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  • CRAO: Promising Results From Emergency Protocols

    By Peggy Denny, Contributing Writer
    Retina/Vitreous

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    Since acute vision loss from central retinal artery occlusion (CRAO) was first described by von Graefe in 1859, generations of ophthalmic researchers have at­tempted to find effective treatments for this disorder. The natural history of CRAO is dismal; a meta-analysis of studies that included 396 untreated patients reported that only 70 of these patients (17.7%) experienced functional vision recovery to 20/100 or better,1 and a recent large cohort of 794 CRAO patients from Kaiser Permanente (KP) California highlighted this poor visual outcome regardless of time to presentation or any conservative treatment performed.2 Regarding the many patients who did not recover vision, Richard B. Rosen, MD, said, “I can remember, over the years, the faces of people and their look when I told them there was nothing I could do.” Dr. Rosen is Belinda Bingham Pierce and Gerald G. Pierce, MD, Distinguished Chair of Ophthal­mology, Chief of the Retina Service, and Profes­sor, Department of Ophthalmology, Mount Sinai Health System, New York, N.Y.

    Now, growing recognition of the entity not just as an ocular condition but also as a type of arterial ischemic stroke is leading researchers in promising therapeutic directions. The use of thrombolytic strategies in CRAO—akin to the use of tissue plasminogen activator (tPA) and tenecteplase (TNK) in cerebrovascular stroke—has the potential to be a true game changer, according to Dr. Rosen. But whether it lives up to this potential remains to be determined through future research.

    “Eye Stroke” Is a CNS Stroke

    About 95% of CRAOs are caused by an embolus (or emboli; Fig. 1), most often arising from the carotid artery or heart, that lodges in and occludes blood flow through the retinal artery (less than 5% are caused by giant cell arteritis [GCA]).3 If the subsequent ischemia is not reversed, retinal infarction and permanent visual loss occur.

    In their “Updated Definition of Stroke for the 21st Century,” the American Heart Association and American Stroke Association stated that reti­nal cell death attributable to ischemia, along with similar ischemic injury in the brain or spinal cord, is a central nervous system (CNS) stroke.4 More­over, the risk factors for stroke in general apply to eye stroke as well, including high blood pressure, diabetes, high cholesterol levels, smoking, and obesity; and patients presenting with CRAO have a significantly elevated risk of concurrent or subsequent stroke.

    However, despite the Academy Preferred Prac­tice Pattern recommendation that patients with acute symptomatic ophthalmic, central retinal, or branch artery occlusion be immediately referred to the nearest stroke center,5 this does not always occur.6 

    Fundus photo in patient with CRAO shows multiple bright yellow cholesterol emboli both at the disc and along multiple retinal arteries.
    OCCLUSIVE EMBOLI. Left eye fundus photo montage of a 43-year-old man with CRAO shows multiple bright yellow cholesterol emboli both at the disc and along multiple retinal arteries.

    Treatment Controversies

    Well into the 21st century, suggested treatments for acute nonarteritic CRAO included “conserva­tive treatments,” such as ocular massage, anterior chamber paracentesis, vasodilation, breathing into a paper bag, carbogen therapy, and topical IOP-lowering agents. However, none of these therapies showed superiority over untreated outcomes—and, in some studies, they were associated with worse outcomes.5,7,8

    On the basis of the shared pathophysiology between CRAO and stroke, investigators in the 1990s began studying the use of tPA, through either a local intra-arterial (IA) or a systemic intravenous (IV) route, in an attempt to clear the retinal occlusion. The results of thrombolytic therapy have been mixed. Thus far, the only multi­center randomized controlled trial is the Europe­an Assessment Group for Lysis in the Eye Study (EAGLE), conducted between 2002 and 2007 at nine centers in Austria and Germany, which com­pared IA tPA within 20 hours of vision loss against conservative therapy. This trial showed no benefit from IA tPA and, even worse, was stopped early because of adverse events in the IA tPA group.9

    However, the study itself was controversial and “didn’t do the treatment justice,” said John J. Chen, MD, PhD, Professor of Ophthalmology and Neurology, and Neuro-Ophthalmology Fellowship Director at the Mayo Clinic in Rochester, Minne­sota. One drawback is that the mean elapsed time between symptom onset and IA tPA treatment was almost 13 hours, “and we know that if it’s going to work, it should be administered within 4.5 to 6 hours,” he said. None of the patients were treated within 4.5 hours, and less than 10% were treated within 6 hours.1,9

    Despite the current lack of high-level evidence from clinical trials to support thrombolysis for CRAO, the evidence gap may improve soon, said Valérie Biousse, MD. “Three well-designed double-blind, controlled, randomized clinical trials evaluating IV thrombolysis are ongoing in France, Norway, and Germany,” she said, adding that the French trial is completed, and results should be available later this year. Dr. Biousse is Professor of Ophthalmology at the Emory Eye Center and in the Department of Neurology, Emory University School of Medicine in Atlanta.

    Time Is Vision!

    One indisputable, compelling finding has emerged: if any treatment is to be successful, it must be rendered urgently. Although the exact treatment window has not been determined, many stud­ies suggest 4.5 to 6 hours as the optimum. The well-known stroke adage, “Time is brain,” can be adapted for CRAO as “Time is vision.”3

    Thus, several academic medical centers and health care systems have implemented emergency protocols to facilitate rapid diagnosis and timely therapy in hopes of improving visual outcomes in patients with CRAO. Here, experts from four such centers share their experience.

    Emergency Protocols

    Although the protocols in these centers vary according to local resources and populations, they share some important characteristics:

    • They depend on smooth coordination between the emergency, ophthalmology, and neurology departments and have ready access to a stroke center, onsite or remotely.
    • If appropriate, thrombolytic therapy (IV or IA tPA or TNK) is administered to selected patients who present within a defined time window.
    • Whether or not thrombolytic therapy is admin­istered, patients are urgently assessed and sub­sequently followed for stroke and cardiovascular events, which are known to occur at a higher rate in patients with CRAO.10

    A team approach. Dr. Chen said, “We have a protocol developed in conjunction with neurol­ogy, ophthalmology, and our ED physicians. The main role for the ophthalmologist is confirming an acute retinal artery occlusion and ruling out other conditions like a retinal detachment or ischemic optic neuropathy. We are lucky to have ophthalmology residents on call 24/7.

    “If the CRAO is within 4.5 hours, we activate the stroke protocol that has been in place for a long time for cerebrovascular strokes. In the ED, the patient undergoes a CT head scan to make sure there’s no brain bleed, and also blood work to rule out GCA. The stroke neurologists will then inform the patients who are candidates for thrombolytic treatment about risks and benefits.” Dr. Chen added that the Mayo neurology team has switched to using off-label TNK, a genetically modified form of tPA, rather than the original type, alteplase, because it is much easier to administer.

    At Emory, said Dr. Biousse, ophthalmology has a long-standing relationship with stroke neurology. “In all the EDs affiliated with Emory, it’s standard that a diagnosis of acute CRAO triggers a stroke alert, and patients with CRAO are managed exactly like those suspected of having cerebrovascular stroke. They receive the same attention, the same workup, and the same follow-ups with stroke neurology for secondary prevention once they are discharged from the hospital.”

    Access to ocular imaging in the ED is a key part of this process, she said. “Our practice com­pletely changed once there was a nonmydriatic ocular fundus camera in one of our general EDs—it allowed us to make the diagnosis of CRAO immediately and remotely without having to see the patient in person.”

    Caveat: watch for this rare condition. Both Dr. Chen and Dr. Biousse emphasized one critical dif­ference in emergency management of eye stroke versus brain stroke: the need to rule out GCA as the cause of the CRAO. Dr. Biousse said, “For eye stroke, we systematically add GCA screening lab tests to the standard stroke protocol. It’s such a rare cause of brain stroke that the ED and neurol­ogy team might not think of it.” Distinguishing between embolic and arteritic CRAO has a major effect on patient outcome. As Dr. Chen said, “If it’s GCA, tPA won’t do any good, and corticosteroids are administered to protect vision in the other eye.”

    Nuances: time and place of presentation. Even if a good protocol is in place for patients who present to the ED, many people may not realize their visual symptoms warrant a trip there. Instead, depending on the medical center, they may seek help from the eye clinic or an advice line, with varying success.

    Guy V. Jirawuthiworavong, MD, MA, regional neuro-ophthalmologist at Southern California Kaiser Permanente (KP) in La Palma, California, recognizes the challenge of navigating through complex triage scenarios in this large managed-care system, with coverage that may vary depending on the time of day. “If patients come to our outpatient facility with symptomatic vision loss that the ophthalmologist determines is a CRAO, they will be directed immedi­ately to the ED, where there is a stroke neurologist,” who will also evaluate for possible cerebral ischemia.

    Outside of office hours, many patients call the 24/7 advice line, which provides initial triage. Dr. Jirawuthi­woravong said that he gives patients who are already being seen in the eye clinic a “script” for this situation: “I’ve been told that I can reach out to the on-call oph­thalmologist to discuss my loss of vision, which may be considered an emergency or urgent care. I’d like to know their opinion.” This will prompt the advice nurse to immediately involve the on-call ophthalmologist. Depending on the circum­stances, the ophthalmologist may see the patient in person or evaluate the retina in fundus photos taken in the ED.

    Of course, not all patients in this situation have had previous contact with the eye clinic. Dr. Ji­rawuthiworavong said that, fortunately, the triage nurses are trained to assess for possible stroke us­ing the BE-FAST mnemonic to review symptoms.

    BE-FAST: A Key Mnemonic

    The widely used FAST algorithm (face, arm, speech, time) for stroke originated in 1998 in the United Kingdom. More recently, two letters were added to account for other symptoms, including visual changes. This revision was shown to significantly reduce the number of strokes that were missed using FAST alone.1

    B = balance, for vertigo or loss of balance

    E = eyes, for loss of vision, double vision, or nystagmus

    F = face, for drooping or asymmetry

    A = arm, for weakness or lack of coordination in the arm or other limbs

    S = speech, for slurred or garbled speech

    T = time, get help as fast as possible!

    ___________________________

    1 Aroor S et al. Stroke. 2017;48(2):479-481.

    IA vs. IV: Which Is Preferable?

    IA versus IV administration of tPA is a contro­versial topic in CRAO treatment. In the Mount Sinai protocol described by Dr. Rosen, IA is the route of choice. He first became interested in it when David Abramson, MD, and Pierre Gobin, MD, introduced IA chemotherapy for retino­blastoma. “I was so impressed with the ability to reach up into the ophthalmic artery, and I thought that we should be able to do that for retinal occlusions,” Dr. Rosen said. “With IA, you put the tPA right at the mouth of the ophthal­mic artery as it’s branching off the internal carotid, so you use a very small amount of tPA, and it goes right to the target, thereby reduc­ing adverse effects, as Dr. Abramson showed with his work in IA chemo.”

    Dr. Biousse agreed that IA may potentially provide a better outcome in terms of visual recovery and that, by avoiding large systemic doses, there is a lower risk of brain bleed and systemic bleed. The disadvantages, she said, are that the procedure is very invasive and technically challenging, and it requires cathe­ter angiography in an interventional radiology setting. It can only be performed in specialized centers, and ensuring that the right facilities and doctor are available often delays the treatment. Additionally, as shown in the EAGLE trial, there’s a risk of procedure-related compli­cations, especially when performed by people who do not do it every day, she said.

    This is why most doctors prefer the IV route, Dr. Biousse said. “It is fast, and all you need is an IV and a stroke neurologist on the phone for telestroke. You don’t have to transfer the patient, and it’s very safe in the appropriate pa­tients. So, despite some obvious advantages of IA, at Emory we prefer IV tPA or TNK within 4.5 hours.” Outside of that time limit, she added, try to do IA “if you’re lucky enough to be at a center that has access to it.”

    Dr. Jirawuthiworavong said that only IV tPA is used in KP Southern California. Likewise, said Dr. Chen, the IV route is used at the Mayo Clinic in Rochester, though he noted that the Arizona clinic is doing more IA thrombolysis, and it could be an option in select patients in Rochester.

    Imaging and Telemedicine

    “Stroke neurologists have been using what we call telestroke for about 15 or 20 years,” said Dr. Biousse, “because once tPA was shown to dra­matically improve the outcome of patients with a brain stroke, the major obstacle was finding ways for patients in remote areas to receive the drug within the time window for treatment.” Through the telestroke network, a patient in an ED “in the middle of nowhere,” with no stroke coverage, can be diagnosed on the basis of brain imaging taken in the ED and reviewed remotely by a stroke neu­rologist, who can advise on the appropriateness of tPA for that patient.

    Similar tele-eye-stroke strategies can be em­ployed for CRAO, said Dr. Rosen who, with his colleagues, recently published their novel pro­tocol, now referred to as the ROCKET (Rapid OCT-Confirmed EyestroKE Treatment) proto­col, used at Mount Sinai (Fig. 2). It makes use of point-of-care automated OCT imaging that is reviewed remotely by retina specialists through a secure chat line.11 “These OCT devices are now in place in EDs throughout the Mount Sinai system,” he said, adding that the machines are very easy to use. “Many staff members are now trained to take images, send them to the retina group, and we can readily diagnose ischemia versus no ischemia.” If the retina specialist’s assessment confirms that it’s an ischemic retinal artery occlusion, the stroke team moves into high gear; if not, the patient undergoes a dilated ophthalmic evaluation.

    Fundus photography or OCT? Nonmydriatic fundus cameras have long demonstrated their use­fulness in the ED for the diagnosis of many poste­rior segment disorders,12 and more recently, OCT has been employed successfully in this setting.13 Now, several manufacturers are marketing devices that can acquire both types of images at once.

    Although both are useful in diagnosing CRAO, the OCT can detect more subtle signs of damage than the fundus camera and OCT may make it easier to get usable images (Fig. 3). For example, retinal whitening with a cherry-red spot in the macula, which has traditionally been considered the char acteristic marker of CRAO, can be seen on fundus photography. However, said Dr. Chen, the cherry-red spot may not develop for a couple of hours, so very acute CRAO may not be easily seen in fundus photography alone but it may be readily diagnosed on OCT.

    Dr. Biousse described the very early signs of retinal ischemia on OCT: “You see some thickening and hyperreflectivity of the inner retina. On the standard macular OCT, layers of the retina generally look dark gray, but when it’s ischemic, it looks brighter, whiter, with loss of definition of inner layers. And so, you can make the diagnosis very early and be 100% sure that you have a CRAO.”

    In addition, she said that OCT can help establish the time course of the CRAO. “You can’t tell the difference between one hour and two hours, but you can tell the difference between two hours and six hours, or between within four hours and 12 hours of CRAO.” This is especially helpful, she said, in treatment decisions for patients who wake up with vision loss in the morning and don’t know when it occurred.

    Algorithm depicts the emergency protocol for CRAO developed by the Retina Service of the New York Eye and Ear Infirmary of Mount Sinai, in a multispecialty collaborative effort.
    ROCKET PROTOCOL. Algorithm depicts the emergency protocol for CRAO developed by the Retina Service of the New York Eye and Ear Infirmary of Mount Sinai, in a multispecialty collaborative effort.

    Time Window for Treatment

    For cerebral stroke, the time window for IV tPA treatment is generally considered to be 4.5 hours from onset, but the window for IA thrombolysis in CRAO has not been definitively established. “It is a difficult question because we don’t really have any solid data from clinical trials,” said Dr. Biousse. “The treatment window in stroke neurology for IV tPA was established based on efficacy and safety; after 4.5 hours efficacy is reduced, and the risk of brain hemorrhage is high,” and most physicians follow that precedent for CRAO. In addition, she noted that the results of small case series and meta-analyses published in CRAO support that cutoff time.

    However, the treatment window for IA therapy may be longer, with the most commonly accepted cutoff at 6 hours.3 However, Dr. Rosen said that the Mount Sinai protocol allows for IA tPA up to 12 hours. “In the brain, you have a very short window of opportunity. The cortical tissue of the brain will go from being just an ischemic area to a hemorrhagic area after 4.5 hours. So, if you give IV tPA too late, you may make the patient much worse.” He explained that this concern doesn’t ap­ply to using IA in the eye. “The retina is a slightly different modification of the brain tissue, and it doesn’t bleed in the same way,” and there is less risk because the treatment is administered locally rather than systemically.

    Two sets (a fundus photo above an OCT image) of images side by side. Left set depicts patient’s right eye. Right set of images depicts patient’s left eye.
    TWO MODES OF IMAGING. Fundus photos and OCTs for normal right eye (at left) and affected left eye (at right).

    More on Management and Follow-up

    Although all four of these emergency protocols aim to ensure that appropriate patients get rapid thrombolytic treatment, many patients are not eligible because they present too late, have contra­indications, or do not wish to receive the therapy.

    But regardless of whether patients are treated with thrombolysis, these protocols can have a profound effect on their cerebrovascular and car­diovascular health outcomes by connecting them to a stroke neurologist for timely evaluation. For example, at KP, Dr. Jirawuthiworavong said that the patients diagnosed with nonarteritic CRAO will get an MRI of the brain, a CT scan of their neck vessels and the arteries of the head (CTA), as well as cardiac evaluation, which could show evidence of current or impending problems.

    Follow-up. According to the American Heart Association, patients who experienced a CRAO should have long-term follow-up involving multidisciplinary collaboration between neurology, ophthalmology, and primary care. Attention should be focused on secondary prevention by controlling modifiable risk factors and monitoring for subsequent stroke or cardiovascular events.1

    An ophthalmologist should continue to follow the patient for ocular complications caused by retinal ischemia, such as neovascularization of the retina or iris and neovascular glaucoma. Treatment with panretinal photocoagulation, with or without anti-VEGF therapy, may be warranted for neovas­cularization.5

    Key Takeaways

    The paradigm has changed. “It’s critical for the ophthalmic community at large to really under­stand that the standard of care for management of acute CRAO has changed dramatically over the past decade,” said Dr. Biousse. “This is supported by statements from the Academy and the Ameri­can Heart Association.”

    Dr. Chen concurred. “Across the board, the main message is that CRAOs are equal to strokes, so if it’s acute, the patient urgently needs a stroke workup.” In the past, he said, ophthalmologists who saw someone with CRAO would often advise the patient to see their primary care doctor and get a workup within a month. Now, patients who present with acute CRAO within 24 hours should be sent to the ED. “That’s a major paradigm shift, and if doctors aren’t doing that, they just haven’t gotten the message.”

    Imaging speeds communication and manage­ment. Having an easy-to-use imaging system—whether a nonmydriatic fundus camera, an OCT, or a combination device—in the ED is an essential component of any tele-eye-stroke program. And even at centers with an on-call ophthal mologist available 24/7, imaging can shave precious minutes, or even an hour, off the time from presentation at the ED to diagnosis. Given the brief window, this could make the difference between treatment or no treatment. Dr. Jirawuthiworavong said, “It really added another level to our protocol when fundus cameras were placed in the ED at two main hospitals. Now, if the ophthal­mologist is involved in treating other emergency patients, we don’t need to wait until they are done and able to see our patient in person.”

    Educating doctors and the public is paramount. “There is a huge amount of education that needs to be done,” said Dr. Biousse. “Many of us go to local, regional, and national medical and ophthalmology conferences—wherever we have contact with those in our own specialty or others, we should use every opportu­nity to spread the word about treating CRAO as a true emergency, the same as stroke.” It is especially important to educate ED physicians about the link between CRAO and cerebrovascular stroke. Dr. Biousse added that physicians should reach out to their colleagues in the optometry community as well, because optometrists often are the first contact for patients with eye problems.

    “Finally,” she said, “you can have the best doc­tors in the world, and you can have the best EDs in the world, and you can have the best clinical trials in the world—but if the patients themselves do not seek emergency care when they have vision loss, we’ll never get anywhere.”

    Dr. Rosen recalled that some years ago, when dedicated stroke centers and teams were growing, “there were a lot of public service announcements to alert people about signs of a stroke and the im­portance of immediately calling 911. Similarly, we need to press for greater public recognition of the BE-FAST symptoms to get emergency treatment for patients with sudden visual loss.”

    ___________________________

    1 Mac Grory B et al; American Heart Association. Stroke. 2021;52(6):e282-e294.

    2 Shah R et al. Ophthalmol Retina. Published online Dec. 27, 2023.

    3 Dumitrascu OM et al. J Neuroophthalmol. 2020;40(3):333-345.

    4 Sacco RL et al. Stroke. 2013;44(7):2064-2089.

    5 Flaxel CJ et al; Retina and Vitreous Preferred Practice Pattern Panel. Ophthalmology. 2020;127(2):P259-P287.

    6 Meer E et al. Ophthalmic Epidemiol. 2022;29(6):696-702.

    7 Biousse V et al. Ophthalmology. 2018;125(10):1597-1607.

    8 Sharma RA et al. Taiwan J Ophthalmol. 2020;11(1):16-24.

    9 Schumacher M et al. Ophthalmology. 2010;117(7):1367-75.e1.

    10 Wai KM et al. JAMA Ophthalmol. 2023;141(12):1110-1116.

    11 Lema GMC et al. Ophthalmology. Published online Feb. 13, 2024.

    12 Biousse V, Bruce BB, Newman NJ. Ophthalmoscopy in the 21st Century: The 2017 H. Houston Merritt Lecture. Neurology. 2018;90(4):167-175.

    13 Kaplan RI et al. BMJ Open Ophthalmol. 2019;4(1):e000187.

    Meet the Experts

    Valérie Biousse, MD Professor of Ophthalmology at the Emory Eye Center and in the Department of Neurology, Emory University School of Medicine; she is the Reunette Harris Chair of Ophthalmic Research, Vice Chair for Faculty Development, Diversity and Inclusion in the Department of Ophthal­mology, and Director of the Neuro-Ophthalmol­ogy Fellowship at Emory, in Atlanta. Relevant financial disclosures: None.

    John J. Chen, MD, PhD Professor of Ophthalmology and Neurology, and Neuro-Ophthalmology Fellow­ship Director at the Mayo Clinic in Rochester, Minn. Relevant finan­cial disclosures: None.

    Guy V. Jirawuthiworavong, MD, MA Regional neuro-ophthalmologist at Southern California Kaiser Perma­nente in La Palma, Calif. Relevant financial disclosures: None.

    Richard B. Rosen, MD Belinda Bingham Pierce and Gerald G. Pierce, MD, Distinguished Chair of Ophthalmology, Chief of the Reti­na Service, and Professor, Depart­ment of Ophthalmology, Mount Sinai Health System, New York, N.Y. Relevant financial disclo­sures: Canon USA: S; Intalight: S; OcuSciences: S; Optovue: C,P,PS; Topcon Medical Systems: S.

    Full Financial Disclosures

    Dr. Biousse GenSight Biologics: C; Neurophoenix: C. 

    Dr. Chen Horizon Therapeutics: C; UCB: C.  

    Dr. Jirawuthiworavong None 

    Dr. Rosen Abbvie: L; Boehringer Ingelheim: C; Canon USA: S; CellView: C,PS; Guardion Health Sciences: C,US; Intalight: S; Kyoto Pharmaceueticals: C; LumiThera: C; OcuSciences: S; OD-OS: C; Opticology: PS; Optovue: C,P,PS; Regeneron Pharmaceuticals: C; Topcon Medical Systems: S.

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