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Download Outline for NEPOS lecture Diabetic and Hypertensive Retinopathy
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Outline for NEPOS lecture Diabetic and Hypertensive Retinopathy Joshua M. Greene, M.D. Diabetes Epidemic Affects about 21 million Americans 7% of U.S. population » African Americans: 18% Prevalence doubled in past decade » Hispanic Americans: 50% Nearly 30% of those cases are undiagnosed. Diabetes – A Public Health Conern The average lag between onset and diagnosis is 7 years Significant health consequences and costs Can eye care professionals detect diabetes at an earlier stage to reduce or better manage its ocular sequellae? Diabetes – Screening and Diagnosing Oral glucose tolerance test Fasting plasma glucose HbA1c test - gold standard for diagnosis Diabetes: Early Detection via Lens Autoflouresence Direct association between lens autoflourescence and age -Controlling for age, this value is higher in DM pts Fluorophores associated with glaucoma, retinopathy and other diabetic complications Flourescence biomicroscope detects autoflourescence of the crystalline lens Diabetes: Early Detection via Lens Autoflouresence Identify patients with fluorescence ratios significantly higher than expected for their age Clinical research indicates high levels of specificity and sensitivity in detecting diabetes ClearPath DS-120 A non-invasive way to detect patients who are pre-diabetic or those with undiagnosed diabetes Measures lens autofluorescence Risk Factors For Type II Diabetes Increasing age Overweight, especially central adiposity Physically inactive lifestyle Family history of diabetes High-risk ethnic group Low birth weight In women, child weighing > 9 lbs at birth Medical conditions (e.g., polycystic ovary syndrome, pancreatitis, hypertriglyceridemia, acanthosis nigricans) Diabetic Retinopathy Prevalence – Leading cause of blindness in age group 20 - 64 years old in U.S. – 25-50% of diabetics have some form of diabetic retinopathy » 5% of diabetics have proliferative diabetic retinopathy Diabetic Retinopathy Prevalence – Increases with duration of disease » Approximately 20% of T2DM have some DR at time of diagnosis » 50% by seven years' duration » 90% after 17-25 years Diabetic Retinopathy Early pathophysiologic changes – Breakdown of blood-retinal barrier » At level of endothelial cell tight junctions » Aggravated by elevated blood pressure Diabetic Retinopathy Early pathophysiologic changes – Basement membrane thickening – Pericyte loss – Microaneurysm formation Diabetic Retinopathy Neovascularization develops when balance between factors that promote neovascularization and those that inhibit it is upset – Overproduction or activation of angiogenic factors – Reduction in quantity or activity of inhibitory agents Nonproliferative (Background) Microaneurysms – Earliest visible manifestation Dot and blot hemorrhages Hard (lipoprotein) exudates Macular edema Cotton wool spots, venous beading, and IRMA Diabetic Macular Edema Visible thickening of sensory retina, often with decreased transparency of the thickened area Most common cause of decreased vision in diabetic retinopathy More common in patients with type 2 diabetes Increased in patients with poorer diabetic and blood pressure control Ischemic Changes – IRMA (intraretinal microvascular abnormalities) – Venous beading – Large, dark blot retinal hemorrhages – Cotton wool patches – Capillary non-perfusion on fluorescein angiography 4 - 2 - 1 Rule: – Hemorrhages (severe intraretinal) in 4 quadrants » ( ETDRS standard photograph 2A) – Venous beading in 2 quadrants – IRMA (moderately severe) in 1 quadrant » ( ETDRS standard photograph 8A) 4 - 2 - 1 Rule: If any 1 of these is present (severe NPDR): – 15% - 20% chance of high risk PDR developing in 1 year If 2 or 3 of these are present (very severe NPDR): – 40%-50% chance of high risk PDR developing in 1 year Proliferative Diabetic Retinopathy Neovascularization – Growth through and anterior to internal limiting membrane, onto vitreous Proliferative Diabetic Retinopathy Fibrous proliferation with contracture – Anteroposterior vector – Traction ME – Traction RD – TRD/RRD Clinical Diabetic Retinopathy And Diabetic Macular Edema Disease Severity Scale – 5 levels – No apparent retinopathy » DR absent – Mild NPDR » Microaneurysms only – Moderate NPDR » More than microaneurysms » All less than “4-2-1 rule” – Severe and very severe NPDR » Application of “4-2-1 rule” – PDR – +/- macular edema Aggravating Factors in Diabetic Retinopathy – Hypertension – Pregnancy – Poor diabetic control – Nephropathy – Cataract surgery – Elevated total serum cholesterol level – Anemia – Eating disorders – Sleep apnea – Protective Factors Severe chorioretinal scarring Reduced CRA pressure High axial myopia Glaucoma Optic atrophy Current Management of Diabetic Retinopathy Role of medical control Photocoagulation Vitrectomy Potential for retinal drug therapy Diabetic Retinopathy Role of medical control – Blood glucose – Blood pressure – Serum lipids Diabetic Retinopathy Role of blood glucose control – The Diabetic Control and Complications Trial was initiated to determine the effect of improved control of blood glucose on retinopathy in Type I diabetes. DCCT initial results: Development and progression of retinopathy reduced 60% with intensive control vs. standard treatment – Diabetic Control and Complications Trial Significant reduction in nephropathy and neuropathy in intensive control group Diabetic Retinopathy Role of blood glucose control – The United Kingdom Prospective Diabetes Study studied effect of tight control vs. conventional control in Type II diabetes UKPDS Each 1% reduction in updated mean HbA1c was associated with reductions in risk of 37% for microvascular complications (33% to 41%, P<0.0001). Any reduction in HbA1c is likely to reduce the risk of complications, with the lowest risk being in those with HbA1c values in the normal range (<6.0%). Diabetic Retinopathy Role of blood glucose control Rapid improvement of long-standing poor control may accelerate progression of established retinopathy in some eyes over the first year. Diabetic Retinopathy Elevated BP leads to worsening retinopathy (Evaluated in the UKPDS) Elevated cholesterol leads to worsening DME and exudative retinopathy DCCT and UKPDS Implications for Eye Doctors Educate your patients: -Control systemic conditions: Diabetic Retinopathy Photocoagulation for Macular Edema -Photocoagulation evaluated in the DRS (Diabetic Retinopathy Study) and the ETDRS (Early Treatment Diabetic Retinopathy Study) -Performed when patients have clinically significant macular edema (CSME) Clinically Significant Macular Edema (CSME) Thickening of the retina at or within 500 microns of the center of the macula Hard exudates at or within 500 microns of the center of the macula, if associated with thickening of the adjacent retina Zone(s) of retinal thickening one disc area or larger, any part of which is within one disc diameter of the center of the macula Diabetic Retinopathy Photocoagulation for Macular Edema – Technique: Focal (or grid) laser therapy » Treatment of focal leakage sites (focal laser) or areas of diffuse leakage or nonperfusion (grid laser) with argon green or dye yellow laser Focal Laser for CSME Clinically Significant Macular Edema ETDRS data show that focal photocoagulation of CSME substantially reduces the risk of moderate visual loss (doubling of the visual angle) by approx. 50% ETDRS Conclusions: Focal laser treatment also increases the chances for visual gain, and facilitates resolution of retinal thickening. ETDRS Conclusions: In practice, patients are not told that focal laser therapy will result in visual improvement – 42% of eyes gained 1 line of Va – 3% gained 3 or more lines of Va – 15% lost over 3 lines of Va What to Tell Patients About Laser Treatment for Diabetic Macular Edema The untreated eye with CSME has a 30% chance of MVL (doubling of the visual angle, or loss of 3 lines) at three years follow-up. – “Rule of 3’s” – » 30% chance of losing 3 lines of vision in 3 years What to Tell Patients About Laser Treatment for Diabetic Macular Edema Laser treatment is better than no treatment for eyes with CSME. Early treatment (when vision is better) is usually preferred to waiting for VA to drop. Proliferative Diabetic Retinopathy PRP (panretinal photocoagulation, scatter treatment) – Grid of laser spots throughout midperiphery, sparing macular and paramacular area Proliferative Diabetic Retinopathy PRP (panretinal photocoagulation, scatter treatment) – Mechanism of effect (proposed) » Destruction of ischemic retina » Outer retinal thinning » RPE cell neovascular inhibitor Proliferative Diabetic Retinopathy High risk characteristics requiring prompt PRP – NVD greater than or equal to 1/4 - 1/3 disc area – NVD of any size or NVE = or > 1/2 disc area with vitreous or preretinal hemorrhage – Angle Neovascularization – Prompt scatter photocoagulation should be considered for eyes with new vessels in the anterior chamber angle, whether or not high risk PDR is present. Proliferative Diabetic Retinopathy - DRS The DRS demonstrated a 60% reduction in the rate of severe visual loss (less than 5/200) in treated eyes. – 4-year follow-up, incidence SVL » Mild proliferative Control: 21% Treated: 7% » High risk proliferative Control: 28% Treated: 12% ETDRS Conclusions: In Type II diabetes, further analysis of data has demonstrated significant benefit of early scatter treatment (p = 0.0001) – 5 year incidence of SVL or vitrectomy reduced in T2DM with early PRP DR – Role for Early PRP Treat severe nonproliferative or early proliferative retinopathy with additional features – Type II diabetes – Type 1 DM of long duration – Rapid progression – Pregnancy – History of poor patient follow-up Proliferative Diabetic Retinopathy + CSME Focal treatment for clinically significant macular edema should precede PRP for proliferative retinopathy when possible ETDRS Conclusions: – Aspirin treatment (650 mg/day) does not alter progression of diabetic retinopathy, and does not increase the risk of vitreous hemorrhage. – Findings indicate no reason for people with diabetes to avoid taking aspirin when needed for treatment of other problems. Follow-up Schedule for Eyes With NPDR Without CSME – Mild-moderate: 6-12 months – Moderately severe: 4-6 months – Severe: 3-4 months – Very severe: 6 weeks-3 months – Note: special follow-up in pregnancy, to start ideally prior to conception, and at least every 3 months thereafter until parturition Vitrectomy in Diabetic Retinopathy -Goals DRVS The Diabetic Retinopathy Vitrectomy Study has shown relative merit to early vitrectomy for severe vitreous hemorrhage – Recent hemorrhage, duration 1 to 6 months – Visual acuity <5/200 – Macula attached by ultrasound Current Indications For Vitrectomy in Diabetic Retinopathy – Progressive mild iris neovascularization without completed PRP due to opaque vitreous and/or RD Current Indications For Vitrectomy in Diabetic Retinopathy Other Indications For Vitrectomy in Diabetic Retinopathy Visual loss from traction on macula or disc Subhyaloid hemorrhage covering macula if evidence of excessive fibrosis Diabetic macular edema associated with posterior hyaloideal thickening or abnormally thick internal limiting membrane – Diabetic Retinopathy New management options under evaluation – Pharmacologic vitrectomy – Anti-angiogenic therapies Pharmacologic Vitrectomy Medications that are used to “soften” the vitreous -Relief of vitreoretinal traction -Can be primary or adjunctive therapy Pharmacologic Vitrectomy Hyaluronidase (Vitrase) – In phase II & III clinical trials completed for clearing of vitreous hemorrhage in the office without vitrectomy in the OR » Evidence of hemorrhage clearance in 40-60% Pharmacologic Vitrectomy Hyaluronidase (Vitrase) Clinically relevant reduction in vitreous hemorrhage density -Allows the physician to visualize, diagnose, and treat the underlying cause of the hemorrhage At least a 3-line improvement in BCVA (7) Not FDA appvd at this time Pharmacologic Vitrectomy Jetrea (Ocriplasmin, Thrombogenics) -Approved by FDA 10/17/12 for symptomatic VMT -Adjunct to PPV -May induce a PVD Pharmacologic Vitrectomy Jetrea -Phase III trial -25.3 – 34.5% of pts had resolution of vitreomacular traction Pharmacologic Vitrectomy Jetrea -36.7% of pts had closure of their macular hole Pharmacologic Vitrectomy Jetrea -Potential as a surgical adjunct in pts with diabetic traction detachments -Adjunctive therapy in pts with refractory DME and a taut posterior hyaloid Potential for Use of Angiogenic Inhibitors Blockers of VEGF activity TGF-beta Protease inhibitors Chimeric receptor antagonists Neutralizing antibodies Antisense oligonucleotides VEGF Quick note about VEGF -Vascular Endothelial Growth Factor -Plays a major role in the pathology of DR, AMD, and RVO -Promotes inflammation, vascular permeability, and the growth of new, unwanted blood vessels Potential for Use of Angiogenic Inhibitors Blockers of VEGF activity – Systemic therapy – Local therapy PKC- Inhibitor Ruboxistaurin (LY333531) Ruboxistaurin (LY333531) PKC-DRS – Subjects with severe NPDR, followed to the endpoint of high risk PDR requiring laser treatment » No significant difference Ruboxistaurin (LY333531) PKC-DRS – Secondary endpoint: moderate visual loss » 70% risk reduction for 32 mg. RBX vs. Placebo (P<0.05) Ruboxistaurin (LY333531) PKC-DMES – 36% reduction in rate of progression of macular edema from >300 microns to <100 microns from center in group treated with highest dose compared to placebo Potential for Use of Angiogenic Inhibitors – Systemic therapy – Local therapy Management of Diabetic Macular Edema Steroid injections – Sub-Tenon – Intravitreal – Sustained release Steroids for Diabetic Macular Edema Rationale for use – Improve endothelial cell tight junctions – Inhibit VEGF and other cytokines – Anti-inflammatory effect Sub-Tenon’s Injection Steroids Intravitreal Steroids Intravitreal injection of Kenalog has become popular in retinal community in this country despite absence of results of randomized, controlled clinical trials to date Intravitreal Steroids – Diabetic Macular Edema Intravitreal Steroids – Diabetic Macular Edema Intravitreal Steroids – Diabetic Macular Edema Intravitreal Steroids – Diabetic Macular Edema Intravitreal Kenalog Significant potential for adverse effects as well – Procedure related – Drug related Intravitreal Steroids Adverse effects – Procedure related » Subconjunctival hemorrhage » Traumatic cataract » Vitreous hemorrhage » Retinal detachment Intravitreal Steroids Adverse effects – Drug related » Increased intraocular pressure 25-45% 1% not responsive to medical therapy, and require glaucoma surgery Intravitreal Steroids Adverse effects – Drug related » Cataract formation Second most common complication Intravitreal Steroids Pseudohypopyon – Migration of crystalline steroid into the anterior chamber following IVTA. Intravitreal Steroids Adverse effects – Drug related » Sterile vitritis Inflammation due to toxicity of vehicle(99% Benzyl Alcohol) Intravitreal Steroids Endophthalmitis – Culture-proven endophthalmitis has been reported to have an incidence of 0.87% following IVTA Intravitreal Steroids Recent studies suggest that DME with a large cystoid component responds better to STK and IVK, when compared to laser Potential for visual improvement rather than stabilization when compared with laser Anti-VEGF Therapy Macugen Avastin Lucentis Macugen (pegaptanib) Macugen Macugen Avastin (bevacizumab) A full-length recombinant humanized monoclonal antibody directed against VEGF “Pan VEGF” Inhibition (all isoforms) Approved by the FDA for the treatment of metastatic colorectal cancer Avastin (bevacizumab) Cost: $55.00 !! – Compared to » $1000 for single dose Macugen » $2000 for single dose Lucentis Avastin (bevacizumab) Ophthalmology, 2007 Primary Intravitreal Bevacizumab (Avastin) for Diabetic Macular Edema BCVA analysis by subgroups – 32 (41.1%) eyes remained stable – 43 (55.1%) improved ≥2 ETDRS lines of BCVA – 3 (3.8%) decreased ≥2 ETDRS lines of BCVA. Primary Intravitreal Bevacizumab (Avastin) for Diabetic Macular Edema Mean central macular thickness by OCT – Baseline: 387.0±182.8 μm – End of follow-up : 275.7±108.3 at – (P<0.0001). Primary Intravitreal Bevacizumab (Avastin) for Diabetic Macular Edema Baseline (A), 1 week (B), 1 month (C), 3 months (D), 6 months (E) Intravitreal Bevacizumab (Avastin) for PDR Intravitreal Bevacizumab (Avastin) for PDR Intravitreal Bevacizumab (Avastin) for PDR Intravitreal Bevacizumab (Avastin) for PDR - Pre-op Vitrectomy Intravitreal Bevacizumab (Avastin) for PDR Intravitreal Lucentis (Ranibizumab) for Diabetic Retinopathy In August of 2012, Lucentis became the first (and only) VEGF inhibitor FDA approved to treat DME Approved for monthly injections of 0.3mg (vs 0.5mg for RVO and ARMD) Intravitreal Ranibizumab (Lucentis) for Diabetic Retinopathy FDA approval was based on the results of the RISE and RIDE studies Phase III studies 759 total patients randomized to receive: -Sham -0.3mg Lucentis -0.5mg Lucentis Intravitreal Ranibizumab (Lucentis) for Diabetic Retinopathy Monthly injections The primary outcome was the proportion of patients gaining ≥ 15 letters in BCVA from base- line to 24 months. Intravitreal Ranibizumab (Lucentis) for Diabetic Retinopathy Gain of >15 ETDRS letters: -RIDE, 34% 0.3mg vs 12% sham -RISE, 45% 0.3mg vs 18% sham ***VA improvements were maintained through 36 months Intravitreal Ranibizumab (Lucentis) for Diabetic Retinopathy A relationship between the use of Lucentis and CVA cannot be excluded from the aforemetioned data Diabetic Retinopathy - Prognosis Before current treatments, the prognosis for patients with proliferative diabetic retinopathy was blindness within 5 years for more than 50 percent of patients. ETDRS Rates of blindness in ETDRS patients following the development of proliferative retinopathy are remarkably lower. – Legal blindness is reduced to less than 5 percent in 5 years for patients with proliferative retinopathy. – Severe vision loss is reduced to 1 percent. Diabetic Retinopathy – Many patients with diabetic retinopathy will lose substantial vision despite being treated according to the recommendations based on the controlled clinical trials. Diabetic Retinopathy Low vision management and supportive care – Those whose conditions fail to respond to surgery and those for whom further treatment is unavailable should be provided with proper professional support, counseling, rehabilitative and social services. Follow-up Schedule for Eyes With NPDR Without CSME – Mild-moderate: 6-12 months – Moderately severe: 4-6 months – Severe: 3-4 months – Very severe: 6 weeks-3 months – Note: special follow-up in pregnancy, to start ideally prior to conception, and at least every 3 months thereafter until parturition – Close follow-up after cataract surgery, as DR can worsen rapidly in some patients Diabetic Retinopathy Management – Standard of Care – Counseling on importance of control of glucose, BP, lipids Hypertensive Retinopathy Grading (after Scheie) Hypertensive Retinopathy Grade l - slight generalized attenuation of retinal arterioles Grade 2 - more pronounced generalized attenuation of retinal arterioles, focal arteriolar attenuation Grade 3 - severe generalized and focal arteriolar attenuation, retinal exudates, cotton-wool spots and hemorrhages Grade 4 - grade 3 changes plus papilledema – Hypertensive Retinopathy Grade l - generalized attenuation of retinal arterioles Hypertensive Retinopathy Hypertensive Retinopathy Grade 3 - severe generalized and focal arteriolar attenuation, retinal exudates, cotton-wool spots and hemorrhages Cotton-wool Spots Microinfarcts of the retinal nerve fiber layer caused by fibrinoid occlusion of nutrient arterioles. Cotton-wool Spots Swelling due to reduced axoplasmic transport – backlog and accumulation of intracellular products within the nerves Hypertensive Retinopathy Grade 3 - severe generalized and focal arteriolar attenuation, retinal exudates, cotton-wool spots and hemorrhages Hypertensive Retinopathy Grade 3 - severe generalized and focal arteriolar attenuation, retinal exudates, cotton-wool spots and hemorrhages Hypertensive Retinopathy Grade 4 - grade 3 changes plus papilledema Hypertensive Retinopathy Grade 4 - grade 3 changes plus papilledema Hypertensive Retinopathy Grade 4 - grade 3 changes plus papilledema Hypertensive Retinopathy Arteriolar sclerotic changes in hypertensive disease secondary to chronic hypertension – Due to Intimal thickening, media-wall hyperplasia, and hyaline degeneration of the arteriolar wall. Arteriolar Sclerotic Changes in Hypertensive Disease Secondary to Chronic Hypertension – Grade l – » Broadening of arteriolar light reflex » Minimal arteriovenous crossing changes – Grade 2 – » More marked broadening of light reflex » More marked AV crossing changes – Grade 3 – » Copper wire arterioles » More marked AV crossing changes – Grade 4 – » Silver wire arterioles » Severe AV crossing changes Arteriolar Sclerotic Changes in Hypertensive Disease Secondary to Chronic Hypertension – Grade 1 – » Broadening of arteriolar light reflex » Minimal arteriovenous crossing changes Arteriolar Sclerotic Changes in Hypertensive Disease Secondary to Chronic Hypertension – Grade 2 – » More marked broadening of light reflex » More marked AV crossing changes Arteriolar Sclerotic Changes in Hypertensive Disease Secondary to Chronic Hypertension – Grade 3 – » Copper wire arterioles » More marked AV crossing changes Arteriolar Sclerotic Changes in Hypertensive Disease Secondary to Chronic Hypertension – Grade 4 – » Silver wire arterioles » Severe AV crossing changes Hypertensive Retinopathy How do we manage this condition? Hypertensive Retinopathy Management – The only treatment for this disorder is reduction of the blood pressure. – Laser treatment is NEVER used to treat this condition. » Fluorescein angiography is NOT indicated for this disease Hypertensive Retinopathy Clinical course – Arteriolosclerotic changes persist – Hypertensive changes resolve after reduction of systemic blood pressure – Hypertensive Retinopathy Cotton-wool patches – Onset: 24-48 hours – Resolution: 2-l0 weeks Hypertensive Retinopathy Macular star (exudates) – Onset: few weeks – Resolution: months-year Hypertensive Retinopathy Papilledema – Onset: days-weeks – Resolution: weeks-months Hypertensive Retinopathy` Grading Clinical appearance Clinical course THANK YOU!
