Herpes Simplex Keratitis

&
Herpes Zoster Ophthalmicus
 Nine Herpesviruses (HHV) infect humans

HHV1 = HSV1
HHV2 = HSV2
What Organisms?

HHV3 = VZV (causes Varicella Zoster/Chickenpox, remains dormant

in posterior dorsal root ganglion, then reactivates causing Herpes
Zoster/Shingles)
HHV4 = EBV
HHV5 = HCMV
and so on..

Herpes = creep/crawl
HHV Structure
Risk Factors for Viral Keratitis Local

- topical medicine: prostaglandin analogue eg Xalatan, topical steroid

- local trauma
- inflammation : laser surgery eg LASIK, PK, lamellar keratoplasty,
PRK
- periorbital vesicular rash
- follicular conjuctivitis
- h/o HSV keratitis

Systemic

- Immunosuppressed : organ transplant, DM, HIV, Measles, children

- Atopy : asthma, atopy eczema
- H/O orofacial or genital ulceration
 Herpes Simplex Virus 1 & 2

• Primary HSV infection

- blepharoconjuctivits
- follicular conjuctivits
Introduction

• Known as neurotrophic viruses - affinity for sensory

ganglion cells
• Recurrent disease most commonly causes keratitis
 Corneal Layer Nomenclature Alternate Term

Epithelium Dendritic Corneal Ulcer

HSV epithelial keratitis
Geographic Corneal Ulcer
Classification

Non necrotising keratitis

HSV stromal keratitis Interstital keratitis
Stroma without ulceration Immune stromal keratitis

with ulceration Necrotising keratitis

Endothelium
HSV endothelial keratitis Disciform keratitis
 Corneal Layer Nomenclature Alternate Term

Epithelium Dendritic Corneal Ulcer

HSV epithelial keratitis
Geographic Corneal Ulcer
Classification

Non necrotising keratitis

HSV stromal keratitis Interstital keratitis
Stroma without ulceration Immune stromal keratitis

with ulceration Necrotising keratitis

Endothelium
HSV endothelial keratitis Disciform keratitis
 Epithelium
- SPK -> stellate erosion -> dendritic ulcer -> if left untreated, becomes
geographic ulcer
- Reduced corneal sensation
Types of Ulcer
Dendritic ulcer :
Clinical Signs

- branching morphology with terminal bulbs (bigger and centrally located).

For HZO, smaller and peripherally located
- on resolution: Dendrite-shaped scar may remain in superficial stroma =
ghost dendrite
Geographic ulcer :
- large amoeboid ulcer with dendritic advancing edges (dichotomous
branching & terminal bulbs at periphery)
- more common in inmmunocompromised/topical steroid

Metaherpetic (trophic) ulcer :

- chronic recurrent superficial postherpetic disease without any detectable
hsv-activity
- neurotrophicity occurs and corneal healing is problematic
 Epithelium

Types of Ulcer Photo

Dendritic ulcer :
Clinical Signs

branching morphology
terminal bulbs

Geographic ulcer :
large amoeboid ulcer
dendritic advancing edges

Metaherpetic (trophic) ulcer :

smooth border
 Epithelial

- SPK -> stellate erosion -> dendritic ulcer -> if left untreated,
becomes geographic ulcer
Types of Ulcer Photo
Dendritic ulcer :
Clinical Signs

branching morphology with terminal bulbs

Geographic ulcer :
large amoeboid ulcer with dendritic advancing
How to differentiate metaherpetic
edges
from a geographic ulcer?
more common in inmmunocompromised/topical
steroid
Metaherpetic (trophic) ulcer :
chronic recurrent superficial postherpetic disease
without any detectable hsv-activity,
neurotrophicity occurs and corneal healing is
problematic
Metaherpetic
- no live virus
- trophic : arises de novo
- metaherpetic : follows a dendritic or geographic ulcer
* terms used interchangeably
- causes : antiviral medication toxicity, loss of innervation and neural-
derived growth factors, poor tear surfacing, underlying low-grade stromal
inflammation
- often difficult to differentiate from geographic ulcer

Geographic Ulcer Metaherpetic ulcer

Swollen, scalloped borders Smooth, gray, elevated borders

Margin does not stain with Rose Bengal,

Margin stains with Rose Bengal
but stains with fluorescein
- devitalized viral-infected
- fluorescein leaks through poorly
epithelial cells (underwent
adherent cells into stroma and stains
acantholysis)
periphery = reverse staining
 Corneal Layer Nomenclature Alternate Term

Epithelium Dendritic Corneal Ulcer

HSV epithelial keratitis
Geographic Corneal Ulcer
Classification

Non necrotising keratitis

HSV stromal keratitis
Interstital keratitis
Stroma without ulceration
Immune stromal keratitis

with ulceration Necrotising keratitis

Endothelium Disciform keratitis/

HSV endothelial keratitis
Endotheliitis
 Stroma
- immune mediated response to nonreplicating viral particles
- all layers of cornea are affected
- may involve trabecular meshwork and iris

Signs
Clinical Signs

Multiple or diffuse opacities -> corneal vascularisation

Lipid exudation
Scarring or may lead to thinning
AC activity
 Signs Photo
Necrotising keratitis
- inflammation in cornea is due to reaction to live viral
particles in corneal stroma
- corneal melting and perforation
- a/w uveitis and trabeculitis that may lead to recalcitrant
Clinical Signs

glaucoma
Immune stromal keratitis
- manifests as focal, multifocal or diffuse stromal opacitiies
or an immune ring
- stromal edema
- mild AC reaction
Interstitial keratitis
- vascularisation
- with above signs
Keratouveitis
- granulomatous with large 'mutton fat' KPs on endothelium
- synechiae, cataract, glaucoma
- high IOP
 Corneal Layer Nomenclature Alternate Term

Epithelium Dendritic Corneal Ulcer

HSV epithelial keratitis
Geographic Corneal Ulcer
Classification

Non necrotising keratitis

HSV stromal keratitis Interstital keratitis
Stroma without ulceration Immune stromal keratitis

with ulceration Necrotising keratitis

Endothelium
HSV endothelial keratitis Disciform keratitis
 Endothelium (Endotheliitis/Disciform)
- probably results from viral antigen hypersensitivity rather than reactivation
- manifests as overlying stromal edema from endothelial dysfunction
- longstanding stromal edema leads to scar -> major cause of reduced vision
Signs Photo
Clinical Signs

central/paracentral disc of corneal

edema
descemet's folds

mild AC activity

fine KPs
 Endothelium (Endotheliitis/Disciform) -cont
- probably results from viral antigen hypersensitivity rather than reactivation

Signs Photo
Wessely ring
Clinical Signs

- stromal halo of precipitated viral

antigen/host antibody
- immune ring of deep stroma signify
deposition antigen antigen complex
high IOP

chronic anterior uveitis

 - Usually a clinical diagnosis

Ix

Giemsa stain
Investigation

- Multinuclear giant cells

(Tzanck smear)

Viral culture
- IMR
Viral PCR
- DNA lab SDN Bangi

Consider FBS/FBC/RP/LFT
Initial Treatment - medication therapy Diagnosis Treatment Plus Plus
T Acylclovir 400mg 5x/day
OR
ATPF (esp
Occ Acylclovir 3% 5x/day
coexistent
Epithelial keratitis (if available) Gentle debridement
ocular surface
X10-14 days, continues at least 3 days disease)
after healing
Geographic ulcer: 800mg

HSV stromal keratitis T Acylclovir 400mg 5x/day

G Maxidex 0.1% OD-QID
without ulceration X10 weeks++ (if available)
(epithelium intact) X10 weeks++ (tapering dose)
(tapering dose)

T Aclyclovir 400mg 5x/day +- Occ Acylclovir 3% 5x/day

HSV stromal keratitis
X10 weeks++ Once epithelium heals:
with ulceration
(tapering dose) add G Maxidex

Recurrent epithelial/ T Acylclovir BD X1 year++

stromal keratitis (for prophylaxis and depends on cases)

G Maxidex 0.1% QID

x4 weeks++ (titrating down)
T Acylclovir 400mg 5x/day X4
Endotheliitis *Aim for minimum effective dose. weeks ++
Some patients require low dose eg OD
or even maintenance.
Initial Treatment - medication therapy Diagnosis Treatment
T Acylclovir 400mg 5x/day
Plus Plus

ATPF (esp
OR coexistent
Epithelial
Occ Acylclovir 3% 5x/day Gentle debridement ocular
keratitis
X10-14 days, continues at surface
least 3 days after healing disease)

HSV stromal
keratitis without T Acylclovir 400mg 5x/day
G Maxidex 0.1% OD-QID
ulceration X10 weeks++
(epithelium X10 weeks++ (tapering dose)
(tapering dose)
intact)

HSV stromal How400mg

T Aclyclovir frequent +-up???
to follow
5x/day Occ Acylclovir 3%
5x/day
keratitis with X10 weeks++
ulceration Once epithelium heals:
(tapering dose)
add G Maxidex
Recurrent T Acylclovir BD X1 year++
epithelial/ (for prophylaxis and depends
stromal keratitis on cases)
G Maxidex 0.1% QID
x4 weeks++ (titrating down) T Acylclovir 400mg 5x/day
Endotheliitis *Aim for minimum effective dose. X4 weeks ++
Some patients require low dose eg
OD or even maintenance.
Initial Treatment - medication therapy Diagnosis Treatment
T Acylclovir 400mg 5x/day
Plus Plus

ATPF (esp
OR coexistent
Epithelial
Occ Acylclovir 3% 5x/day Gentle debridement ocular
keratitis
X10-14 days, continues at surface
least 3 days after healing disease)

HSV stromal
keratitis without T Acylclovir 400mg 5x/day
G Maxidex 0.1% OD-QID
ulceration X10 weeks++
(epithelium X10 weeks++ (tapering dose)
(tapering dose)
intact)

HSV stromal When

T Aclyclovir 400mg 5x/day +- Occ Acylclovir 3%
to admit?
5x/day
keratitis with X10 weeks++
ulceration Once epithelium heals:
(tapering dose)
add G Maxidex
Recurrent T Acylclovir BD X1 year++
epithelial/ (for prophylaxis and depends
stromal keratitis on cases)
G Maxidex 0.1% QID
x4 weeks++ (titrating down) T Acylclovir 400mg 5x/day
Endotheliitis *Aim for minimum effective dose. X4 weeks ++
Some patients require low dose eg
OD or even maintenance.
 •>1.5mm diameter infiltrate
Indication for Admission

•centrally located (vision threatening)

•hypopyon
Severe infection
•purulent exudate
•complicated ocular and systemic
problem
Poor compliance to meds/TCA

Failure to improve
Precious eye
Paediatrics
 Surgery
Treatment - Surgery

Penetrating keratoplasty (PK)

Conjuctival flap

Amniotic membrane (AM)

Herpetic Eye Disease Study (HEDS)
Aim: to assess the effect of adding steroids and aciclovir to conventional therapy
with trifluridine
- Herpes stromal keratitis, not on steroids trial
Patients who received prednisolone phosphate drops had FASTER resolution
and fewer treatment failures
* limitation: steroid regimen was standardized and not tailored to inflammation

- Herpes stromal keratitis, on steroid treatment

No apparent benefit to adding oral aciclovir to topical corticosteroids and TFT.
However VA improved over 6months in more patients in aciclovir group
* limitation: oral aciclovir was only used for 3 weeks

- HSV epithelial keratitis trial

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

- Aciclovir prevention trial

Oral aciclovir reduced risk of recurrent ocular herpes by 41% and stromal
keratitis by 50%.
Risk of multiple recurrences decreased from 9% to 4%
 Risk of future recurrence

Risk %
H/O HSV stromal keratits 28%
H/O HSV epithelial & endothelial
3%
keratitis
Remember..

High number of previous episodes of

No data
recurrences
Short interval between attacks usually
associated with short interval during No data
future attacks
Neonatal Herpex Simplex Infection

Congenital HSV infection is a rare entity (4%)

Occurs almost 1 in 300,000 deliveries

When to suspect?
üall neonates present in 1st month of life with non specific symptoms
(occasionally 4-6weeks of life)
üany vesicular rash up to 8 weeks old
übody fluid culture for HSV
Neonatal Herpex Simplex Infection 3 subtypes: localised (50%), encephalitis (33%), disseminated (17%)

Ophthalmic sx:
ümicroophthalmia
ükeratitis
üchorioretinitis
üoptic atrophy

Complication
üCorneal complication
üLong standing disciform keratitis- bullous keratopathy
üDeep vascular stromal scarring – secondary lipid keratopathy
üStromal inflammation leads to corneal scarring then astigmatism

Treatment
üIV Aciclovir 20mg/kg TDS X14days,
üif involving CNS/desseminated - X21days
üTopical Trifluorothymidine, Vidarabine
üSteroids contraindicated
Herpes Zoster Opthalmicus

• Neurocutaneous disease caused by HHV3 (VZV)

• Lifetime risk is 20-30% and 50% of those living until
85yo will be affected
• Physical trauma and surgery have been correlated with
development of zoster
 ØInitially, starts with pain along dermatome (Va)
Ø2-3days later, vesicular eruption occurs
ØLesions continue to form for about 3-5days
Signs and Symptoms

CHARACTERISTICS OF RASH
ØUnilateral, do not cross midline
ØCrops of vesicles on an erythematous base
ØAlong dermatome
ØHyperesthetic
ØSevere pain
ØPapule->Vesicle->Pustule->Scab
 Diagnosis

Systemic and cutaneous disease

Epithelial keratitis
Classification

Stromal keratitis

Disciform keratits

Neurotrophic ulcer
 Diagnosis

Cutaneous disease

Epithelial keratitis
Classification

Stromal keratitis

Disciform keratits

Neurotrophic ulcer
 Systemic and Cutaneous Disease

Signs Photo
Viral prodrome and rash
Clinical Signs

-Predominantly within one

dermatome, Va (ophthalmic nerve)
-May be diseeminated in the
immunocompromised
Hutchinson’s sign positive
-Cutaneous involvement of tip of nose,
indicating nasociliary nerve
involvement and likelihood of ocular
complications

*The resultant neurotrophic cornea is vulnerable to bacterial and fungal

keratitis
 Diagnosis

Systemic and cutaneous disease

Epithelial keratitis
Classification

Stromal keratitis

Disciform keratits

Neurotrophic ulcer
 Epithelial keratitis
-Common
-Acute (onset 2-3days after rash, resolves in few weeks)
Signs
SPK with pseudodendrites
Clinical Signs

- tapered end
- elevated with central ulceration
- no terminal bulbs
- relative lack of staining
Anterior stromal infiltrates
 Diagnosis

Systemic and cutaneous disease

Epithelial keratitis
Classification

Stromal keratitis

Disciform keratits

Neurotrophic ulcer
 Stromal keratitis

Signs

Nummular keratitis with stromal granular deposits

Clinical Signs

-Rare
-Occurs early (10 days)

Necrotising interstitial keratitis with stromal infiltrates

Thinning
Perforation
-Rare
-Occurs late (3months-years)
 Diagnosis

Systemic and cutaneous disease

Epithelial keratitis
Classification

Stromal keratitis

Disciform keratits

Neurotrophic ulcer
 Disciform keratitis
-Chronic, uncommon
-Late onset (3months-years)

Signs

Endotheliitis with disc of corneal oedema

Clinical Signs

Descemet’s folds

Mild AC activity

Fine KPs
 Diagnosis

Systemic and cutaneous disease

Epithelial keratitis
Classification

Stromal keratitis

Disciform keratits

Neurotrophic ulcer
 Neutrophic ulcer
-Chronic, uncommon
-Late onset
Signs Photo
Clinical Signs

Persistent epidefect
- Due to corneal nerve damage

Thinning

Perforation
 Conjuctivitis

Secondary microbial keratitis

Complications - Ocular

Episcleritis

Scleritis

Anterior uveitis

Glaucoma
- pupillary block glaucoma secondary to
PS with resultant iris bombe

Posterior subcapsular cataract

 Horner's syndrome
Tonic pupil secondary to herpes zoster
Complications - Ocular

ciliary ganglionitis
 Vitreous hemorrhage
Necrotizing retinitis
Intravitreal injections of antiviral
Complications - Ocular

- acute retinal necrosis (ARN)

therapy, most commonly ganciclovir and
- progressive outer retinal necrosis foscarnet
(PORN)

Retinal hemorrhage

CRAO

Optic neuritis
- due to local transmission of virus within
orbit from 5th to 2nd cranial nerve
Cranial nerve palsies causing
ophthalmoplegia
Complications - Systemic

Stroke (cerebral vasculitis)

Neuralgia
 - Usually a clinical diagnosis

Ix

Viral PCR
-Conjuctival and corneal swabs or AC paracentesis of aqueous in
Investigation

keratouveitis (diagnostic)
-DNA Lab SDN Bangi
 Diagnosis Treatment Plus
Initial Treatment - medication therapy Systemic antiviral:
T Aciclovir 800mg 5x/day
X7-10days
If immunosuppressed, IV
Aciclovir 10mg/kg TDS
Cutaneous disease
*start as soon as rash
appears
(up to 72H of rash onset or
when vesicles still active)

Plus
Epithelial keratitis G ATPF
G Maxidex 0.1%
X4-6weeks (only when Threatened
Stromal and disciform epithelium intact) perforation may
keratitis *Some may require low dose require gluing, BCL or
(OD/EOD) for months or tectonic grafting
even maintenance
Consider tarsorrhaphy
Occ Duratears ON (surgical or medical with
Neurotrophic ulcer G ATPF botulinum toxin-induced
ptosis), AMG or conjuctival
flap
G Atropine
Anterior uveitis G Maxidex 0.1% (cyclopegic for comfort
or AC activity)
 Diagnosis Treatment Plus
Initial Treatment - medication therapy Systemic antiviral:
T Aciclovir 800mg 5x/day X7-
10days
If immunosuppressed, IV
Systemic and Aciclovir 10mg/kg TDS
cutaneous disease *start as soon as rash
appears
(up to 72H of rash onset or
when vesicles still active)

Plus
Epithelial keratitis G ATPF
G Maxidex 0.1%
X4-6weeks
How(only when to follow
frequent Threatened
up???
Stromal and disciform epithelium intact) perforation may
keratitis *Some may require low dose require gluing, BCL or
(OD/EOD) for months or tectonic grafting
even maintenance
Consider tarsorrhaphy
Occ Duratears ON (surgical or medical with
Neurotrophic ulcer G ATPF botulinum toxin-induced
ptosis), AMG or conjuctival
flap
G Atropine
Anterior uveitis G Maxidex 0.1% (cyclopegic for comfort
or AC activity)
 Diagnosis Treatment Plus
Initial Treatment - medication therapy Systemic antiviral:
T Aciclovir 800mg 5x/day X7-
10days
If immunosuppressed, IV
Systemic and Aciclovir 10mg/kg TDS
cutaneous disease *start as soon as rash
appears
(up to 72H of rash onset or
when vesicles still active)

Plus
Epithelial keratitis G ATPF
G Maxidex 0.1%
X4-6weeks (only when to admit?
When Threatened
Stromal and disciform epithelium intact) perforation may
keratitis *Some may require low dose require gluing, BCL or
(OD/EOD) for months or tectonic grafting
even maintenance
Consider tarsorrhaphy
Occ Duratears ON (surgical or medical with
Neurotrophic ulcer G ATPF botulinum toxin-induced
ptosis), AMG or conjuctival
flap
G Atropine
Anterior uveitis G Maxidex 0.1% (cyclopegic for comfort
or AC activity)
 •>1.5mm diameter infiltrate
Indication for Admission

•centrally located (vision threatening)

•hypopyon
Severe infection
•purulent exudate
•complicated ocular and systemic
problem
Poor compliance to meds/TCA

Failure to improve
Precious eye
 Post herpetic neuralgia!!
<4% will have this; persists months-years-permanent
TREATMENT:
Remember..

T Amitriptylline OR T Gabapentin

Capsaicin cream
 Report of the UKM Clinical Pathways & Algorithms for Ophthalmology
Clinicians Workshop 2018 -1st edition
www.aao.org

www.aafp.org
Reference

www.msdmanuals.com