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| ==Historical Perspective== | | ==Historical Perspective== |
| Although diabetes was a well-known disease as from the 2nd century AD, no clinician attempted to link this endocrine disorder with eye-pathology before the middle of the 19th century. In 1846, the French ophthalmologist and Professor of Hygiene in Paris, Appolinaire Bouchardat (1806-1886), reported the development of visual loss in the absence of cataract in diabetics. This was partly reversible and in most cases improvement was associated with better control of diabetes. A few years later, François Tavignot made similar observations.<ref name="Wolfensberger Hamilton 2001 pp. 2–7">{{cite | last=Wolfensberger | first=TJ | last2=Hamilton | first2=AM | title=Diabetic retinopathy--an historical review. | journal=Seminars in ophthalmology | volume=16 | issue=1 | year=2001 | issn=0882-0538 | pmid=15487691 | pages=2–7}}</ref> However, no histopathological specimens were examined and the implication of macular disease in diabetes remained tentative until the invention of the ophthalmoscope.
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| Jäger had inexhaustible patience and exemplary precision in ophthalmoscopy and, in illustrating his findings, meticulously incorporated the smallest details into his pictures. He used the newly developed direct ophthalmoscope in order to produce one of the first atlases containing 21 colour plates of fundus paintings, which were drawn after 20-40 clinical sessions per patient. He described ‘roundish’ or oval, yellowish spots and full or partial thickness extravasations through the retina in the macular region of a diabetic patient.<ref name="Wolfensberger Hamilton 2001 pp. 2–7">{{cite | last=Wolfensberger | first=TJ | last2=Hamilton | first2=AM | title=Diabetic retinopathy--an historical review. | journal=Seminars in ophthalmology | volume=16 | issue=1 | year=2001 | issn=0882-0538 | pmid=15487691 | pages=2–7}}</ref> His findings were controversial at the time and Albrecht von Graefe (1828-1870) claimed that there was no proof of a cause-effect relationship between diabetes and retinal complications. Von Graefe’s scepticism was adopted by many of his colleagues, with the exception of Louis Desmarres (1810-1882) in 1858.
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| No further evidence was presented until 1869, when Henry Noyes (1832-1900) published an article in the USA supporting the link between diabetes mellitus and maculopathy. His observations were confirmed in 1872 by Edward Nettleship (1845-1913) in London, who expanded on this theme in his paper entitled ‘On oedema or cystic disease of the retina’ and presented the first histopathological proof of a cystoid degeneration of the macula in diabetic patients.Five years later, Nettleship published another article with Sir Steven Mackenzie (1791-1868), which described in detail the abnormal retinal changes induced by diabetes.
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| n 1876, Wilhelm Manz (1833-1911) published his seminal paper on ‘Retinitis proliferans’ containing several drawings of fibrovascular degeneration of the optic disc and vitreoretinal adhesions in the retina. Fourteen years later, in 1890, Julius Hirschberg (1843-1925) classified diabetic retinopathy into four types (retinitis centralis punctuate, haemorrhagic form, retinal infarction, and haemorrhagic glaucoma), thus describing the full natural history of diabetic retinopathy. The descriptive term, diabetic retinitis, though erroneous since the disease is not of inflammatory origin, continued to be used for several years.
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| At the beginning of the 20th century there was still the unresolved debate as to whether macular changes were directly related to diabetes or whether they were caused by atherosclerosis and hypertension. Arthur James Ballantyne (1876-1954) of Glasgow suggested that diabetic retinopathy represents a unique form of vasculopathy and his work showed for the first time the role of capillary wall alterations in the development of diabetic retinopathy, as well as the presence of deep waxy exudates in the outer plexiform layer.
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| Today the retinal manifestations of diabetes are classified as Early Non-proliferative Diabetic Retinopathy, Advanced Non-proliferative Diabetic Retinopathy, and Proliferative Diabetic Retinopathy.
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| ==Classification== | | ==Classification== |
| In 1968 a group of experts met in Airlie House, Virginia to discuss what was known at the time about DR. An important outcome of that symposium was the development of a standarized classification of DR[10]. This classification was modified and used in the Diabetic Retinopathy Study (DRS). Briefly, it consisted of comparing stereophotographs in 7 standard photographic fields with the patient’s findings in those same 7 photographic fields[11]. This same classification was modified for use in the Early Treatment of Diabetic Retinopathy Study (ETDRS). It became the gold standard for many years. The modified Airlie House Classification of DR is based on grading of stereophotographs of 7 fields and classifies DR into 13 complex levels ranging from level 10 (absence of retinopathy) to level 85 (severe vitreous hemorrhage or retinal detachment involving the macula)[12]. It is an excellent tool in the research setting but its clinical applicability is limited due to its complexity. Most ophthalmologists do not use this classification in their daily clinical work.
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| The ETDRS introduced the term clinically significant macular edema (CSME). CSME was defined upon slit lamp biomicroscopy as “(1) thickening of the retina at or within 500 μm of the center of the macula; or (2) hard exudate at or within 500 μm of the center of the macula associated with thickening of adjacent retina; or (3) a zone of retinal thickening 1 disc area or larger, any part of which is within 1 disc diameter of the center of the macula”[12]. The ETDRS found that macular photocoagulation was effective in reducing visual loss from CSME.
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| Others have divided diabetic macular edema (DME) into focal and diffuse subtypes[13]. Focal DME was initially defined as edema caused by focal leakage of microaneurysms. Clusters of microaneurysms are usually surrounded by a circinate ring of hard exudate. In contrast, diffuse DME is caused by a generalized breakdown of the inner blood/retinal barrier. Microaneurysm, retinal capillaries and even arterioles contribute to the leakage. Hard exudates are usually not seen in diffuse DME[13]. As time went by, others included FA findings in their definition of diffuse or focal DME. In the ETDRS, the proportion of microaneurysmsal fluorescein leakage was used to differentiate between focal and diffuse DME. Eyes with ≥ 67% of leakage originating from microaneurysms were classified as having focal DME. Eyes with microaneurysmsal leakage between 33% and 66% were determined to have intermediate DME. Eyes with ≤ 33% microaneurysmal leakage were classified as having diffuse DME[14]. Others have also included OCT findings[15,16]. As Browning et al[17] point out, the terms focal and diffuse DME have various definitions and mean different things to different people. Furthermore, since the terms do not seem to predict treatment outcomes they suggest that their use should be discouraged until an agreement is reached[17].
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| INTERNATIONAL CLINICAL DISEASE SEVERITY SCALE FOR DR
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| In an attempt to simplify the classification of DR, a number of experts met and created the International Clinical Disease Severity Scale for DR[18]. This disease severity scale is based upon the findings of the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) and the ETDRS. This new classification is simple to use, easy to remember and based on scientific evidence. There are five stages that are recognized. The first is “no apparent retinopathy”. As the name implies there are no diabetic fundus changes. The second stage is “mild non-proliferative retinopathy” (NPDR). This stage is characterized by the presence of a few microaneurysms. The third stage is “moderate NPDR” which is characterized by the presence of microaneurysms, intraretinal hemorrhages or venous beading that do not reach the severity of the standard photographs 2A (Figure (Figure1A),1A), 6A (Figure (Figure1B)1B) and 8A (Figure (Figure1C).1C). “Severe NPDR”, the fourth stage, is the key level to identify. Data from the ETDRS has shown that eyes in patients with DM type 2 that reach the grade of severe NPDR have a 50% chance of developing high risk characteristics if laser treatment is not instituted[19]. The diagnosis of severe NPDR is based on the 4:2:1 rule of the ETDRS[20]. Using standard photographs 2A, 6A and 8A to compare with the fundus findings, one can easily diagnose severe NPDR[20]. If hemorrhages of at least the magnitude of standard photograph 2A are present in all 4 quadrants, then by definition severe NPDR is present. If 2 quadrants or more have venous beading (VB) of the same magnitude or greater than standard photograph 6A, then by definition severe NPDR is present. If one or more quadrant has intraretinal microvascular abnormalities (IRMA) of the same magnitude or greater than standard photograph 8A, then by definition severe NPDR is present. The final stage is “proliferative diabetic retinopathy” (PDR). PDR is characterized by neovascularization of the disc, neovascularization of the retina, neovascularization of the iris, neovascularization of the angle, vitreous hemorrhage or tractional retinal detachment. With regards to macular edema, it should be noted if macular edema is present or absent. If it is present then it can be further classified as mild, moderate and severe depending on the distance of the exudates and thickening from the center of the fovea[18] (Figure (Figure22).
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| ==Pathophysiology== | | ==Pathophysiology== |
| The exact underlying pathological mechanism of diabetic microvascular disease remains poorly understood. It is believed that exposure to hyperglycemia over an extended period results in biochemical and physiologic changes that ultimately cause endothelial damage. Specific retinal capillary changes such as basement membrane thickening and selective loss of pericytes favor capillary occlusion and retinal nonperfusion.
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| The endothelial barrier decompensation results in serum leakage and retinal edema. The stages of disease result from continuous progression of the retinovascular damage, which leads to clinical presentations from mild to advanced proliferative lesions.<ref name="Mehrzadi Motevalian Rezaei Kanavi Fatemi p. ">{{cite journal | last=Mehrzadi | first=Saeed | last2=Motevalian | first2=Manijeh | last3=Rezaei Kanavi | first3=Mozhgan | last4=Fatemi | first4=Iman | last5=Ghaznavi | first5=Habib | last6=Shahriari | first6=Mansoor | title=Protective effect of melatonin in the diabetic rat retina | journal=Fundamental & clinical pharmacology | publisher=Wiley-Blackwell | date=2018-03-01 | issn=0767-3981 | pmid=29495082 | doi=10.1111/fcp.12361 | page=}}</ref>
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| The prognosis
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| varies among patients and depends mainly on systemic factors such as blood glucose levels, blood
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| pressure, blood lipid profiles.<ref name="Antonetti Klein Gardner pp. 1227–1239">{{cite journal | last=Antonetti | first=David A. | last2=Klein | first2=Ronald | last3=Gardner | first3=Thomas W. | title=Diabetic Retinopathy | journal=The New England journal of medicine | publisher=New England Journal of Medicine (NEJM/MMS) | volume=366 | issue=13 | date=2012-03-29 | issn=0028-4793 | pmid=22455417 | doi=10.1056/nejmra1005073 | pages=1227–1239}}</ref>
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| Numerous hematologic and biochemical abnormalities
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| correlate with the prevalence and severity of
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| retinopathy:
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| * increased platelet adhesiveness
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| * increased erythrocyte aggregation
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| * abnormal levels of serum lipids
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| * defective fibrinolysis
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| * abnormal levels of growth hormone
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| * upregulation of vascular endothelial growth factor (VEGF)
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| * abnormalities in serum and whole-blood viscosity
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| * local and systemic inflammation
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| ==Differentiating Diabetic retinopathy other Diseases== | | ==Differentiating Diabetic retinopathy other Diseases== |
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| ==Epidemiology and Demographics== | | ==Epidemiology and Demographics== |
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