Thrombolysis for Central Retinal Artery Occlusion in 2020: Time Is Vision!

Abstract

Background: Acute nonarteritic central retinal artery occlusion (CRAO) is an eye stroke with poor visual prognosis and no proven effective therapies. Given advances in acute stroke care, thrombolysis in CRAO merits critical re-examination. We review the evidence for intravenous (IV) and intra-arterial (IA) tissue plasminogen activator (tPA) in CRAO management.

Evidence acquisition: MEDLINE, Scopus, and Cochrane online databases were systematically searched from 1960 to present, for reports of acute IV or IA therapy with alteplase or tenecteplase in nonarteritic CRAO patients. English language case reports, case series, interventional studies, or randomized controlled trials were included. The study type, age and number of subjects, the regimen administered, the time since symptoms' onset, visual outcome, and safety reports were noted.

Results: Use of IV thrombolysis with alteplase was reported in 7 articles encompassing 111 patients, with 54% of them receiving IV tPA within 4.5 hours of symptom onset, and none developing symptomatic intracranial or ocular hemorrhage. Six studies described IA alteplase administration, with only 18 of a total of 134 patients (13.4%) treated within the first 6 hours after visual loss. The reported adverse events were minimal. Visual outcomes post-IV and IA thrombolysis were heterogeneously reported; however, most studies demonstrated benefit of the respective reperfusion therapies when administered very early. We found no reports of tenecteplase administration in CRAO.

Conclusions: In 2020, nonarteritic CRAO patients should theoretically receive the same thrombolytic therapies, in the same time window, as patients with acute cerebral ischemia. Eye stroke and teleeye stroke code encounters must include an expert ophthalmologic evaluation to confirm the correct diagnosis and to evaluate for ocular signs that may help guide IV tPA administration or IA management. Future research should focus on developing feasible retinal penumbra imaging studies that, similar to cerebral tissue viability or perfusion imaging, can be incorporated into the thrombolysis decision-making algorithm.

Figure:. Proposed acute management of patients with presumed acute central retinal artery occlusion (CRAO).

1) The diagnosis of acute CRAO must be confirmed before thrombolysis is administered. If patients present to an outpatient eye care center or other practitioner office with symptoms suggestive of acute CRAO, a 911 call should be initiated to facilitate patients’ emergent transport to the closest facilities (e.g., certified Stroke Center) that are able to administer IV alteplase, even if visual loss is isolated (without any neurologic symptoms). If patients present to an ED without access to acute stroke care, either in-person or via telemedicine, emergent transfer to the closest Stroke-Ready Center should be similarly arranged, using emergency medical services or the local hospital policy. In the ED or en route to the ED via a prehospital notification, “eye-stroke code” activation should prompt emergent neurological and ophthalmological evaluations, either in person or via telemedicine. 2) Patients seen early enough to allow for administration of IV alteplase within 4.5 hours of vision loss should undergo the evaluation recommended by the AHA for brain AIS (Table 2). 3) Because of time constraint, the ophthalmologic evaluation should be limited to what is necessary to confirm the diagnosis of acute non-arteritic CRAO and rule-out ocular contraindications to thrombolytic treatment such as vitreous or retinal hemorrhage, hemorrhagic diabetic retinopathy and active choroidal neovascularization (wet age-related macular degeneration). Because classic funduscopic signs of CRAO can be missing very acutely, we recommend macular optical coherence tomography to demonstrate thickening of the inner retinal layers secondary to retinal edema^, in order to rapidly confirm the CRAO diagnosis if necessary. We do not recommend retinal fluorescein angiography which is time consuming and delays appropriate management. Baseline visual acuity should be documented, but formal visual field testing should be delayed until after treatment. Bedside evaluation is preferred for patients presenting to the ED and funduscopic imaging with a nonmydriatic fundus camera should be obtained whenever possible. 4) If systemic contraindications for IV alteplase are identified, as per 2019 AHA guidelines, IAT should be considered. A neuro-interventional specialist should be consulted early to discuss potential IAT. CT angiogram head and neck should not delay the administration of IV alteplase but should be performed prior to IAT in all CRAO patients. CT angiography of the extracranial carotid arteries and intracranial circulation provides useful information on patient eligibility and endovascular procedural planning. Knowledge of vessel anatomy and presence of extracranial vessel dissection, stenosis, and occlusion may assist in planning endovascular procedures or identifying patients ineligible for treatment. Transfers to a Thrombectomy-Capable or Comprehensive Stroke Center should be emergently arranged if patients have an isolated CRAO within 6 hours of visual loss. 5) The patient’ counseling regarding the benefits and risks of IV and IA alteplase should incorporate the findings discussed in the above-mentioned studies (Tables 1 and 3). The potential risks should be discussed during eligibility deliberation and weighed against the anticipated benefits during decision making, emphasizing the lack of randomized controlled trial proving alteplase efficacy in the treatment of CRAO. 6) After the acute thrombolytic intervention is pursued, all patients should be admitted to a Stroke Unit or Intensive Care Unit (depending on institutional protocol) for timely and targeted stroke secondary prevention, as all patients with presumed retinal ischemia (whether transient or permanent) should undergo urgent brain imaging and etiologic testing similar to patients with cerebral ischemia.

Figure:. Proposed acute management of patients with presumed acute central retinal artery occlusion (CRAO).

1) The diagnosis of acute CRAO must be confirmed before thrombolysis is administered. If patients present to an outpatient eye care center or other practitioner office with symptoms suggestive of acute CRAO, a 911 call should be initiated to facilitate patients’ emergent transport to the closest facilities (e.g., certified Stroke Center) that are able to administer IV alteplase, even if visual loss is isolated (without any neurologic symptoms). If patients present to an ED without access to acute stroke care, either in-person or via telemedicine, emergent transfer to the closest Stroke-Ready Center should be similarly arranged, using emergency medical services or the local hospital policy. In the ED or en route to the ED via a prehospital notification, “eye-stroke code” activation should prompt emergent neurological and ophthalmological evaluations, either in person or via telemedicine. 2) Patients seen early enough to allow for administration of IV alteplase within 4.5 hours of vision loss should undergo the evaluation recommended by the AHA for brain AIS (Table 2). 3) Because of time constraint, the ophthalmologic evaluation should be limited to what is necessary to confirm the diagnosis of acute non-arteritic CRAO and rule-out ocular contraindications to thrombolytic treatment such as vitreous or retinal hemorrhage, hemorrhagic diabetic retinopathy and active choroidal neovascularization (wet age-related macular degeneration). Because classic funduscopic signs of CRAO can be missing very acutely, we recommend macular optical coherence tomography to demonstrate thickening of the inner retinal layers secondary to retinal edema^, in order to rapidly confirm the CRAO diagnosis if necessary. We do not recommend retinal fluorescein angiography which is time consuming and delays appropriate management. Baseline visual acuity should be documented, but formal visual field testing should be delayed until after treatment. Bedside evaluation is preferred for patients presenting to the ED and funduscopic imaging with a nonmydriatic fundus camera should be obtained whenever possible. 4) If systemic contraindications for IV alteplase are identified, as per 2019 AHA guidelines, IAT should be considered. A neuro-interventional specialist should be consulted early to discuss potential IAT. CT angiogram head and neck should not delay the administration of IV alteplase but should be performed prior to IAT in all CRAO patients. CT angiography of the extracranial carotid arteries and intracranial circulation provides useful information on patient eligibility and endovascular procedural planning. Knowledge of vessel anatomy and presence of extracranial vessel dissection, stenosis, and occlusion may assist in planning endovascular procedures or identifying patients ineligible for treatment. Transfers to a Thrombectomy-Capable or Comprehensive Stroke Center should be emergently arranged if patients have an isolated CRAO within 6 hours of visual loss. 5) The patient’ counseling regarding the benefits and risks of IV and IA alteplase should incorporate the findings discussed in the above-mentioned studies (Tables 1 and 3). The potential risks should be discussed during eligibility deliberation and weighed against the anticipated benefits during decision making, emphasizing the lack of randomized controlled trial proving alteplase efficacy in the treatment of CRAO. 6) After the acute thrombolytic intervention is pursued, all patients should be admitted to a Stroke Unit or Intensive Care Unit (depending on institutional protocol) for timely and targeted stroke secondary prevention, as all patients with presumed retinal ischemia (whether transient or permanent) should undergo urgent brain imaging and etiologic testing similar to patients with cerebral ischemia.