Lloyd P. Aiello,
Jerry Cavallerano,
Manvi Prakash,
Lloyd M. Aiello
SIGNIFICANCE OF APPROACHING HIGH-RISK PROLIFERATIVE DIABETIC RETINOPATHY AND CLINICALLY SIGNIFICANT DIABETIC MACULAR EDEMA
Studies first demonstrated evidence of the benefit of scatter (panretinal) laser photocoagulation (PRP) surgery to treat diabetic retinopathy (DR) in 1967.[1] (see Table 133.1 for a list of common abbreviations used in this chapter). Since these promising beginnings, dramatic strides in treating proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME) have been made through the effective use of PRP and other surgical techniques. These benefits have been strongly supported by the findings of three major nationwide randomized controlled clinical trials: the Diabetic Retinopathy Study (DRS),[2-15] the Early Treatment Diabetic Retinopathy Study (ETDRS),[16-34] and the Diabetic Retinopathy Vitrectomy Study (DRVS).[35-39] With appropriate diagnosis, timely intervention and careful follow-up, the risk of severe visual loss from PDR can be virtually eliminated.
TABLE 133.1 -- Abbreviations and Definitions
|
PDR |
Proliferative diabetic retinopathy |
|
NPDR |
Nonproliferative diabetic retinopathy |
|
H/Ma |
Hemorrhages or microaneurysms, or both |
|
HE |
Hard exudates |
|
SE (CWS) |
Soft exudates (cotton-wool spots) |
|
VB |
Venous beading |
|
IRMA |
Intraretinal microvascular abnormality |
|
NVD |
New vessels on or within 1 disk diameter of disc margin |
|
NVE |
New vessels elsewhere in the retina outside of disc and 1 disc diameter from disk margin |
|
FPD |
Fibrous proliferations on or within 1 disc diameter of disc margin |
|
FPE |
Fibrous proliferations elsewhere, not FPD |
|
SVL |
Severe visual loss: Visual acuity ?5/200 at two consecutive completed 4-mo follow-up visits |
|
MVL |
Moderate visual loss: A doubling of the visual angle (e.g., 20/40 to 20/80 at two consecutive completed 4-mo follow-up visits) |
|
CSME |
Clinically significant macular edema |
Nevertheless, DR remains a leading cause of new-onset blindness in the United States for citizens between the ages of 20 and 74 years. Today this blindness usually results from nonresolving vitreous hemorrhage, traction retinal detachment, or DME. However, the 5-year risk of severe visual loss (SVL - visual acuity of 5/200 or worse on two consecutive visits 4 months apart) can be reduced to less than 5% if a person with DR approaching or just reaching high-risk proliferative retinopathy (defined below) receives timely PRP. Furthermore, people with clinically significant diabetic macular edema (CSME) can have the risk of moderate visual loss (MVL - doubling of the visual angle i.e., 20/20 to 20/40) reduced to ?12% or less if they undergo appropriate focal laser surgery. Along with the mainstays of current therapy which include laser surgery and intensive glycemic, blood pressure and lipid control, newer and evolving strategies for eye care include oral protein kinase C inhibitors and intravitreal injections of corticosteroids, and antiangiogenic agents. These novel therapies hold the promise of providing additional efficacious treatment modalities, with fewer side effects than present-day interventions.
Since diabetic retinopathy is often asymptomatic in its most treatable stages, its early detection through regularly scheduled evaluations of DR and DME severity is critical. This chapter reviews the prognostic implications of the lesions of diabetic retinopathy and the risks of progression, with particular emphasis on identifying patients at risk of visual loss and in need of laser surgery. The laser treatment techniques are only generally described in this chapter but are discussed in the chapter on Proliferative DR and are carefully detailed in ETDRS Report no 3 & 4.[18,19]
EPIDEMIOLOGY OF DIABETIC RETINOPATHY
The Center for Disease Control and Prevention estimates that 20.8 million people or 7.0% of the total U.S. population have diabetes, of which 6.2 million people are undiagnosed.[40,41] The vast majority (<90%) of diabetic patients have type 2 diabetes, which is usually diagnosed after 40 years of age, although the prevalence of type 2 diabetes is increasing in children and adolescent populations.[42] People with type 1 diabetes have a lack of insulin production, generally requiring insulin therapy, while people with type 2 diabetes initially demonstrate insulin resistance, although they may also eventually require insulin treatment as the disease progresses or to maximize diabetes control. Although, the likelihood of developing some level of diabetic retinopathy during a lifetime is somewhat higher for persons with type 1 diabetes, people with type 2 diabetes account for the majority of clinical cases of diabetic eye disease because of their overall larger numbers.
DR is a highly specific vascular complication common to both type 1 and type 2 diabetes mellitus. Duration of diabetes is a significant risk factor for the development of retinopathy. After 20 years of diabetes, nearly all patients with type 1 diabetes, and more than 60% of patients with type 2 diabetes, have some degree of retinopathy.[43,44] A pooled data analysis of eight population-based surveys estimates that among ?10.2 million US adults known to have diabetes who are age 40 years or older, the prevalence rates for DR and sight-threatening retinopathy are 40.3% and 8.2%, respectively.[45] Overall, DR affects ?4.1 million US adults age ?40 years, and one out of every 12 persons in this age group has advanced, vision-threatening retinopathy.[46]
At the present time, there are no known cures for DR or DME, and no known means to completely prevent these conditions from occurring. Laser photocoagulation surgery reduces the risk of moderate vision loss from DME and severe vision loss from PDR, but in general does not restore vision once loss has occurred. Laser treatment is generally most effective when initiated at the time a person approaches or just reaches 'high-risk PDR' and before the visual acuity is lost from DME.[24] The 5-year risk of SVL from untreated high-risk PDR may be as high as 60%. DME will develop in up to 10% of all diabetic patients. In 4% of cases, DME affects the central fovea, and, up to 30% of patients with CSME will develop MVL.[47] Since PDR and CSME may cause no ocular or visual symptoms when the retinal lesions are most amenable to treatment, the overriding concern is to identify eyes at risk of visual loss and ensure that patients receive timely evaluation and initiation of laser surgery and other interventions when indicated. Even minor clinical errors in diagnosing the severity of retinopathy (Table 133.9) can result in delay in appropriate care plans and significantly increase the person's risk of visual loss.[48]
TABLE 133.9 -- Comparison of the International Clinical DR Scale and the Early Treatment Diabetic Retinopathy Study (ETDRS) Scale of Diabetic Retinopathy
|
International Classification Level of DR |
ETDRS Level of DR |
|
No apparent retinopathy |
Level 10: DR absent |
|
Mild NPDR |
Level 20; very mild NPDR |
|
Moderate NPDR |
Levels 35, 43, 47; moderate NPDR |
|
Severe NPDR |
Levels 53A-E; severe to very severe NPDR |
|
PDR |
Levels 61,65,71,75,81,85; PDR, high-risk PDR, very severe or advanced PDR |
Derived from: (Wilkinson CP, Ferris FL III, Klein RE, et al: Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology 2003; 110:1677-1682. Chew EY: A simplified diabetic retinopathy scale. Ophthalmology 2003; 110:1675-1676. Fundus Photographic Risk Factors for Progression of Diabetic Retinopathy. ETDRS Report Number 12. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 1991; 98(5 Suppl):823-833. Grading Diabetic Retinopathy From Stereoscopic Color Fundus Photographs-an Extension of the Modified Airlie House Classification. ETDRS Report Number 10. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 1991; 98(5 Suppl):786-806.)
|
DR =diabetic retinopathy; NPDR = Nonproliferative diabetic retinopathy; PDR = Proliferative diabetic retinopathy |
In addition, identification and optimum control of coexisting health and medical problems are critically important as they present a significant risk for the development and progression of DR. (Table 133.2). These factors include pregnancy[49-51] and the metabolic syndromes like chronic hyperglycemia,[52-55] hypertension,[56] renal disease,[54] abdominal obesity, hypercholesterolemia, and dyslipidemia.[34,57,58]Cardiovascular and peripheral autonomic neuropathies are associated with the presence of PDR.[59] Patients with these conditions require careful medical evaluation and treatment, diligent follow-up for progression of diabetic retinopathy, and consideration of early laser photocoagulation surgery.
TABLE 133.2 -- Medical Complications
|
Condition |
Comment |
|
Risk Indicators of Diabetic Retinopathy |
|
|
Joint contractures |
Association of retinopathy and contractures has been established. Eye examination is indicated. Care of joint contractures is important. |
|
Neuropathy |
Peripheral neuropathy may result in difficulty handling contact lenses. Neuropathy in lower extremities may alter mobility in such a way that restoration and maintenance of as much vision as possible is important. Cardiovascular autonomic neuropathy is an independent risk factor for proliferative diabetic retinopathy. |
|
Conditions That May Affect the Course of Diabetic Retinopathy |
|
|
Hypertension |
Appropriate medical treatment is indicated for prevention of cardiovascular disease, stroke, and death. Hypertension itself may result in hypertensive retinopathy superimposed on diabetic retinopathy. |
|
Elevated triglycerides and lipids |
Appropriate management to normalize is important. Proper diet and reduced levels may result in less retinal vessel leakage. |
|
Proteinuria; elevated creatinine |
Aggressive management of renal disease is indicated to avoid renal retinopathy, which may increase risk of progression of diabetic retinopathy. |
|
Cardiovascular disease |
Increased risk of cardiac disease, particularly coronary vascular disease, is often associated with an increase in the attenuation and arteriosclerotic closure of the arterial system of the retina. A decreased risk of hemorrhage into the vitreous may result, but there also may be a decrease in retinal function with associated decrease in vision. Management of cardiovascular disease may help relieve some of the ischemic process in the retina. Aggressive cardiovascular management is important. |
|
Clinical trials |
There are no clinical trials that have specifically shown that control of systemic conditions that may affect the eyes (the four previous entries) prevents the progression of diabetic retinopathy. However, clinical experience suggests an association with the systemic benefits of appropriate treatment of these problems. |
Research studies are investigating how lifestyle changes can delay or even prevent the onset of type 2 diabetes in individuals at high-risk such as <20 million Americans with impaired glucose tolerance. The Diabetes Prevention Program, a study looking at preventing type 2 diabetes in people at high risk, found that the development of diabetes was reduced 58% over 3 years by lifestyle interventions including diet and physical activity.[60] The study also found that in some populations the drug metformin reduced the risk of developing diabetes by 31% over 3 years. The group with greatest response consisted of younger (20-40 years old) people 50-80 pounds overweight. Another medication, acarbose, was found to reduce the risk of developing diabetes by 25% over 3 years in the STOP-NIDDM Trial.[61]
FUNDAMENTAL CLINICAL TRIALS
Large randomized clinical trials have largely determined the strategies for appropriate clinical eye care and management of patients with diabetic retinopathy.
The DRS (Table 133.3) conclusively demonstrated that PRP significantly reduces the risk of SVL from PDR, particularly when high-risk PDR is present.
TABLE 133.3 -- Diabetic Retinopathy Study
|
Major Eligibility Criteria |
|||||||||
|
|||||||||
|
Major Design Features |
|||||||||
|
|||||||||
|
Major Conclusions |
|||||||||
|
|
Prepared by M. Davis, M.D. and the ETDRS Research Group for the American Academy of Ophthalmology Diabetes 2000 Program |
|
* |
VA = visual activity |
The ETDRS provided valuable information concerning the timing of PRP for advancing diabetic retinopathy and conclusively demonstrated that focal photocoagulation for CSME reduces the risk of MVL by 50% or more (Table 133.4). Furthermore, the ETDRS demonstrated that both early PRP (before the onset of high-risk PDR) and deferral of treatment 'until and as soon as high-risk PDR developed' are effective in reducing the risk of SVL. PRP, therefore, should be considered as an eye approaches the high-risk PDR and "usually should not be delayed if the eye has reached the high-risk proliferative stage."[24]
TABLE 133.4 -- Early Treatment Diabetic Retinopathy Study
|
Major Eligibility Criteria |
||||||||||||
|
||||||||||||
|
Major Design Features |
||||||||||||
|
||||||||||||
|
Major Conclusions |
||||||||||||
|
Prepared by M. Davis, M.D. and the ETDRS Research Group for the American Academy of Ophthalmology Diabetes 2000 Program.
Subsequent analysis of the ETDRS data shows that early PRP is particularly beneficial for patients with type 2 diabetes.[62] In type 2 diabetes patients, early PRP substantially reduced subsequent visual loss and the need for vitrectomy. In contrast, in type 1 diabetic patients there was no major benefit compared to the waiting for development of high risk characteristics. Consequently, PRP should be considered in patients with severe or very severe nonproliferative diabetic retinopathy (NPDR) levels, or with PDR less than high risk, especially if they have type 2 diabetes.
The DRVS provided guidelines for the most opportune time to consider vitrectomy surgery for patients with type 1 and type 2 diabetes mellitus with vitreous hemorrhage[35,36,39] or severe PDR in eyes with useful vision.[37,38] Early vitrectomy for eyes with recent severe vitreous hemorrhage and visual acuity less than 5/200 was beneficial, especially for patients with type 1 diabetes mellitus. Furthermore, the chances of achieving visual acuity of 10/20 or better increased when early vitrectomy was performed in eyes with severe new vessels, again, especially for patients with type 1 diabetes mellitus. At the present time, the findings of the DRVS should be viewed with the understanding that substantial subsequent developments in vitrectomy instrumentation, techniques, and the application of endo-laser have come into common use after the conclusion of this study.
The multicenter Sorbinil Retinopathy Trial tested whether a daily dose of sorbinil, an aldose reductase inhibitor (ARI), reduces the complications of DR. Over a 3 year period, the drug had no clinically important effect on the course of DR in adults with type 1 diabetes of moderate duration.[63] The group taking sorbinil, however, did show a slightly slower progression rate in microaneurysm count. Findings also showed no beneficial effect of sorbinil on DR.[64] There were complications from the use of this drug in the study population. Nearly 7% of the initial 202 participants had adverse reactions, including toxic epidermal necrolysis, erythema multiforme, and the Stevens- Johnson syndrome. It is unlikely that sorbinil will achieve prophylactic usage because of the hypersensitivity reactions and outcome similarities between the group treated with sorbinil and the control group in the study.
The Diabetes Control and Complications Trial (DCCT) (Table 133.5) was designed to test whether intensive insulin therapy resulting in improved glycemic control could reduce the risk of onset or progression of retinopathy for persons with type 1 diabetes.(Table 133.6)[65-68] The DCCT found that regardless of the baseline level of glycemic control, a 10% reduction of glycosylated hemoglobin level significantly reduced the risk of onset of DR, retarded the progression of DR, and reduced the need for laser treatment. Intensive therapy reduced the risk of onset of retinopathy by 76%, and resulted in a 63% reduction in the risk of progression of retinopathy. In the intensive insulin therapy group, the risk of developing severe NPDR or PDR was reduced by 47%, the risk of developing CSME was reduced by 23%, and the risk of requiring laser surgery was reduced by 56%.
TABLE 133.5 -- Diabetes Control and Complications Trial
|
Major Eligibility Criteria |
|
Type 1 Insulin Dependent Diabetes Mellitus Age 13-39 years |
|
Absence of hypertension, hypercholesterolemia, and severe diabetic or medical complications |
|
Primary-Prevention Cohort |
|
IDDM for one to five years |
|
No diabetic retinopathy of seven-field stereoscopic fundus photography |
|
Urinary albumin secretion < 40 mg/24 hrs |
|
Secondary-Intervention Cohort |
|
IDDM for 1 to 15 years |
|
Very-mild-to-moderate nonproliferative diabetic retinopathy |
|
Urinary albumin secretion < 200 mg/24 h |
|
Major Design Features |
|
Patients randomized to Conventional Treatment or Intensive Treatment Group |
|
Conventional Treatment Group |
|
insulin injections once or twice a day |
|
daily blood glucose tests |
|
daily self-monitoring of urine or blood glucose |
|
clinical visits every three months |
|
education about diet and exercise |
|
Intensive Treatment Group |
|
insulin pump or three or more insulin injections a day |
|
insulin dosage adjusted according to self-monitoring of blood glucose, diet, and exercise |
|
blood sugar tests four or more times/day |
|
diet and exercise plan |
|
initial hospitalization to implement treatment |
|
weekly to monthly clinical visits with frequent telephone contact |
|
Major Conclusions |
|
Reduced clinically meaningful retinopathy by 27-76% |
|
Reduced clinically meaningful nephropathy by 34-57% |
TABLE 133.6 -- PDR AT 1-YR Visit by Severity of Individual Lesion
|
Lesion |
Grade |
PDR in 1 Year (%) |
|
HMA |
Present in 2-5 fields |
9 |
|
Very severe |
57 |
|
|
IRMA |
None |
9 |
|
Moderate in 2-5 fields |
57 |
|
|
VB |
Lacking |
15 |
|
Present in 2-5 fields |
59 |
The Epidemiology of Diabetes Intervention and Complications (EDIC) Study followed the DCCT patient cohort after all patients were converted to intensive insulin therapy. Of major clinical importance was the finding that despite the fact that glycemic control as measured by HbA1c became virtually equivalent between groups, the benefits of early intensive therapy persisted with continuing benefit of reduced rates of retinopathy progression observed in patients who formerly had intensive insulin therapy. Similar risk reductions of other microvascular complications such as renal disease and neuropathy were also observed. Thus, early optimal control of blood glucose is critically important for long-term ocular and systemic outcome.[69,70]
The United Kingdom Prospective Diabetes Study (UKPDS)[71,72] and studies in Japan[73] found similar results in patients with type 2 diabetes and also identified elevated blood pressure as an independent risk factor for the onset and progression of DR. The UKPDS enrolled 3867 patients with newly diagnosed type 2 DM. Intensive blood glucose control with either sulphonylureas or insulin resulted in a 17% risk reduction for progression of DR, a 29% risk reduction in the need for laser photocoagulation surgery, a 23% risk reduction for the development of vitreous hemorrhage, and a 16% risk reduction in legal blindness.
DIAGNOSIS, CLASSIFICATION, AND MANAGEMENT OF DIABETIC RETINOPATHY
RETINAL LESIONS
Various retinal lesions identify the risk of progression of retinopathy and visual loss. (Table 133.6)
Subtle venous caliber changes and retinal 'microaneurysms' are generally the first clinically evident signs of DR. Microaneurysms are saccular outpouchings of retinal capillaries possibly due to endothelial cell proliferation.(Fig. 133.1) Ruptured microaneurysms, decompensated capillaries, and intraretinal microvascular abnormalities result in 'intra-retinal hemorrhages.' The clinical appearance of these hemorrhages reflects the retinal architecture at the level at which the hemorrhage occurs. Hemorrhages in the nerve fiber layer assume a more flame-shaped appearance, coinciding with the structure of the nerve fiber layer that runs parallel to the retinal surface. Hemorrhages deeper in the retina, at which point the arrangement of nerve fibers is more or less perpendicular to the surface of the retina, assume a dot or blot shape.
|
|
|
|
FIGURE 133.1 Standard photograph No. 2A of the Modified Airlee House Classification of Diabetic Retinopathy demonstrating a moderate degree of hemorrhage or microaneurysms, or both. |
'Intra-retinal microvascular abnormalities' (IRMAs) (Fig. 133.2) represent preexisting vessels with endothelial cell proliferation that become 'shunts' through the areas of nonperfusion. IRMAs may be seen adjacent to cotton-wool spots. Multiple IRMAs mark a severe stage of nonproliferative retinopathy with a high risk of development of frank neovascularization. Retinal neovascularization commonly occurs in areas of previously existing IRMA.
|
|
|
|
FIGURE 133.2 Standard photograph No. 8A of the Modified Airlie House Classification of Diabetic Retinopathy demonstrating intraretinal microvascular abnormalities (IRMAs) (arrows). |
'Venous caliber abnormalities' (Fig. 133.3) are indicators of retinal hypoxia. These abnormalities can be venous dilatation, venous beading, or venous loop formation. There are often large areas of nonperfusion adjacent to these veins. PRP may cause these abnormal veins to become less dilated and more regular.
|
|
|
|
FIGURE 133.3 Standard photograph No. 6B of the Modified Airlie House Classification of Diabetic Retinopathy demonstrating venous beading. |
'Proliferative retinopathy' (Fig. 133.4) is marked by development of retinal neovascularization. The rate of growth of these new vessels is variable. They most commonly appear at or near the optic disc (neovascularization of the disk NVD) or elsewhere in the retina (neovascularization elsewhere NVE) and proliferate on the posterior vitreous face. They may also arise in the perifoveal area.
|
|
|
|
FIGURE 133.4 Standard photograph No. 10A of the Modified Airlie House Classification of Diabetic Retinopathy demonstrating neovascularization of the optic disc (NVD) (arrow), covering approximately one quarter to one third of the disc area. |
Patients with high-risk PDR require immediate PRP (see Chapter 135). High-risk PDR is characterized by one or more of the following lesions:
|
. |
NVD that is ?one-quarter to one-third disc area or more in size (i.e., ?1/4 - 1/3 disk area) (Fig. 133.4), |
|
|
. |
NVD > one-quarter disc area in size if fresh vitreous or preretinal hemorrhage is present, and |
|
|
. |
NVE ?1/2 disc area in size if fresh vitreous or preretinal hemorrhage is present (Fig. 133.5). |
|
|
|
|
FIGURE 133.5 Standard photograph No. 7 of the Modified Airlie House Classification of Diabetic Retinopathy demonstrating neovascularization elsewhere (NVE) in the retina greater than one half disk diameter with a fresh hemorrhage present. |
Thus, the evaluation of the diabetic retina for PDR requires attention to the presence, location and extent of new vessels and the presence or absence of preretinal or vitreous hemorrhages.[4]
NONPROLIFERATIVE DIABETIC RETINOPATHY (NPDR) AND EARLY PDR
As described earlier, it is critically important to consider PRP as retinopathy approaches or reaches the high-risk stage of PDR. An eye is considered to be approaching the high-risk stage when there are retinal signs of severe or very severe NPDR or the presence of PDR without high risk characteristics. The baseline severity of retinopathy is closely correlated with the risk of NPDR progression to early PDR and to high-risk PDR (Tables 133.6 to 133.8), making accurate assessment of NPDR severity not only important for identifying timing of laser surgery, but also for determining future follow-up schedules to minimize risk between ophthalmic examinations.
TABLE 133.8 -- General Management Recommendations
|
Natural Course |
Evaluation |
Treatment Strategies |
|||||
|
Rate of Progression to: |
|||||||
|
Level of Retinopathy |
PDR 1 Yr |
HRC[*] 5 Yr |
Color Fundus Photograph |
FA[?] |
PRP[?] |
Focal |
Follow-Up (mos) |
|
Mild NPDR |
5% |
15% |
|||||
|
No macular edema |
No |
No |
No |
No |
12 |
||
|
Macular edema |
Yes |
Occasionally |
No |
No |
4-6 |
||
|
CSME |
Yes |
Yes |
No |
Yes |
2-4 |
||
|
Moderate NPDR |
12-27% |
33% |
|||||
|
No macular edema |
Yes |
No |
No |
No |
6-8 |
||
|
Macular edema (not CSME) |
Yes |
Occasionally |
No |
No |
4-6 |
||
|
CSME |
Yes |
Yes |
No |
Yes |
2-4 |
||
|
Severe NPDR |
52% |
60% |
|||||
|
No macular edema |
Yes |
No |
Rarely |
No |
3-4 |
||
|
Macular edema (not CSME) |
Yes |
Occasionally |
Occasionally after focal |
Occasionally |
2-3 |
||
|
CSME |
Yes |
Yes |
Occasionally after focal |
Yes |
2-3 |
||
|
Very severe NPDR |
75% |
75% |
|||||
|
No macular edema |
Yes |
No |
Occasionally |
No |
2-3 |
||
|
Macular edema (not CSME) |
Yes |
Occasionally |
Occasionally after focal |
Occasionally |
2-3 |
||
|
CSME |
Yes |
Yes |
Occasionally after focal |
Yes |
2-3 |
||
|
Nonhighrisk PDR |
75% |
||||||
|
No macular edema |
Yes |
No |
Occasionally |
No |
2-3 |
||
|
Macular edema (not CSME) |
Yes |
Occasionally |
Occasionally after focal |
Occasionally |
2-3 |
||
|
CSME |
Yes |
Yes |
Occasionally after focal |
Yes |
2-3 |
||
|
Highrisk PDR |
|||||||
|
No macular edema |
Yes |
No |
Yes |
No |
2-3 |
||
|
Macular edema |
Yes |
Yes |
Yes |
Usually |
1-2 |
||
|
CSME |
Yes |
Yes |
Yes |
Yes |
1-2 |
||
|
* |
HRC = highrisk characteristic proliferative retinopathy |
|
? |
FA = fluorescein angiography. |
|
? |
PRP = pan-retinal photocoagulation. |
Nonproliferative Diabetic Retinopathy Severity
DR is broadly classified as NPDR and PDR. DME can occur with either NPDR or PDR and is discussed separately. Accurate diagnosis of a patient's 'DR severity level' is critical because there is a varying risk of progression to PDR and high-risk PDR depending on the specific NPDR severity level.(Fig. 133.6); (Table 133.8)
|
|
|
|
FIGURE 133.6 Life table cumulative event rates of high-risk proliferative retinopathy by level of retinopathy severity scale at baseline in eyes assigned to deferral of photocoagulation in the ETDRS. Level > 35, mild nonproliferative diabetic retinopathy (NPDR); level 43, moderate NPDR; level 47, moderate to severe NPDR; level 53A-D, severe NPDR; level 53E, very severe NPDR; level 61, early proliferative diabetic retinopathy (PDR); level 65, PDR > high-risk PDR.[27] |
'Mild NPDR' is marked by at least one retinal microaneurysm, but hemorrhages and microaneurysms are less than those in ETDRS standard photograph No. 2A (Fig. 133.1 and Table 133.7). No other retinal lesion or abnormality associated with diabetes is present. Those with mild NPDR have a 5% risk of progression to PDR within 1 year and a 15% risk of progression to high-risk PDR within 5 years (Table 133.8).
TABLE 133.7 -- Levels of Retinopathy
|
Nonproliferative Diabetic Retinopathy (NPDR) |
||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||
|
Proliferative Diabetic Retinopathy (PDR) |
||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||
|
Clinically Significant Macular Edema (CSME) |
||||||||||||||||||||||||||||||||||||||||||
|
'Moderate NPDR' (Table 133.7) is characterized by hemorrhages or microaneurysms, or both (H/Ma), greater than or equal to those pictured in ETDRS standard photograph No. 2A. Soft exudates, venous beading, and IRMAs are definitely present in a mild degree. The risk of progression to PDR within 1 year is 12-27%, and the risk of progression to high-risk PDR within 5 years is 33 percent (Table 133.8).
Patients with mild or moderate NPDR generally are not candidates for PRP and can be followed safely at 6-12 month intervals as determined by the examiner. The presence of macular edema, even with mild or moderate degrees of NPDR, requires follow-up in a shorter period, and if CSME is present, focal laser treatment should be considered (Table 133.8). Coincident medical problems or pregnancy will generally necessitate a more frequent period of reevaluation.
'Severe NPDR', based on the severity of H/Ma, IRMAs, and venous beading, is characterized by any one of the following lesions (see Table 133.7):
|
. |
H/Ma × standard photograph No. 2A (Fig. 133.1) in four quadrants, or |
|
|
. |
Venous beading (Fig. 133.3) in two or more quadrants, or |
|
|
. |
IRMAs × standard photograph No. 8A (Fig. 133.2) in at least one quadrant. |
These criteria are often referred to as the '4-2-1-rule' for determination of severe NPDR. Any two or more of the above findings reflects very severe NPDR. Eyes with severe NPDR have a 52% risk of developing PDR within 1 year and a 60% risk of developing high-risk PDR within 5 years. These patients require follow-up evaluation at 2-4 months intervals. Treatment of CSME is strongly indicated because of the risk of the development of PDR and high-risk PDR. In addition, some eyes with macular edema, even if not clinically significant, may require focal treatment in preparation for impending PRP (Table 133.8).
Eyes with very severe NPDR (Table 133.7) have two or more lesions of severe NPDR but no frank neovascularization. There is a 75% risk of developing PDR within 1 year. Patients with very severe NPDR may be candidates for PRP, and, macular edema if present, may require treatment. Very close follow-up evaluation at 2-3 month intervals is important (Table 133.8). For type 2 diabetes, early PRP should be considered for patients with severe or very severe NPDR.[62]
Early Proliferative Diabetic Retinopathy
Diabetic retinopathy marked by NVD or NVE on the retina or by fibrous tissue proliferation is designated PDR. Early PDR does not meet the definition of high-risk PDR (Table 133.7). Eyes with early PDR (> high-risk PDR) have a 75% risk of developing high-risk PDR within a 5-year period. These eyes may prompt PRP; and macular edema, sometimes even if not clinically significant, may benefit from focal treatment before scatter treatment is initiated (Table 133.8).
Patients with severe and very severe NPDR and early PDR (>high-risk PDR) should be considered for early PRP. This is particularly true if there are new vessels in the presence of severe or very severe NPDR, elevated new vessels, or NVD. In the presence of macular edema, patients with severe NPDR or worse should be considered for prompt focal treatment of macular edema, possibly whether the macular edema is clinically significant or not, in preparation for the impending need of PRP which can exacerbate any DME present at the time of treatment (Table 133.8).
INTERNATIONAL CLASSIFICATION OF DIABETIC RETINOPATHY
In an effort to simplify classification and standardize communication, the American Academy of Ophthalmology initiated a project to establish a consensus International Classification of DR and DME.[74,75]This International Classification of DR and DME described five clinical levels of diabetic retinopathy: no apparent retinopathy (no abnormalities), mild NPDR (microaneurysms only), moderate NPDR (more than microaneurysms only but less than severe NPDR), severe NPDR (any of the following: <20 intraretinal hemorrhages in each of four quadrants, definite VB in two or more quadrants, prominent IRMA in one or more quadrant and no PDR), and PDR (one or more of retinal neovascularization, vitreous hemorrhage, or preretinal hemorrhage). Table 133.9 compares levels of DR in the International Classification of DR to ETDRS levels of DR.
The International Classification identified two broad levels of DME: macular edema apparently absent (no apparent retinal thickening or hard exudates (HE) in posterior pole) and macular edema apparently present (some apparent retinal thickening or HE in posterior pole); if present, macular edema was subclassified as 'mild DME' (some retinal thickening or HE in posterior pole but distant from center of the macula), 'moderate DME' (retinal thickening or HE approaching the center of the macula but not involving the center), or 'severe DME' (retinal thickening or HE involving the center of the macula). Table 133.10 compares levels of DME in the International Classification to ETDRS levels of DME.
TABLE 133.10 -- Comparison of International Clinical DME Scale and ETDRS Scale
|
Disease Severity Level |
Findings |
DME vs. ETDRS scale |
|
DME apparently absent |
No apparent retinal thickening or hard exudates (HE) in posterior pole |
No DME |
|
DME apparently present |
Some apparent retinal thickening or HE in posterior pole |
Mild DME: some retinal thickening or HE in posterior pole but distant from center of the macula (ETDRS: DME but not CSME) |
|
Moderate DME: retinal thickening or HE approaching the center but not involving the center (ETDRS: CSME) |
||
|
Severe DME: retinal thickening or HE involving the center of the macula (ETDRS: CSME, center involved) |
|
DME=diabetic macular edema; HE=hard exudates; CSME=clinically significant macular edema. |
This International Classification of DR and DME reduces the number of levels of DR, simplifies descriptions of the categories, and describes the levels without relying on reference to the standard photographs of the Airlie House Classification of DR. Thus, the International Classification simplifies the clinical levels of diabetic retinopathy, easing the communication between clinicians. However, since the International Classification is less detailed than the ETDRS retinopathy severity scale, the International Classification of DR and DME is not a replacement for the ETDRS scale in large clinical trials or studies where precise retinopathy classification is required.
ROLE OF FLUORESCEIN ANGIOGRAPHY IN THE MANAGEMENT OF DIABETIC RETINOPATHY
Fluorescein angiography of the macula in the presence of CSME is fundamental for the detection of treatable lesions, as described below. However, its use to identify lesions such as NVE, NVD, or retinal thickening is generally not necessary as these lesions are usually detectable by clinical exam. Angiographic risk factors for progression of NPDR to PDR have been identified.[26,28] Analysis of data from the untreated (deferred) eyes in the ETDRS indicates that the following lesions are independently related to outcome: (1) fluorescein leakage, (2) capillary loss on fluorescein angiography, (3) capillary dilatation on fluorescein angiography, and (4) the following color fundus photographic risk factors: IRMAs, venous beading, and H/Ma. Hard and soft exudates have an inverse relationship to progression. It is widely accepted that capillary loss as documented on fluorescein angiography is a risk factor for progression of NPDR to PDR.[26,28,76-78] However, capillary dilatation on fluorescein angiography, fluorescein leakage, and capillary loss on fluorescein angiography, and the ETDRS color fundus photographic retinopathy severity levels are all closely correlated. Although the fluorescein angiography abnormalities provide additional prognostic information, the color fundus photographic grading of retinopathy severity levels give the same prognostic results.[27,28] The increased power to predict progression from NPDR to PDR by fluorescein angiography is generally considered "not of significant clinical importance to warrant routine fluorescein angiography."[28]
Periodic follow-up retinal examinations, however, are necessary. The appropriate interval can be determined by skillful grading of seven standard field stereo color fundus photographs or by retinal examination by an ophthalmologist experienced in the management of diabetic eye disease. Since the severity of diabetic retinopathy is predictive of progression and establishes frequency of follow-up, and since initiation of PRP should be considered as diabetic retinopathy approaches the high-risk stage, routine life-long "periodic follow-up of all patients with diabetic retinopathy continues to be of fundamental clinical importance."[28]
Other imaging modalities also add vital information to the evaluation of DR. The introduction of optical coherence tomography (OCT) has permitted evaluation of macular thickening and vitreo-retinal interface abnormalities in a quantitative, highly sensitive and reproducible manner.[79] OCT is valuable in confirming or elucidating subtle macular pathology such as persistent edema, preretinal fibrosis, and vitreo-macular traction that might otherwise be difficult or impossible to appreciate on clinical exam. However, OCT does not provide substantive information on the extent or location of the retinal lesions characterizing NPDR as does photography, nor does it identify the source or activity of retinal leakage as can angiography. Although visual acuity is generally correlated with central macular thickness, the variability is large, making current models of OCT inadequate for use as a surrogate for visual acuity in clinical trials.[80] New spectral domain models of OCT have been approved by the FDA and promise entirely new methods and sensitivity of evaluating retinal pathology that will require study to fully elucidate their role in the clinical management and research investigation of diabetic retinopathy.
DIABETIC MACULAR EDEMA
Diabetes can affect the macula and macular function through a variety of mechanisms including:
|
1. |
Macular edema; i.e., a collection of intra-retinal fluid in the macula, with or without lipid exudates and with or without cystoid changes; |
|
|
2. |
Nonperfusion of perifoveal capillaries, with or without intra-retinal fluid; |
|
|
3. |
Traction in the macula by fibrous or glial tissue causing dragging of the retinal tissue, surface wrinkling, or detachment of the macula; |
|
|
4. |
Intra-retinal or preretinal hemorrhage in the macula; |
|
|
5. |
Lamellar or full-thickness retinal hole formation; |
|
|
6. |
Any combination of the preceding and other mechanisms. |
Diabetic macular edema may be present at any level of retinopathy (Table 133.8). For clinical purposes, 'macular edema' is defined as retinal thickening within two disk diameters of the center of the macula (not fluorescein leakage without thickening). Retinal thickening or hard exudates with adjacent retinal thickening that threatens or involves the center of the macula is considered to be clinically significant.
CSME as defined by the ETDRS includes any one of these lesions (see Table 133.7):
|
1. |
Retinal thickening at or within 500 ?m of the center of the macula (Fig. 133.7); or |
|
|
2. |
Hard exudates at or within 500 ?m s of the center of the macula, if there is thickening of the adjacent retina (Fig. 133.8); or |
|
|
3. |
An area or areas of retinal thickening at least one disk area in size, at least part of which is within 1 disk diameter of the center of the macula (Figs 133.9 and 133.10). |
|
|
|
|
FIGURE 133.7 Schematic representation of clinically significant macular edema (CSME), with thickening of the macula less than 500 ?m from the center of the macula. |
|
|
|
|
FIGURE 133.8 (a) Schematic representation of CSME with hard exudates at or within 500 ?m of the center of the macula, with thickening of the retina adjacent to the exudates. (b) Clinical appearance of hard exudates less than 500 ?m from the center of the macula. There is thickening of the adjacent retina, which is not appreciated without stereoscopic observation. |
|
|
|
|
FIGURE 133.9 Schematic representation of area of thickening, 1 disk diameter in size, part of which is within 1 disk diameter of the center of the macula. |
|
|
|
|
FIGURE 133.10 Clinical photograph showing macular edema greater than 500 ?m from the center of the macula (the edema is not appreciated without stereoscopic evaluation). |
There are particular retinal lesions identified on fluorescein angiography that are amenable to treatment. The 'treatable lesions' associated with macular edema include:
|
1. |
Focal leaks <500 ?m from the center of the macula thought to be causing retinal thickening or hard exudates (Fig. 133.11), |
|
|
2. |
Focal leaks 300 to 500 ?m from the center of the macula thought to be causing retinal thickening or hard exudates if the treating ophthalmologist does not believe that treatment is likely to destroy the remaining perifoveal capillary network (Fig. 133.11), |
|
|
3. |
Areas of diffuse leakage that have not been treated previously (Fig. 133.12), or |
|
|
4. |
Avascular zones, other than the normal foveal avascular zone, not previously treated (Fig. 133.12b). |
|
|
|
|
FIGURE 133.11 (a) There is a small area of retinal thickening just above the center of the macula (poorly appreciated without stereopsis), which is detectable monocularly because of blurring of the choroidal pattern. Several microaneurysms are visible within the thickened area. There are hard exudates around the edges of the edematous patch, some of which extends almost to the center of the macula. Thickening extends to within 500 ?m of the center of the macula (clinically significant macular edema). Visual acuity is 20/15. (b) In the 17- to 18-sec phase of the fluorescein angiogram, microaneurysms and slightly dilated capillaries are visible in the area of thickening. (c) The 7-min phase of the angiogram shows leakage into the retina from the two groups of microaneurysms noted in (b). (d) Treatment has been applied to most of the microaneurysms. (e) Four months later, the appearance of the retina is satisfactory: The center of the macula is flat and most of the thickening noted before treatment has disappeared. Visual acuity remains at 20/15. |
|
|
|
|
FIGURE 133.12 (a) Clinical photograph showing retinal thickening temporal to the center of the macula extending just to the center. Visual acuity is 20/40+3. (b) Early phase of the angiogram shows capillary loss adjacent to the foveal avascular zone, capillary dilatation, and scattered microaneurysms. (c) The 7-min phase of the angiogram shows extensive small cystoid spaces temporal to the center of the macula and above and below it. The center appears uninvolved. (d) The microaneurysms have been treated focally. In addition, laser burns have been applied in a grid pattern to the areas of diffuse leakage. (e) The temporal extent of the grid laser treatment. (f) Four months later, hemorrhages and hard exudates have decreased, and the retinal thickening can no longer be detected. Visual acuity is 20/25. (g) The 7-min phase of the angiogram showing disappearance of most of the cystoid spaces visible in (c). |
Focal laser surgery for CSME consists of either direct laser treatment, grid laser treatment, or a combination of direct laser to focal leaks and grid laser treatment to diffuse leakage or thickened avascular macula. These treatment methods are described in detail elsewhere.[17,19] Table 133.8 summarizes the management recommendations for CSME at the various retinopathy levels.
LASER PHOTOCOAGULATION FOR DIABETIC MACULAR EDEMA AND NONPROLIFERATIVE DIABETIC RETINOPATHY
The 5-year risk of MVL from macular edema in the ETDRS without focal laser treatment was 30%. Focal laser surgery for CSME reduced this risk to 15%,[16] amounting to a 50% reduction in the risk of moderate visual loss. Focal treatment also increased the chance of improvement in visual acuity of one line or more, but in general, vision remains approximately constant. Conversely, PRP was not effective in treating diabetic macular edema and in some cases may have had a deleterious effect on the progression of macular edema.
Eyes with CSME and retinopathy that is approaching high-risk PDR are best treated first with focal photocoagulation for the macular edema 6-8 weeks before initiating PRP. Eyes with mild or moderate NPDR and CSME respond best to prompt focal photocoagulation, with scatter treatment delayed unless severe or very severe NPDR or high-risk PDR occurs. Delaying PRP while focal treatment is being completed in these patients is unlikely to increase the risk of SVL provided that the retinopathy is not progressing rapidly and careful follow-up can be maintained. In contrast, in eyes with CSME and high-risk PDR, delaying PRP while focal treatment is completed usually is not advisable. In these cases, the DME treatment will generally be completed and the PRP begun during the same initial laser treatment session.
Focal treatment was not attended by adverse effects on central visual field or color vision when compared with eyes assigned to deferral of focal treatment.[17] Any harmful effects of early photocoagulation reflected by constriction of the peripheral visual fields were primarily attributable to PRP. Since the principal benefit of laser for CSME is to prevent a further decrease in visual acuity, laser surgery should be considered in all eyes with CSME, especially if the center of the macula is threatened or involved, even if normal visual acuity is present.
The DRS had demonstrated in 1976 that PRP was effective in reducing the risk of severe visual loss from high-risk PDR. Since, the DRS did not provide a clear choice between prompt treatment and deferral of treatment unless there was progression to high-risk PDR, one question of concern for the subsequent ETDRS was whether earlier PRP, before the development of high-risk PDR, justified the side effects and attendant risks of laser surgery. (Table 133.11)
TABLE 133.11 -- Complications and Side Effects of Scatter (Panretinal) Laser Photocoagulation
|
Side Effects |
|
Field constriction and nyctalopia: Depends upon extent and intensity of scatter laser burns |
|
Serous or choroidal detachment |
|
Pain |
|
Peripheral retina-more painful |
|
Use retrobulbar anesthesia as needed |
|
Reassurance |
|
Hypoglycemia |
|
Anxiety, pain, shock, seizure |
|
Complications |
|
Foveal burn |
|
Identify landmarks prior to treatment |
|
Macular edema |
|
May result in permanent decrease in visual acuity |
|
Foveal traction |
|
Do not treat over blood |
|
Avoid puncture of Bruch's membrane |
|
Acute angle-closure glaucoma |
|
Possible but rare |
|
Anterior segment |
|
Posterior synechiae |
|
Cornea and lens burns |
|
Internal ophthalmoplegia |
|
Less frequent with multiple sessions and light to moderately intense burns |
|
Retrobulbar hemorrhage following retrobulbar injection |
|
Continue with treatment |
|
Watch central retinal artery |
|
Retrobulbar anesthesia required infrequently |
|
Loss of follow-up may result from |
|
Pain |
|
Retrobulbar hemorrhage |
|
Intercurrent illness |
|
Lack of caring explanation |
|
Lack of persistent rescheduling |
In the ETDRS, early treatment, compared with deferral of photocoagulation until high-risk PDR developed,[22] was associated with a small reduction in the incidence of SVL, but 5 year rates of SVL were low for both the early treatment group and the group assigned to deferral of treatment (2.6% and 3.7%, respectively). However, for patients with type 2 diabetes, earlier laser photocoagulation, even for eyes with severe or very severe NPDR, does reduce the risk of severe vision loss.[62] Provided careful follow-up can be maintained, PRP is not recommended for eyes with mild or moderate NPDR since the benefits are small and the risks equivalent as compared with treating more severe retinopathy.[24] When retinopathy is more severe (i.e., severe or very severe NPDR and early PDR), PRP should be considered especially in patients with type 2 diabetes[24] as the benefits of early photocoagulation are greater. When both eyes are approaching the high-risk stage, initiating PRP early in at least one eye seems particularly appropriate as optimal timing of photocoagulation may be difficult if both eyes need photocoagulation simultaneously. Also, prompt PRP should be considered for eyes with neovascularization in the anterior chamber angle, whether or not high-risk proliferative retinopathy is present.
Table 133.8 presents the treatment program for DR, and the evaluation and treatment of PDR is discussed extensively in the PDR chapter. Focal photocoagulation for macular edema generally uses a 50 ?m spot size (50-100 ?m in the ETDRS) to photocoagulate discrete lesions (such as microaneurysms that fill or leak during fluorescein angiography) or to place a grid over diffusely thickened areas and nonperfusion. Treatment is placed from 500-3000 ?m from the center of the macula as discussed earlier. Response to treatment is generally asses-sed after 3-4 months and retreatment or a new therapeutic approach considered at that time for persistent or worsening CSME. Complications and side effects of laser photocoagulation are summarized in Table 133.11.
In summary, focal/grid laser photocoagulation reduces moderate visual loss from CSME by 50%. PRP significantly reduces the risk of SVL from PDR but can also exacerbate DME. Thus, treatment of DME in patients approaching high risk retinopathy should be considered before PRP is urgently required (i.e., with the development of high risk PDR). Early PRP reduces the risk of severe visual loss, but the rates of SVL are low. Nevertheless, there is a clear benefit for early treatment in patients with type 2 diabetes. Consequently, it is recommended that PRP not be used for mild to moderate NPDR. For severe NPDR and early PDR, PRP is most appropriate when close follow-up is unlikely, the disease process is progressing rapidly, or for patients with type 2 diabetes.
NOVEL AND EVOLVING THERAPIES FOR DIABETIC RETINOPATHY AND DIABETIC MACULAR EDEMA
The rapid advancement of scientific research over the past decade has tremendously expanded our understanding of the molecular and cellular mechanisms underlying the development of NPDR, PDR and DME. With this added knowledge has come new insight into targets for therapeutic intervention. Currently new agents that may reduce complications of diabetes in the eye are in various stages of evaluation. Among those with significant clinical trial and use are intra-vitreal steroids, intra-vitreal antiangiogenic agents and oral PKC-? inhibitors as agents of particular interest. These agents hold promise not only for additional, possibly more efficacious therapies, but also for fewer associated side effects since they do not share the inherently retinal destructive nature of laser treatment.
The need to evaluate numerous new therapies in a scientifically rigorous and timely manner has prompted development of clinical trial networks. The National Eye Institute funded Diabetic Retinopathy Clinical Research Network (DRCR.net
), initiated in 2002, is a collaborative effort with the goal of facilitating multicentric clinical research to study the effectiveness of new treatments of diabetic retinopathy and diabetic macular edema. The DRCR.net currently includes over 160 participating sites in more than 40 states, representing in excess of 500 physicians and 1000 other personnel.
To date, two DRCR.net studies have been reported. The first study was an observational study evaluating the relationship between OCT measured retinal thickness and visual acuity.[80] Diurnal variation in retinal thickening as measured by OCT was also assessed.[81] The study showed occasional diurnal variation in retinal thickening in patients with CSME but not to an extent that would generally affect clinical trial research. However, it was found that although retinal thickness and visual acuity are modestly correlated, there is substantial variability. Substantial proportions of patients may have paradoxical responses (i.e., improved vision despite retinal thickening, or declining vision with resolution of excess retinal thickening).
The second study compared standard laser (modified ETDRS protocol) with a mild macular grid (MMG) treatment for treating CSME.[82] MMG entailed light burns spread across the macula in areas of both thickened and unthickened retina. Although both MMG and modified ETDRS treatment were found effective in reducing retinal thickening and improving vision in patients with CSME, the magnitude of effect of MMF was not as robust as modified ETDRS and side effects were similar. Thus, the MMG approach is not being evaluated further by large scale studies.
There are three DRCR.net studies currently in the follow-up phase, all involving the treatment of CSME. The first study is comparing peribulbar triamcinolone acetonide (Kenalog) with focal laser (modified ETDRS) photocoagulation. Patients were randomized to receive either laser, steroid (by anterior subtenon or posterior subtenon injection), or both. Completion of the initial primary endpoint follow-up phase presented at a national scientific meeting demonstrated that the peribulbar application of Kenalog did not show any additional benefit to laser treatment alone.[83]
Another study is comparing 1 or 4 mg intra-vitreal injection of a preservative free triamcinolone acetonide with laser for treatment of CSME. This study is currently ongoing. Early studies of intravitreal administration of corticosteroids have shown a transient reduction in excess retinal thickening in patients with CSME. Vision can improve, although this improvement does not always occur, and the effect generally wears off necessitating repetitive injections. Intra-vitreal injection of steroid is associated with development of cataract and the potentially severe side effects of glaucoma and endophthalmitis. (see also PDR chapter for further details on intra-vitreal steroid therapies).
Another set of DRCR.net studies is evaluating the antiangiogenic agents Bevacizumab (Avastin, Genentech, Inc.)[84,85] and Ranibizumab (Lucentis, Genentech, Inc.)[86] for the treatments of CSME. These agents block the potent angiogenic and permeability factor called vascular endothelial growth factor (VEGF). VEGF is known to be involved in mediating PDR and DME and is described in detail in the chapter on PDR. Bevacizumab and Ranibizumab are humanized antibodies or antibody fragments, respectively, that bind all isoforms of VEGF with high affinity. Ranibizumab is FDA approved for the treatment of neovascular age-related macular degeneration (AMD) while bevacizumab is FDA approved for the systemic treatment of certain cancers.
Pegaptanib (Macugen, Eyetech Pharmaceuticals) is an aptamer with high affinity for only the VEGF120 isoform and is FDA approved for the treatment of neovascular AMD. Recently, a pharmaceutically sponsored Phase II trial of pegaptanib intravitreally injected every 6 weeks was completed involving 172 patients. Median visual acuity, visual acuity improvement of 10 or more letters, median retinal thickness and need for photocoagulation were all better after 36 weeks of treatment with 0.3 mg pegaptanib as compared with sham injections.[87] Phase III trials with pegaptanib for diabetic macular edema are currently underway.
The DRCR.net
is currently recruiting or will soon initiate several additional clinical trials. These trials include evaluating if subgroups of DME will benefit from vitrectomy, determining the incidence of macular edema (as measured by OCT) following various modalities of PRP, identifying risks of subsequent DME in patients with subclinical DME, evaluating the effect of adjunctive therapies (steroids or VEGF inhibitors) when used with PRP for the prevention and/or treatment of macular edema, and the effect of adjunctive therapies at the time of cataract surgery to evaluate their ability to prevent and/or improve diabetic macular edema.
At this time, the available clinical evidence suggests that anti-VEGF and possibly other antiangiogenic agents will have a substantial effect on ameliorating neovascular disease. Although it is likely that these will also have benefit for the treatment of CSME, initial data suggests that the effect may be partial and require repetitive administration to maintain the effects. Results of ongoing clinical trials will be necessary before enough is known about the efficacy and side effects of these new agents to assess their impact on the clinical care of diabetic eye disease. The role of these agents for preventing progression of NPDR is theoretical at present and awaits trials specifically designed to address this issue.
PKC-? activation is induced by hyperglycemia through several mechanisms and in part mediates the development of vascular dysfunction, vascular permeability, VEGF expression and VEGF signal transduction. Thus, inhibition of PKC-? might be expected to ameliorate diabetes-induced vascular complications by several mechanisms. The synthesis of a PKC-? isoform-selective inhibitor (ruboxistaurin, Eli Lilly) has provided diverse data to substantiate this hypothesis.[88] Orally ingested ruboxistaurin ameliorates diabetes-induced abnormalities of retinal blood flow, glomerular filtration rate and albumin excretion rate in animals.[89] These data supported the evaluation of orally administered ruboxistaurin in clinical trials as a potential noninvasive and nondestructive inhibitor of the progression of diabetic retinopathy and diabetic macular edema.[90]
Data from two 3-year Phase III trials of ruboxistaurin in patients with moderate to severe NPDR have been reported.[91,92] Results were very similar in both trials. In the larger PKC-DRS2 study, 685 patients with moderate to severe NPDR and no PRP in at least one eye were evaluated after receiving orally administered ruboxistaurin (32 mg/day) over a period of 36 months.[92] Moderate visual loss sustained for at least 6 months (SMVL) occurred in 5.5% of ruboxistaurin-treated patients and 9.1% of placebo-treated patients (40% risk reduction, p=0.03). In individual eyes, ruboxistaurin reduced SMVL by 45% (p=0.01). Mean visual acuity was better in the ruboxistaurin-treated patients from 12 months onward. In ruboxistaurin-treated patients, visual improvement of 15 or more letters was twice as frequent (4.9% vs 2.4%). Ruboxistaurin treatment also reduced progression of macular edema to within 100 mm from the center of the macula and the need for initial laser treatment for macular edema was 26% less frequent in eyes of ruboxistaurin-treated patients. Ruboxistaurin therapy was very well tolerated and has had an excellent safety profile to date.[93] No effect was observed on progression of NPDR severity. The compound has received an 'Approvable' rating by the FDA under the trade name Arxxant (Eli Lilly). Requirements for additional studies for full regulatory approval are currently under discussion.
PRECLINICAL STUDIES
A wide array of other interventions are in various stages of preclinical evaluation. Such studies hold promise for eventually even more effective, more specific and safer therapies than are currently available. However, several years of further investigation will be required before any potential clinical impact is known. Ongoing research is addressing mechanisms contributing to altered retinal blood flow and retinal vascular complications in diabetes.[94,95] Retinal blood flow is decreased in patients who have had diabetes less than 5 years and may be important in the onset of clinical retinopthy.[94] A direct relationship between decreased retinal blood flow and the activation of protein kinase C in the rat model has been shown.[95] Oxidant stress may also be involved in the early progression of DR suggesting that antioxidants may have therapeutic usefulness. Modulators of NPDR may also include vasoactive agents such as angiotensin II, histamine, and oxygen. A wide array of other targets are evolving from the studies of angiogenic agents and their mechanism of action over the past decade based on work initiated by Michelson nearly six decades ago.[96-106]
PATIENT CARE AND GUIDELINES
Although this is an exciting period with new and forthcoming clinical trial data on a variety of novel therapeutic approaches, until we have treatment modalities to prevent or cure diabetic retinopathy, the emphasis for our patients with diabetes remains focused upon early identification, accurate determination of retinopathy severity, optimization of systemic factors, routine careful follow-up and timely laser photocoagulation, vitrectomy surgery and/or novel therapies. Proper care results in substantial reduction of personal suffering and substantial cost savings.[107]
For patients who do not have access to diabetes eye care, novel methods of delivery of such care have been evolving. Ocular telemedicine is one approach that has the potential to extend high quality diabetes eye care to patients who face socio-economic, geographic, or other challenges to care. While some programs have demonstrated a high degree of reliability in identifying level of diabetic retinopathy compared to clinical examination and standard retinal photography, it is important for both patients and health care providers to recognize strengths and limitations of ocular telemedicine programs. To assist in guiding expectations, the American Telemedicine Association has prepared 'Practice Recommendations for Ocular Telemedicine for Diabetic Retinopathy'.
Strict guidelines have been established for the ocular care of people with diabetes (Tables 133.8 and 133.12). All diabetic patients should be informed of the possibility of the development of retinopathy with or without symptoms and the associated threat of visual loss. The natural course and treatment of DR should be discussed and the importance of routine examination stressed. The patient must understand that the risks of diabetes complications in the eye and elsewhere in the body may be reduced by diligent personalized health care and routine follow-up examinations, and that early efforts despite lack of symptoms can yield long term benefits that are lost if care is initiated late. Thus, in many ways, the care of the patient with no or early NPDR is of paramount importance. Patients should be informed of the strong relationship between diabetes control and the subsequent development of ocular and other medical complications. The association of hypertension, dyslipidemia, abdominal obesity, eating disorders, renal disease, pregnancy, joint contractures, cardiovascular disease, and peripheral neuropathy with onset and progression of DR should be noted and care taken to assure that the patient has appropriate medical follow-up for these conditions. Patients with permanent visual impairment, including legal or total blindness, should be informed of the availability of visual, vocational, and psychosocial rehabilitation programs. Diabetic women contemplating pregnancy should have a complete eye examination prior to conception if possible. Since pregnancy may dramatically exacerbate existing retinopathy and may be associated with hypertension, diabetic women should have their eyes examined early in the first trimester of pregnancy and generally at least each trimester thereafter and again 1-2 months post partum. Severe retinopathy may impact optimal delivery methods.
TABLE 133.12 -- Eye Examination Schedule
|
Type of Diabetes Mellitus |
Recommendation Time of First Examination |
Routine Minimal Follow-up[*] |
|
Type 1 Diabetes Mellitus |
5 yr after onset or during puberty |
Yearly |
|
Type 2 Diabetes Mellitus |
At time of diagnosis |
Yearly |
|
During pregnancy |
Prior to pregnancy for counseling |
1-2 months post partum |
|
Early in first trimester |
||
|
Each trimester or more frequently as indicated |
|
* |
Abnormal findings dictate more frequent follow-up examinations. |
CONCLUSIONS
In its earliest stages, DR usually causes no symptoms. Visual acuity may be excellent, and the patient may be completely unaware of even advanced retinopathy. Preservation of vision can be maximized by early initiation of a careful eye care program which includes patient education, close follow-up, and efficient communication between the entire team of health care providers. Accurate assessment of DR severity is essential on an ongoing basis to determine the likelihood of retinopathy progression, risk of vision loss and timing of follow-up and therapy. Optimal control of systemic factors such as blood glucose, blood pressure, and lipids is also critical. All members of the health team share the responsibility of assuring such care is offered to the patient.
Faced with the current inability to prevent or cure diabetic retinopathy, the eye care for patients with diabetes must primarily focus on patient access, early detection, accurate retinopathy assessment, careful medical and ophthalmic follow-up, timely laser photocoagulation and appropriate use of novel therapies. With this approach, and the continuum of connected diabetes eye and medical care evolving from advances in information technology and telemedicine, our twenty-first century mission of preserving vision in patients with diabetes will become increasingly successful.
REFERENCES
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2. Diabetic Retinopathy Study Report Number 1: Preliminary report on effects of photocoagulation therapy. Am J Ophthalmol 1976; 81:1-14.
3. Diabetic Retinopathy Study Report Number 2: Photocoagulation of proliferative diabetic retinopathy. Ophthalmology 1978; 85:82.
4. Diabetic Retinopathy Study Report Number 3: Four risk factors for severe visual loss in diabetic retinopathy. Arch Ophthalmol 1979; 97:658.
5. Diabetic Retinopathy Study Report Number 4: A short report of long-range results. Proceedings of the 10th Congress of International Diabetes Federation, New York, Excerpta Medica, 1980.
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