New Concepts in Diabetes and Its Treatment - part 6 pot

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New Concepts in Diabetes and Its Treatment - part 6 pot

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Chapter X Belfiore F, Mogensen CE (eds): New Concepts in Diabetes and Its Treatment. Basel, Karger, 2000, pp 135–151 Diabetic Retinopathy Toke Bek Department of Ophthalmology, A ˚ rhus University Hospital, A ˚ rhus, Denmark Introduction Diabetes mellitus is a systemic disease that affects all parts of the eye. The majority of these changes have a mild course with no permanent influence on visual function. Transitory changes in the refraction of the lens occur secondary to changes in the blood sugar, and can be prevented by optimizing the metabolic control. Diabetic cataract can nowadays be operated with few complications and with a good visual result, and diabetic eye muscle palsy disappears spontaneously within weeks leaving no adverse consequences for the visual function. Diabetic complications in the retina, diabetic retinopathy, is a somewhat different matter. This complication is presently one of the leading causes of blindness in the western world. From a phylogenic point of view, the retina is an advanced part of the brain, and damage to its neuronal tissue is therefore irreversible and leads to permanent reduction of the visual function. This implies that preventive measures are the cornerstone in the clinical manage- ment of diabetic retinopathy. However, the preventive efforts should be effective at many levels ranging from elimination of risk factors, initiation of screening programmes, optimization of treatment intervention, and by educating diabetic patients in self-care and good life habits. Once vision-threatening changes have developed the patient should be promptly referred to a specialist for clinical evaluation and initiation of relevant treatment to stop or limit the visual damage. This chapter will present an overview of current knowledge related to the clinical management of diabetic retinopathy. The chapter will be introduced with a brief account of the clinical and epidemiologic characteristics of the disease, followed by a description of the practical management of prevention, screening, diagnostics, and treatment of diabetic retinopathy. 135 Table 1. Nomenclature used for diabetic retinopathy Retinopathy Inside the retina In front of the retina (background retinopathy) (neovascularizations) Not vision-threatening Simple 7 Vision-threatening Maculopathy Proliferative retinopathy Clinical Appearance The clinical evaluation and classification of diabetic retinopathy is based on inspection oftheretina throughtheoptics of theeye. Themorphological changes thusobservedintheretinaarecomplexandheterogeneouswhichisreflectedinthe nomenclature used to describe diabetic retinopathy (table 1). Basically, diabetic retinopathycan bedividedintoearly changesthatarenotaccompanied byreduc- tion 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 mic- roaneurysms and small intraretinal haemorrhages (fig. 1). The increased capillary permeabilityleads tothe developmentof whitish hard exudatesconsisting oflipo- protein from the bloodstream (fig. 2). Additionally, cotton-wool spots may de- velop. These are localized unsharply delimited whitish areas in the superficial parts of the retina representing intracellular material that hasaccumulated 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. 136Bek 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. 137Diabetic Retinopathy Fig. 3. Moderate nonproliferative diabetic retinopathy in a right eye. Larger haemor- rhages 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 vascularabnormalities. Theseabnormalitiesare intraretinalmicrovascularab- normalities (IRMA vessels) often representing arteriovenous shunt vessels, and beading and loop formation on the larger venules (fig. 4). These abnormalities 138Bek 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 reduc- tion 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 periph- ery 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. 139Diabetic Retinopathy 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- 140Bek 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 func- tion 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, reti- nopathy 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 macu- lopathy. 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. Prevention Preventing the development of diabetic retinopathy is one of the basic pillars in the management of diabetic eye complications, since the damage that occurs to the retina is irreversible. The two most significant factors now known to limit the risk of developing diabetic retinopathy are tight regulation of the blood glucose and of the blood pressure. For many years it was suspected that exposition to hyperglycaemia accelerated the development of diabetic retinopathy, but it was not established 141Diabetic Retinopathy Table 3. Characteristics of diabetic retinopathy Is frequent Can be prevented Can be detected Can be treated Screening is cost-efficient until a few years ago in the Diabetes Control and Complications Trial (DCCT) study that the risk of developing retinopathy is considerably lowered by tight glycaemic control. Recently, several studies have been published unanimously showing that the risk of developing retinopathy in type 1 as well as in type 2 diabetes can be considerably lowered by antihypertensive treatment. Further- more, it has been shown that treatment with especially ACE inhibitors can reduce the risk for developing retinopathy with an effect that adds to the antihypertensive effect. However, these studies have not been conducted far enough to show that this intervention also has an effect on the visual prognosis. Pregnancy is a definite risk factor for the development of diabetic retinopa- thy. A tight regulation of the blood glucose during pregnancy alone can slow and often halt the development of retinopathy completely, suggesting that the risk of developing retinopathy is to a large extent caused by disturbances in the diabetic metabolism in pregnancy. Since the risk for developing diabetic retino- pathy during pregnancy increases with increasing duration of diabetes, diabetic women should be counselled to have children as early as possible in life. A multitude of studies have been conducted to identify new preventive measures for diabetic retinopathy. These studies have for example shown that aspirin and aldose reductase inhibitors have no beneficial effect on diabetic retinopathy. More recent studies have shown that pharmaceutical intervention on second messengers such as protein kinase C might be a future treatment modality for diabetic retinopathy, and these hypotheses are presently under investigation in clinical trials. Screening Background Even when optimal preventive measures are undertaken, some patients will unavoidably develop vision-threatening retinopathy. Since these changes may not be recognized by the patient before they have advanced to a stage where vision damage is irreversible, early detection is important. Diabetic retinopathy fulfills a number of criteria that makes it appropriate to screen for this complication among the diabetic population (table 3). 142Bek Methods Screening for diabetic retinopathy is performed by inspecting the ocular background through the optics of the eye, supplemented by measurement of the visual acuity. Examination of the Ocular Background Inspection of the ocular background can be done by ophthalmoscopy that enables a qualitative assessment of retinopathy. Alternatively, photography of the ocular background allows a semiquantitative analysis by comparison with standard photographs, or a quantitative computerized analysis of the retinal changes. Examination of the ocular background by ophthalmoscopy has been known for almost 150 years, and this technique is therefore one of the oldest known examination methods in ophthalmology. During ophthalmoscopy the retina is illuminated continuously, and inspection is either done directly or indirectly through a lens positioned with its focal point in the pupil plane of the examined eye. The relevance of doing ophthalmoscopy in diabetic patients was realized during the fifties where it became usual for diabetic patients to survive long enough to develop retinal complications. The advantage of ophthalmoscopy is that only simple equipment is needed for the examination. The disadvantages of this method is that the severity of the retinal lesions cannot be documented in detail, that the retinal changes are difficult to quan- tify, and that the quality and conclusion of the examination depend on the experience and attitude of the examiner. In spite of these weaknesses, ophthal- moscopy has until now been the most important examination technique for early detection of diabetic retinopathy, and globally it is still the most widely used method. During the last decades, increasing focus has been directed at a different technique to screen for diabetic retinopathy by examination of the ocular back- ground with fundus photography. This method has a number of advantages. Firstly,theretinalchanges are documentedsothatit ispossibleto re-evaluatethe retinopathy,and thegrader canconsult otherspecialists ata latertime.Secondly, retinal photography enables a standardized and centralized semiquantitative evaluation of the severity of the changes, and thirdly, photography enables an evaluation of even minimal changes in retinopathy. Fourthly, ophthalmologists need nothave primarypatientcontact. Thus,with technicians doingthe photog- raphy and opthalmologists performing the evaluation of the photographs, more examinations can be carried out with the same specialist resources. Finally, it has been shown that for other than retinal specialists the sensitivity in detecting vision-threatening retinal changes is higher when the retinopathy is evaluated from retinal photographs than by ophthalmoscopy. 143Diabetic Retinopathy With the current development within computerized image analysis it can be expected that withina few years it willbe possible to replace semiquantitative grading of fundus photographs with a fully computerized quantification of the fundus photographic changes. Many initiatives have been taken to start this process, and the results achieved hitherto appear promising. Stereoscopic examination of the ocular background is done by examining the same part of the retina from different angles with the examiner’s two eyes, thus giving an impression of the depth relation of the retinal structures. This can be done directly by binocular inspection of the ocular background, or indirectly by studying stereo photographs of the ocular background. The validity of this technique depends on the examiner’s stereo vision which shows great interindividual variation. The significance of this type of examination lies in its potential for detecting retinal oedema. Until now there has been no documentation of the value of stereoscopic examination of the ocular background for screening for diabetic retinopathy. Measurement of Visual Acuity In most countries there is general agreement that measurement of the visual acuity should be part of the routine screening examination for diabetic retinopathy. The visual acuity may be valuable as a supplement to the inspec- tion of the ocular background, especially if it has to be decided whether the patient should be referred for further evaluation by an ophthalmologist. Thus, in exudative diabetic maculopathy, hard exudates and retinal oedema may be located in the border zone of being clinically significant. A reduced or declining visual acuity in these cases will speak infavour of referral for further evaluation. Similarly, in ischaemic maculopathy with no hard exudates and questionable macular oedema, the visual acuity may be a valuable help in determining whether incipient retinal damage needs referral for further evaluation. Organization In order to ensure that screening efforts are efficient it is necessary that: (1)thehealthsystemisorganizedtopermittheestablishmentofefficientscreening programmes; (2) sufficient resources are made available in the short term (they will always pay back in thelongterm); (3)qualified personnel is available to carry out thescreeningexaminations andevaluations,and (4)patientsaretaughtabout the advantages of screening, and are given motivation to participate. Iceland is a positive example of a country where all these factors have been optimal. This country has succeeded in setting up a screening programme where, in principle, all the country’s diabetic patients are known and followed. In most countries, however, screening efforts do not live up to expectations, for the most part due to social or geographic differences. Generally, screening 144Bek [...]... antihypertensive treatment in these individuals, e.g in patients with microalbuminuria long before too severe hypertension Of note, patients with essential hypertension do show insulin resistance and/ or hyperinsulinemia Since insulin resistance is also a mechanism involved in the pathogenesis of type 2 diabetes, insulin resistance may also contribute to BP elevation in diabetes Indeed, elevated BP is found early in. .. impairment and blindness Suggested Reading Aiello LP, Gardner TW, King GL, Blankenship G, Cavallerano JD, Ferris FL, Klein R: Diabetic retinopathy Diabetes Care 1998;21:143–159 Diabetes Control and Complications Trial Research Group: The effect of intensive diabetes treatment on the progression of diabetic retinopathy in insulin-dependent diabetes mellitus Arch Ophthalmol 1995;113: 36 51 Early Treatment. .. Fax +45 861 2 165 3, E-Mail veyetb@post8.tele.dk Diabetic Retinopathy 151 Belfiore F, Mogensen CE (eds): New Concepts in Diabetes and Its Treatment Basel, Karger, 2000, pp 152–173 Chapter XI Nephropathy and Hypertension in Diabetic Patients Carl Erik Mogensen Medical Department M (Diabetes and Endocrinology), Kommunehospitalet, ˚ ˚ Arhus University Hospital, Arhus, Denmark Introduction Strict and steady... background by eliminating the corneal refraction, enables treatment of the retinal periphery through built -in angled mirrors, and dampens voluntary or reflectory eye movements The treatment is done by applying burns with a distance of one burn in between but avoiding retinal vessels, and the energy of the burns is adjusted to produce a distinct retinal whitening Proliferative Diabetic Retinopathy In proliferative... microalbuminuria or overt proteinuria, supporting the idea that a self-perpetuating process exists This increase is most pronounced in type 1 diabetic patients; clear data are more difficult to obtain in type 2 diabetes, because so many patients are treated with antihypertensive drugs and discontinuation of treatment is not justifiable Still an increase is seen, especially with 24-hour monitoring In type 1 diabetes, ... almost always be established clinically Bek 1 46 Table 4 Characteristics of new vessels in proliferative diabetic retinopathy requiring photocoagulation treatment and intraretinal microvascular abnormalities not requiring treatment New vessels requiring photocoagulation treatment Intraretinal microvascular abnormalities not requiring photocoagulation Preretinal May cross their feeder vessel Always emerge... sittings lasting more than 15 min are tiring for both the patient and the treating ophthalmologist The risk to consider with this treatment is accidental photocoagulation in the foveal area, which is less likely to occur when treatment is done through angled mirrors During treatment the patient’s eye is subjected to a strong blaze, and there may occasionally be a distinct stinging pain when the laser treatment. .. control, BP elevation and to some extent 152 dietary proteins, and the modification by treatment – will be the main issues for discussion here BP Glomerular Pressure and Potential Genetic Factors , In the past decades there has been a growing interest in the nature of diabetic renal disease, mainly focusing on BP, glomerular pressure and protein leakage as related to structural and biochemical abnormalities... associated with retinal detachment, in which case operation will give no benefit for vision Treatment Retinal Photocoagulation Retinal photocoagulation is the only known treatment modality with a documented effect on diabetic retinopathy The treatment itself, however, may incur impairment of vision and should therefore only be performed by ophthalmologists with special interest and training within this field... reduction in GFR Also patients with persistent microalbuminuria usually maintain intact GFR, though a subsequent fall in GFR can be predicted, with progression to macroalbuminuria and possibly partly related to previous hyperfiltration Only with the development of proteinuria (macroalbuminuria) is there a significant decline in GFR Antihypertensive treatment may reduce or even normalize albumin excretion, and . established clinically. 146Bek Table 4. Characteristicsofnewvesselsinproliferative diabeticretinopathyrequiringphoto- coagulation treatment and intraretinal microvascular abnormalities not requiring treatment New. effect of intensive diabetes treatment on the progression of diabetic retinopathy in insulin-dependent diabetes mellitus. Arch Ophthalmol 1995;113: 36 51. Early Treatment Diabetic Retinopathy Study. prevention, screening, diagnostics, and treatment of diabetic retinopathy. 135 Table 1. Nomenclature used for diabetic retinopathy Retinopathy Inside the retina In front of the retina (background retinopathy)

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