Ординатура / Офтальмология / Английские материалы / Diabetic Retinopathy_Lang_2007

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Antonia M. Joussen Department of Ophthalmology

Heinrich-Heine University Duesseldorf Moorenstraße 5

DE–40225 Duesseldorf

Tel. 49 0211 81 17321, Fax 49 0211 81 16241, E-Mail joussena@googlemail.com

barrier (BRB) demonstrated by fluorescein leakage, capillary closure, and alterations in the neuronal and glial cells of the retina. These alterations may be monitored by a variety of methods, including retinal microaneurysm counting on eye fundus images, fluorescein leakage, retinal thickness measurements and psychophysical and electrophysiological testing.

A combination of these methods using multimodal imaging has contributed to identifying different phenotypes of diabetic retinopathy. They show different types and rates of progression which suggest the involvement of different susceptibility genes. The identification of different phenotypes has opened the door for genotype characterization, different management strategies and targeted treatments.

A new paradigm of diabetic retinopathy management is developing. Diabetic retinopathy must be detected and diagnosed earlier, and treatment must be commenced earlier. The ultimate goal should not be merely to prevent blindness, but to help patients enjoy their lives to their full potential, and to provide a clearer indication of when more active treatment, either systemic or local, or both, is justified.

Diabetic retinopathy is a chronic retinal disorder that eventually develops, to some degree, in nearly all patients with diabetes mellitus. Diabetic retinopathy is characterized by gradually progressive alterations in the retinal microvasculature and is the leading cause of new cases of legal blindness among Americans between the ages of 20 and 74 years of age [1].

Diabetic retinopathy occurs in both type 1 (also known as juvenile-onset or insulin-dependent diabetes) and type 2 diabetes (also known as adult-onset or noninsulin-dependent diabetes). All the features of diabetic retinopathy may be found in both types of diabetes, but characteristically, the incidence of the main causes of vision loss, macular edema and retinal neovascularization is quite different for each type of diabetes [1].

Diabetic retinopathy in type 1 diabetes induces vision loss mainly due to the formation of new vessels in the eye fundus and development of proliferative retinopathy, whereas in type 2 diabetes, vision loss is most commonly due to macular edema, and proliferative retinopathy is relatively rare.

It is apparent from the data available from a variety of large longitudinal studies that the evolution and progression of diabetic retinopathy vary according to the type of diabetes involved, showing dissimilarities among different patients even when belonging to the same type of diabetes, and that diabetic retinopathy does not necessarily progress in every patient to proliferative retinopathy.

There is accumulated evidence indicating that only the nonproliferative stage of diabetic retinopathy (NPDR) is directly due to the systemic disease and associated hyperglycemia and other metabolic alterations. Proliferative

Fig. 1. Diabetic retinopathy. Fundus photography of the posterior pole showing typical alterations, predominantly microaneurysms and hemorrhages.

retinopathy occurs in diabetic eyes only after the development of widespread ischemia due to capillary closure. Neovessels in the retina are a direct result of retinal ischemia and not influenced by the diabetic metabolic control. Its course and management are not different from other situations in the retina where there is abnormal new vessel formation.

Following these concepts closely, we can state that in diabetes, a retinopathy develops that may ultimately result in extensive retinal ischemia. If that occurs, independently of diabetic metabolic control, neovascularization may develop. Proliferative retinopathy is, in fact, a complication of diabetic retinopathy, such as retinal detachment in diabetes is a complication of proliferative retinopathy. Both occur independently of the course of systemic diabetic disease and are not influenced by changes in metabolic control.

Therefore, we will attempt to characterize diabetic retinopathy, i.e. the alterations occurring in the retina as a direct result of the systemic diabetic disease.

The Initial Alterations in Diabetic Retinopathy

The fundus abnormalities that are identified on clinical examination of mild to moderate NPDR include microaneurysms and/or hemorrhages, which appear as small red dots on the fundus images, and exudates (fig. 1).

Fig. 2. Diabetic retinopathy. Fluorescein angiography showing fluorescent dots (microaneurysms) and diffusion of fluorescein around the lesions (fluorescein leakage).

Therefore, the initial stages of NPDR are characterized by the presence of microaneurysms and indirect signs of vascular hyperpermeability and capillary closure, i.e. both hard and soft exudates or cotton wool spots, respectively.

It is particularly important to realize that the course and rates of progression of the retinopathy vary between patients. Microaneurysms, for example, may come and go. Once you get a microaneurysm you do not necessarily continue to have that microaneurysm. Microaneurysms may disappear due to vessel closure (fig. 2), which is an indication of worsening of the retinopathy because of progressive vascular closure [2]. Hemorrhages will obviously come and go as the body heals them. Clinical improvement may be apparent, but in reality, may mask the worsening of the disease.

The initial pathological changes occurring in the diabetic retina are characteristically located in the small retinal vessels of the posterior pole of the retina, i.e. in the macular area. The structural changes in the small vessels include endothelial cell and pericyte damage and thickening of the basement membrane [3].

Pericyte damage has been reported as one of the earliest findings in diabetic retinal disease since the introduction of retinal digest studies [4]. However, pericyte apoptosis is more readily detectable than endothelial cell apoptosis, most probably because the pericytes are encased in the basement membrane and thus less accessible to clearing mechanisms, whereas apoptotic endothelial cells slough off into the capillary lumen and are cleared by blood flow.

The alteration in the Blood-Retinal Barrier (BRB) demonstrated by fluorescein leakage is one of the earliest findings in diabetic retinal disease (fig. 3).

Fig. 3. Diabetic retinopathy. Fluorescein angiography showing multiple microaneurysms and a few areas of capillary closure.

It appears to directly lead to clinically significant macular edema, which remains the most frequent cause of visual loss in diabetes.

Altered autoregulation and progressively decreased retinal blood flow associated with retinal vascular alterations (endothelial cells and pericytes) facilitate the development of progressive capillary closure, a hallmark of progression of diabetic retinal disease. Capillary closure may be identified in the initial stages of NPDR by the presence of occluded capillaries surrounding the foveal vascular zone (FAZ). Finally, capillary closure leads to retinal ischemia, which creates the conditions for the development of the most dreaded complications of proliferative retinopathy. It is now generally accepted that at least three processes can contribute to retinal capillary occlusion and obliteration in diabetes: proinflammatory changes, microthrombosis and apoptosis [5].

Characterization of Retinopathy Phenotypes

It is well recognized that the duration of diabetes and the level of metabolic control are major risk factors for development of diabetic retinopathy.

However, these risk factors do not explain the great variability that characterizes the evolution and rate of progression of the retinopathy in different diabetic individuals. There is clearly great individual variation in the presentation and course of diabetic retinopathy. There are many diabetic patients who

after many years with diabetes never develop sight-threatening retinal changes, maintaining good visual acuity. However, there are also other patients that even after only a few years of diabetes show a retinopathy that progresses rapidly and may not even respond to laser photocoagulation treatment.

We have recently performed a prospective 3-year follow-up study of the macular region in 14 patients with type 2 diabetes mellitus and mild nonproliferative retinopathy, using multimodal macula mapping [6].

In a span of 3 years, eyes with minimal changes at the start of the study (levels 20 and 35 of the Early Treatment Diabetic Retinopathy Study-Wisconsin grading) were followed at 6-month intervals in order to monitor progression of the retinal changes.

The most frequent alterations observed, by decreasing order of frequency, were leaking sites [7], areas of increased retinal thickness and microaneurysms/ hemorrhages.

Leaking sites were a very frequent finding and reached very high BRB permeability values in some eyes. These sites of alteration in the BRB, well identified in leakage maps, maintained, in most cases, the same location on successive examinations, but their BRB permeability values fluctuated greatly between examinations, indicating reversibility of this alteration.

Areas of increased retinal thickness were another frequent finding. They were present in every eye at some time during the follow-up and were absent, at baseline, in only 2 of the 14 eyes. This confirms previous observations by our group [6] and by others [8].

The number of microaneurysms and small hemorrhages increased in most eyes during the 3-year follow-up period. This was particularly well demonstrated when the location of each microaneurysm was taken into consideration. This increase in the number of microaneuryms may be the most reliable indicator of retinal vascular damage and remodeling of the retinal circulation, particularly in the initial stages of diabetic retinopathy.

Increased rates of microaneurysm accumulation were registered in eyes that had more microaneuryms at baseline and higher values of BRB permeability during the study. In summary, in this study, the rate of microaneurysm formation appears to have the potential to be a good indicator of retinopathy progression. We realized that by combining different imaging techniques, multimodal imaging of the macula made apparent three major patterns occurring during the follow-up period of 3 years. Pattern A included eyes with reversible and relatively little abnormal fluorescein leakage, a slow rate of microaneurysm formation and a normal FAZ (fig. 4a). This group appeared to represent eyes presenting slowly progressing retinal disease. Pattern B included eyes with persistently high leakage values, indicating an important alteration in the BRB, high rates of microaneurysm accumulation and a normal FAZ (fig. 4b).

100

80

70

60

50

40

b

30

20

10

c

Fig. 4. Multimodal images taken at 0-, 12-, 24and 36-month visits (left to right) showing for each visit the FAZ (black contour), retinal leakage analyzer results and retinal thickness analyzer results. The retinal leakage analyzer color-coded maps of the BRB permeability indexes are shown; retinal thickness analyzer views show white dot density maps of the percent increases in retinal thickness. Pattern A: note the little amount of retinal leakage over the 4 represented visits and the normal FAZ contour. This patient showed a slow rate of microaneurysm formation. Pattern B: note the high retinal leakage showing a certain degree of reversibility and the normal FAZ contour. This patient showed a high rate of microaneurysm accumulation over the 3-year follow-up period. Pattern C: note the reversible retinal leakage and the development of an abnormal FAZ contour. This patient showed a high rate of microaneurysm formation.

All these features suggest a rapid and progressive form of the disease. This group may identify a ‘wet’ form of diabetic retinopathy. Pattern C included eyes with variable and reversible leakage and an abnormal FAZ (fig. 4c). This group is less well characterized considering the small number of eyes that showed an abnormal FAZ. It may be that abnormalities of the FAZ may occur as a late development of groupsA and B or progress rapidly as a specific ‘ischemic’form (table 1).

We have now extended our observations by following 57 patients with type 2 diabetes for 7 years; at the time of enrollment, all eyes presented mild NPDR.