David Levy, MD, FRCP
An important diagnosis, as there is a very high risk of progression to proliferative retinopathy and significant visual loss. Pre-proliferative changes are characterized by the following.
- Multiple (> 5) cotton-wool spots.
- Multiple large blot hemorrhages.
- Venous abnormalities: irregularities, beading, looping or reduplication.
- Intraretinal microvascular abnormalities: these resemble new vessels, and branch abnormally (in frequency, number and angulation) but they are intraretinal, so do not cause preretinal or vitreous hemorrhage. It is very difficult for the non-expert to spot them, but like true proliferative retinopathy they are unlikely to occur in isolation, without apparent background changes.
Prompt ophthalmological referral is needed for careful follow-up and possible laser treatment. Despite the dramatic retinal appearances, most patients do not have visual symptoms; discuss the importance of attending appointments….
This comprises NVE (retinal new vessels; new vessels elsewhere), arising from veins, usually at a bifurcation, and NVD (new vessels at the optic disc). Growth factors, especially vascular endothelial growth factor (VEGF), released from ischemic retina, lead to proliferation. Proliferating vessels lie in the preretinal space, between the retina and the posterior surface of the vitreous, and may bleed into the preretinal space or the vitreous. Although proliferative retinopathy is characteristic of type 1 diabetes, it frequently occurs in type 2, just as maculopathy is not restricted to type 2 diabetes. Proliferative changes in type 2 patients are associated with advanced coronary artery disease. In the VADT baseline cohort (mean age 62 years, very long duration of 21 years), median Agatston coronary artery calcification score in these patients was about 1000, where a score over 400 suggests a high risk of occlusive coronary artery disease . At the very least, simple cardiac screening tests should be carried out in these high-risk patients, but this requires a high level of integrated diabetes care that is just as important as a retinal screening and referral service. Paradoxically, as retinal screening becomes more efficient, patients may be less likely to be known to their specialist diabetes teams: patients attending retinopathy clinics have a very high rate of associated complications, especially microalbuminuria (about 70% in those with proliferative retinopathy), and there is a high smoking rate (16%) . This is an important message for primary care teams.
Treatment of proliferative retinopathy is with panretinal (scatter) laser photocoagulation using green-only lasers. How laser treatment works is still not understood, but it must be applied to areas of capillary non-perfusion and retinal ischemia. Severe visual loss is reduced by about 50%, but it is destructive treatment and it is important for patients to understand that it stabilizes, but does not improve, visual function. Fortunately, the loss of peripheral and night vision that often occurred with heavy peripheral laser treatment is less common now. Effective treatment, usually requiring 2000 or more retinal burns in each eye over two or more sessions, is demanding for operator and patient alike. Macular oedema can worsen after panretinal laser treatment.
Maculopathy is retinopathy occurring at or close to the fovea. It is common, occurring in 10% of the VADT cohort, was two to three times more prevalent in Hispanic and African-American groups, and was associated with diastolic hypertension and amputation. Visual impairment is usually caused by macular oedema, macular ischemia, or a combination of the two. Neither can be diagnosed with direct ophthalmoscopy, though the presence of oedema can be inferred from the frequent finding of a grey patch of retina with central microaneurysms and surrounding (circinate) exudates. Optical coherence tomography is now the most important technique for measuring and monitoring macular oedema. Macular ischemia can only be definitively diagnosed using fluorescein angiography, though it is not usually needed.
Ophthalmologists use the term ‘clinically significant macular oedema’ (CSMO; CSME in North America) to describe patterns of macular oedema that if not laser treated will result in significant visual loss. Laser treatment is generally effective where the central macula is involved and visual acuity is 6/9 (20/30) or worse. Other varieties of maculopathy are less responsive, and careful clinical judgement and discussion with the patient is required. Focal laser treatment is used to treat localized retinal thickening; where there is diffuse macular oedema, often associated with circinate exudates, grid laser treatment, avoiding the fovea, is often effective. In long-standing macular oedema, large macular plaques of exudate can occur. While resistant to laser treatment, intensive lipid lowering may help plaque regression. Since these patients usually have other vascular complications, statin treatment is in any case mandatory, but this is one situation where targeting very low LDL levels (e.g. < 1.5 mmol/ L, 60 mg/dL) may be helpful, though evidence is sparse. Diabetic maculopathy often does not respond to standard treatment (despite ophthalmologists’ frequent requests to diabetes teams, tight glycemic control of itself does not improve it), and intravitreal and systemic drugs are frequently used off-licence (see below). Maculopathy is strongly associated with obstructive sleep apnoea (OSA) in men.
Advanced diabetic eye disease
Advanced diabetic eye disease is visual loss caused by the complications of proliferative retinopathy or maculopathy. Retinal ischemia, common to all forms of severe retinopathy, induces a fibrovascular response. The resulting fibrous tissue leads to traction effects, i.e. avulsion of retinal blood vessels, tractional retinal detachment and neovascularization of the iris.
Avulsion of retinal blood vessels causes hemorrhage.
- Preretinal (subhyaloid) hemorrhage. Boat-shaped with a horizontal fluid level, and may be precipitated by hypoglycemia or Valsalva manoeuvre. They often form inferotemporal to the optic disc. If hemorrhage obscures the macula, the presentation is with acute visual loss; elsewhere, there may only be ‘floaters’. Preretinal hemorrhage implies proliferative changes, which may be obscured by the hemorrhage. If detected on routine retinal screening, urgent referral is needed, as it may presage a visually catastrophic vitreous hemorrhage.
- Vitreous hemorrhage. Again, usually associated with proliferative changes. They are large dense hemorrhages causing acute visual loss. Spontaneous clearing and improvement in vision occurs very slowly, over months, but there is a risk of further bleeds with less chance of resolution. Vitrectomy, usually with endolaser photocoagulation, can achieve impressive results.
Neovascularization of the iris (rubeosis iridis), usually associated with widespread retinal ischemia or tractional retinal detachment, may lead to rubeotic glaucoma when the canal of Schlemm, draining the aqueous humour, blocks off. Pain is intense, it is difficult to treat, and the visual prognosis is poor. It is fortunately exceedingly rare in modern practice.
- Nathan DM, Zinman B, Cleary PA et al. Modern-day clinical course of type 1 diabetes mellitus after 30 years’ duration: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications and Pittsburgh epidemiology of diabetes complications experience (1983–2005). Arch Intern Med 2009;169:1307–16. PMID: 19636033.
- Hariprasad SM, Mieler WF, Grassi M, Green JL, Jager RD, Miller L. Vision-related quality of life in patients with diabetic macular oedema. Br J Ophthalmol 2008;92:89–92. PMID: 17584999.
- Beulens JW, Patel A, Vingerling JR et al. Effects of blood pressure lowering and intensive glucose control on the incidence and progression of retinopathy in patients with type 2 diabetes mellitus: a randomised controlled trial. Diabetologia 2009;52:2027–36. PMID: 19633827.
- Chew EY, Ambrosius WT, Davis MD et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. ACCORD Study Group and ACCORD Eye Study Group. N Engl J Med 2010;363:233–44.
- Chaturvedi N, Porta M, Klein R et al. Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials. Lancet 2008;372:1394–402. PMID: 18823656.
- Sjølie AK, Klein R, Porta M et al. Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): a randomised placebo-controlled trial. Lancet 2008;372:1385–93. PMID: 18823658.
- Reaven PD, Emanuelle N, Moritz T et al. Proliferative diabetic retinopathy in type 2 patients is related to coronary artery calcium in the Veterans Affairs Diabetes Trial (VADT). Diabetes Care 2008;31:952–7. PMID: 18316393.
- Al-Ansari SA, Tennant MT, Freve MD, Hinz BJ, Senior PA. Short report: sub-optimal diabetes care in high-risk diabetic patients attending a specialist retina clinic. Diabetic Med 2009;26:1296–300. PMID: 20002485.
- Shah AS, Chen SH. Cataract surgery and diabetes. Curr Opin Ophthalmol 2010;21:4–9. PMID: 19935423.
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David Levy, MD, FRCP, Consultant Physician, Gillian Hanson Centre, Whipps Cross University Hospital; Honorary Senior Lecturer
Queen Mary University of London London, UK
This edition first published 2011, © 2011 by David Levy. 1st edition 1998 (Greenwich Medical Media/Cambridge University Press) 2nd edition 2006 (Altman Publications)