1. DIAGNOSIS AND TREATMENT OF HERPES SIMPLEX KERATITIS UPDATE XVI JORNADAS DE OFTALMOLOGIA DR. BENJAMIN BOYD AUGUST, 2005

2. RICHARD L. RICHARD L. ABBOTT, M.D. PROFESSOR OF OPHTHALMOLOGY UCSF FRANCIS I. PROCTOR FOUNDATION

3. HUMANS ARE THE HUMANS ARE THE ONLY NATURAL RESERVOIR OF HSV HSV 1 OROPHARYNX HSV 2 GENITAL AREA

4. VIDARABINE TRIFLURIDINE IDOXURIDINE

5. HSV OCULAR DISEASE Approx. 1/2 million people in U.S. Approx. 20-45% of world population Approx. 50,000 active episodes annually Approx. 20,000 new cases annually By age 5….60% of population infected Only 6% develop clinical manifestations

6. PRIMARY HERPES SIMPLEX Acquired from environment ( oral lesions, saliva) Not from viral latency Unilateral vesicular blepharoconjuntivitis Pruritic vessicles of lids, skin, eyelid margin Follicular conjunctivitis Palpable preauricular lymph node PEK (RARE dendrite)

7. Look for vessicles

10. Vessicles

11. INFECTIOUS EPITHELIAL KERATITIS Corneal vessicles (PEK) Dendrite Geographic (Amoeboid) ulcers Marginal ulcers ( Limbal KC) May be associated with conjunctivitis

12. TREATMENT Primary Herpes Simplex Oral Acyclovir Topical Trifluridine Observation (self-limited)

13. TYPICAL CORNEAL DENDRITE Of first importance in making the clinical diagnosis Dendron (Greek- “Tree”) True ulcer – extends through BM

15. AVOID ROSE BENGAL IF CULTURE

16. DDX: DENDRITIC KERATITIS HSV HZV Healing epithelium Thimerosal (Toxicity) SCL

18. HZV

19. SOFT CONTACT LENS

20. HEALING EPITHELIUM

21. THIMERASOL TOXICITY

22. HEALING EPITHELIUM

23. HSV

24. GEOGRAPHIC (AMOEBOID) ULCER “Wide” dendrite DDX epithelial defect – scalloped border 4-20% of initial lesions +/-Associated with previous steroid use

27. LIMBAL (MARGINAL) HSV-I KERATITIS Atypical presentation More resistant to Rx DDX: Staph marginal infiltrate – No epithelial defect –Progress circumferential –Associated with blepharitis –Typical location 2, 4, 8, 10

28. INCREASED INFLAMMATION WBC INFILTRATION

29. TREATMENT Infectious Epithelial Keratitis Goal: Purpose: Diagnosis: –Eliminate virus in short time –Decrease potential risk for immune-mediated disease –Decrease structural damage –Clinical, culture, PCR

30. TREATMENT Infectious Epithelial Keratitis Gentle debridement Topical antivirals (10-14 days max) –Viroptic 1% q 2h or –Vira A 5X/day If no response 72 hours – STOP Resistance rate - 3%

34. TREATMENT Infectious Epithelial Keratitis If slow healing, consider toxicity If epith ulcer persists, consider neurotrophic Avoid steroids

35. ACYCLOVIR REGIMEN 400 mg 5x/day for 10-14 days Reduce to b.i.d. for 10 days Very safe Headaches, GI upset Watch dose renal disease

36. HSV IRIDOCYCLITIS 1-9% of all non-traumatic anterior uveitis May occur independently Live virus in aqueous Average time to resolution: 4 weeks Treat with topical steroids, cycloplegics, and PO Acyclovir Watch IOP – Trabeculitis

39. SECTOR IRIS ATROPHY See in both Simplex and Zoster Older patient - probably Zoster If in doubt - treat with Zoster doses

40. STROMAL KERATITIS 2% of initial episodes 20-48% of recurrent HSV Disciform (Immune only) Necrotizing (direct viral invasion) Metaherpetic (post-herpetic trophic ulcer)

42. IMMUNE (INTERSTITIAL) STROMAL KERATITIS (DISCIFORM) Cell mediated immune response to viral antigens in stroma or endothelium

43. DISCIFORM KERATITIS +/- Previous HSV epithelial keratitis Non-necrotizing Focal, multifocal, or diffuse area of edema Mild lymphocytic stromal inflammatory infiltrate- chronic and recurrent Epithelium intact Descemet’s folds and KP

44. DISCIFORM KERATITIS Differential diagnosis –HSV –HZV –Vaccinia –Mumps –Varicella

46. STROMAL DISEASE Treatment goals –Eradicate HSV –Limit scarring –Limit lipid deposition

47. TREATMENT Stromal Keratitis Treatment depends on severity and location of inflammation –Necrotizing keratitis –Interstitial keratitis –Immune rings –Limbal vasculitis –Disciform keratitis

48. TREATMENT Disciform Keratitis Conservative - self limited Oral Acyclovir 400mg 5x/day Topical steroid - rapid taper No topical antiviral (poor penetration)

50. NECROTIZING STROMAL KERATITIS WBC’s (dense infiltrate with overlying defect Blood vessels Thinning Scarring Necrosis and perforation

54. TREATMENT N ecrotizing Stromal Keratitis Never studied by HEDS Acyclovir and topical steroids Taper slowly Maintain steroid at lowest dose Recurrence into visual axis Surgery

55. STEROID TAPER Pred Acetate qid > bid > qd > qod 4-6 weeks between steps Look for KP or edema Switch to weaker steroid Ask if redness when miss drop

56. NEUROTROPIC KERATOPATHY POST HERPETIC EROSION (Metaherpetic Keratitis) Follows severe epithelial disease Basement membrane damage Non-healing epithelial defect Clinical course

59. TREATMENT Neurotrophic Keratopathy Goal: Purpose: Diagnosis: –Decrease exposure to toxic substances –Increase lubrication –Decrease risk 2º infection –Decrease risk of stromal melting –Rolled borders of epithelium

61. TREATMENT T rophic Epithelial Defect Protect ocular surface Non preserved lubricants Therapeutic contact lens Gentle debridement Amniotic membrane Tarsorrhaphy

64. ENDOTHELIITIS Inflammatory reaction of endothelium Corneal stromal edema without infiltrate (disciform, diffuse, linear) KP, Stromal/epithelial edema, iritis Responds to steroids

65. REACTIVATION HSV Hormonal changes Ultraviolet light Surgery of eye Systemic infection Latanoprost

66. REACTIVATION HSV Stress Fever Immunosuppression Trauma (CL wear) 9.6% first year 36% @ 5 years 63% within 20 years HEDS: 18% recurrence rate

67. RECURRENT HSV Reactivation in latently infected cells Disease pattern affected by: –Strain of virus (Can block subsequent infection by another strain) –Genetic constitution of host

69. PROPHYLAXIS FOR HSV KERATOPLASTY Use oral acyclovir –Pre-op:400mg qid for 3 days –Post-op:400mg qid for 7 days 400mg bid for 3months No controlled studies available

74. TREATMENT Stromal Keratitis If corneal perforation: –Surgical adhesive –Lamellar patch graft –PKP Use of oral Acyclovir

76. VALACYCLOVIR (Valtrex) Absorbed rapidly from GI tract Converted into Acyclovir (Prodrug) Plasma levels 3 times higher than same dose with Acyclovir Do Not Use with renal disease and HIV Dose: 1 Gram qd

78. FAMCICLOVIR MOA similar to Acyclovir Inhibits HSV DNA synthesis Rapidly absorbed from GI tract Intracellular 1/2 life is 10-20 times longer Lactose intolerance

79. FAMCICLOVIR Dose: 500mg bid-tid Side effects similar to Acyclovir More expensive cost

80. CIDOFOVIR PENCICLOVIR Variation in chemical structure Inhibit DNA polymerase Less resistance

81. VALTREX AND FAMVIR Not more effective than Acyclovir Cost issue Compliance issue

82. HEDS STUDY RESULTS Oral antiviral prophylaxis reduces recurrences of epithelial and of stromal keratitis Use of topical steroids is of benefit in stromal keratitis Use of oral acyclovir may be of help in iridocyclitis Prophylactic oral acyclovir helps prevent recurrences of herpetic keratitis, particularly stromal with a history of recurrence