47-year-old Hispanic male with hyperlipidemia and hypertension and history of severe non-proliferative diabetic retinopathy
Presents complaining of worsening vision in right eye
Previously 20/40 OU
Status post pan-retinal photocoagulation (PRP) OU in April 2016
Exam Findings
VA: 20/200 || 20/40
Pupils: Round and Reactive OD and OS, 3+ RAPD OD
IOP: 15, 17
Extraocular movements intact
Slit lamp exam: normal, aside from trace cataract OU
Figure 1: Optos photo of right eye. Media clear, note blurring of superior margin of disc without obscuration of the small or large disc vessels. Mild-moderate venous tortuosity, loss of foveal reflex, dot blot hemorrhages, flame hemorrhages in four quadrants. Scattered cotton wool spots. Panretinal photocoagulation (PRP) in the periphery.Figure 2: Optos photo of left eye. Media clear, disc with sharp margins, diffuse cotton wool spots along the arcades. Macula flat.Figure 3: Laminar phase fluorescein angiogram of right eye. Note venous tortuosity, widespread patches of capillary drop out, microaneurysms in four quadrants, window defects in the location of PRP scars.Figure 4: Late venous phase fluorescein angiogram of right eye. Again, there is venous tortuosity, extensive capillary drop out with minimal macular leakage, microaneurysms in four quadrants and window defects in the location of PRP scars.Figure 5: Late venous phase fluorescein angiogram of left eye, notable for microaneurysms, capillary drop out, diffuse late leakage with minimal macular leakage, window defects in the location of PRP scars.Figure 6: OCT macula of right eye. Poor study (3/10 signal strength) demonstrating marked intraretinal fluid.
Differential Diagnosis
Worsening diabetic retinopathy with macular edema
Central Retinal Vein Occlusion (CRVO)/ Branch Retinal Vein Occlusion (BRVO)
Hyperviscosity retinopathy
Waldenstrom macroglobulinemia
Multiple myeloma
Blood dyscrasias
Ocular Ischemic Syndrome
Diagnosis
Central Retinal Vein Occlusion (CRVO)
Clinical features of CRVO
Ischemic versus non-ischemic
Intermediate or indeterminate when they are neither clearly ischemic or non-ischemic
Non-ischemic, mild or venous stasis retinopathy
Good VA, no RAPD, mild visual field changes
Mild dilation and tortuosity of all branches of the central retinal vein as well as dot- and flame-shaped hemorrhages in all quads of the retina
Macular edema
Fluorescein angiography: prolonged circulation time, breakdown of capillary permeability, minimal nonperfusion areas
Anterior segment Neovascularization is uncommon
Ischemic, complete, non-perfused or hemorrhagic retinopathy
Poor vision
RAPD
Dense central scotoma
Marked dilation and tortuosity of all branches of the central retinal vein as well as more extensive dot- and flame-shaped hemorrhages in all quads of the retina
Fluorescein Angiography: prolonged circulation time, breakdown of capillary permeability, widespread capillary nonperfusion
IRIS NEOVASCULARIZATION IN ischemic CRVO
Up to 60 percent
Three to five months after the onset of symptoms
Highest predictor is poor presenting visual acuity (CVOS: Central Vein Occlusion Study)
CRVO: Risk Factors
Age: 90 percent are over age 50
Hypertension
Diabetes mellitus
Hyperlipidemia
Elevated IOP or POAG
Retinal Vein Occlusion: Proposed elements of pathophysiology
Retina drained by occluded vessels becomes ischemic and produces hypoxia-related gene products, including VEGF
Macular edema after CRVO is typically due to diffuse capillary leakage and not due to focal microaneurysmal dilatation similar to that seen in early diabetic retinopathy
Retinal nonperfusion (RNP) has been demonstrated to progress over time
It is presumed that high levels of VEGF contribute to progressive RNP
Contributions of USC Roski Eye Institute ophthalmologist Ronald L. Green, MD: histopathologic study of 29 eyes with CRVO:
Figure 7: From Ronald L. Green, MD, histopathology. Section through optic nerve with patent central retinal artery (asterisk), to the right thrombus in the central retinal vein.Figure 8: From Ronald L. Green, MD, histopathology. Section through optic nerve at the optic nerve head. Again, patent central retinal artery (asterisk), posteriorly, at the level of the lamina cribrosa, thrombus in the central retinal vein (arrow head), diffuse hemorrhage in the retrolaminar portion of the optic nerve nasally (arrows).Figure 9: From Ronald L. Green, MD, histopathology. Higher power of thrombus showing entrapped pockets of erythrocytes proximally (asterisks), aggregation of platelets (circle), fibrin (arrowhead) and adherence to wall of vein where endothelium is absent (arrows).
Average age: 62.9 years
Men: 61 percent
In 24 eyes, the thrombosed area at the level of and posterior to the lamina cribrosa
In five eyes, anterior to the lamina cribrosa
Fresh thrombus observed in three, recanalized in 26, endothelial cell proliferation in 14, chronic inflammation in 14, arterial occlusive disease in 7, Cystoid Macular Edema in 26
The Central Retinal Vein narrows as it traverses the lamina cribrosa in the normal eye
Further narrowing or increased turbulence of flow through a partial barrier may predispose to CRVO
In systemic hypertension, there is a thickening of the wall of the artery, which may impinge on the vein (their juxtaposition)
Flow through this portion of the vein can become turbulent and damage the endothelium
Treatment of CRVO
CVOS: GRID
Eyes with VA 20/50 to 20/200 with angiographic Macular Edema due to CRVO
Randomly assigned to grid photocoagulation (n=77) v no treatment (n=78)
Significantly reduced the amount of macular edema by FA
At 12 months annual visit, no measurable macular edema was present in 21 (31 percent) of treated eyes
But no differences between groups in visual acuity
Conclusion: Grid macular laser does not improve vision in macular edema secondary to CRVO
CVOS: Panretinal Photocoagulation (PRP)
Question: can PRP prevent anterior segment neovascularization in ischemic CRVO, or is it more appropriate to treat once neovascularization occurs?
Methods: 181 eyes randomly assigned to treatment with PRP versus close observation
Results: The development of neovascularization was not statistically significant different between groups
Degree of neovascularization correlated with amount of non-perfused retina (P=0.0001) and extent of retinal hemorrhage (P=0.03)
Conclusion: prophylactic PRP does not prevent anterior segment neovascularization in ischemic CRVO
Treatment for macular edema in CRVO
The Relate Trial
Double-masked randomized controlled trial
Comparing 0.5mg and 2mg ranibizumab monthly injections for six months in patients with macular edema from retinal vein occlusion (RVO)
To determine if scatter-grid reduces the need for injections and improves long-term outcomes in patients with RVO
81 patients with RVO: 39 with CRVO and 42 with BRVO
77 made it to six months
77 re-randomized to PRN (as needed) arms: Ranibizumab + laser or Ranibizumab only for recurrent macular edema
Comparison of visual outcomes in patients treated with 0.5 v 2.0mg Ranibizumab
No differences across groups
Central subfield thickness (CST) in patients treated with 0.5 v 2.0 mg Ranibizumab
BRVO: No statistically significant difference between groups
CRVO: Significantly decreased CST in 2.0mg group at 24 weeks compared to 0.5mg
Scatter + Grid laser on visual outcomes:
Overall, no significant differences in BCVA or CST between injections or injections + laser groups from week 24 to 144
In addition, mean number of injections greater for CRVO patients in the laser + injections group (p=0.5)
Summary and Future Directions
No role for laser for treatment of CME or for prevention of neovascularization
Anti-VEGF mainstay of treatment
No difference in 0.5 v 2.0 mg Ranibizumab per Relate Trial
Identifying known risk factors and who warrants work up
<50
No known hypertensive disease
Understanding mechanism of ischemia in CRVO may lead to alternative treatments and drug development
References
A randomized clinical trial of early panretinal photocoagulation for ischemic central vein occlusion. The Central Vein Occlusion Study Group N report. Ophthalmology. 1995 Oct;102(10):1434-44.
McCannel CA, Atebara NH, Kim SJ, Leonard BC, Rosen RB, Sarraf D, et al. Retina and Vitreous. In: Louis B Cantor, Christopher J Rapuano, George A Cioffi, editors. Basic and Clinical Science course. San Francisco: American Academy of Ophthalmology; 2017.
Tan MH, McAllister IL, Gillies ME, Verma N, Banerjee G, Smithies LA, et al. Randomized controlled trial of intravitreal ranibizumab versus standard grid laser for macular edema following branch retinal vein occlusion. Am J Ophthalmology. 2014 Jan;157(1):237-247.
Campochiaro PA, Wykoff CC, Shapiro H, Rubio RG, Ehrlich JS. Neutralization of vascular endothelial growth factor slows progression of retinal nonperfusion in patients with diabetic macular edema. Ophthalmology. 2014 Sep;121(9):1783-9.
Campochiaro PA, Hafiz G, Mir TA, Scott AW, Solomon S, Zimmer-Galler I, et al. Scatter Photocoagulation Does Not Reduce Macular Edema or Treatment Burden in Patients with Retinal Vein Occlusion: The RELATE Trial. Ophthalmology. 2015 Jul;122(7):1426-37.
Mir TA, Kherani S, Hafiz G, Scott AW, Zimmer-Galler I, Wenick AS, et al. Changes in Retinal Nonperfusion Associated with Suppression of Vascular Endothelial Growth Factor in Retinal Vein Occlusion. Ophthalmology. 2016 Mar;123(3):625-34.
Green WR, Chan CC, Hutchins GM, Terry JM. Central Retinal Vein Occlusion. Retina. 2005 Jul;25(SUPPLEMENT):27-55.
Evaluation of grid pattern photocoagulation for macular edema in central vein occlusion. The Central Vein Occlusion Study Group M report Ophthalmology. 1995 Oct;102(10):1425-33.
Contact
Hossein Ameri, MD, PhD, Assistant Professor of Clinical Ophthalmology, ameri@med.usc.edu
