JOSEPH SOWKA, OD, FAAO
FT. LAUDERDALE, FL
jsowka@nova.edu
ALAN G. KABAT, OD, FAAO
MEMPHIS, TN
alan.kabat@alankabat.com
ANDREW GURWOOD, OD, FAAO
PHILADELPHIA, PA
agurwood@salus.edu
Course Description: Case presentations provide a springboard for in-depth discussion of several
challenging posterior segment conditions. Emphasis is placed on understanding the
presentation, pathophysiology and management of the various clinical entities.
Learning Objectives/Outcomes: At the conclusion of this course, the attendee will be able to:
1. Identify the pathophysiology, clinical presentation and management of central retinal vein
occlusion;
2. Identify the pathophysiology, clinical presentation and management of central retinal artery
occlusion;
3. Identify the pathophysiology, clinical presentation and management of diabetic retinopathy;
4. Identify the pathophysiology, clinical presentation and management of age-related macular
degeneration;
5. Discuss the newest pharmacologic entities used to manage choroidal neovascularization;
6. Identify the pathophysiology, clinical presentation and management of central serous
chorioretinopathy.
CENTRAL RETINAL VEIN OCCLUSION
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Thrombotic phenomenon: Properties of the blood and central retinal vein act in concert to
cause thrombotic occlusion. Causes partial or complete blockage of venous return
 Vein inflammation
 Vascular flow and/or vessel wall abnormalities stimulate vein thrombosis
 Hypercoagulability states, elevated viscosity, and systemic states of decreased
thrombolysis promote thrombus formation. (i.e., changes in blood constituents)
 Turbulent blood flow causing thrombus formation at lamina
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 Laminar constriction site is the nidus for occlusion. Intraluminal pressure of the vein
decreases, rendering it susceptible to collapse. Compression by an arteriolosclerotic
CRA further affects flow and thrombus formation. CRV and CRA share common sheath
passing through lamina cribrosa.
 External factors such as increased IOP in POAG and papilledema (causing increased
pressure in the optic nerve sheath) may cause further compression and contribute to
occlusion.
Other factors that result in compression include: orbital tumor and abscesses, cavernous
sinus thrombosis, and retrobulbar intranerve sheath injection.
Systemic diseases influence thrombus formation through:
 External compression
 Primary thrombus formation (Antiphospholipid antibodies, hypercoagulable states,
thrombogenic conditions)
 Degenerative or inflammatory disorders of the vein itself
Central Retinal Vein Occlusion: Symptoms
 Blurred vision
 Loss of visual field
 Disturbances in visual field
 Photopsia, in rare cases
 Rarely asymptomatic
 Smaller occlusions (BRVO, HRVO) may be asymptomatic
Central Retinal Vein Occlusion: Clinical Signs
 Dilated, tortuous veins
 Deep and superficial hemorrhages
 Disc edema
 Macular edema
 Posterior (uncommon) and anterior segment (more common) neovascularization
 Collateral vessels
 Pre-existing vascular anastomoses in vascular area
 Collateral circulation is present to some degree in all organ systems. The extent to
which collateral circulation prevents ischemia depends upon the time frame of the
occlusion and the extent of collateral circulation for that organ and that individual.
 Bypasses vascular bed occlusion
 Beneficial- does not leak NaFl on FA
 Larger caliber than neovascularization
 Most commonly involves a communication between the retinal veins and the choroidal
veins in response to retinal vascular occlusion
 Collaterals of the disc are more common than in the retina for CRVO; other vascular
occlusions are more likely to have retinal collateral vessels.
Clinical Pearl: Acute CRVO may cause angle closure glaucoma due to hemorrhagic choroidal
expansion.
Central Retinal Vein Occlusion: Causes of Vision Loss
 Macular edema: this is the main cause of vision reduction in CRVO. Potentially reversible or
treatable
 RPE atrophy: occurs secondary to chronic macular edema and results in permanent
vision reduction. This is the reason that macular edema just can’t be left to persist
indefinitely
 Macular ischemia: presents with severe, irreversible vision loss. This is often the cause
when the vision loss is much more dramatic than the clinical picture.
 Retinal hemorrhage (common)
 Vitreous hemorrhage (rare)
 Tractional retinal detachment (rare)
 Neovascular glaucoma (common) in ischemic cases
 Vascular endothelial growth factor (VEGF) is released by hypoxic retina to stimulate growth
of new blood vessels (neovascularization)
 VEGF is the source for edema and neovascular disease. It also destabilizes vascular
membranes leading to fluid leakage and edema.
Central Retinal Vein Occlusion: Non-ischemic (Perfused)
 Majority of cases (about 70%)
 Acuity >20/200- low risk for neovascularization unless converts to ischemic form
 Good prognosis
 5-20% progress from non-ischemic to ischemic CRVO
 83% of ‘indeterminate’ CRVO convert to ischemic CRVO over 4 months
 Over 3 years, 34% of perfused eyes progressed to ischemic CRVO
Central Retinal Vein Occlusion: Ischemic (Non-Perfused)
 Minority of cases (about 30%)
 Acuity < 20/200- high risk for neovascularization
 Initial VA is typically count fingers
 Extensive superficial hemorrhages
 Multiple CWS
 Poor capillary perfusion (10 or more cotton wool spots or 10 DD capillary non-perfusion on
fluorescein angiography)
 Turbid, orange, edematous retina
 Poor visibility of choroidal detail
 (+) RAPD
 Poor prognosis
 Very high risk of neovascularization or the iris and angle and a low/ moderate risk of disc/
retinal neovascularization.
Central Retinal Vein Occlusion: Systemic Considerations
 Hypertension*
 Diabetes mellitus*
 Elevated homocystein levels*
 Cardiovascular disease (some studies feel that the CRVO pt. has no greater incidence of
cardiovascular disease than age matched controls)
 Hyperviscosity syndromes:
 Hypergammaglobulinemia, paraproteinemia, hyperfibrinogenemia, cryofibrinogenemia
 Hyperviscosity states:
 Malignancy, paraproteinemia, nephrotic syndrome, chronic lung disease, Behcet's
disease.
 AIDS: Infectious vasculitis
 Collagen vascular disease:
 Lupus and lupus-like diseases- Antiphospholipid antibodies, common in these diseases,
interfere with endothelial cells and prevent interaction with platelets and
anticoagulants, thus increasing thrombus formation.
 Primary antiphospholipid antibody syndrome
 Same reasons as collagen vascular disease, but phenomenon is primary entity
 This is the most common cause of CRVO in young healthy adults (under age 50). Very
important
 Syphilis:
 Infectious vasculitis
 Sarcoid:
 Localized vein inflammation
 Polycythemia (hyperviscosity)
 Leukemia (blood dyscrasia-hyperviscosity)
 Autoimmune disease:
 Infectious vasculitis and antiphospholipid antibodies
 Oral contraceptive use (causes a potentially hyperviscosity state)
 Head injuries
 Carotid artery disease:
 Slow flow and increased viscosity
 Hyperlipidemia
 Mitral valve prolapse
 Migraine
 Pressure profusion abnormalities at ONH
 Retrobulbar compression
 Sickle cell disease (blood dyscrasia- hyperviscosity) - elevated hematocrit
 Increased erythrocyte aggregation
 Decreased plasma volume (causing increased viscosity and erythrocyte aggregation)
*Most experts feel that only these conditions must be examined for in the typical elderly vein
occlusion patient and that more detailed evaluations should be reserved for special cases
such as bilateral cases or in patients who are young (<50 yrs). In younger patients, testing
for antiphospholipid antibodies is important.
Central Retinal Vein Occlusion: Management
 Fluorescein angiography: questionable usage. Not appropriate early in the course as
fluorescein is blocked by extensive hemorrhage. Possible angiographic features include:
 Macular and retinal hyperfluorescence from edematous leakage
o Decreased size of foveal avascular zone
 Hypoperfusion from retinal ischemia or blood blockage
o Increase size of foveal avascular zone
 Delayed venous filling time
 Pupil testing
 Retinal photography
 Gonioscopy to rule out angle neovascularization
 IOP measurements
 Co-management with primary care physician to identify and treat any underlying systemic
disease
 Referral to retinologist if NVD, NVE, NVI, NVG (for PRP), or macular edema develops. Results
of CRVO Study- N and M studies:
 Prophylactic PRP to prevent neovascularization inappropriate; therapeutic PRP once
neovascularization develops very effective
 Laser photocoagulation of macular edema (as for diabetic macular edema) not
beneficial in cases of CRVO and hence not done
 Newest treatments: intravitreal injection of steroids and anti-VEGF drugs (Avastin, Lucentis)
for macular edema. Stabilizes vascular membranes and reduces vascular permeability.
Very effective (both for macular edema and neovascularization)- Avastin is off label use.
 EYLEA (aflibercept) is a recombinant fusion protein consisting of portions of human VEGF
receptors 1 and 2. It is considered a VEGF-trap in that it causes VEGF to bind with it rather
than retinal VEGF receptors and reduces retinal effects of VEGF
 May have higher affinity for VEGF-A, thus potentially more therapeutic effect and fewer
injections
CENTRAL RETINAL ARTERY OCCLUSION
Central Retinal Artery Occlusion: Clinical Picture
 Painless, sudden loss of monocular vision
 Vision is count fingers to hand motion to no light perception
 Retinal edema causing white appearance to fundus
 Mean age is 60's
 Cherry red macula due to underlying choriocapillaris perfusion and lack of overlying
structures within this area.
 Optic atrophy ensues eventually
Central Retinal Artery Occlusion: Pathophysiology
 Etiology is typically emboli from carotid artery or heart lodging in central retinal artery at
laminar constriction. Emboli of cardiac origin are more likely than emboli of carotid origin
to cause artery occlusion
 Other possible etiologies:
 Giant cell arteritis (GCA)
 Intraluminal thrombosis\
 Hemorrhage under atherosclerotic plaque
 Vasospasm
 Dissecting aneurysm
 Hypertensive arteriolar necrosis
 Circulatory collapse
Central Retinal Artery: Heroic Treatment
 Paracentesis to reduce IOP and allow less compression on CRA to allow emboli to pass
further.
 Carbogen
 Patient is hospitalized and breathes Carbogen 5-10 minutes every hour for 24 hours.
Using pure oxygen is worse because there will be a reflex constriction of the blood
vessels. Carbogen increases CO2 levels, which causes a rebound vasodilation.
 Hyperbaric oxygen therapy
 Some anecdotal success, but has to be done immediately and this is rarely possible
 Digital massage to transiently elevate IOP and have rebound IOP decrease and subsequent
arterial dilation
 Breathing into a brown paper bag in order to increase blood CO2 levels.
 Fibrinolytic agents (clot-busters: urokinase, streptokinase)
 1-24 hour window of opportunity
 Treatment vs no treatment: 1/4 line difference in Snellen acuity. Overall, heroic measures
do not affect final visual acuity (only anecdotal success).
 If the cause is inflammatory thrombosis from GCA, these heroic measures will do nothing
because there is no embolus to dislodge.
Central Retinal Artery Occlusion: Systemic Considerations
 General atherosclerosis
 Arterial hypertension
 Diabetes
 Carotid atherosis
 Cardiac/ cardiovascular disease
 Giant cell arteritis
 Infectious endocarditis
 Cardiac valvular disease
 Rheumatic heart disease
 Mitral valve prolapse
 Mural thrombus after MI
 Atrial myxoma
 IV drug use
 Lipid emboli
 Pancreatitis
 Purtscher's retinopathy
 Head, neck, retrobulbar corticosteroid injections
 HZV
 Migraine
 Malignancy
 Trauma
 Hyperlipidemia
 Syphilis
 Mucormycosis
 Hemoglobinopathy
 Sickle cell disease
 Oral contraceptives
 Platelet and clotting factor abnormalities
 Systemic lupus erythematosus
 Antiphospholipid antibodies from lupus cause prolonged partial thromboplastin time
 Primary antiphospholipid antibody syndrome
 Polyarteritis nodosa
 Homocystinuria
 Pregnancy
 Optic disc drusen
 Prelaminar compression of CRA, leading to turbulence and thrombus formation
Central Retinal Artery Occlusion: Complications
 CVA
 Myocardial infarction: main cause of death
 Low survivorship: 9 year mortality of 56% (compared to 17% in age matched group)
 Neovascularization uncommon because tissue abruptly dies, not slowly starves as in vein
occlusions
Central Retinal Artery Occlusion: Management
 Stat ESR/ C-reactive protein if over 60 years old
 Co-management with primary care physician to identify and treat any underlying systemic
disease
 Internal medicine/ Cardiology referral
 Monitor for complications Q3mos
 Heroic measures generally not helpful
DIABETIC RETINOPATHY
Diabetic Retinopathy: Pathophysiology
 Thickening of capillary basement membrane (which may lead to closure)
 Prevents pericytes from being in contact with endothelial cells
 May increase leakage potential
 Pericyte dropout
 Increases leakage potential
 Leads to breakdown of blood-retina barrier
 Focal loss leads to bulging of capillaries and microaneurysm formation
 Weakened capillaries
 Allows for microaneurysm formation and leakage
 Dot & blot hemorrhages- inner nuclear and outer plexiform layers- deep
 Flame shaped hemorrhages- NFL (superficial)
 Macular edema: leaking aneurysms and capillaries in macular area
This is the most common cause of visual reduction in diabetic retinopathy.
However, this is not the most common cause of severe, irreversible vision reduction
(that would be anterior and posterior segment neovascularization with subsequent
neovascular glaucoma and tractional retinal detachment, as well as macular
ischemia)
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Fluid leakage and lipid accumulation: exudate
Capillary closure: hypoxia
 Leads to intraretinal microvascular abnormalities (IRMA), cotton wool spots
(CWS), neovascularization, vitreous hemorrhage, tractional retinal detachment
and release of Vascular Endothelial Growth Factor (VEGF) which increases
vascular permeability and retinal edema
Diabetic Retinopathy: Distinctions and Classifications
 Non-Proliferative Diabetic Retinopathy (NPDR) - according to Early Treatment of Diabetic
Retinopathy Study (ETDRS)
 Numerous fundus finding exclusive of neovascularization
 Proliferative Diabetic Retinopathy
 Anything also found in NPDR
 Neovascularization
Diabetic Maculopathy
 Can occur in any stage in NPDR or PDR
 Hard exudates
 Dot & blot hemorrhages
 CSME
 CSME is the only treatable form of diabetic maculopathy
 Poor prognosis if:
 Hard exudates in fovea
 Poor initial acuity
 Longstanding duration
 Broken perifoveal capillary net
 Good prognosis if:
 Exudates are away from foveal avascular zone
 Good acuity
 Short duration
 Intact perifoveal net
Treating Diabetic Macular Edema: Early Treatment Diabetic Retinopathy Study (ETDRS):
 FA to identify leakage area
 Argon laser
 CSME only treated
 Moderate vision loss = doubling of the visual angle (e.g., Going from 20/20-20/40)
 Focal photocoagulation of CSME reduces risk of moderate vision loss by 50%
 Treat all leaking microaneurysms more that 500 microns from the fovea
 Focal microaneurysm leakage on FA - focal photocoagulation
 Diffuse leakage on FA - grid photocoagulation
 Re-evaluate in 2-4 mos (need for additional treatment common)
 Treat CSME before PRP (if needed) as PRP can worsen CSME
 Cataract extraction can worsen CSME
Newest treatments for Diabetic Macular Edema
 Intravitreal injection of steroids for macular edema.
 Stabilizes vascular membranes and reduces vascular permeability.
 Intravitreal injection of anti- antigenic (anti-VEGF) drugs such as Avastin (bevacizumab) and
Lucentis (ranibizumab)
 Stabilizes vascular membranes and reduces vascular permeability by down regulating
VEGF (which increases vascular permeability).
 EYLEA® (aflibercept)
 VEGF-trap
 Binds to VEGF
WET (EXUDATIVE) AMD: CHOROIDAL NEOVASCULARIZATION
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8-20% of cases of AMD are wet (actually, up to 12% may be unknown, according to
Framingham study)
Presence of exudate, hemorrhages, or suspected gray-green lesion as this implies that
choroidal neovascularization and wet AMD has formed. However, hemorrhage or
exudation may obscure part or all of CNVM
 Choroidal Neovascularization
 Bruch's disruption
 Diffuse thickening of Bruch’s with soft drusen which predisposes to breaks in
Bruch’s membrane
 Presence of VEGF enhances development
 Other diseases can cause Bruch’s disruption
 RPE/ Bruch's breaks
 Diffuse thickening with soft drusen predisposes Bruch’s membrane to breaks
 Soft drusen often precursor, but not always
 Chronic Inflammation Theory
 Higher number of lymphocytes, macrophages, fibroblasts found in Bruch’s
membranes of patients with AMD
 Inflammation causes breaks in Bruch’s membrane?
 Implication are not yet understood
 Choroidal neovascular membrane (CNVM) infiltrates from choriocapillaris
 Under the RPE and sensory retina
 RPE detachment with turbid fluid or blood may represent CNVM
 Round/oval gray-green elevation
 Don’t look only for gray-green appearance. Look for fluid and blood.
 Associated findings:
 Lipid exudate
 Blood
 Sensory RD
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Classic CNVM
 Well defined membrane on angiogram
 About 10% of cases
 Occult CNVM
 About 90% of cases
 Ill defined membrane on angiogram
 CNVM may be subfoveal, juxtafoveal (1-199 microns from center of macula), or
extrafoveal (> 200 microns from center of macula
 FA and possibly indocyanine green (ICG) imaging: hot spots with late spread of
hyperfluorescence.
 Must get FA within 72 hrs because membranes can grow 10 microns/day;
Suspected/actual CNVM is an ocular urgency
 ICG may be indicated to better visualize outline of membrane
 ICG dye absorbs and emits fluorescence in the near IR spectrum
 Better able to penetrate hemorrhage, melanin, fluid
 Better for occult CNVM detection
Hypoxia and VEGF
RPE tear
Serous RPE detachments
Hemorrhagic RPE/sensory retinal detachments
10% risk of wet AMD in 4.3 yrs if pt. has bilateral macular drusen
90% of pts. who are legally blind from AMD have wet AMD
VA 20/200-20/800
Wet (Exudative) AMD: Disciform Scarring:
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Fibrovascular material following CNVM development
Most cases of CNVM progress to this stage
Replaces most of sensory retina, RPE
May continue to grow and invade new areas
Results in death of tissue and severe visual loss
Yellow-brown-black (RPE hyperplasia)
 Surgical excision may modestly improve vision
Wet AMD: Management
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Laser photocoagulation
Photodynamic therapy (PDT)
Intravitreal steroid injection
Anti-angiogenic factors
 Avastin, Lucentis, Eyelea
UV protection
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Anti-oxidant vitamin therapy
Macular drusen - home amsler
Low vision consult
Wet AMD: Anti-angiogenic Therapy
Macugen (pegaptanib sodium)
 Oligonucleotide with high affinity for VEGF, preventing its uptake by endothelial receptors
 Intravitreal injection q 6 weeks
 Historical at this point. FDA approved and available but not used
Lucentis (ranibizumab)
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Recombinant anti-VEGF antibody fragment that binds to VEGF
Intravitreal injection q 4 weeks
FDA approved and more successful than Macugen
 94% of eyes with stable or improved vision at 98 days
 On average, two lines of vision gained
 26% of eyes improved three or more lines at 98 days
EYLEA (aflibercept)

Recombinant fusion protein consisting of portions of human VEGF receptors 1 and 2. It is
considered a VEGF-trap in that it causes VEGF to bind with it rather than retinal VEGF
receptors and reduces retinal effects of VEGF
 May have higher affinity for VEGF-A, thus potentially more therapeutic effect and fewer
injections
Avastin (bevacizumab)
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
Anti-colon cancer drug; accidentally found when patients with wet AMD patients
undergoing chemotherapy reported improved vision
Not FDA approved for this use (monthly intravitreal injection for AMD), but very popular
and economical
CENTRAL SEROUS CHORIORETINOPATHY (CSC)
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Sometimes known as idiopathic central serous chorioretinopathy (ICSC)
Serous retinal or pigment epithelial detachments in macular area
Loss of foveal reflex
Transient and potentially recurrent
 Recurrence rate is 20-30%
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Breakdown of RPE cells allowing seepage to occur into sensory retina
Typically, a focal conduit through RPE into sensory retina
 Theorized to occur secondary to vasomotor instability or sympathetic nervous excitation
Predisposing conditions such as drusen are absent
RPE detachment can commonly occur simultaneously
 RPE separates from Bruch's; retina separates from RPE
Due to RPE disruption, there may be associated RPE hyperplasia
Male: female 10:1
20-50 yrs (mid 30's). This should not be diagnosed in a patient over age 55 yrs
 Must look for CNVM in older pts.
Type A personality
Caucasian
FA appearance: smokestack with 1 or 2 well demarcated cavities.
 Sensory RD is diffuse
 RPE detachment is well demarcated
Presents with decreased VA, metamorphopsia, hyperopic shift
Highly associated with steroid use (of all kinds)
PDT has shown some decent effect; anti-VEGF treatment has had only limited success
Central Serous Chorioretinopathy: Management
 Home amsler and observation
 Discontinue all steroids
 Excellent prognosis
 60% recover 20/20
 1-6 mos course
 Self-limiting
 RPE decompensation may complicate matters. "sick RPE syndrome"
 Focal dysfunction of RPE resulting in slow, chronic oozing through RPE
 Retina and RPE remain flat
 Poor prognosis
 Decreased VA with RPE changes
 Possible CNVM formation
 Direct photocoagulation to leaking areas in severe or non-remitting cases
 Treatment does not affect rate of recurrence or final acuity; it only hastens the process
 Laser may aggravate pre-existing choroidal neovascular membrane or ICSC. This is ‘like
putting fertilizer on a weed’.