Fungal corneal ulcer

common type of ulcer in tropical countries

1. Fungal Corneal ulcer Dr. K. Vasantha M.S., F.R.C.S., Edin Director RIO Chennai (Rtd)

2. Watering, pain and redness usually following injury with vegetative matter Defective vision. More if the ulcer is in the center Lid edema, muco purulent discharge Circum corneal congestion, sometimes conjunctival congestion also. Chemosis if there is severe inflammation Signs will be more than the symptoms Signs and symptoms

3. Opacity in the cornea which will take up fluorescein stain as the epithelium will be abraded. Pupil will be constricted and sluggishly reactive due to irritation to the iris. This toxic reaction can produce hypopyon which will be sterile in bacterial ulcer. In fungal ulcer fungal hyphae may be present. Signs

4. Stage of progressive infiltration Stage of active ulceration Stage of regression Stage of cicatrization Stages

5. When you see an ulcer the following tests must done to find the causative organism Smear KOH suspension Culture Detection of antigens, antibodies and endotoxins Immunoglobulins PCR Confocal microscopy Investigations

6. Gram stain: for bacteria, yeasts, cysts of Acanthamoeba. Can detect 60 – 70% of bacteriae. Fungal hyphae are Gram negative or faintly stained walls with unstained protoplasm Giemsa: viral and Chlamydia inclusion bodies, polymorphs and mononuclear cells besides the above microbes Ziehl-Neilson: Mycobacteria and Nocardia Stains used

7. Acridine orange: bacteria, fungi and Acanthamoeba cysts Calco flour white: fungi and Acanthamoeba will appear bright white Need a fluorescent microscope Gomori Methenamine silver: best for fungi. Cell wall and septa stain black against green background

8. Differential staining

9. KOH suspension: use of KOH suspension is to remove the other fibers leaving the fungal elements which are resistant. Very useful as it can be done quickly and treatment can be started if fungal ulcer is present Can detect fungus, Nocardia, Pythium and Acanthamoeba cysts Ink and Lacto Phenol cotton blue also can be used to see the fungal elements Staining

10. Many branching septate fungal filaments are seen in KOH

11. Lactophenol cotton blue preparations of slide cultures of Aspergillus fumigatus Curvularia species

12. Acanthamoeba – seen with saline Trophozoit e Cyst

13. Apply topical anesthetic and wait for 3 – 5 mins for the anesthetic to drain off Use a Kimura’s spatula or a surgical blade to take the sample. This is preferably done under a slit lamp. The spatula can be sterilized with flame or 70% alcohol. Contamination by eye lashes is avoided by using a speculum Collecting and processing the samples

14. Chocolate agar: Haemophilus Thioglycollate broth: both aerobic and anaerobic Non nutrient agar with E. coli – Acanthamoeba Thayer Martin agar: to isolate Neisseria Lowenstein Jenson for Mycobacteria Culture

15. Fungal mediums Sabouraud’s Dextrose Agar (SDA) ( 25°C ) Blood Agar : for aerobic bacteriae and fungi esp. Fusarium Brain-heart infusion medium( 37°C ) filamentous fungi and Yeast It might grow within 24 hrs also, Usually 2-3 days Fungal medium should be retained for a week to declare negative result

16. Confocal microscopy for Acanthamoeba cysts (10 to 20 microns), fungi (>200 microns), Pythium, some bacteria and Microsporidia Aspergillus antigen can be detected by using Aspergillus kit Investigations

17. In the following slides you will see the typical characteristics of fungal ulcers with Dry ulcer Hyphate margins Satellite lesions Thick cheesy hypopyon which is immobile and has a convex surface Pigmentation – dematiacious fungi Endothelial plaques Fungal ulcer

18. Early fungal ulcer

19. Dry ulcer with convex hypopyon - fungal

20. Hyphate margin with corneal abscess

21. Pigmented ulcer

22. Hyphate margins

23. With endothelial deposit

24. Satellite lesions and cheesy hypopyon

25. Severe chemosis

26. See the CCC and scleral involvement

27. Thick cheesy hypopyon

28. Stromal abscess and edema of the cornea

29. It is difficult to treat a fungal ulcer as Only few drugs are freely available Penetration of the drugs is very poor Poor bio availability of the drugs due to the poor penetration Toxicity of the systemic drugs Drug sensitivity cannot be determined Treatment

30. Atropine eye drops are given to cause dilatation and cycloplegia. This will reduce pain as ciliary spasm which is the cause for the pain is relieved Dilatation will break any synechiae and also prevent synechiae from forming Atropine reduces the tear secretion and there by increases the lysozomal content of the tears It also separates the corneal lamellae and helps in penetration of the drops applied Treatment

31. If chronic dacryocystitis is present sac excision has to be done As diabetes may predispose to infection and delay healing, this must be checked for History must be taken regarding use of immunodepressants and immunosuppression Treatment

32. Natamycin 5% suspension hourly for 2 days and then 2 hourly. Dosage is then adjusted depending up on the response. Administration of the drug during the night should be insisted. Econazole 2%, Fluconazole 0.3%, Voriconazole 1% or Amphotericin 0.1 to 0.25% can also be used Basic Treatment of a fungal ulcer

33. Amphotericin B 5 to 10 micro grams/0.1ml in 5 % dextrose can be injected in to the anterior chamber esp. for Aspergillus Can be repeated after 3 days Removing the cheesy hypopyon and the aqueous humor will also help. Fresh aqueous will have more lysozymes which will help in healing. Can be given intra stromal 0.02mg/ml. Not for Fusarium Intra cameral injection

34. Complications: cataract, hyphema, corneal edema, iritis due to suppression of T suppressor cells and activation of pro inflammatory cells There is also the danger of breaching the natural barrier there by spreading the infection to deeper tissues Glaucoma Endothelial damage Amphotericin

35. If the ulcer is not healing with above measures VCZ can be injected in to the stroma around the ulcer. 50 to 100 micro grams/0.1ml This has to be divided in to 5 doses and injected in to the stroma around and close to the ulcer Used for recalcitrant cases, deep stromal ulcer, after DSEK for inter face infection, Infection after PRK Natamycin also has been tried. Not effective and causes increased vascularization Intra stromal Voriconazole

36. See the air bubble in A.C following AMB injection

37. Mycotic ulcer treatment study MUTT found No advantage of topical Voriconazole over Natamycin MUTT II found - Oral Voriconazole as add on therapy to topical anti fungal drugs did not show any benefit. In Fusarium keratitis there was less incidence of perforation, but it was not significant. Oral Ketoconazole also did not show much benefit Between oral VCZ and Ketoconazole, Voriconazole was found to be better MUTT study

38. Scleral or limbal involvement Pediatric cases Peripheral ulcer Recalcitrant cases Post keratoplasty Endophthalmitis Systemic treatment is given

39. Polyenes Azoles Pyrimidines Allyl amines Echinocandins Heterocyclic benzofurans Antifungal drugs- classification

40. Polyenes are fungicidal. Interacts with ergosterol present in the fungal cell wall and leads on to extrusion of vital contents of the cell, causing death. Natamycin acts by inhibiting the amino acid and glucose transport. This causes a reversible and ergosterol specific action without altering the permeability Large polyenes : Nystatin, Amphotericin B Small polyene : Natamycin Mechanism of action

41. Fungi static at low concentration, fungicidal at high concentration 14 alpha – sterol demethylase inhibitor Inhibits ergosterol synthesis, causing increased cell membrane permeability and lysis Imidazoles: miconazole, clotrimazole, econazole and ketoconazole Triazole: voriconazole, posaconazole, fluconazole, itraconazole, ravaconazole Azoles

42. Pyrimidine: Interferes with pyrimidine metabolism as well as RNA, DNA and protein synthesis. E.g.- 5-Flucytosine Allylamine: Squalene epoxidase inhibitor which inhibits ergosterol synthesis – Terbinafine Echinocandins : fungicidal – inhibits the beta – 1,3 –d- glucan synthase leading on to increased permeability E.g. Caspofungin Heterocyclic benzofurans: fungi static – interferes with microtubules - Griseofulvin Mechanism of action

43. Also called Pimaricin Produced by Streptomyces natalensis Has a broad spectrum for filamentous fungi like Fusarium, Aspergillus, Curvularia Does not enter the anterior chamber Has to be applied every hour for initially. Reduced to 6 to 8 times later and continued as 4 times per day for 4 weeks after clinical healing of the ulcer Adverse effect: Particles remaining in the eye and causing irritation Anti fungal drugs - Natamycin

44. 1% solution is prepared from the parentral formulation Acts against Candida, Cryptococcus, Aspergillus Inhibits growth of Fusarium to some extent. For this drops have to be applied every hour and not every two hours which is used for other fungi It enters the a.c. and vitreous Should be given 1 hour before or 2 hours after meals as acidic medium will reduce the absorption of drugs Best for recalcitrant cases not responding to N atamycin Voriconazole

45. Inhibits cytochrome P 450 dependant 14 alpha sterol demethylase an enzyme needed for synthesis of ergosterol It has fungicidal action on Aspergillus It also induces release of tumor necrosis factor alpha in monocytes Mechanism of action

46. Visual disturbances which starts 30 minutes after taking the drugs and last for 30 minutes Photophobia and color vision changes Visual hallucinations Skin rash, contact dermatitis Steven Johnson’s Liver toxicity, bone toxicity Skin cancer and melanomas in long term use Teratogenic Adverse effects of Voriconazole

47. Produced by Streptomyces nodosus Broad spectrum, highly active against Cryptococcus and Candida Poorly soluble in water. Photosensitive. Hence must be stored in the dark and refrigerated at 2 – 8 degrees Topical 0.15% Intra vitreal liposomal AMB was found to be effective for Candida endophthalmitis in animals Combination with Fluconazole gives good results Amphotericin B

48. Renal failure and electrolyte imbalance (avoided with IV fluids) Hepatotoxicity Can be used during pregnancy Side effects with systemic AMB

49. An Imidazoles active against dermatophytes, yeasts, molds. Limited action against filamentous fungi and some bacteriae Dose 200-400 mg/day taken with meal as acidic medium is needed for absorption. So if the patient is taking antacids the absorption will be less CYP3A4 enzymes are needed for the metabolism of this drug. So if CYP3A4 substrate drugs like dofetilide, quinidine, cisapride are given serious adverse reactions will occur due to accumulation Ketoconazole

50. No significant benefit seen if added to Natamycin It is hepatotoxic, renal toxic , can cause hyperglycemia, hyperlipidemia , hypertension, infertility QT prolongation Anaphylaxis Anorexia or increased appetite Insomnia and nervousness Ketoconazole

51. 1% solution and ointment. Oral 200 mg/day for Aspergillus Active against Candida, Aspergillus, and minimal action against Fusarium and Mucorales Ocular concentration is low as it is protein bound Hepatotoxic, rash, headache, GI upset Teratogenic Itraconazole

52. Broad spectrum – Candida, Aspergillus, Fusarium, Mucorales Oral suspension is absorbed well with high fat meals Poor penetration as it is protein bound Oral 200mg/ q.i.d with topical 10% prepared from oral solution Fever, NVD, headache, hypokalaemia, rash, purpura, uremic syndrome, pulmonary embolus, adrenal insufficiency, hypersensitivity, ECG changes Teratogenic Posaconazole

53. Echinocandins : Topical Caspofungin 0.5-1% helps in Candida, Aspergillus and Alternaria. Used for refractory cases Stable for 28 days if refrigerated Micafungin 0.1% - Candida and Alternaria Headache, GI upsets, hepatotoxic Antifungals

54. Fluconazole: for Candida 100-200mg/day Steven Johnsons’, headache, rash, gastritis, hepatotoxic Teratogenic Flucytosine: converted to 5 fluorouracil which inhibits intracellular DNA synthesis Active against Candida and Cryptococcus, limited against Aspergillus Poor penetrance. Fusarium is resistant Antifungals

55. Patient will feel better Reduction in chemosis and conjunctival congestion Lack of progression of the ulcer Rounding off of the edges. In fungal ulcer the feathery margin will be blunted Reduction in the cellular infiltrate and hypopyon Reduction in edema of the cornea around the ulcer If hypopyon reappears secondary bacterial infection should be suspected in a fungal ulcer How to assess healing

56. Even when an ulcer heals a scar is produced which will cause defective vision A small peripheral scar may not affect vision . If the scar is central mechanical obstruction to vision is caused. A nebular opacity or a peripheral opacity especially one with iris adherence can cause astigmatism and affect vision Complications of corneal ulcer

57. Leucoma

58. Even when the ulcer heals there is a complication – scar When you see a leucoma one must look for adherence In the above slide if you see from the clear area above you can see whether there is adherence and if any cataract is there The pupil should be dilated and if there is clear cornea on any one side of the scar, vision and fundus must be checked Thinner scars can be macula or nebula Leucoma

59. Small adherent leucoma pulling the pupil down

60. An ulcer may perforate as the stroma dissolves due to infection and by the action of neutrophils If the perforation is in the periphery the iris plugs the leak and the ulcer may heal with an adherent leucoma If the perforation is in the center a fistula will form. When this ulcer heals an anterior polar cataract may form Sometimes if a small ulcer perforates it may help in healing as it acts like a paracentesis Complications

61. Before the ulcer perforates the Descemet’s membrane will with stand for some time as it is elastic. This will cause the membrane to bulge forward giving raise to Descemetocoele At this stage and for small perforations glue with either bandage or bandage contact lens can be used to seal the perforation Perforation

62. Descemetocoele – with small pigment

63. Disappearance of hypopyon may only mean reduction in the secondary bacterial infection Therapeutic keratoplasty must be considered if the infection is spreading fast. It should be tried before the peripheral cornea gets involved as the wound will not heal well. Chances for rejection will be more as one has to choose a large graft if the ulcer involves the periphery Sclero corneal graft do not have a good prognosis Further measures

64. Compliance must be checked If Natamycin is used one can see the white granular deposits on the ulcer and in the fornix Cleanliness of the periocular surface must be insisted If total ulcer or panophthalmitis ensues, evisceration may have to be done If the ulcer does not heal

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