Choroidal thickening with serous retinal detachment in BRAF/MEK inhibitor-induced uveitis: A case report.

BACKGROUND: Immune checkpoint inhibitors have revolutionized the treatment of patients with unresectable metastatic malignant melanoma. In addition to systemic side effects, several usually mild ocular adverse effects have been reported. We report a case of rarely reported vision-threatening bilateral panuveitis with serous retinal detachment, thickened choroid, and chorioretinal folds associated with dabrafenib and trametinib targeted therapy for B-Raf proto-oncogene serine/threonine kinase (BRAF) mutant metastatic cutaneous melanoma. CASE SUMMARY: A 59-year-old female patient with metastatic melanoma treated with dabrafenib and trametinib presented with blurry vision and central scotoma lasting for 3 d in both eyes. Clinical examination and multimodal imaging revealed inflammatory cells in the anterior chamber, mild vitritis, bullous multiple serous retinal detachments, and chorioretinal folds in both eyes. Treatment with dabrafenib and trametinib was suspended, and the patient was treated with topical and intravenous corticosteroids followed by oral corticosteroid treatment with a tapering schedule. One and a half months after the disease onset, ocular morphological and functional improvement was noted. Due to the metastatic melanoma dissemination, BRAF/mitogen-activated protein kinase inhibitors were reintroduced and some mild ocular adverse effects reappeared, which later subsided after receiving oral corticosteroids. CONCLUSION: Patients on combination therapy with dabrafenib and trametinib may rarely develop severe bilateral panuveitis with a good prognosis. Further studies have to establish potential usefulness of ophthalmological examination for asymptomatic patients. Furthermore, appropriate guidelines for managing panuveitis associated with dabrafenib and trametinib should be established.

The Role of VHL in the Development of von Hippel-Lindau Disease and Erythrocytosis.

Von Hippel-Lindau disease (VHL disease or VHL syndrome) is a familial multisystem neoplastic syndrome stemming from germline disease-associated variants of the VHL tumor suppressor gene on chromosome 3. VHL is involved, through the EPO-VHL-HIF signaling axis, in oxygen sensing and adaptive response to hypoxia, as well as in numerous HIF-independent pathways. The diverse roles of VHL confirm its implication in several crucial cellular processes. VHL variations have been associated with the development of VHL disease and erythrocytosis. The association between genotypes and phenotypes still remains ambiguous for the majority of mutations. It appears that there is a distinction between erythrocytosis-causing VHL variations and VHL variations causing VHL disease with tumor development. Understanding the pathogenic effects of VHL variants might better predict the prognosis and optimize management of the patient.

VISUAL OUTCOMES IN PATIENTS WITH DIABETIC MACULAR EDEMA TREATED WITH DEXAMETHASONE IMPLANT IN ROUTINE CLINICAL PRACTICE.

The aim was to evaluate visual outcomes of the real-life usage of dexamethasone (DEX) implants in diabetic macular edema (DME) patients and evaluate the possible additional visual acuity (VA) gain with combined treatment. We retrospectively reviewed medical records of DME patients treated with DEX implants. The mean best-corrected visual acuity (BCVA) and mean central retinal thickness (CRT) at baseline and one year were compared. BCVA improved from 58.4±14.9 letters at baseline to 62.4±14.5 letters at one-year evaluation (p=0.002). The mean change in BCVA was 5.2±11.1 letters. CRT decreased from 485.7±146.3 µm at baseline to 391.5±129.0 µm at one year (p<0.001). The mean change in CRT was -89.6±143.3 µm. Patients received a mean of 2.0±0.7 DEX implants. Study eyes were also divided into a group receiving DEX implant monotherapy and a group receiving DEX implant and vascular endothelial growth factor inhibitor (anti-VEGF) therapy. Changes in BCVA and CRT and the number of DEX implant injections were compared between the two groups. No difference in VA gain was found between the eyes receiving monotherapy and the eyes receiving combined treatment. In conclusion, DEX implant therapy was effective in gaining vision in DME patients. No additional VA gain was achieved with combined treatment.

Correlations between vitreous cytokine levels and inflammatory cells in fibrovascular membranes of patients with proliferative diabetic retinopathy.

Purpose: The purpose of this study was to investigate the levels of cytokines in the vitreous, and their correlation with the density of inflammatory cells in fibrovascular membranes (FVMs) in patients with proliferative diabetic retinopathy (PDR) to evaluate intraocular inflammatory conditions with regard to disease activity. Methods: Thirty-three patients (33 eyes) with PDR requiring vitreoretinal surgery because of FVMs and tractional detachment were enrolled in the study, and compared with 20 patients (20 eyes) with macular hole (MH; control group). All patients underwent complete ophthalmological examinations before surgery. The activity of the disease was noted in patients with PDR. Samples of vitreous and blood were taken, and cytokine (MCP-1, IL-8, IL-6, VEGF, IL-1ß, TNF-α, MIP-1α, MIP-1ß, IL-10, and IL-12) levels were measured using cytometric bead array (CBA). Samples of FVMs were analyzed with immunohistochemical methods for the presence of inflammatory cells (CD45+, CD14+, CD3+, CD4+, CD8+, and CD19+ cells), and the numerical areal density was calculated (NA). Spearman's correlation was used to assess the association between variables. The Mann-Whitney test was used to assess the differences between independent groups. The Wilcoxon signed-rank test was used for assessing differences between two related groups. A p value of less than 0.05 was considered statistically significant. Results: Patients with active PDR had statistically significantly higher levels of MCP-1 (p = 0.003), VEGF (p = 0.009), and IL-8 (p = 0.02) in the vitreous in comparison with those with inactive PDR. CD45+, CD14+, CD3+, CD4+, CD8+, and CD19+ cells were identified in FVMs for patients with PDR. Statistically significantly higher numerical areal density of T lymphocytes (CD3+, CD4+, and CD8+) was demonstrated in patients with active PDR in comparison with patients with inactive PDR. Moderate to strong correlations were found between either MCP-1 or IL-8 in the vitreous, and the numerical areal density of cells (CD45+, CD3+, CD4+, and CD8+) in the FVMs, and weaker between either MCP-1 or IL-8 in the vitreous and the numerical areal density of CD14+ cells in the FVMs. Conclusions: The correlation of cytokine (MCP-1 and IL-8) vitreous levels with the density of inflammatory cells in FVMs, and differences in cytokine levels in the vitreous between patients with active and inactive PDR, and between the vitreous and serum in PDR indicate the importance of local intraocular inflammation in patients with PDR.

Anti-VEGF Treatment of Diabetic Macular Edema: Two-Year Visual Outcomes in Routine Clinical Practice.

PURPOSE: The purpose of this study was to evaluate 2-year visual outcomes in patients with diabetic macular edema (DME) treated with anti-VEGF agents in a routine clinical setting. METHODS: The medical records of patients treated with ranibizumab or aflibercept due to DME at the Eye Hospital, University Medical Centre Ljubljana, Slovenia, between January 2016 and March 2019 were retrospectively reviewed. After applying inclusion and exclusion criteria, 123 patients (123 eyes) were included in the study. RESULTS: Baseline visual acuity (VA) was 60.9 ± 15.2 letters (median 63; range 7-85). Baseline central retinal subfield thickness (CRT) was 440.7 ± 132.5 µm (median 430; range 114-1000). No significant change in VA over 2 years was found (mean change +2.1 ± 16.8 letters (median 2; range -53-52)). However, there was a significant change in VA in the subgroup with baseline VA <70 letters (mean change +5.7 ± 17.9 letters (median 5; range -52-52)). VA gains of ≥15 letters were achieved in 25 eyes (20.3%). Changes in CRT were significant over 2 years. Patients received 4.5 ± 2.1 (median 5, range 1-9) and 2.6 ± 2.3 (median 2, range 0-8) injections in the first and second years, respectively. CONCLUSIONS: The two-year visual outcomes in this retrospective analysis appear to be comparable to previously reported outcomes in routine clinical practice. Our analysis provides some information about the effectiveness of anti-VEGF treatment in routine clinical practice in Slovenia. More intensive treatment should be implemented in the management of patients in order to achieve better visual outcomes.

Dexamethasone implant in the management of diabetic macular edema from clinician's perspective.

The aim of this article is to provide an overview of characteristics and principles of use of dexamethasone implant in patients with diabetic macular edema (DME). The condensed information about patient selection, dosing, and postinjection management is provided to make the clinician's decisions easier in real-life practice. DME is a common complication of diabetes and the leading cause of visual loss in the working-age population. Inflammation plays an important role in the pathogenesis of DME. The breakdown of the blood-retinal barrier involves the expression of inflammatory cytokines and growth factors, including vascular endothelial growth factor (VEGF). Steroids have proved to be effective in the treatment of DME by blocking the production of VEGF and other inflammatory cytokines, by inhibiting leukostasis, and by enhancing the barrier function of vascular endothelial cell tight junctions. Dexamethasone intravitreal implant has demonstrated efficacy in the treatment of DME resistant to anti-VEGF therapy and in vitrectomized eyes. Data from clinical trials suggest that dexamethasone implant can be considered as first-line treatment in pseudophakic eyes. Dexamethasone implant is also the first-line therapy in patients not suited for anti-VEGF therapy, pregnant women, and patients unable to return for frequent monitoring. It has been shown that the maximum effect of dexamethasone implant on visual gain and retinal thickness occurs approximately 2 months after injection. Various treatment regimens are used in real-life situations, and reported reinjection intervals were usually <6 months. The number of retreatments needed decreased over time. Treatment algorithms should be personalized. Postinjection management and follow-up should consider potential adverse events such as intraocular pressure elevation and cataract.

PREDICTING VISUAL OUTCOMES OF SECOND EYE VITRECTOMY FOR PROLIFERATIVE DIABETIC RETINOPATHY.

PURPOSE: To investigate predictive factors for visual outcome in the second operated eye of patients undergoing bilateral vitrectomy for proliferative diabetic retinopathy. METHODS: Clinical records of 55 patients undergoing bilateral vitrectomy for proliferative diabetic retinopathy at the University Eye Hospital Ljubljana between January 2009 and December 2014 were examined retrospectively. Statistical analysis was performed to identify variables associated with good visual outcomes. RESULTS: Mean preoperative visual acuity was 6/181 Snellen (1.48 ± 0.47 logarithm of minimal angle of resolution [logMAR]). The follow-up period after vitrectomy was at least 1 year and mean postoperative visual acuity improved to 6/31 Snellen (0.71 ± 0.62 logMAR). On univariate analysis, variables predicting good postoperative vision (6/12 Snellen or better) were the following: absence of macular detachment (P = 0.009), previously performed full panretinal laser (P = 0.03), and good vision in the previously vitrectomized fellow eye (P < 0.001). On multivariate analysis, the absence of macular detachment (P = 0.001) and good vision in the previously vitrectomized fellow eye (P < 0.001) were both independently associated with good visual outcome. CONCLUSION: In patients undergoing second eye vitrectomy for complications of proliferative diabetic retinopathy, the visual acuity of previously operated fellow eye and the presence of macular detachment in the eye due for vitrectomy may be strong independent predicting factors for visual outcome.

Visual Acuity, Retinal Sensitivity, and Macular Thickness Changes in Diabetic Patients without Diabetic Retinopathy after Cataract Surgery.

Aim. Functional and morphological macular study after cataract surgery in a group of diabetics without diabetic retinopathy compared to nondiabetics to evaluate the effect of surgical oxidative stress on diabetic retina. Methods. Prospective, comparative study. Preoperative eye exam, best corrected visual acuity (BCVA) measured by ETDRS letters, and optical coherence tomography (OCT) were followed by standard cataract surgery. The follow-up visits at 1, 3, and 6 months postoperatively included BCVA, OCT, and microperimetry, to analyze changes within and between the groups. Results. The BCVA improved significantly in diabetics and controls: 64.2 to 81.0 and 61.9 to 82.1 ETDRS at 6 months, respectively. The central macula at OCT significantly thickened in both groups, while the central 5 fields, corresponding to the microperimetry area, subclinically thickened from 284.20 to 291.18 µm at 6 months only in diabetics (p = 0.026). A matching slight decrease in the microperimetry sensitivity from 1 to 6 months was found also only in diabetics, with mean average difference -0.75 dB (p = 0.04). Conclusion. Underlying diabetes does not influence the surgical outcome in diabetics without diabetic retinopathy. However, slight thickening of wider macula and corresponding decrease in retinal sensitivity observed in diabetics 6 months postoperatively might influence visual function on long term.

Epiretinal membrane inflammatory cell density might reflect the activity of proliferative diabetic retinopathy.

PURPOSE: Diabetic retinopathy (DR) has features of chronic low-grade inflammation. The purpose of our study was to investigate whether the presence of inflammatory cells in fibrovascular membranes (FVMs) from patients with proliferative diabetic retinopathy (PDR) is associated with the activity of PDR and visual acuity improvement after vitreoretinal surgery. METHODS: Forty FVMs from 40 patients with PDR were obtained during vitrectomy, prepared by using the agar sandwich method, and examined using light microscope and immunohistochemistry methods to define the presence and density of inflammatory cells: CD45+ cells (leukocytes), CD4+ cells (T helper lymphocytes), CD8+ cells (T cytotoxic lymphocytes), CD19+ cells (B lymphocytes), and CD14+ cells (monocytes/macrophages). For each FVM, the inflammatory cell density defined as numerical areal density was calculated. The number of vessels was defined as the volume density of vessels. RESULTS: Among 40 patients with PDR, 33 patients had active PDR and 7 quiescent PDR. Significant differences in cell densities for CD4+, CD8+, and CD19+ cells were observed between patients with active and quiescent PDR. B lymphocytes were present in membranes of active PDR only. No correlation was observed between numerical areal density of inflammatory cells and the volume density of vessels. No association was found between visual acuity improvement after surgery and cell densities. CONCLUSIONS: Lymphocyte infiltration of FVMs might be associated with the activity of retinopathy but not with visual acuity improvement after surgery.

Floating vitreous cyst: two clinical cases.

PURPOSE: To report two cases of solitary unilateral vitreous cyst. METHODS: A complete ocular examination, fundus photography, B-scan ultrasound and spectral-domain optical coherence tomography were performed in both patients. RESULTS: The first patient (a 39-year-old man) presented with transient blurred vision in the right eye. The second patient (a 78-year-old man) reported transient blurred vision in the right eye when changing head position. He was referred to the Eye Hospital because of vitreomacular traction in the other eye. After examination, a diagnosis of vitreous cyst was made in both cases. CONCLUSIONS: Vitreous cysts are rare clinical findings. They can occur in normal eyes or in eyes with certain ocular pathologies. When a cyst floats into the visual axis area, it can disturb visual function; therefore, patients usually report transient blurring of vision. A prompt clinical examination is necessary for differentiating this rare condition.

Functional and molecular characterization of ex vivo cultured epiretinal membrane cells from human proliferative diabetic retinopathy.

Characterization of the cell surface marker phenotype of ex vivo cultured cells growing out of human fibrovascular epiretinal membranes (fvERMs) from proliferative diabetic retinopathy (PDR) can give insight into their function in immunity, angiogenesis, and retinal detachment. FvERMs from uneventful vitrectomies due to PDR were cultured adherently ex vivo. Surface marker analysis, release of immunity- and angiogenesis-pathway-related factors upon TNF α activation and measurement of the intracellular calcium dynamics upon mechano-stimulation using fluorescent dye Fura-2 were all performed. FvERMs formed proliferating cell monolayers when cultured ex vivo, which were negative for endothelial cell markers (CD31, VEGFR2), partially positive for hematopoietic- (CD34, CD47) and mesenchymal stem cell markers (CD73, CD90/Thy-1, and PDGFR ß ), and negative for CD105. CD146/MCAM and CD166/ALCAM, previously unreported in cells from fvERMs, were also expressed. Secretion of 11 angiogenesis-related factors (DPPIV/CD26, EG-VEGF/PK1, ET-1, IGFBP-2 and 3, IL-8/CXCL8, MCP-1/CCL2, MMP-9, PTX3/TSG-14, Serpin E1/PAI-1, Serpin F1/PEDF, TIMP-1, and TSP-1) were detected upon TNF α activation of fvERM cells. Mechano-stimulation of these cells induced intracellular calcium propagation representing functional viability and role of these cells in tractional retinal detachment, thus serving as a model for studying tractional forces present in fvERMs in PDR ex vivo.

A flow cytometric analysis of vitreous inflammatory cells in patients with proliferative diabetic retinopathy.

The purpose of this study was to investigate inflammatory cells in vitreous from patients with proliferative diabetic retinopathy (PDR) using flow cytometric analysis. Twenty-eight patients with PDR requiring vitrectomy because of macular traction or tractional retinal detachment were enrolled in the study (n = 28), and 6 patients with macular hole (MH) formed the control group. Samples of vitreous and peripheral venous blood were obtained at the beginning of vitrectomy. T lymphocytes were found in vitreous from patients with PDR, and CD4/CD8 ratio was higher in vitreous (median 4.3) compared to blood (median 1.9; P = 0.003). No B lymphocytes were detected in vitreous. The percentage of histiocytes/macrophages was significantly higher in vitreous (median 62.1) in comparison with blood (median 5.5; P < 0.0001). No lymphocytes were detected in vitreous of the control group. There were more T lymphocytes in vitreous from patients with active PDR. No association between cells in the vitreous and visual acuity improvement after surgery was found. In conclusion, T lymphocytes are found in vitreous from patients with PDR and reflect the activity of PDR but do not seem to predict visual prognosis. Higher CD4/CD8 ratio in vitreous compared to blood from patients with PDR is consistent with local inflammatory response in PDR.

Efficacy of 12-month treatment of neovascular age-related macular degeneration with intravitreal bevacizumab based on individually determined injection strategies after three consecutive monthly injections.

PURPOSE: To report the results of intravitreal treatment with bevacizumab in neovascular age-related macular degeneration (AMD) after a loading dose (LD) of three monthly injections followed by an optical coherence tomography (OCT)-guided strategy, based on best-corrected visual acuity (VA) and number of injections required over 1 year. METHODS: A series of consecutive cases of 149 eyes of 147 patients received three or more intravitreal injections of bevacizumab (1.25 mg) for neovascular AMD over a 1-year period. The patients underwent ophthalmological examinations: measurement of the VA, fluorescein angiography, dilated fundus examination at baseline; VA, OCT and dilated fundus examination at monthly follow-up visits. Repeated injections were given each month for the first 3 months (LD); thereafter, injections were only administered if leakage or macular oedema were present. RESULTS: Mean baseline VA was 51 ± 14 letters, which improved to 58 ± 15 letters (p < 0.0001; n = 149) at first evaluation (15 ± 2 weeks), 59 ± 15 letters (p < 0.0001; n = 143) at second evaluation (25 ± 2 weeks) and 57 ± 16 letters (p < 0.0001; n = 132) at third evaluation (51 ± 3 weeks). The baseline mean central retinal thickness (344.6 µm) and total macular volume (8.6 mm(3) ) decreased at first evaluation, to 219.0 µm (p < 0.0001) and 7.2 mm(3) (p < 0.0001), respectively. The mean number of injections per patient treated for 1 year was 5.1 (range 3-9). No systemic side-effects were noted. CONCLUSION: Treatment of neovascular AMD with intravitreal bevacizumab administered in LD of three monthly injections and followed by an OCT-guided strategy provides functional and anatomical improvements for up to 1 year.