ATHANASIOS NIKOLAKOPOULOSPAPANIKOLAOU HOSPITAL

THESSALONIKI-GREECE

Diabetic macular edema (DME) is a major source of vision loss inpeople with diabetes mellitus.DME affects up to 25% of people after 10 years of diagnosis of diabetes and will develop in more than 40% of patients with type 1 diabetes over the course of their lifetimes.

Klein R, Klein B, Moss S, Cruickshanks KC. The Wisconsin Epidemiologic Study of Diabetic Retinopathy XV. The long term incidence of macular edema. Ophthalmology 1995; 102: 7-16.Javitt JC, Canner JK, Sommer A. Cost effectiveness of current approaches to the control of

retinopathy in type I diabetes. Ophthalmology 1989; 96: 255-264.

Laser photocoagulation (focal/grid) Anti-VEGF agents Combined therapy (laser photocoagulation + anti- VEGF)

Early Treatment Diabetic Retinopathy Study Research Group. Focal photocoagulation treatment of diabetic macular edema. Relationship of treatment effect to fluorescein angiographic and other retinal characteristics at baseline. ETDRS report number 19. Arch Ophthalmol. 1995; 113: 1144-1155.

Elman MJ, Aiello LP, Beck RW et al. Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating ranibizumab plus prompt of deferred laser or triamcinolone plus prompt laser for DME. Ophthalmology 2010; 117: 1064-1077.

Nasrallah et al (1988): the incidence of PVD was lower in patients with DME.

Hikichi and colleagues (1997): after PVD spontaneous resolutionof DME in 55% of diabetic patients

ATTACHED VITREOUS RISK FACTOR FOR DME

Lewis et al 1992: vitrectomy can improve visual prognosis in some eyes with DME and macular traction (“taut posterior hyaloid”)

It is known that the diabetic vitreous is abnormal with enzyme-mediated vitreous collagen crosslinking and non-enzymatic glycation; with reduced permeability potentially increasing the concentration of a pre-macular growth factor soup.

Sebag J. Abnormalities of human vitreous structure in diabetes. Graefes Arch Clin Exp Ophthalmol 1993; 231(5): 257–260.Sebag J, Buckingham B, Charles MA, Reiser K. Biochemical abnormalities in vitreous of humans with proliferative diabetic retinopathy. Arch Ophthalmol 1992; 110(10): 1472–1476.Sebag J, Nie S, Reiser K, Charles MA, Yu NT. Raman spectroscopy of human vitreous in proliferative diabetic retinopathy. Investig Ophthalmol Vis Sci 1994; 35(7): 2976–2980.

Transvitreal oxigenation

Relief of vitreomacular traction

Improved growth factor diffusion away from the perimacular area

Cambridge Ophthalmology SymposiumEye (2008) 22, 1337–1341; doi:10.1038/eye.2008.84; published online 25 April 2008Vitrectomy for diabetic macular oedemaD A H Laidlaw

Edema duration Expansion of laser scars Extent of ischemia and exudation Permanent photoreceptore and capillary damage which

precludes anatomical or visual benefits

Laidlaw

FUNDUS EXAMFUNDUS EXAM

FAGFAG

OCTOCT

Vitreous baseOptic discPerifoveal/macular regionVesselsPosterior lens - Weigert’s ligament

SURGICAL TREATMENT (25GPPV)Release any vitreomacular tractionRemove the vitreous cortex (kenalog assisted)Remove as much vitreous gel as possible

Peel off any ERM

ILM peeling BB assisted

Caused by partial posterior vitreous detachment: the posterior hyaloid is incompletely detached from the posterior pole and remains attached to the optic disc and the foveal center exerting traction on the foveal tissue.Traction on macular tissue produces gradual anatomic and functional deterioration in proportion to traction forces (anterior-posterior or tangenzial) and their duration of action.

Ocriplasmin (microplasmin) is a truncated form of the human serine protease plasmin that retains its enzymatic properties. is believed to primarily target the fibronectin, laminin, and type IV collagen fibers that adhere the vitreous to the retina.designed specifically for use in the eye is delivered via an intravitreal injection. The goal of any pharmacologic separation of the vitreoretinal interface is to create a clean separation of the posterior vitreous cortex and the inner limiting membrane (ILM) of the retina.

Offers complete PVD without mechanical manipulation at the retina thereby minimizing the risk of iatrogenic damageAn intravitreal injection is less traumatic than vitrectomy and can be given early before advanced stages of the disease have developedCleaving the vitreous cortex from the retina changes the molecular flux across the vitreoretinal interface and improves both oxygen supply to and clearance of vascular endothelial growth factor from the retina1.

Gandorfer A, Putz E, Welge-Lüssen U, Grüterich M, Ulbig M, Kampik A. Br J Ophthalmol. 2001;85(1):6-10.2. Sakuma T, Tanaka M, Mizota A, Inoue J, Pakola S. Invest Ophthalmol Vis Sci.2005;46(9):3295-3299.

The ocriplasmin (microplasmin) phase III program, consists of 2 multicenter, randomized, placebo controlled, double-masked trials. These trials were designed to evaluate a single dose of 125μg ocriplasmin vs placebo administered intravitreally for the treatment of patients with sVMAThe primary end point of these trials was looking at pharmacologic resolution of symptomatic vitreomacular adhesion.652 patients were enrolled in these trials at 90 centers in 7 countries across the United States and Europe

Both TG-MV-006 (US only) and TG-MV-007 (EU and US) trials of ocriplasmin vs placebo:Met the primary end point: achieving a statistically and clinically significant improvement in the resolution of VMA26.5% of subjects had pharmacological resolution of VMA at day 28Demonstrated pharmacological resolution of VMA in 34% of subjects without an epiretinal membrane40.6% of subjects had pharmacological closure of FTMH at day 28, which was mainained at month 613.4% of subjects had inductionof total PVD Visual acuity and visual function questionnaire outcomes favoredocriplasminOcriplasmin was generally well tolerated

28-49% SHOWED AN IMPROVED VISUAL OUTCOME

REMOVAL OF EPIRETINAL MEMBRANES MAY FAVORABLY EFFECT VISUAL OUTCOME OF VITRECTOMY

Diabetic Retinopathy Clinical Research Network Writing Committee on behalf of the DRCR.net, Haller JA, Qin H, Apte RS, Beck RW, Bressler NM, Browning DJ, Danis RP, Glassman AR, Googe JM, Kollman C, Lauer AK, Peters MA, Stockman ME. Vitrectomy outcomes in eyes with diabetic macular edema and vitreomacular traction. Ophthalmology. 2010 Jun;117:1087-1093.e3

VITREOUS AND TRACTION REMOVAL IN ALMOST ALL CASES

REMOVAL OF THE EPIRETINAL TISSUE AND ILM

PERMANENT RESULTS IF SUCCESFULL

JUST AN INTRAVITREAL INJECTION

POSSIBLE EARLIER USE ?

A STAGE BEFORE VITRECTOMY?

From the literature the strongest indication for vitrectomy in DME is when there is also macular traction.Better visual outcomes in patient when we remove the epiretinalmembranes with or without ILM.The early Results of ocriplasmin showed that can also remove the traction with an injection only in more than 30%.But we have to wait to see if it can be used in an early, pre - vitrectomy stage, or in combination treatments for DME.If VITREOUS IS A RISK FACTOR in DME both can create a better access for further anti-VEGF treatment in eyes with resistance to anti-VEGF due to attached vitreous and the perifoveal area membranes