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 the most common 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.

Diabetic retinopathy

Pathophysiology²

The exact mechanism by which diabetes leads to DR is not fully understood. Growth hormones, haematological abnormalities (changes predisposing to a sluggish circulation), abnormalities in the aldose reductase pathway and vasoproliferative factors have all been put forward as possible contributors.³ The end point 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. These processes result in 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 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 (by residual healthy retina) 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 under 'Risk factors', below).

Classification

Classification is based on which part of the retina is affected and the degree of pathology seen on slit-lamp examination of the eye. It is not necessarily correlated to the degree of vision which may be almost normal until the very late stages of the disease when little can be done to save it. Broadly speaking, diabetic retinopathy falls into two types:

• Diabetic retinopathy
• Diabetic maculopathy

The two can occur independently of each other but overlap is common. There are then further subclassifications of each:^4,5

Epidemiology

• Blindness is one of the most feared complications of diabetes; it is the most common cause of blindness in working age people in England, Wales and Scotland.⁶
• One study has found that macular oedema is present in 9% of the diabetic population.⁷
• In type 1 diabetes, microaneurysms start to appear after 5 years in 25% of cases, 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 a similar pattern finally affecting 10-20% of cases.
• In type 2 diabetes, these changes may be found at diagnosis because subclinical hyperglycaemia may have been present for a prolonged preceding period.⁸ Over 25 years, there is a significant cumulative rate of progression to diabetic retinopathy (83%), to diabetic macular oedema (29%) and clinically significant macular oedema (17%).⁶

Risk factors

• Progression of retinopathy is associated with the severity and length of time that hyperglycaemia exists:³ 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.⁶
• Renal disease, as evidenced by proteinuria and elevated urea/creatinine levels, is an excellent predictor of the presence of retinopathy.³
• Pregnancy can be associated with a rapid progression of DR,⁹ particularly if:¹⁰
  • There is severe baseline retinopathy.
  • There is poor glycaemic control at conception, during pregnancy or in the postpartum period.
  • There is rapid improvement of diabetic control.
  • The diabetes has been present for a long time.
  • The patient is hypertensive (chronic or pregnancy-induced).
  See separate article Eye in Systemic Disease for more information on the eye in pregnancy.
• There is marked individual variation in susceptibility to retinopathy for a given vascular risk profile.
• It is thought that intraocular surgery may possibly increase the risk of progression of DR.⁴

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

Presentation

History

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 'Screening', 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 'Eye conditions less commonly associated with diabetes', below) is the one situation where the patient will present with acute pain; urgent referral is essential.

Examination

Examination seeks to establish the presence (or absence) of diabetic retinopathy and, if this is present, which type (retinopathy, maculopathy) and its severity. Without a slit-lamp magnification of the fundus or fundal photographs, it is difficult to make an accurate assessment¹¹ but here are a few pointers if you want to make a preliminary assessment:

• Always start with checking the patient's visual acuity. Acute reduction is not a good sign and suggests urgency in the referral (and caution about prognostic outcome when discussing this with the patient).
• The best view is obtained by dilating the pupil but remember that the patient won't be able to drive for 3-4 hours afterwards.
• Before 'homing in' on the fundus, check the red reflex: spots within this suggest a vitreous haemorrhage.
• Start at the disc and systematically work your way out along each main arterial branch (effectively: up and out, down and out, up and in, down and in). End with the macula ('look directly at the light' - make this bit quick, as it is not very comfortable).
• When looking at the vessels, note any little red dots (dot haemorrhages or small aneurysms), irregular notching (venous beading) and any new vessels (these tend to be thinner and more disorganised than pre-existing vessels).
• As you go along, note any well-demarcated creamy/yellow lesions often appearing like clusters of spots (hard exudates) and any paler lesions with less well defined edges (cotton wool spots).
• It is not really possible to assess for CSMO without a slit lamp but presence of any haemorrhages over the macula is an important finding.

This examination should be able to give you an idea as to the degree of diabetic retinopathy. It is worth noting that there is no set glycaemic threshold that will predict the presence or otherwise of diabetic retinopathy.¹²

Screening¹

Waiting for the diabetic to present with visual problems is not a good strategy. By this time, the condition may be advanced and irreversible.
Thus, in order to catch DR early, screening is mandatory:

• All patients with type 1 diabetes, over the age of 12 (some say 11),⁶ must have an annual retinal examination (or more frequently if clinically indicated).
• All patients with type 2 diabetes should have an annual retinal examination as soon as the diagnosis is made (the diabetes may have been present for a number of years before the diagnosis is made, so there is a greater risk of DR being present at the time of diagnosis).
• Pregnant diabetic women benefit from more frequent screening:⁵
  • Ideally, a preconception review helps to establish baseline retinopathy.¹³
  • Patients need to be reviewed at 12/40, 20-24/40 and 30-34/40. More frequent reviews are required if there is:
    • Severe retinopathy
    • Maculopathy
    • Poor diabetic control
  • Fluorescein angiograms should be avoided but retinal laser treatment is safe.

Digital retinal photography with mydriasis should be used as the gold-standard screening test to detect diabetic retinopathy,⁶ although photography without mydriasis can be sufficient if no more than one photograph is required.¹¹ Indirect slit-lamp ophthalmoscopy also meets sensitivity and specificity criteria¹¹ but lacks a hard record to allow comparisons for quality assurance.⁶ The photographs are examined and graded, producing different levels of screening depending on the observer's expertise. (Computerised digital analysis is proving to be a very effective and sensitive alternative to the labour-intensive examination of photographs by screeners but it is not yet the norm in the UK).⁶ Other measurements in the screening process 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 if there are the resources and the expertise.

In general, the UK is doing very well with its DR screening targets. It is a world leader in diabetic retinopathy screening, having offered 85.7% of eligible diabetic patients the screening programme.¹⁴ 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 'Internet and further reading' reference, below. The importance of educating individuals regarding the need for screening has been highlighted in the National Institute for Health and Clinical Excellence (NICE) diabetes guidelines document, so that attendance is not reduced by ignorance of need or fear of outcome.¹¹

Diagnosis⁶

The gold standard for diagnosis is dilated retinal photography with accompanying ophthalmoscopy if the retinal photographs are of inadequate quality (e.g. cataract clouding view). If DR is present, it is classified as above. Further investigation such as optical coherence tomography (a sort of visual biopsy obtained in a similar fashion to an ultrasound scan but using light waves) or fluorescein angiography may be required to refine the diagnosis further and to guide management.

Investigations

Fundus photography and examination are sufficient for most patients. However, optical coherence tomography is playing an increasingly important role in assessing the presence of macular oedema (and then recording its progression over several visits) and fluorescein angiography may be helpful where CSMO is present (to guide laser treatment) and where the vision is unexpectedly poor (to assess for macular ischaemia).⁵

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 and managed through improved diabetic control and ophthalmological intervention. The management options outlined below come hand-in-hand with patient education about their disease and lifestyle issues surrounding its management.⁴

Primary prevention¹⁵

• Optimal glycaemic control (usually aiming to bring HbA1c levels to <7%, ideally around 6.5%) is associated with improved long-term outcomes and delayed progression of retinopathy.¹⁶
  • The Diabetes Control and Complication Trial (DCCT)¹⁷ showed that tight glycaemic control (HbA1c 7.2 vs 9%) was associated with a 76% reduction in retinopathy, a 60% reduction in neuropathy and a 54% reduction in nephropathy in type I diabetics.⁴
  • The UK prospective Diabetes Study (UKPDS) found that tight glycaemic control (HbA1c 7% vs 7.9%) in patients with type 2 diabetes was associated with a 17% reduction in the risk of progression of DR, a 29% reduction in the need for laser treatment and a 16% reduction in the risk of developing legal blindness over a 10-year period. However, in some cases, particularly with pre-proliferative and proliferative retinopathy, intensive glycaemic control (e.g. HbA1c at 6.0%) can initially bring on a decompensation and worsening of symptoms and signs and is also associated with increased mortality.^6,18
• Good control of blood pressure (target: 140/80 mm Hg or lower)^6,19 reduces the progression of diabetic retinopathy significantly (the UKPDS demonstrated a 47% reduction in risk of moderate visual loss and 35% reduction in the need for laser treatment after nine years). Further, it is associated with a 32% reduction in diabetes-related deaths.⁴
• The Early Treatment of Diabetic Retinopathy Study (ETDRS) suggests that lipid-lowering agents may decrease the risk of vision loss in patients with diabetic retinopathy.²⁰ The suggested target cholesterol level is <4.0 mmol/L and a low-density lipoprotein <2.0 mmol/L.
• A good, balanced diet and exercise should be discussed with the patient.³ Some authors have suggested that a pedometer and scales may be more valuable than laser treatment, medication or surgery in the long term.[60543]
• Address the issue of smoking.

There have been more recent trials looking at what can be done for those individuals in whom glycaemic and blood pressure control is good but DR is progressive:¹⁸

• The Diabetic Retinopathy Candesartan Trials (DIRECT) looked at the effect of candesartan, an angiotensin II receptor blocker, on these patients and found somewhat equivocal results. In patients with type 1 diabetes, there was a modestly reduced incidence of retinopathy by 18% but there was no effect on the progression of existing retinopathy. In patients with type 2 diabetes, there was a significantly increased regression of existing retinopathy by 34% and progression was reduced by 13% (this last finding was not statistically significant).
• The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was more promising, showing that fenofibrate, a lipid-lowering fibrate, reduced the need for laser treatment of sight-threatening diabetic retinopathy (either for macular oedema or proliferative retinopathy) by 31% over five years.

So, this remains a developing area with potential for an improved outlook for these patients in the future.

Ophthalmic intervention⁶

Most patients with DR do not need treatment. If they do, there are several treatment modalities available:

Laser photocoagulation:
• This has been the mainstay of treatment for the past 25 years: the aim is to induce regression of new blood vessels and reduce central macular thickening. 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.³
• Laser treatment can arrest the progression of DR but is unlikely to restore any lost vision.
• Treatment can be targeted on to specific areas (focal treatment) or delivered over the entire periphery of the retina (panretinal photocoagulation (PRP)) where 1,200-1,600 burns may be placed on the retina over 2-3 sessions. The choice depends on the nature of the DR: macular oedema is treated with focal laser burns whereas retinopathy is more amenable to PRP. If there is both retinopathy and maculopathy, macular oedema is often treated first and separately before treatment with PRP.
• 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!
• The decision as to whether to carry out laser treatment is not always clear-cut (e.g. asymptomatic patients with CSMO but no visual loss).²¹
Intravitreal steroids:²²
• A large trial has demonstrated that intravitreal steroids were initially more effective than treatment with laser photocoagulation but that two years post-treatment, eyes treated with laser actually had better visual acuity and less maculopathy.
• The mechanism of action of corticosteroids is not fully understood.
• This treatment modality is associated with complications (see 'Complications', below).
Intravitreal triamcinolone:²¹
• This appears to reduce CSMO and improve visual acuity in more advanced cases.
• It may be used as primary or adjunctive therapy.
• The effect is maximal after a week but may last up to six months.
Anti-vascular endothelial growth factor treatments:²¹
• In recent trials, anti-vascular endothelial growth factor drugs have performed extremely well in the treatment of macular oedema and restoring lost vision (unlike laser treatment).
• Pegaptanib (Macugen®), Bevacizumab (Avastin®)⁷ and ranibizumab (Lucentis®) have all been investigated with promising results.
• Currently, both price and the frequency of attendance required (both for the injections and the follow-up) limit the use of these treatments in clinical practice.
Surgery:
• A vitrectomy (removal of the vitreous) may be required following an intravitreal bleed in proliferative diabetic retinopathy.
• Not only does it physically remove the blood to allow vision through a clear media, but any retinal detachment can also be repaired. Intra-operative PRP reduces the stimulus for neovascularisation.

The type and urgency of the treatment is dictated by the nature and the severity of the DR and is assessed by the examining ophthalmologist.

Complications

The main complication of diabetic retinopathy is visual loss secondary to:⁵

• Macular oedema.
• Macular ischaemia.
• Vitreous haemorrhage.
• Tractional retinal detachment.

However, treatment modalities are also associated with risks.

• Complications of focal/grid photocoagulation:²⁴
  • Impaired central vision.
  • Paracentral scotoma.
  • Choroidal neovascularisation.
  • Epiretinal membrane formation.
  • Worsening of macular oedema in a minority.

• Complications of panretinal photocoagulation:²⁴
  • 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 the cornea or lens.
• Complications of intravitreal steroids⁶ and triamcinolone:²¹
  • Cataract formation.
  • Raised intraocular pressure.

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.²⁴ Those who have panretinal photocoagulation have their risk of severe visual loss reduced by 50%, compared with untreated individuals with a similar severity of disease.²¹

Other eye conditions associated with diabetes

Cataracts

A classic diabetic cataract is rare. Hyperglycaemia is reflected in high levels of glucose in the aqueous, which diffuse 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.⁴

Eye conditions less commonly associated with diabetes

• 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 separate article Primary 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.
• Other eye conditions more commonly found in diabetics include dry eye, corneal abrasions, anterior uveitis, ocular ischaemic syndrome, papillitis and orbital infections.⁴
• Corneal abnormalities may also be found in these patient groups.³
• 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.

Eye conditions rarely associated with diabetes

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 separate articles Examination of the Eye and Pupillary Abnormalities) and rhino-orbital mucormycosis.

Document references

1. Diabetic Retinopathy Screening Statement, National Service Framework; Dept of Health (April 2008)
2. Kanski J. Clinical Ophthalmology: A Systematic Approach (5th Ed) Butterworth Heinemann (2003)
3. Bhavsar AR et al; Retinopathy, Diabetic, Proliferative, eMedicine, Oct 2009
4. Denniston AKO, Murray PI. Oxford Handbook of Ophthalmology (OUP), 2008
5. Jackson TL. Moorfields Manual of Ophthalmology, Mosby (2008)
6. Ockrim Z, Yorston D; Managing diabetic retinopathy. BMJ. 2010 Oct 25;341:c5400. doi: 10.1136/bmj.c5400.
7. Arevalo JF, Garcia-Amaris RA; Intravitreal bevacizumab for diabetic retinopathy. Curr Diabetes Rev. 2009 Feb;5(1):39-46. [abstract]
8. Younis N, Broadbent DM, Vora JP, et al; Incidence of sight-threatening retinopathy in patients with type 2 diabetes in the Liverpool Diabetic Eye Study: a cohort study.; Lancet. 2003 Jan 18;361(9353):195-200. [abstract]
9. Vestgaard M, Ringholm L, Laugesen CS, et al; Pregnancy-induced sight-threatening diabetic retinopathy in women with Type 1 Diabet Med. 2010 Apr;27(4):431-5. [abstract]
10. Diabetic Retinal Screening Website
11. Diagnosis and management of type 1 diabetes in children, young people and adults, NICE Clinical Guideline (July 2004)
12. Wong TY, Liew G, Tapp RJ, et al; Relation between fasting glucose and retinopathy for diagnosis of diabetes: three Lancet. 2008 Mar 1;371(9614):736-43. [abstract]
13. Care recommendations - The provision of services in primary care, Diabetes UK
14. Diabetes, National Service Framework; Dept of Health
15. Turner RC, Holman RR; Lessons from UK prospective diabetes study. Diabetes Res Clin Pract. 1995 Aug;28 Suppl:S151-7. [abstract]
16. Mohamed Q, Gillies MC, Wong TY; Management of diabetic retinopathy: a systematic review. JAMA. 2007 Aug 22;298(8):902-16. [abstract]
17. No authors listed; The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993 Sep 30;329(14):977-86. [abstract]
18. Liew G, Mitchell P, Wong TY; Systemic management of diabetic retinopathy. BMJ. 2009 Feb 12;338:b441. doi: 10.1136/bmj.b441.
19. No authors listed; Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ. 1998 Sep 12;317(7160):703-13. [abstract]
20. Chew EY, Klein ML, Ferris FL 3rd, et al; Association of elevated serum lipid levels with retinal hard exudate in diabetic Arch Ophthalmol. 1996 Sep;114(9):1079-84. [abstract]
21. Mavrikakis E et al, Macular Edema, Diabetic, eMedicine, Oct 2010
22. Grover D, Li TJ, Chong CCW; Intravitreal steroids for macular edema in diabetes. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD005656. DOI: 10.1002/14651858.CD005656.pub2
23. Clinical Knowledge Systems; Diabetes type 2 - Management. Scenario: Managing eye problems (July 2010)
24. Bhavsar AR et al; Retinopathy, Diabetic, Background, eMedicine, Oct 2009

Internet and further reading

• University of Birmingham (hosted); Detailed information on how to avoid and deal with diabetic retinopathy
• Gillett M, Dallosso HM, Dixon S, et al; Delivering the diabetes education and self management for ongoing and newly BMJ. 2010 Aug 20;341:c4093. doi: 10.1136/bmj.c4093. [abstract]
• Royal College of Ophthalmologists, Diabetic Retinopathy Screening Preferred Practice Guidance (September 2010); Scroll down to guideline

Acknowledgements