RETINAL
VASCULAR DISEASE
Diagnostic
Workup for Vascular Occlusive Disease
Pinpointing
etiology is the first step.
To
determine the diagnostic workup for retinal vascular disease, you need to know
the etiology. Once you truly understand the disease process, your workup can
be directed very well," said Sharon Fekrat, MD, associate professor, Albert Eye
Research Institute, Duke University Eye Center, speaking at the May 2006 Retinal
Physician Symposium.
Retinal vascular occlusions can be either arterial (central,
branch or cilioretinal) or venous (central, branch or hemi). And most retinal vascular
occlusions in elderly patients are due to either embolic disease in arterial occlusions,
or degenerative changes in the vessel wall leading to thrombosis, Dr. Fekrat said.
ARTERIAL OCCLUSIONS
The majority of arterial occlusions are
embolic and can be endogenous or, less commonly, exogenous. "They're often cholesterol,
platelet-fibrin, calcific or other. They can be thrombotic — either a hypercoagulable
state or degenerative vessel wall — or they can be vasculitic — either
inflammatory or infectious. Less commonly, they can be of a vasospastic nature,"
Dr. Fekrat said.
Understanding relevant risk factors is another important component
to the workup. "The cardiovascular risk factors that predispose patients to thromboembolism
in arterial occlusion include hypertension, elevated cholesterol, diabetes, smoking
and, increasingly, homocysteinemia," Dr. Fekrat said.
Past and family history of thrombosis or embolism also should
raise a red flag when diagnosing retinal vascular conditions. "We look at vascular
risk factors, such as smoking, hypertension, diabetes, obesity, the male gender,
age and lipid profile," Dr. Fekrat said. "The initial workup for patients who have
arterial occlusions includes a cardiovascular assessment. I contact the patient's
internist or cardiologist, or both, to have them evaluate the blood pressure and
possibly perform a transesophageal cardiac echo as well as a carotid Doppler," Dr.
Fekrat said.
The initial workup for arterial occlusions — all of this
directed from the risk factors and the etiology — should include CBC platelets,
lipid profile, fasting plasma homocysteine and fasting glucose. Dr. Fekrat recommends
referring younger patients to a hematologist for further evaluation.
VENOUS OCCLUSIONS
The diagnosis and workup of retinal venous
occlusions is more challenging and less directed because the etiology is poorly
understood. "According to the Eye Disease Case Control Study, the risk factors for
branch retinal vein occlusion (BRVO) can help direct our work-up," Dr. Fekrat said.
"There is an increased risk for BRVO in people who have treated or untreated systemic
hypertension, cardiovascular disease, glaucoma, higher body mass index, and higher
serum alpha-2 globulin levels," she said.
Dr. Fekrat recommends checking the fasting plasma homocysteine
levels in any patient who has risk factors for hemiretinal vein occlusion at any
age. "If elevated, it's easy to lower this with oral folate," she said.
Intravitreal
Triamcinolone For RVO
NEI
study examines the risk/benefit ratio of intravitreal steroid injections.
Based primarily on anecdotal experience, intravitreal
triamcinolone acetonide (Kenalog) (IVTA) is being used widely for treating retinal
vein occlusion. "We know triamcinolone downregulates inflammatory markers. It
also reduces the blood retinal barrier and vascular permeability, and that can lead
to a reduction of the optic disc edema as well as reabsorption of macular edema,"
said Sharon Fekrat, MD, associate professor, Albert Eye Research Institute, Duke
University Eye Center. "We also know that the effect may be transient; that the
half-life is just about 3 weeks in a non-vitrectomized eye and even shorter in eyes
that have had vitrectomy, and that macular edema can return. Repeat injections are
often required."
In the short-term, these injections apparently provide an
anatomical benefit to many patients and a visual acuity benefit to some patients
with retinal vein occlusion, but, says Dr. Fekrat, there are many unanswered questions.
"We don't know how quickly we should reinject. We don't know if the patient is more
likely to have IOP problems if we reinject sooner than 4 months. Nor do we know
the implications of sustained delivery devices," she said.
Triamcinolone is generally nontoxic in the 4-mg and 8-mg doses
that are typically used in the United States, but single or repeated injections
of higher doses that are used elsewhere around the world may be more likely to show
some toxicity, according to Dr. Fekrat. "We know that the current preparation we
use is preserved and that the level of preservative is safe, but at higher concentrations,
these substances can be potentially toxic. Perhaps the injection of unsafe levels
of preservative is responsible for some of the pseudo-endophthalmitis cases that
we've seen," she said.
ONGOING STUDY
Further information is needed, and Dr. Fekrat
pointed out, the NEI-sponsored SCORE (Standard Care vs. Corticosteroid for Retinal
Vein Occlusion) study could provide it. "We have this wonderful study, and we really
should try to recruit patients so we can finally get some solid answers about some
of our treatments," she said.
The SCORE study is a Phase 3 randomized controlled, multicenter,
unmasked trial designed to determine if the benefits of steroids outweigh the risks
in eyes with retinal vein occlusions. The primary objective is to look at the visual
acuity outcome in eyes randomly assigned to intravitreal injection of triamcinolone
for macular edema, branch or hemiretinal vein occlusion and central retinal vein
occlusions and compare it to outcomes of those treated with standard of care. "This
should be very interesting particularly with respect to the proportion of those
with 15-letter improvement at 1 year," Dr. Fekrat said.
"The study is looking at injection-related events, as well as
steroid-related toxicities. It should answer a lot of our questions about safety,"
Dr. Fekrat said. Inclusion criteria have been broadened to encourage recruitment.
Anti-VEGF Injectables Show Promise
Ongoing
studies and anecdotal reports support further exploration.
Anecdotal evidence, as well as several ongoing
studies, suggest that intravitreal anti-VEGF injectables offer promise for retinal
vascular disease management.
RAVE TRIAL
The RAVE (Rubeosis Anti-VEGF) Trial is examining
the use of ranibizumab (Lucentis, Genentech) for ischemic central retinal vein occlusion
(CRVO). According to David M. Brown, MD, an estimated 30% of CRVO is the ischemic
form. Some 70% of patients develop rubeosis, and 50% develop neovascular glaucoma
(NVG). Most rubeosis develops in the first 3 months, but if no NVG develops, most
rubeosis regresses spontaneously after 9 months as collaterals enlarge. "Two-thirds
of the CRVO patients who meet ischemic criteria develop rubeosis," Dr. Brown said.
"The hypothesis of the RAVE trial is that monthly intravitreal
injections of ranibizumab will control the neovascular drive in ischemic CRVO, and
that if we avoid neovascularization of the iris (NVI) and NVG long enough, we'll
get collateral formation and won't have to keep injecting indefinitely," Dr. Brown
said.
Early results indicate that monthly intravitreal ranibizumab controls
the neovascular drive in ischemic CRVO, and that edema in ischemic CRVO is in large
part mediated by VEGF. "The big question is: After nine injections, will the edema
and the NVI return," Dr. Brown said. "If so, we'll need a RAVE-plus trial where
we add laser or another therapy. This may be our best chance to treat a disease
that, thus far, has been untreatable."
PEGAPTANIB FOR CRVO
Dr. Brown also reported on the 30-week outcomes
of pegaptanib sodium injection (Macugen, [OSI] Eyetech, Pfizer) for CRVO. The data
emerged from the initial report of the Exploratory Phase 2 Trial that is looking
at the safety and efficacy of pegaptanib when given by intravitreal injection every
6 weeks in patients with recent vision loss due to macular edema (determined by
OCT) secondary to CRVO. For inclusion in the trial, subjects had to have CRVO that
occurred within 6 months prior to baseline. Their best-corrected visual acuity had
to be 20/50 to 20/400; and their central retinal thickness had to be greater than
or equal to 250 μm at baseline.
"The 30-week data after five injections of a dose (0.3 mg) larger
than that used to treat AMD indicates that patients improve by about two lines,"
Dr. Brown said. This very early data does not provide information with regard to
when the therapy can stop, or if or how soon the occlusion will return once the
therapy concludes, he pointed out.
BEVACIZUMAB FOR EDEMA FROM RVO
Philip J. Rosenfeld, MD, PhD, reported on
the use of intravitreal bevacizumab (Avastin, Genentech) for macular edema from
retinal vein occlusions. "Right now, what's available is mostly anecdotal evidence,
and it indicates the treatment looks promising," Dr. Rosenfeld said.
So far, the response has been unpredictable with respect to the
duration of efficacy. "Just because it lasts 2 or 3 months the first time you inject
does not mean it will last that long the next time, so we can't predict from the
outset how often a patient will need to return for treatment," Dr. Rosenfeld said.
By the same token, he noted, he has patients who are so pleased with the result,
they are happy to return whenever necessary for another injection. Based on early
outcomes, Dr. Rosenfeld suggests considering intravitreal bevacizumab before triamcinolone,
but to consider intravitreal triamcinolone if the bevacizumab injections are needed
too frequently or if fluid persists in the macula.
CRVO
Surgery Relies on Neurovascular Compression
All
roads lead to retinal blood flow restoration.
Radial
optic neurotomy (RON) is a technically feasible procedure for the surgical treatment
of central retinal vein occlusion (CRVO). Unresolved or recurrent cystoid macular
edema (CME) and macular pigmentation in a percentage of patients continues to present
a challenge, according to E. Mitchel Opremcak, MD, Columbus, Ohio, who pioneered
the RON procedure.
Dr. Opremcak presented outcomes on a large series of patients
with CRVO and severe vision loss on which he performed RON. "The anatomy of the
optic disc, including the cribriform plate and the scleral ring, may contribute
to the development of retinal vaso-occlusive diseases. Neurovascular compression
within the confined space at this location — the scleral outlet — may
play a pathoetiologic role in CRVO," Dr. Opremcak said. "We developed this surgical
procedure to open this space and relieve pressure on the central retinal vein."
Dr. Opremcak reported on 117 consecutive patients with CRVO and
severe vision loss defined as 20/200 or worse who underwent pars plana vitrectomy
and RON. The patients were observed with serial fundus photography, fluorescein
angiography and biomicroscopy for anterior segment neovascularization. Snellen visual
acuity was also noted.
Surgical relaxation of the scleral outlet was associated with
clearing of the intraretinal hemorrhage, and 95% of patients achieved improved blood
flow. Visual acuity improved in 71% of patients, with an average gain of 2.5 lines.
Two or more lines were gained in 53% of patients, and four or more lines were gained
in 25% of patients. "Visual fields improved dramatically," said Opremcak. Investigators
noted no serious complications with this procedure. Anterior segment neovascularization
was found in 6% of the study cohort.
"This procedure works for hemicentrals, as well," Dr. Opremcak
said. "Most of the hemis have two vessels going out rather than one, and if you
decompress one of them you get resolution of the hemicentral vein occlusion.
Despite RON's success, some patients have unresolved or recurrent
CME and macular pigmentation. Dr. Opremcak tried adjunctive triamcinolone acetonide
along with RON in a group of these patients. Among these 63 patients, persistent
CME and macular pigmentation were noted in 17% and 28%, respectively. These outcomes
were similar to those noted among patients undergoing RON alone without intravitreal
triamcinolone. Elevated IOP was noted in 25% of patients, and one patient developed
endophthalmitis following the combination treatment.
"Now I'm waiting 3 to 6 weeks after RON and injecting bevacizumab
or pegaptanib, and I've seen tremendous CME improvement within a week, but within
6 to 8 weeks it recurs," Dr. Opremcak said. The next step will be to evaluate this
to see whether biologics or injection therapies will be helpful in treating the
CME that persists even after RON, he added.
Retinal Physician, Issue: September 2006