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)
