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Ocular Malignancies Miscellaneous Diabetic Macular Edema B.P. Guliani MS B.P. Guliani MS, Rajshekhar Vemparala MS, Sandeep Gupta MS, V.S. Gupta MS Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi D iabetes Mellitus, a multisystem disorder is rising in epidemic proportions. India has 31.7 million diabetic subjects at present as per the World Health Organization (WHO) estimates. The prevalence of (IDDM) is 10-15% of the diabetic population. By 2030, an estimated 439 million individuals worldwide will have this Most of them (appox.139 million) will be from ASIA. Diabetic Retinopathy is a frequent complication of Diabetes mellitus and is leading cause of blindness among patients aged 20-74 years. Approximately 25% of patients with IDDM will have some degree of retinopathy 5 years after diagnosis NIDDM may go undiagnosed for 4-7 years, with patients often presenting with some degree of retinopathy at the time of diagnosis. After 20 yrs of Diabetes almost all IDDM and more than 80% NIDDM have some degree of retinopathy. Diabetic Retinopathy progresses from mild to advanced stage and Diabetic Macular Edema (DME), a visually threatening complication of Diabetic Retinopathy can develop at any stage of Diabetic Retinopathy. What is CSME (Figure 1) 1. Retinal edema and or thickening at or within 500 mm of centre of fovea. 2. Hard exudates at or within 500 mm of centre of fovea with adjacent edema which may be outside 500 mm limit. 3. Retinal edema one disc area or larger, any part of which is within one disc diameter (1500 mm) of centre of fovea. • The International Clinical Diabetic Retinopathy and Diabetic Macular Edema Disease Severity What is DME Pathologically macular edema is collection of intra-retinal fluid due to break in blood retinal barrier. Angiographically it can be focal, diffuse and ischemic. Clinical trials from time to time have changed the definition of DME and hence management protocols for Diabetic macular Edema are also changing. Early Treatment Diabetic Retinopathy Study (ETDRS)1 1984 defined Diabetic Macular Oedema as CSME and suggested grid /focal photocoagulation treatment protocols for its management. ETDRS group provided grading guidelines that are considered to be the gold standard and have been used to grade DR in research studies. Figure 1: Schematic representation of CSME www. dosonline.org l 47 Miscellaneous: Diabetic Macular Edema Diabetic Macular Edema Disease Severity scale (DRS Report 7)2 Proposed Disease Severity Level Findings observable upon dilated ophthalmoscopy DME DME apparently absent DME apparently absent No apparent retinal thickening or hard exudates in posterior pole DME apparently present Some apparent retinal thickening or hard exudates in posterior pole DME present Mild DME (some retinal thickening or hard exudates in posterior pole but distant from the center of the macula) Moderate DME (retinal thickening or hard exudates approaching the center of the macula but not involving the center) Severe DME (retinal thickening or hard exudates involving the center of the macula) Scales were therefore proposed they are designed to be more clinically relevant and to facilitate communication between clinicians. • With the advent of OCT concept of Diabetic Macular Oedema has changed. It is friendlier and treatment oriented. It is being used in most of the clinical trials for Macular Oedema (ME) due to Diabetes and vascular occlusions Morphological patterns on OCT in DME Brian Y. Kim et al described different Morphological patterns on OCT in DME3 1. Diffuse retinal thickening (DRT) appears as increased retinal thickness with areas of reduced intraretinal reflectivity (arrow) compared with retina without thickening. Flow Chart: Showing pathogenesis of Diabetic Macular edema 2. Diabetic cystoid macular edema (CME) the large, ovoid areas of low reflectivity, separated by highly reflective septae that represent intra-retinal cystoid-like cavities 3. Posterior hyaloidal traction (PHT). Tangential traction exerted by the PHT is identified on OCT as a highly reflective band over the retinal surface. 4.Serous retinal detachment (SRD) not associated with posterior hyaloidal traction (PHT). A dark accumulation of subretinal fluid in seen beneath the highly reflective and dome-like elevation of detached retina (arrowhead). The highly reflective band, which represents the outer surface of detached retina, helps to differentiate a SRD from intraretinal fluid. 5. Posterior hyaloidal traction (PHT) and traction retinal detachment (TRD). PHT is seen as the highly reflective signal arising from the inner retinal surface. The TRD is identified as the area of low signal underlying the highly reflective border of detached retina (asterisks). TRDs often take on the peaked-shaped configuration as seen in this OCT scan. Pathogenesis of DME The exact pathophysiology of DME is still unclear. Retinal vascular dysfunction causes hypoxia in diabetic eye disease, 48 l DOS Times - Vol. 20, No. 6 December, 2014 Figure 2: Diabetic macular edema which up-regulates the production of VEGF. VEGF induces vascular permeability due to its pro-permeability factor and its activity has been shown to be 50,000 times more potent than that of histamine4. Increased vaso-permeability may also occur as a result of breakdown of the blood retinal barrier due to many factors: Flow chart. Diagnosis of DME: Diagnosis of DME is done by +90D fundus examination, Fundus Fluorescein Angiography and Macular OCT. Ocular Malignancies Figure 5: Cystoid macular edema Figure 3: Types of edema on FFA Figure 6: NSD 2. Cystoid edema (Figure 5). 3. Neurosensory detachment with other features: This a emergency situation as NSD is there (Figure 6). 4. VMT: Prognosis for this stage is bad. Surgical management is the only option (Figure 7). Figure 4: Spongy edema • Fundus examination: accurate assessment of thickening and edema is done by +90 D slit lamp fundus examination (Figure 2). • Fundus fluorescein angiography: To assess for type of edema i.e. focal, diffuse, ischemic (Figure 3) which helps to decide about the type of treatment to be given to patient. • Macular OCT: Following patterns of macular OCT are seen in our cases of Diabetic macular edema: 1. Spongy edema (Figure 4). • Central macular thickness map: Central macular thickness map is always seen before taking any decision regarding management. It has nine subfields (Figure 8). • Treatment of Diabetic macular edema Without treatment, 50% of eyes with DME will lose 2 or more lines of vision within two years of diagnosis. Even though the incidence of DME can be reduced with systemic control of serum glucose, hypertension, and hypercholesterolemia, there is need for ocular treatment. Focal laser, intra-vitreal anti-VEGF agents, corticosteroids and surgical treatment are different modalities for treatment of DME. A. Systemic parameters: Control of modifiable risk factors like Anaemia, uncontrolled hyperglycaemia, High level of HbA1c, Dyslipidemia, HT, Protein urea does help in better prognosis for Diabetic macular edema. www. dosonline.org l 49 Miscellaneous: Diabetic Macular Edema I. Focal vs. grid photocoagulation Focal Grid 500-3000 micrometer area Areas of diffuse leakage away from foveal center 50-100 micrometer size individual MA spot 50-200 spot size 0.1 seconds 0.1 seconds Burnt to whitening Light intensity burns Figure 7: VMT are not treated directly and small mild burns are placed throughout the macula for DME. At 12 months after treatment, the mild macular grid technique was less effective at reducing optical coherence tomographymeasured retinal thickening than the current modified ETDRS laser photocoagulation approach. It was concluded that modified ETDRS focal photocoagulation should continue to be a standard approach for treating DME. Limitations with laser therapy Figure 8: Central macular thickness subfields B. Laser: Laser therapy has been the mainstay of treatment for CSME since the landmark ETDRS in 1985. ETDRS is a randomized, prospective study which reported effect of laser in Diabetic macular edema,evaluation of photocoagulation and aspirin treatment of diabetic patients with Clinically Significant Macular Edema (CSME) and severe NPDR with VA 20/200 or better. It concluded. 1. Focal/direct and grid photocoagulation decreased risk of moderate visual loss and reduced retinal thickening (loss of 15 letters). 2. In all cases of CSME3 years follow up reduced the risk Of moderate visual loss in Mild and moderate NPDR BY 50%. 3. Laser scars tend to increase in time hence 17% in treated group and 5% in non-treated group had three line improvement at 5 year follow up. 4. Sub retinal fibrosis leading to SRNVM due to laser. 5. No role of aspirin. 6.It suggested parameters of focal and grid photocoagulation. A recent, randomized, controlled trial compared modified ETDRS direct/grid photocoagulation technique with mild macular grid-laser technique, in which micro aneurysms 50 l DOS Times - Vol. 20, No. 6 December, 2014 Some eyes with CSME are refractory to treatment with photocoagulation. A significant proportion of patients experience progressive worsening of vision despite laser photocoagulation. Limitations with laser photocoagulation treatment includes significant risks and adverse effects such as central and paracentralscotomata, loss of color vision, progressive enlargement of laser scars (‘‘laser creep’’), and occasional secondary choroidal neovascularization. C. Intravitreal anti-VEGFs: Dual mechanism of Anti-angiogenesis and Antipermeability makesantivegf to be used in treatment of DME. It reduces the central macular thickness. Ranibizumab is FDA approved for the treatment of DME.0.05ml/0.5mg in a prefilled syringe is given monthly for the months with reviewing central macular thickness map on OCT every month. There after injection can be given as and when there is increase in central macular thickness. In our experience LASER treatment when the thickness is reduced is effective way of treatment of DME. D. Intravitreal injection Triamcinolone acetonide (IVTA): Mechanism of action of IVTA is by inhibition of VEGF, other cytokines, growth factors and regulating endothelial cell tight junctions. Its Anti-inflammatory effect contributes to reduction of edema. Increase diffusion by modulation of ca channels also account for efficacy of corticosteroid in decreasing Macular edema. It is given in the dose of 0.1 ml (4mg). Its main disadvantage is its short duration of action. Besides complications related to Intravitreal injection, it has risk of Glaucoma (24%) and Cataract (62%). Intravitreal implant: Dexamethasone is approved by FDA in pseudophakia with DME Ocular Malignancies II. Mild macular grid vs. modified macular grid5 Burn Characteristic Direct/Grid Photocoagulation (Modified-ETDRS Mild Macular Grid Photocoagulation Technique) Technique Direct Treatment Directly treat all leaking microaneurysms in N.A. areas of retinal thickening between 500 and3000 microns from the center of the macula (but not within 500 microns of disc) Change in MA Color with Not required, but at least a mild gray-white burn N.A. Direct Treatment should be evident beneath all microaneurysms Burn Size Treatment for Direct 50 microns N.A. Burn Duration for Direct 0.05-.1 sec Treatment N.A. Grid Treatment Applied to all areas with diffuse leakage or Applied to entire area described below non-perfusion within area described below for for treatment (including unthickened treatment retina) Area Considered for Grid 500 to 3000 microns superiorly, nasally and 500 to 3000 microns superiorly, nasally Treatment inferiorly from center of macula 500 to 3500 and inferiorly from center of macula microns temporally from macular center 500 to 3500 microns temporally from macular center Burn Size for Grid Treatment No burns are placed within 500 microns of disc No burns are placed within 500 microns of disc Burn Duration Treatment for Grid 50-200 microns 50 microns Burn Intensity Treatment for Grid 0.05-.1 sec 0.05-.1 sec Burn Separation for Grid Barely visible (light gray) Treatment 2 burn widths apart Intravitreal implant: Fluocinolone acetonide Approved in Europe only The Fluocinolone Acetonide in Diabetic Macular Edema (FAME) study, a 36-month, phase III study, compared fluocinolone acetonide with that of sham injection in patients with persistent or recurrent DME. Treatment efficacy was similar for low- and high-dose fluocinolone acetonide but the benefit-to risk profile was more favorable with the low dose. Fluocinoloneacetonide. Another phase II/III study showed that there was no significant difference in the proportion of eyes gaining ≥15 letters between patients treated with fluocinolone or standards of care after 3 years post implant. Risks of concerns related to corticosteroid treatment in DME patients included high incidence of premature cataract formation and increased IOP. The risk for interventional procedures, such as cataract surgery, laser trabeculoplasty, and incisional glaucoma Barely visible (light gray) 200 to 300 total burns evenly distributed over the treatment area outlined above (approx. 2 to 3 burn widths apart) surgery, increases treatment morbidity. Cardiovascular adverse events are commonly reported with fluocinolone acetonide treatment. E. Surgery for DME: With the advent of OCT, vitreoretinal interface disorders as cause of DME surgical treatment for DME is usually reserved for mechanical causes of the edema. Surgery includes vitrectomy with detachment of the posterior hyaloid, if present, and peeling of any associated epiretinal membranes, with or without internal limiting membrane removal. Theoretically, vitrectomy, with or without membrane removal, may help improve DME via multiple mechanisms. These mechanisms include the release of abnormal vitreomacular adhesions, elimination of free and bound VEGF loads, and improved diffusion of oxygen to the retina from the vitreous cavity6. AGEs are believed to promote mechanical changes in the vitreous and at the www. dosonline.org l 51 Miscellaneous: Diabetic Macular Edema vitreous-retinal interface. Vitrectomy may help remove the AGEs from the vitreoretinal interface or remove abnormally adherent vitreous that could promote DME7. Posterior vitreous detachment has been associated with spontaneous resolution of DME. Eyes with DME have been shown to have a lower incidence of PVD compared to eyes without DME. • Limitation: Although vitrectomy may clear the vitreous of its VEGF load, one caveat is that Intravitreal medications may also be cleared more quickly once the vitreous is removed. For example, intravitreal triamcinolone acetonide is cleared 1.5 times faster in vitrectomized eyes than nonvitrectomizedeyes. Future developments in the management paradigms for diabetic macular edema-(Based on web search) Bevacizumab or Laser Therapy (BOLT) study Bevacizumab or Laser Therapy (BOLT) study was a phase II RCT comparing the effects of repeated intravitrealbevacizumab (ivB) and laser therapy. Results at 2 years showed that patients who were treated with ivB had +8.6 mean letter gain compared with a mean loss of -0.5 letters with laser. The proportion of patients who gained ≥10 letters was significantly greater for ivB than for laser (49% vs 7%, P=.001). No patient lost ≥15 letters with ivB but 14% patients in the laser group sustained ≥15 letters loss (P=.03). • Vivid East-DME (NCT01783886), • Japanese Safety Study of VEGF Trap-Eye in DME (VividJapan NCT01512966), • Study of Intravitreal Administration of VEGF TrapEye (BAY86-5321) in Patients with DME (Vista; NCT01363440) Corticosteroids: Currently four corticosteroid-based intra-vitreal implants are under development • The dexamethasone biodegradable implant • The helical triamcinolone acetonide implant • The fluocinolone acetonide implant Conclusions Early diagnosis with timely OCT, Systemic control of Hypertension, Dyslipaedemia, hypergycaemia, HbA1C, Correct decision regarding antiVEGF, LASER or corticosteroids may prevent visual morbidity due to DME. References 1. Early Treatment Diabetic Retinopathy Study Research Group. Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report Number 2. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology. 1987;7:761-74 2. Wilkinson CP, Ferris FL, Klein RE, Lee PP, et al. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales Ophthalmology 2003;9:1677–82. 3. Brian Y. Kim, Scott D. Smith, Peter K. Kaiser, Optical Coherence Tomographic Patterns of Diabetic Macular Edema AJO 2006;142: 405-12. The phase II, double-masked, active-controlled DME and VEGF Trap-Eye: Investigation of Clinical Impact (DA VINCI) study, compared the effects of intravitrealaflibercept compared to those of standard laser treatment. Results at 52 weeks showed greater VA gains for aflibercept (9.712.0 letters) than for laser treatment (-1.3 letters). Patients who were treated with VEGF Trap-Eye were more likely to experience gains of ≥10 and ≥15 letters than those who received laser treatment. 4. Bhagat N, Grigorian RA, Tutela A, et al. Diabetic macular edema: Pathogenesis and treatment. SurvOphthamol. 2009;54:1-32. 5. Fong DS, Strauber SF, Aiello LP et al.; Writing Committee for the Diabetic Retinopathy Clinical Research Network. Comparison of the modified Early Treatment Diabetic Retinopathy Study and mild macular grid laser photocoagulation strategies for diabetic macular edema. Arch. Ophthalmol. 2007;4:469-80. 6. Stefansson E. The therapeutic effects of retinal laser treatment and vitrectomy. A theory based on oxygen and vascular physiology. ActaOphthalmol Scand. 2001;79:435-40. Other trials for the use of Aflibrecept 7. Mitchell P, Wong TY. Diabetic Macular Edema Treatment Guideline Working Group. Management paradigms for diabetic macular edema. Am J Ophthalmol. 2014;157:505-13. (DA VINCI) study • VEGF Trap-Eye in Vision Impairment due to DME (Vivid-DME; NCT01331681), 52 l DOS Times - Vol. 20, No. 6 December, 2014