Background

Thrombolytic agents catalyze the breakdown of fibrin-based thrombi that commonly are implicated in embolic stroke, including RAO [ ]. Clinically, thrombolysis has well-established benefits for acute cerebral ischemia, and the Cochrane Library’s systematic review concluded thrombolytic therapy with tissue plasminogen activator (tPA) given up to 6 hours after stroke reduces the risk of death or dependency. This benefit was apparent despite an increase in symptomatic intracerebral hemorrhage (ICH), a feared complication of this therapy [ ].

Intravenous thrombolysis for central retinal artery occlusion

Intravenous thrombolysis (IVT) for CRAO has been described for a half-century, however, foundational support for this practice, in particular with modern thrombolytic agents, has more definitively emerged within the past decade [ ]. In a 2015 patient-level meta-analysis, Schrag and colleagues reported that, concerning visual recovery from 20/200 or worse to 20/100 or better, systemic thrombolysis was beneficial at 4.5 hours or earlier after vision loss compared with the natural history group (17 of 34 [50.0%] vs 70 of 396 [17.7%]; odds ratio, 4.7 [95% CI, 2.3–9.6]; P <.001). No benefit was apparent when thrombolysis was provided at after a time point from vision loss [ ]. An updated meta-analysis reported a visual recovery rate of 37.3% among patients treated with alteplase, a biosynthetic form of human tissue-type plasminogen activator, within 4.5 hours because time last known well, compared with the 17.7% recovery rate in those without treatment. A low risk of hemorrhagic complications occurs in the included studies; indeed, no case of symptomatic ICH in patients treated was noted within 4.5 hours [ ].

These data, largely based on observational studies, have served as a motivation for clinical trials comparing IV thrombolysis to placebo for CRAO. At present, there are 3 such clinical trials registered on clinicaltrials.gov underway in Europe.

Intraarterial thrombolysis for central retinal artery occlusion

Intraarterial thrombolysis (IAT) has had an important role in acute cerebral ischemia for more than 2 decades. The endovascular approach permits a high concentration of lytic agent to be delivered directly to the clot and increases lysis rates compared with IVT, while minimizing systemic exposure and hemorrhagic complications [ ].

For CRAO, the procedure involves super-selective microcatheterization of the ostium of the ophthalmic artery. Catheter-associated complications can include arterial dissection, catheter-induced vasospasm, and distal embolization of clot. Furthermore, a greater human resources requirement exists compared with IVT, because the procedure must be carried out in a catheterization laboratory with monitored anesthesia care [ ].

To date, a single randomized controlled trial (RCT) of IAT for CRAO has been reported. The European Assessment Group for Lysis in the Eye carried out a prospective, randomized, and multi-center study that compared the conservative treatment to IAT for patients with CRAO within 20 hours of vision loss. Because of similar efficacy and a higher rate of adverse reactions in the IAT group, the study was stopped after the first interim analysis [ ]. However, as no patient was treated within 4.5 hours, and only 4 of 41 were treated within 6 hours, the role of IAT at earlier time points after vision loss from CRAO is not yet defined. No active randomized trials of IAT for CRAO are currently registered on clinicaltrials.gov .

Alternative modalities of thrombolysis delivery

Intraocular endovascular delivery of thrombolytic agent during pars plana vitrectomy has been described [ , ]. In this technique, retinal arterial cannulation at the optic disc is performed with a microneedle and tPA is administered directly into the retinal circulation. A non-randomized study reported improved VA in eyes treated with this approach compared with conservative measures (ocular massage and intraocular pressure [IOP] lowering drops) although the clinical significance of VA improvement was questionable [ ]. Further study is required before such an approach should be considered. It is noteworthy that the time required for arranging a vitrectomy in the operating room would extend the delay to treatment with thrombolysis.

Neurovascular secondary prevention

As detailed previously, patients with BRAO and CRAO experience an increased short- and long-term risk of vascular events including stroke, MI, as well as death [ ]. Hence, an imperative exists for both urgent etiologic workup (ie, to reduce short-term stroke risk) and long-term vascular risk factor optimization. Multidisciplinary collaboration between the vision care provider, neurologist, primary care provider, and others is essential [ ]. In this regard, the vision care provider’s obligations following diagnosis of acute RAO include referral to an emergency department (ED) or (for subacute presentations) a stroke prevention service on an urgent basis.

Ocular secondary prevention

Ocular neovascularization (NV) is detected in 16% of eyes after CRAO. Anterior segment neovascularization is most common and can produce neovascular glaucoma [ ]. The average time from CRAO to NV diagnosis is approximately 3 months, although NV may be detected as early as 1 week after CRAO [ , ]. Risk factors for ocular NV after CRAO include absence of angiographic retinal reperfusion, diabetes, history of stroke, chronic kidney disease, and increasing age [ ]. As BRAO is associated with less extensive retinal ischemia (and, therefore, reduced pro-angiogenic stimulus), NV typically is not observed following BRAO [ ]. The American Academy of Ophthalmology’s professional guidelines for retinal artery occlusions advise that patients with more extensive retinal ischemia be followed closely. Panretinal photocoagulation treatment is recommended for patients who develop NV after RAO [ ].

In addition to monitoring for neovascular sequelae, the vision-care provider (ophthalmologist or optometrist) has critical roles to play after RAO, including optimizing remaining vision and preserving the health of the fellow eye [ ].

Acute arteritic central retinal artery occlusion

Clinical suspicion and prompt empiric treatment with glucocorticoids are critical to reduce the risk of fellow-eye vision loss when CRAO is because of GCA [ ]. Our standard practice for vision-involving suspected GCA, including patients who present with possible arteritic CRAO, is to offer treatment with 3 days of intravenous methylprednisolone 1000 mg daily, followed by high dose oral prednisone while a temporal artery biopsy is arranged. Recently, it has been proposed that the interleukin-6 receptor blocker tocilizumab may have a role because acute rescue therapy in patients with glucocorticoid-resistant GCA whereby further vision loss would otherwise be imminent, but further research is needed [ ].

Pre-hospital delay

Delay in presentation after vision loss from RAO is common. In a US study, among 484 patients with recent CRAO, Shah and colleagues reported 247 (51%) presented within 4.5 hours of vision loss, whereas 86 (17.8%) sought care after more than 24 hours [ ]. Other studies have described even less favorable times-to-presentation. In another US-based study of 91 patients with acute non-arteritic CRAO, only 20.9% presented within 4 hours of symptom onset [ ]. In a German study of 101 patients admitted for CRAO, almost 60% presented later than 4.5 hours [ ].

The first point of contact with the health care system may not be able to provide thrombolysis, and transfer to stroke center will introduce additional delay. In a report of 181 patients with CRAO referred to a tertiary care stroke center, only 62 (34%) were seen at that institution within 24 hours [ ].

As compared to the symptoms of acute cerebral ischemia, where significant efforts have been made to raise public awareness about the possibility of stroke, the urgency of acute vision loss may not be recognized by the layperson. In Ardila Jurado and colleagues’s Swiss study of 32,816 patients, the symptom-to-door time was greater for patients with CRAO than for those with cerebral stroke: 852 mins versus 300 mins on average, respectively [ ]. Revision of the widely-promoted acronym for stroke symptomatology–FAST (Face, Arms, Speech, Time) to include other stroke symptoms–Balance, Eyes to BE-FAST has been proposed as a strategy to increase public awareness [ ]. Further public education campaigns may be required.

In-hospital delay to diagnosis

Providers in acute care settings who encounter a patient with sudden vision loss may not readily consider RAO as a differential diagnosis and are not necessarily equipped to confirm the diagnosis clinically [ ]. The use of nonmydriatic fundus photography in the ED provides numerous benefits over direct ophthalmoscopy including improved detection of relevant abnormalities by ED physicians and the ability to remove review [ , ]. The latter point is particularly salient because timely in-person ophthalmologic consultation is not always available in acute care settings. Increasingly, calls are being made for ED-based fundus photography to have a central role in minimizing door-to-diagnosis time for CRAO [ , ]. Integrating optical coherence tomography (OCT) into ED workflows may further assist with making a prompt diagnosis [ ]. Collaboration between ophthalmology, neurology, and emergency medicine departments will be required for the successful implementation of this technology at the institutional level.

Fundus photography

The characteristic cherry red spot of CRAO appears after several hours of retinal ischemia; its absence on color fundus photos in the presence of other early fundus changes (segmental blood flow and retinal arteriolar attenuation) may indirectly suggest retinal viability [ ].

Optical coherence tomography

OCT provides structural information about the retina that can complement clinical assessment and fundus photography. OCT-derived metrics in recent CRAO correlate with visual outcomes [ , ]. Retinal edema detected by OCT develops in a time-dependent fashion within hours of CRAO [ ]. In a retrospective analysis of 66 patients with recent (<48 hours) CRAO, OCT retinal thickness measures identified eyes with ischemia onset less than 4.5 hours with sensitivity of 100% and specificity of 94.3% [ ]. The ability of these markers to inform treatment decision-making remains to be studied in a prospective setting.

OCT angiography (OCTA) permits non-invasive 3-dimensional visualization of retinal microvasculature and for this reason is worthy of mention in a discussion of multimodal assessment of RAO [ ]. With further technological refinements, it is plausible that OCTA will play a role in assessing retinal viability after RAO in the acute setting, but at this time such a role is not clearly defined.

Future directions

Additional techniques currently limited to research settings may have a role in retinal viability assessment in the future. These tools, which include Retinal Function Imager and Photoacoustic Imaging, have been summarized in a recent review by Mac Grory and colleagues [ ].

Hyperbaric oxygen

Hyperbaric oxygen (HBO) has been described as a primary treatment for CRAO, although it is not accepted as an evidence-based practice [ ]. Treatment protocols involve up to 24 hours of exposure to 100% oxygen at 2.0 to 2.8 atm [ ]. HBO may allow impaired inner retinal oxygenation to be supplemented by diffusion of oxygen from the choroidal circulation in the setting of supraphysiologic oxygen tension. HBO is theorized to maintain tissue viability until normal perfusion is restored, either spontaneously or because of intervention (such as thrombolysis); as such, it is a potential neuroprotective strategy. A 2018 meta-analysis of 7 RCTs of oxygen therapy for RAO (including 6 that used HBO) found a significant benefit for VA improvement for patients receiving oxygen therapy versus the control group who did not (OR, 5.61 [95% CI, 3.60–8.73]; P <.01); hyperbaric was superior to normobaric treatment. Most included studies had a low risk of bias, however, the clinical significance of VA improvement was not discussed; furthermore, many of the included studies used other interventions such as ocular massage or IOP-lowering therapies and none used thrombolysis [ ]. Centers with access to hyperbaric oxygen therapy can consider how to integrate this treatment into institutional protocols for acute treatment of RAO.

Hypothermia

Therapeutic hypothermia has proven neuroprotective effects in conditions that produce global cerebral ischemia such as cardiac arrest. In this context, systemic cooling decreases cerebral metabolic demand and reduces oxygen requirements, hence, neuronal death is reduced or delayed and superior neurologic outcomes are observed as a result [ ].

Local cooling of the eye or retina may provide a neuroprotective effect for RAO. In rats with experimental CRAO, cooling of the eye with an external icepack reduced retinal cell death in 1 study [ ]. Cooling of enucleated bovine eyes to 21°C prolonged retinal ganglion cell (RGC) ischemic tolerance compared to 37°C [ ]. Even mild degrees of local hypothermia may be beneficial in RAO: in an organ culture model, cooling to 30°C increased RGC survival after ischemia [ ]. Human data are lacking but retinal cooling may be feasible with as simple a technique as an application of an icepack to the closed eyelids as soon as suspicion for CRAO is raised.