LASIK in Patients With Herpes Simplex Virus
Since LASIK was approved in the United States, there has been a question of whether it is safe to perform in a patient with herpes simplex virus (HSV) related ocular disease. As a large majority of the population (60-90%) is seropositive for HSV-1, this question is extremely relevant, yet there is only a small body of literature examining the potential complications of LASIK in a patient with a history of ocular herpes.
Currently the US FDA does not consider a history of HSV ocular infection an absolute contraindication to LASIK surgery, but it does cite a history of ocular HSV symptoms as a potential source of complications.
Ocular Manifestations of HSV
Ocular HSV usually presents as keratitis, an infection and inflammation of the superficial layer of the cornea. Herpetic keratitis, if left untreated, can lead to significant corneal scarring and vision loss, and is one of the leading causes of blindness worldwide.
Primary infection occurs via direct contact of mucus membranes to the viral particles. Latency occurs once the virus itself is in the sensory neurons and travels retrograde to the sensory ganglia, where it integrates within the host genome and remains for the duration of the host’s life. Primary infection most commonly presents with blepharoconjunctivitis. Ocular symptoms more commonly occur when latency is disrupted.
When latency is disrupted, infectious viral particles travel anterograde down the neuron and manifest as infection. Reactivation of HSV in skin and mucosal infections is linked with increased stress, trauma, fever, UV exposure and recent infection, however reactivation of ocular HSV infection has not been linked to these factors.
Ocular HSV reactivation is linked to excimer laser treatment, topical ocular medications such as epinephrine, beta-blockers and prostaglandins, and immunosuppression, most notably immunosuppression with topical ocular corticosteroids. Recurrent ocular HSV infection is typically unilateral, with only 3% of patient demonstrating bilateral disease. The presence of bilateral disease should raise the question of immune dysfunction.
Antibodies to HSV can be found in over 90% of the population, however far fewer develop symptoms of infection, and of those only a minority ever experience ocular involvement .
Those who do experience ocular HSV are likely to experience recurrent symptoms. Recurrence of the ocular HSV is reported at 9% at one year, 23% at two years, 40% at three years and 67% at 10 years,.
Herpetic keratitis presents acutely with pain, blurred vision and watery discharge.
Diagnosis can usually be made via slit-lamp examination, which usually reveals dendritic lesions of the cornea, follicular reaction of the conjunctiva, or vesicles on the eyelid and periorbita.
Laboratory testing is usually not needed, but can be performed if clinical suspicion is high and presentation is atypical. Laboratory specimens should be taken by scraping the epithelial lesions. Tissue culture, antigen detection techniques (ELISA), and PCR may be helpful in establishing the diagnosis in atypical cases . Serologic testing is not helpful due to a high prevalence in the general population.
Types of Disease
Recurrent HSV infection can infect almost any ocular tissue, including the eyelid, conjunctiva, cornea, iris, uveal tract, trabecular meshwork, retina, and optic nerve. One of the most common presentation of clinically recognizable HSV infection is epithelial keratitis. While ocular herpes infection can manifest in alternate ways (herpetic blepharitis, conjunctivitis, retinitis or scleritis), these presentations are rare. There are four recognized types of herpetic keratitis.
Epithelial keratitis is the most commonly recognized form of ocular HSV infection. PAtients present with foreign body sensation, photophobia, injection, and blurred vision. Disease presents as dendritic lesions or geographic ulcerations of the cornea, which can be seen with fluorescein dye. Most cases resolve spontaneously. However with treatment it shortens the clinical course and might reduce associated herpetic neuropathy, subepithelial scarring and risk of immune-mediated diseases of the cornea. With treatment most symptoms resolve in two to three weeks.
Stromal keratitis rarely occurs with an initial presentation of ocular HSV infection, but becomes increasingly common with recurrent infections (up to 20-60%). It is the most common infectious etiology of blindness in the United States. Each recurrent episode increases the risk of future episodes. Stromal disease can occur due to the virus itself or due to the immune mediated inflammatory response to infection.
Endotheliitis (formerly disciform keratitis) is corneal stromal edema with underlying endothelial keratic precipitates. It is a common form of recurrent HSV ocular disease and is thought to be related to immune reaction to the virus, rather than the virus itself.
While uveitis is a common condition, when it occurs with keratitis, HSV infection should be considered the most likely etiology. It will typically present with an elevated intraocular pressure due to trabeculitis.
Treatment of HSV keratitis is based on whether symptoms are due to active disease or related to an immune response.
Topical and oral antiviral medications are equally effective in treating of epithelial keratitis due to HSV reactivation. Combination therapy with both topical and oral antivirals has not been shown to be any more effective or improve outcomes compared to treatment with one or the other.
Antivirals with topical corticosteroids is the standard of care for treatment of stromal keratitis.
Topical corticosteroids with antiviral therapy are an effective treatment for endotheliitis caused by HSV reactivation.
Treatment should be tailored to address the keratitis (see above), and the uveal component will resolve with adequate treatment of corneal component.
Preventing recurrence is critical, as repeated reactivation of ocular HSV can result in corneal scarring and eventually visual impairment. In randomized-controlled trials, oral acyclovir has proven effective in reducing the number of ocular HSV outbreaks in patients with a documented history of ocular HSV.
Reactivation of HSV After LASIK
Animal models have linked both PRK and LASIK to reactivation of ocular HSV in rabbits, yet there is only a smattering of reports of post-LASIK HSV reactivation in humans. To further convolute the picture, recent retrospective studies have failed to show a connection between HSV reactivation and LASIK, and several reports indicate that perioperative antivirals may be adequate to prevent reactivation in these patients.
LASIK and PRK have both been shown to reactivate ocular HSV and induce viral shedding in rabbits.
The literature contains several reported cases of post-LASIK HSV reactivation. Three patients had a history of ocular herpes, two had a history of herpes labialis and one reported no previous herpetic disease. Reactivation occurred on postoperative day one in two patients, within two months in two patients and after two years in one patient. No patient was pretreated with antivirals, and only one patient received antiviral medication postoperatively (prior to symptom onset). Symptoms fully resolved in all cases with antiviral therapy,,,,.
Case Series and Studies
Two small case studies found no reactivation of HSV after perioperative administration of antiviral therapy in patients with a documented history of ocular HSV infection. The value of these studies is limited by the small number of patients included (3 in one study and 5 in the second),.
In a retrospective examination of 48 patients with a history of ocular herpes, no patient experienced HSV reactivation during the postoperative window (range of 1-28 months) despite only 13 patients receiving perioperative antiviral treatment, and 10 patients receiving pre and postoperative antiviral therapy.
Antiviral therapy has long been known to significantly reduce the reactivation of genital and orofacial HSV infection, and is also effective in prophylaxis and treatment of ocular HSV. There is a small, but growing, body of literature that seems to support the theory that judicious use of pre, peri and post-LASIK antiviral treatment significantly reduces the risk of HSV reactivation in both animal models and in clinical practice.
Twice daily doses of acyclovir, beginning one day prior to LASIK surgery and extending seven days, were found to significantly reduce the incidence of HSV reactivation and the number of days of viral shedding in rabbits .
In several small case studies of LASIK in patients with a history of herpetic keratitis, perioperative antiviral treatment was administered and no patient developed reactivation of ocular HSV. All patients had been free of ocular symptoms for at least one year at the time of surgery,.
In a retrospective study of 48 LASIK patients with a history of ocular herpes infection, thirteen were given perioperative antiviral therapy. None of the patients in the study developed reactivation of HSV keratitis during the follow-up window.
There is no consensus on the safety of LASIK surgery in patients with a history of ocular HSV infection, although the limited data does allow for some reasonable recommendations and assumptions.
Each year there are an estimated 48,000 occurrences of herpetic keratitis. With the overwhelming popularity of LASIK surgery, the expected incidence of HSV reactivation following LASIK would be expected to be significantly higher. Either HSV reactivation following LASIK is an uncommon complication, or it is an under-recognized phenomena. Clearly more research is needed to elucidate this discrepancy. In the meantime, providers must decide how to handle patients with a history of herpetic keratitis who are requesting LASIK. Using the data available, several recommendations seem reasonable.
- Prospective patients should be symptom free at the time of surgery and should also be at least one year removed from any prior ocular or labial HSV outbreak.
- Prospective patients should not have any evidence of stromal disease on examination.
- Prospective patients should have normal topography, pachymetry and corneal sensitivity.
- Perioperative and postoperative antiviral therapy should be given to all patients with a history of ocular HSV infection.
- Patients should be well informed regarding the remote risk of HSV reactivation following LASIK.
- Liesegang TJ. Herpes simplex virus epidemiology and ocular importance. Cornea 2001; 20(1):1
- Cunningham AL, Diefenbach RJ, Miranda-Saksena M, et al. The cycle of human herpes simplex virus infection: virus transport and immune control. J Infect Dis 2006; 194 suppl1:S11
- Herpetic Eye Disease Study Group. Predictors of recurrent herpes simplex virus keratitis. Cornea 2001: 20:123
- Cantor LB, Rapuano CJ, Cioffi GA. Infectious diseases of the external eye: Basic concepts and viral infections. BCSC. 2016; 8(4): 92-107.
- Leisegang TJ, Melton J, Daly PJ, Ilstrup DM. Epidemiology of ocular herpes simplex: incidence in Rochester Minnesota 1950-1982. Arch Ophthalmol 1989; 107:1155-1159
- Young RC, Hidge DO, Liesegang TJ, Baratz KH. Incidence, recurrence and outcomes of herpes simplex virus eye disease in Olmsted County, Minnesota 1976-2007: the effect of oral antiviral prophylaxis. Arch Ophthalmol. 2010; 128:1178
- Laetoulle M, Auquier P, Conrad H, et al. Incidence of herpes simplex virus keratitis in France. Ophthalmology 2005;112:888
- Shuster JJ, Kaufman HE, Nesburn AB. Statistical analysis of the rate of recurrence of herpesvirus ocular epithelial disease. Am J Ophthalmol 1981;91:328
- Sugar A. Herpes simplex keratitis. UpToDate. Nov 2011
- Holland EJ, Schwartz GS. Classification of herpes simplex virus keratitis. Cornea 1999;18:144
- Cook SD. Herpes simplex virus in the eye. Br J Ophthalmol 1992;76:365
- Inoue Y. Immunologic aspects of herpetic stromal keratitis. Semin Ophthalmol. 2008;23:221
- Suzuki T, Ohashi Y. Corneal endotheliitis. Semin Ophthalmol. 2008;23:235.
- Guess S, Stone DU, Chodosh J. Evidence-based treatment of herpes simplex vius keratitis: a systematic review. Ocul Surf 2007;5:240
- Knickelbein JE, Hendricks RL, Charukamnoetkanok P. Management of herpes simplex virus stromal keratitis: an evidence-based review. Surv Ophthalmol 2009; 54:226
- Wilhelmus KR, Gee L, Hauck WW, et al. Herpetic Eye Disease Study: A Controlled trial of topical corticosteroids for herpes simplex stromal keratitis. Ophthalmology 1994;101:1883
- Herpetic Eye Disease Study Group. Acyclovir and the prevention of recurrent herpes simplex virus eye disease. N Engl J Med 1998:339;300
- Dhaliwal DK, Romanowski EG, Yates KA, et al. Experimental laser in situ keratomileusis induces the reactivation of latent herpes simplex virus. Am J Ophthalmol 2001;131:506-507
- Rojas-Silva V, Rodriguez-Conde R, Cobo-Soriano R. Laser in situ keratomileusis in patients with a history of ocular herpes. J Cataract and Refract Surg 2007;33:1855-1859
- Davidorf JM. Herpes simplex keratitis after LASIK [letter]. J Refract Surg 1998;14:667
- Perry HD, Doshi SJ, Donnenfeld ED. Herpes simplex reactivation following laser in situ keratomileusis and subsequent corneal perforation. CLAO J 2002;28:69-71
- Gomez Garcia S, Pinero Bustamonte AM, Gutierrez Sanchez E, et al. Herpes simplex keratitis following laser in sity keratomileusis. Arch Soc Esp Oftalmol 2004;79:139-142
- Levy J, Lapid-Gortzak R, Klemperer Itamar et al. Herpes simplex virus keratitis after laser in sity keratomileusis. J Refract Surg 2006;22:509-511
- Jarade EF, Tabbara KF. Laser in situ keratomileusis in eyes with inactive herpetic keratitis. Am J Ophthalmol 2001; 132:779-780
- de Rojas Silva MV, Diez-Feijoo E, Javaloy J, et al. Prophylactic perioperative antiviral therapy for LASIK in patients with inactive herpetic disease. J Refract Surg 2005; 22:404-405