41 Retinal vein occlusion

Background

Retinal vein occlusion is a common clinical condition that forms a serious threat to visual acuity, particularly in older people.

Aetiology and risk factors

There is an increasing incidence of retinal vein occlusion (RVO) with age, with greater than 50% of patients being over 65.1 There is an approximately equal sex distribution.2 Established cardiovascular risk factors are the predominant medical associations for both central (CRVO) and branch (BRVO) vein occlusions. The main risk factor for both types of vein occlusion is hypertension, and is more prevalent in BRVO.2–4 Inadequately controlled hypertension is associated with recurrence of RVO in the same or fellow eye. Hyperlipidaemia (cholesterol ≥ 6·5 mmol/l) is the predominant association in the younger age group of RVO patients, and is associated in up to 50% of older patients.3,5,6 Diabetes mellitus is associated with RVO, which may be due to an increase of other cardiovascular risk factors.4,5,7 Interestingly, there is no direct evidence linking smoking to retinal vein occlusion.2,8 Primary open angle glaucoma has been implicated in the aetiology of CRVO, but not of BRVO.5 Myeloproliferative disorders are an important association, occurring in 1% of patients presenting with retinal vein occlusion. Thrombophilic abnormalities have been implicated but their significance in the aetiology is unclear. The subject is thoroughly reviewed by Fegan.9 Kirwan et al.10 looked at a case series of 588 retinal vein occlusion patients including women on the combined oral contraceptive pill and on hormone replacement therapy (HRT), and suggested that RVO is a contraindication to the use of the contraceptive pill, but also that HRT was not a major risk factor for retinal vein occlusion. In patients less than 50 years of age with BRVO, there are usually underlying systemic conditions such as hypertension or hyperlipidaemia.11 Patients in the younger age group with CRVO, however, present a particular problem in investigation and management, and other rare associations may need to be investigated, such as use of the oral contraceptive pill, optic disc vasculitis, and thrombophilic factors.

Prognosis

Some 65–80% of CRVO is non-ischaemic, with 7–20% of these converting to the ischaemic type.12 The visual prognosis is unpredictable, and mainly depends on the degree of involvement of the macula and on the length of time that macula oedema is present. In one study, two-fifths retained good visual acuity but two-fifths fared very badly.13 A greater proportion of younger people (less than 50 years old) with CRVO are thought to have a benign outcome, with spontaneous regression of the occlusive event being more common. However, at least 20% of patients have poor visual outcome with severe neovascular complications.

Question

Do patients with retinal vein occlusion experience a better visual outcome and/or less neovascular glaucoma when treated with anticoagulants, fibrinolytic agents, antiplatelet drugs or steroids?

The evidence

We found four randomised controlled trials investigating the use of these agents for retinal vein occlusion.14–17

The first study, published in 1973, described results in 12 patients (three women, nine men) ranging from 33 to 69 years old, who were assigned to either fibrinolysis

(intravenous streptokinase) or fibrinolysis with anticoagulants (intravenous heparin) using Horbach’s randomising model.14 Five patients had branch vein occlusions and seven had central vein occlusions. Outcome measures were visual acuity, macular morphology and fluorescein angiographic features. The results were not presented with statistical analysis as the numbers were small. The authors reported an improvement in central visual function in the streptokinase group after eight days, which was sustained until the final follow up reported at 90 days, with most of the anticoagulant alone group showing no improvement in vision.

In the following year another randomised controlled trial investigated the role of streptokinase in the treatment of central retinal vein occlusion.15 Forty patients were randomised (details not given) to receive intravenous

streptokinase or no therapy. There was no statistically significant difference in visual acuity between the groups at the outset of the trial, and no significant difference between the treated and control groups in the final visual acuity at 12 months. Three of the control group developed thrombotic glaucoma, compared with none in the treatment group, although the authors comment on the low rate of the complication even in the untreated group compared with data from other studies. The authors concluded that the hazards of the treatment, including vitreous haemorrhage, and the lack of evidence for a definite benefit for visual outcome, meant that streptokinase has no useful role to play in the management of central vein occlusion.

Hyperaggregation of platelets has been implicated in the aetiology of retinal vein occlusion, suggesting the possible role of inhibitors of platelet aggregation in the management of this condition. A double-blind randomised controlled trial investigating the use of ticlopidine was published in 1984.16 Eighty-nine patients (46 men and 43 women, from “less than 40” to “over 80” years of age) were assigned to oral treatment or placebo (randomisation methods are not described). Thirty-five patients had central vein occlusion and 54 had branch vein occlusion. In the BRVO group, a statistical significant improvement in visual acuity was achieved in the treatment group at six months, with the same trend in the CRVO group, but this did not reach statistical significance. The main complication of treatment was gastric irritation.

Abnormal blood viscosity has also been implicated in the aetiology of retinal vein occlusion, leading to investigation into the role of troxerutin, an inhibitor of platelet and red cell aggregation.17 Fifty-three patients were included in a prospective, randomised double-masked controlled trial, of whom 27 had central vein occlusion and 26 had branch vein occlusion. A total of 20 women and 33 men were included, ranging in age from 36 to 85 years. Methods for randomisation were not specified. At two years, a significant improvement was seen in the treatment group, both in terms of visual acuity and decrease in macular oedema. No complications of the treatment were described.

Comment

Anticoagulants (such as heparin), fibrinolytic agents (such as streptokinase and tissue plasminogen activator) and antiplatelet drugs (such as aspirin, prostacyclin, and ticlopidine) would seem to be logical treatments, but results from trials have been disappointing, with limited evidence of benefit owing to adverse effects of retinal and vitreous haemorrhage. To date these trials have been small, and have used a variety of follow up periods and outcome measures. Some authorities advocate the use of steroids in CRVO in the younger age group, but there is no published evidence to support this.

Question

Do patients with BRVO or CRVO experience a better visual outcome and/or less neovascular glaucoma when treated with haemodilution?

The evidence

Isovolaemic haemodilution is used to reduce blood viscosity, with the intention of improving retinal circulation. We found eight papers describing five randomised controlled trials of haemodilution in the management of retinal vein occlusion.12,18–23 The main features of each trial are listed in Table 41.1.

The first of these randomised controlled trials, published in 1985,18 compared the effect of isovolaemic haemodilution with and without prior xenon-arc panretinal photocoagulation on visual acuity following central retinal vein occlusion. Seven of the 17 patients who had haemodilution retained a better visual acuity at one year, compared with only one of 17 in the control group. The authors commented that the haemodilution seemed to be more effective in patients with ischaemic than with non-ischaemic CRVO.

The same group published another study19 omitting the panretinal photocoagulation. Only non-ischaemic patients were investigated, so that the effect of haemodilution could be compared with no treatment. At one year, six out of 13 haemodiluted patients retained better visual acuity, compared with none of 11 control group patients.

Wolf et al. published a series of papers looking at the short-term,20 intermediate-term21 and long-term results22 of haemodilution in 40 patients with central retinal vein occlusion. They performed a single-blind randomised prospective investigation, and found a statistically significant improvement in visual acuity at one year for the treated group compared with the control group.21 This improvement was sustained after three years.22 There was no statistically significant difference between the two groups in the progression to ischaemic central vein occlusion.

However, in 1996, Luckie et al.12 published the results of a randomised controlled trial investigating the effect of haemodilution on 59 patients with central retinal vein occlusion, stating that the incidence rates for improvement in visual acuity and iris neovascularisation were not different between the treated and control groups. Moreover, this trial found that the incidence rate of deterioration in visual acuity was 5·3 times higher in the treated group.

Finally, the role of haemodilution in patients with reduced visual acuity secondary to branch retinal vein occlusion was investigated by Chen et al.,23 who found a statistically significant difference in visual acuity at one year, with the treated group having a better outcome.

Comment

Analysis of the available randomised trials shows the effects of haemodilution to be inconsistent, although results from further trials are awaited. Double-masked studies are not possible as “placebo haemodilution” cannot be performed. The procedure is not without complications, particularly in the elderly, and those with respiratory problems or ischaemic heart disease.

Question

Is it possible to ameliorate morbidity and mortality associated with retinal vein occlusion?

The evidence

Retinal vein occlusions are associated with an increase in vascular causes of death (both cerebral and cardiovascular) in large prospective follow up studies.8,24 It is now proven that drug treatment of hypertension reduces the severity of its complications, and additional therapy of aspirin reduces the cardiovascular event rate.8,24 Recent trials of reducing cholesterol levels using statins have shown reduction of cardiovascular morbidity and mortality.8 The risk of future cardiovascular disease in retinal vein occlusion patients may be calculated using the Framingham algorithm, and this risk estimate may be used to guide decisions about preventive treatment for cardiovascular disease in these patients.25 There is evidence for the roles of treatment of hypertension, lipid lowering and the regular use of aspirin in reducing morbidity from cardiovascular disease.

Question

Do patients with retinal vein occlusion experience a better visual outcome and/or less neovascular glaucoma with medical management of underlying systemic risk factors?

The evidence

This question is pertinent in cases of “pre-occlusive” retinal vein occlusion, sometimes referred to as “venous stasis”. These patients should undergo medical investigation for underlying systemic risk factors and should be treated urgently, as it is potentially possible to prevent progression or to reverse the existing occlusion.8 Antiplatelet agents may be of benefit. In exceptional circumstances other measures may be considered, but there is only anecdotal evidence of their benefit, and they may be potentially harmful.

Comment

In all cases of retinal vein occlusion, involvement of the fellow eye is a concern. Several studies have demonstrated that recurrence of retinal vein occlusion may occur in the affected eye or in the fellow eye in 9–15% of patients over a five-year follow up period.1,8 In view of the poor potential visual outcome for patients with recurrent retinal vein occlusion, this aspect has been studied, but not in controlled trials. The available data support the concept that recurrence of retinal vein occlusion may be reduced by medical treatments of underlying cardiovascular risk factors with the addition of aspirin/persantin.

Question

When should laser treatment be given to patients with BRVO or CRVO?

The evidence

Disc or retinal neovascularisation following BRVO is an indication for photocoagulation to the ischaemic retina (sector photocoagulation). The available evidence suggests that waiting until vitreous haemorrhage occurs before using laser treatment does not adversely affect the visual prognosis.

The two principal papers that provide this evidence come from the Branch Vein Occlusion Study Group26 and Hayreh et al.27 The Branch Vein Occlusion Study Group set up a randomised controlled trial to investigate the effect of argon laser scatter photocoagulation in branch vein occlusions in 316 patients. One hundred and seventy-three men and 146 women patients were randomised either to a treated group or an untreated control group by a computer-generated random allocation schedule issued by the study coordinator. Results from this study showed that there was significantly less neovascularisation and less vitreous haemorrhage in the treated eyes compared with the untreated group. This study suggested that peripheral scatter treatment should be applied after rather than before the development of neovascularisation.

These findings were confirmed in a second randomised controlled trial from Hayreh’s group, who also looked at the effect of scatter photocoagulation on peripheral visual fields. Two hundred and seventy-one patients were allocated to treatment or no treatment using a random number table, and a follow up of five years was provided. This paper echoed the recommendations of treatment only following development of neovascularisation, particularly in view of their demonstration of the detrimental effects of photocoagulation on peripheral visual fields in this study.

Evidence supports the use of argon laser panretinal photocoagulation (PRP) when iris new vessels or angle new vessels are visible following central retinal vein occlusion.

The largest study investigating this treatment is from the Central Vein Occlusion Study group.28 This was a multicentre, randomised controlled clinical trial. Of a total of 725 patients recruited in the entire Central Vein Occlusion Study, 90 were assigned to receive immediate PRP and 91 to close observation with PRP only administered at the first sign of iris or angle neovascularisation. The patients ranged from 20 to 92 years with a mean age of 65, and were assigned using computer-generated random allocation. The results showed that prophylactic PRP did not totally prevent iris or angle neovascularisation, and that prompt regression of such neovascularisation was more likely to occur in eyes

that had not been treated previously. The study advised “frequent” follow up in the early months in all untreated patients with features of retinal ischaemia, including undilated iris examination and detailed examination of the angle by gonioscopy. In circumstances where regular follow up is impractical, prophylactic treatment may be appropriate.

Question

Is there a proven benefit to macular oedema from laser treatment or chorioretinal anastomosis following BRVO or CRVO?

The evidence

In the Branch Vein Occlusion Study Group publication,29 139 eyes were randomly assigned to laser treatment or no treatment using computer-generated random allocation. At three years treated patients had a gain of at least two lines of visual acuity from baseline. This led the group to recommend argon laser photocoagulation for macular oedema as described in the study.

In the same year, Shilling and Jones30 found that treatment of macular oedema by laser in some patients did not significantly alter their visual prognosis. They investigated 90 patients in two groups (methods not specified); the first with macular oedema and a broken perifoveal capillary ring on fluorescein angiography, and the second with macular oedema and intact or broken perifoveal capillary rings. The research showed that treatment with argon laser photocoagulation to areas of retina with incompetent capillaries did not significantly improve the visual prognosis at one year, and that patients with an intact perifoveal arcade have a better visual prognosis than those with a broken arcade.

Patients with severe visual loss (less than 6/60 vision) are unlikely to benefit from laser treatment and those in whom symptoms have been present for more than a year are likely to have a limited benefit from photocoagulation.

A paper by Battaglia et al.31 looked at grid pattern argon laser treatment specifically in macular branch vein occlusion, using 99 patients randomly assigned to control group, early grid at three months or delayed grid at six to 18 months. The mean age of the patients was 70 years, but no other population data were provided. Results showed that neither early nor delayed grid laser treatment reduced macular oedema more than the natural evolution, and visual acuity was not improved.

Macular oedema following CRVO causes visual loss but randomised controlled trials have failed to indicate benefit from grid treatment. The most important of these is the

Central Vein Occlusion Study Group M Report,32 which looked at laser treatment for macular oedema in a subset of the 725 patients recruited to the main study. Computergenerated random assignment of 155 patients to grid treatment (77 patients) or to observation (78 patients) was used to examine the role of grid laser for macular oedema in perfused central vein occlusion. Visual acuity had to be 20/50 or worse, and macular oedema was judged using fluorescein angiography. Patients with non-perfusion were excluded. Interestingly, although the treatment reduced the angiographic evidence of macular oedema, there was no difference in visual acuity between the treated and untreated groups at any point during the three-year follow up period, and the study group therefore did not support macular grid photocoagulation for this population.

Chorioretinal anastomosis is an experimental treatment for improving retinal blood flow following CRVO. This technique shows promise but the results of randomised clinical trials are not yet available. Trials of other treatments such as optic nerve sheathotomy to improve retinal circulation and pars plana vitrectomy in the management of macular oedema are underway.

Implications for research

The literature search performed for this chapter reveals several areas requiring further evaluation. First, the role of rheologic factors in the aetiology of retinal vein occlusion, and their manipulation in management and prophylaxis needs further investigation. The role of steroids in young patients with central vein occlusion requires scientific evaluation. However, small numbers of patients, and favourable prognosis in a subset of these, will provide a challenge in study design. Surgical techniques of chorioretinal anastomosis, optic nerve sheathotomy and pars plana vitrectomy for macular oedema have all provided some preliminary results that show promise, and require larger randomised controlled trials to complete their evaluation.

Implications for practice

The evidence presented in this chapter may have some impact on current management of retinal vein occlusions. In the first instance, the available data on the effect of haemodilution suggest that this treatment may be suitable for some patients in some cases. Patients who are medically fit, with vein occlusion affecting only one eye could be considered, and experienced advice may need to be sought. Secondly, the timing and indications for scatter treatment both in branch and central vein occlusions vary in different

units around the country. This also applies to the frequency of follow up of newly diagnosed cases. The evidence base provides guidelines for practice in these situations.

Acknowledgements

This chapter was written with the help of the Royal College of Ophthalmologists Vein Occlusion Study Group, in particular Mr John Shilling (Consultant, St Thomas’ Hospital) and Dr Paul Dodson (Consultant, Birmingham Heartlands Hospital).

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Diabetic retinopathy is the most frequent cause of visual loss in the working age population, even though laser treatment has been available for almost three decades. The risk of retinopathy is directly related to the degree and duration of hyperglycaemia.

For both type 1 and type 2 diabetic patients, strict metabolic control has been shown to reduce the incidence and progression of early retinopathy. Intensive therapy of elevated blood pressure, using atenolol or captopril, reduces diabetic retinopathy progression and decreases diabetesrelated death and stroke in type 2 diabetes.

Laser treatment is effective in treating high risk proliferative diabetic retinopathy and clinical significant macular oedema.

Diabetic patients with vitreous haemorrhage and active fibrovascular proliferation profit from early vitrectomy.

Retinal photography with mydriasis appears to be the most effective strategy for screening for diabetic retinopathy. Though annual screening is proposed in guidelines, data for screening intervals are conflicting, suggesting individualised approaches especially in high risk patients.

With the exception of antiplatelet agents which are not contraindicated in people with retinopathy when used to prevent macrovascular disease, no other pharmacotherapy slows progression of retinopathy. Several clinical trials in progress may find newer more effective therapies to prevent visual loss.