VIRAL KERATITIS

Herpes Simplex Keratitis

DEFINITION
Keratitis is a general term to describe inflammation of cornea, the outermost part of the
eye that covers the pupil and iris (the colored ring around the pupil). Viral keratitis is a corneal
inflammation that caused by virus infection.

ETIOLOGY
Herpes simplex keratitis is caused by herpes simplex virus type I (HSV1), a double
stranded DNA virus made up of an icosahedral shaped capsid surrounding a core of DNA and
phosphoproteins of viral chromatin. HSV I and HSV II are differentiated by virus specific
antigens. HSV I typically affects the oropharynx region while HSV II usually involves the
genital area, though studies shown that both viruses may affect either location.
HSV I is presumed to gain access to the cornea via direct contact or via the trigeminal
nerve from oral infection. Initial infection typically remains asymptomatic. The virus then travels
via sensory nerve axons to establish latent infection, in ocular disease this usually involves the
trigeminal ganglion. After the original infection, the virus lies in a dormant state, living in nerve
cells of the skin or eye usually along any branch of trigeminal ganglion especially during
immunocompromised states. Reactivation can also be triggered in number of other ways
including stress, sun exposure, fever, trauma, menstruation and certain medications.
Once herpes simplex is present in the eye, it typically infects the eyelids, conjunctiva and
cornea. It may also infect the inside of the eye, however this is much less common.

RISK FACTOR
Risk factors for development of primary HSV involve direct contact with infected
lesions, but also may result as exposure to asymptomatic viral shedding in saliva. Risk factors for
reactivation of disease have been postulated to include sunlight, trauma, heat, menstruation,
stress, infectious disease and immunocompromised states.

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SIGNS
They typically present as conjunctivitis that can involve inflammation of the eyelids,
marked by inflammatory vesicles and ulcers, and can include dendritic lesions in the corneal
epithelium. The lesions start as punctuate vesicular eruptions in the corneal epithelium, but
quickly coalesce into dendritic shaped lesions. The lesions can progress to enlarged non-linear
lesions referred to as geographic lesions. These lesions can be distinguished from the
neurotrophic keratopathy that can develop in patients with recurrent herpes infectious epithelial
keratitis by virtue of the swollen epithelial cells and scalloped borders at the margins of herpetic
lesions. Therefore, the apparent diagnostic features for Herpes Simplex Keratitis are the dendritic
appearance which possess terminal bulbs and follows the nerve pattern throughout the cornea,
also the long course with the tendency to recurrence. The ulcer is superficial and never perforate.
HSK never become vascularized and the affected part may hyposthesia.

SYMPTOMS
The symptoms of keratitis usually include pain, tearing, redness, and blurring of vision.
The pain may be mild to severe, depending on the cause and extent of the inflammation.
Sensitivity to light may also be present. The feeling of something in the eye and having excess
tears from the eye might also be disturbing to the patient. To the observer, the eye may appear
red and watery; and if the cornea has extensive keratitis, the normally clear cornea may look gray
or have white to gray areas.

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DIAGNOSTIC PROCEDURES
The diagnosis of HSV is often made clinically, however, laboratory tests are available to
confirm the diagnosis in difficult cases (and in all cases of neonatal herpetic infection). Serologic
testing may be performed but is usually not helpful in recurrent disease as most adults are
laterally infected with HSV. However, conjunctival scrapings, impression cytology specimens
and scrapings from vesicular lesions on the skin may be tested by cytology, culture, or
polymerase chain reaction (PCR) for the presence of HSV.

Clinical diagnosis
The clinical diagnosis of HSV may be suggested by the presence of the multiple
arborizing dendritic epithelial ulcers with terminal bulbs. The bed of the ulcer stains with
fluorescein, while the swollen corneal epithelium at the edge of the ulcer typically stains with
rose bengal. Several dendrites may also coalesce to form a geographic epithelial ulcer. In
addition, there may be mild conjunctival injection, ciliary flush, mild stromal edema and
subpeithelial white blood cell infiltration. Following resolution of the primary infection, a "ghost
dendrite" may be visible just beneath the prior area of epithelial ulceration.

Laboratory test
Specimen Collection
Specimens are directly collected by vigorously swiping the exposed conjunctiva with a
plastic soft-tipped applicator. Cornea samples using soft-tipped applicators and spatulas can also
be obtained to maximize the yield of viable HSV and antigen. Topical anesthetic can be applied
to the conjunctiva and should be applied to the cornea. Collected samples are placed in 2.0 ml of
viral transport medium. Viral culturettes can also be used for transportation to the laboratory and
these can be transferred to the viral medium. All laboratory testing can be processed from the 2.0
ml of chlamydial transport medium. HSV can be fastidious and should be transported to the
laboratory without unnecessary delay.

PCR
PCR is performed for HSV (1 or 2) on specimens collected by soft-tipped applicators,
metal spatulas, or jeweler's forceps, and placed in 2.0ml of chlamydia transport medium.
Intraocular fluid or vitrectomy specimen can be supplied directly or increased to a volume of 0.4
ml with chlamydia transport medium. 0.4 ml of the medium is supplied for PCR testing.

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AmpliVue HSV 1+2 Assay

AmpliVue HSV 1+2 Assay (Quidel) is a rapid colorimetric test for the qualitative
detection and differentiation of Herpes simplex virus (HSV-1 and HSV-2) nucleic acids.
Specimens are collected the same as for PCR- by soft-tipped applicators, metal spatulas, or
jeweler's forceps, and placed in 2.0ml of chlamydia transport medium. 20 ul of transport media is
used for the test, which can usually be completed within one hour and ten minutes.

Cell Culture

The "gold" standard for HSV laboratory testing is cell culture. Collected samples are
layered on a monolayer of cells in test tubes. If present, HSV will present as cytopathic effect of
rounded cells. We have use A549 cells as the cell-line for testing HSV. This is a human
carcinoma continuous cell-line. When samples are positive for HSV, cytopathic effect is
generally present within one to three days. It is rare, but sometimes one to two weeks is
necessary to isolate HSV in cell culture. Cell culture will confirm an HSV diagnosis but it may
not provide timely results for immediate patient care. All virology laboratories can offer cell
culture isolation for HSV.

( HSV CELL CULTURE )

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ELVIS

ELVIS (Enzyme Linked Viral Induced System) is another cell culture test but the
results are ready in ONE day. Cells infected with HSV commence a cascade of reactions that
results in the accumulation of beta-galactosidase in the cells. Viral samples are layered on the
specially engineered cell line in a shell vial and centrifuged. The vial is incubated for one day
(overnight), fixed, and stained with a substrate that reacts with the beta-galactosidase. The
reactions result in a blue-color change in the cells that are observed with an inverted microscope.
ELVIS testing may also be limited in its availability.

( ELVIS HSV CULTURE )

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DIFFERENTIAL DIAGNOSIS
The differential diagnosis of HSV epithelial keratitis includes other infectious keratitis, in
particular Acanthamoeba keratitis, varicella zoster virus epithelial keraititis, Epstein-Barr virus
epithelial keratitis, adenovirus epithelial keratitis, Chlamydia epithelial keratitis, and other
bacterial epithelial keratitis when the stroma is not yet involved. Noninfectious causes of
dendritiform and/or geographic epithelial ulcerations include epithelial regeneration lines after
abrasion, or in neurotrophic keratopathy, recurrent epithelial erosion, persistent epithelial defect,
exposure keratopathy, Thygesons superficial punctuate keratitis, limbal stem cell failure, cornea
verticillata from amiodarone deposition and Fabrys disease, tyrosinemia, and epithelial lesions
from topical beta-blockers. Neurothropic keratopathy and persistent epithelial defect can also be
consequences of recurrent and/or severe HSV keratitis.
The differential diagnosis of HSV stromal keratitis without ulceration includes any cause
of interstitial keratitis, including syphilis, Cogans syndrome, varicella zoster virus keratitis,
Epstein-Barr virus keratitis, measles keratitis, mumps keratitis, Lyme disease, and others.
The differential diagnosis of HSV stromal keratitis with ulceration includes all forms of
microbial keratitis , including from infection by bacteria, fungi, and Acanthamoeba, varicella
keratopathy, and neurothropic keratopathy.

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TREATMENT

Treatment of HSV is diametrically different for epithelial and stromal keratitis, reflecting
the fact that epithelial disease is caused by live replicating virus while stromal disease is
essentially an immune response to viral antigen. Prompt and appropriate treatment may minimize
the risk of scarring, the major cause of morbidity from HSVK.

Infectious epithelial keratitis

Though epithelial keratitis spontaneously resolves in approximately 50% of cases,
treatment is advised for ulcers larger than 4 mm, marginal ulcers, and ulcers with underlying
stromal in ammation. Topical antivirals, the mainstay of treatment, are very effective and have a
low incidence of resistance. Gentle wiping debridement is a very good adjunct therapy as
infected cells are poorly adherent. This results in much faster resolution, less in ammation, and
consequently less scarring.

Stromal keratouveitis
The mainstay of treatment is topical corticosteroids as they decrease inflammation and,
therefore, scarring. Simultaneous antiviral prophylaxis is recommended, as evidence suggests
that HSV reactivation while on corticosteroids results in severe epithelial disease or necrotizing
keratitis. Oral antivirals are preferred as they decrease the risk of HSV reactivation at the
ganglion level and do not have the corneal toxicity associated with topical antivirals. Aggressive
topical and systemic antivirals along with corticosteroids are necessary in necrotizing keratitis
and focal serous iritis.

Metaherpetic keratitis
The basic principle is surface support including elimination of toxic medications, punctal
occlusion, artificial tear supplements, bandage contact lenses, autologous serum tears, and
amniotic membrane grafts. The cautious use of topical corticosteroids may be necessary if there
is significant underlying inflammation.

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MEDICATIONS

Antivirals
All current antivirals are nucleoside analogs that competitively inhibit viral DNA
polymerase (Table). They may also interfere with host DNA synthesis and cause significant
toxicity. Acyclovir and ganciclovir are the most specific for viral polymerase and thymidine
kinase and, therefore, are the least toxic.

Corticosteroids
Typically, 1% prednisolone acetate or 0.1% dexamethasone is used. The frequency should
be based on the severity of inflammation and tapering must be very gradual to prevent rebound
inflammation.

Surgery
Surgery is usually performed when corneal scarring limits vision. However, surgery also
may be necessary as a therapeutic measure in patients with nonhealing ulcers or impending
perforations from necrotizing keratitis.

Penetrating keratoplasty (PKP)

It is preferable to wait at least 6 months after an episode of HSVK before attempting
corneal transplantation as the success rate increases in a quiescent eye. Unfortunately, the results
of corneal transplantation for HSVK are uniformly poor. Reactivation and rejection occur in 44%
and 46%, respectively, by two years. Prophylactic acyclovir started prior to surgery and
continued for at least 6 months decreases the risk of failure. Lamellar grafts are not
recommended as recurrence occurs at the interface.

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Conjunctival flap
This may be useful in patients with medical contraindications for surgery or chronically
inflamed keratitis. Ambulatory vision is possible through the flap.

Amniotic membrane (AMT)

AMT aids the healing of neurotrophic ulcers in HSVK, presumably by decreasing in
ammatory cell and matrix metalloproteinase levels in the cornea.

FUTURE DIRECTIONS

Heat shock and glycoprotein subunit vaccines have shown some promise in clinical trials in
decreasing the number and severity of recurrences. Immunomodulatory factors such as cytokines
may serve as adjuncts to corticosteroid therapy by skewing the immune response towards milder
disease. Newer antivirals such as topical ganciclovir, recently approved in the United States, and
cidofovir may be more effective and cause less toxicity compared to current therapy. Interferon,
while ineffective as monotherapy, increases the eficacy of antivirals, and other agents such as
nerve growth factor and apolipoprotein E mimetic peptide have shown a benefit in animal
models of HSVK. Gene therapy may prove to be useful in the future, ribozymes and small
interfering RNAs have shown promise in cell culture experiments, but their instability in vivo
has been a barrier to clinical use.

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COMPLICATIONS
Potential complication of HSV keratitis include adverse reaction to aciclovir: topical
aciclovir needs to be applied frequently and can give rise to significant local irritation. Oral
aciclovir comes with a long list of possible side-effects, including gastrointestinal disturbances,
dermatological problems, headache, fatigue and a myriad of rare but more serious side-effects.
Recurrence of HSV keratitis is of 20% by two years, 40% by five years and 67% by seven years,
with increasing risk after each episode. Corneal complications of herpetic eye disease range from
epitheliopathy to frank neurotrophic or metaherptic ulcers. Long standing disciform keratitis may
also result in bullous keratopathy. Late complications of deep vascular stromal scarring include
secondary lipid keratopathy. Finally, stromal inflammation may lead to visually significant
corneal scarring, visual impairment and irregular astigmatism. Other more rare complications
may also occur such as corneal perforation, secondary glaucoma, systemic disease in the
immunocompromised individual.

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.

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REFERENCES

https://www.aao.org/eye-health/diseases/herpes-keratitis

https://en.wikipedia.org/wiki/Herpes_simplex_virus

http://eyewiki.org/Herpes_Simplex_Virus_Keratitis

https://www.aao.org/eye-health/diseases/herpes-keratitis-cause

http://www.mayoclinic.org/diseases-conditions/keratitis/basics/complications/con-20035288

http://eyewiki.org/Herpes_Simplex_Virus_Keratitis#Complications

http://www.medicinenet.com/keratitis/page3.htm

http://www.mayoclinic.org/diseases-conditions/keratitis/basics/symptoms/con-20035288

http://www.alpfmedical.info/visual-acuity/viral-keratitis.html

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3529813

http://patient.info/doctor/herpes-simplex-eye-infections

https://www.google.com.eg/url?sa=t&rct=j&q=&esrc=s&source=web&cd=2&cad=rja&uact=8
&ved=0ahUKEwjcqZ2w96fRAhXJzRQKHaXiBd8QFgghMAE&url=https%3A%2F%2Fwww.
aao.org%2FAssets%2F6564936e-9929-48b6-93cd-
15872a1b388e%2F635732518522630000%2Fhsv-keratitis-treatment-guideline-harvard-
pdf&usg=AFQjCNHjHrGtb4JEAC8-
XJ0sKVB2ym6qYA&sig2=aP6ulN15tPf2jk9zkWDtPQ&bvm=bv.142059868,d.d24

Ophthalmology, fourth edition - Myron Yanoff & S. Duker

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