Signs and Symptoms
The herpes simplex virus (HSV) is a common pathogen in developed regions of the world and a frequent source of ocular infection. Nearly 60% of the American population is seropositive for HSV-1 and another 17% is seropositive for HSV-2.1 Initial ocular infection by HSV tends to be seen in younger patients, with an approximate average age of 24 years.1,2
Recurrence of the HSV infection may occur at any age and while the Recurrence Factor Study (RFS) of the Herpetic Eye Disease Study (HEDS) II did not conclude any specific trigger factors to be associated with the development of signs and symptoms, other reports in the literature have identified causative factors, which include fever, hormonal changes, ultraviolet sun exposure, psychological stress, ocular trauma, trigeminal nerve manipulation, steroid use, ocular surgery, exposure to ultraviolet radiation, immunosuppressive agents and glaucoma treatment with prostaglandin analogs.3-7 There is no recognized racial or gender predilection in HSV keratitis.1
Epithelial keratitis is actually the second most common ocular manifestation of HSV; in a series of patients with herpetic ocular infection, epithelial keratitis was encountered in 12.2% overall, while stromal keratitis was noted in 25.4%.8,9
HSV epithelial keratitis typically presents as a unilateral red eye with a variable degree of pain or irritation. Associated photophobia and epiphora are common. Vision may or may not be affected, depending upon the location and extent of the corneal lesion. Bilateral HSV keratitis may be encountered in a small percentage of cases, though it is more common in children and those with immune or atopic disease.10,11
The hallmark finding in HSV keratitis involves a dendritic ulceration of the corneal epithelium, which may be accompanied by a stromal keratitis in more severe presentations. These lesions often begin as a nondescript, punctate keratopathy but quickly coalesce to form the familiar branching patterns (arborizing, dendritic) that stain brightly with sodium fluorescein dye. Also, because the virus invades and compromises the epithelial cells surrounding the ulcer, the leading edges (the so-called “terminal end-bulbs”) tend to exhibit staining with rose bengal and/or lissamine green dye. Secondary anterior uveitis is often encountered with the keratitis, particularly when treatment is delayed.9 Other epithelial manifestations include geographic ulcers and marginal ulcers.
Rarely, a vesicular skin rash affecting the ocular adnexa or a follicular conjunctivitis may accompany the epithelial keratitis, although these findings are more typical of the initial, primary infection and less common with recurrent HSV.9 One initial non-ocular manifestation that is seen is a vesicular papillomacular rash that sometimes affects the skin of the lids but more commonly results in a “fever blister” or “cold sore” in or around the mouth; this is referred to as herpes labialis.
HSV keratitis can be caused by either Type-1 or Type-2 herpes simplex. Infection by HSV-1 predominantly affects the upper half of the body (e.g., eyes and mouth) whereas HSV-2 is mainly associated with diseases of the lower half of the body (e.g., genitalia and perianal region).12 The virus is transmitted via bodily fluids and affects the skin and mucous membranes of the infected host.1 Primary herpetic infections are generally encountered in children and young adults.1,2
HSV is a pathogen that establishes what is known as a lytic and latent infection.13 Reactivation from latency occurs intermittently and chronically, serving as a life-long source of recurrent infection. In this complex process, HSV has the capability of simultaneously triggering and neutralizing innate immunity, creating a dynamic equilibrium between the virus and the innate immune system; when the immune system prevails, the signs and symptoms are negligible. When the virus prevails, more substantial signs and symptoms ensue.13
After resolution of the initial infection, the herpes virus migrates along local nerves to regional ganglia and remains dormant until reactivated by specific stimuli.14 On average, patients experience recurrences at a rate of 0.6 episodes per year.15 HSV infection can affect any of the three branches (ophthalmic, maxillary, mandibular) of the trigeminal nerve (cranial nerve V). This can then lead to latency in the trigeminal ganglion. While it is traditionally thought that reactivation spreads down the nerve axon from the ganglion to the corneal epithelium, interneuronal spread of the virus within the ganglion can cause ocular disease (epithelial keratitis) without primary infection in the cornea.
While many of the ocular manifestations related to HSV are immune (e.g., delayed hypersensitivity reaction) or inflammatory in nature (e.g., stromal and disciform keratitis, iridocyclitis), epithelial keratitis represents infection by live virus.16,17 Cytokines characteristic of Th1 cells (in particular IFN- and IL-2) have been shown to dominate in HSV keratitis in addition to mechanisms by nonspecific, antigen-independent effector cells such as neutrophils, basophils and monocytes. More recently, the migration and maturation of dendritic cells within the corneal stroma of patients with HSV keratitis have been recognized as contributors to recurrent disease, suggesting a role for delayed type hypersensitivity in the immunopathogenesis of HSV keratitis.17
Viral replication in most cases is confined to the corneal epithelium, with stromal invasion impeded by early responding nonspecific defense mechanisms.13,17 These are rapidly complemented by the specific, mainly cellular, immune response.13,17,18 As the epithelial cells die, a dendritic ulcerative keratitis results. After several recurrences, the corneal stroma may become involved.16,17 Disciform stromal scarring, conjunctivitis and uveitis are natural sequelae to the corneal inflammation.17
HSV epithelial keratitis must be managed quickly and aggressively to prevent penetration into deeper corneal tissues with subsequent scarring and vision loss. The treatment of choice consists of topical and oral antiviral therapies. For over 30 years, the only readily available topical treatment for this condition has been trifluridine 1% ophthalmic solution (Viroptic, Monarch Pharmaceuticals). In most instances, the initial dosage of trifluridine is one drop every two hours up to nine times daily for HSV epithelial keratitis; as regression of the dendrites ensues, the dosage may be tapered to Q3-4H until complete resolution is seen, over a period of seven to 10 days.19,20
More recently, ganciclovir 0.15% ophthalmic gel (Zirgan, Bausch + Lomb) has emerged as an alternative to trifluridine; the advantage of this medication is less frequent initial dosing at just five times daily (approximately every three hours while awake) until the corneal ulcer heals, and then three times per day for another seven days. Additionally, ganciclovir demonstrates greatly reduced corneal toxicity as compared to trifluridine, primarily because it is only taken up by virus-infected cells.16,21,22 Gentle debridement of the ulcer bed to remove active viral particles has been advocated as an adjunctive therapy to topical antiviral agents, as it may hasten the speed of resolution.19 Cycloplegia (homatropine 2% TID-QID or even atropine 1% BID) may be initiated, depending upon the severity of the uveitic response and the patient’s subjective discomfort.
Oral antiviral agents can also effectively treat HSV epithelial keratitis, and may be used in a variety of scenarios.23-25 Oral medications should be considered in patients who lack the dexterity to independently instill eye drops with regular frequency, where there is a history of toxicity or other adverse response to topical antiviral therapy, or where the topical preparations are cost prohibitive. The oral antiviral agents work because they are able to generate pharmacotherapeutic levels in the tears. Options for managing HSV epithelial keratitis include acyclovir 200mg to 400mg five times daily, valacyclovir 500mg three times daily or famciclovir 250mg to 500mg two to three times daily for 21 days; of these, generic acyclovir is typically the least expensive.
The Acyclovir Prevention Trial (APT of the HEDS II) demonstrated that oral antiviral medications may further serve a preventative role by reducing the frequency and severity of recurrent infective outbreaks.26,27 Acyclovir 400mg BID is the most commonly used regimen for prophylactic suppression, but valacyclovir 500mg once daily may be used for those who are intolerant of acyclovir.28
It is well established that the herpes simplex virus replicates more rapidly in the presence of certain immunosuppressive agents, hence worsening the course of the disease. Indeed, reports of corticosteroids exacerbating HSV ocular infections date back 50 years or more.29 For this reason, topical steroids are generally considered a contraindication when managing active HSV epithelial keratitis. However, the Stromal Keratitis Not on Steroids (SKN) arm of HEDS I demonstrated that judicious topical steroid use can be a beneficial adjunct when used under the umbrella of topical or oral antiviral agents, following several days of effective antiviral therapy; this is particularly true in cases of associated stromal inflammation.30,31
When managed appropriately, HSV epithelial keratitis resolves without scarring, although there is potential for subtle epithelial irregularities and progressive corneal hypoaesthesia with recurrent attacks.32 Should stromal keratitis develop secondary to the epitheliopathy, the potential for corneal opacification increases dramatically. Penetrating or lamellar keratoplasty may be indicated in such cases.33,34
It should be noted that while treatment of this condition is often straightforward when identified and managed early, HSV remains the most common infectious cause of unilateral blindness in the developed world.35
• A unilateral red eye in an adult patient that is inconsistent with the symptoms (i.e., the patient seems to be in far less discomfort than the appearance of the eye would indicate) must make the practitioner suspicious for HSV keratitis, particularly if the individual has a previous history of similar infections.
• Recurrent episodes induce greater damage to the corneal nerves, leading to hypoesthesia. The cotton-wisp test used for measuring corneal sensitivity is positive in cases of HSV keratitis when one cornea is less sensitive to the touch of the wisp then the other. It should be used whenever HSV is suspected.
• Consider a history of prolonged sun exposure or extreme psychological stress to be significant in diagnosing HSV epithelial keratitis.
• The majority of adverse steroid-related outcomes in HSV epithelial keratitis have arisen from improper diagnosis where topical steroid (alone or in combination) use was initiated without antiviral coverage. Judicious use of a topical steroid concurrent with and following several days of antiviral treatment can help reduce scarring should the stroma become inflamed. Beware of toxicity related to topical antiviral medications. Some chronic cases may seem resistant to therapy when, in reality, the virus has been killed and the medication is perpetuating a non-healing pseudodendrite or a neurotrophic keratopathy.
• Not every case of HSV epithelial keratitis manifests in a classic dendritic appearance, especially early in the disease course. Factors such as duration since onset, medication use, atopic disease or a history of corneal transplantation can significantly alter the presentation. Always consider HSV in the differential of atypical or unusual epitheliopathies.
• At the initial presentation of HSV epithelial keratitis, we educate patients about the role of long-term suppressive therapy with low-dose oral acyclovir and give the patient this option. At the second outbreak, we more strongly recommend ongoing suppressive therapy.
1. Farooq AV, Shukla D. Herpes simplex epithelial and stromal keratitis: an epidemiologic update. Surv Ophthalmol. 2012;57(5):448-62.
2. Uchio E, Hatano H, Mitsui K, et al. A retrospective study of herpes simplex keratitis over the last 30 years. Jpn J Ophthalmol. 1994;38(2):196-201.
3. Shtein RM, Stahl RM, Saxe SJ, et al. Herpes simplex keratitis after intravitreal triamcinolone acetonide. Cornea. 2007;26(5):641-2.
4. Barequet IS, Wasserzug Y. Herpes simplex keratitis after cataract surgery. Cornea. 2007;26(5):615-7.
5. Miyajima S, Sano Y, Sotozono C, et al. Herpes simplex keratitis after ophthalmic surgery. Nippon Ganka Gakkai Zasshi. 2003;107(9):538-42.
6. Rezende RA, Uchoa UB, Raber IM, et al. New onset of herpes simplex virus epithelial keratitis after penetrating keratoplasty. Am J Ophthalmol. 2004;137(3):415-9.
7. Dios Castro E , Maquet Dusart JA . Latanoprost-associated recurrent herpes simplex keratitis. Arch Soc Esp Oftalmol. 2000;75(11):775-778.
8. Xu F, Sternberg MR, Kottiri BJ, et al. Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA. 2006;296(8):964-73.
9. Miserocchi E, Fogliato G, Bianchi I, et al. Clinical Features of Ocular Herpetic Infection in an Italian Referral Center. Cornea. 2014 Jun;33(6):565-70.
10. Chong EM, Wilhelmus KR, Matoba AY, et al. Herpes simplex virus keratitis in children. Am J Ophthalmol. 2004;138(3):474-5.
11. Souza PM, Holland EJ, Huang AJ. Bilateral herpetic keratoconjunctivitis. Ophthalmology. 2003;110(3):493-6.
12. Garweg JG, Halberstadt M. The pathogenesis of herpetic keratitis. Klin Monatsbl Augenheilkd. 2002; 219(7):477-86.
13. Ma Y, He B. Recognition of herpes simplex viruses: toll-like receptors and beyond. J Mol Biol. 2014 Mar 20;426(6):1133-47.
14. Saini JS, Agarwala R. Clinical pattern of recurrent herpes simplex keratitis. Indian J Ophthalmol. 1999;47(1):11-4.
15. Rowe AM, St Leger AJ, Jeon S, et al. Herpes keratitis. Prog Retin Eye Res. 2013;32(1):88-101.
16. Sahin A, Hamrah P. Acute Herpetic Keratitis: What is the Role for Ganciclovir Ophthalmic Gel? Ophthalmol Eye Dis. 2012;4:23-34.
17. Hawthorne KM, Dana R, Chodosh J. Delayed type hypersensitivity in the pathogenesis of recurrent herpes stromal keratitis. Semin Ophthalmol. 2011;26(4-5):246-50.
18. Garweg JG, Halberstadt M. The pathogenesis of herpetic keratitis. Klin Monatsbl Augenheilkd. 2002; 219(7):477-86.
19. Wilhelmus KR. Therapeutic interventions for herpes simplex virus epithelial keratitis. Cochrane Database Syst Rev. 2007;24(1):CD002898.
20. Labetoulle M. The latest in herpes simplex keratitis therapy. J Fr Ophtalmol. 2004;27(5):547-57.
21. Matthews T, Boehme R. Antiviral activity and mechanism of action of ganciclovir. Rev Infect Dis. 1988;10 Suppl 3:S490-4.
22. Croxtall JD. Ganciclovir ophthalmic gel 0.15%: in acute herpetic keratitis (dendritic ulcers). Drugs. 2011;71(5):603-10.
23. Higaki S, Itahashi M, Deai T, et al. Effect of oral valaciclovir on herpetic keratitis. Cornea. 2006;25(10 Suppl 1):S64-7.
24. Sozen E, Avunduk AM, Akyol N. Comparison of efficacy of oral valacyclovir and topical acyclovir in the treatment of herpes simplex keratitis: a randomized clinical trial. Chemotherapy. 2006;52(1):29-31.
25. Wilhelmus KR. Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis. Cochrane Database Syst Rev. 2010;(12):CD002898.
26. Herpetic Eye Disease Study Group. Oral acyclovir for herpes simplex virus eye disease: effect on prevention of epithelial keratitis and stromal keratitis. Arch Ophthalmol. 2000;118(8):1030-6.
27. Langston DP. Oral acyclovir suppresses recurrent epithelial and stromal herpes simplex. Arch Ophthalmol. 1999;117(3):391-2.
28. Miserocchi E, Modorati G, Galli L, Rama P. Efficacy of valacyclovir vs acyclovir for the prevention of recurrent herpes simplex virus eye disease: a pilot study. Am J Ophthalmol. 2007;144(4):547-51.
29. Crompton DO. Corticosteroids exacerbate ocular herpes simplex. Med J Aust. 1964;2(12):950-4.
30. Barker NH. Ocular herpes simplex. Clin Evid. 2006;(15):917-23.
31. Knickelbein JE, Hendricks RL, Charukamnoetkanok P. Management of herpes simplex virus stromal keratitis: an evidence-based review. Surv Ophthalmol. 2009;54(2):226-34.
32. Hamrah P, Sahin A, Dastjerdi MH, et al. Cellular changes of the corneal epithelium and stroma in herpes simplex keratitis: an in vivo confocal microscopy study. Ophthalmology. 2012;119(9):1791-7.
33. Li J, Ma H, Zhao Z, et al. Deep anterior lamellar keratoplasty using precut anterior lamellar cap for herpes simplex keratitis: a long-term follow-up study. Br J Ophthalmol. 2014;98(4):448-53.
34. Wu SQ, Zhou P, Zhang B, et al. Long-term comparison of full-bed deep lamellar keratoplasty with penetrating keratoplasty in treating corneal leucoma caused by herpes simplex keratitis. Am J Ophthalmol. 2012;153(2):291-299.e2.
35. Pepose J, Keadle T, Morrison L. Ocular herpes simplex: changing epidemiology, emerging disease patterns, and the potential of vaccine prevention and therapy. Am J Ophthalmol. 2006;141(3):547-57.