EASDEC European Association for the Study of Diabetic Eye Complications

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Screening and Monitoring Diabetic Retinopathy

John G. O'Shea MD FRCSE (Ophth), David A. Infeld MB BS FRCSE (Ophth)
Birmingham and Midland Eye Centre,Dudley Rd, Birmingham B18 7QU, U.K.
Telephone +44-121-5543801, Fax44-121-507 6791

Screening and Monitoring Diabetic Retinopathy

World-wide it is estimated that over 2.5 million people are blind due to diabetes (DM), the fourth leading cause of world blindness and an ever increasing problem in developing nations.(1,2) The most frequent ocular complication of diabetes mellitus is diabetic retinopathy (DR). ( 1,2,3,4,5,6 )

Table- Diabetic Retinopathy and Other Leading Causes of World Blindness

( The World Health Organisation (1992) definition of blindness is vision less than 3/60 in the better eye with best available spectacle correction. )

Diabetes mellitus is the most common cause of blindness amongst individuals of working-age ( 20-65 years). The prevalence of blindness due to DR in Western Communities is estimated as between 1.6-1.9/ 100,000.

( The above is currently accepted international terminology- Source: Diabetes Care 1997; 20: 1183-7) 

Loss of vision commonly occurs from either complications of diabetic macular oedema or ischaemia, vitreous haemorrhage, or tractional retinal detachment.

( 1,2,3,4) Macular oedema is now the leading cause of loss of vision amongst Western diabetic patients. It develops earlier and is more severe in Type 2 diabetes, i.e. non-insulin dependent diabetes mellitus. (7,8,9) The treatment of macular oedema has therefore been the subject of leading international studies. In these studies sight threatening diabetic macular oedema is referred to as Clinically Significant Macular (O)edema. (CSME) (7,8,9)

About 2% of type 2 diabetics have CSME at diagnosis and 10.2% have other signs of DR already present when their diabetes is discovered. (5) Mitchell and co- workers found that 15.8 % of undiagnosed diabetics in an elderly Australian population had signs of DR, according to the recent Blue Mountains Eye Study. Indeed it may often take from 9-12 years for type 2 diabetes to be diagnosed. (5)

Cumulative risk of developing diabetic retinopathy.

The risk of loosing vision due to DR increases with the duration of diabetes and with ageing (5). The cumulative risk is therefore higher in Type 1 than in Type 2 DM. Maculopathy in type 1 diabetics is often due to drop out of the perifoveal capillaries with non perfusion and the consequent development of an ischaemic maculopathy.

Enlargement of the foveal avascular zone is frequently seen on fluorescein angiography. Ischaemic maculopathy is also not uncommon in type 2 diabetics, particularly if they are hypertensive or have intercurrent renal disease ( 1,4 )

Pathophysiological changes in diabetic retinopathy.

In diabetic retinopathy there are well documented pathophysiological changes to the retina which include retinal capillary closure, thrombosis, non-perfusion but also capillary leakage. DR primarily a disease of the retinal microvasculature. An important pathological event is the loss of capillary pericytes, modified smooth muscle cells, which support the vascular endothelium of the retina. (1,2,3,4 )

It has also been postulated that platelet abnormalities in diabetics may contribute to diabetic retinopathy. There are three steps in platelet coagulation: initial adhesion, secretion, and further aggregation. It has been shown that the platelets in diabetic patients are "stickier" than platelets of non-diabetics They secrete prostaglandins that cause other platelets to adhere to them (aggregation) and blockage of the vessel and endothelial damage.

In type 1 diabetes the vascular changes occur mainly in the mid-peripheral retina.

There is retinal ischaemia causing release of vasoformative substances and new vessel formation, neovascularization. (1) In Type 2 diabetes the vascular changes occur more commonly at the posterior pole. The main pathological changes are due to macular oedema. (1) . Let us now briefly review the clinical picture of diabetic retinopathy and the current clinical classification of the disease. We will then discuss the strategies available to detect and to treat the disease.

Microaneurysms

Retinal microaneurysms are focal dilatations of retinal capillaries, 10 to 100 microns in diameter, and appear as red dots. They are usually seen at the posterior pole, especially temporal to the fovea. They may apparently disappear whilst new lesions appear at the edge of areas of widening capillary non-perfusion. Microaneurysms are the first ophthalmoscopically detectable change in diabetic retinopathy.

Beginning as dilatations in areas in the capillary wall where pericytes are absent, microaneurysms are initially thin-walled. Later, endothelial cells proliferate and lay down layers of basement membrane material around themselves.

Fibrin and erythrocytes may accumulate within the aneurysm. Despite multiple layers of basement membrane, they are permeable to water and large molecules, allowing the accumulation of water and lipid in the retina. Since fluorescein passes easily through them, many more microaneurysms are usually seen on fluorescein angiography than are apparent on ophthalmoscopy (1,2,3,4,)

Retinal Haemorrhages

When the wall of a capillary or microaneurysm is sufficiently weakened, it may rupture, giving rise to an intraretinal haemorrhage. If the hemorrhage is deep (i.e., in the inner nuclear layer or outer plexiform layer), it usually is round or oval ("dot or blot")

Dot haemorrhages appear as bright red dots and are the same size as large microaneurysms. Blot haemorrhages are larger lesions they are located within the mid retina and often within or surrounding areas of ischaemia. (1,2,3,4,)

If the hemorrhage is more superficial and in the nerve fiber layer, it takes a flame or splinter shape, which is indistinguishable from a hemorrhage seen in hypertensive retinopathy. They often absorb slowly after several weeks. Their presence strongly suggests the co-existence of systemic hypertension.

Diabetics with normal blood pressure may have multiple splinter haemorrhages. Nevertheless, when an ophthalmologist sees numerous splinter haemorrhages in a diabetic patient, the patient's blood pressure must be checked because a frequent complication of diabetes is systemic hypertension. (1,2,3,4,)

Cotton Wool Spots

Cotton wool spots result from occlusion of retinal pre-capillary arterioles supplying the nerve fibre layer with concomitant swelling of local nerve fibre axons. Also called "soft exudates" or "nerve fibre layer infarctions" they are white, fluffy lesions in the nerve fibre layer. Fluorescein angiography shows no capillary perfusion in the area of the soft exudate. They are very common in DR, especially if the patient is also hypertensive. (1,2,3,4,5 )

Hard exudates ( Intra-retinal lipid exudates )

Hard exudates ( Intra-retinal lipid exudates ) are yellow deposits of lipid and protein within the sensory retina. Accumulations of lipids leak from surrounding capillaries and microaneuryisms, they may form a circinate pattern. Hyperlipidaemia may correlate with the development of hard exudates. (1,2,3,4 )

Clinically Significant Macular Oedema ( CSME )

Clinically Significant Macular Oedema is due to leakage from capillaries and microaneurysms. (7,8,9 ) It is very difficult to detect using a direct ophthalmoscope- it is seen as retinal thickening on slit-lamp examination with a plano- concave diagnostic contact lens or +90 dioptre lens. CSME is defined as follows ( Table).

Laser grid photocoagulation reduces the risk of visual loss by 50% at 2 years (7,8,9 )

 Macular oedema is thus an important manifestation of DR because it is now the leading cause of legal blindness in diabetics. The intercellular fluid comes from leaking microaneurysms or from diffuse capillary leakage .It should be stressed however that current regimes now lay emphasis on the treatment of retinal thickening by grid laser than direct treatment of microaneuyrisns and other discreet lesions. (7,8,9).

Ischaemic Maculopathy

Maculopathy in type 1 diabetics is often due to drop out of the perifoveal capillaries with non perfusion and the consequent development of an ischaemic maculopathy.

Enlargement of the foveal avascular zone (FAZ) is frequently seen on fluorescein angiography. Ischaemic maculopathy is not uncommon in type 2 diabetics, maculopathy in this group may show both changes due to ischaemia but also retinal thickening. ( 1,4 )

Late non proliferative changes

Intra-retinal microvascular abnormalities ( IRMA) are abnormal, dilated retinal capillaries or may represent intraretinal neovacularization which has not breached the internal limiting membrane of the retina. (1,2,3,4). They indicate severe non-proliferative diabetic retinopathy that may rapidly progress to proliferative retinopathy. Venous beading has an appearance resembling sausage-shaped dilatation of the retinal veins. (1,2,3,4) It is another sign of severe non proliferative diabetic retinopathy.

Proliferative diabetic retinopathy

Retinal ischaemia due to widespread capillary non perfusion results in the production of vasoproliferative substances and to the development of neovascularization. Neovascularization can involve the retina, optic disc or the iris ( rubeosis iridis). (1,2,3,4, ) Rubeosis iridis is a sign of severe proliferative disease, it may cause intractable glaucoma. (1,2,3,4,).

Bleeding from fragile new vessels involving the retina or optic disc can result in vitreous or retinal haemorrhage. Retinal damage can result from persistent vitreous haemorrhage. (1,2,3,4 ) . Pre-retinal haemorrhages are often associated with retinal neovascularization, they may dramatically reduce vision within a few minutes.

Late Disease

Contraction of associated fibrous tissue formed by proliferative disease tissue can result in deformation of the retina and tractional retinal detachment. (1,2,7 )

Table A clinical classification of diabetic retinopathy ( Source 1,2,3,4)

Clinically significant macular oedema (CSME )

Monitoring Diabetic Retinopathy

Potentially blinding lesions, such as proliferative retinopathy or maculopathy, may develop before the patient notices any visual impairment. (1,4,6,7,8,9) Early treatment with retinal laser photocoagulation can slow the progression of diabetic retinopathy, regular screening and monitoring of diabetic patients is therefore imperative. ( 10,11,12,13,14,15 )

Screening for diabetic eye problems should ideally include the following,

1. The history of any visual symptoms or changes in vision

2. Measurement of visual acuity (unaided, with spectacles / pinhole as necessary)

3. Iris examination by slit lamp biomicroscopy prior to pupil mydriasis.

4. Pupil mydriasis. ( tropicamide 0.5 % ) -the risk of precipitating angle closure glaucoma is actually very small. Patients should be accompanied by a relative and instructed not to drive home.

5. Examination of the crystalline lens by slit lamp biomicroscopy.

6. Fundus examination by slit lamp biomicroscopy using diagnostic contact lens or slit lamp indirect ophthalmoscopy.

Slit Lamp Biomicroscopy

The direct ophthalmoscope enables adequate examination of only the posterior pole whilst the indirect ophthalmoscope provides insufficient magnification. Slit lamp examination ( using either indirect ophthalmoscopy with a convex aspheric lens or diagnostic contact lens) yields much more information by providing stereoscopic assessment of retinal thickening and proliferative retinopathy, particularly important when assessing possible retinal traction. It is therefore imperative to facilitate cost-effective screening more that more practitioners are trained in slit lamp biomicroscopy of the fundus with emphasis on detection and monitoring of diabetic eye disease. (10,11,12,13,14,15,16)

A protocol for diabetic screening

Type 2 diabetic patients without retinopathy should be assessed at the time of diagnosis and bi-annually thereafter. (1,2,4,) Patients with diabetes and mild non-proliferative retinopathy should be assessed every 12 months by a suitably experienced practitioner.

Screening doctors should always look, in particular, for the onset of clinically significant macular oedema ( CSME ).(1,4,6,7,8,9)

Type 1 (Juvenile Onset) diabetics rarely develop retinopathy until after eight years of diabetic life. The current recommendation is that screening is unnecessary for at least the first five years of the disease and that patients without retinopathy should be screened annually after the onset of puberty until the onset of non-proliferative diabetic retinopathy (NPDR). (1,4)

Pregnancy

Diabetic retinopathy may worsen during pregnancy. Screening should therefore be undertaken at confirmation of pregnancy and every two months during pregnancy if no retinopathy is present, or monthly, if retinopathy is present. (1,17 )

Retinal status should not preclude pregnancy since contemporary methods of management can result in satisfactory ocular and pregnancy outcomes even in the presence of advanced diabetic microvascular disease providing sufficient care is taken. ( 1,17 )

____________________________________________________________________

Table 4- Suggested referral protocol for sight threatening diabetic retinopathy( Source 1,2,3,4,5 - based on American Academy of Ophthalmology protocols)

Patients should be referred to an ophthalmologist with expertise in diabetic retinopathy immediately if the following lesions are seen during screening examination

Proliferative diabetic retinopathy, new vessels (neovascularization) involving the optic disc or the retina

preretinal haemorrhage

vitreous haemorrhage

recent retinal detachment

rubeosis iridis

1 Severe non-proliferative diabetic retinopathy (pre-proliferative retinopathy)

multiple cotton wool spots

blot haemorrhages in multiple quadrants

retinal vein beading or retinal venous loops ( IRMA ) ( 1,2,3,4)

2 Non-proliferative retinopathy with macular involvement

clinically significant macular oedema ( CSME ) ( 7,8,9)

other e.g. ischaemic maculopathy

In general, any patient who has more than mild to moderate retinopathy should be under the care of a physician with expertise in diabetic eye disease.

_____________________________________________________________________

In summary, diabetics without retinopathy who are otherwise well should be examined bi-annually. Patients with diabetes and mild non-proliferative retinopathy should be assessed every 12 months by a suitably trained and experienced practitioner. The frequency of monitoring DR should be increased in special circumstances such as pregnancy, renal failure or other intercurrent illness. (1,2,3,4)

Cost effective community screening for DR

The current consensus of opinion from Europe and the United States is that screening for DR by suitably trained and experienced practitioners is cost effective and results in reduced morbidity due to blindness. (6,19,20,21,22,23,24, 25 ) An inter -disciplinary approach is commonly used, optometrists for example are becoming increasingly involved in the care of diabetics. (10,11,12, 20,21)

The characteristics of a good screening programme being that the target patients in the community are found and seen at the prescribed intervals, and that the practitioners who conduct the screening have adequate training, that is they must be familiar with both the manifestations of diabetic eye disease and, if possible, with slit lamp biomicroscopy or with methods of photoscreening. ( 19,20,21,22,23,24 ) Patient education and growing community awareness concerning diabetes is likely to bring newly diagnosed and undiagnosed diabetics into the screening system. (5,19,20,21,22,23,24, 25)

Photoscreening

An alternative to slit lamp biomicroscopy is the photoscreening of diabetic patients with a fundus camera. Photoscreening is very popular in some parts of the United Kingdom and the USA - the physician or ophthalmologist subsequently examining the photographs for evidence of DR - this approach also obviates the need to be proficient with a slit lamp and also provides a permanent record of the contemporary status of DR. (6,20) The camera can also be bought to remote rural areas and the pictures later examined.

Photoscreening will not always detect subtle signs of DR , such as retinal thickening, and a success rate of 80-92% in detecting DR is claimed by researchers. There are numerous photographic techniques used ranging from a single photograph to a 9 photograph collage. Three photographs spread across the posterior pole are now widely regarded as being most cost efficient.

Photography also plays an important part in epidemiological research, for example the Blue Mountains Eye Study used Carl Ziess 30 degree stereo photographs in combination with non-stereo photographs of the peripheral retina to evaluate and grade DR objectively. (5) Fundus photography is therefore an important tool in detection of DR and research and improvements in technology with undoubtedly increase its effectiveness as a screening tool. (5,6)

 Further aspects of the ocular care of diabetics

 Factors that can worsen diabetic retinopathy- and indeed the general prognosis of diabetes, include poor diabetic control, systemic hypertension, hyperlipidaemia, cigarette smoking, diabetic nephropathy, anaemia, pregnancy and cataract surgery.

Hyperlipidaemia is directly correlated with the development of exudative maculopathy.

It is now proven that good diabetic control may slow the development and progression of diabetic retinopathy. ( 1,2,6,25,26,27,28,29,30,31,32,33,34,35,36 ) In these trials glycated haemoglobin is kept below 7%’

Paradoxically diabetics may initially actually experience worsening of retinopathy as hyperglycaemic control is improved, cleanly ophthalmic review is warranted if major changes to therapy are made. (33)

Systemic hypertension

Systemic hypertension is a common associated finding. It is often secondary to diabetic nephropathy. It is important that hypertension, if present, be controlled as this can slow the progression of diabetic retinopathy. (1,4 ,6)

Diabetic nephropathy

Diabetic retinopathy is a common prelude to the development of renal disease.

Diabetic nephropathy accelerates the progression of retinopathy, especially macular oedema, inter alia via increased levels of fibrinogen and lipoprotein and associated hypertension. (1) The visual prognosis is better if the nephropathy is treated by renal transplantation rather than by dialysis.(1) Any anaemia resulting from renal disease must be most aggressively treated.

Pregnancy

Pregnancy may accelerate the progression of diabetic retinopathy. (17)

Cataract surgery

Cataract surgery may lead to progression of pre-existing macular oedema and proliferative diabetic retinopathy. However, cataracts may impede fundoscopy and therefore interfere with the treatment of diabetic retinopathy. If possible, diabetic retinopathy should be treated prior to cataract surgery. (1,2 )

Tightening of Glycaemic control

Tightening of glycaemic control may initially produce worsening of retinopathy. The postulated mechanism includes lowering of retinal blood low or overproduction of IGF-1 by the liver. It is therefore recommended that monitoring of retinopathy is increased if major changes to glycaemic control are made particularly in previously poorly controlled diabetics. Ideally glycated haemoglobin ( HbA1c) should be maintained below 7%. (36,37,38)

The EUCLID study is currently looking into the prophylactic treatment of macular oedema with the Angiotensin Converting Enzyme (ACE) Inhibitor Lisinopril in type 1 diabetics who are not hypertensive. Preliminary reports are encouraging. At any rate, tight control of hypertension is of paramount importance. (35)

The current treatment of diabetic retinopathy

Physicians should be aware of the role of laser photocoagulation in the care of diabetics. It is important to note that the patient may in fact have normal visual acuity yet meet the criteria for urgent laser therapy (1,4)

Proliferative retinopathy has a very poor prognosis if untreated. If untreated, 50% of patients with retinal neovascularization are blind within 5 years; 50% of patients with optic disc neovascularization are blind within 2 years. (1,2,3,4)

Panretinal laser photocoagulation for proliferative DR

The mainstay of treatment of diabetic retinopathy is retinal laser photocoagulation, an ablative treatment. Laser therapy is highly effective; the rate of severe visual loss at 2 years due to proliferative disease can be reduced by 60%. (1,4,7,8,9)

Laser photocoagulation causes a retinal burn which is visible on fundoscopy. Retinal and optic disc neovascularization can regress with the use of retinal laser photocoagulation. (1,2,4 )

Rubeosis iridis requires urgent panretinal photocoagulation to prevent ocular pain and blindness from glaucoma. (3,4)

Macular laser grid therapy for CSME

The indications for laser therapy now include CSME which is treated with a macular laser grid. Early referral and detection of disease is important as treatment of maculopathy is far more successful if undertaken at an early stage of the disease process. There is a reduction in the rate of loss of vision by 50% at 2 years with macular grid therapy. (1,2,7,8,9)

Pregnant patients should undergo laser therapy if the usual indications are met. (17)

Technique of laser photocoagulation

The technique of laser photocoagulation delivery involves the application of eyedrops

( for pupil dilatation and corneal anaesthesia ) and the application of an optical contact lens. (2) Photocoagulation is generally not a painful procedure unless a large burn size is made. Mild proliferative retinopathy is usually treated with at least 600 burns placed between the retinal equator and the retinal vascular arcades. A complete panretinal photocoagulation treatment requires at least 1200 burns. (1,2,3,4,39)

Complications of laser photocoagulation

Although laser therapy can be highly effective in preventing blindness, it is associated with numerous complications. (1,3,4)

Retinal vein occlusion can follow inadvertent photocoagulation of a retinal vein. Rarely, there may be loss of central acuity from inadvertent photocoagulation of the fovea. Vitreous haemorrhage can follow photocoagulation of retinal or choroidal vessels. (1,3,4)There may be visual field restriction, decreased contrast sensitivity, impaired night vision or impaired colour vision. Visual field constriction may impair fitness to drive although ophthalmologists increasingly strive to avoid this most undesirable problem. (1,3,4,39)

Headache can sometimes follow laser therapy. The headache is usually

relieved with rest and simple analgesia. Glaucoma must be excluded if the headache is severe or persistent. (1,3,4,39)

Summary

The early detection of diabetic retinopathy (DR) leads to a marked reduction of morbidity due to visual loss. Major international studies all indicate therapy is best instituted before serious complications develop, screening of our diabetic population and of our elderly population to detect undiagnosed DR should therefore be undertaken. Key lesions of diabetic retinopathy have been described and screening protocols suggested. Laser photocoagulation, the principal form of therapy, is also described as are means of modifying lifestyle to decrease the morbidity of diabetic retinopathy.

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