Viral KeratitisViral Keratitis

Dr. Humberto ValbuenaDr. Humberto Valbuena

Herpes Simplex Herpes Simplex -Background-Background:: Herpes simplex virus (HSV) keratitis encompasses a variety of disease Herpes 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 and A 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.

PathophysiologyPathophysiology Primary HSV-1 infectionPrimary HSV-1 infection occurs most commonly in the mucocutaneous distribution of occurs most commonly in the mucocutaneous distribution of

the trigeminal nerve. the trigeminal nerve.

After the primary infection, the virus spreads from the infected epithelial cells to 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 nearby sensory nerve endings and is transported along the nerve axon to the cell body located in the trigeminal ganglion. body located in the trigeminal ganglion.

The virus genome enters the nucleus of a neuron, where it persists indefinitely in a The virus genome enters the nucleus of a neuron, where it persists indefinitely in a latent state.latent state.

Recurrent HSV infectionRecurrent HSV infection Traditionally has been thought of as reactivation of virus in the Traditionally has been thought of as reactivation of virus in the

sensory ganglion, which migrates down the nerve axon to produce a sensory 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 within Recent evidence suggests that the virus may subsist latently within corneal tissue, serving as a potential source of recurrent disease corneal tissue, serving as a potential source of recurrent disease

and also donor-derived HSV in transplanted corneasand also donor-derived HSV in transplanted corneas

FrequencyFrequency::

In the US:In the US: Approximately 20,000 new cases of ocular HSV occur in the United States Approximately 20,000 new cases of ocular HSV occur in the United States

annually, and more than 28,000 reactivations occur in the United States annually, 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 in Of 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 corneal 0.15%. 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 HSV keratitis is one of the most frequent causes of corneal blindness in the United States and a leading indication for causes of corneal blindness in the United States and a leading indication for corneal transplantation.corneal transplantation.

Age:Age: Most HSV recurrent eye disease occurs in adults. However, herpetic Most HSV recurrent eye disease occurs in adults. However, herpetic keratitis in children almost always involves the corneal epithelium and is keratitis in children almost always involves the corneal epithelium and is marked by a disproportionate risk of binocular disease, a high recurrence marked by a disproportionate risk of binocular disease, a high recurrence rate, and amblyopia as a complication. rate, and amblyopia as a complication.

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 recurrent A history of prior episodes in patients with recurrent

disease may exist.disease may exist.

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

Infectious epithelial keratitis Infectious epithelial keratitis

characterized by

Corneal vesicles

Dendritic ulcers

Geographic ulcers

Neurotrophic keratopathy Neurotrophic keratopathy

The earliest signs of neurotrophic keratopathy include an irregular corneal surface and punctate epithelial erosions.

In contrast to the irregular shape andscalloped borders of an infectious geographic ulcer, a neurotrophic ulceris typically oval with smooth borders and often lies within the interpalpebral fissures.

Corneal stromal inflammation Corneal 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.

Endotheliitis Endotheliitis

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

CausesCauses Infectious epithelial keratitisInfectious epithelial keratitis results from active viral replication results from active viral replication

within the corneal epithelium.within the corneal epithelium.

Neurotrophic keratopathyNeurotrophic keratopathy results mainly from decreased corneal results mainly from decreased corneal innervation and tear secretion as a result of a prior HSV infection of innervation 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 the arises from direct infection of the corneal stroma and the resultant severe host inflammatory corneal stroma and the resultant severe host inflammatory response.response.

ISKISK is an antibody-complement cascade triggered by retained viral is 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 to is believed to be primarily an immunologic reaction to an antigen in endothelial cells; however, the role of live virus has an antigen in endothelial cells; however, the role of live virus has been speculated.been speculated.

WORKUPWORKUP Lab StudiesLab Studies: :

HSV keratitis is primarily a clinical diagnosis based on characteristic HSV 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 show Epithelial scrapings with Giemsa stain may show multinucleated giant cellsmultinucleated giant cells

Viral cultures obtained within several days of onset of disease and prior to Viral 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 for Commercially 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 tap Polymerase 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 future may have future application in HSV keratitisapplication in HSV keratitis

TREATMENTTREATMENT Medical CareMedical Care

Antiviral therapy, oral or topical, is an effective treatment of epithelial herpes Antiviral therapy, oral or topical, is an effective treatment of epithelial herpes infection infection

Either topical Either topical trifluridine 1%trifluridine 1% solution 9 times daily solution 9 times daily vidarabine 3%vidarabine 3% ointment 5 times daily has equal efficacy in ointment 5 times daily has equal efficacy in

treating a dendritic ulcer; however, trifluridine is more effective than treating 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 be at 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 better as effective as topical therapy for epithelial keratitis and may be a better alternative for patients with preexisting ocular surface disease and who are alternative 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 corticosteroid are treated with combined corticosteroid and antiviral therapyand antiviral therapy

Neurotrophic keratopathyNeurotrophic keratopathy are managed with nonpreserved lubricants, eyelid are managed with nonpreserved lubricants, eyelid patching, and bandage contact lenses patching, and bandage contact lenses

Surgical Care:Surgical Care:

Irregular astigmatism resulting from chronic stromal keratitis may be Irregular 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 corneal Patients with visually significant corneal opacities or corneal perforations may require penetrating keratoplasty for visual perforations may require penetrating keratoplasty for visual rehabilitation. rehabilitation.

The prognosis for a successful graft approaches 80% in eyes The prognosis for a successful graft approaches 80% in eyes without inflammation prior to surgery. without inflammation prior to surgery.

Prophylactic antiviral therapy following penetrating keratoplasty Prophylactic antiviral therapy following penetrating keratoplasty decreases the rate of recurrent HSV dendritic keratitis and possibly decreases the rate of recurrent HSV dendritic keratitis and possibly improves graft survival.improves graft survival.

Herpes zoster ophthalmicusHerpes zoster ophthalmicus Background:Background:

Varicella-zoster virus (VZV) is a member of the Herpesviridae Varicella-zoster virus (VZV) is a member of the Herpesviridae family. It is the etiologic agent of varicella (chickenpox), the primary family. 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 by involves the tissues innervated by the ophthalmic division of the trigeminal nerve . The sequelae of the ophthalmic division of the trigeminal nerve . The sequelae of herpes zoster ophthalmicus can be devastating and include chronic herpes zoster ophthalmicus can be devastating and include chronic ocular inflammation, visual loss, and debilitating painocular inflammation, visual loss, and debilitating pain. .

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 the herpes zoster ophthalmicus, ), where it remains latent for the lifetime of the individual individual

It also may suggest that the ganglia are infected hematogenously during It also may suggest that the ganglia are infected hematogenously during the viremic phase of varicella and that the frequency of the dermatome the viremic phase of varicella and that the frequency of the dermatome involvement in herpes zoster reflects the ganglia most often exposed to involvement in herpes zoster reflects the ganglia most often exposed to reactivating stimuli. reactivating stimuli.

Frequency:Frequency: In the USIn the US::

Regarding primary infection, more than 90% of the population is infected Regarding primary infection, more than 90% of the population is infected by adolescence, and approximately 100% are infected by 60 years of by adolescence, and approximately 100% are infected by 60 years of age. age.

Herpes zoster affects about 10-20% of the population. The rate is Herpes 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 patients herpes zoster occur per year; and approximately 250,000 of the patients thus examined develop herpes zoster ophthalmicus. A subset of 50% of thus 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.

Mortality/Morbidity:Mortality/Morbidity: In the United States, as many as 10,000 hospitalizations and In the United States, as many as 10,000 hospitalizations and

approximately 100 deaths occur per year as a result of complications from approximately 100 deaths occur per year as a result of complications from VZV infection. 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 affects VZV 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.

CLINICALCLINICAL History:History: Patients with herpes zoster often report a Patients 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 the Acute orbital and globe lesions develop within 3 weeks of the rash. rash.

Recurrence is a characteristic feature of herpes zoster Recurrence is a characteristic feature of herpes zoster ophthalmicus. Relapse may occur as late as 10 years after ophthalmicus. 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 rash red eye (usually unilateral), decreased vision, skin/eyelid rash and pain, fever, malaise, and tearing.and pain, fever, malaise, and tearing.

PhysicalPhysical:: Herpes zoster ophthalmicusHerpes zoster ophthalmicus

Vesicular rashes involving the ophthalmic division of the Vesicular 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 in proposed that the cutaneous involvement in the distribution of the nasociliary nerve heralds ocular the distribution of the nasociliary nerve heralds ocular involvement. involvement.

Time has proven him correct Time has proven him correct (Hutchinson sign).(Hutchinson sign). It is now It is now accepted that severe ocular complications can occur with a accepted that severe ocular complications can occur with a vesicular rash anywhere on the foreheadvesicular rash anywhere on the forehead..

Herpes zoster ophthalmicus with Hutchinson sign

Dendritic keratitis

Corneal ulcer

Sclerokeratouveitis secondary to infection with the varicella-zoster virus.

WORKUPWORKUP Herpes zoster is diagnosed mostly on the basis of the characteristic Herpes zoster is diagnosed mostly on the basis of the characteristic

pain and appearance of the dermatomal rashes. More often than pain 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 lesions On rare occasion that a differential diagnosis of several skin lesions must be made, confirmatory laboratory examinations may be must be made, confirmatory laboratory examinations may be undertaken. These tests include undertaken. These tests include

morphologicmorphologic immunomorphologicimmunomorphologic viral isolationviral isolation serologic serologic cellular immunity testscellular immunity tests

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 of Treatment 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 inhibit nortriptyline, 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 glaucoma Additional 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 antidepressants with 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 include and 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 include and targeted at viral polymerase include vidarabine, foscarnet, and cidofovir vidarabine, foscarnet, and cidofovir (hydroxyphosphonylmethoxypropyl)..(hydroxyphosphonylmethoxypropyl)..

ComplicationsComplications Pavan-Langston reviewed complications of untreated herpes zoster Pavan-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%)

Keratoconjunctivitis Epidemic Keratoconjunctivitis Epidemic Background:Background: Epidemic keratoconjunctivitis (EKC) is a type of adenovirus ocular infection. This group Epidemic keratoconjunctivitis (EKC) is a type of adenovirus ocular infection. This group

of infections also includes pharyngoconjunctival fever and many other adenoviral strains of 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, superficial With a distinguishing corneal involvement that ranges from diffuse, fine, superficial keratitis to epithelial defects to subepithelial opacities keratitis to epithelial defects to subepithelial opacities

Pathophysiology:Pathophysiology: More than 50 serotypes have been isolated, and at least 19 documented serotypes More than 50 serotypes have been isolated, and at least 19 documented serotypes

cause EKC. The most commonly associated serotypes include adenovirus 8, 19, and cause EKC. The most commonly associated serotypes include adenovirus 8, 19, and 3737

Physical:Physical:

An ipsilateral preauricular lymphadenopathy is one of the classic An 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 earliest Follicular reaction, mainly in the lower palpebral conjunctiva (the earliest

and most common sign)and most common sign) Papillary hypertrophy Papillary hypertrophy Subconjunctival and petechial hemorrhageSubconjunctival and petechial hemorrhage

In severe cases, membranous and pseudomembranous In severe cases, membranous and pseudomembranous conjunctivitis can be seen in one third of cases, conjunctivitis can be seen in one third of cases,

One of the distinguishing features of EKC is corneal One 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 documented Corneal involvement has been well documented 3-4 days3-4 days after onset of after onset of symptoms in the form of symptoms in the form of diffuse fine epithelial keratitisdiffuse fine epithelial keratitis that stains with that 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-white characterized 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 beneath can 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

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 cidofovir cidofovir..

Gracias……………..Gracias……………..