Diabetic retinopathy

Latest in Diabetic Eye Disease 2019
Study material for MD Ophthalmology

1. DIABETIC RETINOPATHY

2. INTRODUCTION PATHOGENESIS CLASSIFICATION SIGNS TREATMENT ADVANCED DIABETIC EYE DISEASE

3. Retinopathy Iridopathy (minor iris defects) Unstable refraction Recurrent styes Xanthelasmata Accelerated senile cataracts NVG Ocular motor nerve palsies Reduced corneal sensitivity Risk of vascular occlusion Papillopathy Pupillary light near dissociation Wolfram Xd (progressive optic atrophy & neurological/ systemic abnormalities) Acute-onset cataract Rhino-orbital mucormycosis INTRODUCTION OPHTHALMIC COMPLICATION OF DM COMMON UNCOMMON RARE

4. PREVALANCE DR in diabetes is 40% Type 1 > Type 2 Sight threatening DR in 10% PDR 5 – 10 % in DM Type 1 DM – after 30 yrs 90% PDR Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR)

5. RISK FACTORS Duration of DM Diagnosis < 30 yrs – DR after 10 years in 50% Diagnosis > 30yrs – DR after 10 years in 90% Stronger predictor for PDR than maculopathy Poor glycaemic control Tight control is beneficial But, sudden improving can progress DR Raised HbA1c increases the risk of PDR Pregnancy Rapid progression in Greater pre pregnancy severity of retinopathy Poor pre pregnancy DM control Too rapid control during 1 st trimester Pre- eclampsia DME resolves spontaneously after pregnancy Puberty leads to progression of DR

6. Hypertension Very common in type 2 DM Should be rigorously controlled ( <140/80 mmHg) Particularly beneficial in type 2 + DME CVD & stroke are predictive Nephropathy Associated with worsening of DR Treatment of renal disease improves DR Other Hyperlipidemia Smoking Cataract surgery Obesity Anaemia ?? Vit D deficiency LIMITED ACCESS High myopia Choroidal degeneration Old chorioretinopathy PROTECTIVE FACTORS ?? due to low metabolic needs

7. PATHOGENESIS Endothelial damage Pericyte loss BM thickening Decompensation of endothelial barrier Serum leakage & retinal Oedema

8. CLASSIFICATION NPDR No DR Review in 12 months Very mild NPDR Review (most) in 12 months Micro-aneurysms only Mild NPDR Review 6-12 months Any / all of : microaneurysms , retinal haemorrhages , exudates, CWS, up to the level of moderate NPDR No IRMA, No beading Moderate NPDR Review in 6 months Within 1 year, PDR in 26% High risk PDR in 8% Severe retinal haemorrhages (20) in 1 -3 quadrants / mild IRMA Venous beading in 1 quadrant CWS Severe NPDR Review in 4 months Within 1 year, PDR in 50% High risk PDR in 15% The 4-2-1 rule; one or more of: Severe haemorrahges in ALL 4 quadrants Venous beading in ≥ 2 quadrants Moderate IRMA in ≥ 1 quadrant Very severe NPDR Review in 2 – 3 months Within 1 year, high risk PDR in 45% Two or more from above

9. PDR Early (mild-mod) PDR Consider PRP If not, can review in 2 months NVD / NVE insufficient to meet high risk High risk PDR PRP asap NVD > 1/3 dics area Any NVD + VH NVE > ½ disc area + VH Advanced diabetic eye disease PPV Vision threatening preretinal / VH TRD NVI ETDRS CLASSIFICATION

10. CLINICAL CLASSIFICATION BACKGROUND DR (BDR) Microaneurysms Dot and blot haemorrhages Exudates DIABETIC MACULOPATHY Odema and ischaemia PREPROLIFERATIVE DR (PPDR) CWS Venous changes IRMA PDR NVD NVE ADVANCED DIABETIC EYE DISEASE TRD Persistent VH NVG

11. SIGNS MICROANEURYSMS Localized outpunchings ( saccular ) of the capillary wall Focal dilatation where pericytes are absent Fusion of two arms of a capillary loop Develop in the inner capillary plexus (inner nuclear layer) Adjacent to areas of capillary non perfusion Loss of pericytes >> endothelial proliferation >> “cellular” microaneurysms Sequela Breakdown of BRB >> leaking of plasma Thrombosis Earliest sign of DR

12. Tiny dots often temporal to the fovea Indistinguishable from dot hemorrhages Allows differentiation from hemorrhages

13. RETINAL HAEMORRHAGES Flame shaped haemorrhages Retinal nerve fibre layer L arger superficial pre capillary arterioles Dot / blot haemorrhages Intraretinal ( Compact middle layers of retina ) Venous end of capillaries Deeper dark round haemorrhages Middle retinal layers Haemorrhagic retinal infarcs Extent is a marker for progression to PDR

14. EXUDATES Caused by chronic localized retinal oedema At the junction between normal and oedema Lipoprotein and lipid filled macrophages Mainly in outer plexiform layer Hyperlipidaemia is a risk factor Surrounds a leaking aneurysm Number and size ↑ with time If leaking ceases they absorb spontaneously (months) Chronic – crystalline cholesterol deposition Not seen in FFA ( hypofluorescence only with large dense exudates) Exudate not shown in FFA

15. DIABETIC MACULAR OEDEMA (DMO) Most common cause of visual impairment Fluid between the OPL & INL Later involves the IPL & NFL >> full thickness With central accumulation Cystoid macular oedema Flower petal pattern on FA 1. Focal maculopathy Well circumscribed retinal thickening with complete/ incomplete rings of exudate FA – focal hyperfluorescence 2. Diffuse maculopathy Diffuse thickening + cystoid changes Scattered microaneurysms + small haemorrhages FA - mid/ late phase diffuse hyperfluorescence

16. focal diffuse

17. Types of macular oedema Diffuse Retinal Thickening (DRT) Most common Responds well to anti VEGF Cystoid Macula Oedema (CMO) Outer – responds well to antiVEGF Inner – poor prognosis Have to look for photoreceptor continuity (4)

18. CLINICALLY SIGNIFICANT MACULAR OEDEMA (CSMO) Retinal thickening within 500 µm Exudates within 500 µm + retinal thickening (which maybe outside ) Retinal thickening of ≥ 1500 µm area with any part within 1500 µm 4 year incidence of CSME Mild NPDR 12% Moderate NPDR 23%

19. ISCHAEMIC MACULOPATHY Macula may look normal despite ↓ VA FA shows capillary non perfusion at the fovea (↑ FAZ) and other areas

20. COTTON WOOL SPOTS Accumulation of neuronal debris within the NFL Small fluffy whitish superficial lesions that obscure underlying blood vessels FFA – focal hypofluorescence due to, Local ischemia Masking of choroidal fluorescence

21. VENOUS CHANGES Generalized dilatation and tortuosity Looping Beading (focal narrowing and dilatation) Sausage like segmentation

22. INTRARETINAL MICROVASCULAR ABNORMALITIES (IRMA) Arteriolar- venular shunts Seen adjacent to areas of marked capillary hypoperfusion Does not cross major blood vessels FA – focal hyperfluorescence with adjacent areas of capillary dropout but no leakage IRMA TELANGIECTASIA In DR In retinal vein occlusion Leaks only from the tips Leaks along the length No exudates Exudates and oedema Endothelial tight junctions

23. ARTERIAL CHANGES Subtle arteriolar dilatation – an early marker of ischemia Peripheral narrowing ‘Silver wiring’ Obliteration

24. PROLIFERATIVE RETINOPATHY Over 1/4 th of the retina has to be non perfused before PDR develops New vessels at disc (NVD) Neovascularization on or within 1 disc diameter of the optic nerve head New vessels elsewhere (NVE) Neovascularization further away from the disc New vessels on the iris (NVI) ( rubeosis iridis ) Can progress to NVG FA – highlights during early phase and irregular expansion of hyperfluorescence due to leaking

25. Retinal haemorrhage Retinal ischemia Microaneurysms Neovascularization IRMA Venous beading

26. Indications for FFA in DR To differentiate IRMA from NVE (neovascularization) To demonstrate capillary dropouts To identify macular ischemia

27. TREATMENT

28. GENERAL Patient education Compliance and regular review Strict glycaemic control Optimized HbA1c delays progression of DR (DCCT*, UKPDS*, ACCORD*) Risk factor control Systemic hypertension Hyperlipidaemia Fenofibrate 200mg daily FIELD* , ACCORD* Independent of whether the patient is already on statins Stop smoking No definitive evidence Other modifiable factors Anaemia <12 g/ dL increased the DR risk by twofold Renal failure (proteinuria) Aspirin (650mg / day) – doesn’t slow progression & doesn’t cause VH; So, no change in regime (ETDRS*)

29. Parameter Treatment Goal Hemoglobin A1C < 6.5% for patients who meet the following criteria: Short duration of diabetes Long life expectancy No concurrent illness Goal can be achieved without significant hypoglycemia or other adverse effects of treatment <7.0%, a reasonable goal for many patients <8.0% for patients who meet the following criteria: History of severe hypoglycemia Limited life expectancy Advanced microvascular or macrovascular complications Extensive comorbid conditions Long-standing T2D in which A1C goal has been difficult to obtain despite intensive efforts Fasting plasma glucose (FPG) 80-130 mg/ dL 2-hour postprandial glucose (PPG) <180 mg/ dL BP should be 130/80 mmHg LDL –C < 100 mg/ dL HDL-C >40 mg/ dL TGD <150mg/ dL

30. Diabetes Control and Complications Trial ( DCCT ) – TYPE 1 DM HbA1c 9.1 to 7.3 reduced the progression of retinopathy by 76% Metabolic legacy effect UK Prospective Diabetes Study ( UKPDS ) – TYPE 2 DM HbA1c 7.9 to 7.0% reduced microvascular complications by 25% Metabolic legacy effect SBP 154 to 144mmHg reduced microaneurysms , exudates & CWS No legacy effect for BP control Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) HbA1c 7.4 to 6.5% reduced progression by 42% Thiazolidinediones (rosiglitazone) not cardioprotective Intensive BP control has no significant effect Statin + fenofibrate better than Statin alone (statins are avoided in pregnancy) ADVANCE Pioglitazone increased macula oedema by 2.6x Diabetic Retinopathy Candesartan Trials ( DIRECT ) RAS blockade (esp. candersatan ) reduced DR progression (should be withheld in pregnancy) Fenofibrate Intervention and Event Lowering in Diabetes ( FIELD ) 200mg / day reduced the requirement for laser

31. DMO Rx 1. Laser photocoagualation Focal Grid 2. Subthreshold micropulse diode laser Minimizes collateral damage to retina / choroid 3. Intravitreal anti-VEGF 4. Intravitreal steroids Risk of increased IOP Psedophakic – beneficial Phakic – no significant benefit over laser (cataracts++) Sustained release IV implants available 5. Pars plana vitrectomy ME + VMT Dexamethasone – Ozurdex Fluocinolone acetonide – Iluvien Triamcinolone acetonide trabs scleral helical implant – I- vation

32. FLT studies Early Treatment Diabetic Retinopathy Study ( EDTRS ) In CSMO the rate of moderate visual loss reduced from 24% to 12% in 3 years with macular laser Increased the chance of moderate visual gain Reduces retinal thickening DRCR.net Protocol A Modified EDTRS focal/grid laser was better than mild macular grid laser* over 1 year * MMG – burns are lighter and more diffuse in nature and are distributed throughout the macula in both areas of thickened and unthickened retina

33. Anti-VEGF studies Ranibizumab for Edema of the mAcula in Diabetes ( READ 2 ) Anti-VEGF alone or with laser is better than laser alone Bevacizumab Or Laser Treatment study (BOLT ) Favourable outcomes in IVB in ci-CSME DME and VEGF Trap-Eye: Investigation of Clinical Impact ( DA VINCI ) Better outcomes in aflibercept over laser Rx in ci-CSME Study of Ranibizumab injections in subjects with CSDME with center involvement secondary to diabetes mellitus ( RISE and RIDE ) Ranibizumab rapidly and sustainably improved vision Reduced the risk of further vision loss Improved m acula oedema Low rates of ocular and nonocular side effects

34. Safety and Efficacy of Raibizumab in D iabetic Macula Edema ( RESOLVE ) Ranibizumab better than sham at 1 year RESTORE Ranbizumab +/- laser better than laser alone DRCR.net protocol I Ranibizumab with prompt (3-10 days) /deferred (≥ 24/52) laser was better than laser +/- triamcinolone Ranibizumab + laser = triamcinolone + laser in pseudophakics (but high IOP +) DCRC.net protocol T 2 year results – no significant deference among 3 anti-VEGF drugs in serious adverse effects or visual improvement Aflibercept has greater visual improvement over bivacizumab in 1 year, with < 6/18 The average no. of injections halved in the second year

35. Intravitreal steroid studies DRCR.net Protocol B Triamcinolone 4mg better than 1mg Laser group had better VA in 2 years (cataracts) Macula Edema: Assessment of implantable Dexamethasone in diabetes ( MEAD ) At 3 years implant group had a significant improvement of BCVA regardless of the lens status Vision loss in 1 year due to cataract Fluocinolone Acetonide intravitreal implant for diabetic Macula Edema ( FAME ) Sustained BCVA improvement over 3 years

36. RECOMMENDATIONS CSMO not involving fovea should be Rx with FLT CSMO involving fovea but > 6/9 VA can undergo micropulse laser or observe for ↑ leakage CSMO involving fovea and < 6/9 VA should be considered for anti-VEGF injections Initial induction monthly for 3-6 months Then Rx as needed Ant-VEGF + differed laser is an option Pseudophakics with CSMO involving fovea can be considered for intravitreal steroids ± laser In resistant cases IV TA Sustained release steroids PPV (in VMT) FOLLOW UP Macular laser – 3 monthly AntiVEGF – monthly for 1 year, then taper Steroids – frequently for IOP

37. In PREGNANCY Blood glucose control Laser (FLT) S teroids If refractory Only in 2 nd and 3 rd trimester Risk of IOP, cataracts should be discussed Anti VEGF As the last resort Lack long-term safety data (?Miscarriages, ? P reeclamsia ) Preferably in 3 rd trimester

38. How to do laser for CSMO?? ( modified ETDRS protocol) Focal treatment Spot 50 – 100 µm Duration 50 – 100 ms Power – mild whitening (start from 80 mW ) Test shot – to inferior retina (superior VF loss, risk of bleeding will tract down) Only few shots (at the microaneurysm ) Grid treatment Spot 50µm Duration 50 ms Power – mild whitening (50 mW ) Diffuse grid Focal + Grid Avoid treating within 500 µm of the foveal center Treat only areas of macular thickening and leaking microaneurysms

39. OCT parameters in DME IS-OS junction / ELM The integrity of the ellipsoid zone gives good results Hyperreflective dots (HRDs) More the number, poorer the response Choroidal thickness Reduces with treatment, hence initial thick choroid is a good prognostic factor Disorganization of inner retinal layer (DRIL) Poor prognosis

40. PDR Rx LASER Rx PRP is the mainstay with intravitreal and other Rx as adjunctive DRS study* – PRP reduced visual loss in PDR from 26% to 9% In coexisting DMO – laser for this should be carried out first or, adjunctive intravitreal ( antiVEGF / steroids) Discomfort is greatest in the periphery and over the horizontal neurovascular bundle >> tends to worsen with each session Single or multiple sessions Mild PDR – 3000 spots Mod PDR – 4000 spots Severe PDR – 7000 spots Initial treatment 2000 spots of 500 µm size, then +/- retreatment in 1-3 months MAP ASS trial - 1500, 20ms PRP burns in a single session is safe

41. Early Treatment Diabetic Retinopathy Study ( ETDRS ) Deferral of PRP was preferable at least until retinopathy was approaching high risk Consider PRP before the development of high risk PDR esp. in type 2 DM Indicators of regression Blunting of vessel tips Shrinking and disappearance of NV Ghost vessels / Fibrosis Regression of IRMA Decreased venous changes Absorption of retinal haemorrhages Disc pallor Side effects of laser Pain VH Visual field loss Reduction of accommodation Dimness of vision Nyctalopia CNV Macular burn Macular oedema (transient) Increased IOP Angle closure Pre/sub retinal fibrosis Poor pupillary reaction Poor dilatation TRD

42. Early Treatment Diabetic Retinopathy Study ( ETDRS ) Very severe NPDR has a 48.5% risk of progression to PDR within 1 year Early PRP reduced the progression to high risk PDR by 50% in the full scatter group PRP should be considered in severe/ very severe NPDR in : Older patients with type 2 DM Poor retinal view Prior to cataract surgery Only eye Regular follow up not reliable Difficulty to examine Recommended 500um spot size, 100ms duration, moderate intensity, 0.5 – 1 spacing With modern machines, shorter duration (10-50ms), smaller burns (300-400um), wider spacing (1-1.5) recommended, for less side effects, but may need more frequent top up

43. Early Treatment Diabetic Retinopathy Study ( ETDRS ) ( contd …..) Early scatter photocoagulation… Small reduction in the risk of severe vision loss Not indicated for eyes with mild to moderate DR Most effective in patients with type 2 DM Diabetic Retinopathy Study (DRS) PRP reduces severe vision loss by 50% at 5 years (PDR/ severe NPDR) High risk PDR benefited the most

44. Anti-VEGF Indications Attempted resolution of persistent VH Initial Rx of rubeosis iridis Rapid control of very severe PDR TARGETED RETINAL PHOTOCOAGUALTION (TRP) Scatter laser to peripheral capillary non perfused areas

45. DCRC.net protocol S Ranibizumab resulted in no more than 5 letters worse VA than PRP in 2 years ( both are equally effective ) Ranibizumab group Better average VA Less visual field loss Fewer no. of vitrectomies Higher no. of treatments and visits Anti-VEGF drugs Bevacizumab ( Avastin ) 1.25mg > complete antibody targeting vessel growth Ranibizumab ( Lucentis ) 0.5mg > humanized monoclonal antibody fragment, binds non selectively and inhibits all isoforms of VEGF-A Aflibercept ( Eylea ) 2mg > recombinant fusion protein that binds to VEGF-A, VEGF-B, PlGF

46. Advanced diabetic eye disease

47. Clinical features Haemorrhage Preretinal ( retrohyaloid ), Intragel (VH), or both VH takes longer to clear Altered blood becomes compacted on the posterior vitreous face to form an ‘ochre membrane’ Tractional RD Progressive contraction of fibrovascular membranes PVD is often incomplete Rubeosis iridis May lead to NVG Eyes in severe retinal ischaemia

48. Indications for PPV 1. Severe persistent VH If no NVI - PPV within 3 months of initial VH Outcome might be better in early PPV Anti-VEGF as an adjunct 2. Progressive tractional RD Extra macular traction can be observed 3. Combined TRD + RRD Should be treated urgently 4. Premacular retrohyaloid haemorrhage If dense and persistent YAG hyaloidectomy is often successful 5. Diffuse DME with VMT 6. Fibrovascular proliferation 7. Ghost cell glaucoma 8. Anterior segment neovascularization Ghost cell glaucoma should be suspected in post PPV elevated IOP in the early period (2-6/52)

49. Diabetic Retinopathy Vitrectomy Study ( DRVS ) Benefit of early vitrectomy for severe VH was seen in type 1 DM, but no advantage in type 2 Early vitrectomy was beneficial for patients with better than 20/400 plus one of the following, Severe neovascularization and fibrous proliferation Fibrous proliferation and mod VH Mod neovascularization, severe fibrous proliferation,& mod VH When anti VEGF is given pre op – (3 – 5 das prior) WHY??, To regress new vessels Easy to peel off ILM / membranes

50. Rubeosis iridis management NVI alone Immediate full PRP NVI + NVA Prompt PRP + IV antiVEGF NVG cycloablative laser Cryotherapy Drainage tube Trabeculectomy + MMC Blind with NVG Palliative Mx Topical Steroids and Atropine

51. FOLLOW UP TYPE INITIAL EVALUATION FOLLOW UP Type 1 5 years after diagnosis Yearly† Type 2 At time of diagnosis Yearly† Pregnancy (type 1 or 2) Soon after conception & early in the first trimester < mod NPDR – 3-12 months > Severe NPDR – 1-3 months GDM No need No need † 5 - 10 % of patients WITHOUT DR can develop DR within 1 year

52. DIABETIC PAPILLOPATHY ?? Uncommon variant of AION Bilateral , more diffuse isc swelling Mainly in young diabetics Mild painless visual impairment Have to exclude raised intracranial pressure Resolution over several months with disc pallor Final VA > 6/12 in 80%

53. NON DIABETIC RETINOPATHY Upto 10% over 40 without DM Usually very mild Microaneurysms , dot/blot hemorrhages, CWS Associated with increased cerebro /cardiovascular risk Maybe a marker of preclinical diabetes Evaluation and optimal management of systemic vascular risk factors needed