OVERVIEW

In nearly all cases, the diagnosis of epithelial HK is made entirely on clinical grounds without the need for viral diagnostic testing. Even in academic centers HSV culture and advanced methods of viral detection are infrequently attempted, with such methods typically limited to complicated or atypical cases. Patient history and examination and, most importantly, the finding of an epithelial defect with the classic dendritic appearance on slit lamp examination, are typically sufficient to make the diagnosis. Most randomized, controlled trials that have evaluated antiviral therapy have likewise depended solely on clinical criteria for the HK diagnosis.1

REFERENCES

  1. Guess S, Stone DU, Chodosh J. Evidence-based treatment of herpes simplex virus keratitis: a systematic review. Ocul Surf. 2007;5:240-50.

CLINICAL PRESENTATION

Patients with HK typically present with the classic signs and symptoms of ocular infection, including unilateral tearing, photophobia, gritty or “foreign body” sensation, and/or visual changes.1,2,3 Patients may report ocular discomfort or pain. However, those with repeated recurrences may have reduced or absent corneal sensation due to damage to the terminal branches of the trigeminal nerve. Such patients may complain of mild discomfort, but little or no pain.4,5

In the experience of the panel, intraocular pressure (IOP) may be elevated, particularly if associated with comorbid iritis. Although unilateral in the great majority of cases, studies have found ocular HSV in both eyes in between 1% and 12% of cases, depending upon study criteria.6,7 Bilateral or prolonged HK suggests the presence of a comorbid condition such as atopy, immunodeficiency, or immunosuppression related to transplantation.6

REFERENCES

  1. Al-Dujaili LJ, Clerkin PP, Clement C, et al. Ocular herpes simplex virus: how are latency, reactivation, recurrent disease and therapy interrelated? Future Microbiol. 2011;6:877-907.
  2. Pavan-Langston D. Diagnosis and management of herpes simplex ocular infection. Int Ophthalmol Clin. 1975;15:19-35.
  3. Usatine RP, Tinitigan R. Nongenital herpes simplex virus. Am Fam Physician. 2010;82:1075-82.
  4. Guess S, Stone DU, Chodosh J. Evidence-based treatment of herpes simplex virus keratitis: a systematic review. Ocul Surf. 2007;5:240-50.
  5. Taylor PB, Tabbara KF. Peripheral corneal infections. Int Ophthalmol Clin. 1986;26:29-48.
  6. Liesegang TJ. Herpes simplex virus epidemiology and ocular importance. Cornea. 2001;20:1-13.
  7. Souza PM, Holland EJ, Huang AJ. Bilateral herpetic keratoconjunctivitis. Ophthalmology. 2003;110:493-6.

CLINICAL HISTORY

Because nonocular primary HSV infections are almost never recognized as such, most patients are diagnosed with HK at the time of their first or a recurrent ocular infection.1 In the experience of the panel, patients presenting with a first ocular occurrence are typically young adults, teenagers, or children. Patients with reactivation of latent ocular HSV infection may be able to recall prior ocular outbreaks characterized by similar symptoms.

In contrast, patients with primary ocular HSV infection or first ocular occurrence of a nonocular primary infection (eg, orolabial HSV infection) often have an unremarkable ocular and past medical history. Patients with reactivation of latent HSV may report antecedent ocular trauma or intense UV light exposure.2

REFERENCES

  1. Liesegang TJ. Herpes simplex virus epidemiology and ocular importance. Cornea. 2001;20:1-13.
  2. Toma HS, Murina AT, Areaux RG Jr, et al. Ocular HSV-1 latency, reactivation and recurrent disease. Semin Ophthalmol. 2008;23:249-273.

CLINICAL APPEARANCE

Most patients with their first episode of ocular HSV present with isolated keratitis. However, concomitant infection of adjacent tissues may be evident, therefore a careful examination of the periocular skin, regional lymph nodes, and conjunctiva is appropriate.1 Examination of patients with primary infection or first ocular infection may reveal active or recently healed HSV dermatoblepharitis, blepharoconjunctivitis, or, rarely, conjunctivitis alone.1,2,3 Dermatologic involvement—in the form of grouped vesicular or vesiculopustular eruption on the eyelid and adjacent skin—is common among patients with primary infection. Preauricular lymphadenopathy may also be present.4 Isolated dermatoblepharitis or conjunctivitis may resolve spontaneously, or may progress to keratitis, typically within 7 to 10 days.1

HSV conjunctivitis can produce a follicular reaction indistinguishable from mild forms of adenovirus conjunctivitis. However, unlike adenovirus, HSV conjunctivitis rarely forms pseudomembranes. The presence of dendrites on the conjunctiva—although not “classic” in appearance—can help confirm this diagnosis. With recurrence, conjunctivitis may occur without eyelid or corneal involvement; therefore HSV should be included in the differential diagnosis when patients present with follicular conjunctivitis alone.3

REFERENCES

  1. Dawson CR, Togni B. Herpes simplex eye infections: clinical manifestations, pathogenesis and management. M Surv Ophthalmol. 1976;21:1221-35.
  2. Uchio E. Takeuchi S, Itoh N, Matsuura N, Ohno S, Koki A. Clinical and epidemiological features of acute follicular conjunctivitis with special reference to that caused by herpes simplex virus type . Br J Ophthalmol. 2000;84:968-72.
  3. Kim T, Chang V. Part two: the clinical perspective: Advances in the management of ocular herpetic disease. Candeo Clinical/Science Communications. 2011:10-15.
  4. Guess S, Stone DU, Chodosh J. Evidence-based treatment of herpes simplex virus keratitis: a systematic review. Ocul Surf. 2007;5:240-50.

 
OPTIMAL USE OF CORNEAL STAINS
 

EPITHELIAL HERPETIC KERATITIS: KEY ASPECTS OF THE CLASSIC PRESENTATION

HSV IMAGES: EXTERNAL

CORNEAL APPEARANCE

Early in its course, prior to formation of a dendritic ulcer, HK may appear as small, raised corneal vesicles. Application of fluorescein stain aids in the visualization of the vesicles by pooling around their edges. Corneal vesicles are the ocular corollary to vesicles that appear on skin and mucous membranes in early dermatologic HSV eruptions.1 Punctate or linear epithelial ulceration may also precede the formation of a classic dendritic lesion.2

Prior to the formation of classic dendrites, thin branching lesions may give the appearance of pseudodendrites of VZV infection, which lack central ulceration or terminal bulbs.1,2 In time, pre-dendritic HSV lesions coalesce to form the classic dendritic appearance of HK, characterized by a branching shape and bulbous termini.1 Punctate satellite lesions or stellate lesions may also be observed.3

Fluorescein staining reveals damaged corneal epithelial cells at the ulcer base and edges.2 Rose bengal and lissamine green lightly stain the base, and help demonstrate the raised edges surrounding the ulcer that contain active HSV.4 A typical appearance of dendritic ulceration on slit lamp examination provides evidence of HK sufficient to warrant treatment.

REFERENCES

  1. Kim T, Chang V. Part two: the clinical perspective: Advances in the management of ocular herpetic disease. Candeo Clinical/Science Communications. 2011:10.
  2. Guess S, Stone DU, Chodosh J. Evidence-based treatment of herpes simplex virus keratitis: a systematic review. Ocul Surf. 2007;5:240-50.
  3. Dawson CR, Togni B. Herpes simplex eye infections: clinical manifestations, pathogenesis and management. Surv Ophthalmol. 1976;21:1221-35.
  4. Taylor PB, Tabbara KF. Peripheral corneal infections. Int Ophthalmol Clin. 1986. 26: 29-48.

HSV IMAGES: CORNEAL

STAINS

Topical instillation of water-soluble stains, such as fluorescein, rose bengal, and lissamine green B, aid in visualization of corneal and conjunctival defects and may be useful in the diagnosis of HK. Each of these agents has a unique chemical structure and set of properties that enables it to highlight distinct pathological features.1

Fluorescein is an orange dye that, when taken up by damaged epithelial cells and viewed under blue light, emits a bright green fluorescence. Fluorescein is used primarily to aid in the diagnosis of erosions, corneal abrasion, and keratitis. It may be applied to the cornea using fluorescein- impregnated filter paper or via 0.25% solution.1

Rose bengal solution may be used in the evaluation of dendritic herpetic keratitis, superficial punctate keratitis, and other conditions. Rose bengal stains damaged epithelial cells at the margins of HSV-induced dendritic ulcers bright red, but stains the ulcer base poorly. Recent research has shown that rose bengal has a cytotoxic effect on animal and human corneal cells. It has also been shown to inhibit growth of protozoa, bacteria, and viruses. For this reason, tissue specimens for viral cultures or PCR should be taken in advance of diagnostic staining with rose bengal. Some advocate the use of topical anesthetics before rose bengal to prevent the ocular irritation associated with this dye; others argue that this may contribute to false positive staining results.1

Lissamine green is a synthetic dye with a staining profile similar to that of rose bengal.1 Lissamine green stain is more easily seen over the white sclera than the black pupil so, like rose bengal, it is more helpful in visualizing conjunctival than corneal tissue. Lissamine green, however, has not demonstrated cytotoxicity to human cells and may be better tolerated by patients. Unlike rose bengal, lissamine green has not been shown to inhibit viral growth in vivo, although for reasons that are not known, it may interfere with HSV detection by PCR.1,2 Viral contact with materials present in collection swabs may also contribute to inaccurate testing results. In order to minimize false negative findings, it is recommended that clinical specimens being tested for HSV by PCR be collected before staining with either rose bengal or lissamine green, and that sampling be performed with a cotton-tipped swab rather than a calcium alginate swab.2

REFERENCES

  1. Kim J. The use of vital dyes in corneal disease. Curr Opin Ophthalmol. 2000;11:241-7.
  2. Seitzman GD, Cevallos V, Margolis TP. Rose bengal and lissamine green inhibit detection of herpes simplex virus by PCR. Am J Ophthalmol. 2006;141:756-8.

CONTINUE TO DIFFERENTIAL DIAGNOSIS

OVERVIEW

In the experience of the committee members, the differential diagnosis of HK includes healing abrasion, drug-related effects, and corneal infection caused by Acanthamoeba, fungal, bacterial, or other viral pathogens.1,2,3 The condition most clinically akin to herpetic keratitis, and the one with which it may be most easily confused, is varicella zoster virus (VZV) keratitis, which is associated with herpes zoster ophthalmicus.

REFERENCES

  1. Pavan-Langston D. Diagnosis and management of herpes simplex ocular infection. Int Ophthalmol Clin. 1975;15:19-35
  2. Taylor PB, Tabbara KF. Peripheral corneal infections. Int Ophthalmol Clin. 1986;26:29-48.
  3. Garg P. Fungal, mycobacterial, and nocardia infections and the eye: an update. Eye. 2012;26:245-51.

VZV

Varicella zoster virus (VZV) is the etiologic agent of both varicella (chickenpox) and its reactivation state, herpes zoster—or, more colloquially, “shingles.” Like HSV, VZV is a herpes virus that can establish latency in the trigeminal ganglion and reactivate along the ophthalmic branch of the trigeminal nerve to cause infectious keratitis. Unlike HSV, reactivation of VZV typically happens only once in life, in approximately 30% of adults.1,2 Prior to the introduction and widespread implementation of the varicella vaccine in 1995, nearly all children acquired infection with the highly contagious virus and developed chickenpox, a selflimited disease characterized by fever, malaise, and a diffuse vesicular rash.

Following recovery from primary infection, VZV establishes latency in sensory root ganglia, which is maintained by a strong T-cell-mediated immune response. In most individuals, VZV-specific immunity after natural infection is life-long, and the virus remains latent. However, in approximately 20% to 30% of individuals, latent VZV reactivates along one or more sensory dermatomes, causing shingles (related, it is thought, to waning T-cell immunity with advancing age).2

Unlike HSV, herpes zoster is characteristically more common and more severe with advancing age and among immunocompromised individuals. The varicella vaccine program has markedly altered the epidemiology of not only varicella, but also shingles. The incidence of shingles is increasing as the proportion of elderly individuals in the population expands; and it is also increasing among adults in the 40- to 50-year-old age range. This is thought to be a result of the near disappearance of childhood chickenpox since the vaccine was introduced—exposure to cases of chickenpox may have served as a physiologic “booster vaccine” to exposed mid-life adults.2

REFERENCES

  1. Pavan-Langston DR. Herpes Zoster: Antivirals and pain management. Ophthalmology. 2008;115:S13-20.
  2. Ta CN. The changing epidemiology of ocular shingles. Topics in Ocular Antiinfectives. 2011;16:5-7.

VZV KERATITIS

Herpes zoster ophthalmicus (HZO) results from VZV reactivation in the trigeminal ganglia and travels through the ophthalmic division of the fifth cranial nerve.1 HZO occurs in approximately 10% to 20% of individuals with shingles, making it the second most common anatomical site of VZV reactivation after the torso.1 HZO is typically associated with a painful, unilateral rash extending above and/or below the eye along the sensory dermatome. Over the course of several days to weeks, dermatologic lesions may evolve from maculopapular to vesiculopustular to crusted.1

Approximately 50% of HZO cases that do not get treatment within the first 72 hours of the appearance of the rash will develop ocular involvement.1 Corneal complications include punctate or pseudodendritic epithelial keratitis, stromal infiltrate, endotheliitis, and neurotrophic keratitis. HZO may be associated with significant morbidity, including visual loss.

REFERENCES

  1. Liesegang TJ. Herpes zoster ophthalmicus natural history, risk factors, clinical presentation, and morbidity. Ophthalmology. 2008;115(2 Suppl):S3-12.

KEY DIFFERENTIATORS

Because their pathophysiology, treatment, and prognosis are different, differentiating HSV from VZV ocular disease is important. In the clinical experience of the panel, ocular HSV tends to present in young to middle-aged individuals, whereas VZV is generally seen in older patients. Distinguishing characteristics of herpes zoster ophthalmicus (HZO) include a prodrome of fever, malaise, headache, or pain/tingling along the forehead or scalp; HZO may be accompanied by changes in affect, including moodiness, depression, and insomnia.1 The HZO rash is frequently associated with exquisite pain, and distribution along a sensory dermatome is unique to VZV. HZO affects the deep dermis, may cause periorbital edema and ptosis, and can result in permanent scarring. By contrast, HSV only affects the epidermis.1

Although rare among patients with HZO, VZV (like HSV) can cause significant keratitis in the absence of skin involvement.1 In such cases, a key to differentiation is the appearance of the fluorescein-stained corneal lesions. Both agents may cause punctate epithelial keratitis early in the infection, but in contrast to the true dendrites associated with HSV, VZV keratitis is characterized by pseudodendrites, which stain less intensely, are elevated, and appear as tapering lines without central ulceration or terminal bulbs.2

REFERENCES

  1. Liesegang TJ. Herpes zoster ophthalmicus natural history, risk factors, clinical presentation, and morbidity. Ophthalmology. 2008;115(2 Suppl):S3-12.
  2. Ta CN. The changing epidemiology of ocular shingles. Topics in Ocular Antiinfectives. 2011;16:5-7.

ACANTHAMOEBA

Acanthamoeba keratitis (AK) is a rare, severe, protozoan infection that may be mistaken for HK due to a similar dendritic pattern on the corneal epithelium early in the course of the disease. In the clinical experience of the committee, Acanthamoeba-induced lesions appear elevated and lack the terminal bulbs which help to distinguish HK lesions. Patients with AK commonly have a history of contact lens wear or trauma, and may complain of severe pain that seems disproportionate to physical findings.1

REFERENCES

  1. Joslin CE, Tu EY, Shoff ME, et al. The association of contact lens solution use and Acanthamoeba keratitis. Am J Ophthalmol. 2007;144:169-80.

VZV IMAGES: EXTERNAL

VZV IMAGES: CORNEAL

DENDRITES VS PSEUDODENDRITES

OTHER CONDITIONS

The differential diagnosis of HSV keratitis also includes infections caused by Epstein-Barr Virus (EBV), Cytomegalovirus (CMV), and a variety of bacterial and fungal pathogens. Ocular complications of CMV and EBV infection are not encountered with great frequency, even among cornea specialists. Like HSV and VZV, CMV and EBV are members of the herpes virus family, and both are globally endemic. In contrast to HSV, which persists in neuroganglia, CMV and EBV establish latency in white blood cells, such as T cells and monocytes.1 Ocular disease related to CMV most commonly occurs among immunodeficient individuals.1 However, CMV keratitis, predominantly endotheliitis, has been reported in immunocompetent persons as well.2 Systemic EBV infection may be associated with a wide range of ocular manifestations including epithelial keratitis.3

Non-infectious processes that may be mistaken for HSV keratitis include healing abrasions and drug-related toxicity. Healing corneal abrasions may have a dendritiform appearance. However, they do not demonstrate a classic, “tree-branching” pattern and lack terminal bulbs.

Patients on topical ophthalmic medication for the treatment of HSV infection or other conditions may develop keratitis medicamentosa which may be misdiagnosed as progressive or intercurrent HSV infection. 4 Medicamentosa is a toxic reaction to topical ophthalmic medication or a combination of medications and is characterized by redness and/or erosions of the conjunctiva and cornea that may range from mild to severe.5 When an allergic component is present, patients may also experience itching, swelling and redness of periorbital tissue; eosinophils may be present in affected tissue.4

REFERENCES

  1. Pavan-Langston D. Part one: the research perspective. Advances in the management of ocular herpetic disease. Candeo Clinical/Science Communications. 2011;1-9.
  2. Kandori M, Inoue T, Takamatsu F, et al. Prevalence and features of keratitis with quantitative polymerase chain reaction positive for cytomegalovirus. Ophthalmology. 2010;117:216-22.
  3. Matoba AY. Ocular disease associated with Epstein-Barr virus infection. Surv Ophthalmol. 1990;35(2):145-50.
  4. Pavan-Langston D. Diagnosis and management of herpes simplex ocular infection. Int Ophthalmol Clin. 1975;15:19-35.
  5. Stern GA, Killingsworth DW. Complications of topical antimicrobial agents. Int Ophthalmol Clin. 1989;29:137-42.


CONTINUE TO LABORATORY EVALUATION

LABORATORY EVALUATION

Herpetic keratitis is a clinical diagnosis. Under most circumstances, the observation of classic dendritic keratitis serves as the basis for initiation of treatment with topical antiviral therapy. However, multiple laboratory techniques are available to assist diagnosis under rare circumstances, such as complicated cases, neonatal cases, or cases in which a definitive diagnosis is necessary.1

REFERENCES

  1. Guess S, Stone DU, Chodosh J. Evidence-based treatment of herpes simplex virus keratitis: a systematic review. Ocul Surf. 2007;5:240-50.

DIRECT VISUALIZATION

Corneal specimens taken from the edge of the ulcer may be directly examined for evidence of HSV infection. Light microscopy may reveal the presence of multinucleated giant cells on Giemsa stain, and intranuclear (Cowdry type A) inclusions on Papanicolaou stain. Electron microscopy may reveal the presence of HSV particles in the nuclei of epithelial cells, and enveloped or mature viral particles in the cytoplasm.1,2

REFERENCES

  1. Taylor PB, Peripheral corneal infections. Int Ophthalmol Clin. 1986;26:29-48.
  2. Dawson CR, Herpes simplex eye infections: clinical manifestations, pathogenesis and management. Surv Ophthalmol. 1976;21:1221-35.

DNA DETECTION

PCR may be used to detect the presence of HSV DNA in clinical specimens that contain live or inactive virus. HSV PCR has been shown to be more sensitive than standard or accelerated cell culture.1,2 PCR may be used to establish the diagnosis in the face of a negative HSV culture, or as the primary definitive laboratory modality.1,2 PCR results are typically available within 24 to 48 hours when performed in an in-house facility, or within 3 to 5 days when an outside facility is used.2

REFERENCES

  1. Kowalski RP, Thompson PP, Cronin TH. Cell culture isolation can miss the laboratory diagnosis of HSV ocular infection.
  2. Thompson PP, Kowalski RP. A 13-year retrospective review of polymerase chain reaction testing for infectious agents from ocular samples. Ophthalmol. 2011;118:1449-53.

VIRAL CULTURE

HSV may be recovered from untreated dendritic ulcers by swabbing the ulcer with a soft-tipped applicator and inoculating it into 2.0 mL of viral transport medium or placing in a viral culturette.1 Current options for viral detection include cell culture, an enzyme-linked virusinducible system (ELVIS®), and polymerase chain reaction (PCR). Culture in cellular medium was traditionally considered the gold standard for HSV detection, since it indicates the presence or absence of active infection. However, false negative results are common, particularly among patients exposed to topical antiviral treatment or whose eyes have been stained with rose bengal or lissamine green.2,3

False negative results may also occur among untreated patients without such exposures, which may be a result of the body’s natural immune reaction to the infection or other factors that affect viral transfer and growth in vitro.4

When positive, cell cultures show zones of virus-induced cytopathology within 1 to 3 days of inoculation, though it may take up to 1 to 2 weeks on rare occasions.1 Due to potentially lengthy turnaround time, standard HSV culture is not useful for rapid clinical diagnosis. The ELVIS® HSV ID/Typing system is an accelerated version of standard virus culture, producing results within 24 hours of medium inoculation. It uses a specially engineered cell line that, when infected with HSV, induces the expression of the enzyme beta-galactosidase, which is detectible by staining. 1 Compared with various other methods of cell culture, ELVIS® has demonstrated a high degree of sensitivity and specificity of clinical HSV detection.5-9

REFERENCES

  1. Lab Diagnostic Testing: Herpes simplex virus. Available at: http:// eyemicrobiology.upmc.com/Herpes.htm accessed on August 23, 2012.
  2. Taylor PB, Tabbara KF. Peripheral corneal infections. Int Ophthalmol Clin. 1986;26:29-48.
  3. Seitzman GD, Cevallos V, Margolis TP. Rose bengal and lissamine green inhibit detection of herpes simplex virus by PCR. Am J Ophthalmol. 2006;141:756-8.
  4. Kowalski RP, Thompson PP, Cronin TH. Cell culture isolation can miss the laboratory diagnosis of HSV ocular infection.
  5. Stabell EC, O’Rourke SR, Storch GA, Olivo PD. Evaluation of a genetically engineered cell line and a histochemical beta-galactisidase assay to detect herpes simplex virus in clinical specimens.
  6. Patel N, Kauffmann L, Baniewicz G, Forman M, Evans M, Scholl D. Confirmation of low-titer, herpes simplex virus-positive specimen results by the enzyme-linked virus-inducible system (ELVIS) using PCR and repeat testing.
  7. Turchek BM, Huang YT. Evaluation of ELVIS HSV ID/typing system for the detection and typing of herpes simplex virus from clinical specimens. J Clin Virol. 1999;12:65-9.
  8. LaRocco MT. Evaluation of an enzyme-linked viral inducible system for the rapid detection of herpes simplex virus. Eur J Clin Microbial Infect Dis. 2000;19:233-5.
  9. Crist GA, Langer JM, Woods GL, Procter M, Hillyard DR. Evaluation of the ELVIS plate method for the detection and typing of herpes simplex virus in clinical specimens. Diagnos Microbiol Infect Dis. 2004;49:173-7.

CONTINUE TO TREATMENT

 

Legal Notice
US/ZGN/13/0010
©2014 Bausch & Lomb Incorporated