Wow, That’s a Lot of Blood… Diagnosing and Managing Retinal Occlusions

Wow, That’s a Lot of Blood…

Diagnosing and Managing Retinal Occlusions

Erin F. Swift, OD, FAAO is an attending optometrist at the San Diego VA Medical Center and past president of the San Diego County Optometric Society.

A 66 year old white male walks into your office with the chief complaint of transient vision loss OD that began two days prior.  He reports his vision would “fade in and out” and this has occurred 6-10 times in the past two days.  He also reports some episodes lasting a few minutes, but up to several hours.  He denies headaches, scalp tenderness, jaw pain or any other neurological symptoms.  The patient also denies increased floaters or flashes of light.  His medical history is largely unremarkable; negative for hypertension, diabetes mellitus, or heart disease and significant only for hyperlipidemia.  His current medications include simvastatin and sildenafil.  The patient’s ocular history is also unremarkable.  His  best corrected acuity is 20/20 OD and OS with refraction.  Pupils, gross confrontation fields, and extraocular motility are all normal OU.  He denies metamorphopsia or scotoma with Amsler grid testing OD and OS.  Anterior segment evaluation is normal OU with stable IOP from previous exams.  However, with dilated exam, you see this (Pic 1).  The dilated fundus exam OD showed ~20-30 large blot hemorrhages along the superior temporal arcade.  Many smaller dot hemorrhages were noted along the inferior arcade as well.  One very large pre-retinal hemorrhage was also found along the superior nasal arcade.  Approximately 15-20 dot hemorrhages were located near the fovea, within the macula OD.  Peripherally, ~5 blot hemes were noted in all quadrants.  The blood vessels OD were mildly tortuous, but of normal color and caliber.  The optic nerve was healthy, no pallor or edema noted.  Examination OS was unremarkable; normal blood vessels, macula, background, and peripheral appearance in all quadrants.  The optic nerve was also healthy and symmetrical to OD.

Pic 1

So, what do you think and what do you do?  Differential diagnoses that need to be  considered include central retinal vein occlusion, ocular ischemic syndrome, retinopathy due to a hypercoagulable or inflammatory disorder, a space occupying lesion in the orbit, severe hypertensive retinopathy, and severe nonproliferative diabetic retinopathy.  The last two are unlikely as the patient has no history of hypertension or diabetes; also unlikely due to unilateral presentation.  Papillophlebitis also presents with similar findings, but is typically found in patients less than 50 years of age.  Therefore, the patient was diagnosed with central retinal vein occlusion OD based on ocular signs and patient symptoms.  The other differentials were eventually ruled out with further testing and follow-up.  As for treatment and management, the patient was referred for an OCT and fundus photos in two days to document retinal appearance and rule out macular edema (none was noted).  A carotid duplex ultrasound was also ordered for the patient to rule out stenosis or blockage of the carotid arteries.  Recent lab work indicated normal CBC, fasting glucose, and lipid panel.  Additional blood testing was ordered including:  PT, PTT, homocystiene and ESR to rule out hypercoaguable or inflammatory disorder in the absence of hypertension or atherosclerotic disease.  The patient was given a return appointment for 5 weeks (patient was leaving town for 25 days the next week) and told to return sooner pending vision changes.

He returned for follow-up 5 weeks later and reported decreased vision OD for three weeks.  He also reported ~3 additional episodes of amaurosis fugax since last exam.  Entering acuities with his most recent glasses was 20/60 OD (no improvement with pinhole) and 20/20 OS.  Pupils, gross confrontation fields, and extraocular motility were normal OU.  The patient still denied metamorphopsia or scotomas on Amsler grid OD and OS, but reported OD view was “much blurrier” than OS.  Anterior segment evaluation and intraocular pressures were normal and stable OU.  No neovascularization of the iris was found OD or OS.  Dilated fundus examination of OD showed extensive hemorrhaging in all four quadrants, worse from previous exam (Pic 2).  Also, new onset macular edema and optic nerve head edema was noted OD.  Dilated fundus exam findings of OS were unremarkable and stable to previous exams.  Again, what do you think and what do you do?  The patient is obviously worse than initial presentation with decreased vision OD and new macular and optic nerve edema.  The carotid ultrasound results came back normal, as did the additional blood work checking for abnormal blood clotting or inflammation.  What caused the occlusion and why is he now so much worse?  A brain/orbits MRI was ordered to rule out space occupying lesion around the orbit that could be causing compression on the central retinal vein.

Pic 2

The patient was also referred to a retinal specialist for evaluation and treatment of the macular edema.  An Avastin injection was recommended and performed OD with no complications.  The patient was given warning signs and told to return in 1 month or sooner as needed.  The MRI results were available and reviewed with patient; normal with no masses or infarcts detected near globe/orbits.  Possible “chronic microvascular ischemic or hypertensive changes” were noted by the radiologist, but overall unremarkable findings.  The patient presented for a six week follow-up of CRVO s/p one Avastin injection OD.  He reported good vision OD and OS with no pain OU; entering acuities were 20/20 OD and OS.  Anterior segment evaluation and intraocular pressures were normal and stable OU; no neovascularization of the iris was noted OD or OS.  Dilated fundus examination OD showed further improvement; minimal retinal hemorrhaging, a single cotton wool spot, and trace swelling of the optic nerve head were present (Pic 3).  No macular edema was detectable with clinical examination OD and was confirmed with OCT.  No further treatment was recommended at that time.  The patient was instructed to return to clinic in three months for follow-up.  He was educated about possible recurrence of visual symptoms and to present to clinic sooner needed.

Pic 3

Retinal vein occlusions (RVO) are a sight threatening disorder occurring in ~1% of the population¹.  RVO is the second most common vascular retinal disease behind diabetic retinopathy².  It typically happens to older adults, the average age of first occurrence is 70 and ~50% of cases occur in those over age 65².  Since over half of incidences occur in those over the age of 65, it is important to properly diagnose and manage these conditions as our population ages.  The exact pathogenesis of RVO is unknown, but most agree it is a multifactorial disease that leads to reduced outflow of venous blood, usually by thrombosis formation³.  The anatomy of how the central retinal artery and vein enter/exit the eye plays a key role in occlusive disease.  Central retinal vein occlusions (CRVO) usually occur in the area of the lamina cribrosa where the artery and vein share a common adventitial sheath⁴.  This environment is susceptible to occlusion in three ways: obstruction of the vein from external compression, vessel wall disease, and hemodynamic disturbances³.  Unfortunately, this also coincides with Virchow’s Triad of thrombosis formation consisting of degenerative changes to the vessel wall, hypercoagulability of the blood, and venous stasis⁴.  Neurovascular compression and inflammation have also been implicated in contributing to the reduction of perfusion to the retinal vein².  Many risk factors are associated with RVO, including but not limited to: hypertension, DM, atherosclerosis, hyperviscosity syndromes, inflammatory diseases, and anatomical compression of the retinal vessels within the lamina cribrosa².

                CRVO is usually subdivided into two categories, non-ischemic and ischemic.  The Central Vein Occlusion Study differentiated the two by area of capillary non-perfusion; at least 10 disc diameters of retinal non-perfusion as determined with fluorescein angiography was designated as ischemic⁵.  Although that is the standard most clinicians follow, not all agree.  Hayreh et al contend the presence of a relative afferent pupillary defect and reduced electroretinography amplitude is more sensitive and specific in defining ischemia³.  All agree that non-ischemic cases have better visual prognosis than ischemic.  Clinical signs of CRVO include extensive retinal hemorrhaging, dilated and tortuous retinal veins, and cotton wool spots².  Macular edema, optic disc edema, and neovascularization also may occur depending on severity⁴.  Non-ischemic clinical findings are typically less severe and account for 75-80% of cases³.  Visual prognosis is usually based on presence and duration of macular edema and macular ischemia, with chronicity leading to a poorer outcome⁴.  Secondary complications of neovascularization such as vitreous hemorrhages, glaucoma, and retinal detachment can also lead to vision loss³.

                Until recently, treatment for CRVO was largely unsuccessful.  Treatment options attempted to date include medical therapy, surgical and laser options, and intravitreal injections (Table 1).  Generally, medical therapies have been found ineffective with a high rate of complication³.  Surgical options have also been explored to treat CRVO with limited success.  Some small studies have noted minimal improvement in visual outcome versus no treatment, but the data is largely inconclusive².  The aforementioned treatments of CRVO are all designed to eliminate the occlusion itself.  As we know, CRVO does not cause vision loss directly, but secondarily through macular edema or complications from neovascularization.  Recent studies have targeted those areas for treatment, rather than the direct site of occlusion, with better success. 

The first large, multicenter study to address vision loss from macular edema due to CRVO was the Central Vein Occlusion Study (CVOS).  The primary goals of the study were to determine if early or preventative panretinal photocoagulation (PRP) was effective in preventing iris neovascularization in eyes with ischemic CRVO and also ascertain if macular grid-pattern laser photocoagulation improved visual acuity in eyes with reduced vision due to macular edema from CRVO⁵.  The study concluded that PRP reduces, but does not eliminate the risk of anterior segment neovascularization in ischemic CRVO.  Therefore, prophylactic PRP is not recommended, but careful and frequent gonioscopy should be performed at all follow-up exams and PRP is indicated in the presence of anterior segment neovascularization⁶.  With regard to treatment for macular edema associated with CRVO, the CVOS determined there was no statistically significant benefit in visual acuity between eyes treated with grid pattern laser and those not treated⁵.  Because of this finding, the standard of care became to monitor CRVO with macular edema, as opposed to eyes with macular edema associated with BRVO in which grid laser was found beneficial².

                Subsequently, the Standard Care versus Corticosteroid for Retinal Vein Occlusion (SCORE) Study was completed and examined if intravitreal injections of triamcinolone (1mg or 4mg concentration) improved visual acuity in eyes with vision loss secondary to macular edema from CRVO, as compared with the standard of care (no treatment)⁷.  Acceptable safety profiles were also taken into account.  The results of the study concluded intravitreal corticosteroids do improve visual outcome in eyes with macular edema at 12 months compared with no treatment¹⁶.  In addition, it was found the 1mg dose had similar efficacy to the 4mg dose with a superior safety profile.  Common side effects in the treated groups include cataract formation and increased IOP, which was dose-dependent (greatest in 4mg group, followed by 1mg, then untreated)⁸.  Smaller studies have reported similar results; they also conclude the treatment may be more beneficial for eyes with non-ischemic CRVO than ischemic.  Similarly, implantation of an intravitreal dexamethasone delivery system has been attempted and seems to be as efficacious and safe as multiple intravitreal corticosteroid injections².

                Finally, the most recent endeavors to treat vision loss from CRVO related macular edema is with intravitreal anti-VEGF injections.  Several large, multicenter, randomized studies have studied the effects of Lucentis and Eylea to improve visual acuity and macular appearance due to macular edema from CRVO.  Both the CRUISE and BRAVO studies found clinically significant improvement of visual acuity and decreased macular thickness as measured by OCT with Lucentis when compared to placebo injection⁹.  Lucentis also proved to be safe and well tolerated with few adverse events.  The COPERNICUS and GALILEO studies found similar results using Eylea¹⁰.  The exact dosage and injection schedule of anti-VEGF agents has yet to be defined with any study, but reinjection every 4-8 weeks as needed for persistent macular edema seems to be the accepted time frame⁷.  At this time, anti-VEGF injections provide the most effective and safest treatment to restore vision in eyes with macular edema secondary to CRVO.

                Macular edema and neovascular complications are the primary causes of vision loss for CRVO.  Many treatment options have been studied to determine the most efficacious and safe procedure to prevent further visual decline and improve visual function and morphology; intravitreal anti-VEGF injections prove the best option to date.  Regardless of treatment strategy, prompt diagnosis and treatment is essential to produce the most favorable visual outcome for patients with vision loss from CRVO.  The patient in this case study is somewhat unique in that a retinal venous occlusion occurred in the absence of risk factors.  While most are caused by vascular abnormalities, it is important to rule out metastatic or undiagnosed causes that could lead to further problems and require additional systemic treatment. 

Table 1:  Treatment for CRVO

References

1. McIntosh, R., et al.  Natural history of retinal vein occlusion: an evidence-based systematic review.  Ophthalmology.  2010; 117(6): 1113-1123.

2. Buehl, W., Sacu, S., Schmidt-Erfurth, U.  Retinal Vein Occlusions.  Developments in Ophthalmology.  2010; 46: 55-72.

3. Hayreh, S.  Retinal vein occlusion.  Indian Journal of Ophthalmology.  1994; 42: 109-132.

4. Rehak, M., Wiedmann, P.  Retinal vein thrombosis: pathogenesis and management.  Journal of Thrombosis and Haemostasis.  2010; 8: 1886-1894.

5. The Central Vein Occlusion Study Group.  Baseline and early natural history report: the central vein occlusion study.  Arch Ophthalmology.  1993; 111: 1087-1097.

6. The Central Vein Occlusion Study Group.  A randomized clinical trial of early panretinal photocoagulation for ischemic central vein occlusion: the central vein occlusion study group N report.  Ophthamology.  1995; 102(10): 1434-1444.

7. Mohamed, Q., McIntosh, R., Saw, S., Wong, T.  Interventions for central retinal vein occlusion: an evidence-based systematic review.  Ophthalmology.  2007; 114(3): 507-517.

8. Scott, I., et al.  Baseline predictors of visual acuity and retinal thickness outcomes in patients with retinal vein occlusion: standard of care versus corticosteroid for retinal vein occlusion study report 10 (SCORE).  Ophthalmology.  2011; 118(2): 345-352.

9. CRUISE Research Group.  A Phase III, multicenter, randomized, sham injection-controlled study of the efficacy and safety of ranibizumab injection compared with sham in subjects with macular edema secondary to central retinal vein occlusion.  Nov 2009.  Unpublished Clinical Study Report.

10. Heier, JS, et al.  Intravitreal aflibercept injection for macular edema due to central retinal vein occlusion: two-year results from the COPERNICUS study.  Ophthalmology. 2014 Jul;121(7):1414-1420.