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Young woman has decreased vision, red, irritated eye
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A 33-year-old white female was referred to our clinic for a corneal evaluation. She complained of decreased vision and a red, irritated right eye. She reported that it had been ongoing for about 2 weeks and seemed to have gotten slightly worse over the past week.
Her medical history was insignificant other than she reported that she smokes. She had no known drug allergies and was taking no systemic medications. She reported taking two ocular medications: Refresh Optive (carboxymethylcellulose 0.5% and glycerin 0.9%, Allergan) four times daily in the right eye and Viroptic (trifluridine, Monarch) three times daily in the right eye. She denied contact lens wear.
Upon further questioning, the patient reported that she has had approximately two episodes over the past 6 months of a red, irritated right eye that resolved with treatment with Viroptic. She felt that this time the medication did not seem to be working as it had in the past.
Her uncorrected visual acuity was 20/25 OD and 20/30 OS, and best-corrected acuity was 20/25 OD and 20/20 OS. Her pupils were equal, round and reactive to light, with no afferent pupillary defect. Motilities were full and smooth, and confrontation visual fields were full in both eyes. IOP was normal at 11 mm Hg OU.
Anterior segment photograph of the right cornea.
Images: Smith H
Anterior segment evaluation revealed a mildly swollen upper right lid with +1 injection of the conjunctiva, which was greater nasally. Corneal evaluation revealed a dense circinate immune ring paracentral/nasal with no overlying epithelial defect. Corneal neovascularization was also present nasally, encroaching onto the cornea about 2 mm
Corneal stromal disease can be challenging, both diagnostically and therapeutically. Conditions to consider within the differential diagnosis of acquired stromal haze include interstitial keratitis, corneal scarring/trauma, stromal dystrophies and endotheliitis.
This patient’s ocular history guides us in the direction of herpetic stromal keratitis (herpes mediated interstitial keratitis). Stromal herpes simplex virus (HSV) is a common manifestation of recurrent herpetic eye disease, with recurrence ranging from 20% to 61%, according to Farooq and colleagues. As in this case, a prior history of herpetic eye infections can be helpful in drawing conclusions about the underlying cause of any stromal disease.
Hillary Smith
It has been well established that the most common culprit of herpetic eye disease is HSV type 1 and, rarely, HSV type 2. Research by Frank and colleagues suggests that more than 90% of adults exhibit antibodies to HSV-1. Most cases of initial systemic infection occur in childhood with few symptoms. The majority of cases of symptomatic herpes are reactivations of the virus. The most common site of infection is the trigeminal nerve (95% of cases) affecting the overlying skin and mucous membranes (including the eye). The virus will remain in the trigeminal nerve until a biological stressor allows it to become active.
Herpetic corneal disease can be classified based on the main corneal structure involved: epithelium, stroma, endothelium and corneal nerves. Determining the structure involved can be beneficial in deciding the best therapy. Epithelial keratitis is characterized by dendritic lesions of the epithelium and is caused by live virus. Epithelial keratitis is the most common initial presentation of HSV. Active stromal keratitis is characterized by infiltration of lymphocytes and neovascularization in the absence of overlying ulceration. Inactive disease is characterized by the presence of stromal haze and ghost vessels. Stromal keratitis can be further classified as necrotizing, representing only 7% of cases, and non-necrotizing, representing the majority of stromal herpetic disease, according to Dartt and colleagues. Endotheliitis (disciform keratitis) is an inflammation of the endothelium leading to stromal haze and often accompanied by iritis. Neurotrophic keratitis is caused by damage to the corneal nerves leading to ulceration. HSV can present in a variety of ways, requiring careful examination.
Stromal HSV represents as a hypersensitivity within the cornea to viral antigen; two main theories exist as to why this hypersensitivity reaction occurs. One theory described by Frank and Hendricks postulates that the virus has a coat protein called UL6, which is similar to proteins found in the human cornea. The immune system then attacks the offending virus and normal tissue alike. Another theory reported by Mott and colleagues postulates the viral protein known as glycoprotein K induces CD8+ T cells to invade the cornea. CD8+ cells are thought to be responsible for corneal scarring. More than likely, it is a combination of these two factors that lead to stromal edema and scarring.
Treatment, but no cure
It is important to remember that there is no known cure for herpetic disease. Treatment is aimed at shortening duration and reducing symptoms during an outbreak. Treatment of herpetic corneal disease should be tailored based on the presentation, whether the incident is more infectious or inflammatory in nature. Despite best therapy, patients can still have significant scarring and reduction of best-corrected visual acuity. It is important to educate the patient about the possibility of both scarring and future recurrences.
Our mainstay of treatment for stromal HSV includes topical steroids and antivirals. While we must always use caution with placement of steroids on a cornea with live, active virus, stromal HSV is primarily inflammatory in nature. Oral antivirals are usually given in combination with topical steroids to quell any flare-up of active virus.
The Herpetic Eye Disease Study (HEDS) I and II have shaped the way we treat herpetic stromal disease. This research found that the use of topical steroids (eight drops of 1% prednisolone) decreased the persistence/progression of stromal disease vs. placebo. However, they found no difference in visual outcome or recurrence of disease at 6 months with topical steroids. The addition of oral acyclovir vs. placebo showed no improvement in resolution time or final visual outcome, but did result in more patients experiencing visual improvement at 6 months.
This anterior segment photograph demonstrates epithelial keratitis.
Preventing recurrences, our patient
So, is there a way to prevent recurrences? The HEDS II study found that oral acyclovir in a prophylactic dosage of 400 mg twice daily reduced the rate of recurrence of any form of ocular herpes in the following year by 41%. However, new studies are suggesting that we may need to use more caution when placing a patient on prophylactic treatment. A study by van Valzen and colleagues found that acyclovir prophylaxis of 1 year predisposed patients to antiviral-resistant recurrent herpetic keratitis. Further studies are needed, but this new data may change the way we prescribe prophylactic treatment in the future.
Our patient was started on Durezol (difluprednate 0.05%, Alcon) four times daily and oral acyclovir 400 mg three times daily. She was asked to discontinue the Viroptic due to its toxic nature to the cornea. Her neovascularization regressed within the first week of treatment, and after 2 weeks of treatment she has minimal stromal haze remaining.
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Disclosure: Smith has no relevant financial disclosures.