SHAWN RICHARDS, MD MOSES LAKE CLINIC MOSES LAKE, WA Common Retinal Diseases

Anatomy Review

Retina Photosensitive neurosensory tissue Photoreceptors  Rods – Rhodopsin  Cones – Vitamin A and opsin Support cells Ganglion cells

Retinal Layers

David King, PhD

Anatomy of the Retina Macula  Fovea – avascular, cones  Foveola – only photoreceptors Equatorial retina – mainly rods Peripheral retina  Ora serrata  Pars plana

Retinal Layers

Retinal Vasculature Central Retinal Artery  Branch of Ophthalmic Artery  From Internal Carotid Artery  Inner 2/3 of retina Central Retinal Vein Capillaries – inner blood-retina barrier

Retinal Pigment Epithelium Serves many functions  Photoreceptor metabolism  Outer blood-retina barrier  Potential space

Common Retinal Diseases Diabetic eye disease  Retinopathy  Edema Age Related Macular Degeneration (ARMD)  Non-exudative  Exudative Vitreomacular traction (VMT) Posterior Vitreous Detachment (PVD)

Diabetes Mellitus Prevalence  Leading Cause of Blindness in pts. Ages  Second leading cause overall Progression  At onset of Type I  No Retinopathy  After 7 years  50% have some DR  Rare in Kids under 10  After 20 years  99% w/ Type I  60% w/ Type II

Diabetes Mellitus Earliest signs in the eye  Loss of pericytes - Leads to endothelial cell decompensation  Basement membrane thickening - Hyperglycemia is a stimulus for increased protein synthesis, especially glycoproteins which are an important component of B.M. These lead to capillary occlusion, decrease nutrient diffusion and leakage

Loss of Pericytes

Pathogenesis Sorbitol Toxicity  When glucose concentration is high, the aldose reductase pathway is used  Aldose reductase converts glucose to sorbitol and fructose  Sorbitol and fructose enter cells easily but cannot exit easily, thus causing osmotic effects.  This causes cataract, neuropathy, and retinopathy.  Aldose reductase also converts galactose to galactitol which causes the galactosemia cataract.

Pathogenesis Circulatory Changes  Hyperglycemia causes loss of autoregulation  The severity of loss is proportional to severity of DR  Autoregulation is improved after PRP Hyperglycemia causes increased oxygen utilization  Increased oxygen utilization leads to  Relative hypoxia  Vasodilation  Upregulation of VEGF

Diabetic Retinopathy Classification of diabetic retinopathy:  Nonproliferative Diabetic Retinopathy (NPDR)  Mild, Moderate, Severe, Very Severe  Proliferative Diabetic Retinopathy (PDR)  Early, High-risk, advanced  Progression is in a stepwise fashion

Nonproliferative Diabetic Retinopathy (NPDR) NPDR – (background)  Limited to Retina by ILM  Hemorrhages: Dot-Blot, Flame  Hard exudates (lipid deposition in outer and inner plexiform layers)  Capillary microaneurysms

NPDR  Macular edema: focal or diffuse  Venous Dilation and Beading  Intraretinal Microvascular Abnormalities (IRMA)  Capillary occlusions Cotton wool spots (RNFL infarcts) “soft exudates, SE” Areas of non-perfusion on fluorescein angiography

NPDR The ETDRS 4:2:1 rule  Severe NPDR is defined as  Severe hemorrhages in 4 quadrants Or  Venous abnormalities in 2 or more quadrants Or  Intraretinal microvascular abnormality (IRMA) in one or more quadrants One of the above: severe - 15% chance of developing proliferative retinopathy within one year Two or more: very severe - 45% chance of developing proliferative retinopathy within one year

Proliferative Diabetic Retinopathy (PDR) Extraretinal fibrovascular extension (above ILM):  Neovascularization of disc (NVD)  Neovascularization elsewhere (NVE) Vitreous hemorrhage (VH) Tractional retinal detachment (TRD)  Or combined tractional/rhegmatogenous RD Increased risk of CVA, MI, diabetic nephropathy and death

Proliferative Diabetic Retinopathy High Risk Characteristics determined by the Diabetic Retinopathy Study (DRS)  NVD greater then 1/4 to 1/3 disc area  Any NVD with VH  NVE with VH

Causes for Vision Loss Macular Ischemia (Capillary Occlusion) Sequelae from neovascularization  NVG, NVD, NVE, VH, RRD, TRD, Combined RRD/TRD, Laser, etc. Macular Edema (Capillary Leakage)

Macular Ischemia

Sequelae From Neovascularization Panretinal Photocoagulation (PRP) Rational: conditions which destroy retina seem to prevent diabetic retinopathy Technique: 1600 to 2000 burns, 500 micron spot size burns from 2DD temporal to the FAZ out to the periphery. Theories for the efficacy of PRP  Decreases quantity of vasoproliferative factors  Improves the diffusion of oxygen from the choroid  Reduces retinal oxygen demand Studies supporting PRP  Diabetic Retinopathy Study  Early Treatment Diabetic Retinopathy Study (ETDRS)

PanRetinal Photocoagulation

Diabetic Retinopathy Study Panretinal photocoagulation (PRP)  Eyes with PDR or very severe NPDR  The DRS proved the effectiveness of PRP at preventing severe vision loss at 5 years Four major risk groups. V.A. < 5/200 with RX:without RX 1. NVD <1/2 DD (+VH)4.3%:25.6% 2. NVD>1/2 DD (-VH)8.5%:26.2% 3.NVD>1/2 DD (+VH)20.1%:36.9% 4.NVE>1/2DD (+VH)7.2%:29.7%

Early Treatment Diabetic Retinopathy Study (ETDRS) Scatter (PRP) Laser vs. observation  Patients had mild NPDR to early PDR Aspirin 650 mg vs. placebo

ETDRS Results:  Aspirin use recommended in DM  PRP for high risk PDR reduces the incidence of severe visual loss (VA<20/800) from 30% to 15% over a three year period.  NVI is not part of “HRC” but is ominous and PRP is indicated.

ETDRS Results Treatment of severe NPDR and with PDR less than HRC.  Early PRP reduces the rate at which eyes with severe NPDR and early PDR progress to HRC by 50%, but that PRP causes an early reduction in visual acuity.  PRP not recommended for mild to mod NPDR

ETDRS Results: Most retina specialists do not give PRP to eyes with severe NPDR and neovascularization less than HRC. However, some strongly consider PRP in patients who:  Have severe bilateral NPDR  Have rapidly progressing NPDR  Have had a poor outcome in one eye  Cannot be relied upon to return for follow-up  Are pregnant

But what if…

Vitreous Hemorrhage in PDR B scan if too dense Observe if no RD PRP when able Consider other factors (fellow eye, previous PRP, NVI, patient needs)

Diabetic Vitrectomy Indications  Dense, nonclearing VH  TRD involving or threatening the macula  Combined TRD and RRD  Diffuse DME associated with posterior hyaloid traction  Significant recurrent VH despite maximal PRP Diabetic Retinopathy Vitrectomy Study  Type I DM with dense VH – better visual outcomes with early PPV (1-6 months)  Type II DM with dense VH – no difference in visual outcome

Diabetic Macular Edema Most common cause of visual loss in diabetics  Also the most treatable Due to abnormal retinal vasculature permeability Types  Focal – leakage from specific capillary lesions  Diffuse – widespread retinal capillary abnormalities Diagnosis  Slit lamp biomicroscopy  Fluorescein angiography

Diabetic Macular Edema The Role of fluorescein angiography  To prove that the patients decreased vision is caused by macular edema and not by ischemia.  To identify leaking microaneurysms and areas of NV  To identify areas of diffuse capillary leakage  To identify areas of capillary non-perfusion

Fluorescein Angiography

Risks  Pain  Extravasation  Nausea/vomiting – 10%  Anaphylaxis – 0.001%  Death Considerations  Pregnancy  Renal disease

Optical Coherence Tomography Based on imaging reflected light Analogous to ultrasound – optical vs. acoustic reflectivity Produces cross-sectional images of ocular tissue  Micrometer resolution Noninvasive, noncontact Quick No Death

Optical Coherence Tomography

Diabetic macular edema - ETDRS  Eyes with diabetic macular edema  Vision of 20/200 or better  Argon grid laser  End point was a doubling of the visual angle  20/30  20/60  20/40  20/80  3 year results – doubling of visual angle  Treated --12%  Untreated – 24%  Treated eyes had an increased chance of halving of the visual angle

Diabetic Macular Edema Definition of clinically significant macular edema from ETDRS:  Retinal thickening at or within 500 microns of the center of the foveal avascular zone (FAZ)  Hard exudates at or within 500 microns of the center of the FAZ, If associated with edema  Retinal thickening one disc area or larger within one disc area of the FAZ Visual acuity is not a criterion for treatment

Diabetic Macular Edema ETDRS treatment strategy  Try to close all leaking microaneurysms  End point: whitening or blackening  Do not treat within 500 microns of the center of the FAZ  Use a grid (100 or 200 micron) pattern in areas of:  Diffuse capillary leakage  Areas of capillary nonperfusion

Diabetic Macular Edema Prognosis is not good with:  Significant central capillary nonperfusion  Severe cystoid macular edema  Hard exudates in the FAZ  Visual acuity 20/200 or less Nevertheless, these eyes can have a statistically significant improvement over untreated eyes with laser therapy

Diabetic Macular Edema Follow up:  The treatment may cause an initial worsening of vision  It may take a few months before the benefits are seen  Indications for retreatment.  Persistent macular edema  Do not retreat for residual hard exudates if not associated with macular edema.

Diabetic Macular Edema Follow up continued:  Consider treatment as close as 300 microns of the center of the FAZ if:  There is residual macular edema  Leaking spots can be clearly identified  The treatment will not increase foveal capillary nonperfusion

Diabetic Macular Edema Risks of grid/focal laser  Paracentral scotoma  Transient increased edema  Choroidal neovascularization  Subretinal fibrosis  Laser creep  Inadvertent foveal burn

That was 1985

Diabetic Retinopathy Clinical Research Network 854 eyes Vision between 20/32 and 20/320 Diabetic macular edema Four arms  Ranibizumab + prompt laser  Ranibizumab + deferred laser  Triamcinolone + prompt laser  Sham injection + prompt laser

Diabetic Retinopathy Clinical Research Network 12 month results – visual acuity increase  Ranibizumab + prompt laser – 9 letters(P<0.001)  Ranibizumab + deferred laser – 9 letters (P<0.001)  Triamcinolone + prompt laser – 4 letters  Sham injection + prompt laser – 3 letters 12 months results – CMT decrease  Ranibizumab + prompt laser – 131 um(P<0.001)  Ranibizumab + deferred laser – 137 um(P<0.001)  Triamcinolone + prompt laser – 127 um(P<0.001)  Sham injection + prompt laser – 102 um

RESTORE Study 354 patients Vision between 20/32 and 20/160 Visual impairment due to DME Three arms  Ranibizumab + sham laser  Ranibizumab + laser  Sham injection + laser  Ranibizumab and ranibizumab + laser were superior to laser alone at 12 months  Improvement of BCVA  Mean central retinal thickness

RESTORE Study 12 month results – visual acuity increase  Ranibizumab + sham laser6.1 lettersP<  Ranibizumab + laser5.9 lettersP<  Sham injection + laser0.8 letters 12 month results – CMT decrease  Ranibizumab + sham laser118.7 umP<0.001  Ranibizumab + laser128.3 umP<0.001  Sham injection + laser 61.3 um

Diabetic Macular edema 2 weeks ago  Vision 20/400  CMT of 498 Treated with intravitreal ranibizumab 0.3 mg 10 days later  Vision 20/80  CMT of 354

Diabetes Control and Complications Trial Type 1 diabetics Slow development +/- progression 726 pts w/o DR 715 pts w/ mild to mod DR Treatment and Control Groups  Treatment—4 injections per day or pump—  End goal was hgb A1C <6.1%  Control – 1 to 2 injections per day Mean follow up – 6.5 years

DCCT Results  Treatment Group:  Decreased risk of development of retinopathy by 76%, nephropathy - 54%, neuropathy - 60%.  Slowed progression of retinopathy by 54%  Mortality was higher in the Treatment Group, but the difference was not statistically significant between the groups

Clinical Observation Type I: Initial exam 5 years after diagnosis Type II: At time of diagnosis If pt. becomes pregnant: examine in first trimester and then as needed based upon examination and control Mild – 9 months Mod – 6 months Severe/CSME – 2-4 months PDR – 2-3 months

Prevention is best medicine Some abnormalities are reversible with good control in humans  Vitreous fluorophotometry  Photostress test  Oscillatory potential  Capillary basement membrane thickness

Role of the Practitioner Tight Blood Sugar/Blood Pressure/lipid control D/C Smoking Control of glucose is good no matter how long (DCCT), especially if before retinopathy develops

Hypertensive Retinopathy Vasoconstriction  Arteriole narrowing Arteriosclerosis  Copper and silver wiring  Arterio-venous nicking

Hypertensive Retinopathy Retinal hemorrhage Macular edema and exudate Optic disc edema  Due to acute, severe HTN Treatment – Control blood pressure

Age Related Macular Degeneration Leading cause of severe central visual acuity loss in people over 50 years of age Affects 15 million North Americans Types  Nonexudative (dry) – 85-90%  Exudative (wet) – 10-15%

ARMD Risk – Framingham Eye Study  65 to 74 years old – 6.4%  Over 75 years old – 19.7% Risk factors  Family history- Hypertension  Smoking- Hypercholesterolemia  Hyperopia- Female gender  Light iris color- Cardiovascular disease

Nonexudative ARMD Drusen Focal hyperpigmentation Geographic atrophy

AREDS Daily supplementation  Vitamin C – 500 mg  Vitamin E – 400 IU  Beta carotene – 15 mg  Zinc oxide – 80 mg  Cupric oxide – 2 mg In patients with intermediate ARMD or advanced unilateral ARMD  25% reduction of risk for progression to advanced ARMD  19% risk reduction in rates of moderate vision loss by 5 years

Indications for Vitamins Individuals with high risk for progression and vision loss  Extensive intermediate drusen  At least one large druse  Noncentral geographic atrophy  Advanced ARMD in one eye Smokers – avoid beta carotene  Possible increased risk of thromboembolic events

Exudative ARMD Choroidal neovascular membrane  Subretinal fluid  Subretinal blood  Subretinal lipid  Irregular elevation of the RPE  Subretinal gray-white lesion  Cystoid macular edema

Exudative ARMD Choroidal neovascular membrane Classic Occult

Treatment Nothing Conventional laser Photodynamic therapy  Light activated - short-lived reactive oxygen radicals

Treatment Laser photocoagulation

Colon Cancer Bevacizumab  Full length monoclonal antibody to VEGF Ranibizumab  Antibody fragment (Fab) to VEGF

MARINA Study 716 patients Minimally classic or occult CNVM Three arms  0.3 mg ranibizumab monthly  0.5 mg ranibizumab monthly  Sham injection monthly

ETDRS Chart

MARINA Study 12 month results  Lost less than 15 letters  0.3 mg – 94.5%(P<0.001)  0.5 mg – 94.6%(P<0.001)  Sham – 62.2%  Gained 15 or more letters  0.3 mg – 24.8%(P<0.001)  0.5 mg – 33.8%(P<0.001)  Sham – 5.0%

MARINA Study 12 month results  Average change in visual acuity  0.3 mg – 6.5 letter increase(P<0.001)  0.5 mg – 7.2 letter increase(P<0.001)  Sham – 10.4 letter decrease

ANCHOR Study 423 patients Predominantly classic CNVM 3 arms  0.3 mg ranibizumab monthly + sham PDT  0.5 mg ranibizumab monthly + sham PDT  Sham injection monthly + PDT

ANCHOR Study 24 month results  Lost less than 15 letters  0.3 mg – 89.9%(P<0.001)  0.5 mg – 90.0%(P<0.001)  PDT – 65.7%  Gained 15 or more letters  0.3 mg – 34.0%(P<0.001)  0.5 mg – 41.0%(P<0.001)  PDT – 6.3%

ANCHOR Study 24 month results  Average change in visual acuity  0.3 mg – 8.1 letter increase(P<0.001)  0.5 mg – 10.7 letter increase(P<0.001)  PDT – 9.8 letter decrease

Anti VEGF Cost Ranibizumab - $2,000 per injection Bevacizumab - $50 per injection  Off label Difference  $1,950 per injection  $23,400 per year Ramen noodles  117,000 packs

CATT Study 1,107 patients Neovascular ARMD – no differentiation 4 arms  Ranibizumab 0.5 mg monthly  Ranibizumab 0.5 mg as needed  Bevacizumab 1.25 mg monthly  Bevacizumab 1.25 mg as needed

CATT Study 24 month results  Average change in visual acuity  Ranibizumab 0.5 mg monthly – 8.8 letter increase  Bevacizumab 1.25 mg monthly – 7.8 letter increase P = 0.21  As needed both inferior  One or more serious adverse events  Ranibizumab – 31.7%  Bevacizumab – 39.9% P = 0.004

Lifestyle Changes Smoking Ultraviolet light Obesity

Vitreous Humor

80% of the volume of the eye Collagen, water, and hyaluronic acid Sites of attachment  Base – around the ora serrata  Retinal vessels  Optic nerve  Macula

The Aging Vitreous Destabilization  Crosslinking of collagen fibers  Free radical damage  Decrease in network density of collagen fibers Shrinkage of vitreous  Traction on points of strongest attachment

Vitreomacular Traction

Macular hole

Vitreomacular Traction Treatment  Pars plana vitrectomy  Posterior hyaloid release Risks  Infection  Retinal tears  Bleeding But now…

Ocriplasmin Recombinant protease Activity against fibronectin and laminin  Components of the vitreoretinal interface

Ocriplasmin MIVI-TRUST study group  652 patients  Vision worse then 20/25  Vitreomacular traction on OCT  Two arms  Single intravitreal injection of ocriplasmin (125 μg)  Single placebo injection  Primary end point  Resolution of vitreomacular adhesion  Secondary end points  Nonsurgical closure of a macular hole  Change in best-corrected visual acuity

Ocriplasmin MIVI-TRUST study group  Vitreomacular adhesion resolved – 28 days  Ocriplasmin-injected eyes26.5%P<0.001  Placebo-injected eyes 10.1%  Nonsurgical closure of macular holes – 28 days  Ocriplasmin-injected eyes 40.6%P<0.001  Placebo-injected eyes 10.6%  Improvement in best-corrected visual acuity by at least 3 lines – 6 months  Ocriplasmin-injected eyes12.3%P=0.02  Placebo-injected eyes6.4%

Posterior Vitreous Detachment Common associations  Age  Increased axial length Other associations  Aphakia  Trauma  Inflammatory disease

Posterior Vitreous Detachment Incidence  Less then 10% before 50 years of age  63% after 70 years of age Symptoms  Flashing lights  New floaters  Decreased vision (less common)

Posterior Vitreous Detachment Associated retinal tears

Posterior Vitreous Detachment Who has retinal tears?  15% of all patients with PVD  50-70% of all patients with PVD and vitreous hemorrhage  10-12% of patients PVD but no vitreous hemorrhage

Retinal Tears Treatment  Observation  Laser demarcation (barrier) Take home message – new flashes and floaters need seen that day

Questions?

References Ranibizumab for neovascular age-related macular degeneration. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY; MARINA Study Group. N Engl J Med Oct 5;355(14): Ranibizumab for neovascular age-related macular degeneration.Rosenfeld PJBrown DMHeier JSBoyer DSKaiser PKChung CYKim RYMARINA Study Group N Engl J Med. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR study. Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T; ANCHOR Study Group. Ophthalmology Jan;116(1):57-65.e5. doi: /j.ophtha Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR study.Brown DMMichels MKaiser PKHeier JSSy JPIanchulev TANCHOR Study Group Ophthalmology. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two- year results. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Martin DF, Maguire MG, Fine SL, Ying GS, Jaffe GJ, Grunwald JE, Toth C, Redford M, Ferris FL 3rd. Ophthalmology Jul;119(7): doi: /j.ophtha Epub 2012 May 1. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two- year results.Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research GroupMartin DFMaguire MGFine SLYing GSJaffe GJGrunwald JEToth CRedford MFerris FL 3rd Ophthalmology. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol Dec;103(12): Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group.