9/16/17
HSV Epithelial Keratitis: 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 cornea? 40,000 cases of severe monocular blindness per year (global) Re-activates
Leading cause of infectious blindness in the western world
1 9/16/17
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 ¡ Uveitis 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
3 9/16/17
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 Eye Disease 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??
5 9/16/17
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 Photophobia 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
6 9/16/17
Case History Exam findings
21 year old Jewish male 20/20 OD, OS CC: red eye x 2 days Eye watery Painful 6/10 360 red, follicles inferior palpebral conjunctiva 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 ptosis 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)
8 9/16/17
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
9 9/16/17
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.
10 9/16/17
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 glaucoma. 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. “Herpes Simplex Keratitis” 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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