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DR - Gaurav Shukla DR - Jyoti Batra DR - Uma Sridhar
DR - Gaurav Shukla DR - Jyoti Batra DR - Uma Sridhar
GAURAV SHUKLA
DR.JYOTI BATRA
DR.UMA SRIDHAR
Viruses
Viruses are small (10–400 nm in diameter)
infectious units with a single- or double-stranded
nucleic acid genome
Direct contact
Salivary droplets
Direct oral contact
Pathophysiology
Enters a peripheral
nerve
Travels by axonal
transport to neuronal
cell bodies
Into the nucleus of
the neuron on the
superior cervical
ganglia and the
trigeminal ganglia.
HSV cycle –
• HSV is epitheliotrophic
Vesicular blepharitis
Primary or secondary HSV
Usually benign, self-limited
+/- Follicular conjunctivitis
Epithelial/stromal involvement
Epithelial Herpes
Hypoesthesia
Nasal Hypoesthesia/Lesions
Labial Hypoesthesia/Lesions
Conjunctival Follicles
Watery Discharge
Pre-auricular lymphadenopathy
HSV Ocular Signs
Ocular
manifestations are
varied
Blepharitis
Conjunctivitis
Keratitis
Uveitis
Retinitis
Dendrite is
pathognomonic
HSV ocular infection different from that associated with
Adenovirus include-
Cutaneous or eyelid margin vesicles, or ulcers on the
bulbar conjunctiva (HSV)
Oral antiviral
therapy speeds
resolution of
signs and
symptoms
Antiviral medicines used in treatment of Herpes Simplex Virus
Ocular Disease
Antiviral Route Form Frequency Action
Idoxuridine Topical 0.1% Hourly while Inhibits viral thymidine
solution awake kinase, thymidylate
kinase and DNA
polymerase
Vidarabine Topical 3% 5 times daily Inhibits viral DNA
ointment polymerase
Trifluridine Topical 1% Every 2 Inhibits viral
solution hours while thymidylate synthetase
awake
Acyclovir Topical 3% 5 times daily Activated by viral
ointment thymidine kinase to
Oral 200/400/ 400 mg 5 inhibit DNA polymerase
800 DT times daily
Ophthalmology 2004, 2; 475-482
Recurrent ocular infection
PATHOGENESIS
Recurrent HSV infection - by reactivation of the virus
in a latently infected sensory ganglion,
Visualized by fluorescein
staining Usually multiple
and small dendrites with
“terminal bulbs” in
primary infection
Live virus
Debridement can be curative
Corneal sensation is
diminished
Herpetic stromal keratitis
can be non-necrotizing
Stromal Keratitis (interstitial or disciform)
or
Presents as corneal
stromal and epithelial
edema in a round or oval
pattern
Corneal stromal
vascularization is
common
Active immune stromal keratitis.
Inactive immune stromal keratitis.
Presentations
Irritation
Pain
Watering
Photophobia
Occasional blurring of vision
Corneal sensations temp reduced or absent
Management
Many past controversies regarding the optimal
management of HSV stromal keratitis have been resolved
by the HEDS trial
Diagnosis - by a unilateral
presentation associated with an
elevated IOP with or without focal
iris transillumination defects.
Complications of infectious epithelial
keratitis
Complications of herpetic eye disease affect all layers of
the cornea
Resolve without corneal scar formation
Subepithelial scarring
Dense stromal scarring
Corneal thinning
Dendritic epitheliopathy
Neurotrophic keratopathy
stromal keratitis
Metaherpetic Ulcer
Chronic STERILE
macroulceration
NO stromal infiltration
Epithelium unable to
heal
May be Assoc. with
toxicity of antiviral
drops
TX: Stop or taper off
antiviral drugs
Lubrication
Large
neurotrophic
ulcer
Neurotrophic Treatment
Treatment
Lubricants
Bandage CL, patching
Conjunctival flap or tarsorrhaphy
Management-
Identify-
Epithelial keratitis
Superficial Stromal Keratitis
Necrotizing Stromal Keratitis
Endothelial keratitis
Neurotrophic keratitis
Treatment
Sign dependent
Epithelial Herpes
Cytology
Cultures
ELVIS (modified culture)
Enzyme Linked Viral
Inducible System
Immunoassays
Enzyme-Linked
Immunosorbent Assays
(ELISA)
Direct Fluorescent
Antibody Test
HerpCheck
Epithelial HSV Treatment
Trifluridine (Viroptic)
Artificial Tears
Acyclovir (Zovirax)
Adjunctive therapy
Vidarabine (Vira-A)
Idoxuridine
Epithelial Debridement
Cidofovir 0.2% and 1% (Vistide), qid
FDA approved for CMV (1996), I.V.
Interferes with DNA polymerase
Local toxicity
Antiviral resistance
HEDS Trials
5 Studies
1994 - 1997
HEDS study One:
Oral acyclovir for herpes simplex for STROMAL
keratitis (n = 104)
PO acyclovir (n=51) vs. topical steroids and trifluridine
(n=53)
Included both necrotizing and non-necrotizing stromal
keratitis
No clinically significant beneficial effect of oral
acyclovir in treating HSV stromal keratitis
receiving concomitant steroid and trifluridine gtts.
Barron BA, Gee L, Haouck WW, et al. Herpetic Eye Disease study. A controlled trial of oral acyclovir for herpes simplex
stromal keratitis. Ophthalmol 1994, 101:1883-1896.
HEDS: study Two
Topical corticosteroids for herpes simplex
STROMAL keratitis (n=106)
Placebo (n=49) vs. steroid group (n=57) tapered over 10
weeks. Both groups received topical trifluridine.
Corticosteroid tx reduced the risk of persistent or
progressive stromal keratouveitis by 68%
Topical Steroid treatment was significantly
better than placebo in reducing persistence or
progression of stromal inflammation and in
shortening the duration.
Wilhelmus KR, Gee L, Hauck WW et al. Herpetic Eye Disease Study Group. A controlled trial of topical corticosteroids
for herpes simples stromal keratitis. Ophthalmol 1994, 101:1883-1896.
HEDS: study Three
Evaluate adding oral acyclovir to a regimen of
topical prednisolone phosphate and trifluridine
for HSV iridocyclitis. (n=50)
10-week course of acyclovir 400 mg 5x/day
Treatment failure in 50% of the acyclovir treated group
(n=22) vs. 68% in placebo (n=28)
Possible benefit of PO acyclovir for HSV
iridocyclitis. # pts too small for statistically
significant result.
Herpetic Eye Disease Study Group. A controlled trial of oral acyclovir for iridocyclitis caused by herpes simplex virus.
Arch Ophthalmol 1996, 114:1065-1072.
HEDS: study Four
Oral acyclovir for the PREVENTION of stromal
keratitis or HSV iritis in patients with
EPITHELIAL keratitis. (n=287)
3 week course of PO acyclovir 400 mg 5x/day (n=153) vs.
placebo (n=134) in addition to trifluridine for their
epithelial disease.
Stromal keratitis or iritis developed in 11% of the
acyclovir group and in 10% of the placebo
No benefit of 3-week course of PO acyclovir
for pts with epithelial disease in preventing
HSV stromal keratitis or iritis.
The Herpetic Eye Disease Study Group: the epithelial keratitis trial. A controlled trial of oral acyclovir for the prevention of
stromal keratitis or iritis in patients with herpes simplex virus epithelial keratitis. Arch Ophthalmol 1997, 115:703-712.
HEDS: study Five
Oral acyclovir as prophylaxis for the prevention of
recurrent ocular HSV disease. (n=346)
12 month treatment period at 400 mg BID (n=357) vs.
placebo (n=346)
Recurrence of any type of ocular HSV was 19% in
acyclovir group and 32% in the placebo group.
The Herpetic Eye Disease Study Group: acyclovir for the prevention of recurrent herpes simplex virus eye disease. N
Engl J Med 1998, 339:300-306.
HEDS: Trial Five
In a subset of patients with a history of stromal
keratitis, the probability of recurrent stromal
keratitis was 14% in the acyclovir group and 28% in
placebo group.
The probability of a recurrence of nonocular
(orofacial) HSV disease was also lower in the
acyclovir group (19% vs 36%)
Oral acyclovir prophylaxis for one year
significantly reduces the risk of recurrent
ocular and orofacial HSV, especially in pts with
previous stromal keratitis.
The Herpetic Eye Disease Study Group: acyclovir for the prevention of recurrent herpes simplex virus eye disease. N
Garcia DD, Farjo Q, Musch DC, et al. Effect of prophylactic oral acyclovir after penetrating keratoplasty for herpes
simplex keratitis. 2007, 26:930-934.
Recent review (2007) on tx of HSV epithelial
keratitis support the use of topical trifluridine and
topical or oral acyclovir, and suggest a possible
additional benefit for topical interferon.
Wilhelmus KR. Therapeutic interventions for herpes simplex virus epithelial keratitis. Cochrane Database Syst. Rev
2007, 1:CD002898
One year suppression therapy with PO
valacyclovir (500 mg QDay) was shown to be as
effective and as well tolerated as acyclovir (400 mg
BID) in reducing the rate of recurrent ocular HSV
disease
Miserocchi E, Modorati G, Galli L, et al. Efficacy of valacyclovir vs. acyclovir for the prevention of recurrent herpes simplex
eye disease. A pilot study. 2007, 144:547-551.
Herpes Zoster Virus
Varicella-Zoster
Long History
VZV causes a primary infection (varicella, or
chickenpox)
Subsequent latency, occasionally followed later by
recurrent disease (zoster, or shingles)
Systemic malignancy
Radiation injury
HZV Infection
Primary infection-from a contagious individual
Initially infects the upper respiratory mucosa or
conjunctiva.
Infects the capillary endothelium
spreads locally to the epidermis
As with HSV, VZV latency occurs in neural ganglia and, in
approximately 20% of infected individuals, reactivates
later.
Of all cases with zoster, 15% involve the ophthalmic
division of CN V (trigeminal)
Pathology
Trigeminal nerve
Infiltrated with lymphocyte
Infiltration of the Long Post Ciliary Nerve
Causes demyelination
Sensory cells
Sensory nucleus in the brainstem
Herpes Zoster Signs and Symptoms
Ophthalmic Signs Non-Eye Signs/Sx
Mucopurulent Redness & warmth
discharge Dermatological pain
Fine punctate epithelial Tic Douloureux
keratitis Vesicular skin lesions
Dendritic keratitis
Fever
Malaise
Depression.
Most common
dermatome=T3 to L3 &
supplied by CN 5
Skin Lesions
60% experience
dermatomal pain
before skin lesions.
Macule-Papules –
vesicle-pustule
Vesicles - Serous fluid
Pustule- pus filled-
ruptured
become covered with
crusts.
Lesions do not cross
the midline of the face
Hutchinson sign
Vesicles on the tip of the
nose, or vesicles on the side
of the nose, precedes the
development of
ophthalmic herpes zoster
This occurs because
the nasociliary branch of the
trigeminal nerve innervates
both the cornea and the
lateral dorsum of the nose as
well as the tip of the nose.
Associated Findings
Fatigue
Malaise
Low-grade fever
Depression
Ocular Findings
Punctate epithelial
keratitis (PEK)
As early as one or two days
after the initial skin rash.
Follicular conjunctivitis
Pseudodendritic keratitis
w/o terminal bulbi
Stromal inflammation
Neurotrophic keratitis
Rare Findings
Disciform keratitis
Uveitis, retinitis.
Nummular corneal
infiltrates = characteristic
of zoster stromal keratitis