DRY AGE RELATED MACULAR DEGENERATION

DRY ARMD

1. Dry Age related Macular Degeneration DR SHRUTI LADDHA

2. Introduction : ARMD: Defined as the loss of macular function because of the degenerative changes of ageing. It is the leading cause of irreversible vision loss and blindness in people aged > 65 years. It was responsible for 8.7% of all blindness worldwide in 2007, and this figure is expected to double by 2020. ARMD was found to be second cause of severe visual loss after cataract.

3. AMD: TERMINOLOGY Referred as senile macular degeneration, a name given by Haab as early as 1885. Age-related macular degeneration has recently been named by Professor A C Bird and coworkers who performed the International ARM Epidemiological study group. The disorder is either referred to age related maculopathy (ARM) or age-related macular degeneration (AMD).

4. The UN estimates the number of people with AMD are about 20-25 million worldwide. WHO’s estimate is 8 million people with severe visual impairment. Prevalence of AMD in >75 year age group varies from 1.2% to 29.3% in different . AMD: PREVALANCE

5. AMD: PREVALANCE 3 population based studies; the Beaver Dam Eye Study, Blue Mountain Eye Study and the Rotterdam study report the over- all prevalence rates to be 1.7% in US, 1.4% in Australia and 1.2% in Netherlands respectively. In South India, the prevalence is 1.1% whereas, another study from North India reports the prevalence rate to be 4.7%.

6. POSTULATED RISK FACTORS : Ageing The Framingham Eye study (1976) showed the prevalence – 65-74 years- 11% – 75-85 years- 28% Gender Blue Mountains study (2002) suggests that 5- year incidence of neovascular AMD among women is double that of men. Smoking The Beaver Dam Study (1992) disclosed a relationship between the development of exudative lesions and a history of smoking

7. POSTULATED RISK FACTORS : Cardiovascular Risk factors Hypertension: Rotterdam study (2003) suggests positive correlation between high blood pressure and increased incidence of AMD. Light Initially postulated hypothesis: UV-damage by photo-oxidative damage via reactive oxygen intermediates. The Blue Mountains Eye Study (2002) disclosed no relationship between light and AMD.

8. POSTULATED RISK FACTORS : Nutrition Several studies (including AREDS) have described the beneficial effects of dietary carotenoids, anti-oxidants, Zn and omega-3 fatty acid in slowing the course of the disease. Exogenous Post Menopausal Oestrogen The use of exogenous supplements in post

9. GENETICS Family history of macular degeneration: Autosomal dominant with variable penetration In first degree relative with macular degeneration, chances is about 2.5 times. Macular Degeneration Gene: Few studies have described the increased risk of AMD associated with polymorphisms of complement factor H (HF1/CFH) single nucleotide polymorphisms on 1q32, 6p21, and 10q26 are the risk for development of AMD

10. RETINAL PIGMENT EPITHELIUM The retinal pigment epithelium (RPE) is a single layer of hexagonally shaped cells & attached to the photoreceptor layer. Functions - Maintain the p hotoreceptors Absorption of stray (noise ) ligh t Formation of the outer blood retinal barrier Phagocytosis and regeneration of visual pigment

11. Each RPE cell is responsible for a diurnal cycle of engulfing photoreceptor outer segments that have been shed The rod outer segments being digested by day and the cone outer segments by night After phagocytosis –RPE lysosomes degrade the photoreceptor outer segment

12. In ARMD -After phagocytosis by the aged RPE, the lysosomal degradation enzymes may fail to “recognize” these abnormal molecules, causing molecular degradation to fail with accumulation of lipofuscin in the RPE lysosomes. The normal, young RPE is composed of a single layer of hexagonal cells of equal size and degree of pigmentation. With age- plemorphism

13. Bruch’s membrane separates the RPE from vascular choroid. Bruch’s membrane is composed of an inner and outer collagenous zone (ICZ and OCZ) separated by an elastic layer (EL). Linear relation exist between the age and thickness of Bruchs membrane. Function of Bruch’s membrane is to provide support to the retina. Choroid capillaries are a layer of fine blood vessels that nourishes the retina and provides O 2.

14. Young Old Early AMD Advanced AMD

15. T Y P ES

16. DRY AMD Accounts for about 90% of all cases Also called atrophic, non-exudative or drusenoid macular degeneration Clinically , dry AMD may manifest- Stage of drusen and/or hyperpigmentation Stage of incipient atrophy (non geographic Atrophy) Stage of geographic atrophy

17. DRY AMD D r u s e n

18. Insufficient oxygen and nutrients damages photoreceptor molecules With ageing, the ability of RPE cells to digest these molecules decreases Excessive accumulation of residual metabolic debris and hyaline material (drusen) Further disruption of RPE/photoreceptor metabolism Cause variable amount of depigmentation and eventually atrophy of overlying RPE RPE membrane and cells degenerate and atrophy sets in and central vision is lost

19. Drusen: Drusen are aggregation of hyaline material located between Bruch’s membrane and RPE. Drusen are composed of metabolic waste products from photoreceptors. Hypo/hyper pigmentation of RPE may be present.

20. Types: Small: <63 µ Intermediate: 63-124 µ Large: >125 µ Hard: generally small (<63 µ), bright yellow, solid appearing drusen with well defined margins may be asymptomatic Soft: larger (>63 µ), pale yellow, ill defined, fluffy margins High risk for neovascular AMD

21. Soft Drusen: Membranous: 63-175 µ Pale, shallow appearing drusen Granular: About 250 µ Solid appearing drusen Serous: >500 µ Have pooled serous fluid blister like appearance May result in serous PED

22. HISTOPATHOLOGY y neo-vascular AMD. Drusen appear as focal areas of the eosinophilic material between the basement membrane of RPE & BM. Deposits on the internal side of RPE basement membrane called –basal laminar deposits & on its external aspects called – basal linear deposits. Basal linear deposits are believed to form soft drusen with the pa ssage of time Drus en

23. Diagnostic criteria Degenerative disorder in persons >50 years, characterized by the presence of any of the following: Soft drusen (>63 µ) RPE abnormalities- areas of hypo/hyperpigmentation (excluding pigment surrounding small, hard drusen) Visual acuity (VA) is not a criterion for the diagnosis

24. RPE degeneration, seen as: Focal areas of hypo- and hyper- pigmentation (‘stippling’) Associated with progression to late AMD with Visual loss Eventually areas of atrophy of the RPE revealing underlying large & deep choriodal vessels ‘Geographic atrophy’ = end stage or Late advanced stage of Dry AMD

25. DRY AMD

26. Symptoms:- Gradual mild to moderate impairment over months or years Both eyes usually affected but often asymmetrically Vision may fluctuate, & is often better in bright light Signs:- Intermediate-large soft drusen may confluent Focal hyper &/or hypopigmentation of RPE Slow/progressive atrophy of RPE and photoreceptors Drusenoid RPE detachment Advanced form = Geographic Atrophy

27. Geographic Atrophy (GA) Clinical Features:- Signs/Symptoms:- Marked decrease VA (unless foveal sparing) Central field loss (positive scotoma) Difficulty recognizing faces Difficulty reading if large scotoma Difficulty in dim light/adapting Soft drusen present in early stages (significant risk factor for GA – due to RPE detachment) Decreased retinal thickness and increased visualisation of choroidal vessels Sharply demarcated pale area Choroidal vessels sometimes white

28. OCT IN DRY ARMD

29. Atrophic form or “Dry AMD” is defined by areas of RPE atrophy, often resulting from regression of confluent soft drusen. areas of atrophy, usually perifoveal, gradually spread to become confluent, forming a partial, then complete ring, and finally involving the center of the macula. Histologically, RPE atrophy is accompanied by a loss of the outer nuclear layer, and the outer plexiform layer becomes in direct contact with basal laminar deposits.

30. Dry AMD is characterized by the absence of an exudative reaction. Thinning and loss of the RPE are clearly visualized, but maintenance of the straight line representing Bruch’s membrane is an important sign. The external limiting membrane and IS/OS interface are severely altered and/or no longer visible and become disrupted early. In the most severe forms, the outer nuclear layer is no longer visible in the zones of atrophy. The outer plexiform layer comes directly in contact with Bruch’s membrane.

31. DRY AMD –INITIAL STAGE The external limiting membrane was readily visible almost everywhere and was raised by numerous drusen. In area of atrophy , the IS/OS interface and external limiting membrane were no longer visible and were replaced by a moderately dense zone masking the outer nuclear layer

32. SAME PATIENT AFTER 6 MONTHS localized juxtafoveal atrophy in the de-pigmented area of the RPE, which was now clearly visible. In this zone, the outer retinal layers were no longer visible, apart from the outer nuclear layer. There is RPE at the edges of the atrophy and the alterations of the outer retinal layers over each large drusen.

33. SAME PATIENT AFTER 1 YEAR the area of atrophy was slightly larger and the outer nuclear layer had completely disappeared in this zone, which induced a juxtafoveal scotoma that interfered with reading

34. EXTRAFOVEAL DRY AMD RPE was clearly visible with numerous drusen. Atrophy of the RPE over the hyper-fluorescent spots and visibility of the straight line of Bruch’s membrane with marked back-shadowing. Anterior to the RPE, the ELM and IS/OS interface were clearly visible and were disrupted over the area of atrophy. Disruption of the ELM and IS/OS interface and especially loss of the outer nuclear layer. The outer plexiform layer was in contact with Bruch’s membrane.

35. Dry AMD: Advanced Perifoveal and Subfoveal Form anterior to the RPE, the IS/OS interface and external limiting membrane were no longer visible over the zone of atrophy. The outer nuclear layer was also lost, bringing the outer plexiform layer in contact with Bruch’s membrane, which confirmed the localized atrophy of the RPE and photoreceptors in this zone.

36. Macular Atrophy Following RPE Tear In the elevated zone, the RPE was irregular, rolled up, and hyper-reflective (reactive proliferation of the RPE that invaded all of the outer retinal layers). The IS/OS interface and external limiting membrane were occasionally visible but not clearly identified. In the atrophic zone, the outer retinal layers were absent, bringing the outer plexiform layer in contact with Bruch’s membrane and confirming photoreceptor atrophy.

37. Macular Atrophy due to Vitelliform Macular Dystrophy Spectralis * horizontal section : almost complete disappearance of the RPE in the central subfoveal zone. Persistence of several scattered hyper-reflective islands anterior to Bruch’s membrane. Loss of the IS/OS interface. The ELM and outer nuclear layer were normal Spectralis * vertical section : the RPE was preserved but with accumulation of fairly dense hyper-reflective material that appeared to proliferate anteriorly in the outer nuclear layer.

38. The typical SD-OCT characteristics of geographic atrophy include Loss of the outernuclear layer (ONL) Loss of the outer hyperreflective bands (external limiting membrane [ELM], ellipsoid zone, interdigitation zone, inner part of the RPE-Bruch’s membrane [BM] complex resulting in direct apposition of the outer plexiform layer (OPL) and BM A choroidal signal enhancement that is explained by increased penetration of the light through the area of RPE atrophy

39. Baseline visit shows a large drusenoid retinal pigment epithelial detachment (PED) with signs predictive for pending atrophy such as hyper-reflective foci ( arrow ) and hyper-transmissions within the PED ( arrowhead ), presumably due to RPE breakdown. After 1 year the large drusenoid PED has partially collapsed with an adjacent area of outer retinal subsidence ( arrow ), a sign for nascent geographic atrophy ( nGA ). Two years after baseline the PED has completely collapsed, leaving drusen-associated atrophy with the characteristic hyper-transmission into the choroid ( area between arrows ) resulting from loss of the RPE, photoreceptor, and choriocapillaris

40. The typical SD-OCT characteristics of geographic atrophy include Loss of the outernuclear layer (ONL) Loss of the outer hyperreflective bands (external limiting membrane [ELM], ellipsoid zone, interdigitation zone, inner part of the RPE-Bruch’s membrane [BM] complex resulting in direct apposition of the outer plexiform layer (OPL) and BM A choroidal signal enhancement that is explained by increased penetration of the light through the area of RPE atrophy

41. Hard Drusen Fundus photograph of the right eye showing multiple discrete drusen at the fovea Arteriovenous phase showing discrete early hyperfluorescence The hyperfluorescence at the drusen has increased in the mid arteriovenous phase Fading of the hyperfluorescence is seen in the late phase The RPE atrophy overlying the drusen allows the background choroidal fluorescence to be seen as transmitted hyperfluorescence FFA-DRUSEN

42. Soft Drusen Fundus photograph of the RE showing large soft Drusen Faint hyperfluorescence is seen at the drusen in early AV phase Further increase in the hyperfluorescence is noted Maximum hyperfluorescence is seen in the late phase due to staining of the soft drusen. Due to the hydrophobic nature of the soft drusen material, the entry of the dye into the drusen is delayed. Hence, the soft drusen do not show hyperfluorescence until the late stages.

43. Fundus photograph showing large atrophic patches arranged in an annular fashion around the fovea. RPE alteration is noted in the foveal region Arteriovenous phase shows relative hypo-fluorescence in the region of atrophy. Irregular hyper-fluorescence is seen at the rest of the macula Normal scleral staining is seen through the atrophic areas making them appear hyperfluorescent in the late phase Early hypofluorescence within an atropic lesion indicates non filling of the underlying atrophic choriocapillaris along with atrophy of the RPE FFA-GEOGRAPHIC ATROPHY

44. DRY AMD: COURSE AND VISUAL PROGNOSIS Patients with only drusen not have much loss of vision, but require additional magnification of the text and more intense lighting to read small points. Presence of large drusen (>63 microns in diameter) is associated with a risk of the late form of the disease like CNV. Geographic atrophy- severest form of the dry AMD

45. AREDS Categories: No AMD (AREDS category 1) No or a few small (<63 micrometres in diameter) drusen. Early AMD (AREDS category 2) Many small drusen or a few intermediate-sized (63- 124 micrometres in diameter) drusen, or macular pigmentary changes. Intermediate AMD (AREDS category 3) Extensive intermediate drusen or at least one large (≥125 micrometres) drusen, or geographic atrophy not involving the foveal centre. Advanced AMD (AREDS category 4) Geographic atrophy involving the foveal centre (atrophic, or dry, AMD) Choroidal neovascularisation (wet AMD) AMD: STAGING

46. Investigations History : Gradual change = non-exudative Sudden change = exudative Visual Symptoms :- VA for Distance and ne ar & improve with PH Difficulty in reading/recognising faces, driving Difficulty with changing light / adapting after bright light Distortion of images mostly with exudative changes Less common symptoms include night glare, photopsia (flickering or flashing lights), visual hallucinations ( Charles Bonnet syndrome ) & abnormal dark adaptation

47. Amsler grid test : Assesses distorted & scotoma , small irregularities in the central field of vision ( 10degree) Ophthalmoscopy : T o detect drusen, as well as neovascularization Fluorescein and ICG angiography : Determines the presence and location of wet AMD Optical coherence tomography

48. MANAGEMENT Antioxidants : AREDS-1 study & follow-up AREDS-2 Study use of high dose of multivitamins & antioxidants decreases the risk of progression of ARMD in those with high risk characteristics as age >55 with one or more of following Extensive intermediate or At least one large Drusen GA in one or both eyes Late AMD in one eye ( greatest benefit in AREDS1) AREDS1 Formula AREDS2 Formula Vitamin E 400IU Vitamin E 400IU Vitamin C 500mg Vitamin C 500mg Beta Carotene 15mg ( Vit A 2500IU) Leutin 10mg Zinc 80mg Zeaxanthin 2mg Copper (Cupric Oxide) 2mg Zinc 25-80mg Copper 2mg

49. D i a g n o s i s R e c o m m e n d e d Treatment Observation with no medical or surgical therapies Antioxidant vitamin and mineral supplements as recommended in the AREDS reports No clinical signs of AMD (AREDS category 1) Early AMD (AREDS category 2) Advanced AMD with bilateral subfoveal geographic atrophy or disciform scars Intermediate AMD (AREDS category 3) Advanced AMD in one eye (AREDS category 4)

50. Dry ARMD:- 1) Antioxidant sup p limentation & Risk factors modulation Low Vision Aids Anti-inflammatory drugs- Sirolimus (Rapamycin) macrolide , obtained from fungus, immunosuppressant & used intravitreal Intravitreal Steroids as FA implants (sustain release upto 36 months)

51. 4. Complement Inhibition- POT-4 neutralize early AMD inflammatory component & it is a Intravitreal gel sustain release system ARC1905 a C5 inhibitor Aptamer prevents C5a production Eculizumab a Antibody against C5, currently approved only for PNH Lampalizumab a monoclonal antibody, used as intravitreal monthly 5. Neurotrophic Factors- NT501 a genetically modified RPE intravitreal implant, shown retinal thickness as early as 4 months. 6. AL-8309A- topical solution, light induced oxidative damage

52. 7) Reduction of Retinal Toxins- In Dry AMD lipofuscin (a waste products) accumulates at leading edge of lesion ACU-4429 & Fenretinide (Oral doses) prevents accumulation of lipofuscin Choroidal Blood Perfusion Enchancers- MC-1101 as Topical drug, shown to increase mean choroidal blood flow Other Options Photocoagulation of Drusen Saffron (20mg/day) a neuroprotective effect Intravitreal neuroprotective drug Brimonidine Surgery like Retinal translocation, Subretinal Stem cell Transplantation

53. REHABILATATION Low vision aids- – Individual who experiences untreatable visual loss & effects the daily life. Reading lamps & simple magnifiers may be beneficial. Closed circuit television & scanning devises are also available to provide