Two thousand five hundred years ago, Hippocrates used the word herpes (after the Greek verb to creep or to crawl) to describe spreading cutaneous lesions. Two strains, herpes simplex 1 (HSV-1) and varicella-zoster virus (VZV) have been associated with uveitis and glaucoma.
HSV and VZV are the most commonly associated infectious causes of anterior uveitis.1 HSV-1 keratouveitis is typically unilateral, with granulomatous keratic precipitates found inferiorly or in Arlt's triangle. The uveitis tends to have an acute, recurrent course.2 Small and medium-sized keratic precipitates have also been observed.3 Iris atrophy is sectoral and may be associated with pupillary dilation.4,5 HSV-1 typically presents with corneal disease, although laboratory analysis has confirmed the diagnosis of HSV-1 in eyes with no prior keratitis.
Patients are generally young, lack a dermatomal vesicular lesion at presentation, and have a decreased prevalence of vitritis compared with those suffering from VZV ocular disease. Patients with HSV tend to have a greater inflammatory response with posterior synechiae, a lower incidence of cataract at presentation, and a lack of chorioretinal scars compared with those who have rubella-associated uveitis.6
ASSOCIATION WITH GLAUCOMA
The IOP of patients with HSV-related keratouveitis is usually normal on initial presentation. Falcon and Williams conducted a retrospective study of 50 patients who had elevated IOP associated with HSV keratouveitis. All had recurrent HSV disease prior to presenting with elevated IOP, and none had increased pressure on initial presentation of ocular herpetic disease. Patients who presented with elevated IOP had either stromal keratitis disease (96%) or a metaherpetic ulcer (4%). None of them presented with a dendritic or amoeboid ulcer. The patients whose IOPs rose were more likely to have concomitant uveitis than those who did not develop high IOP. In a study by Sungur et al of patients with HSV and VZV stromal keratitis, the total incidence of ocular hypertension was 47% during the period of active uveitis, and there was a 13% incidence of persistently elevated IOP during the remission period (secondary glaucoma).7
There are many possible etiologies for the development of glaucoma associated with HSV keratouveitis. Although secondary angle closure may occur due to pupillary block by posterior synechiae, one study found that all patients who developed glaucoma had open angles.8 IOP is thought to rise due to an increase in aqueous viscosity from elevated aqueous proteins, fibrin, and inflammatory cells.9-11 Damage to the cells within the trabecular meshwork by HSV-1 infection has also been implicated as a possible cause of elevated IOP with HSV-associated uveitis.12 Severe alterations in the anterior segment after HSV infection have been noted.11 Clinical observations of elevated IOP during periods of increased uveitis have been confirmed in animal models of herpetic keratouveitis.13
The management of HSV-associated glaucoma requires the treatment and prevention of HSV ocular disease and the control of elevated IOP as needed. Although the Herpetic Eye Disease Study (HEDS) did not directly examine the management of glaucoma, it did specify treatment protocols for the management of HSV-associated ocular disease. 14 The findings of HEDS may be summarized as follows:
- Acyclovir had no significant beneficial effect for treating HSV stromal keratitis in patients taking topical trifluoridine and topical steroids.15
- Treatment with topical steroids was better than placebo at reducing the risk of persistent or progressive stromal keratouveitis.16
- The benefit of oral acyclovir for the treatment of HSV iridocyclitis was not statistically significant.17
- Oral acyclovir had no apparent benefit for the prevention of stromal keratitis and iritis in patients with HSV epithelial keratitis.18
- Long-term prophylaxis with acyclovir helped to reduce the recurrence of HSV ocular disease.19
Ganciclovir ophthalmic gel (Zirgan; Bausch + Lomb) has advantages over the use of topical trifluridine for the treatment of HSV dendritic keratitis, including less corneal toxicity and less frequent dosing.20 Topical ganciclovir, however, has not demonstrated any benefit for the treatment of other HSV-associated ocular disease. Valacyclovir and famciclovir are relatively new oral antiviral agents used for the treatment of HSV infection. The former has been shown to be as effective as acyclovir at reducing the recurrence of HSV ocular disease.21 All three oral agents are associated with infrequent systemic side effects, the most common of which are nausea, headache, sore throat, flu-like symptoms, and diarrhea. The table presents estimates of the cost of yearly therapy with these drugs.
Together with antiviral treatment, topical steroids have a beneficial effect on the treatment of intraocular inflammation, which often initially reduces IOP.22 If the IOP remains high despite the control of intraocular inflammation, topical and oral IOP-lowering medications (including b-blockers, oral and topical carbonic anhydrase inhibitors, and topical a-agonists) can be considered. There has been some concern about the use of topical prostaglandin analogues in the treatment of glaucoma associated with uveitis, although a recent study demonstrated a benefit with minimal side effects.23 In addition, there have been anecdotal reports of reactivation of HSV with the use of topical hypotensive medications such as b-blockers, prostaglandins, and prostamides. 24-28 Whether or not this association differs from what is prevalent in the general population, however, is a subject of controversy.29 Because IOP may rise prior to or after topical steroid therapy, physicians must exercise caution when prescribing these agents. If a patient's IOP remains high on maximally tolerated medical therapy, surgical options may be considered. Filtration surgery is infrequently required to control IOP in patients with HSV-related glaucoma.8
For uveitic glaucoma in general, trabeculectomy tends to be more successful with the use of an antimetabolite Z(50%-67%) than without it (30%).30-32 The use of mitomycin C shows no demonstrable benefit over the use of 5-fluorouracil.32-34 Glaucoma drainage device surgery is currently the procedure of choice in this population, given its higher postoperative success rate at controlling IOP (1- to 2-year success rate over 90%).35,36 We have found that postoperative hypotony is greatly reduced after a drainage device procedure using a valved rather than a nonvalved implant. Preoperative topical and systemic corticosteroid treatment may help to manage ocular inflammation and to minimize postoperative fibrosis. Cyclodestructive procedures such as diode laser therapy have proven effective but have a higher rate of hypotony than in eyes with nonuveitic glaucoma, possibly due to the chronic decrease in aqueous production associated with uveitis.37
Ocular hypertension and glaucoma may be associated with HSV. These patients' IOPs are typically elevated during periods of increased uveitis and may be persistently high during remission. Topical IOP-lowering agents can successfully manage increased IOP, although surgical intervention may be necessary in recalcitrant cases.
Steven V. L. Brown, MD, is a partner at Chicago Glaucoma Consultants, glaucoma section director and associate professor of ophthalmology at Rush University Medical Center, and a clinician educator at University of Chicago Pritzker School of Medicine. Dr. Brown may be reached at (847) 510-6000; firstname.lastname@example.org.
Madhu S. R. Gorla, MD, is a partner at Chicago Glaucoma Consultants, director of medical student education and assistant professor of ophthalmology at Rush University Medical Center, and a clinician educator at University of Chicago Pritzker School of Medicine. Dr. Gorla may be reached at (847) 510-6000; email@example.com.
- Jakob E, Reuland M, Mackensen F, et al. Uveitis subtypes in a German interdisciplinary uveitis center—analysis of 1916 patients. J Rheumatol. 2009;36:127-136.
- Jap A, Chee S. Viral anterior uveitis. Curr Opin Ophthalmol. 2011;22:483-488.
- Van der Lelij A, Ooijman FM, Kijlstra A, Rothova A. Anterior uveitis with sectoral iris atrophy in the absence of keratitis: a distinct clinical entity among herpetic eye diseases. Ophthalmology. 2000;107:1164-1170.
- Tugal-Tutkun I, Otuk-Yasar B, Altinkurt E. Clinical features and prognosis of herpetic anterior uveitis: a retrospective study of 111 cases. Int Ophthalmol. 2010;30:559-565.
- Goldstein DA, Mis AA, Oh FS, Deschenes JG. Persistent pupillary dilation in herpes simplex uveitis. Can J Ophthalmol. 2009;44:314-316.
- Wensing B, Relvas L, Caspers L, et al. Comparison of rubella virus- and herpes virus-associated anterior uveitis: clinical manifestations and visual prognosis. Ophthalmology. 2011;118:1905-1910.
- Sungur G, Hazirolan D, Yalvac I, et al. Incidence and prognosis of ocular hypertension secondary to viral uveitis. Int Ophthalmol. 2010;30:191-194.
- Falcon MG, Williams HP. Herpes simplex keratouveitis and glaucoma. Trans Ophthal Soc UK. 1978;98:101-104.
- Peretz WL, Tomasi TB. Aqueous humor proteins in uveitis. Immunoelectrophoretic and gel diffusion studies on normal and pathological human aqueous humor. Arch Ophthalmol. 1961;65:20-23.
- Epstein DL, Hashimoto JM, Grant WM. Serum obstruction of aqueous outflow in enucleated eyes. Am J Ophthalmol. 1978;86:101-105.
- Hogan MJ, Kimura SJ, Thygeson P. Pathology of herpes simplex keratouveitis. Trans Am Ophthalmol Soc. 1963;61:75-99.
- Tiwari V, Clement C, Scanlan P, et al. A role for herpesvirus entry mediator as the receptor for herpes simplex virus 1 entry into primary human trabecular meshwork cells. J Virol. 2005;79(20):13173-13179.
- Townsend WM, Kaufman HE. Pathogenesis of glaucoma and endothelial changes in herpetic keratouveitis in rabbits. Am J Ophthalmol. 1971;71:904-910.
- Sudesh S, Laibson P. The impact of the herpetic eye disease studies on the management of herpes simplex virus ocular infections. Curr Opin Ophthalmol. 1999;10:230-233.
- Barron BA, Gee L, Hauck WW, et al. Herpetic Eye Disease Study. A controlled trial of oral acyclovir for herpes simplex stromal keratitis. Ophthalmology. 1994;101:1871-1882.
- 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;101:1883-1896.
- The Herpetic Eye Disease Study Group. A controlled trial of oral acyclovir for iridocyclitis caused by herpes simplex virus. Arch Ophthalmol. 1996;114:1065-1072.
- The Herpetic Eye Disease Study Group. The epithelial keratitis trial. A controlled trial of oral acyclovir for the prevention of stromal keratitis or iritis in patients with herpes simplex virus epithelial keratitis. Arch Ophthalmol. 1997;115:703-712.
- The Herpetic Eye Disease Study Group. Acyclovir for the prevention of recurrent herpes simplex virus eye disease. N Engl J Med. 1998;339:300-306.
- Kaufman HE, Haw WH. Ganciclovir ophthalmic gel 0.15%: safety and efficacy of a new treatment for herpes simplex keratitis. Curr Eye Res. 2012;37(7):654-660.
- Miserocchi E, Modorati G, Galli L, Rama P. Efficacy of valacyclovir for the prevention of recurrent herpes simplex virus eye disease: a pilot study. Am J Ophthalmol. 2007;144(4):547-551.
- Thygeson P. Chronic herpetic keratouveitis. Trans Am Ophthalmol Soc. 1967;65:211-226.
- Horsley M, Chen T. The use of prostaglandin analogs in the uveitic patient. Semin Ophthalmol. 2011;26(4-5):285-289.
- Hill JM, Shimomura Y, Dudley JB, et al. Timolol induces HSV-1 ocular shedding in the latently infected rabbit. Invest Ophthalmol Vis Sci. 1987;28:585-590.
- Deai T, Fukuda M, Hibino T, et al. Herpes simplex virus genome quantification in two patients who developed herpetic epithelial keratitis during treatment with antiglaucoma medications. Cornea. 2004;23:125-128.
- Wand M, Gilbert CM, Liesegang TJ. Latanoprost and herpes simplex keratitis. Am J Ophthalmol. 1999;127:602-604.
- Ekatomatis P. Herpes simplex dendritic keratitis after treatment with latanoprost for primary open angle glaucoma. Br J Ophthalmol. 2001;85:1008-1009.
- Kroll DM, Schuman JS. Reactivation of herpes simplex virus keratitis after initiating bimatoprost treatment for glaucoma. Am J Ophthalmol. 2002;133:401-403.
- Bean G, Reardon G, Zimmerman TJ. Association between ocular herpes simplex virus and topical ocular hypotensive therapy. J Glaucoma. 2004;13:361-364.
- Jampel HD, Jabs DA, Quigley HA. Trabeculectomy with 5-fluorouracil for adult inflammatory glaucoma. Am J Ophthalmol. 1990;109:168-173.
- Patitsas CJ, Rockwood EJ, Meisler DM, et al. Glaucoma filtering surgery with postoperative 5-fluorouracil in patients with intraocular inflammatory disease. Ophthalmology. 1992;99:594-599.
- Ceballos EM, Beck AD, Lynn MJ. Trabeculectomy with antiproliferative agents in uveitic glaucoma. J Glaucoma. 2002;11:189-196.
- Prata JA, Neves RA, Minckler DS, et al. Trabeculectomy with mitomycin C in glaucoma associated with uveitis. Ophthalmic Surg. 1994;25:616-620.
- Wright MM, McGehee RF, Pederson JE. Intraoperative mitomycin-C for glaucoma associated with ocular inflammation. Ophthalmic Surg Lasers. 1997;28:370-376.
- Da Mata A, Burk SE, Netland PA, et al. Management of uveitic glaucoma with Ahmed Glaucoma Valve implantation. Ophthalmology. 1999;106:2168-2172.
- Ceballos EM, Parrish RK, Schiffman JC. Outcome of Baerveldt glaucoma drainage implants for the treatment of uveitic glaucoma. Ophthalmology. 2002;109:2256-2260.
- Murphy CC, Burnett CA, Spry PG, et al. A two centre study of the dose response relation for transscleral diode laser cyclophotocoagulation in refractory glaucoma. Br J Ophthalmol. 2003;87:1252-1257.