2Classification of severity of diabetic retinopathy Lesions presentSeverityNonproliferativeNo retinal lesionsNo retinopathyNo lesions other than microaneurysmsMicroaneurysms onlyMicroaneurysms plus retinal hemorrhage,hard exudateMild NPDR,venous loops,or bothMild NPDR plus cottonwool spots and/or IRMAModerate NPDRPresence of one of the following features:microaneurysms plus venous beading and/or H/MA ≥ Standard photograph 2A in four quadrants,or marked venous beading in two or more quadrants, or moderate IRMA(standard photograph 8A in one or more quadrants)Severe NPDRTwo or more of the above features described in severe NPDRVery severe NPDRProliferativeNew vessels and/or fibrous proliferations;or preretinal and/or vitreous hemorrhagePDR without HRCNVD≥standard photograph 10A;or less extensive NVD,if vitreous or preretinal hemorrhage is present;or NVE≥half disc area,if vitreous or preretinal hemorrhage is presentPDR with HRCExtensive vitreous hemorrahage precluding grading,retinal detachment involving the macula,or phthisis bulbi or enucleation secondary to a complication of diabetic retinopathyAdvanced PDR
3SIMPLIFIED CLASSIFICATION OF DIABETIC RETINOPATHY ln an attempt to improve communication between the ophthalmologists and the primary care physicians caring for patients with diabetes and between clinicians worldwide, a recent international classification of diabetic retinopathy and macular edema was developed. This classification is based on the data collected in the clinical trials and epidemiologic studies of diabetic retinopathy and it simplifies the ETDRS classification ofdiabetic retinopathy for clinical.With the introduction of this new simplified scale, it is hoped that these systems will be valuable in improving both screening of individuals with diabetes and communication and discussion among individuals caring for these patients.
4EPIDEMIOLOGY OF DIABETES AND DIABETIC RETINOPATHY The Centers for Disease Control estimate that 18.2 millionAmerican have diabetes and 5.2 million don't know they haveit . Type 2 diabetes accounts for up to 95% of aIl diabetes cases ,affecting 8% of the population aged 20 and older. Among the population 60 years and older, 18.6% are affected with diabetes . The prevalence of type 2 diabetes has tripled in the last 30 years , much of it due to an increase in obesity.
5Among the estimated 10.2 million individuals in the USA older than 40 years of age and with known diabetes, the prevalence rates of diabetic retinopathy and vision-threatening diabetic retinopathy were 40.3% and 82%, respectively. This translates to 4.1 million adults over the age of 40 years having diabetic retinopathy; one in every 12 known persons with diabetes has severe visionthreatening diabetic retinopathy.
6Data from population-based studies such as the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) provide valuable information regarding both the prevalence and the risk factors associated with the development of diabetic retinopathy.
7ln the younger-onset group, which consists of patients whose age at diagnosis of diabetes was less than 30 years and who were taking insulin at the time of the examination (presumably those with type 1 diabetes), retinopathy, either proliferative or nonproliferative, was seen in 13% of patients with less than a5-year duration of diabetes and in 90% of patients with a duration of 10 to 15 years.
8PDR, the most vision-threatening form of the disease, is present in approximately 25% of patients with type 1 diabetes and a 15-year duration of the disease.
9For patients with an onset of diabetes at 30 years of age or older (those with type 2 diabetes) and a duration of diabetes less than 5 years, 40% of those taking insulin and 24% of those not taking insulin have retinopathy.
10These rates increase to 84% and 53%, respectively, with an increased diabetes duration of 15 to 19 years. PDR develops in 2% of patients with type 2 diabetes and a duration less than 5 years and 25% of patients with a duration of 25 or more years of diabetes.
11The prevalence of diabetic macular edema did not vary as much by diabetes type. The prevalence of diabetic macular edema is approximately 18% to 20% in patients with either type 1 or type 2 (insulin-taking) diabetes.
12RISK FACTORS FOR PROGRESSION OF RETINOPATHY Severity of retinopathyAs retinopathy progresses from the mild to moderate to severe and then very severe stages, the risk of developing PDR or visualloss also increases.
13ln the ETDRS, eyes with very severe NPDR or mild to moderate PDR, or both, had a 60-fold increased risk of developing high-risk PDR after 1 year of follow-up, compared with eyes with mild NPDR (48.5% versus 0.8%).
14After 5 years of follow-up, there was still a fivefold increased risk (74.4% versus 14.3%).
15For patients with bilateral moderate NPDR, the 4-year risk of progression to PDR was increased by 40-fold when compared with patients who had microaneurysms in only one eye.
16Diabetic retinopathy disease severity scale Proposed disease severity levelFinding observable upon dilated ophthalmoscopyNo apparent retinopathyNo abnormalitiesMild nonproliferative diabetic retinopathyMicroaneurysms onlyModerate nonproliferative diabetic retinopathyMore than just microaneurysms but less than severe nonproliferative diabeticretinopathySevere nonproliferative diabetic retinopathyAny of the following:•More than 20 intraretinal hemorrhages in each of four quadrants•Definite venous beading in more than two quadrants•Prominent intrartinal microvascular abnormalities in more than one quadrant and no signs of proliferative retinopathyProliferative diabetic retinopathyOne or more of the following:•Neovascularization•Vitreous/preretinal hemorrhageDiabetic macular edema disease severity scaleDiabetic macular edema apparently absentNo apparent retinal thickening or hard exudates in posterior poleDiabetic macular edema apparently presentSome apparent retinal thickening or hard exudates in posterior poleIf diabetic macular edema is present,it can be categorized as follows:Diabetic macular edema present•Mild diabetic macular edemaSome retinal thickening or hard exudates in posterior pole but distant from the center of the macula•Moderate diabetic macular edemaRetinal thickening or hard exudates approaching the center of the macula but not involving the center•Severe diabetic macular edemaRetinal thickening or hard exudates involving the center of the macula
17Glycemic controlThe relationship of glucose control and the chronic complications of diabetes has been extensively studied in observational studies.These studies all demonstrated that increased severity of diabetic retinopathy is associated with poorer glucose contral.
18Randomized , controlled clinical trials of glycemic control were designed to address the causal role of glucose control in diabetic complications.ln the Diabetes Control and Complications Trial (DCCT),1441 patients with type 1 diabetes were randomly assigned to either conventional or intensive insulin treatment and followed for a period of 4 to 9 years.
19Conventional treatment was characterized by one or two daily insulin injections, daily self-monitoring of urine or blood glucose, and diet and exercise education. Hemoglobin A1c (HbA1c) values were not used to guide treatment, unless an upper limit of 13% was exceeded.
20Intensive treatment consisted of insulin administered three or more times daily by injection or an external pump, with dose adjusted according to self-monitored blood glucose results performed at least four times per clay, as weIl as anticipated dietary intake and exercise, and with the goal of lowering HbA1c (measured monthly) to within the nondiabetic range (< 6.05%).
21The DCCT demonstrated that intensive insulin treatment is associated with a decreased risk of either the development or progression of diabetic retinopathy in patients with type 1 diabetes.
22In patients without any visible retinopathy when enrolled in the DCCT, the 3-year risk of developing retinopathy was reduced by 75% in the intensive insulin treatment group compared with the standard treatment group. However, ever in the intensively treated group, retinopathy could not be completely prevented over the 9-year course of the study.
23The benefit of the strict control was also evident in patients with existing retinopathy (50% reduction in the rate of progressionof retinopathy compared with controls). At 6- and 12-month visits, a small adverse effect of intensive treatment on retinopathy progression was seen, similar to that described in other trials of glucose control.
24However, in eyes with little or no retinopathy at the time of initiating intensive glucose control, this early worsening of retinopathy is unlikely to threaten vision. When the DCCT results were stratified by hemoglobin A1 C (HbA1 C) levels, there was a 35% to 40% reduction in the risk of retinopathy progression for every 10% decrease in HbA1C (e.g., from 8% to 7.2%).
25Furthermore, there was a statistically significant reduction in both diabetic neuropathy and nephropathy with intensive blood glucose control in the DCCT.
26With an additional 7 more years of foIlow-up when the HbA1Cs in both treatment groups were not statistically significant (8.1 % versus 8.2%, P = 0.09), the rate of progression of retinopathy remained statistically significantly less in those treated with the intensive therapy than in the conventional therapy.
27The intensive glycemic control over a period of 6 The intensive glycemic control over a period of 6.5 years conferred benefits weIl beyond the period of treatment. These data have resulted in recommendations for achieving intense control with HbA1C level below 7% as soon as the diagnosis of diabetes is made.
28The effect of glycemic control on the incidence and progression of diabetic retinopathy is similar in patients with type 2 diabetes, as assessed in observational studies and randomized studies conducted in Japan and the UK.
29Findings in a study of Japanese patients with type 2 diabetes have shown that multiple insulin-injection treatment reduced the onset ofretinopathy from 32% to 8% and reduced a two-step progression retinopathy from 44% to 19%, compared with people receiving conventional insulin treatments over 6 years.
30ln the UK Prospective Diabetes Study (UKPDS), the largest and longest study of patients with type 2 diabetes, there was a 25% reduction in the risk of the "any diabetes-related microvascular end point," including the need for retinal photocoagulation in the intensive treatment group compared to the conventional treatment group.
31After 6 years of follow-up,a smaller proportion of patients in the intensive treatment group than in the conventional group had a two-step progression(worsening) in .diabetic retinopathy(P<0.01).
32Epidemiologic analysis of the UKPDS data showed a continuous relationship between the risk of microvascular complications and glycemia,so for every percentage point decrease in HbA1C (e.g., 9% to 8%), there was a 35% reduction in the risk of microvascular complications.
33The results of both the DCCT and UKPDS show that, although intensive therapy of glucose does not prevent retinopathy completely , it reduces the risk of the development and progressionof diabetic retinopathy. This may be translated clinically to both preservation of vision and reduction in therapy such as laserPhotocoagulation.
34Hypertension The findings of observational studies assessing the importance of blood pressure in theprogressing of NPDR are inconsistent.Hypertension
35However, in the UKPDS a randomized comparison of more intensive blood pressure control versus less intensive blood pressure control in persons with type 2 diabetes demonstrated that intensive blood pressure control was associated with a decreased risk of retinopathy progression
36Tight blood pressure control resulted in a 37% reduction in microvascular diseases, predominantly reduced risk of retinal photocoagulation, when compared to less tight control.
37A previously published study of blood pressure medication in diabetic retinopathy suggested that there might be a specific benefit of angiotensin-converting enzyme (ACE) inhibition and blood pressure reduction, even in normotensive persons, on the progression of diabetic retinopathy.
38The UKPDS included a randomized comparison of beta-blockers and ACE inhibitors in the tight blood pressure control arm of that study. Benefits fromtight blood pressure control were present in both the beta-blocker and ACE inhibitor treatment groups, with no statistically significant difference between them.
39This suggests that the treatment effect is more likely to be secondary to blood pressure reduction than to a specific effect of ACE inhibitors.
40Elevated serum lipid levels The WESDR, a population-based study, and the ETDRS found that elevated levels of serum cholesterol were associated with increased severity of retinal hard exudate.
41ln dependent of the accompanying macular edema, the severity of retinal hard exudate at baseline was associated with decreased visual acuity in the ETDRS. The severity of retinal hard exudate was also a significant risk factor for moderate visual loss (15 letters or more loss) during the course of the study.
42More recently, the DCCT investigators also evaluated the association of severity of retinopathy and retinal hard exudates with serum lipids.
43They found that the severity of retinopathy was associated with increasing triglycerides and inversely associated with high-density lipoprotein cholesterol.
44The NMR-LSP results showed an increasing severity of retinopathy with small and medium very-low-density lipoprotein and inversely with very-low-density lipoprotein size. These data support thepotential role for dyslipoproteinemia in the pathogenesis of diabetic retinopathy.
45Elevated serum triglyceride levels were also associated with a greater risk of developing high-risk PDR in the ETDRS patients.
46ln a study in Pittsburgh, elevated triglycerides, as well as elevated low-density lipoprotein cholesterol, were found to be associatedwith PDR.
47Although these are all observational findings, the data are compelling to recommend lowering elevated serum lipids in patients with diabetic retinopathy to reduce the risk of visual loss.
48ln addition to reducing the risk of cardiovascular disease , reducing the risk of visual loss should be another motivating factor for patients to lower elevated serum lipids.
49Pregnancy and diabetic retinopathy Diabetic retinopathy may be accelerated during pregnancy because of the pregnancy itself or the changes in metabolic control.
50ln fact, both the pregnancy and changes in metabolic control may play important roles in accelerating the, progression of diabetic retinopathy.
51Ideally, patients who are planning to become pregnant should have their eyes examined before they attempt to conceive and should make every attempt to lower their blood glucoselevels to as near normal as possible for the health of the fetus, as well as their own health.
52During the first trimester, another eye examination should be performed; subsequent follow-up will depend on the findings at the time of this examination.
53Pregnant women with less than severe NPDR should be examined every 3 months, whereas those with more severe stages should be seen every 1 to 3 months, as recommended by the AmericanAcademy of Ophthalmology Preferred Practice Pattern.
54Other systemic risk factors Diabetic nephropathy, as measured by albuminuria , proteinuria ,or renal failure, is found to be a risk factor associated with progression of retinopathy in some, but not aIl, studies.
55Anemia has also been reported to be associated with progression of diabetic retinopathy in two small case series and two epidemiologicstudies.
56There was a progressive increase in the risk of development of high-risk PDR with decreasing hematocrit in an adjusted multivariate model in the ETDRS.
57This may add substantially to the evidence supporting the importance of anemia as a risk factor for diabetic retinopathy.
58History of diabetic neuropathy and cardiovascular autonomic neuropathy have also been suggested to be associated with increased risk of progression of Retinopathy.
59Eye examination schedule Routine minimum follow - upRecommended time for first examinationTime of onset of diabetes mellitusAnnually5 years after onsetLess than 30 years of ageAt time of diagnosisAge 30 and olderAt least every 3 monthsBefore or soon after conceptionBefore pregnancy
60Recommended follow-up schedule Status of retinopathyFollow-up(months)No retinopathy or microaneurysms only12Mild/moderate NPDR without macular edema6-12Mild/moderate NPDR with macular edema that is not clinically significant4-6Mild /moderate NPDR with clinically significant macular edema3-4Severe/very severe NPDR
61Diabetes Control and Complication trial: rates of progression from nonproliferative diabetic retinopathy to proliferative diabetic retinopathy and crude relative risks (RRs),by follow-up time periodTime period(years)Conventional(C) rate(cases/person-years)*Intensive(I)rateCrude RR,I:C0-10.86(3/351)0.55(2/362)0.651.5-31.60(11/688)1.41(10/711)0.883.5-51.86(12/646)0.88(6.681)0.475.5-93.97(20/504)0.69(4/580)0.17Modified from Diabetes Control and Complications Trial Research Group. The effect of intensive diabetes treatment on the progression of diabetic retinopathy in insulindependent diabetes mellitus. Arch Ophthalmol1995; 113:36-51.*Rates in cases per 100 person-years at risk.
62Clinically important EW‡ Early* worsening(EW) in Diabetes Control and Complications Trial patients assigned to intensive treatmentClinically important EW‡CWS/IRMA EW†Baseline retinopathy severityNo . (%) with EWNo . of patients0(0.0)3484(1.1)No retinopathy14014(10.0)MA only , one eye2(1.8)10924(22.0)MA only , both eyes6(7.3)8229(48.3)60Mild NPDR6(18.8)32NANA§Moderate NPDRModified from Diabetes Control and Complications Trial Research Group. Early worsening of diabetic retinopathy in the diabetes control and complications trial. Arch Ophthalmol1998; 116: CWS, Cottonwool spot; IRMA, intraretinal microvascular abnormalities; MA, microaneurysms; NPDR, nonproliferative diabetic retinopathy. *Within 6 to 12 months of beginning intensive treatment. †Cottonwool spots or intraretinal microvascular abnormalities. ‡Development of macular edams or of proliferative diabetic retinopathy or severe NPDR. §Not applicable; CWS/lRMA at baseline. .
63Indications for photocoagulation Treatment should be carried out promptly in most eyes with PDR that have well-established NVD or vitreous or preretinal hemorrhage. Treatment is particularly urgent when localized fresh vitreous or preretinal hemorrhageis present because of the risk that dispersion of the hemorrhage throughout the vitreous or recurrent bleeding may soon make treatment more difficult or impossible.
64When visible or suspected new vessels seem insufficient to explain the hemorrhage, special consideration should be given to other possible causes, such as fresh retinal tears, partially avulsed retinal veins, or small patches of new vessels that have been completely avulsed from the disc or retina.
65Complete avulsion of a small new vessel patch from its connections to the disc or retina should be considered as a possible explanation of a recent vitreous hemorrhage when the detached posterior vitreous surface can be seen anterior to the disc or retina and contains a subtle opacity, suggesting a small patch of empty new vessels. This occurrence is uncommon, but not rare, and has a good prognosis. Usually no trace can be seen on the disc or retina of the previous new vessel patch and no treatment is necessary.
66Progressive contraction of fibrous proliferations leading to displacement or detachment of the macula sometimes follows scatter photocoagulation for high-risk characteristics in eyes with extensive fibrous proliferations.
67Few such eyes were included in the DRS, but analyses of them indicated that outcome was better with photocoagulation than without it and suggested that it is only excessively heavy treatment that should be avoided.
68When high-risk characteristics are definitely present, scatter photocoagulation should usually be carried out, despite the presence of fibrous proliferations or localized traction retinal detachment. Areas of fibrous proliferations and retinal detachment should be avoided, and treatment strength should be mild to moderate. It may be desirable to divide treatment between several episodes.
69Of course, photocoagulation is not indicated when PDR is entering the stage of regression, with few or no new vessels and extensive fibrous proliferations.
70Extensive neovascularization in the anterior chamber angle is a strong indication for scatter photocoagulation, if it is feasible , regardless of the presence of high-risk characteristics. Remarkable regression of these new vessels often occurs soon after scatter photocoagulation; if this treatment is carried out before extensive closure of the angle has occurred, full-blown neovascular glaucoma can be prevented.
71When opacities of the media preclude retinal photocoagulation, cryoapplications or vitrectomy with endophotocoagulation may be used, with or without additional direct photocoagulation of the new vessels in the anterior chamber angle.
72The presence of extensive retinal hemorrhage, IRMAs, venous beading, and opaque small arteriolar branches, often accompanied by prominent soft exudates, suggests rapidly progressive closure of the retinal capillary bed and severe retinal ischemia. New vessels are usually present in such eyes but may be relatively unimpressive . Severe retinal ischemia increases the urgency to initiate scatter photocoagulation, whether or not DRS high-risk characteristics are present, since eyes so affected appear to be at greater risk of anterior segment neovascularization.
73Patients should be aware of this risk and the risk of a sudden decrease in central vision , which may occur with occlusion of the remaining arterioles supplying the macula. The clinical impression that scatter photocoagulation may precipitate such an occlusion has led to the suggestion that initial scatter treatment be divided between three or four episodes in the hope of reducing this risk.
74The ETDRS recommended that scatter, treatment not be used in eyes with mild to moderate NPDR but that it be considered for eyes approaching the high-risk stage (i.e., eyes with very severe NPDR or moderate PDR) and that it usually should not be delayed when the high-risk stage is present.The ETDRS recommended that scatter, treatment not be used in eyes with mild to moderate NPOR but that it be considered for eyes approaching the high-risk stage (i.e., eyes with very severe NPDR or moderate PDR) and that it usually should not be delayed when the high-risk stage is present.
75A policy of continued observation would be expected to spare only a minority of eyes from the risks of treatment, while increasing the risk that rapid progression might occur between follow-up visits and that entry into the high-risk stage might be marked by occurrence of a large vitreous hemorrhage, making satisfactory treatment difficult. In choosing between prompt treatment and deferral, the commitment of the patient to careful follow-up and the state of the fellow eye are important factors.
76If visual function decreased in the fellow eye after scatter photocoagulation, deferral of treatment in the second eye may be desirable. On the other band, in a patient whose first eye had an unfortunate outcome without photocoagulation or one with photocoagulation only after PDR was advanced, prompt treatment may be preferable, particularly if close follow-up will be difficult.
77These initial ETDRS recommendations were made without regard to patient age or type of diabetes. Subsequent analyses of ETDRS data suggest that, among patients whose retinopathy is in the severe NPDR to non-high-risk PDR range, the benefit ofprompt treatment is greater in those who have type 2 diabetes (or are older than 40).
78In the type 2 group, the 5-year rate of severe visual loss or vitrectomy was about 5% in eyes assigned to early photocoagulation versus 13% in eyes assigned to deferral, whereas in the type 1 group the rates were about 8% in both treatment groups.
79Greater responsiveness to photocoagulation in older versus younger patients has also been observed in other studies.
80Systemic factors should also be considered in deciding whether to initiate treatment in patients with very severe NPDR or moderate PDR. Clinical impression suggests that progression of retinopathy may accelerate during or with the development of renal failure.
81If photocoagulation is deferred until high-risk characteristics develop, and this occurs in the later stages of pregnancy or when renal transplantation or dialysis is required, these more pressing problems may make it difficult to complete photocoagulation according to a schedule considered optimal from the ophthalmologic point of view. Asalready mentioned.
82Scatter photocoagulation and macular edema Macular edema sometimes increases, at least temporarily, after scatter photocoagulation, and this may be followed by transient or persistent reduction of visual acuity.
83Both the ETDRS and the DRS support the clinical impression that eyes with macular edema requiring scatter treatment are at less risk of visual acuity loss when focal or grid treatment to reduce the macular edema precedes scatter photocoagulation.
84If a delay of scatter treatment seems undesirable, the ETDRS protocol can be used, combining focal/grid treatment for macular edema with scatter treatment in the nasal quadrants at the first episode of photocoagulation and adding scatter in the temporal quadrants at one or more subsequent episodes.
85Certainly, scatter treatment should not be delayed when the risks of vitreous hemorrhage or neovascular glaucoma seem high, regardless of the status of the macula.
86Number of episodes used for scatter treatment The new technique of optical coherence tomography was used in a recent study comparing shorter versus longer spacing between episodes of scatter photocoagulation.
87Among the techniques currently in use, the number of episodes in which initial scatter treatment is carried out varies from one to four or more. Those techniques using a smaller number of larger burns tend toward a single episode with retrobulbar anesthesia, whereas those using a larger number of smaller burns nearly always divide treatment into two or more episode.
88Multiple episodes make it easier to avoid retrobulbar anesthesia and its occasional complications, but theymay cause delays and inconvenience for patients who must travel Iong distances for treatment. Angle-closure glaucoma secondary to serous detachment of the peripheral choroid and ciliary body is less common when scatter treatment is carried out in two or more sessions over a period of 1 or 2 weeks, and some observers believe that small losses in visual acuity may also be less common.
89Thirty-six patients with severe nonproliferative or early proliferative retinopathy and 20/20 vision in each eye at baseline received scatter photocoagulation in the following manner: in one eye, one quadrant was treated every week for 4 weeks and in the other eye, one quadrant was treated every other week for 8 weeks.
90OCT assessment of macular thickness was performed at baseline , before each session of photocoagulation , and at 16 weeks, the end of the follow-up period. Four of 36 eyes in the weekly treatment group and 3 of 36 in the biweeklygroup developed center-involved macular edema with decreased visual acuity (from 20/40 to 20/200), which was treated with photocoagulation.
91At baseline , mean retinal thickness was 191 µm in the central zone of the macular grid (1000 µm in diameter) in both groups. Thickness increased progressively after each weekly treatment to a maximum of 275 µm at week 4 and then decreased to 225 µm at 16 weeks.
92The increase was less after the biweekly treatments and at 16 weeks was closer to, but had not reached, the baseline value. There was little change in retinal thickness outside the central zone with either treatment technique.