Wet Age Related Macular Degeneration and Choroidal Neovascular Membrane

This is a wet form of advanced ARMD, causes vision loss due to abnormal blood vessel growth (choroidal neovascularization)
The vessels from choriocapillaries, grow into the layers of retina through the defects in the bruch’s membrane
They cause bleeding and leakage of fluid, proteins and ultimately leading to a neovascular membrane
CNVM is characterized clinically and angiographically as occult, classic or mixed occult- classic CNVM
Anatomically as Type 1,2,3
By Topography – Subfovel, juxtafoveal, extrafoveal

Depending on cause PED is classified and has specific patterns of FA
Fibrovascular PED : irregular elevation of RPE (which is neither as bright nor as discrete as in classic CNV) often with stippled hyperfluorescence present in midphase of FA leakage or staining by late phase
Drusenoid PED : coalescence of drusen – show staining, often with fading fluorescence in late phase and as absence of leakage
Serous PED: seen as dome-shaped detachment of RPE, exhibiting bright diffuse hyperfluorescence with progressive pooling in a fixed space
Hemorrhagic PED: manifests as dark elevation of RPE due to underlying blood, showing blocked fluorescence throughtout all phases of angiography

1. Wet AMD and CNVM Dr Sambandha Khati 2 nd year resident LEIRC, NAMS 1

2. Neovascular or “WET” ARMD - CNVM This is a wet form of advanced ARMD, causes vision loss due to abnormal blood vessel growth (choroidal neovascularization) The vessels from choriocapillaries , grow into the layers of retina through the defects in the bruch’s membrane They cause bleeding and leakage of fluid, proteins and ultimately leading to a neovascular membrane CNVM is characterized clinically and angiographically as occult, classic or mixed occult- classic CNVM Anatomically as Type 1,2,3 By Topography – Subfovel , juxtafoveal , extrafoveal 2

3. Wet AMD Pathology : Presence of Choroidal neovascularization with formation of subretinal /choroidal neovascular membrane (SRNVM/CNVM) CNVM lead to hemorrhage and fibrovascular proliferation and subsequent scarring Age related Bruch’s membrane change may be especially important in exudative macular degeneration 3

4. Photoreceptors and pigment epithelium send a distress signal to choriocapillaries to make new vessels New vessels grow behind the macula Breakdown in the Bruch’s membrane Blood vessels are fragile Leak blood and fluid Scarring of macula Potential for rapid and severe visual damage 4

5. In 1948, Michaelson hypothesized : Diffuse, hypoxia – induced, angiogenic “factor X” was responsible for iris and retinal neovascularization associated with ischemic retinopathies Animal and human studies strongly suggest that vascular endothelial growth factor (VEGF) represents factor X VEGF-A : strongly associated with angiogenesis, therefore – target of most current anti- VEGF treatments. 5

6. Hallmark of Neovascular AMD Presence of neovascularization within macula Neovascularization may result from : Ingrowth of choroidal neovascularization (CNV) from choriocapillaries under macular region May arise predominantly within retina and is known as retinal angiomatous proliferation (RAP) Advanced neovascular AMD : retinal –choroidal anastomosis ( communication between retinal circulation and choroidal circulation ) is common 6

7. Choroidal Neovascularization CNV in the fovea is the major cause of severe central vision loss in AMD Patient often present with an otherwise unexplained, fairly sudden decrease in VA, central metamorphopsia , or a relative central scotoma 7

8. Risk factors Modifiable : Smoking : 2 fold increase in risk, effect lasts even after stopping Obesity : higher BMI increases the chances Anti-oxidants : carotenoids and lutein decreases AMD Dietary fat intake Hypertension : esp high diastolic BP Cardiovascular risk factors Cataract surgery Sunlight exposure (controversial) 8

9. Non-modifiable : Age : increases with each decade Gender : female > male esp after 75 years Ethnicity : white >black Gender factors : familial cases seen in 10-20% cases Iris colour : dark colour is protective 9

10. Signs of CNV may include the presence of Subretinal fluid Subretinal or sub-pigment epithelial blood Subretinal or intraretinal lipid Subretinal pigment ring Irregular elevation of the pigment epithelium Subretinal gray-white lesion Cystoid macular edema Sea fan pattern of subretinal small vessels 10

11. CNV lesion is well demarcated and its location may be determined by closest point to the FAZ Lesion location is classified topographically as follows Subfoveal : under the center of FAZ Juxtafoveal : 1-199 um from the center of FAZ Extrafoveal : >200um and <2500um from center of FAZ 11

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13. FA of classic subfoveal CNV A few specks of blood at the fovea FA arteriovenous phase shows “lacy” hyperfluorescence Venous phase : shows more intense hyperfluorescence Late phase : shows persistent hyperfluorescence due to staining 13

14. FA of occult CNV Specks of blood at the fovea (B-D) FA shows diffuse hyperfluorescence but the limits of the membrane cannot be defined 14

15. Anatomical classification of CNVM Type 1 – neovascularization, new vessels originating from the choriocapillaries 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 Type 2 – neovascularization, the CNV occupies the subneurosensory compartment between the RPE and inner retina. On examination, the membrane will appear as a lacy or gray-green lesion, less common than type 1 neovascularization 15

16. Type 3 – neovascularization result from new blood vessels sprouting from the deep capillary plexus of the retina and growing downward towards 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 discolouration , often associated with retinal exudate 16

17. Type 1 CNVM : Sub-RPE CNVM, usually related to occult CNVM on FFA Type 2 CNVM : Subretinal CNVM (superficial to the RPE), usually corresponds to classic membranes on FFA Type 3 CNVM : retinal angiomatous proliferation 17

18. Variations : Retinal Angiomatosis Proliferans Has been termed Type III CNVM Characterized by predominantly intraretinal NV 3 stages : Stage 1 : intraretinal neovascularization Stage 2 : Subretinal neovascularization Stage 3 : CNV clearly determined clinically / angiographically RCA ( retino -choroidal anastomoses seen as Hair-pin appearance on FFA 18

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21. Retinal Pigment Epithelial Detachment Pathogenesis Pigment epithelial detachment (PED) from the inner collagenous layer of Bruch membrane is caused by disruption of the physiological forces maintaining adhesion Mechanism -> reduction of hydraulic conductivity of a thickened and dysfunctional Bruch membrane, thus impending movement of fluid from the RPE towards the choroid Immune- mediated processes may also be important The different types are : Serous PED Fibrovascular PED Drusenoid PED Hemorrhagic PED 21

22. PED (Pigment epithelium Detachment) Depending on cause PED is classified and has specific patterns of FA Fibrovascular PED : irregular elevation of RPE (which is neither as bright nor as discrete as in classic CNV) often with stippled hyperfluorescence present in midphase of FA leakage or staining by late phase Drusenoid PED : coalescence of drusen – show staining, often with fading fluorescence in late phase and as absence of leakage Serous PED: seen as dome-shaped detachment of RPE, exhibiting bright diffuse hyperfluorescence with progressive pooling in a fixed space Hemorrhagic PED: manifests as dark elevation of RPE due to underlying blood, showing blocked fluorescence throughtout all p hases of angiography 22

23. Serous PED Symptoms bluured central vision and metamorphopsia , induced hypermetropia . Signs Orange dome shaped elevation with sharply delinated edges, often with a paler margin of subretinal fluid A pigment band on the dome indicates chronicity Sub RPE or subretinal blood and retinal lipid are particularly suggestive of CNV 23

24. Serous detachment of the RPE Clinical appearance FA shows a well demarcated oval area of hyperfluorescence which increases in intensity but not in area with time : ‘pooling’. A notch in the circumscribed area may signify the presence of CNV ICGA shows hypofluorescence with a faint ring of surrounding hyperfluorescence OCT shows separation of the RPE from Bruch membrane 24

25. Drusenoid PED Drusenoid PED develops from confluent large soft drusen Sign : Shallow elevated pale areas with irregular scalloped edges that are often bilateral FA shows early diffuse hypofluorescence with patchy relatively faint early hyperfluorescence , progressing to moderate irregular late staining ICGA shows predominantly hypofluorescene OCT shows homogenous hyperreflectivity within the PED, in contrast to the optically empty appearance of a serous PED. There will usually be no subretinal fluid 25

26. Fibrovascular PED By definition (Macular Photocoagulation Study Classification) fibrovascular PED represents a form of ‘occult’ CNVM Signs : The PED is much more irregular in outline and elevation than in serous PED FA shows markedly irregular granular or ‘stippled’ hyperfluorescence , with uneven filling of the PED, leakage and late staining ICGA demonstrate CNV more effectively OCT will demonstrate the PED, which will be optically denser than a serous PED and fibrous proliferation as deeper scattered reflections Subretinal fluid will be demonstrated 26

27. Hemorrhagic PED Symptoms consists of sudden impairment of central vision Sign Elevated dark red dome shaped lesion with a well defined outline The blood may break through into the subretinal space assuming a more diffuse outline and a lighter red colour FA exhibits dense masking of background 27

28. RPE rip/tear It occurs as a complication of serous or fibrovascular PED It occurs at the border of attached and detached RPE due to stretching forces of the underlying fluid or from the contractile forces of the f ibrovascular tissue Clinically, it is seen as area of hypopigmentation with hyperpigmented wavy border on one side due to rolling in of the free edge of torn RPE Massive sub retinal hemorrhage and breakthrough vitreous hemorrhage though unusual complications of AMD, are seen sometimes and result in sudden profound visual loss both central as well as peripheral 28

29. Presentation when the fovea is involved is with sudden worsening of central vision Sign : A crescent shaped pale area of RPE dehiscence is seen, next to a darker area corresponding to the retracted and folded flap FA late phase shows hypofluorescence over the flap due to the thickened folded RPE, with adjacent hyperfluorescence over the exposed choriocapillaris where the RPE is absent. The two areas are separated by a well-defined linear border OCT shows hyperreflectivity adjacent to the fold 29

30. Course of untreated CNV Extensive lipid deposition Bleeding ‘ disciform ’ scarring Extensive exudative retinal detachment in end-stage disease 30

31. End stage CNV that has progressed to fibrovascular scar : disciform scar Late phase fluorescein angiogram showing staining of the subretinal fibrous tissue and extensive leakage from the disciform scar Optical coherence tomogram of same patient illustrating disorganization and edema of the retina and underlying fibrous tissue 31

32. Other clinical presentation of exudative ARMD Retinal pigment epithelial detachment Retinal pigment epithelial tears Disciform scars Breakthorugh vitreous hemorrhage Massive subretinal hemorrhage 32

33. R PE detachment or PEDs Fibrovascular PEDs (pattern of occult CNV) Serous detachments of the RPE Clinically : sharply demarcated, dome shaped elevations of the RPE and overlying neurosensory retina. Accompanying RPE atrophy and pigment figure formation RD (not sharply demarcated borders) may result from : Breakdown of the physiologic RPE pump Disruption of the tight junction between adjacent RPE cells 33

34. C. Hemorrhagic detachment of the RPE . Discretely elevated dark green of red mound Hemorrhagic RD Extensive vitreous hemorrhage D. Drusenoid PEDs (coalescence of Drusen ) 34

35. Retinal Pigment epithelial tears Associated with PEDs, either secondary to or unassociated with laser photocoagulation PEDs: tears occur at the junction of attached and detached RPE (stretching forces from the fluid) When the RPE tears, the free edge of the RPE retracts and rolls towards the mound of fibrovascular tissue 35

36. Disciform scars Both treated and untreated CNV may progress to a fibrovascular scar involving the choroid, RPE and most of the neurosensory retina Clinically, white to yellow lesions Disciform fibrovascular scars may continue to grow, with neovascularization recurring along their edges, invading previously unaffected areas Choroidal folds emanation from the scar 36

37. Breakthrough vitreous hemorrhage C/o of severe and sudden visual loss involving the peripheral visual field. Pain result from stretching of the nerve fibers within the choroid Massive subretinal hemorrhage (rare) Anticoagulation or antiplatelet therapy may contribute to this. If total hemorrhagic RD occurs, secondary ACG may develop C/o of sudden visual loss followed by pain 37

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39. AMD staging : AREDS categories 39

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41. Differential diagnosis of neovascular AMD Macroaneurysms Vitelliform detachments Polypoidal choroidal vasculopathy Central serous chorioretinopathy Inflammatory conditions Small tumors such as choroidal melanoma 41

42. Progression of ARMD 42

43. Recent advances on wet ARMD and CNVM Key Mechanisms Beyond VEGF (Vascular Endothelial Growth Factor): Angiopoietin-2 (Ang-2), Platelet-Derived Growth Factor (PDGF), Placental Growth Factor ( PlGF ) Inflammation: Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF- α), NOD-like Receptor Protein 3 (NLRP3) inflammasome , Neutrophil Extracellular Traps (NETs) Complement System Dysregulation: Complement Factor H (CFH), Complement component 3 (C3), Complement component 5 (C5) 43

44. Recent advances on wet ARMD and CNVM Genetic & Cellular Insights Genome-Wide Association Studies (GWAS) identifying new AMD risk loci Epigenetic regulation in Retinal Pigment Epithelium (RPE): DNA methylation, histone modification Bruch’s membrane dysfunction → altered RPE signaling → Choroidal Neovascularization (CNV) 44

45. Reference OPHTHALMOLOGY, Myron Yanoff Clinical Ophthalmology, 9 th edition, Kanski Principles and Practice of Ophthalmology, Vol.2, Albert & Jakobiec RETINA, Vol.2, Stephen J. Ryan 45

46. Next class Management of Wet ARMD - Dr. Prabhat Devkota 46