Retinal vein occlusions 3

Retinal Vein Occlusions:“Finding Neo”

Veterans Health System of the Ozarks02/05/13

RETINAL VEIN OCCLUSIONS• 2nd most common retinal vascular

disease after Diabetic Retinopathy

• 3 TYPES (incidence):1. BRVO (0.6% in 5yr BD study)2. CRVO (0.2% in 5yr BD study)3. HEMIRETINAL VO (~0.06% or 10x less

common than BRVO) – not as well studied

Retinal Vein Occlusion

• Pathogenesis– Incompletely understood

• Clotting mechanism has many PRO and ANTIthrombotic factors

– thrombus (clot) occurs mostly at site of arteriolar/artery-venule/vein crossing change within the common adventitial sheath

Thrombi are caused by: endothelial injury, abnormal flow, and hypercoagulability.

BRVOsignificantly increased risk with

-hypertension-cardiovascular disease-smoking-increased Body Mass Index-higher serum alpha 2 globulin

-like Protein Cother important risk factors

-hyperlipidemia/atherosclerosis-diabetes (often excluded from VO studies)-high intraocular pressure

CRVOIncreased risk with: – SYSTEMIC

• BRVO risk factors (mostly systemic vascular)• Other vascular disease

– vasculitis (sarcoid, syphilis, SLE, other collagen vascular diseases),

• Abnormal blood flow– low physical activity (including prolonged bedrest)– Certain meds MAY: diuretics and oral contraceptives, – Blood component mutations:

» Homozygous for hyperhomocysteinemia,» Factor V Leiden and others

CRVOIncreased risk with: – OCULAR

• Certain optic disc area features affecting the course of the central retinal vessels:

– high cup to disc ratio, ION, tilted nerve head, ON drusen

• Increased intraorbital pressure – retrobulbar compression (thyroid eye disease,

orbital tumor), – head trauma with orbital fracture


In general: Emphasis on controlling known risk factors in older patients and investigating potentially unknown risk factors in younger patients and in rare simultaneous bilateral cases

BRVOKEY FEATURES:• Segmental retinal involvement within

distribution of involved occluded vein– WEDGE SHAPED WITH APEX NEAR SITE OF

OCCLUSION• Dilated tortuous vessels• Superficial and deep hemes, CWS’s• Optic disc swelling• Macular edema (perfused/nonperfused)• Optociliary shunt vessels on the disc• Neovascularization of the retina/post. pole


http://www.willseye.org/sites/all/files/imagecache/health-library-gallery-full/BRVO%201.JPG



CRVOKEY FEATURES:

• 4 quadrants of retinal involvement • Dilated, tortuous veins (even in mild)• Superficial &/or deep retinal hemes (even in

mildest)• CWS• Optic nerve swelling/hemes (hyperemia in mild)• Macular/retinal swelling• Optociliary shunt vessels on disc• Neovascularization of the iris (less commonly of

the optic disc and retina)

• http://www.willseye.org/sites/all/files/imagecache/health-library-gallery-full/CRVO%202.JPG

http://www.willseye.org/sites/all/files/imagecache/health-library-gallery-full/CRVO%202.JPG

http://www.willseye.org/sites/all/files/imagecache/health-library-gallery-full/CRVO%202.JPG

HRVO-Least common-~20% of humans have a 2 trunked CRV just

posterior to the lamina cribrosa-usually superior or inferior half of retina

involved though can be 1/3 or 2/3rd-distribution of neo distinct from CRVO since

posterior pole > anterior segment

www.revoptom.com

http://www.google.com/imgres?imgurl=http://www.revoptom.com/CMSImagesContent/2008/8/2_13945_2.gif&imgrefurl=http://www.revoptom.com/content/d/retina_quiz/i/807/c/15072/dnnprintmode/true/%3Fskinsrc%3D%255Bl%255Dskins/ro2009/pageprint%26containersrc%3D%255Bl%255Dcontainers/ro2009/simple&usg=__94a_pT7I9EDFEy_miMJ5beqg2F0=&h=421&w=348&sz=76&hl=en&start=19&zoom=1&tbnid=lElkswKm4s4RkM:&tbnh=125&tbnw=103&ei=fZcEUfaOJuGzyAHayIDgBw&prev=/search%3Fq%3Dhemiretinal%2Bvein%2Bocclusion%26hl%3Den%26gbv%3D2%26tbm%3Disch&itbs=1

BRVO Fluorescein Angiography

• Retina image bank• http://www.google.com/imgres?imgurl=http://imagebank.asrs.org/Content/imagebank/AEC3BE05-A54A-4F11-AB71-D99FDB18E07F/Miscellaneous/Non-perfused-BRVO-OS-003.jpg/image-full

%3Bmax%24643,0.ImageHandler&imgrefurl=http://imagebank.asrs.org/file/833&usg=__bkHuFDclI1HvuTMf9172iOx2Imc=&h=495&w=496&sz=207&hl=en&start=9&zoom=1&tbnid=4h0H1kzV3w13EM:&tbnh=130&tbnw=130&ei=itoFUf-AE8XGygG2p4H4Cw&prev=/search%3Fq%3DBRVO%2Bnonperfusion%26um%3D1%26hl%3Den%26gbv%3D2%26tbm%3Disch&um=1&itbs=1

Usually Unilateral

• CVOS: 3 of 711 patients had bilateral vein occlusions

THE OTHER EYE:• CVOS: 9% of eyes with CRVO’s have had a

prior vascular occlusion in the fellow eye• After a CRVO the annual risk of any retinal

vascular occlusion in the fellow eye is 1% per year

Differential diagnosis

• Diabetic and hypertensive retinopathies – generally bilateral, involving all four quadrants

Major Studies

• Multicenter Randomized Controlled trials– BVOS(“Luck,” “Branches,” Grid is Good)– CVOS (“POE,” 20/200, NVGlau) – FOCUS WILL BE ON THE ABOVE STUDIES

BECAUSE THEY EXAMINE WHAT HAPPENS IN VOs WITHOUT TREATMENT and “WHO GETS LASER?”

• Others– MEDICAL MACULAR TX

BVOS: A CLINICAL QUESTION• The increasing use of photocoagulation therapy in the late

1960s and early 1970s, along with the increasing expertise in fluorescein angiography, aided recognition of the disease, study of the nature and course of the disease, and small trials of photocoagulation therapy for the complications of macular edema and neovascularization, as reviewed in 1978. From these important studies, it became evident that many patients who did not undergo laser photocoagulation did not develop visual loss from macular edema or neovascularization, which increased the difficulties of evaluating photocoagulation therapy effect. Consequently, it became clear that a prospective, randomized, controlled clinical trial was required to answer questions about treatment efficacy.

BVOS

• "Can peripheral scatter argon laser photocoagulation prevent the development of neovascularization?“

• And by extension: "Can peripheral scatter argon laser photocoagulation prevent vitreous hemorrhage?"

BVOS

• Eyes with vision loss due to conditions other than BRVO were excluded

BRVO Groups include:• Group I = pts have had a BRVO with 5DD of

retinal involvement but no neovascularization at initial visit

• Group II = pts had + NVD/NVE at initial visit or at some point during study

BVOS

Fig 2.—Kaplan-Meier plot of cumulative proportion of group Ieyes that developed neovascularization by follow-up time intreated and control patients (P = .009, log rank test).

LASER BEFORE NEO

BVOS

Fig 3.—Kaplan-Meier plot of cumulative proportion of group IIeyes that developed vitreous hemorrhage by follow-up time intreated and control patients (P = .005, log rank test).

LASER AFTER NEO

BVOS

• Prevention of neovascularization (and by extension vitreous heme) with laser was not found

• Neovascularization developed in a smaller proportion of eyes after laser treatment, so some did benefit from early laser tx.

• The greater benefit of laser tx came to the eyes that ALREADY HAD NEO and were A LOT LESS LIKELY to have VITR HEME after laser tx.

Laser before neo vs Laser after neo

LESS BENEFICIAL vs MORE BENEFICIALAS A RESULT: LASER FOR NEO FROM BRVO

BECAME THE STD OF CARE

BVOS

• Although the Branch Vein Occlusion Study was not designed to determine whether peripheral scatter treatment should be applied before rather than after the development of neovascularization, data accumulated in this study suggest that peripheral scatter treatment should be applied after the development of neovascularization rather than before the development of neovascularization.

BVOS

• What other guidance is provided by the data?• Natural History of BRVO – “Approximately

50% rule” - important for management and pt education because it answers a clinical question that initiated the study

BVOS: Natural History of BRVO

Approximately 50% of all eyes with at least 5DD of involvement (a Gr I entry criteria) will have at least 5DD of capillary nonperfusion (ischemic BRVO). (the other 50% will be nonischemic BRVOs – did not find conversion rate from nonischemic to ischemic)

A NEW GROUP, GROUP X:Group X (5DD nonperfusion, nontreated): Of the

eyes in this group, 41% developed neovascularization.

• (study text does not match graphed data well)• Approximately 50% of eyes with 5DD of

nonperfusion will develop neovascularization• (the other ~50+% will not develop neo)THIS

ANSWERS A CLINICAL QUESTION THAT INITIALLY PROMPTED THE STUDY NAMELY WHY DO SOME BUT NOT ALL PTS BENEFIT FROM LASER


Going back to Group II:Group II (+ NVD/NVE): Of the 41 (nontreated)

eyes, 61% developed vitreous hemorrhage.• Approximately 50++% of eyes with

neovascularization from BRVO will develop vitreous heme


Fig 4.—Visual acuity distribution for allgroup II eyes with vitreous hemorrhagethat were never treated. Boxes indicatefirst visit and acuity at which first vitreoushemorrhage was noted; LP, light perception; and mi, missed visit.

BVOS• “Can macular argon laser photocoagulation

improve visual acuity in eyes with macular edema reducing vision to 20/40 or worse?”(LAST BUT NOT LEAST,… GROUP III)

• Summary recommendations reflect the importance of macular perfusion to the success of grid laser tx.

• GRID LASER BECAME THE GOLD STD OF TX’ING CERTAIN TYPES OF ME FROM BRVO AFTER THIS STUDY

Summary of change in visual acuity since initial visit for eyes that were evaluated at the 3rd year visit

Group III Control (No. =35) Treated (No. = 43)Percent gaining two or more lines at two consecutive visits

37% (13) 65% (28) ↑Percent losing two or more lines at two consecutive visits

17% (6) 12%(5) ↓Percent with VA 20/40 or better at 3rd yr visit 34%(12) 60%(26) ↑Percent with Visual acuity 20/200 or worse at 3rd year visit

23%(8) 12%(5) ↓Avg VA at 3rd year visit 20/70 20/40-20/50Avg number of lines gained at 3rd year visit 0.23 1.33 ↑

Now turning to CVOS• CVOS examines more variables than BVOS• CVOS isolates and explores the relationship

between those variables linked to progression in order to DEFINE HIGH RISK CHARACTERISTICS FOR PROLIFERATION – AS WAS DONE IN BVOS

CVOS: GROUP P• The first CVOS pt group is Group P (P for

PERFUSED CRVO)• TABLE 6 (Next Slide) shows the PROPORTION

OF PERFUSED PTs PROGRESSING by VARIABLES WHICH MAY BE INVOLVED IN THEIR PROGRESSION

• Table 6 was published in the preliminary report. A similar table was not published in the final report, but the final report added that moderate to severe venous tortuosity IS associated with progression out of Group P

CVOS GROUP P: LIST OF VARIABLESProgression is defined as the presence of any of the

following by the 4-month visit: 10 disc areas of nonperfusion, transfer to group I, 2 clock hours of iris neovascularization, or angle neovascularization.

CVOS GROUP P: LIST OF VARIABLESProgression is defined as the presence of any of the

following by the 4-month visit: 10 disc areas of nonperfusion, transfer to group I, 2 clock hours of iris neovascularization, or angle neovascularization.

CVOSTHE PROPORTION OF PATIENTS THAT PROGRESSED FROM THE PERFUSION GROUP TO OTHER MORE ADVANCED GROUPS WAS 0.16

THEREFORE ALL OF THE PROPORTIONS FOR ALL OF THE VARIABLES ARE COMPARED TO 0.16 TO SEE WHICH ARE THE MOST DIFFERENT.

CVOS

too few pts < 50

more males in study

too few patients

not sign. different proportion

pt’s with DR excluded

“MARGINAL SIGNIFICANCE”

HIGH CORRELATION


HIGH CORRELATION









3 ISOLATED VARIABLES

CVOS: ↑ # of Risk Factors ↑ Risk of Progression

Figure 3. Group P progression (INV and/or ANV, group I, or nonperfusion) by number of risk factors present at entry. Risk factors are duration of central vein occlusion of less than 1 month, visual acuity of worse than 20/200, and five to nine disc areas of nonperfusion. Error bars represent 95% confidence intervals. See the text, introductory section, and Table 1 for explanation of groups.

ADDITIVE INTERACTION BETWEEN HIGH RISK CHARACTERISTICS/ VARIABLES

CVOS A SHORT SUMMARY SO FAR• So an initially perfused CRVO is more at risk of

progressing to a nonperfused CRVO if– visual acuity worse than 20/200 AND– 5-9DD of capillary nonperfusion AND– (moderate to severe venous tortuosity) are present

than any one alone.• THE RELATIONSHIP BETWEEN VISUAL ACUITY AND

AMOUNT OF NONPERFUSION IS EASIER TO EXPLORE BECAUSE IT IS MORE QUANTIFIABLE

• THE RELATIONSHIP BETWEEN VISUAL ACUITY AND AMOUNT OF NON PERFUSION IS NOT ONLY ADDITIVE BUT ALSO “HIGHLY CORRELATED” (next slide) MEANING THEY BOTH INCREASE TOGETHER SOMEHOW

CVOS

Figure 1. Proportion of patients developing iris neovascularization (INV)and/or angle neovascularization (ANV) (2-clock hours of INV or any ANV)during the study period by number of disc areas of nonperfusionmeasured at baseline.

CVOS

Figure 2. Proportion of patients developing iris neovascularization (INV)and/or angle neovascularization (ANV) (2-clock hours of INV or any ANV)during study period by Snellen visual acuity measurement at baseline.

CVOS – HIGHLY CORRELATED• GREATER CAPILLARY NONPERFUSION AND A

WORSE INITIAL VISUAL ACUITY ARE EACH RELATED TO AN INCREASE IN PROPORTION OF EYES DEVELOPING INV/ANV ( NVGlau)

THIS PART OF BOTH GRAPHS ARE THE SAME

CVOS

• THE CORRELATION BETWEEN VISUAL ACUITY AND CAPILLARY NON PERFUSION WAS NOT EXPLORED IN MORE DETAIL PERHAPS BECAUSE THE MECHANISTIC DETAILS ARE NOT AS RELEVANT TO CLINICAL PRACTICE AS IS THE ABILITY TO LEGITIMATELY GUESSTIMATE CAPILLARY NONPERFUSION BY A VISUAL ACUITY MEASURE

A CLOSER LOOK AT 20/200

• CVOS states that 20/200 is the level of acuity that is most concerning; but why?

CVOS – evidence for 20/200 marker<1mo since onset subgroup:At ≤ 20/200 majority are ischemic CRVOs & large rise in proportion of eyes with INV/ANV

The tipping point

CVOSNOW WE KNOW WHICH EYES ARE MOST AT RISK. WE

KNOW HOW THE RISK FACTORS INTERACT. WE KNOW THE SIGNIFICANCE OF 20/200. BUT WE STILL NEED TO MENTION THE MAIN CONCERN.

• the primary concern is prevention of neovascular glaucoma by careful attention to the development of INV and prompt treatment if it occurs. There is concern that the patient with a visual acuity worse than 20/200 is likely to have a nonperfused occlusion.

• THIS OUTCOME IS MUCH MORE SERIOUS THAN THE VITREOUS HEME CAUSED BY BRVO NEO

Figure 3. Kaplan-Meier survival curve showing cumulative proportion ofpatients who had developed iris neovascularization (INV) and/or angleneovascularization (ANV) by study month.

CVOSAnterior segment neovascularization and therefore Neovascular Glaucoma can develop very quickly initially and then less quickly (but never zero slope) as time goes on – frequent f/u early and long term f/u necessary

ADDITIONAL CVOS NATURAL HX• Number with ischemia: In the first 4 months of

follow-up, 81 (15%) of the 547 eyes with perfusion converted to ischemia… a total of 34% after 3 years.

• Rate of ischemia: The development of ischemia was most rapid in the first 4 mos and progressed continuously throughout the entire duration of follow-up. – MAY ALWAYS NEED TO LOOK FOR NEO IN OLD CRVO

• A result of ischemia: Iris neovascularization of at least 2-clock hours, and/or angle neovascularization (ANV) developed in 117 (16%) of the 714 eyes.

CVOS - LOOKING FOR NEONecessary Clinical information upon diagnosis of Central Retinal Vein OcclusionBest Corrected Visual Acuity Intraocular pressureUndilated slit-lamp examinationGonioscopyFluorescein Angiography*

*If the perfusion status is not clinically obvious and if the media and retinal hemorrhage do not obscure retinal capillary detail, then a fluorescein angiogram would be a useful clinical adjunct

BVOS vs CVOSBVOS CVOSconcern for posterior segment neovascularization and vitreous hemorrhage

concern for anterior segment neovascularization and neovascular glaucoma/blind painful eye

high risk characteristic for proliferation is 5 DD of capillary nonperfusion

high risk characteristics for proliferation including 5-9 DD of capillary nonperfusion and VA worse than 20/200

certain macular edemas are treatable with grid laser.

grid laser should not be used for macular edema for reasons unknown.

Ischemia and Neovascularization

• Ischemia is often but not always or immediately a prelude to neovascularization therefore PRP for neo is performed not PRP for ischemia

A Brief Word on Other StudiesRELATE TO TX OF MACULAR EDEMA (ME) • SCORE

– Steroid injections for certain ME’s from CRVO • OSURDEX steroid implant for ME’s from VO• CRUISE and BRAVO

– Lucentis (Anti-VEGF agent) for ME’s from VO

(Eyelea (VEGF Trap) approved for ME after CRVO)THE ABOVE STUDIES and the OCT MAY HAVE

CHANGED THE STD OF CARE SO THAT FLUORESCEIN’s are LESS RELIED UPON FOR MGT

Management

• VO– Consult for Macular edema

• BRVO– Monitor at 2-4 month intervals for first year and

less often thereafter looking for signs of neovascularization (usually posterior) (PRP for neo)

– Possible Fluorescein angiography to confirm neo or to assess perfusion status of macular edema in anticipation of grid laser

Management

• CRVO– Monthly monitoring looking for earliest signs of

neovascularization (usually anterior) (PRP for neo) for first 6-8 months, less often thereafter for next 2 to 3 years

– Possibly no Fluorescein angiography needed unless the outcome impacts treatment decisions

CVOS Q&A

• WHO WILL GET WORSE?• HOW DO WE ADVISE PATIENTS?• WHAT’S AT RISK VISIONWISE?

CVOS

• WHO WILL GET WORSE?– Over time 1/3 will get worse– Pts with worse VA (and greater capillary

nonperfusion and mod to sev venous tortuosity)• HOW DO WE ADVISE PATIENTS?

– Frequent F/u especially in 1st 4 months– Long term f/u for long term risk of progression

• WHAT’S AT RISK VISIONWISE?– Potential for a blind painful eye

References

• Stephen J. Ryan’s Retina• Albert & Jakobiec's Principles & Practice of

Ophthalmology, 3rd ed.• CVOS• BVOS• Dr. Edward Deglin

Health & Medicine

Retinal vein occlusions 3