11.1 Pre-proliferative retinopathy

By definition, this stage precedes overt neovascularization, and is characterized 

by venous beading and dilatation, large blot retinal haemorrhages, cotton-wool 

spots (in the absence of systemic hypertension), intra-microvascular abnormalities, 

and areas of capillary underperfusion as shown by fluorescein angiography61. 

However, the definition of pre-proliferative retinopathy is difficult since not all 

patients who develop proliferative retinopathy pass through the preproliferative 

phase, and many do not show all the features described above. Accordingly, we 

recommend the concepts of ‘high risk’ and ‘low risk’ retinopathy (see section 2 on 

clinical classification).

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It is, however, an important stage to recognize since 10 to 50 % of patients with

‘high risk’ (pre-proliferative) retinopathy will develop overt proliferative changes 

within 1 year62. Such patients require at least 4 monthly follow up to allow the 

earliest detection of proliferative changes. On theoretical grounds, all patients 

should go through the preproliferative stage. That this is not the case may well 

be due to the relatively transient nature of the some of the lesions. In addition, 

pre-proliferative retinopathy in the presence of a posterior vitreous detachment 

cannot a priori progress to proliferative retinopathy although rubeosis iridis can 

still occur (see below). Cotton wool spots have a time course of 6-12 months, 

and blotch haemorrhages as well as IRMA’s disappear once extensive capillary 

closure has developed.

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Opinions differ on whether to treat pre-proliferative retinopathy. Most studies 

have failed to show any benefit, provided that adequate follow up is achieved63. 

In mild forms where less than two of the features of the condition are present,

and particularly where there are only a few cotton wool spots, progression is not 

certain and indeed spontaneous regression may occur64.  In the United States 

the preferred practice in cases of bilateral pre-proliferative retinopathy is to 

treat one eye with pan-retinal photocoagulation and observe the second eye 

at three monthly intervals.

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11.2 Rubeosis iridis

This is a manifestation of severe retinal ischaemia and heralds the onset of 

rubeotic glaucoma. In the presence of clear media, further immediate 

photocoagulation should be applied since regression can be induced although 

this is perhaps better documented following central retinal occlusion65. However 

rubeosis is often associated with advanced PDR rendering it impossible to apply 

further laser due to vitreous haemorrhage. In these circumstances prompt 

vitreous surgery is required to enable preoperative photocoagulation to be carried 

out (see above). The results of the Early Vitrectomy Study show the benefits of 

surgery in eyes with severe neovascularization and vitreous haemorrhage54; the 

presence of rubeosis indicates that surgery cannot be further delayed. Ultrasound 

examination is mandatory to exclude retinal detachment, since co-existing rubeosis 

implies a poorer prognosis for surgery (see above).

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Glaucoma due to rubeosis responds poorly to standard trabeculectomy procedures66. 

When trabeculectomy is combined with mitomycin-C however, the results are more 

encouraging67, and compares favourably with other anti-proliferative agents such as 

5-Fluorouracil68 as well as other surgical procedures such as drainage tubes and cyclo-

cryotherapy. When it is possible to apply further photocoagulation, trabeculectomy 

with mitomycin should be delayed for 1-4 weeks to allow as much regression of the 

rubeosis as possible prior to surgery66. In eyes which are already blinded by rubeotic 

glaucoma, topical steroids together with atropine is the appropriate palliative 

treatment.

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11.3 Systemic hypertension

In both IDDM and NIDDM patients systemic hypertension is commoner than in non-

diabetics69,70 (see risk factors above). Since it is well recognized that systemic 

hypertension hastens the development of background and proliferative 

retinopathy4,5,20,71, it is important that ophthalmologists identify signs of coexisting 

hypertensive retinopathy. Some of the features of accelerated hypertensive 

retinopathy such as retinal haemorrhages, cotton wool spots and capillary closure 

are similar to diabetic changes, but there are often subtle differences with, in 

particular, flame shaped retinal haemorrhages being characteristic of hypertension. 

The thickening of the arterial wall of the retinal vessels together with A-V nipping 

are also consistent features of systemic hypertension.

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Whilst the association between hypertension and diabetic retinopathy is established, 

there are few studies regarding the effects of treatment of hypertension on diabetic 

retinopathy. In one reported study, it has been shown that treating hypertension 

minded result in improvement of retinopathy72. Since both diabetic retinopathy and 

nephropathy are the result of microangiopathy, it should be the concern of those 

treating patients with retinopathy to attend to concomitant hypertension. ACE 

inhibitors appear to control hypertension well in these circumstances and may 

therefore be the drugs of choice.

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At the present time, it is reasonable to expect ophthalmologists to recognize the 

effects of hypertension on diabetic retinopathy and if not already diagnosed, to 

draw it to the attention of the physicians. It should be realized however, that 

prevention of the visual damage associated with retinopathy can only be achieved 

in the early stages. Treatment of established maculopathy or PDR is not 

accompanied with visual improvement, only with halting the disease process.

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11.4 Retinal vein occlusion

Diabetes is recognized as a predisposing factor in the causation of retinal venous 

occlusion73. Many cases of branch or central vein occlusion occur in diabetics 

without retinopathy in which the management is the same as in non-diabetics 

ie pan-retinal laser photocoagulation if significant areas of capillary non-perfusion 

have been identified by fluorescein angiography, in order to prevent retinal 

neovascularization or rubeosis iridis74. Although the natural history of branch 

retinal vein occlusion is probably little different in diabetics without retinopathy, 

there is a significant higher rate of neovascular glaucoma75 and such patients 

require evaluation of the extent of retinal ischaemia by fluorescein angiography 

to enable timely photocoagulation to be applied. 

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Retinal venous occlusion occurring in patient with established diabetic retinopathy 

may prove more difficult to assess and treat. Where there are already extensive 

haemorrhages and exudates from diabetic retinopathy, the subsequent development 

of a venous occlusion can be missed and must be considered where ‘asymmetric 

retinopathy’ has developed