Central Retinal Vein Occlusion

Management of CRVO(continued)

C. PHOTOCOAGULATION TREATMENT

In the management of CRVO, panretinal photocoagulation has been widely advocated as the treatment of choice. The presumed role of panretinal photocoagulation in retinal diseases is to prevent development of neovascularization in eyes with retinal ischemia.

Non-ischemic CRVO: Since there is no retinal ischemia in this type of CRVO, and thereby no risk of developing neovascularization,⁵ there is no scientific basis at all for doing panretinal photocoagulation in non-ischemic CRVO. Moreover, panretinal photocoagulation is not a harmless procedure; it can produce loss of peripheral visual fields in CRVO ( see below - Figures 16,17) and may cause defective vision in the dark. Some ophthalmologists advocate the use of macular grid photocoagulation for microcystic macular edema; however, a recent multicenter CRVO photocoagulation study revealed that it has no beneficial effects in these eyes and does not improve visual acuity²². In my experience, some patients may land up with much worse central scotoma from such a treatment. Thus, photocoagulation has no role whatsoever in the management of non-ischemic CRVO.

Ischemic CRVO: It has been almost universally accepted that prophylactic panretinal photocoagulation is the treatment of choice to prevent neovascular glaucoma or treat neovascular glaucoma itself. I have found little definite scientific proof in support of this assumption.²³ Therefore, we investigated this in a 10-year prospective study, to find out its effect on ocular neovascularization, particularly neovascular glaucoma associated with ischemic CRVO. The results, which were very surprising, were published in 1990.²³ In summary, our study showed that, on comparing the lasered eyes versus the non-lasered eyes, there was no statistically significant difference between the two groups in the incidence of development of: (a) angle neovascularization, (b) neovascular glaucoma, (c) retinal and/or optic disc neovascularization, and (d) vitreous hemorrhage, and (e) in visual acuity. Our study did show a statistically significant (p=0.04) difference in the incidence of iris neovascularization between the two groups, with iris neovascularization less prevalent in the lasered group than in the non-lasered group, but only when the laser was performed within 90 days after the onset of CRVO; however, iris neovascularization per se produces no harmful effect in the eye and as such is of little importance. The most important result of this study was the markedly deleterious effect of panretinal photocoagulation on the peripheral visual fields, because the lasered group suffered a significantly (p<0.03) greater loss than the non-lasered group (Figures 16,17). Thus, contrary to the prevalent impression, our study showed that panretinal photocoagulation has no statistically significant beneficial effect in reducing neovascular glaucoma. On the other hand, it markedly damages the peripheral visual field, and may convert an eye with normal peripheral vision into almost a blind eye.

Figure 16
I-4e=Blue III-4e=Brown V-4e=Red

Recently, a multicenter clinical trial by "the Central Vein Occlusion Study" (CVOS) group investigated the role of panretinal photocoagulation in ischemic CRVO.⁴ The purpose of that study was twofold: (1) to find out whether prophylactic panretinal photocoagulation prevents development of iris and angle neovascularization, and (2) whether panretinal photocoagulation prevents progression of iris/angle neovascularization to neovascular glaucoma.

1. In answer to the first question, the study reported that "prophylactic panretinal photocoagulation does not totally prevent" development of iris/angle neovascularization and concluded that prompt regression of iris and angle neovascularization in response to panretinal photocoagulation is more likely to occur in eyes that have not been treated previously prophylactically. This study should lay to rest the claims that prophylactic panretinal photocoagulation in ischemic CRVO prevents the development of iris and angle neovascularization.
2. As for the second aspect of the study, the authors recommended "careful observation with frequent follow-up examinations in the early months (including undilated slit-lamp examination of the iris and gonioscopy) and prompt panretinal photocoagulation of eyes in which 2’clock iris/angle neovascularization develops." I have serious reservations regarding the validity of the findings in the CVOS, as to whether panretinal photocoagulation in ischemic CRVO actually prevents the development of neovascular glaucoma. Such a multicenter, multimillion dollar study conducted under the aegis of the National Institute of Health carries tremendous prestige and its conclusions become a weighty verdict. Thus, it is vital to discuss this aspect of the study at some length, to place its results in their true perspective for the ophthalmic community. I have discussed that elsewhere.²⁴

The most important feature of any study is its design, because that can determine its conclusions and their validity. Based on my clinical and experimental study on CRVO during the past 30 years, I have some important concerns about the baseline design of the study.²⁵ It is now well-accepted that neovascular glaucoma is a complication only of ischemic CRVO and is NOT seen in non-ischemic CRVO. For a study claiming beneficial effects of panretinal photocoagulation on anterior segment neovascularization in ischemic CRVO, it is imperative to ask at least the following three very basic questions:

1. Did all the patients in the study have ischemic CRVO?
2. Were the results of panretinal photocoagulation therapy better than the natural history of anterior segment neovascularization in untreated ischemic CRVO?
3. What are the side-effects and complications of the therapy?

1. Did all the patients in the study have ischemic CRVO? The first logical step in conducting such a study is to differentiate ischemic from non-ischemic CRVO accurately. The design used in the study to differentiate the two types of CRVO at the baseline entry level has serious problems, including the following:
   1. The investigators used "10 disc area of retinal capillary nonperfusion" on fluorescein angiography as almost the sole criterion for differentiation between ischemic and non-ischemic CRVO. There are many pitfalls in using this criterion. All the available evidence indicates that the more marked the retinal ischemia, the earlier and more frequent is the ocular NV.⁵ Anterior segment neovascularization in ischemic CRVO depends upon the global retinal ischemia.⁵ The CVOS also showed that iris/angle neovascularization correlated with the amount of nonperfused retina (p=0.0001).⁴ The study itself proved that their criterion of 10 disc area retinal capillary nonperfusion was not an appropriate one to differentiate the two types of CRVO; they found that eyes with less than 30 disc diameters of nonperfusion and no other risk factor are at low risk for iris/angle neovascularization, "whereas eyes with 75 disc diameters or more (i.e., eyes that show virtually no intact capillaries in the posterior pole) are at highest risk".⁴ This has also been our experience. Also, "eight standard views" by 30^o fundus photography (utilized in a proportion of their cases) do not usually outline the peripheral retinal vascular bed satisfactorily, and therefore do not reveal the changes in the entire peripheral part of the retinal vascular bed - which is frequently the first area to develop capillary nonperfusion.^2,5 Moreover, the "10 disc area of retinal capillary nonperfusion" may simply represent focal retinal ischemia seen in some non-ischemic CRVO.
      
      In contrast to the criterion of "10 disc area of retinal capillary nonperfusion" , our study² showed that, during the acute phase, the information provided by four visual function tests (i.e. visual acuity, kinetic perimetry, RAPD and ERG), taken together, is far superior, not only in separating the ischemic from non-ischemic CRVO more effectively and reliably than fluorescein angiography alone, but also in giving good information about the extent of global retinal ischemia (as discussed above). Thus, fluorescein angiography is a weak staff to lean upon in making such a differentiation during the early acute phase of CRVO, because angiography at this stage may provide no information or misleading information on retinal capillary non-perfusion in at least one third of patients (see above).² As is evident from the above discussion, this was also proved by the CVOS.
   2. There is also other evidence in the CVOS baseline data²⁵ suggesting that some of their non-ischemic CRVO eyes probably had ischemic CRVO initially, and vice versa. For example:
      1. In the CVOS baseline information, 21% of the eyes classified as having ischemic CRVO had a visual acuity of 20/20 to 20/100²⁵ - we found that in only 1.7% of eyes with ischemic CRVO.²
      2. In their eyes where panretinal photocoagulation was not done until they developed iris/angle neovascularization, the neovascularization developed in 35% of the eyes overall, during the study period.⁴ As discussed above, we investigated the same in our natural history study on ocular neovascularization in ischemic CRVO, and found that 70% of ischemic CRVO eyes develop iris NV⁵ (Figure 15) - double the incidence seen in the ischemic CRVO cases in CVOS. This, again, suggests that some of the 91 eyes in the CVOS group did not have ischemic CRVO.
      3. In the CVOS baseline data²⁵, at 4-month follow-up at least 16% of the non-ischemic CRVO eyes "developed evidence of ischemia" (i.e. converted to ischemic CRVO)²⁵ - this is a far higher incidence than that reported in the literature²⁶ and seen by us³. In our 500 eyes with non-ischemic CRVO studied prospectively, we found the cumulative chance of conversion only 8-9% at 6 months after the onset.³ This suggests again that some of their "non-ischemic CRVO" eyes probably had ischemic CRVO to begin with. As discussed above, this may have been caused by a fluorescein angiographic artifact, because during the very early stages of ischemic CRVO, in spite of retinal ischemia, angiography may show minimal retinal capillary non-perfusion; we have found that the extent and severity of retinal capillary nonperfusion in ischemic CRVO tends to increase with time.^2,5
         
         From the above discussion, it is evident that the criterion of "10 disc area of retinal capillary obliteration" is a poor and unreliable parameter for differentiating ischemic from non-ischemic CRVO, as well as for predicting ocular neovascularization. Thus, their baseline data²⁵ suggest that they had a mixture of both ischemic and non-ischemic CRVOs in their two types of CRVO - such a mixture has the potential of giving misleading information.
2. Are the results of panretinal photocoagulation therapy better than the natural history of anterior segment neovascularization in untreated ischemic CRVO? In judging the outcome of any therapy, the first and most important essential is to know the natural history of the disease. The authors of the CVOS assumed that any ischemic CRVO eye with 2 clock hours of iris/angle neovascularization is certain to go on to develop neovascular glaucoma and therefore deserves prompt mandatory panretinal photocoagulation.⁴ But this is a false assumption and ignores the natural history of iris and angle neovascularization. We studied this important aspect in our prospective natural history study on ocular neovascularization in ischemic CRVO.⁵ Our findings are shown in figure 15. About one third of the eyes with iris neovascularization and about one quarter with iris/angle neovascularization never developed neovascular glaucoma on follow-up.⁵ Our criterion of neovascular glaucoma was persistent elevated IOP above 21 mmHg. Iris neovascularization may be worrisome and an indication for closer observation but I have followed some ischemic CRVO eyes with iris/angle neovascularization very closely for years, and found they never progressed to develop neovascular glaucoma, and the iris and angle neovascularization resolved spontaneously. The primary objective of panretinal photocoagulation is to prevent development of neovascular glaucoma. In my studies iris/angle neovascularization on their own have no long-term deleterious complications - it is only if such an eye develops neovascular glaucoma that the eye suffers damage. Much more importantly, by treating all patients with iris neovascularization, and not randomizing them to "treatment" or "no treatment", the study left a serious cloud over its use of iris neovascularization as an outcome measure for development of neovascular glaucoma, because about one third of the eyes treated with panretinal photocoagulation, which would never have developed neovascular glaucoma (Figure 15), were unnecessarily subjected to the risk of developing marked and crippling peripheral visual field loss (as discussed above).²³ In our study on argon laser panretinal photocoagulation in ischemic CRVO²³, although eyes with panretinal photocoagulation showed a significantly (p=0.04) less prevalent iris neovascularization in the panretinal photocoagulation group than in the control group, there was no statistically significant difference between the two groups in angle neovascularization and neovascular glaucoma.
3. What are the side-effects and complications of the therapy? Most importantly, no consideration was given in the CVOS design to obtaining information on the effect of panretinal photocoagulation on peripheral visual fields. Eyes with ischemic CRVO almost always have a large permanent central scotoma, resulting in poor central visual acuity. Like our study²³, the CVOS⁴ also showed no beneficial effect from panretinal photocoagulation on visual acuity. In spite of a large central scotoma, untreated eyes usually retain good "getting around" peripheral vision because their peripheral fields are preserved (similar to age-related macular degeneration), if the eye does not develop uncontrolled neovascular glaucoma (see visual fields before panretinal photocoagulation in Figures16,17). But in our study²³, as discussed above, we found a statistically significant (p<0.03) worsening of peripheral visual fields, with marked loss, in eyes treated with panretinal photocoagulation as compared to those in the control non-laser group; figures 16 and 17 includes some examples of that. Following panretinal photocoagulation, the large central scotoma combined with severe loss of peripheral visual fields may virtually blind the eye. Should we destroy most of an eye's remaining useful peripheral vision with panretinal photocoagulation unless we are quite certain that, without treatment, every eye with iris and angle neovascularization is destined for a painful death? This study does not provide justification for that.
   
   A study with such flaws in its basic design has the potential to provide misinformation which may retard rather than advance knowledge, with regard to the role of panretinal photocoagulation in ischemic CRVO. Although our study²³ and that reported by CVOS⁴ both deal with the role of argon laser panretinal photocoagulation in ischemic CRVO, because of the difference in the basic designs of the two studies, they are very different.
   
   It could very well be argued that this is simply my opinion, which might not necessarily be accepted by the authors of the study. As is customary, the Editor of Ophthalmology (where this study was published) sent my comments to the authors of the CVOS Group for their comments. Following was their response²⁷: "Dr. Hayreh raises a number of excellent points, based on his extensive research and clinical studies over the past decades. .…. We agree with Dr. Hayreh that our minimum criteria of 10 disc areas of retinal capillary nonperfusion for defining ischemic vein occlusion is a low risk for development of iris neovascularization (INV)…. We also agree with Dr. Hayreh that when there is too much intraretinal hemorrhage to evaluate perfusion on the fluorescein angiogram, such eyes are likely to be nonperfused (ischemic CRVO). ……We agree that INV never develops in many eyes with ischemic vein occlusion. ….. Dr. Hayreh is correct that we were not willing to follow the natural history of eyes in which INV was developing because of our fear that neovascular glaucoma would develop quickly; consequently, we do not have information about the natural history after INV develops in untreated eyes."
   
   Difference in response to panretinal photocoagulation of ischemic CRVO compared with proliferative diabetic retinopathy: Another important question that needs to be answered here: if panretinal photocoagulation helps to reduce the incidence of neovascular glaucoma in proliferative diabetic retinopathy, why it does not do the same in ischemic CRVO? But the two disease processes are entirely different. The original rationale for advocating panretinal photocoagulation in ischemic CRVO was the proven beneficial effect of panretinal photocoagulation on ocular neovascularization in proliferative diabetic retinopathy; however, this did not take into consideration the marked disparities in the disease processes between ischemic CRVO and proliferative diabetic retinopathy and in their responses to panretinal photocoagulation. Proliferative diabetic retinopathy is a chronic, slowly progressive disease in a person with an incurable basic systemic disease. By contrast, ischemic CRVO is an acute catastrophe associated with severe and extensive retinal ischemia but with a self-limiting course. One can compare ischemic CRVO to a hurricane which develops suddenly, lasts for a short period but inflicts extensive, devastating damage to a house, whereas diabetic retinopathy is like a slow leak which gradually undermines the house over the years, slowly and insidiously. Measures which would successfully control the damage caused by a slow leak are useless against a hurricane! The extent of retinal ischemia, and hence the quantity of the presumed vasoproliferative factor(s), in ischemic CRVO is many, many times that in average proliferative diabetic retinopathy. Panretinal photocoagulation may be able to cope with the mild amount of retinal ischemia seen in the usual proliferative diabetic retinopathy but is totally inadequate and ineffective when there is the severe, extensive, sudden retinal ischemia of ischemic CRVO. This basic fact has been totally ignored by the advocates of panretinal photocoagulation.

Conclusion of role of panretinal photocoagulation in ischemic CRVO

As is evident from the discussion above, there is no scientifically valid proof so far that panretinal photocoagulation is safe and effective in prevention or management of neovascular glaucoma in acute ischemic CRVO. In spite of that and ignoring the fact that panretinal photocoagulation is highly destructive to the remaining peripheral visual fields in most of the acute ischemic CRVO cases (Figures 16,17), there are authors who still actively advocate its use.^4,28