Retinal Artery Occlusion

BackgroundThe critical time from onset of complete occlusion of the central retinal artery (CRA) to functionally significant inner retinal infarction represents a window of opportunity for treatment and also has medical-legal implications, particularly when central retinal artery occlusion (CRAO) complicates therapeutic interventions. Here, we review the evidence for time to infarction from complete CRAO and discuss the implications of our findings.MethodsA Medline search was performed using each of the terms "central retinal artery occlusion", "retinal infarction", "retinal ischemia", and "cherry red spot" from 1970 to the present including articles in French and German. All retrieved references as well as their reference lists were screened for relevance. An Internet search using these terms was also performed to look for additional references.ResultsWe find that the experimental evidence showing that inner retinal infarction occurs after 90-240 min of total CRAO, which is the interval generally accepted in the medical literature and practice guidelines, is flawed in important ways. Moreover, the retinal ganglion cells, supplied by the CRA, are part of the central nervous system which undergoes infarction after non-perfusion of 12-15 min or less.ConclusionsRetinal infarction is most likely to occur after only 12-15 min of complete CRAO. This helps to explain why therapeutic maneuvers for CRAO are often ineffective. Nevertheless, many CRAOs are incomplete and may benefit from therapy after longer intervals. To try to avoid retinal infarcton from inadvertent ocular compression by a headrest during prone anesthesia, the eyes should be checked at intervals of less than 15'.

Neuroinflammation is often associated with blood-brain-barrier dysfunction, which contributes to neurological tissue damage. Here, we reveal the pathophysiology of Susac syndrome (SuS), an enigmatic neuroinflammatory disease with central nervous system (CNS) endotheliopathy. By investigating immune cells from the blood, cerebrospinal fluid, and CNS of SuS patients, we demonstrate oligoclonal expansion of terminally differentiated activated cytotoxic CD8+ T cells (CTLs). Neuropathological data derived from both SuS patients and a newly-developed transgenic mouse model recapitulating the disease indicate that CTLs adhere to CNS microvessels in distinct areas and polarize granzyme B, which most likely results in the observed endothelial cell injury and microhemorrhages. Blocking T-cell adhesion by anti-α4 integrin-intervention ameliorates the disease in the preclinical model. Similarly, disease severity decreases in four SuS patients treated with natalizumab along with other therapy. Our study identifies CD8+ T-cell-mediated endotheliopathy as a key disease mechanism in SuS and highlights therapeutic opportunities.

BackgroundNo evidence-based therapy exists for non-arteritic central retinal artery occlusion (NA-CRAO). Retinal ischemic tolerance is low; irreversible damage occurs within four hours of experimental NA-CRAO. In previous randomized trials evaluating intra-arterial or intravenous thrombolysis (IVT) in NA-CRAO, only one patient was treated this early. In December 2013, the Departments of Neurology & Stroke and Ophthalmology at University Hospital Tuebingen, Germany, decided to treat patients using IVT within 4.5 hours of NA-CRAO, the therapeutic window established for ischemic stroke.Materials and methodsConsecutive NA-CRAO patients with severe visual loss received IVT after exclusion of intracranial hemorrhage. Follow-up was conducted at day 5 (d5) and day 30 (d30). Visual outcomes were compared to the conservative standard treatment (CST) arm of the EAGLE-trial.ResultsUntil August 2016, 20 patients received IVT within 4.5 hours after NA-CRAO with a median onset-to-treatment time of 210 minutes (IQR 120-240). Visual acuity improved from baseline mean logarithm of the minimum angle of resolution 2.46±0.33 (SD) (light perception) to 1.52±1.09 (Snellen equivalent: 6/200) at d5 (p = 0.002) and 1.60±1.08 (Snellen equivalent: 6/240) at d30. Compared to the EAGLE CST-arm, functional recovery to reading ability occurred more frequently after IVT: 6/20 (30%) versus 1/39 (3%) at d5 (p = 0.005) and at d30 5/20 (25%) versus 2/37 (5%) (p = 0.045). Two patients experienced serious adverse events (one angioedema and one bleeding from an abdominal aortic aneurysm) but recovered without sequelae.ConclusionsIVT within 4.5 hours after symptom onset may represent an effective treatment of NA-CRAO. Randomized trials are warranted to evaluate efficacy and safety of early IVT in acute NA-CRAO.

ImportanceCentral retinal artery occlusion (CRAO) is a disabling subtype of acute ischemic stroke. It is not known whether intravenous (IV) thrombolysis delivered within 4.5 hours of time last known well (LKW) improves visual outcomes.Study designSystematic review and individual participant data meta-analysis.ObjectiveThe objective of this study is to determine whether IV thrombolysis improves visual outcomes among patients with acute non-arteritic CRAO when administered within 4.5 hours of time LKW compared with placebo, no IV thrombolysis, and/or anti-thrombotic therapy.Evidence review planThis study is prospectively registered through PROSPERO (#1154900). We will include randomized controlled trials (RCTs) that enroll patients with non-arteritic CRAO presenting within 4.5 hours of time LKW. We will not include non-controlled interventional studies or retrospective studies. We will search MEDLINE, Embase, the Cochrane Library, Web of Science, and the ClinicalTrials.gov registry from inception through the date of commencement of the systematic review. We will assess the risk of bias using the Cochrane Risk of Bias Tool 2.0. We will contact the corresponding author(s) of any studies identified that meet the study selection criteria. We will inspect, harmonize, and collate trial datasets. The primary end point will be attainment of a final best corrected visual acuity (BCVA) equal to or better than 20/63 (logarithm of the minimum angle of resolution [logMAR] of ≤0.5). Secondary end points will include shift analyses of key visual acuity outcome categories according to the World Health Organization (WHO) International Classification of Disease (ICD)-11, final BCVA considered as a continuous variable, final BCVA equal to or better than 20/100 (logMAR of ≤0.7), final BCVA equal to or better than 20/200 (logMAR of ≤1), a quantitative measure of visual field function (where available), global disability (modified Rankin Scale score [mRS]), and key safety end points (including symptomatic intracranial hemorrhage [sICH] and other systemic hemorrhage). We will fit a series of mixed logistic and linear regression models with trial, and trial by treatment interaction terms as random effects. To probe for sources of heterogeneity, we will pursue a series of subgroup and sensitivity analyses. Finally, a GRADE assessment will be presented.Conclusions and relevanceCompletion of the proposed study will permit a synopsis of the interventional literature on IV thrombolysis for CRAO, generate a pooled estimate of the treatment effect, and allow exploration of sources of heterogeneity. Such results may be of interest to healthcare professionals, guideline development bodies, policymakers, payors, and future patients with CRAO.RegistrationThis systematic review is prospectively registered: PROSPERO #1154900.