Clinical Appearance

The clinical evaluation and classification of diabetic retinopathy is based on inspection of the retina through the optics of the eye. The morphological changes thus observed in the retina are complex and heterogeneous which is reflected in the nomenclature used to describe diabetic retinopathy (table 1). Basically, diabetic retinopathy can be divided into early changes that are not accompanied by reduction in vision and late changes accompanied by visual reduction.

Early Changes Not Accompanied by Visual Reduction The most usual name for this retinopathy stage is nonproliferative diabetic

retinopathy, but older terms are also used, such as simple retinopathy, or background retinopathy which alludes to the fact that the changes remain inside the ocular background.

Nonproliferative diabetic retinopathy is caused by changes in the retinal mi- crocirculation leading to compromised barrier function of the retinal capillaries. The changes first appear temporally from the fovea consisting of capillary microaneurysms and small intraretinal haemorrhages (fig. 1). The increased capillary permeability leads to the development of whitish hard exudates consisting of lipo- protein from the bloodstream (fig. 2). Additionally, cotton-wool spots may develop. These are localized unsharply delimited whitish areas in the superficial parts of the retina representing intracellular material that has accumulated in the nerve fibres because of disturbances in their axoplasmic flow (fig. 3). The retinal changes characterizing nonproliferative diabetic retinopathy are reversible, and often noticeable dynamic changes are seen at repeated examinations, so that the same number of lesions are present, however located in different places.

Late Changes Accompanied by Visual Reduction Nonproliferative diabetic retinopathy can develop into one or both of

two different types of retinopathy accompanied by visual reduction, namely proliferative diabetic retinopathy and diabetic maculopathy.

Fig. 1. Minimal nonproliferative diabetic retinopathy in a right eye. A few red dots representing haemorrhages and/or microaneurysms are seen temporally in the macular area which is the dark area surrounding the dark spot in the centre of the image (arrows).

Fig. 2. Slight nonproliferative diabetic retinopathy in a left eye. Several whitish hard exudates have developed inside the macular area.

Proliferative Diabetic Retinopathy Proliferative diabetic retinopathy develops secondary to occlusion of the

retinal capillaries in the retinal periphery with a consequent stimulation of vascular new growth. Clinically, both a preproliferative and a true proliferative stage can be differentiated.

Fig. 3. Moderate nonproliferative diabetic retinopathy in a right eye. Larger haemorrhages and whitish lesions with fluffy borders representing cotton-wool spots have developed.

Fig. 4. Preproliferative diabetic retinopathy in a right eye. Many large haemorrhages are seen temporally in the macular area and there is calibre variation of the lower temporal branch vein (arrow). Hard exudates within one disk diameter of the fovea indicate the presence of clinically significant macular oedema.

Preproliferative diabetic retinopathy is characterized by many cotton-wool spots, larger blot haemorrhages temporally in the macular area, and a variety of vascular abnormalities. These abnormalities are intraretinal microvascular abnormalities (IRMA vessels) often representing arteriovenous shunt vessels, and beading and loop formation on the larger venules (fig. 4). These abnormalities

Fig. 5. Proliferative diabetic retinopathy in a left eye. A large neovascularization has developed from the optic disk and has given rise to a preretinal haemorrhage that extends arcuately along the lower temporal branch vein.

develop secondary to changes in the retinal haemodynamics that result from occlusion of the capillary bed in the retinal midperiphery and periphery. At this stage the retinopathy will often become proliferative within a few months.

Proliferative diabetic retinopathy is characterized by outgrowth of new vessels from the larger venules in the retina and on the optic nerve head (fig. 5). This neovascular process is assumed to be caused by growth stimulation from cytokines released from the ischaemic areas in the retinal periphery where the capillary bed is occluded. However, the newly formed blood vessels do not grow out to replace the occluded retinal vessels. Rather, they grow aberrantly into the vitreous body. Preretinal neovascularizations can lead to visual reduction because of spontaneous haemorrhages into the vitreous body. The cause of this vascular rupture is unknown, but may be caused by attachments of the new vessels to the posterior hyaloid membrane that break secondary to movements of the vitreous body. Finally, neovascularizations may contain connective tissue that shrinks and causes tractional retinal detachment (fig. 6).

In some cases the vasostimulatory cytokines released in the retinal periphery diffuse to the anterior eye chamber to cause neovascularization in the iris

(rubeosis iridis) (fig. 7) and in the anterior chamber angle. The resulting blocking of the aqueous drainage from the eye will lead to neovascular glau- coma. The high intraocular pressure may endanger the intraocular blood flow and consequently the visual function, and if the rise in intraocular pressure is rapid, severe acute pain may develop.

Fig. 6. Severe proliferative diabetic retinopathy in a left eye. The new vessels contain whitish fibrous tissue that covers most of the view of the fundus. Shrinkage of this fibrous tissue may lead to tractional retinal detachment.

Fig. 7. Iris rubeosis. New vessels in the iris (arrows) have made the pupil immobile. The small pupil together with the white cataractous lens seen behind the pupil opening makes inspection as well as treatment of the fundus background impossible.

Diabetic Maculopathy Diabetic maculopathy is nonproliferative diabetic retinopathy complicated

by retinal oedema. When the oedema area becomes large enough or is too close to the fovea, it becomes vision-threatening (fig. 4) and is termed clinically significant macular oedema (table 2). The oedema may be exudative or ischae-

Table 2. Clinically significant macular oedema is defined as presence of one or both of the criteria shown

1. Oedema and/or exudates within one-half disk diameter from the fovea 2. Oedema and/or exudates with a size of one disk diameter or more, part of which is located

within a zone of one disk diameter from the fovea

mic. The exudative form is most frequent, and it may be both focal or diffuse. Exudative diabetic maculopathy is accompanied by hyperpermeability of the

macular vessels. When the oedema, the exudates, and the haemorrhages extend towards the fovea, central vision may become threatened, partly by blocking light access to the retinal photoreceptors, and partly because of a direct de- structive effect on the neuronal components of the retina. Ischaemic oedema develops secondary to occlusion of macular capillaries similarly to capillary occlusion in the retinal periphery, with a subsequent fallout of neuronal function in the affected area. If the areas close to the fovea are included, visual acuity may drop. Frequently, mixed types of maculopathy occur with exudative and ischaemic retinal oedema located in different parts of the macular area.

Epidemiology Almost all persons having diabetes mellitus will eventually develop non-

proliferative diabetic retinopathy. In countries with good diabetes care, retinopathy does not develop until after 10 years of diabetes duration, whereas retinopathy may be present at the time of diagnosis in type 2 diabetes. Nonpro- liferative diabetic retinopathy can later be complicated by one or both of the two late complications, proliferative diabetic retinopathy and diabetic maculopathy. In type 1 diabetes the most frequent vision-threatening complication is proliferative diabetic retinopathy, whereas in type 2 diabetes the most frequent vision threat is diabetic maculopathy.

Clinical Appearance