Plasma Proteomics to Identify Drug Targets and Potential Drugs for Retinal Artery Occlusion: An Integrated Analysis in the UK Biobank.

Retinal artery occlusion (RAO), which is positively correlated with acute ischemic stroke (IS) and results in severe visual impairment, lacks effective intervention drugs. This study aims to perform integrated analysis using UK Biobank plasma proteome data of RAO and IS to identify potential targets and preventive drugs. A total of 7191 participants (22 RAO patients, 1457 IS patients, 8 individuals with both RAO and IS, and 5704 healthy age-gender-matched controls) were included in this study. Unique 1461 protein expression profiles of RAO, IS, and the combined data set, extracted from UK Biobank Plasma proteomics projects, were analyzed using both differential expression analysis and elastic network regression (Enet) methods to identify shared key proteins. Subsequent analyses, including single cell type expression assessment, pathway enrichment, and druggability analysis, were conducted for verifying shared key proteins and discovery of new drugs. Five proteins were found to be shared among the samples, with all of them showing upregulation. Notably, adhesion G-protein coupled receptor G1 (ADGRG1) exhibited high expression in glial cells of the brain and eye tissues. Gene set enrichment analysis revealed pathways associated with lipid metabolism and vascular regulation and inflammation. Druggability analysis unveiled 15 drug candidates targeting ADGRG1, which demonstrated protective effects against RAO, especially troglitazone (-8.5 kcal/mol). Our study identified novel risk proteins and therapeutic drugs associated with the rare disease RAO, providing valuable insights into potential intervention strategies.

Retinal Artery and Vein Occlusion Risks after Coronavirus Disease 2019 or Coronavirus Disease 2019 Vaccination.

PURPOSE: To evaluate the incidence of new retinal artery occlusion (RAO) and retinal vein occlusion (RVO) after the diagnosis of coronavirus disease 2019 (COVID-19) or vaccination against COVID-19 and compare the incidences with the population with neither. DESIGN: Nationwide population-based cohort study. PARTICIPANTS: From a nationwide population-based cohort, 8 418 590 patients were categorized into control (group 1), COVID-19 infection (group 2), and COVID-19 vaccination (group 3) groups. METHODS: The cumulative incidence of RAO and RVO was calculated in groups 1, 2, and 3 using the Kaplan-Meier method. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) based on the Poisson distribution for RAO and RVO according to each group and subgroup using Cox proportional hazards models, with group 1 as the reference. We conducted univariable and multivariable analyses for the risk factors of RAO and RVO according to each subgroup. MAIN OUTCOME MEASURES: Cumulative incidence and risks of incidence of RAO and RVO from the index date to day 60. RESULTS: In multivariable analysis, no significant increase in RAO and RVO risks after COVID-19 or COVID-19 vaccination were observed in either men or women. These results were observed consistently across various conditions in sensitivity analyses. In subgroup analysis, individuals who were vaccinated before infection showed no significant increase in RAO or RVO risks in both sexes compared with the control group. In the subgroup analysis of vaccinated patients, the HRs of RAO and RVO for different vaccine types did not show an increase compared with the control group; however, an exception was observed in women who received mRNA-1273 vaccines, who showed a higher RAO HR (4.65; 95% CI, 1.27-17.03; P = 0.021). CONCLUSIONS: Within 60 days of COVID-19 diagnosis or vaccination, RAO and RVO occurred rarely. We observed no increase in the HR of RVO and RAO relative to COVID-19 or COVID-19 vaccination except for a possible increase in the RAO HR in women who received mRNA-1273, for which the raw incidence was extremely low. Further investigation is required to validate this result. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

A Remote Consult Retinal Artery Occlusion Diagnostic Protocol.

PURPOSE: To report a novel protocol for diagnosis of retinal artery occlusions at the point of care using OCT and a remote consult model. DESIGN: Retrospective case series and evaluation of a diagnostic test or technology. PARTICIPANTS: Adult patients who presented with painless monocular vision loss and were diagnosed with a nonarteritic retinal artery occlusion. METHODS: OCT machines were placed in the stroke center or emergency department at 3 hospitals within our health system. Patients who presented with painless monocular vision loss were evaluated by the stroke neurology service and an OCT was acquired. The images were interpreted remotely by the retina service. An in-house ophthalmology consult was not required to make the final treatment decision. Eligible patients were treated with intra-arterial tissue plasminogen activator (IA-tPA). Patients were followed by ophthalmology during their admission when an in-house consultation service was available or otherwise evaluated immediately after discharge. MAIN OUTCOME MEASURES: Visual acuity (VA) before and after treatment with IA-tPA; time from last known well (LKW) to treatment; and time from presentation to treatment. RESULTS: In the first 18 months since the protocol went live, 59 patients were evaluated. Twenty-five patients (42%) had a confirmed retinal artery occlusion based on OCT and follow-up examination. Ten patients were eligible for treatment, and 9 patients received treatment with IA-tPA. There was a statistically significant improvement in mean VA from logarithm of the minimum angle of resolution (logMAR) 2.14 to logMAR 0.7 within 24 hours after treatment (P = 0.0001) and logMAR 1.04 after 4 weeks (P = 0.01). Clinically significant improvement was noted in 66% of patients within 24 hours and maintained through 1 month in 56% of all treated patients. The mean time to treatment from LKW was 543 minutes and from presentation at the stroke center was 146 minutes. CONCLUSIONS: We report the successful implementation of a remote consult protocol using point-of-care automated OCT. This novel paradigm demonstrates the potential utility of remote consult services for the diagnosis of time-sensitive ophthalmic emergencies. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Prostanoid signaling in retinal vascular diseases.

The vasculature of the retina is exposed to systemic and local factors that have the capacity to induce several retinal vascular diseases, each of which may lead to vision loss. Prostaglandin signaling has arisen as a potential therapeutic target for several of these diseases due to the diverse manners in which these lipid mediators may affect retinal blood vessel function. Previous reports and clinical practices have investigated cyclooxygenase (COX) inhibition by nonsteroidal anti-inflammatory drugs (NSAIDs) to address retinal diseases with varying degrees of success; however, targeting individual prostanoids or their distinct receptors affords more signaling specificity and poses strong potential for therapeutic development. This review offers a comprehensive view of prostanoid signaling involved in five key retinal vascular diseases: retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration, retinal occlusive diseases, and uveitis. Mechanistic and clinical studies of these lipid mediators provide an outlook for therapeutic development with the potential to reduce vision loss in each of these conditions.

Improved visual outcomes of central retinal artery occlusion with local intra-arterial fibrinolysis beyond the conventional time window.

Local intra-arterial fibrinolysis (LIF) is a promising therapeutic option for CRAO. However, the narrow time window of 6 h has greatly limited the application of LIF. In this study, we explored the efficacy of LIF beyond the conventional time windows and compared the result with conservative therapy. This prospective study included 179 CRAO patients with baseline visual acuity (VA) ≤ 20/400 treated at Renmin Hospital of Wuhan University. The mean time from vision loss to presentation was 5.5 days. 58 patients received conventional standard therapy (CST) alone.121 patients underwent LIF. Main outcome was VA improvement ≥ 0.3 logMAR. Secondary outcome was a favorable VA outcome of 20/200 or better. Logistic regressions were performed to identify predictors of visual improvement. 43% patients in the LIF group experienced VA improvement versus 19% with CST (P = 0.002). LIF was associated with 4.0-fold higher likelihood of visual improvement compared to CST (P = 0.001). Poor baseline VA (light perception or no light perception) and shortened prothrombin time (PT) were associated with greater chance of visual improvement with LIF. However, LIF showed no significant advantage over CST for favorable VA outcomes. No major complications occurred. LIF beyond the therapeutic time window improved vision in functionally blind CRAO patients and showed better efficacy when compared with CST. PT may be a potential predictor of visual outcome after LIF. Our findings could complement existing time-based treatment guidelines and potentially allow for personalized decisions on the use of LIF beyond time windows.

Retinal artery occlusion in young patients without typical cardiovascular risk factors: etiologies, prognosis, and suggested work-up.

PURPOSE: To understand the etiology, work-up, and secondary systemic and ocular events of retinal artery occlusion (RAO) in young patients (≤ 45 years old) without typical cardiovascular risk factors. METHODS: Retrospective longitudinal case series of 18 young patients with RAO and without typical cardiovascular risk factors evaluated at the University of Michigan Medicine Health System between the year 2000 and 2022. Laboratory and imaging studies performed at the time of RAO diagnosis, along with systemic and ocular events during follow-up, were recorded. These data were combined with data from a literature review of 74 similar patients experiencing a RAO. RESULTS: Fifteen (83%) of patients were female and 10 (56%) suffered a branch retinal artery occlusion (BRAO). 56% of patients had one risk factor associated with cryptogenic stroke, most commonly a migraine history (33%). The most frequent etiology of RAO was vasculitis (28%), followed by idiopathic (22%) and patent foramen ovale (PFO, 17%). Three out of four patients with idiopathic RAOs developed new migraines around the time of RAO diagnosis, whereas none of the patients with a clear etiology had new onset migraines (n = 14). No patients suffered a stroke or myocardial infarction (MI) in the follow-up period (average 3.6 years ± 3.2 years). Two patients (11%) suffered a repeat RAO, both of whom were diagnosed with a vasculitis. Patients with isolated retinal vasculitis required repeat fluorescein angiograms for up to 2 years after the initial event to definitively identify the vasculitic etiology of the RAO. When our data are pooled with similarly healthy patients from previously published RAO series, structural/functional cardiac abnormalities and vasculitides are the most common identifiable etiologies for RAOs in this group. CONCLUSION: The most common identifiable etiologies of RAO in young patients with low cardiovascular risk are structural/functional cardiac abnormalities and vasculitides, with a small range of additional causes/associations accounting for remaining cases. We suggest a focused work-up algorithm to rapidly identify etiologies in this group while minimizing unnecessary testing. The long-term risk of systemic or ocular secondary events in these patients is low regardless of the etiology of their RAO.

Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in retinal artery occlusion: a meta-analysis.

PURPOSE: The goal of this meta-analysis is to examine the association between Neutrophil-to-Lymphocyte Ratio (NLR) and Platelet-to-Lymphocyte Ratio (PLR) in patients with Retinal Artery Occlusion (RAO). The analysis aims to provide insight into the potential of NLR and PLR as inflammatory biomarkers for RAO. METHODS: Following PRISMA guidelines, a systematic search in PubMed, Embase, and Scopus identified eight eligible studies. The analysis assessed serum NLR and PLR levels in RAO and non-RAO groups by employing standardized mean differences (SMDs). Sensitivity analyses and publication bias were examined. The diagnostic performance of these markers was evaluated with a quantitative synthesis. RESULTS: The meta-analysis, involving 1,444 participants, demonstrated significantly elevated NLR (SMD = 0.88, 95% CI: 0.49-1.28, P < 0.001) and PLR (SMD = 0.45, 95% CI: 0.16-0.73, P < 0.001) levels in individuals with RAO. Significant heterogeneity was noted. Sensitivity analysis showed robustness and no significant publication bias was found. Summary results of diagnostic performance revealed promising discriminatory power for NLR and PLR. CONCLUSIONS: The results support a possible connection between systemic inflammation, as indicated by NLR and PLR, and the occurrence of RAO. Although there was heterogeneity, sensitivity analyses showed the findings to be robust. While immediate diagnostic applications are limited, understanding the role of NLR and PLR in the pathological process of RAO provides valuable insights for developing future predictive models, risk management approaches, and treatment strategies. Further research exploring mechanistic insights and conducting prospective studies is warranted to validate their clinical utility. KEY MESSAGES: What is known Retinal artery occlusion (RAO) is a serious condition with potential links to systemic inflammation and thrombosis. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are emerging inflammatory markers. What is new This is the first meta-analysis examining the association between NLR, PLR and RAO. Elevated NLR and PLR levels were observed in patients with RAO compared to controls. NLR and PLR show potential as indicators of systemic inflammation in RAO pathogenesis.

Central retinal artery occlusion after intravitreal brolucizumab injection for treatment-naïve neovascular age-related macular degeneration; a case report.

BACKGROUND: To report a case of central retinal artery occlusion (CRAO) after intravitreal injection of brolucizumab for a treatment-naïve neovascular age-related macular degeneration (nAMD) patient without comorbid cardiovascular disease history. CASE PRESENTATION: A 79-year-old Asian male without a cardiovascular disease history such as diabetes or hypertension underwent three times of monthly consecutive intravitreal brolucizumab injections for treatment of progressed nAMD in his left eye. Two days after the third injection, the patient presented with acute painless visual loss. Typical retinal whitening with a cherry red spot was observed on the fundus photograph, and retinal swelling with hyper-reflectivity was also identified on the optical coherence tomography (OCT) scan. On the fundus fluorescein angiography, arm-to-retina time and arteriovenous transit time were remarkedly delayed, but clinical findings suggesting an intraocular inflammation (IOI) were not observed. Therefore, CRAO was diagnosed, and anterior chamber paracentesis was administrated immediately. However, there had been no improvement in visual acuity during the follow-up period of three months, despite prolonged oral steroid and anti-platelet agent medication. CONCLUSIONS: In rare cases, patients without cardiovascular comorbidities can develop CRAO after intravitreal brolucizumab injection without gross evidence of IOI. Therefore, CRAO should always be in consideration and careful observation is required after intravitreal brolucizumab injection for nAMD patients with old age, even if the patient does not have any other cardiovascular disease history.

Incidence rates of retinal vascular occlusive diseases from 2011 to 2020 in South Korea: a nationwide cohort study.

BACKGROUND: Retinal vascular occlusions, including retinal vein occlusion and retinal artery occlusion, are common causes of visual impairment. In order to evaluate the national medical burden and help improve ophthalmic health care policy planning, we investigated the incidence of retinal vascular occlusive diseases from 2011 to 2020 in Korea. METHODS: This study is a nationwide population-based retrospective study using data from the Korea national health claim database of the Health Insurance Review and Assessment (HIRA) service. We identified retinal vascular occlusive diseases registered from January 1, 2009, to December 31, 2020, according to the retinal vascular occlusion code (H34) and its sub-codes from international classification of disease, tenth revision diagnosis code. We used data from the entire Korean population based on the 2015 census of the population in Korea to calculate standardized incidence rates. RESULTS: We identified 348,775 individuals (male, 161,673 [46.4%]; female, 187,102 [53.6%]) with incident retinal vascular occlusion (H34), 10,451 individuals (males, 6,329 [60.6%]; females, 4,122 [39.4%]) with incident central retinal artery occlusion (H34.1), and 252,810 individuals (males, 114,717 [45.4%]; females, 138,093 [54.6%]) with incident retinal vein occlusion (H34.8) during the 10-year study period. The weighted mean incidence rate of retinal vascular occlusion was 70.41 (95% CI, 70.18-70.65) cases/100,000 person-years. The weighted mean incidence rate of central retinal artery occlusion was 2.10 (95% CI, 2.06-2.14) cases/100,000 person-years. The weighted mean incidence rate of retinal vein occlusion was 50.99 (95% CI, 50.79-51.19) cases/100,000 person-years. CONCLUSION: The total retinal vascular occlusion and retinal vein occlusion showed a decreasing trend until 2020. However, the central retinal artery occlusion decreased until 2014 and remained stable without a significant further decline until 2020. The incidence of total retinal vascular occlusion and retinal vein occlusion was higher in females than in males, while the incidence of central retinal artery occlusion was higher in males. All retinal vascular occlusive diseases showed an increasing incidence with older age; the peak age incidence was 75-79 years for total retinal vascular occlusion and retinal vein occlusion, and 80-85 years for central retinal artery occlusion.

Analysis of the Effect of Superselective Ophthalmic Artery Thrombolysis for Central Retinal Artery Occlusion.

INTRODUCTION: The aim of the study was to investigate the clinical efficacy of superselective ophthalmic artery thrombolysis for central retinal artery occlusion (CRAO). METHODS: Retrospective study of CRAO patients who attended the Department of Ophthalmology of Affiliated Hospital of Weifang Medical University from January 2022 to July 2023, 138 CRAO patients with onset time of 1-3 days were selected for the study. Among them, 86 patients refused thrombolytic treatment and chose to adopt traditional treatment, which was categorized as the control group; 52 patients adopted superselective ophthalmic artery thrombolytic treatment, which was categorized as the observation group. The visual acuity of the patients treated with traditional modality on the 4th day after the onset of the disease and the visual acuity of the patients treated with superselective ophthalmic artery thrombolysis on the 1st postoperative day were recorded, and the visual acuity improvement after different modalities of treatment was compared between the two groups. RESULTS: In the control group, 77 (89.5%) of the treated patients had no improvement in visual acuity, 9 (10.5%) had improvement, 0 (0.0%) had significant improvement, and the total improvement was 9 (10.5%); in the observation group, 18 (34.6%) of the treated patients had no improvement in visual acuity, 21 (40.4%) had improvement, 13 (25.0%) had significant improvement, and the total improvement was 34 (65.4%). The total improvement rate of treatment in the observation group was 65.4%, which was significantly higher than the 10.5% in the control group, and the difference was statistically significant (p < 0.05). CONCLUSION: Superselective ophthalmic artery thrombolysis for patients with CRAO is clinically effective, promotes improvement in patient vision, and has a high safety profile.

Eye stroke protocol in in the emergency department.

BACKGROUND: Visual outcomes of acute central and branch retinal artery occlusions (CRAO/BRAO) are poor and acute treatment options are limited by delayed diagnosis. In the hyper-acute setting, the ocular fundus may appear "normal", making recognition challenging, but is facilitated by retinal optical coherence tomography (OCT), which is seldom available in emergency departments (ED). We evaluated the use of non-mydriatic ocular fundus photographs (NMFP) combined with OCT to facilitate ultra-rapid remote diagnosis and stroke alert for patients with acute vision loss presenting to the ED. METHODS: Prospective evaluation of all CRAO/BRAO between 06/06/2023-06/06/2024 who had NMFP-OCT in our general ED affiliated with a stroke center. RESULTS: Over 1 year, 22 patients were diagnosed with CRAO, 4 with BRAO. Five patients presented within 4.5 hours of vision loss onset, 6 within 4.5 to ≤12 hours and 15 within >12 to 24 hours. On average, NMFP-OCT was performed within 141 minutes of presentation to the ED (range 27- 422 minutes). Diagnosis of acute RAO was made remotely with NMFP-OCT within 4.5 hours in 4 patients, 2 of whom received intravenous thrombolysis. Of the 9 patients with NMFP-OCT within 12 hours of symptom onset, 5 patients had subtle retinal whitening on color fundus photograph, but all had OCT inner retinal hyper-reflectivity/edema. CONCLUSION: Implementation of NMFP-OCT in a general ED enables rapid remote diagnosis of CRAO/BRAO and facilitates initiation of an eye stroke protocol in acute patients. OCT complements color fundus photography and provides greater diagnostic accuracy in hyperacute cases with near-normal appearing ocular fundi.

A case series on treatment of central and branch retinal artery occlusion with intravenous tenecteplase: Tenecteplase for retinal artery occlusions.

OBJECTIVES: Central and branch retinal artery occlusions are disabling ischemic strokes of the retina for which established acute treatments are lacking. This is the first published report of the use of intravenous tenecteplase (TNK) for retinal artery occlusion, in which we describe the clinical course of four patients with central retinal artery occlusion (CRAO) and one patient with branch retinal artery occlusion (BRAO). MATERIALS AND METHODS: Patients were retrospectively recruited to the study from two stroke centers. Clinical course was determined from review of electronic medical records. The primary outcomes of interest were short and long term complications as well as visual acuity at presentation and at any subsequent follow up. RESULTS: There were no hemorrhagic complications. None of the four patients with CRAO experienced functional visual recovery (defined as improvement to 20/100 or better). The patient with BRAO had functional visual recovery. CONCLUSIONS: Intravenous TNK may be a safe and reasonable treatment for CRAO and BRAO.

IV Thrombolysis for central retinal artery occlusion - Real-world experience from a comprehensive stroke center.

OBJECTIVES: Central retinal artery occlusion (CRAO) is a stroke of the retina potentially amenable to intravenous thrombolysis (IVT). We aimed to determine feasibility of an emergency treatment protocol and risk profile of IVT for CRAO in a comprehensive stroke center (CSC). METHODS: We performed a retrospective, observational cohort study including patients with acute CRAO admitted to a CSC over 4 years. Patients are offered IVT if they present with acute vision loss of ≤ 20/200 in the affected eye, have no other cause of vision loss (incorporating a dilated ophthalmologic exam), and meet criteria akin to acute ischemic stroke. We collected socio-demographic data, triage data, time from onset to presentation, IVT candidacy, and rates of symptomatic intracranial hemorrhage (sICH)- or extracranial hemorrhage. RESULTS: 36 patients presented within the study period, mean (standard deviation (SD)) age of 70.7 (10), 52 % female, and median time (Q1, Q3) to ED presentation of 13.5 (4.3, 18.8) h. Patients within 4.5 h from onset presented more commonly directly to our ED (66.6 % vs 37.1 %, p = 0.1). Nine patients (25 %) presented within the 4.5 h window. Of those eligible, 7 (77 %) received IVT. There were no events of intracranial or extracranial hemorrhage. CONCLUSIONS: Our study confirmed that IVT for acute CRAO is feasible. We found a high rate of treatment with IVT of those eligible. However, because 75 % of patients presented outside the treatment window, continued educational efforts are needed to improve rapid triage to emergency departments to facilitate evaluation for possible candidacy with IVT.

Aetiology, Diagnosis and Treatment of Arterial Occlusions of the Retina-A Narrative Review.

Arterial occlusions of the retina are potentially sight-threatening diseases which often result in profound visual loss. The aim of this narrative review is to provide an overview of the aetiology, discuss major risk factors, describe the management and systemic assessments and evaluate existing therapies. For this review, an extensive literature search in PubMed was performed. Emboli from the heart or the carotid arteries can cause ophthalmic artery occlusion (OAO), central retinal artery occlusion (CRAO) and branch retinal artery occlusion (BRAO). Most patients with arterial occlusions have vascular risk factors such as arterial hypertension, hyperhomocysteinaemia, carotid stenosis and atrial fibrillation, which also increase the risk of cerebral stroke and myocardial infarction. Therapies such as ocular massage, thrombolysis and anterior chamber paracentesis have been suggested but are still equivocal. However, it is evident that retinal artery occlusion should be immediately treated and accompanied by interdisciplinary collaboration, since early diagnosis and the proper treatment of possible risk factors are important to reduce the risk of further damage, recurrences, other vascular diseases and mortality.

Thrombolytic Therapy for Central Retinal Artery Occlusion in an Academic Multi-Site Stroke Centre.

Central retinal artery occlusion (CRAO) is a subtype of acute ischaemic stroke leading to severe visual loss. A recent American Heart Association scientific statement proposed time-windows for thrombolysis in CRAO similar to acute ischaemic cerebral strokes. We aimed to review our academic multi-site stroke centre experience with intravenous (IVT) and intra-arterial thrombolysis (IAT) in CRAO between 1997 and 2022. Demographic, clinical characteristics, thrombolysis timeline, concurrent therapies, complications, and 3-month follow-up visual acuity (VA) were collected. The thrombolysed cohort follow-up VA was compared with an age, gender and baseline VA matched cohort of CRAO patients that received conservative therapies. Thrombolytic therapy was administered to 3.55% (n = 20) of CRAO admissions; 13 IVT (mean age 68, 61.5% male, 12 alteplase and 1 tenecteplase, all embolic aetiology, 1 CRAO mimic) and 7 IAT (mean age 55, 85.7% male, 3 post-operative and 3 embolic). Additional conservative CRAO-targeting therapies was received by 60%. The median time from onset of visual loss to IVT was 158 minutes (range 67-260). Improvement by at least two Snellen lines was achieved by 25% with 12.5% improving to 20/100 or better. Intracranial haemorrhage post IVT occurred in 1/13 (7.6%). The median time from onset of visual loss to IAT was 335 minutes. Improvement by at least two Snellen lines was achieved by 42%. No difference in 3-month VA was noted between patients that received thrombolysis, either alone (n = 8) or combined with other therapies, and those that received conservative therapies. Our results suggest that the management of acute CRAO remains heterogeneous. The lack of obvious benefit of thrombolysis in our small series supports the need for randomizsd clinical trials comparing thrombolysis to placebo to guide hyperacute CRAO management.

[Thrombolysis treatment and multi- disciplinary management of central retinal artery occlusion in comparison with traditional ophthalmological treatment options]. / Arteria centralis retinae elzáródás thrombolysiskezelése és multidiszciplináris ellátása a hagyományos szemészeti kezelési formákkal összehasonlítva.

Background and purpose:

The management of central retinal artery occlusion (CRAO) has long been conservative therapy with limited efficacy carried out in ophthalmology departments together with etiolo­gi­cal investigations lacking a standardised protocol. However, CRAO is analogous to ischemic central nervous system stroke and is associated with increased stroke risk, thus, systemic thrombolysis treatment and multidisciplinary management can be beneficial. Since May 2022, at Semmelweis University CRAO patients diagnosed within 4.5 hours are given intravenous thrombolysis therapy and undergo etiologic workup based on current stroke protocols. Here we report our experience with the multidisciplinary, protocol-based management of CRAO in comparison with former non-protocol based ophthalmological conservative treatment.

We reviewed CRAO patients’ data treated conservatively and with paracentesis within 6 hours at the Department of Ophthalmology between 2013 and 2022 including changes in visual acuity, neurolo­gical and cardiovascular findings compared to those in the thrombolysis project. 

Of the 78 patients receiving non-protocol care, visual improvement was seen in 37% with natural course, 47% with conservative treatment and 47% with paracentesis. Four patients had significant carotid stenosis (2 underwent endarterectomy), 1 carotid dissection, 6 cardioembolism and 1 giant cell arteritis. Of the 4 patients within 4,5 hours, 3 gave their consent to the clinical trial and were treated with thrombolysis and underwent a full etiological assessment. 
2 pa­tients had improved visual acuity, 2 pa­tients had significant carotid stenosis and underwent endarterectomy, 1 patient was started on anticoagulation for newly diagnosed atrial fibrillation.

CRAO patients presenting within 4,5 hours are rare and more patients are needed in our study to establish the efficacy of thrombolysis. However uniform protocollized evaluation helps identifying embolic sources thus, avoiding further and potentially more serious thromboembolic events.

High prevalence of thrombophilic risk factors in patients with central retinal artery occlusion.

INTRODUCTION: Central retinal artery occlusion (CRAO) is a common cause of blindness and visual morbidity. In the majority of cases, it is related to thrombotic embolism. Nevertheless, the role of inherited or acquired thrombophilic risk factors in CRAO pathogenesis has not been comprehensively studied. METHODS: In 126 CRAO patients (66 [52.4%] men, median age 55 [range: 18-80] years) and 107 matched controls (56 [52.3%] men, median age 53 [range: 34-78] years) we evaluated classical atherosclerotic risk factors, including serum lipid profile and glucose level, analyzed intima-media complex thickness (IMT) of external carotid arteries, and performed transthoracic echocardiography. Furthermore, we established the prevalence of inherited and acquired thrombophilic risk factors, such as factor V Leiden (FVL) and prothrombin 20210 G/A genetic variants, plasma activity of factor (F) VIII, protein C and antithrombin activity, and free protein S levels. We also assessed the presence of antiphospholipid antibodies (APLA) and evaluated blood homocysteine in all enrolled subjects. Additionally, we estimated the occurrence of Val34Leu polymorphism of the A subunit of coagulation factor XIII (FXIII-A) in both groups as a potential thrombosis-protecting factor. RESULTS: Among traditional atherosclerotic risk components, obesity/overweight and hypercholesterolemia were the most common in the CRAO group and occurred in 103 (81.7%) and 85 (67.5%) patients, respectively. CRAO patients also had elevated IMT and altered echocardiographic parameters, indicating diastolic cardiac dysfunction. In thrombophilia investigations, at least one laboratory risk factor occurred in 72.2% (n = 91) of CRAO patients, with APLA as the most frequent, detected in 38.1% (n = 48) of them (almost seven times more frequent than in controls, p < 0.001). Deficiencies in protein C activity and free protein S levels were also common in the CRAO group, reported in 17.5% (n = 22) and 19.8% (n = 25) of patients, respectively. Interestingly, among two analyzed prothrombotic genetic variants, only the FVL was related to CRAO, with the allelic frequency 2.4 times more prevalent than in controls (p = 0.044). Finally, the CRAO group was characterized by hyperhomocysteinemia, almost twice as common as in controls (p = 0.026). Antithrombin deficiency, elevated FVIII, and FXIII-A Val34Leu polymorphism were not associated with CRAO. CONCLUSIONS: Our findings suggest that thrombophilia plays a vital role in the pathogenesis of CRAO. Thus, proper laboratory screening should be considered in the primary and secondary prevention of those episodes, with implementing appropriate therapy as needed.

Susac syndrome: challenges in the diagnosis and treatment.

Susac syndrome is a disorder thought to be mediated by an autoimmune response towards endothelial cells, leading to a characteristic clinical triad of encephalopathy, visual disturbances due to branch arterial occlusions and sensorineural hearing impairment. Although it is a rare disease, three reasons make it important. First, given its variable presentation, Susac syndrome is underdiagnosed. Second, it is considered an important differential diagnosis in different neurological, psychiatric, ophthalmological and hearing disorders, and consequently is frequently misdiagnosed. Third, in many cases, Susac syndrome is diagnosed and treated late, with significant irreversible sequelae including dementia, blindness and hearing loss. Neuropathology findings derived from both Susac syndrome patient tissue and novel transgenic mouse models indicate cytotoxic CD8+ T cells adhere to microvessels, inducing endothelial cell swelling, vascular narrowing and occlusion, causing microinfarcts. Anti-endothelial cell antibodies are present in serum in 25% of Susac syndrome patients, but it is unclear whether they are aetiologically related to the disease, or an epiphenomenon. The clinical triad comprising encephalopathy, branch arterial occlusions, and sensorineural hearing impairment is considered pathognomonic, although great variability is found in presentation and natural course of disease. At first evaluation, only 13-30% of patients exhibit the full clinical triad, making diagnosis difficult. Retinal fluorescein angiography, optic coherence tomography, MRI and tonal audiometry are helpful methods for diagnosing and monitoring disease activity during treatment. By contrast, there are no reliable objective immune markers to monitor disease activity. Immunosuppression is the current treatment, with high-dose corticosteroid therapy as the mainstay, but additional therapies such as intravenous immunoglobulins, cyclophosphamide, rituximab and mycophenolate mofetil are often necessary, because the disease can be devastating, causing irreversible organ damage. Unfortunately, low rates of disease, variability in presentation and paucity of objective biomarkers make prospective controlled clinical trials for Susac syndrome treatment difficult. Current immunosuppressive treatments are therefore based on empirical evidence, mainly from retrospective case series and expert opinion. In this review, we draw attention to the need to take consider Susac syndrome in the differential diagnosis of different neurological, psychiatric, ophthalmological and hearing disorders. Furthermore, we summarize our current knowledge of this syndrome, in reference to its pathophysiology, diagnosis and management, emphasizing the need for prospective and controlled studies that allow a better therapeutic approach.

Retinal vascular occlusions in COVID-19 infection and vaccination: a literature review.

PURPOSE: Abnormal hypercoagulability and increased thromboembolic risk are common in patients with coronavirus disease (COVID-19). COVID-19 has been suggested to cause retinal vascular damage, with several studies on COVID-19 patients with retinal vascular occlusions. We reviewed and investigated studies on retinal vascular occlusions in patients diagnosed with COVID-19 and in those vaccinated for COVID-19. METHODS: Studies that reported retinal vascular occlusion in COVID-19 patients or in vaccinated people were identified using the terms "retinal occlusion," together with "severe acute respiratory syndrome coronavirus 2", "SARS-CoV-2," "COVID-19," "coronavirus," and "vaccine," through systematic searches of PubMed and Google Scholar databases until January 7, 2022. RESULTS: Thirteen cases of retinal artery occlusion (RAO) and 14 cases of retinal vein occlusion (RVO) were identified among patients diagnosed with COVID-19. Half of the patients with RAO or RVO revealed no systemic disorders except current or past COVID-19, and ocular symptoms were the initial presentation in five cases. Among patients with RAO, most presented with central RAO at 1-14 days of COVID-19 diagnosis, with abnormal coagulation and inflammatory markers. Among those with RVO, two-thirds presented with central RVO and one-third with RVO. Eleven cases with acute macular neuroretinopathy (AMN) and/or paracentral acute middle maculopathy (PAMM) were reported among patients with COVID-19, presenting scotoma resolved spontaneously in most cases. Among the 26 cases vaccinated with either mRNA or adenoviral vector vaccines for COVID-19 and presenting retinal vascular occlusions, there were more RVO cases than RAO cases, and ocular symptoms mostly occurred within 3 weeks after vaccination. One case presented bilateral AMN and PAMM after COVID-19 vaccination. CONCLUSION: Retinal vascular occlusions might be a manifestation of COVID-19, although rare, especially in patients at risk of systemic hypercoagulability and thromboembolism. For COVID-19 vaccines, the causal relationship is controversial because there are few case reports of retinal vascular occlusions after COVID-19 vaccination.

Efficacy and safety of intra-arterial thrombolysis in patients with central retinal artery occlusion: a systematic review and meta-analysis.

PURPOSE: To investigate the efficacy and safety of intra-arterial thrombolysis (IAT) in patients with central retinal artery occlusion (CRAO). METHODS: PubMed and EMBASE were searched for potentially eligible studies that reported IAT in CRAO patients from inception to Nov 8, 2021. Standard mean difference (SMD) was pooled to compare visual acuity (VA) at baseline with final in IAT patients. The rates and odds ratios (OR) were meta-analyzed to compare VA improvement in IAT with non-IAT patients, stratified to different times from onset to procedure, different definitions of VA improvement, and three CRAO stages. Adverse effects were recorded. RESULTS: Fifteen studies were included, enrolling 507 CRAO patients who received IAT and 296 CRAO patients who did not. VA was significantly improved from baseline to final VA in IAT patients (SMD [LogMAR] 0.70, 95% CI [0.51, 0.90]). VA improvement rate was higher in IAT patients than that in non-IAT (56% vs 32%, OR 3.55, 95%CI [1.74, 7.24]), with greater OR in IAT within 6 h from onset to procedure (OR 4.60, 95%CI [1.24, 16.99]) than that beyond 6 h (OR 3.36, 95%CI [1.43, 7.85]). The benefit remained consistent when VA improvement was defined as ≥ 3 lines on the Snellen chart (OR 4.68, 95%CI [2.10, 10.41]) and was even greater when CRAO was incomplete. Five patients had a symptomatic intracranial hemorrhage and 21 patients had ischemic stroke or transient ischemic attack after IAT. CONCLUSIONS: IAT treatment has certain potential in ameliorating VA in CRAO patients, which should be balanced against cerebral complications.