Pathogenesis
The capillaries in diabetics undergo well-recognized changes, the hall mark of which is thickening of the Basement Membrane (BM) of the capillary endothelium.In addition Lo univers~ll BM thickening in the entire capillary bed, vascular capillary cells undergo other changes, depending on the tissue (see below). The cnd result of vascular damage is loss of function of the tissue bed served by Lhe affected capillaries.The pathogenesis of these changes is directly related lo llypei-glycemia. It has been clearly shown that the greater the duration of diabetes the greater the prevalence of rllicrovascular coinplications. It has also been shown in the DCCT trial that the correction of hyperglyce~nia can effectivcly pl-event Lhcse complications from occurring (primary prevention), and if they are present at Lhe time of intensive treatment to produce euglycemia, then the changes can regress (secondruy prevention).
How does hypesglycemia produce these vascular changes?
If sorbilol is formed rapidly in large amounts, sjnce the degradation to fructose is a slow process, there is an accumulation of sorbitol in the cell. Sot'bitol cannot diffuse across cell membranes and causes osmotic changes that damage the cell. This mechanism is the basis of changes in the lens of the eye leading to fortnalioi~ of cataracts.
Some mechanisms involved a1 the inolecular level are believed Lo be as follows:
1) Sorbitol Pathway: When intracellular glucose is very high, metabolism of glucose via the sorbitol pathway;
The capillaries in diabetics undergo well-recognized changes, the hall mark of which is thickening of the Basement Membrane (BM) of the capillary endothelium.In addition Lo univers~ll BM thickening in the entire capillary bed, vascular capillary cells undergo other changes, depending on the tissue (see below). The cnd result of vascular damage is loss of function of the tissue bed served by Lhe affected capillaries.The pathogenesis of these changes is directly related lo llypei-glycemia. It has been clearly shown that the greater the duration of diabetes the greater the prevalence of rllicrovascular coinplications. It has also been shown in the DCCT trial that the correction of hyperglyce~nia can effectivcly pl-event Lhcse complications from occurring (primary prevention), and if they are present at Lhe time of intensive treatment to produce euglycemia, then the changes can regress (secondruy prevention).
How does hypesglycemia produce these vascular changes?
If sorbilol is formed rapidly in large amounts, sjnce the degradation to fructose is a slow process, there is an accumulation of sorbitol in the cell. Sot'bitol cannot diffuse across cell membranes and causes osmotic changes that damage the cell. This mechanism is the basis of changes in the lens of the eye leading to fortnalioi~ of cataracts.
Some mechanisms involved a1 the inolecular level are believed Lo be as follows:
1) Sorbitol Pathway: When intracellular glucose is very high, metabolism of glucose via the sorbitol pathway;
Secondly, under these situations the uptake of a substance myoinositol is decreased and this interferes with electrical activity in neuronal tissues. In peripheral nerves which are myelinited, myelin sheaths can be disrupted due to sorbitol accumulatioll and osmotic damage; also nerve conduction is impaired because of myoinositol depletion.
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| Sorbitol Pathway |
Nonenzymatic Glycosyhtion of Proteins: When glucose levels are elevated for long periods, it gets linked to the amino group of proteins without m y enzymatic process involvement. The reaction is slow and depending on the half-life of the protein reaches an equilibiiurn over several weeks. Later, further chemical reactions take place that make the glycosylation irreversible, and are termed Advanced Glycosylation Endproducts (AGE). The AGE are believed to generate free radicals, get attached to basement membranes, and cause functional abnormalities of vascular tissues.
The following molecules are known to become glycosylated and are known to be involved in developinent of complications of diabetes: LDL (low density lipoproteins), albumin, hemoglobin, collagen etc. Glycosylated heinoglobin (HBAiC) is' now routinely estimated in clinical laboratories, as it is an indicator of longterm (three months) average glycemic control (see below, section).
Vascular Dysfunction in Diabetes Mellitus
As a result of the above disturbances, the microcirculation in diabetics have the following functional abnormalities:
1) Coagulation: Due to effects on prostaglandins, von Willebrands Factor, TPA (tissue plasminogen activator), PA1 (plasminogen activator inhibitor), there is a tendency to increased coagulability in the micro-circulation.
2)Permeability: The vasculat~~rebecomes more permeable and leakage of albumin and lipids.
3) Contractility andflow: Some vascular beds show increased flow as in gloomerl,whereas in others there is decreased flow as in retinopathy. There appears to be a reduced action of nitric oxide which is a major component of EDW(endothelium dependent relaxation Factor).Diabetic Retinopatlmy The specific abnormalities which occur in sequence in the retinal vascular bed are listed below:
1) Loss of pericyte number and function.
2) Outpouching of capillrvy walls to foinl microaneurysms.
3) Closure of retinal capillaries and arterioles.
4) Increased vascular permeability.
5) Proliferation of new vessels and fibrosis.
6) Contractioll of fibrous bands causing vitreous heinol~hage and retinal detachment.
Factors 1-4 cause hypoxia of the retina. This provokes formation of new vessels(neo-vascularization) in an effort to increase oxygen supply. However, the new vessels are fragile and cause fibrosis.These pathologic processes produce wcll-described changes in the retina and these can be visualized by ophthalmoscopy and fluorescein nngiogi-aphy. The classification of retinopathy in diabetes is broadly into:
1) Background retinopathy (non-proliferative (NPDR).
2) Diabetic maculopathy.
3) Pre- proliferative retinoparhy.
4) Proliferative retinopathy.
Background Retinopathy (Non-proliferative Diabetic Retinopathy)
This is diagnosed when the fundoscopy shows the following:
2) Dot and blot heinorrl~ages.
3) Hard exudates,
4) Cotton-wool spots.
1) Micro-aneurysms is a sinall outpouching of a capillary wall due to loss of supporting pericytes. They appcar as red dots when viewed by white light, and are more clearly visible when seen with a green light as black dots.
2) The dot hemorrhages, appear sligl~tly larger than micro-aneurysms and are ddue to blood leakage in the deeper layer of the retina. When the hemon-hages are in the superficial nerve fibre layer they tend to form streaks or blots. These are Few in number and scattered throughout the fundus. Large blotchy hemorrhages represent a severer degree of retinopathy.
3) Hard exudates are yellowish white in colour with well defined edges, and have a circinate form when seen in clusters. These represent leakage of plasma fluid into which lipoprotein is deposited, When present away from the macula region these exudates do not theaten vision. They eventually disappear as the leaking area seals off, only to appear in new areas of leakage.
4)Cotton-wool spots represent local retinal ischemia. They appear as fluffy white with ill defined bordess. In isolation these are not serious ,but in association with deep blotchy hemorrhages they have a worse prognosis.
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| Schematic Diagrams of Diabetic Retinopathy ' |
Maculopathy
This is more common in older type two diabetics as compared with young type one diabetics. Tiis has great vision-threatening potential. There is focal vascular leakage of plasma into the macular area; when the leakage is at the fovea (crater-like area at the centre of macula, and is the site of central vision), because of the radiating a~mngement of the nerve fibres, the exudates form a "macul:u. star". When the leakage is diffuse; then there is widespread macula edema.
Pre-proliferative Diabetic Retinopathy
This is a more advanced stage oS baclcground retinopathy, featuring larger blotchy hemorrhages, and many cotton w o ~ spots.Small vascular loops can be seen and these represent shunts between venules and capillaries. These are known as IRMA (intra- retinal micro-vascular abnorlnalities). The retinal veins may also give at1 appearance of a "String of sausages". Pre-proliferative stage does not invariably progress to proliferative retinupathy, but the risk is high as 50 per cent. There is some controversy regcarding laser photo-coagulation a1 this stage.
Proliferative Retinopathy
When a large part of the retinal capillary bed becomes ischemic, then new vessel formation (neovascularization ) occurs in an attempt to reperfuse the retina. These vessels are extremely fragile and are mainly situated at the optic disc, and are very liable to bleed. Fluorescien angiography can identify new vessels which lend to leak profusely as they lack endothelial tight junctions. Ilemot~hage from new vessels into the vitreous results in sudden visual loss. The other complication of new vessels is that a fibrous tissue web accoinpanies them, and over time the fibl.ous tissue undergoes contraction. The retina is then liable to undergo detachment and visual loss is again incurred.New vessels at this stage can proliferate onto the iris (rubeosis iridis) and into the anterior chamber of the eye. This can obstruct the drainage of aqueous humour and lead to rise of intraocular pressure, or rubeotic glaucoma.Vitre-retinal surgery is the only hope, if successful of regaining any vision.
Management
The cornerstone of manageinent of diabetic retinopathy is prevention and early detection. Good glycelnic control is the best insurance against it's occurrence.
Screening for Retinopathy
The risk for developing retinopathy rises with the duration of the disease. It is rare in the first five years of onset. Since the onset of the disease is identifiable only in type one disease, it is recommended that for type two diseases, it is recommended that fundus examination should be done at the time of diagnosis, and repeated annually.For Q p e one, annual examinations can occur annually from 5'" year of onset.Pregnancy is associated with progression of retinapathy, hence ophthalmological examination should be done at that time.
Treatment
Exudative maculopathy and proliferative retinopathy require laser photocoagulation.Maculopatlzy: The aim of laser [harpy is to seal off the site of lecakage. Focal laser burns are applied to points of leakage.Proliferative Retinopathy: In proliferative retinopatthy the aim of laser treatlneilt is to induce regression of new vessels. The laser is not applied to the vessels themselves but to the ischemic retina. Widespread burns are produced in a technique known as pan retinal photocoagulation. These buins destroy the deep portion of ischemic retina which is thought to produce a vaso-proliferative substance which causes new vessel formation. Alternatively, laser treatment cause thinning of the outer layers of the retina. This reduces the metabolic needs of the retina, which can then derive sufficient nutrients from diffusion from the c11o1-oids. The burns do not destroy the superficial layer of the retina which contains the nerve fibres, hence vision is retained. However,some peripheral vi;qion is lost.
Other Non-retinal Ocular Lesions in Diabetics
Mononeuropatlty: A diabetic can suddenly complain ol' double vision due to paralysis of any of the extra-ocular muscles supplied by the 3"', 4'", 6'" nerves. A thorough physical exanination of the CNC is required to rule out other possible causes, but CT Scan and MRI of the brain are rarely warranted. The 4Ih nerve is least likely to be involved, and the 3rd the most likely. The pupil is usually not involved in 3'" nerve palsy, i.e., it is not dilated and unresponsive to light as in usual 3"' nerve paralysis. The reason is that the pupillay fibres are located at the surface and most of then vascular injury affects the deeply placed fibres. The nerve lesions are self-limited and the patient can be reassured that the pasalysis will recover in 2 to 6 months.
2) Cataracts: These occur earlier in diabetics and progress more rapidly. They are 1.6 times more common in diabetics than in the general population.
This is more common in older type two diabetics as compared with young type one diabetics. Tiis has great vision-threatening potential. There is focal vascular leakage of plasma into the macular area; when the leakage is at the fovea (crater-like area at the centre of macula, and is the site of central vision), because of the radiating a~mngement of the nerve fibres, the exudates form a "macul:u. star". When the leakage is diffuse; then there is widespread macula edema.
Pre-proliferative Diabetic Retinopathy
This is a more advanced stage oS baclcground retinopathy, featuring larger blotchy hemorrhages, and many cotton w o ~ spots.Small vascular loops can be seen and these represent shunts between venules and capillaries. These are known as IRMA (intra- retinal micro-vascular abnorlnalities). The retinal veins may also give at1 appearance of a "String of sausages". Pre-proliferative stage does not invariably progress to proliferative retinupathy, but the risk is high as 50 per cent. There is some controversy regcarding laser photo-coagulation a1 this stage.
Proliferative Retinopathy
When a large part of the retinal capillary bed becomes ischemic, then new vessel formation (neovascularization ) occurs in an attempt to reperfuse the retina. These vessels are extremely fragile and are mainly situated at the optic disc, and are very liable to bleed. Fluorescien angiography can identify new vessels which lend to leak profusely as they lack endothelial tight junctions. Ilemot~hage from new vessels into the vitreous results in sudden visual loss. The other complication of new vessels is that a fibrous tissue web accoinpanies them, and over time the fibl.ous tissue undergoes contraction. The retina is then liable to undergo detachment and visual loss is again incurred.New vessels at this stage can proliferate onto the iris (rubeosis iridis) and into the anterior chamber of the eye. This can obstruct the drainage of aqueous humour and lead to rise of intraocular pressure, or rubeotic glaucoma.Vitre-retinal surgery is the only hope, if successful of regaining any vision.
Management
The cornerstone of manageinent of diabetic retinopathy is prevention and early detection. Good glycelnic control is the best insurance against it's occurrence.
Screening for Retinopathy
The risk for developing retinopathy rises with the duration of the disease. It is rare in the first five years of onset. Since the onset of the disease is identifiable only in type one disease, it is recommended that for type two diseases, it is recommended that fundus examination should be done at the time of diagnosis, and repeated annually.For Q p e one, annual examinations can occur annually from 5'" year of onset.Pregnancy is associated with progression of retinapathy, hence ophthalmological examination should be done at that time.
Treatment
Exudative maculopathy and proliferative retinopathy require laser photocoagulation.Maculopatlzy: The aim of laser [harpy is to seal off the site of lecakage. Focal laser burns are applied to points of leakage.Proliferative Retinopathy: In proliferative retinopatthy the aim of laser treatlneilt is to induce regression of new vessels. The laser is not applied to the vessels themselves but to the ischemic retina. Widespread burns are produced in a technique known as pan retinal photocoagulation. These buins destroy the deep portion of ischemic retina which is thought to produce a vaso-proliferative substance which causes new vessel formation. Alternatively, laser treatment cause thinning of the outer layers of the retina. This reduces the metabolic needs of the retina, which can then derive sufficient nutrients from diffusion from the c11o1-oids. The burns do not destroy the superficial layer of the retina which contains the nerve fibres, hence vision is retained. However,some peripheral vi;qion is lost.
Other Non-retinal Ocular Lesions in Diabetics
Mononeuropatlty: A diabetic can suddenly complain ol' double vision due to paralysis of any of the extra-ocular muscles supplied by the 3"', 4'", 6'" nerves. A thorough physical exanination of the CNC is required to rule out other possible causes, but CT Scan and MRI of the brain are rarely warranted. The 4Ih nerve is least likely to be involved, and the 3rd the most likely. The pupil is usually not involved in 3'" nerve palsy, i.e., it is not dilated and unresponsive to light as in usual 3"' nerve paralysis. The reason is that the pupillay fibres are located at the surface and most of then vascular injury affects the deeply placed fibres. The nerve lesions are self-limited and the patient can be reassured that the pasalysis will recover in 2 to 6 months.
2) Cataracts: These occur earlier in diabetics and progress more rapidly. They are 1.6 times more common in diabetics than in the general population.
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