This document discusses viruses, specifically herpes simplex virus (HSV). It provides details on HSV including that it is a double stranded DNA virus that can establish latent infections in sensory ganglia. It then describes the various clinical manifestations of HSV infection, including epithelial keratitis, stromal keratitis, iridocyclitis, and neurotrophic keratitis. The document outlines treatments for different manifestations of HSV infection, noting that topical antivirals and corticosteroids are commonly used depending on the specific presentation. It also summarizes findings from the Herpes Eye Disease Study trials regarding optimal treatment approaches.

1. DR.GAURAV SHUKLA

2. Viruses-
 Viruses are small (10 – 400 nm in diameter)
infectious units with a single- or double-stranded
nucleic acid genome
 A protein capsid shell, with or without an external
lipid envelope

3.  Herpes Simplex Virus (HSV)
 Herpes Zoster Virus (HZV)
 Epstein-Barr Virus (EBV)
 Cyto-Megalo Virus (CMV)
 Adeno-Viral Infections
 Epidemic Keratoconjuctivitis (EKC)
 Pharyngoconjunctival Fever (PFC)

4. Herpes Simplex Virus
 Herpes virus infections have been prevalent as early as
ancient Greek times.
 Hippocrates is known to have described the cutaneous
spreading of herpes simplex lesions
 Greek word "herpes" to mean "to creep or crawl"

5.  Enveloped linear double stranded DNA viruses.
 Genome - long and short fragments
 Three subfamilies:-
 Alphaherpesviruses - HSV-1, HSV-2, VZV
 Betaherpesviruses - CMV, HHV-6, HHV-7
 Gammaherpesviruses - EBV, HHV-8
 Set up latent or persistent infection following primary
infection
 Reactivation - periods of immunosuppression
 Both primary infection and reactivation - more serious in
immunocompromised patients.

6.  HSV is highly ubiquitous
 Leading cause of unilateral corneal blindness in the
developing world.
 80%-90% of adults have been infected
 25% have ocular manifestation of disease
 95% of clinical disease is seen as a reoccurrence
 Reoccurrence of can be triggered by variety of sources
 Ocular HSV tends to be a unilateral disease with
only one eye affected by primary disease in
approximately 80-90% of cases

7. Modes of infection
 HSV - commonly acquired in adolescence than in
childhood
 IP = 3-9 days
 Humans are natural reservoir of HSV
 Children with primary disease
 Adults with recurrent disease
 Healthy asymptomatic carrier

8. Transmission of infection
 Direct contact
 Salivary droplets
 Direct oral contact

9. 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.

11. HSV cycle –
• HSV is epitheliotrophic
• Affects ectodermic tissue
Attach to sp receptor on human cells‣‣ enter cells by
pinocytosis‣‣ viral DNA released into cells ‣‣ In the nucleus
thymidine kinase and DNA polymerase are formed‣‣ Viral
proteins are synthesized in cytoplasm‣‣ transferred to
nucleus‣‣ nuclear caspid is assembled‣‣ it gains envelope
breaking through nuclear membrane

13. Latency
 Ganglia in a latent
state.
 Reactivated, it travels
via the axons to the
cornea
 Shed and produce
recurrent disease in
cornea

14. Primary infection
 Occurs by direct inoculation
 Newborns protected by anti-herpetic antibodies
 Most cases subclinical
 Primary HSV-1 infection -commonly on skin and mucosal
surfaces innervated by CN V.
 HSV manifests by ---
Cutaneous involvement
Vesicular periocular skin eruptions, vesicular ulcerative
blepharitis
Acute follicular conjunctivitis.

15. Keratoconjunctivitis
- Punctate keratitis
-Diffuse branching epithelial keratitis
-Microdendrite
Stromal reaction is not seen

16. Recurrent Infections
Predisposing factors:
-Stress
-Recent fever, flu
-Surgical dental procedures
-Exposure to UV rays
-Emotional & physical exhaustion
-Menstrual stress
-Steroids
-Immunosuppresant

17. Primary Ocular HSV Infection
 Typically manifests - blepharoconjunctivitis.
 The conjunctival inflammatory response - follicular
and palpable preauricular lymph node.
 Vesicular blepharitis
 Primary or secondary HSV
 Usually benign, self-limited
 +/- Follicular conjunctivitis
 Epithelial/stromal involvement

20. Epithelial Herpes
 Hypoesthesia
 Nasal Hypoesthesia/Lesions
 Labial Hypoesthesia/Lesions
 Conjunctival Follicles
 Watery Discharge
 Pre-auricular lymphadenopathy

21. HSV Ocular Signs
 Ocular
manifestations are
varied
 Blepharitis
 Conjunctivitis
 Keratitis
 Uveitis
 Retinitis
 Dendrite is
pathognomonic

22.  HSV ocular infection different from that associated with
Adenovirus include-
 Cutaneous or eyelid margin vesicles, or ulcers on the
bulbar conjunctiva (HSV)
 Dendritic epithelial keratitis (HSV)
 Conjunctival membranes or pseudo-membrane
(adenovirus)

23. Wellard and schwartz classification
 (1) Infectious epithelial keratitis,= Cornea vesicles,
dendritic ulcer, geographic ulcer, and marginal ulcer.
 (2) Neurotrophic keratopathy= Punctate epithelial
erosions and neurotrophic ulcer.
 (3) Stromal keratitis=Necrotizing stromal keratitis
and immune stromal keratitis.
 (4) Endothelitis, =Disciform, diffuse, and linear.
Wellard , schwartz Department of Ophthalmology, University of Minnesota, Minneapolis 55455-0501,
Cornea 1999 Mar;18(2):144-54

24. Laboratory evaluation
 Serologic tests for neutralizing or complement-fixing
immunoglobulins may show a rising antibody titer during
primary infection
 No diagnostic assistance during recurrent episodes
 Indicated in complicated cases when the clinical diagnosis
is uncertain and in all cases of suspected neonatal herpes
infection

25.  Vesicular fluid can be cultured
 Scrapings from the vesicle base
 Conjunctival scrapings or impression cytology specimens
can be similarly analyzed by culture, antigen detection, or
PCR.

26.  MANAGEMENT
Primary ocular
HSV infection is
a self-limited
condition.
 Oral antiviral
therapy speeds
resolution of
signs and
symptoms

28. Recurrent ocular infection
 Pathogenesis -
 Recurrent HSV infection - by reactivation of the virus
in a latently infected sensory ganglion,
 Transport of the virus down the nerve axon to sensory
nerve endings, and subsequent infection of ocular
surface epithelia

29. Corneal Signs-
Patients with primary ocular HSV infection can develop epithelial
keratitis.
There are many presentations dependent of the strain of the virus.
We can have punctate keratitis, or dendritic lesions.

30. Corneal Signs-
 Punctate keratitis
 Dendritic ulcers
 Geographic ulcers
 Stromal keratitis
 Endothelitis

31. Lesions:-
Dendritic ulcer-
 Most characteristic lesion,
occurs in corneal epithel.
 Typical branching, linear
pattern with feathery edges
and terminal bulbs at ends.
 Visualized by fluorescein
staining Usually multiple
and small dendrites with
“terminal bulbs” in
primary infection

32. Dendritic keratitis -
Debridement can be curative
Live virus
Risk of recurrence is 30% within 2 years
This patient suffers from herpetic keratitis.
Fluorescein staining reveals dendritic ulcer typical of herpes
keratitis.

34. Recurrent herpes simplex virus dendritic ulcer with an
adjacent stromal scar.

36.  Epithelial Keratitis
 Usually single “beefier”
dendrites
 Live virus
 Assoc. with decrease
corneal sensation and
patchy iris atrophy
 Can leave “ghost
dendritic” scar when
healed (as in primary
infection)

37.  Dendritic epithelial lesions include-
 VZV (see the discussion later in the chapter)
 Adenovirus (uncommon)
 EBV (rare)
 Epithelial regeneration line
 Neurotrophic keratopathy (postherpetic, diabetes)
 Soft contact lens wear (thimerosal)
 Topical medications (antivirals, β-blockers)
 Acanthamoeba epithelial keratitis
 Epithelial deposits (iron lines, Fabry disease,
tyrosinemia type II, systemic drugs)

38. Geographic ulceration
 Form of chronic dendritic
disease.
 Particularly with use of
topical corticosteroids
 Delicate dendritic lesions
take a broader form.
 Corneal sensation is
diminished

39. Stromal Keratitis-
 Herpetic stromal keratitis
can be non-necrotizing
(interstitial or disciform)
or
 Necrotizing, and different
forms may present
simultaneously

40. Direct viral invasion of the stroma
An immune process
White
Heavily Infiltrated
Necrotic
Thinning
Near Perforation

41.  Long-standing or multiply recurrent HSV interstitial
keratitis = corneal vascularization.
 The differential diagnosis of herpetic interstitial
keratitis includes-
 VZV keratitis
 Acanthamoeba keratitis
 syphilis
 EBV keratitis
 Mumps keratitis
 Sarcoidosis

42. Disciform keratitis-
 Most common form of stromal
disease in HSV infection.
 Edematous stroma without
significant infiltration and
without vascularization.
 Edema is most prominent
sign.
 Keratic precipitates may lie
directly under disciform lesion
but may also involve the
endothelial lesion.
Vaughan & Asbury’s General
Ophthalmology 16th Edition, 136

43.  Herpetic disciform
keratitis is a Primary
Endothelitis
 Presents as corneal
stromal and epithelial
edema in a round or oval
pattern
 In Disciform keratitis,
disc-shaped stromal
edema and kps appear
out of proportion to the
degree of ant chamber
reaction

44. Disciform Endothelitis
 Central corneal edema
 Keratic precipitates
 Iritis
 Responds well to
corticosteroids

45.  Necrotizing herpetic keratitis
appears as suppurative corneal
inflammation
 It may be severe, progress
rapidly, and appear clinically
indistinguishable from
fulminant bacterial or fungal
keratitis
 Corneal stromal vascularization
is common

47. Active immune stromal keratitis.

48. Inactive immune stromal keratitis

49. Presentations -
 Irritation
 Pain
 Watering
 Photophobia
 Occasional blurring of vision
 Corneal sensations temp reduced or absent

50. Management
 Many past controversies regarding the optimal
management of HSV stromal keratitis have been
resolved by the HEDS trial
 HEDS findings showed that topical corticosteroids
given together with a prophylactic antiviral reduce
persistence or progression of stromal inflammation
and shorten the duration of HSV stromal keratitis
 Long-term suppressive oral acyclovir therapy reduces
the rate of recurrent HSV keratitis and helps preserve
vision.

52. Stromal Herpes Treatment
 Topical Corticosteroids
 Trifluridine
 Artificial Tears
 Monitor closely

53.  Iridocyclitis-
 Granulomatous or non
granulomatous iridocyclitis may
accompany necrotizing stromal
keratitis or occur independently of
corneal disease.
 Main feature= Elevated intraocular
pressure (IOP) caused by
trabeculitis and/ may be found in
patients with HSV iridocyclitis.
 Diagnosis - by a unilateral
presentation associated with an
elevated IOP with or without focal
iris transillumination defects.

54. 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

55.  Metaherpetic Ulcer
 Chronic sterile macro-
ulceration
 No stromal infiltration
 Epithelium unable to
heal
 May be Associated with
toxicity of Antiviral
drops
 TX: Stop or taper off
antiviral drugs
 Lubrication

56. Large
neurotrophic
ulcer

57. Neurotrophic Ulcer Treatment
 Treatment-
 Lubricants
 Bandage Contact Lens, patching
 Conjunctival flap or tarsorrhaphy

58. Management-
 Identify-
 Epithelial keratitis
 Superficial Stromal Keratitis
 Necrotizing Stromal Keratitis
 Endothelial keratitis
 Neurotrophic keratitis
 Treatment-
 Sign dependent

59. Epithelial Herpes
 Cytology
 Cultures
 ELVIS (modified culture)
 Enzyme Linked Viral
Inducible System
 Immunoassays
 Enzyme-Linked
Immunosorbent Assays
(ELISA)
 Direct Fluorescent
Antibody Test
 HerpCheck

60. Epithelial HSV Treatment
 Trifluridine (Viroptic)
 Artificial Tears
 Acyclovir (Zovirax)
 Adjunctive therapy
 Vidarabine (Vira-A)
 Idoxuridine
 Epithelial Debridement

61.  Cidofovir 0.2% and 1% (Vistide), qid
 FDA approved for CMV (1996), I.V.
 Interferes with DNA polymerase
 Local toxicity
 Antiviral resistance

62. HEDS Trials
5 Studies
1994 - 1997

63. 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.

64. 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.

65. 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.

66. 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.

67. 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.

68. 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 non-ocular
(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
Engl J Med 1998, 339:300-306.

69.  Prophylactic oral
acyclovir use after PK
for HSV keratitis is
associated with
decreased episodes
of rejection and
improved graft
survival
Garcia DD, Farjo Q, Musch DC, et al. Effect of prophylactic oral acyclovir after penetrating keratoplasty for herpes
simplex keratitis. 2007, 26:930-934.

70.  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

71.  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.

72. 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)
 Primary VZV infection = direct contact with VZV skin
lesions or respiratory secretions via airborne droplets.

73.  Highly contagious for naive individuals
 VZV infection = Self limited infection of childhood
rarely associated with long-term sequelae
 Infection of adults or immunosuppressed can be fatal

74. HZV Risk Factors -
 Age-
 Immunodeficient conditions:-
 AIDS
 SLE
 Radiation Therapy
 Immuno-suppresion from medical therapies
 Systemic malignancy
 Radiation injury

75. 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)

76. Pathology-
 Trigeminal nerve
 Infiltrated with lymphocyte
 Infiltration of the Long Post Ciliary Nerve
 Causes demyelination
 Sensory cells
 Sensory nucleus in the brainstem

78. Herpes Zoster Signs and Symptoms
 Ophthalmic Signs-
 Mucopurulent discharge
 Fine punctate epithelial
keratitis
 Dendritic keratitis
 Non-Eye Signs/Sx-
 Redness & warmth
 Dermatological pain
 Tic Douloureux
 Vesicular skin lesions
 Fever
 Malaise
 Depression.
 Most common
dermatome=T3 to L3 &
supplied by CN 5

79. 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

80. 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.

81. Associated Findings-
 Fatigue
 Malaise
 Low-grade fever
 Depression

82. Ocular Findings
 Punctate epithelial
keratitis (PEK)
 As early as one or two days
after the initial skin rash.
 Follicular conjunctivitis
 Pseudo-dendritic keratitis
 w/o terminal bulbi
 Stromal inflammation
 Neurotrophic keratitis
 Rare Findings-
 Disciform keratitis Uveitis,
retinitis.

83.  Nummular corneal
infiltrates = characteristic
of zoster stromal keratitis
 Chronic corneal stromal
inflammation can lead to
corneal vascularization &
lipid keratopathy

84. Diagnosis-
 Clinical Presentations (mainly)
 Scraping from ulcer base, conjunctival Scrapings
or corneal impression cytology
 Immunological Reaction
 FAMA
 Fluorescent antibody to viral membrane antigen
 ELISA
 PCR
 Cytology

85. Prevention-
 A varicella-zoster vaccine was approved by the US
Food and Drug Administration (FDA) showed-
 a 50% reduction in incidence of zoster and
 a 66% reduction in postherpetic neuralgia

86. Treatment Objectives
1. Treat the eye
2. Treat the dermatitis
3. Treat the post-herpetic pain

87. Treatment -
 Dermatitis
 Topical Idoxuridine
 Topical Acyclovir
 Systemic Acyclovir
 Valcylcovir
 Famcyclovir

88.  The current recommendation for HZO is-
 Oral famciclovir 500 mg 3 times per day,
 valacyclovir 1 g 3 times per day,
 Acyclovir 800 mg 5 times per day for 7–10 days,
 Best if started within 72 hours of the onset of skin lesions
 Intravenous Acyclovir therapy (10 mg/kg every 8 hours)
is indicated in patients at risk for disseminated zoster
due to immunosuppression.

89. Chronic Pain –Postherpetic Neuralgia
 Cimetidine
 Tricyclic antidepressants
 Amitryptilline , Desipramine,clomipramine,
carbamazepin
 Corticosteroids
 Amantadine

90. Ocular Disease
 Must rule out H. simplex
 Topical corticosteroids
 Oral acyclovir
 Artificial Tears

91. Adenoviral Infections
 Adeno- (Greek): meaning of a gland or glands.
 Forty-nine serotypes subdivide into 6 distinct
subgroups (A–F) on the basis of genetic sequencing.
 D adenoviruses are strongly associated with epidemic
keratoconjunctivitis
 Gland: A specialized group of cells or organ that
separates certain elements from the blood and
secretes them.

92. Adenoviral Infections -
• Adenovirus- small, non-enveloped, DS-DNA
• Resistant to lipid solvents
• At least 49 identified Serotypes
 Most adenoviral eye disease presents clinically as 1 of 3 classic
syndromes:
 Simple follicular conjunctivitis (multiple serotypes)
 Pharyngoconjunctival fever (most commonly serotype 3 or 7)
 Epidemic keratoconjunctivitis (EKC; usually serotype 8, 19, or
37, subgroup D)

93. EKC
 Usually transferred by hands, instruments, and
solutions.
 Epidemics usually arise from optometrists and
ophthalmologists offices.
 Adenovirus can survive 35 days on a variety of surfaces
 Patients remain infectious for 14 days after onset of
symptoms

94. Clinical Symptoms
 Foreign Body Sensation
 Tearing
 Photophobia
 Sore Throat
 Breathing Problems
 Ptosis
 Ecchymosis

95. Clinical Signs-
 Follicular Conjunctivitis
 Tender and enlarged Pre
Auricular nodes
 Hyperemic Conjunctiva
 Petechial or subconjunctival
hemorrhage
 Fibrinous Discharge
 Pseudo-membrane
formation
 Subepithelial corneal
infiltrate

96. 21 day course
 Initial 7 days: exposure to onset of symptoms
 Days 7 & 8: conjunctival changes
 Days 9 & 10: appearance of Punctate Epithelial Keratitis
 Days 11 & 12: appearance of Sub Epi Infiltrate

97. Diagnosis -
 Usually Clinical
 Cytology-conjunctival
 Fluorescent Immuno-Assay
 Serology

98. Treatment -
 Mostly Palliative
 Cold compresses
 Limit exposure to others
 Artificial tears
 Topical vasoconstrictors
 Mild Topical Corticosteroids
 Especially with visually impairing SEI

99.  Always exclude HSV before any treatment
 Clean Instruments, counter-tops, hands, tonometer
tips
 Alcohol cleaners are ineffective.
 Follow-up Visits-
 Symblepharon formation
 Sweep Fornices

100. Thankyou