9/16/17

HSV Epithelial : Avoiding the Initial Misdiagnosis — No financial disclosures

MIKA MOY, OD, FAAO CHRISTINA WILMER, OD, FAAO UC BERKELEY, SCHOOL OF OPTOMETRY

Typical HSV Epithelial Keratitis Avoiding the Initial Misdiagnosis

— Dendrite — Too early for dendrite? — Previous Episodes — No history yet — Decreased K sensitivity — Normal K sensitivity — Other treatments have failed — No treatments yet — Rose Bengal staining — No Rose Bengal Staining

Herpes Simplex Infection Mechanism

— HSV antibodies ¡ 62% of adolescents — Direct contact with ¡ 90% over 60 years old mucous membrane — Subclinical: 94% — Travels up nerve

— Ocular HSV infections globally — Dormant in ¡ 1,000,000 new/year Trigeminal ganglion ¡ 9,000,000 recurrent/year — Latency in ? — 40,000 cases of severe monocular blindness per year (global) — Re-activates

— Leading cause of infectious blindness in the western world

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HSV Keratitis Signs and Symptoms Key History

— Dendrite? — Recurrence** ¡ Not initially ¡ 40% of HSV epithelial keratitis recur — Stellate lesions on the cornea — Pain level — Systemic considerations ¡ Stress, fatigue, immune issues? ¡ Disproven? — Timing

http://static.imt.ie/wp-content/uploads/2011/04/Classic-dendritic-ulcer-in-Herpetic-Keratitis.jpg

Recurrence Triggers Typical Testing HSV

— Psychological stress — Corneal Sensitivity — Systemic infection — Rose Bengal Staining — Menstruation — Lissamine Green Staining — Sunlight exposure — CL wear — Eye injury

— **Recall bias**

HEDS Group, Arch of Ophth, 2000

Typical Testing to Confirm HSV Testing to Confirm HSV

— Decreased Corneal — Rose Bengal Sensitivity ¡ Stains dead cells ¡ Proportional to the number of previous episodes

¡ Slightly reduced number of corneal subepithelial nerves — Lissamine Green ¡ Stains dead cells — Often not diagnostically ¡ Less discomfort than RB helpful ¡ Uptake problems?

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What About IOP? Clinical Pearls: First Episode

— Does HSV elevate IOP? — Upper Lid Edema ¡ — Corneal Edema ÷ Not first episode ¡ Disproportionate to lesion ¡ Stromal Disease — Rose Bengal staining ÷ Not first episode ¡ Not too much — Not Diagnostic — Not usually helpful: ¡ IOP ¡ K sensitivity

Falcon et al. Trans Ophthal Soc UK 1978 Jones et al. Intl Oph Clinics 2007

Herpes Simplex Tx 400 vs. 800: Where’s the Literature?

— Topical antiviral — There are no studies ¡ Trifluridine 1% q2h x 14 days — What’s the harm? ¡ Ganciclovir 0.15% 5x/day until ulcer heals then TID x 7 days ¡ Pregnancy risk category B ¡ Drug interactions — Oral antiviral ¡ Side effects ¡ 400mg acyclovir 5x/days for 10 days ¡ 800mg acyclovir 5x/days for 10 days — Manufacturer recommendation? ¡ Acyclovir not as effective against HZ Thymidine Kinase — Frequent follow-up compared to HSV — Debridement?

How Do Antivirals Work Other Antivirals

— Interfere with viral DNA replication • Famciclovir (Famvir) ¡ Selective for cells with viral thymidine kinase ¡ 250mg tid x 10 days ¡ Inhibition of viral DNA polymerase ¡ 500 mg tid x 10 days = $183 — Valacyclovir (Valtrex) ¡ 1000mg bid x 10 days ¡ 1000mg tid x 10 days = $224 — Acyclovir ¡ 400mg 5x/day x 10 days ¡ 800 mg 5x/day x 10 days = $38

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What about the Kidneys? Case

— Creatinine Clearance — 24 year old white female ¡ Oral: <25 to require decreased frequency of dosing — Presents with bilateral red eyes ¡ Male: 97-137 — She is in pain ¡ Female: 88-128 — Light sensitive — Metabolized, excreted through kidneys — Having a hard time opening her eyes ¡ Caution with oral antibiotics ÷ Examples: ¢ Bacitracin ¢ Polymyxin B ¢ Neomycin

Dx and Tx Clinical Exam — Bilateral disease is rare — Bilateral case. Are there concerns? ¡ Suspect underlying immune condition ¡ Souza et al, 1.3% bilateral, Wilhelmus et al 3% ¡ More common in young patients

Other Considerations: Bilateral HSV Treatment: Our Patient

— Treatment options are same — 800 mg Acyclovir 5x/day x 10 days ¡ Oral — 5% Homatropine OU BID ¡ Topical — Bloodwork ordered — A/C reaction present: cycloplegic ¡ HIV test ¡ No auto-immune Sx — Additional History: ¡ Autoimmune questions ¡ Stress/Lifestyle (HIV) ¡ Referral for blood work?

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What If We Don’t Treat Appropriately? Recurrent Cases of HSV

— — HSV epitheliitis will self- Maintenance dose of antiviral medications resolve ¡ Acyclovir 400mg bid ÷ HEDS study: 45% decrease in rate of recurrence — 10% of epithelial pt. will ¡ Valacyclovir 500mg qd develop stromal — Inflammation is culprit — 23% will have recurrent stromal disease ¡ Reduce odds: Tx epithelial disease quickly

The Epithelial Keratitis Trial, The Herpetic Study Group

Resistance? Resistance?

Anywhere from 0.1-7% resistant HSV found in immunocompetent and immunocompromised patients

Resistance Fluoroquinolones in Bacteria

— Acyclovir and trifluridine use same mechanism — Block Topoisomerase II (DNA gyrase) ¡ Therefore, NOT additive ¡ Unwinds tight DNA coils ¡ Block viral thymidine kinase — Block Topoisomerase IV — Resistant HSV ¡ Separates DNA to allow for cell division ¡ Able to use HOST thymidine kinase

What should we do when there is resistance??

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Fluoroquinolones in HSV When to use topical fluoroquinolones?

— HSV uses Topoisomerase II for replication — Adjunctive therapy only — Exact mechanism unknown — When primary anti-viral: ¡ Slow to work ¡ Persistent lesion ¡ Pt. knows they don’t get better without it ¡ Immune-compromised pt?

— Not often

Take Home Points: HSV Case History: Textbook Case

— Diagnostic Pearls — 25 year old male ¡ Upper Lid Edema — Started 3 days ago ¡ Corneal Edema ÷ Disproportionate to lesion — Worsening ¡ Rose Bengal staining — Red, painful eye — Zirgan less toxic, but more expensive — — 800 mg Acyclovir 5x/day for keratitis more effective — Tearing than 400 with few risks — Swollen upper lid — Consider adding Fluoroquinolone if slower response to treatment

Important Data Dx and Tx

— VA 20/20 OD and OS — HSV Keratitis — 360 conj. injection — 800 mg acyclovir 5x/day x 10 days — Edematous lids — Corneal edema significant — Or Zirgan 5x/day until ulcer heals then — Area stains with NaFl and TID x 7 days Rose Bengal — Pain management? — Pain 8/10 — RTC? — Mild A/C

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Case History Exam findings

— — 21 year old Jewish male 20/20 OD, OS — — CC: x 2 days Eye watery — — Painful 6/10 360 red, follicles inferior palpebral — — Watery Multi-focal NaFl pick up — — Recently sick A/C clear — Does not wear CL

Working Diagnosis/Treatment Plan But . . .

— Adenovirus with infiltrates — Pain? 6/10 — Acuity still good—no steroid treatment indicated — NaFl pattern too strong — Consider betadine treatment — Rose Bengal staining? ¡ Tends to be subtle — Artificial tears ¡ Along “spine” — Council patient on hygiene — Timing? — RTC 1 week

Adenovirus vs. HSV Keratitis Antivirals and Adenovirus

Adenovirus HSV Keratitis Ganciclovir 0.15% NPAT Little to no pain Moderate to severe pain Days to recovery 7.7 days 18.5 days Anterior chamber quiet Frequent anterior chamber Pts. With SEI 2 of 18 7 of 18 involvement SEI after 10-14 days Stellate lesions form quickly Tabbara et al, ARVO, 2005 Minimal to no corneal edema Extensive corneal edema compared to Dosage Rat Model lesion size Ganciclovir 3% Lowers virus shedding Follicles Minimal follicles Little to no upper lid edema Upper lid edema/protective Ganciclovir 1% No effect Does not improve with antivirals Speedy improvement with oral Ganciclovir 0.15% No effect antivirals Trousdale, et al, Cornea, 1994

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Final Diagnosis/Treatment Plan Case History

— HSV keratitis — 20 y/o female — 800 mg Acyclovir 5x/day x 10 days — CC: Red, irritated eye x 2 weeks, Sx worsening ¡ Or Zirgan 5x/day slightly — Ibuprofen as needed for pain — D/C CL wear x 12 hours — RTC 1 day — Pain 4/10

— One day follow-up ¡ Pt. pain 1/10 ¡ Cornea 90% improved

Important Data CLARE vs. (Stellate) HSV Keratitis

— VA 20/20: OD, OS — A/C clear CLARE HSV Keratitis — Infiltrates mid-periphery 360 Little to moderate pain Moderate to severe pain — Hyperemia 360 Anterior chamber quiet Frequent anterior chamber involvement — Improvement with D/C CL? SEI form quickly Stellate lesions form quickly ¡ Not sure

Improves with D/C CL wear Does not improve with D/C CL wear — Most lesions: no NaFl stain Photophobia possible Photophobia possible — No Rose Bengal staining Improves with topical steroid Worsens with topical steroid — Corneal sensitivity: not done — IOP: not done

Differential Diagnosis Tentative Diagnosis/Treatment

— CLARE — CLARE ¡ Steroid? ¡ CL abuser ¡ Antibiotic Cover? ¡ Moderate pain ¡ Benign neglect? ¡ SEI present ¡ 2 week course — D/C CL wear ¡ Minimal corneal edema ¡ No UL edema — Follow-up? — HSV ¡ Moderate pain ¡ Focal lesions (not very stellate)

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Case History Exam Findings

— 24 year old male — Acuity unaffected — Wears one day contact lenses — A/C quiet — Irritation last night after removing CL — Epi defect with — Worse upon awakening clear base — Hyperemia 1+ — Pain 4/10

Dx and Tx Exam Findings Follow-Up

— Corneal Abrasion — No improvement — Tobramycin QID Sn/Sx — No BCL — Acuity unaffected — Ibuprofen — A/C 6 cpv — RTC 24 h — Epi defect larger ¡ Edges heaped ¡ Base transluscent ¡ + Rose Bengal — Hyperemia 1+ — Pain 4/10

Dx and Tx Could we have Dx on Day 1?

— 800 mg Acyclovir po 5x/day — Pt was worse in the morning — Homatropine 5% oph sol’n in office — Abrasion: ¡ Tx of HSV will resolve the iritis. ¡ Pt abraded upon CL removal ¡ No steroid needed ever? ¡ Re-abraded upon awakening — Follow-up 24 hours — HSV: ¡ Infection worsening is the reason for increased Sx ¡ No other signs: ÷ Edema — One day follow-up: Cornea clear ÷ Upper lid swelling ÷ No history of HSV keratitis

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Case History Exam Findings

— 21 year old male — 20/20 OD, OS — Presents with pain, redness, tearing — A/C clear — This has happened 3 times before — 360 red 1+ — PCP previously dx pt with eye infection — Pain improving since awakening 4/10

— Now what?

RCE vs. HSV Keratitis More Important Data

— History of injury to eye? Recurrent Corneal HSV Keratitis ¡ Basketball injury (finger in eye) Erosion ¡ 1 year ago Pain improves throughout day Pain profile steady or worsens Frequently H/O Trauma Not contributory — Three previous episodes Signs of corneal dystrophy Not contributory ¡ All started upon awakening Possible A/C A/C more likely ¡ All improved through the day Recurrent Recurrent (40% epithelial recur) — Sought care for one from PCP: Painful Painful ¡ Antibiotic given Corneal Edema Corneal Edema — Rose Bengal?

Final Diagnosis Case History

— 19 year old NCAA swimmer — Recurrent Corneal Erosion — CC: Got Icy Hot in left eye 2 days ago — Pt. improved on Tx. — Flushed with water — Went to Urgent Care yesterday — They irrigated with water — His eye still bothers him. He is concerned.

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Exam Findings Differential

— 20/20 s Rx OD, OS — Toxic keratitis — LUL edema — Healing abrasion — Conjunctival hyperemia 360 — HSV keratitis secondary to eye injury? — Vertical corneal linear lesion ¡ Corneal edema surrounding ¡ Concentrated nasally — 6/10 pain — Quiet A/C — Watery eye — No previous history of eye infections

Differential History Questions to help?

— Toxic keratitis — HSV — Compared to yesterday morning, are ¡ Matches history ¡ Linear you better, worse, or about the same? ¡ Punctate erosions match ¡ Stains with Rose Bengal ¡ ¡ Pain ¡ Lid edema — Healing abrasion ¡ Pain ¡ Base is translucent ¡ Linear ¡ Matches history ¡ Pain

History Questions to help? Top Factors Influencing Diagnosis

— Compared to yesterday morning, are — Compared to yesterday morning, are you better, worse, or about the same? you better, worse, or about the same? ¡ Better ¡ Better — Time Course? ¡ Can you develop a dendrite in 2 days? ÷ Natural progression of disease ¡ If so, would symptomatology improve this quickly without meds? — Elevation?

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Tentative Dx and Tx Take Home Points: HSV

— Healing abrasion/Toxic — Diagnostic Pearls keratopathy ¡ Upper Lid Edema ¡ Corneal Edema ÷ Disproportionate to lesion — NPAT q1h+ ¡ Rose Bengal staining — Zirgan less toxic, but more expensive — RTC 24 hours — 800 mg Acyclovir 5x/day for keratitis more effective than 400 — If worsens: consider — Consider adding Fluoroquinolone if slower response infectious cause to treatment

References

— Herpetic Eye Disease Study Group: Psychological Stress and other Potential Triggers for Recurrences in Herpes Simplex Virus Eye Infections, Arch Ophthalmol 118(12):1617-1625, 2000. — Velzen M, van de Vijver DA, van Loenen FB, Osterhaus AD, Remeijer L, Verjans GM. Acyclovir Prophylaxis Predisposes to Antiviral-Resistant Recurrent Herpetic Keratitis. J Infect Dis. 2013 Nov;208(9):1359-1365. Epub 2013 Jul 30. PubMed PMID: 23901090. — Farooq AV, Shukla D. Herpes simplex epithelial and stromal keratitis: an epidemiologic update. Surv Ophthalmol. 2012 Sep;57(5):448-62. doi: 10.1016/j.survophthal.2012.01.005. Epub 2012 Apr 28. Review. — Mottola C. In vitro antiviral activity of fluoroquinolones against African swine fever virus. Vet Microbiol. 2013 Jul 26;165(1-2):86-94. doi: 10.1016/j.vetmic.2013.01.018. Epub 2013 Jan 29. — A.M. Rowe, A.J. St. Leger, S. Jeon, D.K. Dhaliwal, J.E. Knickelbein, R.L. Hendricks, Herpes keratitis, Progress in Retinal and Eye Research, Volume 32, January 2013, Pages 88-101 — Colin, J, Ganciclovir Ophthalmic Gel, 0.15%: a valuable tool for treating ocular herpes. Clin Ophthal.2007:1(4) 441- 453. — Falcon MG, Williams HP. Herpes simplex keratouveitis and . Trans Ophthal Soc UK. 1978;98:101-104 — Jones R et al Herpes Simplex Virus: An Important Etiology for Secondary Glaucoma. Int Ophthalmol and Clin 2007 Spring; 47(2):99-107. — Holland E, Brilakis H, Schwartz G. “” Cornea, Second Edition. El Sevier Mosby 2005: 1043- 74 — Liesegang TJ, Melton LJ 3rd, Daly PJ, Ilstrup DM. Epidemiology of ocular herpes simplex. Incidence in Rochester, Minn, 1950 through 1982. Arch Ophthalmol. Aug 1989;107(8):1155-9. — Pavan-Langston D, Manual of Ocular Diagnosis and Therapy, 4th ed. Editorial Services of New England 1996 — Casser L, Fingeret M, Woodocome HT. Atlas of Primary Eyecare Procedures. 2nd ed. Stamford, CT: Appleton and Lange, 1997 — White ML, Chodosh JC. “HSV Keratitis: A Treatment Guideline” AAO Preferred practice patterns. Oct. 2016

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