Clinicians urge prevention and early, aggressive treatment for herpes

Ocular herpes infections are presenting more often in the optometric practice, and experienced clinicians advocate for early detection and aggressive management.

Herpetic eye disease is the most common infectious cause of corneal blindness in developed countries, according to the National Institutes of Health.

The global incidence of herpes simplex virus (HSV) keratitis is roughly 1.5 million, including 40,000 new cases of severe monocular visual impairment or blindness each year, according to research from Farooq.

Optometrists should feel comfortable treating the condition and be familiar with treatment options, as the incidence of herpes zoster has increased more than four times over the last 6 decades, according to a study from Kawai.

Most clinicians agree that an oral antiviral, such as Valtrex (valacyclovir, GlaxoSmithKline) or acyclovir is the best first-line option against an acute HSV dendritic keratitis.

“We generally go straight to orals in our ophthalmology practice,” Primary Care Optometry News Editorial Board member Jill C. Autry, OD, RPh, said in an interview with PCON. “I think most optometrists, if they have that scope in their state, should go with orals. We can expect to see that trend more. MDs have historically been more comfortable prescribing them, with their training, but the tide is shifting in optometric practices as well.”

Patrick Vollmer, OD, FAAO, prefers using acyclovir as opposed to trifluridine due to its dosing frequency and no risk of corneal toxicity.

“Doctors need to always be aware of the cost and dosing frequency of drugs and the impact that it has on patient compliance,” he said in an interview.

Practicing in a rural area can be an issue for drug availability, Greg Caldwell, OD, FAAO, told PCON. “Sometimes the pharmacy may not be able to get Zirgan (ganciclovir ophthalmic gel 0.15%, Bausch + Lomb) or Viroptic (trifluridine, Pfizer) for 24 to 48 hours. When that happens, go with an oral antiviral like Valtrex 1,000 mg three times daily for either simplex or zoster to reduce the viral load. Do not delay treatment due to availability; treat orally, as soon as possible.”

If Autry has a patient with severe dendritic keratitis, such as a large dendrite or multiple dendrites, she will double up and prescribe Zirgan and orals.

“Oral antivirals are often sufficient to control the outbreak,” PCON Editorial Board member Joseph P. Shovlin, OD, FAAO, said in an interview. “There are always exceptions, with potential resistance being a possibility and compliance issues that may explain a less-than-anticipated or desired response. Any resistance raises concern for immunosuppression or compromised state.”

Iritis with elevated IOP

A hallmark sign of herpes in the eye is iritis with elevated IOP, according to Caldwell.

As the virus is killed by the immune system, the corneal dynamics pump the protein into the anterior chamber, then the fluid dynamics of the protein get caught in the trabecular meshwork, creating inflammation that disallows the fluid to drain and causes the pressure to elevate, he explained.

At this point, treat the infection with an oral antiviral, then use a glaucoma medication to lower IOP, he said.

“When you feel the eye isn’t in an infectious state, use a steroid to treat the inflammation, clear the iritis and help with IOP decrease, as the trabecular meshwork will not be inflamed,” Caldwell continued.

He also suggests covering it prophylactically with Zirgan or Viroptic to make sure there is no rebound infection.

Oral antivirals are well tolerated in most age groups and disease states, but if a patient has kidney issues, the dosage may need to be lowered, according to Autry.

To lower IOP, Vollmer uses an aqueous suppressant such as timolol 0.5% over a prostaglandin, because prostaglandins are contraindicated in the setting of HSV and may promote herpes virus activity, he said.

Zoster occurring earlier

Although the occurrence of herpetic eye disease has increased over the past decade, the mean age of presentation at disease onset has decreased, according to a study by Emma C. Davies, MD, and colleagues, where they investigated the age of occurrence of herpes zoster ophthalmicus over time.

The results of the study suggest that the routine use of the varicella vaccination in children remains a possible explanation for the increased number of cases at a younger age, as patients no longer receive immunological boosts from exposure to children with chickenpox, Davies said. Other possible explanations for increased occurrence of herpes zoster ophthalmicus at a younger age were not found in the study, particularly because there was no increase in the number of people with an immunocompromised state.

Davies said the most common underlying condition for bilateral herpes simplex infection is atopy/eczema, so practitioners should ask about a patient’s history of these conditions.

Recurrent zoster infections in a short period of time may signal reduced cell-mediated immunity, according to Shovlin.

“My first inclination would be to test for HIV where there is obvious immunosuppression or compromise,” he said

He treated a patient who had her third bout with zoster within 18 months and had a thymoma.

“A thymus gland anomaly would certainly make sense, as it relates directly to cell-mediated immunity,” Shovlin added.

Davies said her group does not recommend a systemic workup to evaluate for an underlying immunodeficiency state in the setting of herpes zoster ophthalmicus at a younger age, recurrent herpetic eye disease or bilateral herpes simplex infection.

“We ask questions, but we don’t do an extensive workup because people can have herpes zoster at a younger age, have frequent recurrences or have bilateral herpes simplex infection without immunosuppression,” Davies said.

She recommended that the provider ask whether the patient is on an oral steroid or other immunosuppression medication, has a history of eczema or atopy, or has chronic infection/disease, but she does not recommend further diagnostic testing.

Vaccination

Zostavax (Merck Sharp & Dohme) is a live attenuated virus vaccine approved for preventing herpes zoster in patients 50 years and older.

It is recommended that those 60 years and older get vaccinated; however, “our study makes us want to advocate for the vaccine at a younger age, like 50 years.” Davies said.

“In most cases, patients will maintain reasonable levels of immunity after having a bout of shingles for about 3 to 5 years, and it likely makes sense to wait for 3 years for vaccination,” Shovlin added. “A Kaiser series [Tseng et al.] recently showed recurrence rates of 1:200 up to 5 years following an outbreak, with or without the vaccine.”

In the case of a patient with long-term recurrent HSV keratitis, receiving the vaccination depends on when the last flare was, how serious it was and whether there is a central scar or any visual loss, Davies said.

There have been reports of zoster vaccine causing a flare in ocular symptoms, she added.

Vollmer noted that having a case of shingles is much more effective in preventing future flare-ups than having the shingles vaccine. Having shingles powerfully reboots the immune system to help prevent a subsequent disease outbreak, he said.

“Once a patient has shingles, the risk of recurrence drops somewhere between 2% and 5% (Tseng et al.),” he said.

Shovlin added that all patients older than 60 years should be advised on vaccination unless they have had a recent case of shingles.

Post-herpetic neuralgia

Post-herpetic neuralgia (PHN) is more likely to occur in older patients and in those who do not receive antivirals within 72 hours of the outbreak, according to our experts.

Advancing age, severity of acute zoster pain and rash, a painful prodrome, chronic illness and ocular or upper body involvement are all risks for PHN, Shovlin said.

PHN is seen in up to 75% of patients older than 70 years, although only 2% are affected after 5 years (Herpetic Eye Disease Study Group), according to Vollmer.

Davies said the best treatment is tricyclic antidepressants, such as nortriptyline 25 mg once nightly or Neurontin (gabapentin, Pfizer) 600 mg nightly, with a slow up-taper in divided doses. She warns that both treatments can make patients drowsy.

“The patients most likely to get neuralgia are ones that wait longer for treatment and let the body treat it and older patients – they need to be diagnosed as early as possible,” Caldwell said. “Once they are healed from the outbreak and have neuralgia, it is tough to treat. This is neurogenic pain and it needs treatment like Lyrica (pregabalin, Pfizer). You don’t want to use narcotic pain medication.”

Shovlin warns that oral steroids and antivirals do not prevent PHN.

He suggests treatment with one or more of the following: rapid administration of oral antivirals, cool compress, topical capsaicin, analgesics, lidocaine patch, cimetidine, amitriptyline, gabapentin, pregabalin, nerve block and acupuncture.

Herpetic neurotrophic corneal ulcers

The treatment goals of neurotrophic keratitis are to prevent the progression of corneal damage and to promote epithelial healing, Vollmer said.

The therapy must be prompt and based on disease progression, which is divided into three stages based on the Mackie classification.

According to the American Academy of Ophthalmology, in stage 1 the disease is generally treated with preservative-free artificial tears and ointment as well as possible punctal occlusion. Any current topical medications should be discontinued, if possible, according to Vollmer.

In stage 2, the epithelial defect must be treated to prevent a corneal ulcer from developing and to promote healing. Prophylactic antibiotic drops are generally added to the preservative-free artificial tears. A lateral tarsorrhaphy may be recommended, which may close the epithelial defect. If a tarsorrhaphy is released too soon, Vollmer warned, epithelial breakdown will follow. Other treatment options include an injection of botulinum A toxin into the upper eyelid levator muscle or amniotic membrane placement over the epithelial defect, he added.

In stage 3, the disease demands immediate attention to stop the stromal lysis and prevent perforation, Vollmer continued. In cases of stromal melting, topical collagenase inhibitors such as N-acetylcysteine, tetracycline or medroxyprogesterone may be administered.

Amniotic membranes have been extremely helpful in different levels of treatment, according to Caldwell.

“The virus comes through the trigeminal nerve and can create decreased corneal sensitivity, where patients end up with a neurotrophic ulcer, and amniotic membranes help heal ulcers,” he said.

Fuch’s heterochromic iridocyclitis

Fuch’s heterochromic iridocyclitis is a chronic nongranulomatous condition typically diagnosed at about 40 years of age, Vollmer said. The cause remains uncertain, but it may be associated with the rubella virus.

Shovlin noted that rubella is the major concern and should be reported directly to the state department of health.

Fuch’s has a multifactorial disease process, he continued, and 5% to 10% of cases are bilateral (Tse et al.). Features include heterochromia, iritis, stellate keratic precipitates across the entire corneal endothelium (not just inferiorly), cataracts (posterior subcapsular is the most common), Russell’s blisters (iris crystals) and difficult-to-control glaucoma. Iris heterochromia may be a direct result of a sympathetic dysfunction. Fuch’s may be associated with toxoplasmosis, herpes simplex, cytomegalovirus and rubella.

Early, adequate treatment

Our experts stressed the significance of recognizing HZV early and initiating treatment as early as possible.

“It’s also necessary to connect patients with a specialist to minimize corneal scarring and schedule routine follow-ups, as flares can happen at any point in the future,” Davies said.

“We are getting more herpes zoster in those around 40 years old,” she continued. “This puts pressure on providers and the community to educate patients on the vaccine, which can save people’s vision.”

“One thing we need to do as eye doctors is realize how beneficial orals can be in many eye diseases we see,” Autry said. “We need to be more proactive in prescribing orals, even though it wasn’t the way we were taught in our didactic education. I think that it’s important and our responsibility to talk to our elderly patients about the vaccine, even in patients who haven’t had zoster.”

She also recommended reminding patients about important health procedures such as mammograms and colonoscopies, as well as flu vaccines.

“Take responsibility in the systemic care of patients,” Autry said. “The eye is an extension of the body; we must remember this even as eye doctors.”

Herpetic eye disease can manifest in a myriad of ways and should be considered in cases of non-healing epithelial defects, corneal ulcers or stromal thinning, Davies said.

“In treating herpetic eye disease, it is often a fine balance between when to use and when not to use a topical steroid,” she continued. “Often these cases should be referred to an eye specialist comfortable with the various presentations of herpetic eye disease.”

“Oral antivirals, like other oral medications, can have significant side effects,” Shovlin warned. “There is not a spate of complications, but prescribers must be aware of excretion problems and must confirm adequate renal clearance, especially with high-dose, prolonged use.

“It’s wise to check creatinine levels prior to prescribing oral antivirals,” he added. “For example, there may be additional concern for TTP/HUS [thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome] in patients with a reduced or suppressed immune system (i.e., HIV patients or transplant recipients for both bone marrow and renal transplants) with the use of Valtrex.”

Caldwell explained that the Herpetic Eye Disease Study 2 [Wilhelmus KR et al.] taught clinicians that using a maintenance dose decreases the recurrence rate, but most patients refuse it even after the second or third episode.

“Make sure your records reflect the patient declined this recommendation, in case the patient does end up losing vision,” he said. “The other side is, if the patient elects to go on a maintenance dose, these medications are cleared through the kidneys. Work with the patient’s primary care physician and get kidney function tests.

“Don’t be afraid to treat this condition,” Caldwell continued. “We understand it better than ever, and the topical and oral medications today work well.” – by Abigail Sutton

• References:
• Davies EC, et al. Br J Ophthalmol. 2016;doi:10.1136/bjophthalmol-2015-307157.
• Farooq AV, et al. Surv Ophthalmol. 2012;doi:10.1016/j.survophthal.2012.01.005.
• Herpetic Eye Disease Study Group. N Engl J Med. 1998;339(5):300-306;doi:10.1056/NEJM199807303390503.
• Kawai K, et al. Clinical Infectious Diseases. 2016;63(2):221-226;doi.org/10.1093/cid/ciw296.
• Tse BC, et al. Fuchs Heterochromic Iridocyclitis and Secondary Glaucoma. American Academy of Ophthalmology. Modified January 20, 2015. Accessed June 26, 2017.
• Tseng HF, et al. J Infect Dis. 2012;206(2):190-196;doi:10.1093/infdis/jis334.
• Wilhelmus KR, et al. Ophthalmology. 1994;101(12):1883-1896;doi.org/10.1016/S0161-6420(94)31087-6.

• For more information:
• Jill C. Autry, OD, RPh, practices at the Eye Center of Texas with various locations around Houston. She lectures on pharmaceutical and ocular disease topics nationwide. She can be reached at: jillautry@gmail.com.
• Greg Caldwell, OD, FAAO, is in private practice in Duncansville and Johnstown, Pa., and serves on many American Optometric Association committees and boards. He can be reached at: grubod@gmail.com.
• Emma C. Davies, MD, is an instructor in ophthalmology at Harvard Medical School. She can be reached at: Emma_Davies@MEEI.HARVARD.EDU.
• Joseph P. Shovlin, OD, FAAO, practices at Northeastern Eye Institute, serving Scranton, Wilkes-Barre and Hazelton areas in Pennsylvania. He is also the president of the American Academy of Optometry. He can be reached at: jpshovlin@gmail.com.
• Patrick Vollmer, OD, FAAO, practices at Visual Eyes Optometric in Shelby, N.C. He can be reached at: patrickvollmer23@gmail.com.

Disclosures: Caldwell reports he has lectured for Allergan, BioTissue, Envolve, Optovue and Shire. Shovlin reports he is on the global advisory panel for Allergan, Johnson & Johnson Vision and Shire. Autry, Davies and Vollmer report no relevant financial disclosures.