Prospective randomized study comparing micropulse diode laser photocoagulation and argon green laser photocoagulation for treatment of clinically significant diabetic macular oedema Thesis Submitted by Moataz Hamed Mohamed M.B.B.Ch, M.Sc. (Ophthalmology) In Partial Fulfillment of MD Degree in Ophthalmology Under Supervision of Prof. Dr. Mostafa Mostafa Bahgat Professor of Ophthalmology Faculty of Medicine Cairo University Prof. Dr. Nihal Adel Hassan Professor of Ophthalmology Faculty of Medicine Cairo University Prof. Dr. Ihab Saad Othman Professor of Ophthalmology Faculty of Medicine Cairo University Cairo University Faculty of Medicine 2012
Acknowledgement Acknowledgement I would like to express my gratitude to Kasr Al-Ainy, our great school, for every piece of information I have learned. I would like to express my deep gratitude and appreciation to Prof. Dr. Mostafa Mostafa Bahgat, Professor of Ophthalmology- Cairo University, for his valuable advices, continuous support, scientific additions and sincere help throughout the work. My profound thanks, respect and deep gratitude to Prof. Dr. Nihal Adel Hassan, Professor of Ophthalmology- Cairo University, for her fruitful advices and help throughout the work. My deepest gratitude and appreciation to Prof. Dr. Ihab Saad Othman, Professor of Ophthalmology- Cairo University for his fruitful assistance and valuable suggestions throughout the work. Special thanks to all my Professors and colleagues in the Ophthalmology department, Faculty of medicine, Cairo University for their encouragement and help. My deepest thanks to my family to them I owe everything. Moataz Hamed
Abstract The purpose of this study is to assess effect of micropulse diode laser (MPDL) on best corrected visual acuity (BCVA), central foveal thickness(cft), contrast sensitivity measured at 5 spatial frequencies and on macular scar formation during treatment of clinically significant diabetic macular oedema (CSME) as compared to conventional argon green laser (CGL) treatment. This is a single-center, prospective, interventional, comparative study. Twenty four patients (40 eyes) with diabetic CSME were randomly assigned to MPDL (n=20) or CGL (n=40) photocoagulation. Micropulse diode laser photocoagulation is superior to CGL treatment for CSME regarding contrast sensitivity improvement and macular scar formation. Micropulse diode laser photocoagulation is equally effective as CGL treatment for CSME regarding BCVA and central foveal thickness. Key Words: Micropulse, Argon, laser, diabetic macular oedema, contrast sensitivity, macular scar, visual acuity, foveal thickness.
Table of contents Table of contents Subject Page - List of figures ii - List of tables vii - List of abbreviations viii - Introduction 1 - Aim of the work 2 - Review: Anatomy of the macula Definition, Epidemiology, Natural history and classification Pathogenesis of diabetic macular oedema Histopathology Diagnosis of diabetic macular oedema Treatment of DME 3 3 6 12 21 23 29 Micropulse diode 42 - Patients and methods 56 - Results 63 - Discussion 84 - Conclusion 95 - Summary 96 - References 99 - Arabic Summary i
List of figures List of figures No 1 The anatomical fovea and foveola are contained within the center of the anatomical macula. 2 Section in the region of the foveola. the inner cellular layers are absent and there is an increased density of pigment in the RPE. 3 Focal DME. 4 Diffuse DME. 5 Ischemic maculopathy. 6 Diabetic retinal pigment epitheliopathy. 7 Optical coherence tomography showing focal macular oedema. 8 Schematic presentation of the inner and outer BRBs and their relative location. 9 Schematic diagram illustrating the course of AGE formation on a hypothetical fibrilar protein. 10 Schematic of tight junction proteins. 11 Schematic diagram showing the site of action of different anti- VEGF. 12 Effects of posterior vitreous detachment on diabetic retinopathy. 13 Posterior precortical vitreous pocket. 14 Histopathology of exudates. 15 Correlation between OCT, fluorescein angiography and fundus biomicroscopy. 16 OCT shows A) sponge-like retinal swelling B) Newly developed cystoid macular edema. C) Established cystoid macular edema. D) SRD. 17 OCT demonstrating diffuse retinal thickening. 18 OCT of a patient with diabetic cystoid macular edema. ii
List of figures 19 OCT demonstrating posterior hyaloidal traction. 20 OCT of a serous retinal detachment. 21 OCT of a patient with posterior hyaloidal traction and traction retinal detachment. 22 Examples of laser treatment techniques (focal and grid). 23 ETDRS-modified protocol versus standard ETDRS photocoagulation: difference in laser burns. 24 Mild macular grid. 25 Schematic diagram showing steroids role in reducing DME. 26 CW Mode (100% Duty Cycle). 27 MicroPulse Mode (10% Duty Cycle). 28 Topcon TRC 50IX retinal camera 29 SD OCT RTvue 30 (A) OcuLight SLx diode laser with micropulse mode. (B) OPTO Advant Green Laser 31 Mean best corrected visual acuity (BCVA) at baseline,3 and 6 months. 32 Mean central macular thickness at baseline, 3 and 6 months. 33 Color fundus photo and FFA show diffuse macular oedema. OCT shows diffuse retinal thickening (CMT= 318µm). 34 6 months after argon grid, there is decreased oedema (CMT=299µm). Laser marks are seen in FFA. 35 Color fundus photo and FFA show diffuse macular oedema. OCT shows diffuse retinal thickening (CMT= 351µm). 36 6 months after argon grid, there is decreased oedema and hard exudates (CMT=335µm). Laser marks are seen in FFA. 37 Color fundus photo and FFA show focal macular oedema. OCT shows CMT=252µ. 38 6 months after focal argon treatment, there is decreased oedema (CMT=240µm). Laser scars are seen in color fundus photo. iii
List of figures 39 Color fundus photo and FFA show diffuse macular oedema, hard exudates, dot and blot haemorrhages. OCT shows cystoid macular oedema. (CMT= 486µm). 40 6 months after MPDL grid, there is decreased oedema (CMT=451µm). No laser marks are seen in color photo or FFA. 41 Color fundus photo and FFA show focal macular oedema. OCT shows CMT=283µm. 42 6 months after focal MPDL treatment, there is decreased oedema (CMT=278µm). No laser marks are seen in FFA. 43 Upper OCT shows diffuse macular oedema (CMT=394µm). Middle OCTshows 3 months after MPDL grid (CMT=367µm). Lower OCT shows 6 months after MPDL (CMT=329µm). 44 Upper OCT shows focal macular oedema (CMT=309µm). Lower OCT 6 months done after focal MPDL (CMT=282µm). 45 Upper OCT shows diffuse macular oedema (CMT=394µm). Lower OCT is 6 months after MPDL grid (CMT=368µm). 46 Mean contrast sensitivity of CGL group and MPDL group at baseline showing no statistical significant difference between both groups. 47 Mean contrast sensitivity of CGL group and MPDL group at 3 months showing no statistical significant difference between both groups. 48 Mean contrast sensitivity of CGL group and MPDL group at 6 months showing no statistical significant difference between both groups. 49 Mean contrast sensitivity of CGL group at baseline, 3 and 6months showing no statistical significant improvement between baseline and following visits at different spatial frequencies. 50 Mean contrast sensitivity of MPDL group at baseline, 3 and 6 months showing statistical significant improvement in contrast sensitivity at spatial frequencies 6 and 12 and no statistical significant difference at the other spatial frequencies. 51 6 months after argon laser grid (Upper) fundus photo showing laser scars. (Lower) FFA showing laser marks. iv
List of figures 52 Upper OCT showing SRD with CMT=318 µm. Lower OCT (6 months after MPDL grid) shows no SRD with CMT=282 µm. 53 Upper OCT showing SRD with CMT=354µm. Lower OCT (6 months after CGL grid) shows no SRD with CMT=290 µm. 54 A)Fundus photo and FFA shows CSME with hard exudates. B) Fundus photo and FFA shows reduction of CSME and hard exudates. Laser marks are seen at FFA. 55 A) Color fundus photo showing CSME and hard exudates. B) FFA showing cystoid macular oedema. C) OCT showing cystoids macular oedema (CMT= 415µm). 56 3 months after Argon grid A) Color fundus photo and B) FFA showing persistent macular oedema and laser marks. C) OCT shows persistent cystoids macular oedema (CMT=548µm). This patient had argon supplemental treatment. 57 3 months after supplemental treatment. OCT shows persistent cystoid oedema (CMT=629 µm). Intravitreal TAC is given. 58 1 month after TAC injection. A) Color phundus photo shows decreased macular oedema and laser scars. B) FFA shows laser marks. C) OCT shows reduction of macular oedema. (CMT=303µm) 59 A)Color fundus photo showing CSME and hard exudates. B) FFA showing diffuse macular oedema. C) OCT showing diffuse retinal thickening (CMT= 260µm), hyper-reflective areas with back shadowing denoting hard exudates. 60 3 months after MPDL grid A) Color fundus photo shows increased hard exudates which correlated with elevated serum cholesterol and triglycerids. B) FFA showing persistent macular oedema. No laser marks seen at FFA. C) OCT shows SRD with CMT=375µm. This patient had MPDL supplemental treatment. 61 3 months after supplemental treatment. OCT shows persistent SRD with CMT=395 µm. Intravitreal TAC is given. v
List of figures 62 1 month after TAC injection, there is improvement of macular thickening (CMT=253µm) however FFA shows persistent leakage, so this patient needs further laser photocoagulation. Persistent hard exudates need tight serum cholesterol control. vi
List of tables List of tables No 1 Diabetic Macular Edema Disease Severity Scale. 2 Correlation between visible-threshold, histological threshold and subthreshold treatment power. 3 Baseline clinical characteristics of the two groups. 4 Central macular thickness in CGL and MPDL groups. 5 Mean contrast sensitivity and SD at baseline and follow up visits. 6 P value for improvement in contrast sensitivity between follow up visits for CGL group showing no statistical significant improvement between baseline and following visits at different spatial frequencies. 7 P value for improvement in contrast sensitivity between follow up visits for MPDL group showing statistical significant improvement in contrast sensitivity at spatial frequencies 6 and 12 and no statistical significant difference at the other spatial frequencies. vii
List of Abbreviations List of abbreviations Abbreviation Stands for BRB Blood-retinal barrier DME Diabetic macular oedema RPE Retinal pigment epithelial AGE Advanced glycation end-products GDNF Glial-cell derived neurotropic factor VEGF-A Vascular Endothelial Growth Factor-A ICAM-1 Intercellular adhesion molecule-1 RAGE AGE receptor PEDF Pigment epithelium derived factor ILM Internal limiting membrane ZO Zonula occludens PKC Protein kinase C PVD Posterior vitreous detachment PDR Proliferative diabetic retinopathy OCT BDR Optical coherence tomography Background diabetic retinopathy CSME Clinically significant macular edema viii
List of Abbreviations ETDRS DR PDR NPDR Early treatment diabetic retinopathy study Diabetic retinopathy Proliferative diabetic retinopathy Non proliferative diabetic retinopathy FAZ Foveal avascular zone CRT DRCR. Net Central retinal thickness Diabetic retinopathy clinical research network SRD CME Nd:YAG Nd:YLF laser Serous Retinal detachment Cystoid macular edema Neodymium-doped yttrium aluminum garnet Neodymium-doped yttrium lithium fluoride TAC AMD MPD ICG CW MPDL Triamcinolone Age-related macular degeneration Micropulse diode Indocyanine green Continuous wave Micropulse diode laser photocoagulation CGL Green laser photocoagulation FAF Fundus autofluorescence CMT Central macular thickness metdrs Modified early treatment diabetic retinopathy study ix
List of Abbreviations ND-SDM HD-SDM DC FFA SD-OCT CFT PRP SD BCVA Cpd Normal-density subthreshold diode micropulse High-density subthreshold diode micropulse Duty cycle Fundus fluorescein angiography Spectral domain Optical coherence tomography Central foveal thickness Panretinal photocoagulation Standard deviation Best corrected visual acuity Cycle per degree x
Introduction Introduction While complications of PDR lead more frequently to severe visual loss, the most common cause of visual impairment among diabetic patients is diabetic macular edema (DME). (Joussen et al., 2007 and Coscas et al, 2010) The Early Treatment of Diabetic Retinopathy Study (ETDRS) showed that visible end point focal laser photocoagulation reduces the risk of moderate vision loss in patients with clinically significant diabetic macular oedema (CSME) by 50% at 3-year follow up. (Early Treatment Diabetic Retinopathy Study Research Group, 1985) The conventional green laser (CGL) treatment is applied in a focal or grid pattern and produces a visible burn in the retina. Enlargement of laser scars after treatment has been reported. (Writing Committee for the Diabetic Retinopathy Clinical Research Network, 2007) Laser burns at various levels of intensity are believed necessary for a successful treatment of CSME, but have never been proven to be a prerequisite in the mechanism of action of laser photocoagulation. Conversely, recent understanding of the modification of gene expression mediated by the healing response of the RPE to thermal injury suggests that the useful therapeutic cellular cascade is activated, not by laser-killed RPE cells, but by the still-viable RPE cells surrounding the burned areas that are reached by the heat diffusion at sublethal thermal elevation. New strategies have been developed for laser treatments that minimize the chorioretinal damage while maintaining at least similar treatment efficacy. (Dorin., 2004; Lavinsky et al., 2011) Sub-threshold micropulse diode laser (MPDL) has recently been shown to be effective in the treatment of CSME and seems to have a theoretical advantage, since the laser burns will affect deeper layers with relative sparing of the inner neurosensory retina, thus reducing the scarring and paracentral scotomas post-treatment. (Figueira et al., 2008) 1
Introduction Aim of the work This work aims at assessing the effectiveness of micropulse diode laser versus conventional argon green laser for the treatment of clinically significant diabetic macular oedema regarding: Best corrected visual acuity, Central macula thickness measurement by OCT, Contrast sensitivity and Post laser scarring. 2
Topography of the retina: Review of literature Anatomy of the macula 3 Review of literature The area centralis The area centralis or central retina is divisible into the fovea and foveola, with a parafoveal and a perifoveal ring around the fovea. This region of the retina, located in the posterior fundus temporal to the optic disc, is demarcated approximately by the upper and lower arcuate and temporal retinal vessels and has an elliptical shape horizontally. With an average diameter of about 5.5 mm, the area centralis corresponds to approximately 15 of the visual field and it is adapted for accurate diurnal vision and colour discrimination. (Tripathi and Tripathi., 1984) The fovea The fovea, which marks the approximate centre of the area centralis, is located at the posterior pole of the globe, 4 mm temporal to the centre of the optic disc and about 0.8 mm below the horizontal meridian. It has a diameter of 1.85 mm (which represents 5 of the visual field) and an average thickness of 0.25 mm. At the centre of the fovea, the layers of the retina are thinner so that a central concave indentation, the foveola, is produced. The downward-sloping border which meets the floor of the foveal pit is known as the clivus. (Tripathi and Tripathi., 1984) The foveola The foveola, which measures 0.35 mm in diameter and 0.13 mm in thickness, represents the area of the highest visual acuity in the retina, even though its span corresponds to only 1 of the visual field. This is due partly to the sole presence of cone photoreceptors and partly to its avascular nature. The foveola usually appears deeper red than does the adjacent retina because of the rich choroidal circulation of the choriocapillaris which shines through it. (Tripathi and Tripathi., 1984) The macula lutea It is an oval zone of yellow colouration within the central retina. The yellow colour can be observed approximately 5 mm in diameter, in the central retina. This finding may explain the apparent confusion in the use of the terms macula, macular area, and macula lutea clinically and
Review of literature histologically. The yellow colouration probably arise from the presence of the carotenoid pigment, xanthophyll, in the ganglion and bipolar cells. Within the area centralis two other regions are distinguished outside the fovea: the parafovea (0.5 mm in width) and the perifovea (1.5 mm in width) Figure (1). (Tripathi and Tripathi., 1984) Figure (1) The anatomical fovea and foveola are contained within the center of the anatomical macula. (Skuta and Cantor, 2011) General architecture of the retina As seen in cross-section by light microscopy, the retina is represented by 10 layers sclerad to vitread they are: l. retinal pigment epithelium; 2. photoreceptor layer of rods and cones; 3. external limiting membrane; 4. outer nuclear layer; 5. outer plexiform layer; 6. inner nuclear layer; 7. inner plexiform layer; 8. ganglion cell layer; 9. nerve fibre layer; 10. internal limiting membrane. Figure (2). (Snell R. and Lemp., 1998) At the fovea the only layers that are present are the retinal pigment epithelium, the photoreceptors (cones only), the external limiting membrane, the outer nuclear layer (which contains the nuclei of the cone cells), the inner fibres of the photoreceptors (the so-called 'Henle's fibre' layer), and the internal limiting membrane. The primary neurons in the visual pathway are the photoreceptors, which constitute the layer of rods 4
Review of literature and cones, the outer nuclear layer and the outer plexiform layer. The external limiting membrane is a histologically identifiable attachment site between the photoreceptors and the Muller cells. Bipolar, horizontal, amacrine and interplexiform cells constitute the second-order neurons. The ganglion cell layer and the nerve fibre layer form the conductive network internal to the inner plexiform layer and external to the internal limiting membrane. This network of third-order neurons and their respective axonal processes send the information gathered by the photoreceptors for further processing by the visual cortex. The internal limiting membrane makes intimate contact with the vitreous body, which also contributes in part to the architecture of the former. The Müller cells extend between the two limiting membranes and, together with other glial cells, constitute the neuronal connective tissue cells of the retina. (Bron et al., 1997) Figure (2) Section in the region of the foveola. the inner cellular layers are absent and there is an increased density of pigment in the RPE. The incident light falls directly on the photoreceptor outer segments, reducing the potential for distortion of light by overlying t issue elements. GCL = ganglion cell layer; IPL = inner plexiform layer; INL = inner nuclear layer; OPL = outer plexiform layer; ONL = outer nuclear layer; IS = inner segment of photo receptors; OS = outer segment of photoreceptors; RPE = retinal pigment epithelium. (Skuta and Cantor, 2011) 5
Review of literature Definition, Epidemiology, Natural history and Classification of DME While complications of PDR lead more frequently to severe visual loss, the most common cause of visual impairment among diabetic patients is diabetic macular edema (DME). (Joussen et al., 2007 and Coscas et al, 2010) Definition of Diabetic Macular Edema Diabetic macular edema is defined as retinal thickening caused by the accumulation of intraretinal fluid and/or hard exudates within 2 disk diameters of the center of the macula, the fovea. (Coscas et al, 2010) Clinically significant macular edema is defined by the Early Treatment Diabetic Retinopathy Study to include any of the following features: (1) Thickening of the retina at or within 500 µm of the center of the macula; (2) Hard exudates at or within 500 µm of the center of the macula, if associated with thickening of the adjacent retina (not residual hard exudates remaining after the disappearance of retinal thickening); (3) Zone or zones of retinal thickening 1 disk area or larger, any part of which is within 1 disk diameter of the center of the macula. The term clinically significant macular edema (CSME) was coined to characterize the severity of the disease and to provide a threshold level to apply laser photocoagulation. (Early Treatment Diabetic Retinopathy Study Research Group, 1985) Epidemiology In the Wisconsin Epidemiologic Study of Diabetic Retinopathy, the incidence of diabetic macular edema is closely associated with the degree of diabetic retinopathy and the duration and type of the disease. (Klein et al., 1984) The 10-year rate of developing DME was 20.1% in patients with type I diabetes, 13.9% in patients with type II diabetes not using insulin, and 25.4% in type II diabetes patients using insulin. The incidence of macular edema over the 10-year period was associated with higher levels of glycosylated hemoglobin and more severe retinopathy in both younger- and older-onset groups, and increased diastolic blood pressure in the older-onset group. (Klein et al., 1995) The 25-year cumulative incidence in persons with type 1 diabetes mellitus is 29% for macular edema and 17% for clinically significant macular edema and the strongest and most consistent associations were 6
7 Review of literature with glycemia and to a lesser extent systolic and diastolic blood pressure and nephropathy as manifest by gross proteinuria. (Klein et al., 2009) Natural history The natural history of DME is characterized by a slow progression of retinal thickening until the center of the macula is involved, causing visual acuity deterioration. Spontaneous resolution of DME is rare and usually secondary to improvement in systemic risk factors, such as glycemic control, hypertension, or hypercholesterolemia. If untreated, 24% of eyes with DME and foveal involvement experience moderate visual loss (defined as a doubling of the visual angle (eg, a decrease from 20/20 to 20/40 or from 20/50 to 20/ 100), a drop of 15 or more letters on ETDRS visual acuity charts, or a drop of 3 or more lines of Snellen equivalent) after 3 years. (Early Treatment Diabetic Retinopathy Study Research Group, 1985) Classification of Diabetic Macular Edema There are two subtypes of diabetic macular edema, focal and diffuse forms. Focal macular edema refers to localized areas of retinal thickening, caused by foci of vascular abnormalities, primarily microaneurysms, and less commonly intraretinal microvascular abnormalities. These have an increased tendency for fluid leakage, which is usually accompanied by hard exudates. The hard exudate pattern can be either focal or (often) ring-shaped Figure (3). (Coscas et al, 2010) Diffuse macular edema is caused by a general diffuse leakage from dilated retinal capillaries (and from microaneurysms and arterioles) throughout the posterior pole of the retina. It is characterized by a more widespread thickening of the macula secondary to generalized abnormal permeability of the retinal capillary bed that appears to be diffusely dilated. Diffuse macular edema tends to occur without significant exudation. It can usually be observed in both eyes with the degree of leakage being similar or extensively different Figure (4). (Coscas et al, 2010) Cystoid macular edema, often associated with diffuse macular edema, results from a generalized breakdown of the blood with fluid accumulation in a petaloid pattern, primarily in the outer plexiform and inner nuclear layers. (Coscas et al, 2010) There are also classifications for ischemic and exudative macular edema. In most cases, a hybrid type of these two can be observed. Ischemic maculopathy is defined by the presence of rarefaction and occlusion of the perifoveal capillary network, with doubling of the extension of the FAZ Figure (5). (Coscas et al, 2010)