Vein occlusion guidelines
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Retinal vein occlusion (RVO) involves thrombosis of retinal veins, leading to macular edema and ischemia. There are two main types: central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO). CRVO has a worse prognosis, with ischaemic CRVO associated with severe vision loss. Treatment options for macular edema include anti-VEGF drugs like ranibizumab and aflibercept, as well as steroid implants like Ozurdex. Clinical trials show these options can significantly improve vision in RVO patients with macular edema. Treatment is usually initiated with 3 monthly injections, with retreatment as needed based on OCT and vision assessments.
Vein occlusion guidelines
- 1. Retinal Vein Occlusion : The Evidence -based Story By Dr/Reyad Abo-yossif Ophthalmology specialist
- 2. Introduction • Retinal vein occlusion (RVO) is the second most common retinal vascular disease after diabetic retinopathy
- 4. pathology • Central retinal vein occlusion (CRVO) results from thrombosis of the central retinal vein when it passes through the lamina cribrosa • Branch retinal vein occlusion (BRVO) is caused by venous thrombosis at an arterio-venous crossing where an artery and vein share a common vascular sheath.
- 6. complications • The two main complications of RVO are macular oedema (MO), and retinal ischaemia leading to iris and retinal neovascularisation.
- 8. classification • Both CRVO and BRVO can be broadly classified into ischaemic and non-ischaemic types based on the area of capillary non-perfusion. • Differentiating both subtypes is important because it allows us to predict the natural history for these patients and how they will respond to therapy. • The Central Retinal Vein Occlusion Study (CVOS) defined ischaemic CRVO as fluorescein angiographic evidence of >10 disc areas of capillary non-perfusion on seven-field fundus fluorescein angiography.
- 9. Natural history Central retinal vein occlusion • Ischaemic CRVO is associated with one or more of the following characteristics: • poor visual acuity of < 6/60; • relative afferent pupillary defect; • presence of multiple dark deep intraretinal haemorrhages, • presence of multiple cotton wool spots, • degree of retinal vein dilatation and tortuosity, and • fluorescein angiography showing >10 disc areas of retinal capillary non-perfusion on seven-field fluorescein angiography; • electrodiagnostic tests (particularly ERG) which show reduced b- wave amplitude, reduced b : a ratio and prolonged b-wave implicit time on the electroretinogram
- 11. • The ischemic subtype of CRVO accounts for about 20% of cases and is associated with worse initial presenting visual acuity (VA) and poor visual prognosis even after edema resolution • Approximately, 30% may convert to an ischaemic CRVO over 3 years owing to an increase in area of non-perfusion. • More than 90% of patients with ischaemic CRVO have a final visual acuity of 6/60 or worse.
- 12. • CRVO in younger patients (< 50 years of age) has been thought to have a more benign outcome in a greater proportion of patients, with spontaneous regression of the venous occlusive event being more common. However, at least 20% of patients develop poor visual outcome with severe neovascular complications. • The causation of RVO in the younger person is still unclear in most cases. A role for dehydration in such cases has been suggested but remains unproven.
- 13. • Only 20% of patients of CRVO who present with an initial visual acuity of 35–65 ETDRS letters (Snellen equivalent 6/60 to 6/18) are likely to improve spontaneously. • Non-ischaemic CRVO may resolve completely without any complications. Follow-up of such cases for at least 2 years is usually recommended; however, the development of disc collaterals and the resolution of MO for at least 6 months may indicate adequate reperfusion (although not fool proof), and should allow the discharge of the patient from clinical supervision
- 14. Natural history Branch retinal vein occlusion • On the basis of the Branch Retinal Vein Occlusion study (BVOS), the prognosis of BRVO is better than CRVO with approximately 50–60% of untreated BRVO cases retaining a visual acuity ≥ 6/12 after 1 year.
- 16. • Approximately, 20% of untreated MO due to BRVO experience significant deterioration of visual acuity over time.
- 17. Laterality • The majority of RVO cases present as a unilateral condition. However, 5–6% present with evidence of bilateral BRVO and 10% of the BRVO patients will have fellow eye involvement over time. • Similarly, ~ 10% of CRVO patients present with bilateral involvement at baseline and 5% may have fellow eye involvement over a 1-year period
- 18. Risk factors • The risk factors of RVO include hypertension , diabetes , hyperlipidemia, hyperhomocysteinaemia, blood dyscrasias, systemic inflammatory diseases, glaucoma, and shorter axial length. • Rarely, retrobulbar external compression from thyroid eye disease, orbital tumour, or retrobulbar haemorrhage may be a cause.
- 20. Recommended investigations of RVO • Checking the BP, serum glucose, FBC and ESR will detect associations with RVO that require urgent action such as severe hypertension, uncontrolled diabetes with end-organ damage, or rarely, blood conditions such as leukaemia. • A raised ESR may point to an inflammatory condition or a blood disorder such as myeloma • The history, ocular examination and initial test results may direct further investigations.
- 21. Oestrogen-containing hormone? • It is recommended that oestrogen-containing hormone replacement therapy and oral contraceptives not be commenced in those women with a history of RVO. • However, the continued use in a patient who develops RVO does not appear to be associated with a higher rate of recurrence. • The decision about whether to continue these oestrogen-containing therapies in a woman with RVO should be made on a case by case basis.
- 22. Treatment algorithm for CRVO • Non-ischaemic CRVO • Baseline: Visual acuity measurement, colour fundus photographs, and fluorescein angiography, OCT, intraocular pressure (IOP), gonioscopy (if ischaemic CRVO is suspected) are recommended.
- 23. If no iris or angle NV is noted and there is OCT evidence of MO: • (a) If visual acuity is 6/96 or better, then commence on either intravitreal anti-VEGF therapy, or Ozurdex implant. • (b) If visual acuity is < 6/96, then the potential for significant improvement in visual acuity is minimal and the risk of ocular neovascularisation is high.However, eyes with VA < 6/96 may be offered treatment as some of these eyes may respond. The patients should be watched for NVI/NVA. • (c) If visual acuity is better than 6/12, then it is reasonable to observe the patient for spontaneous resolution as per the judgment of the treating ophthalmologist.
- 24. Choice of agent • Ranibizumab and aflibercept are the two anti- VEGF agents recommended by NICE for MO owing to CRVO. • Dexamathasone implant (Ozurdex, Allergan) is also recommended by NICE for this condition.
- 25. Ranibizumab • The major ranibizumab CRVO trial CRUISE and its extension studies HORIZON and RETAIN • Patients were given a loading dose of 6 monthly injections and were then shifted to a PRN protocol.
- 26. CRUISE • The study showed that after 12 months of follow- up there was a significant improvement in the VA in the ranibizumab-treated groups with a mean increase of 13.9 letters in both the 0.3 mg and the 0.5mg dose compared with a mean of 7.3 letters in the sham/0.5mg group. • The visual gains achieved after the first 6 monthly doses could be maintained during the next 6 months using a pro re nata (PRN) protocol
- 27. Aflibercept • Two major RCTs evaluated the effects of aflibercept on CRVO namely COPERNICUS and GALILEO.
- 28. Steroids • The efficacy of steroids has been demonstrated previously in two major trials; SCORE and GENEVA. • • The SCORE study looked at the effects of two doses of triamcinolone (1 and 4 mg) compared with observation and the results showed that at 1 year 27 and 26% of subjects had a 15- letter improvement compared with the observation group that showed 7%. • In addition, the mean visual gain was − 1.2 letters in both the 1 and 4 mg groups compared with − 7 letters in the observation group. • There was no difference in OCT macular thickness between the different groups at 1 year, which reinforces a moderate correlation between OCT thickness and visual acuity in patients with retinal vein occlusion.
- 30. • There is no visual acuity or central macular thickness restriction in the commencement of treatment with any of these agents. • Anti-VEGF is preferred in eyes with a previous history of glaucoma and younger patients who are phakic. • Ozurdex may be a better choice in patients with recent cardiovascular events and in those who do not favour monthly injections.
- 31. Laser ttt • The first major study to assess the effects of GRID photocoagulation in improving visual acuity in eyes with macular edema was the CVOS study. • there were no differences between the treated and untreated eyes in terms of visual acuity. However, treatment did reduce angiographic evidence of macular edema, although this did not translate to improvements in visual outcomes.
- 32. Retreatment. • At each follow-up visit, visual acuity, OCT macular thickness and IOP should be assessed and the presence of NVI/NVA assessed.
- 33. • If Anti-VEGF is the first line of treatment, then monthly intravitreal injections are continued until maximum visual acuity is achieved, which is defined as stable visual acuity for three consecutive monthly assessments while on Anti- VEGF therapy. • If no improvement in visual acuity over the course of the first three injections is observed, then cessation of treatment may be considered and is recommended after six injections.
- 34. • Patients who achieve visual acuity stability should be monitored monthly and treatment with Anti- VEGF is resumed when monitoring indicates loss of visual acuity due to MO secondary to CRVO. • Monthly injections should then be administered again until stable visual acuity is reached for three consecutive monthly assessments (implying a minimum of two injections).
- 35. • If Ozurdex is the first line of treatment, then retreatment may be required at four to six monthly intervals until visual stability is obtained. • Patients should be monitored for raised IOP and formation or progression of cataract.
- 36. A recommended protocol • A recommended protocol for CRVO patients would include a loading dose of three monthly injections of ranibizumab or aflibercept or unlicensed bevazicumab. • At 3 months patients should be assessed for fluid on OCT.
- 38. • We believe that there are two main patterns of response; good or early responders and partial/non-responders based on the data from Bhisitkul et al that classified patients based on CFT after 3 monthly injections.
- 39. • The group with fluid at 3 months will be further categorized using the definition proposed by Sharareh et al into : • those who have less than a 1% reduction in MO after 3 injections (the non-responders) • and those who respond with at least a 10% reduction in MO (the partial responders). • Patients showing no fluid activity (early responders) after 3 monthly injections should be followed up monthly and injected using a PRN protocol for the first year and with gradual monthly extensions of the follow-up period during the second year to maintain gains.
- 40. • Patients showing residual fluid at 3 months should be categorized into partial or non- responders. Partial responders may complete the 6 loading doses as previously used in the major studies like CRUISE, after which they should be reassessed. If they still show fluid activity, then they may be offered a switchin treatment protocols.
- 41. • Non-responders after 3 monthly injections may be offered one of three choices; dexamethasone implants alone or in combination with bevazicumab/ranibizumab or a switch to an alternate anti-VEGF (preferably aflibercept if ranibizumab or unlicensed bevacizumab was used).
- 42. • Patients in the non-responders and partial responders group should be followed monthly for 1 year at least after achieving dryness. These patients should have their follow-up periods extended very cautiously with an attempt to identify a fixed period of recurrence before which patients will receive an anti-VEGF injection.
- 43. • Finally, we advocate a patient-centric individualized approach in dealing with CRVO and awareness that this is a chronic disease that requires close follow-up and continuous care for years to ensure that early successes are not lost down the line.
- 44. Stopping treatment • Stopping ranibizumab and aflibercept therapy should be considered if after three consecutive monthly treatments, visual acuity has not improved by at least five letters and CMT has not reduced from baseline. • However, reduction in retinal oedema without VA improvement or deterioration (ie, stable VA) may be accepted as a favourable, but suboptimal outcome. • Ozurdex should be used with caution in eyes with raised IOP.
- 45. Switching agents. • If an anti-VEGF agent is stopped owing to lack of efficacy, there is no randomised controlled trials that provide evidence that switching to another anti-VEGF agent may be effective. However, given our experience with switching anti-VEGF agents in neovascular age related macular degeneration, it may be worthwhile switching to another anti- VEGF agent and further monthly injections for 3 months may be given to assess the efficacy of the switch.
- 46. • There is a good rationale to switch from Ozurdex to an anti-VEGF agent and vice versa as the different mode of actions of these agents may aid in resolution of MO. • However, the long-term outcomes of sequential or combination treatment of anti- VEGF agents and steroids remain unclear.
- 47. Ischaemic CRVO If iris or angle neovascularisation occurs and the anterior chamber angle is open. • Urgent PRP is recommended and with review at 2 weeks initially and then less frequently as regress of NV occurs. • PRP plus intravitreal bevacizumab (off- licence) can be repeated if NVI/NVA persist.
- 49. If iris or angle NV are present with a closed angle and raised IOP. • Urgent PRP is recommended with cyclodiode- laser therapy/tube-shunt surgery. The latter is preferable if the angle closure is established. • If the IOP is normal or normalises with the above therapy, intravitreal bevacizumab can be considered. • If the IOP is significantly elevated, then it should be managed as above with topical and medical management in addition.
- 51. • If an ischaemic CRVO is present without NVI/NVG and limited follow-up is likely and especially but not necessarily only if the FFA shows >30 DA nonperfusion, then prophylactic PRP should be considered. • MO in eyes with ischaemic CRVO is treated in the same way as those with non-ischaemic CRVO. However, the guarded prognosis should be explained to the patient.
- 52. Treatment algorithm for BRVO Non-ischaemic BRVO • 1. If VA better than 6/12, then it is reasonable to regularly observe progress for 3 months.
- 53. 2. If VA is 6/12 or worse with MO and haemorrhages are not masking fovea: • (a) FFA is recommended to assess foveal integrity. • (b) If no macular ischaemia is identified, regularly observe for 3 months if MO is mild and in opinion of clinician likely to spontaneously improve (30% chance). • (c) If mild to moderate macular ischaemia is present consider treatment with ranibizumab or Ozurdex if spontaneous improvement is unlikely. • (d) If severe macular ischaemia is present—no treatment is recommended, and regularly observe for NV formation.
- 54. 3. If VA 6/12 or worse, or there is progressive deterioration of VA+macular oedema and haemorrhages are masking macula. • (a) Monthly ranibizumab or baseline Ozurdex for 3 months. • (b) Perform FFA at 3 months to assess foveal integrity. • (c) If severe macular ischaemia is found to be present at 3 months, then no treatment will likely be beneficial and further therapy should be carefully considered.
- 56. At 3 months follow-up • 1. Consider modified-grid laser photocoagulation if persistent MO, no or minimal macular ischaemia and other treatments unsuccessful or unavailable. • 2. If VA ≥ 6/9 or no macular oedema detected, then continue to observe if initially observed. If on anti- VEGF or Ozurdex therapy, then continue as suggested in MO due to CRVO.
- 57. Further follow-up • 1. If under observation only, then follow-up 3 monthly intervals for 18 months. • 2. In case of recurrence or new MO, consider reinitiating intravitreal ranibizumab, or Ozurdex therapy.
- 58. Ischaemic BRVO • (a) Watch carefully for NV. • (b) If NVE—consider sector laser photocoagulation applied to all ischaemic quadrants. Intravitreal bevacizumab (off-licence) may also be given in combination with laser. • (c) Follow-up at 3 monthly intervals for up to 24 months.