Highlights & Basics
- Age-related macular degeneration is a potentially progressive maculopathy characterized by drusen formation, macular pigmentary changes, geographic atrophy, and neovascularization of the choriocapillaris with exudation.
- Sudden-onset of blurring or distortion of vision is often the presenting symptom in the neovascular form.
- Leading cause of adult blindness in industrialized nations.
- Typically affects people ages >55 years.
- Diagnosis and treatment are highly specialized and involve consultation with a retinal specialist.
Quick Reference
History & Exam
Key Factors
sudden-onset blurring or distortion of vision
drusen
macular pigmentary changes
geographic atrophy
choroidal neovascularization
Other Factors
progressive loss of vision in one or both eyes
fibrovascular pigment epithelial detachment (neovascular AMD)
fibrovascular scar formation
reticular pseudodrusen
Diagnostics Tests
1st Tests to Order
Amsler grid
optical coherence tomography
optical coherence tomography angiography
Other Tests to consider
fluorescein angiography
indocyanine green angiography
autofluorescence imaging
Emerging Tests
genotyping
Treatment Options
acute
early stage (AREDS 1 and 2)
observation ± specialist referral
risk factor modification
intermediate-stage (AREDS 3)
antioxidant and mineral supplementation
risk factor modification
specialist referral
Definition
Vignette
Common Vignette
Epidemiology
Etiology
Pathophysiology
Images
Early AMD (Age-Related Eye Disease Study Group [AREDS] category 2)
Intermediate AMD (Age-Related Eye Disease Study Group [AREDS] category 3)
Late AMD with central geographic atrophy (Age-Related Eye Disease Study Group [AREDS] category 4)
Late AMD with choroidal neovascularization with exudation (Age-Related Eye Disease Study Group [AREDS] category 4)
Fibrovascular scar from end-stage AMD (Age-Related Eye Disease Study Group [AREDS] category 4)
High resolution optical coherence tomography image showing subretinal and intraretinal fluid
Optical coherence tomography image showing outer retinal hyperreflective lesion, subretinal and intraretinal fluid
High resolution optical coherence tomography image showing hyperreflective scar
Fluorescein angiogram showing active choroidal neovascularization
Optical coherence tomography angiography image showing hyperreflective lesion which corresponds with a network of choroidal neovascularization; this has proliferated in between the neurosensory retina and retinal pigment epithelium
Diagnostic Approach
Clinical evaluation
Ophthalmic exam
- Patients in the early stages of disease will typically have medium-sized drusen.Image
- Patients with intermediate disease will typically have pigmentary changes, and medium and/or large drusen.Image
- Late-stage disease is characterized by geographic atrophy and/or neovascular AMD. The signs of neovascular AMD include subretinal hemorrhage, retinal pigment epithelial detachment, retinal edema, cysts, and lipid exudates. Longstanding neovascular disease can present with severe visual loss and a fibrovascular scar with or without subretinal fluid.Images
- Reticular pseudodrusen are small drusen-like deposits that form between the photoreceptors and retinal pigment epithelium. The reticular form is particularly associated with progression to geographic atrophy, but pseudodrusen are also associated with progression to choroidal neovascularization (CNV).
Imaging
- Test for or confirm the presence of subretinal or intraretinal fluid, and the degree of retinal thickening (which may not be apparent on biomicroscopy alone).Images
- Determine the volume of intraretinal or subretinal fluid before initiating treatment for CNV
- Monitor qualitative and quantitative changes in volume of subretinal and intraretinal fluid over time in response to treatment
- Confirming the presence of fibrosis and a hyperreflective (fibrovascular) scar.Image
- Fluorescein angiography can be used to rule out the presence of active CNV, unless the CNV is blocked by hemorrhage.Image
- The presence of drusen (hyperfluorescence and hypofluorescence), geographic atrophy (transmission defects), and CNV (expanding hyperfluorescence) can be confirmed using fluorescein angiography.
- It may assist in distinguishing classic CNV from occult CNV. Classic CNV presents with early well-defined expanding hyperfluorescence, whereas occult CNV exhibits late "stippled" or diffuse hyperfluorescence. However, a lesion with characteristics of both types of CNV may be seen on angiography.
Risk Factors
History & Exam
Tests
Differential Diagnosis
Differentiating Signs/Symptoms
- Signs and symptoms may be similar to exudative AMD, particularly occult forms.
- Hemorrhagic pigment epithelial detachment is particularly suggestive of this condition.
Differentiating Tests
- Indocyanine green angiography demonstrates characteristic choroidal polyps.
Differentiating Signs/Symptoms
- Multiple, discrete, often calcified drusen.
- Symmetric in both eyes.
- May be associated with choroidal neovascularization or pseudovitelliform macular lesions.
- Demographic may be different: may be seen in younger patients and nonwhite ethnicities.
Differentiating Tests
- No differentiating tests: differentiated on the basis of history and clinical exam.
Differentiating Signs/Symptoms
- Present in patients with high myopia.
- Associated with typical features of high myopia: tilted nerve head and posterior staphyloma.
- May be associated with macular pigmentary changes and choroidal neovascularization.
- Drusen not present.
- Demographic may be different: may be seen in younger patients and nonwhite ethnicities.
Differentiating Tests
- No differentiating tests: differentiated on the basis of history and clinical exam.
- Refraction may reveal high myopia: may not be seen if a patient has undergone refractive surgery, such as laser-assisted in situ keratomileusis, or cataract surgery with intraocular lens implantation.
Differentiating Signs/Symptoms
- High incidence in people residing in the Mississippi River Valley and nearby areas.
- Peripapillary atrophy and punched-out chorioretinal scars in the macula and periphery observed.
- Drusen not present.
- May be associated with choroidal neovascularization.
- Demographic may be different: may be seen in younger patients and nonwhite ethnicities.
Differentiating Tests
- No differentiating tests: differentiated on the basis of history and clinical exam.
Differentiating Signs/Symptoms
- May be associated with choroidal neovascularization.
- Characterized by the presence of angioid streaks on fundoscopic exam.
- Drusen not present.
- Demographic may be different: may be seen in younger patients and nonwhite ethnicities.
- May be associated with Ehlers-Danlos syndrome, Paget disease, pseudoxanthoma elasticum, and sickle cell disease.
Differentiating Tests
- No differentiating tests: differentiated on the basis of history and clinical exam.
- Fluorescein angiography may be useful to confirm the presence of angioid streaks.
Differentiating Signs/Symptoms
- May be associated with rupture of Bruch's membrane with subsequent choroidal neovascularization.
- Drusen not present.
- Usually unilateral.
- Demographic may be different: may be seen in younger patients and nonwhite ethnicities.
- Other findings of ocular trauma may be present.
Differentiating Tests
- No differentiating tests: differentiated on the basis of history and clinical exam.
Differentiating Signs/Symptoms
- Drusen not present.
- Usually unilateral.
- Demographic may be different: may be seen in younger patients and nonwhite ethnicities.
Differentiating Tests
- No differentiating tests: differentiated on the basis of history and clinical exam.
Differentiating Signs/Symptoms
- Lipofuscin/vitelliform deposition in between neurosensory retina and retinal pigment epithelium. Macular pigmentary changes.
Differentiating Tests
- Lipofuscin deposition may cause increased autofluorescence. Fluorescein angiography, optical coherence tomography, and/or indocyanine green angiography can often help distinguish entities that may mimic AMD.
Differentiating Signs/Symptoms
- Retinal hemorrhages and exudates.
Differentiating Tests
- Fluorescein angiography, optical coherence tomography, and/or indocyanine green angiography can often help distinguish entities that may mimic AMD.
Differentiating Signs/Symptoms
- Small aneurysms, hemorrhages, exudates.
Differentiating Tests
- Fluorescein angiography, optical coherence tomography, and/or indocyanine green angiography can often help distinguish entities that may mimic AMD.
Criteria
- No or a few small (<63 micrometers in diameter) drusen.
- Intermediate-sized (63-124 micrometers in diameter) drusen.
- Intermediate drusen and pigmentary changes, or at least one large (≥125 micrometers) druse.
- No or a few small (<63 micrometers in diameter) drusen.
- Many small drusen, or a few intermediate-sized (63-124 micrometers in diameter) drusen, or mild abnormalities of the retinal pigment epithelium (RPE).
- Extensive intermediate drusen, or at least one large (≥125 micrometers in diameter) druse, or geographic atrophy not involving the foveal center.
- Geographic atrophy involving the foveal center (atrophic, or dry, AMD)Image
- Neovascular maculopathy (exudative, wet AMD), including CNV, serous and/or hemorrhagic detachment of the retina or RPE, retinal hard exudates, subretinal and sub-RPE fibrovascular proliferation, or disciform scar (subretinal fibrosis).Images
Screening
Routine eye exam
Treatment Approach
- reducing the rate of progression of intermediate age-related macular degeneration (AMD) to late AMD, and
- treating choroidal neovascularization (CNV) when present.
Specialist referral
- any patient who reaches Age-Related Eye Disease Study Group (AREDS) category ≥3 in one eye,
- patients who experience subjective visual changes or abnormality on Amsler exam, or
- when diagnosis is uncertain and/or atypical features are present.
Risk factor modification
Patients with early AMD (AREDS 1 and 2)
Patients with intermediate AMD (AREDS 3)
Patients with advanced AMD: atrophic (dry) (AREDS 4)
Patients with advanced AMD: exudative (wet) (AREDS 4)
Intravitreal injection with VEGF inhibitors
Biosimilars
Thermal laser photocoagulation
Photodynamic therapy (PDT) using verteporfin
Treatment Options
early stage (AREDS 1 and 2)
observation ± specialist referral
Comments
- The Age-Related Eye Disease Study Group (AREDS) classifies AMD as category 1 in patients with no or a few small (<63 micrometers in diameter) drusen; and category 2 in patients with many small drusen or a few intermediate-sized (63-124 micrometers in diameter) drusen, or mild abnormalities of the retinal pigment epithelium.[35]
- There is no known effective treatment for these categories, and management is based on observation and risk factor modification.
- Evaluation by an ophthalmologist specializing in diseases of the retina is recommended at any point in the disease process, particularly for patients: who experience subjective visual changes or abnormality on Amsler exam; or in whom the diagnosis is uncertain and/or atypical features are present.
risk factor modification
Comments
- Patients with AMD are encouraged to stop smoking; to eat a balanced diet that has a low glycemic index and is rich in fruits, vegetables, and fish high in omega-3 fatty acids; and to modify cardiovascular risk factors (including lowering cholesterol and saturated fat intake and controlling hypertension).[9][23] [24] [25] [26] [27]
- Supplementation with omega-3 long-chain polyunsaturated fatty acids does not influence the risk of progressing to advanced AMD.[41]
intermediate-stage (AREDS 3)
antioxidant and mineral supplementation
Comments
- The Age-Related Eye Disease Study Group (AREDS) classifies AMD as category 3 in patients with extensive intermediate drusen or at least one large (≥125 micrometers in diameter) druse, or geographic atrophy not involving the foveal center.[35]
- Replacement is recommended with vitamin C, vitamin E, beta-carotene, and zinc; lutein/zeaxanthin is also a suitable replacement for beta‐carotene among people who smoke.[26] [44] Although systematic reviews indicate that antioxidant vitamin and mineral supplementation may delay progression to late AMD, they do not show that supplementation prevents or delays the onset of AMD.[44] [45] A diet of fruits and vegetables rich in antioxidants may also be protective.[46] [47] [48] [49]
- Dose depends on formulation used.
risk factor modification
Comments
- Patients with AMD are encouraged to stop smoking; to eat a balanced diet that has a low glycemic index and is rich in fruits, vegetables, and fish high in omega-3 fatty acids; and to modify cardiovascular risk factors (including lowering cholesterol and saturated fat intake and controlling hypertension).[23] [27] However, supplementation with omega-3 long-chain polyunsaturated fatty acids does not influence the risk of progressing to advanced AMD.[41]
specialist referral
Comments
- Evaluation by an ophthalmologist specializing in diseases of the retina is recommended at any point in the disease process, but may be particularly necessary for any patient who reaches Age-Related Eye Disease Study Group (AREDS) category ≥3 in one eye; for patients who experience subjective visual changes or abnormality on Amsler exam; or when diagnosis is uncertain and/or atypical features are present.
advanced-stage atrophic (dry) (AREDS 4)
observation
Comments
- The Age-Related Eye Disease Study Group (AREDS) classifies AMD as category 4 atrophic (dry) in patients with geographic atrophy involving the foveal center.[35]
- No current treatment has been shown to be effective.
- Repeat eye examination after 6 to 24 months may be considered for patients who remain asymptomatic, and these patients should be seen as soon as possible if they develop symptoms suggestive of choroidal neovascularization.[23]
risk factor modification
Comments
- Patients with AMD are encouraged to stop smoking; to eat a balanced diet that has a low glycemic index and is rich in fruits, vegetables, and fish high in omega-3 fatty acids; and to modify cardiovascular risk factors (including lowering cholesterol and saturated fat intake and controlling hypertension).[23] [27] However, supplementation with omega-3 long-chain polyunsaturated fatty acids does not influence the risk of progressing to advanced AMD.[41]
specialist referral
Comments
- Evaluation by an ophthalmologist specializing in diseases of the retina is recommended at any point in the disease process, but may be particularly necessary for any patient who reaches Age-Related Eye Disease Study Group (AREDS) category ≥3 in one eye; for patients who experience subjective visual changes or abnormality on Amsler exam; or when diagnosis is uncertain and/or atypical features are present.
antioxidant and mineral supplementation
Comments
- Patients who have progressed to intermediate or advanced AMD in at least one eye can consider taking micronutrient supplements, which may decrease the risk of progression to advanced or late AMD in the less-involved eye.[23]
- Replacement is recommended with vitamin C, vitamin E, beta-carotene, and zinc; lutein/zeaxanthin is also a suitable replacement for beta-carotene among people who smoke.[26] [44] Although systematic reviews indicate that antioxidant vitamin and mineral supplementation may delay progression to late AMD, they do not show that supplementation prevents or delays the onset of AMD.[44] [45] A diet of fruits and vegetables rich in antioxidants may also be protective.[46] [47] [48] [49]
- Dose depends on formulation used.
advanced-stage exudative (wet) (AREDS 4)
extrafoveal choroidal neovascularization (CNV)
intravitreal vascular endothelial growth factor inhibitor
Primary Options
- ranibizumab intravitreal
0.5 mg intravitreally into affected eye(s) once monthly for the first 3 months; treatment interval may be individualized according to disease activity under specialist guidance
- ranibizumab intravitreal
- aflibercept intravitreal
standard-dose regimen: 2 mg intravitreally into affected eye(s) every 4 weeks for 3 doses, followed by 2 mg every 8 weeks; high-dose regimen: 8 mg intravitreally into the affected eye(s) every 4 weeks for 3 doses, followed by 8 mg every 8-16 weeks; treatment interval may be individualized according to disease activity under specialist guidance
- aflibercept intravitreal
- brolucizumab intravitreal
6 mg intravitreally into affected eye(s) once monthly for 3 months, followed by 6 mg every 8-12 weeks; treatment interval may be individualized according to disease activity under specialist guidance
- brolucizumab intravitreal
- faricimab intravitreal
6 mg intravitreally into affected eye(s) once monthly for 4 months, followed by 6 mg every 8 weeks (at weeks 20, 28, 36, and 44), 12 weeks (at weeks 24, 36, and 48), or 16 weeks (at weeks 28 and 44); treatment interval may be individualized according to disease activity under specialist guidance
- faricimab intravitreal
Secondary Options
- bevacizumab
1.25 mg intravitreally into affected eye(s) once monthly for the first 3 months; treatment interval may be individualized according to disease activity under specialist guidance
- bevacizumab
Comments
- The Age-Related Eye Disease Study Group classifies AMD as category 4 exudative (wet) in patients with neovascular maculopathy, including CNV, serous and/or hemorrhagic detachment of the retina or retinal pigment epithelium (RPE), retinal hard exudates, subretinal and sub-RPE fibrovascular proliferation, or disciform scar (subretinal fibrosis).[35]
- Intravitreal injection with vascular endothelial growth factor inhibitors represents the first-line treatment for CNV.[23] [51] Ranibizumab, aflibercept, brolucizumab, and faricimab are approved for this condition.[52] [53] [54] [55] [56] [57] Bevacizumab is not licensed for intravitreal injection, but head-to-head studies indicate that its efficacy is similar to that of ranibizumab.[58] [59] [60] Bevacizumab that has been repackaged for intravitreal injection with inadequate aseptic technique has, however, been associated with endophthalmitis.[61] One systematic review of randomized controlled trials comparing bevacizumab and ranibizumab did not detect a difference in systemic safety between the two drugs.[62]
- Treatment is given as soon as possible after identification of CNV activity, to prevent irreversible retinal damage.
- The "treat-and-extend" dosing approach has become increasingly popular; it aims to proactively continue treatment by sequentially increasing treatment interval or reducing it as necessary, typically at 2-4 week intervals, up to a maximum of 12-16 weeks, depending on the drug used. The aim is to treat at an individualized interval that maintains disease stability.[65] [66] [67] [68]
- Ranibizumab, aflibercept, brolucizumab and faricimab have been approved for ''treat-and-extend'' or ''personalized'' dosing regimens, thereby reducing the number of patient visits and injections and lowering direct annual medical costs, compared with monthly injections.[64] A higher dose of aflibercept, given up to every 16 weeks, has been approved in the US for neovascular AMD based on the outcomes of the PULSAR trial.[69] [70] This has the potential to enable more patients to be treated at longer intervals. However, maximum dose intervals should follow local guidance.
- Fixed dosing at extended intervals has been reported in the HAWK and HARRIER studies of brolucizumab versus aflibercept.[71] Adverse events of intraocular inflammation, vasculitis, and retinal occlusive vasculitis have been reported in relation to brolucizumab at slightly higher rates than with other VEGF inhibitors.[71] [72] [73]
- Following the early termination of the MERLIN trial, which trialed the off-label use of brolucizumab with a 4-week dosing interval, the drug company confirmed that clinicians should not treat patients with brolucizumab at intervals of less than 8 weeks, following the first three doses; this includes individualized dosing under specialist guidance.[74] The UK Medicines and Healthcare products Regulatory Agency (MHRA) recommends that after the three loading injections, doses of brolucizumab should be given at least 8 weeks apart to reduce adverse events.[75]
- Faricimab is a bispecific antibody that can simultaneously bind and neutralize VEGF-A and angiopoietin-2. The phase 2 STAIRWAY study assessed the extended durability of faricimab dosed up to every 16 weeks. A proportion of patients receiving 12-weekly and 16-weekly doses showed outcomes comparable to monthly ranibizumab. Faricimab is approved in the US and Europe for the treatment of wet AMD based on the results of four phase 3 studies (TENAYA, LUCERNE, YOSEMITE and RHINE) that found faricimab was well tolerated and noninferior for visual gains over a year when given at intervals of up to 4 months and compared with aflibercept given every 2 months.[52] [76]
- Treatment response is monitored closely with optical coherence tomography (OCT).
- Fluorescein +/- indocyanine green angiography is typically taken at baseline and only intermittently thereafter, depending on patient response. OCT angiography has reduced the need for fluorescein angiography.
- Significant risks of treatment by intravitreal injection include a small risk of endophthalmitis, damage to the lens, and retinal detachment; in particular, the risk of endophthalmitis can be reduced by using appropriate aseptic techniques.[77] [78] [79] [80] [81] [82] Patients are made aware of signs indicative of endophthalmitis (pain, decreased vision, light sensitivity, and increasing redness) and retinal detachment (flashing lights, new floaters, and partially obscured visual field). If endophthalmitis develops, prompt treatment with intravitreal antibiotics is recommended.
- Where available, biosimilars can be used according to local guidelines.
risk factor modification
Comments
- Patients with AMD are encouraged to stop smoking; to eat a balanced diet that has a low glycemic index and is rich in fruits, vegetables, and fish high in omega-3 fatty acids; and to modify cardiovascular risk factors (including lowering cholesterol and saturated fat intake and controlling hypertension).[23] [27] However, supplementation with omega-3 long-chain polyunsaturated fatty acids does not influence the risk of progressing to advanced AMD.[41]
specialist referral
Comments
- Evaluation by an ophthalmologist specializing in diseases of the retina is recommended at any point in the disease process, but may be particularly necessary for any patient who reaches Age-Related Eye Disease Study Group (AREDS) category ≥3 in one eye; for patients who experience subjective visual changes or abnormality on Amsler exam; or when diagnosis is uncertain and/or atypical features are present.
antioxidant and mineral supplementation
Comments
- For reducing risk of second eye involvement, if second eye not affected yet.
- Patients who have progressed to intermediate or advanced AMD in at least one eye can consider taking micronutrient supplements, which may decrease the risk of progression to advanced or late AMD in the less-involved eye.[23]
- Replacement is recommended with vitamin C, vitamin E, beta-carotene, and zinc; lutein/zeaxanthin is also a suitable replacement for beta-carotene among people who smoke.[26] [44] Although systematic reviews indicate that antioxidant vitamin and mineral supplementation may delay progression to late AMD, they do not show that supplementation prevents or delays the onset of AMD.[44] [45] A diet of fruits and vegetables rich in antioxidants may also be protective.
- Dose depends on formulation used.
thermal laser photocoagulation
Comments
- The Age-Related Eye Disease Study Group (AREDS) classifies AMD as category 4 exudative (wet) in patients with neovascular maculopathy, including CNV, serous and/or hemorrhagic detachment of the retina or retinal pigment epithelium (RPE), retinal hard exudates, subretinal and sub-RPE fibrovascular proliferation, or disciform scar (subretinal fibrosis).[35]
- Thermal laser photocoagulation is a rarely used method of ablating CNV.
- Treatment is given as soon as possible after identification of CNV activity, to prevent irreversible retinal damage. This treatment may only be considered for small, well demarcated extrafoveal CNV; it is no longer a treatment for subfoveal CNV given its destructive nature.[87] [88] A retinal specialist's opinion is required to assess the risk of the laser causing the side effect of a scotoma in the visual field.
- Treatment response is monitored closely with fluorescein angiography and optical coherence tomography.
- Although thermal laser photocoagulation can be considered for small extrafoveal CNV, the first-choice treatment for extrafoveal CNV is intravitreal injection with vascular endothelial growth factor inhibitors.
risk factor modification
Comments
- Patients with AMD are encouraged to stop smoking; to eat a balanced diet that has a low glycemic index and is rich in fruits, vegetables, and fish high in omega-3 fatty acids; and to modify cardiovascular risk factors (including lowering cholesterol and saturated fat intake and controlling hypertension).[23] [27] However, supplementation with omega-3 long-chain polyunsaturated fatty acids does not influence the risk of progressing to advanced AMD.[41]
specialist referral
Comments
- Evaluation by an ophthalmologist specializing in diseases of the retina is recommended at any point in the disease process, but may be particularly necessary for any patient who reaches Age-Related Eye Disease Study Group (AREDS) category ≥3 in one eye; for patients who experience subjective visual changes or abnormality on Amsler exam; or when diagnosis is uncertain and/or atypical features are present.
antioxidant and mineral supplementation
Comments
- For reducing risk of second eye involvement, if second eye not affected yet.
- Replacement is recommended with vitamin C, vitamin E, beta-carotene, and zinc; lutein/zeaxanthin is also a suitable replacement for beta-carotene among people who smoke.[26] [44] Although systematic reviews indicate that antioxidant vitamin and mineral supplementation may delay progression to late AMD, they do not show that supplementation prevents or delays the onset of AMD.[44] [45] A diet of fruits and vegetables rich in antioxidants may also be protective.[46] [47] [48] [49]
- Dose depends on formulation used.
juxtafoveal choroidal neovascularization (CNV)
intravitreal vascular endothelial growth factor inhibitor
Primary Options
- ranibizumab intravitreal
0.5 mg intravitreally into affected eye(s) once monthly for the first 3 months; treatment interval may be individualized according to disease activity under specialist guidance
- ranibizumab intravitreal
- aflibercept intravitreal
standard-dose regimen: 2 mg intravitreally into affected eye(s) every 4 weeks for 3 doses, followed by 2 mg every 8 weeks; high-dose regimen: 8 mg intravitreally into the affected eye(s) every 4 weeks for 3 doses, followed by 8 mg every 8-16 weeks; treatment interval may be individualized according to disease activity under specialist guidance
- aflibercept intravitreal
- brolucizumab intravitreal
6 mg intravitreally into affected eye(s) once monthly for 3 months, followed by 6 mg every 8-12 weeks; treatment interval may be individualized according to disease activity under specialist guidance
- brolucizumab intravitreal
- faricimab intravitreal
6 mg intravitreally into affected eye(s) once monthly for 4 months, followed by 6 mg every 8 weeks (at weeks 20, 28, 36, and 44), 12 weeks (at weeks 24, 36, and 48), or 16 weeks (at weeks 28 and 44); treatment interval may be individualized according to disease activity under specialist guidance
- faricimab intravitreal
Secondary Options
- bevacizumab
1.25 mg intravitreally into affected eye(s) once monthly for the first 3 months; treatment interval may be individualized according to disease activity under specialist guidance
- bevacizumab
Comments
- The Age-Related Eye Disease Study Group classifies AMD as category 4 exudative (wet) in patients with neovascular maculopathy, including CNV, serous and/or hemorrhagic detachment of the retina or retinal pigment epithelium (RPE), retinal hard exudates, subretinal and sub-RPE fibrovascular proliferation, or disciform scar (subretinal fibrosis).[35]
- Intravitreal injection with vascular endothelial growth factor inhibitors represents the first-line treatment for CNV.[23] [51] Ranibizumab, aflibercept, brolucizumab, and faricimab are approved for this condition.[52] [53] [54] [55] [56] [57] Bevacizumab is not licensed for intravitreal injection, but head-to-head studies indicate that its efficacy is similar to that of ranibizumab.[58] [59] [60] Bevacizumab that has been repackaged for intravitreal injection with inadequate aseptic technique has, however, been associated with endophthalmitis.[61] One systematic review of randomized controlled trials comparing bevacizumab and ranibizumab did not detect a difference in systemic safety between the two drugs.[62]
- Treatment is given as soon as possible after identification of CNV activity, to prevent irreversible retinal damage.
- The "treat-and-extend" dosing approach has become increasingly popular; it aims to proactively continue treatment by sequentially increasing treatment interval or reducing it as necessary, typically at 2-4 week intervals, up to a maximum of 12-16 weeks, depending on the drug used. The aim is to treat at an individualized interval that maintains disease stability.[65] [66] [67] [68]
- Ranibizumab, aflibercept, brolucizumab, and faricimab have been approved for "treat-and-extend'' or "personalized" dosing regimens, thereby reducing the number of patient visits and injections and lowering direct annual medical costs, compared with monthly injections.[64] Higher doses of aflibercept, given up to every 16 weeks, have been approved in the US for neovascular AMD based on the outcomes of the PULSAR trial.[69] [70] This has the potential to enable more patients to be treated at longer intervals. However, maximum dose intervals should follow local guidance.
- Fixed dosing at extended intervals has been reported in the HAWK and HARRIER studies of brolucizumab versus aflibercept.[71] Adverse events of intraocular inflammation, vasculitis, and retinal occlusive vasculitis have been reported in relation to brolucizumab at slightly higher rates than with other VEGF inhibitors.[71] [72] [73]
- Following the early termination of the MERLIN trial, which trialed the off-label use of brolucizumab with a 4-week dosing interval, the drug company confirmed that clinicians should not treat patients with brolucizumab at intervals of less than 8 weeks, following the first three doses; this includes individualized dosing under specialist guidance.[74] The UK Medicines and Healthcare products Regulatory Agency (MHRA) recommends that after the three loading injections, doses of brolucizumab should be given at least 8 weeks apart to reduce adverse events.[75]
- Faricimab is a bispecific antibody that can simultaneously bind and neutralize VEGF-A and angiopoietin-2. The phase 2 STAIRWAY study assessed the extended durability of faricimab dosed up to every 16 weeks. A proportion of patients receiving 12-weekly and 16-weekly doses showed outcomes comparable to monthly ranibizumab. Faricimab is approved in the US and Europe for the treatment of wet AMD based on the results of four phase 3 studies (TENAYA, LUCERNE, YOSEMITE and RHINE) that found faricimab was well tolerated and noninferior for visual gains over a year when given at intervals of up to 4 months and compared with aflibercept given every 2 months.[52] [76]
- Treatment response is monitored closely with optical coherence tomography (OCT).
- Fluorescein +/- indocyanine green angiography is typically taken at baseline and only intermittently thereafter, depending on patient response. OCT angiography has reduced the need for fluorescein angiography.
- Significant risks of treatment by intravitreal injection include a small risk of endophthalmitis, damage to the lens, and retinal detachment; in particular, the risk of endophthalmitis can be reduced by using appropriate aseptic techniques.[77] [78] [79] [80] [81] [82] Patients are made aware of signs indicative of endophthalmitis (pain, decreased vision, light sensitivity, and increasing redness) and retinal detachment (flashing lights, new floaters, and partially obscured visual field). If endophthalmitis develops, prompt treatment with intravitreal antibiotics is recommended.
- Where available, biosimilars can be used according to local guidelines.
risk factor modification
Comments
- Patients with AMD are encouraged to stop smoking; to eat a balanced diet that has a low glycemic index and is rich in fruits, vegetables, and fish high in omega-3 fatty acids; and to modify cardiovascular risk factors (including lowering cholesterol and saturated fat intake and controlling hypertension).[23] [27] However, supplementation with omega-3 long-chain polyunsaturated fatty acids does not influence the risk of progressing to advanced AMD.[41]
specialist referral
Comments
- Evaluation by an ophthalmologist specializing in diseases of the retina is recommended at any point in the disease process, but may be particularly necessary for any patient who reaches Age-Related Eye Disease Study Group (AREDS) category ≥3 in one eye; for patients who experience subjective visual changes or abnormality on Amsler exam; or when diagnosis is uncertain and/or atypical features are present.
antioxidant and mineral supplementation
Comments
- For reducing risk of second eye involvement, if second eye not affected yet.
- Replacement is recommended with vitamin C, vitamin E, beta-carotene, and zinc; lutein/zeaxanthin is also a suitable replacement for beta-carotene among people who smoke.[26] [44] Although systematic reviews indicate that antioxidant vitamin and mineral supplementation may delay progression to late AMD, they do not show that supplementation prevents or delays the onset of AMD.[44] [45] A diet of fruits and vegetables rich in antioxidants may also be protective.[46] [47] [48] [49]
- Dose depends on formulation used.
subfoveal choroidal neovascularization (CNV)
intravitreal vascular endothelial growth factor inhibitor
Primary Options
- ranibizumab intravitreal
0.5 mg intravitreally into affected eye(s) once monthly for the first 3 months; treatment interval may be individualized according to disease activity under specialist guidance
- ranibizumab intravitreal
- aflibercept intravitreal
standard-dose regimen: 2 mg intravitreally into affected eye(s) every 4 weeks for 3 doses, followed by 2 mg every 8 weeks; high-dose regimen: 8 mg intravitreally into the affected eye(s) every 4 weeks for 3 doses, followed by 8 mg every 8-16 weeks; treatment interval may be individualized according to disease activity under specialist guidance
- aflibercept intravitreal
- brolucizumab intravitreal
6 mg intravitreally into affected eye(s) once monthly for 3 months, followed by 6 mg every 8-12 weeks; treatment interval may be individualized according to disease activity under specialist guidance
- brolucizumab intravitreal
- faricimab intravitreal
6 mg intravitreally into affected eye(s) once monthly for 4 months, followed by 6 mg every 8 weeks (at weeks 20, 28, 36, and 44), 12 weeks (at weeks 24, 36, and 48), or 16 weeks (at weeks 28 and 44); treatment interval may be individualized according to disease activity under specialist guidance
- faricimab intravitreal
Secondary Options
- bevacizumab
1.25 mg intravitreally into affected eye(s) once monthly for the first 3 months; treatment interval may be individualized according to disease activity under specialist guidance
- bevacizumab
Comments
- The Age-Related Eye Disease Study Group classifies AMD as category 4 exudative (wet) in patients with neovascular maculopathy, including CNV, serous and/or hemorrhagic detachment of the retina or retinal pigment epithelium (RPE), retinal hard exudates, subretinal and sub-RPE fibrovascular proliferation, or disciform scar (subretinal fibrosis).[35]
- Intravitreal injection with vascular endothelial growth factor inhibitors represents the first-line treatment for CNV.[23] [51] Ranibizumab, aflibercept, brolucizumab, and faricimab are approved for this condition.[52] [53] [54] [55] [56] [57] Bevacizumab is not licensed for intravitreal injection, but head-to-head studies indicate that its efficacy is similar to that of ranibizumab.[58] [59] [60] Bevacizumab that has been repackaged for intravitreal injection with inadequate aseptic technique has, however, been associated with endophthalmitis.[61] One systematic review of randomized controlled trials comparing bevacizumab and ranibizumab did not detect a difference in systemic safety between the two drugs.[62]
- Treatment is given as soon as possible after identification of CNV activity, to prevent irreversible retinal damage.
- The "treat-and-extend" dosing approach has become increasingly popular; it aims to proactively continue treatment by sequentially increasing treatment interval or reducing it as necessary, typically at 2-4 week intervals, up to a maximum of 12-16 weeks, depending on the drug used. The aim is to treat at an individualized interval that maintains disease stability.[65] [66] [67] [68]
- Ranibizumab, aflibercept, brolucizumab, and faricimab have been approved for ''treat-and-extend'' or "personalized" dosing regimens, thereby reducing the number of patient visits and injections and lowering direct annual medical costs, compared with monthly injections.[64] Higher doses of aflibercept, given up to every 16 weeks, have been approved by the FDA for neovascular AMD based on the outcomes of the PULSAR trial.[69] [70] This has the potential to enable more patients to be treated at longer intervals. However, maximum dose intervals should follow local guidance.
- Fixed dosing at extended intervals has been reported in the HAWK and HARRIER studies of brolucizumab versus aflibercept.[71] Adverse events of intraocular inflammation, vasculitis, and retinal occlusive vasculitis have been reported in relation to brolucizumab at slightly higher rates than with other VEGF inhibitors.[71] [72] [73]
- Following the early termination of the MERLIN trial, which trialed the off-label use of brolucizumab with a 4-week dosing interval, the drug company confirmed that clinicians should not treat patients with brolucizumab at intervals of less than 8 weeks, following the first three doses; this includes individualized dosing under specialist guidance.[74] The UK Medicines and Healthcare products Regulatory Agency (MHRA) recommends that after the three loading injections, doses of brolucizumab should be given at least 8 weeks apart to reduce adverse events.[75]
- Faricimab is a bispecific antibody that can simultaneously bind and neutralize VEGF-A and angiopoietin-2. The phase 2 STAIRWAY study assessed the extended durability of faricimab dosed up to every 16 weeks. A proportion of patients receiving 12-weekly and 16-weekly doses showed outcomes comparable to monthly ranibizumab. Faricimab is approved in the US and Europe for the treatment of wet AMD based on the results of four phase 3 studies (TENAYA, LUCERNE, YOSEMITE and RHINE) that found faricimab was well tolerated and noninferior for visual gains over a year when given at intervals of up to 4 months and compared with aflibercept given every 2 months.[52] [76]
- Treatment response is monitored closely with optical coherence tomography (OCT).
- Fluorescein +/- indocyanine green angiography is typically taken at baseline and only intermittently thereafter, depending on patient response. OCT angiography has reduced the need for fluorescein angiography.
- Significant risks of treatment by intravitreal injection include a small risk of endophthalmitis, damage to the lens, and retinal detachment; in particular, the risk of endophthalmitis can be reduced by using appropriate aseptic techniques.[77] [78] [79] [80] [81] Patients are made aware of signs indicative of endophthalmitis (pain, decreased vision, light sensitivity, and increasing redness) and retinal detachment (flashing lights, new floaters, and partially obscured visual field). If endophthalmitis develops, prompt treatment with intravitreal antibiotics is recommended.
- Where available, biosimilars can be used according to local guidelines.
risk factor modification
Comments
- Patients with AMD are encouraged to stop smoking; to eat a balanced diet that has a low glycemic index and is rich in fruits, vegetables, and fish high in omega-3 fatty acids; and to modify cardiovascular risk factors (including lowering cholesterol and saturated fat intake and controlling hypertension).[23] [27] However, supplementation with omega-3 long-chain polyunsaturated fatty acids does not influence the risk of progressing to advanced AMD.[41]
specialist referral
Comments
- Evaluation by an ophthalmologist specializing in diseases of the retina is recommended at any point in the disease process, but may be particularly necessary for any patient who reaches Age-Related Eye Disease Study Group (AREDS) category ≥3 in one eye; for patients who experience subjective visual changes or abnormality on Amsler exam; or when diagnosis is uncertain and/or atypical features are present.
antioxidant and mineral supplementation
Comments
- For reducing risk of second eye involvement, if second eye not affected yet.
- Replacement is recommended with vitamin C, vitamin E, beta-carotene, and zinc; lutein/zeaxanthin is also a suitable replacement for beta-carotene among people who smoke.[26] [44] Although systematic reviews indicate that antioxidant vitamin and mineral supplementation may delay progression to late AMD, they do not show that supplementation prevents or delays the onset of AMD.[44] [45] A diet of fruits and vegetables rich in antioxidants may also be protective.[46] [47] [48] [49]
- Dose depends on formulation used.
photodynamic therapy using verteporfin
Comments
- Photodynamic therapy (PDT) using verteporfin for subfoveal CNV lesions (that are predominantly classic on fluorescein angiography) is inferior to VEGF inhibitors, and is no longer recommended as a first-line treatment. Combinations of intravitreal VEGF inhibitors plus PDT have been studied, but there is a lack of evidence that they confer an advantage over intravitreal VEGF inhibitors alone.[23] [90] [91] [92]
- Patients receiving photodynamic therapy need to cover all skin surface areas when in sunlight following treatment, to avoid developing a burn-like photosensitivity reaction. Patients with porphyria should not receive photodynamic therapy.
- PDT, in combination with VEGF inhibitors, may be considered in the management of idiopathic polypoidal choroidal vasculopathy.[93]
risk factor modification
Comments
- Patients with AMD are encouraged to stop smoking; to eat a balanced diet that has a low glycemic index and is rich in fruits, vegetables, and fish high in omega-3 fatty acids; and to modify cardiovascular risk factors (including lowering cholesterol and saturated fat intake and controlling hypertension).[23] [27] However, supplementation with omega-3 long-chain polyunsaturated fatty acids does not influence the risk of progressing to advanced AMD.[41]
specialist referral
Comments
- Evaluation by an ophthalmologist specializing in diseases of the retina is recommended at any point in the disease process, but may be particularly necessary for any patient who reaches Age-Related Eye Disease Study Group (AREDS) category ≥3 in one eye; for patients who experience subjective visual changes or abnormality on Amsler exam; or when diagnosis is uncertain and/or atypical features are present.
antioxidant and mineral supplementation
Comments
- For reducing risk of second eye involvement, if second eye not affected yet.
- Replacement is recommended with vitamin C, vitamin E, beta-carotene, and zinc; lutein/zeaxanthin is also a suitable replacement for beta-carotene among people who smoke.[26] [44] Although systematic reviews indicate that antioxidant vitamin and mineral supplementation may delay progression to late AMD, they do not show that supplementation prevents or delays the onset of AMD.[44] [45] A diet of fruits and vegetables rich in antioxidants may also be protective.[46] [47] [48] [49]
- Dose depends on formulation used.
Emerging Tx
Stereotactic radiation therapy
Ranibizumab port delivery system
Complement inhibitors
Prevention
Primary Prevention
Secondary Prevention
Follow-Up Overview
Prognosis
Age-Related Eye Disease Study Group (AREDS) category 2 (early AMD)
AREDS category 3 (intermediate AMD)
AREDS category 4 (advanced AMD)
Monitoring
Complications
Citations
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Key Articles
Referenced Articles
Guidelines
Diagnostic
Summary
Includes a summary of the recommendations for initial and follow-up evaluation of AMD.Published by
American Academy of Ophthalmology
Published
2022
Summary
Evidence-based recommendations for the eye evaluation of adults without known ocular conditions or risk factors, or with previously identified conditions or risk factors, or with recurrent or new symptoms.Published by
American Academy of Ophthalmology
Published
2020
Summary
Approach to the diagnosis of AMD.Published by
American Academy of Ophthalmology
Published
2019
Summary
Describes appropriate exam procedures for the evaluation of the eye health and vision status of adult patients.Published by
American Optometric Association
Published
2015
Summary
Recommendations regarding when and how frequently to perform eye exams.Published by
American Academy of Ophthalmology
Published
2015
Treatment
Summary
Practice guidelines for the care process of vision rehabilitation, including recommended interventions for reading, daily living activities, safety, community participation, and psychosocial well-being.Published by
American Academy of Ophthalmology
Published
2022
Summary
Includes a summary of the management recommendations for age-related macular degeneration.Published by
American Academy of Ophthalmology
Published
2022
Summary
Recommendations regarding the treatment of non-neovascular AMD and neovascular AMD.Published by
American Academy of Ophthalmology
Published
2019