Added value of OCT in evaluating the presence of leakage in patients with age-related macular degeneration treated with PDT

Background Evaluating the presence of leakage on fluorescein angiography (FA) in patients with age-related macular degeneration (AMD) retreated with photodynamic therapy (PDT) can be difficult. New diagnostic tools such as optical coherence tomography (OCT) might help to optimize PDT management.Methods Thirty AMD patients scheduled for regular follow-up FA in conjunction with PDT treatment were also scanned with OCT. Follow-up data at 9 months were retrieved from the patients’ medical records. Inter-observer agreement [kappa (κ) coefficient] for the presence of leakage on FA, for OCT parameters for leakage, and agreement between FA and OCT evaluations were calculated. The indication for retreatment was evaluated using the leakage analysis based on FA alone, OCT alone, and both examinations combined, and compared to the actual follow-up of the patients at 9 months.Results Agreement between the two observers for the presence of leakage on FA was moderate (κ=0.51). OCT agreement between the two observers for the presence of leakage was good (κ=0.85). Agreement between FA and OCT for the presence of leakage was poor (κ=0.16). Follow-up data at 9 months on all patients were analyzed. Seven out of 30 patients were not retreated at the time of examination, and four of these patients (57%) remained stable without further treatment. Twenty-three patients did receive a PDT treatment at the time of examination; and eight of these patients did not show leakage on OCT, and five of these patients (62%) remained stable without additional treatment. In contrast, only three out of 15 patients (20%) with leakage on both FA and OCT remained stable during this 9 month follow-up period.Conclusions Inter-observer agreement for the presence of leakage was moderate for FA and good for OCT. There was considerable disagreement between leakage as judged by OCT and by FA. OCT could be of help in the decision regarding PDT retreatment. Assuming that 57% of the patients without leakage either on FA or OCT would remain stable without retreatment, the rate of probable ineffective retreatment could be reduced from 35% to 20%.There was no financial support for this study. The authors have full access to the data and will allow Graefe’s Archive for Clinical and Experimental Ophthalmology to review the data if requeste.d     

Protection against methylglyoxal-derived AGEs by regulation of glyoxalase 1 prevents retinal neuroglial and vasodegenerative pathology

Aims/hypothesis

Methylglyoxal (MG) is an important precursor for AGEs. Normally, MG is detoxified by the glyoxalase (GLO) enzyme system (including component enzymes GLO1 and GLO2). Enhanced glycolytic metabolism in many cells during diabetes may overpower detoxification capacity and lead to AGE-related pathology. Using a transgenic rat model that overexpresses GLO1, we investigated if this enzyme can inhibit retinal AGE formation and prevent key lesions of diabetic retinopathy.

Methods

Transgenic rats were developed by overexpression of full length GLO1. Diabetes was induced in wild-type (WT) and GLO1 rats and the animals were killed after 12 or 24?weeks of hyperglycaemia. N ^??-(Carboxyethyl)lysine (CEL), N ^??-(carboxymethyl)lysine (CML) and MG-derived-hydroimidazalone-1 (MG-H1) were determined by immunohistochemistry and by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MSMS). Müller glia dysfunction was determined by glial fibrillary acidic protein (GFAP) immunoreactivity and by spatial localisation of the potassium channel Kir4.1. Acellular capillaries were quantified in retinal flat mounts.

Results

GLO1 overexpression prevented CEL and MG-H1 accumulation in the diabetic retina when compared with WT diabetic counterparts (p?GLO1 overexpression (p?GLO1 diabetic animals showed fewer acellular capillaries than WT diabetic animals (p?Conclusions/interpretation Detoxification of MG reduces AGE adduct accumulation, which, in turn, can prevent formation of key retinal neuroglial and vascular lesions as diabetes progresses. MG-derived AGEs play an important role in diabetic retinopathy.     

CD34 marks angiogenic tip cells in human vascular endothelial cell cultures

The functional shift of quiescent endothelial cells into tip cells that migrate and stalk cells that proliferate is a key event during sprouting angiogenesis. We previously showed that the sialomucin CD34 is expressed in a small subset of cultured endothelial cells and that these cells extend filopodia: a hallmark of tip cells in vivo. In the present study, we characterized endothelial cells expressing CD34 in endothelial monolayers in vitro. We found that CD34-positive human umbilical vein endothelial cells show low proliferation activity and increased mRNA expression of all known tip cell markers, as compared to CD34-negative cells. Genome-wide mRNA profiling analysis of CD34-positive endothelial cells demonstrated enrichment for biological functions related to angiogenesis and migration, whereas CD34-negative cells were enriched for functions related to proliferation. In addition, we found an increase or decrease of CD34-positive cells in vitro upon exposure to stimuli that enhance or limit the number of tip cells in vivo, respectively. Our findings suggest cells with virtually all known properties of tip cells are present in vascular endothelial cell cultures and that they can be isolated based on expression of CD34. This novel strategy may open alternative avenues for future studies of molecular processes and functions in tip cells in angiogenesis.     

Eye problems due to contact lenses; an advisory report from the Health Council of the Netherlands

In a recent report, the Committee on Health Risks of Contact Lenses from the Health Council of the Netherlands evaluated the health risks of contact lens wear in the Netherlands. Contact lens-related eye disease appears to be common, with an incidence of approximately 80,000 persons per year, who suffer from self-limiting or mild conditions. Such conditions are multifactorial, caused for example by chronic hypoxia, tear-film dysfunction or inadequate fit of the lens. They can range from ocular irritation to giant papillary conjunctivitis, a common cause of permanent lens intolerance. A very serious complication of contact lens wear is infectious keratitis, caused by bacteria or fungi. This is most common in users of permanent-wear soft lenses (20 per 10,000 persons per year) and can lead to a severe loss of vision. Therefore, the Committee has recommended that permanent-wear lenses should not be used. Moreover, lens fitting and follow-up of contact lens wearers should be a prerequisite for optometrists and ophthalmologists. However, the Dutch government has not taken action with respect to this last recommendation.     

Blood-brain barrier integrity is unaltered in human brain cortex with diabetes mellitus

Diabetes-related cognitive dysfunction has been recognized for many years in humans, but the pathogenesis of this condition is poorly understood. Evidence from animal studies suggests that altered function of the blood-brain barrier (BBB) could be a potential cause contributing to this disease. This study aimed to investigate whether the permeability of the BBB is affected in the brains of persons with diabetes mellitus (DM). On postmortem prefrontal and temporal cortex of diabetic patients and controls, immunohistochemical stainings were carried out using specific antibodies against three proteins (PAL-E, IgG and albumin), which are considered as markers for the vascular permeability status of the BBB. Rare or no PAL-E staining was found in the capillaries of the prefrontal and temporal cortex parenchyma, in both DM and control materials. IgG and albumin were localized in and directly around blood vessel walls in the prefrontal and temporal cortex. No obvious differences in the staining pattern of IgG and albumin were observed between brain samples of persons with DM and controls. This study suggests that the BBB in diabetic patients is well maintained.     

Orbital irradiation for Graves' ophthalmopathy: Is it safe? A long-term follow-up study

PURPOSE: We evaluated the frequency of long-term complications of orbital irradiation (radiation-induced tumors, cataract, and retinopathy) in comparison with glucocorticoids. DESIGN: We conducted a follow-up study in a cohort of 245 Graves' ophthalmopathy patients who had been treated with retrobulbar irradiation (20 Gy in 2 weeks) and/or oral glucocorticoids between 1982 and 1993 in our institution. Irradiated patients were compared with nonirradiated patients. METHODS: Data on mortality and cause of death were obtained. Living patients were invited to participate in a follow-up study. Possible retinopathy was assessed in a masked fashion and defined as the presence of > or =1 hemorrhages and/or microaneurysms on red-free retina photographs. If >5 lesions were present, patients were categorized as suffering from definite retinopathy. Cataract was assessed using the Lens Opacity Classification System II score. MAIN OUTCOME MEASURES: Mortality, prevalence of retinopathy, prevalence of cataract, and type of cataract. RESULTS: Thirty-seven of the 245 patients had died, none of them from an intracranial tumor. Mortality was similar in the irradiated (27/159 [17%]) and nonirradiated patients (10/86 [12%]; P = 0.264). One hundred fifty-seven of the 208 living patients (75%) consented to participate in a follow-up ophthalmologic investigation; the mean follow-up time (+/- standard deviation) was 11+/-3 years. Possible retinopathy was present in 15% of patients, 22 of the irradiated and 1 of the nonirradiated patients (P = 0.002). In 5 patients (all had been irradiated), definite retinopathy (i.e., >5 retinal lesions) was present. Of these, 3 had diabetes mellitus, and 1 had hypertension. Diabetes was associated with both possible (P = 0.029) and definite (P = 0.005) retinopathy, with a relative risk of 21 (95% confidence interval, 3-179). The prevalence and severity of cataract were similar in the radiotherapy group (29%) and the glucocorticoid group (34%); it should be noted that 88 of 104 of the irradiated patients were also treated with oral glucocorticoids. CONCLUSION: The data suggest that orbital irradiation for Graves' ophthalmopathy is a safe treatment modality, except possibly for diabetic patients.     

Role of VEGF-A in endothelial phenotypic shift in human diabetic retinopathy and VEGF-A-induced retinopathy in monkeys

The endothelium-specific antigen PAL-E, associated with transport vesicles in non-barrier endothelium, is almost absent from barrier capillaries in the normal brain and retina. We have recently demonstrated that only leaking retinal capillaries in diabetic retinopathy (DR) in humans characteristically express PAL-E. Here we investigated the relation between the expression of the PAL-E antigen and vascular endothelial growth factor-A (VEGF) in human post-mortem eyes of individuals with diabetes mellitus (DM) and in experimental VEGF-induced retinopathy in cynomolgus monkeys. Cryosections were cut of eyes of 41 individuals with and 30 individuals without DM and eyes of 2 cynomolgus monkeys who received 4 injections of 0.5 microg VEGF in the vitreous of one eye and PBS in the other. The sections were stained with antibodies against VEGF, PAL-E and endogenous markers for microvascular leakage. Specific retinal vascular staining for VEGF was only observed in 10 out of the 41 cases with DM. These 10 cases also had marked uniform PAL-E staining and widespread vascular leakage. In contrast, diabetic patients without microvascular leakage and controls were negative for VEGF and PAL-E. Likewise, PAL-E was found only in the leaky retinal vessels of monkey eyes injected with VEGF. These results indicate that increased expression of the PAL-E antigen in retinal endothelium in conditions with microvascular leakage is related to VEGF and suggest that VEGF directly or indirectly induces PAL-E. PAL-E expression may reflect important endothelial changes involved in the disturbance of the blood-retina barrier in DR.