Pinnacles of Awareness in AMD
How milestones in our understanding of disease mechanisms are shaping modern standards of care, allowing for meaningful intervention prior to vision loss.
By Joseph J. Pizzimenti, OD, FAAO
Release Date: September 15, 2019
Expiration Date: August 26, 2022
Estimated time to complete activity: 2 hours
Educational Objectives: After completing this activity, the participant should be better able to:
- Describe the histopathology of AMD.
- Evaluate strategies, tools and technologies that can aid in the diagnosis and monitoring of patients with AMD.
- Discuss modern approaches to diagnosing and managing AMD.
- Understand the practical challenges associated with diagnosing AMD using only traditional subjective clinical assessment and structural tests.
- Outline the benefits of a functional diagnostic test for AMD.
Target Audience: This activity is intended for optometrists engaged in the care of patients with AMD.
Faculty/Editorial Board: Joseph J. Pizzimenti, OD, FAAO, Rosenberg School of Optometry University of the Incarnate Word
Continuing Education Credit: This activity, COPE Activity Number 118000 is accredited by COPE for continuing education for optometrists. This course is COPE approved for 2 hours of CE credit. Course ID is 64462-PS. Check with your local state licensing board to see if this counts toward your CE requirement for relicensure.
Reviewed by: UAB School of Optometry
Disclosure Statements: Joseph J. Pizzimenti, OD, FAAO: Consulting fees from Carl Zeiss Meditec, MacuLogix, Eye Promise
Planners, Managers and Editorial Staff: The Review Education Group planners, managers and editorial staff have nothing to disclose.
This activity is supported by an independent educational grant from MacuLogix. The content of this activity was prepared independently by Review Education Group without input from members of MacuLogix.
It was the 1980s and, as a third-year intern, I was feeling proud of myself for detecting and correctly diagnosing macular drusen in one of my older patients. Later, at an end-of-the-day debriefing, my preceptor asked me to briefly explain how age-related drusen come about. While I was able to toss out a few sentences about normal macular function, when it came to abnormal retinal metabolism in AMD, I was at a complete loss for words.
The next day I received several printed articles in my student mailbox with a note to the effect of: “Joe, if you are serious about your patients’ retinal health, you need to understand both normal and abnormal functional anatomy. Be able to intelligently talk about theories of AMD pathogenesis the next time I see you.” I took these words to heart.
One of the publications I found in my mailbox was a landmark review of AMD pathogenesis by R. W. Young.1 As a result of reading this and the other articles, I learned that the clinical and histopathological features of AMD involve a complex relationship—with age, heredity, environmental and systemic factors, thickening of Bruch’s membrane, and the formation of basal laminar and basal linear deposits, pigmentary disturbances and drusen all having significant roles.1
After graduation, and for many years following, I continued my investigation into the pathogenesis of AMD and grew increasingly passionate about how various diagnostic approaches might help us detect—and ultimately manage—the disease before it causes irreversible damage and loss of visual acuity. It was a slow and arduous climb, but we have finally reached a peak in our understanding of AMD. Equipped with this broader view of what causes AMD, we’ve been able to develop appropriate tools and improve diagnostic and management standards to a degree that was unimaginable only a few short years ago.
Why Pathogenesis Matters
When we think of AMD, our minds automatically race to choroidal neovascularization (CNV), geographic atrophy (GA), severe vision loss, and a lifetime of intravitreal injection therapy. We’re so fixated on what happens at the end of the road that we fail to recognize and appreciate what optometrists can do along the way to minimize vision loss. But to truly appreciate how we can affect change in AMD, it’s essential to understand what causes it in the first place.
Figure 1. Large drusen are rich in lipids, protein, and cholesterol.
Obviously, age-related changes occur in the eyes of each and every one of our patients. But what makes AMD different and what causes some patients to turn the corner and others to remain relatively healthy? In short, AMD represents a pathologic stage of an otherwise normally occurring deteriorative process. Therefore, our challenge as clinicians is to determine which patients are going to fall off that cliff and develop true AMD and which ones will never progress to a pathologic state.
This used to be exceedingly difficult since age-related structural changes take place in the eyes of almost all of our older patients. Fortunately, newer methods are allowing us to detect functional markers earlier in the disease continuum, which allows us to intervene early and with confidence.
Histopathology and Lipid Deposition
Retinal health is contingent upon the relationship between photoreceptors and the retinal pigment epithelium (RPE).2 Indeed, the accumulation of photo-oxidized debris within and under the RPE is now considered the initiating cause of AMD.3 The primary lesion appears to reside in the RPE, likely resulting from its high rate of molecular degradation. RPE cells, in response to many negative stimuli, go through morphological changes such as hypertrophy, atrophy and intraretinal migration.4
AMD and Cataracts
Structural signs of macular degeneration can be difficult to view or detect through a cloudy crystalline lens, but early disease identification is imperative, especially in patients who are considering a presbyopia-correcting IOL. Loss of contrast sensitivity is present even in mild forms of AMD, making implantation of a multifocal IOL a relative contraindication1—or at least a reason to proceed with extreme caution. Since both macular degeneration and multifocal IOLs reduce patients’ contrast sensitivity, one would face a compounded reduction in contrast sensitivity and perhaps decreased visual outcomes.2 And this happens more often than you might suppose.
In a study presented at the XXXIV Congress of the European Society of Cataract and Refractive Surgeons,3 researchers asserted that screening is needed. Their retrospective chart review identified 193 patients who underwent dark adaptation testing within a 13-month period. A total of 27 patients had both a normal fundus exam and normal corneal topography, making them candidates for multifocal IOLs. Of these 27 eyes, 17 (63%) had normal dark adaptation and 10 (37%) had abnormal dark adaptation. In other words, if all 27 of these patients opted to undergo cataract surgery with a multifocal IOL, more than one-third of them would likely experience problems that could not have been anticipated if dark adaptation had not been measured preoperatively.
2. Braga-Mele R, Chang D, Dewey S, et al. ASCRS Cataract Clinical Committee. Multifocal intraocular lenses: relative indications and contraindications for implantation. J Cataract Refract Surg. 2014 Feb;40(2):313-22.
3. McKeague M, Pyfer M. Using dark adaptation time to assess macular function prior to cataract surgery. Presented at XXXIV Congress of the European Society of Cataract and Refractive Surgeons Free Paper Session. September 12th, 2016.
Beginning early in life, and continuing throughout the decades, RPE cells gradually accumulate pockets of molecular debris.1 These residual bodies (lipofuscin) are remnants of the incomplete degradation of abnormal molecules that have been damaged within the RPE cells or derived from phagocytized rod and cone membranes.1
Cholesterol deposition in the RPE/Bruch’s choriocapillaris complex is the forerunner to drusen. More specifically, drusen can be described as extracellular deposits of lipids and proteins under the RPE. Furthermore, cholesterol in a druse acts in the same way as cholesterol found in carotid arteries of patients with atherosclerosis, as both involve lipoprotein retention. In AMD, lipidation of Bruch’s membrane impairs transport of compounds necessary for the health of the RPE and photoreceptors.5
Histopathological studies have shown that the RPE cells deposit locally generated cholesterol beneath the RPE cell layer (basal laminar deposits) and in Bruch’s membrane (basal linear deposits) before drusen are formed.6,7 This cholesterol accumulation impairs normal transport of vital nutrients, including vitamin A, across Bruch’s membrane and causes oxidative stress, inflammation and a localized vitamin A deficiency. Although these deposits may not become visible drusen for several years after their formation, this is where they begin. In other words, when cholesterol becomes sufficiently deposited, damage is well underway as it builds over time to become a visible druse. So what does it mean to have subclinical AMD?
In subclinical disease, a condition has no (or only minimally recognizable) clinical findings. While it is not yet clinically detectable, subclinical disease is destined to become clinical disease. This is not the same as preclinical disease. A preclinical disease is in the stage of progression immediately before clinical symptoms begin.8 Not all diseases have a recognizable preclinical stage. But in those that do, it refers to the time when early changes are taking place (for example, in the retina) that are detectable through certain tests but not yet showing as a clearly recognizable condition. Whereas pre-clinical disease will usually soon progress to the clinical stage with characteristic signs and symptoms, a subclinical condition may remain latent or not progress until some future time.8 That’s great news for patients who are diagnosed with AMD at a subclinical stage.
Figure 2. Non-exudative AMD on fundus autofluorescence showing (dark) areas of RPE atrophy.
Later, the basal laminar/basal linear deposits and subsequent drusen may trigger the further contamination of the RPE/Bruch’s membrane/choriocapillaris complex. In eyes that continue to progress over time, loss of vision results from cellular death due to degeneration and atrophy of the RPE, and/or from the effects of neovascular membranes that invade from the choroid.1In AMD, an inflammatory response to the accumulated lipid material may likewise ensue.5,9 This activates complement factors and other immune system components, leading to RPE atrophy and/or induction of a pro-angiogenic state and choroidal neovascularization (CNV). For this reason, elimination of large, lipid-rich, sub-RPE drusenoid deposits is regarded as a potential benefit to patients.5,9,10
Rods, Cones and the Macula
The macula is a relatively large area, 6mm in diameter, or 21.5 degrees of visual angle.11 The small, cone-dominated fovea is only 0.8mm in diameter (2.75 degrees). The central 300µm of the fovea, or foveola, is totally rod-free. So why do rods matter in AMD? First, the cone-rich fovea is surrounded by a rod-dominated parafovea (1mm to 3mm from the fovea or 3.5 to 10 degrees from fixation).11 In healthy, young adults, rods outnumber cones in the macula by 9:1. Therefore, the macula may be described as cone-enriched but rod-dominated.
Rods are responsible for our most sensitive motion detection, peripheral vision and night vision.12 Curcio and colleagues reported that in maculae of older adults without visible drusen and pigmentary disturbances, the number of cones was stable through the ninth decade. However, the number of rods in the maculae of the same eyes decreased by 30%, with the greatest loss occurring in the parafovea.13
Further research found that the foveal cone mosaic of eyes with thick basal laminar deposits and large drusen appeared surprisingly similar to that of age-matched controls, and the total number of foveal cones was normal.14 By contrast, in the parafovea of those same eyes, the cones appeared large and misshapen, and very few rods remained. In fact, in those eyes with late AMD, virtually all surviving photoreceptors in the macula were cones, a reversal of the normal predominance of rods.
It appears that in AMD, there is preferential loss of rods over cones. Why does this occur? Psychophysics may help to uncover some answers. The classic dark adaptation function describes the recovery of retinal sensitivity after a bright flash of light. It consists of an early portion exclusively mediated by cones, a transition to rod function (rod-cone break), and a later portion exclusively mediated by rods.15
Figure 3. A rod-mediated dark adaptation (or rod intercept) time of 16 minutes. RIT greater than 6.5 minutes indicates a high likelihood of degenerative activity.
Studies of photopic and scotopic sensitivity strongly correlate to histopathologic findings showing that rods are at risk for degeneration in both aging and AMD.16,17 Researchers also found slowing of the rod-mediated component of dark adaptation and earlier involvement of rods relative to cones in aging and AMD.17 Mean scotopic sensitivity within 18 degrees of fixation was significantly lower in early AMD patients as a group than in age-matched controls without AMD. This finding was most severe within 9 degrees of fixation, suggesting that scotopic sensitivity deficits within the parafovea may be an early sign or, at least, a harbinger of disease.17
Why the rods of the central retina, which share a common light exposure and support system with the neighboring cones, are preferentially vulnerable to aging still remains to be determined. Fortunately, tests of rod function, particularly those that evaluate dynamic properties, may enable detection of AMD at its incipient stages.16,17
Measuring Subclinical Disease
Standard color fundus photography, although historically useful for classifying the stage of AMD, may not readily identify some common early and intermediate manifestations.18 Indeed, alterations to the RPE may not be clinically detectable by funduscopy or photography. Consider that drusen and subretinal drusenoid deposits become clinically visible at 30µm, while changes in RPE cells are substantially smaller.19
Despite these limitations, we must endeavor to find novel ways to improve our capacity to detect disease before it’s too late and somehow overcome the current grim statistics. Up to 78% of AMD patients have substantial, irreversible vision loss in one eye at first treatment.20,21 Why aren’t we doing a better job of catching disease earlier?
In short, while we may be excellent diagnosticians, evaluating the fundus for small drusen and early pigmentary disturbances can be quite challenging. A recent study published in JAMA Ophthalmology revealed that optometrists and ophthalmologists failed to diagnose AMD about 25% of the time—even when they knew their findings would later be reviewed.22
The cross-sectional study included 1,288 eyes (644 adults). Each patient in the study had digital color fundus photos taken, which were reviewed by masked, trained graders who determined the presence or absence of AMD findings according to the Clinical Age-Related Maculopathy Staging (CARMS) system.23 The results revealed that one of four eyes studied was not diagnosed with AMD during the dilated fundus examination, despite these eyes having macular characteristics indicative of AMD in the fundus photos. Furthermore, 30% of the undiagnosed eyes in the study had large drusen, a well-known risk factor for progression to advanced disease.22
Make no mistake, there are significant practical challenges associated with diagnosing AMD using only traditional subjective clinical assessment. For this reason, it is imperative that we begin to look beyond what we can visualize structurally. One way to do this is with risk assessment, such as advanced age, a history of smoking, heredity (genetics) and Macular Pigment Optical Density (MPOD) measurement. Another is with functional diagnostic testing using dark adaptometry.
Because rod deterioration happens in the earliest stages of AMD, dark adaptation becomes affected much earlier than visual acuity declines.24 Impaired dark adaptation identifies subclinical AMD at least three years before it can be seen with imaging, OCT or clinical examination.25 Furthermore, impaired dark adaptation is a functional biomarker of true subclinical disease, as opposed to a less definitive indication of risk. In fact, the updated preferred practice patterns of the American Academy of Ophthalmology26 indicate that an initial history should consider difficulties in dark adaptation.
Dark adaptometry measures how long it takes for the eye to adapt from bright light. Dark adaptation assessments proved to be highly sensitive (90.6%) and highly specific (90.5%) to the development of AMD.27
Evidence for the Benefits of Earlier Management
Vision loss from AMD can be functionally and emotionally debilitating, as it can make it difficult, or even impossible, to read, drive, enjoy certain hobbies and maintain an independent lifestyle.28 So imagine if we could detect subclinical AMD in patients before clinical signs present. Would you want to get them started on nutraceuticals and lifestyle and dietary modifications as early as possible in an effort to slow or delay disease progression? Aside from supplementation, current medical treatment options for AMD are only indicated in patients whose disease leads to the development of CNV. However, there’s plenty we can do for patients before they reach that stage. Most critically, we can monitor them very closely so that prompt co-management with a retinologist for appropriate treatment with antiangiogenic agents can be initiated promptly should CNV develop.
Figure 4. A CNV lesion, as revealed with Cirrus 5000 OCT with Angioplex (Zeiss).
Consider how much better second eye outcomes are compared to first eye outcomes.29 More frequent examinations and consistent structural and functional testing can make a meaningful difference. When you know a patient has AMD—however early the stage—moving from a 12-month follow-up interval to a six-month (or even shorter in some cases) may be useful for monitoring disease progression.30
Just as in pre-diabetes, our patients with subclinical AMD can implement nutrition and lifestyle measures in an effort to protect against sight-threatening disease. But which ones are appropriate in early-stage AMD? As was discussed above, based on our current understanding of AMD pathogenesis, the stages of subclinical, early and intermediate AMD represent different clinical manifestations of the same underlying disease process. Therefore, all of the following non-medical treatments should be considered at first detection, regardless of the disease stage:
• Smoking cessation. Smoking is the largest modifiable risk factor for the progression of both CNV and GA,31 so it is critical to emphasize this with patients. Surprisingly, in a recent study, 90% of patients with AMD said they were not advised to stop smoking.32
• Nutritional supplements. Although there is debate about which supplements are most appropriate at various stages of disease, the evidence suggests prescribing a high-quality, broad-spectrum antioxidant formula. In fact, nutritional trials and related studies have demonstrated a slowing of progression for established AMD.33-36
• Lifestyle modification. Following a healthy diet rich in leafy greens, fresh produce and omega-3 rich fish, exercising regularly and maintaining overall health are sound goals37 that may act synergistically to prevent or delay onset or progression of AMD. Research shows that individuals who followed a healthy diet, engaged in physical exercise and avoided smoking had substantially lower risk of early AMD compared with those who did not follow these healthy lifestyles.38,39
• Systemic disease management. Cardiovascular disease, diabetes, hypercholesteremia and obesity have been associated with increased risk of AMD and/or progression of AMD.40,41 High body mass index and abdominal obesity are independent risk factors for progression to advanced AMD.40
• Retinal light protection. Epidemiological evidence suggests that chronic sunlight exposure increases the risk of incident AMD and its progression.42 As such, it is advisable for patients at risk for, or with early signs of, AMD to wear quality sunglasses that significantly reduce the transmittance of high energy visible light (HEVL).
It’s Time to Elevate AMD Care
An understanding of normal functional anatomy, as well as abnormal retinal physiology helps us provide optimal care because it expands our view beyond end-stage disease and clarifies how we can make a meaningful impact before it’s too late. A microscopic cholesterol layer is a hallmark defect of AMD, and even though it is not yet visible in living eyes using current diagnostic tools, it is detectable using functional tests.6,24
It’s time to look forward instead of backwards. The current AMD grading scales, though useful in research and for documentation purposes, won’t help optometrists raise standards in caring for this devastating disease. Furthermore, these staging schemes were created before we had information about the link between impaired dark adaptation function and AMD. This is now well established and must therefore drive our clinical practice protocols.
We can make a meaningful difference in countless lives and families. Clinical AMD is more prevalent than glaucoma and diabetic retinopathy combined.43,44 How many of these patients are we diagnosing while they still have 20/20 vision? It’s time to raise the bar and set our sights higher.
Joseph J. Pizzimenti, OD, FAAO is a full-time faculty member of the Rosenberg School of Optometry at the University of the Incarnate Word in San Antonio, TX.
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31. Smith W, Assink J, Klein R, et al. Risk factors for age-related macular degeneration: Pooled findings from three continents. Ophthalmology. 2001 Apr;108(4):697-704.
32. Caban-Martinez AJ, Davila EP, Lam BL, et al. Age-related macular degeneration and smoking cessation advice by eye care providers: a pilot study. Prev Chronic Dis. 2011 Nov;8(6):A147.
33. Age-Related Eye Disease Study 2 Research Group Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: The Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA. 2013 May 15;309(19):2005-15.
34. van Leeuwen R, Boekhoorn S, Vingerling JR, et al. Dietary intake of antioxidants and risk of age-related macular degeneration. JAMA. 2005 Dec 28;294(24):3101-7.
35. Ranard KM, Jeon S, Mohn ES, et al. Dietary guidance for lutein: consideration for intake recommendations is scientifically supported. Eur J Nutr. 2017 Dec;56(Suppl 3):37-42.
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37. Carneiro Â, Andrade JP. Nutritional and lifestyle interventions for age-related macular degeneration: a review. Oxid Med Cell Longev. 2017;6469138.
38. Mares JA, Voland RP, Sondel SA, et al. Healthy lifestyles related to subsequent prevalence of age-related macular degeneration. Arch Ophthalmol. 2011 Apr;129(4):470.
39. McGuinness MB, Le J, Mitchell P, et al. Physical activity and age-related macular degeneration: a systematic literature review and meta-analysis. Am J Ophthalmol. 2017 Aug;180:29-38.
40. Seddon JM, Cote J, Davis N, et al. Progression of age-related macular degeneration: association with body mass index, waist circumference, and waist–hip ratio. Arch Ophthalmol. 2003 Jun;121(6):785-92.
41. Choudhury F, Varma R, McKean-Cowdin R, et al. Los Angeles Latino Eye Study Group. Risk factors for four-year incidence and progression of age-related macular degeneration: the Los Angeles Latino Eye Study. Am J Ophthalmol. 2011 Sep;152(3):385-95.
42. Sui G-Y, Liu G-C, Liu G-Y, et al. Is sunlight exposure a risk factor for age-related macular degeneration? A systematic review and meta-analysis. Br J Ophthalmol. 2013 Apr;97(4):389-94.
43. Kempen JH, O’Colmain BJ, Leske MC, et al. Eye Diseases Prevalence Research Group. The prevalence of diabetic retinopathy among adults in the United States. Arch Ophthalmol. 2004 Apr;122(4):552-63.
44. Klein R, et al. Prevalence of age-related macular degeneration in the US population. Arch Ophthalmol. 2011;129(1):75-80.