Unmasking Herpetic Eye Disease

Ocular herpes simplex and zoster are inevitable foes that no primary eye provider can evade. Early identification and treatment can lead to fewer complications and preserved vision. Similarly, being aware of the systemic implications and long-term effects and knowing when to comanage early with primary care can result in reduced long-term systemic effects of viral infections. This article discusses common ocular presentations of ocular herpes simplex and zoster, treatment options, and systemic effects of these viruses.

HERPES SIMPLEX VIRUS

Herpes simplex virus (HSV) is notorious for being a great masquerader and can be difficult to diagnose. The good news is that, once identified, it can be readily treated. With treatment, HSV keratitis typically resolves within 2 weeks, typically with no or minimal visual impact.

Antibodies to HSV are present in 100% of people older than 60 years. Ocular HSV infections can cause inflammation of the eyelids, conjunctiva, iris, retina, and cornea.¹ Ocular HSV is the most common cause of corneal blindness in high-income countries and the most common cause of unilateral corneal blindness worldwide.¹

The rate of recurrence for persons with one occurrence of ocular HSV is 10% at 1 year and 50% at 10 years, and it increases with subsequent episodes.¹ Once a person is infected by HSV, it resides in the ganglion cells for life and can reactivate at any time. It is commonly thought that triggers include sun exposure, menstruation, and stress; however, recent studies have not shown a correlation with psychological stress.²

OCULAR HSV PRESENTATION

Primary ocular HSV tends to present as a follicular conjunctivitis or keratitis. It is almost always unilateral, which helps differentiate it from other viral follicular conjunctivitides. It may also present with vesicles on the eyelids. Primary infection often goes undiagnosed as mild pink eye that self-resolves.

There is no good evidence to suggest that treating the primary infection with a course of antiviral medications reduces recurrence. However, recognizing the primary infection can help guide decisions on prophylactic treatment in the future. This is where culturing can play a pivotal role in care.

HSV keratitis can be divided into epithelial, stromal, and endothelial presentations. For me, identifying the anatomy is a key step in determining treatment. I approach HSV on a spectrum from active viral replication to immune-mediated response to guide my treatment. Identifying the anatomy involved can be helpful in deciphering the mechanism. Epithelial disease and endotheliitis indicate majority active viral replication, whereas stromal disease is largely an immune-mediated response.

HSV Epithelial Keratitis Presentation

Epithelial HSV may present as the classic dendrite with terminal bulbs or geographic lesions. The geographic ulcers are sometimes hard to differentiate from a healing corneal abrasion with irregular borders or neurotrophic keratitis. However, the bodies of both dendrites and geographic lesions stain with fluorescein (Figure 1), and the edges stain with lissamine green or rose bengal. This is not the case with abrasions or neurotrophic disease.

A hallmark step in identifying corneal HSV is reduced corneal sensitivity that tends to be proportional to the number of previous episodes. Very few conditions reduce corneal sensitivity. The trick is to check for this before instilling anesthetics during an examination. To take advantage of this diagnostic technique, it is therefore crucial to break the habit of instilling combination proparacaine/fluorescein drops when evaluating a patient with pink eyes or corneal disease.

HSV Stromal Keratitis Presentation

There are two presentations of stromal keratitis: ulcerative stromal keratitis, also referred to as necrotizing stromal keratitis (epithelial defect and stromal involvement), and immune stromal keratitis, also referred to as interstitial keratitis (epithelium fully intact with stromal involvement). Stromal keratitis is a result of a largely immune-mediated response.

HSV Endothelial Keratitis Presentation

HSV endotheliitis presents with stromal edema from endothelial dysfunction and can be diffuse, disciform, or linear. Endotheliitis is active viral replication in the anterior chamber that results in inflammation. The patient may have keratitic precipitates, anterior chamber reaction, or IOP elevation from trabeculitis.

OCULAR HSV TREATMENT

HSV Epithelial Keratitis Treatment

The main question in determining treatment is whether this is an active replicating virus or largely an immune response. With epithelial disease, it is mainly viral replication, and it is contraindicated to start the patient on a topical steroid. The Herpetic Eye Disease Study found that with topical or oral antiviral treatment, epithelial disease typically resolved within 2 weeks (Figure 2).² If epithelial disease lasts more than 14 days or does not appear to be improving with topical treatment, the clinician should suspect that the topical antiviral is causing toxicity to the ocular surface and switch to an oral antiviral. If the patient is taking only an oral antiviral and epithelial disease is not resolved within 14 days, one should then consider a different diagnosis. Another treatment option is debridement to lessen the viral load and accelerate resolution.

HSV Stromal Keratitis Treatment

Stromal keratitis represents an immune-mediated response and therefore requires aggressive topical steroids with a slow taper in addition to oral antiviral medications. Necrotizing stromal keratitis can move fast with a risk of perforation. It is a result of an antigen-antibody-complement–mediated immune reaction and active viral replication.³ These patients tend to have vision-limiting corneal scarring even when treated appropriately. There is no prospective clinical trial providing a defined protocol for these cases. I, along with the majority of clinicians I have worked with start patients on oral antivirals for a couple of days before beginning the topical steroid. My general rule of thumb is to hold off on starting a topical steroid if there is evidence of epithelial disease or a defect. I wait for the epithelial defect to heal and then start the topical steroids to tame the immune response and reduce scarring. A bandage contact lens with a topical antibiotic can sometimes accelerate the healing process of the epithelium. Treating necrotizing keratitis is a fine balance of addressing the replicating virus and attacking the immune response, making every case its own unique challenge.

Immune stromal keratitis has low viral replication and is largely an immune-related response.⁴ Therefore, topical steroids with oral antiviral medications are indicated. Topical antiviral medications do not penetrate as effectively and therefore are not recommended. For these patients, I tend to start the steroid and antiviral medication on the same day.

It is important to note that the steroid taper in herpetic stromal keratitis should be slow, exceeding 10 weeks according to The Herpetic Eye Disease Study,² and some patients require long-term low-dose steroids to prevent inflammation. If there is a concurrent trabeculitis or steroid response resulting in increased IOP, a topical hypotensive medication can be added to prevent glaucoma. I tend to avoid using prostaglandin analogues for this purpose due to the potential for increasing inflammation. The Herpetic Eye Disease Study found that prostaglandin analogues can even be an inciting factor of herpetic epithelial keratitis and that physicians should consider avoiding them altogether in patients with previous HSV keratitis.²

HSV Endothelial Keratitis Treatment

Endotheliitis indicates active viral replication in the anterior chamber.⁴ Therefore, oral antiviral treatment is necessary and a topical corticosteroid is added to dampen the inflammation. Topical antiviral medications will not penetrate to effectively treat endotheliitis.

Although it is less common, HSV can cause inflammation in any tissue of the eye including the retina and optic nerve, and a full eye exam with dilation is indicated in any patient who presents with ocular HSV.

Tables 1 and 2 can help clinicians make a systematic treatment plan for ocular HSV.⁵

VARICELLA ZOSTER VIRUS

Another herpes virus that can have ocular manifestations is varicella zoster virus (VZV). Herpes zoster (HZ) is a secondary manifestation of VZV infection, the primary manifestation being chicken pox. More than 95% of adults in developed countries are VZV-positive.⁶ There are more than a 1 million new cases of HZ each year in the United States, and more than 20% of those will develop herpes zoster ophthalmicus (HZO).⁷

VZV typically presents as a unilateral painful rash following the dermatome of the trigeminal nerve. When it affects branch V1 of that nerve, it can involve the eye and is termed HZO. Hutchinson sign, in which a rash affects the tip of the nose, may indicate ocular involvement, as V1 innervates the tip of the nose and the cornea.

Age greater than 50 years and immunosuppression are key contributing factors to VZV reactivation; however, do not be too quick to rule out VZV in younger patients, as this has been on the rise in recent years.⁸

It is important to remind patients with HZ that VZV is contagious to those who have not had chicken pox. A person newly infected will get chicken pox, not shingles. Additionally, patients with HZ should avoid being around people with weakened immune systems such as elderly, pregnant, or immunosuppressed individuals.^9,10

HZO PRESENTATION

HZO commonly presents as a keratitis. It can arise as an acute keratitis or a chronic-relapsing keratitis that is more difficult to treat. The acute keratitis can yield punctate keratitis or pseudodendrites that stain poorly with fluorescein or rose bengal, which can help differentiate the lesion from a “true” dendrite as seen in HSV keratitis. These pseudodendrites (Figure 3) do not respond to topical antivirals. Nummular keratitis presents as plaques on the stroma in areas of previous epithelial disease and likely represents an immune response.³

HZO can affect any tissue in the eye, not only the cornea. Less common presentations of HZO include retinitis, iridocyclitis, sclerokeratitis, and trabeculitis; therefore, a full eye exam with IOP and dilation is indicated in all patient with shingles.

Chronic or recurrent HZO may present with recurrent mucous plaques similar in mechanism to filamentary keratitis, disciform keratitis, or interstitial keratitis with corneal neovascularization.

HZ can also rarely affect the cranial nerves (CNs), resulting in palsies and double vision. The most common CN affected is CN VI, and effects include a lateral rectus palsy and horizontal double vision. The double vision is transient and should fully resolve upon treatment with high dose oral antiviral medications. However, resolution is typically slower than resolution of the dermatome rash or keratitis and tends to take several months.

Zoster sine herpete is an atypical presentation of VZV, in which there is a dermatomal distribution of pain and there can be ocular involvement but there is no development of rash. Therefore, classic corneal findings for HZO without the rash should still prompt a high position for VZV on the differential diagnosis.

Although the main concern of eye care providers may be HZO, we cannot overlook the fact that VZV is a systemic condition. VZ can reside in any ganglia and therefore can cause deafness (CN VIII) and paraparesis (vertebral ganglia).

Additionally, there is a significantly increased risk of stroke for 1 month following an HZ infection (1.78) and even higher risk if it manifests as HZO (2.05).¹¹ Lin and colleagues found a 4.5-fold greater risk of stroke at 1 year in patients with HZO than in a control cohort.

Postherpetic neuralgia (PHN; ie, persistent pain lasting more than 3 months after outbreak) is the number-one complication of HZ, and it occurs in 30% of individuals with HZO. It is also the most common pain-related cause of suicide in individuals over 70 years old.¹³ With this in mind, it is vital to emphasize to patients with HZO the importance of getting the shingles vaccine; this should be at the top of your list, along with collaborating with the patient’s primary care physician to manage pain and other systemic complications, even if the patient’s ocular symptoms are fully resolved.

HZO TREATMENT

The accepted treatment for HZO is doubling the dose of oral antivirals recommended for HSV and adding a topical steroid if there is no epithelial disease. No prospective, randomized, placebo-controlled clinical trial has demonstrated whether or not long-term antiviral treatment shows a benefit. This is a goal of the ongoing Zoster Eye Disease Study.

Lo et al performed a survey of ophthalmologists participating in this study to determine what the current standard treatment is. Most providers said they treat stromal disease with topical steroids and high-dose oral antivirals, with 1 g oral valacyclovir three times daily being the antiviral regimen of choice. Survey respondents said that patients are kept on oral antivirals as long as topical steroids are being enlisted for treatment and no less than 7 days. This treatment pattern held true whether the patient presented with acute or chronic HZO.¹⁴

Although antiviral medications have excellent safety profiles, they are processed in the kidney and can cause kidney injury. For patients who have any diagnosed kidney dysfunction or who are taking antiviral medications long-term, I obtain labs for albumin-to-creatinine ratio and glomerular filtration rate to ensure that it is safe to use an antiviral medication.

Antiviral treatment within 72 hours of onset reduces viral shedding, severity and duration of rash, and incidence of ocular involvement.³ It has also been shown to reduce the incidence and severity of PHN.³ PHN can be managed with topical anesthetics such as lidocaine, oral gabapentin or pregabalin, and tricyclic antidepressants. I prefer to comanage the PHN with the patient’s primary care physician, who is more integrally involved in following the patient’s systemic health.

VACCINATION

Fortunately, there are now vaccines available to help prevent reactivation of HZ. Two vaccines are currently available. Zostavax (zoster vaccine live, suspension for subcutaneous injection, Merck), which is a live virus vaccine, was approved by the FDA in 2006, and Shingrix (zoster vaccine recombinant, adjuvanted, suspension for intramuscular injection, GlaxoSmithKline Biologicals) was approved in 2017.

The Advisory Committee on Immunization Practices (ACIP) recommends Shingrix as the preferred vaccine and advises that those who were previously vaccinated with Zostavax should be revaccinated with Shingrix. The ACIP recommends Shingrix for all immunocompetent patients older than 50 years.¹⁰

Shingrix is a two-dose vaccine that is more than 95% effective at preventing HZ and PHN.⁹ The protection remains greater than 85% for at least 4 years,⁹ and it is projected to remain above baseline at 15 years.¹³ The availability of this vaccine now offers great promise to patients with HZO.