2. Herpes SimplexHerpes Simplex
-Background-Background::
Herpes simplex virus (HSV) keratitis encompasses a variety of diseaseHerpes simplex virus (HSV) keratitis encompasses a variety of disease
processes that HSV can cause in the human cornea.processes that HSV can cause in the human cornea.
A variety of clinical manifestations of both infectious disease andA variety of clinical manifestations of both infectious disease and
immunologic disease, such asimmunologic disease, such as
infectious epithelial keratitis,infectious epithelial keratitis,
neurotrophic keratopathy,neurotrophic keratopathy,
necrotizing stromal keratitis,necrotizing stromal keratitis,
immune stromal keratitis (ISK),immune stromal keratitis (ISK),
endotheliitis, can affect all levels of the cornea.endotheliitis, can affect all levels of the cornea.
3. PathophysiologyPathophysiology
Primary HSV-1 infectionPrimary HSV-1 infection occurs most commonly in the mucocutaneousoccurs most commonly in the mucocutaneous
distribution of the trigeminal nerve.distribution of the trigeminal nerve.
After the primary infection, the virus spreads from the infected epithelialAfter the primary infection, the virus spreads from the infected epithelial
cells to nearby sensory nerve endings and is transported along the nervecells to nearby sensory nerve endings and is transported along the nerve
axon to the cell body located in the trigeminal ganglion.axon to the cell body located in the trigeminal ganglion.
The virus genome enters the nucleus of a neuron, where it persistsThe virus genome enters the nucleus of a neuron, where it persists
indefinitely in a latent state.indefinitely in a latent state.
4. Recurrent HSV infectionRecurrent HSV infection
Traditionally has been thought of as reactivation of virus in theTraditionally has been thought of as reactivation of virus in the
sensory ganglion, which migrates down the nerve axon to produce asensory ganglion, which migrates down the nerve axon to produce a
lytic infection in ocular tissue.lytic infection in ocular tissue.
Recent evidence suggests that the virus may subsist latently withinRecent evidence suggests that the virus may subsist latently within
corneal tissue, serving as a potential source of recurrent diseasecorneal tissue, serving as a potential source of recurrent disease
and also donor-derived HSV in transplanted corneasand also donor-derived HSV in transplanted corneas
5. FrequencyFrequency::
In the US:In the US:
Approximately 20,000 new cases of ocular HSV occur in the United StatesApproximately 20,000 new cases of ocular HSV occur in the United States
annually, and more than 28,000 reactivations occur in the United Statesannually, and more than 28,000 reactivations occur in the United States
annually.annually.
Of the US population, a history of external ocular HSV infection is present inOf the US population, a history of external ocular HSV infection is present in
0.15%. HSV keratitis is one of the most frequent causes of corneal0.15%. HSV keratitis is one of the most frequent causes of corneal
blindness in the United States with 500,000 people experiencing HSV-blindness in the United States with 500,000 people experiencing HSV-
related ocular disease.related ocular disease.
Mortality/Morbidity:Mortality/Morbidity: HSV keratitis is one of the most frequent causesHSV keratitis is one of the most frequent causes
of corneal blindness in the United States and a leading indication for cornealof corneal blindness in the United States and a leading indication for corneal
transplantation.transplantation.
Age:Age: Most HSV recurrent eye disease occurs in adults. However, herpeticMost HSV recurrent eye disease occurs in adults. However, herpetic
keratitis in children almost always involves the corneal epithelium and iskeratitis in children almost always involves the corneal epithelium and is
marked by a disproportionate risk of binocular disease, a high recurrencemarked by a disproportionate risk of binocular disease, a high recurrence
rate, and amblyopia as a complication.rate, and amblyopia as a complication.
6. CLINICALCLINICAL
History:History:
Patients with HSV keratitis may complain of the following:Patients with HSV keratitis may complain of the following:
PainPain
PhotophobiaPhotophobia
Blurred visionBlurred vision
TearingTearing
RednessRedness
A history of prior episodes in patients with recurrentA history of prior episodes in patients with recurrent
disease may exist.disease may exist.
7. PhysicalPhysical::
HSV keratitis may be divided into 4 categoriesHSV keratitis may be divided into 4 categories::
Infectious epithelial keratitisInfectious epithelial keratitis
Neurotrophic keratopathyNeurotrophic keratopathy
Stromal keratitisStromal keratitis
EndotheliitisEndotheliitis
9. Neurotrophic keratopathyNeurotrophic keratopathy
The earliest signs of neurotrophic
keratopathy include an irregular corneal
surface and punctate epithelial erosions.
In contrast to the irregular shape and
scalloped borders of an infectious
geographic ulcer, a neurotrophic ulcer
is typically oval with smooth borders and
often lies within the interpalpebral fissures.
10. Corneal stromal inflammationCorneal stromal inflammation
Necrotizing stromal keratitis,
characterized by dense stromal infiltrate,
ulceration, and necrosis
ISK may present clinically with focal,
multifocal, or diffuse cellular infiltrates;
immune rings; neovascularization; or
ghost vessels at any level of the cornea.
11. EndotheliitisEndotheliitis
Clinical signs of endotheliitis include
keratic precipitates (KP), overlying stromal
and epithelial edema, and absence of
stroma infiltrate or neovascularization.
A mild-to-moderate iritis is frequently seen.
-Disciform
-Diffuse
-Linear
12. CausesCauses
Infectious epithelial keratitisInfectious epithelial keratitis results from active viral replicationresults from active viral replication
within the corneal epithelium.within the corneal epithelium.
Neurotrophic keratopathyNeurotrophic keratopathy results mainly from decreased cornealresults mainly from decreased corneal
innervation and tear secretion as a result of a prior HSV infection ofinnervation and tear secretion as a result of a prior HSV infection of
the sensory nerves.the sensory nerves.
Necrotizing stromal keratitisNecrotizing stromal keratitis arises from direct infection of thearises from direct infection of the
corneal stroma and the resultant severe host inflammatorycorneal stroma and the resultant severe host inflammatory
response.response.
ISKISK is an antibody-complement cascade triggered by retained viralis an antibody-complement cascade triggered by retained viral
antigen within the stroma.antigen within the stroma.
EndotheliitisEndotheliitis is believed to be primarily an immunologic reaction tois believed to be primarily an immunologic reaction to
an antigen in endothelial cells; however, the role of live virus hasan antigen in endothelial cells; however, the role of live virus has
been speculated.been speculated.
13. WORKUPWORKUP
Lab StudiesLab Studies::
HSV keratitis is primarily a clinical diagnosis based on characteristicHSV keratitis is primarily a clinical diagnosis based on characteristic
features of the corneal lesion.features of the corneal lesion.
Epithelial scrapings with Giemsa stain may showEpithelial scrapings with Giemsa stain may show multinucleated giant cellsmultinucleated giant cells
Viral cultures obtained within several days of onset of disease and prior toViral cultures obtained within several days of onset of disease and prior to
antiviral therapy have a sensitivity of up to 70%antiviral therapy have a sensitivity of up to 70%
Commercially available HSV antigen detection tests are very specific forCommercially available HSV antigen detection tests are very specific for
detecting herpes infection, but they are limited by their lower sensitivity.detecting herpes infection, but they are limited by their lower sensitivity.
Polymerase chain reaction from a tear sample or from an anterior chamber tapPolymerase chain reaction from a tear sample or from an anterior chamber tap
may detect viral DNA in cases of herpetic keratitis or keratouveitis.may detect viral DNA in cases of herpetic keratitis or keratouveitis.
Imaging StudiesImaging Studies::
High resolution optical coherence tomography (OCT)High resolution optical coherence tomography (OCT) may have futuremay have future
application in HSV keratitisapplication in HSV keratitis
14. TREATMENTTREATMENT
Medical CareMedical Care
Antiviral therapy, oral or topical, is an effective treatment of epithelial herpesAntiviral therapy, oral or topical, is an effective treatment of epithelial herpes
infectioninfection
Either topicalEither topical trifluridine 1%trifluridine 1% solution 9 times dailysolution 9 times daily
vidarabine 3%vidarabine 3% ointment 5 times daily has equal efficacy inointment 5 times daily has equal efficacy in
treating a dendritic ulcer; however, trifluridine is more effective thantreating a dendritic ulcer; however, trifluridine is more effective than
vidarabine for treatment of a geographic ulcer.vidarabine for treatment of a geographic ulcer.
Oral acyclovirOral acyclovir at a dose of 2 g per day for 10 days has been reported to beat a dose of 2 g per day for 10 days has been reported to be
as effective as topical therapy for epithelial keratitis and may be a betteras effective as topical therapy for epithelial keratitis and may be a better
alternative for patients with preexisting ocular surface disease and who arealternative for patients with preexisting ocular surface disease and who are
at high risk for toxicity from topical medications.at high risk for toxicity from topical medications.
Stromal keratitis and endotheliitisStromal keratitis and endotheliitis are treated with combined corticosteroidare treated with combined corticosteroid
and antiviral therapyand antiviral therapy
Neurotrophic keratopathyNeurotrophic keratopathy are managed with nonpreserved lubricants, eyelidare managed with nonpreserved lubricants, eyelid
patching, and bandage contact lensespatching, and bandage contact lenses
15. Surgical Care:Surgical Care:
Irregular astigmatism resulting from chronic stromal keratitis may beIrregular astigmatism resulting from chronic stromal keratitis may be
correctable with rigid gas-permeable contact lenses.correctable with rigid gas-permeable contact lenses.
Patients with visually significant corneal opacities or cornealPatients with visually significant corneal opacities or corneal
perforations may require penetrating keratoplasty for visualperforations may require penetrating keratoplasty for visual
rehabilitation.rehabilitation.
The prognosis for a successful graft approaches 80% in eyesThe prognosis for a successful graft approaches 80% in eyes
without inflammation prior to surgery.without inflammation prior to surgery.
Prophylactic antiviral therapy following penetrating keratoplastyProphylactic antiviral therapy following penetrating keratoplasty
decreases the rate of recurrent HSV dendritic keratitis and possiblydecreases the rate of recurrent HSV dendritic keratitis and possibly
improves graft survival.improves graft survival.
16. Herpes zoster ophthalmicusHerpes zoster ophthalmicus
Background:Background:
Varicella-zoster virus (VZV) is a member of the HerpesviridaeVaricella-zoster virus (VZV) is a member of the Herpesviridae
family. It is the etiologic agent of varicella (chickenpox), the primaryfamily. It is the etiologic agent of varicella (chickenpox), the primary
infection, and herpes zoster, the reactivation.infection, and herpes zoster, the reactivation.
Herpes zoster ophthalmicusHerpes zoster ophthalmicus involves the tissues innervated byinvolves the tissues innervated by
the ophthalmic division of the trigeminal nerve . The sequelae ofthe ophthalmic division of the trigeminal nerve . The sequelae of
herpes zoster ophthalmicus can be devastating and include chronicherpes zoster ophthalmicus can be devastating and include chronic
ocular inflammation, visual loss, and debilitating painocular inflammation, visual loss, and debilitating pain..
17. PathophysiologyPathophysiology
After primary infection, VZVAfter primary infection, VZV enters the dorsal root ganglia (trigeminal =enters the dorsal root ganglia (trigeminal =
herpes zoster ophthalmicus, ), where it remains latent for the lifetime of theherpes zoster ophthalmicus, ), where it remains latent for the lifetime of the
individualindividual
It also may suggest that the ganglia are infected hematogenously duringIt also may suggest that the ganglia are infected hematogenously during
the viremic phase of varicella and that the frequency of the dermatomethe viremic phase of varicella and that the frequency of the dermatome
involvement in herpes zoster reflects the ganglia most often exposed toinvolvement in herpes zoster reflects the ganglia most often exposed to
reactivating stimuli.reactivating stimuli.
18. Frequency:Frequency:
In the USIn the US::
Regarding primary infection, more than 90% of the population is infectedRegarding primary infection, more than 90% of the population is infected
by adolescence, and approximately 100% are infected by 60 years ofby adolescence, and approximately 100% are infected by 60 years of
age.age.
Herpes zoster affects about 10-20% of the population. The rate isHerpes zoster affects about 10-20% of the population. The rate is
approximately 131 per 100,000 person-years in white individuals.approximately 131 per 100,000 person-years in white individuals.
According to Pavan-Langston's reviewAccording to Pavan-Langston's review, 1 million consultations for, 1 million consultations for
herpes zoster occur per year; and approximately 250,000 of the patientsherpes zoster occur per year; and approximately 250,000 of the patients
thus examined develop herpes zoster ophthalmicus. A subset of 50% ofthus examined develop herpes zoster ophthalmicus. A subset of 50% of
these patients develops complications of herpes zoster ophthalmicus.these patients develops complications of herpes zoster ophthalmicus.
19. Mortality/Morbidity:Mortality/Morbidity:
In the United States, as many as 10,000 hospitalizations andIn the United States, as many as 10,000 hospitalizations and
approximately 100 deaths occur per year as a result ofapproximately 100 deaths occur per year as a result of
complications from VZV infection.complications from VZV infection.
Race:Race: whites is twice that of African Americans.whites is twice that of African Americans.
Sex:Sex: No known sex predilection exists.No known sex predilection exists.
Age:Age:
Primary infection with VZV is a childhood disease.Primary infection with VZV is a childhood disease.
VZV reactivation or herpes zoster is primarily a disease that affectsVZV reactivation or herpes zoster is primarily a disease that affects
healthy older adults.healthy older adults.
Incidence increases with age, peaking in the seventh decade of life.Incidence increases with age, peaking in the seventh decade of life.
20. CLINICALCLINICAL
History:History: Patients with herpes zoster often report aPatients with herpes zoster often report a
history of chickenpox.history of chickenpox.
Herpes zoster ophthalmicusHerpes zoster ophthalmicus
Acute orbital and globe lesions develop within 3 weeks of theAcute orbital and globe lesions develop within 3 weeks of the
rash.rash.
Recurrence is a characteristic feature of herpes zosterRecurrence is a characteristic feature of herpes zoster
ophthalmicus. Relapse may occur as late as 10 years afterophthalmicus. Relapse may occur as late as 10 years after
onset.onset.
Symptoms of herpes zoster ophthalmicusSymptoms of herpes zoster ophthalmicus may include eye pain,may include eye pain,
red eye (usually unilateral), decreased vision, skin/eyelid rashred eye (usually unilateral), decreased vision, skin/eyelid rash
and pain, fever, malaise, and tearing.and pain, fever, malaise, and tearing.
21. PhysicalPhysical::
Herpes zoster ophthalmicusHerpes zoster ophthalmicus
Vesicular rashes involving the ophthalmic division of theVesicular rashes involving the ophthalmic division of the
trigeminal nerve. Crusting begins on the fifth to sixth day.trigeminal nerve. Crusting begins on the fifth to sixth day.
In 1864,In 1864, HutchinsonHutchinson proposed that the cutaneous involvement inproposed that the cutaneous involvement in
the distribution of the nasociliary nerve heralds ocularthe distribution of the nasociliary nerve heralds ocular
involvement.involvement.
Time has proven him correctTime has proven him correct (Hutchinson sign).(Hutchinson sign). It is nowIt is now
accepted that severe ocular complications can occur with aaccepted that severe ocular complications can occur with a
vesicular rash anywhere on the foreheadvesicular rash anywhere on the forehead..
24. WORKUPWORKUP
Herpes zoster is diagnosed mostly on the basis of the characteristicHerpes zoster is diagnosed mostly on the basis of the characteristic
pain and appearance of the dermatomal rashes. More often thanpain and appearance of the dermatomal rashes. More often than
not, laboratory tests are unnecessary.not, laboratory tests are unnecessary.
On rare occasion that a differential diagnosis of several skin lesionsOn rare occasion that a differential diagnosis of several skin lesions
must be made, confirmatory laboratory examinations may bemust be made, confirmatory laboratory examinations may be
undertaken. These tests includeundertaken. These tests include
morphologicmorphologic
immunomorphologicimmunomorphologic
viral isolationviral isolation
serologicserologic
cellular immunity testscellular immunity tests
25. TREATMENTTREATMENT
Medical CareMedical Care: I: Include antiviral agents, systemic corticosteroids, antidepressants,nclude antiviral agents, systemic corticosteroids, antidepressants,
and adequate pain control.and adequate pain control.
Treatment of acute herpes zoster ophthalmicus is optimal if started within 72 hours ofTreatment of acute herpes zoster ophthalmicus is optimal if started within 72 hours of
rash onset. Pavan-Langston has outlined the following protocol for treatment:rash onset. Pavan-Langston has outlined the following protocol for treatment:
Oral antiviral drugsOral antiviral drugs (eg, famciclovir 500 mg 3 times/d [tid], valacyclovir 1 g tid, or acyclovir(eg, famciclovir 500 mg 3 times/d [tid], valacyclovir 1 g tid, or acyclovir
800 mg 5 times/d for 7 d)800 mg 5 times/d for 7 d)
Tricyclic antidepressantsTricyclic antidepressants nortriptyline, amitriptyline, or desipramine 25 mg, (to inhibitnortriptyline, amitriptyline, or desipramine 25 mg, (to inhibit
acute and prolonged postherpetic neuralgia [PHN]).acute and prolonged postherpetic neuralgia [PHN]).
Additional topical corticosteroids, antibiotics, cycloplegics, antivirals, and glaucomaAdditional topical corticosteroids, antibiotics, cycloplegics, antivirals, and glaucoma
medications as necessary for keratitis, iritis, or glaucoma.medications as necessary for keratitis, iritis, or glaucoma.
Treat late PHNTreat late PHN with tricyclic antidepressantswith tricyclic antidepressants
Virustatic agents that are dependent on viral thymidineVirustatic agents that are dependent on viral thymidine kinase phosphorylationkinase phosphorylation
and targeted at viral polymerase includeand targeted at viral polymerase include acyclovir, valacyclovir, penciclovir,acyclovir, valacyclovir, penciclovir,
famciclovir, Sorivudine, and bromovinyldeoxyuridine.famciclovir, Sorivudine, and bromovinyldeoxyuridine.
Virustatic agents that not dependent on viral thymidine kinase phosphorylaseVirustatic agents that not dependent on viral thymidine kinase phosphorylase
and targeted at viral polymerase includeand targeted at viral polymerase include vidarabine, foscarnet, and cidofovirvidarabine, foscarnet, and cidofovir
(hydroxyphosphonylmethoxypropyl)..(hydroxyphosphonylmethoxypropyl)..
26. ComplicationsComplications
Pavan-Langston reviewed complications of untreated herpes zosterPavan-Langston reviewed complications of untreated herpes zoster
ophthalmicus and noted the followingophthalmicus and noted the following::
Severe acute pain (90%)Severe acute pain (90%)
Infectious, scarring rash (85%)Infectious, scarring rash (85%)
Conjunctivitis, episcleritis, and scleritis (75%)Conjunctivitis, episcleritis, and scleritis (75%)
Lid distortion (70%)Lid distortion (70%)
Infectious and/or immune keratitis (55%)Infectious and/or immune keratitis (55%)
Uveitis (45%)Uveitis (45%)
PHN, 20-60% (age <40-60 y)PHN, 20-60% (age <40-60 y)
Glaucoma and/or cataract (10%)Glaucoma and/or cataract (10%)
Neuro-ophthalmic (8%)Neuro-ophthalmic (8%)
27. Keratoconjunctivitis EpidemicKeratoconjunctivitis Epidemic
Background:Background:
Epidemic keratoconjunctivitis (EKC) is a type of adenovirus ocular infection. This groupEpidemic keratoconjunctivitis (EKC) is a type of adenovirus ocular infection. This group
of infections also includes pharyngoconjunctival fever and many other adenoviral strainsof infections also includes pharyngoconjunctival fever and many other adenoviral strains
that produce nonspecific follicular conjunctivitisthat produce nonspecific follicular conjunctivitis
With a distinguishing corneal involvement that ranges from diffuse, fine, superficialWith a distinguishing corneal involvement that ranges from diffuse, fine, superficial
keratitis to epithelial defects to subepithelial opacitieskeratitis to epithelial defects to subepithelial opacities
Pathophysiology:Pathophysiology:
More than 50 serotypes have been isolated, and at least 19 documented serotypesMore than 50 serotypes have been isolated, and at least 19 documented serotypes
cause EKC. The most commonly associated serotypes include adenovirus 8, 19, andcause EKC. The most commonly associated serotypes include adenovirus 8, 19, and
3737
28. Physical:Physical:
An ipsilateral preauricular lymphadenopathy is one of the classicAn ipsilateral preauricular lymphadenopathy is one of the classic
findings.findings.
Other clinical signs include the following:Other clinical signs include the following:
Swelling and erythema of the lidSwelling and erythema of the lid
Conjunctival hyperemiaConjunctival hyperemia
ChemosisChemosis
Follicular reaction, mainly in the lower palpebral conjunctiva (the earliestFollicular reaction, mainly in the lower palpebral conjunctiva (the earliest
and most common sign)and most common sign)
Papillary hypertrophyPapillary hypertrophy
Subconjunctival and petechial hemorrhageSubconjunctival and petechial hemorrhage
In severe cases, membranous and pseudomembranousIn severe cases, membranous and pseudomembranous
conjunctivitis can be seen in one third of cases,conjunctivitis can be seen in one third of cases,
29. One of the distinguishing features of EKC is cornealOne of the distinguishing features of EKC is corneal
involvement, which is usually mild and transientinvolvement, which is usually mild and transient..
Corneal involvement has been well documentedCorneal involvement has been well documented 3-4 days3-4 days after onset ofafter onset of
symptoms in the form ofsymptoms in the form of diffuse fine epithelial keratitisdiffuse fine epithelial keratitis that stains withthat stains with
both fluorescein or rose bengal.both fluorescein or rose bengal.
One week after the onsetOne week after the onset,, focal epithelial keratitis may developfocal epithelial keratitis may develop. This is. This is
characterized by central ulceration and irregular borders with gray-whitecharacterized by central ulceration and irregular borders with gray-white
dots.dots.
About 2 weeks after onset, subepithelial infiltratesAbout 2 weeks after onset, subepithelial infiltrates can appear beneathcan appear beneath
the focal epithelial lesions, persisting for weeks to years.the focal epithelial lesions, persisting for weeks to years.
In rare cases, disciform keratitis or anterior uveitis can occur.In rare cases, disciform keratitis or anterior uveitis can occur.
There is no change in corneal sensationThere is no change in corneal sensation
30. TREATMENTTREATMENT
Medical CareMedical Care:: Supportive management includes the following:Supportive management includes the following:
Artificial tearsArtificial tears
Cold compressesCold compresses
Cycloplegic agents for severe photophobiaCycloplegic agents for severe photophobia
Topical corticosteroidsTopical corticosteroids
Research is ongoing for topical agents that have antiviral activity.Research is ongoing for topical agents that have antiviral activity.
One drug that holds promise in this area isOne drug that holds promise in this area is cidofovircidofovir..
