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1.  Optical Coherence Tomography for Age-Related Macular Degeneration and Diabetic Macular Edema 
Executive Summary
Objective
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.
Methods
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.  Association Between Diabetic Macular Edema and Cardiovascular Events in Type 2 Diabetes Patients 
Medicine  2015;94(33):e1220.
Abstract
Diabetic macular edema (DME) is the main cause of visual loss associated with diabetes but any association between DME and cardiovascular events is unclear.
This study aims to describe the possible association between DME and cardiovascular events in a multicenter cross-sectional study of patients with type 2 diabetes.
Two thousand eight hundred seven patients with type 2 diabetes were recruited from diabetes and nephrology clinical institutional centers participating in the DIAB 2 NEPHROGENE study focusing on diabetic complications. DME (presence/absence) and diabetic retinopathy (DR) classification were based on ophthalmological report and/or on 30° color retinal photographs. DR was defined as absent, nonproliferative (background, moderate, or severe) or proliferative. Cardiovascular events were stroke, myocardial infarction, and lower limb amputation.
Details regarding associations between DME and cardiovascular events were evaluated.
The study included 2807 patients with type 2 diabetes, of whom 355 (12.6%) had DME. DME was significantly and independently associated with patient age, known duration of diabetes, HbA1c, systolic blood pressure, and DR stage. Only the prior history of lower limb amputation was strongly associated with DME in univariate and multivariate analyses, whereas no association was found with regard to myocardial infarction or stroke. Moreover, both major (n = 32) and minor lower limb (n = 96) amputations were similarly associated with DME, with respective odds ratio of 3.7 (95% confidence interval [CI], 1.77–7.74; P = 0.0012) and of 4.29 (95% CI, 2.79–6.61; P < 0.001).
DME is strongly and independently associated with lower limb amputation in type 2 diabetic patients.
doi:10.1097/MD.0000000000001220
PMCID: PMC4616429  PMID: 26287408
3.  Comorbidity and health care visit burden in working-age commercially insured patients with diabetic macular edema 
Purpose
To examine the comorbidity profile and update estimates of health care resource utilization for commercially insured, working-age adults with diabetic macular edema (DME) relative to a matched comparison group of diabetic adults without DME. Additional comparisons were made in the subgroup of pseudophakic patients.
Patients and methods
A retrospective matched-cohort study of commercially insured diabetic adults aged 18–63 years was conducted using medical and outpatient pharmacy claims (July 1, 2008–June 30, 2013). Outcomes included diabetes-related and ocular comorbidities and health care resource utilization (any health care visit days, outpatient visit days, inpatient visit days, emergency room visits, eye care-related visit days, unique medications) in the 12-month post-index period.
Results
All diabetes-related and ocular comorbidities were significantly more prevalent in DME cases versus non-DME controls (P<0.05). A significantly greater proportion of DME cases utilized eye care-related visits compared with non-DME controls (P<0.001). DME cases had almost twice the mean number of total health care visit days compared to non-DME controls (28.6 vs 16.9 days, P<0.001), with a minority of visit days being eye care-related (mean 5.1 vs 1.5 days, P<0.001). Similar trends were observed in pseudophakic cohorts.
Conclusion
This working-age DME population experienced a mean of 29 health care visit days per year. Eye care-related visit days were a minority of the overall visit burden (mean 5 days) emphasizing the trade-offs DME patients face between managing DME and their overall diabetic disease. Insights into the complex comorbidity profile and health care needs of diabetic patients with DME will better inform treatment decisions and help optimize disease management.
doi:10.2147/OPTH.S114006
PMCID: PMC5153291  PMID: 27994438
health care resource utilization; diabetes; real-world evidence; pseudophakic; retinal disease
4.  Resource Use and Costs Associated With Diabetic Macular Edema in Elderly Persons 
Archives of ophthalmology  2008;126(12):1748-1754.
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1001/archopht.126.12.1748
PMCID: PMC2630411  PMID: 19064859
5.  Risk for Cardiovascular Disease Early and Late After a Diagnosis of Giant-Cell Arteritis 
Annals of internal medicine  2014;160(2):73-80.
Background
Involvement of large arteries is well-documented in giant-cell arteritis (GCA), but the risk for cardiovascular events is not well-understood.
Objective
To evaluate the risks for incident myocardial infarction (MI), cerebrovascular accident (CVA), and peripheral vascular disease (PVD) in individuals with incident GCA in a general population context.
Design
Observational cohort study.
Setting
U.K. primary care database.
Patients
3408 patients with incident GCA and 17 027 age- and sex-matched reference participants without baseline cardiovascular disease (MI, CVA, or PVD).
Measurements
Diagnoses of GCA, outcomes, and cardiovascular risk factors were identified from electronic medical records. One combined and 3 separate cohort analyses were conducted for the outcomes of MI, CVA, and PVD. The association of GCA with study outcomes is expressed with hazard ratios (HRs) with 95% CIs after adjustment for potential cardiovascular risk factors.
Results
Among 3408 patients with GCA (73% female; mean age, 73 years), the incidence rates of MI, CVA, and PVD were 10.0, 8.0, and 4.2 events per 1000 person-years, respectively, versus 4.9, 6.3, and 2.0 events per 1000 person-years, respectively, among reference participants. The HRs were 1.70 (95% CI, 1.51 to 1.91) for the combined outcome, 2.06 (CI, 1.72 to 2.46) for MI, 1.28 (CI, 1.06 to 1.54) for CVA, and 2.13 (CI, 1.61 to 2.81) for PVD. The HRs were more pronounced in the first month after GCA diagnosis (combined HR, 4.92 [CI, 2.59 to 9.34]; HR for MI, 11.89 [CI, 2.40 to 59.00]; HR for CVA, 3.93 [CI, 1.76 to 8.79]; HR for PVD, 3.86 [CI, 0.78 to 19.17]).
Limitation
Information on temporal arterial biopsies was not available, and there was a substantial amount of missing data on cardiovascular risk factors.
Conclusion
Giant-cell arteritis is associated with increased risks for MI, CVA, and PVD.
Primary Funding Source
National Institute of Arthritis and Musculoskeletal and Skin Diseases.
PMCID: PMC4381428  PMID: 24592492
6.  Temporal Trends in Percutaneous Coronary Intervention Associated Acute Cerebrovascular Accident (From the 1998–2008 Nationwide Inpatient Sample [NIS] Database) 
The American journal of cardiology  2014;114(2):206-213.
Acute cerebrovascular accident (CVA) after percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) and coronary artery disease (CAD) is associated with high morbidity and mortality. Nationwide Inpatient Sample from 1998 to 2008 was utilized to identify 1,552,602 PCIs performed for ACS and CAD. We assessed temporal trends in the incidence, predictors and prognostic impact of CVA in a broad range of patients undergoing PCI. The overall incidence of CVA was 0.56% (95% confidence interval (CI), 0.55%–0.57%). The incidence of CVA remained unchanged over the study period (adjusted p for trend = 0.2271). The overall mortality in the CVA group was 10.76% (95% CI, 10.1%–11.4%). The adjusted odds ratio (OR) of CVA for in-hospital mortality was 7.74 (95% CI, 7.00–8.57; p<0.0001); this remained high but decreased over the study period (adjusted p for trend <0.0001). Independent predictors of CVA included older age (OR, 1.03, 95% CI, 1.02–1.03; p<0.0001), disorder of lipid metabolism (OR, 1.31, 95% CI, 1.24–1.38; p<0.001), history of tobacco use (OR, 1.21, 95% CI, 1.10–1.34; p=0.0002), coronary atherosclerosis (OR 1.56, 95% CI, 1.43–1.71; p<0.0001), and IABP use (OR 1.39, 95% CI, 1.09–1.77; p=0.0073). A nomogram for predicting the probability of CVA achieved a concordance index of 0.73 and was well calibrated. In conclusion, the incidence of CVA associated with PCI has remained unchanged from 1998–2008 in face of improved equipment, techniques and adjunctive pharmacology. The risk of CVA associated in-hospital mortality is high; however, this risk has declined over the study period.
doi:10.1016/j.amjcard.2014.04.044
PMCID: PMC4089901  PMID: 24952927
Acute Cerebral Hemorrhage; Acute Cerebral Infarction; Percutaneous Coronary Intervention
7.  Age, gender, insulin and blood glucose control status alter the risk of ischemic heart disease and stroke among elderly diabetic patients 
Background
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.
Conclusions
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; http://www.umin.ac.jp/ctr/index.htm).
doi:10.1186/1475-2840-10-86
PMCID: PMC3200162  PMID: 21978180
Elderly; Diabetes mellitus; Insulin; Cerebral ischemia; Ischemic heart disease
8.  Green-light fundus autofluorescence in diabetic macular edema 
AIM
To evaluate the role of central green-light fundus autofluorescence (FAF) in diabetic macular edema (DME).
METHODS
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.
RESULTS
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.
CONCLUSION
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.
doi:10.3980/j.issn.2222-3959.2013.01.16
PMCID: PMC3580255  PMID: 23549658
diabetic macular edema; fundus autofluorescence; optical coherence tomography
9.  Coronary Artery Calcium and Incident Cerebrovascular Events in an Asymptomatic Multi Ethnic Cohort. MESA 
JACC. Cardiovascular imaging  2014;7(11):1108-1115.
Objective
We assessed the predictive value of coronary artery calcium (CAC) score for CVA events in an asymptomatic multi-ethnic cohort.
Background
The coronary artery calcium (CAC) score, a measure of atherosclerotic burden, has been shown to improve prediction of coronary heart disease events. However, the predictive value of CAC for cerebrovascular (CVA) events is unclear.
Methods
CAC was measured at baseline exam of participants (N=6779) of the Multi Ethnic Study of atherosclerosis (MESA) and then followed for an average of 9.5(2.4) years for the diagnosis of incident CVA defined as all strokes or TIAs.
Results
During the follow up 234(3.5%) adjudicated CVA events occurred. In Kaplan Meier analysis the presence of CAC was associated with a lower CVA event - free survival versus CAC absent (Log rank χ2 = 59.8, p<0.0001). Log transformed CAC was associated with increased risk for CVA after adjusting for age, gender, race/ethnicity, BMI, systolic and diastolic blood pressure, total cholesterol, HDL-C, cigarette smoking status, blood pressure medication use, statin use and interim atrial fibrillation[hazard ratio(95% CI): 1.13(1.07 – 1.20),p<0.0001]. The ACC/AHA recommended CAC cut off was also an independent predictor of CVA and strokes [HR (95%CI): 1.70(1.24–2.35),p=0.001 and 1.59(1.11–2.27), p=0.01 respectively]. CAC was an independent predictor of CVA when analysis was stratified by gender or race/ethnicity, and improved discrimination for CVA when added to the full model (c statistic: 0.744 vs. 0.755). CAC also improved the discriminative ability of the Framingham stroke risk score for CVA.
Conclusion
CAC is an independent predictor of CVA events, and improves the discrimination afforded by current stroke risk factors or the Framingham stroke risk score for incident CVA in an initially asymptomatic multi-ethnic adult cohort.
doi:10.1016/j.jcmg.2014.07.009
PMCID: PMC4254694  PMID: 25459592
Coronary artery calcium score; cerebrovascular disease; risk prediction; prevention
10.  Safety and Feasibility of Quantitative Multiplexed Cytokine Analysis From Office-Based Vitreous Aspiration 
Purpose
The goals of this study were to evaluate the safety of office-based vitreous sampling, and determine the utility of these samples with multiplex cytokine analysis.
Methods
Vitreous samples were collected from office-based needle aspiration and the rate of adverse events during follow-up was reviewed. The vitreous cytokine concentrations in a subset of patients with diabetic macular edema (DME) were analyzed using a 42 plex-cytokine bead array. These results were compared with vitreous cytokine concentrations in proliferative diabetic retinopathy (PDR) and controls (macular hole, epiretinal membrane, symptomatic vitreous floaters) from pars plana vitrectomy.
Results
An adequate volume of vitreous fluid (100–200 μL) was obtained in 52 (88%) of 59 office-based sampling attempts. The average length of follow-up was 300 days (range, 42–926 days). There were no complications, including cataract, retinal tear or detachment, and endophthalmitis. Two patients (3%) had posterior vitreous detachments within 3 months. Vitreous cytokine concentrations were measured in 44 patients: 14 controls, 13 with DME, and 17 with PDR. The concentration of ADAM11, CXCL-10, IL-8, and PDGF-A were higher in PDR compared with controls and DME. The concentration of IL-6 was higher in PDR compared with controls, but not compared with DME.
Conclusions
Office-based vitreous aspiration is safe and yields high-quality samples for multiplex vitreous cytokine analysis. Significant elevations of vitreous cytokines were found in PDR compared with DME and controls, including the novel finding of elevated ADAM11. As such, office-based aspiration is a safe and effective means to identify vitreous factors associated with vitreoretinal disease.
doi:10.1167/iovs.15-18721
PMCID: PMC4904801  PMID: 27273720
vitreous humor; cytokine; diabetic retinopathy; growth factors
11.  Lack of Correlation Between Diabetic Macular Edema and Thickness of the Peripapillary Retinal Nerve Fibre Layer 
Introduction:
We compared the thickness of the peripapillary retinal nerve fiber layer (RNFL) in patients with diabetic macular edema (DME) and/against the thickness in the normal population.
Methods:
This cross-sectional study compared the RNFL thickness in patients with DME (DME group) using optical coherence tomography (OCT) to a comparable group of healthy (nondiabetic) patients (control group). Measurements were performed in different/the four peripapillary quadrants and in the macula region for the fovea, parafoveal, and perifoveal areas. The mean RNFL thickness was compared between both groups.
Results:
There were fifty eyes of fifty nonglaucomatous diabetic patients with DME (29 with nonproliferative diabetic retinopathy [PDR] and 21 with PDR), and fifty eyes in the control group. The macular regions were significantly thicker in the DME group compared to the control group. The central foveal thickness was 149 μ thicker in eyes with DME compared to the control group (P < 0.001). The difference in total RNFL thickness between groups was not significant (4.4 μ [95% confidence interval: −3.1 to +12]). The between-group differences in peripapillary RNFL thickness by age group, glycemic control, history of intravitreal treatments, and refractive errors were not statistically significant (P > 0.05, all comparisons).
Conclusion:
Peripapillary RNFL thickness measurements were not significantly influenced by DME. Hence, OCT parameters could be used to monitor/early detect glaucomatous eyes even in the presence of DME.
doi:10.4103/0974-9233.186097
PMCID: PMC4968144  PMID: 27555707
Diabetes; Diabetic Macular Edema; Glaucoma; Optical Coherence Tomography; Retinal Layer Thickness
12.  Using Patient-Level Data to Develop Meaningful Cross-Trial Comparisons of Visual Impairment in Individuals with Diabetic Macular Edema 
Advances in Therapy  2016;33:597-609.
Introduction
The aim of this study was to assess the impact of baseline characteristics on visual outcome of patients with diabetic macular edema and compare the results of clinical trials with different patient populations.
Methods
A model was created with patient-level data from the RESPOND/RESTORE trials to estimate the impact of baseline characteristics on increases in best-corrected visual acuity (BCVA) with anti-vascular endothelial growth factor therapies, measured by letters gained on the Early Treatment Diabetic Retinopathy Study scale from baseline to month 12. Mean BCVA gains with ranibizumab 0.5 mg pro re nata or laser photocoagulation monotherapy were predicted, assuming baseline characteristics equivalent to those in the VIVID-DME/VISTA-DME trials. These results were compared with the gain with aflibercept 2.0 mg every 8 weeks in VIVID-DME/VISTA-DME. Sensitivity analyses assessed outcome robustness.
Results
Baseline BCVA and central retinal thickness differed significantly between trials. In unadjusted data, patients in RESPOND/RESTORE receiving ranibizumab gained an additional 6.6 letters [95% confidence interval (CI): 4.5–8.7] compared with patients receiving laser monotherapy. After adjusting data to assume baseline characteristics equivalent to VIVID-DME/VISTA-DME, patients receiving ranibizumab were predicted to gain an additional 9.9 letters (95% CI: 7.3–12.4) compared with those receiving laser monotherapy. These results were similar (0.1-letter difference in favor of aflibercept; 95% CI: −2.9 to 3.2; P = 0.94) to the gain in BCVA in patients receiving aflibercept in VIVID-DME/VISTA-DME compared with those receiving laser monotherapy (10.0 letters, 95% CI: 8.3–11.7).
Conclusion
After adjusting for baseline characteristics, the difference in letters gained between patients receiving ranibizumab versus aflibercept was non-significant across trials, highlighting the importance of adjusting for baseline characteristics in future comparisons.
Funding
Novartis Pharma AG.
Electronic supplementary material
The online version of this article (doi:10.1007/s12325-016-0310-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s12325-016-0310-0
PMCID: PMC4846684  PMID: 26951552
Aflibercept; Diabetic macular edema; Ophthalmology; Ranibizumab; Vascular endothelial growth factor
13.  Clinical utilization of anti-vascular endothelial growth-factor agents and patient monitoring in retinal vein occlusion and diabetic macular edema 
Purpose
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.
Results
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).
Conclusion
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.
doi:10.2147/OPTH.S60893
PMCID: PMC4155807  PMID: 25210429
anti-vascular endothelial growth factor; bevacizumab; ranibizumab; diabetic macular edema; retinal vein occlusion; intravitreal
14.  Choroidal thickness in patients with diabetic retinopathy 
Purpose
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.
Results
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).
Conclusion
Diabetes changes the CT. CT was found to be significantly decreased in the DME and PDR groups.
doi:10.2147/OPTH.S59395
PMCID: PMC3971934  PMID: 24707168
choroidal thickness; diabetic retinopathy; optical coherence tomography
15.  Dexamethasone intravitreal implant in previously treated patients with diabetic macular edema: subgroup analysis of the MEAD study 
BMC Ophthalmology  2015;15:150.
Background
Dexamethasone intravitreal implant 0.7 mg (DEX 0.7) was approved for treatment of diabetic macular edema (DME) after demonstration of its efficacy and safety in the MEAD registration trials. We performed subgroup analysis of MEAD study results to evaluate the efficacy and safety of DEX 0.7 treatment in patients with previously treated DME.
Methods
Three-year, randomized, sham-controlled phase 3 study in patients with DME, best-corrected visual acuity (BCVA) of 34–68 Early Treatment Diabetic Retinopathy Study letters (20/200–20/50 Snellen equivalent), and central retinal thickness (CRT) ≥300 μm measured by time-domain optical coherence tomography. Patients were randomized to 1 of 2 doses of DEX (0.7 mg or 0.35 mg), or to sham procedure, with retreatment no more than every 6 months. The primary endpoint was ≥15-letter gain in BCVA at study end. Average change in BCVA and CRT from baseline during the study (area-under-the-curve approach) and adverse events were also evaluated. The present subgroup analysis evaluated outcomes in patients randomized to DEX 0.7 (marketed dose) or sham based on prior treatment for DME at study entry.
Results
Baseline characteristics of previously treated DEX 0.7 (n = 247) and sham (n = 261) patients were similar. In the previously treated subgroup, mean number of treatments over 3 years was 4.1 for DEX 0.7 and 3.2 for sham, 21.5 % of DEX 0.7 patients versus 11.1 % of sham had ≥15-letter BCVA gain from baseline at study end (P = 0.002), mean average BCVA change from baseline was +3.2 letters with DEX 0.7 versus +1.5 letters with sham (P = 0.024), and mean average CRT change from baseline was −126.1 μm with DEX 0.7 versus −39.0 μm with sham (P < 0.001). Cataract-related adverse events were reported in 70.3 % of baseline phakic patients in the previously treated DEX 0.7 subgroup; vision gains were restored following cataract surgery.
Conclusions
DEX 0.7 significantly improved visual and anatomic outcomes in patients with DME previously treated with laser, intravitreal anti-vascular endothelial growth factor, intravitreal triamcinolone acetonide, or a combination of these therapies. The safety profile of DEX 0.7 in previously treated patients was similar to its safety profile in the total study population.
Trial registration
ClinicalTrials.gov NCT00168337 and NCT00168389, registered 12 September 2005
doi:10.1186/s12886-015-0148-2
PMCID: PMC4628378  PMID: 26519345
Corticosteroid; Dexamethasone; Diabetic retinopathy; Drug delivery; Implant; Macular edema
16.  Intravitreal steroids for macular edema in diabetes 
Background
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.
Objectives
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.
doi:10.1002/14651858.CD005656.pub2
PMCID: PMC3804331  PMID: 18254088
17.  Patient Characteristics and Comorbidities Associated With Cerebrovascular Accident following Acute Myocardial Infarction in the United States 
International journal of cardiology  2014;175(2):323-327.
Background
Although cerebrovascular accident (CVA) is a relatively infrequent complication of acute myocardial infarction (AMI), the occurrence of CVA in patients with AMI is associated with increased morbidity and mortality. We wanted to assess post-AMI CVA rate in the United States and identify associated patient characteristics, comorbidities, type of AMI, and utilization of invasive procedures.
Methods
This is an observational study from the Nationwide Inpatient Sample, 2006–2008. Using multivariate regression models, we assessed predictive risk factors for post-AMI CVA among patients admitted for AMI.
Results
Among the 1,924,413 patients admitted for AMI, the overall rate of CVA was 2% (Ischemic stroke: 1.47%, transient ischemic attack [TIA]: 0.35% and hemorrhagic stroke: 0.21%). In this sample of AMI patient, higher incidence of CVA was associated with: CHF (Adjusted odds ratio [AOR] 1.71; 95% confidence interval [CI], 1.58–1.84,), age over 65 AOR, 1.65; 95% CI, 1.60–1.70, alcohol abuse AOR, 1.60; 95% CI, 1.49–1.73, cocaine use AOR, 1.48; 95% CI, 1.29–1.70, atrial fibrillation AOR, 1.43; 95% CI, 1.39–1.46, Black race AOR, 1.35; 95% CI, 1.30–1.40, female gender AOR, 1.32; 95% CI, 1.29–1.35, peripheral vascular disease [PVD] AOR, 1.26; 95% CI, 1.22–1.30, coronary artery bypass graft (CABG) AOR, 1.22; 95% CI, 1.17–1.27, P <0.0001, STEMI AOR, 1.17; 95% CI, 1.14–1.20 and teaching hospitals AOR, 1.09; 95% CI, 1.06–1.12.
Conclusion
Female gender, older age (age ≥ 65), black ethnicity, comorbidities including CHF, PVD, atrial fibrillation as well as STEMI and undergoing CABG were associated with the highest risk of CVA post- AMI.
doi:10.1016/j.ijcard.2014.05.024
PMCID: PMC4121439  PMID: 24874908
Cerebrovascular Accident; Transient Ischemic Attack; Stroke; Acute Myocardial Infarction
18.  Association between Sickle Cell Trait and the Prevalence and Severity of Diabetic Retinopathy 
PLoS ONE  2016;11(7):e0159215.
Purpose
To determine whether Sickle cell trait (SCT) is associated with an increased severity of diabetic retinopathy.
Methods
This was a single center retrospective study case control study of 100 eyes of 100 patients with diabetes mellitus (DM) with SCT (SCT group) and 100 eyes of 100 age-matched patients with DM without SCT (control group). The main outcome measure was the difference in the prevalence of sight threatening DR [here defined as diabetic macular edema (DME) and/or proliferative diabetic retinopathy (PDR)], between the SCT and control groups. Secondary outcome measures included differences in visual acuity, ocular comorbidities, intraocular pressure, glycemic control as assessed by random blood glucose measurement, diabetes duration, nephropathy, hyperlipidemia and hypertension.
Results
The SCT group had statistically significantly shorter duration of DM (median [25% quartile] 15 [8.3] years versus 20 [14.7] years, respectively)(P<0.001) and presented with statistically better metabolic control (mean difference 1.6 mmol/l, (95% confidence interval [CI], 0.1–3.3;P = 0.03). The prevalence of PDR and/or DME was significantly lower in the SCT group (58%) compared to the control group, (95%)(P<0.001). The absence of SCT (adjusted odds ratio [AOR] = 24; 95% CI, 8–72; P<0.001) and longer duration of DM (AOR = 1.1 [95% CI, 1.02–1.13]; P = 0.003) were independent predictors of PDR and/or DME.
Conclusions
SCT seems to protect against the development and progression of DR. This may have implications for monitoring and screening. Prospective studies are required to confirm this association. If true, this association may indicate an increased blood glucose buffering capacity of abnormal hemoglobin.
doi:10.1371/journal.pone.0159215
PMCID: PMC4944991  PMID: 27414024
19.  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) 
Purpose:
To estimate the short-term variability of macular thickness in eyes with refractory and regressed diabetic macular edema (DME).
Methods:
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.
Results:
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.
Conclusions:
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
20.  Metabolic predictors of ischemic heart disease and cerebrovascular attack in elderly diabetic individuals: difference in risk by age 
Background
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.
Methods
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.
Results
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.
Conclusions
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
doi:10.1186/1475-2840-12-10
PMCID: PMC3598716  PMID: 23302697
Elderly; Diabetes mellitus; Cardiovascular diseases; HDL-C; LDL-C/HDL-C ratio
21.  Serum Sodium and Potassium Levels in Cerebro-vascular Accident Patients 
Background:
We aim to assess serum sodium and potassium levels in patients with different types of cerebro-vascular accidents (CVA) in comparison to control group.
Methods:
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.
Results:
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).
Conclusion:
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
22.  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.
doi:10.1177/2042018813512360
PMCID: PMC3855829  PMID: 24324855
diabetic macular edema; diabetic retinopathy; intravitreal anti-VEGF therapy; vascular endothelial growth factor A
23.  Matrix Metalloproteinase-1 and Matrix Metalloproteinase-9 in the Aqueous Humor of Diabetic Macular Edema Patients 
PLoS ONE  2016;11(7):e0159720.
Purpose
To assess the concentrations of matrix metalloproteinase (MMP)-1 and MMP-9 in the aqueous humor of diabetic macular edema (DME) patients.
Method
The concentrations of MMP-1 and MMP-9 in the aqueous humors of 15 cataract patients and 25 DME patients were compared. DME patients were analyzed according to the diabetic retinopathy (DR) stage, diabetes mellitus (DM) duration, pan-retinal photocoagulation (PRP) treatment, recurrence within 3 months, HbA1C (glycated hemoglobin) level, and axial length.
Results
The concentrations of MMP-1 and MMP-9 of the DME groups were higher than those of the control group (p = 0.005 and p = 0.002, respectively). There was a significant difference in MMP-1 concentration between the mild non-proliferative diabetic retinopathy (NPDR) group and the proliferative diabetic retinopathy (PDR) group (p = 0.012). MMP-1 concentrations were elevated in PRP-treated patients (p = 0.005). There was a significant difference in MMP-9 concentrations between the mild NPDR group and the PDR group (p < 0.001), and between the moderate and severe NPDR group and the PDR group (p < 0.001). The MMP-9 concentrations in PRP treated patients, DM patients with diabetes ≥ 10 years and recurrent DME within 3months were elevated (p = 0.023, p = 0.011, and p = 0.027, respectively). In correlation analyses, the MMP-1 level showed a significant correlation with age (r = -0.48, p = 0.01,), and the MMP-9 level showed significant correlations with axial length (r = -0.59, p < 0.01) and DM duration (r = 049, p = 0.01).
Conclusions
Concentrations of MMP-1 and MMP-9 were higher in the DME groups than in the control group. MMP-9 concentrations also differed depending on DR staging, DM duration, PRP treatment, and degree of axial myopia. MMP-9 may be more important than MMP-1 in the induction of DM complications in eyes.
doi:10.1371/journal.pone.0159720
PMCID: PMC4965102  PMID: 27467659
24.  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.
Objective
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.
Methods
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.
Results
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.
Conclusion
The RCRI is a useful tool in pre-operative risk stratification. It should perhaps be further updated to improve its predictive accuracy.
doi:10.1016/S0019-4832(12)60047-9
PMCID: PMC3860848  PMID: 22572486
Non-cardiac surgeries; Peri-operative evaluation; Revised cardiac risk index
25.  Navigated macular laser decreases retreatment rate for diabetic macular edema: a comparison with conventional macular laser 
Background
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).
Methods
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.
Results
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).
Conclusion
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.
doi:10.2147/OPTH.S38559
PMCID: PMC3551463  PMID: 23345966
navigated focal laser; macular laser; Navilas®; diabetic macular edema; diabetes mellitus; diabetic retinopathy

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