Roberto dell'Omo

Diabetic Retinopathy: Vascular and Inflammatory Disease

Diabetic retinopathy (DR) is the leading cause of visual impairment in the working-age population of the Western world. The pathogenesis of DR is complex and several vascular, inflammatory, and neuronal mechanisms are involved. Inflammation mediates structural and molecular alterations associated with DR. However, the molecular mechanisms underlying the inflammatory pathways associated with DR are not completely characterized. Previous studies indicate that tissue hypoxia and dysregulation of immune responses associated with diabetes mellitus can induce increased expression of numerous vitreous mediators responsible for DR development. Thus, analysis of vitreous humor obtained from diabetic patients has made it possible to identify some of the mediators (cytokines, chemokines, and other factors) responsible for DR pathogenesis. Further studies are needed to better understand the relationship between inflammation and DR. Herein the main vitreous-related factors triggering the occurrence of retinal complication in diabetes are highlighted.

TNF-Alpha Levels in Tears: A Novel Biomarker to Assess the Degree of Diabetic Retinopathy

We assess the level of tumour necrosis factor alpha (TNF-alpha) in tear fluids and other serum parameters associated with diabetes in different degrees of diabetic retinopathy. We have performed a prospective, nonrandomized, observational study. Study population consisted of 16 healthy subjects (controls) and 32 type 2 diabetic patients: 16 affected by proliferative diabetic retinopathy (PDR) and 16 with nonproliferative retinopathy (NDPR, background/preproliferative). Body mass index, urinary albumin, blood glucose, HbA1c, and tear levels of TNF-alpha were measured in all subjects. The value of glycaemia, microalbuminurea, and Body mass index in diabetic retinopathy groups were higher than those in control group (P < 0.05). Glycemia in NPDR: 6.6 mmol/L (range: 5.8–6.3); in PDR: 6.7 mmol/L (range: 6.1–7.2); in control: 5.7 mmol/L (range: 4.9–6.1); microalbuminurea in NPDR: 10.6 mg/L (range: 5.6–20); in PDR: 25.2 mg/L (range: 17–40); in control: 5.3 mg/L (range: 2.6–10); Body mass index in NPDR: 26 Kg/m2 (range: 20.3–40); in PDR: 28 Kg/m2 (range 20.3–52); in control: 21 Kg/m2 (range 19–26). The TNF-alpha concentrations in tears increase with the severity of pathology and were lower in control group than in diabetic subjects. In the end, the level of TNF-alpha is highly correlated with severity of diabetic retinopathy and with nephropathy. Tear fluid collection may be a useful noninvasive method for the detection of proliferative diabetic retinopathy.

Low fluence rate photodynamic therapy combined with intravitreal bevacizumab for neovascular age related macular degeneration.

Aims To report the efficacy and safety of intravitreal bevacizumab (IVB) alone versus IVB plus low-fluence photodynamic therapy (PDT) in age-related macular degeneration (AMD) patients and to verify the occurrence of a synergistic effect of the combined approach on visual acuity, size and morphology of lesion, as well as on the treatment rate. Method Prospective comparative interventional study on 85 patients with treatment-naive classic, or predominantly classic, subfoveal choroidal neovascularisation secondary to AMD. Patients were randomly assigned to group 1 (IVB injections) and group 2 (IVB plus low fluence PDT). In group 2, the PDT with verteporfin was delivered with a low fluence rate (300 mW/cm2 for 83 s, 25 J/cm2). The follow-up was scheduled at 1, 3, 6, 9 and 12 months. Results The eye without recurrence received a mean of 2.8 (group 1) versus 1.4 (group 2) IVB injections, whereas the eyes with recurrence received a mean of 3.2 (group 1) versus 2.2 (group 2) IVB injections. The difference in reinjection rate between the two groups was statistically significant (p=0.03, ANOVA test). Visual acuity improvement was not statistically significant between the two groups (p=0.31). Conclusion The combination of IVB with low fluence PDT for the treatment of classic or predominantly classic neovascular AMD works in a synergistic fashion with a significant reduction in IVB reinjections rate.

Topical Nonsteroidal Anti-Inflammatory Drugs for Macular Edema

Nonsteroidal anti-inflammatory drugs (NSAIDs) are nowadays widely used in ophthalmology to reduce eye inflammation, pain, and cystoid macular edema associated with cataract surgery. Recently, new topical NSAIDs have been approved for topical ophthalmic use, allowing for greater drug penetration into the vitreous. Hence, new therapeutic effects can be achieved, such as reduction of exudation secondary to age-related macular degeneration or diabetic maculopathy. We provide an updated review on the clinical use of NSAIDs for retinal diseases, with a focus on the potential future applications.

Pharmacotherapy of intraocular pressure: part I. Parasympathomimetic, sympathomimetic and sympatholytics.

Elevated intraocular pressure (IOP) has been recognized as the major risk factor for the development of glaucoma and a wide range of options are now available to reduce it: medical treatment, laser, filtering, or cyclodestructive surgery (alone or in combination). All these modalities act by decreasing eye pressure and, thereby, protecting the optic nerve head from a mechanic direct and/or vascular indirect insult. Topical medical therapy represents the first-choice treatment and, in most cases, it effectively controls IOP, avoiding the occurrence of further optic nerve damage. All medications lower IOP in two main ways: decreasing the production of aqueous humour or by increasing its outflow from the eye. Consequently, antiglaucoma drugs either suppress aqueous humour formation (β-adrenergic antagonists, carbonic anhydrase inhibitors, and alpha-2-adrenergic agonists) or raise aqueous humour outflow throughout the conventional (e.g., pilocarpine) or uveoscleral (prostaglandin FP receptor agonists, and prostamides) route. In addition, fixed and unfixed combinations of antiglaucoma compounds have also been available for patients requiring more than one type of medication. This review, which is part one of two (please see Expert Opinion on Pharmacotherapy 10 (17)) briefly considers the characteristics of sympathomimetic, sympatholytics and parasympathomimetic commonly employed in the medical treatment of glaucoma, mainly the primary open-angle form, focusing the discussion on the clinical evidence supporting the use of these three classes of compound.

Natural evolution of fundus autofluorescence findings in multiple evanescent white dot syndrome: a long-term follow-up.

Purpose: The purpose of the study was to investigate the natural evolution of fundus autofluorescence (FAF) findings in eyes with multiple evanescent white dot syndrome. Methods: This was a retrospective, observational case series of nine eyes of eight consecutive patients with multiple evanescent white dot syndrome who underwent color fundus photographs, fluorescein and indocyanine green angiography, and FAF photography in two referral practices. Results: The mean follow-up was 8.6 months (range, 3-14 months). In the acute/ subacute phase, FAF showed 1) hypoautofluorescent areas, ≤50 μm in size, mostly concentrated around the optic disk and posterior pole; and 2) areas of increased autofluorescence usually found in correspondence to the white dots seen ophthalmoscopically. During the follow-up period, some of the hypoautofluorescent areas faded away, others persisted; the areas originally showing increased autofluorescence variably tended to: 1) become smaller and more demarcated; 2) retract centripetally becoming small hyper-autofluorescent areas surrounded by an hypoautofluorescent halo; 3) turn into areas of decreased autofluorescence; or 4) disappear without becoming hypofluorescent. Conclusion: Multiple evanescent white dot syndrome represents a unique model to study the natural evolution of FAF findings in chorioretinal affections, from the acute phase to resolution; FAF findings, evaluated along with fluorescein and indocyanine green angiography features, can expand our understanding about retinal pigment epithelium and retinal involvement in this rare chorioretinal disorder.

Relationship between different fluorescein and indocyanine green angiography features in multiple evanescent white dot syndrome

Objectives: To study the relationship between different fluorescein and indocyanine green angiographic features in a case series of multiple evanescent white dot syndrome (MEWDS) and to gain insight into its pathophysiological nature. Methods: Retrospective review of seven patients (eight eyes) with MEWDS (selected based on clinical and angiographic manifestations of the disorder) examined using slit-lamp biomicroscopy and studied using fluorescein angiography (FA) and indocyanine green angiography (ICGA). Results: In the clinically affected eyes, FA early phases revealed hyperfluorescence in three eyes and a combination of hyper- and hypofluorescence in five eyes; the following relationships between FA and ICGA were found: (1) areas of early hypo- and late hyperfluorescence (staining and leakage) on FA corresponding to areas of early hypo and late hypo-,iso or hyperfluorescence on ICGA; (2) early and late hyperfluorescence (staining but very faint, if any, leakage) on FA corresponding to normal early ICGA and intermediate-late hypofluorescence; (3) areas of hypo- and hyperfluorescence on ICGA without a clear counterpart on FA. Conclusions: Angiographic features may vary in eyes with similar clinical signs of MEWDS. Such variability could reflect the different anatomical structures involved during the natural evolution of the disease. Angiographic studies suggest that both, inner and outer choroid, are involved in this disorder. The final outcome is not affected by the initial angiographic presentation.

Aqueous humor levels of vascular endothelial growth factor before and after intravitreal bevacizumab in type 3 versus type 1 and 2 neovascularization: a prospective, case-control study.

PURPOSE To determine the aqueous levels of vascular endothelial growth factor (VEGF) in patients with type 3 neovascularization (NV) secondary to age-related macular degeneration (AMD) and to compare the levels of those with type 1 and 2 NV secondary to AMD before and after administration of intravitreal bevacizumab (IVB). DESIGN Prospective, case-control study. METHODS Aqueous samples were collected from 29 eyes of 29 patients with untreated wet AMD at baseline (day of the first IVB), month 1 (day of the second IVB), and month 2 (day of the third IVB). Among them, 10 eyes presented with type 1, 9 with type 2, and 10 with type 3 NV. A group of 14 aqueous samples from 14 patients who underwent cataract surgery without other ocular or systemic disease comprised the controls. Main outcome measures were concentration of VEGF at baseline and after IVB in the 3 NV groups; secondary outcome measures included best-corrected visual acuity (BCVA) and central macular thickness (CMT) changes after IVB. Levels of VEGF were determined by commercially available enzyme-linked immunosorbent assay kits. RESULTS VEGF concentrations in aqueous humor at baseline were higher in patients with type 3 NV when compared to controls (P = .0001) and type 1 and 2 NV patients (P = .002 and P = .0001 respectively). At month 1, levels of VEGF were significantly reduced compared to baseline (P < .05) and significantly lower compared to the controls (P < .005) in each NV group. These low levels were maintained at the 2-month interval. BCVA significantly improved in type 1 and 2 NV groups (P < .05). CMT significantly reduced in each NV group compared to baseline (P < .05). CONCLUSION In eyes with untreated wet AMD, aqueous levels of VEGF are significantly higher in type 3 NV than in type 1 or 2 NV. Regardless of the type of NV, aqueous VEGF levels significantly reduce 1 month after IVB as compared to both the baseline measurements and the values recorded in age-matched controls. These decreases are maintained at 2 months after administering a second IVB 30 days after the initial injection.

Vitreous Mediators in Retinal Hypoxic Diseases

The causes of retinal hypoxia are many and varied. Under hypoxic conditions, a variety of soluble factors are secreted into the vitreous cavity including growth factors, cytokines, and chemokines. Cytokines, which usually serve as signals between neighboring cells, are involved in essentially every important biological process, including cell proliferation, inflammation, immunity, migration, fibrosis, tissue repair, and angiogenesis. Cytokines and chemokines are multifunctional mediators that can direct the recruitment of leukocytes to sites of inflammation, promote the process, enhance immune responses, and promote stem cell survival, development, and homeostasis. The modern particle-based flow cytometric analysis is more direct, stable and sensitive than the colorimetric readout of the conventional ELISA but, similar to ELISA, is influenced by vitreous hemorrhage, disruption of the blood-retina barrier, and high serum levels of a specific protein. Finding patterns in the expression of inflammatory cytokines specific to a particular disease can substantially contribute to the understanding of its basic mechanism and to the development of a targeted therapy.

Restoration of foveal thickness and architecture after macula-off retinal detachment repair.

PURPOSE To investigate the foveal changes after repair of macula-off rhegmatogenous retinal detachment (RRD). METHODS Prospective comparative case series. Twenty-four eyes of 24 patients with macula-off/fovea-on detachment (n = 9) and fovea-off detachment (n = 15) were studied. Serial optical coherence tomography (OCT) images taken at the same location were recorded at months 1, 3, 6, and 12 after operation. Fellow eyes were used as controls. RESULTS No significant changes of the central foveal thickness (CFT) were recorded in the fovea-on group over the follow-up. From month 1 to month 12, CFT increased significantly in the fovea-off group (P < 0.00001). In this group, a significant increase of the Henle fiber and outer nuclear layer (HFL + ONL, P = 0.007), external limiting membrane (ELM)-ellipsoid zone (EZ; P = 0.03), and EZ-retinal pigment epithelium (RPE) thicknesses (P < 0.00001) was recorded. Significant restoration of the integrity of the ELM in the fovea-off group (P < 0.001) and of the EZ and cone interdigitation zone in the fovea-on group and the fovea-off group was observed (P = 0.02 and P < 0.001, and P = 0.002 and P < 0.001, respectively). Twelve months after operation the foveal bulge restored in 8 of 15 eyes of the fovea-off group. Multiple regression analysis showed that in the fovea-off group BCVA correlated with EZ-RPE thickness at months 1 and 12, whereas the improvement of BCVA during the 12 months follow-up correlated with the increase of ELM-RPE thickness. CONCLUSIONS Optical coherence tomography scans taken serially at the same location showed a progressive increase of HNL+ONL, ELM-EZ, and EZ-RPE thicknesses and restoration of the integrity of outer retinal bands after repair of fovea-off RRD. The use of software able to rescan at exactly the same area is crucial to correctly follow and interpret the reconstitution of the retinal bands and to correlate them to BCVA recovery.