Download Central Retinal Artery Occlusion: Pathophysiology

RETINAL GRAND ROUNDS:
Diana Shechtman, O.D., FAAO
Associate Professor of Optometry
Nova Southeastern University
[email protected]
Joseph Sowka, O.D., FAAO, Diplomate
Professor of Optometry
Nova Southeastern University
[email protected]
Disclosure: Dr. Sowka is a Speaker Bureau Member for the following companies: Alcon, Carl
Zeiss Meditec, and Vision Service Plan (VSP). Dr. Sowka has received lecture support from
Allergan. Dr. Sowka has no financial interest in any product mentioned.
Dr. Shechtman has received lecture honoraria or served on an advisory boards or speaker
bureaus for the following companies: VSP, Sightpath, Alcon, Allergan, B&L, Essilor, ZeaVision
& CZM. Dr. Shechtman has no direct financial interest in any of the products or instrumentation
mentioned in this presentation.
Dear Colleagues:
This course is designed to bring you the latest information regarding management of retinal and
uveal conditions. We have included in our handout some key points regarding these clinical
entities to satisfy the course requirements, however we vastly prefer to have an engaging
dialogue with our audience – this cannot unfortunately be encapsulated in a handout. Please
realize that these “notes” are neither exhaustive nor organized consistent with our presentation.
They simply represent some facts about the entities which we may or may not cover.
We hope you understand our philosophy and enjoy the program!
Systemic Manifestations of Hypertension
 Arteriolosclerosis: applies to arterioles
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Atherosclerosis: applies to medium and large muscular arteries
Arteriosclerosis: broad term meaning thickening of vascular walls
Thrombus: aggregation of fibrin, platelets, etc. on vessel walls (mural thrombi as found in
atrial fibrillation) or ulcerated artery plaque
Emboli: A loose piece of thrombus flowing in vascular system
Hypertensive Retinopathy
 Arteriolosclerotic vessel changes
 Some classification schemes include vessel changes in hypertensive retinopathy and
others don’t
 Elschnig’s spots – subtle choroidal infarcts
 CWS
 Flame shaped hemorrhages
 Macular edema (rare)
 Macular star/ ring of exudates
 Disc edema
Clinical Pearl: A patient manifesting disc edema from hypertension has malignant
hypertension and this should be considered an emergency. Patients who develop disc
edema from hypertension typically have BP in the 250/150 mm hg range.
Clinical Pearl: In order for CWS to form from hypertension, autoregulatory
mechanisms must be overcome. For this to happen, the patient must have at least 110
mm hg diastolic readings.
Hypertensive Retinopathy: Clinical Course
 Arteriosclerotic changes persist
 Hypertensive changes can resolve after reduction of systemic blood pressure
Clinical Pearl: Hypertensive retinopathy is frequently confused with diabetic
retinopathy. Remember: Hypertensive retinopathy is mostly a dry eye condition
(multiple CWS, rare hemorrhage, edema, and exudates) whereas diabetic
retinopathy is a wet eye condition, (rare CWS, extensive hemorrhages, edema,
and exudates).
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
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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 retrobulbar intranerve sheath injection.
Systemic diseases influence thrombus formation through:
1. External compression
2. Primary thrombus formation (Antiphospholipid antibodies)
3. Degenerative or inflammatory disorders of the vein itself
Central Retinal Vein Occlusion: Symptoms
 Blurred vision
 Loss of 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
Clinical Pearl: Acute CRVO may cause angle closure glaucoma due to hemorrhagic
choroidal expansion.
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Central Retinal Vein Occlusion: Causes of Vision Loss
 Macular edema: this is the prime 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
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: Ischemic (Non-perfused) Vs. Non-ischemic (perfused)
 Non-ischemic CRVO will have more dot & blot hemorrhages whereas ischemic will have
retinal details obscured by flame-shaped hemorrhages. The presence of cotton wool spots
indicates areas of retinal infarct and ischemia. The retina in non-ischemic CRVO will be
relatively normal whereas it will be orange, turbid, edematous, and sick looking in ischemic
CRVO.
 Fluorescein angiography: 10 or more disc diameters of retinal non-perfusion on FA define
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ischemic CRVO. This does not guarantee that the patient will develop neovascular
complications, but the odds are that they will. They may develop neovascularization with less
ischemia than this.
Pupil defects: the ischemic CRVO will have a relative afferent pupillary defect due to
destruction of the retina due to non-perfusion. Non-ischemic CRVO will typically do not
have an APD.
Visual acuity: Non-ischemic CRVO typically has acuity > 20/200; ischemic CRVO typically
has acuity worse than 20/200 (i.e., finger counting at several feet).
Clinical Pearl: Most clinicians generally equate an ophthalmoscopically visible CWS with
one DD of non-perfusion.
Clinical Pearl: Ischemic CRVO typically has vision in the CF range and an afferent pupil
defect. If vision is better than 20/200, and there is no APD, then it most likely is nonischemic. However, it may convert over time.
Brain teaser: Why is neovascularization of the anterior segment so prevalent in ischemic
CRVO while posterior segment neovascularization is so rare?
Central Retinal Vein Occlusion: Systemic Considerations
 Hypertension*
 Diabetes mellitus*
 Elevated homocysteine 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
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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 hemorrhage.
 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 unremitting 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)- off label use
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Radial optic neurotomy – surgically cutting the nasal disc to decompress this “compartment
syndrome” – very radical
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Standard Care vs. Corticosteroid for Retinal Vein Occlusion (SCORE) -CRVO.
 The SCORE-CRVO study evaluated the effectiveness and safety of intravitreal
triamcinolone in patients with macular edema secondary to a perfused central retinal vein
occlusion. The randomized trial compared the primary outcome (gain in visual acuity
letter score of 15 or more letters from baseline in 12 months) of patients who received no
treatment, 1-mg of preservative-free intravitreal triamcinolone, or 4-mg of preservativefree intravitreal triamcinolone.
 7%, 27%, and 26% of participants achieved the primary outcome in observation, 1-mg,
and 4-mg groups, respectively.
 For the participants included in the study, intravitreal triamcinolone proved to be a
superior treatment option when compared to observation. The 1-mg group and 4-mg
group showed similar effectiveness, but the 1-mg participants experienced less adverse
effects on the lower dose. 1-mg dose of intravitreal triamcinolone should be considered
for one to two years to improve vision loss secondary to macular edema following a
CRVO.
The SCORE Study Research Group. Arch Ophthalmology. 2009;127(9):1101-1114.
New Insight into the Management of BRVO and CRVO: BRAVO and CRUISE Studies
 Two phase 3 multicenter, prospective clinical trials assessing the safety, tolerability, and
efficacy of intravitreal ranibizumab (Lucentis) injections (compared with sham placebo) in
the treatment of macular edema secondary to BRVO and CRVO.
 The BRAVO trial includes patients with BRVO or hemiretinal vein occlusion, the CRUISE
trial patients with CRVO.
 Secondary endpoints include evaluating the efficacy of the treatment in improving other
visual acuity measures, anatomic outcomes, and patient-reported measures of visual function.
 Patients are randomized 1:1:1 to either sham injection, ranibizumab 0.3 mg, or ranibizumab
0.5 mg. They receive monthly injections for 6 months. During the second 6-month period,
patients are evaluated monthly and treated on a PRN basis.
 In BRAVO, patients are eligible for rescue laser therapy, if necessary
 Data from the BRAVO study in branch-RVO showed at month six, patients who received 0.3
mg of Lucentis had a mean gain from baseline BCVA of 16.6 letters and patients who
received 0.5 mg of Lucentis had a mean gain of 18.3 letters. In the CRUISE study in centralRVO, at month six, patients who received 0.3 mg of Lucentis had a mean gain from baseline
BCVA of 12.7 letters and patients who received 0.5 mg of Lucentis had a mean gain of 14.9
letters. In both trials, a statistically significant mean gain in BVCA was observed as early as
day seven for both doses of Lucentis compared with sham. The studies were not designed to
compare the two doses of Lucentis.
 The two doses of ranibizumab used in the BRAVO study showed a statistically significant
improvement in best corrected visual acuity at 6 months compared with sham injection. The
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safety profile of ranibizumab was consistent with previous experience, and no new adverse
events were observed.
In CRUISE, CRVO patients treated either with a 0.3 mg dose or a 0.5 mg dose were three
times more likely to gain 15 letters of vision than sham-treated patients.
 Patients in the treatment arms also demonstrated a rapid decrease in central foveal
thickness, with a reduction of 400 µm on day 7 and 433.7 µm (0.3 mg group) and 452.3
(0.5 mg group) at the end of the study; by comparison, there was a reduction in central
foveal thickness of only 167.7 µm in the sham group.
Clinical Pearl: Though both CRUISE and BRAVO show benefit, these are only 6 month
results. We don’t know what will happen at 12 months.
New Insight into the Management of BRVO and CRVO: Ozurdex
 The first sanctioned intravitreal steroid implant to treat macular edema associated with retinal
vein occlusion
 0.7mg dexamethasone intravitreal delivery implant indicated for treatment of macular edema
associated with central retinal vein occlusion or branch retinal vein occlusion.
 The effects of Ozurdex typically persist for 1-3 months but clinically its action has been
shown to be longer. This delivery system extends therapeutic effects over several months
decreasing the number of re-injections.
Clinical Pearl: New understanding of autoimmunity suggests that young patients with
CRVO be tested for primary antiphospholipid antibody syndrome, especially if there
are no other concurrent conditions present
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
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Vasospasm
Dissecting aneurysm
Hypertensive arteriolar necrosis
Circulatory collapse
Clinical Pearl: In 2-10% of cases, the cause is thrombosis formation due to giant cell
arteritis. If the cause is GCA, bilateral involvement can occur in hours to days. GCA
must always be considered as a cause of CRAO in the elderly!
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.
 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.
Clinical Pearl: In patients over the age of 60 years, CRAO may be caused by giant cell
arteritis. You must get an ESR and C-reactive protein on every patient over the age of
60 years with CRAO because if the cause is GCA, the patient will progress to bilateral
vision loss in hours to days.
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
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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
Associated conditions can cause CRAO through several mechanisms:
1. Contributing to emboli formation
2. Trauma (via compression, vasospasm, or direct vessel damage)
3. Coagulopathies
4. Collagen vasculopathies
5. Inflammation (GCA)
6. Other (idiopathic)
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 CRVO
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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
Emboli: Just the Facts
 May be symptomatic (AF or TIA) or asymptomatic
 The main factor associated with retinal emboli is smoking
 Three types of plaques: Fischer, Hollenhorst, calcific
 Fischer- fibrin/platelet aggregate (carotid in origin, also walls of arteries and valves of heart)
 Dull gray or white
 Readily migrate through vascular system producing symptoms (AF)
 Hollenhorst- cholesterol (carotid in origin)
 Refractile, glistening, yellow
 Most common (87%) of all emboli
 Typically do not occlude artery
 Malleable and allows for blood to pass though the artery may appear totally blocked
 Will readily break up and move distally, so will not be seen typically in patients
complaining of AF
 common cause of AF
Calcific (cardiac)
 Dull white and non-refractile
 Usually from valvular calcification
 Most likely to cause artery occlusion and stroke
Clinical Pearl: The patient most likely to manifest a, asymptomatic retinal emboli is an
older hypertensive man that smokes. Smoking cessation is absolutely essential for these
patients.
Visible Retinal Emboli: Mortality
 15% within 1 yr.; 29% within 3 yrs; 54% within 7 yrs
 Cardiac death more prevalent than stroke
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Clinical Pearl: The literature does not support carotid evaluation for patients with
asymptomatic retinal emboli because the majority does not have significant carotid
stenosis. There is no definitive management of these patients. It’s best to refer them
for an atherosclerotic evaluation and let the internist decide what to do.
Idiopathic Juxtafoveal Retinal Telangiectasia (IJRT)
 Also known as macular telangiectasia
 A similar condition to Coat’s disease and may be a variation
 A cause of macular edema and reduced acuity
 A developmental anomaly with subsequent leakage
 Hard exudates and RPE hyperplastic abnormalities
 This condition is greatly under-diagnosed
 Always consider this condition in patients presenting with idiopathic parafoveal
edema or dot/blot hemorrhages especially if there is no history of ischemic vascular
disease
Idiopathic Juxtafoveal Retinal Telangiectasia: Management
 Conservatism
 Photocoagulation with grid argon green or krypton red if there is progressive loss of
vision
 Intravitreal injection of Avastin/ steroids
 PDT
 Consider testing for HTN and DM in patients with parafoveal hemorrhaging. If these
diseases are not present, then telangiectasia is the likely cause.
 There is no strong relationship between this condition and any systemic disease
RPE Hypertrophy
 Also referred to as congenital hypertrophy of the retinal pigment epithelium
(CHRPE)
 Represents enlargement of RPE cells
 Usually very dark
 May be lightly colored
 Bear tracks
 Large, scalloped borders
 Lacunae (extremely diagnostic), which will enlarge and multiply over time
 Relationship to colorectal CA (multiple areas) – Gardner’s syndrome
 Familial adenomatous polyposis (FAP) - a hereditary bowel disorder with
propensity to malignancy
 Patients with 4 or more RPE hyperplasia-like lesions and a family history of FAP
(or colorectal cancer) should undergo routine colonoscopy
 Patients with Gardner’s syndrome have lesions that are slightly different from
typical RPE lesions in that they are multiple and scattered and pisciform
 Well demarcated and clear due to superficial level
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Very small (finding a snowball in a snowstorm) to several disc diameters (very scary,
but just as benign)
Some flat enlargement occurs in majority over time, but this is extremely difficult to
document without photographs
 Likely due to flattening and shifting of cells to account for RPE normal aging
attrition
RPE hypertrophic lesions themselves are totally benign
 No malignant potential
Ocular Histoplasmosis Syndrome
 Fungal disease: Histoplasma capsulatum
 Associated with bird (pigeon, chicken) feces
 Actually in soil fertilized by bird feces
 Actually found in bat feces
 Ohio - Mississippi River Valley (or any river valley region)
 Inhaled fungus
 Inhaled mycelial spores of Histoplasma capsulatum
 These spores undergo transformation to the yeast phase in the lung, and from here
it is disseminated via the bloodstream to the rest of the body (including the eye
where it causes choroidal infection)
 Flu-like illness
 Retinal lesions reactivate 10-30 yrs later
 Affects ages 20-50
 Rare in patients of African descent
 Circumpapillary choroidal scarring
 Peripheral atrophic Histo spots & peripheral scars
 Punched-out lesions
 Large (1 DD) or small
 Hypo- or-hyper pigmented
 Foci of previously present inflammatory reaction
 Site of infection with Histoplasma organism
 Macular compromise
 Granulomatous inflammatory mass
 Diagnosis is made by presence of peripapillary scarring and at least one peripheral
Histo spot
 Invisible choroiditis
 Not a fundus finding because it is not visible. May possibly be seen on FA
 Due to an accumulation of inflammatory cells at an inflammatory focus
 Will eventually result in an atrophic Histo spot
Ocular Histoplasmosis Syndrome: Maculopathy
 Macular granuloma
 Bruch's disruption
 Choroidal neovascularization
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 4th most common cause of CNVM
Sub-RPE hemorrhage with subsequent disciform scarring
Lipid exudate
Ocular Histoplasmosis Syndrome: Treatment
 Routine f/u when inactive
 Home amsler to monitor for neovascularization
 Oral, depot steroids when active
 Some advocate that steroids are ineffective
 Photocoagulation for juxtafoveal neo
 Laser tx is mainstay for Histo
 30% recurrence rate for neo regrowth
 Risk factors are younger age and females
 Neo can spontaneously involute without treatment
 PDT commonly used
 Anti-angiogenic drugs are used as well
 60% of untreated patients develop 20/200 or worse vision
 30% chance of fellow eye involvement within 7 yrs
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