This activity is supported by an educational grant from Regeneron.

Seeing the Signs: Identifying and Managing Patients With Age-Related Macular Degeneration

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Faculty and Moderator

Ajay Kuriyan, MD, MSAssociate ProfessorSidney Kimmel Medical CollegeThomas Jefferson UniversityVitreoretinal SurgeonWills Eye HospitalPhiladelphia, Pennsylvania

Richard F. Spaide, MDPartnerVitreous Retina Macula

Consultants of New YorkNew York, New York

MODERATOR Mary Knudtson, DNSc, NP, FAANProfessor of Clinical NursingUniversity of California, IrvineIrvine, CaliforniaNurse PractitionerJumpstartMDWalnut Creek, California

• Dr Knudtson has no relevant financial relationships to disclose.

• Dr Kuriyan: consulting: Alimera Sciences, Allergan, Bausch & Lomb, Novartis, Optos, Recens Medical, Regeneron, Spark Therapeutics; contracted research: Second Sight; consulting/contracted research: Genentech/Roche.

• Dr Spaide: consulting: Genentech, Heidelberg Engineering, Regeneron, Roche; consulting/royalties: Topcorn Medical; royalties: Dutch Ophthalmic Research Center.

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Faculty Disclosures

Learning Objectives• Recognize early, mid-, and late clinical signs of AMD to prompt timely

referral of patients for treatment

• Describe the risks and benefits of treatment options for AMD to patients and their families/caregivers

• Identify lifestyle and dietary modifications that patients can make to reduce the risk of AMD progression and improve their quality of life

4AMD = age-related macular degeneration.

Age-Related Macular Degeneration: Overview• A disorder of the macula (responsible for central, high-acuity, but not

peripheral vision)• Leading cause of irreversible vision loss in developed countries• Most common reason for blindness and vision loss in older people• Central vision is lost, but peripheral vision remains intact• Early detection and prompt treatment are key to preserving vision

5American Academy of Ophthalmology. Preferred Practice Pattern. 2019. Mitchell. Lancet. 2018;392:1147. Pugazhendhi. Int J MolSci. 2021;22:1170. www.nei.nih.gov/learn-about-eye-health/eye-conditions-and-diseases/age-related-macular-degeneration.

• Characterized by ≥1 of the following:

– Retinal pigment epithelium (RPE) abnormalities, eg, hypo- or hyperpigmentation

– Medium-size or larger drusen (sub-RPE lipid deposits)

– RPE geographic atrophy (GA), macular neovascularization (MNV), polypoidalchoroidal vasculopathy, reticular pseudodrusen, and/or retinal angiomatous proliferation

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AMD Overview (cont’d)Macular Neovascularization

Image courtesy of Richard F. Spaide, MDAmerican Academy of Ophthalmology. Preferred Practice Pattern. 2019. Mitchell. Lancet. 2018;392:1147.

• Patients are typically ≥50 years old

• Prevalence is increasing as population ages

‒ US: approximately 10 million, 6.5% of adults over age 40

• Late-stage AMD is more common among women than among men (longer life span)

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Prevalence of AMD

American Academy of Ophthalmology. Preferred Practice Pattern. 2019. Pugazhendhi. Int J Mol Sci. 2021;22:1170. Klein. Arch Ophthalmol. 2011;129:75. www.nei.nih.gov/learn-about-eye-health/eye-conditions-and-diseases/age-related-macular-degeneration.

0

2

4

6

8

10

12

50 60 70 80 90

Pred

icte

d Pr

eval

ence

%

Age (years)

Estimated Prevalence of Wet AMD by Age Among People of European Ancestry

• Increasing age

• Northern European ancestry• Family history of AMD: having a first-

degree relative with AMD can increase risk substantially

• Genetic component

Nonmodifiable Risk Factors

8American Academy of Ophthalmology. Preferred Practice Pattern. 2019. Pugazhendhi. Int J Mol Sci. 2021;22:1170. Lambert. Prog Retin Eye Res. 2016;54:64.

• Cigarette smoking– Predominant modifiable risk factor

• Diet– High dietary fat intake (in some but

not all studies)– Low intake of foods rich in omega-3

fatty acids (eg, fish, but not fish oil pills)

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Modifiable Risk Factors

American Academy of Ophthalmology. Preferred Practice Pattern. 2019. Pugazhendhi. Int J Mol Sci. 2021;22:1170. Lambert. Prog Retin Eye Res. 2016;54:64.

https://www.livemint.com/Leisure/837VwioJMAP8g2Y9ycfKWL/Second-hand-smoke-can-affect-your-childs-intelligence.html

• Loss of vision

– Dry AMD accounts for ~20% of legal blindness (20/200 or worse in better eye) in US– Without treatment, <10% of patients with wet AMD retain 20/40 vision at 1 year, and

vision of up to 75% declines to 20/200

• Medical risks– Increased risk of falls

– Up to 50% decrease in physical activity– Increase in mortality risk (including cardiovascular)

– Functional deficits, eg, driving, reading

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Impact on Vision and Overall Health

Mitchell. 2018;392:1147. Mitchell. Trans Vis Sci Tech. 2020;9:42. www.nei.nih.gov/learn-about-eye-health/eye-conditions-and-diseases/age-related-macular-degeneration.

• Depression

• Stress, frustration, anxiety

• Loss of independence and confidence

• HRQoL (similar to or lower than with other chronic conditions, including cancer)• Burden of treatment

– Direct medical costs of treatment– Need for patients (and caregivers) to keep frequent medical appointments

• Can accelerate cognitive impairment, including dementia

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Impact on Quality of Life

HRQoL = health-related quality of life.Mitchelll. Lancet. 2018;392:1147. Mitchell. Trans Vis Sci Tech. 2020;9:42. Schultz. Ophthalmol Ther. 2021. Epub ahead of print; Spooner. Clin Ophthalmol. 2018;12:2483.

Common example in lay press

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Effects on Vision: Incorrect Portrayal

Wrong!

Courtesy of Richard F. Spaide, MD.

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“American Gothic”

Courtesy of Richard F. Spaide, MD.

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“American Gothic”

Courtesy of Richard F. Spaide, MD.

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Macular Degeneration

Courtesy of Richard F. Spaide, MD.

• Not completely understood

• Complex, etiology comprising several factors, including oxidative stress, inflammation, abnormal cell traffic through Bruch’s membrane, and release of angiogenic stimuli, among others

• With age, drusen accumulate in the area between the RPE and the inner collagenous zone of Bruch’s membrane

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Pathophysiology of AMD

Pugazhendhi. Int J Mol Sci. 2021;22:1170. Rastoin. Int J Mol Sci. 2020;21:4627.

• Dry (nonexudative, atrophic) AMD– Slow degeneration of RPE and retinal photoreceptors– Can progress to either late-stage dry AMD (GA) or wet AMD

• Wet (exudative, neovascular) AMD– Stimulated by VEGF, abnormal vessels grow under the retina (MNV)

and can leak fluid and blood– Rapid deterioration of vision

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Types of AMD

Cunningham. JAAPA. 2017;30:18. American Academy of Ophthalmology. Preferred Practice Pattern. 2019; www.nei.nih.gov/learn-about-eye-health/eye-conditions-and-diseases/age-related-macular-degeneration.

20%

80%

Prevalence

Wet Dry

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Wet vs Dry AMD: Effects

90%

10%

Cause of Severe Vision Loss

Wet Dry

Cunningham. JAAPA. 2017;30:18.

• Take a thorough history, including symptoms, vision changes and their timing, family history, lifestyle, use of drugs and supplements that might affect vision

• Ophthalmoscopic evaluation

• Imaging studies (fluorescein angiography, optical coherence tomography [OCT], OCT angiography, color photography of the fundus)

• Visual acuity testing

• Determination of disease stage/severity

• Appraisal of risk to determine how often patients should be evaluated: eg, family and smoking history

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Assessment

American Academy of Ophthalmology. Preferred Practice Pattern. 2019; Marra. JAGS. 2016;64:369. Cunningham. JAAPA. 2017;30:18. Prall.. emedicine.medscape.com/article/1226030-overview.

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Direct Ophthalmoscope

Courtesy of Richard F. Spaide, MD.www.optomed.com/us/age-related-macular-degeneration.

• Commonly taught to and used by primary care clinicians

• However, field of view is narrow (7 mm2)

• Inadequate for detecting AMD

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Drusen: First Identified Sign of Dry AMD

Courtesy of Richard F. Spaide, MD.

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Focal Hyperpigmentation: Next Stage in AMD Development

Courtesy of Richard F. Spaide, MD.

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Focal Hyperpigmentation and Geographic Atrophy

Atrophy

Focal Hyperpigmentation

Courtesy of Richard F. Spaide, MD.

• Helen is a 68-year-old woman who reports increasing difficulty with reading over the past few years, in her left eye more than in her right eye

• Past medical history: nothing remarkable aside from cigarette smoking(~½ pack/day)

• Current medication: calcium, multivitamin

• When asked about changes in her vision, she reveals that she has blurry areas in the center of her vision

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Case Study: Helen

• Gaps exist in primary care recognition of AMD• In a large study:

– Trained personnel observed signs of AMD in ~25% of eyes not diagnosed as having AMD by primary care providers

– 30% had large drusen that could have been treated with nutritional supplements if diagnosed

• Need to question patients, especially older ones who may not report symptoms– Also important in rural areas without easy

access to specialists

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Detection of AMD in Primary CareSample Questions

How was your vision 10 years ago?How is your reading?What can’t you do now that you were able to do before?Have you noticed that straight lines have become distorted or wavy?Have you noticed any dark or blurry areas in the center of your vision?How has your vision changed in the last 3 months?

American Academy of Ophthalmology. Preferred Practice Pattern. 2019; Neely. JAMA Ophthalmol. 2017;135:570. Marra. JAGS. 2016;64:369.

• Examination reveals some visual distortion, several intermediate drusen,and 2 large drusen

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Case Study (cont’d): Helen

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Age-Related Eye Disease Study (AREDS)AREDS Simplified Severity Score

Singh. Retina Today. 2020;(suppl):5.

*Early AMD is often asymptomatic; distorted vision, difficulty with daily tasks may be the only clue

Category Characteristics

1 (No AMD)

• No or a few small drusen (<63 µm diameter)

2 (Early AMD)*

• Several small drusen• Few intermediate drusen (63-124 µm)• RPE abnormalities

3 (Intermediate

AMD)

• Several intermediate drusen + ≥1 large drusen (≥125 µm)

• GA not involving center of fovea4 (Advanced/

Late AMD)• GA involving fovea and/or features of

neovascular AMD

5-Year Risk of Developing Late AMD

Even

t Rat

e (%

)

AREDS Severity Score

0

10

20

30

40

50

0 1 2 3 4

0.53

12

25

50

• Helen is diagnosed with intermediate dry AMD

• There is no drug treatment for her condition; the most important goal now is to prevent progression to more advanced dry AMD or to wet AMD

• The most important thing she can do to prevent progression is stop smoking

• She should take AREDS-2 supplements and follow a diet rich in fruits, vegetables, and fish, such as the Mediterranean diet

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Case Study (cont’d): Helen

• No treatments are approved for dry AMD– Several treatments are in trials for intermediate- and advanced-stage

dry AMD– None have shown good efficacy-to-risk ratios

• For example: intravitreal stem cell injections can have devastating outcomes, such as hemorrhagic retinopathy, vitreous hemorrhage, and ocular hypertension leading to severe vision loss

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Treatment for Dry AMD

Samanta. Asia Pac J Ophthalmol. 2021. Epub ahead of print. Waugh. Health Technol Assess. 2018;22:1. Kuriyan. New Engl J Med. 2017;376:1047.

• Overall goals: Minimize vision loss, improve function, prevent progression to advanced dry or wet AMD

• AREDS supplement formula can slow progression of dry AMD but does not prevent AMD– Initially consisted of vitamins C and E, beta-carotene, copper, and zinc– AREDS-2 replaced beta-carotene with lutein and zeaxanthin because of

evidence of potential harm of beta-carotene to smokers– Taking AREDS supplements can reduce MNV risk in fellow eye of patient with

advanced AMD in one eye

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AREDS Supplements for Dry AMD

Samanta. Asia Pac J Ophthalmol. 2021. Epub ahead of print. Waugh. Health Technol Assess. 2018:22;1. www.nei.nih.gov/learn-about-eye-health/eye-conditions-and-diseases/age-related-macular-degeneration.

• Smoking cessation

• Physical activity (important for reducing progression risk)

• Diet– Mediterranean diet: high in fruits, vegetables, legumes, fish

• Large study showed 41% reduction in risk of advanced AMD with this diet• Benefit seen with fish but not with omega-3 fatty acid supplements

– Foods rich in lutein and zeaxanthin (eg, leafy green vegetables, corn, eggs, pistachios)

• “Whatever is good for your heart is good for your eyes”

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Lifestyle Approaches for Dry AMD

American Academy of Ophthalmology. Preferred Practice Pattern. 2019. www.merckmanuals.com/professional/eye-disorders/retinal-disorders/age-related-macular-degeneration-amd-or-armd. Cunningham. JAAPA. 2017;30:18. www.webmd.com/diet/foods-high-in-lutein.

• At a visit 2 months later, Helen reports that she has stopped taking her multivitamin and started taking AREDS-2 supplements

• She has gradually shifted to following a Mediterranean diet

• She has begun cutting down on cigarettes, with the intention of stopping completely within the next 2 months

• Examination reveals no new signs

• Helen should return in 6 months, and she should self-assess regularly and call immediately if she notices any other changes in her vision

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Case Conclusion

• Family history and/or early symptoms

• Should have regular examinations and vision testing

• Should be encouraged to self-assess regularly—eg, with the Amsler grid

• Referral to an ophthalmologist

– Nonurgent (next available appointment): gradual changes (weeks to months)

– Urgent (within 48 hours): sudden vision loss (1 day-1 week)– Ophthalmoscopic detection of macular drusen may prompt referral of patients with risk factors

– When referring, inform ophthalmologist of any drugs patient is taking that may affect vision

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Patients at Particular Risk for AMD

American Academy of Ophthalmology. Preferred Practice Pattern. 2019. Cunningham. JAAPA. 2017;30:18. Marra KV et al. JAGS. 2016;64:369.

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Amsler Grid for Self-Assessment• Low sensitivity, but may be useful for reminding patients to self-assess

for vision changes and contact their care providers

www.aao.org/eye-health/tips-prevention/facts-about-amsler-grid-daily-vision-test. www.verywellhealth.com/amsler-grid-4768092.

• Sylvia, a 72-year-old patient with an initial diagnosis of dry AMD, says she is experiencing a sudden decrease in vision in her right eye

• Past medical history includes hypertension and atrial fibrillation

• Sylvia has never smoked cigarettes

• Medications: aspirin 81 mg/day, rosuvastatin, hydrochlorothiazide, spironolactone, metoprolol, AREDS supplement

• Her primary care clinician sends her immediately to an ophthalmologist, who does a full workup and recommends VEGF inhibitor injections

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Case Study: Sylvia

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Case Study (cont’d): Sylvia

• First-line treatment for wet AMD

• Revolutionized treatment of wet AMD; visual acuity on an eye chart is maintained within 3 lines of baseline in approximately 90% of patients after 2 years of anti-VEGF injections

• Block VEGF in multiple pathogenic pathways– Help reduce number of abnormal vessels in retina and slow leaking

• Significantly improve quality of life with improvements in vision

– Also improve mental health and emotional well-being

• Generally well tolerated; no significant safety or efficacy differences between bevacizumab, ranibizumab, and aflibercept

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Intravitreal Injections of VEGF Inhibitors

Baumal. Am J Manag Care. 2020;26:S103. Pugazhendhi. Int J Mol Sci. 2021;22:1170. Finger. BMC Ophthalmology. 2020;20:294. www.aao.org/eye-health/tips-prevention/facts-about-amsler-grid-daily-vision-test. Zhao. Acta Ophthalmol. 2021. Epub ahead of print.

• Recombinant VEGF-targeted monoclonal antibody (MAb)

• Off-label use for ophthalmic therapy (approved for several forms of cancer)

• Similarly effective and less costly than approved VEGF inhibitors, but…

• Must be compounded by a pharmacy, which allows for possible contamination and dilution of potency– Variations in concentration of active drug and silicone oil droplets have been

seen with repackaged syringes– Periodically, counterfeit versions have been identified

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Bevacizumab

American Academy of Ophthalmology. Preferred Practice Pattern. 2019. Zhao. Acta Ophthalmol. 2021. Epub ahead of print; Cannon. Am J Manag Care. 2019;25:S182. Holekamp. Am J Manag Care. 2019;25:S172.

• Recombinant humanized Fab fragment of murine VEGF-A‒targeted MAb

• FDA approval in 2006 based on results of MARINA and ANCHOR trials– At 24 months, between 89% and 93% of patients had retained visual acuity,

and 30% to 37% had experienced vision improvement• Available in single-dose vial and prefilled syringe

– Study found that the incidence of endophthalmitis was significantly lower, and that of vision loss higher, with prefilled syringe than with vial

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Ranibizumab

Zhao. Acta Ophthalmol. 2021. Epub ahead of print. Samanta. Asia Pac J Ophthalmol. 2020;9:250. Holekamp. Am J Manag Care. 2019;25:S172. Lucentis PI.

• Fusion protein that binds to VEGF-A and also blocks placental growth factor

• FDA approval in 2011 based on results of VIEW 1 and 2– At 12 months, between 94% and 95% of patients had maintained visual

acuity, and 29% to 38% had experienced vision improvement– Showed that 2-month between-dose intervals were effective

• Single-dose prefilled syringe approved in 2019

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Aflibercept

American Academy of Ophthalmology. Preferred Practice Pattern. 2019. Zhao. Acta Ophthalmol. 2021. Epub ahead of print. Samanta. Asia Pac J Ophthalmol. 2020;9:250. Aflibercept PI.

• Single chain antibody fragment

• FDA approval in 2019 based on results of HAWK and HARRIER trials– At 96 weeks, between 29% and 34% of patients had experienced vision

improvement– Effective at 12-week interval for >50% of patients

• Rare but dangerous adverse events (AEs) have occurred (eg, retinal vasculitis, retinal artery occlusion, severe vision loss)– Prescribing information now includes these potential complications– Possibility of immune reaction causing these AEs– This scale of AEs has not been seen with the other 3 AMD drugs

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Brolucizumab

Samanta. Asia Pac J Ophthalmol. 2020;9:250. Brolucizumab-dbll PI.www.reviewofophthalmology.com/article/beovu-labeling-to-be-updated-due-to-side-effects.

• Novel drugs (eg, conbercept, faricimab, anti-VEGF biosimilars)

• Longer-lasting medications (eg, abicipar pegol)

• Gene therapy, delivered via intravitreal, subretinal, or suprachoroidal injection

• Port delivery system– Extended-release therapy– Increases risk of injury and infection

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Potential Treatment Advances

Kim HM, Woo SJ. Pharmaceutics. 2021;13:108. Samanta. Asia Pac J Ophthalmol. 2020;9:250. Pugazhendhi. Int J Mol Sci. 2021;22:1170. www.brightfocus.org/macular/article/gene-therapy-advances-age-related-macular.

Routes of administration

• The ophthalmologist has given Sylvia her initial injection of aflibercept

• At her next primary care visit, Sylvia asks about the possible protocols for between-injection intervals

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Case Study (cont’d): Sylvia

• AAO: no consensus about treatment intervals for anti-VEGF therapy – 1 goal: to reduce frequency of visits and lighten burden on patient and family

• 3 protocols– Fixed intervals: monthly or bimonthly; no adjustment based on outcomes– PRN: based on presence of sub- or intraretinal fluid – Treat and extend: now largely standard practice

• Interval extended or reduced based on disease activity • Better overall outcomes than with PRN method • Lower treatment burden than fixed intervals

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Ongoing Therapy

AAO = American Academy of Ophthalmology.American Academy of Ophthalmology. Preferred Practice Pattern. 2019. Mitchell. Lancet. 2018;392:1147. Baumal. Am J Manag Care. 2021;26:S103. Ross. Eye. 2020;34:1825.

• Sylvia is on a treat-and-extend aflibercept regimen and has had a good initial response

• She will continue to see her ophthalmologist regularly for assessment and treatment

• She is a bit depressed by the prospect of indefinite treatment

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Case Study (cont’d)

• Some patients’ AMD may not respond to VEGF inhibitors– Photodynamic or laser photocoagulation therapy are generally less

effective at improving vision than anti-VEGF injections and are not widely recommended

– Depression is common among patients whose treatment did not meet expectations

‒ Consider antidepressant prescription, referral to mental health counseling, and support groups

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Beyond Anti-VEGF Therapy

American Academy of Ophthalmology. Preferred Practice Pattern. 2019. Cunningham. JAAPA. 2017;30:18.

• Advise all patients, especially older patients, to have their eyes examined regularly

• Emphasize that AMD is a chronic disease requiring ongoing treatment, but total vision loss is rare

• Review lifestyle measures

– Smoking cessation (most important), diet, exercise

– Supplements: beneficial in general but not shown to be effective treatment for late AMD

• Refer for visual rehabilitation, but manage expectations: optimal use of existing vision rather than improvement in vision

– These services have been shown to reduce patient anxiety and improve visual function

– May offer low-vision devices (eg, high-powered glasses, magnifiers, special computer software)

• Stress importance of reporting changes in vision to healthcare providers

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Patient Education

American Academy of Ophthalmology. Preferred Practice Pattern. 2019. Marra. JAGS. 2016;64:369. www.nei.nih.gov/sites/default/files/2019-06/2014_Speaker_Guide_Released.pdf.

• Because Sylvia was only mildly depressed at her last visit, she will try other measures before taking antidepressants

• She joined a support group, meeting regularly with other patients with AMD, and she says that the sense of not being alone in this has helped her feel better

• She and her ophthalmologist are assessing her responses to therapy and gradually lengthening the intervals between injections

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Case Conclusion

• Technologies are being studied to facilitate remote screening for AMD and monitoring status between treatments, but by its nature, anti-VEGF therapy cannot be delivered remotely

• Retrospective, observational study: delaying anti-VEGF injections resulted in reduced visual acuity and a need for shorter intervals between injections

• Ensure patient and staff safety, eg, cleaning surfaces, requiring personal protective equipment, spacing out appointments, maintaining distance between patients

• Assure patients that you and your staff are practicing all safety protocols

• Consider fixed between-injection intervals, with patients reporting any changes, to avoid frequent assessment visits

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AMD Management in the Era of COVID-19

Sim. Asia Pac J Ophthalmol. 2021;10:39. Ashkenazy. Clin Ophthalmol. 2021;15:413. Korobelnik. Graefes Arch Clin Exp Ophthalmol. 2020;258:1149. Korobelnik. Graefes Arch Clin Exp Ophthalmol. 2020;258:1335.

• Cigarette smoking is the most prominent modifiable AMD risk factor

• Advise patients to have their eyes examined regularly

• Ask questions to elicit information that might indicate possible AMD

• Sudden vision changes should prompt urgent referral to ophthalmology

• Wet AMD represents the smallest percentage of cases but the greatest proportion of serious vision loss

• Currently there is no treatment for dry AMD aside from lifestyle measures and AREDS supplements

• Injection of VEGF inhibitors has shifted the treatment paradigm for wet AMD

• Patients should be advised to self-assess, take advantage of low-vision aids, and report changes to their healthcare providers promptly

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PCE Takeaways

Q&A