Vitrectomy and external drainage of subretinal fluid containing high concentration of vascular endothelial growth factor for advanced coats disease.

This study investigated the surgical outcomes of Coats disease and the role of external drainage (XD) of subretinal fluid (SRF). The study is a multicenter retrospective interventional case series of 26 consecutive eyes of 26 patients who underwent surgeries for advanced Coats disease with retinal detachment. Main outcomes measured were: 1) comparison of complete SRF resolution with or without XD, and 2) variables that were associated with functional postoperative best-corrected visual acuity (BCVA) defined as BCVA of 0.1 or better, 3) intraocular vascular endothelial growth factor (VEGF) levels. Complete SRF resolution was achieved in all 14 eyes in which XD had been performed and in 75% of 12 eyes in which XD had not been performed (P = .03). Multivariable logistic regression analysis revealed that initial BCVA was the only variable associated with functional postoperative BCVA (odds ratio 3.24, 95% CI 0.93-11.33; P = .04). Markedly elevated VEGF levels were noted in the SRF compared with those in the vitreous humor (49,760 ± 52,990 vs. 707 ± 611 pg/mL, P = .03). XD seems to provide better anatomical success than without XD in the treatment of advanced Coats disease as XD could effectively eliminate substantial amount of VEGF in the SRF.

Oral Ursodeoxycholic Acid Crosses the Blood Retinal Barrier in Patients with Retinal Detachment and Protects Against Retinal Degeneration in an Ex Vivo Model.

Rhegmatogenous retinal detachment (RD) is a threatening visual condition and a human disease model for retinal degenerations. Despite successful reattachment surgery, vision does not fully recover, due to subretinal fluid accumulation and subsequent photoreceptor cell death, through mechanisms that recapitulate those of retinal degenerative diseases. Hydrophilic bile acids are neuroprotective in animal models, but whether they can be used orally for retinal diseases is unknown. Ursodeoxycholic acid (UDCA) being approved for clinical use (e.g., in cholestasis), we have evaluated the ocular bioavailability of oral UDCA, administered to patients before RD surgery. The level of UDCA in ocular media correlated with the extent of blood retinal barrier disruption, evaluated by the extent of detachment and the albumin concentration in subretinal fluid. UDCA, at levels measured in ocular media, protected photoreceptors from apoptosis and necrosis in rat retinal explants, an ex vivo model of RD. The subretinal fluid from UDCA-treated patients, collected during surgery, significantly protected rat retinal explants from cell death, when compared to subretinal fluid from control patients. Pan-transcriptomic analysis of the retina showed that UDCA upregulated anti-apoptotic, anti-oxidant, and anti-inflammatory genes. Oral UDCA is a potential neuroprotective adjuvant therapy in RD and other retinal degenerative diseases and should be further evaluated in a clinical trial.

Genetic factors associated with treatment response to reduced-fluence photodynamic therapy for chronic central serous chorioretinopathy.

Purpose: Reduced-fluence photodynamic therapy (RFPDT) has proven effective for some patients with chronic central serous chorioretinopathy (cCSC). Several clinicodemographic factors influencing treatment response have been identified, but associations with genetic factors have not been examined. Therefore, we investigated the associations of single nucleotide polymorphisms (SNPs) implicated in cCSC pathogenesis with clinical outcome following RFPDT. Methods: This was a retrospective study of 87 eyes from 87 patients with cCSC who underwent RFPDT and were followed up for more than 12 months. Patients were divided into a good response group (53 patients) and a poor response group (34 patients) based on either persistence or recurrence of subretinal fluid detected with spectral domain optical coherence tomography after the first application of RFPDT. SNPs in the genes encoding age-related maculopathy susceptibility protein 2 (ARMS2, SNP rs10490924) and complement factor H (CFH, SNP rs800292) were genotyped using TaqMan technology. Results: There were no statistically significant differences in the baseline characteristics between the response groups except the degree of hyperfluorescence on indocyanine green angiography (ICGA; p = 0.011). The minor (T) allele frequency of ARMS2 (rs10490924) were statistically significantly lower in the good response group than in the poor response group (24.0% versus 41.0%, p = 0.021). Further, the good response frequency was statistically significantly lower in patients with at least one minor allele (GT or TT) compared to the homozygous major allele group (GG; p<0.05). The baseline best-corrected visual acuity (BCVA) at 12 months after RFPDT was statistically significantly better in the GG carriers than in the GT or TT carriers (p<0.01). Logistic regression analysis showed less intense hyperfluorescence on ICGA, and the T allele of ARMS2 (rs10490924) was statistically significantly associated with poor response to PDT treatment (p = 0.012, p = 0.039, respectively). Conclusions: Carriers of the ARMS2 rs10490924 minor allele (GT or TT) demonstrated a higher subretinal fluid persistence or recurrence rate and poorer visual outcome following RFPDT. In addition to the ICGA findings, genotyping of ARMS2 (rs10490924) may assist in the selection of patients with cCSC most likely to benefit from RFPDT.

A Swine Model of Selective Geographic Atrophy of Outer Retinal Layers Mimicking Atrophic AMD: A Phase I Escalating Dose of Subretinal Sodium Iodate.

PURPOSE: To establish the dose of subretinal sodium iodate (NaIO3) in order to create a toxin-induced large animal model of selective circumscribed atrophy of outer retinal layers, the retinal pigment epithelium (RPE), and photoreceptors, by spectral-domain optical coherence tomography (SD-OCT) and immunocytochemistry. METHODS: Fifteen male and female healthy Yorkshire pigs received unilateral subretinal escalating doses of NaIO3 under general anesthesia. In all the animals, volumes of 0.1 to 0.2 mL NaIO3 were injected into the subretinal space of the area centralis through a 23/38-gauge subretinal cannula. Control SD-OCTs were performed 1 and 2 months after the surgery, at which time pigs were euthanized and eyes enucleated. Globes were routinely processed for histologic and immunohistochemical evaluation. RESULTS: Spectral-domain OCT and immunohistochemistry revealed circumscribed and well-demarcated funduscopic lesions, limited to the outer retinal layers in pigs treated with 0.01 mg/mL subretinal sodium iodate. CONCLUSIONS: The swine model of a controlled area of circumscribed retinal damage, with well-delimited borders, and selectively of the outer layers of the retina presented herein shows several clinical and histologic features of geographic atrophy in AMD. Therefore, it may represent a valuable tool in the investigation of new emerging regenerative therapies that aim to restore visual function, such as stem cell transplantation or optogenetics.

Minimally invasive curved-micro-drainer (CMD) capable of innocuous drainage of subretinal fluid for the treatment of retinal detachment.

Retinal detachment is a serious vision threatening disease. Current consensus for the treatment of retinal detachment is to reattach the retina onto the choroid layer by drainage of accumulated subretinal fluid. Although several surgical methods have been developed, no satisfactory visual outcome has been obtained without surgical complications such as unintended puncture and hemorrhage of the retina and choroid tissue. In this study, we developed a novel Curved-Micro-Drainer (CMD) for the innocuous drainage of subretinal fluid. It is a curved structure with a 15° beveled tip that is 5 mm in length, with an 80 µm inner diameter and a 100 µm outer diameter. This high inner-to-outer diameter ratio of CMD with a 100 µm outer diameter allows efficient drainage of highly viscous subretinal fluid in a minimally invasive manner. In addition, the curved structure precisely matches the spherical ocular structure, which facilitates the CMD insertion into the subretinal space without choroid tissue damage. We demonstrate that the optimized CMD allows for the innocuous drainage of the viscous subretinal fluid from the porcine eye, whereas the traditional hypodermic needle (31-gauge) induces severe retinal and choroid damage. CMD can overcome a critical safety issue and is a potential alternative to conventional surgical interventions for the innocuous drainage of subretinal fluid.

The Origin of Subretinal Fluid in Optic Disc Pit Maculopathy.

A surgical approach for the drainage of fluid leaking over the pit in optic disc pit maculopathy is described, and a theory of the origin of fluid is discussed. In two cases, complete fluid-air exchange was performed. The air infusion pressure was decreased to 5 mm Hg, and the collected fluid was drained by raising the infusion pressure to 25 mm Hg. The fluid inside the back-flush needle was routed via a microcentrifuge tube. Biochemical analyses of the fluids were conducted in order to find their origin. Results of the first and second case were comparable to normal cerebrospinal fluid (CSF) levels (chloride: 125 mmol/L, 122 mmol/L; sodium: 146 mmol/L, 147 mmol/L; potassium: 2.8 mmol/L, 3.0 mmol/L; protein: 29 mg/dL, 18.4 mg/ dL; and glucose: 60 mg/dL, 57 mg/dL, respectively). These findings suggest that the origin of subretinal fluid found in the submacular space in optic disc pit maculopathy is CSF.

Optical Intensities of Different Compartments of Subretinal Fluid in Acute Vogt-Koyanagi-Harada Disease.

PURPOSE: To investigate the optical intensity in different compartments of subretinal fluid in acute Vogt-Koyanagi-Harada (VKH) disease by using spectral domain optical coherence tomography (SD-OCT). METHODS: Fifty acute VKH eyes and 25 cases with acute central serous chorioretinopathy (CSCR) were included in this retrospective comparative study. The optical intensities of subretinal fluid, vitreous humour and the entire scanned region displayed by SD-OCT were measured with Image J by three independent readers. In the VKH eyes with subretinal septa, the subretinal fluid was segmented into two types of compartments, supra-septa space and sub-septa space. Optical intensity ratios of different compartments of subretinal fluids divided by vitreous humour or the entire scanned region were compared. RESULTS: The measurement of optical intensity was highly reproducible (intraclass correlation coefficient> 0.9). The optical intensity of the supra-septa space divided by the vitreous humour was significantly higher compared to that of sub-septa space in VKH (mean difference = 4.27 ± 5.15, p <0.001). The optical intensity ratio of the supra-septa space (1.14 ± 0.12), but not subsepta space (1.05 ± 0.05) in VKH, was significantly higher compared to that of the subretinal space in VKH without the subretinal septa (1.07 ± 0.08), and the subretinal fluid in CSCR (1.08 ± 0.09). Similar results were found for the optical intensity ratios divided by the entire scan region. CONCLUSION: The optical intensity in the supra-septa space of VKH is higher compared to the sub-septa space in VKH, subretinal space in VKH and CSCR, suggesting that the components in these spaces are different.

Detection of Mycobacterium tuberculosis Genome in Subretinal Fluid of Patients with Latent Tuberculosis Infection.

PURPOSE: To test our hypothesis that Mycobacterium tuberculosis (MTB) DNA may be present in retinal pigment epithelium (RPE) cells in individuals with latent tuberculosis (TB) infection. METHODS: A total of 100 patients with rhegmatogenous retinal detachment (without any signs of endogenous uveitis in either eye) underwent pars plana vitrectomy (PPV) with internal tamponade. All were subjected to tuberculin skin test. None had manifest systemic TB disease. The subretinal fluid collected during surgery was subjected to multitargeted polymerase chain reaction (PCR) targeting three genes of MTB (IS6110, MPB64 and protein b). RESULTS: In total, 16 patients had latent TB, of which TB PCR was positive in six patients. CONCLUSIONS: We demonstrate presence of MTB genome in the subretinal fluid containing RPE cells from individuals with latent TB infection, who did not have any evidence of intraocular TB or manifest systemic TB disease, and suggest that MTB can be sequestrated in the RPE cells in latent TB.

Chemokine CXCL-1: activity in the vitreous during proliferative vitreoretinopathy.

The aim of this study was to investigate CXCL-1 chemokine levels in the vitreous during rhegmatogenous retinal detachment (RRD) with and without proliferative vitreoretinopathy (PVR) and identify possible correlations with clinical parameters (extent and duration or RRD and PVR grade). Vitreous samples from patients with primary RRD with or without PVR were collected and assayed using a double antibody enzyme-linked immunosorbent assay (ELISA). Eleven vitreous samples from organ donors were employed as a control group. CXCL-1 levels were measured in 35 vitreous samples from 35 RRD patients. Mean CXCL-1 levels (64·82 ± 6·47 pg/ml) were significantly higher (P = 0·048) compared to controls. There was a significant positive correlation between CXCL-1 levels and the extent of the detachment (r = 0·794, P = 0·006). Peak CXCL-1 levels coincided with 3+ quadrant RRD, an interim of 29-60 days' duration and PVR grade B. Increased CXCL-1 levels may be indicative of mild inflammation in the detached retina and the adjacent vitreous. The results of the present study may provide novel insight into the complex interactions taking place during the early and late stages of RRD complicated by PVR.

Longitudinal optical density analysis of subretinal fluid after surgical repair of rhegmatogenous retinal detachment.

PURPOSE: To investigate optical coherence tomography-derived reflectivity and optical density (OD) characteristics of persistent subretinal fluid (SRF) in eyes after surgical repair of macula-off rhegmatogenous retinal detachment. METHODS: Retrospective case series of nine eyes with macula-off rhegmatogenous retinal detachment that underwent surgical repair with either scleral buckling or vitrectomy with or without scleral buckling. Major inclusion criteria included 1) availability of high-quality optical coherence tomography scans at 2 or more time points, and 2) sufficient SRF for optical coherence tomography sampling without including tissue edges. Demographic, clinical, and optical coherence tomography imaging data were collected on all eyes. Optical density and SRF height measurements were obtained using a manual image segmentation method with ImageJ. Optical density measurements were standardized by conversion to optical density ratios to facilitate comparison between different visits and eyes. Correlations were assessed for significance through both univariate and multivariate regression analyses. RESULTS: Optical density ratio measurements increased with time after surgery, and this was statistically significant (P = 0.001, R = 0.331). Subretinal fluid height measurements decreased in all eyes. There was a significant correlation between optical density ratios and log of SRF height (P ≤ 0.001, R = 0.485). In multivariate analysis, neither optical density ratios nor SRF height was a statistically significant predictor of visual acuity. CONCLUSION: Changes in optical density ratios of the residual SRF after retinal detachment repair may be representative of changes in the SRF composition over time. This is in agreement with previous biochemical studies and may serve as a noninvasive method of assessing SRF content in vivo.

Increased vascular endothelial growth factor level in the subretinal fluid of eye with vasoproliferative retinal tumors.

PURPOSE: To describe a level of vascular endothelial growth factor (VEGF) in the subretinal fluid obtained from a case with vasoproliferative retinal tumors (VPRTs). METHODS: A 30-year-old male patient presented with VPRTs subsequent to long-standing rhegmatogenous retinal detachment. RESULTS: The patient was treated with encircling scleral buckling, cryopexy, and intravitreal bevacizumab injection. The protein level of VEGF in the subretinal fluid was measured and compared with those in the subretinal fluid obtained from patients with rhegmatogenous retinal detachment. Vascular endothelial growth factor level in the subretinal fluid from a patient with VPRTs was 12,997.9 pg/mL, whereas the mean VEGF concentration in the subretinal fluid from 4 patients with rhegmatogenous retinal detachment was 2.1 ± 2.8 pg/mL. CONCLUSION: The current data provide the evidence that VEGF production has increased in eyes with VPRTs and anti-VEGF therapy is theoretically effective for the treatment of VPRTs.

Amino acid and vascular endothelial growth factor levels in subretinal fluid in rhegmatogenous retinal detachment.

PURPOSE: To study the concentrations of amino acids and vascular endothelial growth factor (VEGF) in subretinal fluid (SRF) of cases with rhegmatogenous retinal detachment (RRD). The relevance of the results with postoperative anatomic and functional success in RRD was investigated. METHODS: Fifty-three patients were included in this prospective study. The study group consisted of 46 patients who had scleral buckling surgery with the diagnosis of RRD, and SRF was obtained during the surgery. The control specimens consisted of vitreous samples of seven patients who were diagnosed with pars plana vitrectomy without RRD. Study cases were divided into three groups, corresponding to the duration of retinal detachment. Clinical characteristics, including best corrected visual acuity (BCVA) and anatomic status at month 6, were recorded. Concentrations of 15 selected amino acids were quantified by using high performance liquid chromatography, and VEGF levels were measured with enzyme immunoassay. RESULTS: When compared with the control group, SRF concentrations of aspartate, citrulline, glutamate, and glycine increased significantly in the study group (p<0.05). Statistical analysis showed that concentrations of alanine, isoleucine, leucine, methionine, phenylalanine, threonine, tyrosine, and valine decreased (p<0.05). SRF levels of glutamine, taurine, and serine had no significant change. SRF VEGF levels were significantly higher than the vitreous samples of the controls (p<0.001). Time-dependent changes and interactions between VEGF and amino acids were observed. There was no correlation between the concentrations of amino acids or VEGF with the parameters of BCVA and anatomical success. CONCLUSIONS: Significant changes occur in concentrations of amino acids and VEGF in SRF of cases with RRD. Our results suggest that several mechanisms contribute to the pathophysiology.

Differential optical density of subretinal spaces.

PURPOSE: We investigated the optical density characteristics of 3subretinal spaces in neovascular age-related macular degeneration (AMD), diabetic retinopathy (DR), rhegmatogenous retinal detachment (RRD), central serous retinopathy (CSR), retinoschisis (RS), and pseudophakic cystoids macular edema (PCME). METHODS: Patients in whom subretinal fluid (SRF) was detected by optical coherence tomography (OCT), and whose earliest OCT scans showed sufficient SRF for sampling that did not include tissue edges, were chosen for study. The highest quality B-scan containing SRF (as graded by the OCT image acquisition software) was analyzed. Optical density measurements were obtained using ImageJ, an open code Java-based image processing software. RESULTS: The diagnoses of the 71 patients who met the inclusion criteria were AMD in 17, DR in 7, RRD in 18, CSR in 17, RS in 8, and PCME in 4. Optical density ratios (ODRs) were calculated as SRF OD divided by vitreous OD. ODRs were significantly higher in patients with AMD, DR, CSR, and PCME than in those with RRD and RS. No significant difference in vitreous reflectivity was detected between the former and latter patients. CONCLUSIONS: The finding that disease states produce significant changes in optical density ratios calls for further investigation of the possible usefulness of the parameter in differentiating between disease states, determining the outcome of various retinal diseases, and designing therapies aimed at treating the disease by correcting the abnormal density.

Antiangiogenic isoforms of vascular endothelial growth factor predominate in subretinal fluid of patients with rhegmatogenous retinal detachment and proliferative vitreoretinopathy.

BACKGROUND: In proliferative vitreoretinopathy (PVR), a nonangiogenic eye disease that is characterized by the formation of mainly avascular membranes, vascular endothelial growth factor (VEGF) levels are found to be upregulated. Recently, it was discovered that VEGF is alternatively spliced to form the angiogenic (VEGF xxx) and antiangiogenic (VEGF xxx b) family of isoforms. Previous studies on expression of VEGF in PVR samples have not distinguished between the two families of isoforms. METHODS: We measured total VEGF and VEGF xxx b levels in subretinal fluid of patients with PVR (n = 10) and in patients with uncomplicated rhegmatogenous retinal detachment (n = 27) using enzyme-linked immunosorbent assay. RESULTS: : We found total VEGF levels to be 2- to 3-fold elevated in the PVR group as compared with the rhegmatogenous retinal detachment group (P = 0.047). Antiangiogenic VEGF xxx b isoforms predominated (>60% of total VEGF) in the majority of rhegmatogenous retinal detachment and PVR samples investigated, although a wide variability of isoform ratios was observed within both groups. CONCLUSION: The absence of an increased ratio of VEGF xxx to VEGF xxx b in patients with PVR as compared with patients with uncomplicated rhegmatogenous retinal detachment may explain a lack of blood vessels in PVR membranes. Elevated VEGF levels indicate that this cytokine may play a role in the pathogenesis of PVR that is not related to angiogenesis.