and patients receive more injections with monthly and treat-and-extend dosing than with PRN. However, patients require more frequent clinic visits with PRN than with treat-and-extend dosing.[77]

Long-term data suggest that PRN dosing may result in slightly worse visual outcomes than monthly injections after a year. Although this difference may be clinically insignificant after a year, it may become significant 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, usually from the iodine-based antiseptic used to clean the ocular surface. Floaters may be caused by bubbles in the syringe or by the medication itself. Serious adverse events rarely occur, and can include vitreous hemorrhage or endophthalmitis.[78] Several studies have also explored potential systemic adverse events related to intravitreal anti-VEGF administration, including the risk of myocardial infarction, stroke, non-ocular hemorrhage, or thromboembolic events. There is currently inadequate evidence to suggest an increase in systemic morbidity or mortality from the intravitreal administration of anti-VEGF agents.[79] However, this theoretical risk is still important to discuss with patients, especially those deemed higher risk.

Other treatments are still under investigation.

Abicipar pegol is a non-monoclonal antibody developed with designed ankyrin repeat proteins (DARPin) technology, with VEGF binding affinity similar to aflibercept.[80] Like brolucizumab, its use may be limited due to higher reported rates of intraocular inflammation.[81] It was not approved by the FDA, citing an unfavorable risk-benefit ratio. Studies evaluating the role of abicipar pegol in wet AMD included CEDAR,[82] SEQUOIA,[82] CYPRESS,[83] BAMBOO,[83] MAPLE, and REACH.[80]

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 currently underway.[84] Additionally, several sustained-release delivery devices are in development to help decrease the burden of frequent intravitreal injections and help reduce the potential for undertreatment.[85]

Ranibizumab port delivery system (PDS) was FDA approved on 22 October 2021, and requires refill exchanges every 24 weeks. It was shown to be non-inferior to monthly ranibizumab; however, the PDS had a higher risk of adverse events compared to ranibizumab monthly injections, including higher rates of endophthalmitis, retinal detachments, vitreous hemorrhages, conjunctival erosions, and conjunctival retractions.[86]

Other agents that are being evaluated for wet AMD include OPT-302 (targets VEGF-C and VEGF-D), KSI-301 (anti-VEGF-A), anti-PDGF (platelet-derived growth factor) agents (rinucumab, pegpleranib, X-82, DE-120, CLS-AX), gene therapy using various vectors including AAV (adeno-associated virus vector) to produce anti-VEGF agents (including VEGF receptor, ranibizumab, aflibercept; endostatin, and angiostatin), anti-tissue factor agents, and sustained release devices to release various drugs including ranibizumab and sunitinib (targets VEGF-A and PDGF).[87]Topical medications that are being evaluated in wet AMD include agents targeting anti-VEGF-A and PDGF (pazopanib, regorafenib, PAN-90806), squalamine (targets VEGF, PDGF, and b-FGF or basic fibroblast growth factor), and LHA510 (targeting tyrosine kinase).[87] Oral medications evaluated for the management of wet AMD include X-82 (tyrosine kinase inhibitor that inhibits VEGF and PDGF receptors) and AKST4290 (targets CCR3 the receptor for eotaxin).[87]

Other Treatments

Before the widespread use of anti-VEGF therapy, several other treatment modalities were employed for wet AMD.

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.[88] Because laser photocoagulation destroys the overlying retinal tissue, this treatment should not be used for fovea-involving lesions, which are more likely to be visually devastating for patients.

Photodynamic therapy 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.[89] 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, and it comes with the risk of cataract progression and retinal detachment.[90] Other surgical approaches for patients with CNV and vision loss include macular translocation surgery and mechanical displacement of subretinal hemorrhage with gas. There is still insufficient evidence to recommend macular translocation to patients unless a patient has a severe, bilateral disease that does not respond to anti-VEGF therapy.[91]

Pneumatic displacement of submacular hemorrhage, using intravitreal air or gas injection with face-down positioning, may improve a patient’s visual acuity.[92] Even in these patients, anti-VEGF therapy may be sufficient without surgical intervention.[93] Other approaches to the management of massive submacular hemorrhage include intravitreal or subretinal tissue plasminogen activator (t-PA), intravitreal gas, intravitreal anti-VEGF agent, pars plana vitrectomy, subretinal air injection, or various combinations of therapies.[94] Subretinal injections of agents usually need pars plana vitrectomy.

Radiation therapy has been considered for CNV in wet AMD, but studies have not found a clear benefit.[95] Radiation therapy in combination with intravitreal ranibizumab is inferior to the as-needed use of ranibizumab monotherapy.[95] There is currently no evidence to 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 (adeno-associated virus) vector expressing an anti-VEGF-A Fab similar to ranibizumab. Subretinal delivery of the medication has been shown to be generally safe and well-tolerated.[96] Phase 2 and 3 trials are currently underway to test the safety and efficacy of subretinal and suprachoroidal delivery of RGX-314.

Differential Diagnosis

The differential diagnosis for choroidal neovascularization (CNV) from wet age-related macular degeneration (AMD) should include other causes of CNV. These include the following:

Degenerative	Wet AMD Pathological myopia Angioid streak[97]
Inflammatory	Presumed ocular histoplasmosis syndrome (POHS)Punctate inner choroidopathy (PIC)Serpiginous choroiditis Serpiginous-like choroiditisMultifocal choroiditis Sympathetic ophthalmiaVogt Koyanagi Harada syndromeOcular tuberculosis[98][99]ToxocariasisToxoplasmosisRubella
Trauma	Choroidal ruptureLaser burnsIatrogenic (after vitreoretinal surgery)
Inherited retinal disorders	Best vitelliform macular dystrophyFundus flavimaculatus
Optic nerve disorders	Optic disc drusen
Tumors	Choroidal osteoma[100] Choroidal hemangiomaChoroidal 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 there is a poor view with dilated retinal examination. Diagnosis can be established by evaluating the patient’s fellow eye or obtaining a thorough history. Other potential causes of vitreous hemorrhage include the following:

Proliferative diabetic retinopathy;
Retinal tear or retinal detachment;
Hemorrhagic posterior vitreous detachment; and
Neovascularization from other causes (ie, vein occlusions, radiation retinopathy, or sickle cell retinopathy).

Polypoidal choroidal vasculopathy (PCV) is a subtype of wet age-related macular degeneration (AMD) that is more common in patients with Asian ancestry. It is characterized by orangish-red, bulb-like subretinal polyps associated with adjacent subretinal hemorrhage or exudates. ICGA is an essential tool in the diagnosis of PCV, and recurrent disease is more common among PCV patients than those with wet AMD. Patients with PCV may benefit more from PDT than typical wet AMD patients.[101]

Peripheral exudative hemorrhagic chorioretinopathy is a disease of older individuals, characterized by peripheral subretinal or sub-RPE hemorrhage or exudates, that may sometimes reach the posterior pole.[102] 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.[103] Treatment options include anti-VEGF agents, laser, photodynamic therapy, pars plana vitrectomy, and cryotherapy.[103] Peripheral exudative hemorrhagic chorioretinopathy may simulate choroidal melanoma.[104]

Retinal angiomatous proliferation (RAP, type 3 macular neovascularization) 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 usually starts at the deep capillary plexus and then grows outwards. 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).[105] Stage 3 is characterized by retinal-choroidal anastomosis and vascularized PEDs.[105] Treatment is similar to type 1 and 2 macular neovascularization.

Prognosis

More than 2 to 3 years without treatment, 50-60% of eyes with wet age-related macular degeneration and subfoveal choroidal neovascularization (CNV) will lose 6 or more lines of vision, compared to 20% to 30% of eyes with any submacular CNV.[106][107][108] Classic CNV is associated with worse visual outcomes than occult or minimally classic CNV, and up to half of the patients with no classic lesions on initial presentation may develop classic CNV within a year after diagnosis.[109][110]

Eyes with large subretinal hemorrhages that involve the fovea often have poor visual outcomes, although some eyes have surprisingly good visual recovery, suggesting that prompt treatment (such as with intravitreal anti-vascular endothelial growth factor medications or surgery) is still beneficial.[111] Retinal pigment epithelium 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.[112]

Complications

Untreated, wet age-related macular degeneration (AMD) leads to irreversible loss of vision in a majority of patients. Even with treatment, vision loss can still occur. Patients with vision loss from AMD often report a diminished quality of life.[113] They report significantly more emotional distress, poorer health, and less independence in daily activities than people with other chronic illnesses.[114]

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 age-related macular degeneration (AMD). Any change in near or distance vision may also indicate developing choroidal neovascularization, and patients should be instructed to contact their ophthalmologist without delay.[22] 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. They should regularly see their primary care physician and control any underlying systemic disorders. Select patients should also be encouraged to regularly use Age-Related Eye Disease Study (AREDS) or AREDS2 ingredients. These vitamins have been shown to prevent the progression to advanced AMD in patients with an intermediate disease or advanced disease in one eye.[115][116]

Patients who already have severe vision loss may benefit from visual rehabilitation and referral to a low-vision clinic, where they can learn about resources to help them function with their limited vision. Several low-vision tools can be offered, including handheld magnifiers, closed-circuit television viewers, or accessibility applications on common electronic devices, including both smartphones and tablets. In addition, they should be counseled on the availability of large-print periodicals, audiobooks, and other resources offered by their local library, and available through the Library of Congress. They 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 age-related macular degeneration (AMD) are usually evaluated by an interprofessional healthcare team which may include a referral to a retina specialist. Primary care providers, optometrists, and general ophthalmologists play a key role in recognizing the signs and symptoms of worsening wet AMD and referring patients to a retina specialist (or other clinicians trained in the evaluation of wet AMD and administration of 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 will help yield the best possible patient outcomes in wet AMD. [Level 5]

Although some believe that only retina specialists are qualified to administer intravitreal anti-vascular endothelial growth factor agents, there is a shortage of such specialists, especially in rural areas. This, along with the growth of the aging population in the United States and other developed countries, has led to more comprehensive ophthalmologists learning how to evaluate and treat patients with wet AMD. Despite this trend, comprehensive ophthalmologists should understand that care for patients with wet AMD requires complex decision-making on the basis of individual vitreoretinal pathology. Consultation or co-management with a retina specialist is recommended. [Level 5]

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.[117][118] [Level 3]

(Click Image to Enlarge)

Optical coherence tomography (OCT) image of an eye before (top) and four weeks after (bottom) intravitreal aflibercept injection. There is a significant reduction in subretinal fluid (hyporeflective area under the retina) post-injection.
Contributed by Samuel D. Hobbs, MD

(Click Image to Enlarge)

Amsler grid as seen by a normal eye (left) and one with wet age-related macular degeneration (ARMD) (right), demonstrating distortion and a paracentral scotoma. All patients with macular drusen should be educated on the importance of regular Amsler grid use to check for new-onset distortion or scotomas that may indicate conversion from dry to wet ARMD.
Contributed by Samuel D. Hobbs, MD

(Click Image to Enlarge)

Fundus photo of a left eye demonstrating drusen with a submacular hemorrhage, a complication of wet (exudative or neovascular) age-related macular degeneration.
Contributed by Samuel D. Hobbs, MD

(Click Image to Enlarge)

<p>Optical coherence tomography (OCT) image showing neovascular age-related macular degeneration (AMD) with subretinal fluid, retinal pigment epithelial detachment (PED), and subretinal hyperreflective material (SHRM)

Optical coherence tomography (OCT) image showing neovascular age-related macular degeneration (AMD) with subretinal fluid, retinal pigment epithelial detachment (PED), and subretinal hyperreflective material (SHRM).

Mutali Musa, OD

(Click Image to Enlarge)

<p>Optical coherence tomography (OCT) image showing wet age-related macular degeneration (AMD) with fibrovascular retinal pigment epithelial detachments (PED) and intraretinal fluid

Optical coherence tomography (OCT) image showing wet age-related macular degeneration (AMD) with fibrovascular retinal pigment epithelial detachments (PED) and intraretinal fluid.

Mutali Musa, OD

(Click Image to Enlarge)

Intraocular Hemorrhage, Hemorrhagic Choroidal Neovascular Membrane

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

(Click Image to Enlarge)

<p>Optical coherence tomography (OCT) image showing peripapillary choroidal neovascular membrane (CNVM) with subretinal hyperreflective material (SHRM) and subretinal fluid (SRF)

Optical coherence tomography (OCT) image showing peripapillary choroidal neovascular membrane (CNVM) with subretinal hyperreflective material (SHRM) and subretinal fluid (SRF).

Mutali Musa, OD

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retinal angiomatous proliferation
Contributed by Sabareesh Muraleedharan,MS, Aravind eye hospital, Madurai.

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FA (A) and ICGA (B) of the left eye of a patient with PCV
Contributed by Sabareesh Muraleedharan,MS, Aravind eye hospital, Madurai

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