Herpetic keratitis

Herpetic Keratitis
Tukezban Huseynova, MD

The online presentation is available on
Eye-Dr. Tuti – YouTube Channel

Dr. Tukezban Huseynova
Introduction

Introduction
➢ HSV keratitis has multiple presentations that can be challenging for the clinician
➢ The main corneal manifestations include infectious epithelial keratitis, neurotrophic keratopathy,
necrotizing stromal keratitis, immune stromal keratitis, and endotheliitis
➢ To treat HSV keratitis successfully, the clinician must recognize the infectious as well as immune
components of the keratitis being treated
➢ The most common treatment error is an underutilization of topical corticosteroids for immune
stromal keratitis
➢ Herpes viruses are double-stranded DNA viruses
➢ There are three subfamilies of herpesviruses: alpha-, beta-, and gamma-herpesviruses
➢ The human viruses included in alpha-subfamily are herpes simplex virus type-1 (HSV-1), HSV-2,
and varicella-zoster virus (VZV)

Pathogenesis

Chronology of infection
Pathogenesis
1. Initial corneal infection 3. Lantency in TG
Trigeminal Ganglion
4. Reactivation in TG
6. Renewed corneal infection
Virus
2. Retrograte transport through neurons
5. Anterograte transport through neurons
Ophthalmic Nerve

Factors of herpetic desease activation
Pathogenesis
➢Sunlight
➢Trauma (including surgery)
➢Contact lens wear
➢Heat
➢Abnormal body temperature
➢Hormonal change
➢Emotional stress
➢Other infectious desease
➢Glaukoma medications
➢Immunocompromised and trigeminal nerve manipulation

Clinical presentation

Manifestation and classification of Herpetic Keratitis
➢Infectious epithelial keratitis
➢Neurotrophic epithelial keratitis
➢ Immune stromal keratitis
➢ Endotheliitis
Epithelial Involvement
Stromal Involvement
➢ Necrotizing stromal keratitis
Endothelium Involvement

I. Infectious epithelial keratitis
➢ Dendrite
➢ Herpetic epithelial keratitis
➢ Infectious epithelial herpes
➢ Limbal keratoconjunctivitis
Alternate terms
➢Cornea vesicles
➢Dendritic ulcer
➢Geographic ulcer
➢Marginal ulcer
Recommended nomenclature and types
➢Lacrimation
➢Photophobia
➢Irritation
➢Blurred vision
➢Pain
General symptoms

Infectious epithelial keratitis
clinical presentation with corneal vesicles
Branching vesicular
lesion
Corneal vesicles
Coalesced corneal
vesicles
❑ Punctate Keratitis
„Cornea. Fundamentals, Diagnosis and management – Fourth Edition“, Mark J. Mannis, Edward J. Holland (2017)
„Herpes symplex virus, Epithelial Keratitis“, Helena M. Tabery (2010)

Branching vesicular
lesion
Isolated epithelial
involvement
Punctate Keratitis

The plaques enlarge to form branching dendrites
Coalesced corneal
vesicles
❑ Dendritic Keratitis
Paracentral dendritic ulcers
Multiple dendritic ulcers
„Cornea Atlas, Third Edition“, Jay H Krachmer, David A Palay (2014)
„Copeland and Afshari‘s principles and practice of Cornea“, Robert A Copeland Jr, Natalie A Afshari (2013)

Coalesced corneal
vesicles
Dendritic Keratitis
Central dendritic ulcer
Paracentral dendritic ulcers
Multiple dendritic ulcers
true ulcer
Earliest
stage
of
epithelial
keratitis
Epithelial keratitis
stain spreading
1 week later
Fluorescein staining over time
After 1 minute After 3 minutes

Some of the dendrites enlarge into geographic ulcers
❑ Geographic ulcers
Amoeboid ulcer
Swollen epithelial borders
„Corneal ulcers diagnosis and management“, Hugh R Taylor, Peter R Laibson (2008)

Geographic ulcers
large geographic ulcer
epitheliolysed cells
„Manual of Cornea“, A Samuel Gnanadoss (2008)

result from active viral desease like that of dentritic ulcer
❑ Marginal ulcers
Amoeboid ulcer
limbal injection
anterior stromal
infiltrate Fluorescein staining
reveals ulceration
Note: Marginal Ulcer (MU)
- Uncommon
- Confused with staphylococcal
marginal desease
- Progresses without antiviral
therapy
- MU progresses centrally

Infective
Differentiation between
HSV marginal keratitis and staphylococcal marginal keratitis
Etiology Immunologic response to staphylococcal antigen
Epithelial defect Present (always) Generally absent, may occur late in the course
Progression Centrally Circumferentially
Limbal injection More Minimal
Lucid interval between
limbus and ulcer
Absent Present
Neovascularization Present (often) Absent
Blepharitis Absent or unrelated Usually
Location Any meridian Generally 2, 4 8 10 O’clock
Features

Sequelae of infectious epithelial keratitis
Dendritic ulcer or
Geographic ulcer
o Can be with complete
resolution of the infectious
lesion without residual
evidence of prior infection
“Ghost figures”
Ring infiltrate
Stromal scaring
Scars as:
o gray-white, subepithelial
opacities
o “ghost figures”or “footprints”
o Dense stromal scarring
accompanied by thinning and
decreased vision
Stromal desease
o Infectious or Necrotizing
keratitis represents
true viral infection of
the stroma
o Immune Keratitis, is mediated
by antibody-complement
reactions to viral antigen

Sequelae of infectious epithelial keratitis
“Ghost figures”
Ring infiltrate
subepithelial
scarring
“ground glass”

II. Neurotrophic Keratopathy
➢Punctate Epithelial Erosions
➢Neurotrophic Ulcer
➢ Trophic Ulcer
➢ Neurotrophic Ulcer
➢ Metaherpetic Ulcer
➢ Indolent Ulcer
Alternate terms
➢Chronic use of topical medications
➢Impared corneal innervation
➢Due to decreased tear secretion
Possible reasons

Neurotrophic Keratopathy
➢Round/oblong or square shape with smooth borders and rolled up epithelium
➢The stroma at the ulcer bed has a grey-white opacification
➢ Has thickended borders
Characteristics
Complications
➢Stromal scarring
➢Neovascularization
➢ Necrosis
➢Perforation
➢Secondary bacterial infection

Features of infectious epithelial keratitis compared to neurotrophic ulcer
Features
Infectious epithelial keratitis Neurotrophic keratitis
Etiology active viral infection
Location no specific predilection
Continued…….
- impaired corneal innervation
- damaged epithelial BM
- stromal inflammation
- toxicity from topical medications
most often intrapalbebral cornea
Morphology Dendritic ulcer:
- branching shape
- terminal bulbs
- swollen epithelium at borders
Geographic ulcer:
- scallop shaped
- swollen epithelium at borders
PEK and boggy epithelium;
- may have dendritic shape
Neurotrophic ulcer:
- smooth
- round or oval
- heaped-up epithelium at border

Features of infectious epithelial keratitis compared to neurotrophic ulcer
Features
Infectious epithelial keratitis (IEK) Neurotrophic keratitis (NK)
Treatment - topical antivirals
- debridement
- lubrication
- elimination of toxic topical therapy
- bandage contact lens
- amniotic membrane
- tape or surgical tarsorrhaphy
Staining “+” with dendritic or geographic ulcer
“-” rare, If detected at vesicle stage
“+” with epithelial defect
“-” with intact epithelium
Course Usually resolves within 2 weeks - chronic
- may occur after IEK
- suspect if IEK lasts > 14 days

Clinical Samples
Neurotrophic Ulcer
smooth borders
Metaherpetic Keratitis
Thickened and
rolled up margins
Neurotrophic Keratolysis
Necrotizing stroma

III. Stromal Keratitis
➢ Necrotizing stromal keratitis
➢ Immune stromal keratitis
➢ Viral necrotizing keratitis
➢ Ulcerating interstitial keratitis
Alternate terms
May also present as:
➢ Limbal Vasculitis
➢ Immune ring of Wessely
➢Necrotic interstitial keratitis
➢Endotheliitis with/without
trabeculitis

Stromal Keratitis
Results from direct viral invasion of the stroma
❑ Necrotizing stroma keratitis
The clinical findings
➢Necrosis
➢Ulceration
➢Dense infiltration of the stroma
Replicating Virus
&
Severe host inflamatory response
+
destructive intrastromal inflammation
thinning and perforation
necrotic ulceration with stromal
infiltration

Stromal Keratitis
Due to viral antigen within the stroma
❑ Immune (interstitial) stromal Keratitis
➢Stromal Infiltration, can be with:
- anterior chamber reaction
- ciliary flush
- significant discomfort
➢Haze and stromal edema (in the
acute phase)
➢Punctate lesions in mid stroma
➢Neovascularization
- Sectoral
- Single fond of vessel
- Complete
Immune ring (Wessely ring)
Lipid Keratopathy
Note: Immune stromal
keratitis may present
days to years after an
episode of infectious
epithelial keratitis

Stromal Keratitis
Immune stromal Keratitis
Wessely ring

Stromal Keratitis
fine punctate
opacities in the
mid stroma
Wessely ring anterior
stromal
scarring
Double immune ring of Wessely

Stromal Keratitis
Stromal Inflammation
Vascularization
Lipid
Keratopathy
heavy lipid
deposition
Chronic stromal scar

IV. Endotheliitis
➢ Topical corticosteroids
Management
➢Unclear
➢Immunologic Reaction
Pathogenesis
➢Stromal and epithelial Edema
➢No infiltrates
➢Keratic precipitates (KP)
➢Iritis

Endotheliitis
Classification of HSV endotheliitis
KP, keratic precipitates

Endotheliitis
The most common presentation of endotheliitis
❑ Disciform Endotheliitis
➢Photophobia
➢Moderate ocular discomfort
➢Limbal Injection
➢Iritis with KP
➢Visual Acuity is reduced depending on the location of the edema
➢Round or disk-shaped area of stromal edema (central or paracentral)
➢Ground –glass appearance of the stroma
➢Clear demarcation line between involved and uninvolved cornea

Endotheliitis
Disciform Endotheliitis Clinical samples
Stromal haze
keratic precipitates
. Chronic stromal and
epithelial edema
stroma is free
of infiltrate

Endotheliitis
The rare presentation of endotheliitis
❑ Diffuse Endotheliitis
➢Photophobia, pain
➢Limbal Injection
➢Scattered KP over the entire cornea
➢Visual acuity is reduced due to diffuse stromal
edema
➢Failure in controling the inflammation leads to
scaring, neovascularization, persistent edema
and loss of vision

Endotheliitis
❑ Linear Endotheliitis
➢Photophobia, pain
➢Limbal Injection
➢Line of KP, progresses centraly from the
limbus
➢Visual Acuity due to diffuse stromal edema
➢Well demarcated line between the area of
edematous and nonedematous cornea
linear KP

Endotheliitis
Linear Endotheliitis The clinical samples
Advancing stromal and epithelial
edema (1)
Microcystic
edema
360 degrees of peripheral stromal and
epithelial edema (1)

Laboratory Investigations

Laboratory investigations
➢General clinical examination
In case of typical presentation
➢ Giemsa staining
➢ Polymerase chain reaction (PCR)
➢ Viral culture
➢ Immunological tests
In case of atypical presentation (lab. analysis)

Therapy

➢ Acyclovir can preferentially inhibit HSV DNA by binding to DNA polymerase and acting as a chain
terminator
Acyclovir
Antiviral agents
Therapy
➢ Acyclovir has been the mainstay of systemic treatment for HSV for several decades
➢ Gertrude Elion and George Hitchins received the 1988 Nobel prize for the development of acyclovir,
among other drugs
➢ At a dose of 400 mg five times daily, therapeutic aqueous humor levels can be achieved
➢ Gancyclovir was also noted to be significantly better tolerated by patients and was approved by the
FDA in 2009, as a 0.15% ophthalmic gel
Gancyclovir

Indications for oral antivirals
Antiviral agents
Therapy
➢ Patients with frequently recurrent infectious epithelial keratitis and post penetrating keratoplasty
patients with history of HSV keratitis
➢ Patients who experience two or more episodes of infectious epithelial keratitis per year may be
candidates for prophylactic treatment with oral acyclovir, 400 mg twice a day
➢ Valacyclovir, 500 mg once daily, can also be used as prophylaxis

Therapy
Advantages of ORAL Antivirals over TOPICAL Antivirals
1. Use of topical antiviral agents does not prevent the recurrence of
infectious epithelial keratitis
2. Chronic usage of topical antiviral medications leads to toxic
keratopathy and conjunctival scarring

The Herpetic Eye Disease Study
Therapy
➢ Oral antiviral prophylaxis reduces recurrences of epithelial and of stromal keratitis,
particularly stromal with a history of recurrence
➢ Use of topical corticosteroids is of benefit in stromal keratitis
➢ Use of oral acyclovir may be of help in iridocyclitis
Note: The HEDS has established that long-term
(one year) oral antiviral therapy, with a dose of
acyclovir 400 mg twice a day, can reduce the
recurrence of epithelial keratitis and stromal
keratitis

Suppress the inflammation by interfering with the normal immunologic response to various stimuli
Corticosteroids
Therapy and resistance patterns
➢ Advantages of steroid use in ocular disease include inhibition of
- cellular infiltration
- opacification
- scarring, inhibition
- release of toxic enzymes
- neovascularization
➢ Disadvantages include
- exacerbation and spread of active viral infection
- stimulation of viral replication
- enhancement of collagenolytic enzyme production
- corneal thinning

Strategies for initial management

Physical gentle debridement of the ulcer with a sterile cotton tipped applicator
Topical antiviral medications (every three hours)
Prophylaxis with a broad spectrum antibiotic
Topical cycloplegics in case of significant photophobia or ciliary spasm
Topical corticosteroids ONLY in case of severe immune stromal inflammation
Oral antiviral therapy should be also added to the topical therapy

Disconiuation of all unnecessary topical medications, especially topical antivirals
Frequent use of nonpreserved artificial tears
Prophylaxis with a broad spectrum antibiotic
In severe cases of a boggy rolled epithelium – gentle depridment
In case of secondary inflamation – topical corticosteroids
Therapeutic soft contact lens – in case of nonhealing neurotrophic ulcer (short term)
Surgical (or medical with botulinum toxin) Tarsoraphy or conjuntival flap

Surgical management

Surgical management
➢Temporary or permanent tarsorrhaphy
➢Conjunctival flap
➢Amniotic membrane
➢Penetrated Keratoplasty
➢Lamellar keratoplasty (DALK)
➢Descemet membrane Endothelial Keratoplasty,
(DMEK)
(Courtesy: Medical Photographic Imaging Centre, Royal Victorian Eye and Ear Hospital, Melbourne)
Graft
herpes
recurrence

Surgical management
(Courtesy: Medical Photographic Imaging Centre, Royal Victorian Eye and Ear Hospital, Melbourne)
Graft
Note: Complications after transplantation in herpetic eyes include:
- corneal graft rejection
- herpes recurrences within the graft
- persistent epithelial defect
- corneal melting
- secondary infection
- graft failure

Herpetic keratitis

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