for ophthalmic residents

1. Herpetic eye disease
Othman Al-Abbadi, M.D

2. Herpes simplex keratitis
To Vichhey

3. Introduction
• Herpetic eye disease is the most common infectious cause of corneal
blindness in developed countries
• 60% of corneal ulcers in developing countries
• 10 million people worldwide may have herpetic eye disease
• Herpes simplex virus (HSV)
• Two subtypes are HSV-1 and HSV-2 => neuronal ganglia
• HSV-1 causes infection above the waist (principally the face, lips and eyes)
• HSV-2 causes acquired infection (genital herpes). Rarely HSV-2 transmitted to the eye
• HSV transmission is facilitated in conditions of crowding and poor hygiene

4. Introduction
• Primary infection
• Usually occurs in childhood
• Spread by droplet transmission, or less frequently by direct inoculation
• It is uncommon during the first 6 months of life (maternal antibodies)
• Symptom
• Mild fever, malaise and upper respiratory tract symptoms
• Blepharitis and follicular conjunctivitis (usually mild and self-limited)
• Treatment
• If necessary, involves topical acyclovir ointment
• There is unfortunately no evidence that antiviral treatment at this stage reduces the
likelihood of recurrent disease

5. Introduction
• Recurrent infection
• After primary infection: the virus is carried to the sensory ganglion for that
dermatome
• Subclinical reactivation
• Can periodically occur
• Are contagious
• Clinical reactivation
• A variety of stressors such as fever, hormonal change, ultraviolet radiation, trauma, or
trigeminal injury
• The pattern of disease
• Depend on the site of reactivation

6. Introduction
• Recurrent infection
• The rate for ocular recurrence
• After one episode is about 10% at 1 year and 50% at 10 year
• The higher the number of previous attacks the greater the risk of recurrence
• Risk factors for severe disease
• Which may be frequently recurrent, include atopic eye disease, childhood,
immunodeficiency or suppression, malnutrition, measles and malaria

7. Epithelial keratitis
1. Clinical features
Epithelial (dendritic or geographic) keratitis is associated with active virus
replication
•Presentation
• May be at any age with
• Mild discomfort
• Redness
• Photophobia
• Watering
• Blurred vision

8. Epithelial keratitis
1. Clinical features
•Signs in chronological order
• Swollen opaque epithelial cells arranged in a coarse punctate or stellate
pattern
• Central desquamation results in a linear-branching (dendritic) ulcer
• The ends of the ulcer have characteristic terminal buds and the bed of the
ulcer stains well with fluorescein
• Margin of the ulcer stain with rose Bengal
• Corneal sensation is reduced
• Mild associated subepithelial haze is typical
• Elevated IOP may occur
• Mild subepithelial scarring may develop after healing

10. Residual subepithelial haze

11. Epithelial keratitis
2. Treatment
•Topical
• Aciclovir 3% ointment or ganciclovir 0.15% gel (5 times daily)
• Trifluridine (up to nine times a day)
•Debridement
• Protect adjacent healthy epithelium from infection
• Eliminated the antigenic stimulus to stromal inflammation
•Oral antiviral
• Probably indicated in most immunodeficient patients, poorly tolerated, or in resistant cases
•Interferon
• Combination => speed healing
•Skin lesions
• Treated with acyclovir cream five times daily

12. Epithelial keratitis
2. Treatment
•IOP control
• If glaucoma treatment is necessary, prostaglandin derivatives should probably be avoided
•Tropical steroids
• Are not used unless significant disciform keratitis is also present
•Slow healing or frequent recurrence
• Combination of two topical agents with oral valaciclovir or famiciclovir

13. Disciform keratitis (Endotheliitis)
• The exact aetiology: controversial
• It may be active HSV infection of keratocytes or endothelium, or a
hypersensitivity reaction to viral antigen in the cornea
• Presentation (Symptoms)
• Gradual onset of blurred vision which may be associated with haloes around lights
• Discomfort and redness are common but tend to be milder than in purely epithelial disease

14. Disciform keratitis
• Signs
• A central zone of stromal oedema often with overlying epithelial oedema
• Keratic precipitates underlying the oedema
• Folds in Descement membrane in severe cases
• A surrounding immune ring of stromal haze
• IOP may be elevated
• Reduced corneal sensation
• Healed lesions
• Faint ring of stromal or subepithelial opacification and thinning,
• Superficial or deep vascularization

15. Epithelial and stromal oedema

16. keratic precipitates

17. Wessely ring

18. scarring from recurrent disease

20. Disciform keratitis
2. Treatment
• Initial treatment
• Topical steroids (prednisolone 1% or dexamethasone 0.1%) with antiviral cover, both
q.i.d for not less than 4 weeks
• Subsequently prednisolone 0.5% once daily is usually a safe dose at which to
stop topical antiviral cover
• With active epithelial ulceration
• Try to keep the steroid intensity as low as possible for adequate effect (b.d or t.i.d)
• With a more intensive antiviral (5 times daily)
• Topical cyclosporine 0.05%
• Particularly in presence of epithelial ulceration
• To facilitate tapering of topical steroids

21. Necrotizing stromal keratitis
• This rare condition is
• Result from active viral replication within the stromal, though immune-mediated
inflammation is likely to play a significant role
1. Signs
• Stromal necrosis and melting, often with profound interstitial opacification
• Anterior uveitis with keratic precipitates underlying the area of active stromal infiltration
• An epithelial defect may be present
• Progression to scarring, vascularization and lipid deposition is common
2. Treatment
• Similar to that of aggressive disciform keratitis
• Oral antiviral supplementation, initially at the upper end of the dose range, is commonly used.
• The restoration of epithelial integrity is critical

23. Neurotrophic ulceration
• Neurotrophic ulceration
• Caused by failure of re-epithelialization resulting from corneal anaesthesia
• Often exacerbated by other factors such as drug toxicity
1. Signs
• A non-healing epithelial defect, sometimes after prolonged topical treatment
• The stromal beneath the defect is grey and opaque and may become thin
• Secondary bacterial or fungal infection may occur
2. Treatment
• Topical steroid to control any inflammatory component should be kept to a minimum

25. Iridocyclitis
• Can occur without signs of active corneal inflammation, and may be
associated with direct viral activity.
• IOP elevation is common and is often presumed to be due to
trabeculitis; steroid-induced IOP elevation may also be relatively
common in herpetic iritis.
• The aetiology may be missed unless there is a history of previous
herpes simplex keratitis.
• Aqueous sampling for PCR may be diagnostic.
• Treatment is primarily with topical steroids, but adjunctive oral
aciclovir may be given

27. Prophylaxis
• Long-term oral aciclovir reduces the rate of recurrence of epithelial
and stromal keratitis by about 50% and is usually well tolerated
• Considered in patients with frequent debilitating recurrence,
particularly if bilateral or involving the only eye
• The standard dose of aciclovir is 400 mg b.d
• Excretion is via the kidney, so renal function should be checked
periodically during long-term treatment
• Oral valaciclovir 500 mg once daily or famiciclovir are alternatives
• The prophylactic effect decrease or disappear when the drug is
stopped

28. Complication
• Secondary infection
• Glaucoma
• Cataract
• Iris atrophy

29. Keratoplasty
• A trial of a rigid contact lens is often worthwhile prior to committing
to surgery.
• Recurrence of herpetic eye disease and rejection are common and
threaten the survival of corneal grafts.
• Topical antivirals given during a rejection episode may reduce epithelial viral
reactivation but toxicity may delay re-epithelialization.
• Prophylactic oral aciclovir (400 mg twice daily) improves graft survival and
should be given to patients undergoing penetrating keratoplasty for herpetic
eye disease.

30. • Conclusion: There was NO
statistically or clinically
significant beneficial effect of
oral acyclovir in treating HSV
stromal keratitis in patients
receiving concomitant topical
corticosteroids and trifluridine
with regard to time to
treatment failure, proportion
of patients who failed
treatment, proportion of
patients whose keratitis
resolved, time to resolution,
or 6-month best-corrected
visual acuity. Visual acuity
improved over 6 months in
more patients in the acyclovir
group than in the placebo
group.

31. • Purpose: To evaluate the efficacy of topical corticosteroids in treating herpes simplex
stromal keratitis
• Conclusions: The topical corticosteroid regimen used in this study was significantly
better than placebo in reducing persistence or progression of stromal inflammation
and in shortening the duration of herpes simplex stromal keratitis. Postponing
steroids during careful observation for a few weeks delayed resolution of stromal

32. Acyclovir for the Prevention of Recurrent
Herpes Simplex Virus Eye Disease
New England Journal, 1998
• Background
• Long-term treatment with antiviral agents has been shown to prevent recurrences of
genital and orofacial herpes simplex virus (HSV) disease, but it is uncertain whether
prophylactic treatment can prevent recurrences of ocular HSV disease
• Methods
• We randomly assigned 703 immunocompetent patients who had had ocular HSV
disease within the preceding year to receive 400 mg of acyclovir or placebo orally
twice daily. The study outcomes were the rates of development of ocular or
nonocular HSV disease during a 12-month treatment period and a 6-month
observation period
• Conclusions
• After the resolution of ocular HSV disease, 12 months of treatment with acyclovir
reduces the rate of recurrent ocular HSV disease and orofacial HSV disease. Long-
term antiviral prophylaxis is most important for patients with a history of HSV
stromal keratitis, since it can prevent additional episodes and potential loss of vision

33. Herpes Zoster Ophthalmicus

34. Herpes Zoster Ophthalmicus
• Herpes zoster ophthalmicus (HZO) is the term used for shingles involving
the dermatome supplied by the ophthalmic division of the fifth cranial
(trigeminal) nerve.
• Varicella-zoster virus (VZV) causes both chickenpox (varicella) and shingles
(herpes zoster)
• VZV belongs to the same subfamily of the herpes virus group as HSV
• After an episode of chickenpox the virus travels in a retrograde manner to
the dorsal root and cranial nerve sensory ganglia, where it may remain
dormant for decades
• Reactivation occur after VZV-specific cell-mediated immunity has faded.
• Re-exposure to VZV via contact with chickenpox, or by vaccination, may
reinforce immunity and protect against the development of shingles.

35. Mechanisms of ocular involvement
1. Direct viral invasion may lead to conjunctivitis and epithelial
keratitis.
2. Secondary inflammation and occlusive vasculitis may cause
episcleritis, scleritis, keratitis, uveitis (including segmental iris
infarction), optic neuritis and cranial nerve palsies.
• Inflammation and destruction of the peripheral nerves or central ganglia,
or altered signal processing in the central nervous system (CNS) may be
responsible for post-herpetic neuralgia.
1. Reactivation causes necrosis and inflammation in the affected
sensory ganglia, causing corneal anaesthesia that may result in
neurotrophic keratopathy.

36. Risk of ocular involvement
1. The Hutchinson sign
• involvement of the skin supplied by the external nasal nerve.
• The sign correlates strongly with ocular involvement, but there is no apparent
correlation between the severity of the nasal rash and that of ocular
complications.
1. Age
• most frequently in the sixth and seventh decades.
• In the elderly, signs and symptoms tend to be more severe and of longer duration.
1. AIDS patients tend to have more severe disease, and shingles can be an
early indicator of human immunodeficiency virus (HIV) infection.
• The development of shingles in children or young adults classically has prompted a
search for immunodeficiency or malignancy.

38. Acute shingles
• Prodromal phase precedes the appearance of the rash.
• Lasts 3–5 days
• Characterized by tiredness, fever, malaise and headache.
• Skin lesions
• Painful erythematous areas with a maculopapular rash develop*, and may be confused with
cellulitis or contact dermatitis.
• The rash respects the midline, which may aid in distinguishing shingles from HSV skin
infection; pain is also markedly worse in shingles. Bilateral disease is very rare.
• Within 24 hours, groups of vesicles (Fig. 6.17C) appear and these become confluent over 2–4
days.
• Although the rash itself does not affect the lower eyelid in HZO, boggy oedema of the upper
and lower lids is common (see Fig. 6.17B) and often spreads to the contralateral side of the
face.
• The vesicles often pass through a pustular phase before they crust (Fig. 6.17D) and dry after
2–3 weeks.
• The lesions heal to leave residual skin destruction and depigmented scars (Fig. 6.17F).
• Zoster sine herpete is shingles without a rash; this may be more common than
previously realized.

39. early erythema and oedema

40. vesicular stage

41. mixed vesicular and pustular rash
beginning to show crusting with boggy
oedema

42. Severe rash

43. Scarring and depigmentation

44. Treatment
• Oral antiviral
• Optimally given within 72 hours of rash onset;
• Reduces the severity and duration of the acute episode and the risk of post-herpetic
neuralgia.
• Patients presenting later than 72 hours but still at the vesicular stage also derive
benefit from treatment.
• Aciclovir (800 mg five times daily for 7–10 days) has been the mainstay of treatment,
but newer agents such as valaciclovir 1 g three times daily or famciclovir 250–500 mg
three times daily have more convenient regimens, are better tolerated and are at
least as effective as aciclovir.
• IV aciclovir
• 5–10 mg/kg three times daily is generally indicated only for severe disease,
particularly encephalitis, and for moderate–severe immunocompromise

45. Treatment
• Systemic steroids
• Prednisolone 60 mg daily for 4 days, then 40 mg for 4 days, then 20 mg for 4 days
• somewhat controversial but are commonly used in moderate–severe disease, particularly for
neurological complications.
• They should be given only in conjunction with a systemic antiviral, the course of which will
typically require extension. They should probably be avoided in immunodeficiency. A
moderate reduction in acute pain and accelerated skin healing is conferred, but steroids
have no effect on the incidence or severity of post-herpetic neuralgia.
• Symptomatic treatment of skin lesions is by drying, antisepsis and cold
compresses.
• Patients with shingles can transmit chickenpox so that contact with people not
known to be immune (particularly pregnant women) and immunodeficient
individuals should be avoided at least until crusting is complete.

46. Acute eye disease
• Acute epithelial keratitis develops in over 50% of patients within 2
days of the onset of the rash and usually resolves spontaneously
within a few days.
• characterized by dendritic lesions that are smaller and finer than herpes
simplex dendrites, and have tapered ends without terminal bulbs**
• The lesions stain better with rose Bengal than with fluorescein.
• Treatment, if required, is with a topical antiviral.
• Conjunctivitis (follicular and/or papillary) is common
• often occurs in conjunction with lid margin vesicles.
• Treatment is not required in the absence of corneal disease.
• Episcleritis occurs at the onset of the rash and usually resolves
spontaneously. A mild non-steroidal anti-inflammatory may be used if
necessary.

49. Acute eye disease
• Nummular keratitis usually develops at the site of epithelial lesions
about 10 days after the onset of the rash.
• characterized by fine granular subepithelial deposits surrounded by a halo of
stromal haze*.
• The lesions fade in response to topical steroids but recur if treatment is
discontinued prematurely.
• Stromal (interstitial) keratitis * develops in about 5% 3 weeks after
the onset of the rash;
• significant scarring can occur *
• usually responds to topical steroids but require slow tapering.

50. Nummular keratitis

51. Stromal keratitis

52. Scarring following stromal keratitis

53. Acute eye disease
• Disciform keratitis
• less common than with herpes simplex infection but may lead to corneal
decompensation.
• Treatment is with topical steroids.
• Anterior uveitis affects at least a third of patients and can be
associated with sectoral iris ischaemia and atrophy**
• Posterior uveitis
• Progressive retinal necrosis is an aggressive retinitis usually occurring in
immunodeficient individuals. Acute retinal necrosis can also be caused by
VZV.
• Posterior segment examination should always be performed in patients with
HZO.

54. iris atrophy in a typical sectoral pattern

55. sectoral iris atrophy on transillumination

56. Acute eye disease
• IOP should be monitored as elevation is common, including steroid-
induced.
• Prostaglandin derivatives should be avoided if treatment is necessary.
• Neurological complications may require intravenous antivirals and
systemic steroids.
• Cranial nerve palsies affecting the third (most common), fourth and sixth
nerves usually recover within 6 months.
• Optic neuritis is rare.
• CNS manifestations are rare but include encephalitis, cranial arteritis, and
Guillain–Barré syndrome

57. Chronic eye disease
• Neurotrophic keratopathy
• similar to that seen in HSV infection
• in up to about 50%
• relatively mild and settles over several months.
• Scleritis may become chronic and lead to patchy scleral atrophy**
• Mucous plaque keratitis
• develops in about 5%
• most commonly between the third and sixth months.
• characterized by elevated mucous plaques staining with rose Bengal*
• Treatment involves a combination of topical steroid and acetylcysteine.
• Untreated, plaques resolve after a few months, leaving a faint diffuse corneal
haze.

58. Scleral atrophy

59. Scleral atrophy

60. Mucous plaque keratitis

61. Chronic eye disease
• Lipid degeneration may develop in eyes with persistent severe
nummular or disciform keratitis*
• Subconjunctival scarring may occur.
• Eyelid scarring
• result in ptosis, cicatricial entropion and occasionally ectropion, trichiasis, lid
notching and madarosis

62. Lipid degeneration

63. Relapsing eye disease
• In the relapsing phase lesions may reappear years after an acute
episode, which may have been forgotten
• Eyelid scarring may be the only diagnostic clue
• Reactivation of keratitis, episcleritis, scleritis or iritis can occur

64. Post-herpetic neuralgia
• Defined as pain that persists for more than one month after the rash
has healed.
• Develops in up to 75% of patients over 70 years of age.
• Pain may be constant or intermittent, worse at night and aggravated
by minor non-painful stimuli (allodynia), touch and heat.
• Generally improves slowly over time, with only 2% of patients
affected after 5 years.
• Neuralgia can impair the quality of life, and may lead to depression of
sufficient severity to present a danger of suicide.
• Patients severely affected should be referred to a specialist pain
clinic.

65. Treatment
• Local
• Cold compresses.
• Topical capsaicin 0.075% or lidocaine 5% patches
• Systemic treatment may be used in a staged fashion
• Simple analgesics such as paracetamol.
• Stronger analgesics such as codeine.
• Tricyclic antidepressants, e.g. nortriptyline, amitriptyline, initially 25 mg
nightly adjusted up to 75 mg for several weeks if necessary.
• Carbamazepine 400 mg daily for stabbing pain.
• Gabapentin (300–600 mg up to three times daily), sustained-release
oxycodone (10–30 mg twice daily), or both.

67. • Seventy-one nonimmunocompromised patients with herpes zoster
ophthalmicus, presenting within seven days of onset of characteristic skin
eruption, were enrolled in a prospective, longitudinal, randomized, double-
masked, placebo-controlled trial with oral ac yclovir. In a previous interim report
we noted more prompt resolution of dermatomal signs and symptoms with
acyclovir treatmeet. There was also a reduction of viral shedding in acyclovir-
treated patients coupled with a trend to greater rate of microdissemination of
the virus in placebotreated patients (Cobo LIVI, et al. Ophthalmology 1985;
92:1574–83). While further substantiating these findings, we report that a ten-
day course of treatment with oral acyclovir (600 mg, five times a day) is well-
tolerated and significantly reduces the incidence and severity of the most
common complications of herpes zoster ophthalmicus: dendritiform keratopathy,
stromal keratitis, and uveitis. While this acyclovir treatment regimen reduces the
zoster-related pain during the acute phase of the disease, especially in patients
treated within 72 hours of onset of skin lesions, it has no evident effect on either
incidence, severity, or duration of post-herpetic neuralgia in the patients studied