diabetic retinopathy gyans

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DIABETIC RETINOPATHY Pathogenesis , Classification Recent Studies Dr Gyanendra Lamichhane, MD Lumbini Eye Institute Bhairahawa, Nepal

REFERENCES : 

REFERENCES Clinical ophthalmology - jack .j kanski 6th edition AAO series -- Retina and vitreous ( 2004-2005) Davidson's principle and practice of medicine 19th edition Current perspectives of diabetic retinopathy John G Osheha Websites www.diabetic retinopathy. Com 6) Vitreo-retinal diseases ,2nd edition

Coverage : 

Coverage Introduction Epidemiology and incidence Risk factors Etiopathogenesis Classification Causes of vision loss in Diabetic Retinopathy Few recent studies

Introduction : 

Introduction Refers to involvement of retina in a patient with DIABETES Q) Why should we know about diabetic retinopathy? i) leading cause of blindness among patients aged 20- 74 yrs ii) Ophthalmologist may be the first to diagnose Diabetes mellitus iii) Early detection and timely management can save the vision iv) Commonest category attending retina clinic 400 out of 1100 ( 36%)

Incidence : 

Incidence About 17 million people in USA( 6.2%) have Diabetes Prevalence of blindness in western countries is (1.6 -1.9 / 100000) Will affect 239 million people by 2010 Most of them (appox.139 million) will be from ASIA

Risk factors : 

Risk factors Duration - Diabetes diagnosed before 30 yrs of age, incidence of DR after 10 yrs 50% 30 yrs is 90% - type I rarely develop retinopathy with in 5 yrs of onset - 5% of type 2 DM have DR at presentation ( KANSKI 6th edition)

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After 20 yrs of Diabetes almost all type I and more than 60% type II have some degree of retinopathy ( www.priory.com) incidence of proliferative retinopathy is more in type I DM

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Poor metabolic control- tight control delay onset and progression Pregnancy – i) diabetic with no retinopathy incidence increase by 10% ii) 4% with NPDR progress to PDR iii) some regression after delivery Hypertension- systolic mainly worsening of DR and development of PDR

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Nephropathy -worsening of DR -protein urea , elevated BUN ,creatinine are excellent predictor of DR -treatment of renal disease improves DR and better response to LASER Hyperlipidemia Smoking & obesity Cataract surgery- may leads progression of macular edema

Pathogenesis : 

Pathogenesis exact mechanism is unknown. Exposure to hyperglycemia over an extended period : biochemical & physiologic changes in vascular endothelium microangiopathy affecting the retinal precapillary arterioles, capillaries and venules features of – micro vascular occlusion micro vascular leakage due to due to i) capillary changes i) capillary changes ii) hematological changes

Micro vascular occlusion : 

Micro vascular occlusion A. Capillary changes- loss of pericytes, thickening of BM damage &proliferation of endothelial cells B. Hematological changes- rouleaux formation of RBC, increased platelets adhesiveness, abnormal serum lipids, increased VEGF, abnormalities in serum and whole blood viscosity.

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Micro vascular occlusion Retinal ischemia and hypoxia VEGF A-V shunt Neovascularisation capillary drop out (disc, retina, iris) ( IRMA)

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Microvascular Leakage: ( capillary changes mainly) ed no. of pericytes loss of vessel wall integrity distension of capillary wall  outpouchings  Micro aneurysms leakage breakdown of blood-retinal barrier  leakage of plasma constituents  Intraretinal Haemorrhage, Retinal Oedema (Diffuse & Localized) & Exudates

Micro vascular leakage : 

Micro vascular leakage Micro aneurysms-localized saccular out pouching of vessel wall

Classification : 

Classification 1 ) Non –proliferative mild moderate severe 2) Proliferative 3) Diabetic Maculopathy focal exudative diffuse exudative ischemic mixed 4) Advanced Diabetic eye disease hemorrhages ( pre retinal ,VH) retinal detachment neovascular glaucoma

Terminologies : 

Terminologies Micro aneurysms - saccular out pouching of retinal capillaries - inner nuclear layer -earliest detectable change -tiny, round red dot initially temporal to fovea - venous end of capillary FFA – early hyper fluorescence with late leakage

Microaneurysms in FA : 

Microaneurysms in FA

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Other causes of micro aneurysm i) retinal vein occlusion ii) hypertension How to differentiate? arterial site more in periphery How to differentiate from DOT HAEMORRHAGE? near blood vessel sharply defined leak on FFA ( confirmatory)

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Hemorrhages Intraretinal Nerve fiber layer ( dot blot, venous end) flame shaped arteriolar end Why dot shaped? Why flame shaped? INL NFL

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Soft Exudates (Cotton-wool Spots) - indistinct fuzzy margin - focal infraction of retinal nerve fiber layer -small, whitish, fluffy superficial lesions -axoplasmic stasis - post equatorial retina due to more NFL

Cotton wool spots : 

Cotton wool spots

FFA of Cotton wool spot : 

FFA of Cotton wool spot

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Hard exudates - outer plexiform layer - waxy yellow distinct margin -clumps or circinate pattern

Intra Retinal Micro vascular Abnormalities ( IRMA) : 

Intra Retinal Micro vascular Abnormalities ( IRMA) -arterio- venous shunt by- passing capillaries -fine redline from arteriole to venule -Histology- dilated vascular channel with newly formed endothelial cell and immature tight junction ( leakage on FFA ) tight junction mature ( no leakage on FFA ) -distinguishing features i) intra-retinal location ii) failure to cross major retinal vessels iii) absence of leakage on FFA

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Retinal edema- initially between OPL and INL -later IPL and NFL -retinal thickening FFA hyper fluorescence due to leakage

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Venous changes - looping , beading -dilatation Arteriolar change - narrowing -silver wiring -obliteration resembling BRAO

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Cotton-wool spots Venous irregularities Dark blot haemorrhages Intraretinal microvascular abnormalities (IRMA)

Classification of NPDR : 

Classification of NPDR No Retinopathy no retinal lesion Very mild NPDR few Micro aneurysm only Mild NPDR -micro aneurysm+ retinal hemorrhage+ hard exudates Moderate NPDR -mild NPDR 2-3Q+ cotton wool spots Severe NPDR- (4:2:1) 1 of the below H/Ma in all 4 quadrant VB in 2 or more quadrant IRMA in1 quadrant Very Severe NPDR: 2 or more of above 4:2:1 Risk of progressing to PDR with in 1 yr is 15% in severe NPDR and 45% in very severe NPDR ( ETDRS study)

MILD NPDR : 

MILD NPDR

Moderate NPDR : 

Moderate NPDR

Severe NPDR : 

Severe NPDR

Proliferative Diabetic Retinopathy ( PDR) : 

Proliferative Diabetic Retinopathy ( PDR) affects 5-10% of the diabetic population IDDM are at increased risk Features: Neovascularization -hallmark New Vessels at Disc (NVD) New Vessels Elsewhere (NVE) New Vessels at Iris (NVI)-rubeosis iridis Vitreous Detachment with fibro vascular proliferation Vitreous Haemorrhage Preretinal Haemorrhage

Pathogenesis of New Vessels : 

Pathogenesis of New Vessels micro vascular occlusion retinal ischemia and hypoxia release of vasoproliferative substances ( VEGF ) endothelial proliferation esp. from vein passes through defect in ILM between retina and post. Vitreous face ( scaffold)

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Stages of evolvement of new vessel i) fine new vessel with minimal fibrosis ii) increasement in both new vessel and fibrosis iii) regression of new vessel , leaving residual fibro vascular proliferation in posterior hyaloids TRACTIONAL RD HAEMORRHAGE ( SUDHYALOID,VITREOUS) one fourth of the retina has to non perfused before PDR develop

Clinical assessment of Neovascularisation : 

Clinical assessment of Neovascularisation NVD new vessel in the disc or with in 1DD around disc Mild – less than 1/3rd disc area Severe - if > 1/3rd NVE arise from retinal vein at arterio-venous crossing superotemporal, inferotemporal superonasal , inferonasal Mild - <1/2 disc area in extent Severe- >1/2 area in extent.

High risks characters : 

High risks characters High risk for visual loss within 2 years. i) Mild NVD with hemorrhage 26% risk of vision loss, treatment 4% ii) Severe NVD without hemorrhages Loss 26% , treatment 9% iii) Severe NVD with hemorrhage loss 37% ,treatment -20% iv) Severe NVE with hemorrhage loss 30% treatment 7%

Diabetic Maculopathy : 

Diabetic Maculopathy involvement of the fovea by oedema and/or hard exudates ischemia most common cause of visual impairment in diabetic pts edema is due to- 1) dilatation of the capillaries 2)Destruction of capillary walls ischemia Closure of capillaries->hypoxia and micro infarct CLASSIFICATION Focal Maculopathy Diffuse Maculopathy - with cystoid macular oedema Ischaemic Maculopathy Mixed Maculopathy Clinically Significant Macular Oedema (CSMO)

Focal exudative : 

Focal exudative Circumscribed retinal thickening Associated complete or incomplete circinate hard exudates Focal leakage on FA

Diffuse exudative : 

Diffuse exudative Diffuse retinal thickening Obliteration of landmark leads to localization of FOVEA difficult Generalized leakage on FA

Ischaemic : 

Ischaemic Macula appears relatively normal dark blot hemorrhage Capillary non-perfusion on FA Enlargement of the FAZ

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Clinically significant macular edema Hard exudates within 500 m of centre of fovea with adjacent edema which may be outside 500 m limit Retinal edema one disc area or larger any part of which is within one disc diameter (1500 m) of centre of fovea Retinal edema within 500 m of centre of fovea

Advanced diabetic eye disease : 

Advanced diabetic eye disease Uncontrolled proliferative diabetic retinopathy causes: hemorrhage preretinal intragel retinal detachment Non rhegmatogenous /rhegmatogenous neovascular glaucoma

Causes of vision loss in Diabetic Retinopathy : 

Causes of vision loss in Diabetic Retinopathy 1) macular edema 2) macular ischemia 3) vitreous and pre retinal hemorrhage 4) tractional or combined detachment

Management of Diabetic Retinopathy : 

Management of Diabetic Retinopathy

Presentation Layout: : 

Presentation Layout: Introduction Diagnosis Clinical Trials in Diabetic Retinopathy Classification Management : Medical / Surgical General Management Recommendation

Introduction : 

Introduction Diabetic Retinopathy leading cause of blindness of 20-64yrs in world mainly in urban population. Early detection and management can save the eyes Commonest disease attending our retina clinic 400 out of 1100 (36%)

Introduction cont… : 

Introduction cont… Successful management of diabetic retinopathy depends upon- early, aggressive & consistent control of blood glucose level regular dilated fundus evaluation timely & appropriate management

Risk Factors : 

Risk Factors Diabetes diagnosed <30yrs of age have incidence of Retinopathy in 50% after 10yrs of onset and 90% after 30yrs of onset. Type 1 rarely develops in DR with in 5yrs onset 5% of type 2 Diabetes have Retinopathy at presentation.

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CLINICAL TRIALS IN DIABETIC RETINOPATHY

Clinical Trials in Diabetic Retinopathy: : 

Clinical Trials in Diabetic Retinopathy: Diabetic Retinopathy Study (DRS) – 1976-1989 Early Treatment Diabetic Retinopathy Study (ETDRS) – 1985-1996 Diabetic Retinopathy Vitrectomy Study (DRVS) – 1985-1990 Diabetes Control and Complication Trial (DCCT) – 1993-1995 United Kingdom Prospective Diabetes Study (UKPDS) – 1977-1999

Diabetic Retinopathy Study (DRS): : 

Diabetic Retinopathy Study (DRS): Randomized, prospective clinical trial PDR or bilateral severe NPDR with VA 20/100 or better 1742 participants.One eye assigned to photocoagulation and one no PRP Outcome variable :visual acuity of 5/200 (2/60) on two consecutive follow up examination 4 m apart demonstrated ≥ 50 % reduction in the rate of SVL in eyes treated with PRP compared to untreated control group during a follow-up up to 5 years DRS recommended prompt treatment of eyes with High-risk PDR

High-Risk PDR: : 

High-Risk PDR: any one of the following: mild (1/4 to 1/3 disc area) NVD with Vitreous Hemorrhage moderate to severe NVD with/without Vitreous Hemorrhage moderate (1/2 disc area) NVE with Vitreous Hemorrhage any combination of three of the four Retinopathy Risk Factors: the presence of Vitreous or Preretinal Hemorrhage the presence of new vessels location of new vessels on or near the optic disc moderate to severe extent of new vessels

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NVD > 1/3 disc in area NVE > 1/2 disc in area + haemorrhage

Early Treatment Diabetic Retinopathy Study (ETDRS): : 

Early Treatment Diabetic Retinopathy Study (ETDRS): randomized, prospective study evaluation of photocoagulation and aspirin treatment of diabetic patients with Clinically Significant Macular Oedema (CSME) and severe NPDR with VA 20/200 or better

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Hard exudates at or within 500 m of centre of fovea with adjacent oedema which may be outside 500 m limit Retinal oedema one disc area or larger, any part of which is within one disc diameter (1500 m) of centre of fovea Retinal oedema at or within 500 m of centre of fovea Clinically Significant Macular Oedema:

Severe NPDR : 

Severe NPDR Any one of following(4:2:1rule) Diffuse intraretinal haemorrhage and microaneurysms in 4 quadrants Venous beading in 2 quadrants Intraretinal microvascular abnormalities (IRMA) in 1 quadrant

Early Treatment Diabetic Retinopathy Study (ETDRS):… : 

Results: Macular Edema Focal photocoagulation decreased risk of moderate visual loss and reduced retinal thickening. Early scatter photocoagulation scatter PRP - not recommended for eyes with mild or moderate NPDR ≥ severe NPDR – consider scatter PRP Aspirin use No role Early Treatment Diabetic Retinopathy Study (ETDRS):…

Diabetic Retinopathy Vitrectomy Study (DRVS): : 

Diabetic Retinopathy Vitrectomy Study (DRVS): randomized, prospective clinical trial the role of VITRECTOMY in managing eyes with very severe PDR and vitreous haemorrhage from PDR

Diabetic Retinopathy Vitrectomy Study (DRVS):… : 

Diabetic Retinopathy Vitrectomy Study (DRVS):… Results: In type I DM patients with severe vitreous haemorrhage - significant benefit of early vitrectomy (35.6%) In type II DM - no advantage of early vitrectomy (15.9%) In eyes with very severe PDR - showed advantage of early vitrectomy .

Diabetes Control and Complications Trial (DCCT): : 

Diabetes Control and Complications Trial (DCCT): randomized, prospective clinical trial study of control of blood glucose slow in progression of Diabetic Retinopathy Type 1 Diabetes Mellitus Results: intensive insulin therapy reduced risk of developing retinopathy by 76% and slow progression of retinopathy by 54%.

United Kingdom Prospective Diabetes Study (UKPDS): : 

United Kingdom Prospective Diabetes Study (UKPDS): randomized, prospective clinical trial evaluation of the effect of intensive blood glucose control and intensive control of blood pressure in type 2 diabetes reduce microvascular complication and progression of retinopathy. Result: intensive glucose control slowed progression of retinopathy control of HTN with a beta blocker or an ACE inhibitor proved beneficial for both macrovascular and microvascular complications.

MANAGEMENT : 

MANAGEMENT

Management of Diabetic Retinopathy : 

Management of Diabetic Retinopathy Medical Management Surgical Management

Medical Management: : 

Medical Management: Hypertension: associated with higher risk of progression of Diabetic Macular Edema and Diabetic Retinopathy Advanced diabetic renal disease and Anaemia: adverse influence on DR Pregnancy: associated with worsening of DR Good glycemic control reduce progression to severe NPDR and PDR

Surgical Management: : 

Surgical Management: Panretinal Photocoagulation (PRP) Peripheral retinal cryotherapy Sub-Tenon / intravitreal Triamcinolone acetonide Intravitreal Anti VEGF, Bevacizumab (Avastin) Vitrectomy

Laser Photocoagulation: : 

Laser Photocoagulation: recommended for eyes with High-risk PDR and CSME mechanism by which laser photocoagulation works- exact mechanism - unknown decreases the production of vasoproliferative factors by eliminating some of the hypoxic retina stimulates the release of antiangiogenic factors (vasoinhibitors) from the RPE by thinning the retina, PRP increases oxygenation of the remaining retina and so decreases vasodilation & endothelial cell proliferation

Laser Photocoagulation:… : 

Scatter Laser Treatment (PRP) High risk PDR also for severe and very severe NPDR Scatter Laser Treatment (PRP): Goal- to cause regression of existing neovascular tissue and to prevent progressive neovascularization in future Laser Used: Argon, Diode,Red, Green Amount of therapy- determined by clinical response Full PRP-  1200 burns of 500 m size, separated from each other by ½ burn width, at 0.1 second duration, in two or more sessions Laser Photocoagulation:…

Laser Photocoagulation:… : 

Laser Photocoagulation:… Scatter Laser Treatment (PRP):… avoided in areas of prominent fibrovascular membranes, vitreoretinal traction, and tractional RD

Scatter Laser Treatment : 

Scatter Laser Treatment Side effects: decrease night vision , color vision and peripheral vision, loss of 1 or 2 lines of visual acuity , macular edema.

Laser Photocoagulation:For CSME : 

Laser Photocoagulation:For CSME Two types of Laser Treatment for CSME FOCAL Laser Treatment GRID Laser Treatment

Laser Photocoagulation:… : 

Laser Photocoagulation:… Focal Laser Treatment: For local leakage (guided by FFA) Laser Used: Argon applied to all leaking microaneurysmsbetween 500 and 3000 m from the centre of the fovea Parameters: 50-100 m spot size 0.1 second or less duration attempt to whiten or darken microaneurysms

Focal Laser Treatment: : 

Focal Laser Treatment: Complications: Paracentral scotoma Transient increase edema Decreased vision Choroidal neovascularisation Subretinal fibrosis Photocoagulation scar expansion.

Laser Photocoagulation:… : 

Laser Photocoagulation:… Grid Pattern Laser Treatment: For diffuse leakage or zones of capillary non-perfusion adjacent to the macula Laser Used: Argon applied to all areas of diffuse leakage or capillary non-perfusion more than 500 m from the centre of the macula and 500 m from the temporal margin of the optic disc Parameters: 50-100 m spot size 0.1 second or less duration spots spaced at least one burn width apart

Peripheral Retinal Cryotherapy: : 

Peripheral Retinal Cryotherapy: used to treat eyes with High-risk PDR in which the media are too hazy for PRP benefits- regression of NVD, NVE & NVI Complication- development of tractional RD in 25-38% of eyes should be avoided in patients with tractional RD

Pars Plana Vitrectomy in Diabetic Retinopathy : 

Pars Plana Vitrectomy in Diabetic Retinopathy INDICATIONS: Dense, non clearing vitreous hemorrhage Tractional retinal detachment involving macula Combined tractional and rhegmatogenous retinal detachment Diffuse diabetic macular edema associated with posterior hyaloidal traction Recurrent vitreous hemorrhage despite maximal PRP

VITRECTOMY INDICATION CONT…. : 

VITRECTOMY INDICATION CONT…. Severe progressive fibrovascular proliferation Dense premacular hemorrhage Anterior segment neovascularisation with media opacity preventing PRP Red blood cell induced glaucoma

CURRENT STANDARD : VITRECTOMY TECHNIQUE : 

CURRENT STANDARD : VITRECTOMY TECHNIQUE Lens removal / IOL elective for view Vitrectomy—remove as much vitreous as is necessary and safe Membrane removal or segmentation Retinal reattachment as needed Laser burns, one burn width apart from arcades to periphery

Vitrectomy – blood removal : 

Vitrectomy – blood removal

Mild NPDR : 

Mild NPDR At least one microaneurysm +few dot hemorrhages 5% risk PDR within 1yr. & 15% risk High Risk-PDR 5yrs Mild NPDR- Follow up- 12 months Mild NPDR + Macular edema-FFA, Follow-up in 4-6 months Mild NPDR + CSME: FFA, Focal laser & 2-4 months follow up

Moderate NPDR : 

Moderate NPDR Soft exudates , Venous beading, mild NPDR 2-3 quadrant 12-27% -PDR 1yr No Macular edema: Follow up- 6-8 months + Macular edema - FFA, & Follow up- 4-6 months + CSME- FFA & focal laser + Follow up 2-4months.

Severe NPDR : 

Severe NPDR Any one of following: haemorrhage or microaneurysm in 4 Q venous beading in 2 Q,IRMA in 1Q 15% -High Risk PDR-1yr No Macular Edema - PRP- Follow up 3-4 months +Macular Edema- FFA, oc. PRP after focal + CSME – FFA , Focal laser + oc. PRP,Follow up 2-3 months

Very Severe NPDR: : 

Very Severe NPDR: 2 or more lesions of severe NPDR with no sign of neovascularisation 75% develops into PDR in 1 year FFA PRP If CSME – Focal Laser Close Follow up 2-3 months

Intravitreal injection of Triamcinolone acetonide for Diabetic Macular Edema : 

Intravitreal injection of Triamcinolone acetonide for Diabetic Macular Edema Action: inhibition of VEGF and other cytokines and growth factors and regulating endothelial cell tight junctions. Anti-inflammatory effect contribute to reduction of edema. Increase diffusion by modulation of ca channels also account for efficacy of corticosteroid in decreasing Macular edema.

Intravitreal injection of Triamcinolone acetonide for DME cont…. : 

Intravitreal injection of Triamcinolone acetonide for DME cont…. Injection site : Inferotemporal quadrant to avoid drug deposition in front of visual axis Dose : 0.1ml (4mg) Disadvantage : short duration of action Complications : Cataract Glaucoma Endopthalmitis

Intravitreal bevacizumab(Avastin) therapy for persistent diffuse diabetic macular edema:Haritoqloc c et al 2006 Germany : 

Intravitreal bevacizumab(Avastin) therapy for persistent diffuse diabetic macular edema:Haritoqloc c et al 2006 Germany Purpose:To evaluate efficacy of bevacizumab (Avastin) for treatment of diabetic macular edema Method:Prospective study included 51 pts with diffuse diabetic macular edema.All pt were treated with 0.05ml injection containing 1.25mg of bevacizumab.70% received 2 doses of intravitreal injection.

Intravitral bevacizumab cont…. : 

Intravitral bevacizumab cont…. Results: All pts completed 6 wks followup.All pt had undergone previous treatment as focal laser therapy 35% ,PRP 37% , vitrectomy 12% intravitreal injection of triamcinolone 33% Conclusion:Improvement of visual acuity and decrease in retinal thickness.Mean retinal thickness by OCT 501micrometer reduced to 377micrometer.

Intravitreal bevacizumab (Avastin) treatment of diffuse diabetic macular edema.Kumar Atul et al AIIMS,India Jan2007 : 

Intravitreal bevacizumab (Avastin) treatment of diffuse diabetic macular edema.Kumar Atul et al AIIMS,India Jan2007 Method:19 pts with diffuse diabetic macular edema were given 2 intravitreal injection of bevacizumab 1.25mg in 0.05ml in 6 wks apart Results: All eyes received PRP before but had no improvement in vision.Visual acuity improved from 20/494 to 20/295 in 3 months.Mean central macular thickness was 492micrometer reduced to 369micrometer at end of 6 months.

Intravitral bevacizumab cont… : 

Intravitral bevacizumab cont… Conclusions: Intravitreal bevacizumab resulted in significant decrease in macular thickness and improvement in vision .

Timetable based on Age Of Patient or Pregnancy: : 

Age of Onset of DM  First Eye Exam  Follow up minimum: 0-30 yrs  within 5 yrs of diagnosis  annually  31 yrs  upon diagnosis  annually pregnancy  before conception or early in first trimester  every 3 months or at discretion of ophthalmologist Timetable based on Age Of Patient or Pregnancy:

Suggested Follow-up: : 

Suggested Follow-up: Normal or Rare Microaneuyrsms - Annually Mild NPDR - Every 9 months Moderate NPDR - Every 6 months Severe NPDR - Every 4 months CSME - Every 2 - 4 months PDR - Every 2 - 3 months

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GENERAL MANAGERAL RECOMMENDATATION

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PRP for - High-risk PDR occasionally for - non-high-risk PDR severe or very severe NPDR Focal/Grid Laser for - CSME usually for High-risk PDR with macular oedema occasionally for - Non-high-risk PDR with macular oedema very severe / severe NPDR with macular oedema

Diabetic Retinopathy cont…. : 

Diabetic Retinopathy cont…. Intravitreal administration of corticosteroids Peripheral Retinal Cryotherapy Vitrectomy

Diabetic Retinopathy cont….. : 

Diabetic Retinopathy cont….. Good Control Of Blood Sugar Level. Regular Follow up as sugested by Ophthalmologist All above prevents the occurance and progression of Diabetic Retinopathy.

Thank You : 

Thank You THANK YOU

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