Herpes Simplex Keratitis
- Author: Jim C Wang (王崇安), MD; Chief Editor: Hampton Roy, Sr, MD more...
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:
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.
HSV keratitis remains primarily a clinical diagnosis based on characteristic features of the corneal lesion. If the diagnosis is in doubt, however, laboratory diagnosis can be made using the following :
Giemsa stain - Scrapings of the corneal or skin lesions show multinucleated giant cells
Papanicolaou stain - This shows intranuclear eosinophilic inclusion bodies
Immunohistochemistry looking for viral antigens
Polymerase chain reaction (PCR) assay 
See Workup for more detail.
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.
See Treatment and Medication for more detail.
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.
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.
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.
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.)
Although more common as a manifestation of recurrent HSV infection, HSV keratitis may also be seen during a primary infection. (See Workup.)
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%.
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.
HSV infection is ubiquitous, with an estimated one third of the population worldwide suffering from recurrent infections.
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]
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.
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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