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FUNGAL CORNEAL ULCER

Arundhati Dvivedi final year p.g Dept.of Ophthalmology

Introduction:

• Fungal Keratitis is one of the most difficult forms of microbial keratitis to diagnose & to treat successfully

• Constitute 44% of all corneal ulcers in India • Fungi are eukaryotic, heterotrophic organisms & typically forms

reproductive spores.

• Fungus may be a part of normal external ocular flora. (3-28% of normal eyes)

CLASSIFICATION • Filamentous Septate Fungi (Non Pigmented): 1.Fusarium 2.Aspergillus

• Filamentous Septate Fungi(Pigmented): 1.Alternaria 2.Curvularia

• Filamentous Non Septate: 1.Mucor 2.Rhizopus • Yeasts: 1.Candida 2.Cryptococus

• Dimorphic fungi: 1.Histoplasma 2.Coccidioides and 3.Blastomyces

EPIDEMIOLOGY • Overall incidence is low- 6-20%

• Aspergillus most common organism worldwide.

• Incidence varies geographically: • Western countries: Candida, Aspergillus, Fusarium • In India: Aspergillus (27-64%) • Fusarium (6-32%) • Penicillium (2-29%) • Rural>urban • 21-50 years, males • Monsoon,early winter due to humidity & during harvest seasons • However, in colder climates, where Candida infections predominate

RISK FACTORS • OCULAR : • Trauma (M/C)-veg matter ,mud , animal matter – most common • Contact lens use: • Cosmetic Lens- filamentous • Therapeutic Lens- Yeast

• Indiscriminate use of Topical Medications- Corticosteroids and

Broad Spectrum Antibiotics

• Corneal Sx- Penetrating Keratoplasty, LASIK.

• Chronic Keratitis- Herpes Simplex, Herpes Zoster,Vernal/allergic keratitis

SYSTEMIC: Immunocompromised State- HIV, Leprosy Patients on immunosuppressives , Diabetes Mellitus , ICU patients

PATHOGENESIS • Fungi are saprophytic pathogenic organisms.

• Fungi gain entry into stroma through a defect in epithelial barrier.

release toxins and proteolytic enzymes

• Host response-PMNs at the site of defect from tears & limbal vessels

• Release of cytokines & interleukins

• Necrosis & sloughing of epithelium, Bowman’s membrane & stroma

• Progressive invasion of cornea & increase in size of ulcer • A saucer shaped defect with projecting walls above the normal

surface due to swelling of tissue resulting from fluid imbibition by corneal stroma with grey zone of infiltration

CLINICAL FEATURES

Symptoms: •Foreign body Sensation •Slow onset increasing pain •Watering •Photophobia •Clinical signs are more severe than symptoms. Signs: •Conjunctival injection •Epithelial defect •Anterior chamber reaction

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Specific: • Feathery edges with fluffy margins • Infiltrate • Elevated edges • Satellite lesions • Endothelial plaque • Grey/brown Pigmentation( s/o dermaticeous fungi like Curvularia) • Hypopyon ( non Sterile, thick & immobile) • Yellow line of demarcation • Immune Ring (Wesseley)

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Yeast: •A “collar button” configuration is typical of the keratitis associated with a small ulceration and an expanding discrete stromal infiltrate

•Confocal microscopy is rarely available, but may permit identification of organisms in vivo.

Evaluation • Visual acuity • Slit lamp examination • KOH mount • IOP measurement with tonopen • B scan • Culture and senitivity.

• Systemic investigations- 1. Blood sugar levels 2. Complete blood picture 3. Liver function tests 4. Renal function tests

• scrapings of corneal ulcers are obtained, from the most active regions.

• The eye is anesthetized with topical anesthetic

• A heat-sterilized platinum spatula or blade no.15 or 11,is used to firmly scrape the leading edges of the ulcer.

• Multiple areas of a large ulcer should be sampled. • care must be exercised not to precipitate perforation. • calcium alginate swab moistened with soy broth can be used.

• Scrapings should be placed on a slide for staining and directly applied to

culture media, such as plates and broth, to maximize the chance of recovery.

• Multiple C streaks should be used on agar plates, because it is often difficult to identify an organism recovered in culture as the offending pathogen, and growth outside of the C streak might indicate contamination.

KOH mount

• Potassium hydroxide (KOH) preparation is used for the rapid detection of fungal elements in clinical specimen

• KOH is a strong alkali. • When specimen is mixed with 20% w/v KOH, it softens, digests and

clears the tissues , surrounding the fungi so that the hyphae and conidia (spores) of fungi can be seen under microscope.

Procedure for KOH mount • The scrapings are placed directly onto a microscope slide and are

covered with 10% or 20% potassium hydroxide.

• The slide is left to stand until clear, normally between five and fifteen minutes, in order to dissolve cells and debris.

• To enhance clearing dimethyl sulfoxide can be added to the slide. To make the fungi easier to see lactophenol cotton blue stain can be added.

• The slide is gently heated to speed up the action of the KOH.

• Adding calcofluor-white stain to the slide will cause the fungi to become fluorescent, making them easier to identify under a fluorescent microscope.

• Place the slide under a microscope to read.

KOH mount

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Stains: •Gram Stain •Giemsa Stain

•Gomorie Methenamine Silver •PAS Stain •lectins

Fluoroscent Microscopy:

•Acridine Orange •Calcoflour white

•Potassium Hydroxide Wet Mount (10-20%w/v)

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• Lactophenol cotton blue-for quick evaluation of fungi, stains chitin in the cell wall of fungi.

• PAS- stains polysaccharide in the cellwall of fungi.

• Gomori methenamine Silver nitrate outlines fungi in black due to silver precipitating on the fungal cell wall.

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• SDA with Chloramphenicol -inhibits bacterial growth

• Cycloheximide to inhibit saprophytic fungi and some yeasts(including C.neoformans)

• Cycloheximide will prevent the growth of opportunistic pathogens -Aspergillus

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• Culture Media • Blood Agar

• Chocolate Agar

• Sabouraud’s dextrose Agar

• Thioglycollate Broth

• Brain Heart Infusion Broth / Solid Media

• Positive culture expected in 90% cases, within 72 hrs in 83% cases

within 1 week in 97% cases

• Increasing Humidity of medium by placing inoculated agar plates in Plastic bags enhance fungal growth.

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Candida on SDA

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• Candida albicans grows rapidly in culture, reaching maturity in as little as three days. Colonies are cream coloured, raised, entire, smooth & butyrous.

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Newer Methods

•Electron Microscopy •Polymerase Chain Reaction

SCRAPING

•Advantage: •Provide initial debridement of organisms- reduce the fungal load •Improve penetration of drugs

•Methods: •Surgical Blade •26 gauge needle •Diamond tipped motorized burr •Diagnostic Superficial Keratectomy/Corneal Biopsy

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• Corneal biopsy: Done in Minor OT with Topical Anaesthesia

• 2-3 mm dermatologic trephine on anterior corneal stroma incorporating both clinically infected & adjacent clear cornea.(Avoiding Visual Axis)

• Anterior Chamber Tap:

• Hypopyon

• or Endothelial Plaque

COMPLICATIONS:

1. Scleritis 2. Impending perforation 3. Endophthalmitis 4. Glaucoma

TREATMENT

MEDICAL •Topical: •Natamycin5% •Amphotericin B 0.15% •Cycloplegics •Antibiotics •IOP lowering medication

• SYSTEMIC: • Fluconazole • Voriconazole

• SURGICAL 1. Debridement

2.Therapeutic Penetrating

Keratoplasty

3.Conjunctival Flap

4.Flap + Keratectomy

5.Flap + Penetrating Graft

6.Lamellar Graft

7.Cryotherapy ( In Kerato scleritis)

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Anti fungals

• POLYENES: • Amphotericin B, Natamycin • Binds to ergosterol in fungal cell membrane & cause the membrane to

become leaky.

• AZOLES: • Ketoconazole

• Fluconazole

• Voriconazole

• Inhibits CYP P450 14 a demethylase enzyme involved in conversion of

lanosterol to ergosterol

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• PYRIMIDINES:

• Flucytosine

• Causes Faulty RNA Synthesis & non competitive inhibitor of Thymidylate Synthesis

• ALLYLAMINES: Terbinafine

• Ergosterol Biosynthesis inhibitor

• ECHINOCANDINS: Cell wall Synthesis inhibition by D-glucan synthesis inhibition

• Capsofungin , Micafungin

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• Topical

• Natamycin 5% is Initial drug of choice.

• Topical Amphotericin B 0.15% added in c/o worsening , candida &

aspergillus

• oral or Topical Azole added in c/o Fusarium

• Indication for Systemic antifungals:( voriconazole 1st choice)

• Severe deep keratitis

• Scleritis

• Endophthalmitis

• Prophylactic t/t after Penetrating Keratoplasty for Fungal Keratitis

• Virulent Fungus

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• Topical : initially 5% Natamycin- hrly :day time n 2 hrly : night

:+ fluoroquinolones for 2⁰ bacterial infections. • Bd eye checkups under slitlamp

• Resolving -give Natamycin 2 hrly ->2 wks

• worsening -topical Amphotericin B 0.15%/fluconazole 2% is given.

• CandidiaI - Ampho B 0.15%/ fluconazole 0.3% 1st choice

• Echinocandins , Ampho: not effective against fusarium • Nata 5% = econazole1% = voriconazole0.5 μg/ml.

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• VORICONAZOLE- derived from Fluconazole

• wider spectrum of activity against Candida,

• Aspergillus

• and Fusarium • exerts its effect from inhibition of cytochrome P450 dependant 14

alpha sterol demethylase , an enzyme involved in the ergosterol biosynthetic pathway.

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Intracameral therapy

• In severe keratomycosis not responding to topical natamycin • It ensures adequate drug delivery into AC and avoid surgical

intervention in the acute stage of the disease.

• performed under strict aseptic conditions.

• If the infection involves the anterior capsule of the lens, care should be taken to avoid injury to the lens.

• 5 μg ampho B in 0.1 mL 5% dextrose through a paracentesis • Injections repeated in case of inadequate response

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• Length of treatment is based on clinical response of individual.

• If toxicity is suspected and if adequate t/t has been given for 4 - 6 weeks treatment should be discontinued & patient is observed for reccurence in follow up.

• Subconjunctival injections:

• reserved in cases of scleritis, severe keratitis , endophthalmitis

• Miconazole (preferred) as is least toxic and best toleratedx(5 to 10 mg of 10mg/ml )suspension

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• INTRACORNEAL THERAPY

• for non healing fungal corneal ulcers

• Amphotericin B injection 5-7.5 μg , given near to stromal site of growth.

• raise the local concentration of the antifungal agent enough to be effective in the eradication of the deep corneal infection

• total elimination

• repeated after 48 to 72 hours

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• SIGNS OF IMPROVEMENT

• Decreased pain

• Decreased size of infiltrate.

• Disappeared satellite lesions

• Rounding of feathery margins

• DURATION OF TREATMENT :4 -6 WKS only due to toxicity

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Synergism: •Amphotericin B & flucytosine •Natamycin & Ketoconazole

Antagonism:

•Amphotericin B & Imidazoles

Antibiotics with Antifungal Property:

•Chloramphenicol -fusarium, Aspergillus •Moxifloxacin & tobramycin - Fusarium •Chlorhexidine •Povidone Iodine.

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SURGICAL MANAGEMENT

• 1. Debridement

• 2.Therapeutic Penetrating Keratoplasty

• 3.Conjunctival Flap

• 4.Flap + Keratectomy

• 5.Flap + Penetrating Graft

• 6.Lamellar Graft

• 7.Cryotherapy ( In Keratoscleritis)

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• Debridement: Done every 24 - 48 hrs under topical anaesthesia

• Debulks necrotic material & organisms

• Enhances penetration of topical drugs

• Penetrating Keratoplasty Indication:

• Infectious process progress to limbus or sclera

• Failure of medical t/t

• Recurrence of infection

• To delay or prevent the need for corneal transplant with severe thinning or perforation is managed with TISSUE ADHESIVE(N -BUTYL CYANOACRYLATE)

• BANDAGE CONTACT LENS

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• Technique for Penetrating Keratoplasty :

• Size of trephination should leave 1- 1.5 mm clear zone of clinically uninvolved cornea to reduce residual fungus.

• Interrupted sutures with slight longer bites should be used to avoid cheese wiring

• Irrigation of Anterior chamber with antifungals

• Affected intraocular structures like iris, lens,& vitreous should be excised, the lens should be left untouched to prevent the spread of infection in the posterior segment

• The specimens -mcirobiology and pathology for culture and fixed section examination.

• If involvement of intraocular structures or endophthalmitis is suspected, an antifungal agents :amphotericin B (5μg/0.1ml) or miconazole (25μg/0.1ml)

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• Fungal hyphae usually lie parallel to the cornea to the corneal surface and lamellae.

• A vertical or perpendicular arrangement of fungal hyphae in the corneal stroma: increased virulence and in patients on topical corticosteroid therapy.

• Surgical instruments should be changed to sterile ones once infected tissue removed to avoid recontamination.

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• If endophthalmitis is suspected:

• Intraocular Antifungal injected at the time of keratoplasty. ( Preferably AmphotericinB)

• After Penetrating keratoplasty: • Topical antifungals continued to prevent recurrence.

• If pathology reports are negative for organism at edge of corneal

specimen STOP antifungals after 2 weeks and follow up patient for recurrence.

• If Pathology reports are positive t/t continued for 6 -8 weeks.

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PROGNOSIS: • Factors associated with Treatment Failure:

• Large ulcer size (greater than 14mm square) • Presence of Hypopyon

• Aspergillus as causative organism