Diffuse Vascular Leakage Research Articles

Analysis on the clinical features of sarcoid uveitis

Objective: To analyze the clinical features of patients with sarcoid uveitis. Methods: This was a retrospective case series study. The medical records of 19 086 patients with uveitis admitted to the Department of Ophtalmology, The First Affiliated Hospital of Chongqing Medical University from April 2008 to December 2019 were collected. The general data, medical history, treatment, diagnosis, follow-up, ophthalmic and other auxiliary examinations were retrospectively analyzed. The paired sample Wilcoxon signed rank test was used to compare the best corrected visual acuity (BCVA) of the affected eye at the first visit to the BCVA of the affected eye at the corresponding last visit. Results: A total of 51 patients (97 eyes) with sarcoid uveitis were included, including 15 males (29.4%) and 36 females (70.6%), with a male/female ratio of 1/2.4. There were 46 patients (88 eyes) with presumed sarcoidosis and 5 patients (9 eyes) with definite sarcoidosis. The age of onset was 48 (40, 55) years and 90.2% of patients (46 cases) were involved in both eyes, while 88.2% of the patients (45 cases) were chronic, and only 11.8% (6 cases) showed acute inflammatory response. Anterior uveitis was the most common type (50.5%, 49 eyes). Ophthalmoscopy revealed retinal vasculitis in only 2 eyes (2.1%) and fundus fluorescence angiography (FFA) revealed diffuse vascular leakage of fluorescein in 64 eyes (66.0%). Thirty-one patients (59 eyes) were followed up for≥3 months. Cataract was the most common ocular complication, accounting for 44.1% (26 eyes), and the inflammatory response was controlled in 45 eyes (76.3%) treated with combination of corticosteroids and immunosuppressive agents. The patients were followed up for 21.5 (13.7, 29.3) months. Among 31 patients (59 eyes) followed up for≥3 months, BCVA was≥0.8 in 25 eyes (42.3%) and<0.3 in 15 eyes (25.4%) at the last follow-up, BCVA of 59 affected eyes of 31 patients was better than that at the first visit, the difference was statistically significant (Z=-2.76, P=0.006). Conclusions: Uveitis associated with sarcoidosis or presumed ocular sarcoidosis mainly manifests as a bilateral, chronic anterior uveitis with a subclinical retinal vasculitis. FFA shows subclinical retinal vasculitis in most patients. Glucocorticoid therapy in combination with other immunosuppressive agents can control inflammatory responses and improve visual acuity in most patients.

Fluorescence Angiography with Dual Fluorescence for the Early Detection and Longitudinal Quantitation of Vascular Leakage in Retinopathy

Diabetic retinopathy (DR) afflicts more than 93 million people worldwide and is a leading cause of vision loss in working adults. While DR therapies are available, early DR development may go undetected without treatment due to the lack of sufficiently sensitive tools. Therefore, early detection is critically important to enable efficient treatment before progression to vision-threatening complications. A major clinical manifestation of early DR is retinal vascular leakage that may progress from diffuse to more localized focal leakage, leading to increased retinal thickness and diabetic macular edema (DME). In preclinical research, a hallmark of DR in mouse models is diffuse retinal leakage without increased thickness or DME, which limits the utility of optical coherence tomography and fluorescein angiography (FA) for early detection. The Evans blue assay detects diffuse leakage but requires euthanasia, which precludes longitudinal studies in the same animals. We developed a new modality of ratiometric fluorescence angiography with dual fluorescence (FA-DF) to reliably detect and longitudinally quantify diffuse retinal vascular leakage in mouse models of induced and spontaneous DR. These studies demonstrated the feasibility and sensitivity of FA-DF in detecting and quantifying retinal vascular leakage in the same mice over time during DR progression in association with chronic hyperglycemia and age. These proof-of-concept studies demonstrated the promise of FA-DF as a minimally invasive method to quantify DR leakage in preclinical mouse models longitudinally.

Retinal vascular abnormalities in a patient with an overgrowth syndrome

AbstractPurpose: To present a case report of unilateral vascular abnormalities on the retina of a patient with an overgrowth syndrome.Methods: A 26‐year‐old male who presents hemihypertrophy, hemimegaloencephaly, cutaneous haemangiomas and intellectual disability who underwent a complete ophthalmological examination. A detailed retinal imaging was performed as well as a fluorescein angiography (FA) and optical coherence tomography (OCT).Results: Fundus examination of the right eye revealed retinal vascular tortuosity while on the left eye there was fibrovascular proliferative tissue with new vessels from the optic nerve to retinal temporal vessel arcades and an area of chorioretinal atrophy in the superior‐temporal sector. FA illustrated diffuse retinal vascular leakage around temporal arcades which was more evident in late‐phase fluorescein angiograms, but no ischemic areas were found. An extrafoveal epiretinal membrane was seen by OCT on the left eye. As his visual acuity was adequate (20/20 vision in both eyes), initially a conservative management was considered, with visits every 6 months.Conclusions: Patients with an overgrowth syndrome can present different ocular abnormalities as optic nerve hypoplasia, strabismus, and high myopia but it is not frequent to find retinal vascular abnormalities. These patients would require a strict follow‐up by an ophthalmologist. This case also led us to think of the importance of a multidisciplinary work and how useful is to have a genetic testing and a differential diagnosis from all types of overgrowth disorders associated with ocular manifestations.

Bilateral ocular ischemic syndrome following treatment for laryngeal carcinoma

A 72-year-old male with a history of atherosclerosis and radiation therapy for laryngeal cancer presented with complaints of decreased vision. The exam of the right eye was notable for neovascularization of the iris and significant vaso-occlusive disease of the retina, with non-perfusion of the peripheral retina (Figure 1A). Classical large dot-blot hemorrhages were present in the mid-periphery of left retina consistent with the diagnosis of bilateral Ocular Ischemia Syndrome (OIS) (Figure 1B). Fluorescein angiography demonstrated more severe OIS of the right retina, with global peripheral capillary drop out and optic disc and diffuse vascular leakage (Figure 1C). Far peripheral capillary drop out was seen in the left eye with leaking neovascular vessels near the disc (Figure 1D). CT angiography showed arterial occlusive disease with impairment of carotid artery perfusion of the clinoid segment of the right internal carotid artery on axial CT angiogram, mirroring the severity of retinal ischemia between the two eyes (Figure 2).

DDAH1 Promotes Lung Endothelial Barrier Repair by Decreasing Leukocyte Transendothelial Migration and Oxidative Stress in Explosion-Induced Lung Injury

Explosion-induced injury is the most commonly encountered wound in modern warfare and incidents. The vascular inflammatory response and subsequent oxidative stress are considered the key causes of morbidity and mortality among those in blast lung injury. It has been reported dimethylarginine dimethylaminohydrolase 1 (DDAH1) plays important roles in regulating vascular endothelial injury repair and angiogenesis, but its role in explosion-induced injury remains to be explained. To explore the mechanism of vascular injury in blast lung, 40 C57BL/6 wild type mice and 40 DDAH1 knockout mice were randomly equally divided into control group and blast group, respectively. Body weight, lung weight, and dry weight of the lungs were recorded. Diffuse vascular leakage was detected by Evans blue test. The serum inflammatory factors, nitric oxide (NO) contents, and ADMA level were determined through ELISA. Hematoxylin-eosin staining and ROS detection were performed for histopathological changes. Western blot was used to detect the proteins related to oxidative stress, cell adhesion molecules and leukocyte transendothelial migration, vascular injury, endothelial barrier dysfunction, and the DDAH1/ADMA/eNOS signaling pathway. We found that DDAH1 deficiency aggravated explosion-induced body weight reduction, lung weight promotion, diffuse vascular leakage histopathological changes, and the increased levels of inflammatory-related factors. Additionally, DDAH1 deficiency also increased ROS generation, MDA, and IRE-1α expression. Regarding vascular endothelial barrier dysfunction, DDAH1 deficiency increased the expression of ICAM-1, Itgal, Rac2, VEGF, MMP9, vimentin, and N-cadherin, while lowering the expression of occludin, CD31, and dystrophin. DDAH1 deficiency also exacerbated explosion-induced increase of ADMA and decrease of eNOS activity and NO contents. Our results indicated that explosion could induce severe lung injury and pulmonary vascular insufficiency, whereas DDAH1 could promote lung endothelial barrier repair and reduce inflammation and oxidative stress by inhibiting ADMA signaling which in turn increased eNOS activity.

DIFFUSE RETINAL VASCULAR LEAKAGE AND CONE-ROD DYSTROPHY IN A FAMILY WITH THE HOMOZYGOUS MISSENSE C.1429G>A (P.GLY477ARG) MUTATION IN CRB1.

To describe a specific cone-rod dystrophy phenotype in a family with the homozygous c.1429G>A; p.Gly477Arg mutation in CRB1. The detailed phenotype of subjects with this specific mutation has not been described previously. Clinical examination included full-field electroretinography and high-resolution and widefield retinal imaging and uveitis workup. Molecular genetic analysis included next-generation sequencing of known retinal dystrophy genes and Sanger sequencing for segregation analysis. Three affected male siblings (26, 16, and 8 years old) were diagnosed with cone-rod dystrophy, featuring bilateral macular hypoautofluorescent lesions. In addition, the eldest brother was found to have retinal vascular leakage throughout the retina without telangiectasia. Uveitis laboratory workup was unremarkable. The homozygous c.1429G>A; p.Gly477Arg mutation in CRB1 was found to segregate with disease in this family. To the best of our knowledge, diffuse vascular leakage without telangiectasia or exudation, with bull's eye maculopathy, has not been reported previously in CRB1-cone rod dystrophy. This expands the phenotype complexity associated with CRB1 mutations and confirms that dystrophies associated with mutations in this gene may appear with features of uveitis.

Neutrophil activation in systemic capillary leak syndrome (Clarkson disease).

Systemic capillary leak syndrome (SCLS; Clarkson disease) is a rare orphan disorder characterized by transient yet recurrent episodes of hypotension and peripheral oedema due to diffuse vascular leakage of fluids and proteins into soft tissues. Humoral mediators, cellular responses and genetic features accounting for the clinical phenotype of SCLS are virtually unknown. Here, we searched for factors altered in acute SCLS plasma relative to matched convalescent samples using multiplexed aptamer‐based proteomic screening. Relative amounts of 612 proteins were changed greater than twofold and 81 proteins were changed at least threefold. Among the most enriched proteins in acute SCLS plasma were neutrophil granule components including bactericidal permeability inducing protein, myeloperoxidase and matrix metalloproteinase 8. Neutrophils isolated from blood of subjects with SCLS or healthy controls responded similarly to routine pro‐inflammatory mediators. However, acute SCLS sera activated neutrophils relative to remission sera. Activated neutrophil supernatants increased permeability of endothelial cells from both controls and SCLS subjects equivalently. Our results suggest systemic neutrophil degranulation during SCLS acute flares, which may contribute to the clinical manifestations of acute vascular leak.

Ultra-Widefield Fluorescein Angiography in Intermediate Uveitis

ABSTRACTPurpose: To examine associations between pattern of vascular leakage on ultrawide-field fluorescein angiography (UWFFA) and visual acuity, cystoid macular edema (CME), and inflammatory activity in intermediate uveitis.Methods: Single center cross-sectional, retrospective review of medical records, spectral domain optical coherence tomography (SD-OCT) and angiographic images of intermediate uveitis patients who underwent UWFFA over a 12-month period.Results: Forty-one eyes from 24 patients were included. Twelve eyes (29%) exhibited peripheral leakage, 26 eyes (64%) had diffuse leakage and three eyes (7%) had no leakage. Diffuse leakage was associated with 0.2 logMAR worse visual acuity than peripheral leakage (p = 0.02). There was no statistically significant difference in the odds of having CME when diffuse leakage was compared to peripheral leakage.Conclusion: UWFFA identifies retinal vascular pathology in intermediate uveitis not present on clinical examination. Diffuse retinal vascular leakage was associated with worse visual acuity when compared to peripheral and no leakage patterns.

Use of wide‐field fluorescein angiography in the diagnosis and management of sarcoidosis uveitis

PurposeTo assess the utility of wide field (WF) fluorescein angiography versus conventional angiography in the diagnosis and management of Sarcoidosis posterior uveitis.MethodsTwenty‐three eyes of 12 patients diagnosed with Sarcoidosis disease who underwent WF fluorescein angiography imaging with the Heidelberg scanning laser ophthalmoscope HRA2 using the Staurenghi SLO contact lens between January 2016 and March 2017 were included in our study. Complete clinical and imaging records (WF fluorescein angiography and SD‐OCT) of the patients were retrospectively reviewed. A circle simulating the central 75‐degree field was drawn on WF fluorescein angiography images. We compared the WF fluorescein angiography findings within the circle and the complete image and assessed its impact on patient management.ResultsFourteen eyes of 23 (60.9%) were diagnosed with Sarcoidosis retinal vasculitis. WF fluorescein angiography revealed vasculitis not clinically evident in 9 of 14 eyes (64.3%). Predominant angiographic findings were diffuse vascular leakage in 6 eyes (26.1%), peripheral ischemia in 5 eyes (21.7%), vein sheathing in 12 eyes (52.2%) and multifocal hyperfluorescent spots in 8 eyes (34.8%). Ten eyes (43.5%) had no apparent retinal vasculitis but WF images have shown peripheral changes outside the circle. In four eyes (13%), WF fluorescein angiography showed the vasculitis to be much more extensive than usually seen by simulated conventional FA. WF fluorescein angiography influenced treatment decision in 9 eyes (39.1%).ConclusionsRetinal vasculitis (RV) may be difficult to detect either clinically or with conventional retinal imaging in Sarcoidosis disease. Wide‐field imaging is a useful tool in the diagnosis of RV associated to Sarcoidosis disease even in the absence of clinical retinal vasculitis and may influence management decisions.

Peripheral Findings and Retinal Vascular Leakage on Ultra-Widefield Fluorescein Angiography in Patients with Uveitis

To compare ultra-widefield fluorescein angiography (UWFFA) with simulated conventional fluorescein angiography (FA) to evaluate peripheral pathology and leakage and correlate with clinical activity in patients with uveitis. Retrospective chart review. All uveitis patients initially evaluated with UWFFA (Optos 200Tx) between May 2012 and December 2013 were included in this study, including follow-up visits through August2014. Uveitis status was deemed as having active or inactive inflammation based on clinical examination. Changes to therapy, influence on management, and clinical diagnosis were also noted. UWFFA images were compared with simulated 50-degree FA images to evaluate for peripheral lesions, and leakage location was also graded. Imaging characteristics were then correlated with clinical information. Correlation of leakage on UWFFA with clinical inflammation. An initial set of 243 uveitis patients and a total of 1008 eye images were reviewed. When UWFFA was compared with a simulated 50-degree FA image, UWFFA added additional information regarding the presence of peripheral vascular leakage in 25%, peripheral nonperfusion in 14%, peripheral lesions in 6.6%, and peripheral neovascularization in 3.9% of patients. A total of 600 eye images exhibited fluorescein leakage, of which 21% displayed central leakage only, 11% had central and peripheral leakage, 31% had peripheral leakage only, and 37% had diffuse vascular leakage. Based on peripheral findings on widefield angiography, the treatment was changed in 69 patients (28%). Corresponding eye examinations were reviewed for each imaging session, and of 600 eye images with vascular leakage, 567 eye images were also clinically active, which was 95% sensitive as a surrogate indicator of clinical inflammation. Anterior chamber cell and vitreous haze also significantly correlated with leakage on widefield angiography. Retinal vascular leakage on UWFFA reveals increased pathology and leakage compared with conventional angiography, which can influence management, and accurately identifies and correlates with active inflammation in patients with uveitis. A more objective measure of inflammation in the form of leakage exhibited on UWFFA may help standardize treatment and care of patients with uveitis.

Use of ultra-wide-field retinal imaging in the management of active Behçet retinal vasculitis.

Retinal vasculitis (RV) is an important component of Behçet disease. It may be difficult to detect either clinically or with conventional retinal imaging. The role of ultra-wide-field (UWF) retinal imaging was assessed in the diagnosis and management of RV associated with Behçet disease. A total of 38 eyes of 20 patients with active RV associated to Behçet disease underwent UWF imaging with the Optos scanning laser ophthalmoscope, fundus autofluorescence, and/or fluorescein angiography. This study determined the UWF findings and percentage of patients in whom this imaging modality assisted in diagnosing the extent of vasculitis, planning treatment, and monitoring disease activity. Optos UWF imaging assisted in diagnosing and quantifying the extent of RV in 16 patients (80%), planning medical treatment or laser photocoagulation in 13 of 20 patients (65%), and enhanced disease monitoring in 11 of 20 patients (55%). UWF fluorescein angiography revealed vasculitis not clinically evident in 28 of 33 eyes (84.8%). Predominant angiographic findings were diffuse vascular leakage (75.7%), peripheral retinal nonperfusion (66.7%), optic disk leakage (63.6%), macular leakage (30.3%), and macular edema (27.3%). Eighteen patients (34 eyes) underwent UWF fundus autofluorescence, showing multiple hyperfluorescent spots in retinal periphery in 28 eyes (82.3%). Ultra-wide-field imaging is a valuable tool in the management of patients with RV associated to Behçet disease and can be used for the diagnosis, treatment, and follow-up. Additional studies, including longitudinal evaluations, are needed to elucidate whether these findings or the subsequent management alterations may improve patients' outcomes.

Dexamethasone Intravitreal Implant in Combination with Laser Photocoagulation for the Treatment of Diffuse Diabetic Macular Edema

To evaluate Ozurdex (dexamethasone intravitreal implant [DEX implant]; Allergan, Inc, Irvine, CA) 0.7 mg combined with laser photocoagulation compared with laser alone for treatment of diffuse diabetic macular edema (DME). Randomized, controlled, multicenter, double-masked, parallel-group, 12-month trial. Two hundred fifty-three patients with retinal thickening and impaired vision resulting from diffuse DME in at least 1 eye (the study eye) were enrolled. Patients were randomized to treatment in the study eye with DEX implant at baseline plus laser at month 1 (combination treatment; n = 126) or sham implant at baseline and laser at month 1 (laser alone; n = 127) and could receive up to 3 additional laser treatments and 1 additional DEX implant or sham treatment as needed. The primary efficacy variable was the percentage of patients who had a 10-letter or more improvement in best-corrected visual acuity (BCVA) from baseline at month 12. Other key efficacy variables included the change in BCVA from baseline and the area of vessel leakage evaluated with fluorescein angiography. Safety variables included adverse events and intraocular pressure (IOP). The percentage of patients who gained 10 letters or more in BCVA at month 12 did not differ between treatment groups, but the percentage of patients was significantly greater in the combination group at month 1 (P<0.001) and month 9 (P = 0.007). In patients with angiographically verified diffuse DME, the mean improvement in BCVA was significantly greater with DEX implant plus laser treatment than with laser treatment alone (up to 7.9 vs. 2.3 letters) at all time points through month 9 (P ≤ 0.013). Decreases in the area of diffuse vascular leakage measured angiographically were significantly larger with DEX implant plus laser treatment through month 12 (P ≤ 0.041). Increased IOP was more common with combination treatment. No surgeries for elevated IOP were required. There was no significant between-group difference at month 12. However, significantly greater improvement in BCVA, as demonstrated by changes from baseline at various time points up to 9 months and across time based on the area under the curve analysis, occurred in patients with diffuse DME treated with DEX implant plus laser than in patients treated with laser alone. Proprietary or commercial disclosure may be found after the references.

Bilateral uveitis after phakic intraocular lens implantation and management with adalimumab

A 25-year-old woman with myopia who had an AC pIOL implantation in the left eye and posterior chamber pIOL implantation in the right eye developed bilateral granulomatous panuveitis 2 months after the second surgery. Physical examination showed bilateral Koeppe and Busacca nodules. Fluorescein angiography showed diffuse vascular and retinal pigment epithelial leakage in both eyes. With assessment of sympathetic ophthalmia, treatment with a high-dose systemic steroid was started. Oral cyclosporine and azathioprine were later added. Because the uveitis was not controlled, adalimumab was added. After 6 doses of adalimumab (40 mg subcutaneously), the uveitis subsided and corticosteroid and other immunosuppressive agents were tapered. Refractive AC pIOL implantation should be added to the list of intraocular procedures that may induce sympathetic ophthalmia. Adalimumab may have a therapeutic role in its management.

Fluorescein angiography in uveitis

AbstractPurpose Fluorescein angiography (FA) is an important test in the evaluation and management of patients with uveitis. FA in uveitis is giving information principally on the superficial structures of the fundus (retina, retinal vessels and optic nerve head / disc), on the retinal pigment epithelium, on the choriocapillaris in the first 60 seconds of angiography as well as immediatelly subclinical pathology such as subretinal neovascular membranes.Methods FA is indicated when a posterior segment involvement is present or suspected. It should examine the posterior pole, optic disc, and periphery, with angiograms at early, intermediate, and late phases. FA results should be interpreted in relation to the results of clinical examination and other testsResults There are many roles for FA in the evaluation of patients with uveitis 1. Evaluation of the activity and extent of chorioretinitis: 2. Diagnosis of uveitic entities with typical features. 3. Evaluation of retinal vascular involvement : focal, multifocal, or diffuse retinal vascular leakage, occlusive complications, optic disc or retinal neovascularization, 4.Identication of macular complications 5. Evaluation of optic disc involvement. 6. Monitoring of response to treatmentConclusion FA can be helpful in the diagnosis, treatment, and monitoring of patients with posterior segment inflammation.

Fluorescein Angiography and Visual Acuity in Active Uveitis with Behçet Disease

Purpose: To determine the association of fluorescein angiography characteristics with visual acuity and visual loss during medical treatment in patients with Behçet uveitis. Methods: Ninety-three eyes from 69 Behçet patients with active panuveitis underwent fluorescein angiography, and the characteristic findings by angiography were determined. The patients were followed with immunomodulatory treatment. Results: Diffuse vascular leakage (73.4%), diffuse macular leakage (66.0%), and disc leakage (52.7%) were the predominant angiographic findings on fluorescein angiography. Multivariate logistic regression analysis revealed that a macular window defect and disc neovascularization on fluorescein angiography were associated with poor visual acuity (≤ 20/200) (p < .05). The presence of macular ischemia on fluorescein angiography was significantly associated with the risk of visual loss (≤ 20/200) at 48 months post-treatment (p < .05). Conclusions: These results suggest that fluorescein angiography may be helpful for predicting visual prognosis for Behçet patients with panuveitis.

Posterior segment involvement in ocular Behçet's disease.

Posterior segment involvement, which can lead to blindness with recurrent inflammatory attacks, has a very important prognostic value in ocular Behçet's disease (BD). This study evaluated the frequency and characteristics of posterior segment involvement and the causes of visual impairment in patients with ocular BD. We retrospectively evaluated 257 eyes of the 131 patients who were followed from 1993 to 2001 in the Uveitis and BD division of SSK Ankara Eye Hospital, Turkey. The mean follow-up was 49.2 +/- 27.4 months. Thirty-one of the palents were female (23.6%) and 100 male (76.4%). The mean age was 25.1 +/- 7.9. Fundus changes were observed in 213 (82.9%) eyes and were bilateral in 87%, and vitritis was present in 239 (93%) eyes. The most frequent fundus changes were vascular sheathing in 61 eyes (23.7%), optic atrophy in 46 (17.9%), macular edema in 29 (11.3%), retinal hemorrhage in 23 (9%), macular scar in 21 (8.2%), optic disc paleness in 19 (7.4%), retinal edema in 17 (6.6%), branch retinal vein occlusion in 15 (5.8%). The most common fluorescein angiography findings were diffuse vascular leakage in 98 (38%), hyperfluorescence of the optic disc in 38 (14.8%) and hyperfluorescence of the macula in 29 eyes (11.3%). Visual acuity was <1/10 in 85 (33%) of the eyes. Optic atrophy was the main cause (54.1%) of permanent visual impairment. Posterior segment involvement is the most serious ocular complication of BD, leading to blindness with recurrent attacks. Following patients closely, performing fluorescein angiography in all patients diagnosed as BD even they have no clinical ocular involvement, and early treatment are very important in the prognosis of the disease.