In this section of the supplement, my colleagues and I will present cases from our own practices exhibiting cases of either branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO).
With these cases, we will see how the basic science and clinical trial data that were presented in my introduction article can be used in clinical practice. For each case we will discuss our options for treatment and the rationale for choosing a particular treatment. We also will examine what the results may have been should another treatment path have been chosen.
-David M. Brown, MD, Course Director
CRVO Management
BY DANTE J. PIERAMICI, MD
In this first case, a 63-year-old woman presented
to me with an acute loss of vision over the
last few weeks in her left eye from a central
retinal vein occlusion (CRVO). Her baseline
visual acuity was 20/200 and her central retinal thickness
(CRT) on optical coherence tomography (OCT) was
685 μm. On clinical examination, there were no signs of
neovascularization of the iris, and on fundus examination,
we saw a dense intraretinal hemorrhage in all four
quadrants, swelling of the optic nerve, and macular
edema. Fluorescein angiography confirms swelling of the
optic nerve, with cystoid macular edema in the late phases
of the angiogram. OCT testing confirms marked cystic
edema of the retina, as well as areas of subretinal fluid
(Figure 1).
When deciding how to treat this patient, we considered the following options: (A) observation; (B) laser photocoagulation; (C) intraocular steroid injection; and (D) intravitreal antivascular endothelial growth factor (anti-VEGF) therapy.
The patient appears to have what is typically called a perfused CRVO. There is no evidence of neovascularization of the iris or neovascularization of the angle. But the patient does have significantly decreased visual acuity secondary to severe macular edema.
A: OBSERVATION
One might consider (A) observation in this case
because the patient presented acutely and reported only
3 to 4 weeks of symptoms. Unlike age-related macular
degeneration, where if a patient presents with significant
fluid in and under the retina visual acuity may be irreversibly
lost in a short period of time, patients with
severe CRVO have a larger window of opportunity for
treatment before visual acuity loss becomes irreversible.
B: LASER PHOTOCOAGULATION
The second option is laser photocoagulation (B). This,
in my opinion, is currently not a reasonable option. The
Central Vein Occlusion Study, as mentioned by Dr. Brown
in his introduction, proved laser for macular edema associated
with CRVO to be without benefit.1 Additionally,
given our increased options (eg, [B and C]), laser is not
something that I would consider.
C: INTRAOCULAR STEROID
Regarding option (C), we now have phase 3 clinical evidence
to support the use of steroids for CRVO. Both the
Standard Care vs Corticosteroid for Retinal Vein
Occlusion (SCORE) study-CRVO2 and the 12-month reinjection
data with the dexamethasone sustained delivery
device3 (Ozurdex, Allergan, Inc.) support the use of
steroids for this condition.
Intraocular steroids offer the patient the ability to fairly rapidly reduce the intraocular and subretinal edema, but they do come at some side effect risk. First, my patient is phakic, and so there is concern about the possibility of cataracts. All patients who receive intraocular steroids will eventually develop cataracts, so this must be taken into consideration.
Secondly, a high risk exists for elevated intraocular pressure (IOP) due to steroid. Approximately one-third of patients treated with steroids will at some point develop elevated IOP. Although most of these cases can be managed with topical glaucoma medications, some patients will require glaucoma surgery, so this risk must be discussed with the patient prior to initiating intraocular steroid injections.
Secondly, a high risk exists for elevated intraocular pressure (IOP) due to steroid. Approximately one-third of patients treated with steroids will at some point develop elevated IOP. Although most of these cases can be managed with topical glaucoma medications, some patients will require glaucoma surgery, so this risk must be discussed with the patient prior to initiating intraocular steroid injections.
D: ANTI-VEGF AGENTS
For this patient, I chose option D, intraocular anti-
VEGF agents. Let's see what happened.
Figure 2 shows the treatment of the patient with the corresponding optical coherence tomography (OCT) imaging. The top image clearly shows significant intraretinal and subretinal fluid. Additionally, swelling of the optic nerve edge can be seen on the edge of the OCT. We injected with intravitreal ranibizumab (IVR; Lucentis, Genentech, Inc.) and within 1 week (Figure 2, second row) a marked decrease in the intraretinal edema is evident; however, there is still the presence of persistent subretinal fluid. At 1 month following treatment (Figure 2, third row), subretinal fluid is still present, but the edema and retina continue to thin, and there is associated improvement in visual acuity. It is interesting to note that the subretinal fluid is slightly more resilient to the anti-VEGF agent. Additionally, macular edema can resolve significantly despite the patient not subjectively noticing the improvement for some time. For this patient, we injected again at 1 month. We saw additional reduction in edema at 2 months (Figure 2, fourth row) and injected again. By 3 months, the OCT appeared fairly normal and the visual acuity improved from 20/200 at baseline to 20/40 (Figure 2, fifth row).
At month 3, not only did we see improvement in OCT thickening, but we also saw marked improvement in the fundus photographs and fluorescein angiogram (Figure 3). There is clearly rapid reduction in the intraretinal hemorrhaging and optic nerve swelling. The fluorescein angiogram confirms decreased swelling of the optic nerve and the macula.
Anti-VEGF agents seem to have an effect on anti-permeability of fluid, but they also seem to reduce leakage of intraretinal hemorrhage and leakage of the optic nerve.
This patient does appear to have some early collateralization that is apparent on the optic nerve head.
ONGOING MANAGEMENT
Because the patient looked well at 3 months, it would
reasonable to consider observation from this point.
Along with my recommendation, however, the patient
elected to continue with an additional injection at
month 4 (Figure 4, top row). Interestingly, at 5 months
there was an increase in subretinal fluid (Figure 4, second
row). After injecting again at 5 months, the edema was
fairly resolved by month 6 (Figure 4, third row) after
which we chose to observe. As seen in Figure 4, fourth
row, at month 7 the edema recurred along with slight
reduction in visual acuity. For this patient we decided to
treat again and by month 8 (Figure 4, fifth row), the
edema and visual acuity began to improve. The fundus
and fluorescein images from month 6 show the marked
improvements and collateralization at the optic nerve
head that correlate with the OCT findings (Figure 5).
Although we saw some recurrence of the edema at month 9 (Figure 6, top row), we decided to continue the period of observation. By month 12, the patient continued to do well (Figure 6, third row) and, although there is some fluctuation in OCT findings, the visual acuity and fundus findings continued to improve out to 2 years (Figures 7-9). After over 1 year without another injection, the patient's visual acuity is nearly 20/20 and the OCT is normalized.
DISCUSSION
The resolution of the case presented here is not necessarily
a typical result but may represent approximately
one-third of patients with this type of CRVO. The majority
of patients appear to require anti-VEGF treatment for
an extended period of time.
So what should the clinician do for cases that require 3 to 4 years of treatment?
In my opinion, there are a number of options, the first being to continue treatment. If a patient is responding to treatment and they tolerate the injections well, I consider this a reasonable approach.
The other option for patients who require a long course of treatment may be a combination approach. It may help patients to add a steroid injection or a sustained- delivery device such as the intravitreal dexamethasone device (Ozurdex) to extend the treatment period.
Because we theorize that the continued reoccurrence of the edema in such cases is a result of increased or persistent VEGF expression, we might consider increasing VEGF suppression, not only with an intraocular injection, but with panretinal laser photocoagulation to areas of ischemia. This approach has not been tested in detail to date, but it seems to be rational for these patients. The downside, however, may be a reduction in peripheral or night vision, so if laser is used, the patient must be made aware of the potential side effects.
Overall, during our course of treatment we must be vigilant to the possibility of iris or retinal neovascularization, particularly during periods when we withhold intraocular VEGF therapy.
One final consideration: if a patient with a CRVO who is not responding well to anti-VEGF therapy, it may be worth considering a different anti-VEGF agent, eg, from ranibizumab to bevacizumab (Avastin, Genentech, Inc.) or vice-versa.
In my opinion, this case is successful in illustrating how effective and rapid improvements in visual acuity and anatomical characteristics of the eye can be in response to anti-VEGF therapy. Certainly, there are currently a number of options for our patients with CRVO, making treatment much more satisfying for the physician and patient.
BRVO in a Patient WithFamily History ofGlaucoma
BY ROBERT L. AVERY, MD
This 68-year-old man presented to me with a2-month history of visual loss in his right eyedue to a branch retinal vein occlusion (BRVO).He has a family history of glaucoma, but to hisknowledge does not have the disease. Figure 1 shows hisbaseline fundus photos and optical coherence tomography(OCT) images. His visual acuity was 20/125, centralretinal thickness (CRT) was 612 μm, and the patient hadsignificant intraretinal hemorrhage.
TREATMENT OPTIONS
Our treatment options were (A) observation, (B)intravitreal steroid injection or implant, and C (intravitrealantivascular endothelial growth factor (anti-VEGF).We could not laser at this point because of the hemorrhage.
I decided against observation (A) because the patienthad severe visual impairment and was motivated forimmediate treatment. Because of the patient's family historyof glaucoma, however, I did not want to risk causingthe intraocular pressure (IOP) to rise with a steroid (B).
Thus, I chose to treat this patient with (C) monthlyinjections of the intravitreal agent ranibizumab (IVR;Lucentis, Genentech, Inc.) to clear the significant edema.
At day 7, the patient's visual acuity had improved to20/50 and the CRT had improved to 283 μm (Figure 2A).At 1 month, visual acuity remained at 20/50, butanatomically, the eye improved further to a CRT of 193µm (Figure 2B).
The month 3 findings were visual acuity improvementto 20/40 and CRT on OCT was further improved to 144µm (Figure 3).
At 6-months the intraretinal hemorrhage had essentially resolved (Figure 4). Our last injection of IVR wasat 5 months. We would have considered grid or focallaser if we found the patient had recurrent intraretinalthickening or edema on OCT, but the patient did verywell even after stopping the injections with no recurrentedema after 2 years of follow-up. Adding grid orfocal laser to anti-VEGF can often allow less frequentinjections in persistent cases by treating the underlyingareas of ischemia. In this case, however, the edemaresolved without any permanent vision loss or blindspots from laser.
CONCLUSION
Once this patient's edema had resolved, I stretchedout the interval between visits. I observed the patientfor a possible recurrence of edema or neovascularization.Although this is more common in cases of centralretinal vein occlusion (CRVO), BRVOs can recur aftertherapy is discontinued.
Persistent CRVO in aMonocular Patient
BY DAVID M. BROWN, MD
One of my long-term patients is a 68-year-oldgentleman who is monocular from a previoushunting accident. In 2006, this patient presentedto me with edema and hemorrhage in all fourquadrants of his remaining eye (Figures 1A-D). His visualacuity had decreased to 20/80 and he was no longerable to drive or participate in his favorite hobby, showinghunting dogs, which required that he be able to givethe dogs hand signals 150 yards out in the field. His fluoresceinangiograms did not show much ischemia(Figures2A and B). We could not test for a relative afferentpapillary defect because he was monocular. The patient has hypertension and diabetes, both of whichare under control.
Our options for treating this patient were eitherintravitreal steroid or antivascular endothelial growthfactor (anti-VEGF) agent. At the time, the only availableanti-VEGF agents were pegaptanib sodium(Macugen, Eyetech) and off-label intravitreal bevacizumab(IVB; Avastin, Genentech, Inc.) and the mostcommonly used steroid was intravitreal triamcinoloneacetonide (IVTA; Kenalog, Bristol Myers-Squibb). I consideredthe following options: (A) observation, (B)intravitreal triamcinolone acetonide (IVTA), or (C)intravitreal bevacizumab (IVB). There is a valid role forany other these options and I will explain my thoughtprocess when considering each.
A: OBSERVATION
Observation is a reasonable choice because the presentationis acute in nature. In clinical experience, approximatelyone-third of these cases resolve spontaneously.The edema in this patient, however, persisted and so if Iwere to choose A, the patient would most likely comeback 1 month later with visual acuity decreased to20/100 with no changes, forcing me to choose B or C.
B: STEROID
In 2006, the use of IVTA for this type of case was fairlycommon. I discussed the risk of cataract and glaucomawith the patient and he elected that he preferred not totake the chance, despite the fact that he would mostlikely have to receive more injections with anti-VEGF than steroid. I agreed with the patient because there is agreater likelihood that one- to two-thirds of patients willdevelop cataracts and/or increased intraocular pressure.
C: ANTI-VEGF
In my opinion, the risk-benefit ratio for steroid was notas favorable as anti-VEGF particularly for a monocularpatient. IVB was not, however, without risk. There is a riskassociated with intravitreal injection for endophthalmitisor retinal tear in one in 2,000 patients. The benefit, however,is that when I inject with anti-VEGF, almost everypatient with macular edema responds. Thus, for thispatient, I chose C. In 2006, ranibizumab (Lucentis,Genentech, Inc.) was not approved by the US Food andDrug Administration, so I used IVB.
The patient showed a remarkable improvement andcalled me the next day telling me that he could see hisdogs again. A week later, his edema had resolved and hisvisual acuity was between 20/30 and 20/40.
ONGOING MANAGEMENT DECISIONS
The next step in the decision process is “where do wego from here?” Do we inject this gentleman monthly withanti-VEGF? Do we observe to see if he is lucky enoughthat one shot or several shots will calm the edema?
At the time, we were hesitant to continue anti-VEGFagents with loads because we did not have much data orclinical experience on continuing anti-VEGF for edema sowe chose to observe. At 4 weeks, however, his macularedema was worsening, and by 6 weeks out he was backto 20/80 and his original level of macular edema (Figure3). At that point, we decided to give him monthly injectionsof bevacizumab. For the next 3 years, we continuedthis regimen, adding a treat-and-extend strategy(attempting to extend out to 5 or 6 weeks), but wefound that waiting any longer than 4 weeks to reinjectresulted in recurring edema with decreased visual acuity.
At this point, we were wondering if we had any otheroptions. We chose to switch the patient to intravitrealranibizumab (IVR) when it became available, and consideredpanretinal photocoagulation (PRP) to possibly decrease VEGFproduction. When the patient learned that PRP coulddecrease his peripheral field of vision, he was reticent towardthis choice because of his need to see his dogs out in the field.
CONCLUSION
With the switch from IVB to IVR, the patient has beenable to go from monthly injections to every 5 to 6 weeks,but will he need anti-VEGF therapy forever? We have discussedthe addition of a steroid, but the patient does notwant to do this; he would rather stay with the treatmentthat is working for him.
As a clinician, it is my hope that we will have the abilityto offer a sustained-release anti-VEGF agent for thesepatients in the future, which would provide an importantoption for these difficult, chronic cases.
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