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What You Must Know About Age-related Macular Degeneration: How You Can Prevent

Written By Saturday, March 12, 2022 Add Comment Edit

Brad H. Feldman, Chiliad.D., Vinay A. Shah M.D., Vinay A. Shah K.D., Leo A. Kim, MD, PhD, Koushik Tripathy, Medico (AIIMS), FRCS (Glasgow), Yasser 1000. Elshatory, Dr.

Assigned status Upward to Appointment

 past Leo A. Kim, MD, PhD on Nov 2, 2021.

Fundus photo and fluorescein angiogram of a classic choroidal neovascular membrane in exudative age-related macular degeneration.

Sponsored in part by Boehringer Ingelheim International GmbH

Age-related macular degeneration (ARMD) is an acquired degeneration of the retina that causes significant fundamental visual harm through a combination of non-neovascular (drusen and retinal paint epithelium abnormalities), and neovascular derangement (choroidal neovascular membrane formation). Advanced disease may involve focal areas of retinal pigment epithelium (RPE) loss, subretinal or sub-RPE hemorrhage or serous fluid, as well as subretinal fibrosis. A genetic underpinning is inferred from its predilection to those of European ancestry, although ecology, nutritional, and developmental (ie., aging) processes interact to bear on the degeneration observed in the macula. Newly implicated biochemical pathways combined with a paucity of handling options for the bulk of ARMD (i.e.,dry ARMD) has created fertile ground for novel therapeutics.

Disease Entity

International Classification of Diseases (ICD)

  • ICD-9-CM
  1. 362.51 Nonexudative age-related macular degeneration
  2. 362.52 Exudative historic period-related macular degeneration
  • ICD-10-CM
  1. H35.31 Nonexudative age-related macular degeneration
  2. H35.32 Exudative age-related macular degeneration

Disease

History

Drusen and disciform lesions accept been observed in conjunction for well over 100 years.[1] The hallmark of age-related macular degeneration is the presence of drusen within the macula. The give-and-take druse (singular) is derived from the German word for potato stone or geode.[2]

Key Terms

  • Age-related Macular degeneration (ARMD)
  • Nonexudative, dry, or nonneovascular ARMD (synonyms)
  • Exudative, moisture, or neovascular ARMD (synonyms)
  • Geographic atrophy
  • Choroidal neovascularization and choroidal neovascular membranes

Classification

  • Early ARMD: Defined by the presence of numerous small (<63 microns, "hard") or intermediate (≥63 microns merely <125 microns, "soft") drusen. Note: Small drusen are frequently seen in those 50 and older, and tin can represent an epiphenomenon of aging (therefore, intermediate drusen are more specific for ARMD).[3] [iv]
  • Intermediate ARMD: Macular disease characterized by either extensive drusen of small or intermediate size, or whatsoever drusen of large size (≥125 microns).[4]

124 micron is the boilerplate bore of retinal vein at the optic disc margin.

Intermediate AMD.jpg

  • Advanced ARMD: Defined by the presence of either geographic atrophy or choroidal neovascular membrane (along with its sequelae, such equally subretinal or sub-RPE hemorrhage or serous fluid, and subretinal fibrosis).[4] The figure below demonstrates progressive geographic atrophy over a 29-month period. At that place is also an expanse of choroidal neovascularization forth the junior aspect of the scar with subretinal fibrosis that progresses over these 29 months.

Advanced AMD progression-.png

Macroeconomic illness burden

The costs of ARMD to society and the patient take been divided into direct costs (straight ophthalmologic cost and direct non-ophthalmogic cost) and indirect costs. [v] Direct ophthalmologic costs include the cost of treatments (AREDS, intravitreal injections, laser treatment, diagnostic imaging, etc.). Direct non-ophthalmologic costs include special services and equipment such equally rehabilitation services, low vision aids and transportation services.[5] Measurement of these costs are more diffcult and less pervasive in the literature. Indirect costs include lost productivity and workplace costs.[5] The almanac loss of GDP due to neovascular ARMD in 1 study was calculated to be $5.396 billion, and $24.395 billion for nonneovascular ARMD.[vi]

Etiology

A combination of run a risk factors interplay to modify the Bruch's membrane/choroid complex, the retinal paint epithelium and photoreceptor cells. The initiating events affect one, both, or all of these tissue components. A change in i of these tissue components is thought to impart an influence on the others in such a style that an 'intermediate affliction mechanism" arises[7]. The degenerating retina succumbs to the concluding stop point of geographic atrophy, choroidal neovascularization and pigment epithelial detachment. Treatments targeting intermediate disease mechanisms or initiating illness factors are in the minority, but may offer a more than successful approach to vision preservation than those targeting relatively later steps in ARMD pathophysiology (i.due east., choroidal neovascularization).[7]

Prevalence

The prevalence of advanced ARMD in the Beaver Dam Eye Study was i.6%, with the exudative class being present in one centre ane.ii% of the time, and geographic atrophy in one heart 0.half dozen% of the time.[three] This population represented four,926 people betwixt the ages of 43 to 86 years of age. Similar prevalence data was noted in the Framingham Center Study, which reported a prevalence of exudative ARMD in those older than 52 years of historic period of one.5%.[8] The prevalence of historic period-related macular degeneration sharply increases in those 75 years or older.[3]

Chance Factors

Age

ARMD risk increases with age. The take a chance increases more than iii-fold in patients older than 75 years of age compared to the group of patients between 65-74 years of age (Beaver Dam Eye Study; Framingham Eye Written report).[iii] [8]

Cigarette Smoking

A ten pack-year tobacco smoking history is associated with increased evolution of exudative age-related macular degeneration.[nine] [10] After controlling for misreckoning factors such as socioeconomic status, alcohol consumption and cardiovascular disease, the rates of visually significant ARMD in smokers and non-smokers over the historic period of 75 were calculated in an United Kingdom population-based cross exclusive written report.[11] Current smokers were twice as likely to have ARMD-related vision loss when compared to non-smokers, ex-smokers had a slightly increased take chances (odds ratio of 1.thirteen), and those who had stopped smoking over 20 years before were non at increased risk for developing vision loss from ARMD.[xi]

Genetic susceptibility

In addition to increasing i's take chances of developing ARMD, certain genetic loci have been associated with variable effects on handling response, such as intravitreal anti-VEGF agents.[12]

Complement factor H (CFH) is an important gene in the pathogenesis of ARMD.

Pharmacogenomic studies, such as these, may guide treatment regimens in the futurity, or may at least provide a more than authentic prediction of handling response. Recently, microRNA dysregulation has been linked with the development of ARMD, modulation of which could provide potential treatments for the disease.[thirteen]

Other Risk factors

Cardiovascular disease, Hypertension, Female gender, White race[14], Hypercholesterolemia, Obesity, Hyperopia[15], Family History, Calorie-free Irides

General Pathology

Pathology Vs. Normal Crumbling

Normal aging changes can be observed in the outer retina, RPE, Bruch'south membrane, and choriocapillaris, and many of these changes are hard to separate from those seen in ARMD.[16] In many instances, the designation of normal and abnormal has simply not been established to engagement. Furthermore, since aging is perhaps i of the most important chance factors for historic period-related macular degeneration, the physiological changes in crumbling may mirror the pathophysiological changes in age-related macular degeneration. Cumulative oxidative injury likely underlies changes seen in both aging and ARMD, for example.[17] With age, within the outer retina, the photoreceptors become reduced in density. Inside the RPE, melanin granules diminish, and lipofuscin granules form.[xvi] [17] Sheet-like deposits chosen basal laminar deposits develop below the RPE just to a higher place Bruch's membrane (basal lamina of the RPE). Inside the choriocapillaris, involutional changes are observed. Decreased choroidal claret flow, lumen diameter and choriocapillaris number too occur with aging.[17] Scant, small, hard drusen lonely cannot be pathognomonic for age-related macular degeneration, equally focal deposition of acellular droppings between the RPE and Bruch'due south membrane is plant frequently in aged individuals, and is a normal finding in aging.[3] [18] [17] Age-related drusen, however, are biochemically distinct from drusen associated with ARMD.[19] Large, confluent, or soft drusen are more than likely to exist a mark of age-related macular degeneration than normal aging.[20]

  • Basal laminar deposits- Between RPE and the basement membrane of the RPE. Consists of 'granular lipid-rich textile and Widely spaced collagen fibers'
  • Basal linear deposits- Within the inner aspect of Bruch'due south membrane. Consists of 'phosphol ipid vesicles and electron-dense granules'

Drusen

Drusen are a hallmark of ARMD. On histopathology, nodular drusen appear every bit eosinophilic dome-shaped structures situated between Bruch'south membrane and the displaced, adulterate RPE overlying the drusen. Drusen display dense PAS-positivity. They may become more basophilic with aggregating of calcium. Von Kossa staining may reveal calcific granules or calcific stippling within such calcified drusen. Soft or large drusen may occur with the development of localized detachments of basal laminar or basal linear deposits, which stand for granular textile accumulating between either the RPE and its basement membrane or external to the RPE's basement membrane, respectively. [21] The size and density of drusen are determinant factors in the progression of the illness.[22]

Serous detachments of the RPE

On histopathology, serous RPE detachments can exist associated with thickening of the inner attribute of Bruch's membrane.[21]

RPE atrophy

Histopathologically, RPE atrophy may exist associated with depigmentation, migration and proliferation of RPE cells into the photoreceptor layer. With progression, RPE degeneration is seen, with loss of adjacent photoreceptors, and juxtaposition of Bruch'south membrane to the inner nuclear layer.[21]

Subretinal or sub-RPE neovascularization

Sub-RPE neovascularization is located inside Bruch'south membrane, typically between the thickened inner aspect of Bruch's membrane and the rest of Bruch's membrane. A sub-RPE neovascular membrane can extend subretinally in areas where Bruch'southward membrane is not intact. With discontinuities in Bruch'due south membrane, capillary-like choroidal vessels tin class a subretinal RPE vascular web that can affect serous or hemorrhagic detachments of the neurosensory retina.[21]

Disciform scars or lesions

Fibrous disciform scars are usually results of sub-RPE neovascularization. Gristly tissue develops within Bruch'due south membrane or between the RPE and retina. Hemosiderin is typically nowadays, suggesting a hemorrhagic antecedent issue. RPE hyperplasia may exist a prominent feature of disciform scarring, and lymphocytic infiltrate in the adjacent choroid is occasionally appreciated. Overlying retina undergoes cystic degeneration with photoreceptor loss.[21]

Pathophysiology

Genetic and Biochemical Pathways in ARMD (see [23])

Biochemical pathways and genetic clan studies have shed low-cal on the possible biochemical pathways that become awry in ARMD. Two polymorphisms, Tyr402His at 10q26 (Complement factor H locus), and Ala69Ser (LOC387715) may exist responsible for upward to 50-75% of the genetic risk of ARMD.[24] One caveat of these risk alleles is that they take not been validated in racial groups other than Caucasians. Aside from explaining some of the genetic predisposition in ARMD, these loci have uncovered new biochemical pathways hitherto unlinked to ARMD pathogenesis, providing novel therapeutic targets. Pathway-based treatment modalities targeting oxidative damage, lipofuscin accumulation, inflammation, and derangements in complement activation are quickly proliferating.[25] The following list represents the biochemical pathways implicated in ARMD pathogenesis and the corresponding genetic loci involved.

  • Complement pathway (complement cistron 2[26], complement factor iii[27], complement cistron B[28], complement factor H, complement factor I)[29] [30] [31] [32] [33]
  • Extracellular matrix part, cellular anchoring (Fibulin 5[34] and half-dozen[35] [36])
  • Innate amnesty (Toll-like receptor three and 4)[37] [38] [39] [xl] [41]
  • Proteolysis/Drusen metabolism (HTRA1, serine protease)[42] [43]
  • DNA repair (ERCC6)[44]
  • DNA transcription (RAX2)[45]
  • Lipid signaling/metabolism (transporter protein, ABCA4)[46] [47] [48] [49]
  • Other (LOC387715, hypothetical gene)[fifty] [51]

The Complement Arrangement

The complement system is a three-pronged pathway involved in natural and acquired amnesty. Information technology represents a highly regulated conglomeration of approximately 30 proteins, some of which are prison cell surface receptors, while others possess catalytic activeness. The three prongs of the pathway include the classical, the culling, and the lectin pathways. The classical pathway depends on activation by antigen-antibody complexes, the lectin pathway, on sugar residues, and the culling pathway depends on spontaneous activation. Complement activity may increment in response to surface features on microorganisms. Components in cigarette smoke may as well trigger this activity. Activation of the complement system results in cellular damage that is key in the pathogenesis of dry out and wet forms of ARMD, and this is supported by the presence of many complement system proteins within drusen in patients with ARMD. The alternative pathway becomes activated through a process known as "tickover." Under normal circumstances, proteins expressed on host cells inhibit this tickover process, and in so doing prevent injury to the host. Instances where this inhibition is jeopardized is when factors favoring activation increase locally (or systemically), inhibitors decrease (or their function decreases), or when there is an increased local concentration of alternative pathway components.[52] Therefore, at that place needs to be active, continuous control over the alternative pathway to avert autologous tissue destruction. In ARMD, it is believed that an early "seeding event," such equally an area of retinal pigment epithelium atrophy with cellular debris, induces innate immune arrangement activation at the RPE-choroid-Bruch's membrane complex.[53] Subsequently, complement attack (membrane attack complex activation) leads to collateral damage of retinal tissue. This damage predisposes to geographic atrophy and choroidal neovascular membrane formation. In 2005, iv groups independently reported that a polymorphism at amino acrid position 402 of gene H is associated with ARMD.[54] [55] [56] [57] Gene H is the master soluble inhibitor of the alternative complement pathway. Mutation in factor H in the same region where the polymorphism is encountered has been associated with blazon II membranoproliferative glomerulonephritis, a status wherein drusen also develop.[52] [58]

Principal prevention

Smoking abeyance, reduction in body mass alphabetize, and handling of hypertension are modifiable risk factors that should exist addressed in patients at run a risk for, or who have various stages of ARMD.[4] Based on population based cross exclusive studies, the prevalence of ARMD in ex-smokers is less than in smokers, arguing for a possible do good of smoking abeyance on societal ARMD disease burden.[xi] Studies on the beneficial consequence of dietary antioxidants and omega 3 fatty acids on prevention of AMD accept yielded bereft results.[59] [60]

Diagnosis

The diagnosis of early ARMD is typically made afterwards because a patient's age, physical exam findings, and family unit history, as many patients in early stages of the illness possess no symptoms.

History

Decreased primal visual acuity may not be nowadays in ARMD, especially in early stages, and is not a reliable indicator of illness severity. In fact, advanced ARMD may exist associated with relatively preserved visual acuity (run across time lapse fundus photograph higher up, where a patient had 20/forty vision despite advanced ARMD). Exudative ARMD changes may be associated with astute to subacute drops in vision, or perception of visual distortion such every bit metamorphopsia.

Concrete examination

  • Periodic dilated fundus exams are warranted to identify patients who progress to neovascular ARMD without having symptoms.
  • Amsler filigree

Hypothetical neovascular ARMD change on an Amsler grid.

en.wikipedia.org/wiki/File:Amslergrid_patientAMD.gif

  • The Preferential Hyperacuity Perimeter (PreView PHP, Carl Zeiss Meditec, Dublin, CA/ ForeseeHome) is useful, when available, to place new-onset neovascular ARMD changes.[61]

Signs

  • Drusen
  • Geographic atrophy
  • Subretinal fibrosis
  • RPE changes
  • Subretinal fluid or hemorrhage/hard exudate

Drusen.JPG

Drusen with corresponding OCT.JPG

Symptoms [61]

  • Decreased visual acuity, insidious or sudden-onset
    • Dry ARMD constitutes 85-xc% cases of ARMD, and unremarkably does not cause astringent vision loss.
    • Wet AMD constiutes 10-15% of ARMD cases and is the major crusade of astringent vision loss.
  • Blurred vision
  • Distorted virtually vision
  • Scotoma
  • Visual distortion, metamorphopsia, micropsia
  • Vague visual complaints

Clinical diagnosis

The authentication findings in nonexudative ARMD are drusen, RPE changes, and geographic atrophy. In advanced ARMD, drusen may fade or become resorbed in areas of geographic cloudburst. Big areas of geographic cloudburst may show prominent deep choroidal vessels with cloudburst of the choriocapillaris.

Advanced Nonexudative ARMD-.png

Diagnostic procedures

Fundus Fluorescein Angiography/FFA

Fluorescein angiography and optical coherence tomography are useful in evaluating for the presence of exudative ARMD. Fluorescein angiography is performed when at that place is suspicion for choroidal neovascular membrane (CNVM) formation. ARMD pathology on fluorescein angiography can be organized into hyperfluorescent changes and hypofluorescent changes. Changes in ARMD that cause hypofluorescent changes are few, and include hemorrhage, lipid exudation, and pigment hyperplasia. Causes of hyperfluorescent lesions are more numerous, and include drusen, RPE atrophy (transmission defects), choroidal neovascular membranes, serous pigment epithelial detachments, and subretinal fibrosis or scars (staining defects).[62] Choroidal neovascular membranes can present differently on angiography. Two main designations are 'classic' vs. 'occult.' Fluorescein angioraphic features help distinguish archetype choroidal neovascularization and occult choroidal neovascularization. Differences in angiographic patterns are thought to arise from 'archetype' lesions penetrating the retinal pigment epithelium, and thus being located in front of the RPE, and 'occult' lesions existence sub-RPE.[63] Classic membranes are associated with an early hyperfluorescent area that is well-demarcated, which increases in intensity and extent beyond the early phase boundary by mid- to late-frames. Pooling of fluorescein associated with a concomittant subsensory retinal detachment may besides be appreciated.

Classic CNVM panel.jpg

Occult membranes are presumed when late choroidal leakage is noted without a discernible classic membrane blueprint. Occult membranes are besides presumed when a fibrovascular pigment epithelial detachment (FVPED) is suspected. FVPEDs are associated with irregular RPE acme, and a stippled hyperfluorsescent pattern with or without leakage or pooling. [61]

Types of CNVM on FFA

  1. Classic CNVM- an expanse of detached well-divers bright, fairly compatible lacy hyperfluorescence in the early on phase (usually near the subretinal bleed) that progressively increases in intensity and size with blurring of the margin of hyperfluorescence (leak)
  2. Occult CNVM
    1. a.- Fibrovascular pigment epithelial detachment- Amend appreciated with stereoscopic views. At 1-two minutes, there is an irregular elevation of the RPE with stippled or granular hyperfluorescence . As time passes, the boundary may or may not testify leakage. The margin of FVPED may be apparent in around 1-2 minutes of the FFA or the margin may exist hard to ascertain in some cases.
    2. Late leakage of an undetermined source- In early or mid phase, at that place is no well-defined area of hyperfluorescence like what is seen with classic CNVM or FVPED. The leakage is ordinarily deep/choroidal or at the RPE and late associated with speckled advent and pooling of dye in the subretinal space overlying the speckles.

CNVM Wet AMD.JPG

Occult CNVM.JPG

Optical Coherence Tomography/October

Optical coherence tomography (Oct) offers a non-invasive, high-resolution, optical cross-sectional method that utilized low-coherence interferometry.[64] OCT has become indispensable in the evaluation of patients with ARMD. Imaging helps evaluate for tomographic sequelae of neovascular membranes, too as monitor for treatment responses.

Blazon 1 CNVM= sub-RPE CNVM, normally related to occult CNVM on FFA

Type 2 CNVM= subretinal CNVM (superficial to the RPE), usually corresponds to classic membranes on FFA

Blazon three CNVM= retinal angiomatous proliferation

Massive IRF OCT.JPG

Massive IRF from CNVM.JPG

Laboratory tests

No routine blood tests are available to diagnose ARMD, and although elevated inflammatory markers (e.g., CRP) and certain genetic polymorphisms have been associated with increased risk of developing advanced ARMD, these tests are not routinely employed.

Differential diagnosis

The differential diagnosis of age-related macular degeneration varies profoundly depending on whether choroidal neovascularization is present or not, so it is useful to organize the differential into "nonexudative" vs. "exudative" ARMD.

  • Exudative ARMD: The differential diagnosis of neovascular ARMD includes choroidal neovascularization caused by atmospheric condition other than ARMD, such as ocular histoplasmosis syndrome, pathlogic myopia, chroidal rupture, angioid streaks, or idiopathic causes.[61] In improver, foveal detachments or vitelliform detachments may complicate other weather condition, such as cuticular drusen, or pattern dystrophies. The latter would not be associated with leakage on fluorescein angiography, but rather progressive staining of vitelliform material.[61] Polypoidal choroidal vasculopathy may produce hemorrhagic PEDs that can resemble those in ARMD, merely the absence of drusen, the often peripapillary location of such lesions, and the ameliorate visual acuity outcomes of polypoidal vasculopathy assist distinguish it from ARMD.[65] Choroidal tumors obscured by subretinal hemorrhage or RPE changes may also masquerade for exudative ARMD, but unilaterality and ultrasonography should help distinguish a tumor from ARMD.[61] Central serous retinopathy is an of import differential especially of occult CNVM.
  • Nonexudative ARMD: The differential diagnosis of nonneovascular ARMD includes retinal pigment epithelial changes secondary to fundamental serous chorioretinopathy (CSC), blueprint dystrophy, cuticular drusen, and drug toxicity (e.k., chloroquine toxicity). These atmospheric condition overlap with the various pathological changes observed in dry out ARMD, but either occur in a younger patient population, or are missing fundamental ARMD features, such every bit drusen. For example, CSC may nowadays with multiple serous PEDs and RPE changes, but not drusen. Blueprint dystrophy usually affects patients younger in age than ARMD, and has a fluorescein angiography pattern that is distinct, with early blocked fluorescence with surrounding hyperfluorescence, and belatedly staining of the vitelliform textile.

Management

Observation with chance gene modification and nutritional supplementation is the mainstay of handling for nonexudative ARMD. Withal, current studies are underway to evaluate complement pathway inhibition for the treatment of geographic atrophy in patients with nonexudative ARMD though no handling modality is currently approved by the FDA for the treatment of geographic atrophy. Exudative ARMD is managed with more closely spaced examinations and intravitreal injections of anti-VEGF agents or laser treatments. Patients with advanced affliction in both eyes should undergo evaluation and rehabilitation with low-vision services.[66]

Medical therapy

Nonneovascular ARMD Treatments

Antioxidant and mineral supplementation

Antioxidant and mineral supplementation has been shown to reduce the gamble of progression in ARMD.[67] The daily amounts of antioxidants and zinc in the AREDS conception is[68] [four]:

  • 500 milligrams of vitamin C
  • 400 International Units of vitamin East
  • fifteen milligrams of beta-carotene (equivalent of 25,000 International Units of vitamin A)
  • 80 milligrams of zinc as zinc oxide
  • ii milligrams of copper every bit cupric oxide


Since, high dose zinc supplementation tin lead to a copper-deficiency anemia by inhibiting copper absorption at the level of the enterocyte, copper supplementation was added to the AREDS formula.[4] Cigarette smokers should exist warned nearly the small, merely real potential take chances of lung cancer with high dose beta-carotene supplementation in the AREDS formula. Non-beta-carotene-containing supplements are more than advisable for this subgroup of patients. [66]

Based on information suggesting that increasing intake of lutein + zeaxanthin, and omega-3 long-chain polyunsaturated fatty acids (docosahexaenoic acid [DHA] + eicosapentaenoic acid [EPA]) might reduce the take chances of developing advanced AMD, AREDS2, a randomized, double-masked control trial was started. AREDS2 was designed to examination whether adding lutein + zeaxanthin, DHA + EPA, or lutein + zeaxanthin + DHA + EPA to the AREDS conception further reduces the risk of progression to avant-garde AMD. Another goal of AREDS was to exam the furnishings of eliminating beta carotene and reducing the zinc dose from the AREDS formulation. The following are the modifications of AREDS2:

  • x mg lutein and 2 mg zeaxanthin
  • 350 mg DHA and 650 mg EPA
  • No beta-carotene
  • 25 mg zinc


In AREDS2, lutein/zeaxanthin or DHA/EPA had no additional effect on the risk of advanced AMD. Study participants who took AREDS containing lutein/zeaxanthin and no beta-carotene had a slight reduction in the adventure of advanced AMD, compared to those who took AREDS with beta-carotene and no lutein/zeaxanthin. Chiefly, former smokers who took AREDS with beta-carotene had a higher incidence of lung cancer. Lower zinc oxide doses (25mg) did not significantly increment the risk of advanced AMD, although a trend to more than protection from avant-garde AMD was noted with higher zinc oxide doses (80mg). Newer formulations replace beta-carotene with lutein/zeaxanthin, only proceed the zinc oxide dose the same.

  • 500 milligrams of vitamin C
  • 400 International Units of vitamin Due east
  • lxxx milligrams of zinc as zinc oxide
  • 2 milligrams of copper as cupric oxide
  • 10 mg lutein and 2 mg zeaxanthin
  • No beta-carotene

Neovascular ARMD Treatments

Macular Photocoagulation Studies

Studies performed in the 1980'southward assessed the efficacy of laser photocoagulation in limiting damage acquired by choroidal neovacular lesions. These studies evaluated laser treatment of extrafoveal, juxtafoveal, and subfoveal neovascular membranes[69] [70]. Patients with direct laser photocoagulation to extrafoveal or juxtafoveal sites fared better than those receiving direct laser to subfoveal membranes. While severe vision loss was averted, light amplification by stimulated emission of radiation photocoagulation currently has limited utility because of its high recurrence rates, risk of inducing vision loss (especially with subfoveal membranes), and failure to bear on an improvement in vision from baseline visual vigil. In the era of anti-VEGF therapies, the indications for direct photocoagulation are diminishing.

However, it may be considered in extrafoveal small CNVM.

verteporfin Photodynamic therapy/vPDT

Use of photosensitizers (e.g., verteporfin) that pool in neovascular membranes and after prodice reactive oxygen species upon activation with calorie-free of a specific wavelength was introduced in the late 1990's. In the era of anti-VEGF therapies, the indications for photodynamic therapy are diminishing.

All the same, PDT has a definite part in the management of polypoidal choroidal vasculopathy and fundamental serous chorioretinopathy. EVEREST trial showed that 'afterwards 12 months, combination therapy of ranibizumab plus vPDT was not only noninferior only also superior to ranibizumab monotherapy in best-corrected visual acuity and superior in complete polyp regression while requiring fewer injections'

Anti-VEGF treatments

Optical coherence tomography and anti-vascular endothelial growth gene (VEGF) therapy together have revolutionized the handling of exudative ARMD. Ranibizumab (Lucentis, Genentech, San Francisco, CA), bevacizumab (Avastin, Genentech, San Francisco, CA), and aflibercept (Eylea, Regeneron Pharmaceuticals Inc., Tarrytown, NY), are often used in the treatment of exudative ARMD. Pegaptanib (Macugen, Pfizer) was the first anti-VEGF therapy to recieive FDA approval for the treatment of ARMD in 2004. Information technology is biochemically distinct from subsequent anti-VEGF agents, in that information technology represents an aptamer as opposed to a monoclonal antibody (bevacizumab), monoclonal antibody fragment (ranabizumab), or a receptor-antibody fusion protein (aflibercept, see diagram below). Pegaptanib is a small oligonucleic acid molecule that binds specifically to the VEGF-165 isoform. The most contempo anti-VEGF agent that was recently approved was brolucizumab (Beovu, Novartis, Cambridge, MA), which is a single chain antibiotic fragment against VEGF, which was found to exist non-inferior to aflibercept, and more than than one-half of patients were able to extend to 3 months dosing with brolucizumab within the showtime twelvemonth as demonstrated in the HAWK and HARRIER trials.

In an effort to extend dosing, a new port delivery organization was adult past Genentech to deliver continuous levels of ranibizumab. The ranibizumab port commitment organisation (Susvimo, Genentech, San Francisco, CA) is a unique surgical implant that is placed within the vitreous and provides continuous delivery of ranibizumab. This implant was approved by the FDA in October 2021, and this commitment system tin exist refilled every 6 months. The Archway study showed non-inferiority of the port commitment system compared to monthly ranibizumab injections. 98% of patients were able to get 6 months before their beginning refill.

A schematic of the aflibercept molecule

OCT Wet AMD Treated.JPG

Radiation therapy

Radiotherapy has been used in neovascular ARMD nether the premise that radiation can inhibit the exhuberant cellular proliferation necessary to create the choroidal neovascular membrane. However, studies on efficacy have non shown a clear benefit of this treatment modality.[61]

Anti-VEGF and Anti-Ang2 handling

The first bi-specific antibody therapy for the treatment of neovascular ARMD was recently canonical by the FDA on Jan 31, 2022. Faricimab (Vabysom, Genentech, San Francisco, CA) is a bi-specific antibiotic directed against both VEGF and angiopoietin-2. This dual targeted treatment was dosed upwards to 4 calendar month intervals and was found to be non-junior to aflibercept given every two months in the first year. In the TENAYA and LUCERNE trials, a large majority of patients could exist dosed at 3 months intervals or more, showing improved efficacy and durability of the treatment compared to the anti-VEGF inhibition solitary.

Emerging Treatments

Treatments targeting biochemical pathways implicated in the pathophysiology of ARMD are being tested actively in clinical trials.[71] [25] Agents currently undergoing evaluation in geographic atrophy /advanced AMD are listed in the tabular array below. Treatments include pocket-sized inhibitory RNA molecules, monoclonal antibodies, gene therapy, anti-inflammatory medications, antioxidants, and cell-based therapies.


Information for the following table was retrieved from http://clinicaltrials.gov on 8/2019.[72]

Investigational agent Route of administration Machinery of activity Targeted Pathology Clinical Trial Identification Sponsoring company/institution Written report status Phase of study
Minocycline Oral Inhibition of microglia Geographic atrophy NCT02564978 NEI Recruiting 2
RC28-Eastward Intravitreal Anti-VEGF and Anti-FGF2 Neovascular ARMD NCT03777254 Remegen Recruiting i
OpRegen Subretinal hESC derived RPE Geographic atrophy NCT02286089 Biotime Inc, CellCure Neurosciences Recruiting i, 2a
AAVCAGsCD59 Intravitreal Cistron therapy based expression of sCD59 Neovascular ARMD NCT03585556 Hemera Biosciences Recruiting 1
ADVM-022 Intravitreal Gene therapy based expression of anti-VEGF amanuensis aflibercept Neovascular ARMD NCT03748784 Adverum Biotechnologies, Inc. Recruiting 1
Elamipretide Subcutaneous Mitochondrially targeted anti-oxidant Geographic cloudburst NCT03891875 Stealth BioTherapeutics Inc. Recruiting two
RGX-314 Intravitreal Gene therapy based expression of anti-VEGF Neovascular ARMD NCT03066258 Regenxbio Inc. Recruiting 1,2a
DE-122 Intravitreal Antibody to endoglin Neovascular ARMD NCT03211234 Santen Inc. Recruiting ii
KSI-301 Intravitreal Polymer conjugate anti-VEGF antibiotic Neovascular ARMD NCT03790852 Kodiak Sciences Inc. Recruiting 1b
APL-2 Intravitreal Inhibitor of Complement C3 Geographic Atrophy NCT03525613 Apellis Pharmaceuticals, Inc. Recruiting iii
ALK-001 Oral Modified Vitamin A Geographic Atrophy NCT03845582 Alkeus Pharmaceuticals, Inc. Recruiting 3

Surgery

Submacular surgery in ARMD has included approaches to translocate the macula, either by vitrectomy and retinotomy or by vitrectomy and sclerochroidal foreshortening (achieved externally), notwithstanding these procedures take not gained widespread use. [61] In instances where a large submacular hemorrhage occurs, pneumatic displacement with face up-downwardly posititioning and intraocular gas injection tin can be performed. Some have used vitrectomy, retinotomy, and subretinal injection of tissue plasminogen activator (tPA) in instances of large submacular hemorrhage. The NEI-funded Submacular Surgery Trials (SST) evaluated the visual acuity outcome and complications of excising choroidal neovascular membranes. In patients with large fundamental macular, subretinal hemorrhage due to choroidal neovascularization (new or recurring subsequently laser photocoagulation; Group B protocol), there were no significant difference in BCVA between the surgery and observation arms of the study. The surgical intervention can vary from patient to patient, simply had the goal of removing the unabridged neovascular membrane, any blood, and any scar tissue present. [73]

Complications

Subretinal hemorrhage

Subretinal hemorrhage can cause photoreceptor damage equally the blood is in contact with the photoreceptors and early on treatment is needed. Subretinal hemorrhage may be of varying severity. Massive subretinal hemorrhages are typically idea to exist associated with anticoagulation therapy, specifically, warfarin therapy.[61] Surgical management options has been reviewed elsewhere (Direction of Submacular Hemorrhage).

Vitreous hemorrhage

Suspension-through vitreous hemorrhage secondary to neovascular ARMD is a rare complexity. Sudden peripheral visual field and fundamental vision loss is noted in these instances, to be distinguished from the key field complaints typically noted with ARMD. Other etiologies, such as retinal tears from hemorrhagic posterior vitreous detachments, retinal vascular diseases such every bit diabetic retinopathy or vein occlusions should be considered also.[61]

Diplopia

Diplopia tin occur as a result of the choroidal neovascular membrane "dragging" the fovea. Such patients nowadays with primal binocular diplopia in the presence of peripheral fusion. This syndrome is referred to every bit dragged-fovea diplopia syndrome, and is usually addressed with some form of partial monocular occlusion (Scotch Satin tape).[74]

Legal blindness

Severe central vision loss leading to legal blindness (Visual acuity less than 20/200) is an endpoint more oft seen in neovascular ARMD compared to nonneovascular ARMD. Based on data from the Framingham Eye Study[8] and a case-control report past Hyman et al.[75], the proportions of neovascular and nonneovascular ARMD in patients legally bullheaded in an eye from advanced ARMD were compared.[76] 79% to 90% of legal blindness in advanced ARMD was associated with neovascular, and not nonneovascular disease.[76]

Additional Resource

  • Boyd Yard, Janigian RH. Age-Related Macular Degeneration. American Academy of Ophthalmology. EyeSmart® Eye wellness. https://www.aao.org/center-health/diseases/age-related-macular-degeneration. Accessed March 07, 2019.
  • Porter D, Vemulakonda GA. Drusen. American Academy of Ophthalmology. EyeSmart® Eye health. https://www.aao.org/eye-wellness/diseases/drusen-list. Accessed March 08, 2019.
  • Turbert D, Janigian RH. Avastin. American Academy of Ophthalmology. EyeSmart® Middle health. https://www.aao.org/eye-wellness/drugs/avastin-list. Accessed March 18, 2019.
  • Turbert D, Janigian RH. Lucentis. American Academy of Ophthalmology. EyeSmart® Middle health. https://www.aao.org/eye-wellness/drugs/lucentis-list. Accessed March 18, 2019.
  • Turbert D,Vemulakonda GA. Eylea. American University of Ophthalmology. EyeSmart® Eye health. https://www.aao.org/eye-wellness/drugs/eylea-listing. Accessed March 18, 2019.
  • Turbert D,Vemulakonda GA. Anti-VEGF Treatments. American Academy of Ophthalmology. EyeSmart® Eye health. https://www.aao.org/eye-health/drugs/anti-vegf-treatments-list. Accessed March 18, 2019.
  • Clinicaltrial.gov-U.Due south. National Institutes of Health
  • Retinal information network
  • Webvision
  • The Age-Related Eye Disease Written report ii (AREDS2) Research Group. JAMA. 2013;309(19):2005-2015. doi:10.1001/jama.2013.4997.

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  73. ↑ Surgery for Hemorrhagic Choroidal Neovascular Lesions of Age-Related Macular Degeneration: Ophthalmic Findings, SST Report No. 13fckLR.Submacular Surgery Trials (SST) Research Group*
  74. ↑ De Pool ME, Campbell JP, Broome SO, Guyton DL.fckLRSource (2005). The dragged-fovea diplopia syndrome: clinical characteristics, diagnosis, and treatment. Ophthalmology 112(8): 1455-62.
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