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Herpes Simplex Keratitis

  • Author: Jim C Wang (王崇安), MD; Chief Editor: Hampton Roy, Sr, MD  more...
 
Updated: Dec 07, 2015
 

Practice Essentials

Herpes simplex virus (HSV) keratitis is the most frequent cause of corneal blindness in the United States and the most common source of infectious blindness in the Western world. The prognosis in HSV keratitis, however, is generally favorable with aggressive treatment.

Signs and symptoms

Patients with HSV keratitis may complain of the following:

  • Pain
  • Photophobia
  • Blurred vision
  • Tearing
  • Redness

The earliest sign of active viral replication in the corneal epithelium is the development of small, raised, clear vesicles.

Dendritic ulcers are the most common presentation of HSV keratitis. Prominent features of a dendritic ulcer include a linear branching pattern with terminal bulbs, swollen epithelial borders, and central ulceration through the basement membrane.

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.

Necrotizing stromal keratitis is characterized by dense stromal infiltrate, ulceration, and necrosis. Immune stromal keratitis (ISK) may present clinically with focal, multifocal, or diffuse cellular infiltrates; immune rings; neovascularization; or ghost vessels at any level of the cornea.

Clinical signs of endotheliitis include keratic precipitates (KP), overlying stromal and epithelial edema, and absence of stromal infiltrate or neovascularization. A mild to moderate iritis is frequently seen. Patients present with pain, photophobia, and injection.

See Clinical Presentation for more detail.

Diagnosis

HSV keratitis remains primarily a clinical diagnosis based on characteristic features of the corneal lesion.[1] If the diagnosis is in doubt, however, laboratory diagnosis can be made using the following[2] :

  • Giemsa stain - Scrapings of the corneal or skin lesions show multinucleated giant cells
  • Papanicolaou stain - This shows intranuclear eosinophilic inclusion bodies
  • Viral culture
  • Immunohistochemistry looking for viral antigens
  • Polymerase chain reaction (PCR) assay [3]

See Workup for more detail.

Management

Since most cases of HSV epithelial keratitis resolve spontaneously within 3 weeks, the rationale for treatment is to minimize stromal damage and scarring. Gentle epithelial débridement may be performed to remove infectious virus and viral antigens that may induce stromal keratitis. Antiviral therapy, topical or oral, is an effective treatment for epithelial herpes infection.[4]

See Treatment and Medication for more detail.

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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.[5]

Recurrence

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.[6, 7, 8]

HSV reactivation with the use of latanoprost has been reported in patients with glaucoma. HSV reactivation has also been associated with the use of systemic, local, and topical steroid medications, including intravitreal triamcinolone injection.[9]

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Etiology

Causes of the various manifestations of HSV keratitis include the following:

  • Infectious epithelial keratitis - Results from active viral replication within the corneal epithelium
  • Neurotrophic keratopathy - A poorly understood disease; the cause is thought to be multifactorial
  • Necrotizing stromal keratitis - Arises from direct infection of the corneal stroma and the resultant severe host inflammatory response ; the use of topical corticosteroids without antiviral coverage may be a possible risk factor for its development
  • Immune stromal keratitis - An antibody-complement cascade triggered by retained viral antigen or altered host antigen within the stroma
  • Endotheliitis - Believed to be primarily an immunologic reaction to an antigen in endothelial cells; however, the role of live virus has been speculated

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 (as a result of prior HSV infection of the sensory nerves), exacerbated by long-term use of topical medications, especially antiviral agents. However, evidence suggests that HSV replication may occur in persistent epithelial defects.

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Background

Herpes simplex virus (HSV) keratitis encompasses a variety of disease processes that HSV can cause in the human cornea. 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 (see the images below). (See Pathophysiology, Etiology, and Presentation.)

Herpes simplex virus dendritic ulcer stained with Herpes simplex virus dendritic ulcer stained with rose bengal.
Neurotrophic keratopathy. Neurotrophic keratopathy.

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

Patient education

For patient education information, see the Eye and Vision Center, as well as Corneal Ulcer.

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Epidemiology

Occurrence in the United States

Of adults in the United States, 50-90% have antibodies to HSV-1, indicating previous exposure to the virus. Incidence of ocular HSV infection is about 0.15%.[10]

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

International occurrence

HSV infection is ubiquitous, with an estimated one third of the population worldwide suffering from recurrent infections.[11]

Sex- and age-related demographics

Herpes simplex has a slightly higher male predominance. Most HSV eye disease occurs in adults, developing many years after the primary infection (mean age of presentation, late fifth to early sixth decade of life). Herpetic keratitis in children commonly involves the corneal epithelium and stroma and is marked by a disproportionate risk of bilateral disease, high recurrence rate, and amblyopia.[12, 13]

 

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Prognosis

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

The prognosis in HSV keratitis is generally favorable with aggressive treatment. Even with proper therapy, however, corneal scarring can occur. If the scarring develops centrally, visual acuity can be lost.

Stromal keratitis

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.

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Contributor Information and Disclosures
Author

Jim C Wang (王崇安), MD Vitreo-Retinal and Cornea/Anterior Segment Subspecialist, Department of Ophthalmology, Kaiser Permanente Fontana Medical Center

Jim C Wang (王崇安), MD is a member of the following medical societies: American Academy of Ophthalmology, American Society of Retina Specialists, American Society of Cataract and Refractive Surgery

Disclosure: Nothing to disclose.

Coauthor(s)

David C Ritterband, MD, FACS Assistant Director of Cornea Service, New York Eye and Ear Infirmary; Clinical Professor of Ophthalmology, Icahn School of Medicine at Mount Sinai

David C Ritterband, MD, FACS is a member of the following medical societies: Alpha Omega Alpha, Association for Research in Vision and Ophthalmology, American Academy of Ophthalmology, American College of Surgeons, International Society of Refractive Surgery

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, Pan-American Association of Ophthalmology

Disclosure: Nothing to disclose.

Acknowledgements

Kerry Assil, MD Medical Director and CEO, The Sinskey Eye Institute

Kerry Assil, MD is a member of the following medical societies: American Academy of Ophthalmology, American Medical Association, Association for Research in Vision and Ophthalmology, and Contact Lens Association of Ophthalmologists

Disclosure: Nothing to disclose.

Kilbourn Gordon III, MD, FACEP Urgent Care Physician

Kilbourn Gordon III, MD, FACEP is a member of the following medical societies: American Academy of Ophthalmology and Wilderness Medical Society

Disclosure: Nothing to disclose.

Robert H Graham, MD Consultant, Department of Ophthalmology, Mayo Clinic, Scottsdale, Arizona

Robert H Graham, MD is a member of the following medical societies: American Academy of Ophthalmology, American Medical Association, and Arizona Ophthalmological Society

Disclosure: Medscape/WebMD Salary Employment

Anisha Judge, MD Consulting Staff, Department of Ophthalmology, Kaiser Permanente at West Los Angeles Medical Center

Disclosure: Nothing to disclose.

Simon K Law, MD, PharmD Clinical Professor of Health Sciences, Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, David Geffen School of Medicine

Simon K Law, MD, PharmD is a member of the following medical societies: American Academy of Ophthalmology, American Glaucoma Society, and Association for Research in Vision and Ophthalmology

Disclosure: Nothing to disclose.

Christopher J Rapuano, MD Professor, Department of Ophthalmology, Jefferson Medical College of Thomas Jefferson University; Director of the Cornea Service, Co-Director 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, and International Society of Refractive Surgery

Disclosure: Allergan Honoraria Speaking and teaching; Allergan Consulting fee Consulting; Alcon Honoraria Speaking and teaching; RPS Ownership interest Other; Bausch & Lomb Honoraria Speaking and teaching; Merck Consulting fee Consulting; Bausch & Lomb Consulting; Merck Honoraria Speaking and teaching

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Jack L Wilson, PhD Distinguished Professor, Department of Anatomy and Neurobiology, University of Tennessee Health Science Center College of Medicine

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.

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Herpes simplex virus dendritic ulcer stained with rose bengal.
Herpes simplex virus dendritic ulcer stained with fluorescein.
Large paracentral herpes simplex virus dendritic ulcer.
Recurrent herpes simplex virus dendritic ulcer with an adjacent stromal scar.
Healing herpes simplex virus dendritic ulcer.
Herpes simplex virus geographic ulcer.
Neurotrophic keratopathy.
Large neurotrophic ulcer.
Active immune stromal keratitis.
Inactive immune stromal keratitis.
Disciform endotheliitis with secondary stromal ulceration.
 
 
 
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