Ophthalmologic manifestations in patients with antiphospholipid antibodies: Beware of iatrogenic complications.

BACKGROUND: Antiphospholipid syndrome (APS) is characterized by several clinical manifestations such as venous and arterial thrombosis associated with persistent antiphospholipid antibodies (aPL). Several studies confirmed that retinal vein occlusion was the most common APS ocular manifestation. The purpose of this study was to identify ophthalmologic manifestations in a homogeneous cohort of well-defined persistently aPL-positive patients and to determine variables associated with these manifestations. METHODS: APL-positive patients were selected from two research programs. All ophthalmologic manifestations including those related to APS were recorded. RESULTS: A total of 117 patients were included and 10 of them had APS-related ophthalmologic manifestations (glaucoma, hydroxychloroquine-related maculopathy, anterior acute uveitis, anterior ischemic optic neuropathy). Systemic Lupus Erythematosus (SLE) (OR = 3.4[95%CI; 0.9-12.7), corticosteroids (OR = 9.0 [95%CI; 2.2-37.7]) and aPL-related nephropathy (OR = 7.1 [95%CI; 1.7-30.0]) were significatively associated with the risk of APS-related ophthalmologic manifestations. CONCLUSION: Most of ocular manifestations in this study were iatrogenic related to corticosteroids or hydroxychloroquine. Patients with SLE, small vessel thrombosis in general, or with aPL-related nephropathy in particular, seemed at higher risk to develop APS-related ophthalmologic manifestations thus deserving adequate monitoring.

SERUM LEVELS OF ANTIBODIES AGAINST OXIDATION-SPECIFIC EPITOPES ARE DECREASED IN PATIENTS WITH RETINAL VEIN OCCLUSION.

PURPOSE: Oxidative stress and inflammation have been implicated in the development of retinal vein occlusion (RVO). Oxidation-specific epitopes (OSEs) represent products of oxidative stress that can trigger vascular inflammation and thrombosis. Natural occurring antibodies have been shown to bind oxidation-specific epitopes thereby inhibiting their inflammatory potential and promoting their removal. METHODS: This prospective cross-sectional study included 270 patients with RVO and 81 in-hospital control patients. We measured three types of serum levels of oxidation-specific epitope-specific immunoglobulin M and immunoglobulin G antibodies (anti-copper-oxidized LDL [CuOx-LDL], antiphosphocholine [PC], anti-malondialdehyde-modified LDL [MDA-LDL]). History of arterial hypertension, hyperlipidemia, myocardial infarction, diabetes mellitus, stroke, smoking status, and several laboratory parameters were determined to control for potential confounders. RESULTS: Compared with controls, patients with RVO had significantly lower levels of immunoglobulin M and immunoglobulin G antibodies against CuOx-LDL and PC, and significantly lower levels of immunoglobulin G but not immunoglobulin M antibodies against MDA-LDL. The association between RVO patients and lower levels of these antibodies prevailed upon multivariable adjustment. CONCLUSION: These prospective data show that antibodies against oxidation-specific epitope are lower in patients with RVO compared with control patients and support the concept that oxidative stress and inflammation play key roles in the development and subsequent complications in RVO.

[Correlation from Undiluted Vitreous Cytokines of Untreated Central Retinal Vein Occlusion with Spectral Domain Optical Coherence Tomography]. / Korrelation von intravitrealen Zytokinen und OCT-Parametern bei Zentralvenenverschluss.

PURPOSE: To correlate key inflammatory and pro-angiogenic cytokines from undiluted vitreous fluid of treatment-naïve patients with central retinal vein occlusion (CRVO) with SD-OCT parameters. METHODS: Thirty-five patients (age 71.1 years, 24 phakic, 30 non-ischaemic) underwent intravitreal combination therapy, including single-site 23-gauge core vitrectomy. Twenty-eight samples from patients with idiopathic, non-uveitis floaterectomy served as controls. Levels of interleukin 6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and vascular endothelial growth factor (VEGF-A) were correlated with visual acuity (logMar), category of CRVO (ischaemic or non-ischaemic) and morphological parameters, such as central macular thickness (CMT), thickness of neurosensory retina (Tneuro), extent of serous retinal detachment (SRT) and disintegrity of the IS/OS and others. RESULTS: Mean IL-6 was 64.7 pg/ml (SD ± 115.8), mean MCP-1 1015.7 pg/ml (± 970.1), and mean VEGF-A 278.4 pg/ml (± 512.8), which was significantly higher than the control values of IL-6 6.2 ± 3.4 pg/ml (p = 0.06), MCP-1 253.2 ± 73.5 pg/ml (p < 0.0 000 001) and VEGF-A 7.0 ± 4.9 pg/ml (p < 0.0006), respectively. All cytokines correlated highly with one another (correlation coefficient r = 0.82 for IL-6 and MCP-1; r = 0.68 for Il-6 and VEGF-A; r = 0.64 for MCP-1 and VEGF-A). IL-6 correlated significantly with CMT, TRT, SRT, dIS/OS, and dELM. MCP-1 correlated significantly with SRT, dIS/OS, and dELM. VEGF-A did not correlate with changes in SD-OCT, while it had a trend to be higher in the ischaemic versus the non-ischaemic CRVO groups (p = 0.09). CONCLUSIONS: The inflammatory cytokines were more often correlated with morphological changes assessed by SD-OCT, whereas VEGF-A did not correlate with CRVO-associated changes in SD-OCT. VEGF inhibition alone may not be sufficient to decrease the inflammatory response in CRVO therapy.

Diagnostic Dilemma in Sequential Branch Retinal Vein and Artery Occlusion.

PURPOSE: To report on an unusual case of a branch retinal vein occlusion followed by occlusion of the respective branch retinal artery of the same eye 7 years later, in a young, otherwise healthy man with marginal elevation of antiphospholipid antibodies. CASE REPORT: On first presentation, a 30-year-old male patient was diagnosed as having a branch retinal vein occlusion with the sole risk factor of slightly increased diastolic pressure. On second presentation, 7 years later, a transient occlusion of the respective branch retinal artery was diagnosed on the same patient. Extensive ophthalmologic and general medical evaluations were performed including cardiovascular, coagulation, and immunology testing. Coagulopathy screening revealed slightly elevated titers of anticardiolipin IgM and anti-beta 2 glycoprotein-I IgM antibodies, and aspirin prophylaxis was initiated. CONCLUSIONS: Retinal vascular occlusions are typically associated with well-defined, classical risk factors in older people. In younger, otherwise healthy patients, further autoimmune hypercoagulable disorders are often causal. Our case suggests the contribution of slightly elevated antiphospholipid IgM antibodies, although this remains to be proven.

Controversies in Pharmacological Treatment of Inflammatory Component of Macular Edema.

Macular edema (ME) is a common, final pathway for many different ocular and systemic diseases. The most common diseases include: diabetic retinopathy (DR), retinal vascular disorders (such as central and branch retinal vein occlusion), and uveitis. The complex and multifactorial pathophysiological mechanisms leading to ME, are still poorly understood. Inflammation plays a crucial role in the genesis of ME, as demontrsated by significant increase of different cytokines and chemokines, (besides vascular endothelial growth factors-VEGF) in ocular fluids. Currently, intravitreal steroids and anti-VEGF drugs are the most used treatments in ME of retinal vascular origin. This review will address the most important (with highest level of scientific evidence and longest followup) results on the use of intravitreal steroids and anti-VEGF drugs, starting from molecular basis to the most updated randomized clinical trials.

Increased expression of angiogenic and inflammatory proteins in the vitreous of patients with ischemic central retinal vein occlusion.

BACKGROUND: Central retinal vein occlusion (CRVO) is a common disease characterized by a disrupted retinal blood supply and a high risk of subsequent vision loss due to retinal edema and neovascular disease. This study was designed to assess the concentrations of selected signaling proteins in the vitreous and blood of patients with ischemic CRVO. METHODS: Vitreous and blood samples were collected from patients undergoing surgery for ischemic CRVO (radial optic neurotomy (RON), n = 13), epiretinal gliosis or macular hole (control group, n = 13). Concentrations of 40 different proteins were determined by an ELISA-type antibody microarray. RESULTS: Expression of proteins enriched in the vitreous (CCL2, IGFBP2, MMP10, HGF, TNFRSF11B (OPG)) was localized by immunohistochemistry in eyes of patients with severe ischemic CRVO followed by secondary glaucoma. Vitreal expression levels were higher in CRVO patients than in the control group (CRVO / control; p < 0.05) for ADIPOQ (13.6), ANGPT2 (20.5), CCL2 (MCP1) (3.2), HGF (4.7), IFNG (13.9), IGFBP1 (14.7), IGFBP2 (1.8), IGFBP3 (4.1), IGFBP4 (1.7), IL6 (10.8), LEP (3.4), MMP3 (4.3), MMP9 (3.6), MMP10 (5.4), PPBP (CXCL7 or NAP2) (11.8), TIMP4 (3.8), and VEGFA (85.3). In CRVO patients, vitreal levels of CCL2 (4.2), HGF (23.3), IGFBP2 (1.23), MMP10 (2.47), TNFRSF11B (2.96), and VEGFA (29.2) were higher than the blood levels (vitreous / blood, p < 0.05). Expression of CCL2, IGFBP2, MMP10, HGF, and TNFRSF11B was preferentially localized to the retina and the retinal pigment epithelium (RPE). CONCLUSION: Proteins related to hypoxia, angiogenesis, and inflammation were significantly elevated in the vitreous of CRVO patients. Moreover, some markers known to indicate atherosclerosis may be related to a basic vascular disease underlying RVO. This would imply that local therapeutic targeting might not be sufficient for a long term therapy in a systemic disease but hypothetically reduce local changes as an initial therapeutic approach.

The role of inflammation in the pathogenesis of macular edema secondary to retinal vascular diseases.

Macular edema (ME) is a nonspecific sign of numerous retinal vascular diseases. This paper is an updated overview about the role of inflammatory processes in the genesis of both diabetic macular edema (DME) and ME secondary to retinal vein occlusion (RVO). We focus on the inflammatory mediators implicated, the effect of the different intravitreal therapies, the recruitment of leukocytes mediated by adhesion molecules, and the role of retinal Müller glial (RMG) cells.

[Pathogenesis of retinal vein occlusions].

Retinal vein occlusion (RVO) is a multifactorial disease and its pathogenesis is still not fully understood. Mechanical, hemodynamic, rheological, coagulation, biochemical, and immunological factors are involved. Two currently prevalent theories of RVO pathogenesis are the mechanical theory and the "coagulopathic" theory. The latter implies an imbalance between thrombogenic factors and antithrombogenic protection. According to some authors, endothelial dysfunction plays a large part in thrombosis development, neoangiogenesis, vascular remodeling, intravascular activation of platelets and leucocytes. In recent studies increasing emphasis is being placed on investigation of immune-mediated mechanisms of vein occlusions. RVO can also be associated with combined hypoxic and free radical tissue damage.

Antiphospholipid antibody and risk of retinal vein occlusion: a systematic review and meta-analysis.

BACKGROUND: Retinal vein occlusion (RVO) is a common retinal vascular disease and it is one of the most frequently reported causes of visual damage and blindness in the elderly. The current study investigated the potential association between antiphospholipid antibodies (APLA) and RVO risk by conducting a meta-analysis of case-control studies. METHODS: A systematic literature search of Pubmed and Embase databases was conducted in August 1st, 2014. Odds ratios (ORs) were used to evaluate the associations between APLA and the incidence of RVO. A random-effects model was obtained for the quantitative synthesis. RESULTS: A total of 11 studies were included in this meta-analysis. A meta-analysis of all studies assessing the risk of RVO revealed that APLA was associated with a statistically increased risk of RVO incidence (OR = 5.18, 95% CI = [3.37, 7.95]). The association between anticardiolipin antibodies (ACA) and the risk of RVO was significant (n =8, OR = 4.59, 95% CI = [2.75, 7.66]). However, the association between lupus anticoagulants (LA) and risk of RVO was non-significant (n = 5, OR = 3.90, 95% CI = [0.99, 15.37]). No significant publication bias was found in the 11 selected studies. CONCLUSION: APLA was significantly associated with the risk of RVO. Advanced analyses showed that ACA rather than LA affected the risk of RVO. Additional well-designed and well-conducted epidemiological studies are required to further our understanding of the relationship between APLA and RVO risk.

Antiphospholipid syndrome following toxoplasma retinochoroiditis.

PURPOSE: To report a case of antiphospholipid syndrome (APS) following toxoplasma retinochoroiditis. DESIGN: Interventional case report. METHOD: The patient was a 24-year-old female with an attack of visual loss due to toxoplasma retinochoroiditis concomitant with branch retinal vein occlusion. Retinitis resolved with anti-toxoplasma treatment. However, a recurrent episode of BRVO and vitreous hemorrhage occurred later. RESULT: In systemic evaluation, evidence of APS was detected, including high titers of anti-cardiolipin antibody, increased beta-2 microglobulin and anti-toxoplasma IgG antibody, and also low titers of C3, C4, and CH50. CONCLUSION: Ocular toxoplasmosis should be included in the list of etiologies of secondary APS. Systemic evaluation for detection of APS is a necessary approach to patients with toxoplasma retinochoroiditis and concomitant vascular accident.

[Intravitreal implants: drug carriers and carriers of hope?]. / Intravitreale Implantate: Wirkstoff- und "Hoffnungsträger"?

Immunosuppressive agents are used for the therapy of noninfectious uveitis if intraocular quiescence and freedom from recurrences are not achievable with oral steroids at a low dosage. Partially, severe side effects are tolerated to preserve visual acuity even if the disease is limited to the eyes. Because of this a therapy would be desirable which is highly effective, limited to the eyes and with few side effects. For this fluocinolone acetonide and dexamethasone drug delivery systems were developed. Dexamethasone implants were already approved for the therapy of retinal vein occlusions and are used successfully. Diabetic macular edema would be another possible indication for dexamethasone implants.

Comprehensive analysis of inflammatory immune mediators in vitreoretinal diseases.

Inflammation affects the formation and the progression of various vitreoretinal diseases. We performed a comprehensive analysis of inflammatory immune mediators in the vitreous fluids from total of 345 patients with diabetic macular edema (DME, n = 92), proliferative diabetic retinopathy (PDR, n = 147), branch retinal vein occlusion (BRVO, n = 30), central retinal vein occlusion (CRVO, n = 13) and rhegmatogenous retinal detachment (RRD, n = 63). As a control, we selected a total of 83 patients with either idiopathic macular hole (MH) or idiopathic epiretinal membrane (ERM) that were free of major pathogenic intraocular changes, such as ischemic retina and proliferative membranes. The concentrations of 20 soluble factors (nine cytokines, six chemokines, and five growth factors) were measured simultaneously by multiplex bead analysis system. Out of 20 soluble factors, three factors: interleukin-6 (IL-6), interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1) were significantly elevated in all groups of vitreoretinal diseases (DME, PDR, BRVO, CRVO, and RRD) compared with control group. According to the correlation analysis in the individual patient's level, these three factors that were simultaneously increased, did not show any independent upregulation in all the examined diseases. Vascular endothelial growth factor (VEGF) was significantly elevated in patients with PDR and CRVO. In PDR patients, the elevation of VEGF was significantly correlated with the three factors: IL-6, IL-8, and MCP-1, while no significant correlation was observed in CRVO patients. In conclusion, multiplex bead system enabled a comprehensive soluble factor analysis in vitreous fluid derived from variety of patients. Major three factors: IL-6, IL-8, and MCP-1 were strongly correlated with each other indicating a common pathway involved in inflammation process in vitreoretinal diseases.

[Retinal vein occlusion followed by ischemic optic neuropathy with anticardiolipin IgG antibody: a case report].

BACKGROUND: Anticardiolipin antibodies in the autoimmune mechanism can cause vasculitis, leading to hypercoagulability-related thrombosis. We report a case of retinal vein occlusion followed by ischemic optic neuropathy in a young woman with anticardiolipin IgG antibody. CASE: A 17-year-old woman with dilatation and tortuosity of the retinal veins and retinal hemorrhage in the superior quadrant of the retina OS. Fluorescein retinal angiography showed a delay of filling time in the upper quadrant of the retina and a 3mm-continuous stain along the superior retinal vein. Laboratory tests were repeatedly positive for anticardiolipin IgG antibodies. Although the retinal hemorrhage disappeared 2 months after subtennon injection of 20 mg triamcinolone acetonide (TA), ischemic optic neuropathy occurred 9 months later. CONCLUSIONS: The staining of the vessel wall and the effectiveness of TA suggest that vasculitis may be associated with the pathology of this condition. The presence of anticardiolipin IgG antibodies suggests that autoimmune mechanism is involved in the vasculitis.

Visual prognosis and vitreous cytokine levels after arteriovenous sheathotomy in branch retinal vein occlusion associated with macular oedema.

PURPOSE: To investigate the relationship between vitreous levels of cytokines, including interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF), and visual prognosis after pars plana vitrectomy (PPV) with arteriovenous sheathotomy in patients with branch retinal vein occlusion (BRVO) associated with macular oedema. METHODS: We studied 60 patients with logMAR visual acuity (VA) scores of < 0.3 and visual impairment secondary to BRVO-associated macular oedema. All patients underwent PPV with arteriovenous sheathotomy. At the time of PPV, vitreous samples were collected from the operated eye and vitreous levels of VEGF and IL-6 were measured. Best corrected VA (BCVA) (using a logMAR chart) and foveal thickness (FT) (using optical coherence tomography) were monitored for up to 6 months after PPV. RESULTS: Both BCVA and FT significantly improved after PPV. According to multiple regression analysis, both the improvement in BCVA and decrease in FT were closely related to the vitreous level of IL-6 but not to that of VEGF. The vitreous level of VEGF was strongly correlated with duration of BRVO. CONCLUSIONS: Both improvement in BCVA and decrease in FT were observed after PPV in BRVO patients with macular oedema. Interestingly, these visual prognoses strongly correlate with the vitreous level of IL-6, whereas the duration of BRVO strongly correlates with the vitreous level of VEGF.

Looking into the eyes of patients with antiphospholipid syndrome.

Diagnosis of antiphospholipid syndrome (APS) should be considered in all patients with recurrent systemic or ocular thrombosis in the absence of known risk factors. Because of the frequent ocular involvement in APS patients (as many as 80%), an ophthalmologic assessment should become a routine part of the clinical work-up of all patients in whom APS is highly suspected. The presence of isolated ocular thrombosis with persistently increased titers of antiphospholipid antibodies should be considered as definite APS. Ocular involvement in APS is frequently associated with other manifestations of the central nervous system (CNS), such as transient ischemic attack or cerebral vascular events. Diagnostic tools are needed to better establish a diagnosis of retinal vascular thrombosis. The treatment of isolated ocular APS should be based on the same principles as in all patients with systemic APS. Anticoagulation is aimed to prevent recurrent ocular or cerebral thromboses.

[Bilateral central retinal vein occlusion associated with moderate acute rejection of a cardiac graft]. / Oblitération bilatérale de la veine centrale de la rétine sur un rejet aigu léger de greffe cardiaque.

We report a case of bilateral central retinal vein occlusion following moderate acute rejection of a cardiac transplant. A 27-year-old man was admitted for sudden bilateral decreased vision due to bilateral central retinal vein occlusion. Visual acuity was 20/63 in the right eye and 20/25 in the left eye. This patient had undergone a heart transplant 6 months before and had presented with moderate acute rejection for a few days. The moderate acute rejection phenomenon includes inflammatory lymphocyte infiltrates, reflecting persistent immune response activation. Moderate acute rejection of a cardiac transplant graft might cause a bilateral central retinal vein occlusion.

Antiphospholipid antibodies in ocular arterial and venous occlusive disease.

PURPOSE: It was the aim of this study to evaluate antiphospholipid antibodies (APA), i.e. lupus anticoagulants (LA) and anticardiolipin (ACA) IgG and IgM, in ophthalmic occlusive disease. METHODS: Over a 3.5-year period, APA were evaluated in 368 patients. RESULTS: Eighty-six patients (23.4%), compared to 5% in the general population, tested positive for APA. APA did not differ significantly between patients with venous (20.6%) or arterial (25.5%) occlusive disease. This included 93 patients with central retinal vein occlusion (18% APA positive), 67 with retinal branch vein occlusion (24% APA positive), 41 with central retinal artery occlusion (22% APA positive), 53 with retinal branch artery occlusion (32% APA positive), 71 with anterior ischemic optic neuropathy (23% APA positive), 12 with posterior ischemic optic neuropathy (33% APA positive) and 31 patients with amaurosis fugax (23% APA positive). Excluding patients with accepted main risk factors, APA were positive in 15.3% of 85 patients. CONCLUSION: The high APA prevalence confirms its relevance in ocular occlusive disorders.