Age-related Macular Degeneration Update For color slides:
Joseph J. Pizzimenti, OD, FAAO
Financial Disclosures
Joseph J. Pizzimenti, OD, FAAO n Honoraria n Review of Optometry [email protected] n Optometric Management n Maculogix
n Paid Advisory Board Member n Zeiss n EyePromise/Zeavision n Genentech n Regeneron
Financial Disclosures E-Newsletter n Proprietary Interests n None n Consulting Fees n Zeiss n EyePromise/Zeavision n Stockholder: Zeavision
1 QUESTIONS? optometricretinasociety.org
Check out our E-newsletter
Course Goals
n To provide clinically useful information about AMD n Prevention n Early diagnosis n Treatment and management
AMD Beyond the Post Pole
Peripheral Retinal Changes Associated with Age-Related Macular Degeneration in the Age-Related Eye Disease Study 2
Amitha Domalpally, MD, Traci E. Clemons, PhD, Ronald P. Danis, MD, SriniVas R. Sadda, MD, Catherine A. Cukras, MD, PhD, Cynthia A. Tot h, MD, Thomas R. Friberg, MD, Emily Y. Chew, MD
Ophthalmology Volume 124, Issue 4, Pages 479-487 (April 2017) DOI: 10.1016/j.ophtha. 20 16. 12. 00 4
Co p y ri g h t © 2 017 Terms and Conditions
2 Fi gure 3 AMD
Op h t h a l mo l o g y 2017124, 479-487DOI: (10.1016/j.ophtha.2016.12.004) Co p y ri g h t © 2 017 Terms and Conditions
Fi gure 4 What are the four primary retinal pigments?
o Lutein and Zeaxanthin – found in the macula’s sensory layers o Melanin – found in the RPE o Lipofuscin – found in the RPE
Op h t h a l mo l o g y 2017124, 479-487DOI: (10.1016/j.ophtha.2016.12.004) Co p y ri g h t © 2 017 Terms and Conditions
Xanthophylls and AMD
!OH(3R,3'R,6'R)-Lutein3'36'(3R,3'R)-Zeaxanthin(3R,3'S;meso)-Zeaxanthin*(3S,3'S)-Zeaxanthin(3R,3'S,6'R)-Lutein(3R,6'R)-3-Hydroxy--carotene-3'-oneall-E-Lycopene12561'2'5'Z," (3'-Epilutein) OH 3' £Lutein, zeaxanthin, 6' 3 and their metabolites HO (3R,3'R,6'R)-Lutein OH 3' help form the macular 6' 3 HO (3R,3'S,6'R)-Lutein (3'-Epilutein) * pigment. OH 3'
£Dietary sources include 3 HO (3R,3'R)-Zeaxanthin OH green leafy vegetables 3' 3 HO and orange-yellow (3R,3'S; meso)-Zeaxanthin * OH fruits 3' 3 HO £Act as antioxidants and (3S,3'S)-Zeaxanthin * O (3’-oxolutein) 3' 6' blue light screening Figure 1: Xanthophyll carotenoids found in the human retina and macula. 3 HOAsterisks denote metabolites of dietary lutein and zeaxanthin. compounds (3R,6'R)-3-Hydroxy- !,"-carotene-3'-one*
6' 2' 5' 1' 1 5 2 6 all-E-Lycopene 1 2
6' 2' 5' 1' 5 6 5Z-Lycopene
3 The Importance of Macular Pigment Macular Pigment Optical Density £Filters blue light (MPOD) £Acts as an antioxidantby quenching free radicals £Provides support to sensory retina Heterochromatic Flicker Photometry (HFP)
Risk assessment, early detection and Test Results monitoring of AMD Macular Pigment Optical Density (du) £Macular Pigment Optical Density £MPOD Low Average High
0.10- 0.30 0.30- 0.50 > 0.50
MPOD Summary
MPOD is the IOP £ Macular Pigments are important photo- protectants and antioxidants for £ Low MPOD is a modifiable AMD risk factor £ Increasing MPOD improves visual function AMD £ Measuring MPOD is fast, affordable, accurate, important
4 Questions
For color slides:
About AMD Drusen are the
“Dry” “Wet” earliest clinically Drusen, RPE clumping, CNVM RPE atrophy detectable “Dry” ARMD = 85-90% of all cases ophthalmoscopic sign “Wet” ARMD = 10-15% of all cases of AMD. ** (90% of all cases of severe vision loss)
Mixed Drusen
20% of eyes with dry AMD eventually convert to Wet AMD.**
5 Advanced Atrophic AMD Advanced Neovascular AMD
Fundus Biomicroscopy Both Wet and Dry (Advanced x 2)
**The “gold standard” for the evaluation of new onset choroidal neovascularization (CNV) in AMD patients is Fluorescein Angiography.
Statement of The Problem n The AMD “Epidemic” n AMD is the leading cause of blindness in individuals over the age of 50 in the developed world. n Klein R, Klein BEK, Linton KLP. Prevalence of age-related maculopathy. Ophthalmology. 1992;99:933– 94 3.
6 Prevalence of Ocular Diseases The Burden of Disease
n Glaucoma 4 million
n Diabetic Retinopathy 5 million
n Intermediate AMD 8 million 1
1. Age-Related Eye Disease Study 1 data
Epidemiology AMD: n 2004 data: 15 million affected in the US1 A Changing Environment n 2012 17 million n 2016 20 million n How will these dramatic changes and n Distribution (age) projections impact your practice? n 55–64: 17% of Caucasians have AMD n 65–74: 26% n >75: 42%1
1. Congdon N, et al. Arch Ophthalmol. 2004;122:477.
What is AMD? What is AMD? n AMD is a heterogeneous disorder affecting the RPE/Bruch’s membrane/choriocapillaris complex. n Continuum of Normal Aging and Disease n Early disease is classically characterized by minor n Degenerative changes are observed in vision loss associated with focal or diffuse sub-RPE maculae of most elderly persons to some debris and changes in RPE pigmentation. degree. n Late, advanced disease is characterized by severe vision loss associated with extensive RPE atrophy with or without the sequelae of choroidal neovascularization.
n Zarbi n MA . A ge-related macular degeneration : review of pathogenesis. Eu. J Ophthalmol. 1998:199–20 6.
7 Ter m inology What is AMD?
n Cell Death and Functional Loss * • Age Related Maculopathy (ARM) n Only in some individuals do age-related – age related changes in central retina changes progress to this stage • Examples- drusen, RPE disturbances n Transition From “Normal Aging” to Disease ? • Age Related Macular Degeneration (AMD) n Loss of Visual Acuity – retinal status when vision deteriorates n Funduscopic Appearance n Measurable Loss of Functional Vision *
The 4 Seasons of AMD Stages of AMD n Oxidation Early Intermed. Advanced AMD AMD AMD n Inflammation/Ischemia CNV n Atrophy GA n Neovascularization
Classification of AMD
n Non-exudative (atrophic,“dry”) n Can be performance- degrading Dry AMD is the n Majority of AMD cases
n Exudative (neovascular, new Wet AMD. hemorrhagic, “wet”) n Choroidal NV –devastating to central VA n Minority of AMD cases n Majority of vision loss
8 Projected Prevalence of Advanced The AMD “Epidemic” AMD* in the United States 2.95 How should we as optometrists respond? 3
Prevention 2 1.75 (millions) 1
Early Diagnosis Cases of Number
Early Intervention 0 2000 Year 2020 Improved Visual Outcomes Friedman DS, et al. Arch Ophthalmol. 2004;122:564.
A recent review of the Advanced AMD starts out like this: global prevalence of AMD shows that the number of people with AMD in 2020 is projected to be 196 million, which will increase to 288 million in 2040. Large, ill-defined, and confluent soft drusen**
Intermediate Stage AMD Unfavorable prognostic signs leading to CNVM, GA: • AREDS Category 3 • Extensive intermediate drusen • Soft, large, confluent drusen (63-124µ diameter) • Reticular (pseudo) drusen* • At least one large druse (>125µ) • Focal hyperpigmentation • Geographic atrophy not • Disciform lesion in the fellow eye involving the foveal center • Older age **Soft drusen: Large, ill-defined, and confluent • Poor dark adaptation*
9 AREDS 1 and 2 AMD and Nutrition
”The AREDS 1 Study resulted in a formulation of vitamin C, beta carotene, zinc, and vitamin E that reduced the risk of progression of advanced disease by 25% at 5 years.”
Emily Chew, MD, from the National Eye Institute in Bethesda, Maryland
Beyond AREDS: broad-spectrum antioxidant AREDS 2 Plus It would be naïve to formulae assume that only 6 vitamins/nutrients are important in retinal health
A Rod-centric Model of Disease A Rod-centric Model of Disease
• In maculae of healthy, young adults, rods Patients with pre-AMD often complain of outnumber cones by 9:1. difficulty with activities performed at night • Therefore, the macula may and under low illumination (e.g., driving, be described as cone- enriched but rod-dominated. reading). Mangione CM, Gutierrez PR, Lowe G, Orav EJ, Seddon JM Influence of age-related maculopathy on visual functioning • In AMD, central rods die and health-related quality of life. Am J Ophthalmol. 1999;128:45–53. first, followed shortly by the nearby cones.
10 Early Detection of Degenerative Change in “Subclinical AMD” or “Pre-AMD”
n DA measures the time for Dark Adaptation (RI) retinal adaptation after exposure to a light is the stimulus. n Poor DA is a functional A1C manifestation of early disease. for AMD n Rod intercept (RI) is analogous to A1C.
AdaptDx Pro QUESTIONS? n Eye tracking technology automatically aligns with the eye to capture an accurate measurement of dark adaptation function. n Interactive LCD screen n On-board technician, Theia™, guides patients through the test.
n Powered by artificial intelligence.
Imaging the Macula
Invasive Methods
11 Fluorescein Angiography (FA) FA
n FA answers the question: is the blood- n The “gold standard” for the evaluation retinal barrier intact? of new onset choroidal neovascularization (CNV) in AMD patients.
Conversion to Exudative AMD **Indocyanine green (ICG) is a dye that is used as an alternative to fluorescein.
**20% of dry (non-exudative) AMD eyes progress to wet (exudative) AMD,
Indocyanine Green Angiography Common Causes of CNV
n Clinical CNVM Case
n Exudative AMD n Ocular Histoplasmosis n High Myopia n Angioid Streaks n Choroidal Rupture n Chronic CSC (less common)
12 CNV Variants PCV
Polypoidal Choroidal Vasculopathy (PCV)
Retinal Angiomatous Proliferation (RAP)
PCV RAP
RAP Advanced AMD n Defined as either: n Geographic atrophy (GA) n Atrophy of the RPE and/or photoreceptors, CC n “End-stage” non-exudative (dry) AMD n Choroidal neovascularization (CNV) n Exudative “wet”
n 80-90% of advanced AMD cases are due to CNV.
13 CNVM Size and Progression CNV ---> FV Scar
Average size CNV lesion @ 3300 µ diagnosis 3000-3300μm
Growth = ~10-20 μm/day
To o lar ge, t o o lat e
Olsen, TW Ophthalmology Feb. 2004
Retina Quiz: CNV Tx Retina Quiz: CNV Tx n Which of the following is the main n Which of the following is the main advantage of Photodynamic therapy (PDT) advantage of Photodynamic therapy (PDT) over traditional laser photocoagulation? over traditional laser photocoagulation?
n a. Lower cost for PDT n a. Lower cost for PDT n b. More scar tissue formation in PDT n b. More scar tissue formation in PDT n c. Less scar tissue formation in PDT n c. Less scar tissue formation in PDT * n d. PDT uses a “hotter” laser n d. PDT uses a “hotter” laser
Antiangiogenic Drugs: VEGF Inhibitors
~30% showed improved VA in VEGF binds to receptor ANCHOR, MARINA
14 New Therapy with a Fraternal Name: Brolucizumabe Brolucizumabe
£ Humanized single-chain antibody fragment that inhibits all isoforms of VEGF-A. £ Phase III data from the HAWK and HARRIER trials. £ May allow for an extended interval between intravitreal injections for CNV, thus reducing the treatment burden.
AMD and Drusen Drusen n AMD is a disease resulting from poor “Waste Management”.
n Drusen are “pockets of inflammation” n Recent investigations show that proteins associated with inflammation and immune-mediated processes are prevalent in drusen. Drusen is the earliest clinically detectable feature of AMD.**
AMD: a sick eye in a sick body?
MCP-1 = Monocyte chemoattractant protein-1
15 Parallel Worlds: Heart Disease AMD and Cardiovascular (Heart) Disease and AMD
• Diet – Low fruit/vegetable consumption increases risk of AMD and CVD • Obesity and physical inactivity • C-reactive protein (elevated) •Inflammatory marker • Homocysteine (elevated) • Omega-3 EFA may be beneficial for AMD patients • Cholesterol (elevated) • Serum Iron – Increased amounts may increase AMD and CVD
Optical Coherence Tomography Imaging the Macula OCT uses low-coherence interferometry to obtain real- Non-invasive Methods time, cross-sectional histology of live tissue (virtual biopsy)
The OCT B-scan SD-OCT Healthy Macula w/Layers n Two-dimensional, cross-sectional single cut. n Used for qualitative and quantitative analysis.
Current commercially available Spectral Domain OCT is capable of obtaining 3-5um resolution**
16 **The earliest clinically detectable Drusen/ **OCT: A Virtual Biopsy feature of AMD is Drusen. RPEDs
Reticular (Pseudo)drusen Reticular (Pseudo)drusen (RPD) n Seen as a reticular pattern of small yellow-white lesions often in the superior macula, RPD are a high- risk sign for advanced AMD.
Reticular (Pseudo)drusen Spectral Domain OCT Shows CNV n Presence of RPD is a consistent risk factor for progression to both atrophy and CNV n IS/OS C-scan B-scan
**Current commercially available Spectral Domain OCT is capable of obtaining 3-5 um resolution
17 Vitreomacular Adhesion in AMD Key Point
May hasten progression/conversion from dry to wet disease. C
.
WHAT IS ENHANCED EDI SHOWS DEEPER INTRAORBITAL DEPTH OCT IMAGING? ON, LAMINA, C/S JXN • EDI-OCT • Enhanced-depth imaging (EDI) OCT modifies the standard technique of image acquisition to better reveal the structural details of the choroid.
OCT Structural Changes: FV Scar
18 C-SCAN: En face slices Outer retinal tubulations in CNV (OHS)
ORT is a feature of photoreceptor rearrangement after retinal injury.
81 y/o WM OCTA at RPE Level
Imaging Imaging OCTA
En face OCT angiograms
19 Functional Testing in AMD •Benefits of early detection and treatment of neovascular AMD are evident from both clinical trials and “real-world” outcome studies. •There has been rapid evolution in the sophistication and utility of visual function testing; in particular preferential hyperacuity perimetry (PHP). •Sensitive and specific home monitoring is available for patients at risk for exudative disease.
Structure and Function
n OCT and PHP work synergistically
Case Questions? n 81 Year old Female with a history of arthritis.
n 7 year history of injections with Avastin or Lucentis
cpelino@salu n PMH: AMD OU, Cataracts OU
n OcHx: Injections for Wet AMD in OD
20 Ophthalmic Exam OCT n VA: - OD: 20/400 OS: 20/80 n IOP - OD: 11 OS: 12 n SLE: -OD: NS +1 OS: NS + 1
- DFE: -RPED OD and Geographic Atrophy OS
After Switching to Eylea OD Comparison
7 Years of Avastin and Lucentis
20/400
2 Injections of Eylea
20/50
Another RPED example VA 20/ 50
VA 20/ 25
Six mon s/p IV Lucentis x 6
21 Autofluorescence (FAF) Early AMD: Accumulation of Lipofuscin and Vitamin A Metabolites
n Principle Reduced degradation of cellular debris leads to the accumulation of lipofuscin, n When stimulated with toxic vitamin A metabolites light in the blue range, lipofuscin granules emit yellow fluorescence. n Patterns of fundus autofluorescence may predict which cases will progress more quickly.
Autofluorescence Color
Fundus Autofluorescence FAF Wet AMD
22 FAF - Exudative AMD
Hyperfluorescence FA 36 sec FA 69 sec in FAF
Liakopoulos –Department ofOphthalmology at theUniversity of Cologne
FAF + OCT Multi-Modality Imaging Offers a new perspective of the structure-function relationship within the retina n Color photography n Infrared n Red-free n FAF n Fluorescein Angiography n Indocyanine Green Angiography n OCT/OCT-A
Imaging Simultaneous FAF and OCT Geographic Atrophy
atrophic perilesional area perilesional zone zone junctional zones
n FAF shows areas of hypo-autofluor esc enc e in GA
n OCT outlines the corresponding photoreceptor dropout Adaptive Optics
Images courtesy of Frank Holz, MD –Un i versity Bonn
23 AMD Risk Factors QUESTIONS?
AMD Risk Factors Epidemiology n Non-modifiable n Modifiable n Age n Smoking n Heredity n Cardiovascular disease n Blood lipid status n Sex n Hypertension n Pigmentation n Alcohol consumption n Race n Light exposure (UV, blue) n Iris color n Nutrition n Obesity
Genetics: ARMD-1 Genetics and AMD
£Inherited variation in the complement factor H gene is a major risk factor for drusen. £A single-nucleotide polymorphism (SNP) in the promoter region of HTRA1 (a serine protease gene on chromosome 10q26) is a major risk factor for Wet AMD. £ Chromosome 1 DeWan, A. Science, November 2006:Vol. 314. no. 5801, pp. 989 - 992 Region Displayed: 1q25-q31
24 Example of Genetics and AMD Naturally occurring variations conferring AMD risk Genomics
Marker Allele Odds Ratio Fr eq
H1+H3 (risk) 0.202 >15 CFH Average 0.495 Smoking interacts with CFH (H 2+H 4) 0.303 Gene variants to increase AMD C3 G (risk) 0.18 2.6 rs2230199 C 0.83 risk by 5X compared with ARMS2 T (r is k) 0.17 8.2 rs10490924 G 0.83 genetically similar nonsmokers. Cur r ent (r is k) 0.17 Smoking 3.14 Never 0.55
G (risk) 0.09 mt A 4917G 2.2 Am J Epidemiol. 2009 March 1; 169(5): 633–641. A 0.90
Cigarette Smoking, Ocular & Vascular Disease AMD Gene Associations
£Increased arteriolar stiffness (sclerosis) £Mutations in the TIMP3 gene £Increased Vascular £metalloproteinase inhibitor 3 gene Endothelial Growth £Two variants involved in the HDL cholesterol Factor (VEGF) pathway. production £Human hepatic lipase (LIPC) and cholesterol ester £Development/worsening transfer protein (CETP). of DR £Development/worsening £Proceedings of the National Academy of Sciences (4/2010) of AMD
Johanna Seddon, MD (Tufts U)
“ Don’t smoke; follow a healthful diet rich in dark green leafy vegetables and low in fat; eat fish a few times a It would be naïve to week; maintain a normal weight and waist size; exercise regularly; and control blood pressure and cholesterol.” assume that only 6 vitamins/nutrients are
“Anyone with signs of intermediate-level macular important in retinal health degeneration in both eyes or advanced macular degeneration in one eye should also take dietary supplements that contain lutein, zeaxanthin, vitamin C, vitamin E, and zinc.”
25 The Complement Cascade: Inflammation Example of Genomics A BMI over 30 increases AMD risk by 2.5X.
Nutritional Key AMD-associated Genes Factors
Complement
Oxygen Metabolism
Extracellular Matrix
Cholesterol Metabolism
AREDS 1 and 2 AREDS 1 Grading Scale 1. No drusen or a few small drusen. 2. Pigment abnormalities or non-extensive small or intermediate drusen. 3. Extensive intermediate drusen or any large drusen or non-central atrophy. 4. Good acuity and no advanced AMD in the study eye. Advanced AMD in the fellow eye (choroidal neovacularization or geographic atrophy).
26 Is There a Strategy? USDA Replaces Food Pyramid
£ USDA Food Triangle/My Plate £ 5+ daily portions of fruits & veggies £ at least 1 dark green, leafy veg (spinach, kale) £ Low saturated/trans fat, low cholesterol £ Antioxidant for at risk patients £ L and Z £ CV Dx £ Physical Activity £ Low WL Blue, UV protection
Behavior Modification Behavior Modification
£Physical activity £Sedentary lifestyle £Fish consumption £Smoking £Greens £Excess Alcohol £Smaller portions £Alcohol in moderation £High BMI £Nutritional supplements £HTN, Cholesterol £Blocking blue light from £Diet low in fish, reaching retina green veggies
Conclusions Prevention
£AMD is on the rise. Early Diagnosis
£We must take proactive steps on Early Intervention behalf of our patients. Improved Visual Outcomes
27 Thank you! For color slides: Joe [email protected]
28