Diabetic retinopathy is a major cause of blindness. Although diabetologists focus on the detection and prevention of retinal disease, diabetes has many other effects on the eye, which are summarised in this section. The human eye is a highly complex organ, dependent for function on precise organisation of numerous specialized components – including translucent and refractory structures, neurones, blood vessels, and muscles. Translucency of cornea, aqueous humour, lens, and vitreous humour must be maintained life-long. Refraction occurs primarily at the air-cornea interface, and light is focused on the retina by the flexible yet transparent lens. The retina, which translates visual information into nerve impulses, is embryologically part of the brain: it has a specialized dual circulation which includes two blood-retinal barriers, and the highest blood flow and oxygen consumption per gram of any tissue in the body. Acute and chronic hyperglycaemia, as well as other metabolic abnormalities present in diabetes, can affect every component of the eye, which is therefore a major site for complications in the patient with diabetes (Figure 1).
Diabetic retinopathy is the most common and potentially devastating complication of diabetic eye disease, and is the most common cause of blindness in adults of working age in the UK . It is also largely preventable, and hence of major importance to all those involved in the management of diabetes.
There are however many other ways in which diabetes can affect the eye, ranging from surface damage, changes in the anterior chamber, the lens (cataract), vitreous humour, and optic nerve as well as the retina itself. The spectrum of diabetic eye disease is summarised here and explored in more detail in the "daughter" sections.
Superficial eye damage
Dry eye syndrome occurs more frequently amongst patients with diabetes and is related to both impaired metabolic control and peripheral neuropathy of lacrimal gland innervation. In addition to discomfort for the patient, impaired tear production can also lead to injury of the corneal epithelium.
The cornea is the most anterior part of the eye and is the most densely innervated tissue in the body. It is therefore highly susceptible to diabetic neuropathic damage. This, in combination with impaired tear production, results in an increased susceptibility to corneal infection and injury.
The anterior chamber is the fluid-filled space between the corneal endothelium and the lens. Aqueous humour is produced by the ciliary body, flows through the pupil, reaches the anterior chamber angle and exits the eye. Interruptions to aqueous flow can result in increased intraocular pressure.
Neovascularisation of the iris occurs when new blood vessels are created from pre-existing iris capillaries near the pupillary margin and iris root. There is a higher frequency of neovascularisation in patients with proliferative retinopathy due to retinal ischemia causing increased retinal production of vasoproliferative factors, including vascular endothelial growth factor (VEGF).
These vasoproliferative factors diffuse anteriorly and lead to anterior segment neovascularization of the iris. When the vessels and their supportive fibrous tissue progress into and close the filtration angle of the eye, neovascular glaucoma ensues. This is typically painful, and may result in visual loss if not promptly treated. Management involves initial reduction in intraocular pressure by both medical and surgical means, and later medical treatment with panretinal photocoagulation or anti-VEGF agents to reduce the ischemic drive.
The lens is an avascular complex structure of stratified epithelium. It receives all required nutrients from the aqueous and vitreous humours in which it is bathed. Glucose levels in the aqueous humour are approximately 50% of plasma levels . As a result the lens is exposed to variations in ocular fluid glucose concentration.
Excess glucose in the crystalline lens is converted to sorbitol through the action of aldose reductase. Sorbitol has poor permeability through membranes and tends to accumulate in the lens where it induces apoptosis in epithelial cells leading to the development of cataract.
Population studies including the Beaver Dam Eye Study have confirmed an increased prevalence of cataract in patients with diabetes . Cataract surgery in patients with diabetes plays a dual role: firstly improving vision and, secondly, facilitating accurate retinal screening. However, reports on the effect of cataract surgery on diabetic retinopathy describe mixed results, with some studies suggesting deterioration and others finding no change .
Pre-operative treatment of diabetic retinopathy with photocoagulation therapy may mitigate subsequent worsening of retinopathy . However in patients in whom dense cataract obscures view of the fundus, cataract surgery with photocoagulation inside six months was not associated with progression of retinopathy or development of macular oedema .
The vitreous humour is a clear fluid which is located within the posterior component of the eye between the lens and the retina. It is mainly composed of water with a small (1%) proportion of other materials such as collagen and hyaluronic acid giving it a gelatinous consistency. With age the vitreous changes in composition from a gel to a liquid. This process is accelerated in patients with diabetes. In addition glucose mediated abnormal collagen cross-linking can result in shrinkage of the vitreous with posterior vitreous detachment. During detachment cells or debris released into the vitreous produce floaters in the patient’s field of vision. These can interfere with vision and be bothersome for patients; as the name implies, they drift across the field of vision in contrast to lens opacities which are fixed. Treatment options are limited with surgery offered only in extreme cases.
In the Wisconsin Epidemiologic Study of Diabetic Retinopathy, 3.6% of patients with type 1 diabetes and 1.6% of those with type 2 diabetes were legally blind. In those with type 1 diabetes, all of whom were less than 30 years of age, 86% of blindness was attributable to diabetic retinopathy.
Subsequent studies from the same group found that from 1980 to 2007, the estimated annual incidence of proliferative diabetic retinopathy decreased by 77% and vision impairment by 57% in patients with type 1 diabetes. This is despite an increase in prevalence in diabetes, and reflects improved management of diabetes together with advances in specialised management of eye disease.
Figure 2: Cumulative incidence of a sustained change in retinopathy in patients with type 1 diabetes receiving intensive or conventional therapyThe development and progression of diabetic retinopathy has been linked to the exposure of the retinal vessels to chronic hyperglycaemia. In both the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) the incidence of retinopathy in the intensively treated groups (Figure 2) was significantly less than that found in the control groups and was attributed to the difference in HbA1c .
The Epidemiology of Diabetes Interventions and Complications (EDIC) study examined the effect of the original treatment group in DCCT participants ten years after the study end. Despite no significant difference in HbA1c between follow up groups the former intensive group had a significantly lower incidence of retinopathy progression compared to the former control group . Thus the lower HbA1c during the original study period contributed a later “metabolic memory” effect on the development of retinopathy. This concept suggests that following the initiation of diabetic retinopathy, factors other than chronic hyperglycaemia are operative in its progression.
Pathogenesis of retinopathy
Diabetes affects all major cells of the retina including vascular endothelial cells, podocytes, neurones, glia and pigmented epithelial cells. Brownlee identified a unifying mechanism of diabetes complications with hyperglycemia-induced overproduction of superoxide. This activates four damaging pathways namely the polyol , hexosamine and protein kinase C (PKC) pathways and advanced glycation end product (AGE) formation . These are all involved in the pathogenesis of diabetic retinopathy.
A key initial histopathological change is capillary basement membrane thickening. This has been attributed to accumulation of advanced glycation end products (AGEs) causing increased collagen cross-linking and reduced basement membrane degradation . Subsequently the combination of endothelial cell dysfunction, increased intracapillary pressure and pericyte loss results in increased vascular permeability, which can be detected by leakage of fluorescein from retinal capillaries.
Clinical evidence of these processes is marked by the development of micro-aneurysms, intraretinal hemorrhages, hard exudates and focal areas of retinal ischemia (cotton-wool spots). At this point, the retinopathy is classified as nonproliferative diabetic retinopathy (NPDR). When retinal ischaemia stimulates production of angiogenic growth factors including vascular endothelial growth factor (VEGF) the consequent new vessel formation and proliferation is classified as proliferative retinopathy .
Within these two broad areas of classification, diabetic retinopathy is further graded into mild/moderate or severe retinopathy. One such grading system is derived from the Early Treatment of Diabetic Retinopathy Study. These systems are used extensively in the retinal screening programmes which are available for patients with diabetes throughout the United Kingdom.
When diabetic retinopathy affects the macula it is classified as diabetic maculopathy. The macula is located in the centre of the retina temporal to the optic nerve. The centre of the macula, or fovea, has the highest concentration of cone cells in the retina and is responsible for clear central vision. Breakdown of the blood retinal barrier and vascular leakage at the macula results in macular oedema. This can have devastating effects on central vision and is the commonest cause of blindness in patients with diabetes . Diabetic maculopathy can be subclassified depending on the distribution of disease within the macula and the involvement of surrounding arteries.
Management of Retinopathy
Development and progression of diabetic retinopathy can be prevented or reduced through improved glycaemic and blood pressure control . For patients with established retinopathy, laser photocoagulation is the accepted treatment strategy. Following the Early Treatment in Diabetic Retinopathy Studies, laser therapy is performed for patients with severe pre-proliferative disease, macular oedema or proliferative retinopathy .
Additional therapies include VEGF inhibitors such as bevacizumab, ranibizumab and pegaptanib. These have shown promising effects in patients with macular oedema and as an adjunctive therapy with laser photocoagulation in patients with proliferative retinopathy . Despite the significant cost advantage of bevacizumab over ranibizumab with similar clinical effect, ranibizumab is more commonly used and is the only such agent to have been given approval from the National Institute for Health and Care Excellence (NICE) for the treatment of diabetic macular oedema.This is because intraocular use of bevacizumab is currently unlicenced.
Intravitreal steroid therapy is another antiangiogenic medical therapy for retinopathy which reduces neovascularisation and macular thickening. It is not superior to either laser or VEGF inhibitor therapy but is comparable to the effect of ranibizumab in patients who are pseudophakic. A long acting intravitreal steroid implant has been developed which demonstrated a three year benefit in visual acuity in patients with diabetic macular oedema. It has been licenced in the United Kingdom for this indication. Intravitreal steroids are associated with increased intraocular pressure, cataract formation and endophthalmitis which limit their widespread use .
Fenofibrate has been found to reduce the rate of development of retinopathy and need for laser therapy in patients with type 2 diabetes. This was initially identified in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study and later in the ACCORD eye trial . The benefit was independent of any change in lipids.
The increasing range of medical therapies for diabetic retinopathy will hopefully help to reduce progression of disease and the need for laser photocoagulation therapy. The early detection of diabetes, the wide range of glucose lowering therapies and the adoption of retinal screening programmes will result in diabetic retinopathy being detected earlier in its pathogenesis. Future strategies to identify and treat very early retinopathy may reduce the progression to proliferative disease and potential loss of vision.
Anterior ischemic optic neuropathy is due to microvascular disease of the anterior portion of the optic nerve. It presents with visual impairment and, on fundoscopy, optic disc swelling and later optic nerve pallor. Afferent pupillary and visual field defects are also present.
There are no proven effective treatments for this condition. One retrospective trial demonstrated a benefit of aspirin therapy in preventing anterior ischaemic optic neuropathy in the contralateral eye . Diabetic papillopathy is characterised by acute disc oedema and mild visual impairment. It is considered to be a less severe but reversible form of anterior ischaemic optic neuropathy. It typically improves spontaneously within a year.
Cranial nerve palsies have an incidence of 1% over 25 years in patients with diabetes. This is a 7.5 fold increase compared to those without diabetes . In a study considering all cranial nerve palsies in patients with diabetes the abducens nerve was involved in 50% of cases, the oculomotor in 43% and trochlear in 7% .
Cranial nerve palsies in diabetes are usually attributed to microvascular disease in diabetes. They present with acute onset of double vision. The majority of palsies improve or resolve over 3-6 months and treatment is centred around antiplatelet therapy and targeting vascular risk factors .
The eye is a major site for glycaemic complications in the patient with diabetes through a number of different mechanisms. Optimising glycaemic control and targeting vascular risk factors are the central strategies, but it is important to bear in mind that other treatments can be employed to reduce the risk of these complications.
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