eMedicine Specialties > Ophthalmology > Cornea

Keratitis, Herpes Simplex

Author: Jim C Wang, MD, Cornea and Retina Subspecialist, Department of Ophthalmology, Kaiser Permanente Fontana Medical Center
Coauthor(s): David C Ritterband, MD, Assistant Director of Cornea and External Disease, Clinical Associate Professor, Department of Ophthalmology, New York Eye and Ear Infirmary, New York Medical College
Contributor Information and Disclosures

Updated: Aug 7, 2009

Introduction

Background

Herpes simplex virus (HSV) keratitis encompasses a variety of disease processes that HSV can cause in the human cornea.

Herpes simplex virus dendritic ulcer stained with...

Herpes simplex virus dendritic ulcer stained with rose bengal.

Herpes simplex virus dendritic ulcer stained with...

Herpes simplex virus dendritic ulcer stained with rose bengal.



A variety of clinical manifestations of infectious and immunologic etiologies, such as infectious epithelial keratitis, neurotrophic keratopathy, necrotizing stromal keratitis, immune stromal keratitis (ISK), and endotheliitis, can affect all levels of the cornea.

Neurotrophic keratopathy.

Neurotrophic keratopathy.

Neurotrophic keratopathy.

Neurotrophic keratopathy.



Active immune stromal keratitis.

Active immune stromal keratitis.

Active immune stromal keratitis.

Active immune stromal keratitis.



Although more common as a manifestation of recurrent HSV infection, HSV keratitis may also be seen during a primary infection.

Pathophysiology

HSV is a DNA virus that commonly affects humans. Infection occurs by direct contact of skin or mucous membrane with virus-laden lesions or secretions. HSV type 1 (HSV-1) is primarily responsible for orofacial and ocular infections, whereas HSV type 2 (HSV-2) generally is transmitted sexually and causes genital disease. HSV-2 may rarely infect the eye by means of orofacial contact with genital lesions and occasionally is transmitted to neonates as they pass through the birth canal of a mother with genital HSV-2 infection.

Primary HSV-1 infection occurs most commonly in the mucocutaneous distribution of the trigeminal nerve.  It is often asymptomatic but may manifest as a nonspecific upper respiratory tract infection. After the primary infection, the virus spreads from the infected epithelial cells to nearby sensory nerve endings and is transported along the nerve axon to the cell body located in the trigeminal ganglion. There, the virus genome enters the nucleus of a neuron, where it persists indefinitely in a latent state. Primary infection of any of the 3 (ie, ophthalmic, maxillary, mandibular) branches of cranial nerve V can lead to latent infection of nerve cells in the trigeminal ganglion. Interneuronal spread of HSV within the ganglion allows patients to develop subsequent ocular disease without ever having had primary ocular HSV infection.1

Recurrent ocular HSV infection has traditionally been thought of as reactivation of the virus in the trigeminal ganglion, which migrates down the nerve axon to produce a lytic infection in ocular tissue. Evidence suggests that the virus may also subsist latently within corneal tissue, serving as another potential source of recurrent disease and causing donor-derived HSV disease in transplanted corneas. However, corneal HSV latency as a cause of recurrent disease remains controversial.

A prospective multicenter trial failed to find an association between anecdotal environment triggers (eg, stress, systemic infections, sunlight exposure, menstruation, contact lens wear, eye injury) and ocular HSV recurrence.2,3,4

Frequency

United States

Approximately 20,000 new cases of ocular HSV occur in the United States annually, and more than 28,000 reactivations occur in the United States annually. It is one of the most frequent causes of blindness in the United States with 500,000 people experiencing HSV-related ocular disease.

International

HSV infection is ubiquitous, with an estimated one third of the population worldwide suffering from recurrent infections.

Mortality/Morbidity

HSV keratitis is the most frequent cause of corneal blindness in the United States and is a leading indication for corneal transplantation. HSV keratitis is also the most common cause of infectious blindness in the Western world.

Age

Most HSV eye disease occurs in adults, and it occurs many years after the primary infection. However, herpetic keratitis in children almost always involves the corneal epithelium and is marked by a disproportionate risk of binocular disease, a high recurrence rate, and amblyopia.5

Clinical

History

  • Patients with HSV keratitis may complain of the following:
    • Pain
    • Photophobia
    • Blurred vision
    • Tearing
    • Redness
  • A history of prior episodes in patients with recurrent disease may exist. Among patients with ocular HSV, those with previous stromal involvement have a significantly higher risk of subsequent stromal keratitis; in contrast, patients with epithelial keratitis alone have no increased rate of recurrent HSV disease.

Physical

HSV keratitis may be divided into 4 categories: infectious epithelial keratitis, neurotrophic keratopathy, stromal keratitis, and endotheliitis.

  • Infectious epithelial keratitis is characterized by corneal vesicles, dendritic ulcers, and geographic ulcers.
    • The earliest sign of active viral replication in the corneal epithelium is small, raised, clear vesicles that are analogous to the vesicular eruptions seen in mucocutaneous herpes infection elsewhere in the body. These infectious epithelial vesicles are rarely seen or recognized during a patient's first presentation. However, in patients with a known history of HSV keratitis, infectious epithelial vesicles may be observed even in the absence of any clinical symptoms.
    • Within several hours, these corneal vesicles coalesce into a dendritic pattern. In some patients, particularly patients who are immunocompromised, the recurring infection may be arrested at the vesicle stage. As the disease progresses, a central epithelial defect develops. The resultant dendritic ulcer is the most common presentation of HSV keratitis.
    • Prominent features of a HSV dendritic ulcer include branching terminal bulbs, swollen epithelial borders that contain live viruses, and central ulceration through the basement membrane.
    • If the infectious ulcer enlarges, its shape is no longer linear.  It is then referred to as a geographic ulcer. The swollen epithelial cells and the scalloped or geographic borders differentiate this infectious lesion from the smooth borders of a neurotrophic ulcer.


Herpes simplex virus geographic ulcer.

Herpes simplex virus geographic ulcer.

Herpes simplex virus geographic ulcer.

Herpes simplex virus geographic ulcer.

  • Neurotrophic keratopathy develops in patients with previous HSV epithelial disease. Traditionally thought of as neither infectious nor immunologic in origin, neurotrophic keratopathy arises from impaired corneal innervation and decreased tear formation, exacerbated by long-term use of topical medications, especially antiviral agents. However, evidence suggests that HSV replication may occur in persistent epithelial defects.
    • The earliest signs of neurotrophic keratopathy include an irregular corneal surface and punctate epithelial erosions. These erosions may progress to a persistent epithelial defect and eventual stromal ulceration.
    • In contrast to the irregular shape and scalloped borders of an infectious geographic ulcer, a neurotrophic ulcer is typically oval with smooth borders and often lies within the interpalpebral fissures, located in the central or inferior paracentral area of the cornea. Decreased corneal sensitivity helps confirm the diagnosis. 
    • Complications of neurotrophic keratopathy include stromal scarring, neovascularization, necrosis, and perforation.


Large neurotrophic ulcer.

Large neurotrophic ulcer.

Large neurotrophic ulcer.

Large neurotrophic ulcer.

  • Corneal stromal inflammation may be the primary manifestation of HSV keratitis or may be seen secondary to infectious epithelial keratitis, neurotrophic keratopathy, or endotheliitis.6 The 2 forms of primary stromal involvement are necrotizing stromal keratitis and ISK.
    • Necrotizing stromal keratitis, characterized by dense stromal infiltrate, ulceration, and necrosis, is believed to result from viral replication in stromal keratocytes and severe host inflammatory response. This destructive intrastromal inflammation may lead to thinning and perforation within a short period. The use of topical corticosteroids without antiviral coverage may be a possible risk factor for its development.
    • ISK is a common manifestation of chronic recurrent ocular HSV disease. An antibody-complement cascade to retained viral antigen within the stroma is believed to be the underlying mechanism. ISK may present clinically with focal, multifocal, or diffuse cellular infiltrates; immune rings; neovascularization; or ghost vessels at any level of the cornea. 
    • Significant anterior chamber inflammation may accompany stromal keratitis. 
    • Permanent stromal scarring may lead to profound visual loss. In addition, all stromal keratitis types may develop uveitis, trabeculitis, and secondary glaucoma.


Inactive immune stromal keratitis.

Inactive immune stromal keratitis.

Inactive immune stromal keratitis.

Inactive immune stromal keratitis.

  • Endotheliitis  
    • Clinical signs of endotheliitis include keratic precipitates (KP), overlying stromal and epithelial edema, and absence of stroma infiltrate or neovascularization. A mild-to-moderate iritis is frequently seen.
    • Immunologic reaction to viral antigens within corneal endothelial cells has been proposed as the underlying pathogenesis; however, active viral replication may also play a role. The inflammation directed at the endothelium may cause endothelial decompensation and overlying stromal and epithelial edema.
    • HSV endotheliitis can be classified as disciform, diffuse, or linear. Disciform endotheliitis presents with a round area of corneal edema in a central or paracentral region with a clear demarcation between involved and uninvolved cornea. Diffuse endotheliitis shows scattered KP and may stem from a previous disciform area of involvement. Linear endotheliitis appears as a line of KP progressing centrally from the limbus, with peripheral corneal edema trailing the migrating line of KP. The line of KP can be sectoral or circumferential; it may take on either a straight pattern or a more serpiginous pattern.


Disciform endotheliitis with secondary stromal ul...

Disciform endotheliitis with secondary stromal ulceration.

Disciform endotheliitis with secondary stromal ul...

Disciform endotheliitis with secondary stromal ulceration.

Causes

  • Infectious epithelial keratitis results from active viral replication within the corneal epithelium.
  • Neurotrophic keratopathy is poorly understood.  The cause is thought to be multifactorial and includes decreased corneal innervation and tear secretion (as a result of prior HSV infection of the sensory nerves), toxicity from topical agents, and underlying stromal inflammation. Evidence suggests that active HSV reproduction may also play a role.
  • Necrotizing stromal keratitis arises from direct infection of the corneal stroma and the resultant severe host inflammatory response.
  • ISK is an antibody-complement cascade triggered by a retained viral antigen within the stroma.
  • Endotheliitis is believed to be primarily an immunologic reaction to an antigen in endothelial cells; however, the role of live virus has been speculated.

More on Keratitis, Herpes Simplex

Overview: Keratitis, Herpes Simplex
Differential Diagnoses & Workup: Keratitis, Herpes Simplex
Treatment & Medication: Keratitis, Herpes Simplex
Follow-up: Keratitis, Herpes Simplex
Multimedia: Keratitis, Herpes Simplex
References
Further Reading

References

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  2. Jain V, Pineda R. Reactivated herpetic keratitis following laser in situ keratomileusis. J Cataract Refract Surg. May 2009;35(5):946-8. [Medline].

  3. Khalili MR, Mehdizadeh M, Mehryar M. Herpetic epithelial keratitis after intravitreal injection of bevacizumab (avastin). Cornea. Apr 2009;28(3):360-1. [Medline].

  4. Patel NN, Teng CC, Sperber LT, Dodick JM. New-onset herpes simplex virus keratitis after cataract surgery. Cornea. Jan 2009;28(1):108-10. [Medline].

  5. Hsiao CH, Yeung L, Yeh LK, et al. Pediatric herpes simplex virus keratitis. Cornea. Apr 2009;28(3):249-53. [Medline].

  6. Knickelbein JE, Hendricks RL, Charukamnoetkanok P. Management of herpes simplex virus stromal keratitis: an evidence-based review. Surv Ophthalmol. Mar-Apr 2009;54(2):226-34. [Medline].

  7. Guess S, Stone DU, Chodosh J. Evidence-based treatment of herpes simplex virus keratitis: a systematic review. Ocul Surf. Jul 2007;5(3):240-50. [Medline].

  8. 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. Oct 2007;144(4):547-51. [Medline].

  9. Spelsberg H, Reichelt JA. [Amniotic membrane transplantation in proven ulcerative herpetic keratitis: successful anti-inflammatory treatment in time]. Klin Monatsbl Augenheilkd. Jan 2008;225(1):75-9. [Medline].

  10. Garcia DD, Farjo Q, Musch DC, Sugar A. Effect of prophylactic oral acyclovir after penetrating keratoplasty for herpes simplex keratitis. Cornea. Sep 2007;26(8):930-4. [Medline].

  11. van Lint AL, Torres-Lopez E, Knipe DM. Immunization with a replication-defective herpes simplex virus 2 mutant reduces herpes simplex virus 1 infection and prevents ocular disease. Virology. Nov 25 2007;368(2):227-31. [Medline].

  12. Pepose JS, Keadle TL, Morrison LA. Ocular herpes simplex: changing epidemiology, emerging disease patterns, and the potential of vaccine prevention and therapy. Am J Ophthalmol. Mar 2006;141(3):547-557. [Medline].

  13. de Rojas Silva V, Rodriguez-Conde R, Cobo-Soriano R, Beltran J, Llovet F, Baviera J. Laser in situ keratomileusis in patients with a history of ocular herpes. J Cataract Refract Surg. Nov 2007;33(11):1855-9. [Medline].

  14. Shtein RM, Stahl RM, Saxe SJ, Mian SI. Herpes simplex keratitis after intravitreal triamcinolone acetonide. Cornea. Jun 2007;26(5):641-2. [Medline].

  15. Chong EM, Wilhelmus KR, Matoba AY, Jones DB, Coats DK, Paysse EA. Herpes simplex virus keratitis in children. Am J Ophthalmol. Sep 2004;138(3):474-5. [Medline].

  16. Ekatomatis P. Herpes simplex dendritic keratitis after treatment with latanoprost for primary open angle glaucoma. Br J Ophthalmol. Aug 2001;85(8):1008-9. [Medline].

  17. Gaynor BD, Margolis TP, Cunningham ET Jr. Advances in diagnosis and management of herpetic uveitis. Int Ophthalmol Clin. Spring 2000;40(2):85-109. [Medline].

  18. Herpetic Eye Disease Study Group. Oral acyclovir for herpes simplex virus eye disease: effect on prevention of epithelial keratitis and stromal keratitis. Herpetic Eye Disease Study Group. Arch Ophthalmol. Aug 2000;118(8):1030-6. [Medline].

  19. Herpetic Eye Disease Study Group. Acyclovir for the prevention of recurrent herpes simplex virus eye disease. Herpetic Eye Disease Study Group. N Engl J Med. Jul 30 1998;339(5):300-6. [Medline].

  20. Herpetic Eye Disease Study Group. Predictors of recurrent herpes simplex virus keratitis. Herpetic Eye Disease Study Group. Cornea. Mar 2001;20(2):123-8. [Medline].

  21. Holland EJ, Schwartz GS. Classification of herpes simplex virus keratitis. Cornea. Mar 1999;18(2):144-54. [Medline].

  22. Kaufman HE, Varnell ED, Thompson HW. Trifluridine, cidofovir, and penciclovir in the treatment of experimental herpetic keratitis. Arch Ophthalmol. Jun 1998;116(6):777-80. [Medline].

  23. Liesegang TJ. Classification of herpes simplex virus keratitis and anterior uveitis. Cornea. Mar 1999;18(2):127-43. [Medline].

  24. Liesegang TJ. Herpes simplex virus epidemiology and ocular importance. Cornea. Jan 2001;20(1):1-13. [Medline].

  25. Nesburn AB, Burke RL, Ghiasi H, Slanina SM, Wechsler SL. A therapeutic vaccine that reduces recurrent herpes simplex virus type 1 corneal disease. Invest Ophthalmol Vis Sci. Jun 1998;39(7):1163-70. [Medline].

  26. Remeijer L, Maertzdorf J, Doornenbal P, Verjans GM, Osterhaus AD. Herpes simplex virus 1 transmission through corneal transplantation. Lancet. Feb 10 2001;357(9254):442. [Medline].

  27. Rezende RA, Uchoa UB, Raber IM, Rapuano CJ, Laibson PR, Cohen EJ. New onset of herpes simplex virus epithelial keratitis after penetrating keratoplasty. Am J Ophthalmol. Mar 2004;137(3):415-9. [Medline].

  28. Romanowski EG, Bartels SP, Gordon YJ. Comparative antiviral efficacies of cidofovir, trifluridine, and acyclovir in the HSV-1 rabbit keratitis model. Invest Ophthalmol Vis Sci. Feb 1999;40(2):378-84. [Medline].

  29. Tambasco FP, Cohen EJ, Nguyen LH, Rapuano CJ, Laibson PR. Oral acyclovir after penetrating keratoplasty for herpes simplex keratitis. Arch Ophthalmol. Apr 1999;117(4):445-9. [Medline].

Keywords

herpes simplex keratitis, herpetic keratitis, herpes simplex virus keratitis, HSV keratitis, neurotrophic keratopathy, neurotrophic ulcer, metaherpetic ulcer, trophic ulcer, interstitial keratitis, stromal keratitis, disciform keratitis, keratouveitis, herpetic endotheliitis

Contributor Information and Disclosures

Author

Jim C Wang, MD, Cornea and Retina Subspecialist, Department of Ophthalmology, Kaiser Permanente Fontana Medical Center
Jim C Wang, MD is a member of the following medical societies: American Academy of Ophthalmology, American Society of Cataract and Refractive Surgery, and American Society of Retina Specialists
Disclosure: Nothing to disclose.

Coauthor(s)

David C Ritterband, MD, Assistant Director of Cornea and External Disease, Clinical Associate Professor, Department of Ophthalmology, New York Eye and Ear Infirmary, New York Medical College
David C Ritterband, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Ophthalmology, American College of Surgeons, and International Society of Refractive Surgery
Disclosure: Nothing to disclose.

Medical Editor

Jack L Wilson, PhD, Distinguished Professor, Department of Anatomy and Neurobiology, University of Tennessee at Memphis
Jack L Wilson, PhD is a member of the following medical societies: American Association of Anatomists, American Association of Clinical Anatomists, and American Heart Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Christopher J Rapuano, MD, Professor, Department of Ophthalmology, Jefferson Medical College of Thomas Jefferson University; Co-Chairman of the Cornea Service, Co-Chairman of Refractive Surgery Department, Wills Eye Institute
Christopher J Rapuano, MD is a member of the following medical societies: American Academy of Ophthalmology, American Society of Cataract and Refractive Surgery, Contact Lens Association of Ophthalmologists, Cornea Society, Eye Bank Association of America, International Society of Refractive Surgery, and Pan-American Association of Ophthalmology
Disclosure: Allergan Honoraria Speaking and teaching; Allergan Consulting fee Consulting; Alcon Honoraria Speaking and teaching; Inspire Honoraria Speaking and teaching; RPS Ownership interest Other; Vistakon Honoraria Speaking and teaching

CME Editor

Lance L Brown, OD, MD, Ophthalmologist, Affiliated With Freeman Hospital and St John's Hospital, Regional Eye Center, Joplin, Missouri
Disclosure: Nothing to disclose.

Chief Editor

Hampton Roy Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences
Hampton Roy Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, and Pan-American Association of Ophthalmology
Disclosure: Nothing to disclose.

 
 
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