Retinal-Vein Occlusion clinical practice

The
n e w e ng l a n d j o u r na l
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m e dic i n e
clinical practice
Retinal-Vein Occlusion
Tien Y. Wong, M.D., Ph.D., and Ingrid U. Scott, M.D., M.P.H.
This Journal feature begins with a case vignette highlighting a common clinical problem.
Evidence supporting various strategies is then presented, followed by a review of formal guidelines,
when they exist. The article ends with the authors’ clinical recommendations.
A 69-year-old man, a former smoker with a history of hypertension and hyperlipidemia, presents with acute visual loss in his right eye of 2 weeks’ duration. Examination of the eye reveals a visual acuity of 20/60 and a sectoral area of retinal hemorrhages, cotton-wool spots, and swelling in the center of the retina (macular edema).
A diagnosis of right-branch retinal-vein occlusion is made. How should he be treated?
The Cl inic a l Probl em
Retinal-vein occlusion is a common cause of vision loss in older persons, and the
second most common retinal vascular disease after diabetic retinopathy. There are
two distinct types, classified according to the site of occlusion.1 In branch retinalvein occlusion, the occlusion is typically at an arteriovenous intersection (Fig. 1); in
central retinal-vein occlusion, the occlusion is at or proximal to the lamina cribrosa
of the optic nerve, where the central retinal vein exits the eye (Fig. 2).
Retinal-vein occlusion has a prevalence of 1 to 2% in persons older than 40
years of age2,3 and affects 16 million persons worldwide.4 Branch retinal-vein occlusion is four times as common as central retinal-vein occlusion.4 In a population-based cohort study, the 10-year incidence of retinal-vein occlusion was 1.6%.5
Bilateral retinal-vein occlusion is uncommon (occurring in about 5% of cases),
although in 10% of patients with retinal-vein occlusion in one eye, occlusion develops in the other eye over time.6 Both branch retinal-vein occlusion and central
retinal-vein occlusion are further divided into the categories of perfused (non­
ischemic) and nonperfused (ischemic), each of which has implications for prognosis and treatment.
From the Singapore Eye Research Institute, Singapore National Eye Centre, National University of Singapore, Singapore
(T.Y.W.); the Centre for Eye Research Australia, University of Melbourne, Melbourne, VIC, Australia (T.Y.W.); and Penn
State College of Medicine, Penn State
Hershey Eye Center, Hershey, PA (I.U.S.).
Address reprint requests to Dr. Wong at
the Singapore Eye Research Institute,
Singapore National Eye Centre, 11 Third
Hospital Ave., Singapore 168751, Singapore, or at [email protected]
N Engl J Med 2010;363:2135-44.
Copyright © 2010 Massachusetts Medical Society.
Pathogenesis and Risk Factors
The pathogenesis of retinal-vein occlusion is believed to follow the principles of
Virchow’s triad for thrombogenesis, involving vessel damage, stasis, and hypercoagulability. Damage to the retinal-vessel wall from atherosclerosis alters rheologic
properties in the adjacent vein, contributing to stasis, thrombosis, and thus occlusion. Inflammatory disease may also lead to retinal-vein occlusion by means of
these mechanisms. However, evidence of hypercoagulability in patients with retinalvein occlusion is less consistent. Although individual studies have reported associations between retinal-vein occlusion and hyperhomocysteinemia,7 factor V Leiden
mutation,8 deficiency in protein C or S,8 prothrombin gene mutation,9 and anticardiolipin antibodies,10,11 a meta-analysis of 26 studies suggested that only hyperhomocysteinemia and anticardiolipin antibodies have significant independent associations with retinal-vein occlusion.11
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The
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A
B
C
D
of
m e dic i n e
Figure 1. Branch Retinal-Vein Occlusion in the Superotemporal Quadrant of the Right Eye.
A fundus photograph (Panel A) shows a sectoral area of dilated veins, retinal hemorrhages (white arrows), cottonwool spots (black arrows), and retinal edema, and a fluorescein angiogram (Panel B) reveals blockage (white arrows)
and leakage of dye (yellow arrows). Optical-coherence tomographic scans (horizontal scan in Panel C and vertical
scan in Panel D) show retinal thickening (white arrows), as compared with normal retinal thickness (black arrow),
and macular edema (yellow arrows). N→T denotes a nasal-to-temporal cut of the retinal scan, and I→S an inferiorto-superior cut.
The strongest risk factor for branch retinalvein occlusion is hypertension,12-15 but associations have been reported for diabetes mellitus,13-15
dyslipidemia,15 cigarette smoking,2 and renal disease.16 For central retinal-vein occlusion, an additional ocular risk factor is glaucoma or elevated
intraocular pressure, which may compromise
retinal venous outflow.2
Natural History and Complications
Macular edema, with or without macular nonperfusion, is the most frequent cause of vision
loss in patients with retinal-vein occlusion.17-21
Vision loss may also be due to neovascularization,
leading to vitreous hemorrhage, retinal detachment, or neovascular glaucoma.
The natural history of branch retinal-vein occlusion is variable.22 Many patients with branch
retinal-vein occlusion have a good prognosis,
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with one study showing that half have a return
to 20/40 vision or better within 6 months, without treatment.23 Nevertheless, many patients continue to have poor vision in the affected eye.
Among participants enrolled in the Branch Vein
Occlusion Study, a randomized trial of the effects
of laser treatment for branch retinal-vein occlusion, only a third of untreated eyes with macular
edema and presenting vision of 20/40 or worse
improved to better than 20/40 after 3 years.17
Retinal neovascularization developed in one third
of untreated eyes.17
The visual prognosis is generally worse for
patients with central retinal-vein occlusion, particularly when nonperfused, than in patients with
branch retinal-vein occlusion.6 A systematic review suggested that neovascularization may develop in 20% of eyes and neovascular glaucoma
in 60% when nonperfused central retinal-vein oc-
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clinical pr actice
A
B
C
D
Figure 2. Nonperfused Central Retinal-Vein Occlusion in the Left Eye.
A fundus photograph (Panel A) shows scattered retinal hemorrhages (white arrows), cotton-wool spots (black arrows),
optic-disk edema and hyperemia, and venous dilatation and tortuosity (yellow arrow), and a fluorescein angiogram
(Panel B) reveals areas of capillary nonperfusion (white arrows) and disk leakage (yellow arrow). Optical-coherence
tomographic scans (horizontal scan in Panel C and vertical scan in Panel D) show marked retinal thickening (white
arrows) and edema (yellow arrows). N→T denotes a nasal-to-temporal cut of the retinal scan, and I→S an inferior-tosuperior cut.
clusion is present.6 In addition, in one third of
eyes initially classified as having perfused central retinal-vein occlusion, the occlusion may become nonperfused within the first year.21 Visual
acuity at the time of presentation is a strong
indicator of the ultimate quality of the patient’s
vision. In the Central Vein Occlusion Study, a
randomized trial of the use of laser treatment
for central retinal-vein occlusion, 65% of patients’ eyes maintained 20/40 vision or better if
acuity at the time of presentation was 20/40 or
better, but only 1% achieved this level if acuity
was initially 20/200 or worse.19,21,24
Despite its associations with vascular risk factors, retinal-vein occlusion does not appear to be
an independent risk factor for death from cardiovascular causes.25-27 In a pooled analysis of
two population-based studies, retinal-vein occlusion was not independently associated with inn engl j med 363;22
creased cardiovascular mortality,27 although a
post hoc analysis revealed an association among
persons younger than 70 years of age.
S t r ategie s a nd E v idence
Diagnosis and Assessment
Patients with retinal-vein occlusion typically present with sudden, unilateral, painless loss of
vision. The degree of vision loss depends on the
extent of retinal involvement and on macularperfusion status. Some patients with branch
retinal-vein occlusion report only a peripheral
visual-field defect.
Retinal-vein occlusion has a characteristic
appearance on fundus examination. In branch
retinal-vein occlusion, there is a wedge-shaped
area in which retinal vascular signs (hemorrhages, cotton-wool spots, edema, and venous
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dilatation and tortuosity) arise from an arteriovenous crossing, usually in the superotemporal
quadrant (Fig. 1A). In central retinal-vein occlusion, extensive retinal signs, with dilated and
tortuous veins, are seen in all quadrants, often
along with optic-disk edema (Fig. 2A).
The diagnosis of retinal-vein occlusion is usually made on the basis of the clinical examination alone. Nonperfused central retinal-vein occlusion is suggested by vision that is worse than
20/200, a relative afferent pupillary defect, and
the presence of cotton-wool spots and large, confluent hemorrhages.28 Fundus fluorescein angiography (Fig. 1B and 2B) is commonly performed to assess the severity of macular edema
and perfusion status. Optical-coherence tomography is a noninvasive imaging technique used
to quantify macular edema and assess treatment
response (Fig. 1C, 1D, 2C, and 2D).
Evaluation of patients with retinal-vein occlusion should include a detailed history taking,
clinical assessment, and laboratory investigations
to check for the presence of cardiovascular risk
factors (Table 1). Although evidence is lacking to
of
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show that treatment of hypertension and other
conditions associated with cardiovascular disease
can alter the visual prognosis for patients with
retinal-vein occlusion, this condition should be
considered end-organ damage,29 with appropriate
risk-management strategies routinely instituted.
Tests for coagulation abnormalities (Table 1) are
commonly performed in selected patients, such
as those younger than 50 years of age or those
with bilateral retinal-vein occlusion, although
evidence is lacking to indicate that coagulation
disorders are more common in these patients.
Management
Until recently, laser photocoagulation was the
only treatment supported by data from highquality randomized trials30-32; data are now also
available from several trials assessing the use of
intraocular glucocorticoids and agents inhibiting
vascular endothelial growth factor (VEGF). These
more recent treatment options are increasingly
being used in clinical practice. (For summaries
of the recommendations for the management of
branch retinal-vein occlusion and central retinal-
Table 1. Assessment of Cardiovascular Risk in Patients with Retinal-Vein Occlusion.
History and clinical assessment
Hypertension
Diabetes mellitus
Dyslipidemia
Cardiovascular disease (e.g., stroke, coronary artery disease, peripheral artery disease)
Medications (e.g., oral contraceptives, diuretics)
Hypercoagulable states and hyperviscosity syndromes (e.g., leukemia, polycythemia vera)
Routine investigations
Complete blood count
Renal function (levels of serum electrolytes, urea, creatinine)
Fasting serum levels of glucose and glycated hemoglobin
Fasting levels of lipids
Additional investigations (consider in select cases, such as in patients who are younger than 50 years of age, who have
bilateral retinal-vein occlusion, or who may have thrombophilic or coagulation disorders)
Homocysteine levels
Levels of functional protein C and protein S
Antithrombin III levels
Antiphospholipid antibodies — lupus anticoagulant, anticardiolipin antibodies
Activated protein C resistance — polymerase-chain-reaction assay for factor V Leiden mutation (R506Q)
Factor XII
Prothrombin gene mutation (G20210A)
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clinical pr actice
Table 2. Recommendations for the Management of Branch Retinal-Vein Occlusion.
Intervention
Guidelines
Evidence*
Comments
Macular grid laser photocoagu- Associated with reduced macular edema and improved
lation
vision in patients with macular edema and visual
­acuity ≤20/40
A-I
May not be effective in presence of
macular ischemia
Scatter laser photocoagulation
Recommended for treatment of ischemic retina if retinal
or disk neovascularization is also present
A-I
Intravitreal injection of tri­
amcinolone acetonide
No more effective than macular grid laser photocoag­
ulation in improving visual acuity in patients with
macular edema from branch retinal-vein occlusion
and associated with a higher risk of adverse events
A-I
Intravitreal injection of
­ranibizumab
Associated with greater improvement in visual acuity, as
compared with sham injection, over 12-mo period in
patients with macular edema from branch retinal-vein
occlusion
A-II
May be administered monthly in
0.5-mg doses, depending on persistence or recurrence of macular
edema
Intravitreal dexamethasone
­implant
Associated with more rapid improvement in visual acuity
than sham implant in patients with macular edema
from branch retinal-vein occlusion
B-II
May be administered in 0.7-mg doses
every 6 mo, depending on persistence or recurrence of macular
edema; contraindicated in patients with advanced glaucoma
Hemodilution
Not recommended for routine use to improve visual
­acuity or prevent neovascularization
B-III
Pars plana vitrectomy with
­adventitial sheathotomy
Not routinely recommended to improve visual acuity or
prevent neovascularization
B-III
Ticlopidine, troxerutin
Not routinely recommended to improve visual acuity or
prevent neovascularization
B-III
*For the ranking of the importance of the recommendation with respect to the clinical outcome, A denotes most important or critical for a
good clinical outcome and B moderately important; for the strength of the evidence, I denotes strong evidence in support of the recommendation, II strong evidence in support of the recommendation but lacking in some respects (e.g., longer-term efficacy or safety uncertain),
and III insufficient evidence to provide support for or against the recommendation.
vein occlusion, see Tables 2 and 3, respectively.
For the outcomes of trials conducted to gauge
the effects of various treatments on each condition, see the Supplementary Appendix, available
with the full text of this article at NEJM.org.)
Branch Retinal-Vein Occlusion
Laser Treatment
worse than 20/40 and that in 12% of treated eyes
was worse than 20/200 at 3 years. In eyes with
extensive nonperfusion, scatter laser photocoagulation markedly reduced the risks of retinal
neovascularization (12%, vs. 22% in controls)
and vitreous hemorrhage (29% vs. 60%).18
Glucocorticoids
Grid laser photocoagulation is used for the treatment of macular edema resulting from branch
retinal-vein occlusion, and scatter laser photocoagulation is used for the prevention and treatment of neovascularization. In the Branch Vein
Occlusion Study,17,18 which included patients with
branch retinal-vein occlusion and macular edema
in one or both eyes (a total of 139 eyes were studied), eyes treated with grid laser photocoagulation were almost twice as likely as untreated eyes
to enable patients to read two additional lines on
an eye chart at 3 years (65% vs. 37%).17 However,
in some patients, poor vision persisted despite
treatment; vision in 40% of treated eyes was
Case series have suggested that intravitreal injection of triamcinolone acetonide may be useful for
the treatment of macular edema in patients with
branch retinal-vein occlusion.33 However, the use
of this treatment was not supported by the Standard Care versus Corticosteroid for Retinal Vein
Occlusion (SCORE) Study, a randomized trial in
which 411 patients with branch retinal-vein occlusion and vision loss from macular edema were
treated with intravitreal injection of preservativefree triamcinolone acetonide (1 mg or 4 mg, injected as frequently as every 4 months) or standard care (grid laser treatment of eyes without
dense macular hemorrhage).34 From baseline to
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Table 3. Recommendations for the Management of Central Retinal-Vein Occlusion.
Intervention
Guidelines
Scatter laser photocoagulation
Evidence*
Comments
Not recommended for patients without neovascularization unless regular follow-up is not possible
A-I
Recommended for patients with anterior-segment
neovascularization
A-I
Macular grid laser photo­
coagulation
Not recommended for treatment of macular edema
from central retinal-vein occlusion
A-I
Intravitreal injection of tri­
amcinolone acetonide
Associated with greater improvement in visual acuity,
as compared with observation, in patients with
macular edema from central retinal-vein occlusion
A-I
May be administered every 4 mo in
1-mg doses, depending on persistence or recurrence of macular
edema
Intravitreal injection of rani­
bizumab
Associated with greater improvement in visual acuity,
as compared with sham injection, over 12-mo
­period in patients with macular edema from
­central retinal-vein occlusion
A-II
May be administered every mo in
0.5-mg doses, depending on persistence or recurrence of macular
edema
Intravitreal dexamethasone
­implant
Associated with more rapid improvement in visual
acuity, as compared with sham implant, in patients
with macular edema from central retinal-vein
­occlusion
B-II
May be administered in 0.7-mg doses
every 6 mo depending on persistence or recurrence of macular
edema; contraindicated in patients
with advanced glaucoma
Laser-induced chorioretinal
­anastomosis
May improve visual acuity in patients with nonperfused central retinal-vein occlusion but may be
­associated with significant ocular complications
B-II
Hemodilution
May improve visual outcome in some patients if performed as inpatient procedure following a protocol
with a statistically relevant clinical outcome
B-II
Ticlopidine, troxerutin, epo­
prostenol
Not routinely recommended to improve visual acuity
or prevent neovascularization
B-III
Difficult to generalize recommendation due to variations in protocols
(e.g., inpatient and outpatient) and
use of different agents
*For the ranking of the importance of the recommendation with respect to the clinical outcome, A denotes most important or critical for a
good clinical outcome and B moderately important; for the strength of the evidence, I denotes strong evidence in support of the recommendation, II strong evidence in support of the recommendation but lacking in some respects (e.g., longer-term efficacy or safety uncertain),
and III insufficient evidence to provide support for or against the recommendation.
1 year, the rate of the primary outcome — the
proportion of eyes with an improvement in visual
acuity that enabled patients to read 15 or more
additional letters (or 3 lines) on an eye chart —
was similar among the three groups (27% in the
group treated with the 4-mg dose of triamcinolone, 26% in the group treated with the 1-mg
dose, and 29% in the control group). Adverse
events — principally, elevated intraocular pressure and progression of cataracts — were more
frequent in the groups treated with triamcinolone. The percentage of eyes treated with glaucoma medications was 41% in the group receiving
4 mg of triamcinolone, 8% in the group receiving
1 mg, and 2% in the control group; for cataract
progression, the percentages were 35%, 25%, and
13%, respectively.
An alternative glucocorticoid, dexamethasone,
was evaluated in a randomized trial involving
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1267 patients who had vision loss owing to
macular edema caused by branch retinal-vein
occlusion or central retinal-vein occlusion.35 The
primary end point — the time required to
achieve a visual-acuity gain of 3 lines or more on
an eye chart — was significantly shorter among
patients receiving dexamethasone (in a dose of
0.7 mg or 0.3 mg) than among patients who
received a sham injection. The proportion of
eyes with this degree of improvement was also
significantly higher in both dexamethasone
groups than in the placebo group at 1 month
and 3 months but not at the prespecified time
point of 6 months. Dexamethasone showed
similar benefits in preplanned subgroup analyses of branch and central retinal-vein occlusion,
although details on the extent of improvement
in visual acuity at 3 and 6 months were not
provided. However, the proportion of eyes in
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clinical pr actice
with central retinal-vein occlusion. In the Central
Vein Occlusion Study, patients (155 eyes) with
macular edema caused by central retinal-vein occlusion and vision of 20/50 or worse had no significant improvement in vision after 3 years of
treatment with grid laser therapy, although fluorescein angiographic leakage was reduced.24 In
Anti-VEGF Agents
the same study, scatter laser photocoagulation
Ranibizumab and bevacizumab are anti-VEGF decreased the risk of neovascular glaucoma
agents that are widely used in the treatment of among patients with iris neovascularization.20
neovascular age-related macular degeneration.36,37
Patients with retinal-vein occlusion have higher
Chorioretinal Venous Anastomosis
vitreous VEGF levels than patients with unaffected Chorioretinal venous anastomosis, a procedure in
eyes,38 and case series have suggested beneficial which a bypass for the venous obstruction is creeffects when ranibizumab or bevacizumab is used ated with the use of laser therapy, has been sugfor the treatment of retinal-vein occlusion.39-42 In gested for patients with perfused central retinalthe study of Ranibizumab for the Treatment of vein occlusion.44 In a randomized trial comparing
Macular Edema following Branch Retinal Vein the use of laser-induced chorioretinal venous
Occlusion (BRAVO), 397 patients who had macu- anastomosis with conventional care in 113 palar edema as a result of branch retinal-vein occlu- tients with perfused central retinal-vein occlusion were randomly assigned to receive intraocu- sion, visual acuity did not change in laser-treated
lar injections of 0.3 mg or 0.5 mg of ranibizumab eyes, but in conventionally treated eyes, there was
or sham injections, and both groups receiving a loss of 8 letters (nearly 2 lines) from baseline at
ranibizumab had better visual outcomes than the 18 months (P = 0.03). However, laser-related neosham-injection group.43 The primary outcome, vascularization developed in 20% of laser-treated
mean improvement in visual acuity (the number eyes, and vitrectomy for vitreous hemorrhage
of additional lines that could be read on an eye was performed in 10%. Thus, the potential bene­
chart) at 6 months, was 3 lines in both ranibizu­ fit of chorioretinal anastomosis in perfused cenmab groups as compared with 1 additional line in tral retinal-vein occlusion must be weighed
the sham-injection group. The gain of an addi- against the risk of clinically significant ocular
tional 3 lines (≥15 letters) occurred at a rate of complications.
61% in the group receiving 0.5 mg of ranibizumab
and 55% in the group receiving 0.3 mg, as comGlucocorticoids
pared with 29% in the control group (P<0.001 for Intravitreal injection of triamcinolone was evaluboth comparisons with controls). There were no ated in the SCORE Study in 271 patients with censignificant differences in the incidence of sys- tral retinal-vein occlusion and vision loss due to
temic vascular events, including stroke, among macular edema.45 At 1 year, improvement in vithe three groups. After 6 months, all patients (in- sual acuity, defined as the ability to read an adcluding controls) who had a visual acuity of 20/40 ditional 15 letters (3 lines) or more on an eye
or worse or who had persistent macular edema chart, occurred in 27% of patients receiving 1 mg
were eligible to receive injections of ranibizumab. of triamcinolone, 26% of those receiving 4 mg,
At 12 months, the improvements in vision gained and 7% of controls (P = 0.001 for both compariby patients who had been randomly assigned to sons with controls). Rates of adverse events were
one of the ranibizumab groups were maintained, similar to those among the patients with branch
whereas controls who were subsequently treated retinal-vein occlusion in the SCORE Study.34 The
with ranibizumab had a mean visual improve- study of intravitreal injection of dexamethasone
ment of 12 letters (>2 lines) from baseline.
through an implant was associated with a shorter time to achieve a gain in acuity of 15 letters
Central Retinal-Vein Occlusion
on an eye chart in patients with central retinalLaser Treatment
vein occlusion, as well as in those with branch
Grid laser photocoagulation does not help to re- retinal-vein occlusion, as discussed above.35 In
store vision loss from macular edema in patients both the triamcinolone and dexamethasone studwhich elevated intraocular pressure developed
was higher with dexamethasone treatment than
with the sham injection (4% for both dexamethasone doses vs. 0.7%, P<0.002). Cataract rates
did not differ significantly among the groups at
6 months.
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The
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of
m e dic i n e
ies, elevated intraocular pressure was a significant treated for 2 years with monthly intravitreal inadverse event for patients receiving these drugs.
jections of ranibizumab than among controls
(7.8% vs. 4.2%, P = 0.01).49 Although an increased
Anti-VEGF Agents
rate of vascular events was not identified in trials
Ranibizumab and bevacizumab are widely used of intraocular anti-VEGF agents, more data are
in the treatment of central retinal-vein occlusion, needed to assess whether anti-VEGF treatment
as well as in the treatment of branch retinal-vein increases the risk of cardiovascular events, parocclusion.41,42,46 In the Ranibizumab for the ticularly stroke, in patients with retinal-vein ocTreatment of Macular Edema after Central Reti- clusion.50
nal Vein Occlusion (CRUISE) trial, which included
Data are lacking from randomized trials com392 patients with central retinal-vein occlusion paring glucocorticoids and anti-VEGF therapies
and macular edema, the proportion of patients head to head and assessing the effects of various
with clinically significant improvement in visual combination therapies (e.g., laser plus anti-VEGF
acuity was higher in the ranibizumab groups therapy). Most trials have largely excluded pathan in the sham-injection group (46% of pa- tients with poor visual acuity and nonperfused
tients receiving 0.3 mg of ranibizumab and 48% retinal-vein occlusion, and it is unclear what type
of those receiving 0.5 mg vs. 17% of those under- of treatment is appropriate for these patients.
going sham injection).47 Like the BRAVO trial,43
Other systemic therapies have been tried (e.g.,
which assessed the same ranibizumab interven- hemodilution, streptokinase, and anticoagulants
tion in patients with branch retinal-vein occlu- such as troxerutin and ticlopidine), as have surgision and in those with central retinal-vein occlu- cal approaches (e.g., radial optic neurotomy, persion, the CRUISE study showed no significant formed to improve venous outflow at the optic
between-group differences in the incidence of disc, and vitrectomy with arteriovenous sheathotsystemic vascular events among the patients with omy, performed to relieve venous compression at
central retinal-vein occlusion, and the vision gain the arteriovenous junctions),30-32 but these treatwith ranibizumab treatment was maintained at ments have not been rigorously studied. Surgical
12 months.47
procedures are increasingly being replaced by
intraocular injections, which can be given in a
physician’s office.
A r e a s of Uncer ta in t y
Although retinal-vein occlusion is much more
common in persons older than 50 years of age, it
can also arise in younger persons with no identifiable risk factors.48 In younger patients, retinalvein occlusion may have a different pathogenesis,
but it is not clear whether systemic coagulation
abnormalities are more common in such patients.
Trials of treatments with intraocular glucocorticoid and anti-VEGF agents have had relative­
ly short periods of follow-up. Longer-term trials
are needed to determine whether visual gains will
be maintained after 1 year, to establish optimal
dosing regimens, and to ascertain the risks of
these therapies. In some trials, treatment was
delayed to allow for spontaneous improvement;
thus, it is not clear how different treatments
would compare if used earlier in the course of
disease.
In post hoc analyses of two trials addressing
neovascular age-related macular degeneration,36,37
rates of nonocular hemorrhage, including cerebral hemorrhage, were higher among patients
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Guidel ine s from Profe ssiona l
So cie t ie s
The United Kingdom Royal College of Ophthalmologists has published guidelines for the management of retinal-vein occlusion,51 but these
guidelines do not take into account data from
recent clinical trials.
C onclusions a nd
R ec om mendat ions
The patient described in the vignette has a superotemporal branch retinal-vein occlusion with macular edema. We recommend a thorough ocular
evaluation, including the use of fundus fluorescein angiography to assess macular perfusion and
leakage and optical coherence tomography to
quantify macular edema. Systemic evaluation by
the patient’s general physician and appropriate
management of modifiable cardiovascular risk
factors (e.g., hypertension and hyperlipidemia) are
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clinical pr actice
indicated. We do not recommend further workup
for coagulation abnormalities in this patient.
We would discuss with the patient the risks
and potential benefits of grid laser photocoagulation or intraocular injections of anti-VEGF
agents. The advantages of using grid laser for
first-line treatment of branch retinal-vein occlusion include the availability of longer-term data
from clinical trials showing improvement in visual acuity, lower rates of adverse effects, and
lower costs with this treatment than with antiVEGF therapy. In selected cases (e.g., dense macular hemorrhage that precludes the use of laser
therapy), we would consider intraocular injection
of an anti-VEGF agent for first-line treatment;
References
1. Hayreh SS. Prevalent misconceptions
about acute retinal vascular occlusive disorders. Prog Retin Eye Res 2005;24:493519.
2. Mitchell P, Smith W, Chang A. Prevalence and associations of retinal vein occlusion in Australia: the Blue Mountains
Eye Study. Arch Ophthalmol 1996;114:
1243-7.
3. Klein R, Klein BE, Moss SE, Meuer
SM. The epidemiology of retinal vein occlusion: the Beaver Dam Eye Study. Trans
Am Ophthalmol Soc 2000;98:133-41.
4. Rogers S, McIntosh RL, Cheung N,
et al. The prevalence of retinal vein occlusion: pooled data from population studies
from the United States, Europe, Asia,
and Australia. Ophthalmology 2010;117(2):
313.e1-319.e1.
5. Cugati S, Wang JJ, Rochtchina E,
Mitchell P. Ten-year incidence of retinal
vein occlusion in an older population: the
Blue Mountains Eye Study. Arch Ophthalmol 2006;124:726-32.
6. McIntosh RL, Rogers SL, Lim L, et al.
Natural history of central retinal vein occlusion: an evidence-based systematic review. Ophthalmology 2010;117(6):1113.
e15-1123.e15.
7. Chua B, Kifley A, Wong TY, Mitchell
P. Homocysteine and retinal vein occlusion: a population-based study. Am J Ophthalmol 2005;139:181-2.
8. Greiner K, Hafner G, Dick B, Peetz D,
Prellwitz W, Pfeiffer N. Retinal vascular
occlusion and deficiencies in the protein C
pathway. Am J Ophthalmol 1999;128:6974.
9. Incorvaia C, Lamberti G, Parmeggiani
F, et al. Idiopathic central retinal vein occlusion in a thrombophilic patient with the
heterozygous 20210 G/A prothrombin ge­
notype. Am J Ophthalmol 1999;128:247-8.
10. Lahey JM, Tunç M, Kearney J, et al.
Laboratory evaluation of hypercoagulable
states in patients with central retinal vein
we would inform the patient of the increased
risk of arterial thromboembolic events. Treatment with a dexamethasone implant is another
option, but evidence is lacking to demonstrate an
improvement in visual acuity beyond 3 months.
The patient should be monitored closely for signs
of neovascularization (e.g., new vessels or vitreous hemorrhage), which would require scatter
laser photocoagulation.
Dr. Wong reports receiving consulting fees from Allergan,
Novartis, and Pfizer and speaking fees and grant support from
Allergan; and Dr. Scott reports receiving consulting fees from
Genentech. No other potential conflict of interest relevant to
this article was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
occlusion who are less than 56 years of
age. Ophthalmology 2002;109:126-31.
11. Janssen MC, den Heijer M, Cruysberg
JR, Wollersheim H, Bredie SJ. Retinal vein
occlusion: a form of venous thrombosis or
a complication of atherosclerosis? A metaanalysis of thrombophilic factors. Thromb
Haemost 2005;93:1021-6.
12. Rath EZ, Frank RN, Shin DH, Kim C.
Risk factors for retinal vein occlusions:
a case-control study. Ophthalmology 1992;
99:509-14.
13. Hayreh SS, Zimmerman B, McCarthy
MJ, Podhajsky P. Systemic diseases associated with various types of retinal vein
occlusion. Am J Ophthalmol 2001;131:6177.
14. Elman MJ, Bhatt AK, Quinlan PM,
Enger C. The risk for systemic vascular
diseases and mortality in patients with
central retinal vein occlusion. Ophthalmology 1990;97:1543-8.
15. Wong TY, Larsen EK, Klein R, et al.
Cardiovascular risk factors for retinal
vein occlusion and arteriolar emboli: the
Atherosclerosis Risk in Communities &
Cardiovascular Health studies. Ophthalmology 2005;112:540-7.
16. Cheung N, Klein R, Wang JJ, et al.
Traditional and novel cardiovascular risk
factors for retinal vein occlusion: the Multiethnic Study of Atherosclerosis. Invest
Ophthalmol Vis Sci 2008;49:4297-302.
17. The Branch Vein Occlusion Study
Group. Argon laser photocoagulation for
macular edema in branch vein occlusion.
Am J Ophthalmol 1984;98:271-82.
18. Idem. Argon laser scatter photocoagulation for prevention of neovascularization and vitreous hemorrhage in branch
vein occlusion: a randomized clinical trial.
Arch Ophthalmol 1986;104:34-41.
19. The Central Vein Occlusion Study
Group. Baseline and early natural history
report: the Central Vein Occlusion Study.
Arch Ophthalmol 1993;111:1087-95.
20. Idem. A randomized clinical trial of
early panretinal photocoagulation for is­
chemic central vein occlusion: the Central
Vein Occlusion Study Group N report.
Ophthalmology 1995;102:1434-44.
21. Idem. Natural history and clinical management of central retinal vein occlusion.
Arch Ophthalmol 1997;115:486-91. [Erratum, Arch Ophthalmol 1997;115:1275.]
22. Rogers SL, McIntosh RL, Lim L, et al.
Natural history of branch retinal vein occlusion: an evidence-based systematic review. Ophthalmology 2010;117(6):1094.
e5-1101.e5.
23. Finkelstein D. Ischemic macular edema: recognition and favorable natural
history in branch vein occlusion. Arch
Ophthalmol 1992;110:1427-34.
24. The Central Vein Occlusion Study
Group. Evaluation of grid pattern photocoagulation for macular edema in central
vein occlusion: the Central Vein Occlusion
Study Group M report. Ophthalmology
1995;102:1425-33.
25. Tsaloumas MD, Kirwan J, Vinall H,
et al. Nine year follow-up study of morbidity and mortality in retinal vein occlusion. Eye (Lond) 2000;14:821-7.
26. Christoffersen N, Gade E, Knudsen L,
Juel K, Larsen M. Mortality in patients
with branch retinal vein occlusion. Ophthalmology 2007;114:1186-9.
27. Cugati S, Wang JJ, Knudtson MD, et al.
Retinal vein occlusion and vascular mortality: pooled data analysis of 2 population-based cohorts. Ophthalmology 2007;
114:520-4.
28. Hayreh SS, Rojas P, Podhajsky P, Montague P, Woolson RF. Ocular neovascularization with retinal vascular occlusion.
III. Incidence of ocular neovascularization with retinal vein occlusion. Ophthalmology 1983;90:488-506.
29. Wong TY, Mitchell P. Hypertensive retinopathy. N Engl J Med 2004;351:2310-7.
30. McIntosh RL, Mohamed Q, Saw SM,
n engl j med 363;22 nejm.org november 25, 2010
2143
The New England Journal of Medicine
ownloaded from www.nejm.org at NATIONAL UNIV OF SINGAPORE-CENTRAL LIBRARY on November 25, 2010. For personal use only. No other uses without permission
Copyright © 2010 Massachusetts Medical Society. All rights reserved.
clinical pr actice
Wong TY. Interventions for branch retinal
vein occlusion: an evidence-based systematic review. Ophthalmology 2007;114:83554.
31. Mohamed Q, McIntosh RL, Saw SM,
Wong TY. Interventions for central retinal
vein occlusion: an evidence-based systematic review. Ophthalmology 2007;114:50719.
32. Lazo-Langner A, Hawel J, Ageno W,
Kovacs MJ. Low molecular weight heparin
for the treatment of retinal vein occlusion: a systematic review and meta-analysis of randomized trials. Haematologica
2010;95:1587-93.
33. Jonas JB, Akkoyun I, Kamppeter B,
Kreissig I, Degenring RF. Branch retinal
vein occlusion treated by intravitreal triamcinolone acetonide. Eye (Lond) 2005;
19:65-71.
34. Scott IU, Ip MS, VanVeldhuisen PC,
et al. A randomized trial comparing the
efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular edema
secondary to branch retinal vein occlusion:
the Standard Care vs Corticosteroid for
Retinal Vein Occlusion (SCORE) study report 6. Arch Ophthalmol 2009;127:111528. [Erratum, Arch Ophthalmol 2009;127:
1655.]
35. Haller JA, Bandello F, Belfort R Jr,
et al. Randomized, sham-controlled trial
of dexamethasone intravitreal implant in
patients with macular edema due to retinal vein occlusion. Ophthalmology 2010;
117(6):1134.e3-1146.e3.
36. Brown DM, Kaiser PK, Michels M,
et al. Ranibizumab versus verteporfin for
neovascular age-related macular degeneration. N Engl J Med 2006;355:1432-44.
37. Rosenfeld PJ, Brown DM, Heier JS,
et al. Ranibizumab for neovascular agerelated macular degeneration. N Engl J
Med 2006;355:1419-31.
38. Aiello LP, Avery RL, Arrigg PG, et al.
Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N
Engl J Med 1994;331:1480-7.
39. Campochiaro PA, Hafiz G, Shah SM,
et al. Ranibizumab for macular edema
due to retinal vein occlusions: implication
of VEGF as a critical stimulator. Mol Ther
2008;16:791-9.
40. Spaide RF, Chang LK, Klancnik JM,
et al. Prospective study of intravitreal ranibizumab as a treatment for decreased
visual acuity secondary to central retinal
vein occlusion. Am J Ophthalmol 2009;
147:298-306.
41. Wu L, Arevalo J, Berrocal MH, et al.
Comparison of two doses of intravitreal
bevacizumab as primary treatment for
macular edema secondary to central retinal vein occlusion: results of the Pan American Collaborative Retina Study Group at
24 months. Retina 2010;30:1002-11.
42. Prager F, Michels S, Kriechbaum 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;93:452-6.
43. Campochiaro PA, Heier JS, Feiner L,
et al. Ranibizumab for macular edema
following branch retinal vein occlusion:
six-month primary end point results of
a phase III study. Ophthalmology 2010;
117(6):1102.e1-1112.e1.
44. McAllister IL, Gillies ME, Smithies
LA, et al. The Central Retinal Vein Bypass
Study: a trial of laser-induced chorioretinal venous anastomosis for central retinal
vein occlusion. Ophthalmology 2010;117:
954-65.
45. Ip MS, Scott IU, VanVeldhuisen PC,
et al. A randomized trial comparing the
efficacy and safety of intravitreal triamcinolone with observation to treat vision
loss associated with macular edema secondary to central retinal vein occlusion:
the Standard Care vs Corticosteroid for
Retinal Vein Occlusion (SCORE) study report 5. Arch Ophthalmol 2009;127:110114. [Erratum, Arch Ophthalmol 2009;127:
1648.]
46. Kinge B, Stordahl PB, Forsaa V, et al.
Efficacy of ranibizumab in patients with
macular edema secondary to central retinal vein occlusion: results from the shamcontrolled ROCC study. Am J Ophthalmol
2010;150:310-4.
47. Brown DM, Campochiaro PA, Singh
RP, et al. Ranibizumab for macular edema
following central retinal vein occlusion:
six-month primary end point results of
a phase III study. Ophthalmology 2010;
117(6):1124.e1-1133.e1.
48. Rouhani B, Mandava N, Olson JL.
Central retinal vein occlusion after intense exercise in healthy patients. Retinal
Cases Brief Rep 2010;4:105-8.
49. Gillies MC, Wong TY. Ranibizumab
for neovascular age-related macular degeneration. N Engl J Med 2007;356:748-9.
50. Wong TY. Age-related macular degeneration and cardiovascular disease in the
era of anti-vascular endothelial growth
factor therapies. Am J Ophthalmol 2009;
148:327-9.
51. Retinal vein occlusion (RVO) interim
guidelines. London: The Royal College of
Ophthalmologists, February 2009. (http://
www.rcophth.ac.uk.)
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