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Corneal Ulcer Treatment, Complication, Prevention

Corneal Ulcer Treatment/Corneal ulcer an inflammatory or more seriously, infective condition of the cornea involving disruption of its epithelial layer with involvement of the corneal stroma, is one of the major causes of monocular blindness after unoperated cataract in many of the developing nations in Asia, Africa and the Middle East. [rx, rx] It is a sight-threatening disorder that affects both males and females across all age groups worldwide [rx].

A corneal ulcer is an inflammatory or more seriously, infective condition of the cornea involving disruption of its epithelial layer with involvement of the corneal stroma. It is a common condition in humans particularly in the tropics and the agrarian societies. In developing countries, children afflicted by Vitamin A deficiency are at high risk for corneal ulcer and may become blind in both eyes, which may persist lifelong. In ophthalmology, a corneal ulcer usually refers to having an infectious cause while the term corneal abrasion refers more to physical abrasions.^[rx]

Types of Corneal Ulcer

Superficial and deep corneal ulcers

Corneal ulcers are a common human eye disease. They are caused by trauma, particularly with vegetable matter, as well as chemical injury, contact lenses and infections. Other eye conditions can cause corneal ulcers, such as entropion, distichiasis, corneal dystrophy, and keratoconjunctivitis sicca (dry eye).

Many micro-organisms cause an infective corneal ulcer. Among them are bacteria, fungi, viruses, protozoa, and chlamydia

Bacterial keratitis – is caused by Staphylococcus aureus, Streptococcus viridans, Escherichia coli, Enterococci, Pseudomonas, Nocardia, N. Gonorrhoea and many other bacteria.
Fungal keratitis – causes a deep and severe corneal ulcer. It is caused by Aspergillus sp., Fusarium sp., Candida sp., as also Rhizopus, Mucor, and other fungi. The typical feature of fungal keratitis is slow onset and gradual progression, where signs are much more than the symptoms. Small satellite lesions around the ulcer are a common feature of fungal keratitis and hypopyon is usually seen.
Viral keratitis – causes corneal ulceration. It is caused most commonly by Herpes simplex, Herpes zoster, and Adenoviruses. Also, it can be caused by coronaviruses & many other viruses. The herpes virus causes a dendritic ulcer, which can recur and relapse over the lifetime of an individual.
Protozoa infection – like Acanthamoeba keratitis is characterized by severe pain and is associated with contact lens users swimming in pools.
Chlamydia trachomatis – can also contribute to the development of a corneal ulcer.

Refractory corneal ulcers

Refractory corneal ulcers – are superficial ulcers that heal poorly and tend to recur. They are also known as indolent ulcers or Boxer ulcers. They are believed to be caused by a defect in the basement membrane and a lack of hemidesmosome attachments.
They are recognized – by undermined epithelium that surrounds the ulcer and easily peels back. Refractory corneal ulcers are most commonly seen in diabetics and often occur in the other eye later. They are similar to Cogan’s cystic dystrophy.

Melting ulcers

Melting ulcers – are a type of corneal ulcer involving the progressive loss of stroma in a dissolving fashion. This is most commonly seen in Pseudomonas infection, but it can be caused by other types of bacteria or fungi. These infectious agents produce proteases and collagenases which break down the corneal stroma.
Complete loss of the stroma – can occur within 24 hours. Treatment includes antibiotics and collagenase inhibitors such as acetylcysteine. Surgery in the form of corneal transplantation (penetrating keratoplasty) is usually necessary to save the eye.

Causes of Corneal Ulcer

Bacterial – The most common etiology of corneal ulcers is infectious, with bacterial pathogens responsible for a majority of the cases.[rx] Ulcers start as keratitis (inflammation of the cornea) after a break in the corneal epithelium allows bacteria to enter. These breaks are most commonly due to contact lens wear, corneal abrasions, and other ocular trauma.[rx] Other risk factors include diabetes, prior ocular surgery, chronic ocular disease, use of corticosteroids, contaminated ocular medications, and agricultural work.[rx] The most common bacterial pathogens are Staphylococcus aureus, coag negative staphylococcus, and Pseudomonas aeruginosa.[rx] Staphylococcus epidermidis and Staphylococcus fusarium species are the most commonly implicated in polymicrobial keratitis with trauma being the most common inciting factor.[rx]
Viral – HSV is a common cause of viral keratitis as well as the most common cause of unilateral infectious corneal blindness in the developed world.[rx] Varicella-zoster and cytomegalovirus can also cause viral keratitis although these are much less common.
Fungal – Fungal etiologies account for only 5 to 10% of all corneal infections. They are more common in warmer, humid parts of the country and are most often precipitated by trauma to the cornea with subsequent exposure to plant or vegetable material.[rx] The most commonly implicated species organisms include Aspergillus, Fusarium, Scedosporium apiospermum, phaeohyphpmycetes, Candida albicans, and other Candida species.[rx]
Protozoan – Acanthamoeba is a free-living protozoan found in freshwater and in soil that can cause keratitis and corneal ulcers primarily in contact lens wearers.[rx]
Autoimmune disease – While most corneal ulcers are infectious it is important to be able to recognize noninfectious causes of corneal ulcers as well. Peripheral ulcerative keratitis (PUK) is a form of noninfectious keratitis found in association with many systemic diseases. After anterior uveitis, PUK is the second most common ocular complication of autoimmune disorders.[rx] Collagen vascular diseases account for 50% of all peripheral ulcerative keratitis cases with rheumatoid arthritis most commonly implicated.[rx] Peripheral ulcerative keratitis also correlates with Wegener granulomatosis, relapsing polychondritis, polyarteritis nodosa, Churg-Strauss syndrome, and microscopic polyangiitis.[rx]
Fusarium – These fungi have been associated with fungal keratitis outbreaks among contact lens wearers who used a certain type of contact lens solution. Now withdrawn from the market, this contact lens solution previously failed to prevent this type of infection.
Acanthamoeba – These common parasites can enter the eye and cause Acanthamoeba keratitis, a very serious eye infection that can result in permanent scarring of the cornea and vision loss. Acanthamoeba microorganisms are commonly found in tap water, swimming pools, hot tubs and other water sources. Contact lens wearers who fail to remove their lenses before swimming significantly increase their risk for a corneal ulcer from Acanthamoeba keratitis. contains useful tips for contact lens wearers who spend a lot of time in the water.)Another cause of corneal ulcer is herpes simplex virus infection (ocular herpes), which can damage the exterior and sometimes even deeper layers of the eye’s surface.
Bacterial infections – These are common in contact lens wearers, especially in people using extended-wear lenses.
Viral infections. The virus that causes cold sores (the herpes simplex virus) may cause recurring attacks. These attacks are triggered by stress, an impaired immune system, or exposure to sunlight. Also, the virus that causes chicken pox and shingles (the varicella virus) can cause corneal ulcers.
Fungal infections – Improper use of contact lenses or steroid eye drops can lead to fungal infections, which in turn can cause corneal ulcers. Also, a corneal injury that results in plant material getting into the eye can lead to fungal keratitis.
Parasitic (Acanthamoeba) infections – Acanthamoeba are microscopic, single-celled amoeba that can cause human infection. They are the most common amoebae in fresh water and soil. When Acanthamoeba enters the eye it can cause a bad infection, particularly for contact lens users.
Abrasions or burns to the cornea caused by injury to the eye – Scratches, scrapes and cuts can become infected by bacteria and lead to corneal ulcers. These injuries can happen from fingernail scratches, paper cuts, makeup brushes and tree branches. Burns caused by corrosive chemicals found in the workplace and at home can cause corneal ulcers.

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Symptoms of Corneal Ulcer

A corneal ulcer may cause pain, a feeling of a foreign body in the eye; tearing and pus or thick discharge draining from the eye may occur. If the ulcer is more centrally located in the cornea, vision might be blurry. There may be an increase in pain when the person looks at bright lights (photophobia).

Redness of the eye
Severe pain and soreness of the eye
The feeling of having something in your eye
Tearing
Pus or other discharge
Blurred vision
Sensitivity to light
Swelling of the eyelids
A white spot on your cornea that you may or may not be able to see when looking in the mirror

Diagnosis of Corneal Ulcer

Inclusion criteria

Resident of study area
Corneal abrasion after ocular injury, confirmed by clinical examination with fluorescein stain and a blue torch
Reported within 48 hours of injury
Subject aged >5 years of age.

Exclusion criteria

Presence of clinically evident corneal infection

Penetrating corneal injury or stromal laceration
Bilateral ocular trauma
Pre‐existing blindness (<6/60) in the non‐traumatised eye
Initiation of topical or systemic antibiotic therapy before examination by study personnel
Incomplete lid closure
Diabetes
Injuries to other vital organs/multisystem injuries requiring hospitalisation
Trichiasis
Dacryocystitis
Not willing to participate.

Treatment of Corneal Ulcer

Fungal infections are treated with topical antifungal drops – [eg, natamycin 5%, amphotericin B 0.15%, and sometimes voriconazole1% (which is less effective)], initially q 1 h during the day and q 2 h overnight. Deep infections may require addition of oral voriconazole 400 mg bid for 2 doses then 200 mg bid, ketoconazole 400 mg once/day, fluconazole 400 mg once then 200 mg once/day, or itraconazole 400 mg once then 200 mg once/day.

If Acanthamoeba is identified – therapy can include topical propamidine 0.1%, neomycin 0.175%, and polyhexamethylene biguanide 0.02% or chlorhexidine 0.02% supplemented with miconazole 1%, clotrimazole 1%, or oral ketoconazole 400 mg once/day or itraconazole 400 mg once then 200 mg once/day. The drops are used q 1 to 2 h until clinical improvement is evident, then gradually reduced to 4 times/day and continued for a number of months until all inflammation has resolved. Polyhexamethylene biguanide and chlorhexidine are not commercially available as ocular agents but can be prepared by a compounding pharmacy.

For all ulcers, treatment may also include a cycloplegic – such as atropine 1% or scopolamine 0.25% 1 drop tid, to decrease the ache of a corneal ulcer and to reduce the formation of posterior synechiae. In severe cases, debridement of the infected epithelium or even penetrating keratoplasty may be required.

When treating a patient with suppurative keratitis the clinician has 3 management options:

Complete microbiological work-up of all ulcers, followed by initial therapy based on the smear results;
Empirical therapy (based on previous clinical experience) with one or more commercially available broad spectrum antimicrobial agents; or
Microbiology work-up of severe ulcers where the history or clinical findings suggest an atypical non-bacterial pathogen.
Subjects meeting the eligibility criteria were started on treatment with 1% chloramphenicol applicaps and 1% clotrimazole ointment. Clotrimazole was chosen because it is a broad spectrum antifungal agent that is effective against both yeasts and filamentous fungi and can be compounded as an ointment.
Verbal informed consent was obtained from the eligible subjects by the VHWs. Subjects were treated with one applicap of antibiotic and 1 cm length of clotrimazole ointment immediately in the affected eye and then were supplied by the VHWs with eight chloramphenicol applicaps and one tube of clotrimazole ointment and instructed to apply the remaining applicaps and ointment two more times the first day and three times a day for the following 2 days.
Treatment with a commercially available antibiotic that has a broad spectrum of activity against gram-negative and gram-positive organisms, such as ciprofloxacin or ofloxacin, seems to be the least expensive first approach. However, there is a risk of development of resistance particularly with ciprofloxacin.

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Microbiological investigations should always be done for the following cases.

Severe ulcers (a rapidly progressing infiltrate which is more than 6mm in diameter or involves deeper stroma or associated with imminent or actual perforation).
Cases where history and clinical examination suggest unusual non-bacterial pathogens.

Initial treatment in fungal keratitis is usually started with natamycin (5%) suspension administered half hourly. Various antifungal agents used in the treatment of keratitis are shown in.

Antifungal Agents used in Keratitis

Polyenes

Nystatin

Amphotericin B

Natamycin

Pyrimidines

Flucytosine

Imidazoles

Clotrimazole

Miconazole

Ketoconazole

Fluconazole

Itraconazole

For Acanthamoeba keratitis, treatment is usually started with polyhexamethylene biguanide (PHMB) 0.02% or chlorhexidine 0.02%. Antifungal and anti-Acanthamoeba therapy is started only when microbiological evidences exists. Modification of therapy is primarily based on clinical response to initial therapy and is guided by the results of culture and sensitivity tests.

Anti-Acanthamoeba Agents used in Keratitis

Antiseptic biocides

Chlorhexidine

PHMB

Aminoglycosides

Neomycin

Paromomycin

Diamidines

Dibromopropamidine

Hexamidine

Management at Secondary Level

More complete management of corneal infections begins at the secondary level of eye care where there is an ophthalmologist and/or an ophthalmic assistant, or a physician trained in managing common eye diseases. At the secondary level:

A corneal scraping should be taken (see page 42).
The patient should be admitted to the hospital to ensure adequate treatment and frequent follow-up.

Specific initial treatment

No fungal elements seen

Instil cefazolin 5% and gentamicin 1.4% drops hourly.
Ciprofloxacin or ofloxacin is a good substitute for gentamicin and cephazolin. If it is not possible to administer hourly drops, a subconjunctival injection can be given.

Fungal elements seen

Natamycin 5% drops hourly or freshly reconstituted amphotericin-B 0.15% as drops hourly. Antibiotics may have a limited role to play in such cases and may occasionally be harmful. Clinical judgment correlated with laboratory tests constitute the best guide in such cases.

Adjunctive treatment

Atropine 1% or homatropine 2% could be used twice a day to dilate the pupil; this helps to prevent synechiae and relieve pain
Oral analgesics will help to minimise pain
Anti-glaucoma medication may be advisable if the intraocular pressure is high
Vitamin A supplementation may be helpful, particularly in countries where Vitamin A deficiency is markedly prevalent.

Five A’s are a useful acronym to remember – Antibiotic/antifungal, Atropine, Analgesics, Anti-glaucoma medications, and Vitamin A.

Subsequent Management

Suppurative keratitis patients should be hospitalised and examined daily, if possible with a slit lamp, so that their response to treatment can be evaluated and the frequency of antibiotics adjusted accordingly.

Reduce the frequency of antibiotic administration when the patient experiences symptomatic improvement (less tearing and photophobia, relief from pain, and improvement in vision) and when the ulcer shows signs of improvement:

Decrease in lid oedema
Decrease in conjunctival chemosis and bulbar conjunctival injection
Reduction in density of the infiltrate and area of epithelial ulceration
Haziness of the perimeter of the ulcer and of the stromal infiltrate
Decrease in inflammation; cells, fibrin, and level of hypopyon
Dilatation of pupil.

In the case of bacterial infection, the inflammatory reaction may be enhanced by endotoxin release during the first 48 hours of treatment; however, definite progression at this stage is unusual and implies that either the organisms are resistant to therapy, or the patient is not instilling the drops as prescribed.^[rx] If the patient is judged to be improving, the dose of antibiotics and/or antifungal drops should be reduced from hourly, to two-hourly, then four-hourly over the next two weeks in case of bacterial ulcers. For fungal ulcers, treatment should be continued with three-hourly drops for at least three weeks.

Guidelines for Referral to a Tertiary centre

Immediate referral on presentation if

The ulcer is in an only eye
The patient is a child
There is impending or actual perforation
A fungal corneal ulcer is suspected but KOH or other fungal stains are not available.

Following initial treatment – if cases of bacterial ulcer fail to show any improvement within three days, and fungal ulcers within a week, patients should be referred to a tertiary care centre.

Commonly recommended antifungal drugs

Drug	Topical	Systemic
Amphotericin-B	0.15-0.5% drops	IV infusion
Natamycin	5% drops	Not available
Econazole	2% drops	Not available
Voricanozole	1% drops	Oral tablets 100–200 mg/day
Ketoconazole	2% drops	Oral tablets 200–600 mg/day
Miconazole	1-2% drops	Intravenous injection
Clotrimazole	1-2% ointment	Not available
Fluconazole	0.2-0.3% drops	Oral tablets 200 mg/day

Preparation of fortified antibiotic eye drops

Antibiotic	Method	Final concentration
Cefazolin/cefuroxime	Add 10 ml sterile water to 500 mg cefazolin powder; mix and use as topical drops. Shelf life: 5 days	50 mg/ml (5%)
Gentamicin (tobramycin)	Add 2 ml parenteral gentamicin (40 mg/ml) to a 5 ml bottle of commercial ophthalmic gentamicin (3 mg/ml)	14 mg/ml (1.4%)
Penicillin G	Add 10 ml of artificial tears to a 1 million unit vial of Penicillin G powder; mix, remove, and place into empty artificial tear bottle or xylocaine vials (30 ml)	100,000 units/ml
Vancomycin	Add 10 ml sterile water to a 500 mg vial of vancomycin powder; mix, add sterile cap, and use	50 mg/ml (5%)
Amikacin	Add 2 ml of parenteral amikacin containing 200 mg to 8 ml artificial tears or sterile water in a sterile empty vial.	20 mg/ml (2%)

However, except for natamycin and fluconazole, others are not available commercially for topical ocular use. The other antifungals have to be prepared using commercially available injectable forms such as amphotericin-B, miconazole, or raw materials such as clotrimazole and voriconazole.

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Other agents such as polyhexamethylene biguanide (PHMB) 0.02%, chlorhexidine 0.02%, povidone-iodine 1.5 to 5% and silver sulfadiazine 1% have been reported to possess the variable antifungal activity and may be used if other drugs are not available.

Natamycin 5% suspension is recommended for treatment of most cases of filamentous fungal keratitis, particularly those caused by Fusarium sp. Topical miconazole 1% (not commercially available for topical use) can be used as an adjunct or supportive therapy. Most clinical and experimental evidence suggests that topical amphotericin-B (0.15 to 0.5%) is the most efficacious agent available to treat yeast keratitis. Amphotericin-B is also recommended for fungal keratitis caused by Aspergillus sp. Oral ketoconazole (200–600 mg/day) may be considered as adjunctive therapy in more severe fungal keratitis due to filamentous fungus. Oral fluconazole (200–400 mg per day) has been used successfully for severe keratitis caused by yeasts. Oral itraconazole (200 mg/day) has broad-spectrum activity against all Aspergillus sp.and Candida but has variable activity against Fusarium sp.

Fungal infection of the deep corneal stroma may not respond to topical antifungal therapy because of poor penetration of these agents in the presence of an intact epithelium. It has been reported that a 5 mm epithelial debridement (as a diagnostic scraping or therapeutic procedure) greatly enhances the penetration of antifungal drugs.

Surgical Treatment

The range of surgical interventions available for management of corneal ulcer may include debridement, corneal biopsy, tissue adhesives, conjunctival flap, tarsorrhaphy, or therapeutic corneal graft. The evisceration of the eye is performed for severe pain, panophthalmitis, or life-threatening complications.

Tarsorrhaphy

This is an old surgical technique that is still very useful today. In suppurative keratitis due to fungal and bacterial infections, tarsorrhaphy is effective in promoting healing, provided the ulcer has been sterilized by effective antibacterial and/or antifungal treatment. Following central tarsorrhaphy, it can be difficult to instill drops and to see the cornea, so it is vital to ensure that the infection is under control before closing the eyelids.
However, tarsorrhaphy often leads to rapid resolution of persistent epithelial defects, whatever the underlying cause. Once tarsorrhaphy is performed it is left in place for at least one to three months. There are different surgical techniques which are described well in many standard ophthalmic textbooks; however, simply suturing the lids together with a non-absorbable stitch can be effective.

Conjunctival flap

The principle of this technique is to promote healing of a corneal lesion by providing adequate nutrition through the conjunctival blood vessels. The flap could be three types:

A total flap covering the entire cornea called Gunderson’s flap.
A pedicle (racquet) flap. A pedicle flap carries its own blood supply from the limbus and is useful for ulcers near the limbus.
A bucket handle flap. This carries its blood supply from both ends of the flap and may be less likely to retract. It is more useful for central corneal ulcers.

This procedure can be performed under local anesthesia. Harvesting adequate bulbar conjunctiva in eyes which have had previous surgery may be difficult. The flap should be as thin as possible, with minimal adherent subconjunctival tissue. Following removal of any remaining corneal epithelium, the flap should be sutured to the cornea with 10-0 nylon sutures.

Supplementary Treatment

Cycloplegic agents such as atropine sulfate 1%, homatropine 1% or cyclopentolate 1% instilled three times a day reduce ciliary spasm and produce mydriasis, thereby relieving pain and preventing synechiae formation. Anti-glaucoma agents are used when intraocular pressure is high.
If required, oral analgesics for pain may be used. The role of topical corticosteroids in the management of suppurative keratitis is controversial and hence they are best avoided.
Simple debridement of necrotic debris in conjunction with intensive topical therapy may help facilitate drug penetration, especially of anti-fungal agents.
Tissue adhesive using N-butyl cyanoacrylate with a bandage contact lens is useful in cases with marked thinning or perforation less than 2mm.
Penetrating keratoplasty is performed in cases with advanced disease at a presentation where there is no response to medical therapy or when a large perforation is present.

Prevention

Although not always a preventable disease, certain steps may help reduce the potentially severe consequences of suppurative keratitis.

Community awareness of risk factors for suppurative keratitides such as minor trauma and the use of contaminated traditional eye solutions in the eye
Early recognition and institution of appropriate therapy by community health workers or ophthalmologists
Prompt referral of advanced cases to tertiary eye care centers

Suppurative keratitis is a sight-threatening disorder. Early clinical suspicion, rational use of laboratory diagnostic procedures and appropriate therapy can go a long way towards reducing ocular damage from this disorder.