Pathogenesis Of Diabetic Macular Edema Research Articles

Changes in Aqueous Concentrations of Various Cytokines After Intravitreal Triamcinolone Versus Bevacizumab for Diabetic Macular Edema

To investigate the changes in aqueous inflammatory and angiogenic cytokine levels after intravitreal injection of triamcinolone or bevacizumab for reducing foveal thickness in diabetic macular edema (DME). Prospective, interventional case series. Twenty-two eyes of 11 patients with bilateral DME and 6 eyes of 6 patients undergoing cataract surgery participated in this study. In each DME patient, 1 eye received an intravitreal injection of 4 mg triamcinolone acetonide and the other eye received 1.25 mg bevacizumab. Aqueous humor samples were obtained before and 4 weeks after the intravitreal injection in the DME group and before the surgery in the control group. Aqueous concentrations of interleukin (IL)-6, IL-8, interferon-induced protein (IP)-10, monocyte chemotactic protein (MCP)-1, platelet-derived growth factor (PDGF)-AA, and vascular endothelial growth factor (VEGF) were measured by multiplex bead assay. Before the administration of the drugs, aqueous levels of IL-8, IP-10, MCP-1, and VEGF were significantly higher in the DME group than in the control group. After intravitreal injection, foveal thickness was more decreased in the triamcinolone acetonide (IVTA) group compared with the bevacizumab (IVBe) group. IL-6, IP-10, MCP-1, PDGF-AA, and VEGF were significantly decreased in the IVTA group, but only VEGF in the IVBe group. Aqueous levels of VEGF were more decreased in the IVBe group than in the IVTA group. These findings suggest that the pathogenesis of DME is not only related to VEGF dependency, but also to other mechanisms suppressed by corticosteroids. We suppose that these cytokines would have an important role in both the pathogenesis of DME and the underlying mechanism of intravitreal injections.

EARLY CHANGE OF CENTRAL MACULAR THICKNESS AFTER INTRAVITREOUS TRIAMCINOLONE OR BEVACIZUMAB IN DIABETIC MACULAR EDEMA OR RETINAL VEIN OCCLUSION

To evaluate the immediate changes after intravitreous triamcinolone acetonide or intravitreous bevacizumab in diabetic macular edema (DME). A nonrandomized interventional study. Type 2 diabetic patients were included. Intravitreous triamcinolone acetonide (4 mg) was injected for 22 eyes with DME and IVB (1.25 mg) for 18 eyes with DME. The early time-dependent changes of central macular thickness were evaluated by optical coherence tomography before and from 1 hour to 1 month after intervention. Intravitreous bevacizumab was also tested in patients with retinal vein occlusion as a control of non-DME. Visual acuity was also examined. Compared with the baseline, central macular thickness of eyes with DME decreased significantly 1 hour after intravitreous triamcinolone acetonide (P < 0.05, Wilcoxon signed rank test), while it did not significantly until 24 hours after IVB. The decrease in central macular thickness was observed significantly from 3 hours after IVB in retinal vein occlusion (P < 0.05, Wilcoxon signed rank test), and it was more evident in retinal vein occlusion than DME after IVB. Visual acuity improved significantly in DME with intravitreous triamcinolone acetonide or IVB at 1 month (P < 0.01 and P < 0.05, respectively, Wilcoxon signed rank test). Factors responsive to triamcinolone acetonide, other than vascular endothelial growth factor, might play an important role in pathogenesis of DME compared with retinal vein occlusion. Although no conclusion can be drawn, immediate decrease in central macular thickness after intravitreous triamcinolone acetonide might indicate the possible involvement of a nongenomic pathway of triamcinolone acetonide action.

Ranibizumab in the treatment of patients with visual impairment due to diabetic macular edema

Diabetic macular edema is the major cause of visual acuity impairment in diabetic patients. The exact etiopathogenesis is unknown and, currently, grid/focal retinal laser photocoagulation represents the recommended treatment. It has been demonstrated that vascular endothelial growth factor (VEGF) plays a key role in the pathogenesis of diabetic macular edema by mediating vascular permeability and accumulation of intracellular and extracellular fluid, and thereby represents an appealing candidate as a therapeutic target for the treatment of diabetic macular edema. The advent of intravitreal anti-VEGF drugs has opened up a new era for the management of diabetic macular edema. At present, three anti-VEGF substances are available for routine clinical use, ie, pegaptanib, ranibizumab, and bevacizumab. The aim of this review is to summarize the evidence supporting the use of ranibizumab in clinical practice. Most of the studies analyzed in this review are prospective, controlled clinical trials that have focused on documenting the therapeutic effect of ranibizumab and its safety, providing encouraging results.

Betacellulin Induces Increased Retinal Vascular Permeability in Mice

BackgroundDiabetic maculopathy, the leading cause of vision loss in patients with type 2 diabetes, is characterized by hyper-permeability of retinal blood vessels with subsequent formation of macular edema and hard exudates. The degree of hyperglycemia and duration of diabetes have been suggested to be good predictors of retinal complications. Intervention studies have determined that while intensive treatment of diabetes reduced the development of proliferative diabetic retinopathy it was associated with a two to three-fold increased risk of severe hypoglycemia. Thus we hypothesized the need to identify downstream glycemic targets, which induce retinal vascular permeability that could be targeted therapeutically without the additional risks associated with intensive treatment of the hyperglycemia. Betacellulin is a 32 kD member of the epidermal growth factor family with mitogenic properties for the retinal pigment epithelial cells. This led us to hypothesize a role for betacellulin in the retinal vascular complications associated with diabetes.Methods and FindingsIn this study, using a mouse model of diabetes, we demonstrate that diabetic mice have accentuated retinal vascular permeability with a concomitant increased expression of a cleaved soluble form of betacellulin (s-Btc) in the retina. Intravitreal injection of soluble betacellulin induced retinal vascular permeability in normoglycemic and hyperglycemic mice. Western blot analysis of retinas from patients with diabetic retinopathy showed an increase in the active soluble form of betacellulin. In addition, an increase in the levels of A disintegrin and metalloproteinase (ADAM)-10 which plays a role in the cleavage of betacellulin was seen in the retinas of diabetic mice and humans.ConclusionsThese results suggest that excessive amounts of betacellulin in the retina may contribute to the pathogenesis of diabetic macular edema.

PRELIMINARY ASSESSMENT OF CELECOXIB AND MICRODIODE PULSE LASER TREATMENT OF DIABETIC MACULAR EDEMA

Inflammation may play an important role in the pathogenesis of diabetic macular edema, a major cause of vision loss in persons with diabetes. The purpose of this study was to evaluate combined antiinflammatory therapy and laser approaches for treating patients with diabetic macular edema. In this prospective, factorial, randomized, multicenter trial, we compared cyclo-oxygenase-2 inhibitor (celecoxib) with placebo and diode grid laser with standard Early Treatment Diabetic Retinopathy Study focal laser treatment in 86 participants with diabetic macular edema. The primary outcome is change in visual acuity of > or = 15 letters from baseline, and the secondary outcomes include a 50% reduction in the retinal thickening of diabetic macular edema measured by optical coherence tomography and a 50% reduction in leakage severity on fluorescein angiography. Visual acuity and retinal thickening data from >2 years of follow-up did not show evidence of differences between the medical and laser treatments. However, participants assigned to the celecoxib group were more likely to have a reduction in fluorescein leakage when compared with the placebo group (odds ratio = 3.6; P < 0.01). This short-term study did not find large visual function benefits of treatment with celecoxib or diode laser compared with those of standard laser treatment. A suggestive effect of celecoxib in reducing fluorescein leakage was observed.

Non surgical approach in diabetic macular edema : the future ?

Abstract Purpose To present the different non surgical therapeutical options of diabetic macular edema Methods The pathogenesis of diabetic macular edema is multifactorial. Hyperglycemia and poor systemic factor balance are major risk factors. Laser treatemnts and antiagiogenic treatments represent the main non surgical options to treat macular edema. Results Focal macular edema remains the best indication of laser treatment. Laser remains also the standard of care of diffuse macular edema but some edemas remain resistant. Several therapeutic options have been proposed : Steroid intravitreal injection and antiVEGF therapy (either PKC inhibitors, VEGF aptamers or VEGF antibodies) represent the future alternative treatments as well as their potential combination. Conclusion Laser remains the main treatment of diabetic macular edema. However, steroids and antiangiogenic agents either isolated or combined represent the main alternative treatment for non responding diffuse macular edema.

Inhibition of Protein Kinase C Is Not Sufficient to Prevent or Reverse Effects of VEGF165on Claudin-1 and Permeability in Microvascular Retinal Endothelial Cells

Pathogenesis of diabetic macular edema is driven by deregulated expression of VEGF. A study of long-term exposure of immortalized bovine retinal endothelial cells (iBRECs) to VEGF(165) clearly confirmed the role of the tight junction protein claudin-1, which almost completely disappeared within 24 hours, an effect that was completely reversed by addition of the VEGF-binding Fab fragment ranibizumab. This study was conducted to investigate whether the VEGF(165)-induced loss of claudin-1 is regulated by protein kinase C (PKC) and indeed affects the barrier function of iBRECs. The effects of various PKC inhibitors on claudin-1 expression and cellular localization in iBRECs treated with VEGF(165) for up to 2 days were studied by Western blot analyses and immunofluorescence microscopy. The permeability of the cell layers was determined by transendothelial electrical resistance measurements. Activation of PKC led to decreased expression of claudin-1, which was blocked by inhibitors of PKCdelta. However, none of the PKC inhibitors significantly affected VEGF(165)-induced effects on cellular localization or expression of claudin-1. Also VEGF(165)-induced higher permeability of iBREC layers could be reversed or prevented by ranibizumab but not by PKC inhibitors. In addition, low claudin-1 expression and its delocalization from the plasma membrane were significantly associated with elevated permeability. In iBRECs, PKC isoforms are not crucially involved in the VEGF(165)-initiated signal transduction that affects permeability and expression of claudin-1. This finding is in contrast to published results concerning only short-term effects of VEGF(165). The results also confirmed that claudin-1 is a highly relevant component of functional tight junctions in retinal endothelial cells.

Advances in the Medical Treatment of Diabetic Retinopathy

Proliferative diabetic retinopathy (PDR) remains the leading cause of blindness among working-age individuals in developed countries (1). Diabetic macular edema (DME), another important event that occurs in diabetic retinopathy, is more frequent in type 2 than type 1 diabetes (2). Whereas PDR is the most common sight-threatening lesion in type 1 diabetes, DME is the primary cause of poor visual acuity in type 2 diabetes. Because of the high prevalence of type 2 diabetes, DME is the main cause of visual impairment for diabetic patients (2). In addition, DME is almost invariably present when PDR is detected in type 2 diabetes (3). Neovascularization caused by severe hypoxia is the hallmark of PDR, whereas vascular leakage caused by the breakdown of the blood retinal barrier (BRB) is the main event involved in the pathogenesis of DME (4,5). Although tight control of both blood glucose levels and hypertension is essential to prevent or arrest progression of the disease, the recommended goals are difficult to achieve in many patients and, consequently, diabetic retinopathy develops during the evolution of the disease. When PDR or clinically significant DME do appear, argon-laser photocoagulation is currently indicated, which the efficacy of has been widely demonstrated (6). However, the optimal period for laser treatment has frequently passed; moreover, it is not uniformly successful in halting visual decline. In addition, argon-laser photocoagulation is associated with moderate visual loss, some diminished visual field, reduced color vision, and reduced contrast sensitivity. The presence of these symptoms led to the prevailing thinking that laser treatment prevents vision loss but rarely results in visual improvement. Intravitreal corticosteroids have been successfully used in the eyes of patients with persistent DME and loss of vision following the failure of conventional treatment (i.e., focal laser treatment and attention to systemic risk factors). However, …

The vitreo-retinal interface in macular diseases

Anomalous posterior vitreous detachment occurs, when the extent of vitreous liquefaction exceeds the degree of weakening of vitreo-retinal adherence and traction is exerted at the vitreo-retinal interface. In the macular region vitreo-macular traction is obviously correlated with macular disorders like macular pucker, epiretinal membrane, macular hole formation, and vitreo-macular traction syndrome. The pathogenesis of diabetic macular edema and exudative age-related macular degeneration is more complex. However, the effectivity of vitrectomy in diabetic macular edema and high incidence of vitreoretinal adhesions in exudative age-related macular degeneration underscore the important role of the vitreous in the pathogenesis of these diseases.

CORRELATION BETWEEN MICROANEURYSMS AND RETINAL THICKNESS IN DIABETIC MACULAR EDEMA

Microaneurysms commonly are believed to be related causally to retinal thickening in diabetic retinopathy, especially by leaking. The hypothesis that thicker areas of retina in diabetic retinopathy have more microaneurysms per unit area than areas that are not as thick was tested. Retinal thickness analysis was performed with a prototype instrument for 27 eyes of 27 diabetic patients and 22 normal eyes of 22 healthy subjects. Maps of retinal thickness were created, and microaneurysms were counted in zones having four levels of retinal thickness. There was no increase in either total microaneurysms or apparent leaking microaneurysms per unit area with increasing levels of retinal thickness (P = 0.77 and 0.87, respectively). Some microaneurysms may not cause thickening, or other factors may contribute to retinal thickening in diabetic retinopathy. The results may have implications on the pathogenesis of diabetic macular edema.

Relationship between Diabetic Macular Edema and Peripheral Th1/Th2 Balance

Purpose: To determine whether inflammatory reactions are involved in the pathogenesis of diabetic macular edema, we examined the relationship between diabetic macular edema and the ratio of T helper 1 (Th1) to T helper 2 (Th2) cells. Methods: Thirty-nine diabetic patients with diabetic retinopathy were evaluated at our hospital between February 2004 and February 2005. Blood samples were collected from each patient, and the ratio of CD4+ Th1 to Th2 cells (Th1/Th2) was determined by flow cytometry after fluorescent antibody staining for intracellular cytokines. Logistic regression analysis was used to determine the association of macular edema with age, gender, HbA_1c level, interval after retinal photocoagulation and Th1/Th2 ratios. Differences in these parameters were also compared between patients with and without macular edema. Results: Logistic regression analysis showed that the Th1/Th2 ratios were significantly associated with macular edema (odds ratio = 0.838; p = 0.02), while other variables were not. The Th1/Th2 ratio was significantly lower in the patients with diabetic macular edema than in those without (p = 0.02; t test). Higher Th1/Th2 ratios tended to be associated with better visual acuity. Conclusions: Shifts in the balance of Th1/Th2 towards a predominance of Th2 may represent an exacerbating factor for diabetic macular edema, although a causal relationship has still not been definitively determined.

Incomplete Posterior Hyaloid Detachment after Intravitreal Pegaptanib Injection in Diabetic Macular Edema

Posterior hyaloid adherences play a role in the pathogenesis of diabetic macular edema (DME). Intravitreal antivascular endothelial growth factor (VEGF) drugs are presently being used to treat DME. The authors report one case of incomplete posterior hyaloid detachment (PHD) following intravitreal pegaptanib to treat DME. This case shows a combined mechanism of DME resolution by anti VEGF and PHD. Prospective, interventional, single case report. One male patient with bilateral DME was treated by intravitreal pegaptanib in his right eye every 6 weeks for 6 months (five injections) and followed for 42 months. Central macular thickness decreased from 511 to 376 microm at month 4 in the treated eye and remained within 10% of this value during follow-up. The posterior hyaloid became taut and partially detached after the third injection and was almost completely detached 1 year later. Visual acuity remained unchanged in both eyes during follow-up. PHD may play an important role in cases where macular thickness is successfully reduced or better acuity is achieved after intravitreal injections.

Comparative Therapy Evaluation of Intravitreal Bevacizumab and Triamcinolone Acetonide on Persistent Diffuse Diabetic Macular Edema

To compare the effect of an intravitreal injection of bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody, with that of triamcinolone acetonide, a corticosteroid for reduction of diabetic macular edema (DME). Prospective, comparative interventional case series. Twenty-eight eyes of 14 patients with bilateral DME participated in this study. In each patient, one eye received an intravitreal injection of 4 mg triamcinolone acetonide and the other eye received 1.25 mg bevacizumab. The clinical course of best-corrected visual acuity (VA) with a logarithm of the minimum angle of resolution chart and averaged foveal thickness using optical coherence tomography was monitored for up to 24 weeks after the injection. Before the injection, foveal thickness and VA were 522.3 +/- 91.3 microm and 0.64 +/- 0.28 microm in the triamcinolone-injected eye, and 527.6 +/- 78.8 microm and 0.61 +/- 0.18 microm in the bevacizumab-injected eye, respectively; there was no significant difference between the eyes. One week after the injection, both eyes showed significant regression of macular edema. The triamcinolone-injected eye (342.6 +/- 85.5 microm and 0.33 +/- 0.21 microm) showed significantly better results than the bevacizumab-injected eye (397.6 +/- 103.0 microm and 0.37 +/- 0.17 microm). However, both eyes showed the recurrence of macular edema with time, even at 24 weeks. Triamcinolone (410.4 +/- 82.4 microm and 0.47 +/- 0.25 microm) kept better results than bevacizumab (501.6 +/- 92.5 microm and 0.61 +/- 0.17 microm). With the generally used concentration, intravitreal injection of triamcinolone acetonide showed better results in reducing DME and in the improvement of VA than that of bevacizumab, suggesting that the pathogenesis of DME is not only attributable to VEGF-dependency, but is also attributable to other mechanisms suppressed by corticosteroid.

Kallikrein-kinin activation by altered vitreous pH: New perspectives for treatment and pathogenesis of diabetic macular edema?

Recently, Gao et al. published an experimental study based on the pathophysiology of diabetic macular edema in Nature Medicine (Nat Med. 2007 Feb;13(2):181-8). They found an increased amount of carbonic anhydrase in the vitreous, which causes a pH shift. This activates the kallikrein-kinin system and leads to increased retinal vascular permeability. In this comment the clinical implications of this article are discussed.

VITREOMACULAR ADHESION AND THE DEFECT IN POSTERIOR VITREOUS CORTEX VISUALIZED BY TRIAMCINOLONE-ASSISTED VITRECTOMY

To study the vitreomacular adhesion and the contractile force of posterior hyaloid, which are shown in triamcinolone acetonide (TA)-assisted pars plana vitrectomy (PPV). Interventional case series. Twenty-eight eyes with diabetic macular edema (DME) without posterior vitreous detachment (PVD) received TA-assisted PPV. Surgical PVD was performed by an aspiration of vitrectomy probe, and the dynamic changes of posterior vitreous cortex and residual vitreous cortex were evaluated. A premacular defect was formed in the detached posterior vitreous cortex during surgical PVD in 27 of 28 eyes. Immediately thereafter, the small defect expanded into a large hole in the detached posterior vitreous cortex in all cases. A residual vitreous cortex was left on the macula in 22 eyes. These observations demonstrate a firm vitreoretinal adhesion in the central macula and suggest that the enlargement of the defect of posterior vitreous cortex may be extrusion of vitreous out through the premacular dehiscence into the preretinal space, or a tangentially contractile force may exist in the posterior vitreous cortex. Both macular adhesion and the traction of vitreous cortex might contribute to the pathogenesis of DME and other vitreomacular disease.

Optical Coherence Tomography Assessment of the Vitreoretinal Relationship in Diabetic Macular Edema

To study the vitreoretinal relationship in diabetic patients with and without diabetic macular edema (DME) using optical coherence tomography. Retrospective case-control study. setting: Institutional practice. patients: Thirty-five consecutive diabetic patients (49 eyes) with DME and 35 sex- and age-matched diabetic control patients without DME (49 eyes). observation procedure: All patients had Early Treatment Diabetic Retinopathy Study visual acuity measurement and biomicroscopic examination of the vitreoretinal interface. OCT was performed to obtain cross-sectional images of the vitreoretinal interface of the macular region. Posterior vitreous detachment (PVD) was staged from 0 to 3 as follows: stage 0: absence of PVD; stage 1: perifoveolar PVD with foveolar attachment; stage 2: incomplete PVD with residual attachment to the optic nerve; and stage 3: complete PVD. Retinal thickness was measured using OCT mapping software in all cases. main outcome measures: Prevalence of the different PVD stages in both groups of eyes. The mean age of the patients was 60 years in both groups. Of the eyes with macular edema, 19 (38.8%) were stage 0, 26 (53.0%) stage 1, 1 (2.0%) was stage 2, and 3 (6.2%) were stage 3. In eyes without DME, the corresponding figures were, respectively, 34 (69.4%), 11 (22.4%), 1 (2.0%), and 3 (6.2%). The prevalence of perifoveolar PVD with foveolar attachment was significantly higher in the group of eyes with DME (P =.006). These results show the high prevalence of perifoveolar PVD with foveolar attachment in diabetic patients with macular edema. Even though PVD is not the main factor involved in the pathogenesis of DME, perifoveolar PVD may have a role in the development of this complication.

Proteomic analysis of vitreous from diabetic macular edema

To identify and analyze diabetic macular edema (DME)-related proteins in the vitreous, en masse, using two-dimensional gel (2D gel) electrophoresis and mass-spectrometry (MS). Vitreous samples were corrected from 20 eyes with pre-proliferative diabetic retinopathy associated with DME (DME group) and without DME (non-DME group). They were subjected to 2D gel electrophoresis, and the spot intensities were compared between the groups. Apparently visible spots were excised from the gel, and the proteins were identified by liquid chromatography tandem MS (LC MS/MS) sequence analysis. We identified 14 proteins from the DME group, and 15 proteins from the non-DME group. The intensity of eight spots was markedly higher in DME than non-DME samples and one spot was detected only in non-DME samples. From the eight spots, six proteins were identified, including PEDF, ApoA-4, ApoA-1, Trip-11, PRBP, and VDBP. On the other hand, Apo H was expressed only in non-DME. Certain vitreous proteins expressed exclusively in DME and lacked in DME. These chemical mediators in the posterior vitreous may play a role in the pathogenesis of DME.

Supplemental oxygen improves diabetic macular edema: a pilot study

Diabetic macular edema (DME) is the most common cause of moderate visual disability in working-age persons in the United States. The pathogenesis of DME is poorly understood. Five patients with chronic DME despite at least one focal laser photocoagulation treatment (nine eyes) received 4 L/min of inspired oxygen by nasal cannula for 3 months. Best corrected visual acuity (VA) and retinal thickness, assessed by optical coherence tomography (OCT), were measured at baseline, during 3 months of oxygen treatment, and after stopping oxygen. After 3 months of oxygen therapy, none of nine eyes with DME ate baseline showed a reduction in thickness of the center of the macula. Foveal thickness (FTH) above the normal range was reduced by an average of 42.5% (range, 14%–100%), excess foveolar thickness (CEN) was reduced by an average of 42.1% (range, 13%–100%), and excess macular volume was reduced by an average of 54% (range, 35%–100%). Statistical analyses suggested that these changes were unlikely to be due to chance (P=0.0077). Three eyes showed improvement in VA by at least 2 lines, one by slightly less than 2 lines, and five eyes showed no change. Three months after discontinuation of oxygen, five of the nine eyes showed increased chickening of the macula compare with when oxygen was discontinued. Supplemental inspired oxygen may decrease macular thickness due to DME, suggesting that retinal hypoxia is involved in the development of DME.—Hans E. Grossniklaus

Relation of diabetic macular edema to cytokines and posterior vitreous detachment

PurposeTo investigate whether angiotensin II (AII) or vascular endothelial growth factor (VEGF) is related to diabetic macular edema (DME) in patients with and without posterior vitreous detachment (PVD). DesignA case-control study. MethodsVitreous fluid samples were obtained at vitreoretinal surgery from 28 eyes of 28 DME patients without PVD, 8 eyes of 8 DME patients with PVD, 14 eyes of 14 nondiabetic patients, and 8 eyes of diabetic patients without retinopathy. The VEGF levels in vitreous fluid and plasma were determined by enzyme-linked immunosorbent assay, while AII levels were measured by radioimmunoassay. ResultsThe vitreous levels of AII and VEGF were significantly higher in DME patients with or without PVD than in nondiabetic patients or diabetic patients without retinopathy (without PVD: P < .0061, P < .0001, P = .0261, and P < .0001; with PVD: P < .0012, P < .0001, P = .0473, and P < .0001, respectively). There was no significant difference in the vitreous levels of AII or VEGF between patients with or without PVD (P = .4948 and P = .6642, respectively). The vitreous level of AII significantly correlated with that of VEGF in DME patients without PVD (P = .576) or with PVD (P = .488). AII and VEGF levels in vitreous fluid were significantly higher than the respective plasma levels. ConclusionsWe found that the vitreous levels of AII and VEGF were elevated in DME patients irrespective of the status of PVD. Angiotensin II and VEGF may be induced in the eyes and be related to the pathogenesis of DME.