1. Retinal Vein Occlusions:
“Finding Neo”
Veterans Health System of the Ozarks
02/05/13

2. 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

3. 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.

4. BRVOsignificantly increased risk with
-hypertension
-cardiovascular disease
-smoking
-increased Body Mass Index
-higher serum alpha 2 globulin
-like Protein C
other important risk factors
-hyperlipidemia/atherosclerosis
-diabetes (often excluded from VO studies)
-high intraocular pressure

5. CRVO
Increased 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

6. CRVO
Increased 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

7. Retinal Vein Occlusion
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

8. BRVO
KEY 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

9. Retinal Vein Occlusion
http://www.willseye.org/sites/all/files/imagecache/heal
th-library-gallery-full/BRVO%201.JPG

10. CRVO
KEY 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)

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

12. 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

13. 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/pag
eprint%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

14. 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=4
h0H1kzV3w13EM:&tbnh=130&tbnw=130&ei=itoFUf-
AE8XGygG2p4H4Cw&prev=/search%3Fq%3DBRVO%2Bnonperfusion%26um%3D1%26hl%3Den%26gbv%3D2%26tbm%3Disch&um=1&itbs=1

15. 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

16. Differential diagnosis
• Diabetic and hypertensive retinopathies –
generally bilateral, involving all four quadrants

17. 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

18. 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.

19. BVOS
• "Can peripheral scatter argon laser
photocoagulation prevent the development of
neovascularization?“
• And by extension: "Can peripheral scatter
argon laser photocoagulation prevent vitreous
hemorrhage?"

20. 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

21. BVOS
Fig 2.—Kaplan-Meier plot of cumulative proportion of group I
eyes that developed neovascularization by follow-up time in
treated and control patients (P = .009, log rank test).
LASER BEFORE NEO

22. BVOS
Fig 3.—Kaplan-Meier plot of cumulative proportion of group II
eyes that developed vitreous hemorrhage by follow-up time in
treated and control patients (P = .005, log rank test).
LASER AFTER NEO

23. 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.

24. • 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 BENEFICIAL
AS A RESULT: LASER FOR NEO FROM BRVO
BECAME THE STD OF CARE

25. 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.

26. 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

27. 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)

28. 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
BVOS: Natural History of BRVO

29. 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
BVOS: Natural History of BRVO

30. Fig 4.—Visual acuity
distribution for all
group II eyes with
vitreous hemorrhage
that were never treated.
Boxes indicate
first visit and acuity at
which first vitreous
hemorrhage was noted;
LP, light perception; and
mi, missed visit.

31. 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

32. 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 20/40-20/50
Avg number of lines
gained at 3rd year visit
0.23 1.33 ↑

34. 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

35. 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

36. CVOS GROUP P: LIST OF VARIABLES
Progression 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.

37. CVOS GROUP P: LIST OF VARIABLES
Progression 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.

38. CVOS
THE 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.

39. 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
not sign. different proportion
HIGH CORRELATION
not sign. different proportion
not sign. different proportion
not sign. different proportion
not sign. different proportion
not sign. different proportion
not sign. different proportion
not sign. different proportion
not sign. different proportion

40. 3 ISOLATED
VARIABLES

41. 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

42. 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

43. 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 nonperfusion
measured at baseline.

44. 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.

45. 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

46. 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

47. A CLOSER LOOK AT 20/200
• CVOS states that 20/200 is the level
of acuity that is most concerning; but
why?

48. 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
tippin
g
point

49. CVOS
NOW 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

50. Figure 3. Kaplan-Meier survival curve showing cumulative proportion of
patients who had developed iris neovascularization (INV) and/or angle
neovascularization (ANV) by study month.
CVOS
Anterior 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

51. 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.

52. CVOS - LOOKING FOR NEO
Necessary Clinical information upon diagnosis of
Central Retinal Vein Occlusion
Best Corrected Visual Acuity
Intraocular pressure
Undilated slit-lamp examination
Gonioscopy
Fluorescein 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

53. BVOS vs CVOS
BVOS CVOS
concern 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.

54. 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

55. A Brief Word on Other Studies
RELATE 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

56. 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

57. 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

58. CVOS Q&A
• WHO WILL GET WORSE?
• HOW DO WE ADVISE PATIENTS?
• WHAT’S AT RISK VISIONWISE?

59. 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

60. References
• Stephen J. Ryan’s Retina
• Albert & Jakobiec's Principles & Practice of
Ophthalmology, 3rd ed.
• CVOS
• BVOS
• Dr. Edward Deglin