DIABETIC RETINOPATHY.pptx ophthalmological

Ophthalmology medical retinopathy diabetic macular disease

1. Diabetic retinopathy by/ shimaa hassan Course instructor/ pof dr Alaa Fadel

2. Diabetes Mellitus Hyperglycemia resulting from body’s inability to produce and/or utilize insulin Type 1 - children and young adults - immune prone - no insulin production - 5% of DM pts Type 2 - mostly adult onset (increase incidence at earlier age) - insulin resistance followed by decreased production - obesity

3. Diabetic Retinopathy (DR) • Implicated by both types of DM • Progressive glycation on retinal blood vessel wall • Initially asymptomatic • Microvascular leakage • Microvascular occlusion

4. Retinal neurodegeneration is an early event ( prior to microvascular damage) High levels of glutamate Overexpression of RAS components (renin / angiotensin) Progressive apoptosis of retinal ganglion cells, outer nuclear layer, photoreceptors , neuroglia of microvasculature Pathogenisis of diabetic retinopathy

5. Chronic hyperglycemia AGEs DAG ROS PKC Retinal vascular damage Increased microvascular permeability Alteration of endothelial tight juntions . Loss of pericytes . Weaking of the capillary walls. Increased secretion of VEGF ( vascular endothelial growth factor). Breakdown of the inner blood-retinal barrier. Microvascular occlusion Thickening of basement membrane . Damage and proliferation of endothelial cells. Deformation and increased rouleaux formation of red blood cells . Increased platelet stickiness abnormal fibrinolysis. Macular oedema Ischaemia / hypoxia VEGF Proliferative DR

6. Microaneurisms First clinical sign of DR. Individual microaneurysms may leak resulting in : dot haemorrhage , oedema and exudate . Spontaneous thrombosis may lead to resorption of haemorrhage oedema and exudate. The thrombosed microaneurysm usually disappears from clinical view, but occasionally remains visible as a white dot.

7. Increased microvascular permeability Dot haemorrhages cannot always be differentiated from microaneurysms as they are similar in appearance but with varying size Hence it is traditional not to attempt differentiate them on clinical examination. Instead the term dot haemorrhage / microaneurysm (H/Ma) is used . Pathogenisis of diabetic retinopathy

8. Ischaemia Increased VEGF Vitreous haemorrhage Neovascularization Fibrovascular proliferation Neovascular glaucoma Tractional retinal detachment Blot hemorrhage Cotton-wool exudates Venous beading Shunts / IRMA

9. Epidemiology Prevalence by 2030 – 439 Million

10. Leading Cause of VL in People of Working Age ( 18- 65 ) In Developed Countries

11. Prevalence of Diabetic Retinopathy after 20 Years of Diagnosis Best Predictor of Diabetic Retinopathy is the Duration of the Disease

12. NHS diabetic eye screening programme Feature based grading classification R1 Background microaneurysm (s) / retinal haemorrhage (s) / venous loop any exudates in the presence of other features of DR any number of cotton wool spots (CWS) in the presence of other features of DR

13. NHS diabetic eye screening programme Feature based grading classification R2 Pre-proliferative venous beading / venous reduplication / multiple blot haemorrhages intraretinal microvascular abnormality (IRMA)

14. R3 Proliferative R3a (Active Proliferative Retinopathy) New vessels on disc (NVD) New vessels elsewhere (NVE) New pre-retinal or vitreous haemorrhage New pre-retinal fibrosis New tractional retinal detachment Reactivation in a previous stable R3s eye NHS diabetic eye screening programme Feature based grading classification

15. R3 Proliferative R3s (Stable post treatment ) Stable pre-retinal fibrosis + peripheral retinal scatter laser Stable fibrous proliferation (disc or elsewhere) + peripheral retinal scatter laser Stable R2 features (from feature based grading) + peripheral retinal scatter laser R1 features (from feature based grading) + peripheral retinal scatter laser NHS diabetic eye screening programme Feature based grading classification If discharged from the Hospital Eye Service a photograph should be taken at or shortly after discharge from the Hospital Eye service (HES) that records these features)

16. classification

17. High-risk PDR was defined as any one of the following: 1 . NVD ≥ 1/3 disc area 2. Any NVD with vitreous hemorrhage 3. NVE ≥ ½ disc area with vitreous hemorrhage High-risk PDR was also defined as three or more of the following high-risk characteristics (HRC’s): 1. Presence of vitreous hemorrhage or pre-retinal hemorrhage 2. Presence of any active neovascularization 3. Location of neovascularization on or within one disc diameter of the optic disc 4. NVD > 1/3 disc area or NVE > ½ disc area

18. Classification based on slit lamp biomicroscopy or retinography Diabetic Macular Edema

19. Classification based on FFA Depending on the location of leakage or loss of blood supply due to capillary loss. DMO can be classified as: • Focal maculopathy : localized leakage (from 1 or more microAn ) • Diffuse/indeterminate maculopathy : generalised thickening of the central macula caused by widespread leakage from dilated capillaries. • Ischaemic maculopathy : enlargement and alteration of the FAZ. • Mixed maculopathy : combined pathology, particularly of diffuse oedema and ischaemia

20. Classification based on OCT

21. Management of diabetic retinopathy Evidence: visual loss could be avoided › Control of glycaemic levels and risk factors › Improving screening programs

22. RISK FACTORS Non-modifiable: Genetic factors, gender and duration of diabetes Modifiable: Glycaemia, blood pressure, lipid levels, anemia, tobacco and obstructive apnea. Additional factors : Carotid arterial disease, pregnancy and renal impairment.

23. The Diabetes Control and Complications Trial (DCCT)1 : After a mean duration of follow-up of 6.5 years DCCT intensive therapy achieved a reduction in mean HbA1c from 76 mmol / mol (9.1%) to 56 mmol / mol (7.3%) with significant reduction in progression of retinopathy (3-step increase on the ETDRS scale) by 76% in the primary prevention group and by 54% in the secondary intervention cohort

24. HBP Intensify therapy aiming for systolic ≤130mmHg in those with established retinopathy and/or nephropathy ( Level A ). Encourage regular monitoring of blood pressure in a health care setting and at home if possible . Recognise that lower pressures may be beneficial overall but evidence is lacking for retinopathy. ( Level B ) Recognise that specific therapies blocking the renin-angiotensin system (RAS ) may have additional benefits, particularly for mild retinopathy, butshould be discontinued during pregnancy. ( Level B ) Establish a personalised mean systolic blood pressure target in all patients who do not have retinopathy, usually < 140mmHg ( Level A).

25. DYSLIPIDEMIA FIELD study1: Treatment with fenofibrate in individuals with type 2 diabetes mellitus reduces the need for laser treatment for diabetic retinopathy, ACCORD Eye study2: Showed a 40% reduction in the odds of having progression of retinopathy over four years in patients allocated to fenofibrate (160 mg formulation/day) in combination with a statin, compared to simvastatin alone .

26. National screening programmes for diabetic retinopathy based on digital retinal photography were developed and implemented in England1 , Scotland2 , Wales3 and Northern Ireland4 between 2002 and 2007: detect any retinopathy detect the presence of sight threatening diabetic retinopathy(STDR) allow precise quality assurance at all steps minimise false positive referral to the hospital eye service NHS diabetic eye screening programme

27. Screening guidance DM type 1 Assess yearly, or more frequently if indicated, by visual acuity and digital photography after mydriasis with tropicamide . Children and adolescents with type I DM should undergo dilated fundus photography annually from age of 12 . If sudden loss of vision, rubeosis iridis , pre-retinal or vitreous haemorrhage , or retinal detachment are detected, refer for emergency review . If new vessel formation, refer for rapid review . If pre-proliferative retinopathy, significant maculopathy, or unexplained change in visual acuity, refer for review.

28. DM type 2 Arrange or perform eye screening at or around the time of diagnosis. Repeat structured eye surveillance annually, unless findings require other action . Perform visual acuity testing as a routine part of eye surveillance programmes . Emergency review by ophthalmologist for: sudden loss of vision, rubeosis iridis , pre-retinal or vitreous haemorrhage , retinal detachment. Rapid review by ophthalmologist for new vessel formation. Refer to ophthalmologist if: there are features of maculopathy, if there are features of pre-proliferative retinopathy any unexplained drop in visual acuity. Screening guidance

29. DM and pregnancy Pregnant women with pre-existing diabetes should be offered retinal assessment by digital imaging following their first antenatal clinic appointment and again at 28 weeks if the first assessment is normal . If any diabetic retinopathy is present, additional retinal assessment should be performed at 16–20 weeks . Women who have pre-proliferative diabetic retinopathy diagnosed during pregnancy should have ophthalmo logical follow-up for at least 6 months following the birth of the baby . Tropicamide alone should be used if mydriasis is required during pregnancy

30. Moderate NPDR : Funduscopy every 4-6 weeks. If progression detected every 2 weeks If high risk characteristics develop photocoagulation should be carried out promptly and monitored by funduscopy . In severe sight threatening retinopath y , laser photocoagulation should be performed before pregnancy or promptly when high risk characteristics develop

31. Background diabetic retinopathy (R1) Can be managed in the community screening programme at appropriate intervals Pre-proliferative diabetic retinopathy (R2) Careful monitoring due to increased risk of progression to proliferative retinopathy . Follow up every 4-6 months Closer follow-ups should be scheduled under the care of ophthalmologists where interval between visits should be based on severity of retinal signs, systemic control and patient factors (Level A ) . If there is concern about patient compliance and where retinopathy is progressive , retinal laser photocoagulation may be considered (Level B): in older patients with type 2 diabetes ( Level 1) where retinal view is difficult prior to cataract surgery: inflammation possibly associated with progression in only eye where first eye lost to PDR where regular clinic attendance is likely to be poor difficult to examine patient for other reasons

32. Follow up recommendations (AAO).

33. Proliferative diabetic retinopathy (R3 ) Gold Standard: panretinal photocoagulation. Aim: prevent blindness . Wherever possible PRP should be delivered the same day or should be arranged within 2 weeks of diagnosis of high risk proliferative diabetic retinopathy PASCAL ( PAttern SCAn Laser) Argon laser Frequency doubled YAG laser with a wavelength of 532 nm Power settings for Pascal are in general twice that of argon for comparable treatments. However, pulse duration is one fifth that of conventiaonl argon laser treatment Produces two major peaks of energy in the 488nm and 514nm wavelengths. This green laser energy is absorbed both by haemoglobin and by pigment epithelium. A burn if gently applied causes blanching of the outer neural retina; a more intense laser burn will produce marked whitening of the entire retinal thickness, a pigment ring surrounding the laser spot develops later.

34. Proliferative diabetic retinopathy (R3) The ETDRS recommended an initial treatment consisted of 1,200 to 1,600 burns of moderate intensity , 500-μm size, one-half to one-spot diameter spacing at 0.1-second duration, divided over at least two sessions (Argon laser ) The use of 1500, 20ms PRP burns in a single session was shown to be a safe regimen in the MAPASS trial . However, for long-term PDR regression, 72% of eyes required top-up PRP treatment PASCAL : 200 μm size spot at 20 ms duration. The usual technique is to deliver the initial treatment posterior to the ora serrata outside the vascular arcade with emphasis on ischaemic retina near NVE but avoiding direct N application

35.  Exact mechanism of action of laser induced resolution of macular edema is not known May be it is due to destruction of oxygen consuming photoreceptors. The oxygen now supplies the inner retina thus relieving hypoxia. Or as the number of total leaking vessels is reduced by being destroyed the edema comes down Or as the size of the vessels comes down due to increased oxygenation leak also is reduced Due to improved blood retinal barrier by the spreading RPE cells which will cover the small defect made by laser

36. Proliferative diabetic retinopathy (R3 ) Side effects of laser: • Pain The cause of the pain is unclear but may be due to direct thermal damage to branches of the posterior ciliary nerves. Pain may be prevented with the use of simple analgesia but on occasion may require periocular anaesthesia , or less frequently general anaesthesia • Vitreous haemorrhage Rare , but laser therapy can cause marked regression of vessels which separate from the posterior hyaloid face and produce vitreous and subhyaloid haemorrhage . • Reduction in visual field is around 40-50% after full PRP . • Secondary choroidal neovascularization If laser application is applied very close to the macula and is of a high energy • Inadvertent foveal burn • Transient macular oedema •It is advisable to treat the maculopathy either at the same time or prior to peripheral scatter retinal photocoagulation

37. Advanced Proliferative diabetic retinopathy (R3a ) Vitreous haemorrhage If laser photocoagulation is not possible, anti-VEGF intravitreal injection and early vitrectomy for vitreous haemorrhage that persists for more than one month should be considered (<3m for DMT2 and <6months DM1 ). Tractional retinal detachment Vitrectomy + dissect fibrovascular membranes and thickened hyaloid face structures or taut ILM. Iris / angle neovascularization Prompt treatment with PRP. There have been recent favourable case reports of the benefits of intravitreal antiVEGF injection in preventing blindness from progression to neovascular glaucoma (NVG ) NVG with useful vision: co-management with glaucoma specialist. NVG blind eye , should be kept pain free ( cycloablation ….) Early

38. Control of systemic risk factors Photocoagulation treatment The modified ETDRS focal/grid was performed as follows: Focal laser : All leaking microaneurysms 500 to 3000μm from fovea treated directly with 50μm spot size, duration 0.05-0.1s. Direct whitenening of the micronaneurysm was not required, but a greyish reaction beneath the microaneurysm was needed. Grid laser was performed from 500 to 3000μm superiorly and inferiorly and to 3500μm temporally. The spots were 2 burn widths apart and no burns were performed within 500μm of the disc. Time between treatments: 3-4 months Management of diabetic macular oedema

39. Intravitreal steroid treatment Preservative free intravitreal triamcinolone ( IVT ( Not in UK) DRCR-net group : IVT monotherapy is inferior to laser treatment at 3-year follow-up . IVT combined with laser is also inferior to ranibizumab with immediate or deferred laser, except in patients who are pseudophakic . A 700 μ g dexamethasone intravitreal drug delivery system ( Ozurdex Allergan) off-label . Recent studies. Anatomic improvement > functional benefit . Non-biodegradable intravitreal insert of Fluocinolone acetonide ( Iluvien reduced frequency of treatment required. Indicated in chronic DMO unresponsive to laser / anti-VEGF . Side effects. Glaucoma (4,8%), Cataract (90%).

40. Intravitreal VEGF inhibitors Pegaptanib ( Macugen )1 was the first anti VEGF treatment (specific to the 165 isoform of VEGF to show a favourable effect on DMO . Usage stopped as doesn’t inhibit VEGF completely, thus lower efficacy Bevacizumab ( Avastin ®) not licensed for intraocular use Recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting VEGF-A (all isoforms ) The typical dose is 1.25mg in 0.05ml in adults Estimated half-life is approximately 20 days

41. RANIBIZUMAB (LUCENTIS) NON BINDING FRAGMENT Makes it Humanized Therefore Less antigenic Fab FRAGMENT Mouse Derived Active against all Isoforms of VEGF High affinity binding site

42. DOSAGE AND ADMINISTRATION • Available as intravitreal injection 10 mg/mL or 0.5 mg (0.05 mL) • Binds to and inhibits the biologic activity of VEGF-A • Vitreous elimination half-life is approximately 9 days.

43. RANIBIZUMAB BEVACIZUMAB • Antibody Fragment. • 48 kilodaltons . • Half Life of 3 days. • Clearance 100 folds faster. • 140 times higher affinity. • Costly. Full Sized Antibody. • 148 kilodaltons . • Half Life 20 days. • Clearance is slow. • Long action & less dosage. • Cost’s less.

44.  Aflibercept (VEGF-Trap-Eye) Eylea ® Recombinant fusion protein consisting of VEGF-binding portions from the extracellular domains of human VEGF receptors 1 and 2, that are fused to the Fc portion of the human IgG1 immunoglobulin Dosage is 2 mg (0.05 mL) administered by intravitreal injection every 4 weeks (monthly) for the first 3 months, followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks (2 months). • t1/2 of free aflibercept in plasma is 5 to 6 days.

45. BEOVU® ( brolucizumab-dbll ) injection is indicated for the treatment of Neovascular (Wet) Age-related Macular Degeneration (AMD). BEOVU® ( brolucizumab )

46. READ study READ – R anibizumab for E dema of m A cula in D iabetes  0.5 mg of Ranibizumab on entry, 1, 2, 4, 6 months  Ranibizumab was found to be effective

47. Group 1 – Ranibizumab0.5 mg baseline, 1, 3, 5th month Group 2 – focal/grid laser baseline and after 3 months if needed Group 3 – 0.5mg Ranibizumab with focal/grid laser baseline and after 3 months if needed Study found that treatment with Ranibizumab was better READ2 study

48. Intravitreal VEGF inhibitors  Ranibizumab ( Lucentis ®)  RESTORE study The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema.

49. Intravitreal VEGF inhibitors  Ranibizumab ( Lucentis ®)  DRCR.net (Diabetic Retinopathy Clinical Research Network) Prompt laser gives no additional benefit and may show worse results in the long term. Initial monotherapy supplemented by delayed laser may be better approach in longer term

50. Intravitreal VEGF inhibitors  Ranibizumab ( Lucentis ®)  RETAIN study.  Efficacy and Safety of Ranibizumab in Two " Treat and Extend " Treatment Algorithms Versus Ranibizumab As Needed in Patients With Macular Edema and Visual Impairment Secondary to Diabetes Mellitus (RETAIN)  Lucentis treat and extend showing similar benefits to prn lucentis with fewer review appointments.

51. Protocols of injection in DME

52. Protocols of injection in DME

53. DMO No centre involving Centre involving Treat according to ETDRS guidelines No vision loss Vision loss due to DMO Ranibizumab Observe and treat according to ETDRS guidelines