June 2018


Pharmaceutical focus
HORV concerns linger for many

by Maxine Lipner EyeWorld Senior Contributing Writer

Bilateral hemorrhagic occlusive retinal vasculitis in a 55-year-old man after cataract surgery with intracameral vancomycin 18 days (right eye) and 11 days (left eye) prior to presentation. Vision is 20/30 in the right eye (A) and no light perception in the left (B). There is severe peripheral ischemia in the right eye (C) and complete non-perfusion in the left eye (D) on fluorescein angiography.
Source: Ryan Terribilini

What to keep in mind

Hemorrhagic occlusive retinal vasculitis (HORV) is a devastating condition that has left many practitioners avoiding prophylactic use of vancomycin for cataract surgery. It can occur even after routine cases, according to Nick Mamalis, MD, professor of ophthalmology, Moran Eye Center, University of Utah, Salt Lake City.
“Initially physicians were seeing an extensive inflammatory vasculitis type of pattern that was occurring in patients after relatively uncomplicated cataract surgery,” Dr. Mamalis said. As practitioners started seeing more of these cases, ASCRS in conjunction with the American Society of Retina Specialists (ASRS) put together a task force to look into the reports to determine why this was occurring.
It started with around six case reports, said Richard Hoffman, MD, clinical associate professor of ophthalmology, Casey Eye Institute, Oregon Health Sciences University, Portland. “After further evaluation and polling, they discovered there were at least 36 eyes of 22 patients (with HORV),” Dr. Hoffman said.1
With this condition, patients appeared fine on the first postoperative day. “There’s a delayed onset of painless visual loss with a mild anterior chamber reaction and a mild-to-moderate vitreous inflammation,” Dr. Hoffman said. “The patients have retinal hemorrhage that is more pronounced in the peripheral retina with vascular occlusion.” There was a predilection for the hemorrhages to be around the veins and to be peripheral, Dr. Hoffman continued, adding that in many patients there was a rapid progression of neovascularization of the iris and neovascular glaucoma.
“I think the other interesting development with this condition is that we found a strong association with vancomycin,” Dr. Hoffman said. “We weren’t sure initially, but after we looked at the 36 eyes that met the criteria, we found that they all received vancomycin.” This was either in the irrigating bottle, injected into the vitreous, or using an intracameral bolus of vancomycin, which was injected into the anterior chamber.
Some patients were initially misdiagnosed as having endophthalmitis, Dr. Hoffman thinks. “The condition differs from endophthalmitis in that the inflammation is much milder,” he said, adding that there were likely patients who were initially presumed to have endophthalmitis and given intravitreal vancomycin as treatment. “Those eyes did the worst out of all of them,” Dr. Hoffman said. “There were seven eyes that received additional treatment with vancomycin, and five of them went on to have no light perception vision.”

The HORV picture

Dr. Mamalis described HORV as a severe hemorrhagic/occlusive vasculitis. “Patients had significant visual loss,” he said. “They had a tremendous amount of inflammation, and it was all associated with the vessels that were in the retina causing widespread hemorrhages and widespread disturbances of the vessels. It was causing an occlusive vasculitis, and we hadn’t seen this before.”
Cases of HORV are typically diagnosed by the characteristics and by the temporal relationship to the cataract surgery. The delayed onset inflammation makes it unique. “Oftentimes, when we see patients with inflammation after cataract surgery, it’s acute,” Dr. Mamalis said, adding that such immediate reactions are usually associate with toxic anterior segment syndrome (TASS), which occurs acutely in the anterior segment. However, this was different because it arose posteriorly in the retina and took place 1–2 weeks after the initial cataract surgery in cases that involved the use of vancomycin.
Dr. Hoffman stressed that HORV is a devastating but very rare condition. “They tended to be bilateral, so they received surgery in one eye and the problem was that this either had a very mild vasculitis or hadn’t even developed when they received surgery in the second eye,” he said, adding that this resulted in bilateral disease of varying severity.
To determine if a case might be HORV requires the use of indirect ophthalmoscopy, Dr. Hoffman explained. If you look at the back of the eye, you see peripheral massive hemorrhages that look like a vasculitis involving the venules. “There’s ischemia of the veins and massive hemorrhages that’s more pronounced in the periphery and just a mild cellular reaction,” Dr. Hoffman said. The distinct clinical onset of HORV sets it apart. For instance, endophthalmitis has a severe cellular reaction with pain and a severe anterior chamber reaction; by contrast HORV patients have a mild anterior reaction and no pain.
Anyone with visual loss and fairly massive peripheral hemorrhages who has received vancomycin either in the irrigating solution or as a bolus should be considered a suspect for having the condition, Dr. Hoffman said. “So far, we don’t have any cases that are confirmed HORV that haven’t received vancomycin,” he said.

Looking at vancomycin use

Despite the HORV risk, there are still some surgeons using vancomycin, Dr. Hoffman noted, adding that because the condition is rare, the paper the task force published did not recommend completely eliminating vancomycin use. “For instance, if you have a patient with MRSA, vancomycin is an ideal medication,” he said. “So there are still surgeons who are using it. In the paper we didn’t recommend they stop using vancomycin, but the surgeon needs to weigh the rare risk of HORV with the risk of endophthalmitis.”
Retina surgeons are still using vancomycin in combination with a gram-negative antibiotic for treating endophthalmitis. “In confirmed or highly suspicious endophthalmitis, I think that’s still being used,” Dr. Hoffman said. “This is extremely rare, so the chances that a retina surgeon is going to create HORV is rare and worth the risk of using vancomycin in that situation.”
Even prophylactically, some are still using it. “I think there are still some surgeons who use vancomycin because they think it’s better than moxifloxacin or cefuroxime, which are the other antibiotics commonly used,” he said. “They think that the risk is relatively low.” In such cases, Dr. Hoffman advised that if vancomycin is used, patients should undergo a dilated fundus examination after the first eye to make sure they’re not developing HORV before they have vancomycin injected into the second eye.
“There’s also a debate about whether or not it’s a good idea to do eyes very close together,” Dr. Hoffman said, adding that some may do one eye and do the second with vancomycin 1 week later. There are even some surgeons who are doing bilateral simultaneous cataract surgery. “I think that it would not be wise to be using vancomycin in those patients because you don’t know if they’re 1 in 1 million until you’ve injected both of their eyes,” Dr. Hoffman said.
“There were some prominent surgeons who were using it and have done thousands of cases with intracameral vancomycin, never had a problem, and decided that it wasn’t worth it,” he said.
Dr. Mamalis said that since the task force report has come out there has been a decrease in the use of vancomycin for prophylaxis of endophthalmitis during cataract surgery. “People are moving to alternatives, which can include cefuroxime and moxifloxacin,” Dr. Mamalis said.
While the task force was careful not to give a blanket condemnation of vancomycin, Dr. Mamalis also urges caution. “There are some who have used vancomycin for tens of thousands of cases for prophylaxis without ever seeing this,” he said. “But now that this has been reported, I think the surgeon has to carefully reevaluate his or her choice of antibiotic for the prevention of endophthalmitis.”

Understanding HORV

HORV cases seem to have declined considerably. “Fortunately, the amount of cases that have been reported have dropped markedly over the past year,” Dr. Mamalis said, adding that he thinks this has to do with practitioners now being aware of the possible link to intracameral vancomycin use. As a result, they are turning to alternative antibiotics.
The crux of what is happening with the vancomycin involves a leukoplastic vasculitis, Dr. Mamalis explained. “It’s thought to be a type III autoimmune reaction, leukoplastic vasculitis, meaning it’s an autoimmune inflammation and it affects the retinal blood vessels,” he said. “You get inflammation around the blood vessels and then an actual occlusion of the blood vessels, hemorrhages, and a subsequent blockage of blood supply to the retina, so there will be areas of non-profusion.” Once that happens, the retina becomes ischemic and secondary conditions such as cystoid macular edema can occur, he continued, adding that just from the ischemia itself, there can be a tremendous amount of damage to the retina.
Dr. Hoffman stressed that the indirect nature of the type III hypersensitivity reaction sets it apart from antibiotics that have a direct toxicity to the retina. “It’s not a direct toxicity, which is why some of these patients are getting small amounts in an irrigating bottle and still having a reaction,” Dr. Hoffman said. “That being said, the more vancomycin they’re exposed to, the more severe the condition is.” While many have wondered whether patients could be skin-tested beforehand to determine if they are among the few who are likely to react, this is not possible. “There’s no way to know beforehand who’s going to react to it,” Dr. Hoffman said. However, if someone is known to have had a reaction to systemic vancomycin, Dr. Hoffman thinks this would likely put them at risk of developing HORV from an intracameral injection.
While there are other antibiotics that can cause direct toxicity to the retina if injected in too high a concentration, this is not comparable, Dr. Hoffman stressed. “If you inject too much tobramycin into the vitreous, the next day the patient has visual loss,” he said. “It’s not a slow onset visual loss that you get from a type III hypersensitivity reaction; it’s immediate toxicity with a completely different clinical picture.” While any antibiotic in the wrong dose could cause toxicity, so far the type III hypersensitivity reaction has only been described with vancomycin.
Given the potentially devastating consequences, Dr. Hoffman encourages practitioners to stop using vancomycin prophylactically. “I would switch to a different antibiotic,” he said, adding that if a physician is set on using vancomycin, he or she might not want to do bilateral simultaneous surgery. While 3–4 weeks between eyes is recommended, if practitioners are not inclined to wait that long, Dr. Hoffman stressed the need to at least delay the second eye for 1 or 2 weeks, since first eyes develop symptoms within 8 days on average.
Dr. Mamalis likewise urged practitioners to think carefully about their choice of antibiotics for trying to prevent endophthalmitis. He is pleased at the marked drop in HORV cases. “People are still monitoring these and looking for cases, but the large outbreak that we had a couple of years ago seems to have subsided,” he said. “The HORV registry and the task force is still looking into this issue and hoping that we’re going to see the incidence continue to drop.”


1. Witkin AJ, et al. Vancomycin-associated hemorrhagic occlusive retinal vasculitis: clinical characteristics of 36 eyes. Ophthalmology. 2017;124:583–595.

Editors’ note: Dr. Hoffman and Dr. Mamalis have no financial interests related to their comments.

Contact information

: rshoffman@finemd.com
Mamalis: nick.mamalis@hsc.utah.edu

HORV concerns linger for many HORV concerns linger for many
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