Herpes simplex keratitis poses diagnostic challenges
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Herpes simplex keratitis is a challenge to diagnose and treat. My guest columnist this month is Sonal S. Tuli, MD, MEd, professor and chair of the department of ophthalmology at the University of Florida.
Amar Agarwal, MS, FRCS, FRCOphth
OSN Complications Consult Editor
The myriad manifestations of herpes simplex keratitis can be difficult to diagnose without a high suspicion, but there are several clues that can point ophthalmologists in the right direction.
Herpes simplex keratitis (HSK) results from reactivation of latent herpes virus in the trigeminal ganglion (TG). The initial infection occurs in childhood by exposure of oral or ocular mucus membranes to secretions containing herpes virus. The virus immediately enters the nerve endings and travels to the TG where, after an initial round of replication, it goes into a state of latency and persists lifelong. The initial round of replication results in the primary infection, manifesting as blepharoconjunctivitis with a vesicular rash around the eyes and follicular conjunctivitis. This can be mistaken for “pink eye” or impetigo but is usually self-limited and resolves without scarring.
The majority of HSK seen in clinical practice is due to recurrence of latent herpes simplex virus (HSV) in the TG. The virus, after replicating, travels back down the nerve to the eye and causes keratitis due to infection of the tissues by live virus, the host’s immunological response to the viral antigen in the corneal tissues, or sequelae due to damage to the TG cells or long-standing inflammation.
Infectious keratitis
The classic lesion is a dendrite, which is caused by infection of corneal epithelial cells by HSV (Figure 1). The lesions have a specific appearance with dichotomous branching and bulbs at the ends of each branch. They appear stuck on due to infectious cells losing intercellular adhesions and therefore can be debrided with little effort. Long-standing dendrites continue to spread peripherally with shedding of the infected cells resulting in a geographic ulcer. These can have underlying inflammation and can leave behind a “ghost dendrite”-shaped scar on the cornea after treatment.
Source: Sonal S. Tuli, MD, MEd
Immune-mediated keratitis
The most commonly seen lesion is focal endotheliitis, in which host lymphocytes target endothelial cells that contain viral antigen, resulting in granulomatous keratic precipitates (Figure 2). These endothelial cells cannot pump fluid out of the cornea, and a disc of the overlying stroma and epithelium becomes edematous with microcystic edema and bullae formation (previously called disciform keratitis). As this primarily involves the endothelium, the anterior chamber is relatively quiet with no or low-grade anterior chamber cell and flare. Early treatment of the endotheliitis can resolve the lesion completely, but in case of long-standing keratitis, even if the inflammation is treated, the epithelial edema and subepithelial scarring may persist. More diffuse endotheliitis can be associated with trabeculitis, which can cause very high IOPs that respond to steroids.
Stromal keratitis without necrosis
This is also called interstitial keratitis wherein the stroma is involved with sparing of the epithelium and endothelium. It can appear as patchy areas of granularity in the corneal stroma but can be missed unless careful examination of the cornea is performed. Treatment of these lesions with steroids can be rewarding as early cases resolve completely with no residual evidence of previous inflammation. However, if untreated, the chronic stromal inflammation results in blood vessel growth into the cornea with deep vascularization.
Stromal keratitis with necrosis
This condition often occurs in patients with repeated episodes of HSK and is the result of an infectious virus along with severe inflammation and can resemble bacterial keratitis (Figure 3). This necrotizing keratitis can cause significant tissue damage and even hypopyon. Distinction from bacterial keratitis can be made by the relative lack of purulent discharge, lack of foreign body sensation and a history of HSK. However, cultures should be taken to confirm the diagnosis.
Keratitis from sequelae of HSK
The most common complication of HSK is the development of a neurotrophic cornea from damage to the TG cells due to replicating virus. The lack of sensation creates an ideal environment for ulceration due to unrecognized trauma, epithelial toxicity from antivirals, lack of tears to wash irritants out of the eye, and the lack of growth factors such as nerve growth factor that help with healing. Once an epithelial defect develops, these factors also prevent healing of the defect, and ulceration of the stroma follows the epithelial defect. This ulcer has classic features of smooth gray edges with minimal inflammation (Figure 4).
Another common complication is lipid keratopathy from the leakage of serum from the blood vessels in the cornea due to long-standing interstitial keratitis. This can cause a sudden loss of vision from the corneal hydration due to the fluid exudation as well as the exuded lipid (Figure 5). The fluid eventually resolves, leaving behind a crystalline white deposit in the stroma. This is the best indication for corneal transplantation due to HSK.
Treatment of HSK
Epithelial disease is treated with oral (acyclovir, valacyclovir, famciclovir) or topical (trifluridine, acyclovir, ganciclovir) antiviral medications. The advantage of oral medications is the lack of ocular toxicity and higher compliance in children, but they can have systemic side effects and are dependent on absorption from the gut and secretion into the tear film. Advantages of topical medications are the lower resistance of HSV to these medications and dependable bioavailability at the ocular surface. Gentle wiping debridement of the lesions can be synergistic with antivirals as infected cells are poorly adherent and can be wiped off easily.
Stromal disease is usually treated with topical steroids under oral antiviral cover. The reason for the antivirals is to prevent spontaneous reactivations of HSV in the TG while the patient is on steroids. The steroids, once started, must be continued until the inflammation is resolved and then tapered slowly over a period of months to prevent rebound inflammation. Stromal keratitis with necrosis is treated with high doses of oral and/or topical antivirals followed by topical steroids.
Conclusion
HSK can present in a variety of forms, and a high index of suspicion is necessary to diagnose this disease in the absence of classic features. Hypoesthesia, granulomatous inflammation and recurrences are clues to HSK.
- For more information:
- Sonal S. Tuli, MD, Med, can be reached at UF Health Eye Center – The Oaks, 6201 W. Newberry Road, Gainesville, FL 32605; email: tulisonal@gmail.com.
- Edited by Amar Agarwal, MS, FRCS, FRCOphth, director of Dr. Agarwal’s Eye Hospital and Eye Research Centre. Agarwal is the author of several books published by SLACK Books, sister company of Healio publisher Ocular Surgery News, including Phaco Nightmares: Conquering Cataract Catastrophes, Bimanual Phaco: Mastering the Phakonit/MICS Technique, Dry Eye: A Practical Guide to Ocular Surface Disorders and Stem Cell Surgery and Presbyopia: A Surgical Textbook. He can be reached at 19 Cathedral Road, Chennai 600 086, India; email: aehl19c@gmail.com; website: www.dragarwal.com.
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