Herpes simplex keratitis & herpes zoster opthalmicus

HSV Keratitis and Herpes Zoster Ophthalmicus

Presenter : Dr.Rasika Thakur Moderator : Dr. Vishram Sangit

Case presentationHSV keratitis

Introduction Pathology and Clinical featuresTreatment

Herpes zoster ophthalmicusIntroduction Pathology and Clinical featuresTreatment

Clinical pattern of Herpes simplex keratitis: A case series

Case scenario 1

Mr X, 24/MCame to us on 29/12/2011 with c/o redness

and watering of RE since 2 monthsBCVA-RE:FC1/2 m,N36,LE:6/6,N6Patient had taken treatment elsewhere ,but

found no relief with Eye drop tobramycinEye drop moxifloxacin and ketorolac Eye ointment neosporin

• Recurrent attack of HSV keratitis

29/12/2011

2/1/2012

5/1/2012 13/1/2012

27/1/2012 1/3/2012

13/9/2012

26/10/2012

30/11/2012

Case scenario ii

Patient Mr.XYZ, 65/MC/o redness and watering since 7 days

18/3/2014

Fortified cefazolin half hourly

Ciplox eyedrop half hourlyAtropin eyedrop TDS

21/3/2014

28/3/2014

2/4/2014

Impression -HSV keratitis with bacterial keratitis

21/4/2014

Mixed corneal ulcer

Introduction

Herpes simplex is the leading cause of infectious corneal blindness*

While not all humans manifest herpes infection, more than 90% carry the latent virus

HSV keratitis is Herpes simplex viral infection of the cornea

*Liedtke W., Opalka B., Zimmermann C.W., Lignitz E.: Age distribution of latent herpes simplex virus 1 and varicella-zoster virus genome in human nervous tissue. J Neurol Sci 1993; 116:6-11

Herpes simplex virus

Life cycle of HSV

Primary HSV infection

Blepharoconjunctivitis Follicular conjunctivitis Lid vesicles and conjunctival dendrites Kaposi’s varicelliform eruption Severe morbidity -multi-system failure or

bacterial superinfection

Darougar S., Hunter P.A., Viswalingam M., et al: Acute follicular conjunctivitis and keratoconjunctivitis due to herpes simplex virus in London. Br J Ophthalmol 1978; 62:843-849

Clinical Importance

Human herpesviruses have in common a state called “latency” where the virus remains dormant in cells and periodically reactivates

Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) have an affinity for the sensory ganglion cells and are therefore called neurotrophic viruses

Recurrent HSV Infections

Multiple factors are thought to cause recurrence including fever, sunlight, irradiation, menses, and emotional stress

Recurrent disease most commonly causes keratitis

HSVK is broadly classified into epithelial and stromal/endothelial keratitis

Epithelial Keratitis

SymptomsFB sensationphotophobiaRednessBlurred vision

Clinical featuresPunctate epithelial keratitisClassic arborizing dendritic epithelial ulcers with

terminal bulbsGeographic epithelial ulcerCiliary flush & conjunctival injection

Epithelial Keratitis

Dendritic ulcerGeographic ulcerMarginal keratitisMetaherpetic (trophic) ulcer

Dendritic ulcerClassic herpetic lesionThe borders are slightly raised,grayish, and stain

with rose bengal as they consist of infected cells that have undergone acantholysis

On resolution, a dendrite-shaped scar, called a ghost dendrite, may remain in the superficial stroma

Geographic ulcer

Immunocompromised, on topical steroids, or have longstanding, untreated ulcers*

Dichotomous branching and terminal bulbs are seen at the periphery

*Wilhelmus K.R., Coster D.J., Donovan H.C., et al: Prognosis indicators of herpetic keratitis. Analysis of a five-year observation period after corneal ulceration. Arch Ophthalmol 1981; 99:1578-1582

Marginal keratitis

Located near the limbus The presence of an epithelial defect and lack of

corneal sensation can aid in diagnosisSignificant stromal inflammationThey are more resistant to treatment and

frequently become trophic ulcers*

*Thygeson P.: Marginal herpes simplex keratitis simulating marginal catarrhal ulcer. Invest Ophthalmol 1971; 10:1006

Treatment

Indications- ulcers larger than 4 mm, marginal ulcers, and ulcers with underlying stromal inflammation

Topical antivirals

Gentle wiping débridement is a very good adjunct therapy as infected cells are acantholytic and are poorly adherent

Wilhelmus K.R.: The treatment of herpes simplex virus epithelial keratitis. Trans Am Ophthalmol Soc 2000; 98:505-532

Metaherpetic (trophic) ulcerTrophic ulcer,if it arises de novo or a

metaherpetic ulcer if it follows a dendrite or geographic ulcer

Causes-Toxicity from antiviral medicationsLack of neural-derived growth factorsPoor tear surfacingLow-grade stromal inflammation

Neurotrophic ulcers start as roughened epithelium, which then breaks down to produce an epithelial defect with smooth margins

Treatment

Stop toxic medicationsTear film supplementationBandage contact lenses Amniotic membraneThe cautious use of topical steroids may be

necessary if there is significant underlying inflammation

Stromal/Endothelial Keratitis

It is an immune-mediated response to nonreplicating viral particles

All layers of the cornea are affected and may involve the trabecular meshwork and iris

It is classified based on the predominant site and type of involvement

Stromal/Endothelial Keratitis

EndotheliitisNecrotizing keratitisImmune stromal keratitisKeratouveitis

Endotheliitis

Manifests as overlying stromal edema from endothelial dysfunction

Longstanding stromal edema leads to permanent scarring and is the major cause of decreased vision associated with HSVK

Endotheliitis

Localized endotheliitis Disc-shaped area of

corneal edema so called disciform keratitis

There is minimal stromal inflammation and no epithelial involvement

Diffuse and linear endotheliitis Accompanied by

trabeculitis with a resulting elevated intraocular pressure

Pseudo-guttae and Descemet’s folds

Necrotizing keratitis

Inflammation in the cornea is due to a reaction to live viral particles in the corneal stroma

Corneal melting and perforationAssociated with uveitis and trabeculitis that may

lead to recalcitrant glaucoma

Necrotizing keratitis

Immune stromal keratitis

Manifests as focal, multifocal, or diffuse stromal opacities or an immune ring

Stromal edema and a mild anterior chamber reaction

It is called interstitial keratitis (IK) if accompanied by vascularization

Keratouveitis

Uveitis is usually granulomatous with large “mutton-fat” keratic precipitates on the endothelium

It can lead to significant morbidity from synechiae, cataracts, and glaucoma

Unilateral uveitis associated with high intraocular pressure is almost always caused by HSV

Treatment

The mainstay of treatment is topical steroids as they decrease inflammation and therefore scarring

Oral antivirals Topical antivirals Aggressive topical and systemic antivirals along

with steroids are necessary in necrotizing keratitis and focal serous iritis

Diagnosis

Diagnostic testing is seldom needed in epithelial HSVK because of its classic clinical features and is not useful in stromal keratitis as there is usually no live virus present

Diagnosis

Culture DNA Testing Fluorescent Antibody TestingTzanck Smear Serum Antibody Testing

HERPETIC EYE DISEASE STUDY (HEDS)

To assess the effect of adding steroids and acyclovir to conventional therapy with trifluridine (TFT)

It was a prospective RandomizedDouble-maskedPlacebo-controlledMulti-center study Divided into six trials: three therapeutic, two

preventive, and one cohort

HEDS

Herpes Stromal Keratitis, Not on Steroids Trial

Compared with the placebo group, patients who received prednisolone phosphate drops had faster resolution and fewer treatment failures

Wilhelmus K.R., Gee L., Hauck W.W., et al: Herpetic Eye Disease Study. A controlled trial of topical corticosteroids for herpes simplex stromal keratitis. Ophthalmology 1994; 101:1883-1895

HEDS

Herpes Stromal Keratitis, on Steroid Treatment There was no apparent benefit to adding oral

acyclovir to topical corticosteroids and TFT. However, visual acuity improved over 6 months in more patients in the acyclovir group than in the placebo group

Barron B.A., Gee L., Hauck W.W., et al: Herpetic Eye Disease Study. A controlled trial of oral acyclovir for herpes simplex stromal keratitis. Ophthalmology 1994; 101:1871-1882

HEDS

Herpes Simplex Virus Iridocyclitis, Receiving Topical Steroids

The trial was stopped because of slow recruitment, but treatment failures occurred at a higher rate in the placebo group than in the acyclovir group, indicating a potential benefit to adding oral acyclovir to the regimen of a topical steroid and an antiviral

A controlled trial of oral acyclovir for iridocyclitis caused by herpes simplex virus. The Herpetic Eye Disease Study Group. Arch Ophthalmol 1996; 114:1065-1072

HEDS

Herpes Simplex Virus Epithelial Keratitis Trial

In the treatment of acute HSV epithelial keratitis with TFT, the addition of oral acyclovir offered no additional benefit in preventing subsequent stromal keratitis or iritis

HEDS

Acyclovir Prevention Trial

Oral acyclovir reduced the risk of any form of recurrent ocular herpes by 41% and stromal keratitis by 50%. The risk of multiple recurrences decreased from 9% to 4%

Although there was no rebound increase in keratitis after discontinuation of the acyclovir, the protection did not persist once the acyclovir was discontinued

Oral acyclovir for herpes simplex virus eye disease: effect on prevention of epithelial keratitis and stromal keratitis. Herpetic Eye Disease Study Group. Arch Ophthalmol 2000; 118:1030-1036

HEDS

Ocular HSV Recurrence Factor Study

No association was found between psychological or other forms of stress and HSV recurrences

Previous episodes of epithelial keratitis were not a predictor for future occurrences while previous, especially multiple, episodes of stromal keratitis markedly increased the probability of subsequent stromal keratitis

Oral acyclovir for herpes simplex virus eye disease: effect on prevention of epithelial keratitis and stromal keratitis. Herpetic Eye Disease Study Group. Arch Ophthalmol 2000; 118:1030-1036

Limitations: Many of the trials had inadequate recruitment or high

dropout rate

Oral acyclovir in the prevention trials was only used for 3 weeks

The steroid regimen was standardized and not tailored to inflammation

TFT was used in both the study and placebo groups in all the therapeutic trials

Current antivirals

Treatment

Steroids1% prednisolone acetate or 0.1%

dexamethasone is usedSurgery

Penetrating keratoplasty (PKP) Conjunctival flap Amniotic membrane (AMT)

FUTURE DIRECTIONS

Heat shock and glycoprotein subunit vaccines have shown some promise in clinical trials in decreasing the number and severity of recurrences of HSVK

while newer medications such as topical ganciclovir and cidofovir may prove to be more effective and cause less toxicity compared to current therapy*

Although monotherapy with interferon has not been found to be effective, it increases the efficacy of acyclovir and ganciclovir when given in combination**

*Colin J., Hoh H.B., Easty D.L., et al: Ganciclovir ophthalmic gel (Virgan; 0.15%) in the treatment of herpes simplex keratitis. Cornea 1997; 16:393-399**Wilhelmus K.R.: The treatment of herpes simplex virus epithelial keratitis. Trans Am Ophthalmol Soc 2000; 98:505-532

Herpes zoster ophthalmicus

Introduction

Recurrent infection of varicella (chickenpox) in the ophthalmic division of the trigeminal dermatome most frequently affecting the nasociliary branch

Epidemiology and clinical Importance

Herpes zoster is a neurocutaneous disease caused by the human herpes virus 3

Member of the herpes virus family (Herpesviridae) and exclusively infects human or simian cells

The lifetime risk is 20–30%, and 50% of those living until 85 years of age will be affected*

Physical trauma and surgery have been correlated with the development of zoster**

*Donahue J.G., Choo P.W., Manson J.E., Platt R.: The incidence of herpes zoster. Arch Intern Med 1995; 155:1605-1609**Evans R.W., Lee A.G.: Herpes zoster ophthalmicus, ophthalmoplegia and trauma. Headache 2004; 44:286-288

Pathogenesis

In temperate climates,primary infection occurs before the age of 10, manifests as chickenpox (varicella)

The virus then establishes a latent state in the sensory ganglia

When there is diminished virus-specific and cell-mediated immunity, the virus may reactivate and spread to the corresponding dermatome along a spinal or cranial nerve to generate the characteristic unilateral vesicular exanthema

Pathogenesis

Begins with a prodrome of influenza-like illness -fatigue, malaise, nausea and mild fever accompanied by progressive pain and skin hyperesthesia

A diffuse erythematous or maculopapular rash then appears over a single dermatome 3–5 days later

These eruptions progress to form clusters of papules and clear vesicles, which then evolve through stages of pustulation and crusting

Clinical manifestations


Eyelids Periorbital edema, pain, and hyperesthesia of

the eyelid skinSecondary bacterial infection may occur

following dermal involvement*Complications- scarring, cicatricial ectropion

or entropion, trichiasis, madarosis, poliosis, or even frank loss of eyelid tissue

*Weiss R.: Herpes zoster following spinal surgery. Clin Exp Dermatol 1989; 14:56-57


Conjunctiva papillary, pseudomembranous, membranous, or follicular reaction

Episclera/Sclera HZV episcleritis and scleritis may be either

localized or diffuse


Cornea Herpes zoster corneal disease can result in

significant vision loss. Five basic clinical forms:

Epithelial keratitis (acute or chronic)Nummular stromal keratitisDisciform keratitisLimbal vascular keratitisNeurotrophic keratitis, with or without corneal perforation


Uveitis- Nongranulomatous or granulomatous

iridocyclitis (anterior uveitis) with keratic precipitates and posterior synechiae

Lens -Posterior subcapsular cataracts


Anterior Chamber Angle and Glaucoma Plugging of the trabecular meshwork due to

the presence of cellular debris, iris pigment, or hyphema

Pupillary-block glaucoma secondary to posterior synechiae, with resultant iris bombe

Peripheral anterior synechiaeChronic open-angle glaucoma-due to damage

to the trabecular meshwork

Chang S.D., De Luise V.P.: In: Tasman W., Jaeger E.A., ed. Duane’s ophthalmology, Vol, 4. Philadelphia, PA: Lippincott Williams & Wilkins; 2001.ch 20 (CD-ROM)


Pupil Horner’s syndrome A tonic pupil secondary to herpes zoster ciliary

ganglionitisOptic Nerve

Neuroretinitis, retrobulbar neuritis, or an ischemic optic neuropathy

Herpes zoster optic neuritis may result from local transmission of the virus within the orbit from the fifth to the second cranial nerve


Vitreous-Vitreous opacities, vitritis, and vitreous hemorrhage

Retina –Retinal hemorrhagesRetinal thrombophlebitisBranch or central retinal artery occlusionRetinal arteritisNecrotizing retinopathy, necrotizing retinitisExudative or rhegmatogenous retinal detachment Ischemic perivasculitis


Extraocular Muscles Ophthalmoplegia 11–31%Affect cranial nerves three, four, and sixCan also manifest as a myositis that may also

lead to ophthalmoplegia


Postherpetic Neuralgia Pain that continues following rash healing Pain has three phases:

Acute pain occurring within 30 days after rash onset

Subacute herpetic neuralgia that persists beyond the acute phase but resolves before 120 days

Chronic PHN that persists 120 days or more after rash onset

Herpes zoster ophthalmicus in acquired

imune deficiency syndrone (AIDS) HZO is an important early clinical marker for

AIDS, especially in high-risk younger patientsHigher incidence, greater severity, and

prolonged course of corneal and uveitic involvement, as well as postherpetic neuralgia

Treatment -prolonged treatment course of intravenous acyclovir

Herpes zoster ophthalmicus in acquired imune deficiency syndrome(AIDS)

Progressive outer retinal necrosis a distinct form of necrotizing herpetic retinopathy

Characterized by multifocal, deep retinal lesions that rapidly progress to confluence with minimal or no intraocular inflammation, an absence of vascular inflammation, and perivenular clearing of retinal opacification

Diagnosis

The diagnosis of herpes zoster disease is based on clinical findings

Direct detection of the virus and indirect serological detection of specific antibodies

Cytologic examination of cutaneous vesicular scrapings reveals multiple eosinophilic intranuclear inclusions (Lipschutz bodies) and multinucleated giant cells (Tzanck preparation)

Electron microscopy VZV-DNA can also be directly detected in clinical

specimens using real-time PCR

Management

Systemic medication-Oral acyclovir (800 mg, five times daily) for 7–

10 daysFamciclovir (500 mg three times daily for 7

days)Valacyclovir (1000 mg three times daily)

Cobo L.M., Foulks G.N., Liesegang T., et al: Oral acyclovir in the treatment of acute herpes zoster ophthalmicus. Ophthalmology 1986; 9

Management of Ocular Manifestation

Palliative therapy including Burow’s solution, cool compresses, mechanical cleansing of the involved skin, and topical antibiotic ointment without steroid are helpful in treating skin lesions

Débridement may also be helpfulNeurotrophic keratitis or the epithelial defects -

nonpreserved artificial tears, eye ointments, pressure patching, or therapeutic soft contact lenses


Tarsorrhaphy, conjunctival flap, or autologous conjunctival transplantation

Steroids should not be used in cases of exposure or neurotrophic keratitis because of the possibility of keratolysis*

Topical cycloplegicsAqueous suppressants and topical corticosteroids

should be used to treat HZO glaucoma

*Liesegang T.: Corneal complications from herpes zoster ophthalmicus. Ophthalmology 1985; 92:316.


Herpes zoster retinitis, optic neuritis, chorioretinitis, acute retinal necrosis syndrome, and progressive outer retinal necrosis are best treated with a combination of systemic steroids and acyclovir i.v

Postherpetic Neuralgia treatment

AnalgesicsAntidepressants (amitriptyline, desipramine,

clomipramine), carbamazepine, and phenytoinFamciclovir and valacyclovir significantly reduce

the duration but not incidenceSteroids have no effect on PHN

Postherpetic Neuralgia treatment

Amitriptyline for 90 days reduced the incidence of pain at 6 months.

Trial of percutaneous electrical nerve stimulation (PENS) in 50 patients suggested a decrease in pain incidence at 3 and 6 months when compared with famciclovir

Clinical pattern of Herpes simplex keratitis: A case series

Dr Vishram Sangit1

Dr Suhas Haldipurkar1,Dr Maninder Setia1,

Mr Anirban Paik1

1 Laxmi Eye Institute, Panvel, Maharashtra

FP-799; Electronic Poster no. 11

Purpose

To study the clinicoepidemiological pattern of Herpes

simplex keratitis in a tertiary eye hospital in western

Maharashtra

Results41 eyes of 40 patients identifiedAll diagnoses – clinicalMean age - 44.4 +/- 18.54 yearsM:F – 27:13Past history of similar episode- 20 patientsHistory of trauma in 7 patientsOnly 2 out of 40 patients reported pain as the presenting complaintRedness and blurring of vision was the most common symptom

reported by 38 patientsMean duration of symptoms before presentation was 17.67 days ( range 2 to 90 days)

Clinical form of HSV Keratitis

Treatment protocols

Epithelial disease- Acyclovir ointment 5 times a day for 3 weeks

Stromal disease- Acyclovir ointment 5 times a day with 1% prednisolone acetate in tapering doses

Endothelitis- Intensive prednisolone acetate 1% with systemic Acyclovir 400 mg 5 times a day

Treatment outcomes

All cases resolved on medical therapy

Mean duration to resolution for entire group was 34.18 +/- 15.85 days

Clinical form

Epithelial Stromal Endothelitis Kerato-uveitis Mixed

Duration (days)

18.6 39.06 29.66 35 35.91

Time to resolution in various forms of HSV keratitis

Mean time to resolution in various forms of HSV keratitis ( days)

Recurrence patternPrimary clinical form developing recurrence during treatment

Clinical form of recurrence in HSV keratitis (%)

ConclusionsStromal form of HSV keratitis is the commonest

presentation in our series followed by mixed variety

HSV keratitis affects people in young and productive age group

Good response to medical therapy achieved in all forms

Resolution of stromal keratitis takes longest while epithelial keratitis takes shortest time

Recurrences are common and clinical form of disease in recurrences can be different from the original disease form

Thank you

Herpes simplex keratitis & herpes zoster opthalmicus

Healthcare

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