Can Insulin Resistance Serve as a Potential Biomarker for the Development of Clinically Significant Macular Oedema in Patients with Type 2 Diabetes Mellitus?

Diabetic macular oedema (DMO) is a thickening of the central retina, or the macula, and is associated with long-term visual loss in people with diabetic retinopathy (DR). Clinically significant macular oedema (CSMO) is the most severe form of DMO. Almost 30 years ago, the Early Treatment Diabetic Retinopathy Study (ETDRS) found that CSMO, diagnosed by means of stereoscopic fundus photography, leads to moderate visual loss in one of four people within three years. It also showed that grid or focal laser photocoagulation to the macula halves this risk. Recently, intravitreal injection of antiangiogenic drugs has been investigated to try to improve vision in people with macular oedema due to DR.Optical coherence tomography (OCT) is based on optical reflectivity and is able to image retinal thickness and structure producing cross-sectional and three-dimensional images of the central retina. It is already widely used because it provides objective and quantitative assessment of macular oedema unlike the subjectivity of fundus biomicroscopic assessment, which is routinely used by ophthalmologists instead of photography. Optical coherence tomography is also used for quantitative follow up of the effects of treatment of CSMO. Disadvantages of using OCT are the cost to purchase it and the need for trained personnel to perform the examinations. To determine the diagnostic accuracy of OCT for detecting macular oedema in people with DR. A secondary objective is to compare the diagnostic accuracy by study-specific characteristics, such as factors related to methodology, patients or OCT. We searched the Cochrane Database of Systematic Reviews (CDSR), the Database of Abstracts of Reviews of Effects (DARE), the Health Technology Assessment Database (HTA) and the NHS Economic Evaluation Database (NHSEED) (The Cochrane Library 2011, Issue 5), MEDLINE (January 1950 to May 2011), EMBASE (January 1950 to May 2011), ISI Web of Science (January 1970 to May 2011), BIOSIS Previews (January 1969 to May 2011), MEDION and the Aggressive Research Intelligence Facility database (ARIF). There were no date or language restrictions in the electronic search for trials. The electronic databases were last searched on 16 May 2011. We checked bibliographies of relevant studies for additional references. We selected studies that assessed the diagnostic accuracy of any OCT model for detecting DMO or CSMO in patients with DR who were referred to eye clinics. Diabetic macular oedema and CSMO were diagnosed by means of fundus biomicroscopy by ophthalmologists or stereophotography by ophthalmologists or other trained personnel. Three authors independently extracted data on study characteristics and measures of accuracy. We assessed data using random-effects hierarchical sROC meta-analysis models. Nine studies (768 participants, 1325 eyes) were included. Prevalence of CSMO was 19% to 65% (median 50%). Study quality was good for half the QUADAS items, whereas unclear or inadequate quality was found in some studies regarding selection criteria, index and reference test masking (blinding), availability of clinical information, uninterpretable results and withdrawals. There was a specific 'unit of analysis' issue because both eyes of the majority of participants were included in the analyses as if they were independent.Central CSMO was the target condition in all but one study and thus our results cannot be applied to non-central CSMO. In eight studies providing data on CSMO (697 participants, 1241 eyes), pooled sensitivity was 0.78 (95% confidence interval (CI) 0.72 to 0.83) and specificity was 0.86 (95% CI 0.76 to 0.93). The median central retinal thickness cut-off we selected for data extraction was 250 µm (range 230 µm to 300 µm).Data from three studies reporting accuracy for detection of DMO (180 participants, 343 eyes) were not pooled. Sensitivities and specificities were about 0.80 in two studies and were both 1.00 in the third study. Central retinal thickness measured with OCT cannot be used as a stand-alone test to diagnose the central type of CSMO and decide on the use of laser photocoagulation in patients who are referred to retina clinics. In fact, there is a substantial disagreement of OCT with the ETDRS definition of CSMO based on clinical examination. Some researchers have observed that OCT can detect macular thickening earlier than clinical examination, but also found that such cases did not necessarily progress to CSMO and need photocoagulation.Care should be taken in applying the conclusions of this review to other test-treatment pathways. In fact, OCT will become an essential tool to manage antiangiogenic therapy, an expanding therapeutic option for patients with macular oedema due to DR, because OCT is a component of the diagnostic algorithms of studies on this new treatment.

Diabetic macular oedema (DMO) is a thickening of the central retina, or the macula, and is associated with long-term visual loss in people with diabetic retinopathy (DR). Clinically significant macular oedema (CSMO) is the most severe form of DMO. Almost 30 years ago, the Early Treatment Diabetic Retinopathy Study (ETDRS) found that CSMO, diagnosed by means of stereoscopic fundus photography, leads to moderate visual loss in one of four people within three years. It also showed that grid or focal laser photocoagulation to the macula halves this risk. Recently, intravitreal injection of antiangiogenic drugs has been investigated to try to improve vision in people with macular oedema due to DR.Optical coherence tomography (OCT) is based on optical reflectivity and is able to image retinal thickness and structure producing cross-sectional and three-dimensional images of the central retina. It is already widely used because it provides objective and quantitative assessment of macular oedema unlike the subjectivity of fundus biomicroscopic assessment, which is routinely used by ophthalmologists instead of photography. Optical coherence tomography is also used for quantitative follow up of the effects of treatment of CSMO. Disadvantages of using OCT are the cost to purchase it and the need for trained personnel to perform the examinations.To determine the diagnostic accuracy of OCT for detecting macular oedema in people with DR. A secondary objective is to compare the diagnostic accuracy by study-specific characteristics, such as factors related to methodology, patients or OCT.We searched the Cochrane Database of Systematic Reviews (CDSR), the Database of Abstracts of Reviews of Effects (DARE), the Health Technology Assessment Database (HTA) and the NHS Economic Evaluation Database (NHSEED) (The Cochrane Library 2011, Issue 5), MEDLINE (January 1950 to May 2011), EMBASE (January 1950 to May 2011), ISI Web of Science (January 1970 to May 2011), BIOSIS Previews (January 1969 to May 2011), MEDION and the Aggressive Research Intelligence Facility database (ARIF). There were no date or language restrictions in the electronic search for trials. The electronic databases were last searched on 16 May 2011. We checked bibliographies of relevant studies for additional references.We selected studies that assessed the diagnostic accuracy of any OCT model for detecting DMO or CSMO in patients with DR who were referred to eye clinics. Diabetic macular oedema and CSMO were diagnosed by means of fundus biomicroscopy by ophthalmologists or stereophotography by ophthalmologists or other trained personnel.Three authors independently extracted data on study characteristics and measures of accuracy. We assessed data using random-effects hierarchical sROC meta-analysis models.Nine studies (768 participants, 1325 eyes) were included. Prevalence of CSMO was 19% to 65% (median 50%). Study quality was good for half the QUADAS items, whereas unclear or inadequate quality was found in some studies regarding selection criteria, index and reference test masking (blinding), availability of clinical information, uninterpretable results and withdrawals. There was a specific 'unit of analysis' issue because both eyes of the majority of participants were included in the analyses as if they were independent.Central CSMO was the target condition in all but one study and thus our results cannot be applied to non-central CSMO. In eight studies providing data on CSMO (697 participants, 1241 eyes), pooled sensitivity was 0.78 (95% confidence interval (CI) 0.72 to 0.83) and specificity was 0.86 (95% CI 0.76 to 0.93). The median central retinal thickness cut-off we selected for data extraction was 250 µm (range 230 µm to 300 µm).Data from three studies reporting accuracy for detection of DMO (180 participants, 343 eyes) were not pooled. Sensitivities and specificities were about 0.80 in two studies and were both 1.00 in the third study.Central retinal thickness measured with OCT cannot be used as a stand-alone test to diagnose the central type of CSMO and decide on the use of laser photocoagulation in patients who are referred to retina clinics. In fact, there is a substantial disagreement of OCT with the ETDRS definition of CSMO based on clinical examination. Some researchers have observed that OCT can detect macular thickening earlier than clinical examination, but also found that such cases did not necessarily progress to CSMO and need photocoagulation.Care should be taken in applying the conclusions of this review to other test-treatment pathways. In fact, OCT will become an essential tool to manage antiangiogenic therapy, an expanding therapeutic option for patients with macular oedema due to DR, because OCT is a component of the diagnostic algorithms of studies on this new treatment.

Influence of Serum Lipids on Clinically Significant versus Nonclinically Significant Macular Edema: SN-DREAMS Report Number 13

To determine the risk factors of clinically significant macular edema (CSME) in patients with non-proliferative diabetic retinopathy (NPDR) in a multi-ethnics Malaysian population. We performed a case control study in which 150 patients with bilateral NPDR and CSME in either eye were compared to 150 patients with bilateral NPDR and no CSME in both eyes. CSME and NPDR were graded according to Early Treatment of Diabetic Retinopathy Study criteria. Student's t-test, odds ratio and multiple logistic regression analysis were performed to analyze the duration of diabetes, body mass index (BMI), blood pressure(BP), total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), triglycerides (TG), fasting blood glucose (FBG), HbA1c, full blood count, serum creatinine and proteinuria between the two groups. Both groups were matched in terms of age, gender and ethnicity. Duration of diabetes, total serum cholesterol, serum LDL, FBG, HbA1c and serum creatinine were significantly higher in the CSME group (P<0.05). The hemoglobin, packed cell volume were significantly lower in the CSME group (p<0.05). There was no significant difference for serum HDL, TG, BMI, systolic and diastolic BP. Multiple logistic regression analysis showed that total serum cholesterol and HbA1c had significantly high odds of developing CSME. HbA1c and total cholesterol are the two most important risk factors associated with CSME in patients with NPDR.

High-resolution stereoscopic digital fundus photography versus contact lens biomicroscopy for the detection of clinically significant macular edema

Our group reported that three diabetic retinopathy (DR) phenotypes: A, characterized by low microaneurysm turnover (MAT < 6) and normal central retinal thickness (CRT); B, low MAT (<6) and increased CRT, and C, high MAT (≥6), present different risks for development of macular edema (DME) and proliferative retinopathy (PDR). To test these findings, 212 persons with type 2 diabetes (T2D) and mild nonproliferative retinopathy (NPDR), one eye per person, were followed for five years with annual visits. Of these, 172 completed the follow-up or developed an outcome: PDR or DME (considering both clinically significant macular edema (CSME) and center-involved macular edema (CIME)). Twenty-seven eyes (16%) developed either CSME (14), CIME (10), or PDR (4), with one eye developing both CSME and PDR. Phenotype A showed no association with development of vision-threatening complications. Seven eyes with phenotype B and three with phenotype C developed CIME. Phenotype C showed higher risk for CSME development, with 17.41 odds ratio (p = 0.010), compared with phenotypes A + B. All eyes that developed PDR were classified as phenotype C. Levels of HbA1c and triglycerides were increased in phenotype C (p < 0.001 and p = 0.018, respectively). In conclusion, phenotype C identifies eyes at higher risk for development of CSME and PDR, whereas phenotype A identifies eyes at very low risk for vision-threatening complications.

Macular edema (ME) is an inflammatory disease characterized by increased microvascular permeability. Here, we proposed that plasma angiopoietin-like protein 2 (ANGPTL2) level may be related to the severity of ME patients with type 2 diabetes mellitus (T2DM). In this cross-sectional study, 172 T2DM patients were recruited and divided into clinically significant macular edema (CSME), non-CSME (nCSME), and control groups. Serum ANGPTL2 level was quantified by ELISA and best corrected vision acuity (BCVA) was detected. After adjust age, sex, body mass index (BMI), and duration of diabetes variables, ANGPTL2 performed statistics difference among CSME-, nCSME-groups, and control group (4.46 [3.97, 4.96, 95%CI] ng/mL in CSME group, 3.80 [3.42, 4.18, 95%CI] ng/mL in nCSME-group, 3.33 [3.03, 3.63, 95%CI] ng/mL in control, P < .01). After adjustment of confounding factors, high levels of circulating ANGPTL2 were related with the diagnosis of ME, BCVA, and C reactive protein (CRP) through univariate regression analysis (P < .05). Meanwhile, in the multiple regression model, ANGPTL2 took the mainly effect proportion for the diagnosis of diabetic macular edema (DME), with a LogWorth value 3.559 (P < .001). Our study suggested that elevated circulating ANGPTL2 may be associated with the development of DME and the severity of visual impairment in patients with type 2 diabetes.

To assess patients with diabetic macular edema quantitatively using optical coherence tomography (OCT). OCT was performed in 14 eyes with diabetic retinopathy and ophthalmoscopic evidence of clinically significant macular edema (CSME) and in 19 diabetic eyes without CSME. Retinal thickness was computed from the tomograms at fovea and other 36 locations throughout the macula. The mean +/- standard deviation foveal thickness was 255.6 +/- 138.9 microm in eyes with CSME, and 174.6 +/- 38.2 microm in eyes without CSME (p = 0.051). Within 2000 microm of the center of the macula, eyes with CSME had significantly thicker retina in the inferior quadrant than those without CSME (p < 0.01). The foveal thickness was correlated with logMAR visual acuity (gamma = 0.68, p < 0.01). OCT identified sponge-like retinal swelling and/or cystoid macular edema in 11 (58%) eyes without CSME, and in 12 (86%) eyes with CSME. Criteria of CSME seem to be insufficient in really identifying macular edema. OCT may be more sensitive than a clinical examination in assessing diabetic macular edema and is a quantitative tool for documenting changes in macular thickening.

Background: Diabetes mellitus (DM) is a major health hazard today. Clinically significant macular oedema (CSME) is the most frequent cause of decreased vision in diabetic patients. The aim of our study was to determine whether CSME in subjects with type 2 DM is associated with lipid profile abnormalities and to compare them with lipid profiles of type 2 diabetics without CSME. Method: This was a cross-sectional case-control study. Hundred consecutive type 2 diabetic patients, 50 patients with and 50 without CSME, who attended the Retina outpatient clinic of a tertiary eye hospital over a one-year period, were included. Determination of the presence of CSME and staging of diabetic retinopathy was done according to modified Early Treatment Diabetic Retinopathy Study guidelines, by a single investigator using slit-lamp biomicroscopy. After obtaining informed consent, blood was drawn from the subjects after overnight fasting. Investigations done were lipid profile, fasting blood sugar, glycated haemoglobin (HbA1c), blood urea, and blood pressure measurement. Results: In our study, only two systemic factors weighed in as predictors of macular oedema: Systolic hypertension and serum lipids. Subanalysis of the lipid fractions yielded two significant correlates of CSME: Total cholesterol and serum triglycerides. Conclusion: A multifaceted healthcare team approach is essential for the management of diabetic patients. Ophthalmologists should evaluate the lipid profile of all diabetic macular oedema (DME) patients. Physicians should promptly refer diabetic patients with deranged lipid profiles to ophthalmologists to look for DME and provide appropriate ophthalmic care.

Diabetic macular edema (DME) was defined in Early Treatment Diabetic Retinopathy Study (ETDRS) studies on the basis of central retinal thickening and hard exudates using fundus stereophotography or biomicroscopy (FP/FB). Clinically significant macular edema (CSME) is the more severe form of DME and needs to be treated. Compared with FP/FB, optical coherence tomography (OCT) provides imaging of retinal thickness and morphology, as well as of the vitreoretinal interface. Clinical examination using FP/FB is cheap and readily available, but is also a subjective method. When biomicroscopy is used, there is no recording of the amount of thickening, and thus, it cannot reliably monitor CSME except for a gross judgment on its presence or absence. Advantages of OCT when compared with FP/FB in patients with DME are its ability to obtain an objective and highly reliable quantitative measure of retinal thickness on a continuous scale, as well as to provide additional morphological details. Clinician suspecting CSME requiring treatment can use Stratus central subfield thickness values below 250 μm to rule out CSME, and values above 300 μm to rule in CSME. Thickness values between 250 and 300 μm still suggest CSME, but treatment decision should be based, even more than usual, on patient’s symptoms and preferences as well as on other clinical features that an ophthalmologist may use to decide on potential treatment outcome. Add 50 μm to the thresholds suggested above when using Cirrus (and possibly other spectral domain) OCT (no CSME: below 300 μm; CSME: above 350 μm); confirmatory research is needed on this correction factor for each spectral-domain device. Retinal-thickness measurement should not be a surrogate for visual acuity measurement in patients with DME. OCT-based predictors of outcome after photocoagulation, vitrectomy, and intravitreal triamcinolone have been proposed, and the prognosis of cases with subclinical macular edema (i.e., thickening using OCT not found using FP/FB) have been studied in case series and need further investigation. Using Stratus OCT, a change in the central subfield thickness exceeding ±11% is likely to represent a true change in a subject if the quality of the scans is acceptable. The repeatability of spectral-domain OCTs is expected to be comparable or better than that of the Stratus OCT in patients with DME, but further research is needed.

Purpose: To investigate the result of posterior sub-tenon triamcinolone acetonide injection combined with panretinal photocoagulation (PRP) in patients with diabetic retinopathy. Methods: A prospective study was performed on patients with diabetic retinopathy who required PRP. The study group consisted of 12 patients (12 eyes) of diabetic retinopathy without clinically significant macular edema (CSME) and 13 patients (13 eyes) with CSME. All patients were injected posteriorly with sub-tenon triamcinolone acetonide (40 mg) one week before PRP. During a six-month follow-up, best-corrected visual acuity, the development of macular edema, changes in fluorescein angiography, and related complications were monitored. Results: During a six-month follow-up, visual acuity was well preserved in patients with diabetic retinopathy without CSME (12 eyes). Only one patient in this group experienced temporary macular edema at 3 months after combined therapy. In the CSME group (13 eyes), the visual acuities of seven patients (53.8%) increased, those of five patients (38.5%) remained same, and one patient's visual acuity (7.7%) decreased in a study period of six months. Fluorescein angiography showed that macular edema was resolved in most patients except in one patient in whom macular edema remained for up to 6 months. Complications from combined therapy occurred in two patients who showed slight and temporary increase of intraocular pressure. Conclusions: Combined treatment with posterior sub-tenon triamcinolone acetonide injection and PRP may provide benefits for patients with diabetic retinopathy who require urgent PRP by preventing exacerbation of macular edema.

Identification of clinically significant macular oedema (CSMO) involves human depth perception, which is subject to a degree of uncertainty. However, although the ability to obtain objective thickness measurements of the central macular region may be advantageous, the topography of the macular region suggests that average thickness measurements represent a simplification of the topographic profile of the region. This study explored the applicability of additional sub-analysis of central macular thickness measurements. The study included 47 eyes of 47 normal subjects and 158 ocular examinations of 38 eyes from 22 diabetic subjects with and without CSMO. All eyes underwent central macular thickness measurements using retinal thickness analysis equipment. Eyes of diabetes subjects were classified as being without CSMO (n = 53), with focal CSMO (n = 50) and with diffuse CSMO (n = 55). The central macular region was subdivided into narrow concentric rings around the foveola, using a new invention, and the thicknesses of the individual concentric rings were calculated. The sensitivity and specificity of the CSMO diagnosis were established using the average thickness and the thicknesses of the concentric rings. The average thickness of the central macular region was found to be 165.1 microm in eyes of normal subjects and 192.3 microm in eyes without CSMO. It increased non-significantly to 198.2 microm in eyes with focal CSMO and significantly to 236.9 microm in eyes with diffuse CSMO. Sensitivity for focal CSMO was 48.0% with average thickness measurements and 83.6% with concentric rings. Corresponding values for detection of diffuse CSMO were 91.7% and 96.1%, respectively. Specificity was 77.4% with average thickness measurements and 79.7% with concentric rings. Thickness measurements of the central macular region can be used to distinguish between eyes with and without diffuse CSMO, but not between eyes with and without focal CSMO. Additional sub-analysis based on concentric rings around the foveola seems to be a useful clinical tool that increases diagnostic certainty in these eyes.

The temporal development of retinopathy and nephropathy in type 1 diabetes mellitus during 15 years diabetes duration

Persistent diabetic macular edema is associated with elevated hemoglobin A1c

Background: Diabetic retinopathy and diabetic macular oedema are more prevalent in patients with coexistent obstructive sleep apnoea (OSA). Objectives: We assessed if treatment of OSA with continuous positive airway pressure (CPAP) might improve visual acuity (VA). Methods: A total of 35 patients with clinically significant macular oedema (CSMO) and OSA [oxygen desaturation index (ODI) ≥10 or apnoea-hypopnoea index (AHI) ≥15] were identified and agreed to be studied. VA (expressed as the logarithm of the minimum angle of resolution, logMAR), macular thickness, fundal photographs, glycosylated haemoglobin (HbA1c) and rhodopsin mRNA were measured twice at baseline and at 3 and 6 months post-CPAP. Fluorescein angiography and the Epworth Sleepiness Scale (ESS) were obtained once at baseline and at 6 months. Results: Three patients withdrew before the first trial visit. Thus, a total of 32 patients (17 males) entered the study, and 4 subsequently withdrew; thus 28 completed 6 months of follow-up. Baseline characteristics of the subjects were as follows [mean (SD or inter-quartile range)]: age 66.2 (7.1) years, body mass index 31.7 (6.3), HbA1c 7.4% (1.44) [57.1 (15.7) mmol/mol], AHI 16.5 (11–25), ODI 16.0 (12–25), ESS 6.5 (4.0–12.0) and duration of diabetes 9.5 years (5.0–16.5). Participants were divided into 13 high and 15 low CPAP compliers (≥ and <2.5 h/night over the 6 months, respectively). At 6 months, the adjusted treatment effect on VA of high compliance versus low compliance was 0.11 (95% confidence interval 0.21 to –0.002; p = 0.047), equivalent to a one-line improvement on the logMAR chart. There was no significant improvement in macular oedema or fundal photographs. Conclusions: This hypothesis-generating, uncontrolled study suggests that ≥2.5 h/night CPAP usage over 6 months in individuals with CSMO and OSA may be associated with improvement in VA. This provides justification for a randomised controlled trial of CPAP therapy in such patients.