General

The cornea is a complex structure which, as well as having a protective role, is responsible for about three-quarters of the optical power of the eye. The normal cornea is free of blood vessels; nutrients are supplied and metabolic products removed mainly via the aqueous humour posteriorly and the tears anteriorly. The cornea is the most densely innervated tissue in the body, and conditions such as abrasions and bullous keratopathy are associated with marked pain, photophobia and reflex lacrimation; a subepithelial and a deeper stromal nerve plexus are both supplied by the first division of the trigeminal nerve.

Dimensions

The average corneal diameter is 11.5 mm vertically and 12 mm horizontally. It is 540 µm thick centrally on average, and thicker towards the periphery. Central corneal thickness varies between individuals and is a key determinant of the intraocular pressure (IOP) measured with conventional techniques.

Structure

The cornea consists of the following layers ( Fig. 6.1 ):

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  The epithelium is stratified squamous and non-keratinized, and is composed of:

  
  
  
  
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    A single layer of columnar basal cells attached by hemidesmosomes to an underlying basement membrane.

    
    
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    Two to three strata of ‘wing’ cells.

    
    
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    Two layers of squamous surface cells.

    
    
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    The surface area of the outermost cells is increased by microplicae and microvilli that facilitate the attachment of the tear film and mucin. After a lifespan of a few days superficial cells are shed into the tear film.

    
    
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    Corneal stem cells are located at the corneoscleral limbus, possibly in the palisades of Vogt. Deficiency may result in chronic epithelial defects and ‘conjunctivalization’ (epithelial instability, vascularization and the appearance of goblet cells). They are thought to be critical in the maintenance of a physiological barrier, preventing conjunctival tissue from growing onto the cornea (e.g. pterygium). Deficiency may be addressed by stem cell auto- or allotransplantation.

  
  
  
  
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  The Bowman layer is the acellular superficial layer of the stroma, and is formed from collagen fibres.

  
  
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  The stroma makes up 90% of corneal thickness. It is arranged in regularly orientated layers of collagen fibrils whose spacing is maintained by proteoglycan ground substance (chondroitin sulphate and keratan sulphate) with interspersed modified fibroblasts (keratocytes). Maintenance of the regular arrangement and spacing of the collagen is critical to optical clarity. The stroma can scar, but cannot regenerate following damage.

  
  
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  Descemet membrane is a discrete sheet composed of a fine latticework of collagen fibrils that are distinct from the collagen of the stroma. The membrane consists of an anterior banded zone that is deposited in utero and a posterior non-banded zone laid down throughout life by the endothelium, for which it serves as a modified basement membrane. It has regenerative potential.

  
  
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  The endothelium consists of a monolayer of polygonal cells. Endothelial cells maintain corneal deturgescence throughout life by pumping excess fluid out of the stroma. The young adult cell density is about 3000 cells/mm ² . The number of cells decreases at about 0.6% per year and neighbouring cells enlarge to fill the space; the cells cannot regenerate. At a density of about 500 cells/mm ² corneal oedema develops and transparency is impaired.

  
  
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  The existence of a sixth corneal layer between the stroma and Descemet membrane has recently been proposed, though some authorities believe this to be a previously described continuation of the posterior stroma.

Anatomy of the cornea

Superficial

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  Punctate epithelial erosions (PEE) , tiny epithelial defects that stain with fluorescein ( Figs 6.2A and B ) and rose Bengal, are generally an early sign of epithelial compromise. Causes include a variety of stimuli; the location of the lesions may give an indication of aetiology:

  
  
  
  
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    Superior – vernal disease, chlamydial conjunctivitis, superior limbic keratoconjunctivitis, floppy eyelid syndrome and mechanically induced keratoconjunctivitis.

    
    
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    Interpalpebral – dry eye (can also be inferior), reduced corneal sensation and ultraviolet keratopathy.

    
    
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    Inferior – chronic blepharitis, lagophthalmos, eye drop toxicity, self-induced, aberrant eyelashes and entropion.

    
    
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    Diffuse – some cases of viral and bacterial conjunctivitis, and toxicity to drops.

    
    
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    Central – prolonged contact lens wear.

  
  

  
  

  
  

  

  
  

  
  

  Superficial corneal lesions. (A) Punctate epithelial erosions stained with fluorescein in dry eye; (B) high-magnification view of punctate epithelial erosions; (C) punctate epithelial keratitis; (D) filaments stained with rose Bengal; (E) loss of lustre in mild corneal oedema; (F) corneal oedema with bullae; (G) superficial vascularization; (H) pannus

  
  

  (Courtesy of Chris Barry – figs E and H)

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  

  
  
  
  
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  Punctate epithelial keratitis (PEK) appears as granular, opalescent, swollen epithelial cells, with focal intraepithelial infiltrates ( Fig. 6.2C ). They are visible unstained but stain well with rose Bengal and variably with fluorescein. Causes include:

  
  
  
  
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    Infections: adenoviral, chlamydial, molluscum contagiosum, early herpes simplex and herpes zoster, microsporidial and systemic viral infections (e.g. measles, varicella, rubella).

    
    
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    Miscellaneous: Thygeson superficial punctate keratitis and eye drop toxicity.

  
  
  
  
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  Subepithelial infiltrates. Tiny subsurface foci of non-staining inflammatory infiltrates. Causes include severe or prolonged adenoviral keratoconjunctivitis, herpes zoster keratitis, adult inclusion conjunctivitis, marginal keratitis, rosacea and Thygeson superficial punctate keratitis.

  
  
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  Superficial punctate keratitis is a non-specific term describing any corneal epithelial disturbance of dot-like morphology.

  
  
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  Filaments. Strands of mucus admixed with epithelium, attached at one end to the corneal surface, that stain well with rose Bengal ( Fig. 6.2D ). The unattached end moves with each blink. Grey subepithelial opacities may be seen at the site of attachment. Dry eye is by far the most common cause; others include superior limbic keratoconjunctivitis, neurotrophic keratopathy, long-term ocular patching and essential blepharospasm.

  
  
• •
  

  Epithelial oedema. Subtle oedema may manifest with loss of normal corneal lustre ( Fig. 6.2E ), but more commonly, abundant tiny epithelial vesicles are seen; bullae form in moderate–severe cases ( Fig. 6.2F ). The cause is endothelial decompensation, including that due to severe acute elevation of IOP.

  
  
• •
  

  Superficial neovascularization ( Fig. 6.2G ) is a feature of chronic ocular surface irritation or hypoxia, as in contact lens wear.

  
  
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  Pannus describes superficial neovascularization accompanied by degenerative subepithelial change ( Fig. 6.2H ).

Deep

• •
  

  Infiltrates are yellow– or grey–white opacities located initially within the anterior stroma ( Fig. 6.3A ), usually associated with limbal or conjunctival hyperaemia. They are stromal foci of acute inflammation composed of inflammatory cells, cellular and extracellular debris including necrosis. The key distinction is between sterile and infective lesions ( Table 6.1 ); ‘PEDAL’ mnemonic: P ain, E pithelial defects, D ischarge, A nterior chamber reaction, L ocation. Suppurative keratitis is caused by active infection with bacteria, fungi, protozoa and occasionally viruses. Non-infectious ‘sterile keratitis’ is due to an immune hypersensitivity response to antigen as in marginal keratitis and with contact lens wear.

  
  

  
  

  
  

  

  
  

  
  

  Deeper corneal lesions. (A) Infiltration; (B) ulceration; (C) lipid deposition with vascularization; (D) folds in Descemet membrane; (E) descemetocoele; (F) traumatic breaks in Descemet membrane

  
  

  (Courtesy of C Barry – figs C–D; R Curtis – fig. F)

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  

  
  
  
  

  Table 6.1

  
  

  Characteristics of infective versus sterile corneal infiltrates

  
  

  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

  	Infective	Sterile
  Size	Tend to be larger	Tend to be smaller
  Progression	Rapid	Slow
  Epithelial defect	Very common and larger when present	Much less common and if present tends to be small
  Pain	Moderate–severe	Mild
  Discharge	Purulent	Mucopurulent
  Single or multiple	Typically single	Commonly multiple
  Unilateral or bilateral	Unilateral	Often bilateral
  Anterior chamber reaction	Severe	Mild
  Location	Often central	Typically more peripheral
  Adjacent corneal reaction	Extensive	Limited

   
  
  
  
  
• •
  

  Ulceration refers to tissue excavation associated with an epithelial defect ( Fig. 6.3B ), usually with infiltration and necrosis.

  
  
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  ‘Melting’ describes tissue disintegration in response to enzymatic activity, often with mild or no infiltrate, e.g. peripheral ulcerative keratitis.

  
  
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  Vascularization occurs in response to a wide variety of stimuli. Venous channels are easily seen, whereas arterial feeding vessels are smaller and require higher magnification. Non-perfused deep vessels appear as ‘ghost vessels’, best detected by retroillumination.

  
  
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  Lipid deposition ( Fig. 6.3C ) may follow chronic inflammation with leakage from corneal new vessels.

  
  
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  Folds in Descemet membrane , also known as striate keratopathy ( Fig. 6.3D ), may result from corneal oedema exceeding the capacity of the endothelium to maintain normal turgescence. Causes include inflammation, trauma (including surgery) and ocular hypotony.

  
  
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  Descemetocoele (US spelling – descemetocele) is a bubble-like herniation of Descemet membrane into the cornea ( Fig. 6.3E ), plugging a defect that would otherwise be full-thickness.

  
  
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  Breaks in Descemet membrane ( Fig. 6.3F ) may be due to corneal enlargement (Haab striae in infantile glaucoma) or deformation such as keratoconus and birth trauma. Acute influx of aqueous into the corneal stroma (acute hydrops) can occur.

  
  
• •
  

  The Seidel test demonstrates aqueous leakage. A drop of 1% or 2% fluorescein is applied and the slit lamp with cobalt blue filter is used to detect the change from dark orange to bright yellow–green occurring with localized dilution at a site of leakage.

Control of infection and inflammation

• •
  

  Antimicrobial agents should be started as soon as preliminary investigations have been performed. The choice of agent is determined by the likely aetiology according to clinical findings. Broad-spectrum treatment is generally used initially, with more selective agents introduced if necessary when the results of investigation are available.

  
  
• •
  

  Topical steroids should always be used with caution as they may promote replication of some microorganisms, notably herpes simplex virus and fungi, and retard reparative processes such as re-epithelialization. Nevertheless, they are vital in a range of conditions for the suppression of destructive vision-compromising inflammation.

  
  
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  Systemic immunosuppressive agents are useful in some conditions, particularly autoimmune disease.

Promotion of epithelial healing

Re-epithelialization is of great importance in any corneal disease, as thinning seldom progresses if the epithelium is intact.

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  Reduction of exposure to toxic medications and preservatives wherever possible.

  
  
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  Lubrication with artificial tears (unpreserved if possible) and ointment. Taping the lids closed temporarily ( Fig. 6.6A ) is often used as a nocturnal adjunct.

  
  

  
  

  
  

  

  
  

  
  

  Methods of promoting epithelial healing. (A) Taping the lids temporarily; (B) bandage contact lens in an eye with a small perforation; (C) central tarsorrhaphy; (D) amniotic membrane graft over a persistent epithelial defect; (E) tissue glue under a bandage contact lens in an eye with severe thinning

  
  

  (Courtesy of S Tuft – figs A, B, D and E; S Chen – fig. C)

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  

  
  
  
  
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  Antibiotic ointment prophylaxis should be considered.

  
  
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  Bandage soft contact lenses should be carefully supervised to exclude superinfection, and duration kept to a minimum. Indications include:

  
  
  
  
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    Promotion of healing by mechanically protecting regenerating corneal epithelium from the constant rubbing of the eyelids.

    
    
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    To improve comfort, particularly in the presence of a large corneal abrasion.

    
    
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    To seal a small perforation ( Fig. 6.6B ).

  
  
  
  
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  Surgical eyelid closure is particularly useful in exposure and neurotrophic keratopathies as well as in persistent epithelial defects. Lid closure may be used as a conservative method to heal an infective ulcer in selected cases, such as an eye with no visual potential in a patient with severe dementia.

  
  
  
  
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    Botulinum toxin injection into the levator muscle to induce a temporary (2–3 months) ptosis.

    
    
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    Temporary or permanent lateral tarsorrhaphy or medial canthoplasty, and occasionally central tarsorrhaphy ( Fig. 6.6C ).

  
  
  
  
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  Conjunctival (Gundersen) flap will protect and tend to heal a corneal epithelial defect and is particularly suitable for chronic unilateral disease in which the prognosis for restoration of useful vision is poor. Buccal mucous membrane is an alternative.

  
  
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  Amniotic membrane patch grafting ( Fig. 6.6D ) for persistent unresponsive epithelial defects.

  
  
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  Tissue adhesive (cyanoacrylate glue) to seal small perforations. The glue can be applied to one side of a bespoke trimmed patch of sterile plastic drape, which is pressed over the defect after the edges are dried with a cellulose sponge. The patch remains in place to seal the defect, and a bandage contact lens is inserted for comfort and to aid retention of the patch ( Fig. 6.6E ).

  
  
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  Limbal stem cell transplantation may be used if there is stem cell deficiency as in chemical burns and cicatrizing conjunctivitis. The source of the donor tissue may be the fellow eye (autograft) in unilateral disease or a living or cadaver donor (allograft) when both eyes are affected. A newer technique involves the in vitro replication of the patient’s own stem cells with subsequent re-implantation of the enhanced cell population.

  
  
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  Smoking retards epithelialization and should be discontinued.

Pathogens

Bacterial keratitis usually develops only when ocular defences have been compromised (see below). However, some bacteria, including Neisseria gonorrhoeae , Neisseria meningitidis , Corynebacterium diphtheriae and Haemophilus influenzae are able to penetrate a healthy corneal epithelium, usually in association with severe conjunctivitis. It is important to remember that infections may be polymicrobial, including bacterial and fungal co-infection. Common pathogens include:

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  Pseudomonas aeruginosa is a ubiquitous Gram-negative bacillus (rod) commensal of the gastrointestinal tract. The infection is typically aggressive and is responsible for over 60% of contact lens-related keratitis.

  
  
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  Staphylococcus aureus is a common Gram-positive and coagulase-positive commensal of the nares, skin and conjunctiva. Keratitis tends to present with a focal and fairly well-defined white or yellow–white infiltrate.

  
  
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  Streptococci. S. pyogenes is a common Gram-positive commensal of the throat and vagina. S. pneumoniae (pneumococcus) is a Gram-positive commensal of the upper respiratory tract. Infections with streptococci are often aggressive.

Risk factors

• •
  

  Contact lens wear , particularly if extended, is the most important risk factor. Corneal epithelial compromise secondary to hypoxia and minor trauma is thought to be important, as is bacterial adherence to the lens surface. Wearers of soft lenses are at higher risk than those of rigid gas permeable and other types. Infection is more likely if there is poor lens hygiene but it can also occur even with apparently meticulous lens care, and with daily disposable lenses.

  
  
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  Trauma , including refractive surgery (particularly LASIK – laser-assisted in situ keratomileusis), has been linked to bacterial infection, including with atypical mycobacteria. In developing countries agricultural injury is the major risk factor, when fungal infection should be considered.

  
  
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  Ocular surface disease such as herpetic keratitis, bullous keratopathy, dry eye, chronic blepharitis, trichiasis and entropion, exposure, severe allergic eye disease and corneal anaesthesia.

  
  
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  Other factors include local or systemic immunosuppression, diabetes and vitamin A deficiency.

General considerations

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  Hospital admission should be considered for patients who are not likely to comply or are unable to self-administer treatment. It should also be considered for aggressive disease, particularly if involving an only eye.

  
  
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  Discontinuation of contact lens wear is mandatory.

  
  
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  A clear plastic eye shield should be worn between eye drop instillation if significant thinning (or perforation) is present.

  
  
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  Decision to treat

  
  
  
  
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    Intensive treatment may not be required for small infiltrates that are clinically sterile and may be treated by lower-frequency topical antibiotic and/or steroid, and by temporary cessation of contact lens wear.

    
    
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    It is important to note that the causative organism cannot be defined reliably from the ulcer’s appearance.

    
    
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    Empirical broad-spectrum treatment is usually initiated before microscopy results are available.

  
  

Local therapy

Topical therapy ( Table 6.4 ) can achieve high tissue concentration and initially should consist of broad-spectrum antibiotics that cover most common pathogens. Initially instillation is at hourly intervals day and night for 24–48 hours, and then is tapered according to clinical progress.

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  Antibiotic monotherapy has the major advantage over duotherapy of lower surface toxicity, as well as greater convenience.

  
  
  
  
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    A commercially available fluoroquinolone is the usual choice for empirical monotherapy and appears to be about as effective as duotherapy.

    
    
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    Ciprofloxacin or ofloxacin are used in countries where widespread resistance to earlier-generation fluoroquinolones has not been identified. Activity against some Gram-positive organisms, particularly some streptococci, may be limited.

    
    
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    Resistance to fluoroquinolones has been reported in some areas (e.g. Staphylococcus spp. in the USA and Pseudomonas in India). Moxifloxacin, gatifloxacin and besifloxacin are new generation fluoroquinolones that largely address this, and also have better activity against Gram-positive pathogens. Moxifloxacin has superior ocular penetration. Novel drug preparations, with higher concentrations or modified vehicles, have been introduced to enhance antibacterial activity.

    
    
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    Ciprofloxacin instillation is associated with white corneal precipitates ( Fig. 6.9 ) that may delay epithelial healing.

    
    

    
    

    
    

    

    
    

    
    

    Ciprofloxacin corneal precipitates

    
    

  
  
  
  
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  Antibiotic duotherapy may be preferred as first-line empirical treatment in aggressive disease or if microscopy suggests streptococci or a specific microorganism that may be more effectively treated by a tailored regimen (see Table 6.4 ).

  
  
  
  
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    Empirical duotherapy usually involves a combination of two fortified antibiotics, typically a cephalosporin and an aminoglycoside, in order to cover common Gram-positive and Gram-negative pathogens.

    
    
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    The antibiotics are not commercially available and must be specially prepared ( Table 6.5 ). A standard parenteral or lyophilized antibiotic preparation is combined with a compatible vehicle such that the antibiotic does not precipitate. Optimally, constitution should take place in the sterile preparation area of a pharmaceutical dispensary.

    
    
    
    

    Table 6.5

    
    

    Preparation of fortified antibiotics

    
    

    
    
    
    
    
    
    
    
    
    
    
    
    
    
    
    
    
    
    

    Antibiotic	Method	Concentration	Shelf-life
    Cephalosporins: cefazolin, cefuroxime, or ceftazidime	500 mg parenteral antibiotic is diluted with 2.5 ml sterile water and added to 7.5 ml of preservative-free artificial tears	50 mg/ml (5%)	24 hours at room temperature; at least 4 days if refrigerated
    Gentamicin	2 ml parenteral antibiotic (40 mg/ml) is added to 5 ml commercially available gentamicin ophthalmic solution (0.3%)	15 mg/ml (1.5%)	Up to 14 days if refrigerated

     
    
    
    
    
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    Disadvantages of fortified antibiotics include high cost, limited availability, contamination risk, short shelf-life and the need for refrigeration.

  
  
  
  
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  Subconjunctival antibiotics are usually only indicated if there is poor compliance with topical treatment.

  
  
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  Mydriatics (cyclopentolate 1%, homatropine 2% or atropine 1%) are used to prevent the formation of posterior synechiae and to reduce pain.

  
  
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  Steroids

  
  
  
  
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    Steroids reduce host inflammation, improve comfort, and minimize corneal scarring. However, they promote replication of some microorganisms, particularly fungi, herpes simplex and mycobacteria and are contraindicated if a fungal or mycobacterial agent is suspected (beware prior refractive surgery and trauma involving vegetation). By suppressing inflammation, they also retard the eye’s response to bacteria and this can be clinically significant, particularly if an antibiotic is of limited effect or bacteriostatic rather than bactericidal.

    
    
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    Evidence that they improve the final visual outcome is mainly empirical, but the recent Steroids for Corneal Ulcers Trial (SCUT) found no eventual benefit in most cases, though severe cases (counting fingers vision or large ulcers involving the central 4 mm of the cornea) tended to do better; a positive culture result was an inclusion criterion, and steroids were introduced after 48 hours of moxifloxacin.

    
    
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    Epithelialization may be retarded by steroids and they should be avoided if there is significant thinning or delayed epithelial healing; corneal melting can occasionally be precipitated or worsened.

    
    
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    Many authorities do not commence topical steroids until evidence of clinical improvement is seen with antibiotics alone, typically 24–48 hours after starting treatment. Others delay their use at least until the sensitivity of the isolate to antibiotics has been demonstrated, or do not use them at all.

    
    
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    Regimens vary from minimal strength preparations at low frequency to dexamethasone 0.1% every 2 hours; a reasonable regimen is prednisolone 0.5–1% four times daily.

    
    
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    Early discontinuation may lead to a rebound recurrence of sterile inflammation.

    
    
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    The threshold for topical steroid use may be lower in cases of corneal graft infection, as they may reduce the risk of rejection.

  
  

Systemic antibiotics

Systemic antibiotics are not usually given, but may be appropriate in the following circumstances:

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  Potential for systemic involvement , when microbiological/infectious disease specialist advice should optimally be sought but should not delay treatment:

  
  
  
  
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    N. meningitidis , in which early systemic prophylaxis may be life-saving. Treatment is usually with intramuscular benzylpenicillin, ceftriaxone or cefotaxime, or oral ciprofloxacin.

    
    
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    H. influenzae infection should be treated with oral amoxicillin with clavulanic acid.

    
    
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    N. gonorrhoeae requires a third-generation cephalosporin such as ceftriaxone.

  
  
  
  
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  Severe corneal thinning with threatened or actual perforation requires:

  
  
  
  
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    Ciprofloxacin for its antibacterial activity.

    
    
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    A tetracycline (e.g. doxycycline 100 mg twice daily) for its anticollagenase effect.

  
  
  
  
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  Scleral involvement may respond to oral or intravenous treatment.

Management of apparent treatment failure

It is important not to confuse ongoing failure of re-epithelialization with continued infection. Drug toxicity, particularly following frequent instillation of fortified aminoglycosides, may give increasing discomfort, redness and discharge despite the eradication of infection.

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  If no improvement is evident following 24–48 hours of intensive treatment, the antibiotic regimen should be reviewed, including contact with the microbiology laboratory to obtain the latest report.

  
  
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  There is no need to change the initial therapy if this has induced a favourable response, even if cultures show a resistant organism.

  
  
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  If there is still no improvement after a further 48 hours, suspension of treatment should be considered for 24 hours then re-scraping performed with inoculation on a broader range of media (see Table 6.2 ) and additional staining techniques requested (see Table 6.3 ). Consideration should be given to the possibility of a non-bacterial causative microorganism.

  
  
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  If cultures remain negative, it may be necessary to perform a corneal biopsy for histology and culture.

  
  
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  Excisional keratoplasty, penetrating or deep lamellar, may be considered in cases resistant to medical therapy, or for incipient or actual perforation (see below).

Perforation

A small perforation in which infection is controlled may be manageable with a bandage contact lens; tissue glue is often adequate for slightly larger dehiscences. A penetrating keratoplasty or corneal patch graft may be necessary for larger perforations, or in those where infection is extensive or inadequately controlled. Occlusive surface repair techniques may be appropriate in some circumstances, such as an eye with no useful visual potential.

Endophthalmitis

No clear protocol exists for the management of this rare complication, but a similar approach to postoperative endophthalmitis should be considered, whilst continuing specific management of the corneal infection. Secondary sterile intraocular inflammation should not be mistaken for intraocular infection.

Visual rehabilitation

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  Keratoplasty (lamellar may be adequate) may be required for residual dense corneal scarring.

  
  
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  Rigid contact lenses may be required for irregular astigmatism but are generally only introduced at least 3 months after re-epithelialization.

  
  
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  Cataract surgery may be required because secondary lens opacities are common following severe inflammation. Even in the absence of severe corneal opacification, surgery may be hampered by corneal haze, posterior synechiae and zonular fragility.

Pathogens

Bacterial keratitis usually develops only when ocular defences have been compromised (see below). However, some bacteria, including Neisseria gonorrhoeae , Neisseria meningitidis , Corynebacterium diphtheriae and Haemophilus influenzae are able to penetrate a healthy corneal epithelium, usually in association with severe conjunctivitis. It is important to remember that infections may be polymicrobial, including bacterial and fungal co-infection. Common pathogens include:

• •
  

  Pseudomonas aeruginosa is a ubiquitous Gram-negative bacillus (rod) commensal of the gastrointestinal tract. The infection is typically aggressive and is responsible for over 60% of contact lens-related keratitis.

  
  
• •
  

  Staphylococcus aureus is a common Gram-positive and coagulase-positive commensal of the nares, skin and conjunctiva. Keratitis tends to present with a focal and fairly well-defined white or yellow–white infiltrate.

  
  
• •
  

  Streptococci. S. pyogenes is a common Gram-positive commensal of the throat and vagina. S. pneumoniae (pneumococcus) is a Gram-positive commensal of the upper respiratory tract. Infections with streptococci are often aggressive.

Risk factors

• •
  

  Contact lens wear , particularly if extended, is the most important risk factor. Corneal epithelial compromise secondary to hypoxia and minor trauma is thought to be important, as is bacterial adherence to the lens surface. Wearers of soft lenses are at higher risk than those of rigid gas permeable and other types. Infection is more likely if there is poor lens hygiene but it can also occur even with apparently meticulous lens care, and with daily disposable lenses.

  
  
• •
  

  Trauma , including refractive surgery (particularly LASIK – laser-assisted in situ keratomileusis), has been linked to bacterial infection, including with atypical mycobacteria. In developing countries agricultural injury is the major risk factor, when fungal infection should be considered.

  
  
• •
  

  Ocular surface disease such as herpetic keratitis, bullous keratopathy, dry eye, chronic blepharitis, trichiasis and entropion, exposure, severe allergic eye disease and corneal anaesthesia.

  
  
• •
  

  Other factors include local or systemic immunosuppression, diabetes and vitamin A deficiency.

General considerations

• •
  

  Hospital admission should be considered for patients who are not likely to comply or are unable to self-administer treatment. It should also be considered for aggressive disease, particularly if involving an only eye.

  
  
• •
  

  Discontinuation of contact lens wear is mandatory.

  
  
• •
  

  A clear plastic eye shield should be worn between eye drop instillation if significant thinning (or perforation) is present.

  
  
• •
  

  Decision to treat

  
  
  
  
  • ○
    

    Intensive treatment may not be required for small infiltrates that are clinically sterile and may be treated by lower-frequency topical antibiotic and/or steroid, and by temporary cessation of contact lens wear.

    
    
  • ○
    

    It is important to note that the causative organism cannot be defined reliably from the ulcer’s appearance.

    
    
  • ○
    

    Empirical broad-spectrum treatment is usually initiated before microscopy results are available.

  
  

Local therapy

Topical therapy ( Table 6.4 ) can achieve high tissue concentration and initially should consist of broad-spectrum antibiotics that cover most common pathogens. Initially instillation is at hourly intervals day and night for 24–48 hours, and then is tapered according to clinical progress.

• •
  

  Antibiotic monotherapy has the major advantage over duotherapy of lower surface toxicity, as well as greater convenience.

  
  
  
  
  • ○
    

    A commercially available fluoroquinolone is the usual choice for empirical monotherapy and appears to be about as effective as duotherapy.

    
    
  • ○
    

    Ciprofloxacin or ofloxacin are used in countries where widespread resistance to earlier-generation fluoroquinolones has not been identified. Activity against some Gram-positive organisms, particularly some streptococci, may be limited.

    
    
  • ○
    

    Resistance to fluoroquinolones has been reported in some areas (e.g. Staphylococcus spp. in the USA and Pseudomonas in India). Moxifloxacin, gatifloxacin and besifloxacin are new generation fluoroquinolones that largely address this, and also have better activity against Gram-positive pathogens. Moxifloxacin has superior ocular penetration. Novel drug preparations, with higher concentrations or modified vehicles, have been introduced to enhance antibacterial activity.

    
    
  • ○
    

    Ciprofloxacin instillation is associated with white corneal precipitates ( Fig. 6.9 ) that may delay epithelial healing.

    
    

    
    

    
    

    

    
    

    
    

    Ciprofloxacin corneal precipitates

    
    

  
  
  
  
• •
  

  Antibiotic duotherapy may be preferred as first-line empirical treatment in aggressive disease or if microscopy suggests streptococci or a specific microorganism that may be more effectively treated by a tailored regimen (see Table 6.4 ).

  
  
  
  
  • ○
    

    Empirical duotherapy usually involves a combination of two fortified antibiotics, typically a cephalosporin and an aminoglycoside, in order to cover common Gram-positive and Gram-negative pathogens.

    
    
  • ○
    

    The antibiotics are not commercially available and must be specially prepared ( Table 6.5 ). A standard parenteral or lyophilized antibiotic preparation is combined with a compatible vehicle such that the antibiotic does not precipitate. Optimally, constitution should take place in the sterile preparation area of a pharmaceutical dispensary.

    
    
    
    

    Table 6.5

    
    

    Preparation of fortified antibiotics

    
    

    
    
    
    
    
    
    
    
    
    
    
    
    
    
    
    
    
    
    

    Antibiotic	Method	Concentration	Shelf-life
    Cephalosporins: cefazolin, cefuroxime, or ceftazidime	500 mg parenteral antibiotic is diluted with 2.5 ml sterile water and added to 7.5 ml of preservative-free artificial tears	50 mg/ml (5%)	24 hours at room temperature; at least 4 days if refrigerated
    Gentamicin	2 ml parenteral antibiotic (40 mg/ml) is added to 5 ml commercially available gentamicin ophthalmic solution (0.3%)	15 mg/ml (1.5%)	Up to 14 days if refrigerated

     
    
    
    
    
  • ○
    

    Disadvantages of fortified antibiotics include high cost, limited availability, contamination risk, short shelf-life and the need for refrigeration.

  
  
  
  
• •
  

  Subconjunctival antibiotics are usually only indicated if there is poor compliance with topical treatment.

  
  
• •
  

  Mydriatics (cyclopentolate 1%, homatropine 2% or atropine 1%) are used to prevent the formation of posterior synechiae and to reduce pain.

  
  
• •
  

  Steroids

  
  
  
  
  • ○
    

    Steroids reduce host inflammation, improve comfort, and minimize corneal scarring. However, they promote replication of some microorganisms, particularly fungi, herpes simplex and mycobacteria and are contraindicated if a fungal or mycobacterial agent is suspected (beware prior refractive surgery and trauma involving vegetation). By suppressing inflammation, they also retard the eye’s response to bacteria and this can be clinically significant, particularly if an antibiotic is of limited effect or bacteriostatic rather than bactericidal.

    
    
  • ○
    

    Evidence that they improve the final visual outcome is mainly empirical, but the recent Steroids for Corneal Ulcers Trial (SCUT) found no eventual benefit in most cases, though severe cases (counting fingers vision or large ulcers involving the central 4 mm of the cornea) tended to do better; a positive culture result was an inclusion criterion, and steroids were introduced after 48 hours of moxifloxacin.

    
    
  • ○
    

    Epithelialization may be retarded by steroids and they should be avoided if there is significant thinning or delayed epithelial healing; corneal melting can occasionally be precipitated or worsened.

    
    
  • ○
    

    Many authorities do not commence topical steroids until evidence of clinical improvement is seen with antibiotics alone, typically 24–48 hours after starting treatment. Others delay their use at least until the sensitivity of the isolate to antibiotics has been demonstrated, or do not use them at all.

    
    
  • ○
    

    Regimens vary from minimal strength preparations at low frequency to dexamethasone 0.1% every 2 hours; a reasonable regimen is prednisolone 0.5–1% four times daily.

    
    
  • ○
    

    Early discontinuation may lead to a rebound recurrence of sterile inflammation.

    
    
  • ○
    

    The threshold for topical steroid use may be lower in cases of corneal graft infection, as they may reduce the risk of rejection.

  
  

Systemic antibiotics

Systemic antibiotics are not usually given, but may be appropriate in the following circumstances:

• •
  

  Potential for systemic involvement , when microbiological/infectious disease specialist advice should optimally be sought but should not delay treatment:

  
  
  
  
  • ○
    

    N. meningitidis , in which early systemic prophylaxis may be life-saving. Treatment is usually with intramuscular benzylpenicillin, ceftriaxone or cefotaxime, or oral ciprofloxacin.

    
    
  • ○
    

    H. influenzae infection should be treated with oral amoxicillin with clavulanic acid.

    
    
  • ○
    

    N. gonorrhoeae requires a third-generation cephalosporin such as ceftriaxone.

  
  
  
  
• •
  

  Severe corneal thinning with threatened or actual perforation requires:

  
  
  
  
  • ○
    

    Ciprofloxacin for its antibacterial activity.

    
    
  • ○
    

    A tetracycline (e.g. doxycycline 100 mg twice daily) for its anticollagenase effect.

  
  
  
  
• •
  

  Scleral involvement may respond to oral or intravenous treatment.

Management of apparent treatment failure

It is important not to confuse ongoing failure of re-epithelialization with continued infection. Drug toxicity, particularly following frequent instillation of fortified aminoglycosides, may give increasing discomfort, redness and discharge despite the eradication of infection.

• •
  

  If no improvement is evident following 24–48 hours of intensive treatment, the antibiotic regimen should be reviewed, including contact with the microbiology laboratory to obtain the latest report.

  
  
• •
  

  There is no need to change the initial therapy if this has induced a favourable response, even if cultures show a resistant organism.

  
  
• •
  

  If there is still no improvement after a further 48 hours, suspension of treatment should be considered for 24 hours then re-scraping performed with inoculation on a broader range of media (see Table 6.2 ) and additional staining techniques requested (see Table 6.3 ). Consideration should be given to the possibility of a non-bacterial causative microorganism.

  
  
• •
  

  If cultures remain negative, it may be necessary to perform a corneal biopsy for histology and culture.

  
  
• •
  

  Excisional keratoplasty, penetrating or deep lamellar, may be considered in cases resistant to medical therapy, or for incipient or actual perforation (see below).

Perforation

A small perforation in which infection is controlled may be manageable with a bandage contact lens; tissue glue is often adequate for slightly larger dehiscences. A penetrating keratoplasty or corneal patch graft may be necessary for larger perforations, or in those where infection is extensive or inadequately controlled. Occlusive surface repair techniques may be appropriate in some circumstances, such as an eye with no useful visual potential.

Endophthalmitis

No clear protocol exists for the management of this rare complication, but a similar approach to postoperative endophthalmitis should be considered, whilst continuing specific management of the corneal infection. Secondary sterile intraocular inflammation should not be mistaken for intraocular infection.

Visual rehabilitation

• •
  

  Keratoplasty (lamellar may be adequate) may be required for residual dense corneal scarring.

  
  
• •
  

  Rigid contact lenses may be required for irregular astigmatism but are generally only introduced at least 3 months after re-epithelialization.

  
  
• •
  

  Cataract surgery may be required because secondary lens opacities are common following severe inflammation. Even in the absence of severe corneal opacification, surgery may be hampered by corneal haze, posterior synechiae and zonular fragility.

Herpes simplex virus (HSV)

HSV is enveloped with a cuboidal capsule and has a linear double-stranded DNA genome. The two subtypes are HSV-1 and HSV-2 , and these reside in almost all neuronal ganglia. HSV-1 causes infection above the waist (principally the face, lips and eyes), whereas HSV-2 causes venereally acquired infection (genital herpes). Rarely HSV-2 may be transmitted to the eye through infected secretions, either venereally or at birth (neonatal conjunctivitis). HSV transmission is facilitated in conditions of crowding and poor hygiene.

Primary infection

Primary infection, without previous viral exposure, usually occurs in childhood and is spread by droplet transmission, or less frequently by direct inoculation. Due to protection by maternal antibodies, it is uncommon during the first 6 months of life, though occasionally severe neonatal systemic disease may occur in which early diagnosis and intravenous antiviral treatment are critical to reduce mortality and disability; the presence of maternal antibodies means that dendritic corneal ulcers may be seen. Most primary infections with HSV are subclinical or cause only mild fever, malaise and upper respiratory tract symptoms. Blepharitis and follicular conjunctivitis may develop but are usually mild and self-limited. Treatment, if necessary, involves topical aciclovir ointment for the eye and/or cream for skin lesions, and occasionally oral antivirals. There is unfortunately no evidence that antiviral treatment at this stage reduces the likelihood of recurrent disease.

Recurrent infection

Recurrent disease (reactivation in the presence of cellular and humoral immunity) occurs as follows:

• •
  

  After primary infection the virus is carried to the sensory ganglion for that dermatome (e.g. trigeminal ganglion) where latent infection is established. Latent virus is incorporated in host DNA and cannot be eradicated with presently available treatment.

  
  
• •
  

  Subclinical reactivation can periodically occur, during which HSV is shed and patients are contagious.

  
  
• •
  

  Clinical reactivation. A variety of stressors such as fever, hormonal change, ultraviolet radiation, trauma, or trigeminal injury may cause clinical reactivation, when the virus replicates and is transported in the sensory axons to the periphery.

  
  
• •
  

  The pattern of disease depends on the site of reactivation, which may be remote from the site of primary disease. Hundreds of reactivations can occur during a lifetime.

  
  
• •
  

  The rate of ocular recurrence after one episode is about 10% at 1 year and 50% at 10 years. The higher the number of previous attacks the greater the risk of recurrence.

  
  
• •
  

  Risk factors for severe disease , which may be frequently recurrent, include atopic eye disease, childhood, immunodeficiency or suppression, malnutrition, measles and malaria. Inappropriate use of topical steroids may enhance the development of geographic ulceration (see below).

Clinical features

Epithelial (dendritic or geographic) keratitis is associated with active virus replication.

• •
  

  Symptoms. Mild–moderate discomfort, redness, photophobia, watering and blurred vision.

  
  
• •
  

  Signs in approximately chronological order:

  
  
  
  
  • ○
    

    Swollen opaque epithelial cells arranged in a coarse punctate or stellate ( Fig. 6.12A ) pattern.

    
    

    
    

    
    

    

    
    

    
    

    Epithelial herpes simplex keratitis. (A) Stellate lesions; (B) bed of a dendritic ulcer stained with fluorescein; (C) margins of a dendritic ulcer stained with rose Bengal; (D) geographic ulcer; (E) persistent epithelial changes following resolution of active infection; (F) residual subepithelial haze

    
    

    (Courtesy of C Barry – fig. B; S Tuft – fig. C)

    
    

    
    

    

    
    

    
    

    

    
    

    
    

    

    
    

    
    

    

    
    

    
    

    

    
    
    
    
  • ○
    

    Central desquamation results in a linear-branching (dendritic) ulcer ( Fig. 6.12B ), most frequent located centrally; the branches of the ulcer have characteristic terminal buds and its bed stains well with fluorescein.

    
    
  • ○
    

    The virus-laden cells at the margin of the ulcer stain with rose Bengal ( Fig. 6.12C ), and this may help distinction from alternative diagnoses, particularly an atypical recurrent corneal abrasion.

    
    
  • ○
    

    Corneal sensation is reduced.

    
    
  • ○
    

    Inadvertent topical steroid treatment may promote progressive enlargement of the ulcer to a geographical or ‘amoeboid’ configuration ( Fig. 6.12D ).

    
    
  • ○
    

    Mild associated subepithelial haze is typical.

    
    
  • ○
    

    Anterior chamber activity may be present, but is usually mild.

    
    
  • ○
    

    Follicular conjunctivitis may be associated; topical antivirals can also cause this.

    
    
  • ○
    

    Vesicular eyelid lesions may coincide with epithelial ulceration.

    
    
  • ○
    

    Elevated IOP is not uncommon (tonometry should be performed on the unaffected eye first; a disposable prism should be used, or a re-usable tonometer prism carefully disinfected after use).

    
    
  • ○
    

    Following healing, there may be persistent punctate epithelial erosions and irregular epithelium ( Fig. 6.12E ) which settle spontaneously and should not be mistaken for persistent active infection. A whorled epithelial appearance commonly results from assiduous, especially prolonged, topical antiviral instillation.

    
    
  • ○
    

    Mild subepithelial haze ( Fig. 6.12F ) may persist for weeks after the epithelium heals; in some cases mild scarring may develop, which tends to become more evident after each recurrence and may eventually substantially threaten vision.

  
  
  
  
• •
  

  Investigation is generally unnecessary as the diagnosis is principally clinical, but pre-treatment scrapings can be sent in viral transport medium for culture. PCR and immunocytochemistry are also available. Giemsa staining shows multinucleated giant cells. HSV serological titres rise only on primary infection, but can be used to confirm previous viral exposure, usually in cases of stromal disease when the diagnosis is in doubt.

  
  
• •
  

  Differential diagnosis of dendritic ulceration includes herpes zoster keratitis, healing corneal abrasion (pseudodendrite), acanthamoeba keratitis, epithelial rejection in a corneal graft, tyrosinaemia type 2, the epithelial effects of soft contact lenses, and toxic keratopathy secondary to topical medication.

Treatment

Treatment of HSV disease is predominantly with nucleoside (purine or pyrimidine) analogues that disrupt viral DNA. The majority of dendritic ulcers will eventually heal spontaneously without treatment, though scarring and vascularization may be more significant.

• •
  

  Topical. The most frequently used drugs are aciclovir 3% ointment and ganciclovir 0.15% gel, each administered five times daily. Trifluridine is an alternative but requires instillation up to nine times a day. The drugs are relatively non-toxic, even when given for up to 60 days. They have approximately equivalent effect, acting preferentially on virus-laden epithelial cells, and penetrating effectively into the stroma; 99% of ulcers heal within two weeks. Idoxuridine and vidarabine are older drugs that are probably less effective and more toxic.

  
  
• •
  

  Debridement may be used for resistant cases. The corneal surface is wiped with a sterile cellulose sponge or cotton-tipped applicator (cotton bud). Epithelium should be removed 2 mm beyond the edge of the ulcer, since involvement extends beyond the visible dendrite. The removal of the virus-containing cells protects adjacent healthy epithelium from infection and eliminates the antigenic stimulus to stromal inflammation. A topical antiviral agent should be used in conjunction.

  
  
• •
  

  Signs of treatment toxicity include superficial punctate erosions, waves of whorled epithelium, follicular conjunctivitis and, rarely, punctal occlusion. Absence of epithelial whorling with a persistent epithelial lesion raises the possibility of poor or non-compliance.

  
  
• •
  

  Oral antiviral therapy (e.g. aciclovir 200–400 mg five times a day for 5–10 days, famciclovir or valaciclovir) is indicated in most immunodeficient patients, in children and patients with marked ocular surface disease. It is an effective alternative to topical treatment when the latter is poorly tolerated, or in resistant cases. The newer oral agents may be better tolerated than aciclovir, and require less frequent dosing, but optimal regimens are not yet defined.

  
  
• •
  

  Interferon monotherapy does not seem to be more effective than antivirals, but the combination of a nucleoside antiviral with either interferon or debridement seems to speed healing.

  
  
• •
  

  Skin lesions (see Ch. 1 ) may be treated with aciclovir cream five times daily, as for cold sores, and if extensive an oral antiviral may be given.

  
  
• •
  

  Cycloplegia , e.g. homatropine 1% once or twice daily can be given to improve comfort if necessary.

  
  
• •
  

  Topical antibiotic prophylaxis is recommended by some practitioners.

  
  
• •
  

  IOP control. If glaucoma treatment is necessary, prostaglandin derivatives should probably be avoided as they may promote herpes virus activity and inflammation generally.

  
  
• •
  

  Topical steroids are not used unless significant disciform keratitis is also present (see below).

  
  
• •
  

  Slow healing or frequent recurrence may indicate the presence of a resistant viral strain, and an alternative topical agent or debridement may be tried. In especially refractory cases, a combination of two topical agents with oral valaciclovir or famciclovir may be effective. A significant minority of resistant cases are due to varicella-zoster virus.

Clinical features

• •
  

  Symptoms. Blurred vision of gradual onset, which may be associated with haloes around lights. Discomfort and redness are common, but tend to be milder than in purely epithelial disease. A clear past history of epithelial ulceration is not always present, and the possibility of a mimicking infection such as acanthamoeba or fungal keratitis should be borne in mind.

  
  
• •
  

  Signs

  
  
  
  
  • ○
    

    A central zone of stromal oedema, often with overlying epithelial oedema ( Fig. 6.13A ); occasionally the lesion is eccentric.

    
    

    
    

    
    

    

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