Treatment Pulse
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Cases Support Treatment For Ocular Herpes

Two Case Studies Underscore The Groundbreaking Efficacy and Safety of Ganciclovir

Jai Parekh, MD, MBA, FAAO; Jay Pepose, MD, PhD; John Sheppard, MD, MMSc

Dr. Parekh: Herpes keratitis is a nemesis that has perplexed all of us in eye care for most of our careers. Ocular herpes is a common cause of corneal blindness in the United States. You may see a case in your practice, usually after a mild primary outbreak has led to a more symptomatic reactivation. There were no new treatment advances for herpes keratitis for about 30 years, until ganciclovir ophthalmic gel 0.15% (Zirgan, Bausch + Lomb). Drs. Pepose and Sheppard and I will discuss the outcomes of two interesting herpes cases treated with Zirgan. Zirgan is indicated for the treatment of acute herpetic keratitis (dendritic ulcers).

Important Risk Information for ZIRGAN

ZIRGAN (ganciclovir ophthalmic gel) 0.15% is indicated for topical ophthalmic use only. Patients should not wear contact lenses if they have signs or symptoms of herpetic keratitis or during the course of therapy with ZIRGAN. Most common adverse events reported in patients were blurred vision (60%), eye irritation (20%), punctate keratitis (5%) and conjunctival hyperemia (5%). Please see the brief summary of the ZIRGAN full prescribing information by clicking this link.

Pinpointing Systemic Manifestation

Dr. Pepose: Let's evaluate the case of a 27-year-old woman who presented with a 4-day history of a nonproductive cough and spiking fever, accompanied by a 2-day history of a red left eye with lid swelling, epiphora and decreased vision. She had crusting right-sided skin lesions consistent with resolving herpes labialis (Figure 1).

Case 1: Presentation

Figure 1. A 27-year-old woman presented with a 4-day history of a nonproductive cough and spiking fever, accompanied by a 2-day history of a red left eye with lid swelling, epiphora and decreased vision.

The patient was otherwise in good health. She was not atopic or immunocompromised, although she had a previous history of fever blisters occurring every few years.

I'll ask the panel at this point, is that a common presentation? Does reactivation occur in many patients who become febrile?

Dr. Sheppard: That's a great question. The presentation you see here is systemic. So the question becomes, is the ocular infection having a systemic manifestation, or is this a primary infection in that particular location? The latter is unlikely in this age group.

In my work with children who have primary ocular disease, I've seen a wealth of systemic manifestations, and they may require systemic agents. The children can become very morbid. They develop many vesicular lesions in the periocular skin, as well as other locations.

Now this patient may be febrile from a cause other than the eye disease—an instigating circumstance such as the common cold. After all, the herpes labialis is a fever blister or cold sore. It's occurring systemically in a patient who most likely has a viral infection. So the underlying immunological stress has resulted in reactivation on the ocular surface.

Atopic Disease: Unilateral or Bilateral?

Dr. Pepose: The exam showed that this patient had uncorrected vision of 20/20 OD and 20/70 OS. She had a mid-peripheral dendritic lesion (Figure 2). The classic dendritic fluorescein stain is a true ulcer; the entire lesion stains with fluorescein, and often the borders will stain with rose bengal. She also had mild corneal hypesthesia, follicular conjunctivitis and no palpable lymphadenopathy.

Case 2: Clinical Examination

Figure 2. The patient had a mid-peripheral dendritic lesion. The classic dendritic fluorescein stain is a true ulcer; the entire lesion stains with fluorescein, and often the borders will stain with rose bengal.

One key thing to consider as we determine if this patient is atopic is the fact that she has a red eye on the left side, but the herpes labialis is on the right. There seem to be some differences in the unilaterality of herpes presentation, depending on whether or not patients are atopic.

In your experience, is it more common to see unilateral presentations in atopic patients?

Dr. Parekh: I tend to see more unilateral cases. In this case, the patient has follicular conjunctivitis, which is likely to be unilateral.

The best way to reach a diagnosis is to evaluate the clinical presentation and listen to the patient's complaints. People talk about assays and so forth, but this patient has corneal hypesthesia, and combined with the other symptoms and the staining, we're looking at one or two diagnoses. The patient probably had a viral prodrome that led her to this state. It looks like there was some bilaterality with the lesion on the right side and the left side. But I think in terms of the oculus, it's unilateral.

Dr. Pepose: Yes. The literature suggests that few atopics are bilateral, but we rarely see bilateral presentation in patients who are non-atopic or non-immunocompromised. You also mentioned a good point in terms of follicular conjunctivitis. I know several of us were involved in the cidofovir injection (Vistike, Gilead Sciences) trial, where we were diagnosing follicular conjunctivitis, and a fair number of cases that we assumed to be adenovirus turned out to be culture-positive for herpes simplex virus. We were sure they were adenovirus. So when you see a patient with follicular conjunctivitis, you have to include herpes simplex in the differential diagnosis.

Dr. Sheppard: I think you made an important point about atopic patients. Far more common than herpes in everybody's practice—even for an external disease specialist—is the routine allergic patient. The incidence of herpetic ocular surface disease is much higher in that population, as well as logarithmically higher in the atopic population. That's why we might see an atypical multiple manifestation presentation where the labialis is contralateral to the presenting ocular lesion.

Similarly, the incidence of bilateral herpes simplex keratitis is incredibly low, but the patients I've seen with bilateral disease have been atopic. These are very difficult patients to manage.

Medication, Debridement and Outcomes

Dr. Pepose: This patient was prescribed Zirgan, taken 5 times a day while she had an active dendrite. I debrided the margin with a cotton swab. Debridement is part of the effort to reduce antigen load. We don't want these patients to progress to stromal disease, so depending on the extent of the lesion, I may choose to debride it.

The ulcer healed in 6 days, and then we lowered the dose to t.i.d. for an additional 7 days. At the final visit, the lid swelling had resolved and the patient was asymptomatic. Dr. Parekh: I debride in 30% of my cases—obviously, with patients who are incredibly symptomatic. Zirgan will work quickly, but if I can reduce the viral load and the antigenicity, then I may prevent future stromal changes.

Treating an Immunocompromised Patient

Dr. Sheppard: A 78-year-old male in my practice was immunocompromised. He had chronic myelogenous leukemia and a very, very high but obviously ineffective white blood cell count of 70,000. And because of his immunocompromised state, he was already on acyclovir (Zovirax, GlaxoSmithKline) prophylaxis for no specific reason other than the fact that he was ill. This patient developed pain, redness, blurred vision and acute foreign body sensation. He had a classic dendrite (Figure 3).

I don't think we need to use impression cytology or viral cultures in most cases of this disease, because although we can make the diagnosis that way, it's clearly delayed and expensive. As ophthalmologists, we see classic presentations in most cases, particularly in those patients who have been incubating for a while.

Based on a clear diagnosis, we needed to address this patient's treatment. We were concerned that he might be acyclovir-resistant or a poor absorber of acyclovir. Furthermore, the volume, the concentration and the pharmacokinetics of the drug in the eye are much higher, more prolonged and more reliable with a topical preparation than they are with a systemic preparation, particularly on the ocular surface.

Case 2: Classic Herpes Dendrite

Figure 3. The 78-year-old patient had a classic herpes dendrite across the inferior cornea.

I put this fellow on a standard regimen of Zirgan 5 times a day. After his epithelial keratitis healed, yielding a punctate keratitis with an epithelial healing line and some negative staining, he continued the medication 3 times a day for another week or two. It was a very interesting demonstration of the superiority of a topical agent.

ZIRGAN: An Excellent Treatment Option

Dr. Sheppard: Zirgan provides us a great option for treating herpetic keratitis.

Patients have a reduced dosing regimen with Zirgan (1 drop in the affected eye 5 times per day—approximately every 3 hours while awake—until the ulcer heals) compared to trifluridine (1 drop every 2 hours while awake—maximum daily dosage of 9 drops—until the cornea ulcer has completely re-epithelialized). Zirgan is also stable at room temperature, so patients don't have to refrigerate it as they do with trifluridine.

Zirgan also has an outstanding vehicle. The gel very readily applies to the eye. My patients tolerate this medicine well, particularly because the herpetic eye is frequently if not always to some extent neurotrophic and therefore more susceptible than a normal eye to the insult of a topical agent.

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Dr. Parekh is Medical Director at The Research Institute/Chief of Cornea & External Diseases at St. Joseph's Regional Medical Center, NJ; President at Star-x Research, LLC; and Anterior Segment Surgeon & Managing Partner at Brar-Parekh Eye Associates in Woodland Park/Edison, NJ. He is also a Clinical Assistant Professor on the Cornea Service at the New York Eye & Ear Infirmary, NY.

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Dr. Pepose is the Founder and Medical Director of the Pepose Vision Institute in St. Louis, Mo. He also serves as Professor of Clinical Ophthalmology at Washington University School of Medicine in St. Louis, Mo.

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Dr. Sheppard is President of Virginia Eye Consultants, based in Norfolk, Clinical Director of the Thomas R. Lee Center for Ocular Pharmacology, and Professor of Ophthalmology and Microbiology at Eastern Virginia Medical School.