Download The ABCs of RVO: A review of retinal venous occlusion

C L I N I C A L
A N D
E X P E R I M E N T A L
OPTOMETRY
REVIEW
The ABCs of RVO: A review of retinal venous occlusion
Clin Exp Optom 2013
Derek MacDonald OD FAAO
Waterloo, Ontario, Canada
E-mail: [email protected]
Submitted: 16 August 2013
Accepted for publication: 22 September
2013
DOI:10.1111/cxo.12120
Retinal vein occlusions are important causes of loss of vision; indeed, they are the second
most common retinal vascular disease, following diabetic retinopathy. For this reason
alone, primary eye-care providers must be well versed in diagnosis and management. Risk
factors, though not universally agreed upon, include but are not limited to advancing age,
systemic hypertension, arteriolarsclerosis, diabetes, hyperlipidaemia, blood hyperviscosity,
thrombophilia, ocular hypertension and glaucoma. Typically, visual loss is secondary to
macular oedema and/or retinal ischaemia. Treatment modalities have included observation, systemic thrombolysis and haemodilution, radial optic neurotomy, chorioretinal anastomosis, vitrectomy, laser photocoagulation and intravitreal injection of anti-inflammatory
and, most recently, anti-vascular endothelial growth factors.
Key words: aflibercept, bevacizumab, macular oedema, pegaptanib, ranibizumab, retinal vein occlusion, sheathotomy, vascular
endothelial growth factor, vitrectomy
In the realm of retinal vascular disease,
retinal vein occlusion (RVO) trails only diabetic retinopathy as a cause of visual loss,
with an incidence estimated to be as high
as 2.6 per cent and a prevalence of one to
two per cent in patients over the age of 40.1–3
This extrapolates to nearly 200,000 cases of
RVO in North America annually.4 RVO may
account for as much as 12 per cent of severe
visual loss, exhibiting no significant gender
or ethnic disparity.5 First described as retinal
apoplexy and haemorrhagic retinitis in the
late 1800s, RVO has been categorised anatomically as central or branch RVO, the
latter being four to six times more common.6
Central RVO blocks all venous outflow,
whereas branch RVO may be occlusion of a
first-order (hemispheric or quadrantic) or
second-order (macular or twig) tributary. A
hemi-central RVO involves blockage of one
of two central retinal vein trunks within the
optic nerve head, an anatomical variation
found in only 20 per cent of the population,
making hemi-central RVO the least common
form of RVO.7,8 Whether hemi-central RVO
is best classified as a variant of central or
branch RVO has yet to be agreed upon.9
The term venous stasis retinopathy and the
modifiers impending, incipient, partial or
incomplete have been used in describing
asymptomatic yet at-risk patients.10 Differential diagnoses include but are not limited to
ocular ischaemic syndrome, papilloedema
and diabetic and radiation retinopathies.11
CLINICAL FEATURES
A patient with RVO typically presents with
symptoms that include a painless and unilateral reduction in central vision and visual
field of variable severity. Prodromal symptoms such as amaurosis fugax that are
common in arterial occlusive disease are
rare in RVO.12 Initially, symptoms depend
primarily upon the severity of macular
oedema and retinal haemorrhaging, later
upon the complications of prolonged retinal
oedema and ischaemia, including secondary
neovascularisation.13 Visual acuity (VA) at
presentation tends to be 6/15 to 6/18 in
both ischaemic and non-ischaemic branch
RVO.14 As many as 99 per cent of eyes with
ischaemic central RVO present with VA of
6/60 or worse and nearly half show significant restrictions in peripheral visual field.
Most also demonstrate a relative afferent
pupillary defect, perhaps the most sensitive
and specific predictor of ischaemic central
RVO.
The ophthalmoscopic appearance of
central RVO has been described poetically
and accurately as a blood and thunder or
‘tomato ketchup’ fundus (Figure 1). Central
RVO exacerbates venous stasis, increases the
© 2013 The Author
Clinical and Experimental Optometry © 2013 Optometrists Association Australia
intraluminal pressure by up to 24 times, upregulates inflammatory mediators, including vascular endothelial growth factor
(VEGF) and compromises the inner bloodretinal barrier.15 This leads to transudation
of blood and plasma from the dilated and
tortuous retinal veins, producing optic nerve
head oedema, and intraretinal haemorrhages and oedema through all four quadrants of the retina, including the macula.
The appearance of hemi-central RVO is
similar but confined to one retinal hemisphere. Chronic macular oedema may
damage glial and retinal pigment epithelial
cells, further reducing retinal fluid clearance. Aqueous flare may be noted, evidence
of the inflammatory nature of RVO.16 The
presence or absence of retinal ischaemia is
an important consideration, particularly in
central RVO, although it has been suggested
that all central RVOs demonstrate ischaemia
to some degree. Ischaemic central and hemicentral RVO (representing 20 to 30 per cent
of both diagnoses) exhibit all retinal morphological alterations to a more severe
extent and are further typified by retinal
nerve fibre layer haemorrhages and numerous cotton wool spots.17 Ischaemia is thought
to result from both inflammation and the
oedema-mediated increase in interstitial
pressure physically compressing capillaries
and compromising perfusion. Pre-existing
Clinical and Experimental Optometry 2013
1
A review of retinal venous occlusion MacDonald
Figure 1. Central retinal vein occlusion. (Image courtesy of Jason
Calhoun, Mayo Clinic, Jacksonville, Florida, USA)
atherosclerosis causing arteriolar insufficiency exacerbates the hypoxia.18 Reduced
blood flow in macular capillaries is worsened
by hyperviscosity, causing further ischaemic damage to the vascular endothelium.19
Ischaemic central RVO may also involve
occlusion of the central retinal artery at the
level of the lamina cribrosa.20,21 It has been
hypothesised that the obstruction in nonischaemic central RVO is posterior to the
lamina cribrosa, allowing anterior central
retinal vein tributaries within the optic nerve
to develop collateral channels, improving
drainage and perfusion.
The retinal appearance of branch RVO
is similar to that of central RVO but confined to the sector drained by the affected
vessel and the absence of optic nerve head
oedema. Four out of five branch RVO are
found at arterio-venous crossings and as
many as two in three are found in the temporal retina due to the high number of
such crossings.22 In nearly two-thirds of
arterio-venous crossings in controls, the
relatively thick-walled arteriole lies superficial to the venule, while in cases of branch
RVO, a more superficial arteriole is essenClinical and Experimental Optometry 2013
2
Figure 2. Branch retinal vein occlusion. (Image courtesy of
Maria Whitman, Carolina Eye Associates, Southern Pines, North
Carolina, USA)
tially universal.23,24 In addition to mechanically compressing the vein against the
retina, a damaged arteriole may trigger
venous constriction through the release of
endothelin-1. Depending upon severity
and proximity to the macula, patient
symptoms vary, with superior temporal
branch RVO tending to be accompanied by
macular oedema twice as often as those in
other quadrants.
RVO is a very elegant example of a red
(haemorrhagic) infarct, whereas retinal
arterial occlusion typifies a white (ischaemic) infarct.25 Regardless of mechanism,
unresolved infarction results in tissue death;
tissue death results in visual loss.
Over time, as many as 77 per cent of
patients presenting with RVO will develop
collateral vessels, alternate pathways of
venous outflow that arise as a compensatory
response to the obstruction. This percentage seems to rise with severity of occlusion.26
Collateral formation in central RVO occurs
at the optic nerve head, whereas that in
branch RVO is most often temporal to the
macula (Figure 2). Should venous outflow
improve naturally or through prompt treat-
ment, collateralisation may become unnecessary. While many clinicians consider
collateralisation to be beneficial, it may not
serve to expedite the resolution of macular
oedema despite reducing interstitial hydrostatic pressure within the retina.27 In fact,
final VA may be worse in the presence of
collaterals, perhaps testament to the severity
of the initial occlusion.
The ophthalmoscopic assessment of RVO
can be complemented through a number of
ancillary investigations. In the presence of
extensive haemorrhaging, as many as one in
three intravenous fluorescein angiographies
may be difficult to interpret at presentation, making fluorescein angiography of
strong predictive value no earlier than three
months. Choroidal filling is normal, while
the amount of perifoveal perfusion and
macular oedema are strong prognostic indicators of the final VA.28 Late-phase fluorescein angiography will show variable staining
of the optic nerve head and retinal veins.
Typically, ischaemic central RVO will show
poor perifoveal perfusion and 10 to 30 plus
disc areas of peripheral capillary nonperfusion. An ischaemic branch RVO will
© 2013 The Author
Clinical and Experimental Optometry © 2013 Optometrists Association Australia
A review of retinal venous occlusion MacDonald
demonstrate five or more disc areas of nonperfusion.29 In central RVO, ischaemia
predisposes to neovascularisation of the
iris and/or the angle. Therefore, although
RVO is characterised as a retinal disease,
careful non-dilated anterior segment biomicroscopic and gonioscopic examination is
essential, with particular attention paid to
the pupillary margin. Neovascularisation of
the iris is noted in 16 to 21 per cent of all
central RVO but 35 to 85 per cent in the
presence of ischaemia, typically within the
first six months. The risk of anterior segment
neovascularisation increases from 16 per
cent in eyes with less than 30 disc areas of
non-perfusion to 52 per cent in eyes with
more than 75.30 Neovascular glaucoma
develops in eight per cent of all central RVO
but as many as 82 per cent of ischaemic
central RVO. Intraocular pressure (IOP)
must be carefully monitored and if left
untreated, neovascular glaucoma can be
devastating, leading to blindness in three
of four cases and phthisis bulbi in one of
four. Anterior segment neovascularisation is
rare in hemi-central and branch RVO but
posterior segment neovascularisation may
arise due to the preservation of viable retinal
vasculature supporting new vessel growth.
This neovascularisation elsewhere typically
arises at the junction of perfused and nonperfused retina.
Given that macular oedema is a common
cause of visual loss, optical coherence
tomography is helpful in documenting
its extent upon presentation and in followup. Cystic intraretinal oedema, diffuse
retinal thickening and subretinal fluid
may be observed. Cystic oedema appears
to be more disruptive than diffuse thickening or subretinal fluid. Preservation of
both the photoreceptor integrity line (the
junction between inner and outer photoreceptor segments or IS/OS line) and the
external limiting membrane are important
prognostic indicators of good post-event
VA.31–33 Thinning of the retinal nerve fibre
layer may indicate more significant retinal
ischaemia. Fundus autofluorescence is increased in the presence of macular oedema
and photoreceptor loss.34 These observations may help explain persistent poor
VA following near-complete resolution
of macular oedema and guide treatment
toward those eyes most likely to realise
improvement.
Strong prognostic indicators of poor
outcome include older age, duration and
degree of VA reduction, and duration and
amount of macular oedema, haemorrhaging and ischaemia at presentation.35,36 In
general, visual outcome is good in nonischaemic RVO, where the primary source of
poor vision is macular oedema but poor in
ischaemic RVO, where macular oedema is a
relatively minor factor.
Prompt resolution of macular oedema is
desirable given that permanent photoreceptor damage can occur within three months.37
Such resolution does not lead to a linear
improvement in VA. In the case of central
RVO, patients with initial VA of 6/12 or
better retain that in 65 per cent of cases and
90 per cent remain better than 6/60. Conversely, 79 per cent of those presenting
with VA of 6/60 or less do not show significant improvement and demonstrate a six
times greater likelihood of developing
neovascular complications. Using a relative
afferent pupillary defect in concert with
analysis of the amplitude of the b-wave electroretinogram, investigators were able to
correctly identify 97 per cent of ischaemic
central RVO. A definitive and prompt differential diagnosis at presentation is critical.
In non-ischaemic central RVO, the average
patient will lose 10 letters of acuity at
six months but only three at 12 months;
however, in ischaemic central RVO an
average loss of 15 letters at six months
becomes 35 by 12 months. Indeed, only
10 per cent of patients presenting with
ischaemic central RVO maintain a final VA
better than 6/120.38 Continued vigilance is
required as conversion to ischaemic central
RVO heralded by acuity dropping to 6/60
or less occurs in up to 34 per cent of initially
non-ischaemic cases within three years,
albeit most rapidly in the first four months.39
That being said, given that much of our
knowledge of the natural history of central
RVO has been derived from post-hoc analyses, any prognostication must be taken with a
grain of salt.40
PATHOPHYSIOLOGY AND
RISK FACTORS
While the pathogenesis of RVO has yet to be
fully elucidated, it appears multifactorial
and different for central versus branch RVO,
although arterial disease is felt to be the
primary aetiology in both presentations.
Studies have suggested a common systemic cardiovascular risk profile, more so
for ischaemic RVO, consistent with diffuse
disease of the vascular endothelium.41 RVO
may be categorised as primary in the absence
© 2013 The Author
Clinical and Experimental Optometry © 2013 Optometrists Association Australia
of contributing systemic disease and secondary in its presence.42,43 Several mechanisms
have been proposed, at least in part dependent upon the anatomical location of the
occlusion.44 Shortly after its initial identification, some attributed central RVO to
thrombosis within the central retinal vein
at or posterior to the lamina cribrosa, while
others blamed intimal wall thickening and
dissection. Arteriolarsclerotic thickening of
an arterial wall where artery and vein share a
common adventitial sheath may cause compression of either the central or a branch
retinal vein. This may ‘pinch off’ the lumen
of the vein at the level of the lamina cribrosa,
where the central retinal vein naturally
narrows in healthy aging eyes, disrupting
laminar flow and increasing the likelihood
of thrombus formation. Akin to other
venous occlusive processes, the Virchow
triad of hypercoagulability, vascular turbulence and stasis and endothelial injury can
explain the pathophysiology of RVO.45
Peripheral arterial disease, coagulopathies, particularly in younger individuals,
complicated diabetes with end-organ
damage, associated with a two-fold increase
in risk of central RVO and hypertension and
hyperlipidaemia, two critical systemic risk
factors for RVO, must be considered.46–48
Diabetes appears to be of more significance
in central RVO, whereas hypertension is
more prevalent in branch RVO.49 Carotid
artery disease is an important comorbidity
requiring investigation.50 Increased blood
viscosity may exacerbate stasis of venous
flow and, in fact, hyperviscosity syndromes
may cause retinopathy clinically indistinguishable from central RVO.51 Dehydration
and smoking both increase blood viscosity
leading to stagnation of microcirculation,
one of the principle causes of capillary
non-perfusion.
Thrombophilia is the propensity to develop venous thrombosis due to abnormal
coagulation. It may be congenital or
acquired and has long been an area of interest, particularly in younger patients, among
whom the pathogenesis of RVO may differ
from that of older patients with coexisting
atherosclerosis. An imbalance in clot formation versus clot breakdown (increased
coagulation and decreased fibrinolysis) has
been reported in patients with central RVO
and predisposes to neovascularisation.52
A meta-analysis of nearly one-half million
patient files indicated a relative risk for
central retinal vein occlusion of nearly 2.5
times in the presence of a hypercoagulable
Clinical and Experimental Optometry 2013
3
A review of retinal venous occlusion MacDonald
state, including hyperhomocysteinaemia, a
recognised risk factor for both arterial and
venous thrombosis.53 There is an increased
risk of RVO in otherwise healthy young
women using oral contraceptive medications, known to increase thrombus formation.54,55 Conversely, the risk of RVO is 70 per
cent lower in post-menopausal women being
treated with exogenous estrogen, consistent
with the reduced cardiovascular risk profile associated with hormone replacement
therapy.56 The factor V Leiden mutation may
increase the risk of RVO through its effects
on activated protein C (an inhibitor of clot
formation).57 Some young patients presenting with RVO demonstrate significantly
increased resistance to activated protein C
and should be counselled on their increased
risk of deep vein thrombosis and pulmonary
embolism, cautioned against smoking and
carefully monitored if using oral contraceptives or undergoing surgery.
Obstructive sleep apnoea (a disorder
characterised by intermittent cessation of
breathing during sleep) is estimated to affect
one in four middle-age men and may independently double the annual incidence of
RVO.58 Patients with RVO and obstructive
sleep apnoea share a number of common
risk factors, including hypertension and
tendencies to hypercoagulate, and hypoxiamediated dilation of the cental retinal artery
may compress the central retinal vein at the
lamina cribrosa.
Systemic vasculitis, as evidenced by
elevated C-reactive protein and erythrocyte
sedimentation rate, may predispose to RVO.
Erythrocyte sedimentation rate seems more
important in females and less important
in branch RVO. While matrix metalloproteinase 2 gene variants appear to increase
susceptibility to RVO, pro-atherosclerotic
inflammation-related gene polymorphisms
at the interleukin and tumour necrosis
factor alleles have not been confirmed
as independent risk factors.59–61 Treatment
with systemic anti-inflammatory agents has
been inconclusive.62
Ocular hypertension is an important
ophthalmic consideration in RVO. Ocular
hypertension may cause physical compression of the central retinal vein as it passes
through the lamina cribrosa, which itself
may be anatomically altered by increased
IOP. This may lead to disturbed laminar
fluid flow and thrombus formation. In the
presence of glaucoma, the incidence of
central RVO may be as high as 4.5 per cent.
Studies have found an odds ratio of 5.4 for a
Clinical and Experimental Optometry 2013
4
history of glaucoma in patients with central
RVO and glaucoma may be found in as many
as 29 per cent of cases of central RVO.63
In patients with central RVO, fellow eyes
demonstrate a statistically higher IOP than
in controls. It has been suggested that
the unique anatomy of the central retinal
vein characterising hemi-central RVO may
predispose to concurrent open-angle glaucoma.64 IOP-lowering therapy helps improve
perfusion in the presence of RVO and may
be considered in the fellow eye, which has
a 10 per cent risk of RVO development.
Indeed, nine per cent of contralateral eyes
may show evidence of prior or concurrent
RVO. Despite lacking elevated IOP, eyes
with normal-tension glaucoma also demonstrate an increased risk of RVO.65 In such
cases, the risk of permanent VA reduction
seems higher, perhaps due to the preexisting vascular insufficiency that may
accompany normal-tension glaucoma and
the fact that branch RVO seems to occur
closer to the optic nerve head, causing more
retinal ischaemia.
Although central retinal vein occlusion
tends to be a disease of the elderly, one in six
is found in patients younger than 55 years.
The clinical course of this subgroup is more
variable and presenting VA does not seem
to be as important a prognostic indicator
as in older patients. Presenting VA tends to
be slightly better at 6/15 versus 6/24,
although final VA is statistically more likely
to drop precipitously, secondary to macular
oedema or vitreous haemorrhage, often
within the first several months. Interestingly,
there is also a greater likelihood of initial
poor acuity improving in younger patients,
albeit slowly. The typical systemic vascular
profile is observed, with two in three having
a history of hypertension, diabetes and/or
hyperlipidaemia. Bilateral central RVO in a
young patient is strongly suggestive of a haematologic or coagulation disorder.66 The
risk of anterior segment neovascularisation
is comparable, while posterior segment
neovascularisation is more common in
younger individuals. Both may occur late in
the clinical course, necessitating vigilant
monitoring.
TREATMENT
Regardless of age, treatment of contributing
systemic vascular conditions is important
to prevent both life- and sight-threatening
complications, including involvement of
the fellow eye.67 RVO may be independently
associated with increased cardiovascular
mortality.68 In male smokers, the 10-year
relative risk of developing cardiovascular
complications after RVO is more than fourfold that of controls. Increased physical
activity and, interestingly, moderate alcohol
consumption decrease the risk of central
RVO.
Treatment of the RVO itself may be
directed at the aetiology or the sequelae of
the occlusion. Reduction of blood viscosity
through haemodilution leads to increased
blood velocity in areas of compromised
retinal microcirculation and improves the
visual prognosis of some patients with
central RVO.69 Due to the risk of increasing
ischaemia, this treatment may be best
avoided in patients with concurrent cardiovascular, renal or pulmonary comorbidities,
describing the majority of patients with
RVO. More targeted treatment early in
the course of moderate non-ischaemic
central RVO, selectively reducing red blood
cell count alone, may improve VA, reduce
central retinal thickness and prevent conversion to ischaemic central RVO, while maintaining a more favourable systemic safety
profile.70
Systemic heparin, streptokinase and tissue
plasminogen activator have been used
(heparin as early as 1938) to ‘tip the balance’
from thrombogenesis to thrombolysis.
Although decreased systemic coagulability
seemed universal after treatment, improvement in vision was not, supporting a multifactorial aetiological hypothesis of central
RVO being due to more than thrombus formation alone. Particularly with streptokinase, secondary and immediate vitreous
haemorrhage exacerbated visual loss in a
number of patients. Building upon its long
track record in the treatment of cardiovascular and cerebrovascular disease, the use
of systemic tissue plasminogen activator
in concert with acetylsalicylic acid, a platelet aggregation inhibitor, was viewed with
optimism; however, a prospective study over
nearly 40 years suggested that patients taking
anticoagulants and/or aspirin at presentation with central RVO consistently showed
more retinal haemorrhaging, poorer VA
and more visual field loss than patients who
were not.71 There may be an important
distinction between the aetiology and treatment of central RVO versus deep vein
thrombosis based upon the role of the adjacent central retinal artery. It is also important to note that patients taking such
medications may be doing so as a result
© 2013 The Author
Clinical and Experimental Optometry © 2013 Optometrists Association Australia
A review of retinal venous occlusion MacDonald
of systemic risk factors that predispose to
central RVO. Some authors have gone as
far as to suggest that warfarin and acetylsalicylic acid are independent risk factors for
central RVO and advise against their use in
treatment. Conversely, others believe that
acetylsalicylic acid increases optic nerve
head blood flow and leads to more rapid
resolution of macular oedema associated
with non-ischaemic central RVO.72 Retinal
endovascular fibrinolysis, the direct injection of tissue plasminogen activator into an
occluded central retinal vein post-vitrectomy
with or without ancillary intravitreal steroid
or scatter laser, promotes visual recovery
superior to natural history, while mitigating
the potential side effects of systemic tissue
plasminogen activator.73,74 Prompt administration of treatment prior to thrombus
organisation appears to improve success.75
Creation of a therapeutic chorioretinal
anastomosis, an alternative drainage pathway bypassing the site of obstruction by
directly connecting venous outflow to the
choroidal bed, may be considered for
perfused RVO. Successful laser anastomosis
creation appears possible in three of four
cases, particularly with direct venous puncture in younger patients with better baseline
VA.76 This results in a relative VA advantage
of eight to 12 letters versus control over 18
months of follow-up. Conversion to ischaemic RVO may be prevented.77 Complications including vitreous haemorrhage and
choroidal neovascularisation seem more frequent with high-intensity laser treatment
and physical incisional surgery and in the
presence of systemic hypertension and
retinal ischaemia.78,79
Arteriovenous sheathotomy, the surgical
separation of retinal artery and vein through
cutting the common adventitial sheath,
may be employed in conjunction with vitrectomy to relieve venous compression in
branch RVO.80 While reduction of macular
oedema and prevention of neovascularisation are often achieved, VA improvement
is more equivocal. In some cases, resolution of macular oedema occurs despite
sheathotomy being anatomically impossible,
raising questions about the relative contributions of decompression versus stand-alone
vitrectomy.81
Given the above and the fact that
vitreomacular traction may exacerbate
macular oedema, vitrectomy alone has
been studied as a means to release traction,
remove angiogenic agents and improve oxygenation to the inner retina.82–85 A number
of inflammatory mediators, including VEGF
and agents within the interleukin and
C-reactive protein families have been isolated and directly correlated with increased
macular oedema in eyes with RVO.86,87 Conversely, the anti-inflammatory activity of
pigment epithelium derived factor appears
to be down-regulated. Given the increasing
popularity of intravitreal injections in the
treatment of macular oedema and the
potential reduction in their efficacy postvitrectomy, this approach is likely to face
continued scrutiny.
The theory of neurovascular compression within the optic nerve at the level of
the lamina cribrosa birthed radial optic
neurotomy as a treatment modality.88 Radial
optic neurotomy involves a radial incision
made parallel to the retinal nerve fibre layer
on the nasal aspect of the optic nerve head to
the level of the lamina cribrosa/scleral ring,
sparing the temporal papillomacular retinal
nerve fibre bundle. In theory, this decompresses the central retinal artery and vein
at an anatomical bottleneck, alleviating a
potential ‘compartment syndrome’. Individual variations, including smaller than
average scleral ring or thickening of the
adventitia, may predispose some patients to
neurovascular compression, further narrowing the lumen of the central retinal vein,
increasing turbulence and the potential for
thrombus formation. In an initial case series,
90 per cent of patients with severe central
RVO experienced anatomical resolution
and rapid clearing of haemorrhaging, with
73 per cent ultimately improving in VA by
an average of five Snellen lines. Subsequent
randomised prospective studies and anatomical rationalisation of the role of compartment syndrome have been equivocal.89,90
It has been hypothesised that at least part
of the success of radial optic neurotomy
is attributable to the accompanying vitrectomy or the induction of an optociliary
anastomosis.91–93 Given the potential for
serious complications, including neovascularisation, globe perforation and catastrophic intraocular haemorrhage due to
laceration of the central retinal artery and
vein and/or the Zinn-Haller arterial circle,
radial optic neurotomy requires an experienced surgeon exercising great care.
Laser photocoagulation was long considered the gold standard for the treatment of
RVO sequelae despite rather modest functional (VA) improvement. The Branch Vein
Occlusion Study concluded that macular
grid photocoagulation is indicated for the
© 2013 The Author
Clinical and Experimental Optometry © 2013 Optometrists Association Australia
reduction of persistent macular oedema secondary to branch RVO when VA is less than
6/12.94 While treatment should be deferred
for three months to allow for the spontaneous improvement that characterises the
natural history of branch RVO, greater
VA improvement was noted when laser
treatment was initiated within 12 months.95
Treatment must be deferred in the face
of significant haemorrhaging and is not
helpful in the presence of macular ischaemia.96 Unlike branch RVO, visual loss in
central RVO is not responsive to grid laser
therapy even in the face of intravenous fluorescein angiographic evidence of a significant reduction in macular oedema.97–99 In
fact, following the Central Vein Occlusion
Study, observation remains the standard of
care for central RVO-associated macular
oedema.100 This difference likely reflects
the diffuse capillary leakage characterising
central RVO as opposed to the more focal
nature of branch RVO. While preventative
peripheral scatter photocoagulation may
be considered in ischaemic branch RVO,
panretinal photocoagulation is only indicated in ischaemic central RVO in the
presence of, but not for the prevention
of, anterior segment neovascularisation.
Panretinal photocoagulation is often successful in inducing regression of the
neovascularisation of the iris and angle
and preventing neovascular glaucoma
through the deliberate destruction of retina
and reduction in stimulus for neovascularisation.101 Neovascularisation shows
two to four times the post-treatment regression in panretinal photocoagulation-naïve
eyes than in repeat treatment.
Over the past decade, the use of antiVEGF agents has revolutionised the treatment of retinal vascular disorders, from
age-related macular degeneration (AMD) to
proliferative diabetic retinopathy to RVO.
The VEGF family was identified in 1989,
although the presence of an angiogenic
‘factor X’ responsible for anterior segment
neovascularisation was proposed 40 years
earlier.102 VEGF-A through to -F and placental growth factor regulate angiogenesis and
vascular permeability.103 VEGF-A, initially
known as vascular permeability factor, has
emerged as the isomer primarily responsible
for ocular angiogenesis, and is generally
abbreviated simply as VEGF. Low levels of
systemic VEGF are critical for normal physiologic function and tissue maintenance.
The primary producers of intraocular VEGF
are the retinal ganglion cells, Müller cells
Clinical and Experimental Optometry 2013
5
A review of retinal venous occlusion MacDonald
and retinal pigment epithelium. VEGF is
up-regulated by ischaemia and inflammatory mediators and evidence of its pivotal
role in ocular angiogenesis accumulated
rapidly. Intraocular administration of VEGF
increased retinal ischaemia and vascular
permeability and elevated intraocular levels
of VEGF were found in many neovascular
syndromes including RVO, which demonstrates concentrations up to 33 times
that observed in healthy eyes.104,105 VEGF
increases vascular permeability by loosening
tight junctions between endothelial cells,
breaks down the inner and outer bloodretinal barrier and promotes endothelial
cell migration and proliferation leading
to neovascularisation.106,107 In cases of
ischaemic central RVO, intraocular levels
of VEGF are driven by severity of ischaemia
and are strongly correlated with future
neovascularisation. There is a direct correlation between VEGF levels and macular
thickness, and an inverse relationship with
VA. While the pathogenesis of vascular
disease is multifactorial, the inhibition
of VEGF alone is sufficient to inhibit
neovascularisation.108
Steroids prevent breakdown of the bloodretinal barrier by, among other mechanisms,
indirectly inhibiting VEGF and other inflammatory mediators, including interleukins
and prostaglandins, critical protagonists
in the final pathway to retinal ischaemia.
Intravitreal injection or implantation of
steroid allows for high intraocular concentrations, while minimising systemic absorption and side effects.109 Over the last decade,
several studies, including the SCORE Series,
have shown intravitreal preservative-free
triamcinolone acetonide to be nearly fivefold superior to standard care (observation as per the Central Vein Occlusion
Study) with respect to VA improvement
in non-ischaemic central RVO.110,111 Eyes
with branch RVO did not respond better to
intravitreal triamcinolone acetonide than to
standard care (grid laser when VA was less
than 6/12 as per the Branch Vein Occlusion
Study). In fact, grid laser proved beneficial
across a wide range of visual acuities
and remained standard care. Intravitreal
triamcinolone acetonide may be effective as
an adjunctive treatment to grid laser. Eyes
with hemi-central RVO appear to respond to
intravitreal triamcinolone acetonide in a
manner akin to branch RVO, suggesting that
the two occlusions share clinical similarities.112 There was no statistically significant
reduction in macular oedema or long-term
Clinical and Experimental Optometry 2013
6
neovascular events in the treatment groups
when compared to standard care. Therefore, the significant improvement in VA
in central RVO was not secondary to a simple reduction in central retinal thickness,
emphasising the importance of inflammation.113 Microperimetry demonstrates improved macular sensitivity in non-ischaemic
central RVO after intravitreal triamcinolone
acetonide.114 The response to intravitreal
triamcinolone acetonide is short-lived,
necessitating administration every four
months for persistent macular oedema
and may demonstrate tachyphylaxis, losing
effectiveness beyond one year despite repeated injections. Dose-dependent steroidspecific side effects include cataract formation and ocular hypertension, the latter in
30 to 50 per cent of cases. Use of the lowest
effective steroid dose provided an adverse
event profile similar to that of observation
alone.115
It has been suggested that the risks of
repeated intravitreal triamcinolone acetonide may be addressed through the use
of sustained-release steroid liquid or
implant.116,117 Due to its relatively short
intravitreal half-life but anticipated longer
duration of effect, the injectable Ozurdex
biodegradable dexamethasone insert may
prove to be the steroid of choice.118 Through
the GENEVA trials investigating both central
and branch RVO, Ozurdex proved safe and
effective in improving VA and reducing
central retinal thickness at 90-days after
initial and repeat treatments.119,120 A mean
10-letter improvement occurring within
90 days wanes to three letters at day 180,
meaning that more frequent injection may
be necessary but does appear successful.121
Duration of macular oedema at initiation
of treatment was a strong independent predictor of post-treatment VA improvement
and macular oedema reduction.122 Intraretinal haemorrhage improves and active
neovascularisation stabilises more rapidly in
treated eyes.123 Ocular hypertension proved
relatively rare, peaking at day 60, typically
responding to topical treatment and normalising by day 180 after initial and repeat
treatment. Cataract progression was more
common following repeat treatment.
Fluocinolone acetonide implants have
shown near-universal cataract formation and
IOP increase to greater than 30 mmHg in
two-thirds of eyes, necessitating filtration
surgery in one-third and explant of the insert
in several. Still, regulators have granted
approval for the treatment of inflammatory
and neovascular syndromes not adequately
addressed by other therapies.124
Research around specific therapeutic
inhibition of the four principle VEGF
isoforms containing 121, 165, 189 and 206
amino acids led to the development of
aptamers (oligonucleotide ligands that
selectively bind to molecular targets), fusion
proteins and antibodies and antibody fragments. Pegaptanib sodium is an RNA
aptamer with a molecular weight of 40
kiloDaltons (kDa) that binds selectively
to VEGF165, the most prevalent isoform in
ischaemia-mediated macular oedema and
ocular angiogenesis.125 Ranibizumab is a
48 kDa antibody fragment that binds to all
VEGF isoforms. Aflibercept is a 115 kDa
pan-VEGF receptor decoy that also binds
placental growth factor.126 These ophthalmic agents are complemented by bevacizumab, a 149 kDa full-length antibody
with two binding sites for all VEGF isoforms approved for systemic treatment of
advanced carcinoma in 2004.
Pegaptanib sodium (Macugen) became
the first aptamer approved for human use in
2004. Its intravitreal use has been evaluated
in diabetic macular oedema, AMD and
central RVO. Specific to the last, intravitreal
pegaptanib at six-week intervals provided a
relative improvement in mean VA of 10 to 12
letters, greater mean decrease in central
retinal thickness and less neovascularisation
than observation alone. Studies again confirmed that decreased macular oedema does
not directly correlate with improved VA.
Intravitreal pegaptanib may be an effective
alternative to intravitreal triamcinolone
acetonide and/or non-selective anti-VEGF
agents. It has been suggested that nonselective or pan-VEGF blockade may be detrimental due to blocking neuroprotective
isoforms of VEGF essential in retinal homeostasis, adaptive response to ischaemic insult
and prevention of apoptosis.127 Further, antiVEGF mediated decreases in nitrous oxide
production by endothelial cells may exacerbate macular ischaemia and reduce collateral formation.128,129
Ranibizumab (Lucentis) and off-label
bevacizumab (Avastin), both non-selective
pan-anti-VEGF agents, have taken the retinal
world by storm. Intravenous bevacizumab
at the oncologic dosage of 5.0 mg/kg
reduces macular oedema and improves VA
in neovascular AMD. In 2005, intravitreal
bevacizumab was first administered to a
patient with AMD refractory to all other
treatments.130 Studies indicated that
© 2013 The Author
Clinical and Experimental Optometry © 2013 Optometrists Association Australia
A review of retinal venous occlusion MacDonald
Figure 3. Central retinal vein occlusion several months after presentation, pre-treatment
(left) and approximately three years after presentation and following 12 doses of
intravitreal bevacizumab (right)
intravitreal bevacizumab is as efficacious as
intravenous administration, while mitigating the risk of transient ischaemic attacks,
stroke and myocardial infarction. Subsequently, intravitreal bevacizumab was considered in a number of ocular neovascular
syndromes, including but not limited to
proliferative diabetic retinopathy, pathological myopia, angioid streaks, peripapillary
choroidal neovascularisation and RVO.
Retinal penetration was good despite its
molecular weight being above the retinal
exclusion limit of 76 kDa. No retinal toxicity
was noted even at intravitreal bevacizumab
doses of 5.0 mg, four times the customary
dose. Given its indications for systemic use,
bevacizumab is supplied in either four or
16 ml vials with a concentration of 25 mg/
ml. Compounding pharmacies must partition it using aseptic techniques to allow
for more typical 1.0 to 1.25 mg off-label
intravitreal bevacizumab dosages.131 Despite
the risk of contamination associated with
compounding, there is significant economic incentive to continue this practice:
intravitreal bevacizumab can be one-fortieth
the price of intravitreal ranibizumab.132 Incidents of endophthalmitis have led some to
suggest compounding single rather than
multiple doses of intravitreal bevacizumab,
increasing costs but minimising risks.133
Eyes with central RVO treated with
intravitreal bevacizumab tend to demonstrate significant decreases in central retinal
thickness within two weeks, preceding peak
improvement in VA (Figure 3).134 VA
improvement was greatest in patients symptomatic for less than three months, while
central retinal thickness decrease was independent of symptom duration. Although
treatment of central RVO may lead to
greater relative reduction in central retinal
thickness, treatment of branch RVO tends to
yield more improvement in VA.135 Intravenous fluorescein angiography demonstrates
a marked reduction in dye leakage within
one week of treatment136 (Figure 4).
Intravitreal bevacizumab is also efficacious
in reducing or inducing regression of
neovscularisation of the iris and angle and
neovascular glaucoma, often dramatically
within days of administration.137–144 Benefits
tend to be sustained at 12 months providing
treatment is continued at intervals no less
frequent than every 12 weeks. Early initiation of treatment proved important, particularly for patients over the age of 70, who
showed a mean VA gain of 21 additional
letters with early versus delayed treatment
despite equivalent central retinal thickness
reduction. Patients not responsive to initial
therapy do not show an enhanced response
to more intensive treatment. Unlike
intravitreal
triamcinolone
acetonide,
intravitreal bevacizumab shows no tendency
toward expedited cataract formation. A mild
anterior chamber reaction has been
reported in approximately 20 per cent of
cases. Electrophysiological testing shows no
retinal toxicity and no local or systemic
adverse effects are consistently reported;
however, isolated cases of post-intravitreal
bevacizumab ‘rebound’ macular oedema
more severe than that noted pre-treatment,
perhaps due to up-regulation of VEGF
receptors, have been documented.145,146
© 2013 The Author
Clinical and Experimental Optometry © 2013 Optometrists Association Australia
Early growth of an epiretinal membrane has
also been noted after intravitreal
bevacizumab, although eyes with chronic
macular oedema are already prone to
epiretinal membrane formation, albeit not
typically as early as several months.
Despite being first-line RVO therapy
for a slim majority of retinal specialists,
intravitreal bevacizumab is being used offlabel, whereas intravitreal ranibizumab has
been approved for a number of ocular
neovascular syndromes, including RVO in
2009.147 Intravitreal ranibizumab inhibits
all isoforms of VEGF, binding with an affinity
of 100 to 140 times that of intravitreal
bevacizumab. Clinical efficacy appears
equivalent to intravitreal bevacizumab with a
comparable administration schedule. The
CRUISE and BRAVO studies indicated that
monthly intravitreal ranibizumab in both
central and branch RVO yields an improvement in Early Treatment Diabetic Retinopathy Study (ETDRS) acuity after six months
of nine to 14 letters above sham treatment,
with the majority of that gain occurring
by day seven.148 The speed of improvement
suggests that the bulk of RVO-induced
macular oedema is VEGF-mediated, rather
than the result of increased venous pressure. In central more so than branch RVO,
early response to intravitreal ranibizumab,
defined as central retinal thickness of
250 μm or less at month three, was a reliable predictor of longer-term treatment
success.149 Maintenance of the central retinal
thickness reduction at month six was two
to three times as common with monthly
intravitreal ranibizumab as with sham treatment: three of four patients with central
RVO and five of six with branch RVO showed
no residual macular oedema after intravitreal ranibizumab. As-needed dosing for a
subsequent six to 18 months maintained
both VA improvement and central retinal
thickness reduction and this emphasised
the importance of regular follow-up and
individualised treatment, particularly for
patients with central RVO.150,151 Control
patients who received intravitreal ranibizumab beginning at month six showed comparable mean central retinal thickness
reduction but less VA improvement than
those treated earlier—more evidence of
the indirect relationship between reduced
macular oedema and improved VA and an
argument in favour of early treatment.152
Intravitreal ranibizumab speeds the resolution of intra-retinal haemorrhage, theoretically allowing for earlier concomitant grid
Clinical and Experimental Optometry 2013
7
A review of retinal venous occlusion MacDonald
Figure 4. Intravenous fluorescein angiography after central retinal vein occlusion showing arterial (left), venous (middle) and late
(right) phases approximately 10 months after presentation, post-intravitreal bevacizumab in six doses.
laser in cases of branch RVO. While CRUISE
and BRAVO suggested that intravitreal
ranibizumab appears to slow the progression
of retinal non-perfusion and may improve
reperfusion in RVO, eyes with significant
pre-existing ischaemia may respond quite
differently to anti-VEGF therapy.153 As with
intravitreal bevacizumab, weaning patients off treatment altogether has proven
difficult.154
Interestingly, one of the purported advantages of intravitreal bevacizumab or ranibizumab versus intravitreal triamcinolone
acetonide and steroid implants is IOP stability;155 however, a statistically significant and
sustained elevation of IOP after intravitreal
bevacizumab or ranibizumab may be noted,
not attributable to the addition of volume
alone, and more so in patients already diagnosed with glaucoma.156,157 Proposed mechanisms include pharmacologic increase,
trabeculitis or physical trabecular meshwork
blockade. The latter may explain the slightly
greater rate of IOP elevation with the larger
molecular weight bevacizumab, although
the compounding required for intravitreal
bevacizumab may be contributory. Given
that the number of patients receiving
intravitreal bevacizumab or ranibizumab is
only likely to increase, more investigation is
necessary.
Aflibercept (Eyelea or VEGF Trap-Eye)
binds both VEGF and placental growth
factor, another mediator of retinal vascularisation and vascular permeability.158
Whereas ranibizumab has a VEGF-binding
affinity 100 to 140 times that of bevacizumab,
aflibercept is even higher, theoretically
allowing for a longer interval between injections and a commensurate reduction in
Clinical and Experimental Optometry 2013
8
treatment cost. Clinical efficacy and systemic
safety in treatment of RVO appear equivalent to bevacizumab and ranibizumab.159–161
In the GALILEO study, intravitreal aflibercept proved superior to sham in the treatment of central RVO-associated macular
oedema, providing a mean VA gain of 18
ETDRS letters and a near 450 μm reduction
in central retinal thickness following six
injections at one-month intervals.162 Similar
efficacy was demonstrated through the
COPERNICUS study, with a mean 17 letter
gain in VA and 457 μm reduction in central
retinal thickness following six monthly injections.163 A 16 letter VA gain and 413 μm
central retinal thickness reduction was maintained after six more months of careful
as-needed dosing. For patients initially
assigned to sham treatment, as-needed dosing beginning at six months produced
impressive reductions in central retinal
thickness but limited improvement in VA.
Again, this implicates chronic macular oedema as a source of irreversible photoreceptor
damage and supports prompt intervention.
Based on these results, FDA approval for
intravitreal aflibercept treatment of central
RVO was granted in late 2012.164
While significant differences between
study designs and populations make direct
comparison of RVO treatments difficult,
there may be advantages to exploit and synergies to leverage. Inter-patient variability
and the multifactorial pathophysiology
of macular oedema highlight the need to
consider complementary or combination
therapy, particularly in the face of inadequate initial response.
A retrospective analysis of treatment
of macular oedema with both intravitreal
triamcinolone acetonide and intravitreal
bevacizumab showed no statistically significant difference in VA until 12 weeks
after treatment, when the intravitreal
bevacizumab-treated group enjoyed an
advantage, which waned as more time
elapsed.165 Central retinal thickness measurements showed no statistical difference at
any point after treatment. Cataract formation was negligible in both groups, while IOP
was significantly higher after triamcinolone
acetonide at weeks four, eight and 12.
Given their effectiveness in isolation, the
combination of bevacizumab plus triamcinolone acetonide has also been studied.
While anti-VEGF injections seem to normalise the retinal appearance more effectively
than intravitreal triamcinolone acetonide,
persistent macular oedema after intravitreal bevacizumab appears amenable to
triamcinolone acetonide in both primary
and repeat treatment.166 Others have
investigated intravitreal bevacizumab plus
Ozurdex and conclude that combination
therapy may be synergistic in improving
VA and lengthening the time required
between treatments, particularly after
central RVO.167 In the case of central RVO, it
may be reasonable to consider a ‘loading
dose’ of six-monthly intravitreal ranibizumab injections followed by ongoing
monthly follow-up with treatment dictated
by VA and/or central retinal thickness. In
the case of branch RVO with macular
oedema, anti-VEGF treatment for the first
six months could be followed by grid laser,
should macular oedema persist or recur.168
In some trials, ischaemic complications were
experienced despite anti-VEGF treatment,
prompting investigators to suggest that con© 2013 The Author
Clinical and Experimental Optometry © 2013 Optometrists Association Australia
A review of retinal venous occlusion MacDonald
current laser treatment may be necessary
for ischaemic central RVO. Panretinal photocoagulation and peripheral scatter laser
remain the most effective treatments for
permanently reducing VEGF expression
and ischaemic complications following
RVO.169 Although laser may lessen the future
anti-VEGF treatment burden, it does not
guarantee visual improvement beyond that
attributed to injection in isolation.
A number of questions remain around the
use of anti-VEGF agents in patients with
RVO.
1. What is the role of intravitreal bevacizumab, ranibizumab or aflibercept in
patients with initial VA better than 6/12?
2. What is the role of intravitreal bevacizumab, ranibizumab or aflibercept
in patients with severely reduced VA,
likely secondary to advanced macular
ischaemia?
3. How long can or should initial intervention be deferred in RVO, realising that
spontaneous improvement is possible in
up to one in three patients but recognising the detrimental effects of prolonged
macular oedema?
4. Can a loading dose followed by a ‘treat
and extend’ philosophy adequately
address persistent or recurrent macular
oedema?
5. Are intravitreal bevacizumab, ranibizumab and aflibercept equivalent in
treating RVO?
A partial answer to the last question may
be alluded to in the results of the CATT study
comparing intravitreal bevacizumab and
ranibizumab in the treatment of neovascular
AMD.170,171 After one year, bevacizumab
and ranibizumab administered at the same
schedule had equivalent effects on VA,
although mean central retinal thickness was
reduced slightly more effectively through
monthly ranibizumab. At the beginning of
year two, some patients initially treated
monthly were switched to as-needed dosing
but all patients retained their original drug
assignment. Such a ‘treat and extend’ or
‘treat and observe’ strategy is the pattern of
many retinal specialists. After two years, a
small difference in mean VA gain was noted
favouring ranibizumab, with the greatest difference between ranibizumab monthly and
bevacizumab as-needed. The bevacizumab
as-needed group also showed a slightly
greater prevalence of residual subretinal
fluid. Similar results were found in the IVAN
trial. There were inconclusive differences in
VA between bevacizumab and ranibizumab
and between continuous and discontinuous
treatment at one year, although retinal
morphologic status favoured continuous
treatment.172 An accompanying metaanalysis of clinical trials concluded that the
two drugs have equivalent effects on VA but
that intravitreal ranibizumab and continuous treatment result in greater reduction in
central retinal thickness.
However, neovascular AMD and RVO are
very different disease processes, making
extrapolation difficult if not ill-advised. The
dramatically elevated VEGF levels that typify
RVO may favour the higher binding affinity
of ranibizumab over that of bevacizumab in
the immediate reduction of central retinal
thickness.173 The CRAVE trial, currently
underway, has been designed to provide
more conclusive answers to this important
question.
There is systemic absorption and distribution following intravitreal bevacizumab,
which has a serum half-life of 20 days, more
so than following ranibizumab with its serum
half-life of only six hours. In fact, a therapeutic effect has been noted in an untreated
eye with branch RVO following contralateral intravitreal bevacizumab injection for
AMD.174 Systemic VEGF levels are reduced
117-fold at day one and four-fold at month
one after intravitreal bevacizumab administration, changes comparable to those
observed with systemic administration.175
Comparative and individual evaluation of
systemic thromboembolic events associated
with intravitreal anti-VEGF treatment has
provided equivocal conclusions. Investigators demonstrated that use of intravitreal
bevacizumab and ranibizumab for AMD
conferred no increased risk of stroke in patients with no prior cerebrovascular history.176
Meta-analyses of major clinical trials indicated that ophthalmic anti-VEGF therapy
did not significantly increase the risk of systemic adverse events.177 The overall relative
risk of systemic adverse events was slightly
greater in the bevacizumab group at both
years one and two of the CATT study (1.3
risk ratio), although major adverse events
appeared to be of equal frequency in this
and other studies.178 A 57 per cent increased
risk of haemorrhagic stroke has been
reported with intravitreal bevacizumab as
compared to ranibizumab, while CATT
sub-analysis suggested the risk of systemic
thromboembolic events was 1.15 per cent
with bevacizumab versus 0.15 per cent with
ranibizumab.179 An Australian populationbased study showed no significant difference
© 2013 The Author
Clinical and Experimental Optometry © 2013 Optometrists Association Australia
in systemic adverse events for patients
treated with bevacizumab or ranibizumab;
however, while myocardial infarction remained rare, it was 2.3 times more likely
in the treatment group.180 Systemic risks do
not appear to be dependent upon frequency
of dosing, and it is important to note that
patients receiving ophthalmic anti-VEGF
therapy often suffer from systemic comorbidities that may predispose them to thromboembolic complications.
The future of retinal vascular disease
management seems likely to include
nanomedicine gene therapy and targeted
drug-delivery systems directed against
integrin peptides and non-VEGF mediators of angiogenesis.181,182 While initially
still requiring intravitreal injection, albeit
with potentially reduced frequency and
improved target specificity, nanoparticle
technology may eventually lend itself to
topical drug delivery. Very recently, systemic
minocycline has been investigated for its
neuroprotective activity in an animal model
of branch RVO.183 Macular oedema is
reduced, inflammatory mediators are
down-regulated, microglial activation is prevented and apoptotic pathways are inhibited. While promising, further investigation
is pending.
CONCLUSION
Retinal vein occlusion is a relatively common
and frequently devastating cause of visual
loss primarily as a result of macular oedema
and retinal ischaemia and has deservedly
received a great deal of attention. First recognised over a century ago, its pathogenesis
remains uncertain, although a variety of systemic and ophthalmic risk factors have been
identified. For many years, the standard of
care remained observation for central RVO
and grid laser for branch RVO, as despite the
efforts of many investigators, no predictably
more effective interventions were identified.
That changed with the advent of intravitreal
injections of anti-inflammatory and antiangiogenic agents, beginning with corticosteroids and evolving to include VEGF
antagonists, including pegaptanib, bevacizumab, ranibizumab and aflibercept. Much
work remains, including the identification
of the most effective single treatment or
treatment combination to minimise risk and
health-care costs, while optimising patient
outcomes in the face of this debilitating
condition.
Clinical and Experimental Optometry 2013
9
A review of retinal venous occlusion MacDonald
ACKNOWLEDGEMENTS
The author is indebted to Dr Thomas
Freddo and Dr Catherine Chiarelli for their
invaluable review and commentary.
REFERENCES
1. Klein R, Klein BE, Moss SE, Meuer SM. The epidemiology of retinal vein occlusion: the Beaver
Dam Eye Study. Tr Am Ophthalmol Soc 2000; 98:
133–143.
2. Karia N. Retinal vein occlusion: pathophysiology
and treatment options. Clin Ophthalmol 2010; 4:
809–816.
3. Wong TY, Scott IU. Retinal-vein occlusion. N Engl
J Med 2010; 363: 2135–2144.
4. The Eye Disease Case Control Study Group. Risk
factors for central retinal vein occlusion. Arch
Ophthalmol 1996; 114: 545–554.
5. Klein R, Klein BE, Lee KE, Cruickshanks KJ,
Gangnon RE. Changes in visual acuity in a population over a 15-year period: the Beaver Dam Eye
Study. Am J Ophthalmol 2006; 142: 539–549.
6. McAllister IL. Central retinal vein occlusion:
a review. Clin Experiment Ophthalmol 2012; 40:
48–58.
7. Rehak J, Rehak M. Branch retinal vein occlusion:
pathogenesis, visual prognosis, and treatment
modalities. Curr Eye Res 2008; 33: 111–131.
8. Hayreh SS, Zimmerman MB. Hemicentral
retinal vein occlusion. Natural history and visual
outcome. Retina 2012; 32: 68–76.
9. Ehlers JP, Fekrat S. Retinal vein occlusion: beyond
the acute event. Surv Ophthalmol 2011; 56: 281–
299.
10. Williamson TH. Central retinal vein occlusion:
what’s the story? Br J Ophthalmol 1997; 81: 698–704.
11. Rehak M, Wioedemann P. Retinal vein thrombosis: pathogenesis and management. J Thromb
Haemost 2010; 8: 1886–1894.
12. Hayreh SS, Zimmerman BH. Amaurosis fugax in
ocular vascular occlusive disorders. Retina 2013;
April 29 [Epub ahead of print].
13. Hahn P, Fekrat S. Best practices for treatment of
retinal vein occlusion. Curr Opin Ophthalmol 2012;
23: 175–181.
14. Jaulim A, Ahmed B, Khanam T, Chatziralli IP.
Branch retinal vein occlusion. Epidemiology,
pathogenesis, risk factors, clinical features, diagnosis, and complications. An update of the literature. Retina 2013; 33: 901–910.
15. Jonas JB. Ophthalmodynamometric assessment of
the central retinal vein collapse pressure in eyes
with retinal vein stasis or occlusion. Graefes Arch
Clin Exp Ophthalmol 2003; 241: 367–370.
16. Noma H, Mimura T, Eguchi S. Association of
inflammatory factors with macular oedema in
branch retinal vein occlusion. JAMA Ophthalmol
2013; 131: 160–165.
17. Miller JW, Le Couter J, Strauss EC, Ferrara N.
Vascular endothelial growth factor A in intraocular vascular disease. Ophthalmology 2013; 120: 106–
114.
18. Laatikainen L, Kohner EM. Fluorescein angiography and its prognostic significance in central
retinal vein occlusion. Br J Ophthalmol 1976; 60:
411–418.
19. Noma H, Funatsu H, Mimura T, Shimada K.
Visual function and serous retinal detachment in
patients with branch retinal vein occlusion and
macular oedema: a case series. BMC Ophthalmol
2011; 11: 29–35.
Clinical and Experimental Optometry 2013
10
20. Hayreh SS, Podhajsky PA, Zimmerman MB.
Natural history of visual outcome in central
retinal vein occlusion. Ophthalmology 2011; 118:
119–133.
21. Campochiaro PA, Bhisitkul RB, Shapiro H, Rubio
RG. Vascular endothelial growth factor promotes
progressive retinal nonperfusion in patients with
retinal vein occlusion. Ophthalmology 2013; 120:
795–802.
22. Zhou JQ, Xu L, Wang S, Wang YX, You QS, Tu Y,
Yang H et al. The 10-year incidence and risk
factors of retinal vein occlusion. Ophthalmology
2013; 120: 803–808.
23. Duker JS, Brown GC. Anterior location of the
crossing artery in branch retinal vein obstruction.
Arch Ophthalmol 1989; 107: 998–1000.
24. Waisbren EC, Salz DA, Brown MM, Brown GC.
Vascular crossing patterns in patients with systemic arterial hypertension. Br J Ophthalmol 2013;
97: 781–784.
25. Hayreh SS, Zimmerman MB. Fundus changes in
central retinal artery occlusion. Retina 2007; 27:
276–289.
26. Goldberg N, Freund KB. Progressive optic
nerve collateralization after serial intravitreal
ranibizumab injections for central retinal vein
occlusion. Retina 2013; 33: 449–450.
27. Saeed MU, Gkaragkani E, Eli K. Emerging roles
for antiangiogenesis factors in management
of ocular disease. Clin Ophthalmol 2013; 7: 533–
543.
28. Chan CK, Ip MS, VanVeldhuisen PC, Oden NL,
Scott IU, Tolentino MJ, Blodi BA et al. SCORE
Study report #11: incidences of neovascular
events in eyes with retinal vein occlusion. Ophthalmology 2011; 118: 1364–1372.
29. Shahid H, Hossain P, Amoaku WM. The management of retinal vein occlusion: is interventional
ophthalmology the way forward? Br J Ophthalmol
2006; 90: 627–639.
30. The Central Retinal Vein Occlusion Study
Group. A randomized clinical trial of early
panretinal photogoagulation for ischaemic
central vein occlusion. Ophthalmology 1995; 102:
1434–1444.
31. Sakamoto A, Tusjikawa A, Ota M, Yamaike N,
Kotera Y, Miyamoto K, Kita M et al. Evaluation of
potential acuity in eyes with macular oedema secondary to retinal vein occlusion. Clin Experiment
Ophthalmol 2009; 37: 208–216.
32. Kang HM, Chung EJ, Kim YM, Koh HJ. Spectraldomain optical coherence tomography (SDOCT) patterns and response to intravitreal
bevacizumab therapy in macular oedema associated with branch retinal vein occlusion. Graefes
Arch Clin Exp Ophthalmol 2013; 251: 501–508.
33. Ota M, Tsujikawa A, Murakami T, Kita M,
Miyamoto K, Sakamoto A, Yamsike N et al.
Association between integrity of foveal photoreceptor layer and visual acuity in branch retinal
vein occlusion. Br J Ophthalmol 2007; 91: 1644–
1649.
34. Sekiryu T, Iida T, Sakai E, Maruko I, Ojima A,
Sugano Y. Fundus autofluorescence and optical
coherence tomography findings in branch retinal
vein occlusion. J Ophthalmol 2012; 2012: 638064.
35. Recchia FM, Carvalho-Recchia CA, Hassan TS.
Clinical course of younger patients with central
retinal vein occlusion. Arch Ophthalmol 2004; 122:
317–321.
36. Scott IU, VanVeldhuisen PC, Oden NL, Ip MS,
Blodi BA, Hartnett ME, Cohen G et al. Baseline
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
predictors of visual acuity and retinal thickness
outcomes in patients with retinal vein occlusion:
standard care versus corticosteroid for retinal vein
occlusion study report 10. Ophthalmology 2011;
118: 345–352.
Manayath GJ. Bevacizumab (Avastin) therapy
for macular oedema in central retinal vein
occusion—long term results. Kerala J Ophthalmol
2008; 20: 355–361.
Mirashi A, Roohipoor R, Lashay A, Mohammadi
SF, Mansouri MR. Surgical induction of
chorioretinal venous anastomosis in ischaemic
central retinal vein occlusion: a non-randomised
controlled clinical trial. Br J Ophthalmol 2005; 89:
64–69.
Shah NJ, Shah UN. Long-term effect of early
intervention with single intravitreal injection of
bevacizumab followed by panretinal and macular
grid photocoagulation in central retinal vein
occlusion (CRVO) with macular oedema: a pilot
study. Eye 2011; 25: 239–244.
Decroos FL, Fekrat S. The natural history of
retinal vein occlusion: what do we really know? Am
J Ophthalmol 2011; 151: 739–741.
Channa R, Smith M, Campochiaro PA. Treatment
of macular oedema due to retinal vein occlusions.
Clin Ophthalmol 2011; 5: 705–713.
Brown DM, Campochiaro PA, Singh RP, Li Z,
Gray S, Saroj N, Rundle AC et al. Ranibizumab
for macular oedema following central retinal
vein occlusion. Ophthalmology 2010; 117: 1124–
1133.
Keane PA, Sadda SR. Retinal vein occlusion and
macular oedema—critical evaluation of the clinical value of ranibizumab. Clin Ophthalmol 2011; 5:
771–781.
Prager F, Michels S, Kreichbaum K,
Georgopoulos M, Funk M, Geitzenauer W, Polak
K, et al. Intravitreal bevacizumab (Avastin) for
macular oedema secondary to retinal vein occlusion: 12-month results of a prospective clinical
trial. Br J Ophthalmol 2009; 63: 452–456.
Stewart MW. The expanding role of vascular
endothelial growth factor inhibitors in ophthalmology. Mayo Clin Proc 2012; 87: 77–88.
Alasil T, Lee N, Keane P, Sadda S. Central retinal
vein occlusion: a case report and review of the
literature. Cases J 2009; 2: 7170–7173.
Lattanzio R, Torres Gimeno A, Battaglia Parodi
M, Bandello F. Retinal vein occlusion: current
treatment. Ophthalmologica 2011; 225: 135–143.
Bertelsen M, Linneberg A, Rosenberg T,
Christoffersen N, Vorum H, Gade E, Larsen M.
Comorbidity in patients with branch retinal
vein occlusion: case-control study. BMJ 2013; 345:
e7885.
Appiah AP, Trempe CL. Risk factors associated
with branch vs. central retinal vein occlusion. Ann
Ophthalmol 1989; 21: 153–157.
Alexander LJ. Primary Care of the Posterior
Segment. East Norwalk, Connecticut: Appleton &
Lange, 1989. p 117–128.
Williamson TH, Rumley A, Lowe GD. Blood
viscosity, coagulation, and activate protein C
resistance in central retinal vein occlusion: a
population controlled study. Br J Ophthalmol 1996;
80: 203–208.
Elman MJ. Thrombolytic therapy for central
retinal vein occlusion: results of a pilot study. Tr
Am Ophthalmol Soc 1996; 94: 471–504.
Stem MS, Talwar N, Comer GM, Stein JD. A longitudinal analysis of risk factors associated with
© 2013 The Author
Clinical and Experimental Optometry © 2013 Optometrists Association Australia
A review of retinal venous occlusion MacDonald
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
central retinal vein occlusion. Ophthalmology 2013;
120: 362–370.
Kohner EM, Pettit JE, Hamilton AM, Bulpitt CJ,
Dollery CT. Streptokinase in central retinal vein
occlusion: a controlled clinical trial. BMJ 1976; 1:
550–553.
Larsson J, Olafsdottir E, Bauer B. Activated
protein C resistance in young adults with central
retinal vein occlusion. Br J Ophthalmol 1996; 80:
200–202.
Koizumi H, Ferrara DC, Brue C, Spaide RF.
Central retinal vein occlusion case-control study.
Am J Ophthalmol 2007; 144: 858–863.
Johnson TM, El-Defrawy S, Hodge WG, Leonard
BC, Kertes PJ, Taylor SAM, Lillicrap DP. Prevalence of factor V Leiden and activated protein C
resistance in central retinal vein occlusion. Retina
2001; 21: 161–166.
Chou KT, Huang CC, Tsai DC, Chen YM, Perng
DW, Shiao GM, Lee YC et al. Sleep apnea and
risk of retinal vein occlusion: a nationwide
population-based study of Taiwanese. Am J
Ophthalmol 2012; 154: 200–205.
Maier R, Steinbrugger I, Haas A, Selimovic M,
Renner W, El-Shabrawi Y, Werner C et al. Role of
inflammation-related gene polymorphisms in
patients with central retinal vein occlusion. Ophthalmology 2011; 118: 1125–1129.
Steinbrugger I, Haas A, Maier R, Renner W, Mayer
M, Werner C, Wedrich A et al. Analysis of
inflammation- and atherosclerosis-related gene
polymorphisms in branch retinal vein occlusion.
Mol Vis 2009; 15: 609–618.
Ortak H, Demir S, Ates O, Sogut E, Alim S, Benli
I. Association of MMP2–1306C/T and TIMP2G418C polymorphisms in retinal vein occlusion.
Exp Eye Res 2013; 113: 151–155.
Mahmood T. Central retinal vein occlusion:
current management options. Pak J Ophthalmol
2009; 25: 1–4.
The Central Vein Occlusion Study Group. Natural
history and clinical management of central retinal
vein occlusion. Arch Ophthalmol 1997; 115: 486–
491.
Huang J, Ozaki H, Umeda N, Hokao K, Kozawa M,
Arita N, Hayashi H et al. Prevalence of glaucoma
in retinal vein occlusion. Poster session presented
at: 5th World Glaucoma Congress; 2013 July 17–20;
Vancouver, BC, Canada.
Sin BH, Song BJ, Park SP. Aqueous vascular
endothelial growth factor and endothelin-1 levels
in branch retinal vein occlusion associated with
normal tension glaucoma. J Glaucoma 2013; 22:
104–109.
Kress WD. Retinal venous occlusions: a systematic
review and update on current treatment options.
Rev Optom 2010; 11: 12–17.
La Spina C, De Benedetto U, Battaglia Parodi M,
Coscas G, Bandello F. Practical management of
retinal vein occlusions. Ophthalmol Ther 2012; 1:
1–10.
Khan Z, Almeida DR, Rahim K, Belliveau MJ,
Bona M, Gale J. 10-year Framingham risk in
patients with retinal vein occlusion: a systematic
review and meta-analysis. Can J Ophthalmol 2013;
48: 40–45.
Hansen LL, Wiek J, Wiederholt M. A randomised
prospective study of treatment of non-ischaemic
central retinal vein occlusion by isovolaemic
haemodilution. Br J Ophthalmol 1989; 73: 895–899.
Glacet-Bernard A, Atassi M, Fardeau C,
Romanet JP, Tonini M, Conrath J, Denis P
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
et al. Hemodilution therapy using automated
erythrocytapheresis in central retinal vein occlusion: results of a multicenter randomized controlled study. Graefes Arch Clin Exp Ophthalmol
2011; 249: 505–512.
Hayreh SS, Podhajsky PA, Zimmerman MB.
Central and hemicentral retinal vein occlusion.
Role of anti-platelet aggregation agents and
anticoagulants. Ophthalmology 2011; 118: 1603–
1611.
Maeda K, Ishikawa F, Ohguro H. Ocular blood
flow levels and visual prognosis in a patient with
nonischaemic type central retinal vein occlusion.
Clin Ophthalmol 2009; 3: 489–491.
Pournaras CJ, Petropoulos IK, Pournaras JA,
Stangos AN, Gilodi N, Rungger-Brandle E. The
rationale of retinal endovascular fibrinolysis in
the treatment of retinal vein occlusion. Retina
2012; 32: 1566–1573.
Bynoe LA, Hutchins RK, Lazarus HS, Friedberg
MA. Retinal endovascular surgery for central
retinal vein occlusion: initial experience of four
surgeons. Retina 2005; 25: 625–632.
Madhusudhana KC, Newsom RSB. Central retinal
vein occlusion: the therapeutic options. Can
J Ophthalmol 2007; 42: 193–195.
McAllister IL, Gillies ME, Smithies LA,
Rochtchina E, Harper CA, Daniell MD, Constable
IJ et al. The Central Retinal Vein Bypass Study: a
trial of laser-induced chorioretinal venous anastomosis for central retinal vein occlusion. Ophthalmology 2010; 117: 954–965.
Fekrat S, Goldberg MF, Finkelstein D. Laserinduced chorioretinal venous anastomosis for
nonischaemic central or branch retinal vein
occlusion. Arch Ophthalmol 1998; 116: 43–52.
Chen CH, Laii CH, Kuo HK. Laser chorioretinal
venous anastomosis for progressive nonischaemic central retinal vein occlusion. Chang
Gung Med J 2005; 28: 866–871.
McAllister IL, Gillies ME, Smithies LA,
Rochtchina E, Harper CA, Daniell MD, Constable
IJ et al. Factors promoting success and influencing complications in laser-induced central vein
bypass. Ophthalmology 2012; 119: 2579–2586.
Opremcak ME, Bruce RA. Surgical decompression of branch retinal vein occlusion via
arteriovenous crossing sheathotomy: a prospective review of 15 cases. Retina 1999; 19: 1–5.
Figueroa MS, Torres R, Alvarez MT. Comparative
study of vitrectomy with and without vein decompression for branch retinal vein occlusion: a pilot
study. Eur J Ophthalmol 2004; 14: 40–47.
Leizaola-Fernandez C, Suarez-Tata L, QuirozMercado H, Colina-Luquez J, Fromow-Guerra J,
Jimenez-Sierra JM, Guerrero-Naranjo JL et al. Vitrectomy with complete posterior hyaloid removal
for ischaemic central retinal vein occlusion: series
of cases. BMC Ophthalmol 2005; 5: 10–14.
Mohamed Q, McIntosh RL, Saw SM, Wong TY.
Interventions for central retinal vein occlusion.
An evidence-based systematic review. Ophthalmology 2007; 114: 507–519.
Stefansson E, Novack RL, Hatchell DL. Vitrectomy prevents retinal hypoxia in branch retinal
vein occlusion. Invest Ophthalmol Vis Sci 1990; 31:
284–289.
Jackson TL, Nicod E, Angelis A, Grimaccia F,
Prevost AT, Simpson AR, Kanavos P. Vitreous
attachment in age-related macular degeneration,
diabetic macular oedema, and retinal vein occlusion. Retina 2013; 33: 1099–1108.
© 2013 The Author
Clinical and Experimental Optometry © 2013 Optometrists Association Australia
86. Okunuki Y, Usui Y, Katai N, Kezuka T, Takeuchi
M, Goto H, Wakabayashi Y. Relation of intraocular concentrations of inflammatory factors and
improvement of macular oedema after vitrectomy
in branch retinal vein occlusion. Am J Ophthalmol
2011; 141: 610–616.
87. Noma H, Mimura T, Masahara H, Shimada K.
Pentraxin 3 and other inflammatory factors
in central retinal vein occlusion and macular
oedema. Retina 2013; July 9.[Epub ahead of
print]..
88. Opremcak EM, Bruce RA, Lomeo MD, Ridenour
CD, Letson AD, Rehmar AJ. Radial optic
neurotomy for central retinal vein occlusion.
Retina 2001; 41: 408–415.
89. Weizer JS, Stinnett SS, Fekrat S. Radial optic
neurotomy as treatment for central retinal
vein occlusion. Am J Ophthalmol 2003; 136: 814–
819.
90. Hayreh SS, Zimmerman MB, Podhajsky PA.
Retinal vein occlusion and the optic disk. Retina
2012; 32: 2108–2118.
91. Tao Y, Jiang YP, Li XX, Yin CY, Yao J. Fundus and
histopathological study of radial optic neurotomy
in the normal miniature pig eye. Arch Ophthalmol
2005; 123: 1097–1101.
92. Garcia-Arumii J, Boixadera A, Martinez-Castillo V,
Castillo R, Dou A, Corcostegui B. Chorioretinal
anastomosis after radial optic neurotomy for
central retinal vein occlusion. Arch Ophthalmol
2003; 121: 1385–1391.
93. Maia M, Farah ME, Aggio FB, Rodrigues EB, de
Souza EC, Magalhaes O Jr. Peripapillary haemorrhagic retinal pigment epithelium detachment
following radial optic neurotomy. Clin Experiment
Ophthalmol 2007; 35: 672–674.
94. The Branch Vein Occlusion Study Group. Argon
laser photocoagulation for macular oedema in
branch vein occlusion. Am J Ophthalmol 1984; 98:
271–282.
95. McIntosh RL, Mohamed Q, Saw SM, Wong TY.
Interventions for branch retinal vein occlusion.
An evidence-based systematic review. Ophthalmology 2007; 114: 835–846.
96. Udaondo P, Garcia-Delpech S, Salom D,
Garcia-Pous M, Diaz-Llopis M. Intravitreal
pegaptanib for refractory macular oedema secondary to retinal vein occlusion. Clin Ophthalmol
2011; 5: 941–944.
97. Arnarsson A, Stefansson E. Laser treatment and
the mechanism of oedema reduction in branch
retinal vein occlusion. Invest Ophthalmol Vis Sci
2000; 41: 877–879.
98. May DR, Klein ML, Peyman GA, Raichand M.
Xenon arc panretinal photocoagulation for
central retinal vein occlusion: a randomised
prospective study. Br J Ophthalmol 1979; 63: 725–
734.
99. The Central Retinal Vein Occlusion Study Group.
Evaluation of grid pattern photocoagulation
for macular oedema in central vein occlusion.
Ophthalmology 1995; 102: 1425–1433.
100. The SCORE Study Research Group. A
randomized trial comparing the efficacy and
safety of intravitreal triamcinolone with standard
care to treat vision loss associated with macular
oedema secondary to central retinal vein occlusion. Arch Ophthalmol 2009; 127: 1101–1114.
101. Laatikainen L, Kohner EM, Khoury D, Blach RK.
Panretinal photocoagulation in central retinal
vein occlusion: a randomised controlled clinical
study. Br J Ophthalmol 1977; 61: 741–753.
Clinical and Experimental Optometry 2013
11
A review of retinal venous occlusion MacDonald
102. Ferrara N. Vascular endothelial growth factor:
basic science and clinical progress. Endocr Rev
2004; 25: 581–611.
103. Shams N, Ianchulev T. Role of vascular
endothelial growth factor in ocular angiogenesis.
Ophthalmol Clin N Am 2006; 19: 335–344.
104. Smit DP, Meyer D. Intravitreal bevacizumab: an
analysis of the evidence. Clin Ophthalmol 2007; 1:
273–284.
105. Ehlken C, Rennel ES, Michels D, Grundel B,
Pielen A, Junker B, Stahl A et al. Levels of VEGF
but not VEGF165b are increased in vitreous of
patients with retinal vein occlusion. Am J
Ophthalmol 2011; 152: 298–303.
106. Priglinger SG, Wolf AH, Kreutzer TC, Kook D,
Hofer A, Strauss RW, Alge CS et al. Intravitreal
bevacizumab injections for treatment of central
retinal vein occlusion. Retina 2007; 27: 1004–1012.
107. Deissler HL, Deissler H, Lang GE. Actions of
bevacizumab and ranibizumab on microvascular
retinal endothelial cells: similarities and differences. Br J Ophthalmol 2012; 96: 1023–1028.
108. Wroblewski JJ, Wells JA 3rd, Adamis AP, Buggage
RR, Cunningham ET Jr, Goldbaum M, Guyer DR
et al. Pegabtanib sodium for macular oedema
secondary to central retinal vein occlusion. Arch
Ophthalmol 2009; 127: 374–380.
109. Moisseiev E, Goldstein M, Waisbourd M, Barak A,
Lowenstein A. Long-term evaluation of patients
treated with dexamethasone intravitreal implant
for macular oedema due to retinal vein occlusion.
Eye 2013; 27: 65–71.
110. Sharma A, Kupperman BD, Kenney MC. Use of
intravitreal triamcinolone in the treatment of
macular oedema related to retinal vein occlusion.
Open Ophthalmol J 2008; 2: 68–72.
111. The SCORE Study Research Group. A
randomized trial comparing the efficacy and
safety of intravitreal triamcinolone with standard
care to treat vision loss associated with macular
oedema secondary to branch retinal vein occlusion. Arch Ophthalmol 2009; 127: 1115–1128.
112. Scott IU, VanVeldhuisen PC, Oden NL, Ip MS,
Domalpally A, Doft BH, Elman MJ et al. Baseline
characteristics and response to treatment of participants with hemiretinal compared with branch
retinal or central retinal vein occlusion in the
Standard Care vs COrticosteroid for REtinal Vein
Occlusion (SCORE) Study. Arch Ophthalmol 2012;
130: 1517–1524.
113. Apte RS. SCOREing in retinal venous occlusive
disease. Arch Ophthalmol 2009; 127: 1203–1204.
114. Noma H, Mimura T. Macular sensitivity and morphology after intravitreal injection of triamcinolone acetonide for macular oedema secondary
to central retinal vein occlusion. Clin Ophthalmol
2012; 6: 1901–1906.
115. Collet L, Larson TA, Bakri SJ. Bevacizumab for
ophthalmic disease. US Ophthalmic Rev 2007; 2:
20–24.
116. Singer MA, Bell DJ, Woods P, Pollard J, Boord T,
Herro A, Porbandarwalla S. Effect of combination
therapy with bevacizumab and dexamethasone
intravitreal implant in patients with retinal vein
occlusion. Retina 2012; 32: 1289–1294.
117. Lim JI, Fung AE, Wieland M, Hung D, Wong V.
Sustained-release intravitreal liquid drug delivery
using triamcinolone acetonide for cystoid
macular oedema in retinal vein occlusion. Ophthalmology 2011; 118: 1416–1422.
118. Chan A, Leung LS, Blumenkranz MS. Critical
appraisal of the clinical utility of the dexametha-
Clinical and Experimental Optometry 2013
12
119.
120.
121.
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
sone intravitreal implant (Ozurdex) for the treatment of macular oedema related to branch retinal
vein occlusion or central retinal vein occlusion.
Clin Ophthalmol 2011; 5: 1043–1049.
Haller JA, Bandello F, Belfort R Jr, Blumenkranz
MS, Gillies M, Heier J, Loewenstein A et al.
Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular
oedema due to retinal vein occlusion. Ophthalmology 2010; 117: 1134–1146.
Haller JA, Bandello F, Belfort R Jr, Blumenkranz
MS, Gillies M, Heier J, Loewenstein A et al. Dexamethasone intravitreal implant in patients with
macular oedema related to branch or central
retinal vein occlusion. Ophthalmology 2011; 118:
2453–2460.
Capone A, Singer MA, Dodwell DG, Dreyer RF,
Oh KT, Roth DB, Walt JG et al. Efficacy and safety
of two or more dexamethasone intravitreal
implant injections for treatment of macular
oedema related to retinal vein occlusion
(SHASTA Study). Retina 2013; July 10. [Epub
ahead of print].
Yeh WS, Haller JA, Lanzetta P, Kuppermann BD,
Wong TY, Mitchell P, Whitcup SM et al. Effect of
the duration of macular oedema on clinical
outcome in retinal vein occlusion treated with
dexamethasone intravitreal implant. Ophthalmology 2012; 119: 1190–1198.
Sadda S, Danis RP, Pappuru RR, Keane PA, Jiao J,
Li XY, Whitcup SM. Vascular changes in eyes
treated with dexamethasone intravitreal implant
for macular oedema after retinal vein occlusion.
Ophthalmology 2013; 120: 1423–1431.
Pearson PA, Comstock TL, Ip M, Callanan D,
Morse LS, Ashton P, Levy B et al. Fluocinolone
acetonide intravitreal implant for diabetic
macular oedema: a 3-year multicenter, randomized, controlled clinical trial. Ophthalmology
2011; 118: 1580–1587.
Ng EW, Shima DT, Calias P, Cunningham ET Jr,
Guyer DR, Adamis AP. Pegaptanib, a targeted
anti-VEGF aptamer for ocular vascular disease.
Nature 2006; 5: 123–132.
Browning DJ, Kaiser PK, Rosenfeld PJ, Stewart
MW. Aflibercept for age-related macular degeneration: a game-changer or quiet addition? Am
J Ophthalmol 2012; 154: 222–226.
Kurihara T, Westenskow PD, Bravo S, Aguilar E,
Friedlander M. Targeted deletion of VEGFA in
adult mice induces vision loss. J Clin Invest 2012;
122: 4213–4217.
Benny O, Nakai K, Yoshimura T, Bazinet L, Akula
JD, Nakao S, Hafezi-Moghadam A et al. Broad
spectrum antiangiogenic treatment for ocular
neovascular diseases. PLoS ONE 2010; 5: 1–14.
Marticorena J, Romano MR, Heimann H,
Stappler T, Gibran K, Groenewald C, Pearce I
et al. Intravitreal bevacizumab for retinal vein
occlusion and early growth of epiretinal membrane: a possible secondary effect? Br J Ophthalmol
2011; 95: 391–395.
Rosenfeld PJ, Moshfeghi AA, Puliafito CA.
Optical coherence tomography findings after an
intravitreal injection of bevacizumab (Avastin)
for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 2005; 36: 331–
335.
Gonzalez S, Rosenfeld PJ, Stewart MW, Brown J,
Murphy SP. Avastin doesn’t blind people, people
blind people. Am J Ophthalmol 2012; 153: 196–
203.
132. Smiddy WE. Economic considerations of macular
oedema therapies. Ophthalmology 2011; 118: 1827–
1833.
133. Al-Qureshi S, Shaikh S. Intravitreous bevacizumab
adult safety data: the evidence so far. Clin Exp
Ophthalmol 2012; 40: 3–5.
134. Epstein DL, Algvere PV, von Wendt G, Seregard S,
Kvanta A. Bevacizumab for macular oedema in
central retinal vein occlusion: a prospective,
randomized, double-masked clinical study. Ophthalmology 2012; 119: 1184–1189.
135. Pai SA, Shetty R, Vijayan PB, Venkatasubramaniam G, Yadav NK, Shetty BK, Babu RB
et al. Clinical, anatomic, and electrophysiologic
evaluation following intravitreal bevacizumab for
macular oedema in retinal vein occlusion. Am
J Ophthalmol 2007; 143: 601–606.
136. Costa RA, Jorge R, Calucci D, Melo LA Jr, Cardillo
JA, Scott IU. Intravitreal bevacizumab (Avastin)
for central and hemicentral retinal vein occlusions. Retina 2007; 27: 141–149.
137. Abegg M, Tappeiner C, Wolf-Schnurrbusch U,
Barthelmes D, Wolf S, Fleischhauer J. Treatment
of branch retinal vein occlusion induced macular
oedema with bevacizumab. BMC Ophthalmol 2008;
8: 18.
138. Badala F. The treatment of branch retinal vein
occlusion with bevacizumab. Curr Opin Ophthalmol
2008; 19: 234–238.
139. Yalamanchi Y, Flynn HW. Hemicentral vein occlusion with macular hemorrhage and oedema
treated with intravitreal bevacizumab. Clin
Ophthalmol 2011; 5: 1509–1513.
140. ul-Hussan M, Qidwai U, ur-Rehman A, Sial N,
Bhatti N. Visual outcome after intravitreal
bevacizumab injection in macular oedema secondary to central retinal vein occlusion. Pak
J Ophthalmol 2011; 27: 84–88.
141. Wu L, Arevalo JF, Berrocal MH, Maia M, Roca JA,
Morales-Canton V, Alezzandrini AA et al. Comparison of two doses of intravitreal bevacizumab as
primary treatment for macular oedema secondary
to central retinal vein occlusion. Retina 2010; 30:
1002–1011.
142. Epstein DL, Algvere PV, von Wendt G, Seregard S,
Kvanta A. Benefit from bevacizumab for macular
oedema in central retinal vein occlusion: twelvemonth results of a prospective, randomized study.
Ophthalmology 2012; 119; 2587–2591.
143. Chilov MN, Grigg JR, Playfair TJ. Bevacizumab
(Avastin) for the treatment of neovascular glaucoma. Clin Experiment Ophthalmol 2007; 35: 494–
496.
144. Gillies MC. Bevacizumab in ophthalmology:
the controversy moves forward. Clin Experiment
Ophthalmol 2010; 38: 333–334.
145. Gutierrez JCM, Barquet LA, Caminal JM, Mitjana
O, Almolda SP, Domenech NP, Goita OP, et al.
Intravitreal bevacizumab (Avastin) in the treatment of macular oedema secondary to retinal vein
occlusion. Clin Ophthalmol 2008; 2: 787–791.
146. Gallego-Pinazo R, Dolz-Marco R, Diaz-Llopis M.
Ranibizumab is not bevacizumab for retinal vein
occlusions. Graefes Arch Clin Exp Ophthalmol 2012;
250: 955–956.
147. Brown DM. Clinical implications of the BRAVO
and CRUISE trials. Retina Today 2010; 4: 38–40.
148. CRUISE Research Group. A study of the efficacy
and safety of ranibizumab injection in subjects
with macular oedema secondary to central retinal vein occlusion. ClinicalTrials.gov—http://
clinicaltrials.gov/ct2/show/NCT00485836
© 2013 The Author
Clinical and Experimental Optometry © 2013 Optometrists Association Australia
A review of retinal venous occlusion MacDonald
149. Bhisitkul RB, Campochiaro PA, Shapiro H, Rubio
RG. Predictive value in retinal vein occlusions
of early versus late or incomplete ranibizumab
response defined by optical coherence tomography. Ophthalmology 2013; 120: 1057–1063.
150. Campochiaro PA, Brown DM, Awh CC, Lee SY,
Gray S, Saroj N, Murahashi WY et al. Sustained
benefits from ranibizumab for macular oedema
following central retinal vein occlusion: twelvemonth outcomes of a phase III study. Ophthalmology 2011; 118: 2041–2049.
151. Heier JS, Campochiaro PA, Yau L, Li Z, Saroj N,
Rubio RG, Lai P. Ranibizumab for macular
oedema due to retinal vein occlusions. Long-term
follow-up in the HORIZON Trial. Ophthalmology
2012; 119: 802–809.
152. Brown DM, Campochiaro PA, Bhisitkul RB, Ho
AC, Gray S, Saroj N, Adamis AP, et al. Sustained
benefits from ranibizumab for macular oedema
following branch retinal vein occlusion: 12-month
outcomes of a phase III study. Ophthalmology 2011;
118: 1594–1602.
153. Mansour AM, Shahin M, Kofoed PK, Parodi MB,
Shami M, Schwartz SG. Collaborative Anti-VEGF
Ocular Vascular Complications Group. Insight
into 144 patients with ocular vascular events
during VEGF antagonist injections. Clin
Ophthalmol 2012; 6: 343–363.
154. Jorge R, Oliveira RS, Messias A, Almeida FP,
Strambe ML, Costa RA, Scott IU. Ranibizumab for
retinal neovascularisation. Ophthalmology 2011;
118: 1004–1005.
155. Wehrli SJ, Tawse K, Levin MH, Zaidi A, Pistilli M,
Brucker AJ. A lack of delayed intraocular pressure
elevation in patients treated with intravitreal
injection of bevacizumab and ranibizumab. Retina
2012; 32: 1295–1301.
156. Hoang QV, Mendonca LS, Della Torre KE, Jung
JJ, Tsuang AJ, Freund KB. Effect on intraocular
pressure in patients receiving unilateral intravitreal anti-vascular endothelial growth factor
injections. Ophthalmology 2012; 119: 321–326.
157. Good TJ, Kimura AE, Mandava N, Kahook MY.
Sustained elevation of intraocular pressure after
intravitreal injection of anti-VEGF agents. Br
J Ophthalmol 2011; 95: 1111–1114.
158. Do DV, Schmidt-Erfurth U, Gonzalez VH, Gordon
CM, Tolentino M, Berliner AJ, Vitti R et al.
The DA VINCI study: phase 2 primary results of
VEGF trap-eye in patients with diabetic macular
oedema. Ophthalmology 2011; 118: 1819–1826.
159. Boyer D, Heier J, Brown DM, Clark WL, Vitti R,
Berliner AJ, Groetzbach G et al. Vascular
endothelial growth factor trap-eye for macular
oedema secondary to central retinal vein occlusion. Ophthalmology 2012; 119: 1024–1032.
160. Brown DM, Heier JS, Ciulla T, Benz M, Abraham
P, Yancopoulos G, Stahl N et al. Primary endpoint
results of a phase II study of vascular endothelial
growth factor trap-eye in wet age-related macular
degeneration. Ophthalmology 2011; 118: 1089–
1097.
161. Heier JS, Boyer D, Nguyen QD, Marcus D, Roth
DB, Yancopoulos G, Strahl N et al. The 1-year
results of CLEAR-IT2, a phase 2 study of vascular
endothelial growth factor trap-eye dosed asneeded after 12-week fixed dosing. Ophthalmology
2011; 118: 1098–1106.
162. Holz FG, Roider J, Ogura Y, Korobelnik JF,
Simader C, Groetzback G, Vitti R et al. VEGF
Trap-Eye for macular oedema secondary to
central retinal vein occlusion: 6-month results of
163.
164.
165.
166.
167.
168.
169.
170.
171.
172.
173.
174.
175.
176.
177.
178.
179.
the phase III GALILEO study. Br J Ophthalmol
2013; 97: 278–284.
Brown DM, Heier JS, Clark WL, Boyer DS, Vitti R,
Berliner AJ, Zeitz O, et al. Intravitreal aflibercept
injection for macular oedema secondary to
central retinal vein occlusion: 1-year results from
the phase 3 COPERNICUS Study. Am J Ophthalmol
2013; 155: 429–437.
Hahn P, Fekrat S. Aflibercept for central retinal
vein occlusion: an ongoing revolution or are we
spinning in place? Am J Ophthalmol 2013; 155:
415–417.
Kim JY, Park SP. Comparison between intravitreal
bevacizumab and triamcinolone for macular
oedema secondary to branch retinal vein occlusion. Korean J Ophthalmol 2009; 23: 259–265.
Ehlers JP, Fekrat S. Differential effects of triamcinolone and bevacizumab in central retinal vein
occlusion. Can J Ophthalmol 2011; 46: 88–89.
Mayer WJ, Wolf A, Kernt M, Kook D, Kampik A,
Ulbig M, Haritoglou C. Twelve-month experience
with Ozurdex for the treatment of macular
oedema associated with retinal vein occlusion. Eye
2013; 27: 816–822.
Shah AM, Bressler NM, Jampol LM. Does laser still
have a role in the management of retinal vascular
and neovascular diseases? Am J Ophthalmol 2011;
152: 332–339.
Spaide RF. Prospective study of peripheral
panretinal photocoagulation of areas of nonperfusion in central retinal vein occlusion. Retina
2013; 33: 56–62.
CATT Research Group. Ranibizumab and
bevacizumab for treatment of neovascular agerelated macular degeneration. Ophthalmology
2012; 119: 1388–1398.
CATT Research Group. Ranibizumab and
bevacizumab for neovascular age-related macular
degeneration. N Engl J Med 2011; 364: 1897–
1908.
Chakravarthy U, Harding SP, Rogers CA,
Downes SM, Lotery AJ, Wordsworth S, Reeves
BC. Ranibizumab versus bevacizumab to treat
neovascular age-related macular degeneration.
Ophthalmology 2012; 119: 1399–1411.
Singer MA, Cohen SR, Groth SL, Porbandarwalla
S. Comparing bevacizumab and ranibizumab for
initial reduction of central macular thickness
in patients with retinal vein occlusion. Clin
Ophthalmol 2013; 7: 1377–1383.
Wu Z, Sadda SR. Effects on the contralateral eye
after intravitreal bevacizumab and ranibizumab
injections: a case report. Ann Acad Med Singapore
2008; 37: 591–593.
Lim LS, Cheung CM, Mitchell P, Wong TY.
Emerging evidence concerning systemic safety of
anti-VEGF agents—should ophthalmologists be
concerned? Am J Ophthalmol 2011; 152: 329–331.
Ueta T, Mori H, Kunimatsu A, Yamaguchi T,
Tamaki Y, Yanagi Y. Stroke and anti-VEGF
therapy. Ophthalmology 2011; 118: 2093–2095.
Campbell RJ, Bell CM, Campbell Ede L, Gill SS.
Systemic effects of intravitreal vascular endothelial growth factor inhibitors. Curr Opin Ophthalmol
2013; 24: 197–204.
Biswas P, Sengupta S, Choudhary R, Home S,
Paul A, Sinha S. Comparing ranibizumab with
bevacizumab. Ophthalmology 2011; 118: 600–
600.e2.
Beaumont P. Bevacizumab: not as good with more
adverse reactions? Clin Experiment Ophthalmol
2011; 39: 588–590.
© 2013 The Author
Clinical and Experimental Optometry © 2013 Optometrists Association Australia
180. Kemp A, Preen DB, Morlet N, Clark A, McAllister
IL, Briffa T, Sanfilippo FM et al. Myocardial
infarction after intravitreal vascular endothelial
growth factor inhibitors. Retina 2013; 33: 920–927.
181. Farjo KM, Ma J. The potential of nanomedicine
therapies to treat neovascular disease in the
retina. J Angiogenes Res 2010; 2: 21.
182. Wang X, Abraham S, McKenzie JAG, Jeffs N, Swire
M, Tripathi VB, Luhmann UFO et al. LRG1 promotes angiogenesis by modulating endothelial
TGF-β signaling. Nature 2013; 499: 306–313.
183. Sun C, Li XX, He XJ, Tao Y. Neuroprotective
effect of minocycline in a rat model of branch
retinal vein occlusion. Exp Eye Res 2013; 113:
105–116.
Clinical and Experimental Optometry 2013
13