HERPETIC KERATOUVEITIS

Signs and Symptoms

Herpetic keratouveitis, as the name implies, manifests anterior uveitis and some form of keratopathy in the presence, or with a history, of herpetic disease. Either herpes simplex or zoster may cause this condition.

The keratopathy may be dendritic keratitis, punctate epitheliopathy, stromal keratitis, epithelial edema, disciform stromal keratitis or endothelialitis.1 Additionally, there will be an anterior chamber reaction with cells and flare, and possibly posterior synechiae. Granulomatous keratic precipitates (KPs) are commonly found, though occasionally the KPs will be non-granulomatous or stellate in appearance.

There will also commonly be a secondary inflammatory glaucoma. Often, the rise in intraocular pressure (IOP) is disproportionate to the relatively mild anterior chamber reaction present.1-5 Common presenting symptoms are pain, photophobia, and varying degrees of vision loss. Conjunctival injection is common. There is also commonly a sectoral atrophy of the iris in eyes with herpetic keratouveitis.6,7 Spontaneous hyphema may also occur.

Despite the name, both herpes simplex and zoster have the capability to cause uveitis even in the absence of keratopathy.6,7 Primary herpetic uveitis with no history of previous corneal disease seems to be more severe than the uveitis in patients with a history of previous herpetic keratopathy. This is true both for the inflammation as well as the secondary glaucoma.6

There is no racial or gender predilection for herpetic keratouveitis. Typically, the disease occurs in elderly patients, likely due to a declining immune system. However, rarely, children and young adults can develop herpetic keratouveitis.8,9 In these cases, the status of the immune system should be investigated.9

Pathophysiology

In herpetic keratouveitis, either live virus or viral byproducts induce an antigen-antibody response. Endothelialitis involves marked pleomorphism of the endothelial cells, suggesting direct herpes simplex virus invasion into the cells. This could be followed by an inflammatory cell attack against the endothelium.4 It is believed that the uveitic response is secondary to the resultant keratitis. However, in the absence of corneal infiltration or other keratopathy, assigning a primary and secondary site of inflammation is controvertible.

Cytokines mediate numerous tissue changes, among them vasodilation and increased vasopermeability. When the uveal vessels dilate an exudation of plasma, white blood cells and proteins traverse extravascular spaces such as the anterior chamber. Small molecular weight proteins may cloud the ocular media, but have little impact otherwise; however, as larger molecular weight proteins like fibrinogen accumulate in the aqueous and/or vitreous, pathological sequelae such as IOP elevation occur.10,11 Secondary IOP elevation occurs from abnormal aqueous humor dynamics precipitated by increased protein content and increased aqueous viscosity. This, combined with other factors, leads to a reduction in outflow through the trabecular meshwork.

Trabecular meshwork outflow can be impeded both by the accumulation of inflammatory cells as well as the impairment of inherent outflow facility by proteinaceous aqueous humor in patients with excessive flare. Flare may be more of a factor in the development of IOP elevation than the amount of inflammatory cells, as outflow facility is greatly reduced in patients with excessive amounts of flare, irrespective of the number of inflammatory cells.12,13 This is due to increased viscosity of the aqueous humor.

Accumulation of inflammatory cells can unquestionably impede aqueous humor outflow through the trabecular meshwork. Inflammatory cellular debris leads to cellular depopulation of the trabecular meshwork. This is likely more significant than simple blockade of the trabecular meshwork by inflammatory cells.14

Though unsubstantiated by histological evaluation, there may be direct inflammation of the trabecular meshwork itself (trabeculitis), leading to a decreased ability to actively filter aqueous humor. This is suggested by conditions such as herpetic keratouveitis and glaucomatocyclitic crisis, where the IOP may be dramatically elevated in the face of relatively mild anterior chamber inflammation.

While the onset of herpetic keratouveitis outbreak typically happens from an endogenous reason, occasionally the nidus may be external and iatrogenic. Herpetic keratouveitis has been noted to be activated following laser peripheral iridotomy performed with either an argon or YAG laser.15,16 Also, herpetic keratouveitis has been seen to be medically induced both by prostaglandin analogs as well at the antimetabolite mitomycin C.17,18

Management

The cornerstone of management for herpetic keratouveitis involves topical cycloplegia and corticosteroids such as prednisolone acetate 1% or loteprednol etabonate 0.5% (Lotemax, Bausch + Lomb) at least on a QID basis. For recalcitrant cases, difluprednate 0.05% (Durezol, Alcon) may be used TID-QID, but close observation for IOP elevation is needed if used on a long-term basis. An adjunctive role for oral antiviral medications has been identified for patients using corticosteroids.19-22 Appropriate doses of oral antiviral agents for treating active ocular disease include acyclovir 400mg five times per day, valacyclovir 1,000mg twice per day and famciclovir 250mg three times per day.

Oral antiviral medications used in conjunction with topical antiviral medications and corticosteroids have long been advocated for the management of herpetic keratouveitis, though there was not much scientific evidence to support this practice. The Herpetic Eye Disease Study (HEDS) attempted to elucidate the benefit, if any, of oral acyclovir in the management of herpetic iridocyclitis in patients already using topical prednisolone sodium phosphate and trifluridine. This arm of the HEDS was discontinued early due to poor patient recruitment. However, while the number of patients recruited in this trial was too small to achieve statistically conclusive results, the trend in the results suggested a benefit of oral acyclovir 400mg, five times daily for the treatment of HSV iridocyclitis in patients receiving topical corticosteroids and trifluridine prophylaxis.23 There is support for the use of prophylactic acyclovir 600mg QD in the prevention of recurrences of herpetic keratouveitis.24

Aqueous suppressants are the mainstay treatment of uveitis related IOP rise. Topical beta-blockers are a viable option, though they may have poor effect in uveitic glaucoma.14,25 Topical carbonic anhydrase inhibitors have been seen to work especially well in lowering the IOP in uveitic glaucoma.14,25 An alpha-2 adrenergic agonist is also an acceptable option.14,25 Miotics must be avoided as they increase vascular permeability and can worsen inflammation.26 Likewise, prostaglandin analogs should also be avoided whenever possible as they may potentiate inflammation.27

Clinical Pearls

Iris stromal atrophy associated with uveitis is highly suggestive of herpetic etiology.

Elevated IOP that is disproportionately high compared to the degree of anterior chamber inflammation is highly indicative of herpetic disease.

Herpes should be considered the primary cause of recurrent uveitis in individuals with a history of herpetic eye disease. A detailed medical evaluation is necessary only when other signs or symptoms indicate the potential for another disease.

Unilateral uveitis associated with high intraocular pressure is almost always caused by herpes.

Herpetic keratouveitis and glaucomatocyclitic crisis may be within the spectrum of the same disease process.

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11. Casey R, Li WW. Factors controlling ocular angiogenesis. Am J Ophthalmol. 1997;124(4):521-9.

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13. Ladas JG, Yu F, Loo R, et al. Relationship between aqueous humor protein level and outflow facility in patients with uveitis. Invest Ophthalmol Vis Sci. 2001;42(11):2584-8.

14. Kok H, Barton K. Uveitic glaucoma. Ophthalmol Clin North Am. 2002;15(3):375-87.

15. Hou YC, Chen CC, Wang IJ, Hu FR. Recurrent herpetic keratouveitis following YAG laser peripheral iridotomy. Cornea. 2004;23(6):641-2.

16. Gaynor BD, Stamper RL, Cunningham ET Jr. Presumed activation of herpetic keratouveitis after Argon laser peripheral iridotomy. Am J Ophthalmol. 2000;130(5):665-7.

17. Kroll DM, Schuman JS. Reactivation of herpes simplex virus keratitis after initiating bimatoprost treatment for glaucoma. Am J Ophthalmol. 2002;133(3):401-3.

18. Rao A, Tandon R, Sharma N, et al. Herpetic keratitis and keratouveitis after mitomycin-C use in glaucoma filtering surgery: a short case series. Eur J Ophthalmol. 2009;19(6):1088-90.

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21. Rihova E, Boguszakova J, Havlikova M, et al. Treatment of herpes simplex keratouveitis with systemic and local administration of acyclovir. Cesk Slov Oftalmol. 1996;52(2):109-14.

22. Bialasiewicz AA, Jahn GJ. Systemic acyclovir therapy in recurrent keratouveitis caused by herpes simplex virus. Klin Monatsbl Augenheilkd. 1984;185(6):539-42.

23. The Herpetic Eye Disease Study Group. A controlled trial of oral acyclovir for iridocyclitis caused by herpes simplex virus. Arch Ophthalmol. 1996;114(9):1065-72.

24. Rodriguez A, Power WJ, Neves RA, Foster CS. Recurrence rate of herpetic uveitis in patients on long-term oral acyclovir. Doc Ophthalmol. 1995;90(4):331-40.

25. Sung VC, Barton K. Management of inflammatory glaucomas. Curr Opin Ophthalmol. 2004;15(2):136-40.

26. Mori M, Araie M, Sakurai M, et al. Effects of pilocarpine and tropicamide on blood-aqueous barrier permeability in man. Invest Ophthalmol Vis Sci 1992; 33:416-23.

27. Sacca S, Pascotto A, Siniscalchi C, et al. Ocular complications of latanoprost in uveitic glaucoma: three case reports. J Ocul Pharmacol Ther. 2001;17(2):107-13.