Diabetic Retinopathy and Diabetic Eye Problems

Diabetes mellitus (DM) is a common metabolic disorder. It manifests itself in different ways in the eye, the most common being as diabetic retinopathy (DR) which is thought to be the commonest cause of blindness among people of working age in the developed world.¹ DR is the main focus of this record but at the end, you will find notes on other conditions associated with diabetes and the eye, including:

• Cataracts
• Rubeosis iridis and glaucoma
• Ocular motor nerve palsies

Pathophysiology²

DR is a microangiopathy whereby there is a combination of microvascular occlusion and leakage. The consequence of occlusion is retinal ischaemia leading to arteriovenous shunts and neovascularisation. Leakage results in intraretinal haemorrhages and localised or diffuse oedema. The end point of these processes are the characteristic features seen at various stages of DR:

• Microaneurysms - physical weakening of the capillary walls which predisposes them to leakages.
• Hard exudates - precipitates of lipoproteins/other proteins leaking from retinal blood vessels.
• Haemorrhages - rupture of weakened capillaries appearing as small dots/larger blots (the haemorrhage is intraretinal) or 'flame' haemorrhages that track along nerve-fibre bundles in superficial retinal layers (the haemorrhage arises from larger and more superficial arterioles).
• Cotton wool spots - build-up of axonal debris due to poor axonal metabolism at the margins of ischaemic infarcts.
• Neovascularisation - an attempt to revascularise hypoxic retinal tissue.

The degree of each of these pathological processes depends on what stage the DR has reached. This is outlined in the classification of DR and influenced by a number of risk factors (see below).

Classification

Classification is based on the degree of pathology seen on slit-lamp examination of the eye. It is not correlated to the degree of vision which may be almost normal until the very late stages of the disease. The six main categories are:

• No background retinopathy
• Background retinopathy - there are signs of microvascular leakage away from the macula.
• Maculopathy - there are signs of microvascular leakage around the macula.
• Preproliferative - occlusion and ischaemia begin to occur in addition to leakage.
• Proliferative - occlusive changes have prompted the release of vasoproliferative substance from the retina resulting in the growth of new vessels.
• Advanced - bleeding occurs from the neovascular fronds ± associated retinal detachment (fibrous traction on the retina as the blood is reabsorbed) and other complications.

Although this is generally a progressive disease process, maculopathy can co-exist with any of the stages. Younger patients are more likely to develop proliferative disease and older individuals more likely to develop maculopathy.

Epidemiology

Blindness is one of the most feared complications of diabetes with an incidence of 50–65 per 100,000 diabetic population per year in Europe.³ In type 1 diabetes, microaneurysms start to appear after 5 years, affect half of cases at 10 years and nearly all patients after 20 years. Proliferative retinopathy, as defined by a formation of new vessels, appears after 10 years and affects about 40% after 20 years. Maculopathy follows similar pattern finally affecting 10–20% of cases. In type 2 diabetes, these changes may be found at diagnosis because sub-clinical hyperglycaemia may have been present for a prolonged preceding period.⁴

Risk factors

• Progression of retinopathy is associated with the severity and length of time that hyperglycaemia exists: if diabetes is diagnosed before the age of 30, the incidence of DR after 10 years is 50%, rising to 90% after 30 years.
• Hypertension and other vascular risk factors such as obesity and dyslipidaemia can influence the onset and progression of retinopathy.
• Pregnancy may occasionally be associated with a rapid progression of DR. Women should have a baseline assessment as soon as the pregnancy is known and further examinations throughout the pregnancy (the frequency of which depend on the initial findings). Go to our record on The Eye in Systemic Disease for more information.
• There is marked individual variation in susceptibility to retinopathy for a given vascular risk profile.

Although smoking is a risk factor in type 1 diabetics, it may actually have a preventative role in some type 2 diabetics.³ However, as this is an independent risk factor for cardiovascular disease and all patients should be encouraged to stop.

Presentation

Presenting complaint

Waiting for the diabetic to present with visual problems is not a good strategy. Many patients retain normal eyesight or experience a minimal (and sometimes unnoticeable) reduction even in the presence of sight-threatening disease (diabetic maculopathy, proliferative disease). It is for this reason that screening for DR is mandatory - see below. There are a few conditions where the patient may become aware of a problem (whether or not they are known diabetics):

• A painless gradual reduction of central vision may be associated with any of the types of DR. Similarly, painless and gradual visual loss is associated with cataract formation (diabetic or otherwise).
• Haemorrhages result in the sudden onset of dark, painless floaters which may resolve over several days.
• Severe haemorrhage may obscure the vitreous altogether resulting in a painless visual loss.
• An acute attack of glaucoma precipitated by rubeosis iridis (see below) is the one situation where the patient will present with acute pain; urgent referral is essential.

Examination

Background retinopathy

• Microaneurysms - outpouchings of capillaries appearing as tiny red dots.
• Hard exudates - appear as yellow-white shiny spots or streaks, often forming clusters or arcs around the macula and other points of capillary leakage.
• Haemorrhages - both dot-blot and flame haemorrhages may be evident.
• Cotton wool spots - appear as creamy patches with indistinct borders.

• Multiple, deep, round haemorrhages, often appear over a short period.
• >5 cotton wool spots.
• Intraretinal microvascular abnormalities (IRMA) - these are flat clusters of abnormal capillaries confined to the retina that do not leak fluorescein when a fluorescein angiogram is performed.
• Abnormalities of veins including dilatation, beading, looping and reduplication.
• Other abnormalities of arteries including occlusion (vessel reduced to thin white line).

• If the oedema or hard exudates involve the fovea or if this becomes ischaemic, the patient is said to have diabetic maculopathy.
• This is the most common form of visual impairment in diabetics (especially type 2).
• The pathology may be focal or diffuse and exudates or ischaemia may prevail.
• This is a sight-threatening situation although the vision may not always be affected if it is detected early enough.
• Clinically significant macular oedema (CSMO) is a specific condition that occurs when the oedema or exudates are within a certain proximity of the fovea and of a certain size. This is relevant as it requires photocoagulation treatment, regardless of the level of visual acuity.

• Appearance of new vessels as fine fronds or arcades of abnormal structure.
• Usually arise on the optic nerve head when they are described as neovascularisation of the disc (NVD). Neovascularisation within three disc diameters of the major optic vessels is described as neovascularisation elsewhere (NVE).
• New vessels are associated with haemorrhage, retinal detachment and glaucoma (if the vessels grow over the trabecular meshwork - see below).
• With NVD, there is a 50% chance of being blind within 5 years and a 30% chance with NVE.
• Vitreous haemorrhages recur commonly and 30% of eyes are blind within one year of first bleed. Laser photocoagulation has considerably improved the prognosis.

• End stage damage that usually leads to blindness, although vitreoretinal surgery has improved the prognosis.
• Vitreous and preretinal haemorrhages occur as new vessels grow forward from the retina and enter the vitreous where they bleed easily.
• Haemorrhages appear as reddish/dark opacities; preretinal or subhyaloid haemorrhages have a horizontal superior surface when patient is upright, as red cells settle within the cavity of the haemorrhage.
• Retinal detachment – occurs as retina is pulled off the underlying choroid by strands of fibrous tissue associated with the formation of new vessels or previous haemorrhages. The retina appears wrinkled or thrown into bumps or folds, possibly with a tear.
• Rubeosis iridis – new vessels grow on the iris and can be seen or they cause a diffuse reddening of the iris; often complicated by glaucoma due to obstruction of the filtration angle in the anterior chamber. Look for circumcorneal injection, fixed irregular pupil, corneal haze and intensely painful eye.

Management

There has been a marked change in emphasis over recent years in the management of diabetic retinopathy. Formerly it was seen as an inevitable and inescapable consequence of diabetes, possibly noted on ophthalmoscopy at annual diabetic clinic review, with intervention often delayed until frank or severe disease existed, when it was least likely to be effective. Nowadays, it should be considered as a preventable/treatable condition that must be carefully monitored for and managed through improved diabetic control and ophthalmological intervention.

• All diabetic patients should have their eyes reviewed as an integral part of their management (see screening below), regardless of the presence of DR or otherwise. This comes hand-in-hand with patient education about their disease and lifestyle issues surrounding its management.
• Good glycaemic control (usually aiming to bring HbA1_c levels to <7%) is associated with improved long-term outcomes and delayed progression of retinopathy.^5,6 However in some cases, particularly with pre-proliferative and proliferative retinopathy, improved glycaemic control can initially bring on a decompensation and worsening of symptoms and signs.
• It is important to address other vascular risk factors, particularly smoking, hypertension⁶ and correction of dyslipidaemia.⁷
• Laser treatment is the mainstay for the management of oedema and haemorrhages:
  • Background retinopathy - mild background DR can simply be observed.
  • CSMO⁶ - treated by laser photocoagulation of specific vessels (focal treatment) or using a grid pattern of laser burns spaced 1 spot-width apart over the affected area where specific leakage points cannot be identified, sparing the macular area. Intravitreal steroid injection is also looking promising: despite the need for vigilance regarding intraocular pressure control and cataract formation (both easily manageable), it does have the benefit of avoiding some of the serious complications that can be associated with laser treatment.⁸
  • Pre-proliferative DR - this needs close observation but is not usually treated (see complications below) unless regular follow-up is not possible or vision in the fellow eye has been lost due to proliferative disease.
  • Proliferative retinopathy - pan-retinal photocoagulation (PRP) is used.⁶ This involves placing laser burns over the entire retina, sparing the central macular area. Moderate intensity burns are placed 1 spot-width apart, except where there is neovascularisation where the whole arterial tree is treated. 1200–1600 burns may be placed on the retina over 2–3 sessions. If macular oedema is present it is often treated first and separately before treatment with pan-retinal photocoagulation. It is thought that the procedure works by reducing the release of vasoproliferative mediators by hypoxic retinal vessels and allowing easier direct diffusion of oxygen from the choroid blood supply.⁹
  • Vitreous haemorrhage - small haemorrhages resolve spontaneously but the patient will be closely monitored: once there is clear vision to the back of the eye, the offending vessels can be lasered. Vitrectomy may be needed in case of long-standing or very severe vitreous haemorrhage. Patients who have suffered vitreous opacification due to haemorrhage may be treated with retinal cryotherapy rather than photocoagulation.
  Laser treatment is carried out in a laser treatment clinic on an outpatient basis. At a later date, the areas of laser treatment are easily identifiable as well demarcated pale spots with distinct dark brown centres - this can be helpful if the patient cannot remember if they have previously had treatment!

Complications

• Of focal/grid photocoagulation:⁵
  • Impaired central vision
  • Paracentral scotoma
  • Choroidal neovascularisation
  • Epiretinal membrane formation
  • Worsening of macular oedema in a minority

• Of pan-retinal photocoagulation:⁹
  • Constriction of visual field
  • Nocturnal diminution of vision/blindness
  • Burns affecting the fovea centralis
  • Worsening macular oedema
  • Serous and/or choroidal detachment
  • Ocular pain
  • Anterior chamber adverse effects e.g. burns affecting cornea or lens

Prognosis

Background retinopathy will eventually progress to the more severe forms in the majority of individuals. If left untreated: 50% of those with proliferative diabetic retinopathy will lose their sight within 2 years¹ and 90% risk losing any useful vision after 10 years. Patients who undergo treatment have their risk of moderate visual loss reduced from 30% to 15% over the subsequent 3 years.⁵ Those who have pan-retinal photocoagulation have their risk of severe visual loss reduced by 50%, compared to untreated individuals with a similar severity of disease.⁹

Prevention

• Improved glycaemic control in the diabetic population, achieved through education, better therapeutics and evolving healthcare support systems.
• Better screening for sight-threatening diabetic retinopathy through the national screening programme.
• Adequate metabolic and ophthalmological intervention in those identified as suffering from retinopathy.

Screening¹

DR and its sequelae are amenable to early detection through a screening programme and subsequent beneficial intervention. The current screening recommendations are:

• All patients over the age of 12 with diabetes need to be invited for an annual screen (national targets are a 70% uptake).
• Digital retinal photography with mydriasis should be used as the gold standard screening test to detect diabetic retinopathy. Indirect slit-lamp ophthalmoscopy also meets sensitivity and specificity criteria but lacks a hard record to allow comparisons for quality assurance.
• Other measurements include assessment of visual acuity, examination of the iris and pupil and checking of the pupillary reflexes. Screening for glaucoma using tonometry may be carried out at the same time.
• There must be an appropriate referral service when abnormalities are detected through good links with hospitals and primary care.

In general, the UK is doing very well with its DR screening targets, having offered 85.7% of eligible diabetic patients the screening programme. However the target is 100% and efforts are still being made to improve screening locally. The screening programme may vary in its execution from region to region, depending on available resources and patterns of provision. It may involve GPs, optometrists, hospital physicians and other healthcare professionals. See the National Screening Committee's details for the programme in each region, via the further reading reference in the internet section below.

A classic diabetic cataract is rare. Hyperglycaemia is reflected in high levels of glucose in the aqueous which diffuses into the lens, affecting its metabolism and producing the cataract. The cataract is manifest as snowflake opacities occurring in the young diabetic. It may resolve spontaneously or mature. More commonly, an age-related cataract is precipitated in the diabetic patient, to form earlier than it would have done otherwise.

• Premature presbyopia and other refractive errors due to the reduced pliability of the lens secondary to an altered metabolism (see comment above, in cataract).
• Rubeosis iridis describes the process when severe ischaemia causes neovascularisation to such an extent that the vessels grow forward and over the iris. The vessels may be seen as large individual entities or else give the iris a generally red appearance. If they block the peripheral trabecular meshwork (through which most of the aqueous drains - see record on Open Angle Glaucoma) on the way, they may precipitate acute glaucoma which needs urgent treatment.
• Occasionally, ocular motor nerve palsies occur, presumably due to the damage of the microvascular supply of these cranial nerves. Patients should be presumed to have an intracranial mass until proven otherwise via imaging. If it is truly a palsy related to diabetic microvasculopathy, it often resolves over a period of months but orthoptic input may be needed.
• Asteroid hyalosis is a condition characterised by little white flecks seen in the vitreous. It can occur for a number of reasons and is usually asymptomatic. Unless very severe and affecting vision, it is left alone.

Other problems are very occasionally seen that can be traced back to diabetes including papillopathy (various problems relating to the optic disc), pupillary light-near dissociation (see our records on Examination of the Eye and Pupillary Abnormalities) and rhino-orbital mucormycosis.