Download Pathophysiology.of.retinal.vein.occlusion

In the name of god
Pathophysiology of retinal vein occlusion
Hamid Fesharaki MD
Eye department Isfahan University of medical sciences
Types of retinal venous occlusion
Central retinal vein occlusion
Branch retinal vein occlusion
Hemi retinal vein occlusion
Branch Retinal Vein Occlusion
• The ophthalmoscopic findings
of acute BRVO include :
• superficial hemorrhages, retinal
edema, and often cotton-wool spots
(NFL infarcts) in a sector of retina
drained by the affected vein . Branch
retinal vein occlusions occur most
commonly at an arteriovenous
crossing.
• The degree of macular involvement
determines the level of visual
impairment.
• When the occlusion does not occur
at an arteriovenous crossing, the
possibility of an underlying
retinochoroiditis should be
considered
Branch Retinal Vein Occlusion
The mean age for patients at the time of
occurrence is their sixties.
The obstructed vein is dilated and
tortuous, and, with time, the
corresponding artery may become
narrowed and sheathed.
The quadrant most commonly affected is
the superotemporal (63%); nasal vascular
occlusions are rarely detected clinically.
A variant of BRVO based on congenital
variation in central vein anatomy may
involve either the superior half or inferior
half of the retina (hemispheric or hemi
central retinal vein occlusion
Branch Retinal Vein Occlusion
The Eye Disease Case-Control Study
identified the following abnormalities
as risk factors for the development of
BRVO:
. history of systemic arterial
hypertension .
cardiovascular disease .
increased body mass index at 20
years of age .
history of glaucoma.
Diabetes mellitus was not a major
independent risk factor.
Branch Retinal Vein Occlusion
• Histologic studies suggest that:
• common adventitia binds
the artery and the vein
together at the
arteriovenous crossing
and that thickening of the
arterial wall compresses
the vein resulting in
turbulence of flow,
endothelial cell damage,
and thrombotic occlusion.
Branch Retinal Vein Occlusion
• The thrombus may extend
histologically to the capillary
bed.
• Secondary arterial narrowing
often develops in the area of
occlusion.
• Visual prognosis in BRVO is
most closely related to the
extent of capillary damage and
retinal ischemia in the macula
Non-perfused BRVO
Branch Retinal Vein Occlusion
• . Fluorescein angiography is used to assess
the extent and location of retinal capillary
nonperfusion.
• The integrity of the parafoveal capillaries
is an important prognostic factor for visual
recovery.
• Vision may be reduced in acute cases from
macular edema, retinal hemorrhage, or
perifoveal retinal capillary occlusion.
• The hemorrhage resolves over time, and
capillary compensation and collateral
formation may permit restitution of flow
with resolution of the edema and
improvement in visual function.
• In other eyes, however, progressive capillary
closure may occur.
Ischemic BRVO with Neovascularization
Branch Retinal Vein Occlusion
• Extensive retinal ischemia
(greater than 5 disc diameters)
results in neovascularization
from the retina or optic nerve
• in approximately 40% of eyes,
and 60% of such eyes will
develop preretinal bleeding if
laser photocoagulation is not
performed.
• Overall, approximately 50%60% of patients with all types
of BRVO will maintain visual
acuity of 20/40 or better after 1
year.
Ischemic BRVO with neovascularization
Retinal vasculitis with BRVO
Retinal Vasculitis with Hemorrhages and Cotton Wool Spots
Central retinal vein occlusion
Dilated and tortuous
Retinal veins
swollen optic disc
intraretinal
hemorrhages
Retinal edema
Type 1 CRVO: A mild, nonischemic form
sometimes referred to as partial, perfused, or
venous stasis retinopathy
Nonischemic CRVO
• Mild (nonischemic)
CRVO is characterized by
• good visual acuity, a
mild afferent pupillary
defect, and mild visual
field changes.
• Funduscopy shows mild
dilation and tortuosity
of all branches of the
central retinal vein as
well as dot-and-flame
hemorrhages in all
quadrants of the retina
Nonischemic CRVO
• Macular edema with decreased
visual acuity and mild optic disc
swelling may or may not be present.
• If disc edema is prominent in
younger patients, a combined
inflammatory and occlusive
mechanism may be present that has
been termed papillophlebitis.
• Fluorescein angiography usually
demonstrates prolongation of the
retinal circulation time with
breakdown of capillary permeability
but minimal areas of nonperfusion.
• Anterior segment
neovascularization is rare in mild
CRVO.
Nonischemic CRVO
Fluorescein Angiography
A mild increase in retinal
circulation time. marked delay
in arteriovenous transit time,
which is longer than 20
seconds, masking by retinal
haemorrhages
vessel wall staining.
Late staining along the large
retinal veins is a characteristic
finding in moderate and severe
degrees of central retinal vein
obstruction.
Partial Central Retinal Vein Occlusion V Papillophlebitis OD
Pathophysiology of CRVO
• Histologic studies suggest that most forms of CRVO
have a common mechanism:
• thrombosis of the central retinal vein at and posterior
to the level of the lamina cribrosa.
• In some instances, an atherosclerotic central retinal
artery may impinge on the central retinal vein, causing
turbulence, endothelial damage, and thrombus
formation.
• central retinal artery and vein share a common
adventitial sheath as they exit the optic nerve head and
pass through a narrow opening in the lamina cribrosa.
Type 2: Ischemic CRVO
is characterized by at least 10
disc areas of retinal capillary
nonperfusion on posterior
pole view fluorescein
angiography
also known as nonperfused,
complete, or
hemorrhagic retinopathy
Ischemic CRVO
Ischemic CRVO
Ischemic CRVO is characterized by rapid onset venous obstruction
resulting in decreased retinal perfusion
severe visual loss usually less than 20/400
marked afferent pupillary defect
Ischemic CRVO
• Variable numbers of cotton-wool spots are frequently found as well
• The visual prognosis is generally poor in ischemic CRVO,
with approximately 10% of eyes achieving vision better
than 20/400
• The incidence of iris neovascularization is high (up to 60%)
Ischemic CRVO
Pathophysiology of CRVO
Because of this narrow entry in the lamina cribrosa, the vessels are in a
tight compartment with limited space for displacement. This anatomical
position predisposes to thrombus formation in the central retinal vein by
various factors:
Ocular compression of the vein:
changes in lamina cribrosa
glaucomatous cupping
inflammatory swelling in optic nerve
orbital compression
Virchow's triad for vascular occlusion
1.Hemodynamic disturbances : hyperdynamic or sluggish circulation
2. Vessel wall changes: vasculitis, endothelial damage, arteriosclerosis
3. Changes in the blood: deficiency of thrombolytic factors, increase in
clotting factors
Pathophysiology of CRVO
Occlusion of the central retinal vein leads to:
backup of the blood in the retinal venous system and
increased resistance to venous blood flow. stagnation of the
blood and ischemic damage to the retina.
It has been postulated that ischemic damage to the retina
stimulates increased production of vascular endothelial
growth factor (VEGF) in the vitreous cavity. Increased levels
of VEGF stimulate neovascularization of the posterior and
anterior segment (responsible for secondary complications
of CRVO).
It has been shown that VEGF causes capillary leakage
leading to macular edema which is the leading cause of visual loss
in both ischemic CRVO and nonischemic CRVO.
Pathophysiology of CRVO
• Unusual diseases that affect clotting mechanisms and
blood viscosity may be associated with a CRVO-like
picture
• Examples include:
• blood dyscrasias (polycythemia vera),
dysproteinemias, and causes of vasculitis (eg,
sarcoidosis, systemic lupus erythematosus), and such
hypercoagulable conditions as
hyperhomocysteinemia, protein S deficiency, and
protein C deficiency.
• Oral contraceptives and diuretics have been
implicated in CRVO.
IschemiC RVO
CRVO Systemic risk factors
• Patients may have premonitory symptoms of transient
•
•
•
•
obscuration of vision prior to overt retinal manifestations.
Systemic associations noted in the Eye Disease Case-Control
Study include :
systemic arterial hypertension
diabetes mellitus
open-angle glaucoma
• Increased intraorbital pressure is a
• rare but potentially important cause of central vein
• hyperlipidemia ?
Pathophysiology of CRVO
• hyperviscosity retinopathy can mimic a typical CRVO.
However, the retinal findings in hyperviscosity
retinopathy are generally bilateral and usually related
to dysproteinemia such as Waldenstrom
macroglobulinemia or multiple myeloma
Diagnostic testing includes serum protein
electrophoresis and measurements of whole blood
viscosity.
• In many cases, the hyperviscosity can be reversed by
plasmapheresis.
Ischemic CRVO
Persistent cystoid macular edema in CRVO
Hemi retinal vein occlusion
Hyperviscosity retinopathy of high altitude
Hyperviscosity retinopathy
CRVO due to Retinal vasculis
Toxoplasma Fulminate retinochoroiditis
Retinal vasculitis due to lupus
Shaken Baby Syndrome
Hematological disorders and other systemic conditions
Conditions that lead to increased blood viscosity such as myeloproliferative disorders are
uncommon but known to be associated with CRVO. Similarly, a number of rare systemic inflammatory
disorders causing systemic vasculitis (such as Behçet’s disease and polyarteritis nodosa) also cause retinal
vasculitis leading to RVO, especially in the younger age group. The cause and management of the RVO here is closely linked to the underlying
systemic disease and its management.
Thrombophilia refers to the propensity to develop thrombosis (usually venous) due to an
abnormality in the coagulation
system. This can be congenital (eg, Factor V Leiden, hyperhomocysteinemia or protein C, protein S and
antithrombin deficiencies) or acquired (eg, antiphospholipid syndrome), and its importance is
potentially greater in the younger age group. However Fegan’s review on CRVO and thrombophilia14 suggested that
there was a lack of consistency between studies in showing a valid association between CRVO and protein C, protein S and antithrombin III
deficiency, and factor V Leiden/activated protein C resistance.
In the antiphospholipid syndrome (APS) antibodies to phospholipid activate the coagulation cascade leading to both arterial and venous
thrombosis. Tests can be done to either detect the antibody (using the anticardiolipin antibody assay) or its effect on coagulation using a test for
lupus anticoagulant. Up to 8% of patients with APS have ocular manifestations and
4 of 8 studies reviewed by Fegan14
showed a significant association of APS in CRVO. Further studies are required to determine the strength of
association between APS and RVO.
Homocysteine is a naturally occurring amino acid not found in protein. There are many causes for hyperhomo-cysteinemia
(including rare enzyme deficiencies leading to homocystinuria) which predisposes to both arterial and
venous thrombosis.14 Several studies have questioned the validity of carrying out exhaustive tests for thrombophilia in RVO in the
absence of a suggestive medical history. However their results have shown notable evidence of an association of hyperhomocysteinemia with
CRVO sufficient to recommend the benefit of checking for hyperhomocysteinemia, which is correctable with folic acid and vitamins B6 and B12
supplements.14–17
On current evidence it would be reasonable to not recommend general thrombophilia screening for all
patients with RVO, but to reserve it for older patients with a past history of thromboembolic events and in
young patients without any other general risk factors.
Conclusion
•
•
•
•
•
•
•
•
The Exact mechanism is nor known
Systemic:
1. Vessel wall
2. Hemodynamic
3. Blood
Ocular:
Glaucoma
Anatomical
Submit
wrt
60
utf-8
hypervisco
Types 3 CRVO
An intermediate form also exists, but more •
than 80% of these eye progress to the severe
ischemic form.
Pathophysiology of RVO
Thrombosis within a retinal vein as described earlier will lead to a partial obstruction of blood flow within
the vein and from the eye. The subsequent increased intraluminal pressure, if sufficiently high, will cause
transudation of blood products into the retina according to Starling’s law. This will result in increased
interstitial (retinal) fluid and protein. The latter will increase the interstitial oncotic pressure which will
impede capillary perfusion and lead to ischemia. As stated by Campochiaro et al21 this ischemia is not an
all or none dichotomy, as those patients classified as nonischemic will still have varying degrees of retinal
ischemia.
It is well recognized that inflammation affects the progression and outcome of vitreoretinal
disease including retinal vein occlusion.22 Yoshimura et al22 have found significantly elevated
vitreous levels of the soluble cytokines interleukin (IL) 6 and 8, monocyte chemoattractant
protein-1, and vascular endothelial growth factor (VEGF) in RVO, and especially in CRVO. Funk et
al23 have also demonstrated elevated
aqueous levels of these same factors in patients with CRVO when
compared with control samples. The exact interaction of these factors remains speculative but an
understanding of the roles that VEGF fulfils is increasing. It is induced by tissue hypoxia such as retinal
ischemia and acts as an angiogenic and vasopermeable factor on endothelial cell membrane bound
receptors with tyrosine kinase activity.24 Ozaki et al25 have demonstrated that the implantation of slow release
pellets of human recombinant VEGF into the vitreous cavity of rabbits and primates leads to retinal vessel
dilatation, breakdown of the blood retinal barrier and retinal new vessel formation. Noma et al have reported
elevated aqueous and vitreous levels of VEGF and IL-6 in patients with BRVO26,27 and CRVO,28,29 compared to controls. The levels of VEGF and
IL-6 correlated with both the severity of macular edema and extent of retinal ischemia (capillary nonperfusion).
It is likely that the sudden retinal ischemia that occurs in BRVO and more so in CRVO will induce excessive
VEGF production. VEGF is produced by the retina from retinal pigment epithelial cells, endothelial cells,
and Muller cells, as well as other types of ocular tissue.22 Boyd et al found a close correlation between aqueous VEGF
levels and the course of iris neovascularization and vascular permeability in patients with ischemic CRVO.30 The excessive vascular
permeability induced by VEGF will likely contribute to the macular edema that also occurs according to Starling’s law as described above. It is
tempting to theorize that even if the primary venous obstruction was overcome (eg, via collateral formation), the macular edema can persist for
much longer due to a self perpetuating cycle of VEGF-induced vascular permeability leading to macular edema, capillary damage, and retinal
ischemia, stimulating further release of VEGF and other inflammatory cytokines leading to chronic macula edema.
cca
c
Fundus autofluorescence can detect, in patients with recent-onset CRVO, a perivenular hypoautofluorescence with a fern-like appearance.
Retinal Vasculitis due to Lupus
stemic Lupus Erythematosis - Vasculitis