9 Treatment of Proliferative Diabetic Retinopathy |
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time for the induction of neovascular growth factors.18 Acute retinal artery occlusion causes abrupt cell death preventing the induction of vascular growth factors in the retina.13,18 In addition, subsequent reperfusion of an occluded retinal artery may also protect against neovascular sequelae.18
Diabetes mellitus is a leading cause of blindness. The complications of neovascularization and macular edema are the most common causes of vision loss in diabetic retinopathy.52 The relatively high prevalence of blindness from diabetes is related to the expanding epidemic of obesity and diabetes.53 About two-thirds of adult Americans are overweight or obese.54 Almost 11% of the US population (23.5 million persons) over the age of 20 years has diabetes. An additional 57 million have prediabetes.55 Although there is high-level evidence that the incidence and progression of diabetic reti-
nopathy may be reduced by intensive control of blood glucose and blood pressure,7,56,57 sustaining
strict diabetes management regimens is difficult.9,10 Furthermore, routine eye examinations for early detection of retinopathy fall short of recommended guidelines.58,59 Thus, diabetic retinopathy is common. About 40% of diabetics 40 years of age or older have diabetic retinopathy, and 8% have vision-threatening retinopathy.60 The average annual progression to proliferative diabetic retinopathy is 1–4% and the cumulative 25-year progression to PDR is 42% among patients with type 1 diabetes mellitus.61,62 The number of persons with diabetic retinopathy is expected to triple by 2050 to 17.7 million.63 The reader is referred to Chapter 3 for additional information regarding the epidemiology of PDR. Given the high prevalence of diabetes and associated retinopathy, appropriate treatment is of paramount importance in preventing blindness.
This chapter focuses on the clinical management of proliferative diabetic retinopathy. The intent is to present a rational approach to problems encountered in the treatment of PDR by incorporating relevant information gleaned from research since the seminal publications of the Diabetic Retinopathy Study (DRS) group, the Early Treatment Diabetic Retinopathy Study (ETDRS) group, and the Diabetic Retinopathy Vitrectomy Study (DRVS)
group. Tables 9.1, 9.2, and 9.3 summarize the salient findings from these studies relevant to proliferative diabetic retinopathy. Additional information from the literature is presented to assist in the process of deciding from among myriad treatment possibilities in order to minimize risk and maximize the benefits of intervention. Also included is a brief discussion of current studies which may lead to potential therapies in the future.
9.2 Laser Photocoagulation
Retinal photocoagulation for diabetic retinopathy has evolved since the initial reports by MeyerSchwickerath using the xenon-arc photocoagulator.64 Technological advances have provided more suitable tools with which the ophthalmologist can treat the retina with more precision and control. In addition, improved understanding of diabetic retinopathy through the work of the Diabetic Retinopathy Study (DRS) led to the routine use of scatter laser treatment (panretinal photocoagulation) of the hypoxic peripheral retina to induce involution
of neovascularization in eyes with high-risk PDR.65,66 Further refinements were made with the
Early Treatment Diabetic Retinopathy Study (ETDRS) with regard to the indications and application of photocoagulation.67,68 Both the ETDRS and the Diabetic Retinopathy Vitrectomy Study
(DRVS) provided high-level evidence in support of vitrectomy for complications of PDR.69–74
Although there have been no large-scale, randomized, controlled, multi-center studies of treatment for PDR since these studies, there has been significant progress. Panretinal photocoagulation (PRP) reduces the 5-year risk of blindness by 90%.58 Improved metabolic control not only is associated with decreased progression of diabetic retinopathy but may also improve response to PRP.75
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Table 9.1 Summary of the Diabetic Retinopathy Study (DRS) reports
DRS #1 (1976)65
Preliminary report of effects of photocoagulation therapy
Eligibility requirements
1.Both eyes with severe NPDR or at least one eye with PDR
2.Visual acuity 20/100
Treatment and follow-up
1.One eye promptly treated with argon or xenon photocoagulation
2.Scatter laser plus direct treatment of non-elevated NVE (argon-treated eyes also underwent direct treatment of NVD and elevated NVE)
3.1727 patients treated (858 argon and 869 xenon)
4.Followed every 4 months
5.End point: <5/200 on two or more consecutive visits (severe visual loss-SVL)
Results at 2-year follow-up analysis
1.57% reduction of SVL between treated and untreated eyes (9.4% untreated eyes vs. 4.1% treated eyes)
2.No difference in benefit between argon and xenon photocoagulation
3.Small loss of vision measured 4 months post-treatment (recovered at 2-year analysis in argon group only)
4.Reduced visual field score in xenon-treated eyes only
Protocol change
1.Consider treating fellow eye if possess high-risk characteristics
2.Direct treatment of NVD and elevated NVE was made optional
DRS #2 (1978)66
Coined the term ‘‘high-risk characteristics’’ (HRC)
1.Disk neovascularization (NVD) > standard photograph 10A
2.Vitreous hemorrhage with any NVD or NVE > ½ disk area
At 1-year analysis of treated eyes, no NV was present in 78.8% of NPDR eyes compared with 21.2% of eyes with moderate-to- severe NVD at baseline
Summary
1.Prompt PRP recommended for eyes with HRC
2.Call for ETDRS to study prompt vs. deferred PRP for eyes < HRC
DRS #10 (1985)760
Natural history: 2-year follow-up data
The presence and extent of NVD was the strongest predictor of SVL
The second strongest predictor was extent of retinal hemorrhage/microaneurysm
DRS #11 (1987)761
Photocoagulation reduces the risk of intraocular hypertension, apparently by preventing neovascular glaucoma
DRS #12 (1987)762
Risk factors for decrease in vision measured 6 weeks following PRP
1.Pre-existing macular edema
2.Intensity of PRP
Recommendations
1.Focal laser of macular edema before PRP
2.Divide PRP into multiple sessions and decrease intensity of burns
DRS #13 (1989)763
Risk factors for SVL despite PRP during 5 years after randomization
1.Increasing NVD (most important factor)
2.Increasing retinal hemorrhages/microaneurysms
3.Increasing retinal elevation (detachment)
4.Increasing proteinuria
5.Increasing hyperglycemia
6.Decreasing treatment density
Note: Treatment density was identified as an independent predictor of visual outcome supporting the practice of repeating PRP if initial treatment does not reduce or stabilize PDR
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Table 9.2 Summary of the Early Treatment Diabetic Retinopathy Study (ETDRS) reports for PDR
ETDRS #3 (1987)68
Technique for photocoagulation of PDR
Scatter (PRP): 500 m (Goldmann) moderately intense burns
Local: confluent treatment of flat NVE
Details described in chapter
ETDRS #8 (1991)764 and ETDRS #20 (1995)765
Effects of aspirin treatment (ASA 650 mg/day) on diabetic retinopathy
1.No clinically important beneficial or harmful effects in eyes with mild-to-severe NPDR or early PDR
2.No prevention of development of high-risk PDR or risk of visual loss
3.No increased risk of vitreous hemorrhage
4.No effect on severity or duration of vitreous hemorrhage
ETDRS #12 (1991)100
Fundus photographic risk factors for progression of diabetic retinopathy
1.Severity of intraretinal microvascular abnormalities
2.Severity of retinal hemorrhages/microaneurysms
3.Severity of venous beading
4.NOT soft exudates (cotton–wool spots)
ETDRS #13 (1991)630
Fluorescein angiographic (FA) risk factors for progression of diabetic retinopathy
1.Fluorescein leakage (particularly, diffuse)
2.Capillary loss and dilation
3.Arteriolar abnormalities (e.g., focal narrowing, pruning, staining)
4.FA risk factors offer increased power to predict progression of DR, but do not offer clinically important information over clinical exam and color photography
ETDRS #17 (1992)69
Pars plana vitrectomy in the ETDRS
1.208 eyes (5.6%) of 3711 enrolled in ETDRS
2.Diabetes mellitus type: 51.9% type 1, 35.1% mixed, and 13% type 2
3.Preoperative PRP initiated in 88% of eyes (>1200 burns in 69%)
4.Primary indication: vitreous hemorrhage (53.9%), retinal detachment (46.1%)
5.Preoperative vision: 66.7% 5/200, 6.2% > 20/100
6.Postoperative vision (1-year): 20.2% < 5/200, 47.6% 20/100, and 24% 20/40
7.Note: endolaser became available early in ETDRS (1983)
ETDRS #18 (1998)102
Risk factors for high-risk PDR and severe visual lossa (SVL)
Baseline risk factors for high-risk PDR
1.Higher glycosylated hemoglobin
2.History of diabetic neuropathy
3.Lower hematocrit
4.Elevated triglycerides
5.Lower serum albumen
6.Type 1 diabetes
Baseline risk factors for severe visual loss
1.Development of high-risk PDR
2.Decreased visual acuity at baseline
Baseline risk factors for SVL before reaching high-risk PDR
1.Decreased visual acuity (or increased extent of macular edema)
2.Female gender
3.Type 2 diabetes
ETDRS #21 (1995)766
Transient decrease in accommodative amplitude of 1/3 diopter measured at the 4-month exam following scatter photocoagulation (P < 0.001)
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Table 9.2 (continued)
ETDRS #24 (1999)615
Causes of severe visual loss in the ETDRS
Persistent severe visual loss was rare due to PRP/vitrectomy 149 eyes of 127 persons (3711 persons in ETDRS)
Causes of severe visual loss (decreasing order of frequency)
1.Vitreous/preretinal hemorrhage (despite vitrectomy) 61 eyes (41%) Of the 61 eyes, 17 eyes with RD (27.9%) and 3 eyes with NVG (4.9%)
2.Macular edema
3.Macular pigmentary change (e.g., past edema or RD)
4.Retinal detachment
5.Narrow or opaque arteries (i.e., ischemia)
Risk factors for persistent severe visual lossb
1.Elevated glycosylated hemoglobin
2.Elevated cholesterol
a<5/200 measured on two consecutive visits 4 months apart b<5/200 without improvement on follow-up examinations
Table 9.3 Summary of the Diabetic Retinopathy Vitrectomy Study (DRVS) reports
DRVS #1 (1985)70
Two-year course of visual acuity in severe PDR with conventional management 744 eyes followed with conventional management
Risk factors for decreased vision: (45% SVL in eyes with NV > 4 disk areas and Va 20/60 at baseline)
Vitrectomy required (25%) in eyes with TRD involving center of macula or severe, nonclearing VH (1-year duration)
DRVS #2 (1985)71
Early Vitrectomy for severe vitreous hemorrhage (VH) in diabetic retinopathy 616 eyes with severe VH ( 5/200) randomized: early vs. 1-year deferral for Vtx Visual acuity 20/40 at 2-year follow-up
Total group: 25% early group vs. 15% deferral group (P ¼ 0.01) Subgroup (type 1 DM): 36% early group vs. 12% deferral (P ¼ 0.0001) Subgroup (type 2 DM): 16% early group vs. 18% deferral
The evidence of a difference in response by type of DM was of borderline significance
Conclusion: Early vitrectomy for acute, severe vitreous hemorrhage hastens return of vision and is especially significant for patients with type 1 diabetes mellitus
DRVS #3 (1988)72
Early vitrectomy for severe PDR with useful vision
370 eyes with advanced, active PDR ( 20/400): early vtx vs. conventional Visual acuity 20/400 at 4-year follow-up
Early vitrectomy group: 44% Conventional management group: 28%
The advantages of early vitrectomy increased with increasing severity of NV
DRVS #4 (1988)73
Clinical application of DRVS #3 (examples)
DRVS #5 (1990)74
Early vitrectomy for severe vitreous hemorrhage in DR. Four-year results 616 eyes described in DRVS #2 with extended follow-up
The proportion of eyes 20/40 was higher in early vtx group than deferral group Up to the 18-month visit, the early group had higher rate of NLP
Eyes with severe VH in patients with type 1 DM benefit from early vitrectomy
DM ¼ diabetes mellitus, DR ¼ diabetic retinopathy, vtx ¼ vitrectomy, NLP ¼ no light perception, SVL ¼ severe visual loss (<5/200 on two or more consecutive 4-month visits)