Severe Proliferative Diabetic Retinopathy Research Articles

Aqueous Levels of Angiopoietin-like 4 and Semaphorin 3E Correlate with Nonperfusion Area and Macular Volume in Diabetic Retinopathy

To investigate the aqueous levels of angiopoietin-like 4 (ANGPTL4), semaphorin 3E (Sema3E), and vascular endothelial growth factor (VEGF) in patients with diabetic retinopathy and to ascertain their association with diabetic retinopathy phenotypes. Prospective, nonrandomized, comparative case series. Of all 104 consecutive patients (104 eyes) who had intravitreal anti-VEGF injections from April 2012 through April 2013 for diabetic macular edema (DME), 51 had severe nonproliferative diabetic retinopathy (NPDR) and 53 had proliferative diabetic retinopathy (PDR). The controls were 54 consecutive nondiabetic patients who had undergone cataract surgery (54 eyes) during the same period. The ANGPTL4, Sema3E, and VEGF levels in aqueous humor samples obtained before intravitreal injections were measured by enzyme-linked immunosorbent assay. Capillary nonperfusion area (NPA) was calculated from encircled angiography using the 7 standard field images described in the Early Treatment Diabetic Retinopathy Study protocol. Total macular volume (TMV) was measured by spectral-domain optical coherence tomography. Aqueous ANGPTL4, Sema3E, and VEGF levels in severe NPDR, PDR, and control groups and their correlations with each other, NPA, and TMV. The severe NPDR and PDR groups had higher aqueous levels of ANGPTL4 and VEGF than the control group (all P < 0.001). The PDR group had higher ANGPTL4 and VEGF levels than the severe NPDR group (both P < 0.001). The aqueous ANGPTL4 levels of all diabetic retinopathy patients correlated positively with NPA (r = 0.820, P = 0.003) and TMV (r = 0.824, P < 0.001). The control group had higher aqueous Sema3E levels than the NPDR and PDR groups (both P < 0.001). Aqueous Sema3E levels correlated negatively with VEGF levels in all subjects (r = -0.57, P = 0.025). The ANGPTL4 may be a candidate target in DME treatment and a biomarker of ischemic-induced retinopathy, including diabetic retinopathy.

A genetic variant regulating miR-126 is associated with sight threatening diabetic retinopathy.

The regulation of miR-126 by rs4636297 single nucleotide polymorphism (SNP) has been implicated in the pathogenesis of neovascularisation by promoting vascular endothelial growth factor, suggesting it could be associated with sight threatening diabetic retinopathy (STDR), but has not been previously investigated or reported. A case control study of 531 individuals with diabetes was genotyped for the rs4636297 SNP, using the Sequenom iPLEX Gold chemistry. STDR included people with severe non-proliferative diabetic retinopathy (NPDR) or proliferative diabetic retinopathy (PDR). Association was tested using logistic regression analysis, adjusting for confounding variables. In an additive model, the A allele of rs4636297 SNP is significantly associated with STDR compared to people with none or mild diabetic retinopathy (DR) (odds ratio (OR) = 2.02, 95% confidence interval (CI) = 1.22-3.35, p = 0.006). The A allele of rs4636297, known to be the non-functional allele for post-translational regulation of miR-126, is associated with STDR. This finding suggests that this locus would be a potential therapeutic target for inhibiting the development of DR.

Effect of cataract surgery on diabetic retinopathy

Objectives The aim of this study was to review articles on the effect of cataract surgery on diabetic retinopathy (DR). Of the reviewed publications, it was found that diabetic patients with mild-to-moderate DR are less likely to show progression of DR after phacoemulsification. Patients with severe nonproliferative diabetic retinopathy and proliferative diabetic retinopathy have high risk of progression. Elevated hemoglobin A1c (HbA1c) at the time of cataract surgery increases the risk for DR progression after surgery. Conclusion Currently, early surgery is favored before the development of significant DR rather than waiting for the cataract to become denser. All efforts should be made to stabilize DR before cataract surgery.

Preoperative prognostic factors in vitrectomy for severe proliferative diabetic retinopathy

PurposeTo investigate the preoperative prognostic factors contributing to extremely poor visual outcome in cases of proliferative diabetic retinopathy after a successful vitrectomy and an uneventful postoperative course. MethodsWe enrolled 28 consecutive eyes of 28 patients with poor preoperative visual acuity (VA), who underwent primary diabetic vitrectomy. The postoperative course was uneventful, and retinal attachment was achieved for at least 6 months in all cases. The cases were separated into the study group (postoperative VA < preoperative VA) and control group (postoperative VA ≥ preoperative VA). Preoperative factors including systemic diseases, demographic data, proliferative diabetic retinopathy severity, and neovascularization status were compared between the two groups. Significant risk factors for poor visual results were determined by logistic regression analysis. ResultsThe creatinine level was significantly higher in the study group (4.07 ± 4.15 mg/dL) than in the control group (1.23 ± 0.46 mg/dL; p = 0.003). Chronic macular detachment was noted in 7/10 eyes (70%) in the study group and in 1/18 eyes (5.6%) in the control group (p = 0.001). Broad fibrovascular proliferation extending to the periphery for more than two quadrants was found in 4/10 eyes (40%) in the study group and in none of the eyes in the control group (p = 0.016). Chronic macular detachment and broad fibrovascular proliferation were significantly associated with poor visual outcome in multiple logistic regression analysis. ConclusionPreoperative chronic macular detachment, broad fibrovascular proliferation, and poor renal function may indicate worse visual results after successful diabetic vitrectomy for cases with severe diabetic retinopathy.

Combined phacoemulsification, vitrectomy and endolaser photocoagulation in patients with diabetic retinopathy and cataract.

To determine the outcomes of early vitrectomy and endolaser photocoagulation effects during phacoemulsification in cataractous eyes with diabetic retinopathy. Descriptive study. Ophthalmology Department Unit-II, DUHS, Civil Hospital, Karachi, and Al-Noor Eye Clinic, Karachi, from February 2009 to December 2010. Consecutive 54 patients with 7-15 years duration of type II diabetes with severe non-proliferative diabetic retinopathy (NPDR) and early proliferative diabetic retinopathy (PDR) who had cataract grade I and II underwent vitrectomy, endolaser photocoagulation and phacoemulsification with IOL implantation. Best corrected visual acuity was main outcomes measure assessed till 6 months follow-up. Out of 54 eyes, 32 patients were females and 22 were males. Majority 47 (87%) eyes gained significant (p<0.001) improvement of best corrected visual acuity of four lines or better while 5 (9.3%) eyes retained stable visual acuity. In only 2 eyes, vision declined to 3/60 or less. Early vitrectomy with phacoemulsification in severe NPDR and early PDR patients, if assisted or augmented with endolaser photocoagulation, maximizes, early visual rehabilitation with less morbidity and may retard progression of retinopathy.

Concentration of the inflammatory cytokines in vitreous of severe proliferative diabetic retinopathy after intravitreal ranibizumab injection

Objective To observe the concentration of the inflammatory cytokines in vitreous of severe proliferative diabetic retinopathy (PDR) after intravitreal ranibizumab injection (IVR).Methods A total of 80 PDR patients (80 eyes) were enrolled in this study.The patients were randomly divided into vitrectomy group (group A) and IVR combined with vitrectomy group (group B),40 eyes in each group.The differences of sex(x2=0.05),age (t=0.59),duration of diabetes (t=0.36),HbA1c (t=0.13) and intraocular pressure (F=0.81) between two groups were not significant (P＞0.05).The eyes in group B received 0.5 mg (0.05 ml) ranibizumab injection at 7 days before operation.The vitreous samples (0.4 ml)were obtained before operation.The concentration of vascular endothelial growth factor (VEGF),interleukin (IL)-6,IL-8,intercellular adhesion molecule-1 (ICAM-1) and connective tissue growth factor (CTGF) were measured by enzyme-linked immunosorbent assays.Results The concentration of VEGF and ICAM-1 were (10.70±3.60),(224.64±90.32) pg/L in group B and (72.38±23.59),(665.61±203.34)pg/L in group A.The differences of VEGF and ICAM-1 concentration between two groups was significant (t=16.34,12.53 ; P＜ 0.001).The concentration of IL-6 and IL-8 were (210.64 ± 80.27),(156.00±57.74) pg/L in group B and (45.78±33.82),(41.07±13.82) pg/L in group A.The differences of IL-6 and IL-8 concentration between two groups was significant (t=11.97,12.24; P＜0.001).There was no difference of CTGF concentration between two groups (t=1.39,P=0.17).The CTGF/VEGF in group B was higher than that in group A (t=14.75,P＜0.001).Conclusions One week after IVR,the concentration of VEGF and ICAM-1 are decreased,while IL-6 and IL-8 increased.There is no obvious change in CTGF,but CTGF/VEGF is increased. Key words: Diabetic retinopathy/therapy; Angiogenesis inhibitors/therapeutic use; Antibodies,monoclonal/therapeutic use; Vascular endothelial growth factors; Chemokines

Prognostic value of multifocal electroretinography and optical coherence tomography in eyes undergoing panretinal photocoagulation for diabetic retinopathy.

To investigate the prognostic utility on visual acuity of multifocal electroretinography (mfERG) and optical coherence tomography (OCT) in diabetic eyes receiving panretinal photocoagulation (PRP). Patients with severe nonproliferative diabetic retinopathy (NPDR) or early proliferative diabetic retinopathy (PDR) who needed PRP were included in this study. The mfERG and OCT data were recorded before PRP, and the final best-corrected visual acuity (BCVA) was recorded at 6 months after PRP. The correlation between pre-PRP data and post-PRP BCVA was analyzed using Pearson's correlation analysis and multivariate linear regression analysis. Among the 42 eyes included, 31 eyes (73.8%) had improvement or remained stable in visual acuity, and 11 eyes (26.2%) had deterioration in BCVA. The final BCVA was significantly correlated with the amplitude and latency of mfERG in all nine sectors, and the amplitude had a stronger correlation than latency. The foveal ellipsoid zone of the photoreceptors and external limiting membrane (ELM) status, as well as the retinal thickness in most sectors, were also correlated with the final BCVA. In a multivariate linear regression model, age, pre-PRP BCVA, amplitude of mfERG in the central sector, and foveal ellipsoid zone status were significantly correlated with the final BCVA. The retinal thickness was correlated with the amplitude or latency of mfERG in some sectors, and the correlation was tighter in temporal and inferior sectors. A lower amplitude of mfERG and disrupted foveal ellipsoid zone status were significantly correlated with a worse visual prognosis in diabetic eyes after PRP.

Incidence of macular edema following single versus 4 session pattern scanning laser panretinal photocoagulation in diabetic retinopathy

AbstractPurpose The purpose of this study was to investigate a change in macular thickness 9 months after single versus 4 sessions of panretinal photocoagulation (PRP) performed with Pattern Scanning Laser (PSL) in diabetic patients and to make a medico‐economic assessment.Methods This prospective, multicenter, randomized trial enrolled patients in 2 arms: single session PRP (group A) and 4 session PRP (group B) between October 2011 and October 2013. Patients had non proliferative severe diabetic retinopathy or proliferative non complicated diabetic retinopathy. The primary endpoint was the difference in macular central retinal thickness (CRT) using spectral domain optical coherence tomography (SD‐OCT) at 9 months. CRT with SD‐OCT, ETDRS visual acuity (VA), pain with Visual Analogic Scale (VAS), were recorded at baseline, 7 days, 1, 3, 6, and 9 months. A medico‐economic assessment was also performed.Results 26 eyes of 26 patients were included. On inclusion, the median CRT was 258 [240‐294] µm in group A and 282 [261‐292] µm in group B (p=0.06), the median VA was 84 [76‐88] letters in group A and 83 [75‐90] letters in group B (p=0.94). At M9, the median CRT was 281 [245‐322] µm in group A and 301[278‐313] µm in group B (p=0.34). At M9, the median VA was 84 [70‐91] letters in group A and 85 [74‐85] letters in group B (0.58). The median VAS value was 3.5 [2.0‐5.0] in in group A and 3.5 [1.0‐7.0] for all sessions in group B. The medico‐economic assessment was in favor of the single session protocol.Conclusion Single session PSL‐PRP seems to be a possible, well tolerated protocol for the treatment of diabetic retinopathy.

Spectral domain ocular coherence tomography finding post vitrectomy and membrane delamination for proliferative diabetic retinopathy

AbstractPurpose To describe the intra‐retinal microstructure using serial spectral domain‐optical coherence tomography (SD‐OCT) following pars plana vitrectomy (PPV) and delamination of fibrovascular membranes for severe proliferative diabetic retinopathy (PDR).Methods This retrospective, interventional case series included 26 eyes. Outcome measures included LogMAR best‐corrected visual acuity (BCVA) and SD‐OCT findings, including automated central 1‐mm subfield retinal thickness, integrity of photoreceptor inner and outer segments junction (IS/OS) and integrity of external limiting membrane (ELM). Two vitreoretinal‐trained observers graded SD‐OCT images.Results The eyes were into 3 groups based on post‐op IS/OS integrity (group 1: IS/OS intact; group 2: IS/OS irregular but not completely disrupted; group 3: IS/OS completely disrupted. Mean BCVA improved significantly in group 1 (n = 9) from 1.64 ± 0.71 preoperatively to 0.33 ± 0.21 (student’s t‐test: p = 0.01), in group 2 (n = 8) the BCVA improved from 1.30 ± 0.75 to 0.63 ± 0.30 (student’s t‐test: p = 0.44) and in group 3 (n = 9) the BCVA improved from 1.65 ± 0.53 to 1.53 ± 0.75 (student’s t‐test: p = 0.47). IS/OS integrity and ELM integrity were positively correlated with final BCVA (Pearson’s coefficient: r = 0.61, p &lt; 0.001 and r = 0.68, p &lt; 0.001, respectively).Conclusion The postoperative intra‐retinal structure at the level of the IS/OS and ELM based on SD‐OCT imaging are positively correlated with final postoperative visual acuity. The IS/OS boundary and ELM continuity appear to be indicators of macular function. These findings may provide prognostic factors for patients with this challenging and blinding disease.

Can optical coherence tomography replace fluorescein angiography in detection of ischemic diabetic maculopathy?

BackgroundWe studied the association between (1) the retinal thickness, volume and structure assessed by optical coherence tomography (OCT), and (2) vascular changes around the fovea in FA to define the role of these methods in the detection of ischemic diabetic maculopathy.MethodsThis retrospective observational study included 51 eyes of 51 patients with severe non-proliferative and proliferative diabetic retinopathy, considering that they present advanced ischemic retinal changes. Based on the clinical examination and presence of leakage on FA, patients with clinically significant macular edema were excluded.On FA, foveal avascular zone (FAZ) corresponds to capillary loss and reflects ischemic processes. Its outline and size were assessed according to the ETDRS standards. Patients were divided in two groups according to the severity of damage of the FAZ outline: ≤ grade 2 (n = 28) and ≥ grade 3 (n = 23).As we expected ischemia-related damage, SD-OCT images were evaluated for retinal structure, volume, total thickness with division into the outer and inner retina (to assess the influence of two, non-overlapping blood sources) and ganglion cell layer thickness.ResultsThe comparisons revealed that at least currently with described methods:1. There is no significant association between FAZ outline and retinal volume, total thickness, and thickness of the outer and inner retina and ganglion cell layer.2. There is no significant association between FAZ outline and following retinal structure characteristics: continuity of the external limiting membrane and inner segment/outer segment junction, and identification of the inner/outer retina boundary.3. The identification of ganglion cell layer boundaries was significantly more difficult in more advanced FAZ outline grades.4. FAZ size is not correlated with the retinal thickness and volume.ConclusionsIn patients with severe non-proliferative and proliferative diabetic retinopathy, it is not possible to predict FAZ outline/size based solely on the measurements assessing volume and thickness or retinal structure evaluation on OCT. Consequently, at present OCT cannot replace FA in the detection of ischemic diabetic maculopathy.

Relationship between diabetic retinopathy, diabetic macular oedema and erectile dysfunction in type 2 diabetics

To investigate the relationship of diabetic retinopathy and diabetic macular oedema with erectile dysfunction in patients with type 2 diabetes. Hospital-based, cross-sectional study. Three hundred twenty-four men with diabetes from the Diabetic Management Project were recruited. Participants underwent a comprehensive interview, a complete eye examination, fasting blood tests, and had retinal and macula assessments using fundus images and optical coherence tomography, respectively. Diabetic retinopathy was categorized as none, mild, moderate, severe non-proliferative and proliferative, and diabetic macular oedema as none, mild, moderate and severe. Erectile dysfunction was defined as problems achieving or maintaining an erection and was assessed using a self-reported questionnaire. Erectile dysfunction. The mean ± standard deviation age of 324 men with type 2 diabetes was 65.2 ± 11.1 years. Compared with patients without diabetic retinopathy, those with any retinopathy (odds ratio 2.06, 95% confidence interval 1.22-3.48, P = 0.007) had a twofold increased odds of having erectile dysfunction. Patients with severe non-proliferative diabetic retinopathy (odds ratio 4.39, 95% confidence interval 1.48-13.0, P = 0.008) and proliferative diabetic retinopathy (odds ratio 2.74, 95% confidence interval 1.44-5.19, P = 0.002) had fourfold and threefold increased odds of having erectile dysfunction, respectively, compared with those without diabetic retinopathy. Diabetic macular oedema, irrespective of presence or severity, was not independently associated with erectile dysfunction. The presence and severity of diabetic retinopathy but not diabetic macular oedema are independently associated with self-reported erectile dysfunction.

Safety and Efficacy of Renal Denervation in a Private Hospital

Methods: ECG-gated retinal fundus photographs were taken of the left eye at 10 s intervals in 15 diabetic and nondiabetic subjects: 1min prior to flicker provocation, 2min with flicker, and 1min of post-flicker. A semi-automated software analysis program, developed in-house, was used to generate ECG-gated photographs, andmeasure retinal vessel calibre. Reactive hyperaemic index (RHI) was also examined (EndoPAT 2000). Subjects with severe proliferative diabetic retinopathy or arrhythmias were excluded. The independent t-test was used to assess statistical significance of data. Results: Mean arterial vasodilation in response to flicker was significantly impaired in subjects with T2DM compared with controls (1.58± 0.52% vs. 3.18± 0.85%, p< 0.001). RHI was also significantly reduced in diabetes comparedwithcontrols (1.69± 0.58vs. 2.18± 0.57,p= 0.01). Conclusion:Retinal artery flicker is impaired in patients with T2DM and may represent a useful, non-invasive method for the assessment of arterial endothelial function in patients at risk of cardiovascular disease. http://dx.doi.org/10.1016/j.hlc.2013.05.058

Retinal Detection of Aberrant Pulsatile Flow Changes As A Novel Measure of Arterial Stiffness in Subjects with Type-2-Diabetes Mellitus

Methods: ECG-gated retinal fundus photographs were taken of the left eye at 10 s intervals in 15 diabetic and nondiabetic subjects: 1min prior to flicker provocation, 2min with flicker, and 1min of post-flicker. A semi-automated software analysis program, developed in-house, was used to generate ECG-gated photographs, andmeasure retinal vessel calibre. Reactive hyperaemic index (RHI) was also examined (EndoPAT 2000). Subjects with severe proliferative diabetic retinopathy or arrhythmias were excluded. The independent t-test was used to assess statistical significance of data. Results: Mean arterial vasodilation in response to flicker was significantly impaired in subjects with T2DM compared with controls (1.58± 0.52% vs. 3.18± 0.85%, p< 0.001). RHI was also significantly reduced in diabetes comparedwithcontrols (1.69± 0.58vs. 2.18± 0.57,p= 0.01). Conclusion:Retinal artery flicker is impaired in patients with T2DM and may represent a useful, non-invasive method for the assessment of arterial endothelial function in patients at risk of cardiovascular disease. http://dx.doi.org/10.1016/j.hlc.2013.05.058

Evaluation of retinal nerve fiber layer thickness in diabetic retinopathy by optical coherence tomography after full scatter panretinal argon laser photocoagulation

PurposeThe aim of this study was to evaluate the retinal nerve fiber layer (RNFL) thickness after full scatter panretinal argon laser photocoagulation in diabetic patients using optical coherence tomography.Patients and methodsThis study was carried out on 40 eyes of 22 patients with the clinical diagnosis of severe nonproliferative and proliferative diabetic retinopathy treated by full scatter panretinal photocoagulation at the ophthalmic diagnostic laser unit, Menoufiya University Hospital.ResultsFollow-up up to 6 months indicated that the percentage reduction in the average RNFL thickness after 6 months of laser treatment was 28.9%, which was statistically significant (P = 0.041). This reduction in the RNFL thickness varied from one retinal quadrant to another, with the most significant change taking place in both the nasal and the inferior quadrants.ConclusionIn the treatment of diabetic retinopathy, maximal effect with lowering number of shots as much as is necessary to avoid decrease RNFL thickness to great degree and so avoiding the optic disc pallor and optic atrophy.

Mauriac syndrome: A rare complication of type 1 diabetes mellitus

Mauriac syndrome: A rare complication of type 1 diabetes mellitus

Direct Effects of PPARα Agonists on Retinal Inflammation and Angiogenesis May Explain How Fenofibrate Lowers Risk of Severe Proliferative Diabetic Retinopathy

In this issue of Diabetes , Chen et al. (1) used rodent models of type 1 diabetes and ischemia-induced retinal neovascularization to examine how the lipid-lowering drug fenofibrate may prevent progression of diabetic retinopathy. Diabetic retinopathy is the sight-threatening complication of diabetes that causes retinal microvascular dysfunction, which in turn leads to diabetic macular edema (DME), formation of exudate deposits, and microhemorrhages. In the advanced proliferative stage of diabetic retinopathy, neovascularization can result in retinal detachment and blindness. Therapeutic options for diabetic retinopathy have been limited. Until recently, intensive glycemic control, with its risks of hypoglycemic events and increased mortality, was the only known means of reducing the progression of diabetic retinopathy (2,3). Laser photocoagulation of the peripheral retinal tissue, intravitreal injection of steroids or vascular endothelial growth factor (VEGF) inhibitors, and vitrectomy can each stabilize or improve vision, but they are all invasive and are associated with various complications. Additional treatment options are needed. An orally available drug that reduces the risk of diabetic retinopathy progression without intensive glycemic control, retinal destruction, or repeated intravitreal injections would be ideal. Type 2 diabetes is often associated with dyslipidemia characterized by elevated triglycerides, reduced HDL cholesterol, and variable LDL cholesterol. Although statins are clearly beneficial, a residual atherogenic dyslipidemia often remains (4). Fibric acid derivatives, such as fenofibrate, stimulate the peroxisome proliferator–activated receptor type α (PPARα) and lead to increased fatty acid β-oxidation, thus decreasing plasma triglyceride and LDL cholesterol levels and increasing HDL cholesterol levels (5). This makes fibrates, in combination with statins, a logical treatment for diabetic dyslipidemia. Recent large-scale clinical studies, including the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and …

Pain score of patients undergoing single spot, short pulse laser versus conventional laser for diabetic retinopathy

To compare pain score of single spot short duration time (20 milliseconds) panretinal photocoagulation (PRP) with conventional (100 milliseconds) PRP in diabetic retinopathy. Sixty-six eyes from 33 patients with symmetrical severe non-proliferative diabetic retinopathy (non-PDR) or proliferative diabetic retinopathy (PDR) were enrolled in this prospective randomized controlled trial. One eye of each patient was randomized to undergo conventional and the other eye to undergo short time PRP. Spot size of 200 μm was used in both laser types, and energy was adjusted to achieve moderate burn on the retina. Patients were asked to mark the level of pain felt during the PRP session for each eye on the visual analog scale (VAS) and were examined at 1 week, and at 1, 2, 4 and 6 months. Sixteen women and 17 men with mean age 58.9 ± 7.8 years were evaluated. The conventional method required a mean power of 273 ± 107 mW, whereas the short duration method needed 721 ± 406 mW (P = 0.001). An average of 1,218 ± 441 spots were delivered with the conventional method and an average of 2,125 ± 503 spots were required with the short duration method (P = 0.001). Average pain score was 7.5 ± 1.14 in conventional group and 1.75 ± 0.87 in the short duration group (P = 0.001). At 1 week, 1 month, and 4 months following PRP, the mean changes of central macular thickness (CMT) from baseline in the conventional group remained 29.2 μm (P = 0.008), 40.0 μm (P = 0.001), and 40.2 μm (P = 0.007) greater than the changes in CMT for short time group. Patient acceptance of short time single spot PRP was high, and well-tolerated in a single session by all patients. Moreover, this method is significantly less painful than but just as effective as conventional laser during 6 months of follow-up. The CMT change was more following conventional laser than short time laser.

Angiofibrotic Response to Vascular Endothelial Growth Factor Inhibition in Diabetic Retinal Detachment

OBJECTIVES To assess the effect of bevacizumab injection on connective tissue growth factor (CTGF) and vascular endothelial growth factor (VEGF) in the ocular fluids of patients with diabetic traction retinal detachment, and to determine whether intraoperative and postoperative complications are decreased in eyes given adjunctive preoperative bevacizumab injection. METHODS Twenty eyes of 19 patients were randomized to receive intravitreal bevacizumab or sham injection 3 to 7 days before vitrectomy for severe proliferative diabetic retinopathy. We collected aqueous samples before injection and at the time of vitrectomy and extracted undiluted vitreous samples. RESULTS Five eyes had decreased vascularization of membranes from preinjection to the time of vitrectomy (all in the bevacizumab treatment arm). Median visual acuities were 20/400 in control eyes at baseline and postoperative month 3 (POM3) and 8/200 in the bevacizumab-treated group at baseline and 20/100 at POM3 (P= .30 between control and bevacizumab-treated groups at POM3). All retinas were attached at POM3. Vitreous levels of VEGF were significantly lower in the bevacizumab group than in the control group (P= .03). Vitreous levels of CTGF were slightly lower in the bevacizumab group compared with the control group, but this difference was not statistically significant (P= .38). Levels of CTGF in the aqueous were strongly correlated with CTGF levels in the vitreous of controls (Spearman correlation coefficient, 0.95 [P< .001]). CONCLUSIONS Intravitreal bevacizumab injection reduces vitreous levels of VEGF and produces a clinically observable alteration in diabetic fibrovascular membranes. Ocular fluid levels of CTGF are not significantly affected within the week after VEGF inhibition. Retinal reattachment rates and visual acuity are not significantly altered by preoperative intravitreal bevacizumab injection at POM3. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01270542.

Association Between Diabetic Retinopathy and Flow-Mediated Vasodilation in Type 2 DM

Objective: Retinal endothelial dysfunction is a key in the etiogenesis of diabetic retinopathy (DR), in patients with type 2 diabetes mellitus (DM). Brachial artery flow-mediated vasodilation (FMD) is a marker of endothelial function associated with production of endogenous nitric oxide. Using FMD, we investigated the relationship between macrovascular function and DR.Methods: We studied 74 patients with type 2 DM, including non-DR (NDR) (n = 30); mild nonproliferative DR (NPDR) (n = 16); moderate NPDR (n = 10); severe NPDR (n = 10); and proliferative DR (PDR) (n = 8); and 21 age-matched controls. We measured FMD in each group. Retinal blood flow and pulsatility ratios were measured using laser Doppler velocimetry.Results: FMD decreased significantly in patients with DM compared with healthy control subjects. No significant differences were found in FMD among the NDR, mild NPDR, and moderate NPDR groups. FMD decreased significantly in the severe NPDR and PDR groups compared with the NDR group. FMD was significantly and negatively correlated with duration of DM and pulsatility ratio.Conclusion: Systemic endothelial dysfunction appears to be associated with DR and vascular abnormalities in patients with type 2 DM.

Intravitreal bevacizumab versus panretinal photocoagulation for treatment‐naïve proliferative and severe nonproliferative diabetic retinopathy

Editor, Panretinal photocoagulation (PRP) is the treatment of choice for proliferative diabetic retinopathy (PDR) and severe nonproliferative diabetic retinopathy (NPDR) (Early Treatment Diabetic Retinopathy Study Research Group 1991). PRP has limitations, including vision loss, visual field defects and nyctalopia. Macular oedema can occur or worsen after PRP (McDonald & Schatz 1985). Media opacities such as cataract and vitreous haemorrhage occasionally preclude adequate laser therapy. An alternative treatment could ameliorate these difficulties. Intravitreal bevacizumab combined with PRP resulted in better regression of Neovascularisation (NV) and less vision loss compared with PRP alone (Mason et al. 2008; Tonello et al. 2008). We investigated intravitreal bevacizumab injections alone without prior PRP in a prospective, paired-eye, randomized pilot study. Potential benefits of intravitreal bevacizumab include preventing macular oedema, treating both PDR and macular oedema concurrently prior to performing PRP, and temporising until vitreous haemorrhage cleared to allow adequate PRP. Patients with type 2 diabetes mellitus and symmetric untreated severe NPDR or PDR without macular oedema or prior intraocular surgery were included. Informed consent was obtained which clearly explained that the standard treatment for their condition was PRP. The patients were notified the eye treated with intravitreal bevacizumab probably would require PRP at the end of the study. Best corrected visual acuity (BCVA), ophthalmologic examination, macular OCT, fundus photography and fluorescein angiography were performed at baseline and serially. Patients were evaluated every 2 months for 12 months total follow-up. The right eye was randomly assigned to treatment with PRP or intravitreal bevacizumab, and the left eye received the other treatment. Eyes randomized to bevacizumab 2.5 mg (0.1 ml) (Avastin, Genentech, San Francisco, CA, USA) were injected every 2 months during the study. Fellow eyes randomized to PRP were treated in two sessions, with a third session only if there was angiographic evidence of neovascular activity at month 4. Fifteen patients were enrolled. Unfortunately, five patients were lost to follow up between the baseline exam and the 2-month visit, and we were unable to ascertain the reasons these patients left. Ten patients (20 eyes) were followed for 12 months. Seven were women and the average age was 53 ± 9 years. Five patients had PDR and five had severe NPDR. Baseline BCVA and central macular thickness (CMT) were not statistically different between groups (p = 0.67 and p = 0.38, Mann–Whitney U test). None of 10 eyes with severe NPDR developed PDR. In 10 eyes with PDR, neovascular leakage completely resolved in four of five eyes treated with bevacizumab and in one of five eyes treated with PRP (p = 0.11, chi-square mid-P exact). Final CMT was significantly less in eyes treated with bevacizumab compared to those treated with PRP, 197 ± 17 μm versus 243 ± 49 μm, respectively (p = 0.012). BCVA (logMAR) pretreatment was −0.12 ± 0.22 and −0.14 ± 0.23 compared with −0.14 ± 0.19 and −0.17± 0.10 post-treatment (p = 0.52 and 0.64, bevacizumab and PRP groups, respectively). None of 10 eyes treated with bevacizumab injections every 2 months developed a complication. Two eyes treated with PRP developed vitreous haemorrhage. Three of 10 eyes treated with PRP developed macular oedema compared with none in the bevacizumab group. As this was a fellow eye controlled study, the effects of glycaemic and blood pressure control would equally impact both eyes of each patient. Intravitreal bevacizumb 2.5 mg injections every 2 months effectively controlled NV and resulted in a thinner CMT than PRP at 1 year. There were no differences in mean BCVA, which was expected given the good baseline vision and the small sample size. In a total of 60 bevacizumab injections, there were no complications, such as endophthalmitis or tractional retinal detachment. The main limitations of this study are the small sample size and the large proportion of patients lost to follow up. Despite the small sample size, the difference in final CMT achieved statistical significance. In summary, repeated intravitreal bevacizumab injections controlled NV in treatment-naïve eyes with PDR and severe NPDR for 1 year, but this finding needs to be confirmed by a larger study. PRP remains the gold-standard treatment for these eyes. In the future, longer-lasting anti-VEGF agents may be able to avoid the complications associated with PRP. Intravitreal bevacizumab may be a useful temporising measure in eyes with macular oedema or vitreous haemorrhage until adequate PRP can be performed, but further study is required.