August 2017

COVER FEATURE

Steroids roundup
Tips for steroid use in HSV


by Ellen Stodola EyeWorld Senior Staff Writer


HSV disciform keratitis

HSV stromal keratitis without ulceration
Source: Vincent de Luise, MD


Experts discuss when to use steroids in patients with herpes simplex virus keratitis, which medications to use, and important information on different ways the disease could manifest

Treating a patient with herpes simplex keratitis can be a tricky feat. The physician first needs to identify the specific type of herpetic corneal disease, and then choose a plan of action for treatment. Problems can go undiagnosed, be misdiagnosed, and be recurrent. Bennie Jeng, MD, professor and chair, Department of Ophthalmology and Visual Sciences, University of Maryland School of Medicine, Baltimore; Francis S. Mah, MD, Scripps Clinic, La Jolla, California; and Vincent de Luise, MD, assistant clinical professor of ophthalmology, Yale University School of Medicine, New Haven, Connecticut, discussed the role of topical steroids in herpes simplex virus (HSV) keratitis, which medications are recommended in these cases, what to look for to diagnose these patients, and how to taper or continue to treat the problem.

Steroids in HSV

Many cases of HSV keratitis are due to an immune response. Most of the time when seeing stromal keratitis, it is an immune-mediated response and not necessarily a necrotizing process, Dr. Jeng said. Additionally, Dr. Jeng said if there is endotheliitis or iritis, this is an immune-mediated response, and steroids are indicated.
When talking about epithelial keratitis, when you have dendrite or pseudodendrite appearance, that’s a little more controversial, Dr. Jeng said. “Usually an active infectious process would be treated with antivirals.”
With HSV, Dr. Jeng said trifluridine can be used. His personal belief is that using oral antivirals penetrates the tear film well enough and are not as toxic. But he noted that topical options work as well, as does gentle debridement of the epithelium.
“Steroids don’t have a role in infectious processes,” he said, adding that if there is a lot of inflammation in the stroma with the actual epithelial infection, you can treat with some steroids. But, Dr. Jeng added, make sure there’s adequate antiviral coverage first. “Because if you just use steroids, the virus will proliferate,” he said.
If you’re talking about an immune-mediated response, like HSV stromal keratitis, the treatment is steroids, Dr. Jeng said. However, he likes to use antivirals just in case. If patients have stromal disease, prophylaxis with antivirals will decrease the chance of them having a repeat episode by almost 50%. Every time the patient has an episode, it’s potentially vision threatening, he added, so you want to protect against this.
Dr. Mah said that there are several different types of disease that HSV can cause in the anterior segment. For example, with epithelial keratitis, he said steroids are rarely, if ever, required, and not needed for most cases.
Generally, he said that stromal keratitis would be the time to use steroids in HSV. He noted the two large studies looking at this use, HEDS and HEDS 2. Both of these used prednisolone acetate 1%, but Dr. Mah noted that multiple steroid options could be used, depending on the severity of the inflammation and severity of the disease.
There are some potential complications that steroids can cause. In a younger patient, cataractogenesis is a concern; therefore, if long-term steroids are required, reducing the dosage and utilizing a less potent steroid is recommended. Approximately 10–20% of the general population are steroid responders who may have elevated IOP after using topical steroids, Dr. Mah said, so again, reducing the dosage and potency while still managing the condition is critical.
If there are concerns about side effects and the patient has been using chronic steroids, Dr. Mah suggested fluorometholone or loteprednol. In addition, he suggested off-label use of cyclosporine to try to avoid some of the side effects.
In terms of prophylaxis, in HEDS and HEDS 2, topical trifluridine was used. Additionally, the use of acyclovir was allowed in HEDS 2.
Dr. Mah said he would often choose valacyclovir over acyclovir due to the improved dosage that could increase compliance with therapy, but famciclovir is also an option now that all three are off patent.
As far as topical, ganciclovir can be used for prophylaxis as well. Dr. Mah’s personal choice is an oral agent, either acyclovir or valacyclovir unless there is a contraindication such as poor renal function.
Dr. de Luise said that for HSV, it’s important to evaluate the corneal epithelium before treating. If HSV stromal keratitis is associated with an epithelial defect, it is treated similarly to HSV epithelial keratitis, he said, with a topical antiviral agent (topical trifluridine or topical ganciclovir) and a topical cycloplegic, administered until the epithelium has healed, with avoidance of topical corticosteroids.
The HEDS group recommended using topical trifluridine four times daily for 3 weeks and 2 times daily thereafter. Topical ganciclovir gel is now available and has lower epithelial toxicity, Dr. de Luise said. “However, because of the risk of toxicity of all topical antivirals on the corneal and conjunctival epithelium, oral antivirals are often used preferentially to topical antivirals.” Oral antiviral prophylaxis options include oral acyclovir 400 mg twice a day, valacyclovir 500 mg once a day, or famciclovir 250 mg twice a day.
Dr. de Luise said that topical or oral antivirals are recommended to prevent or limit epithelial disease during treatment of HSV stromal keratitis with topical corticosteroids. “A common regimen is to administer the topical antiviral in a 1:1 fashion with the topical corticosteroid as often as the therapeutic dose is needed to treat epithelial disease,” he said. The topical corticosteroid and the topical antiviral are tapered together. “Once the topical corticosteroid is down to one drop a day, the topical antiviral can be discontinued,” he said. The lower the
dose and frequency of topical
corticosteroid, the longer the interval between subsequent dose reduction, Dr. de Luise added. “If oral antiviral agents are chosen (in lieu of topical antivirals), they should be maintained in prophylactic doses during corticosteroid treatment.”

Stromal keratitis pearls

Typically, if you’re trying to differentiate between immune and necrotizing stromal keratitis, Dr. Jeng said that necrotizing shows signs like melting, broken down epithelium, and cheesy stroma. With immune keratitis, the epithelium is generally intact and it looks less angry, with no associated melting.
While it can be challenging to diagnose active immune stromal keratitis, Dr. Mah said that generally, there is edema in the cornea and stromal haze. He added that it’s important to look for inflammation in the cornea. Usually, the epithelium is still intact, though not in every case.
Dr. de Luise said it’s important to have a high index of suspicion that what you’re looking at is HSV since it has a large amount of manifestations. It’s important to rule out simplex before thinking of anything else. Each corneal layer can be involved separately or sometimes with other layers. Usually, Dr. de Luise added, epithelial disease of herpes simplex is isolated to epithelium and presents as a dendrite. Most herpetic dendrites stain with fluorescein in the bed and lissamine green on the edges.
There are two types of stromal herpetic keratitis (both of which have some immune components): herpes simplex stromal keratitis without ulceration and herpes simplex stromal keratitis with ulceration. “In patients who have altered immune systems, herpes simplex can manifest as a recurrent stromal condition from a prior epithelial condition,” he said. It could come back deeper in the stroma later on after treated.
Dr. de Luise suggested looking for swelling and white infiltrates in the cornea. “You might think that the keratitis is a bacterial or fungal infection,” he said. “It can be a challenge because with HSV stromal keratitis, microbial cultures are usually negative.”
Tapering steroids
Dr. Mah said that sometimes ophthalmologists think they must get the patient off steroids entirely when treating stromal keratitis with an antiviral prophylactic cover, but this does not necessarily have to be the case. As a cornea specialist, he said, trying to do a transplant on someone who is neurotrophic from HSV or varicella zoster virus is more difficult to manage than a cataract or secondary glaucoma.
“You may not get the patient off steroids, and that’s OK,” Dr. Mah said. First, he will try a typical taper. If the patient is using steroids four times a day, Dr. Mah will go down one drop per week, moving to three times a day, and then after another week, two times a day, and so on. If this is unsuccessful, try doing a slower taper, even using a drop several times a week, then once a week, and then attempt to completely stop. However, some patients may still require steroids, even if it’s just once a week. “The patient and corneal reaction during the slow taper guides you, and the goal is to try to get them off the steroid,” he said. “But sometimes, you must continue using the lowest dose with the lowest potency steroid that will keep the cornea quiet along with the antiviral cover.” He added that it’s important to prevent scarring, or if there already is a scar, you want to prevent it from getting worse.
Dr. de Luise shared his specific plan for tapering in immune stromal HSV without ulceration. Those patients are usually on topical steroids four times a day and oral antivirals in prophylactic doses, he said. He stressed the importance of tapering over a long period of time.
Once you start the steroid, you have to keep it up for a couple of weeks, he said. He added that the oral antivirals also need to be tapered down “one piece at a time.”
If you’re starting out at four times a day, Dr. de Luise said this should be continued for 2–3 weeks, after which time the patient would switch to three times a day. After another few weeks, they would move to two times a day, and so on. Dr. de Luise stressed that the ophthalmologist needs to see the patient a number of times throughout this taper process.
Some patients may be maintained on their oral antiviral medications for years, he said, so after 6 months, he recommended that patients have renal function checks as oral antivirals can be toxic to the kidneys. It may become necessary to decrease the amount of oral antivirals depending on kidney function, in consultation with the patient’s internist or nephrologist, he said.
Dr. de Luise added that topical cyclosporine 2% has been evaluated in several uncontrolled studies in the treatment of herpetic stromal disease without the use of corticosteroids. A role may exist for this medication in those patients unable to use corticosteroids.

Editors’ note: Dr. Mah has financial interests with Bausch + Lomb (Bridgewater, New Jersey), Allergan (Dublin, Ireland), and Alcon (Fort Worth, Texas). Drs. de Luise and Jeng have no financial interests related to their comments.

Contact information

de Luise
: vdeluisemd@gmail.com
Jeng: BJeng@som.umaryland.edu
Mah: Mah.Francis@scrippshealth.org

Tips for steroid use in HSV Tips for steroid use in HSV
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