12.3 Summary of Key Points

Fig. 12.3 (continued)

OD - OS asymmetry

−30

−20

−10

0

Average thickness [ m]

Superior (S)

317

Total 318

Inferior (I)

319

OS - OD asymmentry

m] [ Differance Thickeness

Average thickness [ m]

Superior (S)

337

Total 339

Inferior (I)

340

result in a lamellar or full thickness macular hole (see Fig. 7.17).47

Development of collateral vessels has been hypothesized to be a predictor for improvement or resolution of ME associated with

association.

12.3 Summary of Key Points

¥Macular edema in RVO is more sensitively detected with OCT than by slit lamp biomicroscopy.

¥VEGF and, to a lesser extent, other cytokines mediate ME in RVO.

¥Among BRVOs, approximately 60% have associated ME of which one-third spontaneously resolve.

¥A higher percentage of ischemic BRVOs with ME have spontaneous resolution of ME than of nonischemic BRVOs with ME.

¥An attached vitreous increases the likelihood of ME after BRVO or nonischemic CRVO, but not after ischemic CRVO.

¥The correlation between visual acuity and OCT-measured ME is modest and is reduced through the inßuence of ischemia and macular cell death.

¥Over 90% of cases of CRVO that present to an ophthalmologist have ME. No case of ME with CRVO resolves spontaneously by 1 year, but approximately 30% resolve spontaneously over a longer interval, often with neuroretinal or pigment epithelial scarring and atrophy.

d

100

0

Average thickness ( m)

Fig. 12.5 Fundus images of a 78-year-old man with a double HCRVO. The superior HCRVO is ischemic and the inferior HCRVO is nonischemic. The visual acuity was counting Þngers. (a) Color fundus photograph shows two separate hemicentral retinal veins that do not join on the disc. The increased density of intraretinal hemorrhages superiorly (the blue oval) compared to inferiorly (the black oval) reßects the differential ischemia in the superior and inferior hemiretinas. (b) Frame from the mid-phase ßuorescein angiogram shows the capillary nonperfusion superiorly (the yellow oval) compared to inferiorly (the green oval). (c) Frame from the late-phase

ßuorescein angiogram shows differential ßuorescein leakage with less leakage in the ischemic superior retina (the yellow oval) and more in the nonischemic inferior retina (the green oval). (d) Vertically oriented SD-OCT line scan shows extensive subretinal ßuid (the orange arrow) with differential loss of intraretinal Þne structure and differential morphology of the ME according to level of ischemia. The nonischemic inferior retina has an intact inner segment/outer segment junction lamina (the green oval), whereas the ischemic superior retina has lost these structures (the yellow arrow). The more ischemic superior retina has larger cystoid spaces

Fig. 12.4 This 67-year-old woman with hypertension and a history of a previous stroke presented with acute blurred vision of the left eye of 1-week duration. She knew the date of onset of her problem. The visual acuity was 20/50 in the left eye. (a) Color fundus photograph shows a superior hemicentral retinal vein occlusion. (b) Frame from the early-phase ßuorescein angiogram shows slow Þlling of the superior hemicentral retinal vein (the yellow arrow) compared to the inferior hemicentral retinal vein (the turquoise arrow). (c) Frame from the mid-phase ßuorescein angiogram shows a general pattern of nonischemia but with small regions of capillary nonperfusion (the turquoise oval compared to the yellow oval in normally perfused retina). (d) The spectral domain OCT (SD-OCT) false-color map shows retinal thickening in

zones congruent with leaking retinal vessels (see e). (e) Frame from the late-phase ßuorescein angiogram shows extensive leakage of ßuorescein dye from retinal vessels superiorly. The area of ßuorescein leakage is congruent with the thickening seen on SD-OCT (compare d). (f) The SD-OCT line scan shows acute changes to various retinal layers. The nerve Þber layer (the tan arrow) is thickened nasally. The ganglion cell layer (the orange arrow) can be clearly distinguished from the inner plexiform layer (the turquoise arrow). The inner nuclear layer (the green arrow) has some Þne cysts and is diffusely thickened nasally (compare to the thickness temporal to fovea). The outer plexiform layer appears thinned nasally compared to temporally. The outer nuclear layer has large cysts (the purple arrow)

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43.Ramchandran RS, Fekrat S, Stinnett SS, Jaffe GJ. Fluocinolone acetonide sustained drug delivery device for chronic central retinal vein occlusion: 12-month results. Am J Ophthalmol. 2008;146:285Ð91.

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This chapter covers treatments in current use for retinal vein occlusion (RVO). Over time, many proposed treatments (e.g., radial optic neurotomy for central retinal vein occlusion (CRVO)) have been tried and discarded as evidence accumulates of inefÞcacy or too many adverse events. These treatments are covered, mainly for historical purposes, in Chap. 15. On the other hand, some treatments are not adopted because of impracticality or cost-beneÞt considerations, rather than because of inefÞcacy (e.g., hemodilution for RVO). These therapies are covered in this chapter and are clearly identiÞed as unadopted, with the reason each is not used. Some recently introduced treatments have not withstood the test for efÞcacy Ð a prospective randomized controlled clinical trial Ð but have not been rejected either. These treatments are also covered here and clearly identiÞed as provisional. A table of abbreviations used in this chapter follows (Table 13.1). The abbreviations are spelled out at their Þrst occurrence.

Treatments have been developed to reverse the underlying pathophysiology (e.g., intravenous injection of tissue plasminogen activator to lyse thrombus), to reduce the risk of occurrence of RVO (e.g., folate to reduce plasma homocysteine concentration, or systemic anticoagulation for patients with antiphospholipid antibodies (APLAs)), and to treat the effects of RVO (e.g., intravitreal triamcinolone acetonide injection (IVTI) for macular edema associated with RVO).16,32,274 This chapter covers all three categories of treatments.

Studies vary in quality of design from uncontrolled case series to prospective randomized controlled clinical trials. In the discussion that follows, greater weight is given to studies with high-quality designs. Results from uncontrolled case series are useful for generating hypotheses worth testing in clinical trials and for guiding clinicians facing clinical situations so rare that they do not merit the resources of a trial. A problem with uncontrolled case series is that they must compare their results to some reference group, and thus are forced to choose one from a natural history study or a different treatment study usually drawn from a patient population that differs in geographical origin, racial make-up, age and gender distribution, inßuence of comorbidities, and other potentially confounding factors. These confounders make it impossible to draw valid conclusions about the efÞcacy of the treatment. Such reports usually contain a statement similar to the following: ÒWe believe our results are better than the natural history data outlined in the Central Vein Occlusion StudyÓ (CVOS).176 The problem is that readers want valid comparisons, not beliefs, many of which are falsiÞed once proposed therapies are actually put to the test in a prospective randomized clinical trial. For example, IVTI for branch retinal vein occlusion (BRVO) with macular edema (ME) was common based on the optimism of uncontrolled case series before a randomized clinical trial proved it to be no better than grid laser and with more complications.281 Its use has since been abandoned.

Table 13.1 Abbreviations used in treatment of retinal vein occlusions

Abbreviation

APLAs

ASNV

AVS

BCVA

BRAVO

BRVO

BVOS

COPERNICUS

CRUISE

CRVO

CSMT

CPT

CME

DD

ERG

FAZ

GALILEO

GL

Hz

ILMP

IS/OS

IOP

IVB

IVTI

LCRVA

ME mfERG m

ms nm NVA NVG NVI OCT PRP PEDF

prn

PSTI

Treatment studies prespecify primary and secondary outcomes. Sometimes the primary outcome is not achieved, but a secondary outcome is. An example occurred in a clinical trial involving intravitreal pegaptanib injections (IVPI) for ME associated with CRVO.303 The primary outcome was the proportion of eyes gaining 15 Early Treatment Diabetic Retinopathy Study (ETDRS) or more letters at week 30. The study failed to show a beneÞt of IVPI at the 0.05 level of signiÞcance. However, secondary outcomes such as mean visual acuity, proportion losing 15 or more letters, and mean central retinal thickness did show evidence of beneÞt from the treatment. Although failure to achieve the primary outcome may prevent regulatory approval of the treatment for an indication, clinicians may Þnd the treatment useful in speciÞc situations, usually ones in which more effective therapies have failed.

An important component in the treatment of RVO is the interval of follow-up. This is a more pressing concern in CRVO and hemicentral retinal vein occlusion (HCRVO) than in BRVO. If the follow-up interval is too long, the risk of missing anterior segment neovascularization (ASNV) rises. The CVOS recommended followup intervals based on baseline visual acuity (VA). If the baseline VA is 20/40 or better, the CVOS recommended that the patient should return at least every 2 months for the Þrst 6 months. If the baseline VA is 20/200 or worse, the patient should

return monthly for the Þrst 6 months for undilated slit lamp examination and gonioscopy.278 Patients with baseline visual acuity of 20/50Ð 20/200 should be followed at intervals of 1Ð2 months for 6 months depending on the clinical Þndings.278 The follow-up schedule for CRVO followed at the University of Iowa is a visit every 3 months for three visits, then a visit every 6 months for four visits, then annually, but this schedule may have been dictated as much by the desire to study the disease course in a standardized manner as by clinical necessity.105 Others have recommended schedules intermediate between the extremes of the CVOS recommendations and the University of Iowa template.320 The follow-up interval in BRVO is less critical because the issue of ASNV rarely arises (see Chap. 11). In BRVO, follow-up will usually be dictated by the status of macular edema, which may require intravitreal injections as often as every month for extended periods.

When there are several therapies available for the same condition, clinicians need a way to compare treatments and come to evidence-based decisions regarding relative efÞcacies, costs, and adverse effects. The gold standard in such cases is the prospective randomized controlled clinical trial. There are always more questions, however, than there are trials to answer them, so an index to use in comparing studies in the absence of a head- to-head trial would be helpful. Previous studies have struggled with methods of comparison of different treatments for RVO.79 It is difÞcult to compare the results of a treatment across studies because of the confounding effects of different samples such as differences in duration of disease, differences in diagnostic criteria, and differences in duration and completeness of follow-up. Despite these hazards, the clinician wants to synthesize existing information to arrive at some judgment about the relative merits of treatment options in the absence of deÞnitive comparative trials.

With the advent of optical coherence tomography (OCT), such an index for comparison of macular edema studies can be proposed. Treatments for macular edema (ME) associated with RVO produce two major effects Ð reduction in macular thickening and improvement in VA.

OCT measurements are reproducible and objective. VA measurements are less so, but an assessment of vision is usually the primary outcome, and, despite its drawbacks, VA is the most widely used index of visual performance yet devised. Not all reductions in macular edema produce equivalent improvements in VA. Some treatments produce greater improvement in VA for a given reduction in edema. Therefore, one could use an index termed Òthe VA per thinning ratio (VATR)Ó as a way to compare various treatments for the same disease when there are no comparative trials to allow more judicious comparisons. The deÞnition of VATR follows:

VATR = DVA/DCSMT at a given time T after a treatment, where

VA = visual acuity

CSMT = central subÞeld mean thickness

DVA is given in number of ETDRS letters changed, recalling that 0.02 logMAR change = one ETDRS letter change. DCSMT is the thinning of the macula from the intervention and is given in microns (m). The fact that treatment effects change over time highlights the importance of making comparisons of VATR across studies at the same time, T.

As an example, for BRVO and ME, at 1 month after a single injection of bevacizumab, a VATR of 4.3 letters per 100 m of thinning has been reported.79 Although there are advantages to the use of CSMT as compared to central foveal thickness, some studies report retinal thickness using the latter variable, and we have pooled data from reports using both variables.64 Central foveal thickness and CSMT are highly correlated in diabetic macular edema, and it is reasonable to assume that the same is true in RVO with ME.64

A common issue in treatment of RVO is when to intervene. There have been two schools of thought. In the older literature, cautious observation for 2Ð3 months to look for spontaneous clearing of intraretinal hemorrhage and macular edema was recommended.207 For BRVO, the fraction spontaneously improving is estimated to be 20Ð40%.70,144,277,301 Excessive intraretinal hemorrhage may obscure details of retinal perfusion and prevent laser application. Once clearing occurs,

these obstacles are removed.277 More recently, the idea has been expressed that a window of opportunity exists during which intervention may sal-

vage more viable retinal cells.60,143,151,176,179,190,206,244,

264,272,312 This approach is often favored for intravitreal injection therapies in which presence of intraretinal hemorrhage is not an impediment to application of the therapy. It has also been expressed in discussions on timing of laser chorioretinal venous anastomosis (LCRVA) for CRVO and vitrectomy and arteriovenous sheathotomy (AVS) for BRVO.141,143,151,179,184,206 Even with injectional therapies, there may be a beneÞt from a short period of observation. Rebound macular edema occurring after injectional therapy with bevacizumab may occur more often when injections are begun before 8 weeks after symptom onset.313 Eyes with CRVO and ME tend to show spontaneous thinning, but rarely to normal macular thickness, and the natural history of CRVO, on average, is a decline in VA (see Chap. 7). Thus, a period of waiting may be more harmful in CRVO, in contrast to the situation in BRVO and ME, where the ME spontaneously decreases, on average, and the VA tends to improve.50,218,238,255

A recurrent theme in reports describing therapies for RVO is that there are nonresponders for each one, and nonresponse to one therapy does not imply nonresponse to another.14,75,144 For example, intravitreal injection of bevacizumab may improve macular edema after BRVO when grid laser (GL) fails, or AVS may improve ME in eyes that have failed to respond to IVTI or GL.41,259 As a result, it is helpful to have many efÞcacious therapies for those patients who fail initial treatment. The goal of an evidence-based approach is to provide the knowledge of which therapy is most likely to work with greatest efÞcacy and safety at the least cost.

Certain treatments have the side effect of making others less effective after their application. For example, pars plana vitrectomy changes the pharmacokinetics of intravitreally injected drugs. The intravitreal half-lives of injected drugs are shortened, so vitrectomy tends to be a treatment applied after intravitreal injectional therapy has failed.

Evidence is accumulating that certain cytokine proÞles may correlate with response to various

therapies. For example, eyes with BRVO and ME refractory to IVTI had higher aqueous concentrations of vascular endothelial growth factor (VEGF) than eyes that responded.214 Likewise, nonresponders had higher frequencies of macular ischemia.214

In evaluating treatments for types of RVO, all of which have the potential for a chronic and relapsing course, it is important to prespecify deÞnitions of success, failure, and recurrence. Many studies lack them. Clear deÞnitions apply to speciÞc times after diagnosis, can be applied in routine practice, use reproducible measures that are objective, and involve an improvement in excess of the random variation in the measurement taken (see Chap. 8). For example, the random variation in a best corrected visual acuity (BCVA) is commonly considered to be ± Þve ETDRS letters (i.e., logarithm of the minimal angle of resolution (logMAR) 0.1). Thus, most deÞnitions of success include a cut point for VA improvement of at least ten ETDRS letters (logMAR 0.2).144 An example of clearly deÞned outcomes follows:

Success is deÞned as any one of the following four criteria being met at 12 months after the Þrst treatment:

1.Improvement of best corrected logMAR visual acuity of 0.2 or greater

2.Best corrected visual acuity of 0.7 (20/29) or better

3.Decrease in foveal thickness 30% or more

4.Foveal thickness of 230 m or less by Stratus OCT measurement144

A speciÞc example of a clear deÞnition of recurrent disease is the following one for macular edema:

Recurrence means that either of the following criteria is met before 12 months after the Þrst treatment:

1.Worsening of best corrected logMAR visual acuity of 0.2 or more after an initial improvement

2.Increase in foveal thickness of 30% or more after an initial decrease in foveal thickness144

These are not listed as the optimal outcome measures, but rather as clear ones.