Joseph Sowka, Od, Faao

discussions in

Posterior Segment Disease

JOSEPH SOWKA, OD, FAAO

FT. LAUDERDALE, FL

ALAN G. KABAT, OD, FAAO ANDREW GURWOOD, OD, FAAO

MEMPHIS, TN PHILADELPHIA, PA

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:

Identify the pathophysiology, clinical presentation and management of central retinal vein occlusion;
Identify the pathophysiology, clinical presentation and management of central retinal artery occlusion;
Identify the pathophysiology, clinical presentation and management of diabetic retinopathy;
Identify the pathophysiology, clinical presentation and management of age-related macular degeneration;
Discuss the newest pharmacologic entities used to manage choroidal neovascularization;
Identify the pathophysiology, clinical presentation and management of central serous chorioretinopathy.

CENTRAL RETINAL VEIN OCCLUSION

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

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 retrobulbarintranerve 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 RetinalVein 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

Decreased size of foveal avascular zone

Hypoperfusion from retinal ischemia or blood blockage

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
Polyarteritisnodosa
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)

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

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
Choroidalneovascular 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
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:

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

Laser photocoagulation
Photodynamic therapy (PDT)
Intravitreal steroid injection
Anti-angiogenic factors
Avastin, Lucentis, Eyelea
UV protection
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)

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)