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  • The Causes and Treatment of Central Retinal Vein Occlusion: What Do We Really Know?

    Retina/Vitreous
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    The Central Vein Occlusion Study (CVOS) demonstrated that only 6% of eyes with central retinal vein occlusion (CRVO) and a visual acuity of < 20/50 recover 3 lines of acuity (a halving of the “minimum angle of resolution” such as improving from 20/100 to 20/50) within 1 year.1 These results highlight the need to find ways to help CRVO patients successfully recover vision. Although small, non-randomized case series have been instrumental in bringing new treatments to the fore, there is a need to elevate CRVO research to the next level in order to evaluate the efficacy of these treatments. This requires large, multi-center studies in which several eyes with CRVO are randomized to various treatment modalities, and data are carefully collected in a standardized fashion. This is an altogether different process than the “case series” approach in which researchers compare their data to published CRVO natural history reports including an array of impressive “before and after” retinal imaging studies. While case series are absolutely necessary to introduce new CRVO treatments, only large, multi-center studies can answer the various questions that have arisen regarding the true effect of proposed treatments on CRVO patients.

    What Causes CRVO?

    Of the many important questions that the CRVO case series have spawned is the most basic one of all: What causes CRVO? Green’s landmark study of CRVO demonstrated intraluminal thrombosis in the central vein of eyes with CRVO and suggested thrombosis as the causative factor.2 Thrombosis in the central retinal vein would be expected to decrease or halt retinal venous outflow and retinal perfusion, resulting in diffuse intraretinal hemorrhaging and edema. Furthermore, CRVO in some patients has been associated with hypercoagualable disorders. For these reasons, treatments that address intravascular thrombosis such as systemic, intravitreal, or retinal vein injection of tissue plasminogen activator (t-PA) have been proposed.3-5

    While the published results of these case series focusing on these treatments appear to be an improvement over the expected CRVO natural history, no randomized multi-center studies have been performed to conclusively prove the efficacy of the thrombolytic approach to treatment. Therefore, the observation that these treatments lead to improvement in some eyes with CRVO fails to conclusively prove that intravascular thrombosis is the major causative factor.

    Positive results reported with other CRVO treatment modalities such as intravitreal triamcinolone acetonide injection (IVTA) and radial optic neurotomy (RON) raise further questions regarding the pathophysiology of CRVO. Even though neither of these approaches purport to promote thromblysis in the central retinal vein, the published data and “before and after” retinal imaging studies are every bit as impressive as those presented for treatments that target intravascular thrombosis directly. Therefore, the relative importance of intravascular thrombosis as a causative factor of CRVO is unknown.

    More Questions

    These conflicting data prompt the following question: Does intravascular thrombosis cause CRVO, or is it a secondary phenomenon? If intravascular thrombosis is not the causative factor, then something else must cause the hypoperfusion in CRVO. The results of surgical treatment modalities such as posterior ring section and RON appear to support this latter theory.6,7 Proponents of these modalities believe that CRVO is a “compartment syndrome” in which chronic compression of the central retinal vein by the surrounding optic nerve tissues leads to hypoperfusion, and that relief of these compressive forces allows normalization of retinal perfusion.

    But how is it that treatments as diverse as RON, a surgical procedure in which an incision is made directly into the optic nerve, and 5-minute, office-based procedures like intravitreal t-PA injection both seem to “work” when their proposed mechanisms of action are so fundamentally different? Why should IVTA have any effect in CRVO when it neither causes thrombolysis like t-PA nor loosens tissue around the optic nerve like RON? More recently, intravitreal injection of bevacizumab (Avastin), which blocks vascular endothelial growth factor (VEGF), has been proposed to treat CRVO (Figure 1). The apparent positive results and impressive “before and after” photos from a number of case series add further confusion to the question of what is happening in CRVO.8,9 If VEGF plays a causative role in CRVO, why would RON or t-PA also “work” when they do nothing to block VEGF? 

    Courtesy Leon A. Bynoe, MD.
    Figure 1. Intravitreal Avastin for CRVO.
     

    More Variables

    Finally, the variable course of CRVO also confounds the issue of its causation and how best to treat it. The course of CRVO may range from mild vision loss to neovascular glaucoma with complete loss of vision. Furthermore, some eyes with CRVO spontaneously recover vision, and this must be taken into account when attributing positive outcomes to any particular treatment. While it is true most of the case series report rates of visual recovery far higher than existing natural history data would predict, discrepancies and biases in the areas of patient selection, data collection, and analysis in these series may obscure the true effect of the treatment on CRVO. Even if a treatment truly “works,” how well it works is impossible to know from the data generated only in small case series.

    The Role of Multi-Center Studies

    CRVO is a common retinal vascular disorder that often causes permanent vision loss. For this reason, there has been much interest in developing treatments to promote recovery of vision in CRVO. Although several treatment modalities for CRVO have been proposed in numerous publications (Table 1), most of these recommendations were derived from non-randomized case series that do not go far enough in answering the many questions regarding CRVO, its causation, and its appropriate management.The ophthalmic community is unlikely to ever discover the answers to these important questions without multi-center studies such as the Standard Care versus Corticosteroid for Retinal Vein Occlusion (SCORE) Study. CRVO investigators will continue to have only a partial picture of what causes CRVO and how best to treat it as long as they rely primarily on data from various case series.

    Table 1. Proposed Treatments for Central Retinal Vein Occlusion.

    Non-Surgical

    Surgical

    Grid laser1

    Posterior ring section6

    Panretinal photocoagulation

    Radial optic neurotomy7

    Laser chorioretinal anastomosis10

    Retinal vein injection of t-PA5

    Intravitreal injection of:

    • tissue plasminogen activator (t-PA)3
    • corticosteroid (i.e., Triamcinolonetriamcinolone acetonide)11,12
    • anti-VEGF agents (Avastin)8,9

    Vitrectomy with peeling of the internal limiting membrane

     

    Systemic intravenous t-PA injection4

    References

    1. Evaluation of grid pattern photocoagulation for macular edema in central vein occlusion. The Central Vein Occlusion Study Group M report. Ophthalmology. 1995;102:1425-1433.
    2. Green WR, Chan CC, Hutchins GM, Terry JM. Central retinal vein occlusion: a prospective histopathologic study of 29 eyes in 28 cases. Trans Am Ophthalmol Soc. 1981;79:371-422.
    3. Lahey JM, Fong DS, Kearney J. Intravitreal tissue plasminogen activator for acute central retinal vein occlusion. Ophthalmic Surg Lasers. 1999;30:427-434.
    4. Elman MJ. Thrombolytic therapy for central retinal vein occlusion: results of a pilot study. Trans Am Ophthalmol Soc. 1996;94:471-504.
    5. Weiss JN, Bynoe LA. Injection of tissue plasminogen activator into a branch retinal vein in eyes with central retinal vein occlusion. Ophthalmology. 2001; 108:2249-2257.
    6. Vasco-Posada J. Modification of the circulation in the posterior pole of the eye. Ann Ophthalmol. 1972;4:48-59.
    7. Opremcak EM, Bruce RA, Lomeo MD, et al. Radial optic neurotomy for central retinal vein occlusion: a retrospective pilot study of 11 consecutive cases. Retina. 2001;21:408-415.
    8. Rosenfeld PJ, Fung AE, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for macular edema from central retinal vein occlusion. Ophthalmic Surg Lasers. 2005;36:336-339.
    9. Iturralde D, Spaide RF, Meyerle CB, et al. Intravitreal bevacizumab (Avastin) treatment of macular edema in central retinal vein occlusion: a short-term study. Retina. 2006;26:279-284.
    10. McAllister IL, Constable IJ. Laser-induced chorioretinal venous anastomosis for treatment of nonischemic central retinal vein occlusion. Arch Ophthalmol. 1995;113:456-462.
    11. Ip MS, Kahana A, Altaweel M. Treatment of central retinal vein occlusion with triamcinolone acetonide: an optical coherence tomography study. Semin Ophthalmol. 2003;18:67-73.
    12. Ip MS, Gottlieb JL, Kahana A, et al. Intravitreal triamcinolone for the treatment of macular edema associated with central retinal vein occlusion. Arch Ophthalmol. 2004;122:1131-1136.

    Author Disclosure

    The author states that he has no significant financial relationship with the manufacturer or provider of any product or service discussed in this article or with the manufacturer or provider of any competing product or service.