DINESH and SONALEE, profile picture
Uploaded byDINESH and SONALEE
PPTX, PDF5,645 views

ARMD 2016

Age-related macular degeneration (AMD) is the leading cause of irreversible vision impairment among the elderly, affecting millions and characterized by degeneration of retinal structures. It presents mainly in two forms: dry (non-neovascular) and wet (neovascular), with specific risk factors and treatment options, including vitamin supplementation for dry AMD and anti-VEGF medications for wet AMD. The disease progresses variably, and while new treatments have improved outcomes for wet AMD, management of dry AMD remains limited and requires ongoing patient education regarding risk factors and symptoms.

Embed presentation

Downloaded 357 times
1 / 123
2 / 123
Most read
3 / 123
4 / 123
5 / 123
6 / 123
7 / 123
8 / 123
9 / 123
10 / 123
11 / 123
Most read
12 / 123
13 / 123
14 / 123
15 / 123
16 / 123
17 / 123
Most read
18 / 123
19 / 123
20 / 123
21 / 123
22 / 123
23 / 123
24 / 123
25 / 123
26 / 123
27 / 123
28 / 123
29 / 123
30 / 123
31 / 123
32 / 123
33 / 123
34 / 123
35 / 123
36 / 123
37 / 123
38 / 123
39 / 123
40 / 123
41 / 123
42 / 123
43 / 123
44 / 123
45 / 123
46 / 123
47 / 123
48 / 123
49 / 123
50 / 123
51 / 123
52 / 123
53 / 123
54 / 123
55 / 123
56 / 123
57 / 123
58 / 123
59 / 123
60 / 123
61 / 123
62 / 123
63 / 123
64 / 123
65 / 123
66 / 123
67 / 123
68 / 123
69 / 123
70 / 123
71 / 123
72 / 123
73 / 123
74 / 123
75 / 123
76 / 123
77 / 123
78 / 123
79 / 123
80 / 123
81 / 123
82 / 123
83 / 123
84 / 123
85 / 123
86 / 123
87 / 123
88 / 123
89 / 123
90 / 123
91 / 123
92 / 123
93 / 123
94 / 123
95 / 123
96 / 123
97 / 123
98 / 123
99 / 123
100 / 123
101 / 123
102 / 123
103 / 123
104 / 123
105 / 123
106 / 123
107 / 123
108 / 123
109 / 123
110 / 123
111 / 123
112 / 123
113 / 123
114 / 123
115 / 123
116 / 123
117 / 123
118 / 123
119 / 123
120 / 123
121 / 123
122 / 123
123 / 123
ARMD MANAGEMENT 2016 Indoredrishti.wordpress.com
DR DINESH MITTAL DR SONALEE MITTAL DRISHTI EYE HOSP VIJAYNAGAR INDORE
ARMD
INTRODUCTION • Age-related macular degeneration (AMD) is the leading cause of irreversible visual impairment among the elderly worldwide affecting 30–50 million individuals. Loss of visual acuity typically results from progressive degeneration of the photoreceptors, retinal pigment epithelium (RPE), and choriocapillaris although the earliest manifestation of the disease appears histopathologically as abnormalities within Bruch’s membrane. advanced form of disease is characterized by macular neovascularization, geographic atrophy (atrophy of the RPE, choriocapillaris, and photoreceptors), or both .
• This definition of early ARM excluded small, hard drusen alone, pigment changes alone, and even pigment changes surrounding small, hard drusen for two reasons: • (1) hard drusen become an almost constant finding in the fifth decade; and • (2) a number of diverse processes can cause pigment abnormalities that may not be possible to distinguish from early ARM, so the inclusion of soft drusen makes the definition more specific to ARMD. • However, eyes with numerous small, hard drusen or eyes with pigment abnormalities in the absence of obvious drusen can also progress to soft drusen.
Age-Related Macular Degeneration • Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world in people over 50 years of age. It is estimated that among North Americans, 15 million (85%–90% of all AMD patients) currently have “dry” (nonneovascular, or nonexudative) AMD and 1.7 million people (10%–15% of all AMD patients) have “wet” (neovascular) AMD. An estimated 200,000 new cases of neovascular AMD develop each year in North America.
ARMD • The disease nearly always begins as the non- neovascular or dry form of AMD and may progress to geographic atrophy or the neovascular (wet) form in one or both eyes. When neovascularization occurs, there is commensurate accumulation of fluid, hemorrhage, and lipid exudation within the macula that can culminate in fibrosis referred to as a disciform scar. A patient can have advanced dry AMD in both eyes, advanced wet AMD in both eyes, or dry AMD in one eye and wet AMD in fellow eye. It is controversial whether the wet and dry forms of AMD represent two distinct disease entities or end-stage manifestations of the same disease
OVERVIEW • Once advanced AMD develops in one eye, there is an increased likelihood of having geographic atrophy or neovascularization in the fellow eye. A simplified severity scale based on fundus appearance was established to assess the risk of converting to advanced AMD. Large drusen, any pigment changes, and the disease state of the fellow eye were particularly predictive for developing advanced AMD. The cause of AMD is multifactorial and influenced by age, ethnic background, and a combination of environmental and genetic factors. There is no cure; however, vitamin supplementation, good nutrition, and cessation of smoking can slow the progression of the dry form of AMD while drugs that inhibit vascular endothelial growth factor-A (VEGF-A) have been successful in converting the wet form of AMD back to the dry form
Epidemiology and Risk Factors for ARMD • The only proven treatment available for the dry or nonexudative forms of this disease, comprising 85% of cases, is an antioxidant/mineral supplement which can slow the progression of the disease by 25% over 5 years. For the wet form of the disease, anti-vascular endothelial growth factor (VEGF) treatments have been very effective in preventing severe vision loss. Still, preventive measures are needed to reduce the burden of this disease. Smoking is the most consistently identified modifiable risk factor. Obesity, sunlight exposure, & nutritional factors including antioxidants and dietary fat intake may also affect AMD incidence and progression.
• Within the past 5 years new and improved treatments for the neovascular form of advanced AMD have been adopted throughout the developed world. Therefore, in the years ahead the overall burden of vision loss associated with AMD is anticipated to decline substantially. The same progress has not been made for treatment of advanced non-neovascular AMD (GA); as such, the importance of atrophic AMD as a leading cause of vision impairment is expected to increase. The advanced forms of AMD are those that are frequently associated with visual acuity loss and they are divided into non neovascular atrophic (dry) type and neovascular (wet) type. In atrophic AMD, gradual disappearance of the retinal pigment epithelium (RPE) results in one or more patches of atrophy that slowly enlarge and coalesce. Affected areas have no visual function, since loss of RPE is associated with fallout of photoreceptors. Gass applied the term “geographic atrophy of the retinal pigment epithelium” to this presentation, which is the natural end-result of AMD in the absence of clinical evidence of choroidal neovascularization (CNV).
A. The RPE in a young retina has a homogenous distribution of the melanin granules, a BM without deposits, and a preserved function
B. In dry AMD, the RPE melanin granules are localized basally, and lipofuscin granules increase in number while the efficacy of the disks digestion reduces. Note the formation of drusen between the basement membrane of the RPE and the inner collagen layer of the BM and the thickened BM
C. In wet AMD, CNV develops, and an inflammatory response develops with an influx of lymphocytes and macrophages to the scene. These fragile new vessels leak and lead to subretinal hemorrhage
Nonneovascular AMD • The prototypical lesion of the nonneovascular form of AMD is the druse. Other indicators are abnormalities of the RPE, including hyperpigmentation and atrophy.
Drusen • Clinically, drusen are small, round, yellow lesions located at the level of the RPE, mostly in the • postequatorial retina . Histologically, this material corresponds to the abnormal thickening of the inner aspect of the Bruch membrane . Ultrastructurally, basal laminar deposits (granular, lipid-rich material and widely spaced collagen fibers between the plasma membrane and basement membrane of the RPE cell) and basal linear deposits (phospholipid vesicles and electron-dense granules within the inner collagenous zone of the Bruch membrane) are present
Drusen • Drusen in an extramacular location are of no known visual consequence. Typical drusen deposits are located between the RPE and • Bruch’s membrane and vary widely in number, size, shape, and distribution. Most drusen are 20–100 μm in diameter and are characterized as hard or soft as well as small (< 63 μm), intermediate (> 63 μm but < 125 μm) or large (≥ 125 μm).
Hard drusen vs soft drusen • Hard drusen, which appear as round, discrete yellow-white spots,measure less than 63 μm. These drusen are commonly identified in many populations; they are not age- related and do not carry an increased risk for development of neovascularization, with 80% of the general population older than 30 years manifesting at least one. In contrast, soft drusen are ill defined, with nondiscrete borders, measuring 63 μm or greater . Different population based studies and clinical trials have indicated that large, soft, confluent drusen are age-related and associated with a higher risk for development of advanced AMD with the development of neovascularization. After the age of 70 years, 26% of individuals have large or soft drusen, and 17% have confluent drusen .
FA OF DRUSEN • Typically, small hard drusen hyperfluoresce early in FA studies because of a window defect, whereas larger soft and confluent drusen and drusenoid PEDs slowly and homogenously stain late because of pooling of the fluorescein dye in the sub-PED compartment. However, there is some variability in how drusen appear on FA.
OCT of drusen • SD-OCT imaging of small and large drusen typically reveals sub-RPE nodular elevations or even small RPE detachments with a notable absence of intraretinal and subretinal fluid . • Reticular pseudodrusen are identified above the RPE and beneath the inner segment ellipsoid layer • and are graded according to their degree of elevation . • Enhanced depth imaging (EDI) of the choroid using OCT has permitted more detailed analysis of the choroid in AMD. Choroidal thickness values are typically normal or reduced in nonneovascular AMD.
Abnormalities of the RPE • Several patterns of RPE abnormalities characterize nonneovascular AMD, including focal hyperpigmentation, nongeographic atrophy, and geographic atrophy. Increased pigmentation at the level of the outer retina corresponds to focal hyperpigmentation of the RPE. On FA, these areas typically show blockage, and on SD-OCT, show hyperreflective outer retinal foci. The incidence of focal hyperpigmentations increases with age, and their presence indicates greater risk of progression to the more advanced forms of AMD.
Abnormalities of the RPE • Nongeographic atrophy refers to atrophy that does not cover a contiguous area and may appear as an area of mottling or depigmentation. When the area of absent or attenuated RPE is contiguous, the condition is termed geographic atrophy of the RPE. In areas of GA, the unmasked choroidal vessels are more readily visible, the overlying outer retina may appear thin, and choriocapillaris is attenuated or atrophied. On FA, GEOGRAPHIC ATROPHY shows well-circumscribed round to oval window defects, whereas on SD-OCT, loss of the RPE and the overlying inner segment ellipsoid and photoreceptor layer can be seen. Dense hypoautofluorescence occurs in areas of GA. Fundus autofluorescence is a practical and noninvasive tool to monitor progression of GA
Geographic atrophy • Geographic atrophy often spares the fovea until late in the course of the disease. It may first present as one or more noncontiguous patches of atrophy around the fovea. These patches enlarge and coalesce and may be associated with a dense paracentral scotoma, thereby limiting tasks such as reading. Patients with GA may demonstrate good visual acuity (VA) until late in the course of the disease, when the fovea becomes progressively atrophic, leading to severe visual acuity decline from central blindness and forcing the patient to use noncentral retina and eccentric fixation to read and perform other visual tasks
• Although not all eyes with drusen or PED will develop atrophy, the incidence of atrophy appears to increase with age. Twelve to 20% of patients with GA have severe vision loss .
Management of nonneovascular AMD • Education and follow-up Eyes with soft drusen and RPE hyperpigmentation are at increased risk of developing GA and CNV. As such, patients with nonneovascular AMD should be educated about the symptoms of advanced AMD and instructed to contact an ophthalmologist promptly should these symptoms occur. If reduced visual acuity or reduced vision function (difficulty reading despite good measured visual acuity) is noted, a low vision evaluation should be considered. Periodic examinations are advised to monitor for concurrent, treatable eye disease (eg, cataract, glaucoma) and to re evaluate low vision needs.
Amsler grid • The Amsler grid is a test card for patient home-monitoring use; it contains white grid lines on a black background and a central dot for fixation. Each eye is tested individually with reading glasses and at reading distance to check for any new metamorphopsia, scotoma, or other significant changes in central vision. Any changes noted by the patient should be evaluated urgently .
MICRONUTRIENTS • AREDS first established the benefit of vitamin and zinc supplementation in reducing the risk of vision loss in patients with nonexudative AMD. supplementation with the antioxidant vitamins C (500 mg) and E (400 IU), beta carotene (15 mg), and the micronutrient zinc (80 mg zinc oxide and 2 mg cupric oxide to prevent zinc-induced anemia) in patients with intermediate or stage 3 nonneovascular AMD demonstrated a 25% risk reduction for progression to advanced AMD and a 19% risk reduction in rates of moderate vision loss (≥3 lines of visual acuity) at 5 years.
AREDS • Intermediate AMD was defined as the presence of at least 1 large druse (>125 μm) or nonsubfoveal GA, and advanced unilateral AMD was defined as vision loss due to neovascular AMD or GA in 1 eye. At 10 years, 44% of placebo recipients compared with 34% of the supplement recipients had advanced AMD (a 27% risk reduction). Among participants with no AMD or only early AMD (a few small drusen), there was no measurable benefit. There was no increased mortality among patients taking the AREDS formula
AREDS • A simplified 4-point grading scale was developed by AREDS for classifying the severity of AMD and predicting the disease course based on the following findings: • presence of 1 or more large (>125-μm diameter) drusen (1 point) • presence of any pigment abnormalities (1 point) • for patients with no large drusen, presence of bilateral intermediate (63–124 μm) drusen (1 point) • presence of neovascular AMD (2 points)
AREDS
• Large population-based studies suggest that supplementation with the xanthophylls lutein & zeaxanthin as well as omega-3 long-chain polyunsaturated fatty acids (LCPUFAs: docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]) may also help reduce AMD progression.
AREDS2 study • The AREDS2 study was designed to test whether these observations could be confirmed in a prospective trial. Among the 4000 participants, the study confirmed the overall risk reduction found in the original AREDS study, concluded that lutein and zeaxanthin had similar effects to beta carotene, and found 80 mg of zinc to be the appropriate dose for AMD prophylaxis. Furthermore, LCPUFAs were not found to decrease the rate of progression to advanced AMD. A nonocular effect detected was an increased rate of lung cancer among current and former smokers using beta carotene, a finding other nonophthalmic studies had previously reported. As a result, study’s recommendations for AREDS supplementation were to replace beta carotene with lutein and zeaxanthin and not to add LCPUFAs .
Lifestyle changes • With increasing evidence that environment and health habits influence the development and progression of AMD, patients should be counseled to alter behaviors that put them at risk. Of particular importance are smoking cessation, obesity reduction, and blood pressure control. Cataract surgery has not been linked consistently to the progression of AMD, nor is there strong evidence linking UV (UV-A or UV-B) light exposure to the progression of AMD. It should be noted, however, that there are no negative effects of wearing UV-protective glasses .
Neovascular AMD • The hallmark of the neovascular form of AMD is the presence of CNV. Degenerative changes in the Bruch membrane—such as the accumulation of drusen and the progressive thickening of membrane’s inner aspect that characterize nonneovascular form of AMD—can be associated with a proangiogenic environment, including neovascularization that originates from the choriocapillaris and perforates the outer aspect of the Bruch membrane. These new vessels are accompanied by fibroblasts, resulting in a fibrovascular complex that can leak and bleed and may disrupt and destroy the normal architecture of the RPE–photoreceptor complex, ultimately leading to the formation of a hypertrophic fibrotic disciform scar.
Signs and symptoms of neovascular AMD • Patients with neovascular AMD describe the sudden onset of decreased vision, metamorphopsia, and/or paracentral scotomata. Amsler grid self-testing by patients is highly effective for early detection of neovascular AMD. Clinical signs of CNV may include subretinal or intraretinal fluid, exudate and/or blood, a pigment ring or gray-green membrane, irregular elevation of the RPE or a PED, an RPE tear, and/or a sea fan pattern of subretinal vessels. • Intraretinal blood and cystoid macular edema (CME) may indicate the presence of type 3 neovascularization, which originates from the deep capillary plexus of the retinal circulation.
Anatomical classification of CNV • Three types of CNV are now recognized. In type 1 neovascularization, new vessels originating from the choriocapillaris grow through a defect in the Bruch membrane into the sub–pigment epithelial space. Leakage and bleeding can lead to the development of a vascularized serous or fibrovascular PED. The fibrovascular PEDs are often seen to have an irregular surface contour.
• In type 2 neovascularization, the CNV occupies the subneurosensory compartment between the RPE and the outer segments of the retina . On examination, the membrane will appear as a lacy or graygreen lesion; in AMD, this finding is less common than is type 1 neovascularization.
CNVM • Type 3 neovascularization results from new blood vessels sprouting from the deep capillary plexus of the retina and growing downward toward the RPE. Because of their intraretinal growth, these lesions were originally termed retinal angiomatous proliferations (RAP). On examination, they appear as a small area of red discoloration, often associated with retinal exudate.
• Ultimately, if untreated, these neovascular processes may evolve into a hypertrophic, fibrotic, disciform scar. The retina overlying the scar loses its normal outer retinal architecture, which can lead to severe, permanent central vision loss.
Fluorescein angiographic patterns of CNV • FA patterns of CNV may include classic or occult CNV or combinations of both. • Classic CNV is an area of bright, lacy, and well-defined hyperfluorescence that is identified in the early phase and progressively leaks by the late phases . • Occult CNV consists of 2 forms: • (1) PED, either fibrovascular PED or vascularized serous PED, and • (2) late leakage from an undetermined source
OCCULT CNVM • Fibrovascular PED refers to an irregular elevation of the RPE with progressive, stippled leakage on FA. Alternatively, the PED may pool dye rapidly in a homogenous ground-glass pattern that is consistent with a serous PED but has a notch, or hot spot, indicating vascular tissue in the PED—a vascularized serous PED
Late leakage from an undetermined source • Late leakage from an undetermined source refers to regions of fluorescence at the level of the flat RPE that are ill defined early and best appreciated in the late phases of the angiographic study. The angiographic description of occult CNV may be anatomically related to type 1 neovascularization, whereas that of classic CNV may be related to type 2 neovascularization; this relation is not a hard-and-fast rule, however Type 3 neovascularization, or RAP, may be signaled by the presence of a spot of retinal hemorrhage in the macula.
• FA and indocyanine green (ICG) angiography may demonstrate a focal hot spot and late CME; associated pooling into a PED may also be present. The presence of thick blood, pigment, scar tissue, or a PED may block fluorescence and obscure any underlying CNV. ICG angiography, which employs a dye that is almost fully protein bound and has a longer wavelength nearer the infrared spectrum, may be valuable in penetrating heme and pigment to allow identification of the CNV, which may appear as a hot spot.
SD-OCT patterns of CNV • Type 1 neovascular membranes demonstrate elevation of the RPE and a PED on SD-OCT. A serous PED appears as a sharply elevated, dome-shaped lesion with hollow internal reflectivity and typically no associated subretinal or intraretinal fluid. A fibrovascular PED may or may not be sharply elevated and typically demonstrates a lacy or polyplike hyperreflective lesion on the undersurface of the RPE, with or without signs of contraction. A chronic fibrovascular PED has a multilayered appearance, and a complex fibrovascular scar may be appreciated in sub PED compartment, with or without associated subretinal and/or intraretinal fluid.
SD-OCT patterns of CNV • Type 2 neovascular membranes appear as a hyperreflective band or plaque in the subneurosensory space, with associated subretinal and/or intraretinal fluid. Type 3 neovascular membranes are best appreciated with SD-OCT as a hyperreflective focus emanating from the deep capillary plexus of the retina, with or without associated CME and PED. Recognition of these SD-OCT patterns is crucial for the diagnosis and classification of CNV. Also, SD-OCT is a noninvasive procedure as well as the most important and practical modality for monitoring the response of therapy by assessing regression of the neovascular membrane and resolution of subretinal and intraretinal fluid.
Polypoidal choroidal vasculopathy • Polypoidal choroidal vasculopathy (PCV), initially described as posterior uveal bleeding syndrome, is a variant of choroidal neovascularization (type 1) and is characterized by multiple, recurrent serosanguineous RPE detachments. A network of polyps with associated feeder vessels, similar in appearance to a string of pearls, can be identified with SDOCT adherent to the RPE monolayer of the fibrovascular PED—hence designation of type 1 neovascularization.
Polypoidal choroidal vasculopathy • It is now believed to occur in women and men of all races and to be a variant of neovascular AMD, with same genetic profile. The areas of serosanguineous detachment are often peripapillary and multifocal but may be peripheral, and associated nodular, orange, subretinal lesions may be appreciated. Vitreous hemorrhage may occur more frequently than in classic AMD, and the typical soft drusen of AMD may or may not be present. The natural history and visual acuity outcomes of PCV may be better than those of CNV associated with AMD . ICG angiography and SD-OCT are important techniques for identifying the polyps.
Differential diagnosis of neovascular AMD • A variety of conditions can mimic the neovascular changes of AMD and typically include any disorder that is associated with disruption of the Bruch complex and secondary CNV. • The subretinal fluid of central serous chorioretinopathy can be confused with subretinal fluid or edema associated with CNV and AMD. However, patients with CSC are usually younger and usually do not have associated subretinal hemorrhage unless a secondary CNV has developed. CSC can be further differentiated by characteristic signs including patches of RPE mottling that may assume a • geographic or gutterlike gravitational configuration on wide- field angiographic or autofluorescent imaging and a thick choroid best visualized with EDI-OCT.
Management of neovascular AMD • If neovascular AMD is suspected on clinical grounds, FA and OCT studies can be obtained. SD-OCT is most efficient and reliable tool in diagnosing and distinguishing types 1, 2, & 3 neovascularization and in monitoring response to therapy.
Laser photocoagulation (thermal laser) • From the 1980s through 2000, laser therapy was primary treatment for classic extrafoveal CNV with well-defined boundaries. However, outcomes were poor because of high recurrence rates, as demonstrated in the Macular Photocoagulation Studies. The use of thermal laser treatment is now rare except to treat extrafoveal lesions that are sufficiently far from the foveal center to have minimal risk of iatrogenic foveal laser damage and a lower rate of recurrence.
Photodynamic therapy PDT • Photodynamic therapy PDT was introduced in 2000 as a less-destructive modality for treating CNV than thermal laser and entails the systemic administration of a photosensitizing drug followed by an application of light of a particular wavelength to the affected tissue to incite a localized photochemical reaction. This reaction generates reactive oxygen species, leading to capillary endothelial cell damage & vessel thrombosis. Studies showed that PDT slowed progression but did not prevent significant vision loss in eyes with CNV that had certain lesion characteristics. Use of PDT in the management of exudative AMD is now rare except in recalcitrant cases or eyes with PCV.
Vascular endothelial growth factor (VEGF) is a homodimeric glycoprotein that is secreted in response to hypoxia and ischemia. VEGF induces angiogenesis and vascular permeability. Arrows show the binding site VEGFR
Antiangiogenic therapies • Angiogenesis—the formation of new blood vessels that occurs via sprouting or splitting from existing vessels—is characterized by a complex cascade of events. The first step in the cascade involves vasodilation of existing vessels and increased vascular permeability. This process is followed by degradation of the surrounding extracellular matrix, which facilitates migration and proliferation of endothelial cells. The endothelial cells join together to form a lumen, which becomes a new capillary. The vessels subsequently mature and undergo remodeling to form a stable vascular network. The successful execution of this cascade requires a balanced interplay of growth-promoting and growth-inhibiting angiogenic factors.
Antiangiogenic therapies • Identified activators of angiogenesis include vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), transforming growth factor α (TGF-α) and TGF-β, angiopoietin-1, and angiopoietin-2. Inhibitors of angiogenesis include thrombospondin, angiostatin, endostatin, and pigment epithelium–derived factor (PEDF).
Antiangiogenic therapies • The majority of recent antiangiogenesis research has focused on the inhibition of VEGF. VEGF expression is increased in pigment epithelial cells during the early stages of AMD, suggesting that VEGF plays a causal role in the initiation of neovascularization. In addition, high concentrations of VEGF have been observed in excised CNV and vitreous samples from AMD patients. VEGF is a homodimeric glycoprotein that is a heparin-binding growth factor specific for vascular endothelial cells. It can induce angiogenesis, vascular permeability, and lymphangiogenesis and may act as a survival factor for endothelial cells by preventing apoptosis. There are at least 4 major VEGF isoforms, of which VEGF165 is thought to be the most dominant in AMD.
Pegaptanib • Pegaptanib, an RNA oligonucleotide ligand (or aptamer) that binds human VEGF165 with high affinity and specificity, was the first intravitreal anti-VEGF therapy approved by the US FDA , in 2004. Studies showed that it slowed vision loss, but it has since been supplanted by far more effective agents.
Ranibizumab • Ranibizumab is a recombinantly produced, humanized antibody fragment (Fab) that binds VEGF. Unlike pegaptanib, ranibizumab binds to and inhibits all active isoforms of VEGF-A and their active degradation products. Two studies, MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD) and ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic CNVM in AMD), demonstrated that, at 12 months, 95% of ranibizumab-treated patients experienced vision stabilization or improvement compared with 62% of sham-treated patients and 64% of patients treated with PDT, respectively. More important, approximately 30%–40% of ranibizumab-treated patients experienced vision improvement of 15 letters or more compared with control participants in each study, with an average letter gain of approximately 10 letters . Almost 80% of patients maintained or improved vision after 24 months.
Present status • Sixty-five AMD patients from the MARINA, ANCHOR, and HORIZON studies were evaluated approximately 7 years after baseline recruitment. Of these patients, 23% achieved a best-corrected visual acuity (BCVA) of 20/40 or better, while 37% had BCVA of 20/200 or worse, and almost one-half (43%) of eyes had an unchanged or improved letter score versus baseline. Active fluid was detected by SD-OCT in 68% of study eyes, and macular atrophy, the area of which correlated with vision loss, was detected by fundus autofluorescence in 98% of eyes.
TREAT AND OBSERVE / EXTEND • treatment effect declined in the ranibizumab recipients during quarterly dosing (ie, every 3 months) but not with monthly dosing intervals. These data clarified that quarterly treatment appears to be suboptimal. In general, there are 2 accepted treatment schemes that deviate from the FDA-approved labeling of monthly injections: “treat- and-observe,” or “as-needed,” and “treat-and- extend” approaches to anti-VEGF therapy.
“treat-and-observe,” or “as-needed,” and “treat-and-extend” approaches to anti-VEGF therapy • In the treat-and-observe method, regular treatment is administered until the macula is dry by clinical and OCT-determined criteria, followed by treatment only for signs of recurrent exudation during the maintenance phase. This approach is in contrast to the treat-and extend regimen, in which regular monthly treatment is continued until the macula is dry, after which treatment continues at gradually increasing intervals. In this second approach, injections are administered even with inactive CNV. The goal of this therapy is to cautiously extend the time between injections as far apart as tolerated as long as there are no signs of recurrence.
MONTHLY INJECTIONS NEEDED ONLY FOR THREE MONTHS & • Several clinical trials have evaluated as-needed approaches to anti-VEGF therapy: PrONTO (Prospective Optical Coherence Tomography Imaging of Patients With Neovascular AMD Treated With Intraocular Ranibizumab), SAILOR (Study to Evaluate Ranibizumab in Subjects With Choroidal Neovascularization Secondary to AMD), SUSTAIN (Study of Ranibizumab in Patients with Subfoveal Choroidal Neovascularization Secondary to AMD), and HORIZON (Open-Label Extension Trial of Ranibizumab for Choroidal Neovascularization Secondary to AMD). All of these studies utilized 3 monthly injections followed by various as-needed treatment regimens, determined on the basis of clinical and OCT-guided criteria, and all showed vision and OCT outcomes that were comparable to or reduced from those obtained with MARINA and ANCHOR.
Safety data • Safety data have been favorable for intravitreal ranibizumab therapy. Intravitreal injections are occasionally associated with minor local complications such as subconjunctival hemorrhage and local irritation. However, the incidence of severe, visually compromising complications such as vitreous hemorrhage, retinal detachment, or endophthalmitis is exceedingly low across numerous trials including those just described. Systemic arteriothrombotic events can arise during the course of ranibizumab therapy, but no study has conclusively determined an increased incidence of these events related to injection of the drug.
RISK OF TEAR • Eyes with fibrovascular PEDs may be at increased risk for the development of an RPE tear after anti- VEGF therapy, and this risk may be especially significant with PEDs greater than 600 μm in height. The mechanism of the tear may relate to contraction of the type 1 neovascular membrane beneath the PED that occurs as a result of the anti-VEGF injection.
PROTOCOLS OF TREATMENT: RETREATMENT ALGORITHMS AND MAINTENANCE THERAPY • Fixed Monthly Injections • Initially, there was no clear consensus on retreatment strategies. In the MARINA and ANCHOR studies of ranibizumab, patients received monthly intravitreal injections during 2 years, so each patient received a total of 24 injections. Today, the fixed monthly ranibizumab retreatment schedule has not been widely accepted . Patients were at first treated with three monthly injections of ranibizumab, termed the “loading phase,” followed by a quarterly injection regimen. The results observed were positive but did not equal the MARINA and ANCHOR results. In fact, patients showed less mean gain in VA, and fewer patients experienced 15 or more letters of visual gain. Additionally, if after the loading phase there was a gain in VA, it was not maintained during the study .
As-Required Injections • PrONTO study introduced a dosing regimen characterized by three consecutive monthly intravitreal injections followed by as-needed retreatment based upon signs of recurrence, ophthalmoscopy, OCT, or fluorescein angiography, called the as-needed or PRN protocol . It seems that the PRN dosing regimen is the most widely used today. Ranibizumab was used in PrONTO study, and the dosing regimen was OCT guided and variable. Patients received three monthly intravitreal injections, and retreatment was based upon loss of five letters of VA, new-onset hemorrhage or CNV, increase of central retinal thickness of more than 100 μm documented with OCT, or intraretinal fluid. In the first year of PrONTO study, patients received an average of 5.6 injections of ranibizumab. The results of PrONTO study suggest that 70% of the patients treated with intravitreal ranibizumab showed resolution of edema within 1 month after the first injection, and 90% of the patients showed resolution of fluid after the loading phase . • The CATT study compared ranibizumab and bevacizumab using monthly and as-required retreatment schedules (67). In this study, bevacizumab administered monthly led to a gain of 8.0 letters at 12 months, and bevacizumab administered as-required led to a gain of 5.9 letters. Similarly, ranibizumab administered monthly led to a gain of 8.5 letters at 12 months, and ranibizumab in as-required schedule led to a gain of 6.8 letters. It is clear that a monthly retreatment schedule showed greater gain in VA, but the differences were “inconclusive” for the bevacizumab groups and were not significant for the ranibizumab groups. These studies follow up patients for 12 months, but other studies with longer follow- ups, such as HORIZON and SUSTAIN, have shown that significant visual gain is achieved with monthly injections and the as-required schedule is not as effective as the monthly fixed schedule.
Treat and Extend • Other retreatment schedules are used, in order to minimize the number of injections and visits to the hospital. In the treat-and-extend schedule, the patients are treated with monthly injections until macula is dry and without fluid seen with OCT. The follow-up between injections is lengthened by 1 to 2 weeks until recurrence of fluid is observed. If recurrent fluid is detected on a follow-up visit, the treatment interval is reduced to the previous interval. Treatment schedule is variable and subject to change at every visit, but the time between visits in individualized based on each patient's response to treatment
PrONTO • a ranibizumab study known as PrONTO (Prospective OCT Imaging of Patients with Neovascular AMD Treated with Intraocular Ranibizumab). This phase I/II study explored whether dosing based on the presence of fluid in the macula as detected by OCT could result in fewer injections but achieve visual acuity outcomes similar to the results obtained with monthly dosing.130 The study design mandated three consecutive monthly injections with intravitreal ranibizumab (0.5 mg). Then, from month 3 through month 24, patients were examined monthly with OCT and additional injections were performed only if certain OCT-based criteria were fulfilled .
PrONTO • After one year, the mean improvement in visual acuity from baseline was 9.3 letters (P < 0.001), and at two years it was 11.1 letters (P < 0.001). More than one-third of eyes (35%) in PrONTO gained at least 15 letters of visual acuity at one year and 43% gained at least 15 letters at two years. These visual acuity outcomes were comparable to the outcomes in the MARINA and ANCHOR trials. Moreover, these visual acuity outcomes were achieved with an average of 5.6 out of a maximum of 13 monthly injections the first year and 9.9 injections out of a maximum of 25 monthly injections over two years. The PrONTO study also demonstrated that the onset of action for ranibizumab was rapid with an average decrease in OCT central retinal thickness of about 50 μm at one day, 100 μm at one week, and 150 μm at one month after the first injection .
• Compared with the MARINA and ANCHOR outcomes in which monthly injections were mandated, the OCT-guided retreatment strategy appeared to result in similar visual acuity outcomes with far fewer intravitreal injections. Another OCT-based retreatment strategy known as ‘treat and extend’ has also been proposed, trying to reduce number of injections and number of visits, with visual acuity improvement . Whether it is the PrONTO-style retreatment strategy known as ‘treat and observe’ or the ‘treat and extend’ regimen, the visual acuity outcomes are probably very similar to the outcomes achieved with monthly injections but fewer injections are required. Other studies have explored the ‘treat and observe’ strategy with similar favorable results.
Bevacizumab • Bevacizumab is a full-length monoclonal antibody against VEGF that was approved by the FDA in 2004 for the treatment of metastatic colorectal cancer. It has been described for “offlabel” use via intravitreal and intravenous administration for the treatment of AMD. Both bevacizumab and ranibizumab are manufactured by the same pharmaceutical company, and there are important differences between the drugs: bevacizumab is larger and has 2 antigen-binding domains compared with the single domain for ranibizumab, and cost differences between them are substantial, potentially affecting access to treatment for some patients. Because fragment antibodies in general have shorter systemic half- lives than those of full-length antibodies (2.2 hours for ranibizumab vs ~21 days for bevacizumab), intravitreal injections of ranibizumab have a shorter systemic half-life than intravitreal injections of bevacizumab.
Bevacizumab • Because of the 50-fold lower cost and the purported similar efficacy of bevacizumab compared with ranibizumab, several comparative efficacy studies have been conducted. These studies include CATT (Comparison of Age-Related Macular Degeneration Treatments Trials) in the United States, IVAN (Randomised Controlled Trial of Alternative Treatments to Inhibit VEGF in Age-Related Choroidal Neovascularisation) in the United Kingdom, MANTA (Randomized Observer and Subject Masked Trial Comparing the Visual Outcome After Treatment With Ranibizumab or Bevacizumab in Patients With Neovascular Age-Related Macular Degeneration Multicenter Anti-VEGF Trial in Austria), and GEFAL (Groupe d’Evaluation Français Avastin vs Lucentis) in France .
Bevacizumab • CATT was the first and largest multicenter, randomized clinical trial to compare the relative safety and efficacy of ranibizumab with bevacizumab for the treatment of neovascular AMD. The trial was funded by the US National Eye Institute and studied 1208 patients. Results showed that bevacizumab was noninferior to ranibizumab therapy in monthly or as-needed delivery schedules over 2 years. Mean letters gained from baseline did not differ statistically among the 4 arms of the study: 8.8 letters in the ranibizumab- monthly group, 7.8 letters in the bevacizumab-monthly group, 6.7 letters in the ranibizumab as-needed group, and 5.0 letters in the bevacizumab as-needed group . Systemic adverse events were significantly greater in the bevacizumab (39.9%) than in the ranibizumab (31.7%) group, but death and arteriothrombotic events were not statistically different between the 2 drugs .
AVASTIN
The preparation of individual syringes requires a strict aseptic technique with adequate sterilization procedures
NEEDLE GAUGE AND TECHNIQUE • complications described are temporary increase in intraocular pressure and reflux of bevacizumab with the formation of a subconjunctival bleb . Some ophthalmologists have adopted different intravitreal injection techniques in order to decrease the incidence of reflux taking into consideration intraocular pressure . Some patients may experience elevation of intraocular pressure 30 minutes after the injection.
TREATMENT OF DME VS ARMD • It is important to distinguish wet AMD from DME—these are, indeed, two very different diseases. For patients with wet AMD, we are treating choroidal neovascularization with exudation. For patients with DME, we are only treating edema, the source of which is retinovascular incompetence. While we are trying to get that macula to a satisfactory dry status, the burden over time tends to fall off in DME.
TREATMENT OF DME VS ARMD •In wet AMD, there is more of a continuous burden year after year for an indefinite time frame in most patients. In DME, studies with discontinuous or P.R.N. style therapy such as Protocol I and Protocol T, many patients were eventually able to cease therapy .
TREATMENT OF DME VS ARMD •With wet AMD, whether it is P.R.N. or TREAT- AND-EXTEND (TAE), the mean number of treatments will typically reach a plateau after the first year. It does not tend to decrease much thereafter. But with DME, P.R.N. studies that we have seen, Protocol I in particular, started with a mean of eight to nine injections in year 1, then three to four in year 2, two to three in year 3 and by years 4 and 5, many had no further treatment .
Low vision therapies • Despite the success of intravitreal anti-VEGF pharmacotherapy, a significant number of patients with AMD will ultimately develop bilateral central blindness for which few therapeutic options exist. Recently, an implantable miniature telescope was approved by the FDA that can provide magnification up to a factor of 2.7; in pivotal FDA trials, its use resulted in 2 lines of vision gained in 90% of patients. Eyes need to be monitored carefully for corneal decompensation caused by endothelial cell loss; the corneal transplant rate is projected to be close to 5% at 5 years after the implantation surgery.
Low vision therapies • Low vision rehabilitation Vision loss of any degree has a profound effect on a patient’s activities of daily living including driving and reading. Although the patient and doctor may be focused on therapies, sufficient attention should be given to low vision strategies that improve function and quality of life. Severe vision loss and central blindness resulting from AMD can be devastating, but low vision rehabilitation and the use of optical and nonoptical devices can improve the patient’s functional status and quality of life . Even patients who have undergone successful anti-VEGF therapy may sustain reduced visual acuity in the 20/50–20/70 range and can benefit from low vision interventions such as use of magnification (eg, high- plus lenses, closedcircuit television), improved lighting, and enhanced contrast. Training and visual rehabilitation to use eccentric foci shifted outside of the central scotoma caused by the disciform scar may also be very helpful. To accomplish some of these rehabilitation strategies and best meet patients’ needs, clinicians are encouraged to consider referring patients for low vision consultation and to local low vision centers or state services for the blind.
Light is transmitted through the anterior segment of the eye to reach the posterior elements and reaches the electrodes at either the subretinal or epiretinal layer.
CONCLUSION • AMD continues to be the leading cause of irreversible visual acuity loss worldwide among the elderly. Vitamin supplementation, dietary modifications, and smoking cessation appear to be the most useful strategies to slow the progression of dry AMD. For the treatment of wet AMD, ranibizumab, bevacizumab, and aflibercept have revolutionized the prognosis for patients. For the first time, patients can be treated with the expectation that their vision may improve. However, not all patients improve with 10% losing 15 letters or more over two years as shown in the phase 3 ranibizumab trials, and this vision loss is likely caused by the progression of the underlying dry AMD once the neovascularization has been arrested and the wet AMD has been converted back to dry AMD .
CONCLUSION • With the result from the CATT showing that monthly dosing with anti-VEGF drugs increases the incidence of GA, it seems reasonable to avoid monthly dosing and provide personalized treatment strategies using either the ‘as-needed’ or ‘treat and extend’ regimens. For this reason, the future of AMD therapy rests in developing treatments for the dry form of the disease. The need for effective treatments to prevent the progression of dry AMD is paramount as the prevalence of AMD is expected to double in the coming decades. Genetics offers the best hope in identifying pathways that can be targeted using pharmacotherapies so that visual acuity loss from AMD can be prevented. Although the promise of embryonic stem cells remains eternal as a strategy to recover lost vision, the best strategy to treat AMD will continue to be prevention of vision loss.
THANK YOU DR DINESH DR SONALEE
ARMD 2016

More Related Content

PPTX
Age Related Macular Degeneration - ARMD
byrakshanshetty9591
 
PPTX
Age related macular degeneration
byBulgaa luBgaa
 
PPT
Age related macular degeneration from Optometrist Point of View
byAnis Suzanna Mohamad
 
PPTX
Age related macular degeneration nitin
byNitin Renge
 
PPT
Age related macular degeneration
byDr. Ajay Kumar Singh
 
PPTX
Wet AMD- Aug 2017
bysameerasep13
 
PPT
BRANCH RETINAL VEIN OCCLUSION by Fritz Allen MD COPE ID 31524-CL
byVisionary Ophthamology
 
PPTX
Hypertensive retinopathy
byAnisur Rahman
 
Age Related Macular Degeneration - ARMD
byrakshanshetty9591
 
Age related macular degeneration
byBulgaa luBgaa
 
Age related macular degeneration from Optometrist Point of View
byAnis Suzanna Mohamad
 
Age related macular degeneration nitin
byNitin Renge
 
Age related macular degeneration
byDr. Ajay Kumar Singh
 
Wet AMD- Aug 2017
bysameerasep13
 
BRANCH RETINAL VEIN OCCLUSION by Fritz Allen MD COPE ID 31524-CL
byVisionary Ophthamology
 
Hypertensive retinopathy
byAnisur Rahman
 

What's hot

PPTX
Interstitial keratitis
byAnkush Weginwar
 
PPTX
Intra Oular Lenses
byslidenka
 
PPTX
OCT in glaucoma ppt;1
byRashed-Ul-Hasan Rasu
 
PPT
Optical Coherence Tomography (OCT)
byDr. Shah Noor Hassan
 
PPTX
Traumatic Glaucoma
byshivraj tagare
 
PPTX
Pigment epithelial detachment (PED)
byMd Riyaj Ali
 
PPTX
OCT Angiography
byAnuraag Singh
 
PPT
Eccentric Fixation
byHossein Mirzaie
 
PPTX
Coloboma
byKh.Towkir-Ul- Islam
 
PPTX
ocular Sarcoidosis
bySivateja Challa
 
PPT
Diabetic Maculopathy
byDr. Shah Noor Hassan
 
PPT
Fuchs dystrophy and pseudophakic bullous keratopathy
byunleng
 
PPTX
Corneal graft rejection
byHarsha Prathapasinghe
 
PPT
10-subluxated-lens.ppt
byAdel930879
 
PPTX
Transpupillary Thermotherapy (TTT)
byPushkar Dhir
 
PPTX
BASICS OF PAN RETINAL, SECTOR AND FOCAL RETINAL LASER PHOTOCOAGULATION.pptx
byAVURUCHUKWUNALUJAMES1
 
PPTX
STABILIZATION PROCEDURE FOR REDUCE THE ROTATION OF CONTACT LENCE.pptx
bysonofonouu
 
PPTX
Intra Ocular lens
bydipusarkar2
 
PDF
Evaluation of preperimetric glaucoma
byMalvikaSuresh
 
PPTX
Optic nerve head evaluation in glaucoma
byDr Laltanpuia Chhangte
 
Interstitial keratitis
byAnkush Weginwar
 
Intra Oular Lenses
byslidenka
 
OCT in glaucoma ppt;1
byRashed-Ul-Hasan Rasu
 
Optical Coherence Tomography (OCT)
byDr. Shah Noor Hassan
 
Traumatic Glaucoma
byshivraj tagare
 
Pigment epithelial detachment (PED)
byMd Riyaj Ali
 
OCT Angiography
byAnuraag Singh
 
Eccentric Fixation
byHossein Mirzaie
 
Coloboma
byKh.Towkir-Ul- Islam
 
ocular Sarcoidosis
bySivateja Challa
 
Diabetic Maculopathy
byDr. Shah Noor Hassan
 
Fuchs dystrophy and pseudophakic bullous keratopathy
byunleng
 
Corneal graft rejection
byHarsha Prathapasinghe
 
10-subluxated-lens.ppt
byAdel930879
 
Transpupillary Thermotherapy (TTT)
byPushkar Dhir
 
BASICS OF PAN RETINAL, SECTOR AND FOCAL RETINAL LASER PHOTOCOAGULATION.pptx
byAVURUCHUKWUNALUJAMES1
 
STABILIZATION PROCEDURE FOR REDUCE THE ROTATION OF CONTACT LENCE.pptx
bysonofonouu
 
Intra Ocular lens
bydipusarkar2
 
Evaluation of preperimetric glaucoma
byMalvikaSuresh
 
Optic nerve head evaluation in glaucoma
byDr Laltanpuia Chhangte
 

Similar to ARMD 2016

PPTX
ARMD(age related macular degeneration).pptx
byNaoba Mutum
 
PPTX
DRY AGE RELATED MACULAR DEGENERATION
byShruti Laddha
 
PPTX
armd.pptx
byHarshika Malik
 
PPTX
ARMD_Dr Rizwana Khatoon 2.pptx for ms Ophthal
bysinhamegha21
 
PPTX
ARMD power point Presentation 1 - Dr Nagla hassan
byprof dr Nagla Hassan
 
PPTX
Age Related Macular Degeneration (ARMD) by SACHIN MAHATRA CHHETRI.pptx
byhellopeople2060
 
PPTX
Age related macular degeneration
byDuleepa Baranage
 
PPTX
ARMD_shane_35781.pptx ARMD presentation from medical university explained
bysstanley5
 
PPTX
Age related macular degeneration .......
bydrmehtabjamal
 
PPTX
Age related macular degeneration (
byKshitij Sharma
 
PDF
AGE RELATED MACULAR DEGRNERATION(ARMD).pdf
byAwais irshad
 
PPTX
Age related macular degeneration
byNikita Jaiswal
 
PPTX
AMD diagnosis and management............
byAlshymaa Moustafa
 
PPT
Age-Related Macular Degeneration
byHossein Mirzaie
 
PDF
AMD lecture 12,optics,iraq,collage, optician,pediatric
byAliSaadi16
 
PPT
ARMD . How to detect ?
byKafrELShiekh University
 
PPT
Macular Degeneration
byPranas Pranckevicius
 
PPTX
ARMD with basic retinal anatomy and management of armd
byD-lip Raj Gupta
 
PPTX
Age-related Macular Degeneration
byManoj Khadka
 
PPTX
role of oct in diagnosis and ttt of AMD
byDoaa Mahmoud
 
ARMD(age related macular degeneration).pptx
byNaoba Mutum
 
DRY AGE RELATED MACULAR DEGENERATION
byShruti Laddha
 
armd.pptx
byHarshika Malik
 
ARMD_Dr Rizwana Khatoon 2.pptx for ms Ophthal
bysinhamegha21
 
ARMD power point Presentation 1 - Dr Nagla hassan
byprof dr Nagla Hassan
 
Age Related Macular Degeneration (ARMD) by SACHIN MAHATRA CHHETRI.pptx
byhellopeople2060
 
Age related macular degeneration
byDuleepa Baranage
 
ARMD_shane_35781.pptx ARMD presentation from medical university explained
bysstanley5
 
Age related macular degeneration .......
bydrmehtabjamal
 
Age related macular degeneration (
byKshitij Sharma
 
AGE RELATED MACULAR DEGRNERATION(ARMD).pdf
byAwais irshad
 
Age related macular degeneration
byNikita Jaiswal
 
AMD diagnosis and management............
byAlshymaa Moustafa
 
Age-Related Macular Degeneration
byHossein Mirzaie
 
AMD lecture 12,optics,iraq,collage, optician,pediatric
byAliSaadi16
 
ARMD . How to detect ?
byKafrELShiekh University
 
Macular Degeneration
byPranas Pranckevicius
 
ARMD with basic retinal anatomy and management of armd
byD-lip Raj Gupta
 
Age-related Macular Degeneration
byManoj Khadka
 
role of oct in diagnosis and ttt of AMD
byDoaa Mahmoud
 

More from DINESH and SONALEE

PPTX
Epidemiology of diabetic retinopathy
byDINESH and SONALEE
 
PPTX
Telemedicne in india 2020
byDINESH and SONALEE
 
PPTX
Oct demystified
byDINESH and SONALEE
 
PPTX
Crvo management 2019 doscon
byDINESH and SONALEE
 
PPTX
Diabetic retinopathy management
byDINESH and SONALEE
 
PPTX
SURFACE ABLATION PRK , LASIK , SMILE
byDINESH and SONALEE
 
PPTX
Pentacam demystified 2016
byDINESH and SONALEE
 
PPTX
Intravitreal injection
byDINESH and SONALEE
 
PPTX
Neuro ophthalmology 2016
byDINESH and SONALEE
 
PPTX
Keratitis 2016
byDINESH and SONALEE
 
PPTX
General medicine update for every doctor hypertension
byDINESH and SONALEE
 
PPTX
General medicine update for every doctor
byDINESH and SONALEE
 
PPTX
Intravitreal injection avastin facts and myths
byDINESH and SONALEE
 
PPTX
Endophthalmitis 2016
byDINESH and SONALEE
 
PPTX
CRVO AND NVG MANAGEMENT 2016
byDINESH and SONALEE
 
PPTX
BRVO MANAGEMENT 2016
byDINESH and SONALEE
 
PPTX
Glaucoma management 2016
byDINESH and SONALEE
 
PPTX
Retinal detachment 2016
byDINESH and SONALEE
 
PPTX
Diabetic macular odema update 2016
byDINESH and SONALEE
 
PPTX
Keratoplasty update 2016
byDINESH and SONALEE
 
Epidemiology of diabetic retinopathy
byDINESH and SONALEE
 
Telemedicne in india 2020
byDINESH and SONALEE
 
Oct demystified
byDINESH and SONALEE
 
Crvo management 2019 doscon
byDINESH and SONALEE
 
Diabetic retinopathy management
byDINESH and SONALEE
 
SURFACE ABLATION PRK , LASIK , SMILE
byDINESH and SONALEE
 
Pentacam demystified 2016
byDINESH and SONALEE
 
Intravitreal injection
byDINESH and SONALEE
 
Neuro ophthalmology 2016
byDINESH and SONALEE
 
Keratitis 2016
byDINESH and SONALEE
 
General medicine update for every doctor hypertension
byDINESH and SONALEE
 
General medicine update for every doctor
byDINESH and SONALEE
 
Intravitreal injection avastin facts and myths
byDINESH and SONALEE
 
Endophthalmitis 2016
byDINESH and SONALEE
 
CRVO AND NVG MANAGEMENT 2016
byDINESH and SONALEE
 
BRVO MANAGEMENT 2016
byDINESH and SONALEE
 
Glaucoma management 2016
byDINESH and SONALEE
 
Retinal detachment 2016
byDINESH and SONALEE
 
Diabetic macular odema update 2016
byDINESH and SONALEE
 
Keratoplasty update 2016
byDINESH and SONALEE
 

Recently uploaded

PPTX
1 Digestion of carbohydrates -digestion, absorption, clinical significance
byProf Viyatprajna Acharya
 
PPTX
Foot and ankle examination for ortho residents
bysibasishBrahma1
 
PPTX
Glasgow coma scale .pptx GCS by EYES response VERBAL response MOTOR response
byMAHEK KHAN
 
PPTX
HUMAN ANATOMY OF THE HEAD ( THE SKULL.ppt)
byClevinAswani
 
PPTX
CATARACT SURGERY... KAL AAJ AUR KAL... THE PAST, THE PRESENT AND THE FUTURE.
byirfanrawal
 
PPT
PNEUMONIA presentations, and treatment lll
byenyiramunezero
 
PPTX
A War on Heart Attacks -- Joel Kahn, MD, FACC
byChurch Of Perpetual Life
 
PDF
Smoking Impact Diagnostic Panel: Understanding Smoking's Hidden Impact on You...
byFelixRendon3
 
PDF
Catalysts for Enhanced Patient CARE In Neuroendocrine Neoplasms: Clinical Ado...
byPVI, PeerView Institute for Medical Education
 
PDF
Bachelors in nursing science TOS Sem I KMU (1).pdf
byjesusebagahj73
 
PPTX
chronic bronchitis.pptx By gokulakrishnan
byGOKULAKRISHNAN JANARTHANAN
 
PDF
Key Pharmaceutical Advisory Firms for Early-Stage Biotech Businesses
byk kumar
 
PPTX
2. Physical examination.pptx for nursing students
byDesalegn Emana
 
PPTX
Hormonal IUS (Mirena®) Common Myths.pptx
byWafaa Benjamin
 
PPTX
nderstanding Male Sexual Health: Challenges and Solutions
bySujoy Dasgupta
 
PPTX
Formulation Development & Evaluation of Polyherbal Soap
bypurwaborkar@gmail.com
 
PPTX
1.3 inflamation, introduction to inflamation by Dr Lelaka.pptx
byjustin716667
 
PPTX
ABCDE Assessment What and all comes under assessmnet
byMs. Yagya Koirala
 
PPTX
Basement membrane zone .pptx
bySaiDeshmukh23
 
PDF
1150130-高雄地區第517次小兒科聯合病例討論會--高雄市醫師公會.pdf
byKs doctor
 
1 Digestion of carbohydrates -digestion, absorption, clinical significance
byProf Viyatprajna Acharya
 
Foot and ankle examination for ortho residents
bysibasishBrahma1
 
Glasgow coma scale .pptx GCS by EYES response VERBAL response MOTOR response
byMAHEK KHAN
 
HUMAN ANATOMY OF THE HEAD ( THE SKULL.ppt)
byClevinAswani
 
CATARACT SURGERY... KAL AAJ AUR KAL... THE PAST, THE PRESENT AND THE FUTURE.
byirfanrawal
 
PNEUMONIA presentations, and treatment lll
byenyiramunezero
 
A War on Heart Attacks -- Joel Kahn, MD, FACC
byChurch Of Perpetual Life
 
Smoking Impact Diagnostic Panel: Understanding Smoking's Hidden Impact on You...
byFelixRendon3
 
Catalysts for Enhanced Patient CARE In Neuroendocrine Neoplasms: Clinical Ado...
byPVI, PeerView Institute for Medical Education
 
Bachelors in nursing science TOS Sem I KMU (1).pdf
byjesusebagahj73
 
chronic bronchitis.pptx By gokulakrishnan
byGOKULAKRISHNAN JANARTHANAN
 
Key Pharmaceutical Advisory Firms for Early-Stage Biotech Businesses
byk kumar
 
2. Physical examination.pptx for nursing students
byDesalegn Emana
 
Hormonal IUS (Mirena®) Common Myths.pptx
byWafaa Benjamin
 
nderstanding Male Sexual Health: Challenges and Solutions
bySujoy Dasgupta
 
Formulation Development & Evaluation of Polyherbal Soap
bypurwaborkar@gmail.com
 
1.3 inflamation, introduction to inflamation by Dr Lelaka.pptx
byjustin716667
 
ABCDE Assessment What and all comes under assessmnet
byMs. Yagya Koirala
 
Basement membrane zone .pptx
bySaiDeshmukh23
 
1150130-高雄地區第517次小兒科聯合病例討論會--高雄市醫師公會.pdf
byKs doctor
 

ARMD 2016

  • 1.
  • 2.
    DR DINESH MITTALDR SONALEE MITTAL DRISHTI EYE HOSP VIJAYNAGAR INDORE
  • 5.
  • 6.
    INTRODUCTION • Age-related maculardegeneration (AMD) is the leading cause of irreversible visual impairment among the elderly worldwide affecting 30–50 million individuals. Loss of visual acuity typically results from progressive degeneration of the photoreceptors, retinal pigment epithelium (RPE), and choriocapillaris although the earliest manifestation of the disease appears histopathologically as abnormalities within Bruch’s membrane. advanced form of disease is characterized by macular neovascularization, geographic atrophy (atrophy of the RPE, choriocapillaris, and photoreceptors), or both .
  • 7.
    • This definitionof early ARM excluded small, hard drusen alone, pigment changes alone, and even pigment changes surrounding small, hard drusen for two reasons: • (1) hard drusen become an almost constant finding in the fifth decade; and • (2) a number of diverse processes can cause pigment abnormalities that may not be possible to distinguish from early ARM, so the inclusion of soft drusen makes the definition more specific to ARMD. • However, eyes with numerous small, hard drusen or eyes with pigment abnormalities in the absence of obvious drusen can also progress to soft drusen.
  • 8.
    Age-Related Macular Degeneration • Age-relatedmacular degeneration (AMD) is the leading cause of blindness in the developed world in people over 50 years of age. It is estimated that among North Americans, 15 million (85%–90% of all AMD patients) currently have “dry” (nonneovascular, or nonexudative) AMD and 1.7 million people (10%–15% of all AMD patients) have “wet” (neovascular) AMD. An estimated 200,000 new cases of neovascular AMD develop each year in North America.
  • 9.
    ARMD • The diseasenearly always begins as the non- neovascular or dry form of AMD and may progress to geographic atrophy or the neovascular (wet) form in one or both eyes. When neovascularization occurs, there is commensurate accumulation of fluid, hemorrhage, and lipid exudation within the macula that can culminate in fibrosis referred to as a disciform scar. A patient can have advanced dry AMD in both eyes, advanced wet AMD in both eyes, or dry AMD in one eye and wet AMD in fellow eye. It is controversial whether the wet and dry forms of AMD represent two distinct disease entities or end-stage manifestations of the same disease
  • 10.
    OVERVIEW • Once advancedAMD develops in one eye, there is an increased likelihood of having geographic atrophy or neovascularization in the fellow eye. A simplified severity scale based on fundus appearance was established to assess the risk of converting to advanced AMD. Large drusen, any pigment changes, and the disease state of the fellow eye were particularly predictive for developing advanced AMD. The cause of AMD is multifactorial and influenced by age, ethnic background, and a combination of environmental and genetic factors. There is no cure; however, vitamin supplementation, good nutrition, and cessation of smoking can slow the progression of the dry form of AMD while drugs that inhibit vascular endothelial growth factor-A (VEGF-A) have been successful in converting the wet form of AMD back to the dry form
  • 11.
    Epidemiology and RiskFactors for ARMD • The only proven treatment available for the dry or nonexudative forms of this disease, comprising 85% of cases, is an antioxidant/mineral supplement which can slow the progression of the disease by 25% over 5 years. For the wet form of the disease, anti-vascular endothelial growth factor (VEGF) treatments have been very effective in preventing severe vision loss. Still, preventive measures are needed to reduce the burden of this disease. Smoking is the most consistently identified modifiable risk factor. Obesity, sunlight exposure, & nutritional factors including antioxidants and dietary fat intake may also affect AMD incidence and progression.
  • 12.
    • Within thepast 5 years new and improved treatments for the neovascular form of advanced AMD have been adopted throughout the developed world. Therefore, in the years ahead the overall burden of vision loss associated with AMD is anticipated to decline substantially. The same progress has not been made for treatment of advanced non-neovascular AMD (GA); as such, the importance of atrophic AMD as a leading cause of vision impairment is expected to increase. The advanced forms of AMD are those that are frequently associated with visual acuity loss and they are divided into non neovascular atrophic (dry) type and neovascular (wet) type. In atrophic AMD, gradual disappearance of the retinal pigment epithelium (RPE) results in one or more patches of atrophy that slowly enlarge and coalesce. Affected areas have no visual function, since loss of RPE is associated with fallout of photoreceptors. Gass applied the term “geographic atrophy of the retinal pigment epithelium” to this presentation, which is the natural end-result of AMD in the absence of clinical evidence of choroidal neovascularization (CNV).
  • 14.
    A. The RPEin a young retina has a homogenous distribution of the melanin granules, a BM without deposits, and a preserved function
  • 15.
    B. In dryAMD, the RPE melanin granules are localized basally, and lipofuscin granules increase in number while the efficacy of the disks digestion reduces. Note the formation of drusen between the basement membrane of the RPE and the inner collagen layer of the BM and the thickened BM
  • 16.
    C. In wetAMD, CNV develops, and an inflammatory response develops with an influx of lymphocytes and macrophages to the scene. These fragile new vessels leak and lead to subretinal hemorrhage
  • 17.
    Nonneovascular AMD • Theprototypical lesion of the nonneovascular form of AMD is the druse. Other indicators are abnormalities of the RPE, including hyperpigmentation and atrophy.
  • 20.
    Drusen • Clinically, drusenare small, round, yellow lesions located at the level of the RPE, mostly in the • postequatorial retina . Histologically, this material corresponds to the abnormal thickening of the inner aspect of the Bruch membrane . Ultrastructurally, basal laminar deposits (granular, lipid-rich material and widely spaced collagen fibers between the plasma membrane and basement membrane of the RPE cell) and basal linear deposits (phospholipid vesicles and electron-dense granules within the inner collagenous zone of the Bruch membrane) are present
  • 21.
    Drusen • Drusen inan extramacular location are of no known visual consequence. Typical drusen deposits are located between the RPE and • Bruch’s membrane and vary widely in number, size, shape, and distribution. Most drusen are 20–100 μm in diameter and are characterized as hard or soft as well as small (< 63 μm), intermediate (> 63 μm but < 125 μm) or large (≥ 125 μm).
  • 22.
    Hard drusen vssoft drusen • Hard drusen, which appear as round, discrete yellow-white spots,measure less than 63 μm. These drusen are commonly identified in many populations; they are not age- related and do not carry an increased risk for development of neovascularization, with 80% of the general population older than 30 years manifesting at least one. In contrast, soft drusen are ill defined, with nondiscrete borders, measuring 63 μm or greater . Different population based studies and clinical trials have indicated that large, soft, confluent drusen are age-related and associated with a higher risk for development of advanced AMD with the development of neovascularization. After the age of 70 years, 26% of individuals have large or soft drusen, and 17% have confluent drusen .
  • 27.
    FA OF DRUSEN •Typically, small hard drusen hyperfluoresce early in FA studies because of a window defect, whereas larger soft and confluent drusen and drusenoid PEDs slowly and homogenously stain late because of pooling of the fluorescein dye in the sub-PED compartment. However, there is some variability in how drusen appear on FA.
  • 28.
    OCT of drusen •SD-OCT imaging of small and large drusen typically reveals sub-RPE nodular elevations or even small RPE detachments with a notable absence of intraretinal and subretinal fluid . • Reticular pseudodrusen are identified above the RPE and beneath the inner segment ellipsoid layer • and are graded according to their degree of elevation . • Enhanced depth imaging (EDI) of the choroid using OCT has permitted more detailed analysis of the choroid in AMD. Choroidal thickness values are typically normal or reduced in nonneovascular AMD.
  • 29.
    Abnormalities of theRPE • Several patterns of RPE abnormalities characterize nonneovascular AMD, including focal hyperpigmentation, nongeographic atrophy, and geographic atrophy. Increased pigmentation at the level of the outer retina corresponds to focal hyperpigmentation of the RPE. On FA, these areas typically show blockage, and on SD-OCT, show hyperreflective outer retinal foci. The incidence of focal hyperpigmentations increases with age, and their presence indicates greater risk of progression to the more advanced forms of AMD.
  • 30.
    Abnormalities of theRPE • Nongeographic atrophy refers to atrophy that does not cover a contiguous area and may appear as an area of mottling or depigmentation. When the area of absent or attenuated RPE is contiguous, the condition is termed geographic atrophy of the RPE. In areas of GA, the unmasked choroidal vessels are more readily visible, the overlying outer retina may appear thin, and choriocapillaris is attenuated or atrophied. On FA, GEOGRAPHIC ATROPHY shows well-circumscribed round to oval window defects, whereas on SD-OCT, loss of the RPE and the overlying inner segment ellipsoid and photoreceptor layer can be seen. Dense hypoautofluorescence occurs in areas of GA. Fundus autofluorescence is a practical and noninvasive tool to monitor progression of GA
  • 33.
    Geographic atrophy • Geographicatrophy often spares the fovea until late in the course of the disease. It may first present as one or more noncontiguous patches of atrophy around the fovea. These patches enlarge and coalesce and may be associated with a dense paracentral scotoma, thereby limiting tasks such as reading. Patients with GA may demonstrate good visual acuity (VA) until late in the course of the disease, when the fovea becomes progressively atrophic, leading to severe visual acuity decline from central blindness and forcing the patient to use noncentral retina and eccentric fixation to read and perform other visual tasks
  • 34.
    • Although notall eyes with drusen or PED will develop atrophy, the incidence of atrophy appears to increase with age. Twelve to 20% of patients with GA have severe vision loss .
  • 35.
    Management of nonneovascular AMD •Education and follow-up Eyes with soft drusen and RPE hyperpigmentation are at increased risk of developing GA and CNV. As such, patients with nonneovascular AMD should be educated about the symptoms of advanced AMD and instructed to contact an ophthalmologist promptly should these symptoms occur. If reduced visual acuity or reduced vision function (difficulty reading despite good measured visual acuity) is noted, a low vision evaluation should be considered. Periodic examinations are advised to monitor for concurrent, treatable eye disease (eg, cataract, glaucoma) and to re evaluate low vision needs.
  • 36.
    Amsler grid • TheAmsler grid is a test card for patient home-monitoring use; it contains white grid lines on a black background and a central dot for fixation. Each eye is tested individually with reading glasses and at reading distance to check for any new metamorphopsia, scotoma, or other significant changes in central vision. Any changes noted by the patient should be evaluated urgently .
  • 37.
    MICRONUTRIENTS • AREDS firstestablished the benefit of vitamin and zinc supplementation in reducing the risk of vision loss in patients with nonexudative AMD. supplementation with the antioxidant vitamins C (500 mg) and E (400 IU), beta carotene (15 mg), and the micronutrient zinc (80 mg zinc oxide and 2 mg cupric oxide to prevent zinc-induced anemia) in patients with intermediate or stage 3 nonneovascular AMD demonstrated a 25% risk reduction for progression to advanced AMD and a 19% risk reduction in rates of moderate vision loss (≥3 lines of visual acuity) at 5 years.
  • 38.
    AREDS • Intermediate AMDwas defined as the presence of at least 1 large druse (>125 μm) or nonsubfoveal GA, and advanced unilateral AMD was defined as vision loss due to neovascular AMD or GA in 1 eye. At 10 years, 44% of placebo recipients compared with 34% of the supplement recipients had advanced AMD (a 27% risk reduction). Among participants with no AMD or only early AMD (a few small drusen), there was no measurable benefit. There was no increased mortality among patients taking the AREDS formula
  • 39.
    AREDS • A simplified4-point grading scale was developed by AREDS for classifying the severity of AMD and predicting the disease course based on the following findings: • presence of 1 or more large (>125-μm diameter) drusen (1 point) • presence of any pigment abnormalities (1 point) • for patients with no large drusen, presence of bilateral intermediate (63–124 μm) drusen (1 point) • presence of neovascular AMD (2 points)
  • 40.
  • 41.
    • Large population-basedstudies suggest that supplementation with the xanthophylls lutein & zeaxanthin as well as omega-3 long-chain polyunsaturated fatty acids (LCPUFAs: docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]) may also help reduce AMD progression.
  • 42.
    AREDS2 study • TheAREDS2 study was designed to test whether these observations could be confirmed in a prospective trial. Among the 4000 participants, the study confirmed the overall risk reduction found in the original AREDS study, concluded that lutein and zeaxanthin had similar effects to beta carotene, and found 80 mg of zinc to be the appropriate dose for AMD prophylaxis. Furthermore, LCPUFAs were not found to decrease the rate of progression to advanced AMD. A nonocular effect detected was an increased rate of lung cancer among current and former smokers using beta carotene, a finding other nonophthalmic studies had previously reported. As a result, study’s recommendations for AREDS supplementation were to replace beta carotene with lutein and zeaxanthin and not to add LCPUFAs .
  • 44.
    Lifestyle changes • Withincreasing evidence that environment and health habits influence the development and progression of AMD, patients should be counseled to alter behaviors that put them at risk. Of particular importance are smoking cessation, obesity reduction, and blood pressure control. Cataract surgery has not been linked consistently to the progression of AMD, nor is there strong evidence linking UV (UV-A or UV-B) light exposure to the progression of AMD. It should be noted, however, that there are no negative effects of wearing UV-protective glasses .
  • 45.
    Neovascular AMD • Thehallmark of the neovascular form of AMD is the presence of CNV. Degenerative changes in the Bruch membrane—such as the accumulation of drusen and the progressive thickening of membrane’s inner aspect that characterize nonneovascular form of AMD—can be associated with a proangiogenic environment, including neovascularization that originates from the choriocapillaris and perforates the outer aspect of the Bruch membrane. These new vessels are accompanied by fibroblasts, resulting in a fibrovascular complex that can leak and bleed and may disrupt and destroy the normal architecture of the RPE–photoreceptor complex, ultimately leading to the formation of a hypertrophic fibrotic disciform scar.
  • 49.
    Signs and symptomsof neovascular AMD • Patients with neovascular AMD describe the sudden onset of decreased vision, metamorphopsia, and/or paracentral scotomata. Amsler grid self-testing by patients is highly effective for early detection of neovascular AMD. Clinical signs of CNV may include subretinal or intraretinal fluid, exudate and/or blood, a pigment ring or gray-green membrane, irregular elevation of the RPE or a PED, an RPE tear, and/or a sea fan pattern of subretinal vessels. • Intraretinal blood and cystoid macular edema (CME) may indicate the presence of type 3 neovascularization, which originates from the deep capillary plexus of the retinal circulation.
  • 50.
    Anatomical classification ofCNV • Three types of CNV are now recognized. In type 1 neovascularization, new vessels originating from the choriocapillaris grow through a defect in the Bruch membrane into the sub–pigment epithelial space. Leakage and bleeding can lead to the development of a vascularized serous or fibrovascular PED. The fibrovascular PEDs are often seen to have an irregular surface contour.
  • 51.
    • In type2 neovascularization, the CNV occupies the subneurosensory compartment between the RPE and the outer segments of the retina . On examination, the membrane will appear as a lacy or graygreen lesion; in AMD, this finding is less common than is type 1 neovascularization.
  • 61.
    CNVM • Type 3neovascularization results from new blood vessels sprouting from the deep capillary plexus of the retina and growing downward toward the RPE. Because of their intraretinal growth, these lesions were originally termed retinal angiomatous proliferations (RAP). On examination, they appear as a small area of red discoloration, often associated with retinal exudate.
  • 62.
    • Ultimately, ifuntreated, these neovascular processes may evolve into a hypertrophic, fibrotic, disciform scar. The retina overlying the scar loses its normal outer retinal architecture, which can lead to severe, permanent central vision loss.
  • 63.
    Fluorescein angiographic patterns ofCNV • FA patterns of CNV may include classic or occult CNV or combinations of both. • Classic CNV is an area of bright, lacy, and well-defined hyperfluorescence that is identified in the early phase and progressively leaks by the late phases . • Occult CNV consists of 2 forms: • (1) PED, either fibrovascular PED or vascularized serous PED, and • (2) late leakage from an undetermined source
  • 65.
    OCCULT CNVM • FibrovascularPED refers to an irregular elevation of the RPE with progressive, stippled leakage on FA. Alternatively, the PED may pool dye rapidly in a homogenous ground-glass pattern that is consistent with a serous PED but has a notch, or hot spot, indicating vascular tissue in the PED—a vascularized serous PED
  • 67.
    Late leakage froman undetermined source • Late leakage from an undetermined source refers to regions of fluorescence at the level of the flat RPE that are ill defined early and best appreciated in the late phases of the angiographic study. The angiographic description of occult CNV may be anatomically related to type 1 neovascularization, whereas that of classic CNV may be related to type 2 neovascularization; this relation is not a hard-and-fast rule, however Type 3 neovascularization, or RAP, may be signaled by the presence of a spot of retinal hemorrhage in the macula.
  • 68.
    • FA andindocyanine green (ICG) angiography may demonstrate a focal hot spot and late CME; associated pooling into a PED may also be present. The presence of thick blood, pigment, scar tissue, or a PED may block fluorescence and obscure any underlying CNV. ICG angiography, which employs a dye that is almost fully protein bound and has a longer wavelength nearer the infrared spectrum, may be valuable in penetrating heme and pigment to allow identification of the CNV, which may appear as a hot spot.
  • 69.
    SD-OCT patterns ofCNV • Type 1 neovascular membranes demonstrate elevation of the RPE and a PED on SD-OCT. A serous PED appears as a sharply elevated, dome-shaped lesion with hollow internal reflectivity and typically no associated subretinal or intraretinal fluid. A fibrovascular PED may or may not be sharply elevated and typically demonstrates a lacy or polyplike hyperreflective lesion on the undersurface of the RPE, with or without signs of contraction. A chronic fibrovascular PED has a multilayered appearance, and a complex fibrovascular scar may be appreciated in sub PED compartment, with or without associated subretinal and/or intraretinal fluid.
  • 70.
    SD-OCT patterns ofCNV • Type 2 neovascular membranes appear as a hyperreflective band or plaque in the subneurosensory space, with associated subretinal and/or intraretinal fluid. Type 3 neovascular membranes are best appreciated with SD-OCT as a hyperreflective focus emanating from the deep capillary plexus of the retina, with or without associated CME and PED. Recognition of these SD-OCT patterns is crucial for the diagnosis and classification of CNV. Also, SD-OCT is a noninvasive procedure as well as the most important and practical modality for monitoring the response of therapy by assessing regression of the neovascular membrane and resolution of subretinal and intraretinal fluid.
  • 71.
    Polypoidal choroidal vasculopathy • Polypoidalchoroidal vasculopathy (PCV), initially described as posterior uveal bleeding syndrome, is a variant of choroidal neovascularization (type 1) and is characterized by multiple, recurrent serosanguineous RPE detachments. A network of polyps with associated feeder vessels, similar in appearance to a string of pearls, can be identified with SDOCT adherent to the RPE monolayer of the fibrovascular PED—hence designation of type 1 neovascularization.
  • 72.
    Polypoidal choroidal vasculopathy • Itis now believed to occur in women and men of all races and to be a variant of neovascular AMD, with same genetic profile. The areas of serosanguineous detachment are often peripapillary and multifocal but may be peripheral, and associated nodular, orange, subretinal lesions may be appreciated. Vitreous hemorrhage may occur more frequently than in classic AMD, and the typical soft drusen of AMD may or may not be present. The natural history and visual acuity outcomes of PCV may be better than those of CNV associated with AMD . ICG angiography and SD-OCT are important techniques for identifying the polyps.
  • 74.
    Differential diagnosis of neovascularAMD • A variety of conditions can mimic the neovascular changes of AMD and typically include any disorder that is associated with disruption of the Bruch complex and secondary CNV. • The subretinal fluid of central serous chorioretinopathy can be confused with subretinal fluid or edema associated with CNV and AMD. However, patients with CSC are usually younger and usually do not have associated subretinal hemorrhage unless a secondary CNV has developed. CSC can be further differentiated by characteristic signs including patches of RPE mottling that may assume a • geographic or gutterlike gravitational configuration on wide- field angiographic or autofluorescent imaging and a thick choroid best visualized with EDI-OCT.
  • 75.
    Management of neovascularAMD • If neovascular AMD is suspected on clinical grounds, FA and OCT studies can be obtained. SD-OCT is most efficient and reliable tool in diagnosing and distinguishing types 1, 2, & 3 neovascularization and in monitoring response to therapy.
  • 76.
    Laser photocoagulation (thermal laser) •From the 1980s through 2000, laser therapy was primary treatment for classic extrafoveal CNV with well-defined boundaries. However, outcomes were poor because of high recurrence rates, as demonstrated in the Macular Photocoagulation Studies. The use of thermal laser treatment is now rare except to treat extrafoveal lesions that are sufficiently far from the foveal center to have minimal risk of iatrogenic foveal laser damage and a lower rate of recurrence.
  • 77.
    Photodynamic therapy PDT •Photodynamic therapy PDT was introduced in 2000 as a less-destructive modality for treating CNV than thermal laser and entails the systemic administration of a photosensitizing drug followed by an application of light of a particular wavelength to the affected tissue to incite a localized photochemical reaction. This reaction generates reactive oxygen species, leading to capillary endothelial cell damage & vessel thrombosis. Studies showed that PDT slowed progression but did not prevent significant vision loss in eyes with CNV that had certain lesion characteristics. Use of PDT in the management of exudative AMD is now rare except in recalcitrant cases or eyes with PCV.
  • 78.
    Vascular endothelial growth factor(VEGF) is a homodimeric glycoprotein that is secreted in response to hypoxia and ischemia. VEGF induces angiogenesis and vascular permeability. Arrows show the binding site VEGFR
  • 79.
    Antiangiogenic therapies • Angiogenesis—theformation of new blood vessels that occurs via sprouting or splitting from existing vessels—is characterized by a complex cascade of events. The first step in the cascade involves vasodilation of existing vessels and increased vascular permeability. This process is followed by degradation of the surrounding extracellular matrix, which facilitates migration and proliferation of endothelial cells. The endothelial cells join together to form a lumen, which becomes a new capillary. The vessels subsequently mature and undergo remodeling to form a stable vascular network. The successful execution of this cascade requires a balanced interplay of growth-promoting and growth-inhibiting angiogenic factors.
  • 80.
    Antiangiogenic therapies • Identifiedactivators of angiogenesis include vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), transforming growth factor α (TGF-α) and TGF-β, angiopoietin-1, and angiopoietin-2. Inhibitors of angiogenesis include thrombospondin, angiostatin, endostatin, and pigment epithelium–derived factor (PEDF).
  • 81.
    Antiangiogenic therapies • Themajority of recent antiangiogenesis research has focused on the inhibition of VEGF. VEGF expression is increased in pigment epithelial cells during the early stages of AMD, suggesting that VEGF plays a causal role in the initiation of neovascularization. In addition, high concentrations of VEGF have been observed in excised CNV and vitreous samples from AMD patients. VEGF is a homodimeric glycoprotein that is a heparin-binding growth factor specific for vascular endothelial cells. It can induce angiogenesis, vascular permeability, and lymphangiogenesis and may act as a survival factor for endothelial cells by preventing apoptosis. There are at least 4 major VEGF isoforms, of which VEGF165 is thought to be the most dominant in AMD.
  • 82.
    Pegaptanib • Pegaptanib, anRNA oligonucleotide ligand (or aptamer) that binds human VEGF165 with high affinity and specificity, was the first intravitreal anti-VEGF therapy approved by the US FDA , in 2004. Studies showed that it slowed vision loss, but it has since been supplanted by far more effective agents.
  • 83.
    Ranibizumab • Ranibizumab isa recombinantly produced, humanized antibody fragment (Fab) that binds VEGF. Unlike pegaptanib, ranibizumab binds to and inhibits all active isoforms of VEGF-A and their active degradation products. Two studies, MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD) and ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic CNVM in AMD), demonstrated that, at 12 months, 95% of ranibizumab-treated patients experienced vision stabilization or improvement compared with 62% of sham-treated patients and 64% of patients treated with PDT, respectively. More important, approximately 30%–40% of ranibizumab-treated patients experienced vision improvement of 15 letters or more compared with control participants in each study, with an average letter gain of approximately 10 letters . Almost 80% of patients maintained or improved vision after 24 months.
  • 87.
    Present status • Sixty-fiveAMD patients from the MARINA, ANCHOR, and HORIZON studies were evaluated approximately 7 years after baseline recruitment. Of these patients, 23% achieved a best-corrected visual acuity (BCVA) of 20/40 or better, while 37% had BCVA of 20/200 or worse, and almost one-half (43%) of eyes had an unchanged or improved letter score versus baseline. Active fluid was detected by SD-OCT in 68% of study eyes, and macular atrophy, the area of which correlated with vision loss, was detected by fundus autofluorescence in 98% of eyes.
  • 88.
    TREAT AND OBSERVE/ EXTEND • treatment effect declined in the ranibizumab recipients during quarterly dosing (ie, every 3 months) but not with monthly dosing intervals. These data clarified that quarterly treatment appears to be suboptimal. In general, there are 2 accepted treatment schemes that deviate from the FDA-approved labeling of monthly injections: “treat- and-observe,” or “as-needed,” and “treat-and- extend” approaches to anti-VEGF therapy.
  • 89.
    “treat-and-observe,” or “as-needed,” and“treat-and-extend” approaches to anti-VEGF therapy • In the treat-and-observe method, regular treatment is administered until the macula is dry by clinical and OCT-determined criteria, followed by treatment only for signs of recurrent exudation during the maintenance phase. This approach is in contrast to the treat-and extend regimen, in which regular monthly treatment is continued until the macula is dry, after which treatment continues at gradually increasing intervals. In this second approach, injections are administered even with inactive CNV. The goal of this therapy is to cautiously extend the time between injections as far apart as tolerated as long as there are no signs of recurrence.
  • 90.
    MONTHLY INJECTIONS NEEDED ONLYFOR THREE MONTHS & • Several clinical trials have evaluated as-needed approaches to anti-VEGF therapy: PrONTO (Prospective Optical Coherence Tomography Imaging of Patients With Neovascular AMD Treated With Intraocular Ranibizumab), SAILOR (Study to Evaluate Ranibizumab in Subjects With Choroidal Neovascularization Secondary to AMD), SUSTAIN (Study of Ranibizumab in Patients with Subfoveal Choroidal Neovascularization Secondary to AMD), and HORIZON (Open-Label Extension Trial of Ranibizumab for Choroidal Neovascularization Secondary to AMD). All of these studies utilized 3 monthly injections followed by various as-needed treatment regimens, determined on the basis of clinical and OCT-guided criteria, and all showed vision and OCT outcomes that were comparable to or reduced from those obtained with MARINA and ANCHOR.
  • 91.
    Safety data • Safetydata have been favorable for intravitreal ranibizumab therapy. Intravitreal injections are occasionally associated with minor local complications such as subconjunctival hemorrhage and local irritation. However, the incidence of severe, visually compromising complications such as vitreous hemorrhage, retinal detachment, or endophthalmitis is exceedingly low across numerous trials including those just described. Systemic arteriothrombotic events can arise during the course of ranibizumab therapy, but no study has conclusively determined an increased incidence of these events related to injection of the drug.
  • 92.
    RISK OF TEAR •Eyes with fibrovascular PEDs may be at increased risk for the development of an RPE tear after anti- VEGF therapy, and this risk may be especially significant with PEDs greater than 600 μm in height. The mechanism of the tear may relate to contraction of the type 1 neovascular membrane beneath the PED that occurs as a result of the anti-VEGF injection.
  • 95.
    PROTOCOLS OF TREATMENT: RETREATMENTALGORITHMS AND MAINTENANCE THERAPY • Fixed Monthly Injections • Initially, there was no clear consensus on retreatment strategies. In the MARINA and ANCHOR studies of ranibizumab, patients received monthly intravitreal injections during 2 years, so each patient received a total of 24 injections. Today, the fixed monthly ranibizumab retreatment schedule has not been widely accepted . Patients were at first treated with three monthly injections of ranibizumab, termed the “loading phase,” followed by a quarterly injection regimen. The results observed were positive but did not equal the MARINA and ANCHOR results. In fact, patients showed less mean gain in VA, and fewer patients experienced 15 or more letters of visual gain. Additionally, if after the loading phase there was a gain in VA, it was not maintained during the study .
  • 96.
    As-Required Injections • PrONTOstudy introduced a dosing regimen characterized by three consecutive monthly intravitreal injections followed by as-needed retreatment based upon signs of recurrence, ophthalmoscopy, OCT, or fluorescein angiography, called the as-needed or PRN protocol . It seems that the PRN dosing regimen is the most widely used today. Ranibizumab was used in PrONTO study, and the dosing regimen was OCT guided and variable. Patients received three monthly intravitreal injections, and retreatment was based upon loss of five letters of VA, new-onset hemorrhage or CNV, increase of central retinal thickness of more than 100 μm documented with OCT, or intraretinal fluid. In the first year of PrONTO study, patients received an average of 5.6 injections of ranibizumab. The results of PrONTO study suggest that 70% of the patients treated with intravitreal ranibizumab showed resolution of edema within 1 month after the first injection, and 90% of the patients showed resolution of fluid after the loading phase . • The CATT study compared ranibizumab and bevacizumab using monthly and as-required retreatment schedules (67). In this study, bevacizumab administered monthly led to a gain of 8.0 letters at 12 months, and bevacizumab administered as-required led to a gain of 5.9 letters. Similarly, ranibizumab administered monthly led to a gain of 8.5 letters at 12 months, and ranibizumab in as-required schedule led to a gain of 6.8 letters. It is clear that a monthly retreatment schedule showed greater gain in VA, but the differences were “inconclusive” for the bevacizumab groups and were not significant for the ranibizumab groups. These studies follow up patients for 12 months, but other studies with longer follow- ups, such as HORIZON and SUSTAIN, have shown that significant visual gain is achieved with monthly injections and the as-required schedule is not as effective as the monthly fixed schedule.
  • 97.
    Treat and Extend •Other retreatment schedules are used, in order to minimize the number of injections and visits to the hospital. In the treat-and-extend schedule, the patients are treated with monthly injections until macula is dry and without fluid seen with OCT. The follow-up between injections is lengthened by 1 to 2 weeks until recurrence of fluid is observed. If recurrent fluid is detected on a follow-up visit, the treatment interval is reduced to the previous interval. Treatment schedule is variable and subject to change at every visit, but the time between visits in individualized based on each patient's response to treatment
  • 98.
    PrONTO • a ranibizumabstudy known as PrONTO (Prospective OCT Imaging of Patients with Neovascular AMD Treated with Intraocular Ranibizumab). This phase I/II study explored whether dosing based on the presence of fluid in the macula as detected by OCT could result in fewer injections but achieve visual acuity outcomes similar to the results obtained with monthly dosing.130 The study design mandated three consecutive monthly injections with intravitreal ranibizumab (0.5 mg). Then, from month 3 through month 24, patients were examined monthly with OCT and additional injections were performed only if certain OCT-based criteria were fulfilled .
  • 99.
    PrONTO • After oneyear, the mean improvement in visual acuity from baseline was 9.3 letters (P < 0.001), and at two years it was 11.1 letters (P < 0.001). More than one-third of eyes (35%) in PrONTO gained at least 15 letters of visual acuity at one year and 43% gained at least 15 letters at two years. These visual acuity outcomes were comparable to the outcomes in the MARINA and ANCHOR trials. Moreover, these visual acuity outcomes were achieved with an average of 5.6 out of a maximum of 13 monthly injections the first year and 9.9 injections out of a maximum of 25 monthly injections over two years. The PrONTO study also demonstrated that the onset of action for ranibizumab was rapid with an average decrease in OCT central retinal thickness of about 50 μm at one day, 100 μm at one week, and 150 μm at one month after the first injection .
  • 100.
    • Compared withthe MARINA and ANCHOR outcomes in which monthly injections were mandated, the OCT-guided retreatment strategy appeared to result in similar visual acuity outcomes with far fewer intravitreal injections. Another OCT-based retreatment strategy known as ‘treat and extend’ has also been proposed, trying to reduce number of injections and number of visits, with visual acuity improvement . Whether it is the PrONTO-style retreatment strategy known as ‘treat and observe’ or the ‘treat and extend’ regimen, the visual acuity outcomes are probably very similar to the outcomes achieved with monthly injections but fewer injections are required. Other studies have explored the ‘treat and observe’ strategy with similar favorable results.
  • 105.
    Bevacizumab • Bevacizumab isa full-length monoclonal antibody against VEGF that was approved by the FDA in 2004 for the treatment of metastatic colorectal cancer. It has been described for “offlabel” use via intravitreal and intravenous administration for the treatment of AMD. Both bevacizumab and ranibizumab are manufactured by the same pharmaceutical company, and there are important differences between the drugs: bevacizumab is larger and has 2 antigen-binding domains compared with the single domain for ranibizumab, and cost differences between them are substantial, potentially affecting access to treatment for some patients. Because fragment antibodies in general have shorter systemic half- lives than those of full-length antibodies (2.2 hours for ranibizumab vs ~21 days for bevacizumab), intravitreal injections of ranibizumab have a shorter systemic half-life than intravitreal injections of bevacizumab.
  • 106.
    Bevacizumab • Because ofthe 50-fold lower cost and the purported similar efficacy of bevacizumab compared with ranibizumab, several comparative efficacy studies have been conducted. These studies include CATT (Comparison of Age-Related Macular Degeneration Treatments Trials) in the United States, IVAN (Randomised Controlled Trial of Alternative Treatments to Inhibit VEGF in Age-Related Choroidal Neovascularisation) in the United Kingdom, MANTA (Randomized Observer and Subject Masked Trial Comparing the Visual Outcome After Treatment With Ranibizumab or Bevacizumab in Patients With Neovascular Age-Related Macular Degeneration Multicenter Anti-VEGF Trial in Austria), and GEFAL (Groupe d’Evaluation Français Avastin vs Lucentis) in France .
  • 107.
    Bevacizumab • CATT wasthe first and largest multicenter, randomized clinical trial to compare the relative safety and efficacy of ranibizumab with bevacizumab for the treatment of neovascular AMD. The trial was funded by the US National Eye Institute and studied 1208 patients. Results showed that bevacizumab was noninferior to ranibizumab therapy in monthly or as-needed delivery schedules over 2 years. Mean letters gained from baseline did not differ statistically among the 4 arms of the study: 8.8 letters in the ranibizumab- monthly group, 7.8 letters in the bevacizumab-monthly group, 6.7 letters in the ranibizumab as-needed group, and 5.0 letters in the bevacizumab as-needed group . Systemic adverse events were significantly greater in the bevacizumab (39.9%) than in the ranibizumab (31.7%) group, but death and arteriothrombotic events were not statistically different between the 2 drugs .
  • 108.
  • 109.
    The preparation of individual syringes requiresa strict aseptic technique with adequate sterilization procedures
  • 110.
    NEEDLE GAUGE ANDTECHNIQUE • complications described are temporary increase in intraocular pressure and reflux of bevacizumab with the formation of a subconjunctival bleb . Some ophthalmologists have adopted different intravitreal injection techniques in order to decrease the incidence of reflux taking into consideration intraocular pressure . Some patients may experience elevation of intraocular pressure 30 minutes after the injection.
  • 112.
    TREATMENT OF DMEVS ARMD • It is important to distinguish wet AMD from DME—these are, indeed, two very different diseases. For patients with wet AMD, we are treating choroidal neovascularization with exudation. For patients with DME, we are only treating edema, the source of which is retinovascular incompetence. While we are trying to get that macula to a satisfactory dry status, the burden over time tends to fall off in DME.
  • 113.
    TREATMENT OF DMEVS ARMD •In wet AMD, there is more of a continuous burden year after year for an indefinite time frame in most patients. In DME, studies with discontinuous or P.R.N. style therapy such as Protocol I and Protocol T, many patients were eventually able to cease therapy .
  • 114.
    TREATMENT OF DMEVS ARMD •With wet AMD, whether it is P.R.N. or TREAT- AND-EXTEND (TAE), the mean number of treatments will typically reach a plateau after the first year. It does not tend to decrease much thereafter. But with DME, P.R.N. studies that we have seen, Protocol I in particular, started with a mean of eight to nine injections in year 1, then three to four in year 2, two to three in year 3 and by years 4 and 5, many had no further treatment .
  • 115.
    Low vision therapies •Despite the success of intravitreal anti-VEGF pharmacotherapy, a significant number of patients with AMD will ultimately develop bilateral central blindness for which few therapeutic options exist. Recently, an implantable miniature telescope was approved by the FDA that can provide magnification up to a factor of 2.7; in pivotal FDA trials, its use resulted in 2 lines of vision gained in 90% of patients. Eyes need to be monitored carefully for corneal decompensation caused by endothelial cell loss; the corneal transplant rate is projected to be close to 5% at 5 years after the implantation surgery.
  • 116.
    Low vision therapies •Low vision rehabilitation Vision loss of any degree has a profound effect on a patient’s activities of daily living including driving and reading. Although the patient and doctor may be focused on therapies, sufficient attention should be given to low vision strategies that improve function and quality of life. Severe vision loss and central blindness resulting from AMD can be devastating, but low vision rehabilitation and the use of optical and nonoptical devices can improve the patient’s functional status and quality of life . Even patients who have undergone successful anti-VEGF therapy may sustain reduced visual acuity in the 20/50–20/70 range and can benefit from low vision interventions such as use of magnification (eg, high- plus lenses, closedcircuit television), improved lighting, and enhanced contrast. Training and visual rehabilitation to use eccentric foci shifted outside of the central scotoma caused by the disciform scar may also be very helpful. To accomplish some of these rehabilitation strategies and best meet patients’ needs, clinicians are encouraged to consider referring patients for low vision consultation and to local low vision centers or state services for the blind.
  • 117.
    Light is transmittedthrough the anterior segment of the eye to reach the posterior elements and reaches the electrodes at either the subretinal or epiretinal layer.
  • 120.
    CONCLUSION • AMD continuesto be the leading cause of irreversible visual acuity loss worldwide among the elderly. Vitamin supplementation, dietary modifications, and smoking cessation appear to be the most useful strategies to slow the progression of dry AMD. For the treatment of wet AMD, ranibizumab, bevacizumab, and aflibercept have revolutionized the prognosis for patients. For the first time, patients can be treated with the expectation that their vision may improve. However, not all patients improve with 10% losing 15 letters or more over two years as shown in the phase 3 ranibizumab trials, and this vision loss is likely caused by the progression of the underlying dry AMD once the neovascularization has been arrested and the wet AMD has been converted back to dry AMD .
  • 121.
    CONCLUSION • With theresult from the CATT showing that monthly dosing with anti-VEGF drugs increases the incidence of GA, it seems reasonable to avoid monthly dosing and provide personalized treatment strategies using either the ‘as-needed’ or ‘treat and extend’ regimens. For this reason, the future of AMD therapy rests in developing treatments for the dry form of the disease. The need for effective treatments to prevent the progression of dry AMD is paramount as the prevalence of AMD is expected to double in the coming decades. Genetics offers the best hope in identifying pathways that can be targeted using pharmacotherapies so that visual acuity loss from AMD can be prevented. Although the promise of embryonic stem cells remains eternal as a strategy to recover lost vision, the best strategy to treat AMD will continue to be prevention of vision loss.
  • 122.