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Corneal Workshop:Keratitis Management

Elizabeth Yeu, MDCornea, Cataract, Anterior Segment,

Refractive SurgeryVirginia Eye Consultants

May 1, 2013

Elizabeth Yeu, MDCornea, Cataract, Anterior Segment,

Refractive SurgeryVirginia Eye Consultants

May 1, 2013

Professional Disclosures

n Allergan: Advisory Board, Speakers’ Bureau

n Bausch + Lomb: Advisory Boardn Rhein Medical: Advisory Board

Keratitis

n Bacterialn Herpeticn Blepharokeratitis

Keratitisn Infectious: Microbial keratitis-- “MK”

– Bacterial– Viral– Parasitic: acanthamoeba– Fungal

n Non-infectious– Inflammatory: blepharokeratitis, PUK – Interstitial– Others

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Bacterial Keratitis

n Gram-positive cocci: Staph spp., Strep pneumoniae

n Aerobic gram-negative bacilli: Pseudomonas aerugenosa, Haemophilus influenzae, Moraxella catarrhalis

n Enteric gram-negative bacilli or colonization of normal skin flora: S. aureus, S. epidermides, Serratia spp., Strep viridans

General guidelines

n Ulcer: Epithelial defect + WBC recruitment within stroma– Infectious or sterile

n Infiltrate: grey/white opacities from coalescence of WBCs n Localized or diffusenUsually infectiousn Peripheral (PUK, Mooren’s, marginal keratitis)

more commonly inflammatory and not infectious

General Guidelines

n Appearance of infiltrate– Sharply dilineated, ovoid: gm +– Irregular, indistinct borders: gm –– “Feathery” borders: fungal, strep pneumo– Crystalline: strep pneumoniae– Ring infiltrate:

n Pseudomonas, HSV, acanthamoeba, Neisseria, Corynebacterium, Nocardia, anesthetic abuse

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General Guidelines

n Appearance of infiltrate– Aggressive suppuration (“soupy”): gm (–)– Infiltrate with intact epithelium: sterile,

fungus, H. aegyptius, Neisseria gonorrhoeae, Listeria monocytogenes

– Satellite lesions: fungal, atypical mycobacteria, nocardia

– Raised, “clumpy” borders of gray-white epithelium: neurotrophic or toxic

General guidelines

n Duration– Indolent: acanthamoeba, gm +, fungal– Fulminant: gm (–)

n Amount of tissue destruction and thinning

n Gm (–) spp., particularly pseudomonas aeruginosa, cause great necrosis very quickly

Usual suspects

n CL wear à p. aeruginosan “Spontaneous” MKà enteric/ skin flora n Scleral buckle, canalicular tubes à

atypical mycobacteriumn Vegetation, trauma à fungusn Water-related à acanthamoeba

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Usual suspects

n PKP: gm + organism– Often strep

pneumoniae (steroids)

n Tx: start broad spectrum fluoro

n S. pneumo– Vancomycin 2.5%

n Culture, inc. sutures!

When to refer?

n Culture - Rules of 1-2-3– Within 1 mm of visual axis– Ulcers with 2 or more infiltrates– 3 mm or more in diameter

Indications for Referral

n Anything central, necrosing or thinningn Poor response to single treatmentn Poorly healing epithliumn Extended durationn Post-surgical n Trauma-related: vegetation, FBn Inflammatory melt

Indications for Referral

n If considering immediate referral, prior to starting meds, consider not starting any treatment in order to obtain highest yield on culture

Culturing the cornea

n Chemistry lab set up, alcohol lamp

n Sterile Kimura spatulasn Slidesn Culture plates and tubes

Procedure

n Anesthetize the cornea – Preservative-free tetracaine

n Scrape ulcer base / leading edge of infiltraten Place specimen on slide, then culture media

– Smears – fixing organisms to be stained / observed

– Culture – microbial growth

n Sterilize spatula over flame between slides / cultures

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Culturing the cornea

n Diagnostic

n Commonly, can be THERAPEAUTIC!

Treatment

n D/C CL wearn Primary goal – eliminate the pathogensn Secondary goal – prevent host destructionn Treated as bacterial initiallyn Small infiltrates – empirically (<1.0mm)n Cycloplegics bid-qid

– Cyclopentolate 1%, homatropine 5%, scopolamine 0.25%, atropine 1%

Treatment

n Fluoroquinolones – common standardn Besifloxacin: 3rd generation fluoro, excellent

broad spectrum, inc MRSA and pseudomonasnMoxifloxacin: 4th generation, ? Fungal coverage

n Vision threatening – Fortified antibiotics– Tobramycin/gentamycin (15mg/mL) aggressively

ATC– Cefazolin (50mg/mL), ceftazadime (50mg/ml) or

vancomycin (25mg/mL)

Treatment: Fungal Keratitis

n Natamycin 5%– Suspension– Sticky– Poor penetration common

n Voriconazole 1% – Mold, yeast

n Amphotericin 0.15%– Yeast

Treatment:Acanthamoeba keratitis

n Triple or quad Rx1. Chlorhexadine 0.02%

or PHMB 0.02%2. Propamadine 0.1%

or hexamadine 0.1%3. Itraconazole or

voriconazole p.o.4. Neomycin5. +/- steroids

Steroids? Yes or no?

n Always an interesting topic of discussion ☺

n Yesn No n Maybe so?

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Steroids for Corneal Ulcer Trial

n Objective: To determine whether there is a benefit in clinical outcomes with the use of topical corticosteroids as adjunctive therapy in the treatment of bacterial corneal ulcers

n Results: No significant difference was observed – 3-month BSCVA (P =.82)– Infiltrate/scar size (P = .40)– Time to reepithelialization (P = .44)– Corneal perforation (P > .99)

Srinivasan M, Mascarenhas J, Rajaraman R, Ravindran M, Lalitha P, Glidden DV, Ray KJ, Hong KC, Oldenburg CE, Lee SM, Zegans ME, McLeod SD, Lietman TM, Acharya NR; Steroids for Corneal Ulcers Trial Group.

Steroids?

n Steroids– Aggressive suppuration to â necrosis– Healing bacterial MK– PKP patients, not fungal– “Steroid stress test”

n Exacerbates fungal MK

Potential Treatment Option Collagen cross-linking àRiboflavin phototherapyn In vitro studies: Ribloflavin

phototherapy can eradicate S. aureus, MRSA, P.aeruginosa(Martins SA, et al. IOCS. 2008; 49:3402-2408)

n Help heal refractory bacterial MK and halt thinning

(Panda A, et al. Cornea. 2012 Oct; 31(10):1210-3)

Patient Presentation

n 62 yo WMn h/o hyperopic LASIKn + cataracts à uneventful cataract

surgeryn Loose epithelium near edge of prior

LASIK flap à BCL

Patient Presentation

n POD 1, looks greatn POW 1: “BCL fell out yesterday when I

was poolside, so my wife picked it up, rinsed it off with her solution and put it back in”

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Patient Presentation

n Minimal injection, superotemporal 1x2 mm ant stromal infiltrate, no thinning

n Plan:– D/C BCL– Start moxifloxacin q2 hours ATC

Patient: Clinical course

n Over the next 2 days, infiltrate shrinking in size, but epithelium not quite healing over

à Add FML qid, decrease moxi to qid

Patient Presentation

n Continued therapy for 2 more daysn On return, infiltrate returning slightly

largern ?? Wrong diagnosis or superinfection

Confocal microscopy performed

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Patient Presentation

n Gm stain and CW à hyphael elementsn Voriconazole 1% q1 h ATC,

Voriconazole 200 mg bid

àCulture: Paecilomyces spp.

Clinical scenario

n36 yo male, 2nd opinion of persistent “geographic ulcer”nRed eye OD began ~5w ago

–3rd episode in 5 y

nTrifluridine x4w, at qidnZymar qid

Update: Herpes Keratitis

“Persistent HSV geographic ulcer” OD

Herpetic keratitis

n Regarding herpetic keratitis….n Not too much has changed in the

treatment of HSV keratitis over the years

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HSV: Background

n HSV 1: oral, nasal, ocular, throat soresn HSV 2: genital soresn Neurotrophic and neuroinvasive virusesn HSV-1 and -2 persist in the body

– Become latent and hide from the immune system in the cell bodies of neurons

n After primary infection, reactivation can occur anytime– Ocular HSV infections generally reactivation– HSV blepharitis can be primary infection: more

commonly seen in kids

HSV: Epidemiology

n Worldwide: HSV 65% - 90%n U.S.

– HSV 1: ~ 50% - 80%– HSV 2: ~ 20%

HSV Keratitis

n Epithelialn Stromaln Endotheliitisn Metaherpetic and Neurotrophic

HSV Keratitis

n Epithelialn Stromaln Endotheliitisn Metaherpetic and Neurotrophic

Corneal HSV Disease: Epithelial

n Dendriticn Geographicn Marginal ulcern Infection of epi cellsn Base stains with

fluorescein, infected “balloon” cells stain with rose bengal

HSV Dendritic Keratitis

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HSV Epithelial Keratitis

n Disease course < 2 weeks– 95% spontaneously heal in 14 days– Treatment speeds up resolution

n Topical nOral

Question

n What is your treatment of choice for management of HSV epithelial keratitis?1. Debriding the epithelium2. Topical trifluridine 1% gtt3. Topical ganciclovir 0.15% gel4. Oral anti-viral therapy5. Debriding the epithelium + medicine

HSV Epithelial Keratitis

n Treatment trends:– General ophthalmologist: topical– Cornea: oral– Greater trend towards topical treatment

with topical GCV 0.15 % gel

HSV Epi keratitis:Treatment

n Trifluridine 1% (TFT): 8x/day (q2h) until epithelium heals, usually 5-10 days

n Taper off within 2 weeks

Trifluridine 1%

n Very toxic to epithelium: – Delayed healing

n Conjunctival scarringn Punctal stenosisn Do not use > 2 weeks

HSV Epithelial Keratitis:Treatment

n Ganciclovir gel 0.15% (GCV)– 5x/day while awake x 7 days,

then TID for 7 days

n Side effect profile: – Much less epitheliopathy– Eye irritation (20%), punctate keratitis

(5%), conj hyperemia (5%)

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HSV Epithelial Keratitis:Treatment

n Ganciclovir gel 0.15% (GCV):n Since 1995, the GCV 0.15% available

in 30 countries within Europe, Asia, Africa and South America

n ACV 3% ung and GCV 0.15% gel standard of care in Europe

n Approved by FDA in 2009

HSV Epithelial Keratitis:GCV 0.15% studies

n All phase II/IIII GCV 0.15% studies have been abroad

n GCV 0.15% gel vs. ACV 0.3% ung– GCV as effective as ACV– Less blurring than ACV– Average healing time 7-8 days– 82% - 88% healing rate

HSV Epithelial Keratitis:GCV 0.15% studies

n May be useful as prophylaxis*– 6 patients: 3 s/p PKP, no

recurrences

*Tabbara Kf, Treatment of herpetic keratitis, Ophthalmology, 2005;112:1640.

HSV Epithelial Keratitis

Oral treatment:n Acyclovir 400mg 5x/day (2g/day)n Valacyclovir (Valtrex®) 500mg-1gm TIDn Famcyclovir 125-250mg BIDn In kids: Acyclovir 200mg/5cc qid

HSV Keratitis

n Epithelialn Stromal (15%): immune, necrotizing n Endotheliitisn Metaherpetic and Neurotrophic

Immune-mediated stromal keratitis

n Not active infectionn Occurs up to years after original

epithelial keratitisn Often chronic, recurrent

inflammation

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Stromal keratitis:Clinical appearance

n Epithelium intactn Stromal infiltrationn Edeman Stromal vascularizationà lipid n AC reaction

Herpetic Stromal Keratitis

Corneal HSV Disease: Stromal

nNecrotizing–Necrosis, dense

infiltrate–Epi defect–(+) infected

stromal cells & immune reaction

n Non-necrotizing stromal keratitis– Topical prednisolone 1% 4-8x/day– Topical difludprednate

n NOTE: When steroids > bid, must use anti-viral prophylaxis (topical or oral)

n Necrotizing– Aggressive topical steroids– Anti-viral for ACTIVE HSV disease

Treatment:HSV Stromal Keratitis

HSV Keratitis

n Epithelialn Stromaln Endotheliitis: Disciform, diffuse, linearn Metaherpetic and Neurotrophic

Corneal HSV Disease: Endotheliitis

n Immune reaction involving endothelial cells (? live virus)

n Clinical appearance– KP– Stromal and epithelial edema– Iritis– Minimal to no stromal infiltration

n 3 forms: disciform, diffuse, linear

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Disciform endotheliitis

n Most common n Occurs some

time after infectious epithelial keratitis

n Disc-shaped area of edema over KP

Diffuse and linear HSV endotheliitis

Diffuse: dense retrocorneal plaque

HSV endotheliitis: Treatment

n Disciform– Topical steroids– Anti-viral prophylaxis

n Diffuse and linear– Aggressive topical steroids– Anti-viral to for active infection

HSV Keratitis: Recurrence

n Rate of recurrence:– 1 year: 9.6%– 2 years: 22.9%– 10 years: 49.5%

n Can cause severe vision loss, espepithelial and stromal keratitis

Management: Immune diseases

n (Non-necrotizing) stromal, disciform endotheliitis

n Prednisolone 1% qid to q2hn Anti-viral prophylaxisn Once controlled, very slow

taper of steroidn May always require topical steroid,

even TIW

When prophylaxis?

nPrevent recurrencesn HEDS, ACV x1y ↓ all forms by ~41% (19%

vs. 32%) and stromal keratitis recurrence by 50% (14% vs. 28%)

nPrevent reactivation during steroid use

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Oral prophylaxis

– Acyclovir 400mg bid– Famciclovir 125-250mg qd-bid– Valacyclovir 500mg qd-bid

Topical prophylaxis

–Trifluridine: variablenTID à drop for drop until steroid down

to QD

– GCV gel: ?? No solid recommendations YET ☺n I use BID - TID

HSV Keratitis

n Epithelialn Stromaln Endotheliitisn Metaherpetic and Neurotrophic

When metaherpetic or neurotrophic disease?

n Epi defect on topical anti-viral >2 w n Geographic versus

metaherpetic/neurotrophic ulcer– HSV-infected “balloon” cells stain– Shape of lesion

Geographic Sterile Metaherpetic/ neurotrophic ulcer

n Poor sensationn Oval, rolled edges,

smooth bordersnWithin IPF

Courtesy of MB Hamill, MD

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Management:HSV ulcer> 2 weeks

n Stop topical anti-viraln Change to oral anti-viral prnn No preservativesn Non-preserved ung q2hn BCL n Amniotic membranen Omega-3 FA, Doxycyclinen (+) stromal inflammation: cautious steroids

Neurotrophic Ulcers

n Amniotic membrane transplantn Prokera: Self-retaining,

cryopreserved AMT on 16 mm PMMA ring

Self-retaining AMT

n Fairly easy insertion: exam lanen Can stain cornea with NaFL without

removal n Topical meds penetrate through AMTn AMT soaks up meds

Management:HSV Ulcer > 2 weeks

Surgical optionsn Amniotic membrane, esp if thinn Conjunctival flapn Lateral tarsorrhaphyn Keratoplasty

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Back to the patient…

n36 yo male, 2nd opinion of persistent “geographic ulcer”nRed eye OD began ~5w ago

–3rd episode in 5 y

nTrifluridine x4w, at qidnZymar qid

Back to the patient….

• Poor k sensation OD• Dx: Neurotrophic ulcer

Photos courtesy of S. Pflugfelder, MD

“Herpes….”

“Attacks the weak- worse in atopes, humbles the physician-fools the best of us, mocks your treatment- hides only to return, and returns more than the taxman” -Ivan R. Schwab, MD

Blepharokeratitis

“Blepharokeratoconjunctivitis”

n BKC is disease entity of adolescents-“a syndrome usually associated

with anterior or posterior lid margin blepharitis, accompanied by episodes of conjunctivitis, and a keratopathyincluding punctate erosions, punctate keratitis, phlyctenules, marginal keratitis, and ulceration”

Blepharokeratitis

n Ocular Rosacean Phlyctenulosisn Marginal keratitis

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Ocular Rosacea Ocular Rosacea

Ocular Rosacea

c/o Parag Majmudar, MD

Ocular Rosacea

n Most common in middle-aged femalen Flushed cheeks and nose à

telangiectasis– Vasomotor lability aggravated by coffee,

tea, alcohol, spicy foods, anxiety, hormonal changes

n Rhinophyma (bulbous nose) àsebaceous gland hypertrophy

Ocular Rosacean Etiology: unknownn Colonization of lid margins with flora

(S. epidermides, P. acnes) produce lipases which may alter MG secretions à inflammation

n S. epidermides found only in pustules, not in unaffected skin; may be transported by Demodex mites(Jarmuda S, et al. J Med Microbiol August 2012)

Ocular Rosacea

n Ocular findings ~50%– Blepharitis, MGD, lid thickening,

telangiectasis– Chronic, diffuse conjunctival injection, esp

within IPF

n Corneal involvement ~5-30%

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Ocular Rosacea: Corneal Findings

n Punctate epithelial erosionsn Marginal infiltratesn Corneal pannusn Stromal thinning, perforationn Corneal scars

Phlyctenulosis

Phlyctenulosis

c/o Parag Majmudar, MD

Phlyctenulosis

n Inflammatory raised gelatinous nodules in cornea or conjunctiva

n Hypersensitivity reaction

Phlyctenulosis: etiologyn Most commonly associated with

staphylococcal blepharitisn Others

– TB– P. acnes– N. gonorrheae, Chlamydia – HSV– C. albicans– Endemic parasites

Phlyctenulosis

n More common in children and adolescents

n W > M, 2:1 n Up to half of patients w/ bilateral

presentation

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Phlyctenulosis

n Phlyctenule can migrate towards center of cornea

n + Feeder vesselsn May ulcerate w/ stromal WBC infiltraten Heal with scarringn May lead to significant visual impairment

Marginal Keratitis

c/o EyeRounds.org

Marginal Keratitis Marginal Keratitis

n AKA catarrhal infiltraten Hypersensitivity reaction to

Staphylococcusn ? May be related to Demodex

blepharitis, esp with recurrent disease

Marginal Keratitis

n Creamy white infiltrate(s) in peripheral cornea

n Infiltrate smooth, distinct bordersn Single or multiplen Overlying epi defect smaller than infiltraten 1-2 mm clear zone from limbusn Infiltrate à then epi ulceration à KNV

Marginal Keratitis

n Most commonly occur where cornea crosses lid margin

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Blepharokeratitis: Treatment

n Treat inflammation and blepharitis– Combo steroid/ antibiotic work well

(Tobramycin/dexamethasone)– FML or Pred acetate 1% – Antibiotic ointment to lids

Blepharokeratitis: Treatment

n Oral antibiotic– Doxycycline 20 mg to 200 mg qd/bid(I prefer Doxy 50 mg bid, then taper to qd)

– Minocycline 20 to 40 mg qd– Azithromycin 250 to 500 mg qd x 3 days,

for 3-5 weeksn Azithromycin works wonders in children and

adolescents!

Blepharokeratitis

n Nutritional supplements: O3FA/O6FAn Lid hygienen If recurrent, may consider Demodex txn In-office MG expression

– Probing– IPL– Lipiflow

Device in action

c/o Preeya Gupta, MD

Device in action

Wow…..

Suture Removal

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Suture Removal Conclusion: MK

n Broad spectrum fluoroquinolone– Besifloxacin or moxifloxacin

n Withhold steroids until clinical improvement observed

n 1-2-3 Rule for MK referralsn Do not initiate tx if planning to refer

same day à better yield

Conclusion: HSV

n HSV epithelial keratitis: active infection– No steroid with epithelial defect– Topical tx option less toxic– Reconsider tx or diagnosis if >10-14 days

n Stromal or disciform keratitis à aggressive steroid initially, very slow taper

n Always use oral or topical anti-viral prophylaxis with steroid use

n Geographic ulcer? Be aware of possible neurotrophic/ metaherpetic keratopathy!

Blepharokeratitis

n “Triple therapy”:– Topical steroid– Topical antibiotic ointment or gtt– Oral antibiotic

n O3FA/O6FA

Blepharokeratitis

n Lid hygienen Think Demodex for recurrent disease

or chronic blepharitisn In-office MG expression treatment

THANK YOU ☺