3/4/2017 Herpes Simplex Keratitis: Practice Essentials, Pathophysiology, Etiology

Herpes Simplex Keratitis

Updated: Dec 15, 2016
Author: Jim C Wang (), MD; Chief Editor: Andrew A Dahl, MD, FACS more...

OVERVIEW

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.

http://emedicine.medscape.com/article/1194268-overview#showall 1/5
3/4/2017 Herpes Simplex Keratitis: Practice Essentials, Pathophysiology, Etiology

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 dbridement 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.

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

http://emedicine.medscape.com/article/1194268-overview#showall 2/5
3/4/2017 Herpes Simplex Keratitis: Practice Essentials, Pathophysiology, Etiology

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]

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.

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.)

http://emedicine.medscape.com/article/1194268-overview#showall 3/5
3/4/2017 Herpes Simplex Keratitis: Practice Essentials, Pathophysiology, Etiology

Herpes simplex virus dendritic ulcer stained with rose bengal.

View Media Gallery

Neurotrophic keratopathy.
View Media Gallery

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.

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
http://emedicine.medscape.com/article/1194268-overview#showall 4/5
3/4/2017 Herpes Simplex Keratitis: Practice Essentials, Pathophysiology, Etiology

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]

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.

Clinical Presentation

http://emedicine.medscape.com/article/1194268-overview#showall 5/5