A 50-year-old male skier enters your office with complaints of eye irritation. He presents with classic dendritic keratitis (See Figure 1) and you prescribe topical trifluorothymidine (Viroptic) use every two hours while awake. At the one-week visit, the patient says the eye is feeling better, and you observe that it is starting to heal. Treatment continues and the patient is scheduled to return in two weeks.

At the two-week visit, the patient says that the eye is feeling worse, and you observe that areas that were healing are no longer doing so. The eye appears more inflamed, and the epithelium exhibits a dull appearance. In addition, there is significant staining of the epithelium.

What should you do next?

A) Increase the antivirals or switch to another antiviral regimen;

B) Culture the eye, and switch to topical fortified antibiotics every hour while awake;

C) Stop antivirals, treat the patient with unpreserved drops and ointment, and watch carefully; or

D) Refer to corneal specialists.

If you selected choice A or B as the appropriate treatment, you are in good company … but both are a common mistake in this situation.

Herpes simplex virus is a virus that infects the nerves in the skin or mucous membranes near mucocutaneous junctions. In the cornea, it produces sometimes painful branch-like ulcers, known as dendritic keratitis. It is frequently reoccurring, potentially causing cor­neal opacification.

In the Western world, herpes simplex virus is the leading cause of infectious corneal blindness. In some cases, it can lead to a situation in which even corneal transplantation is unsuccessful. Understanding the herpes simplex virus and how to treat it is crucial for the general ophthalmologist as well as the corneal specialist.

 

Staging the Disease

Proper staging of the disease is critical so that ophthalmologists can un­der­stand what they are seeing and de­termine the most appropriate course of action. Treatment for some stages is contraindicated for treatment of other stages. Unfortunately improper treatment is a common occurrence and the patient's condition often worsens quickly.

Figure 1. A classic herpes simplex dendrite seen in retroillumination.

Many people have contracted the common herpes simplex virus asymptomatically. Even in secondary herpes patients may be unaware of their disease. A very small percentage of pa­tients have symptomatic primary herpes. In certain circumstances in a small percentage of all those who have latent virus in the trigeminal ganglion it can recur and that's the rub. Most commonly Type 1 herpes presents around the lip and around the eye, and it is the eye disease that can be devastating.

Presentation is varied and similar to many other corneal conditions. There­fore, ophthalmologists should keep the possibility of herpes simplex virus in the back of their minds when diagnosing any unusual corneal problem. Understanding the four stages of herpes simplex is critical with regards to the treatment.

Figure 2. An herpetic disciform lesion as seen six weeks after a classical central herpetic dendrite.

 

Stage 1: Active Viral Infection

Unfortunately, each stage is often confused with Stage 1, which is active herpes. This misdiagnosis makes the con­dition immensely worse. The classical Stage 1 is dendritic keratitis, which tends to resolve relatively well even untreated over a period of several weeks. Many patients are almost asymptomatic, with only minor irritation or blurry vision at times.

Ophthalmologists may never clearly see the Stage 1. A topical antiviral regimen is used for treatment of the active disease. This may also present as geographic herpes, one step up from a dendritic keratitis, in which sloughing of the epithelium occurs in the areas between the dendrite.

Geographic herpes is an important diagnosis to identify because it can lead to significant future problems. While fluorescein will stain the epithelial defect, rose bengal can be used to better determine if there is activity. It typically stains the infected epithelial cells so it can be determined if the edge of the lesion of the geographic ulcer indeed is actively infected versus some other problem.

Figure 3. Severe antiviral toxicity complicating advanced metaherpetic disease.

This stage is often associated with early epithelial defects prior to a dendrite all of which help the ophthalmologist realize the patient is in Stage 1.

 

Stage 2: Trophic/Metaherpetic

Trophic and metaherpetic disease is a fairly natural progression from Stage 1 to Stage 2. However, it does often confuse ophthalmologists.

In this stage, the herpes simplex virus has been extremely hard on the corneal epithelium. Neurotrophicity occurs and corneal healing is problematic. In most circumstances, active herpes is not present. Instead, a tro­phic lesion that cannot heal re­mains.

Unfortunately, the clinical tendency is to add additional antivirals in cases with a dendrite or a geographic ulcer that won't heal. However, this only aggravates the problem in a situation such as this (See Stage 4).

The real secret is to recognize the metaherpetic disease and alter the treatment plan. The mainstay for treatment of metaherpetic disease is to remove the patient from all the topical antivirals, especially any products or antibiotic medications with benzalkonium chloride. Ideally, all treatment should cease, and the patient should be placed on frequent use of unpreserved ointments (every one-to-two hours while awake), and then watched very carefully.

There are times when metaherpetic disease is particularly onerous. In particular, one of the common problems is that if the epithelial defect lasts long enough the stroma will start to melt. With herpes simplex virus, it is a common step to go rapidly from a geographic ulcer (where there was profound impact on the epithelium) to an area of melting or chronic ep­i­thelial defect. The last thing needed is additional toxic drops placed into that situation. However, often more an­tivirals and antibiotics are thought to be the answer. In reality, they are further damaging the epithelium's ability to heal.

Figure 4. A corneal melt with aqueous seeping in to the tear film where there was a chronic epithelial defect secondary to herpes simplex. The corneal stroma had been intact one week before.

Stage 3: Immunological Reaction

Immune herpes is a disease related to the immune response to viral particles (or the remnants of the viral particles). The classic disease for this is disciform herpes (See Figure 2) in which there has been a dendrite and then about a month later a central area of edema appears. Treatment in this case usually is steroids, and oral or topical covering antivirals for suppression.

While there are cases in which ste­roids are indicated, such as with herpetic uveitis, they need to be used with extreme caution. In such cases, the only way the issue will be resolved is with the use of judicious steroids. However if an ophthalmologist is un­certain of the optimal treatment, the patient should be referred to a corneal specialist.

For example, if steroids are not used in a classic immune ring around an old dendrite, often the epithelium will slough off in that area and metaherpetic disease could result.

Usually in immune disease, if an an­ti­viral is selected it is prophylactically used for avoidance of recurrence be­cause steroids can enhance both re­cur­rence of the disease as well severity of the recurrence. Today in more and more cases such as this, an oral antiviral is used.

 

Stage 4: Toxicity with Treatment

Stage 4 of the herpes simplex virus can be tricky for the ophthalmologist. Toxicity is not an issue with the oral an­tiviral medications, which are being used more frequently today with great success. However, toxicity is a hallmark (and to be expected) with any of the topical antivirals (See Figure 3).

In most cases if an antiviral has been used relatively frequently for three weeks, signs of toxicity will be present. Under what I call my "three-week rule," if antivirals have been used for three weeks and no improvement is noted or the case is not resolving, then both toxicity and metaherpetic herpes are most likely present.

These two conditions are often present together and they are often missed. A combination of toxicity and metaherpetic disease is a serious combination in which the poor healing ability of the epithelium has been further damaged. It can take a long time to deal with and resolve this type of case. Am­niotic membrane, a conjunctival flap, or bandage contact lenses are often used to protect the area, which needs to be watched carefully.

With the toxicity and metaherpetic disease combination, a patient with an intact corneal stroma can progress to a full thickness melt very quickly (See Figure 4). Treatment for a hole includes gluing it, placing a contact lens, and allowing the eye to stabilize. A small, peripheral hole will heal in most cases. With a central hole, a penetrating keratoplasty may be indicated once the eye is quiet.

Ophthalmologists should look for toxicity. This is very common and often exacerbates the situation, which should be a good tip-off. I recommend that practitioners look at these cases and specifically at the time line and use this staging technique to keep out of trouble.

 

Breaking It Down

With the herpes simplex virus, it is most helpful to break the patient's case down to determine if one or more stages are present simultaneously. After this is done, I then determine the best course of action. On some occasions, I have been referred cases in which the patient has had all four stages of HSV at once.

If this staging technique is used and the clues are found, most clinicians can stage the disease and provide proper treatment successfully.

By utilizing the four key stages technique discussed here it is not usually difficult for an ophthalmologist to determine the best treatment. There is usually an immune disease or some element of uveitis or endothelitis with the hall­mark elements of corneal edema, clear infiltrates in the cornea, and/or glaucoma. (While cells and flare are minimal, if you look carefully you will see some cellular precipitates on the corneal endothelium, that is a sign of an im­munological component.)

However, if an ophthalmologist is unsure, uncomfortable, or unable to stage the case of herpes simplex virus, it is best to refer the patient on to a corneal specialist because of the tendency for the rapid progression of the disease. Hope is never a good strategy!  

 

Dr. Olson is the John A. Moran Presidential Professor and Chair of Ophthalmology and Visual Sciences and director of the John A. Moran Eye Center at the University of Utah. He has no financial interest in any product mentioned in this article.