1. Grand Rounds Conference Reema Syed, MBBS University of Louisville Department of Ophthalmology and Visual Sciences August 7, 2015

2. Subjective CC: Pain and redness, left eye x 2 weeks HPI: 23 year old female with progressively worsening symptoms for 2 weeks. She was recently treated at an urgent care center with “antibiotic eye drops”

3. History POH, PMH: unremarkable Eye Meds: “antibiotic drop” OS QID Systemic Meds: None Allergies: NKDA

4. Objective OD OS OD OS BCVA: 20/20 20/200 Pupils: 5 to 3 mm OU, no rAPD IOP: 1316 EOM: FullFull CVF: FullFull

5. Objective SLE: Unremarkable ODOS External/LidsNormal Conjunctiva/Sclera2+ injection Corneasmall epithelial defect; stromal edema; KPs; neovascularization Anterior Chamber0.5+cell, trace flare IrisNormal LensClear Posterior segmentPoorly visualized

6. Anterior segment OS Corneal stromal edema in a circular form, infero-central epithelial defect 2x2 mm, inferior neovascularization from limbus to edge of ulcer

7. Anterior segment OS KPs underlying zone of edema

8. Impression 23 year old female with herpetic disciform keratitis OS 23 year old female with herpetic disciform keratitis OS Differential diagnosis Bacterial keratitis Bacterial keratitis Neurotrophic ulcer Neurotrophic ulcer

9. Plan Acyclovir 400 mg PO 5 times daily Acyclovir 400 mg PO 5 times daily Vigamox QID OS Vigamox QID OS Cyclopentolate 1% BID OS Cyclopentolate 1% BID OS Pred Forte 1% OS QID Pred Forte 1% OS QID

10. Follow-up Patient lost to follow-up Patient lost to follow-up Stopped using all medicines in few weeks when she felt better Stopped using all medicines in few weeks when she felt better

11. Herpes Keratitis Herpes viruses: Herpes viruses: HSV 1 HSV 1 HSV 2 HSV 2 VZV VZV CMV CMV EBV EBV HHV 8 HHV 8 HHV 6 HHV 6 HHV 7 HHV 7

12. Primary infection: Primary infection: Skin and mucosal surfaces innervated by CN V Skin and mucosal surfaces innervated by CN V Frequently, non-specific URI Frequently, non-specific URI Vesicular blepharitis, follicular conjunctivitis, rarely epithelial keratitis Vesicular blepharitis, follicular conjunctivitis, rarely epithelial keratitis Latent infection: Latent infection: Infected skin and mucosal lesions sensory nerve axons sensory nerve ganglia Infected skin and mucosal lesions sensory nerve axons sensory nerve ganglia Pathophysiology

13. Pathophysiology Recurrent disease: Recurrent disease: HSV-1 OccurrenceMay reactivate frequently Incidence drops with age Typically unilateral, usually same site as 1 o infection but can occur along any of the 3 branches of CN V Causes of reactivation Role of environmental and physiological factors controversial Bilateral recurrent ocular disease in atopic dermatitis Pain upon reactivation Mild-moderate Sensory loss with repeated recurrence Kinchington PR et al. Herpes simplex virus and varicella zoster virus, the house guests who never leave. Herpesviridae. 2012 Jun 12;3(1):5.

14. HSV Epithelial Keratitis Punctate keratitis Punctate keratitis Dendritic ulcer Dendritic ulcer Geographic ulcer Geographic ulcer

15. Management: Management: Self-limited disease, treatment shortens clinical course, reduces herpetic neuropathy and sub-epithelial scarring Self-limited disease, treatment shortens clinical course, reduces herpetic neuropathy and sub-epithelial scarring Topical Trifluridine 1% x8/day – epithelial toxicity with extended use Topical Trifluridine 1% x8/day – epithelial toxicity with extended use Oral Acyclovir 400 mg x5/day or Valacyclovir 500 mg TID – same efficacy as topical antivirals, no ocular toxicity, lower cost Oral Acyclovir 400 mg x5/day or Valacyclovir 500 mg TID – same efficacy as topical antivirals, no ocular toxicity, lower cost HSV Epithelial Keratitis

16. Stromal Keratitis Most common cause of infectious corneal blindness in the US Most common cause of infectious corneal blindness in the US Form of recurrent herpetic external disease associated with the greatest morbidity Form of recurrent herpetic external disease associated with the greatest morbidity Pathogenesis unknown Pathogenesis unknown Cell-mediated immunity to corneal antigens up-reglated by HSV Cell-mediated immunity to corneal antigens up-reglated by HSV Bystander effect of proinflammatory cytokines secreted by infected corneal cells Bystander effect of proinflammatory cytokines secreted by infected corneal cells

17. Non-necrotizing/Interstitial: Non-necrotizing/Interstitial: unifocal or multifocal stromal haze without epithelial ulceration unifocal or multifocal stromal haze without epithelial ulceration Necrotizing: Necrotizing: Rare; severe, rapidly progressive, stromal inflammation with epithelial ulceration; may result in perforation Rare; severe, rapidly progressive, stromal inflammation with epithelial ulceration; may result in perforation Stromal vascularization, scarring Stromal Keratitis

18. Pathogenesis uncertain but may be due to inflammatory reaction to live virus in the endothelium Corneal stromal and epithelial edema, KPs underlying zone of edema, mild iritis Corneal stromal and epithelial edema, KPs underlying zone of edema, mild iritis Disciform (most common), diffuse or linear endotheliitis Disciform (most common), diffuse or linear endotheliitis Associated trabeculitis and IOP Associated trabeculitis and IOP Endotheliitis

19. Management of Stromal Keratitis and Endotheliitis Slow taper of topical steroids is the mainstay Slow taper of topical steroids is the mainstay Topical Trifluridine QID or Acyclovir 400 mg x5/day Topical Trifluridine QID or Acyclovir 400 mg x5/day Long-term prophylaxis for recurrent disease (ACV 400 mg BID) Long-term prophylaxis for recurrent disease (ACV 400 mg BID)

20. The Herpetic Eye Disease Study Topical steroids significantly decreased stromal inflammation and shortened duration of stromal keratitis No benefit to addition of oral Acyclovir to topical Trifluridine and Prednisolone in non-necrotizing stromal keratitis Acyclovir does not prevent stromal keratitis or iritis in patients with epithelial keratitis Acyclovir prophylaxis minimizes recurrent disease in patients with stromal keratitis Barron BA et al. Herpetic Eye Disease Stud. A controlled trial of oral acyclovir for herpes simplex stromal keratitisOphthalmology. 1994 Dec;101(12):1871-82. Wilhelmus KR et al. Herpetic Eye Disease Study. A controlled trial of topical corticosteroids for herpes simplex stromal keratitis. Ophthalmology. 1994 Dec;101(12):1883-95

21. Retrospective study of 87 penetrating keratoplasties in herpetic keratitis at 3 centers in Germany Analyzed the effectiveness of combined systemic acyclovir and immunosuppressive therapy with cyclosporine A or mycophenolate mofetil Graft survival rates and functional outcomes in these high risk keratoplasties, when treated with systemic immunosuppression were comparable with results of normal-risk keratoplasties

22. References BSCS. External Disease and Cornea BSCS. External Disease and Cornea Barron BA et al. Herpetic Eye Disease Stud. A controlled trial of oral acyclovir for herpes simplex stromal keratitisOphthalmology. 1994 Dec;101(12):1871-82. Barron BA et al. Herpetic Eye Disease Stud. A controlled trial of oral acyclovir for herpes simplex stromal keratitisOphthalmology. 1994 Dec;101(12):1871-82. Wilhelmus KR et al. Herpetic Eye Disease Study. A controlled trial of topical corticosteroids for herpes simplex stromal keratitis. Ophthalmology. 1994 Dec;101(12):1883-95 Wilhelmus KR et al. Herpetic Eye Disease Study. A controlled trial of topical corticosteroids for herpes simplex stromal keratitis. Ophthalmology. 1994 Dec;101(12):1883-95 Kinchington PR et al. Herpes simplex virus and varicella zoster virus, the house guests who never leave. Herpesviridae. 2012 Jun 12;3(1):5 Kinchington PR et al. Herpes simplex virus and varicella zoster virus, the house guests who never leave. Herpesviridae. 2012 Jun 12;3(1):5

23. Thank You