Retinal vein occlusion is a common, vision-threatening vascular disorder. The role of inflammation in the pathogenesis and clinical consequences of retinal vein occlusion is a topic of growing interest. It has long been recognized that systemic inflammatory disorders, such as autoimmune disease, are a significant risk factor for this condition. A number of more recent laboratory and clinical studies have begun to elucidate the role inflammation may play in the molecular pathways responsible for the vision-impairing consequences of retinal vein occlusion, such as macular edema. This improved understanding of the role of inflammation in retinal vein occlusion has allowed the development of new treatments for the disorder, with additional therapeutic targets and strategies to be identified as our understanding of the topic increases. 1. Introduction Retinal vein occlusions (RVOs) are the second most common visually disabling disease affecting the retina, after diabetic retinopathy [1]. Obstruction of retinal venous flow leads to damage of the vasculature, hemorrhage, and tissue ischemia [2]. Occlusions affecting the central retinal vein, or central retinal vein occlusion (CRVO), affect the entire retina, while those affecting lesser tributaries of the venous circulation, the so-called branch retinal vein occlusion (BRVO), affect a portion of the retina. Despite the fact that the disease entity has been known to exist for over 100 years, current treatment options often still leave patients with clinically problematic visual disturbances and overall increased morbidity. RVO generally affects patients in middle age and the elderly population [2], and several studies have identified systemic risk factors, such as hypertension, diabetes, systemic vascular disease, glaucoma, and hypercoagulable states [3, 4]. Although proliferative vascular changes can cause significant morbidity (particularly due to subsequent vitreous hemorrhage and neovascular glaucoma), the main reason for decreased visual acuity in both CRVO and BRVO is macular edema [5]. As a result, elucidation of the causes of, as well as treatment for, macular edema has been at the center of large-scale studies on patients with RVO. While the causes for RVO are multifactorial, with local and systemic factors being identified as etiologic, most of the literature generally implicates vascular and inflammatory mediators as being particularly salient [6–8]. Prior to the advent of intravitreal drug delivery, treatment for macular edema for CRVO and BRVO was observation and grid laser photocoagulation,
References
[1]
H. Shahid, P. Hossain, and W. M. Amoaku, “The management of retinal vein occlusion: is interventional ophthalmology the way forward?” British Journal of Ophthalmology, vol. 90, no. 5, pp. 627–639, 2006.
[2]
S. S. Hayreh, M. B. Zimmerman, and P. Podhajsky, “Incidence of various types of retinal vein occlusion and their recurrence and demographic characteristics,” American Journal of Ophthalmology, vol. 117, no. 4, pp. 429–441, 1994.
[3]
H. Koizumi, D. C. Ferrara, C. Bruè, and R. F. Spaide, “Central retinal vein occlusion case-control study,” American Journal of Ophthalmology, vol. 144, no. 6, pp. 858–863, 2007.
[4]
The Eye Disease Case-Control Study Group, “Risk factors for central retinal vein occlusion the eye disease case-control study group,” Archives of Ophthalmology, vol. 114, no. 5, pp. 545–554, 1996.
[5]
M. L. Shahsuvaryan, “Therapeutic potential of intravitreal pharmaco-therapy in retinal vein occlusion,” Indian Journal of Ophthalmology, vol. 5, no. 6, pp. 759–770, 2012.
[6]
R. D. Sperduto, R. Hiller, E. Chew et al., “Risk factors for hemiretinal vein occlusion: comparison with risk factors for central and branch retinal vein occlusion: the eye disease case-control study,” Ophthalmology, vol. 105, no. 5, pp. 765–771, 1998.
[7]
S. Jain, J. R. Hurst, J. R. Thompson, and T. Eke, “UK national survey of current practice and experience of intravitreal triamcinolone acetonide,” Eye, vol. 23, no. 5, pp. 1164–1167, 2009.
[8]
A. Ladjimi, H. Zeghidi, S. Ben Yahia et al., “Intravitreal injection of triamcinolone acetonide for the treatment of macular edema,” Journal Francais d'Ophtalmologie, vol. 28, no. 7, pp. 749–757, 2005.
[9]
The Branch Vein Occlusion Study Group, “Argon laser photocoagulation for macular edema in branch vein occlusion,” American Journal of Ophthalmology, vol. 98, no. 3, pp. 271–282, 1984.
[10]
P. A. Campochiaro, J. S. Heier, L. Feiner et al., “Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study,” Ophthalmology, vol. 117, no. 6, pp. 1102.e1–1112.e1, 2010.
[11]
S. J. McGimpsey, J. V. Woodside, C. Cardwell, M. Cahill, and U. Chakravarthy, “Homocysteine, methylenetetrahydrofolate reductase C677T polymorphism, and risk of retinal vein occlusion: a meta-analysis,” Ophthalmology, vol. 116, no. 9, pp. 1778–1787, 2009.
[12]
J. B. Blice and G. C. Brown, “. Retinal vascular occlusive disease,” in Diseases of the Retina and the Vitreous, R. F. Spaide, Ed., pp. 109–127, WB Saunders, Philadelphia, Pa, USA, 1999.
[13]
R. Ross, “Atherosclerosis-an inflammatory disease,” New England Journal of Medicine, vol. 340, pp. 115–126, 1999.
[14]
H. C. Stary, A. B. Chandler, S. Glagov et al., “A definition of initial, fatty streak, and intermediate lesions of atherosclerosis: a report from the committee on vascular lesions of the council on arteriosclerosis, American Heart Association,” Circulation, vol. 89, no. 5, pp. 2462–2478, 1994.
[15]
N. Cheung, R. Klein, J. W. Jie et al., “Traditional and novel cardiovascular risk factors for retinal vein occlusion: the multiethnic study of atherosclerosis,” Investigative Ophthalmology and Visual Science, vol. 49, no. 10, pp. 4297–4302, 2008.
[16]
I. Steinbrugger, A. Haas, R. Maier et al., “Analysis of inflammation- and atherosclerosis-related gene polymorphisms in branch retinal vein occlusion,” Molecular Vision, vol. 15, pp. 609–618, 2009.
[17]
R. Maier, I. Steinbrugger, A. Haas et al., “Role of inflammation-related gene polymorphisms in patients with central retinal vein occlusion,” Ophthalmology, vol. 118, no. 6, pp. 1125–1129, 2011.
[18]
Y.-J. Song, K.-I. Cho, S.-M. Kim et al., “The predictive value of retinal vascular findings for carotid artery atherosclerosis: are further recommendations with regard to carotid atherosclerosis screening needed?” Heart and Vessels, 2012.
[19]
A. Aydin Kaderli, B. Kaderli, S. Gullulu, and R. Avci, “Impaired aortic stiffness and pulse wave velocity in patients with branch retinal vein occlusion,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 248, no. 3, pp. 369–374, 2010.
[20]
W. R. Green, C. C. Chan, G. M. Hutchins, and J. M. Terry, “Central retinal vein occlusion: a prospective histopathologic study of 29 eyes in 28 cases,” Retina, vol. 1, no. 1, pp. 27–55, 1981.
[21]
F. J. Neumann, I. Ott, N. Marx, et al., “Effect of human recombinant interleukin-6 and interleukin-8 on monocyte procoagulant activity,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 17, pp. 3399–3405, 1997.
[22]
T. van der Poll, H. R. Buller, H. Ten Cate et al., “Activation of coagulation after administration of tumor necrosis factor to normal subjects,” New England Journal of Medicine, vol. 322, no. 23, pp. 1622–1627, 1990.
[23]
E. Ulfhammer, P. Larsson, L. Karlsson et al., “TNF-α mediated suppression of tissue type plasminogen activator expression in vascular endothelial cells is NF-κB- and p38 MAPK-dependent,” Journal of Thrombosis and Haemostasis, vol. 4, no. 8, pp. 1781–1789, 2006.
[24]
C. J. Boushey, S. A. A. Beresford, G. S. Omenn, and A. G. Motulsky, “A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes,” Journal of the American Medical Association, vol. 274, no. 13, pp. 1049–1057, 1995.
[25]
J. C. Chambers, A. McGregor, J. Jean-Marie, and J. S. Kooner, “Acute hyperhomocysteinaemia and endothelial dysfunction,” The Lancet, vol. 351, no. 9095, pp. 36–37, 1998.
[26]
K. A. Hajjar, “Homocysteine-induced modulation of tissue plasminogen activator binding to its endothelial cell membrane receptor,” Journal of Clinical Investigation, vol. 91, no. 6, pp. 2873–2879, 1993.
[27]
G. M. Rodgers and M. T. Conn, “Homocysteine, an atherogenic stimulus, reduces protein C activation by arterial and venous endothelial cells,” Blood, vol. 75, no. 4, pp. 895–901, 1990.
[28]
M. Weger, O. Stanger, H. Deutschmann et al., “Hyperhomocyst(e)inemia and MTHFR C677T genotypes in patients with central retinal vein occlusion,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 240, no. 4, pp. 286–290, 2002.
[29]
M. Cahill, M. Karabatzaki, R. Meleady et al., “Raised plasma homocysteine as a risk factor for retinal vascular occlusive disease,” British Journal of Ophthalmology, vol. 84, no. 2, pp. 154–157, 2000.
[30]
A. Kesler, V. Shalev, O. Rogowski et al., “Comparative analysis of homocysteine concentrations in patients with retinal vein occlusion versus thrombotic and atherosclerotic disorders,” Blood Coagulation and Fibrinolysis, vol. 19, no. 4, pp. 259–262, 2008.
[31]
H. Noma, H. Funatsu, T. Mimura, S. Harino, S. Eguchi, and S. Hori, “Pigment epithelium-derived factor and vascular endothelial growth factor in branch retinal vein occlusion with macular edema,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 248, no. 11, pp. 1559–1565, 2010.
[32]
H. Noma, H. Funatsu, T. Mimura, S. Eguchi, and K. Shimada, “Inflammatory factors in major and macular branch retinal vein occlusion,” Ophthalmologica, vol. 227, no. 3, pp. 146–152, 2012.
[33]
T. Yoshimura, K. H. Sonoda, M. Sugahara et al., “Comprehensive analysis of inflammatory immune mediators in vitreoretinal diseases,” PLoS ONE, vol. 4, no. 12, Article ID e8158, 2009.
[34]
H. Noma, H. Funatsu, T. Mimura, and S. Eguchi, “Vitreous inflammatory factors and serous retinal detachment in central retinal vein occlusion: a case control series,” Journal of Inflammation, vol. 8, article 38, 2011.
[35]
H. Noma, H. Funatsu, T. Mimura, M. Tatsugawa, K. Shimada, and S. Eguchi, “Vitreous inflammatory factors and serous macular detachment in branch retinal vein occlusion,” Retina, vol. 32, no. 1, pp. 86–91, 2012.
[36]
J. W. Lim, “Intravitreal bevacizumab and cytokine levels in major and macular branch retinal vein occlusion,” Ophthalmologica, vol. 225, no. 3, pp. 150–154, 2011.
[37]
A. P. Adamis, “Is diabetic retinopathy an inflammatory disease?” British Journal of Ophthalmology, vol. 86, no. 4, pp. 363–365, 2002.
[38]
S. Nakao, M. Arima, K. Ishikawa et al., “Intravitreal anti-VEGF therapy blocks inflammatory cell infiltration and re-entry into the circulation in retinal angiogenesis,” Investigative Ophthalmology & Visual Science, vol. 53, no. 7, pp. 4323–4328, 2012.
[39]
A. Ossewaarde-Van Norel and A. Rothova, “Clinical review: update on treatment of inflammatory macular edema,” Ocular Immunology and Inflammation, vol. 19, no. 1, pp. 75–83, 2011.
[40]
C. Kaur, W. S. Foulds, and E. A. Ling, “Blood-retinal barrier in hypoxic ischaemic conditions: basic concepts, clinical features and management,” Progress in Retinal and Eye Research, vol. 27, no. 6, pp. 622–647, 2008.
[41]
J. B. Jonas, “Intraocular availability of triamcinolone acetonide after intravitreal injection,” American Journal of Ophthalmology, vol. 137, no. 3, pp. 560–562, 2004.
[42]
J. B. Jonas, “Concentration of intravitreally injected triamcinolone acetonide in aqueous humour,” British Journal of Ophthalmology, vol. 86, no. 9, p. 1066, 2002.
[43]
M. Ip, A. Kahana, and M. Altaweel, “Treatment of central retinal vein occlusion with triamcinolone acetonide: an optical coherence tomography study,” Seminars in Ophthalmology, vol. 18, no. 2, pp. 67–73, 2003.
[44]
J. B. Jonas, I. Akkoyun, B. Kamppeter, I. Kreissig, and R. F. Degenring, “Intravitreal triamcinolone acetonide for treatment of central retinal vein occlusion,” European Journal of Ophthalmology, vol. 15, no. 6, pp. 751–758, 2005.
[45]
M. S. Ip, I. U. Scott, P. C. vanVeldhuisen et al., “A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the standard care vs corticosteroid for retinal vein occlusion (SCORE) study report 5,” Archives of Ophthalmology, vol. 127, no. 9, pp. 1101–1114, 2009.
[46]
I. U. Scott, M. S. Ip, P. C. vanVeldhuisen et al., “A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to branch retinal vein occlusion: the standard care vs corticosteroid for retinal vein occlusion (SCORE) study report 6,” Archives of Ophthalmology, vol. 127, no. 9, pp. 1115–1128, 2009.
[47]
J. A. Haller, F. Bandello, R. Belfort et al., “Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion,” Ophthalmology, vol. 117, no. 6, pp. 1134–1146, 2010.
[48]
W. S. Yeh, J. A. Haller, P. Lanzetta et al., “Effect of the duration of macular edema on clinical outcomes in retinal vein occlusion treated with dexamethasone intravitreal implant,” Ophthalmology, vol. 119, no. 6, pp. 1190–1198, 2012.
[49]
M. Reibaldi, A. Russo, M. Zagari et al., “Resolution of persistent cystoid macular edema due to central retinal vein occlusion in a vitrectomized eye following intravitreal implant of dexamethasone 0.7？mg,” Case Reports in Ophthalmology, vol. 3, no. 1, pp. 30–34, 2012.
[50]
S. Kiss, “Moving beyond laser in treatment of DME, BRVO,” Retina Today, pp. 48–50, 2012.
[51]
P. A. Campochiaro, J. S. Heier, L. Feiner et al., “Ranibizumab for macular edema following branch retinal vein occlusion six-month primary end point results of a phase III study,” Ophthalmology, vol. 117, no. 6, pp. 1102–1112, 2010.
[52]
D. M. Brown, P. A. Campochiaro, R. P. Singh et al., “Ranibizumab for macular edema following central retinal vein occlusion six-month primary end point results of a phase III study,” Ophthalmology, vol. 117, no. 6, pp. 1124–1133, 2010.
[53]
P. A. Campochiaro, D. M. Brown, C. C. Awh et al., “Sustained benefits from ranibizumab for macular edema following central retinal vein occlusion: twelve-month outcomes of a phase III study,” Ophthalmology, vol. 118, no. 10, pp. 2041–2049, 2011.
[54]
D. M. Brown, P. A. Campochiaro, R. B. Bhisitkul et al., “Sustained benefits from ranibizumab for macular edema following branch retinal vein occlusion: 12-month outcomes of a phase III study,” Ophthalmology, vol. 118, no. 8, pp. 1594–1602, 2011.
[55]
E. J. Chung, Y. T. Hong, S. C. Lee, O. W. Kwon, and H. J. Koh, “Prognostic factors for visual outcome after intravitreal bevacizumab for macular edema due to branch retinal vein occlusion,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 246, no. 9, pp. 1241–1247, 2008.
[56]
F. Prager, S. Michels, K. Kriechbaum et al., “Intravitreal bevacizumab (Avastin) for macular oedema secondary to retinal vein occlusion: 12-month results of a prospective clinical trial,” British Journal of Ophthalmology, vol. 93, no. 4, pp. 452–456, 2009.
[57]
M. Kondo, N. Kondo, Y. Ito et al., “Intravitreal injection of bevacizumab for macular edema secondary to branch retinal vein occlusion: results after 12 months and multiple regression analysis,” Retina, vol. 29, no. 9, pp. 1242–1248, 2009.
[58]
L. Wu, J. F. Arevalo, M. H. Berrocal et al., “Comparison of two doses of intravitreal bevacizumab as primary treatment for macular edema secondary to branch retinal vein occlusions: results of the Pan American collaborative retina study group at 24 months,” Retina, vol. 29, no. 10, pp. 1396–1403, 2009.
[59]
T. Ach, A. E. Hoeh, K. B. Schaal, A. F. Scheuerle, and S. Dithmar, “Predictive factors for changes in macular edema in intravitreal bevacizumab therapy of retinal vein occlusion,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 248, no. 2, pp. 155–159, 2010.
[60]
D. L. J. Epstein, P. V. Algvere, G. von Wendt, S. Seregard, and A. Kvanta, “Bevacizumab for macular edema in central retinal vein occlusion: a prospective, randomized, double-masked clinical study,” Ophthalmology, vol. 119, no. 6, pp. 1184–1189, 2012.
[61]
H. Y. Wang, X. Li, Y. S. Wang et al., “Intravitreal injection of bevacizumab alone or with triamcinolone acetonide for treatment of macular edema caused by central retinal vein occlusion,” International Journal of Ophthalmology, vol. 4, no. 1, pp. 89–94, 2011.
[62]
M. A. Singer, D. J. Bell, P. Woods et al., “Effect of combination therapy with bevacizumab and dexamethasone intravitreal implant in patients with retinal vein occlusion,” Retina, vol. 32, no. 7, pp. 1289–1294, 2012.
