Diabetic retinopathy

Essentials

Diabetes causes diabetic retinopathy, i.e. changes in the ocular fundi. It is the most important preventable cause of visual disability in working-age people.
• The changes develop gradually and remain asymptomatic for a long time.
• Good glycaemic control and treatment of all risk factors prevent the development of retinopathy and its progression to a sight-threatening disease.
• Regular examination of the ocular fundi in asymptomatic patients with diabetes (screening and follow-up) helps to find out whether there are changes due to retinopathy and to refer patients to further examinations and treatment, as necessary. Fundus photography is a more sensitive screening method than ophthalmoscopy.
• Monitoring of the ocular fundi can be performed by the patient's general practitioner if the changes are quite mild. As the changes progress, decisions about monitoring as well as the need for any treatment should be made by an ophthalmologist.
• Rehabilitation should be started as soon as sight-threatening changes are noted in the ocular fundi.Diabetes is a risk factor for many ophthalmological diseases, making these diseases more common in people with than without diabetes. Patients should be referred for investigations and treatment based on symptoms and findings. Vascular changes in the ocular fundi due to diabetes, or diabetic retinopathy, are one of the most common diseases associated with diabetes. The changes develop gradually over the years and remain asymptomatic for a long time. Therefore, being asymptomatic does not necessarily mean that a person does not have retinopathy. Ideally, treatment of the changes should be initiated before symptoms occur. Regular examination of the ocular fundi in asymptomatic patients with diabetes (screening) helps to find out whether they have retinopathy, what degree of changes are present and whether the changes require treatment already. Screening will thus prevent visual impairment with a good cost-benefit ratio . Fundus photography is a more sensitive examination method than ophthalmoscopy . Monitoring of the ocular fundi can be performed by the patient's general practitioner until the patient develops more than mild changes. Thereafter, decisions about the frequency and methods of monitoring, as well as the need for any treatment, should be made by an ophthalmologist. Good glycaemic control and treatment of all risk factors decrease the risk of retinopathy and its progression. Patients should be referred to an ophthalmologist for examination and treatment if the changes in the ocular fundi have developed into vision-threatening maculopathy (i.e. clinically significant macular oedema) neovascularization or a state preceding it (preproliferative retinopathy) is observed, or either vitreous haemorrhage due to neovascularization or retinal traction is observed. Rehabilitation should be started as soon as sight-threatening changes are noted in the fundi of a patient with diabetes.

Clinical picture and natural course of the disease

Nonproliferative (background) retinopathy

In nonproliferative retinopathy, the following retinal changes can be found:
• microaneurysms (local dilatation of capillaries) and haemorrhages
• retinal oedema and lipid deposits left behind after the oedema has been reabsorbed (so-called hard exudates)
• microinfarcts (so-called cotton wool spots or soft exudates)
• venopathy, or venous beading
• intraretinal microvascular abnormalities (IRMA), or extensive capillary damage appearing as areas of reticular vascular structures.
• The first retinopathy findings are often microaneurysms or small haemorrhages. The number of aneurysms varies: some may disappear and new ones may appear. An increase in their number indicates progression of the capillary damage.
• Microinfarcts and haemorrhages disappear with time and do not necessarily lead to permanent capillary occlusion.
• IRMA and venous changes indicate permanent capillary occlusion.
• Nonproliferative retinopathy is divided into various degrees of severity. Mild or moderate nonproliferative retinopathy does not require topical treatment of the eye.
• In severe nonproliferative retinopathy (i.e. preproliferative retinopathy) there are scattered IRMA and/or venous abnormalities or several large haemorrhages in the entire fundus. In such cases, the need for laser treatment of the fundus should be individually assessed.Nonproliferative retinopathy is characterised by microaneurysms, haemorrhages, retinal oedema and hard exudates, which are lipid deposits left behind after the oedema has been reabsorbed, venopathy, or venous beading, and intraretinal microvascular abnormalities (IRMA), or extensive capillary damage appearing as areas of reticular vascular structures. Haemorrhages and oedema result from leakage from the veins, the remaining findings from capillary occlusion. The first retinopathy findings are often local dilatation of the retinal capillaries, i.e. microaneurysms, and small haemorrhages. The number of microaneurysms varies: some may disappear with time (and new ones may appear). An increase in their number indicates progression of the capillary damage. Microinfarcts (so-called cotton wool spots or soft exudates) disappear with time, as do haemorrhages, and do not necessarily lead to permanent capillary occlusion. IRMA and venous changes indicate permanent capillary occlusion. Like all structures containing haemoglobin, these can best be seen in good quality black and white images taken with a green filter. Nonproliferative retinopathy is divided into various degrees of severity (mild, moderate and severe, for example). Mild or moderate nonproliferative retinopathy does not require topical treatment of the eye. When scattered IRMA and/or venous abnormalities are present or several dark, or deep, haemorrhages affect the entire fundus, i.e. every quadrant, the patient has severe nonproliferative retinopathy, or preproliferative retinopathy, and the need for laser treatment of the fundus should be individually assessed.

Maculopathy and macular oedema

Diabetic maculopathy (sight-threatening nonproliferative retinopathy, primarily macular oedema) may develop at any stage of the disease and is more likely the more retinopathy changes there are.
• Macular changes often heal spontaneously.
• Macular oedema can be divided into mild, moderate and severe depending on how far from the fovea the lipid exudates and the oedema are situated.
  • Two-dimensional follow-up pictures cannot be used to assess oedema; clinical examination is needed for this, today complemented by optical coherence tomography (OCT).
• Even mild maculopathy may affect the ability to distinguish colours and impair contrast sensitivity.
• In severe maculopathy, vision that allows for general mobility is preserved, but when central visual acuity falls below 0.3, near vision is no longer adequate for reading a newspaper, for example. Various magnifiers may be of benefit at this stage.Diabetic maculopathy (vision-threatening nonproliferative retinopathy, primarily macular oedema) may develop at any stage of the disease and is more likely the more retinopathy changes there are. Macular changes often heal spontaneously. Maculopathy is the most common cause of visual impairment in type 2 diabetes. Even mild maculopathy may affect the ability to distinguish colours and impair contrast sensitivity functions. In severe maculopathy, vision that allows for general mobility is preserved, but when central visual acuity falls below 0.3, near vision is no longer adequate for reading a newspaper, for example. Various magnifiers may be of benefit at this stage.

Proliferative retinopathy

In proliferative retinopathy, neovascularization is observed on the retina and/or the optic disc in addition to nonproliferative retinopathy.
• Neovascularization is due to extensive vascular occlusion and resulting retinal ischaemia and hypoxia.
• Unless the posterior vitreous body has already become detached from the retina , new vessels attach to the posterior surface of the vitreous membrane. As the vitreous body contracts, new vessels are pulled towards the centre of the eye, causing the vessels to easily bleed onto the retina, into the space between the retina and the vitreous membrane and/or directly into the vitreous body.
• Vitreous haemorrhage is the most common cause of sudden loss of vision in type 1 diabetes. The haemorrhage usually heals spontaneously over a few weeks or months, unless it recurs.
  • As vitreous haemorrhage is rarely associated with straining, there is usually no need to restrict exercising in a patient with retinopathy. However, extreme straining should be avoided as long as active neovascularisation is apparent, i.e. for a few weeks after laser treatment.
• Neovasculature attached to the posterior surface of the vitreous membrane, and associated scar tissue, may cause retinal traction and detachment of the vitreous body from the retina . Small peripheral detachments do not affect visual acuity but they may require surgical treatment if there is a tear in the retina or traction on the macula.
• Severe untreated retinal hypoxia may also lead to neovascularisation of the surface of the iris (rubeosis iridis) and the iridocorneal angle, leading to neovascular glaucoma which is difficult to treat.When neovascularization is observed in addition to nonproliferative retinopathy, the state is called proliferative retinopathy. Extensive vascular occlusion and resulting retinal ischaemia and hypoxia lead to neovascularization on the retina and/or optic disc. Unless the posterior vitreous body has already become detached from the retina, new vessels attach to the posterior surface of the vitreous membrane. Leakage from the new vessels causes changes in the vitreous body which starts becoming detached from the retina. As the vitreous body contracts, new vessels are pulled towards the centre of the eye, causing the vessels to easily bleed onto the retina, into the space between the retina and the vitreous membrane and/or directly into the vitreous body. Sudden loss of vision may occur as a result of vitreous haemorrhage . The haemorrhage usually heals spontaneously over a few weeks or months, unless it recurs. Vitreous haemorrhage is the most common cause of sudden loss of vision in type 1 diabetes. Vitreous haemorrhage often occurs in the early hours of the morning and is rarely associated with lifting or straining. There is usually no need to restrict exercising in a patient with retinopathy. However, extreme straining should be avoided as long as active neovascularisation is apparent, i.e. for a few weeks after laser treatment. If the neovasculature and scar tissue growing to support it attach to the posterior surface of the vitreous membrane, they may cause retinal traction and detachment of the vitreous body from the retina . Small peripheral detachments do not affect visual acuity but they may require surgical treatment if there is a tear in the retina and traction on the macula endangering vision. Severe untreated retinal hypoxia may also lead to neovascularization of the surface of the iris (rubeosis iridis) and the iridocorneal angle, leading to neovascular glaucoma which is difficult to treat and may blind the eye.

Epidemiology

• One in two patients with type 1 diabetes, and one in four with type 2 diabetes, have diabetic retinopathy.
• Within 20 years from diagnosis, 80–100% of patients developing type 1 diabetes before the age of 30 will develop nonproliferative retinopathy and 15–50% proliferative retinopathy.
• Only a few patients developing type 1 diabetes after the age of 30 or having type 2 diabetes develop proliferative retinopathy (approximately 20% of those treated with insulin and less than 5 % of those treated with diet or oral antidiabetic drugs).
• Twenty years after diagnosis, 10–25% of patients have sight-threatening maculopathy, or clinically significant macular oedema. Maculopathy is the most common cause of visual impairment due to diabetes in patients with type 2 diabetes.

Risk factors

• Good glycaemic control and good management of blood pressure decrease the risk of diabetic retinopathy and slow down its progression .
  • Retinopathy starts to occur when HbA_1c levels exceed 48 mmol/mol (6.5%). Fluctuations in the levels also add to the risk of progressive retinopathy.
  • Hypertension also increases the incidence of macular oedema, particularly that of refractory macular oedema.
Pregnancy increases the risk of retinopathy temporarily but is not likely to influence the course of the disease in the long run. Retinopathy is not a contraindication to normal delivery.
• Other risk factors include dyslipidaemia, abdominal obesity and anaemia, as well as microalbuminuria and diabetic nephropathy. A family history of diabetic retinopathy is associated with an increased risk of retinopathy.
  • The role of hereditary protective or risk factors is not fully understood but severe forms of the disease appear to run in families.
  A long duration of diabetes increases the incidence of retinopathy. Changes are rare before puberty. As retinopathy worsens, the changes are more likely to progress. Pregnancy increases the risk of retinopathy temporarily but is not likely to influence the progress of the disease in the long run. Retinopathy is not a contraindication to normal delivery. Other risk factors include dyslipidaemia, abdominal obesity and anaemia, as well as microalbuminuria and diabetic nephropathy. A family history of diabetic retinopathy is associated with an increased risk of retinopathy. The role of hereditary protective or risk factors is not fully understood but severe forms of the disease appear to run in families.

Screening methods

• The patient’s family doctor may monitor visual acuity, for example in connection with annual check-ups. This will help to detect the development of cataracts, for example. However, the monitoring of visual acuity alone is not sufficient to exclude retinopathy or to determine its severity. Regular examinations of the fundi are therefore needed.
• To examine the ocular fundi, tropicamide must be used to dilate the pupils. It takes 20–30 minutes to achieve pupillary dilatation (mydriasis). Driving is not recommended for 2–3 hours after pupillary dilatation on account of the reduced ability to tolerate glare.

Ophthalmoscopy

• Requires experience and regular practice.
Examination is complicated by the presence of severe refractive error, media opacities, and a small pupil. No permanent record remains of ophthalmoscopy for future comparison or for attachment to a referral.

Fundus photography

• Fundus photography is a more sensitive screening and monitoring method than ophthalmoscopy.
• Mydriasis is required when a special non-mydriatic fundus camera is used.
• Two images per eye should be obtained of the fundus, one with the optic disc at the centre, the other with the centre of the macula at the centre. A wide field of view (60° vs. 45°) improves the detection of neovascularisation.
• When monochromatic black and white film is used the camera must be equipped with a green filter. Plain digital pictures should be viewed through a green filter. When black and white film is used the camera must be equipped with a green filter. Plain digital pictures should be viewed through a green filter.
• The advantage of photographic screening is the speed of interpretation and the fact that the images will provide a permanent record of the stage of retinopathy and the vasculature. The images should be attached to the referral.
• Fundus photography can be carried out at a regular check-up or separate photography appointment or as a part of a mass screening programme. Photography can be organized as part of an institution's own activity, purchased externally, or by several organizations jointly purchasing a camera which is then shared.
• The pictures should be viewed by a trained health care professional (the ophthalmic photographer, nurse or doctor) at the treatment or screening unit. Any pictures that show more than mild changes suggestive of retinopathy or other abnormality should be sent to an ophthalmologist specialized in diabetic retinal lesions. Referral for evaluation should include a short medical history as well as information on the main risk factors (HbA_1c, blood pressure, lipid values). The patient's family doctor should be informed about the results of the fundus examination, which are shared with the patient at the treatment unit.To avoid any delay, the patient's own doctor may write the referral after initial evaluation.
• If monitoring is done by photography, neither the patient’s family doctor nor the ophthalmologist necessarily sees the patient at the appointment. If so, particular attention should be paid to the flow of information. Patients should be informed in advance that, should the images show anything needing further investigations or treatment, they will be referred to the treatment unit that will invite them directly for examinations and treatment.

Follow-up frequency

See table If the onset of type 1 diabetes occurs in childhood, the first screening is usually carried out at the start of puberty, i.e. at the age of 10, and further screening every other year thereafter. As soon as abnormalities are noted, screening will be carried out annually or more frequently. Patients whose diabetes is diagnosed after puberty are examined at the time of diagnosis and every other year thereafter. As soon as abnormalities are noted, screening is carried out annually or more frequently. Patients with type 2 diabetes are examined at the time of diagnosis and every three years thereafter. As soon as abnormalities are noted, screening is carried out every other year or more frequently. Vision-threatening fundus abnormalities, particularly signs of severe nonproliferative retinopathy, poor glycaemic control, a rapid improvement of glycaemic control after intensification of treatment or nephropathy may be indications for more frequent screening. The fundi should be examined in patients planning pregnancy, or at least as soon as pregnancy has begun, and during pregnancy, particularly in patients who have been diagnosed with retinopathy.

Sight-threatening fundus abnormalities, particularly signs of development of severe nonproliferative retinopathy, poor glycaemic control, a rapid improvement of glycaemic control after intensification of treatment, or nephropathy, may be indications for more frequent examinations than specified in the Table.
• The fundi should be examined in patients planning pregnancy, or at least as soon as pregnancy has begun, and during pregnancy, particularly in patients who have been diagnosed with retinopathy.

Treatment

Good glycaemic control is most important.
• Too rapid correction of longstanding hyperglycaemia should be avoided. This concerns particularly patients with more than mild retinal changes.
• Management of other risk factors
  • Treatment of complicating vascular diseases, particularly hypertension
    • In patients with diabetes, the target blood pressure level is below 140/80 mmHg.
  • The aim is to have blood lipid levels in the recommended target range.
• Other pharmacotherapy
  • Aspirin may slow down the development of early retinopathy. The treatment has not been observed to increase the risk of vitreous haemorrhage. If aspirin is indicated for other reasons, retinopathy is not a contraindication to its use.
  • For severe central macular oedema, the following can be used alone or combined with laser treatment:
    • glucocorticoids injected or implanted into the vitreous body; possible adverse effects include the development of cataracts and increased intraocular pressure
    • anti-VEGF antibodies targeting the endothelial growth factor (such as ranibizumab, bevacizumab or aflibercept).
• Laser photocoagulation of the fundus i.e. laser treatment
• Various surgical proceduresGood basic diabetes management (therapeutic control)Aiming at good therapeutic control is most important. However, too rapid correction of long-lasting hyperglycaemia should be avoided. This concerns particularly patients with more than mild retinal changes. Management of other risk factors Treatment of vascular complicating diseases, particularly hypertension Blood pressure must be closely monitored and treatment started when the readings are repeatedly above 135/85 mmHg. In young and middle aged patients the blood pressure level should not exceed 130/80 mmHg. Blood lipid values should be normalised. Other pharmacotherapy Occlusion of the retinal capillaries has been attempted with acetylsalicylic acid (ASA), and this has indeed been shown to decrease the incidence of microaneurysms. The treatment has not been observed to increase the risk of vitreous haemorrhage. If ASA is indicated for other reasons, retinopathy is not a contraindication to its use. New forms of treatment (intravitreal corticosteroids or anti-VEGF antibodies, such as ranibizumab and bevacizumab) can be used alone or combined with laser treatment for severe central macular oedema.Corticosteroids cause development of cataracts and may increase intraocular pressure. Attempts have been made to develop medicines to treat hyperglycaemia-induced adverse chemical reactions but these have not been sufficiently effective or safe and are not marketed in all countries (for example, protein kinase C beta inhibitors). Laser photocoagulation of the fundi Various surgical procedures

Laser treatment

• Indications for treatment
  • Diabetic maculopathy which has developed into clinically significant macular oedema
    • Laser treatment is administered locally either directly into leaking microaneurysms or vascular areas or indirectly, i.e. by grid laser treatment.
    • The visual loss stops in 50% of patients.
    • Macular oedema should preferably be treated before panretinal photocoagulation.
  • Severe nonproliferative retinopathy (preproliferative retinopathy)
    • N.B.! Laser treatment is not indicated in mild to moderate nonproliferative retinopathy, but an individual monitoring programme must be planned, taking into account the degree of retinopathy and risk factors.
  • Proliferative retinopathy
• Panretinal photocoagulation is started without delay in severe proliferative retinopathy (and in the presence of rubeosis iridis or neovascular glaucoma). The treatment is divided into two or more sessions, using a sufficient size and number of burns, the total number of burns always being defined individually.
  • The aim of the treatment is to create scarring over the ischaemic and hypoxic retina, thus reducing the retinal oxygen demand and consumption and the production of vascular endothelial growth factor, and increasing oxygen uptake from the choroid.
  • Extensive panretinal laser photocoagulation has been shown to reduce severe visual loss to 2–5% five years after the treatment (without treatment up to 50% of patients become blind). A good treatment result is long-lasting. The disadvantages of the treatment are deterioration of night vision and a narrowing of the visual field, if frequent treatment is required.
• In patients with mild or moderate proliferative retinopathy who are regularly monitored, laser treatment should be regional or sectoral and continued as necessary.
• In severe nonproliferative retinopathy, scatter photocoagulation of the midperiphery and/or areas with vascular occlusion slows down both disease progression and visual loss as well as reducing the need for vitreal surgery. Effects on macular oedema vary individually, i.e. the treatment may either increase oedema or help to reduce it, which should be taken into consideration.

Surgical treatment

• Vitreoretinal surgery requires particular familiarity with the techniques.
• Surgery should be carried out without delay if the macula is at risk of tractional detachment or if detachment due to a tear in the retina (rhegmatogenous detachment) is observed.
• The timing of surgery for vitreous haemorrhage that fails to clear is determined by the vision in the fellow eye. In young patients, an observation period of several months should be avoided particularly if no laser treatment has been administered to the ocular fundus. If the fundus cannot be visualised, the status of the retina should be checked with ultrasound.
• If macular oedema is accompanied by problems affecting the vitreous body (vitreofoveal traction, absence of posterior vitreous detachment), vitrectomy may be of benefit.
• If the macula has been detached for a long period of time, the retina and/or the optic nerve have atrophied or the macula is damaged by severe capillary damage, visual acuity may remain poor even if the optic media clear and the retina can be reattached.

Low vision rehabilitation of patients with diabetes

• After a patient's rehabilitation needs have been assessed, low vision rehabilitation consists of vocational rehabilitative measures, adjustment training, introduction to low vision skills as well as advice on the use and purchase of appropriate aids.
• A rehabilitation plan should be drawn up at the treatment unit. Adjustment training courses for patients and relatives are arranged by specialized care units and patient organizations.
• Patients with diabetes should be encouraged to study in order to increase the scope of available employment alternatives.
• Social insurance institutions finance vocational rehabilitation for people whose working ability is at risk. A vocational rehabilitation and investigation plan should be drawn up. A statement by an ophthalmologist is needed for assessing working ability.
• Rehabilitation evaluation may be carried out at the patient’s workplace (visual performance necessary for the work tasks, aids required, appropriate lighting, ergonomic needs and whether it is possible to tailor the job description). The FFVI also organizes coaching to maintain working ability. People with visual disability are re-educated at the Arlainstituutti in Espoo, for example.The planning of the rehabilitation programme and its execution should follow locally designed guidelines and protocols. A range of services may also be provided locally for people with visual impairment and their families. Patients with diabetes should be encouraged to study in order to increase the scope of available employment alternatives. The social and pension insurance institutions organize/finance vocational rehabilitation for people whose working ability is at risk. A vocational rehabilitation and investigation plan can be drawn up by a rehabilitation institution. A statement by an ophthalmologist is needed for assessing working ability. Rehabilitation evaluation may be carried out at the patient’s workplace (visual performance necessary for the work tasks, aids required, appropriate lighting, ergonomic needs and whether it is possible to tailor the job description). If profound visual impairment occurs suddenly, the patient should be provided with crisis therapy at the ophthalmology unit as a part of the initial treatment. In patients with profound visual impairment, rehabilitation usually starts with adjustment training. The cost of any necessary aids is usually reimbursed to the patient. Some basic aids (such as white canes) may be available at the local health centre.

Related resources

• Cochrane reviews
• Literature