Central Retinal Vein Occlsion (CRVO)

RETINAL VEIN OCCLUSION

Dr. Yousaf Jamal
FCPS Resident
Ophthalmology Unit
Hayatabad Medical Complex
18/12/10

Mar 25, 2013

Contents
• Introduction of RVO
• CRVO
– Demographics
– Pathogenesis
– Etiology
– Management
• Hx, examination, investigation
• Treatment
– Trials
– Guidelines
• Summary / Take Home Message
• MCQs

Page 2 Retinal Vein Occlusion Mar 25, 2013

Introduction

• Common vascular disorder
• Second common cause of blindness after
diabetic retinopathy
• Cause…obstruction to venous flow
• Associated risk factors….multifactorial
• Classification
– Site of involvement
– Extent of retinal perfusion


Demographics

• In Australia, prevalence of RVO…
– 0.7% in pts aged 49-60 years to 4.6% in pts older
than 80 years a
• Seasonal variation found…greater than
20,000 patients in the month of January b

a Mitchell P, Smith W, Chang A. Prevalence and associations of retinal vein occlusion in Australia. The Blue Mountains Eye
Study. Arch Ophthalmol. Oct 1996;114(10):1243-7
b Ho JD, Tsai CY, Liou SW, et al. Seasonal variations in the occurrence of retinal vein occlusion: a five-year nationwide population-
based study from Taiwan. Am J Ophthalmol. Apr 2008;145(4):722-728.


Common mechanism

Venous blockage

back pressure on capillaries

endothelial junction dysfunction

leakage of fluid & blood
(edema / hemorrhages)

• Severe nonperfusion leads to ischemia


Predominant associations
Patient Hypertensio Hyperlipidemia Diabetes No Obvious
Group n Mellitus Cause
Age<50 25% 35% 03% 40%
yrs
Age>50 64% 34% 4-15% 21%
yrs
Asian 64% 50% 29% 10.7%

West 83% 33% 38% 8.3%
Indian
Recurren 88% 47% 3% 6%
t cases
• Royal college of ophthalmologists guidelines: Feb. 2009


Classification

• Central retinal vein occlusion (CRVO)
– Non-ischemic CRVO
– Ischemic CRVO
• Branch retinal vein occlusion (BRVO)
– Major BRVO
– Macular BRVO
• Hemicentral retinal vein occlusion (HCRVO)
– Non-ischemic HCRVO
– Ischemic HCRVO

Central retinal vein occlusion

• Painless loss of vision
• Site: occlusion at or posterior to lamina
cribrosa
• Two clinical types
– Ischemic CRVO (I-CRVO)
– Non-ischemic (NI-CRVO)
• ‘Research into CRVO is fraught with challenges, from
accurate disease classification to its treatment; even the
most prestigious trials have become controversial’
• Madhusudhana KC, Newsom RS.Central retinal vein occlusion: the therapeutic options. Can J Ophthalmol.Apr 2007;42(2):193-5.


Demographics

• Prevalence = 0.1% a - 0.5% b
• 15-year cumulative incidence of CRVO to be
0.5% c
• NI-CRVO more common than I-CRVO
• No racial predilection
• Men > women
• >90% CRVO occurs in > 50 yrs age
a Klein R et al. The epidemiology of retinal vein occlusion: the Beaver Dam Eye Study.Trans Am Ophthalmol Soc 2000;98:133– 41.
b Mitchell Pet al. Prevalence and associations of retinal vein occlusion in Australia. The Blue Mountains Eye Study. Arch
Ophthalmol 1996;114:1243–7.
c Klein R et al. The 15-year cumulative incidence of retinal vein occlusion: the Beaver Dam Eye Study. Arch
Ophthalmol. Apr 2008;126(4):513-8.


Pathogenesis

• Virchow triad:
– Loss of vessel wall integrity
– Altered blood flow
– Hypercoagulable state
• Disturbance leads to thrombus
formation & vessel occlusion


• Klein & Olwin postulated:
– Compression of vein by sclerotic central retinal
artery
– Occlusion by primary vessel wall disease
(degenerative or inflammatory)
– Hemodynamic disturbance

Klein BA, Olwin JH. A survey of the pathogenesis of retinal venous occlusion. Arch Ophthalmol 1956;56:207.


Retinal Vein Occlusion Mar 25, 2013

CRVO resistance to venous flow
blood stagnation & ischemia stimulates
production of VEGF (vascular endothelial growth factor)

neovascularization
capillary leakage (edema)


Etiology

• Any factor which directly or indirectly
activates virchow triad….


External compression

– Arteriosclerosis of CRA (HTN, DM,
Hyperlipidemia)
– Glaucoma (5 times more likely to have CRVO)
– Papilledema
– Thyroid eye disease
– Orbital space occupying lesions
– Cavernous sinus thrombosis
– Closed-Head trauma
– Retrobulbar injections *
* Morgan et al. ocular complications associated with retrobulbar injections. Ophthalmology 1988;95:660.


Disease of vessel wall

– Systemic Vasculitis
• TB
• AIDS
• Syphilis
• SLE
– Localized inflammation
• Sarcoidosis
• Serpiginous choroiditis *

* Bluemenkranz et al. atypical serpiginous choroiditis. Arch ophthalmol 1773;1982:100.


Hematological disorders

• Clotting disorders • Paraproteinemia
– Activated protein C – Multiple myeloma
resistance – Cryoglobulinemia
– Lupus anticoagulant • Drugs
deficiency
– Oral contraceptive
– Anticardiolipin antibodies
– Diuretics
– Protein C & Protein S
deficiency • Blood dyscrasia
– Antithrombin III def – Lymphoma
– Antiphospholipid – Leukemia
antibodies – Polycythemia vera
• Nephrotic syndrome – Sickle cell disease


MANAGEMENT


History

• Symptoms
– Painless loss of vision (mild to severe)
– Usually unilateral
• Past & Personal Hx
– HTN, DM, smoking
– Hyperlipidemia
– Bleeding or clotting disorders
– Glaucoma
– Oral contraceptive use
– Head trauma / retrobulbar inj


Examination

– VA & BCVA
– Pupillary reactions
– Congestion of conjunctiva or cornea
– Iris…neovessels
– AC angle…neovessels
– IOP


• Fundus findings
– Retinal hemorrhages in 4 quadrants
– Extensive hemorrhages…blood & thunder
appearance
– Dilated tortuous veins
– Cotton wool spots, macular edema
– Optic disc
• Edema / optociliary shunts / atrophy
– Neovessels
• NVD / NVE……vitreous hemorrhage


• Diagnosing CRVO is not difficult
• Main task…differentiate btw ischemic & non-
ischemic CRVO
• No single criterion is helpful
• Various useful tools…
– Visual acuity, pupillary reflex
– Ocular neovascularization, Fundus findings
– Perimetry, ERG, FFA


Non-Ischemic Ischemic
Frequency 75-80% 20-25%
VA better than 6/60 Worse than 6/60
RAPD Slight or nil Marked
VF defect rare Common
Fundus Less hemorrhages & Extensive hemorrhages &
cotton wool spots cotton wool spots
FFA Good perfusion Non-perfusion > 10 DD
ERG Normal Reduced b-wave amplitude,
reduced b:a ratio
Prognosis 50%...6/60 or better 60%...Rubeosis & NVG


Complications

• Principle causes of visual morbidity
– Macular edema (ME)
– Neovascularization (NVI>NVD>NVE) &
Neovascular glaucoma (100 days)
– Vitreous hemorrhage
– Optic atrophy


Differential diagnosis

• Ocular ischemic syndrome
• Diabetic retinopathy
• Papilledema
• Radiation retinopathy
• Retinopathy due to anemia


Ocular Investigations

• ERG
– Reduced b-wave amplitude
– reduced b:a ratio
– b:a ratio < 1 suggests an I-CRVO
• OCT
– For macular thickness


• Fluorescein angiography
– Very useful for detecting…
• Capillary nonperfusion
• Neovascularization
• Macular edema
– Reliable to differentiate btw I-CRVO & NI-CRVO
– >10 DD retinal nonperfusion is termed as I-CRVO*

* The Central Vein Occlusion Study Group A randomized clinical trial of early panretinal photocoagulation for ischemic
central vein occlusion: The Central Retinal Vein Occlusion Study Group N Report. Ophthalmology 1995;102: 1434-44.


– Limitations
• It provides little information in early stages bcz of
extensive hemorrhages
• Poor quality of angiograms
• Inability to visualize peripheral retina
• Interpretation is subjective & hence variable


• FFA findings
– Delayed arteriovenous transit
– Macular edema
– Staining along the retinal veins
– Micro aneurysms, Arteriovenous collaterals
– NVD, NVE
– Dilated optic nerve head capillaries
– Nonperfusion…hypofluorescence


Systemic investigations

• IT IS THE RESPONSIBILITY OF THE
OPHTHALMOLOGICAL TEAM TO ENSURE
THAT MEDICAL INVESTIGATION AND
TREATMENT IS INITIATED ON DIAGNOSIS
OF RETINAL VEIN OCCLUSION.

Royal college of ophthalmologists guidelines: Feb. 2009


• It is the responsibility of the diagnosing
physician or ophthalmologist to:
– Investigate and interpret results.
– Refer the patient for appropriate medical advice
with urgency according to the severity of
underlying risk factor(s).
– Ensure that specialists in the relevant field should
manage the rarer causes of retinal vein occlusion.
– Ensure that initiation of medical management
occurs within 2 months of diagnosis


Initial medical investigations

• ALL PATIENTS • ACCORDING TO
– FBC & ESR CLINICAL INDICATION
– Renal function tests – Thrombophilia screen
– Random blood glucose – Anticardiolipin antibody
– Lipid profile – CRP
– Plasma protein – Serum ACE
electrophoresis – Autoantibodies
– Thyroid function – CXR
– ECG – Fasting homocystine
levels


Natural history of CRVO

• NI-CRVO
– Completely resolution…10% a
– ME resolves…30% in 6-15 months b
– About 50%...VA is 6/60 or worse a
– 1/3rd progress to I-CRVO in 6-12 months a
– Neovessels develop…33% in 12-15 months b

a Central Vein Occlusion Study Group. Baseline and early natural history report. Arch Ophthalmol. Aug 1993;111(8):1087-95
b McIntosh RL et al. Natural History of Central Retinal Vein Occlusion: An Evidence-Based Systematic Review. Ophthalmology
2010;117:1113–1123


• I-CRVO
– >90%...VA is 6/60 or worse a
– ME resolves…73% in 15 months b
– NVG…>60% in 1-2 yrs a
– About 10% develop RVO in same or fellow eye in
2 yrs
• Vitreous hemorrhage…10 % of CRVO by 9
months b

a Central Vein Occlusion Study Group. Baseline and early natural history report. Arch Ophthalmol. Aug 1993;111(8):1087-95
b McIntosh RL et al. Natural History of Central Retinal Vein Occlusion: An Evidence-Based Systematic Review. Ophthalmology
2010;117:1113–1123


Treatment

• Systemic treatment a
– Anticoagulants…Heparin, warfarin
– Fibrinolytic agents…Streptokinase, tissue
plasminogen activator
– Antiplatelets…Aspirin, prostacyclin
– Hemodilution
• No favorable effects on natural history b

a Mahmood T. CRVO: current management options. Pak J Ophthalmol 2009. 25(1):56-9.
b Mohamed Q et al. interventions for CRVO. an evidence-based systematic review. Ophthalmology. 2007; 114:507-19


• Ocular treatment
– Pharmacotherapy
– Photocoagulation
– New techniques (Surgical)
• Certain clinical trials needs attention


Central Vein Occlusion Study (CVOS)

• More than a decade
• Purpose
– To determine whether photocoagulation therapy
can help prevent iris neovascularization in eyes
with CVO and evidence of ischemic retina.
– To assess whether grid-pattern photocoagulation
therapy will reduce loss of central visual acuity due
to macular edema secondary to CVO.
– To develop new data describing the course and
prognosis for eyes with CVO.

• Eligible pts were divided in 4 groups:
– Group N: Eyes with extensive retinal ischemia
(at least 10 disc areas of nonperfusion) were
randomly assigned to receive panretinal
photocoagulation or no treatment unless iris
neovascularization developed.
– Group M: Eyes with visual loss ascribable to
macular edema were randomly assigned to
receive grid-pattern photocoagulation or no
treatment.

The Central Vein Occlusion Study Group: Evaluation of grid pattern photocoagulation for macular edema in central vein
occlusion. The CVOS Group M Report. Ophthalmol 102: 1425-1433, 1995


– Group P: Eyes with relatively perfused retinas
were followed to provide information about the
natural history of the disease.
– Group I: Indeterminate eyes in which the retina
could not be visualized accurately because of
hemorrhage were followed in a natural history
study.

The Central Vein Occlusion Study Group: Natural history and clinical management of central retinal vein occlusion. Arch
Ophthalmol 115: 486-491, 1997.


• Green argon laser was used for all Tx
• Followed for 3 yrs with photographic images
• Visual acuity was primary outcome factor in
macular edema group

• Clarkson JG, Central Vein Occlusion Study Group: Central vein occlusion study: Photographic protocol and early natural history. .
Trans Am Ophthalmol Soc 92: 203-215, 1994
• The Central Vein Occlusion Study Group: Baseline and early natural history report. Arch Ophthalmol 111: 1087-1095, 1993.


• Results
– Group M--Macular Edema: Macular grid
photocoagulation was effective in reducing
angiographic evidence of macular edema but did
not improve visual acuity in eyes with reduced
vision due to macular edema from CVO.
– Group I--Indeterminate: Eyes with such
extensive Intraretinal hemorrhage that it is not
possible to determine the retinal capillary
perfusion status act as if they are ischemic or
nonperfused

– Group N--PRP for Ischemic CVO: Prophylactic
PRP did not prevent the development of NVI in
eyes with >10 disc areas of retinal capillary
nonperfusion confirmed by FFA. Rather, results of
this RCT demonstrate that it is safe to wait for the
development of early iris neovascularization and
then apply PRP


SCORE-CRVO study

• Standard care vs. COrticosteroids for
REtinal vein occlusion study
• Funded by national eye institute in May 2003
• Multicentered RCT
• 271 participants

SCORE study Report # 5. Arch Ophathalmol. 2009;127:1101.


• Another major study which added to the
armamentarium…CRUISE trial
• CRIUSE: Anti-vascular endothelial growth
factor (VEGF) therapy vs. placebo in CRVO
• Rationale was…
– Ischemic retina releases VEGF which leads to ME
& neovascularization

Campochiaro PA. CRUISE. Retina congress 2009.


• In June 2010, the FDA approved a new
indication for Ranibizumab intravitreal
injection…for the treatment of macular edema
after retinal vein occlusion.
• FDA approved Ranibizumab after CRUISE &
BRAVO trials results.

http://www.medscape.com/viewarticle/724118


The Royal College of Ophthalmologists
Guidelines

• Published in Feb. 2009.
• Macular edema
– Grid laser improves the edema but no
improvement in VA… so not recommended
– IVTA produce anatomical & functional
improvement but effects are short lived.
– Common dose of IVTA…4mg
– Repeated IVTA may not improve vision.*
* Wang L, Song H. Effects of repeated injection of intravitreal triamcinolone on macular oedema in central retinal vein occlusion.
Acta Ophthalmol 2008 May 27. [Epub ahead of print] PMID: 18507724.


– Posurdex* in 350 or 700 µg also improves vision.
– Intravitreal anti-VEGF therapy (CRIUSE) trial was
going on but not published at that time.
– However, now its approved by FDA for RVO.

* Clinicaltrials.gov Identifier NCT 00485836/00486018


• Anterior segment neovascularization
– I-CRVO should be monitored monthly for new
vessels at iris &/or angle
– Pan-retinal photocoagulation is advised when NVI
or NVA are visible
– If logistically not possible…2-3 months follow-up is
adequate


– If regular follow-up not practical…prophylactic
treatment is appropriate a
– IVTA…no proven protective effect on anterior
neovascularization
– Anti-VEGF can be used as an adjuvant to PRP in
pts with anterior segment neovascularization
secondary to I-CRVO b

a Laatikainen, L. A prospective follow-up study of panretinal photocagulation in preventing neovascular glaucoma following
ischaemic central retinal vein occlusion. Graefe’s Arch Clin Exp Ophthalmol 1983; 220:236-239.
b Davidorf FH, Mouser JG, Derick RJ. Rapid improvement of rubeosis iridis from a single bevacizumab (Avastin) injection. Retina
2006; 26(3):354-6.


• Established neovascular glaucoma
– Aim…keep eye pain free.
• Topical steroids
• Atropine
– If there’s visual potential
• Topical pressure lowering agents
• Cycloablation
– Intravitreal and Intracameral anti-VEGF show
regression of iris vessels & angle obstruction


Experimental treatments

– Chorio-retinal anastomosis
– Radial optic neurotomy with PPV a
– Thrombolytic therapies b

• Currently…these are not recommended
except as a part of clinical trials

a Arevalo JF et al ;Pan-American Collaborative Retina Study Group. Radial optic neurotomy for central retinal vein occlusion:
results of the Pan-American Collaborative Retina Study Group (PACORES). Retina 2008; 28(8):1044-52.
b Murakami T et al. Role of posterior vitreous detachment induced by intravitreal tissue plasminogen activator in macular edema
with central retinal vein occlusion. Retina 2007; 27(8):1031-7.


Recommendations for further follow-up

• Follow-up after 6 months for ischemia should
be every 3 months for 1 year
• Non-ischemic eyes…every 3 months for 6
months.
• Subsequent follow-up will depend on laser Tx
& complications.
• Development of disc collaterals +/- resolution
of CRVO should lead to discharge from
clinical supervision


SUMMARY

Summary

• CRVO…potentially blinding
• Local & systemic risk factors
• Young pts need special workup
• Many treatment options…difficult to decide
• Guidelines are helpful


Take home message

• Emphasis should be on:

– Differentiating ischemic & Nonischemic CRVO
– Exploring the risk factors (local & systemic)
– Treating CRVO and Referral to physician for risk
factors
– Proper follow-up


THANKS

MCQs
1. A 69-year-old man presents with sudden onset of
painless, DV in right eye of 1 week's duration.
BCVA was 20/200 OD and 20/25 OS with no
afferent pupillary defect OD. He is diagnosed as
CRVO case with diffuse macular edema. FA
reveals retinal capillary non-perfusion in less than
10 disc areas and diffuse dye leakage in the fovea.
OCT shows large cystic spaces with an increased
foveal thickness of 495 μm.
Based on the results of SCORE-CRVO trial, which of the following
would be the best option for this patient?
1. Intravitreal injection(s) of 1 mg triamcinolone
2. Intravitreal injection(s) of 4 mg triamcinolone
3. Intravitreal injection(s) of either 1 mg or 4 mg triamcinolone
4. Observation

• Ans. 1


…Continued case 1…

• How would treatment differ if the patient is treated
according to the CRUISE trial?
1. Observation
2. Single grid macular laser treatment
3. Monthly intravitreal injections of an anti-VEGF agent
4. Monthly intravitreal injections of a corticosteroid

Ans. 3



• The treating physician opts for intravitreal injection
of an anti-VEGF agent.
Assuming an optimal response, what kind of improvement would
the average patient expect if treated by monthly intravitreal
ranibizumab for 6 months?
1. 1-line gain
2. 2-line gain
3. 3-line gain
4. 4-line gain

Ans. 3



• In fact, in this case, vision in the right eye improves
from 20/200 to 20/80 at 1 month. FT improves from
495 to 360 µm. There is no noted
neovascularization.
Which of the following should be considered if the treating
physician follows the CRUISE trial protocol?
1. Observation
2. Intravitreal injection of an anti-VEGF agent and intravitreal
injection of a corticosteroid
3. Second injection of intravitreal anti-VEGF agent only
4. Intravitreal injection of a corticosteroid only
5. Macular grid laser

Ans. 3



• If the same pt is to be treated by following CVOS
protocol then what would be the be the Tx
1. Prophylactic PRP
2. Macular grid laser
3. IVTA
4. Observation

Ans. 4



• If this pt later develops I-CRVO & have macular
edema but no signs of neovascularization. What
would be the best option while following CVOS
protocol.
1. Immediate PRP
2. PRP on next visit
3. Macular grid
4. IVTA
5. Observation

Ans. 5


MCQ 2

• Features that may help distinguish CRVO from
carotid artery occlusive disease include all of the
following except
1. Dilated retinal veins
2. Tortuosity of retinal veins
3. Retinal artery pressure
4. Ophthalmodynamometry

Ans. 1


MCQ 3

• The most common risk factor for CRVO is
1. Diabetes
2. Hypertension
3. Hyperlipidemia
4. Smoking
5. Glaucoma

Ans. 2


True/false

• Following are true about CRVO
1. Hematological disorders are more common in pts <60 yrs age
than those above 60 yrs
2. Prognosis for younger pt is better than for older pts
3. CVOS shows aspirin can prevent recurrence in affected or
involvement of fellow eye
4. CVOS show clear benefit of prophylactic laser Tx in ischemic
eyes
5. Macular grid laser is useful in presence of ME with VA 6/18

Ans. T, T, F, F, F


True/false

• The following conditions may cause central retinal
vein occlusion in a young patient:
1. protein C deficiency
2. excess protein S
3. Antithrombin III deficiency
4. atrial fibrillation
5. factor V Leiden mutation

Ans. T,F,T,F,T


Next

• Lecture
– Dr. Yousaf Jamal
• Retinal vein occlusion…continued

• Journal club
– Dr. Iqbal


Central Retinal Vein Occlsion (CRVO)

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