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1.  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
2.  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
3.  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
4.  Age, gender, insulin and blood glucose control status alter the risk of ischemic heart disease and stroke among elderly diabetic patients 
We analyzed the effects of insulin therapy, age and gender on the risk of ischemic heart disease (IHD) and cerebrovascular accident (CVA) according to glycemic control.
Methods and Results
We performed a prospective cohort study (Japan Cholesterol and Diabetes Mellitus Study) of type 2 diabetes patients (n = 4014) for 2 years. The primary endpoint was the onset of fatal/non-fatal IHD and/or CVA, which occurred at rates of 7.9 and 7.2 per 1000 person-years, respectively. We divided diabetic patients into four groups based on age (≤ 70 and > 70) and hemoglobin A1C levels (≤ 7.0 and > 7.0%). Multiple regression analysis revealed that IHD was associated with high systolic blood pressure and low HDL-C in patients under 70 years of age with fair glycemic control and was associated with low diastolic blood pressure in the older/fair group. Interestingly, insulin use was associated with IHD in the older/poor group (OR = 2.27, 95% CI = 1.11-5.89; p = 0.026) and was associated with CVA in the older/fair group (OR = 2.09, 95% CI = 1.06-4.25; p = 0.028). CVA was associated with lower HDL-C and longer duration of diabetes in younger/poor glycemic control group. Results by stepwise analysis were similar. Next, patients were divided into four groups based on gender and diabetic control(hemoglobinA1C < or > 7.0%). Multiple regression analysis revealed that IHD was associated with high systolic blood pressure in male/fair glycemic control group, age in male/poor control group, and short duration of diabetic history in females in both glycemic control groups. Interestingly, insulin use was associated with IHD in the male/poor group(OR = 4.11, 95% CI = 1.22-8.12; p = 0.018) and with CVA in the female/poor group(OR = 3.26, 95% CI = 1.12-6.24; p = 0.02). CVA was associated with short duration of diabetes in both female groups.
IHD and CVA risks are affected by specific factors in diabetics, such as treatment, gender and age. Specifically, insulin use has a potential role in preventing IHD but may also be a risk factor for CVA among the diabetic elderly, thus revealing a need to develop improved treatment strategies for diabetes in elderly patients. The Japan Cholesterol and Diabetes Mellitus Study was formulated to evaluate them(Umin Clinical Trials Registry, clinical trial reg. no. UMIN00000516;
PMCID: PMC3200162  PMID: 21978180
Elderly; Diabetes mellitus; Insulin; Cerebral ischemia; Ischemic heart disease
5.  Clinical utilization of anti-vascular endothelial growth-factor agents and patient monitoring in retinal vein occlusion and diabetic macular edema 
To examine the utilization of bevacizumab and ranibizumab and disease monitoring in patients with branch or central retinal vein occlusion (BRVO/CRVO) or diabetic macular edema (DME) in clinical practice.
Patients and methods
This retrospective claims analysis included newly diagnosed patients with one or more bevacizumab or ranibizumab injections. Bevacizumab or ranibizumab utilization was assessed by year of first injection: 2008–2010 cohorts (12-month follow-up), January to June 2011 cohort (6-month follow-up). The main outcome measures were mean annual numbers of injections, ophthalmologist visits and optical coherence tomography examinations, and proportion of patients with additional laser or intravitreal triamcinolone (IVTA) use.
A total of 885 BRVO, 611 CRVO, and 2,733 DME patients treated with bevacizumab were included, with too few ranibizumab-treated patients for meaningful analysis. Across the 2008, 2009, and 2010 cohorts, mean annual numbers of bevacizumab injections increased, but remained low (BRVO 2.5, 3.1, 3.3; CRVO 3.1, 3.1, 3.5; and DME 2.2, 2.5, 3.6, respectively); mean ophthalmologist visits ranged between 4.4 and 6.5, and mean optical coherence tomography examinations ranged between 3.1 and 3.9 across all conditions. A total of 42.0% of BRVO, 16.5% of CRVO, and 57.7% of DME patients received additional laser or IVTA therapy. The number of bevacizumab injections was positively associated with laser use in BRVO (3.3 versus 2.9, P<0.03), and with laser or IVTA use in DME (laser, 3.3 versus 2.7, P<0.03; IVTA, 3.3 versus 3.0, P<0.05).
During the study period (2008–2011), bevacizumab was the main anti-VEGF therapy used in clinical practice for BRVO, CRVO, and DME. Patients treated with bevacizumab were monitored less frequently and received fewer injections than patients in major clinical trials of ranibizumab.
PMCID: PMC4155807  PMID: 25210429
anti-vascular endothelial growth factor; bevacizumab; ranibizumab; diabetic macular edema; retinal vein occlusion; intravitreal
6.  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  PMID: 24707168
choroidal thickness; diabetic retinopathy; optical coherence tomography
7.  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
8.  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
9.  Metabolic predictors of ischemic heart disease and cerebrovascular attack in elderly diabetic individuals: difference in risk by age 
High LDL-cholesterol (LDL-C) and glucose levels are risk factors for ischemic heart disease (IHD) in middle-aged diabetic individuals; however, the risk among the elderly, especially the very elderly, is not well known. The aim of this study was to identify factors that predict IHD and cerebrovascular attack (CVA) in the elderly and to investigate their differences by age.
We performed a prospective cohort study (Japan Cholesterol and Diabetes Mellitus Study) with 5.5 years of follow-up. A total of 4,014 patients with type 2 diabetes and without previous IHD or CVA (1,936 women; age 67.4 ± 9.5 years, median 70 years; <65 years old, n = 1,261; 65 to 74 years old, n = 1,731; and ≥ 75 years old, n = 1,016) were recruited on a consecutive outpatient basis from 40 hospitals throughout Japan. Lipids, glucose, and other factors related to IHD or CVA risk, such as blood pressure (BP), were investigated using the multivariate Cox hazard model.
One hundred fifty-three cases of IHD and 104 CVAs (7.8 and 5.7/1,000 people per year, respectively) occurred over 5.5 years. Lower HDL-cholesterol (HDL-C) and female gender were correlated with IHD in patients ≥75 years old (hazard ratio (HR):0.629, P < 0.01 and 1.132, P < 0.05, respectively). In contrast, systolic BP (SBP), HbA1C, LDL-C and non-HDL-C were correlated with IHD in subjects <65 years old (P < 0.05), and the LDL-C/HDL-C ratio was correlated with IHD in all subjects. HDL-C was correlated with CVA in patients ≥75 years old (HR: 0.536, P < 0.01). Kaplan-Meier estimator curves showed that IHD occurred more frequently in patients <65 years old in the highest quartile of the LDL-C/HDL-C ratio. In patients ≥75 years old, IHD and CVA were both the most frequent among those with the lowest HDL-C levels.
IHD and CVA in late elderly diabetic patients were predicted by HDL-C. LDL-C, HbA1C, SBP and non-HDL-C are risk factors for IHD in the non-elderly. The LDL-C/HDL-C ratio may represent the effects of both LDL-C and HDL-C. These age-dependent differences in risk are important for developing individualized strategies to prevent atherosclerotic disease.
Trial registration
UMIN-CTR, UMIN00000516
PMCID: PMC3598716  PMID: 23302697
Elderly; Diabetes mellitus; Cardiovascular diseases; HDL-C; LDL-C/HDL-C ratio
10.  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
11.  Serum Sodium and Potassium Levels in Cerebro-vascular Accident Patients 
We aim to assess serum sodium and potassium levels in patients with different types of cerebro-vascular accidents (CVA) in comparison to control group.
A comparative cross-sectional study conducted on patients admitted to the emergency department from January to August 2012. Control group consisted of patients admitted to emergency department due to common cold, urinary tract infection, low back pain, cluster, and tension headache or migraine. Serum sodium and potassium levels were measured via standard laboratory methods.
There were 77 patients in control group and 78 in CVA group. Forty nine patients from the CVA group had ischemic CVA, 11 had hemorrhagic CVA and 18 suffered a transient ischemic attack (TIA). Serum sodium level in control group was significantly lower than in patients with TIA, ischemic CVA, and hemorrhagic CVA (P < 0.001). Serum potassium level in control group was higher than patients with TIA, ischemic CVA, and hemorrhagic CVA (P < 0.001). Patients with hemorrhagic CVA showed significantly lower serum potassium level than patients with TIA and ischemic CVA (P < 0.001). Correspondingly, it was observed that serum sodium to potassium ratio was higher in patients with TIA, ischemic CVA, and hemorrhagic CVA (P < 0.001). In patients with hemorrhagic CVA serum sodium to potassium ratio was higher when compared to patients with TIA and ischemic CVA (P < 0.001).
This study shows that higher serum sodium and lower serum potassium level may be associated with higher incidence of CVA. Further studies are paramount to elucidate the role of serum electrolyte levels in vascular events.
PMCID: PMC3743980  PMID: 23966823
cerebro-vascular accident; cross-sectional studies; emergencies; sodium; potassium
12.  Navigated macular laser decreases retreatment rate for diabetic macular edema: a comparison with conventional macular laser 
The purpose of this study was to evaluate and compare clinical outcomes and retreatment rates using navigated macular laser versus conventional laser for the treatment of diabetic macular edema (DME).
In this prospective, interventional pilot study, 46 eyes from 46 consecutive patients with DME were allocated to receive macular laser photocoagulation using navigated laser. Best corrected visual acuity and retreatment rate were evaluated for up to 12 months after treatment. The control group was drawn based on chart review of 119 patients treated by conventional laser at the same institutions during the same time period. Propensity score matching was performed with Stata, based on the nearest-neighbor method.
Propensity score matching for age, gender, baseline visual acuity, and number of laser spots yielded 28 matched patients for the control group. Visual acuity after navigated macular laser improved from a mean 0.48 ± 0.37 logMAR by a mean +2.9 letters after 3 months, while the control group showed a mean −4.0 letters (P = 0.03). After 6 months, navigated laser maintained a mean visual gain of +3.3 letters, and the conventional laser group showed a slower mean increase to +1.9 letters versus baseline. Using Kaplan-Meier analysis, the laser retreatment rate showed separation of the survival curves after 2 months, with fewer retreatments in the navigated group than in the conventional laser group during the first 8 months (18% versus 31%, respectively, P = 0.02).
The short-term results of this pilot study suggest that navigated macular photocoagulation is an effective technique and could be considered as a valid alternative to conventional slit-lamp laser for DME when focal laser photocoagulation is indicated. The observed lower retreatment rates with navigated retinal laser therapy in the first 8 months suggest a more durable treatment effect.
PMCID: PMC3551463  PMID: 23345966
navigated focal laser; macular laser; Navilas®; diabetic macular edema; diabetes mellitus; diabetic retinopathy
13.  A look into Lee's score: peri-operative cardiovascular risk assessment in non-cardiac surgeries—usefulness of revised cardiac risk index 
Indian Heart Journal  2012;64(2):134-138.
The revised cardiac risk index (RCRI/Lee's score) was designed for peri-operative risk assessment before elective major non-cardiac surgeries. Through this article, we report the usefulness of RCRI in our daily practice, while evaluating patients undergoing surgeries of varying risk.
Only referred patients, aged ≥ 40 years, were included. Risk stratification was done using RCRI scoring system. Patients were categorised into 4 classes depending on 0, 1, 2, and ≥3 risk predictors (risk predictors were high-risk surgery, history of ischaemic heart disease (IHD), diabetes on insulin, history of stroke (cerebrovascular accident [CVA]), history of congestive heart failure (CHF) and serum creatinine of >2 mg%). Electrocardiograms (ECG) were done in all patients, while troponin I in intermediate and high-risk patients, and in others if symptomatic. Perioperative cardiovascular events were managed appropriately.
Of the 920 patients included, only 853 patients were analysed as 67 patients were not operated upon. The mean age was 59 ± 11years and 46% of the patients were women. Two hundred and ninety-two underwent high-risk surgeries, 97 patients had history of IHD, 89 had history of CHF, 36 gave history of CVA, 269 patients were diabetics on insulin and 68 had serum creatinine >2 mg%. Number of patients in Lee's classes I, II, III, and IV were 311, 347, 150, and 52, respectively. 26 out of 853 patients had peri-operative events. Of the six variables in RCRI, only history of IHD was an independent predictor of events. Event rates increased as the RCRI class increased, i.e. 1.7%, 2.0%, 6.7%, and 7.7% for classes I–IV, respectively. Age >70 years, poor general medical condition, emergency surgery and left bundle branch block (LBBB) on ECG, were significantly associated with peri-operative events.
The RCRI is a useful tool in pre-operative risk stratification. It should perhaps be further updated to improve its predictive accuracy.
PMCID: PMC3860848  PMID: 22572486
Non-cardiac surgeries; Peri-operative evaluation; Revised cardiac risk index
14.  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
15.  Overexpression of Hemopexin in the Diabetic Eye 
Diabetes Care  2013;36(9):2815-2821.
Hemopexin is a well-recognized permeability factor in the kidney, but its potential role in blood-retinal barrier (BRB) breakdown has not been explored. The main aims of this study were as follows: 1) to determine hemopexin expression in the retina and its content in the vitreous fluid from diabetic patients with diabetic macular edema (DME) and nondiabetic patients, 2) to evaluate the effect of hemopexin on BRB permeability, and 3) to determine whether dexamethasone prevents an eventual hemopexin-induced hyperpermeability.
Biological material included 1) retinas from 10 diabetic donors with nonproliferative retinopathy and from 10 nondiabetic donors and 2) vitreous fluid from 14 patients with DME and 14 nondiabetic patients. Hemopexin and hemopexin receptor mRNA levels were measured by quantitative RT-PCR and hemopexin concentrations by ELISA. The effect of hemopexin on permeability in culture was evaluated in human retinal pigment epithelial (ARPE)-19 cells and bovine retinal endothelial cells. The experiments were repeated in the presence of hemopexin-neutralizing antibodies and dexamethasone.
A higher expression of hemopexin was detected in the retinal pigment epithelium (RPE) from diabetic patients in comparison with nondiabetic control subjects. Intravitreal hemopexin concentration was higher in patients with DME than in nondiabetic subjects. Hemopexin significantly increased permeability in ARPE-19 cells, which was prevented by both hemopexin-neutralizing antibodies and dexamethasone.
Hemopexin is overexpressed in the RPE of diabetic patients with DME and induces the breakdown of RPE cells in vitro. Dexamethasone was able to prevent hemopexin-induced hyperpermeability. Our results suggest that hemopexin can be considered a new pathogenic candidate for DME.
PMCID: PMC3747892  PMID: 23620477
16.  Total and Differential White Blood Cell Counts Predict Eight-Year Incident Stoke in Elderly Japanese-American Men: The Honolulu Heart Program 
Previous studies have found that a higher white blood cell (WBC) count is associated with incident stroke. There have been few studies examining differential WBC counts in elderly or Asian populations. We studied the association between total and differential WBC counts and incident stroke in an older Asian population.
The Honolulu Heart Program is a prospective population-based study of cardiovascular diseases in Japanese-American men that started in 1965. At exam 4 (1991–93), 3,741 men ages 71–93 years participated, and total and differential WBC counts were measured in 3,569 men using a Coulter counter machine. Data on incident stroke (all strokes [ALL-CVA], thromboembolic [TE-CVA] and hemorrhagic [HEM-CVA]) were available through December 1999 (8 years follow-up) from a comprehensive hospital surveillance system. After excluding 227 subjects with prevalent stroke, 3,342 subjects were divided into quartiles of total WBC, neutrophil (segmented and band), granulocyte (neutrophil, eosinophil and basophil), lymphocyte, and monocyte counts for separate analyses.
Age-adjusted incident ALL-CVA rates increased significantly with total WBC quartiles (7.68, 9.04, 9.26, 14.1, per 1,000 person years follow-up, respectively, P = .0014). Relative risks for ALL-CVA for each quartile of total and differential WBC counts were obtained using Cox proportional hazards, using the lowest quartile as the reference group. After full adjustment including age, cardiovascular risk factors, fibrinogen, prevalent CHD, cancer or COPD, and aspirin/NSAID use, the relative risks in the highest quartiles of total WBC, neutrophil, and granulocyte counts were 1.63 (95%CI = 1.05–2.54, P = .03), 2.19 (95%CI = 1.41–3.39, P < .001) and 1.91 (95%CI = 1.25–2.92, P = .003), respectively. These significant associations were also seen for TE-CVA, but not for HEM-CVA. No significant associations were found between lymphocyte or monocyte counts and incident stroke or subtypes.
In elderly Japanese-American men, higher total WBC, neutrophil, and granulocyte counts were independent predictors of overall stroke, as well as thromboembolic stroke. Further studies are needed to establish cut-points and treatment options.
PMCID: PMC4175930
17.  Randomized Trial Evaluating Short-Term Effects of Intravitreal Ranibizumab or Triamcinolone Acetonide on Macular Edema Following Focal/Grid Laser for Diabetic Macular Edema in Eyes Also Receiving Panretinal Photocoagulation 
Retina (Philadelphia, Pa.)  2011;31(6):1009-1027.
To evaluate 14-week effects of intravitreal ranibizumab or triamcinolone in eyes receiving focal/grid laser for diabetic macular edema (DME) and panretinal photocoagulation (PRP).
Three hundred and forty-five eyes with a visual acuity of 20/320 or better, center-involved DME receiving focal/grid laser, and diabetic retinopathy receiving prompt PRP were randomly assigned to sham (n=123), 0.5-mg ranibizumab (n=113) at baseline and 4 weeks, or 4-mg triamcinolone at baseline and sham at 4 weeks (n=109). Treatment was at investigator discretion from 14 to 56 weeks.
Mean changes (±standard deviation) in visual acuity letter score from baseline were significantly better in the ranibizumab (+1±11, P<0.001) and triamcinolone (+2±11, P<0.001) groups compared with the sham group (-4±14) at the 14-week visit, mirroring retinal thickening results. These differences were not maintained when study participants were followed for 56 weeks for safety outcomes. One eye (0.9%, 95% CI: 0.02% to 4.7%) developed endophthalmitis after receiving ranibizumab. Cerebrovascular/cardiovascular events occurred in 4%, 7%, and 3% of the sham, ranibizumab, and triamcinolone groups, respectively.
The addition of 1 intravitreal triamcinolone or 2 ranibizumab injections in eyes receiving focal/grid laser for DME and PRP is associated with better visual acuity and decreased macular edema by 14 weeks. Whether continued long-term intravitreal treatment is beneficial cannot be determined from this study.
PMCID: PMC3489032  PMID: 21394052
proliferative diabetic retinopathy; diabetic macular edema; panretinal photocoagulation; ranibizumab; triamcinolone; randomized clinical trial; Diabetic Retinopathy Clinical Research Network
18.  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
19.  Oral Minocycline for the Treatment of Diabetic Macular Edema (DME): Results of a Phase I/II Clinical Study 
Inflammation contributes significantly to the pathogenesis of diabetic macular edema (DME). In particular, retinal microglia demonstrate increased activation and aggregation in areas of DME. Study authors investigated the safety and potential efficacy of oral minocycline, a drug capable of inhibiting microglial activation, in the treatment of DME.
A single-center, prospective, open-label phase I/II clinical trial enrolled five participants with fovea-involving DME who received oral minocycline 100 mg twice daily for 6 months. Main outcome measurements included best-corrected visual acuity (BCVA), central retinal subfield thickness (CST), and central macular volume using spectral domain optical coherence tomography (SD-OCT) and late leakage on fluorescein angiography (FA).
Findings indicated that the study drug was well tolerated and not associated with significant safety issues. In study eyes, mean BCVA improved continuously from baseline at 1, 2, 4, and 6 months by +1.0, +4.0, +4.0, and +5.8 letters, respectively, while mean retinal thickness (CST) on OCT decreased by −2.9%, −5.7%, −13.9, and −8.1% for the same time points. At month 6, mean area of late leakage on FA decreased by −34.4% in study eyes. Mean changes in contralateral fellow eyes also demonstrated similar trends. Improvements in outcome measures were not correlated with concurrent changes in systemic factors.
In this pilot proof-of-concept study of DME, minocycline as primary treatment was associated with improved visual function, central macular edema, and vascular leakage, comparing favorably with historical controls from previous studies. Microglial inhibition with oral minocycline may be a promising therapeutic strategy targeting the inflammatory etiology of DME. ( number, NCT01120899.)
A pilot phase I/II, proof-of-concept clinical trial investigating the effect of oral minocycline, a microglial inhibitor, for the treatment of DME demonstrates good tolerability and potential efficacy for this clinical indication. ( number, NCT01120899.)
PMCID: PMC3390218  PMID: 22589436
20.  Analysis of Morphological Features and Vascular Layers of Choroid in Diabetic Retinopathy Using Spectral-Domain Optical Coherence Tomography 
JAMA ophthalmology  2013;131(10):1267-1274.
Diabetic retinopathy (DR) is characterized by microaneurysms, capillary nonperfusion, and ischemia within the retina, ultimately leading to neovascularization and/or macular edema. Evidence suggests that choroidal angiopathy may coexist with retinal vascular damage. Recent advances in spectral-domain optical coherence tomography (SD-OCT) permit an efficient visualization of the choroid.
To analyze the morphological features and vascular layers of the choroid in patients with DR using SD-OCT.
A cross-sectional retrospective review identified patients with DR and healthy (control) subjects who underwent 1-line raster scanning from February 1, 2010, through June 30, 2012. Patients were classified into the following 3 groups: nonproliferative DR without macular edema (9 eyes), proliferative DR without macular edema (PDR) (10 eyes), and diabetic macular edema (DME) (14 eyes). Two independent raters experienced in analyzing OCT images evaluated the morphological features and vasculature of the choroid.
New England Eye Center.
Thirty-three eyes of 33 patients with DR and 24 eyes of 24 controls.
Diabetic retinopathy.
Main outcome and measure
Choroidal morphological features and vasculature analysis.
The choroidoscleral interface had an irregular contour in 8 of 9 eyes with nonproliferative DR (89%), 9 of 10 eyes with PDR (90%), and 13 of 14 eyes with DME (93%) compared with 0 of 24 controls. The thickest point of the choroid was displaced from under the fovea, and focal choroidal thinning was observed in eyes with DR. Mean subfoveal choroidal thickness and mean subfoveal medium choroidal vessel layer and choriocapillaris layer thickness were significantly reduced in eyes with PDR (P < .05) and DME (P < .05) compared with controls.
Conclusions and relevance
Choroidal morphological features are altered in patients with moderate to severe DR. The subfoveal choroidal thickness and the subfoveal medium choroidal vessel layer and choriocapillaris layer thicknesses are significantly reduced in patients with PDR and DME. To our knowledge, this is the first study to analyze the morphological features and vasculature of the choroid in DR using SD-OCT. These findings may be clinically useful in predicting the progression of DR.
PMCID: PMC4045010  PMID: 23907153
21.  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
22.  Current status in diabetic macular edema treatments 
World Journal of Diabetes  2013;4(5):165-169.
Diabetes is a serious chronic condition, which increase the risk of cardiovascular diseases, kidney failure and nerve damage leading to amputation. Furthermore the ocular complications include diabetic macular edema, is the leading cause of blindness among adults in the industrialized countries. Today, blindness from diabetic macular edema is largely preventable with timely detection and appropriate interventional therapy. The treatment should include an optimized control of glycemia, arterial tension, lipids and renal status. The photocoagulation laser is currently restricted to focal macular edema in some countries, but due the high cost of intravitreal drugs, the use of laser treatment for focal and diffuse diabetic macular edema (DME), can be valid as gold standard in many countries. The intravitreal anti vascular endothelial growth factor drugs (ranibizumab and bevacizumab), are indicated in the treatment of all types of DME, but the correct protocol for administration should be defined for the different Retina Scientific Societies. The corticosteroids for diffuse DME, has a place in pseudophakic patients, but its complications restricted the use of these drugs for some patients. Finally the intravitreal interface plays an important role and its exploration is mandatory in all DME patients.
PMCID: PMC3797881  PMID: 24147200
Diabetic macular edema; Diabetic retinopathy; Laser, Anti-vascular endothelial growth factor drugs; Intravitreal dexamethasone; Triamcinolone; Vitrectomy
23.  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
24.  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
25.  A Three-year Follow-up of Intravitreal Triamcinolone Acetonide Injection and Macular Laser Photocoagulation for Diffuse Diabetic Macular Edema 
To report the three-year outcomes of macular laser photocoagulation following intravitreal injection of triamcinolone acetonide (IVTA) for diffuse diabetic macular edema (DME).
A prospective, randomized controlled study was completed. Eighty-six eyes of 74 patients with diffuse DME were randomized into two groups. Eyes assigned to the combination group (n = 48) were subjected to macular laser photocoagulation three weeks after IVTA. Eyes in the IVTA group (n = 38) underwent IVTA alone. Central macular thickness was measured by optical coherence tomography, and the number of additional treatments and mean time to recurrence were assessed.
Thirty-seven eyes in the combination group and 26 eyes in the IVTA group completed the three-year follow-up. Recurrence of DME after initial treatment was not observed for nine of the 37 (24.3%) eyes in the combination group or for one of the 26 (3.9$) eyes in the IVTA group (p = 0.028). DME was absent for 19.9 months after treatment in the combination group compared to 10.3 months in the IVTA group (p = 0.027). The mean number of additional treatments was 0.92 in the combination group and 1.88 in the IVTA group (p = 0.001).
Results in the subset of subjects who completed the three-year follow-up demonstrated that laser photocoagulation following IVTA is more effective than IVTA monotherapy for diffuse DME. Combination therapy required fewer additional treatments and resulted in a lower recurrence rate than IVTA monotherapy.
PMCID: PMC3464320  PMID: 23060723
Diabetic retinopathy; Intravitreal injections; Laser therapy; Macular edema; Triamcinolone

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