corneal ulcers: infectious or sterile?...10/15/2019 2 infectious ulcers •results from active...
TRANSCRIPT
10/15/2019
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CORNEAL ULCERS: INFECTIOUS OR STERILE?ZANNA KRUOCH, OD, FAAO, ABO DIPLOMATE, FSLS
UNIVERSITY OF HOUSTON, COLLEGE OF OPTOMETRY
• I have received honorarium from: Essilor / OOGP
• Clinical Assistant Professor – University of Houston, College of Optometry
• Opinions from this lecture are my own
FINANCIAL DISCLOSURES
COURSE EXPECTATIONS
• Introduction
•Etiologies
•Pathophysiology
•Clinical features
•Cases
•Diagnostic assessment
•Treatment and
management
INFECTIOUS VS. STERILE ULCERSUNDERSTANDING THE DIFFERENCES IN ETIOLOGY & PATHOPHYSIOLOGY
SIGNIFICANCE IN…
• Differentiation:
• Treatment & management
• Management:
• Both may result in visually significant opacification
• Both may result in ocular morbidity
CORNEAL ULCERS
• Clinical Presentation:
• Infectious & sterile ulcers both require a significant defect of the overlying epithelium
• Stains with fluorescein and lissamine green/rose bengal
• Presence of inflammation
• Non-ulcer breaks of the overlying epithelium:
• Erosions
• Trauma
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INFECTIOUS ULCERS
• Results from active infection of the cornea (microbial keratitis):• Direct pathogen invasion
• Microbes include bacteria, viruses, parasites, and fungus
• Risk factors: varies for underlying etiology• Contact lens wear and/or abuse
• Trauma
• Age
• Geography
PATHOPHYSIOLOGY OF INFECTIOUS ULCERS
• Invasion of pathogen
• Immune response:
• Polymorphonuclear neutrophils (PMNs) to site Release of matrix metalloproteases (MMPs) Ulcer
• Healing vs. Non-Healing:
• Healing: Macrophages clears debris scarring potentially vision loss
• Non-healing: Progressive keratolysis perforation
CLINICAL FEATURES OF INFECTIOUS ULCER
• Pain and photophobia
• Lid edema
• Hyperemia
• Large with irregular borders
• Corneal reaction
• Anterior chamber reaction
STERILE ULCERS
• Results as a complication of inflammation
• Etiologies of inflammation:
• Ocular surface instability
• Autoimmune diseases
• Ocular surgeries
• Others
Treatment of Acanthamoeba neurotrophic corneal ulcer with topical matrix therapy - Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Corneal-neurotrophic-ulcer-worsening-despite-intensive-treatment_fig1_279308702 [accessed 10 May, 2019]
STERILE ULCERS: ETIOLOGIES
• Ocular surface instability:• Neurotrophic keratopathy
• Exposure keratitis
• Autoimmune conditions:• Rheumatoid arthritis
• Sjogren’s Syndrome
• Wegner’s Granulomatosis
• Contact lenses
• Vitamin A deficiency
• Ocular surgeries
• Mooren’s Ulcer
PATHOPHYSIOLOGY OF STERILE ULCER
• Compromised tear film / unstable ocular surface
• Immune response: PMNs to site Release of MMPs Ulcer
• Healing vs. Non-Healing:• Healing: Macrophages clear debris scarring potentially vision
loss
• Non-healing: Progressive keratolysis perforation
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CLINICAL FEATURES OF STERILE ULCER
• Persistent epithelial defects
• Unstable tear film
• Aqueous deficiency
• Minimal pain
• Anterior corneal edema
• Corneal hypoesthesia
• Smooth, regular borders
Infectious Ulcer Factors Sterile Ulcer
Larger SIZE Smaller
Central LOCATION Peripheral
Decreased VISION No change
Irregular, indistinct BORDERS Round, distinct
ExtensiveADJACENT CORNEAL
REACTIONLimited
Moderate-Severe CHAMBER RXN None-Mild
> 2 mm in size INFILTRATES 0.75 to 1.0 mm in size
Moderate-Severe PAIN Mild
Purulent DISCHARGE Mucopurulent
CASE
CASE: 65 YRO AAF
• CC: Outside referral for corneal ulcer OD
• HPI:
• Dx by ER 2 weeks prior
• Rxed unknown ointment q4h, moxifloxacin gtt every hour
• Associated symptoms:
• Achiness
• Serous discharge that is minimal at this visit
• No pain
CASE
• POH: Advance cataract OD
• PMH: arthritis, HTN
• Medications: Ibuprofen, Lisinopril, cetirizine
• Allergies: NKDA, seasonal allergies
CASE
• VA (sc): OD LP, OS 20/25 PH
20/20
• EOM: USA OD, OS
• CF: FTFC OD, OS
• Pupils: equal, round, reactive, (-)
APD
• IOPs:
• OD: soft; no reading on NCT
• OS: 17 mmHg
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OD
ADNEXA WNL
LIDS/LASHES Thicken eyelids, cloudy / minimal MG expression, telangectasia
CONJ Perilimbal injection 360 with 1+ inferior injection
CORNEA Arcus; 2mmHx3mmV epithelial defect (+)NaFl with smooth borders overlying infiltrative haze
AC (-) C/F
IRIS flat, brown
LENS Advanced cortical opacification
Gif credit to: http://easports.com/nhl
IS THIS CORNEAL ULCER INFECTIOUS OR STERILE?
IS THIS CORNEAL ULCER INFECTIOUS OR STERILE?
Factor Considerations
Size • Infectious ulcers tend to be larger than 2 mm• Sterile ulcers tend to be smaller than 2 mm
Location • Paracentral defects could go either way but the closer to visual axis, more likely to be infectious.
• Other factors will help determine this (adjacent corneal reaction, borders)
Vision • Visual axis obscuration• Adjacent corneal reaction causing decreased vision
IS THIS CORNEAL ULCER INFECTIOUS OR STERILE?Factor Considerations
Borders • Shape of lesion: round/oval vs. irregular• Edges: smooth borders vs. heaped edges
AdjacentCorneal Reaction
• Paracentral defects could go either way but the closer to visual axis, more likely to be infectious.
• Other factors will help determine this (adjacent corneal reaction, borders)
Anterior Chamber Reaction
• Stronger AC reaction indicates more infectious• Hypoypon more likely to be infectious but can
occur in non-infectious
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IS THIS CORNEAL ULCER INFECTIOUS OR STERILE?
Factor Considerations
Infiltrates • Diffuse infiltration tends to be more infectious• Small, round infiltrates are more likely to be sterile
Pain • Sterile ulcers may present with mild ulcers or none at all
• Infectious presents with significant pain and photophobia
Discharge • Majority has reflex (serous) discharge
Factors Case
SIZE Larger
LOCATION Paracentral
VISION No change
BORDERS Somewhat irregular with smooth edges
ADJACENTCORNEAL RXN
Inactive > active
CHAMBER RXN
None
INFILTRATES Distinct haze, minimal edema
PAIN None
DISCHARGE Serous
CASE: CONSIDERATIONS
• Decreased vision: • Lens opacification causing LP?
• B-scan: No detachment
• Prior inflammation?
• Defect with rolled/smooth edges
• Lacks symptoms
• Corneal sensitivity testing:• DECREASED SENSITIVITY!
CASE
• Assessment:
• Neurotrophic keratopathy OD
• Advance cataract OD – contributing to majority of decreased VA
• Plan:
• DC Moxifloxacin. Start Tobradex QID OD with f/u in 2 days. Refer to
PCP for IgG/IgM testing for HSV & VZV.
• Upon keratitis resolution, refer for cataract extraction OD.
FOLLOW-UP 2 WEEKS LATER TOBRADEX + BCL
CASE
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CASE: 47 YRO HM
• CC: Red, painful right eye
• HPI:
• Onset 2 months ago
• Associated symptoms: photophobia, redness
• (-) trauma or CL wear
• Saw OD who Rxed: Durezol 4/3/2/1 schedule and neomycin/polymixin-
b/dexamethasone PRN.
• Feels that condition has worsened
CASE:
• POH: “ Eye infection” OD - 25-30 years ago treated with unknown drops
• PMH: (+) DM – Dx 1 month ago
• MEDS: Metformin, Durezol, Neomycin/Polymixin-B/dexamethasone
• ALL: NKDA
CASE
• VA(sc):
• OD 20/70; PH 20/60
• OS 20/200; PH 20/100
• EOMs: USA OD, OS
• CF: FTFC OD, OS
• Pupils: Equal, round, reactive
without APD OD, OS
• Goldmann IOPs:
• OD 11 mmHg
• OS 18 mmHg
OD OS
OD OS
WNL ADNEXA WNL
(-) Flaking LIDS/LASHES (-) Flaking
Pinguecala nasal CONJ Pinguecala nasal; 3+ diffuse hyperemia
4mm round stromal opacification
CORNEA 2.5x3mm paracentral ulceration with necrotic tissue;
diffuse infiltrations
D&Q AC No apparent reaction
Brown, flat IRIS Brown, flat
Factors Case
SIZE Larger
LOCATION Paracentral
VISION Decreased
BORDERS Irregular, necrotic edges
ADJACENTCORNEAL RXN
Significant
CHAMBER RXN
UTT
INFILTRATES Significant
PAIN Present
DISCHARGE Serous discharge
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CASE: CONSIDERATIONS
•New inflammation related to old inflammation? •HSV / VZV
•Corneal sensitivity testing: Equal OD, OS
CASE: ASSESSMENT
• Infectious keratitis OS:
• Resistance to antibiotic / worsening with steroids
• Etiologies to consider:
• Pseudomonas – timeline not consistent with Pseudomonas
• Fungus
• Acanthamoeba
CASE: PLAN & REFERRAL
•Refer to corneal specialist for evaluation:
• Active infection due to HSV / Fungus / Bacteria.
• Besivance q1h.
• Referral to county hospital.
•County hospital: Positive culture for FUNGUS!
DIAGNOSTIC ASSESSMENT: ESSENTIAL EXAM
•History
•Risk Factors
•Clinical appearance
•Remember the dilated fundus examination!
DIAGNOSTIC ASSESSMENT: OTHER TESTING
•Corneal sensitivity
testing
•Anterior segment OCT
•External Photography
"corneal reflex." Mosby's Medical Dictionary, 8th edition. 2009. Elsevier 12 May. 2019 https://medical-dictionary.thefreedictionary.com/corneal+reflex
DIAGNOSTIC ASSESSMENT: ANCILLARY
•Corneal cultures:
•Microscopy – stains
• Lab cultures
•Confocal microscopy
https://www.cehjournal.org/article/taking-a-corneal-scrape-and-making-a-diagnosis-2015/
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WHEN TO CULTURE: 3-2-1 RULE
•Size: 3 mm in size or wider
•Quantity: 2 or more ulcers
•Location: Within 1 mm of the visual axis
WHEN TO CULTURE
•Poor response to therapy
•Worsening
•Atypical bug
•High risk: Post-surgical, monocular, immunocompromised
STAIN VS. PLATES?
•Benefits of stain: prompt, in-
office
•Benefits of culture: more
variety in media
•Both types of culture increase
likelihood of growth!https://www.cehjournal.org/article/taking-a-corneal-scrape-and-making-a-diagnosis-2015/
DIAGNOSTIC ASSESSMENT: COLLECTION
• Stains and cultures both require collection
• Anesthetic
• Areas to culture:
• Cornea, conjunctiva, lid margins
• Contact lenses, cases
• Collect at base and at edge
• Avoid purulent discharge.
• Remove necrotic tissue.https://www.cehjournal.org/article/taking-a-corneal-scrape-and-making-a-diagnosis-2015/
Stain Organism Considerations
Gram Bacteria, fungi, microsporidia Best for bacteria; can show up for fungus but not definitive
Giemsa Fungi, Acanthomoeba,Microsporidia
Potassium hydroxide with calcofluor
Fungi
Acid-fast stain Mycobacterium, Nocardia
Periodic acid-Schiff (PAS)
Fungus, Acanthamoeba
Media Organism Considerations
Blood agar Bacteria, fungi Does NOT detect Neisseria, Haemophilus, Moraxella
Chocolate agar Haemophilus, moraxela, neisseria
Sabourand dextrose agar Fungi
MacConkey Gram negative bacteria Useful for Pseudomonas due to lactose differentiation
Periodic acid-Schiff (PAS) Fungu, Acanthamoeba
Thioglycolate broth Anaerobic/aerobic bacteria, fungi
Lowensten-Jenson medium Mycobacteria, Nocardia
Non-nutrient agar with E.coli
Acanthamoeba
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CULTURE REPORTS:
• Positive growth in 50-60% of collections
• Growth results: • Typical microbes: 2-14 days
• Atypical microbes: Several weeks for growth
•Sensitivity report:• Effectiveness of anti-microbial agent
• 1-2 days; 7 days; 14 days.
CONFOCAL MICROSCOPY
• Benefits:
• Non-invasive
• Detection of Acanthamoeba, Nocardia, Fungus
• Disadvantages:
• Limited availability
Prospective Study of the Diagnostic Accuracy of the In Vivo Laser Scanning Confocal Microscope for Severe Microbial Keratitis - Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/In-
vivo-confocal-microscopy-IVCM-images-of-Fusarium-sp-culture-positive-ulcer-showing_fig1_306128736 [accessed 12 May, 2019]
EMPIRICAL TREATMENT: STERILE ULCERS
• Address etiology Decrease inflammation
• Topical treatment:• Topical steroids
• Topical immunomodulators
• AMT, autologous serum, scleral contact lenses
https://www.wjgnet.com/2220-3230/full/v4/i2/111.htm
EMPIRICAL TREATMENT: INFECTIOUS ULCERS
• Assumption is bacterial etiology
• Disadvantage Messes up culture!
• Aggressive antimicrobial treatment:
• Loading dose
• Therapy q1-2h during night
• Consider more than 1 anti-infective agent with alternation
• Fortified antibiotics
INFECTIOUS ULCERS: BROAD SPECTRUM
• Fluoroquinolones (4th generation)
• Cephalosporins
• Aminoglycosides
• Tetracyclines
• Trimethoprim-sulfamethazole
• Fortified antibiotics
INFECTIOUS ULCER: STEROIDS?
• Steroids Depressed immune system Proliferation of microbe
• Avoid in first 24-48 hours if you suspect infectious!
• Inflammation Follows Infection:• Steroid for Corneal Ulcer Trial (SCUT)
• Large, randomized study: Role of steroids in corneal ulcer treatment
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STEROID FOR CORNEAL ULCER TRIAL (SCUT)
• No differences at 3 months for measures of VA, scars, or rate of
perforation
• Differences in subgroups: Those treated with steroids had better
VA if…
• Significant decreased vision
• Central location
• Deep ulceration
• As long as it is not Nocardia
EMPIRICAL TREATMENT: UNSURE?
• Treat as infective for first 24-48 hours or epithelial closure
• If improvement likely infectious etiology
• If no improvement
• 1) Inadequate therapy
• 2) Wrong bug
• 3) Not infectious
NON-MEDICAL MANAGEMENT
•Corneal collagen cross-linking
•Amniotic membrane transplantation
•Conjunctival flaps
•Corneal transplantation
https://newgradoptometry.com/everything-need-know-corneal-collagen-cross-linking-cxl/
SUMMARY
•Corneal ulcers are difficult!
• History, symptoms, and clinical features
•Consider cultures:
• 3-2-1 Rule!
• Worsening, poor immune system, monocular
SUMMARY
•Treatment:
• If unsure, assume active infection! Treat aggressive with
antimicrobial agents for first 24-48 hours
• Don’t be afraid of steroids!
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REFERENCES
1. Austin A, Lietman T, Rose-Nussbaumer J. Update on the Management of Infectious Keratitis. Ophthalmology. 2017;124(11):1678-1689.
2. Sharma S. Keratitis. Biosci Rep. 2001;21(4):419-444.
3. Sridhar MS, Sharma S, Reddy MK, Mruthyunjay P, Rao GN. Clinicomicrobiological review of Nocardia keratitis. Cornea. 1998;17(1):17-22.
4. Vemuganti GK, Murthy SI, Das S. Update on pathologic diagnosis of corneal infections and inflammations. Middle East Afr J Ophthalmol. 2011;18(4):277-284.
5. Donzis PB, Mondino BJ. Management of noninfectious corneal ulcers. Survey of Ophthalmology. 1987; 32(2):94-110.
6. https://www.reviewofoptometry.com/article/collecting-a-corneal-culture
7. Papaioannou L, Miligkos M, Papathanassiou M. Corneal Collagen Cross-Linking for Infectious Keratitis: A Systematic Review and Meta-Analysis. Cornea. 2016;35(1):62-71.
8. Alio JL, Abbouda A, Valle DD, Del Castillo JM, Fernandez JA. Corneal cross linking and infectious keratitis: a systematic review with a meta-analysis of reported cases. J Ophthalmic Inflamm Infect. 2013;3(1):47.
9. Palioura S, Henry CR, Amescua G, Alfonso EC. Role of steroids in the treatment of bacterial keratitis. Clin Ophthalmol. 2016;10:179-186.
10.The Steroids for Corneal Ulcers Trial (SCUT): Secondary 12-Month Clinical Outcomes of a Randomized Controlled Trial. Muthiah Srinivasana