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1.  Resource Use and Costs Associated With Diabetic Macular Edema in Elderly Persons 
Archives of ophthalmology  2008;126(12):1748-1754.
To examine trends in resource use and the impact of incident diabetic macular edema (DME) on 1-year and 3-year total direct medical costs in elderly patients.
We used a nationally representative 5% sample of Medicare beneficiaries from 2000 through 2004 to identify patients with incident DME and a control cohort of patients with diabetes mellitus but no history of retinal disease. We summed Medicare reimbursement amounts for all claims and applied generalized linear models to estimate effects of DME on 1-year and 3-year costs. We also examined use of selected imaging techniques and treatments.
After adjustment for demographic characteristics and baseline comorbid conditions, DME was associated with 31% higher 1-year costs and 29% higher 3-year costs. There were significant shifts in the use of testing and treatment modalities. From 2000 to 2004, intravitreal injection increased from 1% to 13% of patients; use of optical coherence tomography increased from 2.5% to more than 40%. Use of laser photocoagulation decreased over time.
After adjustment for demographic variables and baseline comorbid conditions, new-onset DME was a significant independent predictor of total medical costs at 1 and 3 years. Diagnostic and treatment modalities used for DME have changed significantly.
PMCID: PMC2630411  PMID: 19064859
2.  Anti-vascular endothelial growth factor therapy for diabetic macular edema 
Diabetes mellitus is a serious health problem that affects over 350 million individuals worldwide. Diabetic retinopathy (DR), which is the most common microvascular complication of diabetes, is the leading cause of new cases of blindness in working-aged adults. Diabetic macular edema (DME) is an advanced, vision-limiting complication of DR that affects nearly 30% of patients who have had diabetes for at least 20 years and is responsible for much of the vision loss due to DR. The historic standard of care for DME has been macular laser photocoagulation, which has been shown to stabilize vision and reduce the rate of further vision loss by 50%; however, macular laser leads to significant vision recovery in only 15% of treated patients. Mechanisms contributing to the microvascular damage in DR and DME include the direct toxic effects of hyperglycemia, sustained alterations in cell signaling pathways, and chronic microvascular inflammation with leukocyte-mediated injury. Chronic retinal microvascular damage results in elevation of intraocular levels of vascular endothelial growth factor A (VEGF), a potent, diffusible, endothelial-specific mitogen that mediates many important physiologic processes, including but not limited to the development and permeability of the vasculature. The identification of VEGF as an important pathophysiologic mediator of DME suggested that anti-VEGF therapy delivered to the eye might lead to improved visual outcomes in this disease. To date, four different inhibitors of VEGF, each administered by intraocular injection, have been tested in prospective, randomized phase II or phase III clinical trials in patients with DME. The results from these trials demonstrate that treatment with anti-VEGF agents results in substantially improved visual and anatomic outcomes compared with laser photocoagulation, and avoid the ocular side effects associated with laser treatment. Thus, anti-VEGF therapy has become the preferred treatment option for the management of DME in many patients.
PMCID: PMC3855829  PMID: 24324855
diabetic macular edema; diabetic retinopathy; intravitreal anti-VEGF therapy; vascular endothelial growth factor A
3.  Vascular Complications and Diabetes: Current Therapies and Future Challenges 
Journal of Ophthalmology  2012;2012:209538.
Diabetic retinal complications, including macular edema (DME) and proliferative diabetic retinopathy (PDR), are the leading cause of new cases of blindness among adults aged 20–74. Chronic hyperglycemia, considered the underlying cause of diabetic retinopathy, is thought to act first through violation of the pericyte-endothelial coupling. Disruption of microvascular integrity leads to pathologic consequences including hypoxia-induced imbalance in vascular endothelial growth factor (VEGF) signaling. Several anti-VEGF medications are in clinical trials for use in arresting retinal angiogenesis arising from DME and PDR. Although a review of current clinical trials shows promising results, the lack of large prospective studies, head-to-head therapeutic comparisons, and potential long-term and systemic adverse events give cause for optimistic caution. Alternative therapies including targeting pathogenic specific angiogenesis and mural-cell-based therapeutics may offer innovative solutions for currently intractable clinical problems. This paper describes the mechanisms behind diabetic retinal complications, current research supporting anti-VEGF medications, and future therapeutic directions.
PMCID: PMC3261480  PMID: 22272370
4.  Choroidal thickness in patients with diabetic retinopathy 
The aim of the study reported here was to assess choroidal thickness (CT) and central macular thickness (CMT) in patients with diabetic retinopathy.
Materials and methods
A total of 151 eyes from 80 patients from the retina department of Istanbul Training and Research Hospital who had type 2 diabetes mellitus with diabetic retinopathy were studied retrospectively in this cross-sectional research. Patients were divided into three groups: mild–moderate nonproliferative diabetic retinopathy without macular edema (NPDR), mild–moderate nonproliferative diabetic retinopathy with macular edema (DME), and proliferative diabetic retinopathy (PDR). In addition, 40 eyes of 20 healthy individuals comprised a control group. Choroidal thickness was measured from the posterior edge of the retinal pigment epithelium to the choroid/sclera junction at 500-μm intervals up to 1,500 μm temporal and nasal to the fovea. The CMT measurement was obtained for each eye. Serum hemoglobin A1c (HbA1c) levels were measured.
The study included 191 eyes, comprising 151 eyes of 80 patients and 40 eyes of 20 healthy individuals. Of the 151 patient eyes, 61 had NPDR, 62 had PDR, and 28 eyes had DME. There was no statistically significant difference in age between the groups (P>0.05). In both the PDR and DME groups, the CT was statistically significantly decreased compared with the control group (P<0.001, P<0.001 for the PDR and DME groups, respectively). The mean CMT in the DME group was increased significantly compared with both the NPDR and PDR groups (P<0.001, P<0.001, respectively). In all three groups, serum HbA1c levels were found to be increased significantly compared with the control group (P=0.000). We found a statistically weak–moderate negative correlation between central macular and foveal CT (r=−289, P=0.000). There was a statistically strong correlation between CMT and HbA1c levels (r=0.577, P=0.483) and a statistically weak–moderate negative correlation between the central CT and HbA1c levels (r=−0.331, P<0.001).
Diabetes changes the CT. CT was found to be significantly decreased in the DME and PDR groups.
PMCID: PMC3971934
choroidal thickness; diabetic retinopathy; optical coherence tomography
5.  Intravitreal Bevacizumab (Avastin) for Diabetic Retinopathy: The 2010 GLADAOF Lecture 
Journal of Ophthalmology  2011;2011:584238.
This paper demonstrates multiple benefits of intravitreal bevacizumab (IVB) on diabetic retinopathy (DR) including diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) at 24 months of followup. This is a retrospective multicenter interventional comparative case series of intravitreal injections of 1.25 or 2.5 mg of bevacizumab for DME, PDR without tractional retinal detachment (TRD), and patients who experienced the development or progression of TRD after an intravitreal injection of 1.25 or 2.5 mg of bevacizumab before vitrectomy for the management of PDR. The results indicate that IVB injections may have a beneficial effect on macular thickness and visual acuity (VA) in diffuse DME. Therefore, in the future this new therapy could complement focal/grid laser photocoagulation in DME. In PDR, this new option could be an adjuvant agent to panretina photocoagulation so that more selective therapy may be applied. Finally, TRD in PDR may occur or progress after IVB used as an adjuvant to vitrectomy. Surgery should be performed 4 days after IVB. Most patients had poorly controlled diabetes mellitus associated with elevated HbA1c, insulin administration, PDR refractory to panretinal photocoagulation, and longer time between IVB and vitrectomy.
PMCID: PMC3090772  PMID: 21584260
6.  Is there a correlation between structural alterations and retinal sensitivity in morphological patterns of diabetic macular edema? 
Indian Journal of Ophthalmology  2013;61(5):230-232.
Spectral domain optical coherence tomography (SDOCT) enables enhanced visualization of retinal layers and delineation of structural alterations in diabetic macular edema (DME). Microperimetry (MP) is a new technique that allows fundus-related testing of local retinal sensitivity. Combination of these two techniques would enable a structure-function correlation with insights into pathomechanism of vision loss in DME. To correlate retinal structural derangement with retinal sensitivity alterations in cases with diabetic macular edema, using SDOCT and MP. Prospective study of 34 eyes of 30 patients with DME. All patients underwent comprehensive ophthalmic examination, fluorescein angiography, microperimetry and SDOCT. Four distinct morphological patterns of DME were identified- diffuse retinal thickening (DRT), cystoid macular edema (CME), schitic retinal thickening (SRT) and neourosensory detachment (NSD) of fovea. Some retinal loci presented with a mixture of above patterns There was significant difference in retinal thickness between groups (P<0.001). Focal retinal sensitivity measurement revealed relatively preserved retinal sensitivity in areas with DRT (13.8 dB), moderately reduced sensitivity (7.9 dB) in areas with CME, and gross retinal sensitivity loss in areas with SRT (1.2 dB) and NSD (4.7 dB) (P<0.001). Analysis of regional scotoma depth demonstrated similar pattern. Retinal sensitivity showed better correlation to OCT pattern (r=-0.68, P<0.001) than retinal thickness (r=-0.44, P<0.001). Structure-function correlation allows better understanding of the pathophysiology of visual loss in different morphological types of DME. Classification of macular edema into these categories has implications on the prognosis and predictive value of treatment.
PMCID: PMC3730507  PMID: 23548318
Diabetic macular edema; microperimetry; morphology; optical coherence tomography; retinal sensitivity
7.  Diabetic macular edema: Current management 2013 
World Journal of Diabetes  2013;4(6):231-233.
Diabetic retinopathy (DR) is the leading cause of vision loss of working-age adults, and diabetic macular edema (DME) is the most frequent cause of vision loss related to diabetes. The Wisconsin Epidemiologic Study of Diabetic Retinopathy found the 14-year incidence of DME in type 1 diabetics to be 26%. Similarly the Diabetes Control and Complications Trial reported that 27% of type 1 diabetic patients develop DME within 9 years of onset. The most common type of diabetes, type 2, is strongly associated with obesity and a sedentary lifestyle. An even higher incidence of macular edema has been reported in older patients with type 2 diabetes. Within the last 5 years, the use of intravitreal corticosteroids and intravitreal anti-vascular endothelial growth factor (VEGF) agents have come into clinical practice for the management of DME and several recent randomized clinical trials have shown improved effectiveness of ranibizumab compared to focal/grid laser. In this theme issue, we discuss the classification of DR and the treatment options currently available for the treatment of DME including corticosteroids, anti-VEGF agents, combined therapy, enzymatic vitrectomy (vitreolysis), and new therapies.
PMCID: PMC3874480  PMID: 24379911
Diabetic macular edema; Diabetic retinopathy; Diabetic macular edema; Enzymatic vitrectomy (vitreolysis); Focal/grid laser; Intravitreal anti-vascular endothelial growth factor; Intravitreal corticosteroids; New therapies
8.  Association of systemic and ocular risk factors with neurosensory retinal detachment in diabetic macular edema: a case–control study 
BMC Ophthalmology  2014;14:47.
Diabetic macular edema (DME) with neurosensory retinal detachment (NSD) remains an important cause of visual loss in patients with diabetes. The aim of the study was to elucidate the association of systemic and ocular risk factors with NSD in DME.
In a retrospective case–control study, we reviewed clinical records of all the subjects with DME seen between January 2010 and December 2010. Cases and controls were selected based on optical coherence tomography and stereoscopic biomicroscopy review. NSD was defined as subfoveal fluid accumulation under detached retina with or without overlying foveal thickening. The association between the presence of NSD, blood pressure, lipid status and various other biochemical parameters was evaluated.
Group I (cases) included 37 eyes of 33 patients having DME with NSD and Group II (controls) included 30 eyes of 21 patients having DME without NSD. Patients ranged in age (mean ± SD) from 50 to 62 years (56.6 +/-6.78) for cases and from 51 to 65 years (58.4+/-7.84) for controls. The duration of diabetes ranged from 4 to 15 year (mean 9.45+/-6.08) among cases and 4 to 14 years (9.7+/-5.12) among controls. Significant risk factors for NSD were high values of systolic and diastolic blood pressure (p = 0.039 and 0.043 respectively).
High systolic and diastolic blood pressures are independent and significant risk factors for NSD in DME.
PMCID: PMC3984633  PMID: 24716846
Diabetic macular edema; Neurosensory retinal detachment; Risk factors; Blood Pressure
9.  Clinical trials on corticosteroids for diabetic macular edema 
World Journal of Diabetes  2013;4(6):295-302.
Diabetic macular edema (DME) is a common cause of visual impairment in diabetic patients. It is caused by an increase in the permeability of the perifoveal capillaries and a disruption of the blood retinal-barrier. The pathogenesis of DME is multifactorial. Several therapeutic modalities have been proposed for the treatment of DME. Corticosteroid treatments have emerged as an alternative therapy for persistent DME or refractory to conventional laser photocoagulation and other modalities, due to anti-inflammatory, anti-vascular endothelial growth factor and anti-proliferative effects. Many studies have demonstrated the beneficial therapeutic effect of corticosteroids with improvement to both retinal thickness and visual acuity in short-term on the treatment of DME. Peribulbar and intravitreal injections have been used to deliver steroids for DME with frequent injections due to the chronic and recurrent nature of the disease. Steroid-related side effects include elevated intraocular pressure, cataract, and injection related complications such as endophthalmitis, vitreous hemorrhage, and retinal detachment particularly with intravitreal steroid injections. In order to reduce the risks, complications and frequent dosing of intravitreal steroids, intravitreal implants have been developed recently to provide sustained release of corticosteroids and reduce repeated intravitreal injections for the management of DME.
PMCID: PMC3874489  PMID: 24379920
Corticosteroids; Diabetic macular edema; Intravitreal triamcinolone acetonide injection; Intravitreal steroid sustained-release implants; Peribulbar steroid injections; Subtenon’s steroid Injections
10.  Optical Coherence Tomography for Age-Related Macular Degeneration and Diabetic Macular Edema 
Executive Summary
The purpose of this evidence-based review was to examine the effectiveness and cost-effectiveness of spectral-domain (SD) optical coherence tomography (OCT) in the diagnosis and monitoring of patients with retinal disease, specifically age-related macular degeneration (AMD) and diabetic macular edema (DME). Specifically, the research question addressed was:
What is the sensitivity and specificity of spectral domain OCT relative to the gold standard?
Clinical Need: Target Population and Condition
The incidence of blindness has been increasing worldwide. In Canada, vision loss in those 65 years of age and older is primarily due to AMD, while loss of vision in those 18 years of age and older is mainly due to DME. Both of these conditions are diseases of the retina, which is located at the back of the eye. At the center of the retina is the macula, a 5 mm region that is responsible for what we see in front of us, our ability to detect colour, and fine detail. Damage to the macula gives rise to vision loss, but early detection of asymptomatic disease may lead to the prevention or slowing of the vision loss process.
There are two main types of AMD, ‘dry’ and ‘wet’. Dry AMD is the more prevalent of the two, accounting for approximately 85% of cases and characterized by small deposits of extracellular material called “drusen” that build up in Bruch’s membrane of the eye. Central vision loss is gradual with blurring and eventual colour fading. Wet AMD is a less prevalent condition (15% of all AMD cases) but it accounts for 90% of severe cases. It’s characterized by the appearance of retinal fluid with vision loss due to abnormal blood vessels/leakage within weeks to months of diagnosis. In 2003, the Canadian National Institute for the Blind (CNIB) prevalence estimate for AMD was 1 million Canadians, including approximately 400,000 affected Ontarians. The incidence in 2003 was estimated to be 78,000 new cases in Canada, with approximately one-third of these cases arising in Ontario (n=26,000). Over the next 25 years, the number of new cases is expected to triple.
DME is caused by complications of diabetes mellitus, both Type 1 and Type 2. It is estimated that 1-in-4 persons with diabetes has this condition, though it occurs more frequently among those with type 2 diabetes. The condition is characterized by a swelling of the retina caused by leakage of blood vessels at the back of the eye. In early stages of the disease, vision may still be normal but it can degrade rapidly in later stages. In 2003, the CNIB prevalence estimate for DME was 0.5 million Canadians, with approximately 200,000 Ontarians affected. The incidence of DME is more difficult to ascertain; however, based on an annual incidence rate of 0.8% (for those 20 years of age or older) and the assumption that 1-in-4 persons with diabetes is affected, the incidence of DME in Ontario is estimated to be 21,000 new cases per year.
Optical Coherence Tomography
Prior to the availability of OCT, the standard of care in the diagnosis and/or monitoring of retinal disease was serial testing with fluorescein angiography (FA), biomicroscopy (BM), and stereo-fundus photography (SFP). Each of these is a qualitative measure of disease based on subjective evaluations that are largely dependent on physician expertise. OCT is the first quantitative visual test available for the diagnosis of eye disease. As such, it is allows for a more objective evaluation of the presence/absence of retinal disease and it is the only test that provides a measure of retinal thickness. The technology was developed at the Michigan Institute of Technology (MIT) in 1991 as a real-time imaging modality and is considered comparable to histology. It’s a light-wave based technology producing cross-sectional images with scan rates and resolution parameters that have greatly improved over the last 10 years. It’s also a non-invasive, non-contact visual test that requires just 3 to 5 minutes to assess both eyes.
There are two main types of OCT system, both licensed by Health Canada as class II devices. The original patent was based on a time domain (TD) system (available from 1995) that had an image rate of 100 to 400 scans per second and provided information for a limited view of the retina with a resolution in the range of 10 to 20 μm. The newer system, spectral domain (SD) OCT, has been available since 2006. Improvements with this system include (i) a faster scan speed of approximately 27,000 scans per second; (ii) the ability to scan larger areas of the retina by taking six scans radially-oriented 30 degrees from each other; (iii) increased resolution at 5μm; and (iv) ‘real-time registration,’ which was not previously available with TD.
The increased scan speed of SD systems enables the collection of additional real-time information on larger regions of the retina, thus, reducing the reliance on assumptions required for retinal thickness and volume estimates based on software algorithms. The faster scan speed also eliminates image distortion arising from patient movement (not previously possible with TD), while the improvement in resolution allows for clearer and more distinguishable retinal layers with the possibility of detecting earlier signs of disease. Real-time registration is a new feature of SD that enables the identification of specific anatomical locations on the retina, against which subsequent tests can be evaluated. This is of particular importance in the monitoring of patients. In the evaluation of treatment effects, for example, this enables the same anatomic retinal location to be identified at each visit.
Literature Search
A literature search was performed on February 13, 2009 using Ovid MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 2003 to February 2009. The subject headings and keywords searched included AMD, DME, and OCT (the detailed search strategy can be viewed in Appendix 1). Excluded were case reports, comments, editorials, non-systematic reviews, and letters. Abstacts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. In total, 542 articles were included for review.
English-language articles and health technology assessments.
RCTs and observational studies of OCT and AMD or DME.
Studies focusing on either diagnosis or monitoring of disease.
Studies in which outcomes were not specific to those of interest in this report.
Studies of pediatric populations.
Studies on OCT as a screening tool.
Studies that did not assess comparative effectiveness of OCT with a referent, as specified below in “Comparisons of Interest”.
Outcomes of Interest
Studies of sensitivity, specificity.
Comparisons of Interest
Evidence exists for the following comparisons of interest:
OCT compared with the reference “fluorescein angiography” for AMD.
OCT compared with the reference “biomicroscopy” or “stereo or fundus photography” for DME.
Summary of Existing Evidence
No evidence for the accuracy of SD OCT compared to either FA, BM or SFP was published between January 2006 to February 2009; however, two technology assessments were found, one from Alberta and the other from Germany, both of which contain evidence for TD OCT. Although these HTAs included eight studies each, only one study from each report was specific to this review. Additionally, one systematic review was identified for OCT and DME. It is these three articles, all pertaining to time and not spectral domain OCT, as well as comments from experts in the field of OCT and retinal disease, that comprise the evidence contained in this review.
Upon further assessment and consultations with experts in the methodology of clinical test evaluation, it was concluded that these comparators could not be used as references in the evaluation of OCT. The main conclusion was that, without a third test as an arbiter, it is not possible to directly compare the sensitivity and specificity of OCT relative to either FA for AMD and stereo- or fundus – photography for DME. Therefore, in the absence of published evidence, it was deemed appropriate to consult a panel of experts for their views and opinions on the validity of OCT and its utility in clinical settings. This panel consisted of four clinicians with expertise in AMD and/or DME and OCT, as well as a medical biophysicist with scientific expertise in ocular technologies. This is considered level 5 evidence, but in the absence of an appropriate comparator for further evaluation of OCT, this may be the highest level of evidence possible.
Summary of Findings
The conclusions for SD OCT based on Level 5 evidence, or expert consultation, are as follows:
OCT is considered an essential part of the diagnosis and follow-up of patients with DME and AMD.
OCT is adjunctive to FA for both AMD and DME but should decrease utilization of FA as a monitoring modality.
OCT will result in a decline in the use of BM in the monitoring of patients with DME, given its increased accuracy and consistency.
OCT is diffusing rapidly and the technology is changing. Since FA is still considered pivotal in the diagnosis and treatment of AMD and DME, and there is no common outcome against which to compare these technologies, it is unlikely that RCT evidence of efficacy for OCT will ever be forthcoming.
In addition to the accuracy of OCT in the detection of disease, assessment of the clinical utility of this technology included a rapid review of treatment effects for AMD and DME. The treatment of choice for AMD is Lucentis®, with or without Avastin® and photodynamic therapy. For DME the treatment of choice is laser photocoagulation, which may be replaced with Lucentis® injections (Expert consultation). The evidence, as presented in systematic reviews and other health technology assessments, indicates that there are effective treatments available for both AMD and DME.
Considerations for the Ontario Health System
OCT testing is presently an uninsured service in Ontario with patients paying approximately $150 out-of-pocket per test. Several provinces do provide funding for this procedure, including British Columbia, Alberta, Saskatchewan, Newfoundland, Nova Scotia, Prince Edward Island, and the Yukon Territory. Provinces that do not provide such funding are Quebec, Manitoba and New Brunswick.
The demand for OCT is expected to increase with aging of the population.
PMCID: PMC3377511  PMID: 23074517
11.  Quantitative computerized color vision testing in diabetic retinopathy: A possible screening tool? 
Oman Journal of Ophthalmology  2013;6(Suppl 1):S36-S39.
To evaluate the efficacy of a computerized color vision testing (Arden color contrast test) as a screening test for detection of diabetic macular edema (DME).
Materials and Methods:
A consecutive, prospective case series of 83 eyes of 42 diabetic patients with and without macular edema was enrolled. Macular edema was assessed clinically by stereoscopic grading and by central retinal thickness measurement with optical coherence tomography (OCT). Additionally, a computerized chromatest for the protan- and tritan-axis was performed. Analysis of test characteristics included receiver operating characteristic (ROC) curves and calculated sensitivity and specificity.
Sixty-one eyes had clinically significant macular edema (CSME). OCT yielded an area under the ROC curve (AUC) of 0.92. Color vision testing yielded an AUC of 0.82 for the tritan- and 0.80 for the protan-axis. Using a cut off of 199 microns OCT resulted in a 100% sensitivity at 39% specificity. With a cut-off of 4.85, color testing yielded a sensitivity of 100% at a specificity of 8% on the tritan-axis, respectively. Considering OCT instead of clinical examination as a reference standard resulted in a comparable high sensitivity, but low specificity for color vision testing. Disturbance of the tritan axis was more pronounced than for the protan axis in present macular edema and also better correlated (r = 0.46) with retinal thickness measured with OCT.
Computerized, quantitative color testing using the chromatest allows detection of diabetic maculopathy with high sensitivity. However, only a low specificity exists for retinal macular edema, as in diabetic retinopathy (DR) frequently abnormalities of the tritan axis exist before any retinal thickening occurs.
PMCID: PMC3872842  PMID: 24391371
Color vision; diabetic retinopathy; diabetic macular edema; screening; OCT
12.  Green-light fundus autofluorescence in diabetic macular edema 
To evaluate the role of central green-light fundus autofluorescence (FAF) in diabetic macular edema (DME).
A consecutive series of 92 study eyes with diabetic retinopathy were included. Out of those, 51 diabetic eyes had DME and were compared to 41 diabetic eyes without DME. In all subjects, green-light FAF images were obtained, quantified and classified into various FAF patterns. Cross-sectional optical coherence tomography (OCT) scans were obtained for evaluation of Inner/Outer segment (IS/OS) layer integrity, measurements of central RPE-IS/OS layer thickness as well as classification of DME into various subtypes.
Mean central green-light FAF intensity of eyes with DME (1.289±0.140)log did not significantly differ from diabetic patients without DME (1.317±0.137)log. Most classifiable FAF patterns were seen in patients with cystoid DME. Mean central retinal thickness (CRT) of all study eyes with DME was (501.9±112.4)µm compared to (328.2±27.0)µm in diabetic patients without DME. Patients with DME had significantly more disrupted photoreceptor IS/OS layers than diabetic patients without DME (28/51 vs 5/41, P<0.001). Mean RPE-IS/OS thickness of patients with DME (60.7±14.1)µm was significantly (P<0.001) lower than in diabetic eyes without DME (73.5±9.4)µm. Correlation analys1s revealed non-significant correlations of green-light FAF intensity and OCT parameters in all subtypes of DME.
Our results indicate a poor correlation of central green-light FAF intensity with CRT, IS/OS layer integrity or RPE-IS/OS layer thickness in diabetic patients with or without DME and its various subtypes. Thus, central green-light FAF is not suitable for detection of retinal thickening in DME.
PMCID: PMC3580255  PMID: 23549658
diabetic macular edema; fundus autofluorescence; optical coherence tomography
13.  Pharmacologic therapies for diabetic retinopathy and diabetic macular edema 
Diabetic retinopathy (DR) and diabetic macular edema (DME) are leading causes of blindness in the working-aged population of most developed countries. The increasing number of persons with diabetes worldwide suggests that DR/DME will continue to be major contributors to vision loss and associated functional impairment for years to come. Early detection of retinopathy in persons with diabetes is critical in preventing visual loss, but current methods of screening fail to identify a sizable number of high-risk patients. The control of diabetes-associated metabolic abnormalities (ie, hyperglycemia, hyperlipidemia, and hypertension) is also important in preserving visual function, as these conditions have been identified as risk factors for both the development and progression of DR/DME. The non-pharmacologic interventions for DR/DME, laser photocoagulation and vitrectomy, only target advanced stages of disease. Several biochemical mechanisms, including increased vascular endothelial growth factor production, protein kinase C β activation, oxidative stress, and accumulation of intracellular sorbitol and advanced glycosylation end products, may contribute to the vascular disruptions that characterize DR/DME. The inhibition of these pathways holds the promise of the intervention for diabetic retinopathy with higher success rate and also at earlier, non-sight-threatening stages.
PMCID: PMC2704543  PMID: 19668515
14.  SDOCT Imaging to Identify Macular Pathology in Patients Diagnosed with Diabetic Maculopathy by a Digital Photographic Retinal Screening Programme 
PLoS ONE  2011;6(5):e14811.
Diabetic macular edema (DME) is an important cause of vision loss. England has a national systematic photographic retinal screening programme to identify patients with diabetic eye disease. Grading retinal photographs according to this national protocol identifies surrogate markers for DME. We audited a care pathway using a spectral-domain optical coherence tomography (SDOCT) clinic to identify macular pathology in this subset of patients.
A prospective audit was performed of patients referred from screening with mild to moderate non-proliferative diabetic retinopathy (R1) and surrogate markers for diabetic macular edema (M1) attending an SDOCT clinic. The SDOCT images were graded by an ophthalmologist as SDOCT positive, borderline or negative. SDOCT positive patients were referred to the medical retina clinic. SDOCT negative and borderline patients were further reviewed in the SDOCT clinic in 6 months.
From a registered screening population of 17 551 patients with diabetes mellitus, 311 patients met the inclusion criteria between (March 2008 and September 2009). We analyzed images from 311 patients’ SDOCT clinic episodes. There were 131 SDOCT negative and 12 borderline patients booked for revisit in the OCT clinic. Twenty-four were referred back to photographic screening for a variety of reasons. A total of 144 were referred to ophthalmology with OCT evidence of definite macular pathology requiring review by an ophthalmologist.
This analysis shows that patients with diabetes, mild to moderate non-proliferative diabetic retinopathy (R1) and evidence of diabetic maculopathy on non-stereoscopic retinal photographs (M1) have a 42.1% chance of having no macular edema on SDOCT imaging as defined by standard OCT definitions of DME when graded by a retinal specialist. SDOCT imaging is a useful adjunct to colour fundus photography in screening for referable diabetic maculopathy in our screening population.
PMCID: PMC3089611  PMID: 21573106
15.  Interpreting Thickness Changes in the Diabetic Macula: The Problem of Short-Term Variation in Optical Coherence Tomography–Measured Macular Thickening (An American Ophthalmological Society Thesis) 
To estimate the short-term variability of macular thickness in eyes with refractory and regressed diabetic macular edema (DME).
In this retrospective review of consecutive cases from a retina practice, optical coherence tomography (OCT) measurements of macular thickness were extracted from the clinical charts of patients with refractory DME and regressed DME. Variation in macular thickness was defined as maximal central subfield mean thickness (CSMT) minus minimal CSMT during a period of observation in which clinical macular status did not change.
There were 36 eyes of 29 patients in the refractory DME group and 93 eyes of 93 patients in the regressed DME group. Median intervals during which macular status was unchanged and OCTs were collected were 7 months for the refractory DME group and 22 months for the regressed DME group. Baseline CSMTs were 321 μm for the refractory DME group and 217 μm for the regressed DME group. The median variation in CSMT was 89 μm for the refractory DME group and 19 μm for the regressed DME group. Results for total macular volume paralleled those for CSMT.
In consonance with eyes having treatment-naïve DME, eyes with refractory DME have short-term fluctuation in macular thickness larger than OCT measurement variability. In eyes with regressed DME, short-term fluctuation is less than in eyes with refractory DME, yet can also exceed measurement variability. This information is clinically important in deciding whether subsequent treatment is indicated.
PMCID: PMC3016084  PMID: 21212849
16.  Combined Therapy for Diabetic Macular Edema 
Diabetic macular edema (DME) is the main cause of visual impairment in diabetic patients. Macular edema within 1 disk diameter of the fovea is present in 9% of the diabetic population. The management of DME is complex and often multiple treatment approaches are needed. This review demonstrates the benefits of intravitreal triamcinolone, bevacizumab and ranibizumab as adjunctive therapy to macular laser treatment in DME. The published results indicate that intravitreal injections of these agents may have a beneficial effect on macular thickness and visual acuity, independent of the type of macular edema that is present. Therefore, pharmacotherapy could complement focal/grid laser photocoagulation in the management of DME. For this review, we performed a literature search and summarized recent findings regarding combined therapy for DME.
PMCID: PMC3841949  PMID: 24339681
Anti-vascular Endothelial Growth Factor; Diabetic Macular Edema; Macular Laser Photocoagulation
17.  The use of comparative effectiveness research to inform policy decisions on the inclusion of bevacizumab for the treatment of macular diseases in Thailand’s pharmaceutical benefit package 
There is increasing impetus to use pharmaceutical interventions, ie, ranibizumab or bevacizumab, for the treatment of particular macular diseases. This paper describes the evidence and decision-making of the National List of Essential Medicines Committee that recently announced the inclusion of bevacizumab for the treatment of macular diseases in its pharmaceutical benefit package. The findings of a systematic review and meta-analysis in this paper indicate that the intravitreal administration of bevacizumab is superior to nonpharmaceutical treatments for age-related macular degeneration (AMD) and diabetic macular edema (DME), but inconclusive for retinal vein occlusion, given the limited evidence. The study also failed to distinguish among the differences in terms of visual acuity improvement, reduction of central macular thickness, and response to treatment between AMD and DME patients treated with bevacizumab and those treated with ranibizumab. Although bevacizumab was not licensed for AMD and DME, the committee decided to include bevacizumab in the National List of Essential Medicines. It is expected that many patients who are in need of treatment but who are unable to afford the expensive alternative drug, ranibizumab, will be able to receive this effective treatment instead and be prevented from suffering irreversible loss of vision. At the same time, this policy will help generate evidence about the real-life effectiveness and safety profiles of the drug for future policy development in Thailand and other settings.
PMCID: PMC3520463  PMID: 23248574
bevacizumab; macular degeneration; diabetic macular edema; retinal vein occlusion; comparative effectiveness research
18.  Short-term results of intravitreal dexamethasone implant (OZURDEX®) in treatment of recalcitrant diabetic macular edema: A case series 
Oman Journal of Ophthalmology  2012;5(2):79-82.
Dexamethasone Posterior-Segment Drug Delivery System is a novel, biodegradable, sustained-release drug delivery system (OZURDEX®) for treatment of macular edema following retinal vein occlusion and posterior uveitis. However, its potential role in management of diabetic macular edema has not been reported yet.
The aim was to evaluate the safety and efficacy of (OZURDEX®) in patients with recalcitrant diabetic macular edema (DME).
Setting and Design:
A retrospective, interventional case series from a tertiary eye care center in India is presented. Inclusion criteria comprised patients presenting with recalcitrant DME, 3 or more months after one or more treatments of macular laser photocoagulation and/or intravitreal anti-vascular endothelial growth factor (VEGF) injections. Exclusion criteria included history of corticosteroid-responsive intraocular pressure (IOP) rise, cataract extraction, or other intraocular surgery within 3 months. The main outcome measure was visual acuity at 1 and 4 months after OZURDEX® injection. Secondary outcome measures included change in central macular thickness on Optical coherence tomography (OCT) and changes in IOP following intravitreal OZURDEX® implant. Of 18 eyes (17 patients) with recalcitrant diabetic macular edema that underwent OZURDEX® implant, three eyes (two patients) had follow-up of more than 3 months post-injection.
Mean age of patients was 56 years. Mean duration of diabetes mellitus was 16.6 years. Systemic control of DM was good as assessed by FBS/PPBS and HbA1c. The pre-operative mean central macular thickness was 744.3 μm and improved to 144 and 570 μm at months 1 and 4, respectively. Preoperative mean BCVA was 0.6 logMAR units and improved to 0.3 and 0.46 logMAR units at month 1 and 4, respectively. The mean follow-up was 4.3 months (range 4-5 months).
OZURDEX® appears efficacious in management of recalcitrant diabetic macular edema. The results of the ongoing POSURDEX® study will elaborate these effects better.
PMCID: PMC3441033  PMID: 22993460
Dexamethasone; diabetes mellitus; diabetic macular edema; intravitreal implant; OZURDEX®
19.  Automated Detection of Clinically Significant Macular Edema by Grid Scanning Optical Coherence Tomography 
Ophthalmology  2006;113(7):1187.e1-1187.12.
To compare the detection of clinically significant diabetic macular edema (DME) by an optical coherence tomography (OCT) grid scanning protocol and biomicroscopic examination.
Retrospective case series.
Outpatients at the Doheny Eye Institute.
The clinical and imaging records of a consecutive series of 71 eyes of 40 patients referred for DME who underwent OCT using the both the Macular Grid 5 (MG5) scanning protocol (to allow a more evenly distributed sampling of points in the macula) and the standard Fast Macular Thickness Map (FMTM) pattern were reviewed. An automated algorithm was developed to generate a retinal thickness map using the MG5 data, which was then compared with a normative database to identify presumed areas of retinal edema. Clinically significant macular edema (CSME) was also identified by clinical examination and stereoscopic fundus photographs for comparison with the results of the OCT protocols.
Main Outcome Measures
Sensitivity and specificity of scanning protocols.
Optical coherence tomograms were inspected visually, and automatically detected retinal boundaries were found to be correct in 69 of 71 MG5 scans and in 65 of 71 FMTM scans. Macular Grid 5 scanning was performed twice in each eye, and the repeatability (pooled standard deviation) of the total area of edema was 0.48 mm2 (coefficient of variation, 6.8%). Sensitivity and specificity of the MG5 for detection of CSME relative to the clinical examination were 89% and 86%, respectively, with κ being 0.74. Macular Grid 5 and FMTM assessment of foveal CSME also showed good agreement, with κ being 0.68.
The analysis algorithm for the OCT MG5 grid scan seems to be accurate and repeatable. Automated detection of CSME by the MG5 analysis correlated well with the clinical grading and standard OCT analysis (FMTM). Macular Grid 5 provides more information regarding the perifoveal macula than FMTM and may be of value to clinicians in planning treatment and in future studies of macular edema.
PMCID: PMC1779509  PMID: 16647123
20.  Intravitreal steroids for macular edema in diabetes 
Macular edema is secondary to leakage from diseased retinal capillaries and is an important cause of poor central visual acuity in patients with diabetic retinopathy.
This review evaluated the effectiveness and safety of intraocular steroids in treating diabetic macular edema (DME).
Search methods
We searched CENTRAL, MEDLINE, EMBASE in June 2007, reference lists, Science Citation Index and conference proceedings.
Selection criteria
We included randomized clinical trials (RCTs) evaluating any form of intravitreal steroids for treating DME.
Data collection and analysis
Two authors independently assessed eligibility, methodological quality and extracted data. We performed meta-analyses when appropriate.
Main results
Seven studies, involving 632 DME eyes were included. Four examined the effectiveness of intravitreal triamcinolone acetate injection (IVTA), three examined intravitreal steroids implantation (fluocinolone acetonide implant (FAI) or dexamethasone drug delivery system (DDS)). Two trials were at low risk of bias, one was at median risk of bias, two were at high risk of bias and the remaining two were at unclear risk of bias.
The preponderance of data suggest a beneficial effect from IVTA. Comparing IVTA with controls, the mean difference in visual acuity was −0.15 LogMAR (95% CI −0.21 to −0.09) at 3 months (based on three trials), −0.23 LogMAR (95% CI −0.33 to −0.13) at 6 months (two trials), −0.29 LogMAR (95% CI −0.47 to −0.11) at 9 months (one trial), and −0.11 LogMAR (95% CI −0.20 to −0.03) at 24 months (one trial), all in favor of IVTA. The relative risk (RR) for one or more lines improvement in visual acuity was 2.85 (95% CI 1.59 to 5.10) at 3 months (two trials), 1.25 (95% CI 0.66 to 2.38) at 6 months (one trial), and 2.17 (95% CI 1.15 to 4.11) at 24 months (one trial), all in favor of IVTA. We did not find evidence for three or more lines improvement in visual acuity. The mean difference in retinal thickness was −131.97 um (95% CI −169.08 to −94.86) at 3 months (two trials), −135.00 um (95% CI −194.50 to −75.50) at 6 months (one trial), −133.00 um (95% CI −199.86 to −66.14) at 9 months (one trial), and −59.00 um (95% CI −103.50 to −14.50) at 24 months (one trial), all in favor of IVTA. The RR for at least one grade macular edema resolution was 5.15 (95% CI 2.23 to 11.88) at 3 months in favor of IVTA (one trial).
Two trials reported improved clinical outcome when FAI was compared to standard of care. Beneficial effect was also observed in one dexamethasone DDS trial.
Increased intraocular pressure and cataract formation were side effects requiring monitoring and management.
Authors' conclusions
RCTs included in this review suggest that steroids placed inside the eye by either intravitreal injection or surgical implantation may improve visual outcomes in eyes with persistent or refractory DME. Since the studies in our report focused on chronic or refractory DME, the question arises whether intravitreal steroids therapy could be of value in other stages of DME, especially the earlier stages either as standalone therapy or in combination with other therapies, such as laser photocoagulation.
PMCID: PMC3804331  PMID: 18254088
21.  Subthreshold Diode Micropulse Laser Photocoagulation (SDM) as Invisible Retinal Phototherapy for Diabetic Macular Edema: A Review 
Current Diabetes Reviews  2012;8(4):274-284.
To present the state-of-the-art of subthreshold diode laser micropulse photocoagulation (SDM) as invisible retinal phototherapy for diabetic macular edema (DME).
To review the role and evolution of retinal laser treatment for DME.
Thermal laser retinal photocoagulation has been the cornerstone of treatment for diabetic macular edema for over four decades. Throughout, laser induced retinal damage produced by conventional photocoagulation has been universally accepted as necessary to produce a therapeutic benefit, despite the inherent risks, adverse effects and limitations of thermally destructive treatment. Recently, SDM, performed as invisible retinal phototherapy for DME, has been found to be effective in the absence of any retinal damage or adverse effect, fundamentally altering our understanding of laser treatment for retinal disease.
The discovery of clinically effective and harmless SDM treatment for DME offers exciting new information that will improve our understanding of laser treatment for retinal disease, expand treatment indications, and improve patient outcomes.
PMCID: PMC3412206  PMID: 22587512
Subthreshold; invisible; diode laser; micropulse; photocoagulation; phototherapy; photostimulation; diabetes; diabetic retinopathy; diabetic macular edema.
22.  Fluocinolone acetonide and its potential in the treatment of chronic diabetic macular edema 
Diabetic macular edema (DME) is a potentially sight-threatening disease that predominantly affects patients with type 2 diabetes. The pathogenesis is complex, with many contributing factors involved. In addition to overexpression of vascular endothelial growth factor in the diabetic eye, there is an inflammatory pathway that contributes to the breakdown of the blood-retina barrier and nonperfusion. In addition to vascular endothelial growth factor inhibitors, clinical and experimental investigations underline the great potential of steroids in the treatment of DME. Fluocinolone acetonide is currently the only corticosteroid approved for the treatment of DME in Europe. It is manufactured as an intravitreal insert, releasing fluocinolone acetonide at a rate of 0.2 μg per day. Phase III clinical studies have demonstrated that the beneficial effect of the fluocinolone acetonide insert lasts up to 3 years. Improvement in visual acuity was especially remarkable in patients with a prolonged duration of DME of at least 3 years at the initiation of therapy. Cataract formation occurs in nearly all phakic eyes treated, and needs to be considered when the indication for treatment is made. Given the efficacy versus potential complications of the insert, fluocinolone acetonide represents a promising second-line treatment option in patients with DME. Fluocinolone appears to be especially beneficial for patients whose options for visual recovery have seemed limited up until now.
PMCID: PMC3595182  PMID: 23503099
diabetic macular edema; fluocinolone acetonide
23.  Using skew-symmetric mixed models for investigating the effect of different diabetic macular edema treatments by analyzing central macular thickness and visual acuity responses 
Diabetic Macular Edema (DME) is one of the major causes of visual loss and increase in central macular thickness (CMT). The aim of this study was to determine the efficacy of a single intravitreal injection of bevacizumab (IVB) alone or in combination with intravitreal triamcinolone acetonide (IVB/IVT) versus macular laser photocoagulation (MPC) as primary treatment for DME when confounders were considered.
Skew-symmetric bivariate mixed modeling according to best corrected visual acuity (BCVA) and CMT was done on the data of 103 diabetic patients from ophthalmic research center of Labbafinejad medical center (Tehran, Iran) to determine the best DME treatment by adjusting the effect of confounders.
Although there was no significant difference between IVB/IVT (p > 0.05), these two treatments increased BCVA and decreased CMT better than MPC (p < 0.05). The following three groups showed better treatment responses: 1) women, 2) patients with more diabetes duration, 3) patients whose CMT were higher and VA were lower at the beginning of the clinical trial.
Using skew-symmetric mixed effect model as updated statistical method in presence of asymmetric or outlier data, we received different results compared to the same investigation on this study by analyzing BCVA and CMT simultaneously. This research demonstrated the effect of IVB alone or in combination with intravitreal IVB/IVT on visual power and decreasing CMT during follow up.
PMCID: PMC3430022  PMID: 22973326
Best-Corrected Visual Acuity; Central Macular Thickness; Diabetic Macular Edema; Skew-symmetric Mixed Models
24.  Evaluation of Time Domain and Spectral Domain Optical Coherence Tomography in the Measurement of Diabetic Macular Edema 
To evaluate macular thickness and volume measurements and their intrasession repeatability in two optical coherence tomography (OCT) systems: the Stratus OCT, a time domain system, and the Cirrus HD-OCT, a spectral domain system (both by Carl Zeiss Meditec, Inc., Dublin, CA), in the context of diabetic macular edema (DME).
Thirty-three eyes of 33 diabetic patients with clinically significant macular edema (CSME) were scanned in a single session by a single operator on both OCT systems. Macular thickness measurements of nine standard macular subfields and total macular volume were obtained and analyzed. Bland-Altman plots were constructed to assess agreement in macular measurements. Intraclass correlation coefficients (ICCs), coefficients of repeatability (CRW), and coefficients of variation (CVW) were used to assess intrasession repeatability.
Macular thickness in nine retinal subfields and macular volume were significantly higher in the Cirrus HD-OCT system compared with the Stratus OCT system. Subfield thickness and total volume measurements, respectively, were 30 to 55 μm and 3.2 mm3 greater for the Cirrus HD-OCT system compared with the Stratus OCT system. Both Stratus OCT and Cirrus HD-OCT systems demonstrated high intrasession repeatability, with overlapping ranges for CRW, CVW, and ICC. Repeatability measures (CRW and CVW) differed significantly between systems in only one of nine subfields (outer temporal subfield).
Absolute measures of macular thickness and volume in patients with DME differed significantly in magnitude between the Stratus OCT and Cirrus HD-OCT systems. However, both OCT systems demonstrated high intrasessional repeatability. Although the two systems may not be used interchangeably, they appear equally reliable in generating macular measurements for clinical practice and research.
PMCID: PMC2574838  PMID: 18515567
25.  Comparison of Natural Course, Intravitreal Triamcinolone and Macular laser photocoagulation for Treatment of Mild Diabetic Macular Edema 
Purpose: To assess the natural course of the mild diabetic macular edema(DME) and to compare the visual outcomes with the patients with receiving either macular laser photocoagulation or intravitreal injection of triamcinolone acetonide(IVTA).
Methods: 28 eyes with central macular thickness (CMT) of between 250 to 300µm were followed without treatment and 48 eyes with CMT between 300 to 500µm had been divided into 3 subgroups according to treatment. We evaluated the best corrected visual acuity (BCVA) and CMT of natural course group and compared the BCVA and CMT of the patients who had been treated with IVTA or macular laser treatment.
Results: The eyes with DME between 250 to 300µm showed no significant change in BCVA and CMT at 6 month. Among the eyes with DME between 300 to 500µm, all 3 subgroups showed no statistically significant change of BCVA at any follow up period and no significant difference was revealed among the subgroups. All subgroups showed significant reduction of CMT after 1 month and maintained until final follow-up and there was no significant difference among subgroups.
Conclusions: Mild DME between 250 to 500µm did not show significant worsening of BCVA or macular edema without any specific treatment.
PMCID: PMC3558712  PMID: 23372430
Diabetic Macular Edema; Intravitreal triamcinolone; Macular laser photocoagulation.

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