Day 8 (1): Pathology of the Retina and Vitreous Flashcards
What are the causes of retinal edema?
Due to breakdown of the integrity of the INNER blood-retina barrier (retinal vessel endothelium) secondary to:
- Increased intravascular pressure (hydrostatic pressure)
- Vessel ischemia
- Pericyte loss
- Inflammation
- Abnormal vascular formation
- Others:
- Toxic retinopathy: secondary to a toxic agent
- Solar/Photic retinopathy: secondary to prolonged or high intensity exposure to light
- Preeclampsia/Eclampsia-associated retinopathy: retinal arteriolar narrowing due to systemic hypertension and ischemia
How does increased intravascular pressure cause retinal edema?
+ Due to a physical block in retinal VEINS
1. Branch Retinal Vein Occlusion:
- location: arterial-venous crossing due to a shared adventitia
- atherosclerotic artery compresses the vein
- vein lumen narrows, increasing the intraluminal pressure and disturbing the laminar flow of blood
- resulting sheer stress causes endothelial damage and thrombus formation ending in vein occlusion
2. Central Retinal Vein Occlusion
- location: small passages of the cribriform plate
Acute Phase: increased pressure in veins and capillaries
1. Brush-shaped hemorrhages in NFL
2. Cystoid macular edema
- leakage of blood or fluid bet. INL (inner) and OPL (outer) layers
- appearance: soggy, fuzzy macula with loss of normal contour
- OCT: formation of cystoid spaces between INL and OPL
3. Serous/Exudative retinal detachment
- fluid accumulation in the subretinal space
- detachment of the NSR from the RPE
4. Hard exudates
- due to stretching of vein walls and escape of high molecular weight proteins and lipoproteins
- yellow to yellow-white depending on lipid content
- older: white due to decreased lipid content
- maybe discrete or confluent
- resorbed or phagocytosed by macrophages
How does retinal ischemia cause retinal edema?
- Increased VEGF production: EXTRAcellular fluid accumulation
- ischemic retina stimulates RPE cells, macrophages, Muller cells and ganglion cells to secrete VEGF
- larger ischemia = more VEGF
- VEGF: increases vascular endothelial permeability
+ rearrangement of actin filaments in endothelial cell cytoplasm
+ increased phosphorylation and deactivation of tight junctions
+ end-point: defective INNER BRB with escape of fluid from intravascular to extravascular space
- BRVO, CRVO, DM Retinopathy, AMD - Hydropic degeneration: INTRAcellular fluid accumulation
- loss of oxygen leads to a defective Na-K pump and breakdown of the integrity of the plasma membrane
- sudden influx of ions and water into the cells causes cellular swelling and death
- appearance: cotton-wool spots = retinal whitening or opacity
- HPN Retinopathy, BRAO, CRAO, Ocular Ischemic Syndrome
Ocular Ischemic Syndrome
- severe carotid artery occlusive disease (stenosis or occlusion) from atherosclerosis leading to ocular hypoperfusion
How does pericyte loss cause retinal edema?
Pericyte
- specialized contractile mesenchymal cell in CAPILLARIES
- analogue: smooth muscle cells in larger vessels
- function: regulates vascular tone and perfusion pressure
- NORMAL pericyte to endothelial cell ratio: 1:1
Diabetic Retinopathy
- hyperglycemia causes excessive formation of glycosylation products which can result in oxidative stress to the endothelium
- link between pericyte and endothelial cell disrupted causing pericyte hypoxia, apoptosis and loss
- retinal vascular walls become defective and leaky
- loss of vascular tone causes outpouchings in vessel walls
- pericyte to endothelial cell ratio: 1:4
- (+) central MICROaneurysms with surrounding circinate pattern of hard exudates: tiny outpouchings of the vessel walls becoming sites of fluid and lipoprotein leakage
How does inflammation cause retinal edema?
- Pathophysiology: inflammatory reaction causes increased production of VEGF, TNF-alpha, IL1 and other inflammatory mediators causing vascular dilation and leukocytosis
- Also present in DM retinopathy, CRVO and BRVO
- End-point: increased vascular permeability and leaky vessel walls
- Diagnostics:
1. Slit Lamp Biomicroscopy with contact fundus lens: - cystoid macular edema +/- hard exudates
2. Fundus Fluorescein Angiography - petaloid pattern: cysts showing leakage of fluorescein in the Henle’s layer (OPL) are arranged around a central dark zone
- treatment: Corticosteroids to subdue inflammatory reaction
Etiology:
- Location: Anterior Segment vs Posterior Segment
+ anterior: transvitreal transport of prostaglandins from the CB and iris to the retina
- Infection vs Primary Inflammatory Disease (Uveitis) vs Iatrogenic
Examples:
- TB uveitis
- HIV retinitis
- CMV retinitis: partial macular star-formation (hard exudates radiating from the fovea)
- Behcet’s Disease
- Foreign body reaction (parasites, intraocular FB)
- Post-cataract Surgery
How does abnormal vascular formations cause retinal edema?
Newly-formed vessels usually have compromised wall integrity resulting in:
- MACROaneurysms: large outpouching of vessel walls
- Hemorrhages: due to rupture of macroaneurysms
- Macular/Retinal edema
- Hard exudates: implies leakage of intravascular fluid and edema
- Exudative retinal detachment
- Blurring of vision: due to scattering and distortion of light as it encounters the edematous retinal layers with cystoid spaces
Examples:
1. Vascular malformations
2. Coats Disease
- idiopathic, unilateral, progressive telangiectatic neovascularization in the retina
3. Eales Diseases
- idiopathic occlusive vasculitis of the mid-peripheral retina characterized by retinal venous inflammation (periphlebitis), occlusion, and neovascularization
- hallmark: recurrent vitreous hemorrhage
4. Von-Hippel-Lindau
- mutations in the tumor suppressor gene VHL manifest as retinal hemangioblastomas
What are the causes of retinal hemorrhage?
- Increase intravascular hemorrhage
- Weakened vessel walls (aneurysms)
- Fragile neovascularization
- Trauma
- Iatrogenic
How does retinal hemorrhage cause blurring of vision?
- Blocking pathway of light to the foveal photoreceptors and causing scattering of light
- Iron in the blood is toxic to the photoreceptors
- Iron catalyzes conversion of hydrogen peroxide to hydroxyl radicals causing oxidative damage to the retina
What is the relationship between color of the hemorrhage and depth?
Color of hemorrhage differs according to location and chronicity.
Dark red
- outer layers nearer to sclera: RPE, PRL, ONL, OPL
- usually in the subretinal space between NSR and RPE
- pigmented RPE adds to the darker appearance of blood
- retinal vessels crossing over the hemorrhage
Bright red
- inner layers nearer to vitreous: NFL, GCL, IPL, INL
- retinal vessels DO NOT cross over the hemorrhage
Yellow or Gray
- old/chronic hemorrhage
- dehemoglobinized with time
What is the relationship of hemorrhage shape and location?
Shape is influenced by the arrangement of cellular structures or the lack of it wherein they are located.
- Pre-Retinal
- boat: settles on the most dependent area due to gravity
- extra-retinal neovascularization
- pre-retinal space: between NSR and vitreous
+ sub-hyaloid: between vitreous and ILM
+ sub-ILM: between ILM and NFL - Intra-Retinal
- flame, dot, blot: due to tight arrangement of cellular structures in the retinal layers
- diseased retinal vessels
- between NSR layers - Sub-Retinal
- amorphous, spreading, irregular, dome: follows circular contour of the RPE or choroid
- choroidal neovascularization
- sub-retinal space: between NSR and RPE - Choroidal
- almost similar in appearance to sub-retinal hemorrhage
- dome: follows circular contour of the choroid and sclera
- altered choroidal vessel hemodynamics or trauma
- locations:
+ sub-pigment space: at Bruch’s membrane between RPE and choriocapillaris
+ supra-choroidal space: between choroid and sclera
Discuss pre-retinal hemorrhage.
Location: Pre-Retinal Space
1. Sub-hyaloid: between vitreous and ILM
2. Sub-ILM: between ILM and NFL
Note:
1. If exact location could not be ascertained: OCT
2. No significant difference in clinical presentation of the two since both can cause BOV if it blocks path of light into the fovea
3. Important to differentiate exact location because using ND-YAG laser to treat blood in the Sub-ILM will just cause blood to escape into the Sub-hyaloid space
Phases:
1. Acute: large red blob like an egg yolk
2. Sub-Acute: liquefies and settles down after a few days in the most dependent area due to gravity –> boat-shaped
Causes:
1. Extra-retinal neovascularization
2. Valsalva retinopathy
3. Leukemic retinopathy
4. Diabetic retinopathy
5. Macroaneurysm
6. Trauma
7. Shaken Baby Syndrome
Discuss intra-retinal hemorrhage.
Flame-Shaped
- tracks along the axons of the NFL
- comes from ruptured superficial BVs due to increased intraluminal pressure resulting from occlusion of the central retinal vein at the level of the cribriform plate
- periphery: less flame-shaped due to retinal thinning
- e.g. CRVO/BRVO, HPN retinopathy, NPDR, Vasculitis
Blot
- located in the INL or OPL (junction of inner and outer retina)
- round, uniformly shaped hemorrhage limited in size by the tight arrangement of retinal layers
- disruption of deeper capillary networks
- does not usually cause BOV unless located in the fovea
- e.g. CRVO/BRVO, HPN retinopathy, NPDR, Vasculitis
Dot
- also located in the INL or OPL
- disruption of deeper capillary networks
- does not usually cause BOV unless located in the fovea
- either due to:
1. True pinpoint hemorrhage
+ locked by tight arrangement of cells in the retina
+ FFA: HYPOfluorescent
2. Microaneurysms
+ small outpouchings of retinal capillaries or arterioles
+ FFA: HYPERfluorescent
Discuss sub-retinal hemorrhage.
- sub-retinal space: between PRL and RPE
- shape: amorphous, spreading, irregular, dome-shaped following the circular contour of the RPE or choroid
- difficult to differentiate with choroidal hemorrhage based on appearance
- cause: disruption of fragile choroidal neovascularizations growing into the RPE and PRL
- vision is disrupted if macula is involved because:
1. iron is toxic to photoreceptors
2. iron catalyzes conversion of hydrogen peroxide to hydroxyl radicals causing oxidative damage - FFA: leakage of dye from retinal vessels surrounding the area of hemorrhage
- e.g. AMD, Idiopathic Polypoidal Choroidal Vasculopathy, Coat’s Disease
Discuss choroidal hemorrhage.
Locations:
1. Sub-Pigment Space
+ between RPE and choroid in the Bruch’s membrane
2. Supra-Choroidal Space
+ between choroid and sclera
+ rarer
- dome-shaped: follows circular contour of the choroid or sclera
- almost similar in appearance to sub-retinal hemorrhage
- FFA: retinal vessels intact and crossing over the areas of hemorrhage
- causes:
1. disruption of RPE-choroidal attachment (trauma)
2. disruption of fragile choroidal neovascularization (AMD, Coat’s Disease)
3. sudden decompression in a hypertensive patient causing altered choroidal hemodynamics
What are the different retinal membranes?
PRE-Retinal Membranes: between ILM and vitreous
1. Epiretinal membranes: AVASCULAR
2. Proliferative vitreoretinopathy: AVASCULAR
3. Fibroproliferative membranes: VASCULAR
SUB-Retinal Membranes:
4. Chronic retinal detachment bands: AVASCULAR
- between PRL and RPE (subretinal space)
5. Choroidal neovascular membranes: VASCULAR
- between PRL and RPE (subretinal space) or between RPE and choroid in the Bruch’s membrane (subpigment space)
How does retinal membranes cause blurring of vision?
- Inducing retinal edema and thickening
- Retinal surface distortion causing metamorphopsia or image distortion
- Macular detachment
- Blockage of path of light into the photoreceptors
What are Epiretinal Membranes and risk factors for its formation?
- thin sheets of AVASCULAR fibrous tissue that develop on the surface of the macula above the ILM
- white to transparent
- causes BOV by:
1. Retinal edema and thickening causing light scattering
2. Retinal wrinkling causes metamorphopsia - risk factors:
1. Myopia: long AL causes retinal detachment
2. Aging: vitreous liquefaction and detachment
3. Narrow retinal artery diameter
4. Previous cataract surgery: iatrogenic fibrosis
5. Diabetic retinopathy
6. Hypercholesterolemia
7. Idiopathic: vitreoretinal traction causing complete posterior vitreous detachment ~ 95% of cases - clues:
1. Cellophane Maculopathy: (+) sheen similar to glass
2. Macular Pucker/Surface Wrinkling Retinopathy: wrinkling and distortion of the perifoveal vessels
3. Macular Fibrosis - treatment: Surgical removal of membranes to restore the foveal pit
How does Epiretinal membranes form?
Cause: Physical disruption of the ILM
- Posterior Vitreous Detachment: traction of the vitreous causes microdehiscence in the ILM surface
Stage 1: Microglial cells spread over the ILM surface, proliferate and interact with hyalocytes and laminocytes in the vitreous cortex
- activated into fibroblasts which deposit fibrin over the retinal surface
- minor and MICROscopic changes
- INTACT foveal pit
Fibrin contraction causing traction and distortion of the retinal surface: MACROscopic changes
Stage 2:
- Loss of foveal pit (FIRST change)
- Stretching of the ONL (Henle’s Layer)
Stage 3:
- Retinal layers discernible due to edema and thickening (SECOND change)
Stage 4:
- Retinal wrinkling and disruption of layers (THIRD change)
Differential: Proliferative Vitreoretinopathy
- also AVASCULAR
- associated with a retinal TEAR and RRD
- due to RPE differentiation
- NON-contractile
What is Proliferative Vitreoretinopathy?
- Formation of proliferative, contractile AVASCULAR membranes in the vitreous and on both sides of the retina, resulting in tractional retinal detachment with fixed retinal folds.
- MCC of retinal re-detachment post-retinal surgery
- Appearance:
+ acute/fresh: smooth surface
+ chronic: wrinkled “star fold” appearance - BOV due to retinal detachment NOT the PVR
- Seen in: Advanced/Proliferative DM Retinopathy
- Treatment: surgical disruption of membranes
+ high rate of retinal reattachment
+ reattachment not an assurance to recovery of visual function likely due to the chronic macular detachment
How does Proliferative Vitreoretinopathy form?
Cause: Chronic Rhegmatogenous Retinal Detachment
- comparable to an aberrant wound-healing process following tissue insult, specifically, retinal detachment
- nidus for epi/subretinal membrane formation through induction of ischemia and apoptosis arising from separation of the NSR from the choroidal blood flow
- apoptosis triggers a break down in the BRB facilitating the influx of inflammatory mediators and growth factors
- this induces RPE de-differentiation into fibroblast-like cells which migrate through the tear into the inner retinal surface and vitreous where they secrete ECM
- NO inherent contractile ability: contraction happens when fibroblast-like cells interact with the ECM
- contraction of membranes leads to retinal traction and recurrent retinal detachment
- INTRAretinal PVR: due to activated glial tissue that proliferates within the retina causing retinal shortening
Content: Fibroblast-like cells + extracellular matrix
- similar to glial cells on the ILM and RPE cells
Differentials:
1. Subretinal Fibrotic Bands
- etiology unknown
- thick ROPE-like fibrous tissue BUT found in the SUB-retinal space
- also associated with difficulty in reattachment of retina
2. Epiretinal Membranes
- also AVASCULAR
- NOT associated with a retinal tear and RRD
- ONLY the ILM is damaged
- due to microglial differentiation (RPE is intact)
- inherently CONTRACTILE
What are Fibroproliferative Membranes?
- formation of abnormal proliferating blood vessels WITH supporting fibrous membranes extending from the retina to the vitreous
- appearance:
1. white lace-like sheets of membrane +
2. neovascularization: fine, incompletely-formed blood vessels that do not follow the normal dichotomous pattern located only in the membranes
3. ischemic peripheral retina - BOV due to macular traction by the membrane resulting in surface distortion and detachment
- DDX:
1. DM Retinopathy
2. Vaso-occlusive diseases (CRVO,BRVO, OIS)
3. Eales Disease
4. Occlusive Vasculitis
5. Retinopathy of Prematurity
6. Sarcoidosis
7. Sickle Cell Disease
How does Fibroproliferative Membranes form?
Cause: Retinal Ischemia
- signals the increased production of VEGF by RPE, Muller cells, Ganglion cells and macrophages
- VEGF binds to the endothelium of venules causing its activation and secretion of enzymes degrading the BM
- Compromised BV walls causes leakage of inflammatory mediators into the extravascular space with proliferation and migration of activated endothelial cells
- Grow into the vitreous which serve as the scaffolding in which ECM is deposited and remodelled to form fibrous membranes with new blood vessels
Phases:
1. Acute Phase
- (+) thickened white opaque membranes
- (+) abundant vessels in the membrane
2. Burnt-out Phase
- ischemic retina neutralized by supply from neovascularization
- VEGF levels decrease
- thinned out translucent membranes
- sparse or no vessels in the membrane
What are Choroidal Neovascular Membranes?
- Choroidal membrane formation WITH neovascularization located either in the:
1. Subretinal Space: between PRL and RPE
2. Subpigment Space: between RPE and choroid in the Bruch’s membrane - Induced by ischemia causing increased VEGF levels
- Similar to FPM but:
1. new vessels arise from choroid NOT retinal vessels
2. yellowish color due to pigmentation in the RPE
3. intact retinal vessels seen crossing over membranes - BOV due to:
1. retinal surface and layer distortion causing metamorphopsia
2. macular edema and thickening
3. central serous retinopathy: NSR detachment at the macula due to subretinal fluid formation
4. photoreceptor death due to detachment from RPE - signs of increased disease activity:
1. OCT: macular thickening/edema
2. SL + contact fundus lens: subretinal hard exudates and subretinal hemorrhages - treatment: intravitreal Bevacizumab (anti-VEGF)
What are the different abnormal vascular changes to be noted in the retina?
- Vessel dilation
- Vessel atrophy
- Atherosclerotic changes
- Vessel remodelling
- Vasculitic changes
- Neovascularization
